Synthetic methods for carbohydrates

Synthetic Methods for Carbohydrates In Synthetic Methods for Carbohydrates; El Khadem, H.; ACS Symposium Series; Americ...

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Synthetic Methods for Carbohydrates

In Synthetic Methods for Carbohydrates; El Khadem, H.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

T h e c o l o p h o n o n the b o o k c o v e r is a s i m p l i f i e d representation of a r e a c t i o n process i n v o l v i n g a b l o c k i n g g r o u p i n d i c a t e d as a c h o r d of the u p p e r circle.


Synthetic Methods for Carbohydrates H a s s a n S. El K h a d e m , E D I T O R

Michigan Technological University

A symposium sponsored by the Division of Carbohydrate

Chemistry

at the Centennial Meeting of the American Chemical Society, New York, Ν. Y., A p r i l 5 - 6 , 1976.

ACS SYMPOSIUM SERIES 39

AMERICAN

CHEMICAL

SOCIETY

WASHINGTON, D. C. 1976


Library of Congress Data Synthetic methods for carbohydrates. (ACS symposium series; 39 ISSN 0097-6156) Includes bibliographical references and index. 1. Carbohydrates—Congresses. 2. Organoboron com pounds—Congresses. 3. Chemistry, Organic—Synthesis— Congresses. I. el Khadem, Hassan Saad, 1923II. American Chemical Society. Division of Carbohydrate Chemistry. III. Series: American Chemical Society. ACS Symposium series: 39. QD320.S93 547'.78 76-58888 ISBN 0-8412-0365-2

Copyright © 1977 American Chemical Society All Rights Reserved. No part of this book may be reproduced or transmitted in any form or by any means—graphic, electronic, including photo copying, recording, taping, or information storage and retrieval systems—without written permission from the American Chemical Society. PRINTED IN THE UNITED STATES OF AMERICA


A d v a n c e s in C h e m i s t r y Series Robert F . G o u l d , Editor

Advisory Board Donald G Crosby

E. Desmond Goddard Robert A . Hofstader John L. Margrave Nina I. McClelland John B. Pfeiffer Joseph V. Rodricks Alan C. Sartorelli Raymond B. Seymour Roy L. Whistler Aaron Wold


FOREWORD The ACS SYMPOSIUM SERIES was founded in 1974 to provide a medium for publishing symposia quickly in book form. The format of the SERIES parallels that of the continuing ADVANCES IN CHEMISTRY SERIES except that in order to save time the papers are not typeset but are reproduced as they are sub mitted by the authors in camera-ready form. As a further means of saving time, the papers are not edited or reviewed except by the symposium chairman, who becomes editor of the book. Papers published in the ACS SYMPOSIUM SERIES are original contributions not published elsewhere in whole or major part and include reports of research as well as reviews since symposia may embrace both types of presentation.


PREFACE T P he symposium on new synthetic methods was

organized by

the

Carbohydrate Division of the American Chemical Society to commemorate the 100th anniversary of the society.

Chemists from the U S A

and six other countries presented 16 papers during three sessions of the symposium.

T h e invited speakers were all involved in elaborate syn-

thetic work or had developed new and innovative techniques.

They

were either established authorities in the field or younger chemists who had recently produced significant developments worth reporting on such a solemn occasion. Successful synthese desired change to occu molecule. This naturally necessitates extensive use of selective blocking groups, and it is not surprising that two of the chapters in this text are devoted to the study of the applications of new blocking groups. In the course of the rapid development of the chemistry of natural products, certain striking similarities became

apparent between carbohydrate

molecules and their corresponding homocyclic or heterocyclic analogs. This led to a closer interaction between natural product chemists and carbohydrate chemists. A conceptual treatment of the synthetic reactions used by both groups and a close study of the relationship between these carbohydrate molecules and their non-carbohydrate analogs was highly desirable at this time. Stereochemistry has always played an important role in carbohydrate chemistry and is an ever present concern to the synthetic chemist.

With

the advent of readily accessible O R D and C D instruments, greater use has been made of the correlations between optical properties and the configuration and conformation of the products of synthesis to develop stereospecific isomerization that could lead to desired products.

Other

chapters in the present text deal with the synthetic application of reactive starting materials such as glycals, and others review the methods available for the preparation of biologically important derivatives such as thio sugars and heterocyclic compounds. The significance of this book is that it is authored by a large number of prestigious chemists and active younger ones; it is contemporary and, judging from the attendance of the symposium, deals with topics that are both interesting and current. Houghton, Michigan

HASSAN

S.

EL

December 1976 ix


KHADEM

1 Applications of Ethylboron Compounds in Carbohydrate Chemistry R. KÖSTER and W. V. DAHLHOFF Max-Planck-Institut für Kohlenforschung, Mülheim-Ruhr, Germany

The fundamental work of Böeseken (1) in the first half of this centur different a f f i n i t i e compounds. The early investigations demonstrated the stereospecifity of the various polyols and saccharides towards boric acid. One analytical application that developed from this work was the quantitative determination of boron based on the interaction of boric acid with certain hydroxy compounds. However, it i s the preparative aspects that are of interest to carbohydrate chemists, and we will present here some of the uses of organoboron compounds in synthetic work and show the advantages they offer over conventional blocking groups. The most important and well known application of organoboron compounds in sugar chemistry was, and is still, the use of the bifunctional O-phenylboranediyl-ligand as a protective group. Some O-phenylboranediyl derivatives of monosaccharides have been described in the literature (2,3). They have been prepared from phenylboric acid, which is neither as easy to react nor as easy to remove as the O-ethylboron group. The products are often not volatile and cannot be purified by distillation. Usually crystallisation is used to purify the products, but this is often difficult to achieve. In the past three years we have discovered new methods for the preparation of boron derivatives of hydroxy compounds and in particular O-ethylboron compounds. We were thus able to apply our 20 years of experience in the f i e l d of organoboranes to carbohydrate chemistry. The combination of two separate fields of research often brings about new impetus to the development of science. We believe that by combining our expertese in the field of sugars and 1


2

SYNTHETIC

METHODS

FOR

+ 0 ppm) n

2

s


SYNTHETIC METHODS FOR CARBOHYDRATES

CH Ob

CH OH

2

2

.

3 BEt,* HC-Ob

H-C-OH - 3 EtH (RT) 96*/.

CH Ob 2

bp 85*C/10"Torr 2 B E t

• >*|(RT) -2 EtH 1

-EtH

-BEt

s

|(150*C)

bO—v

• MeOH (RT)

ψ

8

0

V

i

HO BEt

#

bp 1 0 3 C /

10'*Torr

NΪ ^ Ί

PhC

•ACjO / Py

76

(

((

(RT)

( 0 · Ο

I

Ο

BEt

·'·

τ

Γ

Ο

}B E t

bp 108*C/ 5 10»Torr

J

I

C

H

3 Î r

0

1

_

\ / O H

^

. B E . /

»-

2

OH

.«,· EtH

P

—

85·/.

S ° ^ ^ O H

h

-

r

^ O H mp

B E t / = a c t . BEt3

36* C

b = BEt,

Figure 7.

1-OAcyl-glycerols

via ethylboron intermediates


1.

KOSTER AND DAHLOFF

Ethylboron

the u s u a l manner, then or 1-0-benzoylglycerol

7

Compounds

deborylated to i n high yields

give (see

1-0-acetylf i g . 7).

The O - e t h y l b o r o n a t i o n o f b u t a n - 1 , 2 , 4 - t r i o l i s t h e seconcT e x a m p l e ( V7). This a l k a n e t r i o l yielded on O - e t h y l b o r o n a t i o n a gas c h r o m a t o g r a p h i c a l l y (V7) pure, Tsomer-free compound i n h i g h y i e l d w h i c h h a d one 2-ethyl-1,3,2-dioxaborinan-ring ( 160'C)

0 b

"3BEt3

w

, HO

®

\

OH HO

OH

( 160*C) -3EtH

J

-3 EtH Et

route

D-Mannitol •

lu

• 6 BEt-

Β

N

B "

Et t

BUC

-«Et

[route y

Et

©

route IV

^ftBuCOB 0 - 3 tBuCOH

)2° .00*0 3 H

2°

b = BEt 2 BEt *= act. B E t 3

Figure 10.

3

Five routes to prepare 1,2:3,4:5,6-tris-O-ethyïboranediyl-O-mannitol

CHiOb ,/

oSj»

\

,/oM»

0-ÇH QBHgQ-Ç) E t / V" R

-IBEt,

Χ

ν

:MeC^0/Py(2gC)

θ \ θ » ^QMe

E

t

{

CHiOH

t

/ X

* MeOH(2Q-(^

oSÇ%/ûMe -1<M«0feBEI

HOV^/OM

Ob

• BEtj* (20'C) • acacH

WacacBEt

x

(20'C)

CH,OH

CH. OH

\ ^ ^ 0 M

M• oAS F y O l J

kpCPhi

-KMeO) Et iB

OCPh

• (MeC) O/Py a

CH,OCMe • M B E P D I B . Py ( 2 0 , C ) -

tBuCOH \ - \ HjO

Ό Me •Co\jË*^Î OCPh

Figure 11.

2,3-Di-e v a c u u m d i s t i l l e d without decomposition and are quite often c r y s t a l l i n e . 6. S e v e r a l o f t h e b i s - O - e t h y l b o r a n e d i y l - d e r i v a t i v e s c a n be p a r t i a l l y a n d s e l e c t i v e l y deborylated w i t h methanol a t room t e m p e r a t u r e . Such s e l e c t i v e d e b o r y l a t i o n s have not been observed f o r any 0 - p h e n y l boranediyl derivatives. 7. The s t r u c t u r e products resemble thos idene compounds. 8 . The O - e t h y l b o r a n e d i y l g r o u p c a n be removed under f a r miTder conditions than the O-isopropylidene g r o u p . T h u s , f o r e x a m p l e , we h a v e b e e n a b l e t o prepare some 1 - 0 - a c y l d e r i v a t i v e s v i a O - e t h y l b o r a n e d i y l i n t e r mediates. Because of these f a c t s , the use of the O - e t h y l boron protective groups offers new p o s s i b i l i t i e s f o r t h e p u r i f i c a t i o n , t h e s e p a r a t i o n a n d many O - d e r i v a t i zations of polyhydroxy compounds.

Literature Cited 1. Böeseken, J., Adv. Carbohydr. Chem. (1949) 4, 189-210. 2. P e r r i e r , R . J . and Prasad, D . , J. Chem. Soc. (1965) 7429-7432. 3. Shafizadeh, F., McGinnis, G.D., and Chin, P . S . , Carbohydrate Res. (1971) 18, 357-361. 4. Köster, R . , B e l l u t , H . , and Fenzl, W., Liebigs Ann. Chem. (1974) 54-68. 5. Köster, R., Binger, P . , and Dahlhoff, W.V., Synth. Inorg. Met.-Org. Chem. (1973) 3, 359-367. 6. Köster, R . , Amen, K.-L., and Dahlhoff, W.V., Liebigs Ann. Chem. (1975) 752-788. 7. Köster, R., F e n z l , W., and Seidel, G., Liebigs Ann. Chem. (1975) 352-372. 8. Dahlhoff, W.V. and Köster, R., Liebigs Ann. Chem. (1975) 1625-1636. 9. Dahlhoff, W.V. and Köster, R., Liebigs Ann. Chem. (1975) 1914-1925. 10. Dahlhoff, W.V. and Köster, R . , Liebigs Ann. Chem. (1975) 1926-1933.


I.

KÖSTER AND DAHLOFF

Ethylboron Compounds

11. Dahlhoff, W.V., Schüßler. W., and Köster, R., Liebigs Ann. Chem. (1976) 387-394. 12. Dahlhoff, W.V. and Köster, R . , J. Org. Chem. (1976) 98 in press. 13. Köster, R. and Dahlhoff, W.V., Liebigs Ann. Chem. (1977), in press. 14. Hoffmann, E.G. and Schroth, G . , Max-Planck-Insti tut für Kohlenforschung, Mülheim-Ruhr. 15. Mynott, R . , Max-Planck-Institut für Kohlenfor schung, Mülheim-Ruhr. 16. Hoffmann, E.G. and Mynott, R . , Max-Planck-Institut für Kohlenforschung, Mülheim-Ruhr. 17. Schomburg, G. and Kandziorowski, F., Max-Planck - I n s t i t u t für Kohlenforschung, Mülheim-Ruhr. 18. cf. Schmidt. O.Th. i n Methods i n Carbohydrate Chem. (1963) 2 and M.L. Wolfrom


21

2 N e w Aspects of Synthesis with Benzylidene Acetals DEREK HORTON and WOLFGANG WECKERLE Department of Chemistry, Ohio State University, Columbus, Ohio 43210

In conjunction with esters and ethers acetals play an important role as protectin Moreover, benzylidene acetal -substituted derivatives by means of a ring-opening reaction (Figure 1), whereby the acetal is treated with N-bromosuccinimide in hot carbon tetrachloride. The process presumably involves bromination at the benzylic position followed by ionic rearrangement, and yields the primary bromide benzoylated at the secondary position. This reaction was applied in the carbohydrate field by Hanessian (1) in 1966 with examples illustrated in Figure 1, and was further extended in the same year by Hullar and coworkers (2). Since then, the reaction has found wide utility in numerous applications. A recent application of acetals novel in the carbohydrate field was described in 1974, when Klemer and Rodemeyer (3) reported the reaction of methyl 2,3:4,6-di-O-benzylidene-α-Dmannopyranoside (1) with two molar equivalents of butyllithium at -30° in tetrahydrofuran (Figure 2). They showed that the dioxolane ring reacts selectively and the dioxane ring is unaffected. Furthermore, the reaction led regiospecifically to the 2-deoxy-3-ketone 2; the only side-product was a trace of a 2,3-unsaturated compound. The foregoing reaction is a specific illustration of a general type of process observed with dioxolanes derived from benzaldehyde, as illustrated in Figure 3. Removal of a proton from 3 by the strong base initiates the reaction, and the subsequent course depends on which proton has been abstracted. If the benzylic proton is removed, the resultant anion 10 then collapses with elimination of benzoate anion to give the alkene 11, as shown in the lower portion of Figure 3. The benzoate anion subsequently reacts with the excess of alkyllithium reagent. If, on the other hand, abstraction of the hydrogen atom attached to one of the other carbon atoms of the dioxolane 3 occurs, the subsequent process leads to an enolate anion (5 or 8), with elimination of benzaldehyde (which then reacts with a second 22


2.

HORTON AND WECKERLE

Benzylidene

D - gluco Figure 1.

23

Acetals

(principal)

Ring-opening reaction of benzylidene acetals with N-bromosuccini mide

methyl 4 , 6 - O - b e n z y l i d e n e 2 - d e o x y - oc- D - e r y t h r o - h e x o p y r a n o s i d 3- uloseFigure 2.

Opening of a 1,3-dioxolane ring: reaction of methyl 2,3:4,6-di-0-benzylideneα-Ό-mannopyranoside (1) with butyllithium


24


Figure 3.

OCH

Possible pathways and products of the butyllithium phenyl-l,3-dioxolane derivatives

OCH

2

reaction with 2-

OCH

2

2

-30 , tetrahydrofuran

12

Large-scale operations yield

Isolation conditions 2 strongly alkaline (ref.3)

ammonium chloridebuffered

Figure 4.

traces (•complex

12 10-20°/ mixture)

e

91°/.

Preparative synthesis of the deoxy ketone 2


2.

HORTON AND WECKERLE

Benzylidene

25

Acetals

molecule of the reagent). After conventional processing, one or other of the corresponding deoxygenated keto products (6 or 9) i s isolated, as shown in the upper half of Figure 3. The outcome of the reaction depends on which of the three hydrogen atoms i n 3 is the more-readily abstracted, and this step determines which of the three possible products ( 6 , 9, or l l ) is formed. The great potential u t i l i t y o?~this reaction by Kleraer and Rodemeyer prompted our evaluation of i t on a large scale, as the ketone 2 was required as an intermediate in a proposed synthesis of daunosamine and related compounds. As shown in Figure k some d i f f i c u l t i e s were encountered i n the scale-up of the reaction as originally described. Although small-scale preparations proceeded satisfactorily, attempts to use quantities of 50 grams or more of compound 1 did not lead to the desired ketone 2, but to complex mixtures containing a wide range of other products besides 2 as indicated by 1.1. c. Fro isolated in relatively lo as a product (12) of chain degradation. The d i f f i c u l t y was traced to decomposition- of compound 2 during the isolation procedure when water was added to the solution. Under these conditions, the mixture becomes strongly alkaline, permitting base-catalyzed degradation of 2, as w i l l be shown later. A modified isolation procedure, whereby the cold reaction mixture (-^0°) is poured into well-stirred, ice-cold, aqueous ammonium chloride permitted the successful, large-scale conversion of 1 into 2. The tetrahydrofuran was evaporated off and~the crystalline product then f i l t e r e d off directly from the aqueous mixture. By this modification, the ketone 2 could be obtained crystalline in 91$ y i e l d (h). The reaction is quite regiospecific, and no 3-deoxy-2keto product could be detected. A major objective i n our laboratory has been the development of a high-yielding synthesis of the amino sugar daunosamine (3amino-2,3 6-trideoxy-L-lyxo-hexose, 21), a constituent of the important antitumor antibiotics daunorubicin (5.,6), carminomycin ( î ) , and adriamycin ( 8 ) . The synthesis of this amino sugar from D-mannose as starting material requires deoxygenation at C-2, amination with inversion at C - 3 , and inversion at C-5 together with deoxygenation at C-6. Having i n hand a high-yielding route to the ketone 2 allowed the development of a very convenient synthesis for î h i s amino sugar, as i l l u s t r a t e d i n Figure 5> affording i t i n a net y i e l d of hOf> from methyl a-D-mannopyranoside 9

5

(i).

The ketone 2 is oximated, and the resultant oxirae 13 is reduced and the product a ç e t y l a t e d , to give a mixture o?~the Dribo (ih) and D-arabino (15) acetamido derivatives. The reduction strongly favor's the ribo^cbmpound, and separation of the two products is readily achieved by exploiting the very low s o l u b i l i t y of the arabino derivative (15) i n most organic solvents, especially in toluene. The r i b ο producTT (ik) is very soluble in this and most other solvents. By this simple separation, pure compounds 1*+


26


and 15 were obtained in 87$ and 12$, respectively. These products were^subjected separately to the action of N-bromosuccinimide to generate the 6-bromides (16 and 17) benzoylated at 0-U. The Dribo isomer ( l 6 ) was then^TreateoTwith technical silver fluoride to bring abouiPelimination of hydrogen bromide and generate the exocyclic enol derivative 18, which was then converted into the debenzoylated analogue 19. ™ ï h e latter undergoes stereospecific reduction with hydrogenTTn the presence of palladium to give the corresponding C-5-inverted product 20, which is the N-acetylated, methyl glycoside of daunosamine. TKe" hydrochloride {"21 ) of the free reducing sugar i s obtained by removal of the N-suSstituent and hydrolysis of the glycosidic group (h). This synthesis also provides a versatile general method for related amino sugars ( 9 , 1 0 ) , as i l l u s t r a t e d in Figure 6. If the elimination—inversion sequence at C-5 i s omitted, compound 16 (g-ribo) can be converted into the corresponding -deoxy derivative 22 and, likewise i t s corresponding β-deoxy analogue 23. In the ribo series, 0deacylation to compound 2k and subsequent hydrolysis affords 3amino-2,3,6-trideoxy-D-riBo-hexose ( 2 6 ) , the optical antipode of the antibiotic constituent ristosamine" ( l l ) . By a similar sequence, the corresponding D-arabino derivative (27) i s obtained; this compound i s the enantiomorph of acosamine (12JT Compound 27, upon Ν,Ν-dimethylation, gives angolosamine, which is a component of the macrocyclic lactone antibiotic angolomycin (13). The f e a s i b i l i t y of the butyllithiura reaction with compounds having a different mode of substitution was next examined, and the results of reactions performed on derivatives of L-rhamnose (Ik) are i l l u s t r a t e d i n Figure 7. Although the f i r s t derivative chosen, methyl 2 , 3 - 0 benzylidene-a-L-rhamnopyranoside (28) has formal similarity to the foregoing compound 1 in that both I~and 28 have the dioxolane ring derived from benzalôTehyde attached~~to a 5^membered sugar ring, there are substantial differences, most importantly because 28 possesses a labile proton. Treatment of 28 with butyllithium~did not lead to a deoxy ketone, but to a mixture of products containing a small proportion of the 2,3-unsaturated product 29 (presumably arising from the U-oxyanion of 28 by abstraction δ Τ the benzylic hydrogen atom and subsequent elimination of a benzoate anion), together with larger proportions of two branchedchain products (30 and 31) that are apparently formed by attack of the b u t y l l i t h î ï ï m reagent upon the keto sugar derivative. The reaction with compound 28 i s more sluggish than with the d i - 0 benzylidenemannoside 1. fro reaction took place at a l l at - 3 O , but at 0° the products' shown were formed. The fact that the reaction must take place by way of an i n i t i a l oxyanion at C-k may influence the outcome of the reaction. Under the more-vigorous conditions required to separate a second proton and generate a doubly-charged species ( 3 2 ) , the enolate (33) of the desired 2deoxy-3-ketone evidentlyêliminates the glycosidic methoxyl group 0


Benzylidene

HORTON AND WECKERLE

2

27

Acetals

13

14

ribo

R = NHAc. R'= Η

~~

1^ m.p. 173* C*] »77 (CHCI ) e

D

15

a r a b j n o R= H; R= NHAc

3

17 mp. 154 - 1 5 5 " [oO *117 (CHCI ) e

D

Ô n

«55°

(1)Ba(OH)

\

2

, (2) HCI

syru M •

syrup W

/Me

3

(water)

n

n e r y i e l d ( f r o m m e t h y l cxD-mannopyranoside)

Figure 5.

16

Synthesis of daunosamine

ribo

R = N H A c , R'= Η 91*/o; s y r u p [<x:

1£

arabino

R=H

.126'

D

;

(CHCI ) 3

23

/

R = NHAc

9 8 · / . ; m.p. 133 - 1 3 4 LoO

e

» 1 3 8 * (CHCI3)

D

Me

;

24

r i b o R= N H A c ; R = H

C«3

D

26

ribo

D- r i s t o s a m i n e -

e

97 /o; syrup • 3 7 * ( CHCI3 )

R = NH3CI; R'= H 81 · / . ; m . p - 1 2 3 - 1 2 5 * ( dec.)

25 arabino

R = H R'= N H A c

8 0 · / . ; m.p. 1 5 5

[<x]

D

;

C«*JD £7

arabino

R:H; 94

β

R'= NH3CI

/ β , m. ρ

Co«3

Figure 6.

• 8 5 * (equil., w a t e r )

-156*

« 1 9 3 * (CHCI3)

D

172 - 1 7 4 *

(dec. )

• 9 4 * (equil., w a t e r )

Synthesis of 3-amino-2,3,6-trideoxy-Oribo- and D- arabino hexoses


e

40 /o

28

SYNTHETIC METHODS

HO A Me

Ο Me BuLi

w

FOR CARBOHYDRATES

\ OMe

0 , tetrahydrof uran

+

29

30

ÎR

syrup

3^

(R =

=OH

C«J -115°

17 /β

R'= B U

;

Bu

;

R'=

OH

β

D

e

44 / .

m.p. 8 8 - 8 9 ° BuLi (2 moles)

67-68°

e

e

C«] -110 (CHCl3)

-88 (CHCI )

D

3

BuLi ( 1 mol )

-MeO~

34

32

PhCH 0 A 2

° v OMc complex 0 , tetrahydrofuran,-

reaction mixture

2 2 ° , benzene

BuLi -30 , tetrahydrofuran

e

40 /o,m.p. M Figure 7.

D

71-72

-301°(CHCI )

Reactions of methyl 2,3-Cybenzylidene-a-L-rhamnopyranosides lithium

3

with butyl-


2.

HORTON AND WECKERLE

Benzylidene

29

Acetals

readily to form the corresponding l-ene-3-one 3^, which would predictably react with the reagent to give a mixture of products (30 and 3 l ) formed by addition of butyllithium to the carbonyl group. ™ In order to impede this competing process, i t was considered necessary to protect the hydroxyl group in the rhamnose derivative 28 by means of a base-stable group. This was achieved by preparation of both the U-benzyl (35) and ^-methyl (36) ethers. However, butyllithium failed to effect a straightforward transformation of the benzylated benzylidene acetal 35> even under a variety of conditions explored; at low temperature^Î~-30 ) no reaction occured, and more-vigorous conditions led to a complex mixture of products. Evidently, the reagent abstracts a proton from the U-O-benzyl group (as indicated by a change of the solution to a yellow-red color), thus hindering removal of a second proton from the dioxolan In contrast, the methyl ether reacted readily with butyllithium at -3O and the reaction was complete after 30 minutes. The product i s the 2-deoxy-3-ketone 37, whose structure is f u l l y supported by conventional characterization data as well as by n. m. r. - and mass-spectral data. A sequence involving oximation, reduction, and hydrolysis thus offers a route from 37 to the Lribo (enantiomer of 26) and L-arabino (enantiomer o?~27) analogues of daunosamine ( 21) ,~>ristosamine ( 1 1 ) , and acosamine ( T 2 ) . In a furthe~effort to demonstrate the generality of the butyllithium reaction with benzylidene acetals having the dioxolane ring-structure, additional examples (15) have been examined. The a l i o analogue 38 of the previously studied manno dibenzylidene acetal 1 was suBJected to the same type of treatment with butyllithium in tetrahydrofuran (Figure 8 ) . The compound reacted readily to generate a deoxy keto sugar 39 having the keto group in the 2-position and deoxygenation at 0-3^ Only traces of the 2,3-unsaturated glycoside (ho) were formed. It is thus evident that compound 38 reactsTSy exactly the reverse of the steric mode observed wiîh the manno derivative 1; the course may be ascribed to i n i t i a l abstraction of the axialfy oriented hydrogen atom (H-2) of 38. In the case of 1, i t is the adjacent hydrogen atom (H-3) thalPis axially dispose? and whose abstraction initiates elimination in the direction observed. The ketone 39 i s a useful intermediate in synthesis. Thus, i t s reduction to~1T pair of epimers at C-2, followed by the opening of the dioxane ring with N-bromosuccinimide, subsequent reduction of the corresponding primary halide, and hydrolysis leads ( l 6 ) to the deoxy sugars paratose (3,6-dideoxy-D-ribo-hexose) and tyvelose (the D-arabino analogue). Furthermore,"reductive amination of compound 39 provides a simple route to a range of 2-araino-2,3dideoxy sugars (15). The next application of the butyllithium reaction was made (15) with compounds having the same general structure as the mannose and aliose derivatives already described, but lacking the 5

o

0


30


glycosidic methoxyl group that leads to complications i n some instances. Thus (Figure 9 ) , 1,5-anhydro-2,3:^,6-di-0benzylidene-D-mannitol (kl) was found to react with butyllithium at 0° (at -30° the reaction proceeded insufficiently rapidly) to give the crystalline 3-ketose k2 i n 66$ yield by the same process that was observed with the glycosides 1 and 36· A dimeric sideproduct (kk) was also encountered, and~this presumably arises from s e l f ^ d d i t i o n of k2, A very minor side-product was the glucal derivative hj, wEbse assigned structure is supported by analytical and spectroscopic data as well as by comparison with an authentic sample (IT). Although the desired ketose was contaminated with the dimer kk, the two could be separated readily because chromatography on s i l i c a gel (with k:1 ether—petroleum ether as eluant) gives the pure 1,5-anhydroketose (^2), whereas the dimer (hk) remains on the column. The reverse course when 1,5-anhydro-2,3:^,6 treated with butyllithium at 0° i n tetrahydrofuran. In this instance, the principal product is the 3-deoxy-2-ketose k6 f u l l y in line with the observations with the corresponding allose derivative 38. Again a glycal derivative (kj) i s encountered in very low~yield, together with a product î K a t has not yet been firmly identified, but which probably arises from self-addition of the 2-ketose k6. As mentioned earlier, scaled-up experiments with methyl 2 , 3 : U,6-di-0-benzylidene-a-D-raannopyranoside (l) and butyllithium i n i t i a l l y led to a degradation product, 3>5-0-benzylidene-ldeoxy-keto-D-erythro-2-pentulose ( 1 2 ) , instead of the desired ketone 2. It was assumed that 2 was- i n i t i a l l y present, and that the pentulose 12 was produced only under the strongly alkaline conditions of î E e isolation procedure. This hypothesis is supported by the fact that 2 could be detected while monitoring the reaction mixture by t. lTc. , and that simple modification of the isolation procedure (by use of a buffer) overcame the problem. Later on, i t was of interest to devise a practical procedure for obtaining this pentulose derivative (12) as a precursor for other synthetic studies. The best results were obtained (15) with a two-phase system u t i l i z i n g stoichiometric amounts of lithium hydroxide, with shaking overnight at room temperature (Figure 10). The structure of 12 was f u l l y supported by infrared (OH, C=0), n.ra.r. , and mass-spectral data, as well as by the preparation of the corresponding acetate k8 the benzoate k9 and the 2 f , V dinitrophenylhydrazone 50. ~T?he product wasTurther identified by direct comparison with literature data for compound 12 prepared in a different way ( 1 8 ) . A possible mechanism for the chain degradation is i l l u s t r a t e d in Figure 11. Under basic conditions, the corresponding enolate (51) of 2 may eliminate the glycosidic methoxyl group to give the enohe 52Γ Hydration of this product and subsequent attack on 53 by hydroxide ion would lead, with elimination of formate, to tKe' 9

9

9


HORTON AND WECKERLE

OCH

Benzylidene

Acetals

,OCH

2

-30*,

2

tetra

hydrofuran

39,

86·/.

m.p. 9 0 - 1 2 0 C«D

D

• 29

E

m.p. 1 5 5 C-allopyranoside (38) with butyllithium y

2 4 · / . , m.p. 2 5 4

-

255

IOCQ - 4 9 ° (CHCI3) m/e

OCH

OCH2

2

un k n o w n

BuLi

(oligomeric,

Ο , tetrahydro f u r a n , 1h

Ο

4 6 8

unsaturated)

Ο 47 5 1 · / . , m.p.

45

1,5-anhydro-2,3: 4,6-

di-O-

benzylidene- D-allitol

Figure 9.

129-131*

[ > ] ρ • 2 0 * (CHCI ) 3

m/e

23

4

3 · / . , m. p. 8 3 - 8 4 *

O D Q • 1 9 5 * (CHCI3) m/ë 2 3 4

Reactions of 1,5-anhydrodi-O-henzylidene hexitols with butyllithium


32

SYNTHETIC METHODS F O R CARBOHYDRATES

m.p. 1 8 0 * COOD

Figure 10.

Base-promoted chain degradation of 2 to

•15*(CHCI ) 3

3,5-O-benzylidene-l-deoxy-

keto-O-erythro-2-pentulose (12)

53

Supoorted

54

12

12

by

λ. 55

β ratio

Figure 11.

R

m.p.

Η

OMe

170 -171"

OMe

Η

194-195

~ 1 1 (estimated from

• 150'(AcOEt) -51*

n.m.r.

(CHCI )

data)

Proposed mechanism for the chain degradation


3

2.

Benzylidene

HORTON AND WECKERLE

33

Acetals OCH

2

(1) HjN-NHg* H 0 , 110, 1h 2

(2) KOH, 100°. 4 h diethyleneglycol Ph^ 56 1,5-anhydro -4,6- Ο -benzylidene- 2,3- d i d e o x y - D - c r y thro -

1,5- an hydro - 4,6- O- benzyl idene-

hex i toi

2- d e o x y - D - erythro-hex -3-ulose

3( R )-phenyl - 1 (S )-6(R)- 2,4,7-trioxabicycloC4.4.0Ddccane 68·/.,

OCH

m.p. 137°.

m/e 220,

r0 vector relative to the electric dipole moment vector, in the more stable conformer; (c) the position of the glycosyl group relative to the dipole moment vector of the heterocycle. The rule may be illustrated for pyrimidine nucleosides by placing the pyrimidine ring along the x axis with the negative end of the dipole moment pointing in the negative direction. Since pyrimidine rings do not have planes of symmetry, they must be aligned arbitrarily in the x, y plane in such a way as to give 77


78

SYNTHETIC METHODS FOR

CARBOHYDRATES

t h e c o r r e c t s i g n o f C o t t o n e f f e c t f o r known n u c l e o s i d e s (6-11). The f i g u r e shows t h e p r o p e r a l i g n m e n t f o r u r a c i l ( a ) , cytosine (b), and thymine (c). The o r i e n t a t i o n of t h e g l y c o s y l group w i t h respect to the base i s d e p i c t e d by the C - l ' - ^ O bonds i n the syn and a n t i o r i e n t a t i o n s , and t h e s i g n o f t h e C o t t o n e f f e c t g i v e n for each conformer. A s t u d y o f t h e d a t a f o r t h e known compounds h a s l e d t o t h e g e n e r a l i z a t i o n s g i v e n b e l o w w h i c h may b e u s e d t o p r e d i c t the s i g n of the Cotton e f f e c t of as-yet-unknown glycosylpyrimidines.

1. For a nucleoside having C - l of the g l y c o s y l group i n the R c o n f i g u r a t i o n , such as a 3 - D - r i b o f u r a n o s y l g r o u p , and having R negative i n the y d i r e c t i o n , i . e . the g l y c o s y l group l y i n g b e l o w t h e b a s e , t h e s i g n o f t h e C o t t o n e f f e c t w i l l be n e g a t i v e i f t h e χ c o m p o n e n t s o f eg ( r o u g h l y r e p r e s e n t e d b y t h e C - l ' - ^ O b o n d ) a n d t h e d i p o l e moment v e c t o r o f t h e b a s e a n d ejj p o i n t i n t h e same d i r e c t i o n . The s i g n o f t h e C o t t o n e f f e c t w i l l be p o s i t i v e i f t h e s e two v e c t o r s p o i n t i n o p p o s i t e d i r e c t i o n s . 2. I f t h e Rgg v e c t o r i s p o s i t i v e i n t h e y d i r e c t i o n , t h e g l y c o s y l group l y i n g above the base, the s i g n of the C o t t o n e f f e c t w i l l b e p o s i t i v e w h e n t h e χ c o m p o n e n t s o f e"s a n d eg a r e i n t h e same d i r e c t i o n , a n d i t w i l l b e n e g a t i v e i f t h e χ c o m ponents are i n opposite d i r e c t i o n s . The i n v e r s i o n o f t h e s i g n above and b e l o w t h e χ a x i s i n r u l e s 1 and 2 i s t o be e x p e c t e d , as a r o t a t i o n o f 180° o f t h e base i n v e r t s the sense of the r i n g i n the x , y p l a n e , and changes to - ë j , owing to the c o n t r i b u t i o n s of the t r a n s i t i o n a l , bondo r d e r t e r m (1) t o e^ a s follows: 1

B S

?

B

X

Γ

8

'

hs

°

~ [^B

X

'

*BSR]

where ë g a n d RggR a r e t h e and Rgg v e c t o r s , respectively, r o t a t e d about the χ a x i s by 180°. I t may a l s o b e s h o w n t h a t a r o t a t i o n o f 180° a r o u n d t h e y a n d χ a c e s w i l l n o t c a u s e an i n v e r s i o n of the sign of the Cotton e f f e c t . 3. I f R g i s e s s e n t i a l l y a l i g n e d w i t h e^, t h e glycosylic b o n d b e i n g a l i g n e d w i t h t h e d i p o l e moment v e c t o r , a s i n 5 glycosylcytosines, the s i g n of the Cotton e f f e c t i s independent R

B


5.

Stereochemistry

E L KHADEM

of

r o t a t i o n about

since spect

the

of Nitrogen

glycosylic

Heterocycles

bond.

This is

to

be

expected,

under these c i r c u m s t a n c e s , r o t a t i o n of the base w i t h r e to the g l y c o s y l group does not change the angle between

e ^ a n d e*g. I n s u c h c a s e s , i f t h e Rgg v e c t o r i s i n t h e same d i r e c t i o n as the v e c t o r , the s i g n of the Cotton e f f e c t is negative;

i t

is

positive

i f

the

two

vectors

oppose

each

other.

For g l y c o s y l groups having the S c o n f i g u r a t i o n of C - l sign of the Cotton e f f e c t i s the reverse of that described the R c o n f i g u r a t i o n .

1

, the for

The f o r e g o i n g r u l e may b e a p p l i e d t o p r e d i c t t h e s i g n o f Cotton e f f e c t of nucleoside analogs i f three requirements

the

are met: (1) The b a s e i t s e l f i s n o t m o d i f i e d i n a n y way w h i c h w o u l d s i g n i f i c a n t l y change i t s d i p o l e moment. Accordingly, 6-azacytidine i s excluded; (2) The s u g a r i s n o t s i g n i f i c a n t l y m o d i f i e d by d e r i v a t i z a t i o n . Thus, for example, 4 - t h i o u r i d i n e and p - t o l u e n e - s u l f o n i c 1

The b a s e i s n o t s t r a i n e 2,5 -anhydrouridine are excluded. Requirments 1 and 2 a r e n e c e s s a r y , a s t h e r e l a t i v e o r i e n t a t i o n o f t h e d i p o l e moment of the base and the a x i s of p o l a r i z a b i l i t y of the g l y c o s y l group i s paramount i n d e t e r m i n i n g the s i g n of the C o t t o n e f f e c t . Re ?

quirement 3 i s n e c e s s a r y because, as p o i n t e d out by M i l e s et a l (4), the s t r a i n e d conformation markedly a l t e r s the electronic s p e c t r a of a n h y d r o n u c l e o s i d e s , and hence t h e i r C o t t o n effects. The r u l e a l l o w s t h e r e p l a c e m e n t o f a c y c l i c g l y c o s y l group b y a h y d r o x y a l k y l c h a i n h a v i n g t h e same c o n f i g u r a t i o n a t C - l , because the l a t t e r also e x i s t s i n favored conformations (12,13) and t h e s i g n o f r o t a t i o n i s g o v e r n e d (14) by the c o n f i g u r a t i o n of C - l ' and by the o r i e n t a t i o n w i t h r e s p e c t to the heterocyclic ?

ring. Application

apply

the

CD R u l e

to

The a b o v e m e n t i o n e d r u l e s c o u l d to other heterocycles attached

cyclic dipole

Other

be to

Heterocycles

g e n e r a l i z e d so as t o hydroxyalkyl chains or

sugars.

1.

the

of

Heterocycles moment

h a v i n g no

plane

of

symmetry

along

the

vector:

The f i g u r e b e l o w d e p i c t s an i d e a l i z e d h e t e r o c y c l e d i p o l e moment v e c t o r p o i n t i n g t o w a r d s t h e n e g a t i v e

having direction

o f t h e χ a x i s and shows a hydroxyalkyl chain or

the predicted s i g n of Cotton e f f e c t s for a c y c l i c sugar attached to the hetero

cycle

relative

at

various

angles

(+)0

(-)O

to

the

dipole

moment

vector.

OH

R

R

0( + )


80

S Y N T H E T I C M E T H O D S FOR

CARBOHYDRATES

The i d e a l i z e d h e t e r o c y c l e does n o t p o s s e s s a p l a n e o f symmetry i n t h e d i r e c t i o n o f t h e d i p o l e moment v e c t o r a n d m u s t b e p r o p e r l y o r i e n t e d a l o n g t h e χ a x i s t o d e f i n e i t s upper and l o w e r h a l v e s b e f o r e one c a n p r e d i c t t h e C o t t o n e f f e c t o f h y d r o x y a l k y l c h a i n s o r c y c l i c s u g a r s a t t a c h e d t o one o f t h e two h a l v e s o f the r i n g . T h i s i s , however, not n e c e s s a r y i f t h e bond l i n k i n g the heterocycle to the saccharide residue i s a l i g n e d w i t h the d i p o l e moment v e c t o r . T h u s , i n t h e h e t e r o c y c l e s h o w n b e l o w w h e r e the bond l i n k i n g the h e t e r o c y c l e to an R c h i r a l c e n t e r i s p o i n t i n g i n a n o p p o s i t e d i r e c t i o n t o t h e d i p o l e moment v e c t o r , t h e s i g n of t h e C o t t o n e f f e c t w i l l be p o s i t i v e , and c o n v e r s e l y , i t w i l l be n e g a t i v e i f b o t h t h e s e v e c t o r s a r e a l i g n e d and p o i n t i n g i n t h e same d i r e c t i o n .

T h i s seems t o be a g e n e r a l r u l e a p p l i c a b l e t o compounds h a v i n g h y d r o x y a l k y l groups attached to h e t e r o c y c l e s or chromophores b y b o n d s a l i g n e d w i t h t h e d i p o l e moment o f t h e h e t e r o c y c l i c ring or chromophore. Such molecules can e x i s t i n a m u l t i t u d e of e n a n t i o m e r i c p a i r s o f c o n f o r m e r s w h i c h w i l l c a n c e l one a n o t h e r ' s e f f e c t on the c i r c u l a r d i c h r o i s m . The c o n f o r m a t i o n o f t h e first c h i r a l c e n t e r n e x t t o the h e t e r o c y c l e w i l l , t h e r e f o r e , have no e f f e c t on t h e s i g n o f t h e C o t t o n e f f e c t , and the l a t t e r w i l l be s o l e l y determined by the c o n f i g u r a t i o n of t h i s f i r s t chiral center. (+)0

R

O H

As mentioned e a r l i e r , i f the s a c c h a r i d e r i n g or h y d r o x y a l k y l c h a i n i n t h e h e t e r o c y c l e shown above i s p e r p e n d i c u l a r t o t h e d i p o l e moment v o c t o r o f t h e h e t e r o c y c l e o r h a s a c o m p o n e n t i n t h e d i r e c t i o n o f t h e y a x i s , i t w i l l be n e c e s s a r y f i r s t to e s t a b l i s h the p o s i t i o n of the sugar residue r e l a t i v e to the d i p o l e moment v e c t o r a n d d e f i n e w h e t h e r i t i s a t t a c h e d t o t h e lower h a l f or the upper h a l f of the h e t e r o c y c l i c r i n g i n order to p r e d i c t the s i g n of the Cotton e f f e c t of the s t a b l e conformer.


5.

E L KHADEM

Stereochemistry

of Nitrogen

Heterocycles

81

This i s because exchanging the p o s i t i o n of the sugar i n these s e m i c i r c l e s w i l l r e s u l t i n an i n v e r s i o n of the s i g n of the C o t t o n e f f e c t (see r u l e 2, p. 2 ) . The means o f d e t e r m i n i n g t h e e x a c t o r i e n t a t i o n of the heterocycle around the χ a x i s presents the main d i f f i c u l t y i n the present r u l e . The p r o p e r a l i g n m e n t o f t h e r i n g i n t h e c a s e of p y r i m i d i n e was a r b i t r a r i l y determined b y s t u d y i n g a l a r g e n u m b e r o f s u b s t i t u t e d p y r i m i d i n e s w h o s e CD c u r v e s were measured and whose c o n f o r m a t i o n had been e s t a b l i s h e d . S i m i l a r s t u d i e s were needed f o r other h e t e r o c y c l e s w h i c h , u n f o r t u n a t e l y , were not as e x h a u s t i v e l y s t u d i e d and whose s t a b l e c o n f o r m a t i o n c o u l d o n l y be g u e s s e d . A review of the l i t e r a t u r e r e v e a l s s e v e r a l examples heterocyclic r i n g s attached to h y d r o x y a l k y l chains or to r i n g s t h a t obey the above g e n e r a l i z e d r u l e f o r CD. These the h y d r o x y a l k y l p y r r o l e s , the h y d r o x y a l k y l i m i d a z o l e s and midazoles discussed i n hydroxyalkyloxadiazole (15) and t h e h y d r o x y a l k y l 1 , 2 , 3 - t r i a z o l e s p r e p a r e d by E l H o r t o n and o t h e r s (16) w h i c h a r e shown i n t h e following:

o=c HCNH,

0=C

Me

H<XJ:H

Me

HC=C I HOCH HCOH I

HCOH I

HCOH I CH.OH

HCOH a. R = Me b. R = OEt

CHjOH


of glycosyl include thio-

Khadem,

SYNTHETIC

METHODS

FOR CARBOHYDRATES

\

HC=N—NH—CO—Ph

I

I

HCOAc

HCOAc

I

I

AcOCH

AcOCH

I

AcOCH

I

AcOCH

I

HCOAc

I

HCOAc

I

CH OAc 2

CH OAc 2

Ph

HC=N—NH—CO—Ph

I

AcOCH ι

AcOCH HCOAc

HCOAc

I HCOAc

I HCOAc

I

I

CH OAc

CHgOAc

2

Ph

Ç

| . P h N

A c O C H

I

2

C

Η

h C H

%

_

^

Ν

_L

2.NH3

r > M . H

3

0

3

2

H

^

+

HOCH

"COM CH OH 2

I.

P h C H

2

NH3

2

N

3

3. H +

2

HOCH I HCOH I

C H O H 2


5.

E L KHADEM All discussed

the

Stereochemistry previous

on page

2,

of Nitrogen

compounds when

the

will

ring

is

83

Heterocycles obey

rules

properly

1,

general, t h i s requires the negative s u b s t i t u e n t or i n t h e r i n g t o be l o c a t e d i n t h e upper h a l f of t h e hydroxyalkyl conformation

2,

and

aligned.

3, In

heteroatom r i n g and the

chain at the bottom. Assuming that the stable for the h y d r o x y a l k y l chain i s that i n which the

oxygen of the h y d r o x y l group the heterocycle w i l l tend to the d i p o l e , then the s i g n of

of the c h i r a l center attached to move away f r o m t h e n e g a t i v e end o f t h e C o t t o n e f f e c t w i l l be d e t e r m i n e d

by t h e c o n f i g u r a t i o n of the f i r s t c h i r a l c e n t e r a t t a c h e d t o t h e ring. I f the c o n f i g u r a t i o n i s R, the Cotton e f f e c t i s p o s i t i v e and i s n e g a t i v e when i t i s S , a s e x e m p l i f i e d b y t h e R o x a d i a z o l e and t h e S t r i a z o l e shown b e l o w :

s

,(-ï

T h i s r u l e may a l s o b e i l l u s t r a t e d b y t h e Newman p r o j e c t i o n s r e p r e s e n t e d i n t h e f o l l o w i n g page w h i c h shows a h e t e r o c y c l i c r i n g drawn behind the p l a n e paper and p e r p e n d i c u l a r to i t , and the f i r s t c h i r a l center attached to i t p r o t r u d i n g towards the observer. I f , as e x p e c t e d , the s t a b l e conformer w i l l tend to h a v e t h e OH a w a y f r o m t h e n e g a t i v e e n d o f t h e d i p o l e m o m e n t v e c t o r , t h e compound w i l l f o l l o w t h e g e n e r a l i z e d r o t a t i o n r u l e by E l Khadem and E l S h a f e i (17) w h i c h s t a t e s t h a t t h e r o t a t i o n of a h y d r o x y a l k y l h e t e r o c y c l e i s determined by the c o n f i g u r a t i o n of the f i r s t the r o t a t i o n

chiral i s (+)

center. and v i c e

When t h i s h a s versa.

an R

configuration,

H

I f t h e s t a b l e c o n f o r m e r i n a l l o f t h e s e compounds d o e s t e n d t o h a v e t h e OH g r o u p w h i c h i s t h e m o s t n e g a t i v e p a r t o f t h e first c h i r a l c e n t e r away f r o m t h e n e g a t i v e e n d o f t h e d i p o l e moment o f t h e r i n g , t h e n a c c o r d i n g t o r u l e 1, t h e R f o r m o f t h e s e compounds w i l l be d e x t r o r o t a t o r y o r have a p o s i t i v e C o t t o n e f f e c t and v i c e versa. 2. Heterocycles moment vector: alkyl

having a plane

of

symmetry

along

the

dipole

Another c l a s s of heterocycles of i n t e r e s t are the hydroxd e r i v a t i v e s of h e t e r o c y c l e s h a v i n g a p l a n e of symmetry


84


along the cycles is

d i p o l e moment a x i s . The u p p e r h a l f o f t h e s e a m i r r o r image of the lower h a l f r e p r e s e n t e d

-c^=}--

heterobelow:

As w i t h the h e t e r o c y c l e s d i s c u s s e d i n the p r e v i o u s s e c t i o n , i f the bond l i n k i n g the h y d r o x y a l k y l c h a i n and t h e h e t e r o c y c l e is a l i g n e d w i t h t h e d i p o l e moment v e c t o r , t h e n t h e s i g n o f t h e C o t t o n e f f e c t w i l l depend o n l y on t h e c o n f i g u r a t i o n of t h e f i r s t chiral center. I t w i l l be p o s i t i v e f o r t h e R compound irre s p e c t i v e of c o n f o r m a t i o n i f t h e bond l i n k i n g the h e t e r o c y c l e to the sugar i s residue p o i n t i n g i n the d i r e c t i o n opposite of that o f t h e d i p o l e moment v e c t o r a n d v i c e v e r s a .

X?'

0

M

I f the bond l i n k i n g the h e t e r o c y c l e to the s a c c h a r i d e r e s i d u e i s p e r p e n d i c u l a r t o t h e d i p o l e moment v e c t o r o r h a s a c o m p o n e n t i n t h a t ^ d i r e c t i o n , t h e n a g a i n t h e same r e l a t i o n s h i p d i s c u s s e d for the group of h e t e r o c y c l e s l a c k i n g a p l a n e of symmetry a l o n g the χ axis w i l l hold true. The o n l y d i f f e r e n c e b e i n g t h a t t h e upper and l o w e r h a l v e s of t h e m o l e c u l e a r e m i r r o r images and t h e m o l e c u l e does not r e q u i r e a proper o r i e n t a t i o n by r o t a t i o n around the χ a x i s . By c o n v e n t i o n , t h e h y d r o x y a l k y l r e s i d u e o r t h e s a c c h a r i d e r i n g w i l l be p u t b e l o w t h e r i n g as shown i n t h e following:

χ

(-) 0

R

0 (+)

T h e s t a b l e c o n f o r m e r w i l l t e n d t o h a v e t h e OH a w a y f r o m t h e n e g a t i v e e n d o f t h e d i p o l e moment v e c t o r i n m o s t c o m p o u n d s . For an R c o n f i g u r a t i o n w i t h a n OH p o i n t i n g a w a y f r o m t h e d i p o l e m o m e n t v e c t o r o f t h e r i n g , t h e C o t t o n e f f e c t w i l l be p o s i t i v e and i t w i l l b e n e g a t i v e i f t h e OH i s p o i n t i n g t o w a r d s i t . This would e x p l a i n why t h e g e n e r a l i z e d r o t a t i o n r u l e b y E l Khadem and E l S h a f e i (17) h o l d s t r u e f o r t h i s group o f compounds.


5.

Stereochemistry

E L KHADEM

The p r e d i c t e d having a

sign

heterocycle

A review heterocyclic

of

this

of

the

rings

which possess

moment

vectors.

H o r t o n and

type

is

to

shown

R

of

hydroxyalkyl

various

groups

positions

of

below:

(-) 0 0 (+)

a plane

of

the

literature reveals to

85

Heterocycles

Cotton effect attached

attached

rings, by

of

an R c o n f i g u r a t i o n

of Nitrogen

several

examples

hydroxyalkyl chains symmetry

along

or

their

to

of glycosyl

dipole

Thes

co-worker

1,2,3-triazoles

(19)

depicted

below:

S,(-)

R, ( + )

A l l the c u s s e d on p .

p r e v i o u s compounds w i l l obey 2. Assuming that the s t a b l e

hydroxyalkyl group of the

chain is that c h i r a l center

r u l e s 1,2, and 3 conformation for

dis the

i n which the oxygen of the h y d r o x y l attached to the heterocycle will

t e n d t o move away f r o m t h e n e g a t i v e e n d o f t h e d i p o l e , t h e n t h e s i g n o f t h e C o t t o n e f f e c t w i l l be d e t e r m i n e d by t h e c o n f i g u r a t i o n of the f i r s t c h i r a l center attached to the r i n g . I f the con formation i s R, the Cotton e f f e c t i s p o s i t i v e and i s n e g a t i v e when i t i s S. H e r e a n d t h r o u g h o u t t h i s w o r k i t i s a s s u m e d t h a t the are >

p r i o r i t y of the groups attached to the f i r s t c h i r a l center OH ^> h e t e r o c y c l i c r i n g > t h e r e s t o f t h e h y d r o x y a l k y l c h a i n H. 3.

Fused r i n g

systems:

The a p p l i c a t i o n o f t h e p r e s e n t r u l e t o f u s e d r i n g systems presents c e r t a i n problems. One a p p r o a c h a p p l i e d t o p u r i n e s b y E l Khadem, K r e i s h m a n , S w a r t z , and E l Khadem (5) was t o t r e a t t h e f u s e d r i n g i n g s u s t e m a s one e n t i t y and t o e s t a b l i s h t h e d i p o l e moment o f t h e w h o l e s y s t e m . The f u s e d r i n g was t h e n a l i g n e d a l o n g t h e χ a x i s i n s u c h a way t h a t t h e known n u c l e o s i d e s i n t h e f a v o r e d c o n f o r m a t i o n gave the e x p e c t e d s i g n of the C o t t o n e f f e c t


86


when rules 1,2, and 3, p. 2, were applied. The adenine and guanine nucleoside analogs represented i n the proper orientation are depicted below:

Another approach to fused ring systems i s to consider only the ring to which the saccharide residue i s attached and to disregard the other ring. One would determine i t s dipole moment and predict the sign of the Cotton effect. For a glycosyl purine linked to positions 7, 8, or 9, one would only consider the dipole moment of the imidazole ring, the R and S configuration of the f i r s t chiral center and i t s orientation relative to the dipole moment of the base i n the most stable conformer. One d i f f i c u l t y which may arise i s how to establish accurately the direction of the dipole moment vector of one of the rings i n a fused ring system since experimentally, the dipole moment measurements are made on the whole purine molecule. However, one can calculate this and usually the dipole moments are only shifted slightly from the dipole moment vectors of the monocyclic system. The following i s a rough representation of the dipole moment vector of the imidazole ring of a purine and the pyridazine ring of a cinnoline oriented i n the proper way to predict the Cotton effect using rules 1, 2 and 3, p. 2.

The treatment of the quinoxaline system may present a problem since the diazine ring i s symmetric and has no dipole moment. However, one may argue that a saccharide residue linked i n position 3 of a quinoxaline ring w i l l be located at the positive end of a dipole moment vector pointing i n the direction of the benzene ring, and that the C 1—0 bond of the stable conformer L


5.

E L

K H A D E M

Stereochemistry

of Nitrogen

87

Heterocycles

w i l l tend to move away from the negative end of the dipole moment in i t s v i c i n i t y .

4. Acyclic chromophores A closer look at acyclic compounds which have the dipole moment vector of their chromophore aligned with the bond linking the chromophore to the hydroxyalkyl chain or glycosyl ring reveals that these compounds have no preferred conformation for the f i r s t chiral center relative to the chromophore. They should, therefore, follow rule 3, p. 2, that governs the sign of the Cotton effect of heterocycle vector aligned with the bond linking the heterocyclic ring to the f i r s t chiral center. Thus, for example, hydroxyalkyl n i t r i l e s have the bond linking the f i r s t chiral center to the sp hybridized orbital of the n i t r i l e group in direct alignment. Accordingly, one would not expect any C-l rotamer to be favored and to predominate. The sign of the Cotton effect w i l l , therefore, depend mainly on the configuration of the f i r s t chiral center. If rule 3, p. 2, is applicable to acyclic chromophores, then one would expect that when the direction of the vector going from the chromophore towards the f i r s t chiral center is opposite to that of the dipole moment vector of the chromophore, the rotation i s positive for an R chiral center. This would explain why the rotation of n i t r i l e s depends on the f i r s t chiral center attached to the CN group and is positive when the f i r s t chiral center has a Dconfiguration (20).

R, ( + )

Other examples of acyclic compounds having the bond linking the chromophore to the first chiral center aligned with the dipole moment vector of the chromophore are the a l k a l i metal salts of aldonic acid. These compounds exist in the ionic carboxylate form and their dipole moment is aligned with the bond linking the carboxylate group to the f i r s t chiral center. Unlike the carboxylic acid whose rotation is not predictable by the present rules, the rotation of the a l k a l i metal salts of sugar acids depends solely on the configuration of the f i r s t chiral center.


88

SYNTHETIC

METHODS FOR CARBOHYDRATES

Since the direction of the bond going from the carboxylate group to the f i r s t chiral bond opposes the dipole moment vector of the carboxylate group, the rotation should be positive for R compounds and negative for S compounds. A rotation rule described i n the literature (21) confirms this expectation. It i s interesting to note that certain acyclic compounds having the dipole moment of their chromophore perpendicular to the bond linking their f i r s t chiral center to the chromophore seem to obey the rules applicable to heterocyclic rings. Thus, for example, the rotation of sugar acid amides and hydrazides depends solely on the configuration of the f i r s t chiral center, positive for R compounds and negative for S (22).

_w

0 H

s , (-)

It should be noted that the above rotation rule i s not applicable to a l l acyclic compounds because of hydrogen bonding. Thus, hydroxyalkyl carboxylic acid do not obey the rule, probably because they exist as equilibrium mixtures with the various lactones.

Literature Cited 1 Miles, D. W., Townsend, L. Β., Robins, M. J., Robins, R. Κ., and Eyring, H., J. Am. Chem. Soc. (1971) 93, 1600-1608. 2 Ingwall, J. S., J. Am. Chem. Soc. (1972) 94, 5487-5495. 3 Ulbricht, T. L. V., in W. W. Zorbach and R. S. Tipson (Eds.), "Synthetic Procedures in Nucleic Acid Chemistry," Vol. 2, pp. 177-213, Wiley-Interscience, New York, 1973. 4 Miles, D. W., Robins, M. J., Robins, R.Κ.,Winkley, M. W., and Eyring, H., J. Am. Chem. Soc. (1969) 91, 831-838. 5 El Khadem, H. S., Kreishman, G. P., Swartz, D. L., and El Khadem, S. Η., Carbohydr. Res. (1976) 47, C1-C4. 6 Emerson, T. R., Swan, R. J., and Ulbricht, T. L. V., Bio chemistry (1967) 6, 843-850. 7 Nishimura, T., Shimizu, Β., and Iwai, I., Biochim. Biophys. Acta (1968) 157, 221-232.


5.

E L KHADEM

Stereochemistry

of Nitrogen

Heterocycles

8

89

Miles, D. W., Inskeep, W. Η . , Robins, M. W., Winkley, M. W., Robins, R. Κ., and Eyring, H . , J. Am. Chem. Soc. (1970) 92, 3872-3881. 9 David, S., and Lubineau, Α., Carbohydr. Res. (1973) 29, 15-24. 10 Miles, D. W., Hahn, S. J., Robins, R. Κ., Robins, M. J., and Eyring, H . , J. Phys. Chem. (1968) 72, 1483-1491. 11 E l Khadem, H. S., Audichya, T. D . , Swartz, D. L., and Kloss, J., Abstr. Pap. Am. Chem. Soc. Meet., (1975) 169, CARB-6. 12 E l Khadem, H. S., Horton, D . , and Page, T. F., J. Org. Chem. (1968) 33, 734-740. 13 E l Khadem, Η . , Horton, D . , Wander, J. D . , J. Org. Chem., (1972) 37, 1630-1635. 14 E l Khadem, H . , J. Org. Chem. (1963) 28, 2478. 15 E l Khadem, Shaban, Μ. Α. Ε., and Nassr, Μ. Α. Μ., Carbohydr. Res. (1972) 23, 103. 16 E l Khadem, Η . , Horton Res. (1971) 16, 409 17 E l Khadem, Η and El-Shafei, A . M . , Tetrahedron Lett. (1963) 27, 1887. 18 Horton, D. and Tsuchiya, T . , Carbohydr. Res. (1966) 3, 257259. 19 E l Khadem, Η . , Adv. in Carbohydr. Chem. (1963) 18, 99. 20 Deulofeu, V . , Adv. i n Carbohydr. Chem. (1949) 149, 4. 21 Levene, P. Α . , J. B i o l . Chem. (1915) 23, 145; Levene, P. A. and Meyer, G. M . , J. B i o l . Chem. (1916) 26, 355; Levene, P. Α . , J . B i o l . Chem., (1925) 63, 95; Schmidt, O. T., Ann. (1930) 483, 115. 22 Hudson, C. S., J. Am. Chem. Soc., (1917) 39, 462; Levene, P. A. and Meyer, G. M . , J. B i o l . Chem. (1917) 31, 623; Votocek, Ε . , Valentin, F. and Leminger, O., Collection Czech. Chem. Communs (1931) 3, 250; Votocek, E. and Allan, Z . , Collection Czech. Chem. Communs. (1936) 3, 313; Votocek, E.and Weichterle, Collection Czech. Chem. Communs. (1936) 8, 322.


6 Synthesis of 2-Amino-2-deoxy-β-D-glucopyranosides Properties and Use of 2-Deoxy-2-phthalimidoglycosyl Halides. R. U. LEMIEUX, T. TAKEDA, and Β. Y. CHUNG Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2

The importance of achieving a reliable method for the preparation of has been commented (1,2). The importance derives mainly from the natural occurrence of numerous oligo- and polysaccharides which possess this linkage and the chemical synthesis of segments of these structures is of interest to a number of immunochemical and enzymological studies. It is not possible to present in this paper, a c r i t i c a l review of the many approaches developed to meet the challenge of establishing the above-mentioned linkage. However, the most employed reactions have involved either reactions of a protected glycosyl halide with alcohol under Koenigs-Knorr or Helferich conditions which employ heavy metal salts such as silver carbonate and mercuric cyanide as promoters (3-6) or a strong-acid promoted reaction of a 1,2oxazoline derivative of the aminosugar with the alco hol (7-9). Although these approaches have made a v a i l able a large number of desired structures, the stereo chemical control and yields achieved have been highly variable and, in general, rather unsatisfactory. The present research was undertaken in the hope of amel iorating this situation. In principle, a most attractive means for the establishment of a 1,2-trans-glycosidic linkage would be to form a cationic species from a derivative of the sugar with participation of the 2-substituent but with the latter substituent so chosen that i t s engagement does not lead to products other than the desired 1,2trans-β-glycoside. The choice of an imide derivative of the aminosugar appeared promising in this regard since it could be anticipated from the work of Akiya and Osawa (10) that engagement of the imide grouping in charge derealization at the anomeric center would 90


6.

LEMiEux E T A L .

2-Amino-2-deoxy-fi-O-glucopyranosides

91

lead only to reactive intermediates. Baker and coworkers (11) prepared 1,3 ,4,6-tetra-(>acetyl-2-deoxy-2-phthalimido-g-D-glucopyranose i n 1954 and observed that treatment of t h i s compound with hy drogen bromide i n a c e t i c acid gave 3 , 4 , 6 - t r i - 0 - a c e t y l 2- deoxy-2-phthalimido-B-D-glucopyranosyl bromide (5) and, indeed, Akiya and Osawa (10) prepared 3-glycosides of simple alcohols from the l a t t e r compound i n high y i e l d using Koenigs-Knorr conditions. At the s t a r t of t h i s i n v e s t i g a t i o n , i t was estab l i s h e d that reaction of e i t h e r 3,4,6-tri-0-acetyl-2deoxy-2-phthalimido-3-D-glucopyranosyl or -β-D-galactopyranosyl bromides with the simple alcohol, 2-propanol, under H e i f e r i c h conditions (12) provided the 3-glycosides i n excellent y i e l d . However, when 2 , 2 , 2 - t r i chloroethanol was used t i o n of 5 was the g l y c o s y product of glycosidation reactions using mercuric cyan ide as promoter. This r e s u l t could be a t t r i b u t e d to the weak n u c l e o p h i l i c i t y of the alcohol which also has a hindered hydroxyl group. For t h i s reason, the promo t i o n of the reaction by the soluble 1:1 complex (13,14) of s i l v e r trifluoromethanesulfonate ( s i l v e r t r i f l a t e ) and 2,4,6-trimethylpyridine ( c o l l i d i n e ) was examined. In the f i r s t e f f o r t to u t i l i z e the s i l v e r t r i f l a t e - c o l l i d i n e complex to promote the reaction of the 3 - bromide (5) with 2,2,2-trichloroethanol, the y i e l d was 60%. However, when greater precaution was taken to exclude water, the y i e l d rose to 89%. Thus i t was apparent that, indeed, the use of the phthalimido pro t e c t i n g group augured well for the development of a generally u s e f u l preparation of 2-amino-2-deoxy-3-Dglucopyranosides. In order to t e s t t h i s hypothesis, i t was decided to attempt the syntheses of three Pjeî o u s l y reported disaccharides;. namely, 3 - D - g l c N A c — — • D-glcNAc (4 JB1, β-D-glcNAc ' > D-glcNAc (1,5), and 3-D-glcNAc—D-gal (6,7). Thus, a comparison of the u t i l i t y of the method with other methods could be achieved under a v a r i e t y of circumstances. The pur pose of t h i s communication i s to present the r e s u l t s obtained and, also, an examination of the chemical pro p e r t i e s of the anomeric 3,4,6-tri-0-acetyl-2-deoxy-2phthalimido-D-glucopyranosyl h a l i d e s . Akiya and Osawa (10) demonstrated that replace ment reactions at the anomeric center of 3,4,6-tri-Oacetyl-2-deoxy-2-phthalimido-D-glucopyranosyl halides provide mainly the 3-anomers. Furthermore, reaction of the l,2-trans-3-bromide was shown not to y i e l d an orthoester under conditions wherein 2,3,4,6-tetra-Oacetyl-D-glucopyranosyl halides do. The marked ob3


92


s t r u c t i o n to formation of l,2-c£s-a-anomers was as signed to a s t e r i c hindrance a r i s i n g from the phthalimido group. These phenomena appeared worthy of f u r ther i n v e s t i g a t i o n . I t proved r e a d i l y p o s s i b l e to obtain pure samples of both the anomeric forms f o r 3,4,6-tri-0-acetyl-2deoxy-2-phthalimido-D-glucopyranosyl c h l o r i d e , bromide and iodide from the known 1,3,4,6-tetra-0-acetyl-2deoxy-2-phthalimido-B-D-glucopyranose using b a s i c a l l y standard conditions. A l l were c r y s t a l l i n e except the α-bromide which was obtained as a chromatographically pure syrup. This unique a v a i l a b i l i t y of both the ano meric forms f o r a g l y c o s y l halide with the halogen as e i t h e r c h l o r i n e , bromine or iodine prompted a b r i e f k i n e t i c i n v e s t i g a t i o n of the reactions with t e t r a ethylammonium h a l i d e s t i c s f o r the anomerizatio s t a r t i n g with the ot-anomers. However, the polarimet r i c rates were not cleanly f i r s t - o r d e r s t a r t i n g with the 3-anomers and examination of products i s o l a t e d a f t e r various i n t e r v a l s of time, showed t h i s to r e s u l t from p a r t i a l h y d r o l y s i s of the 3-halide by traces of water which are i n e v i t a b l y present i n the reaction mixtures, a s i t u a t i o n reminiscent of the experience with the anomeric tetra-O-acetyl-D-glucopyranosyl chlorides (15). Thus, i t was apparent that the phthalimido group can p a r t i c i p a t e i n the o v e r a l l reaction and thereby lead to a c a t i o n i c intermediate which has a strong a f f i n i t y f o r water but which, as indicated by the r e s u l t s of Akiya and Osawa (10) and supported by our experience, does not y i e l d a stable orthoester. That some kind of p a r t i c i p a t i o n occurs was also i n d i cated by the d i f f e r e n t routes of the reactions d i s played by the a- and β-bromides (5 and 6) when reac ted with tetraethylammonium c h l o r i d e (0.02 M) i n acet o n i t r i l e . Whereas the reaction of the a-anomer (6) produced an e s s e n t i a l l y quantitative y i e l d (>90%) of the 3 - c h l o r i d e (3) the reaction of the β-bromide (5) proceeded with extensive (near 50%) retention of con f i g u r a t i o n . At a higher c h l o r i d e ion concentration (0.3 Μ ) , the y i e l d of the α-chloride (4) was 80%. The p a r t i c i p a t i o n of a 2-acyloxy group i n a reac t i o n at an anomeric center i s considered to provide anchimeric assistance by providing a s o l v a t i o n - l i k e influence on the formation of an ion-pair and i s mani fested by the collapse of the intermediate ion-pair to the more stable 1,2-acyloxonium s a l t (15). The experimental basis f o r t h i s opinion i s the demonstration by Lemieux and Hayami (15) that whereas the c h l o r i d e - i o n catalyzed anomerization of 1,2-cis-


6.

LEMiEux E T A L .

2-ΑΊηιηο-2'άβοχΐ^-β-Ό^Ιη€ορι^ταηο8ΐά68

93

t e t r a - O - a c e t y l - a - D - g l u c o p y r a n o s y l c h l o r i d e proceeded a t t h e same r a t e as exchange o f c h l o r i d e i o n w i t h t h e environment, the r a t e of i n c o r p o r a t i o n of r a d i o a c t i v e c h l o r i d e i o n s from t h e e n v i r o n m e n t by t h e 1 , 2 - t r a n s - & c h l o r i d e was much g r e a t e r t h a n t h e r a t e o f 3+a a n o m e r i zation. These r e s u l t s seem b e s t i n t e r p r e t e d on t h e b a s i s o f an a t t a c k by c h l o r i d e i o n on an i n t i m a t e i o n p a i r r e s u l t i n g from spontaneous d i s s o c i a t i o n o f t h e C C l bond w i t h p a r t i c i p a t i o n o f t h e r i n g oxygen atom f o r e f f e c t i v e charge d e r e a l i z a t i o n i n the t r a n s i t i o n state. In the case of the 3 - c h l o r i d e , a t t a c k a t the anomeric c e n t e r o f t h e i o n - p a i r by c h l o r i d e i o n was i n c o m p e t i t i o n w i t h t h e n u c l e o p h i l i c a t t a c k by t h e 2 - a c e t o x y group w i t h t h e former r e a c t i o n l e a d i n g t o t h e i o n t r i p l e t intermediate necessary f o r the anomerization and t h e l a t t e r c o u r s e o f r e a c t i o n l e a d i n g t o t h e 1 , 2 acetoxonium i o n . O r e t e n t i o n o f c o n f i g u r a t i o n o b t a i n e d on r e a c t i o n o f t h e 3-bromide (5) w i t h c h l o r i d e i o n may be r a t i o n a l i z e d as i s d i s p l a y e d i n Scheme 1. The most s t a b l e form o f t h e i n t e r m e d i a t e c a t i o n w h i c h a r i s e s from t h e 3-bromide cannot be p r e d i c t e d b u t presumably i s e i t h e r B , C o r D. I f C, the i o n c o u l d , i n the presence of a l c o h o l , p r o v i d e an o r t h o a m i d e p r o d u c t . However, l i k e A k i y a and Osawa (10), we d i d n o t d e t e c t such compounds i n t h e course of t h i s work. I t i s e x p e c t e d , as i n d i c a t e d i n Scheme 1, t h a t t h e s o l v o l y s i s o f t h e 3-bromide p r o ceeds by way o f a b o a t c o n f o r m a t i o n so as t o b e t t e r o r i e n t a p - o r b i t a l o f t h e r i n g oxygen r e l a t i v e t o t h e C - B r bond (16). As mentioned a b o v e , i t was n o t p o s s i b l e t o o b t a i n t h e same v e l o c i t y c o n s t a n t s (k + k ) f o r a n o m e r i z a t i o n s t a r t i n g w i t h t h e 3-anome?s as^were o b t a i n e d f o r α-anomers and t h e d i f f e r e n c e (about 20%) i s a t t r i b u t e d t o c a p t u r e o f t r a c e s o f w a t e r by t h e i n t e r m e d i a t e c a t i o n (B, C o r D i n Scheme 1) formed by s o l v o l y s i s o f t h e 3-anomer. The v a l u e s o b t a i n e d s t a r t i n g w i t h t h e α-anomers a r e c o n s i d e r e d r e l i a b l e and a r e r e p o r t e d u n d e r one s e t o f c o n d i t i o n s i n T a b l e I . As e x p e c t e d , t h e r a t e s o f a n o m e r i z a t i o n were d i r e c t l y p r o p o r t i o n a l t o t h e h a l i d e i o n c o n c e n t r a t i o n (15). These r e s u l t s are considered of i n t e r e s t w i t h regard to h a l i d e - i o n c a t a l y z e d g l y c o s i d a t i o n r e a c t i o n s (16) s i n c e t h e s e show a much g r e a t e r r e a c t i v i t y o f t h e bromides t h a n t h e c h l o r i d e s (700 t i m e s g r e a t e r ) b u t l i t t l e d i f f e r e n c e (about a f a c t o r o f two) between t h e bromides and i o d i d es. These d i f f e r e n c e s a r e even more r e m a r k a b l e when i t i s _ c o n s i d e r e d t h a t the order of n u c l e o p h i l i c i t y i s C I >Br >I under t h e a p r o t i c c o n d i t i o n s u s e d . Indeed, t h e α - i o d i d e (8) was a t t a c k e d about two t i m e s f a s t e r by ft


94

SYNTHETIC METHODS

FOR

CARBOHYDRATES

Scheme 1


6.

95

2-Amino-2-deoxy^-O-glucopyranosides

LEMiEux E T A L .

tetraethylammonium chloride than by tetraethylammonium bromide. TABLE I Reactions of 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimidoD-glucopyranosyl Halides

-OAcÔ

N

AcO

X" 1

PhthN

AcO AcO

OAc

0

v

PhthN

V

Κ

h r

rel.

Anomerization X = X X = X X = X =

1

X

1

X

-4

4950

1

0.10

6.9

700

0.22

3.15

1600

—

3.3

0.21

15

—

2.0

0.34

= CI

3.25

1.4 χ 10

= Br

1.22

= I

3.05

= OAc

4.5

Reaction X = I, X

1

= Cl

X = I , X = B r

9.3

For 0.02M solutions at 25°C of the g l y c o s y l halide i n a c e t o n i t r i l e and made 0.02M i n t e t r a e t h y l ammonium halide. An average value f o r the 1-acetates anomerized i n 1:1 a c e t i c a c i d - a c e t i c anhydride, 0.1M i n p e r c h l o r i c a c i d (17). X

4 The H-NMR spectra of compounds 1 to 8 required C^ conformation f o r both the anomeric p a i r s . The doublets f o r the anomeric hydrogens of the α-anomers had spacings i n the range 3.5-4.0 Hz and those f o r the 3-forms near 9.0 Hz. For both forms, the spacings found i n the signals f o r H-3 and H-4 were i n the range 9-11 Hz. In l i n e with t h i s conformation, H-3 f o r an α-form was strongly deshielded (18) by the sz/n-axial halogen as compared to H-3 of the 3-anomer (see Table I I ) . In a l l cases, one of the a c e t y l groups produced


96


TABLE I I H and C N u c l e a r M a g n e t i c Resonance P a r a m e t e r s f o r 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-D-giucop y r a n o s y l Compounds Chemical S h i f t s ( C D C 1 , TMS i n t e r n a l )

Compound

3

β-Acetate α-Acetate

(1) (2)

H-l 6.48 6.28

H-3 5.86 6.56

C-l 89.9 90.6

6.20

5.79

85.7

β-Chloride

(3)

α-Chloride

(4)

e-Bromide

(5)

6.43

5.80

78.4

α-Bromide

(6)

6.62

6.67

87.3

3-Iodide

(7)

6.71

5.73

78.2

α-Iodide

(8)

6.97

6.52

75.1

i t s s i g n a l t o e x c e p t i o n a l l y h i g h f i e l d ( 1 . 8 - 1 . 9 ppm). I n d e e d , t h e p l a n e o f t h e p h t h a l i m i d o group would be e x p e c t e d t o be n e a r p e r p e n d i c u l a r t o t h e mean p l a n e o f t h e p y r a n o s e r i n g and t h e r e f o r e have a s p e c i f i c s h i e l d i n g i n f l u e n c e on t h e C-3 a c e t o x y g r o u p . In t h i s o r i e n t a t i o n , t h e c a r b o n y l o f t h e p h t h a l i m i d o group w h i c h i s on t h e α - s i d e o f t h e p y r a n o s e r i n g can e x e r t a s t r o n g non-bonded i n t e r a c t i o n w i t h an a x i a l s u b s t i t u e n t a t C - l . T h a t such an i n t e r a c t i o n does i n f a c t e x i s t i s e v i d e n t from t h e r e l a t i v e c h e m i c a l s h i f t s o f t h e anomeric h y d rogens o f t e t r a a c e t a t e s 1 and 2. As seen from T a b l e I I , t h e s i g n a l f o r t h e β-anomer i s a c t u a l l y 0.2 ppm t o lower f i e l d i n c o n t r a s t , f o r example, to the s i t u a t i o n f o r t h e g l u c o p y r a n o s e p e n t a a c e t a t e s where t h e s i g n a l f o r H - l o f t h e fc-form i s 0.58 ppm t o h i g h e r f i e l d t h a n t h a t o f t h e α-form (18). F o r t h e anomeric 2 - a c e t a m i d o 1,3,4,6-tetra-0-acetyl-2-deoxy-D-glucopyranoses, the s i g n a l f o r H - l o f t h e β-form i s 0.45 ppm t o h i g h e r f i e l d t h a n t h a t o f t h e α-form (19). Strong e l e c t r o s t a t i c s p e c i f i c d e s h i e l d i n g o f t h e anomeric hydrogen o f β - a c e t a t e (1) i s t h e r e f o r e i n d i c a t e d . C l e a r l y , t h e s u b s t i t u t i o n o f t h i s a x i a l hydrogen by a more b u l k y atom must l e a d t o s t r o n g non-bonded i n t e r a c t i o n t h a t would d e s t a b i l i z e t h e m o l e c u l e and i n t h e c a s e o f a n o mers t e n d t o f a v o r t h e β - f o r m . I n d e e d , as seen i n


6.

LEMiEux E T A L .


97

Table I, the i n t e r a c t i o n i s powerful enough to counter the anomeric e f f e c t (20) and lead to anomerization e q u i l i b r i a which favor the β-form. Thus, there can be no doubt that the phthalimido group i s well oriented to well shelter the α-side of the pyranose r i n g and, indeed, provide a p a r t i c i p a t i o n i n reactions at the anomeric center. 13 The C-chemical s h i f t s for C - l of compounds 1 to 8 are l i s t e d i n Table I I . I t i s seen that except for the anomeric iodides, the s i g n a l f o r C - l of the a-anomer i s to lower f i e l d than that of the 3-form (21). Reaction of near 1:1 mixture of the a- and 3 bromides (6 and 5) with 2,2,2-trichloroethanol i n the presence of the s i l v e only a s l i g h t l y lowe when pure 3-bromide was used. I t was apparent that the α-bromide may be s l i g h t l y more prone to dehydrobromination. Nevertheless, there appears l i t t l e ad vantage i n using pure 3-bromide instead of a mixture with i t s α-anomer i n these g l y c o s i d a t i o n reactions. Also, the reaction with the 3-chloride (3) gave the same y i e l d as the 3-bromide (5). Indeed, although the g l y c o s i d a t i o n reactions reported herein u t i l i z e d the 3-bromide, i t l i k e l y w i l l prove advantageous to use the 3-chloride i n such reactions i n view of i t s great er s t a b i l i t y on storage. Also, i n the preparations to be reported, the i n i t i a l reaction temperature i s - 3 0 ° . This was mainly as a precautionary measure since v i r t u a l l y the same y i e l d s were obtained at ambient temp eratures for the g l y c o s i d a t i o n of 2,2,2-trichloro ethanol . The reaction of a halide with s i l v e r t r i f l a t e c o l l i d i n e (1:1) i s extremely rapid as indicated by the appearance of p r e c i p i t a t e d s i l v e r h a l i d e . However, t h i s rapid i n i t i a l reaction may lead, even i n the presence of an alcohol, to g l y c o s y l t r i f l a t e which i n turn provides the glycoside since near the same y i e l d of the 2,2,2-trichloroethyl glycoside was obtained, using the 3-bromide as reagent, when the alcohol was added 10 minutes a f t e r the addition of the s i l v e r t r i f l a t e - c o l l i d i n e complex and the formation of s i l v e r bromide was complete as when the alcohol and the pro moter were added at the same time. Reaction of the 3-bromide (5) with 2,2,2-trichloroethanol i n n i t r o methane and using only c o l l i d i n e to n e u t r a l i z e the l i b e r a t e d a c i d gave mainly (-70%) the product of dehydrobromination (9). Thus, the success of the method appears to r e l y on the l i b e r a t i o n over the course of the reaction or a c a t i o n i c intermediate (B, C or D of


98


CARBOHYDRATES

Scheme 1) which has a pronounced tendency to form the 3-glycoside while avoiding elimination of a proton or forming e i t h e r an orthoamide or an orthoacetate. Thus, a highly promising method f o r e s t a b l i s h i n g β-glycosaminide linkages seemed at hand and t h i s promise was well substantiated by the following syntheses. 2,2,2-Trichloroethyl 4,6-0-benzylidene-2-deoxy-2phthalimido-3-D-glucopyranoside (14) was condensed with the 3-bromide (5) i n nitromethane using the s i l ver t r i f l a t e - c o l l i d i n e complex to form compound 15 i n 82% y i e l d . Although care was taken to exclude water from the reaction mixture, a main by-product appeared to be that from the h y d r o l y s i s of 5 ( t i c ) . A small amount of the glycoseen (9) was also formed. The y i e l d obtained i s to be contrasted to the 25% y i e l d reported by Heyns an (4) densation but usin glycosidation r e a c t i o n . Using the oxazoline method, Zurabyan and coworkers (8) r e a l i z e d an 81% y i e l d i n forming benzyl 3-0-(2-acetamido-3,4,6-tri-0-acetyl-2deoxy-3-D-glucopyranosyl)-2-acetamido-4,6-0-benzylidene-2-deoxy-3-D-glucopyranoside. Acid hydrolyses to remove the benzylidene and a c e t y l groups of 15 p r o v i ded the diphthalimido glycoside (16) which was treated with hydrazine to form the 2,2,2-trichloroethyl 3-0(2-amino-2-deoxy-3-D-glucopyranosyl)-2-amino-2-deoxy3-D-glucopyranoside (17). The e f f e c t of pH on the C NMR spectrum of 17 i s reported i n Table I I I . 2,2,2-Trichloroethyl 3,6-di-0-acetyl-2-deoxy-2phthalimido-3-D glucopyranoside (21) was prepared from 14 by way of the intermediates 19 and 20. Reaction of 21 with a s l i g h t excess of 5 under usual conditions provided a 51% y i e l d of the desired 3 - l i n k e d disaccharide d e r i v a t i v e 22. The y i e l d was r a i s e d to 68% when a d d i t i o n a l mole equivalents of 5 and the promoter were added a f t e r the i n i t i a l reaction had subsided. I t i s apparent therefore that the hydroxyl group of 21 i s indeed quite unreactive (1). In previous syntheses of the disaccharide (chitobiose) (1,5), very s p e c i a l de r i v a t i v e s of D-glucosamine were prepared i n order to make the 4-hydroxyl more r e a d i l y a v a i l a b l e to the g l y cosidation reaction. In spite of t h i s precaution, the y i e l d s achieved i n the glycosidation reaction were 10% (-35% of the α-linkage) (5) and 36% (8% of the α - l i n k age) (1) using Helferich-type condensations. Thus, the present method i s capable of providing f a r super i o r y i e l d s even when using a type of alcohol which i s notorious for i t s u n r e a c t i v i t y . Although some α-gly coside must form i n our present method none has been detected i n any of the reactions so f a r studied. 13


6.

LEMiEux E T A L .


99

The chitobiose d e r i v a t i v e (22) was deacetylated under acid conditions to provide the diphthalimido glycoside (23) which was then converted using hydrazine to 2 , 2 , 2 - t r i c h l o r o e t h y l c h i t o b i o s i d e ( 2 4 ) .

A comparison of the C-NMR t i t r a t i o n curves (22) for the compounds 17 and 24 appears of i n t e r e s t to the subject of conformational preferences about g l y c o s i d i c linkages (20). As seen i n Table I I I , the s h i e l d i n g of C - l of compounds 1 2 , 17 and 24 on protonation of the geminal 2-amino group was 4 . 7 - 5 . 2 ppm, normal 3 s h i f t s (22) f o r t h i s transformation. Normal 3 - s h i f t s (-4.4 ppm) were also observed i n the C - 3 atoms of 17 and 24. These signals could be r e l i a b l y assigned 1


100


from t h e s p e c t r u m f o r t h e s i m p l e g l y c o s i d e 1 2 . How ever, although t h e β - s h i f t f o r C-3 of the c h i t o b i o s e d e r i v a t i v e 24 was n o r m a l , t h a t f o r C - 3 o f t h e 1 ' •> 3 l i n k e d d i s a c c h a r i d e 17 was r e m a r k a b l y h i g h , n a m e l y , 8.6 ppm. T h a t i s , f o r 1 7 , t h e β - s h i f t s o b s e r v e d f o r b o t h C - l and C - 3 o f t h e t e r m i n a l u n i t and C - l were normal b u t t h a t o f t h e a g l y c o n i c C - 3 atom o f t h e n o n - t e r m i n a l u n i t was a b n o r m a l l y h i g h . The two amino groups o f t h e c h i t o b i o s e d e r i v a t i v e 24 a r e e x p e c t e d t o be w e l l s e p a r a t e d a s d i s p l a y e d i n t h e c o n f o r m a t i o n a l f o r m u l a f o r 24 p r e s e n t e d above. Thus, i t i s not s u r p r i s i n g t h a t t h e 3 - s h i f t s o b s e r v e d on p r o t o n a t i o n o f 24 were n o r m a l , l i t t l e i f any c o n f o r m a t i o n a l change o c c u r r i n g on p a s s i n g from t h e f r e e base t o t h e s a l t form. However, c o n s i d e r a t i o n s based on t h e exo-anomeri c e f f e c t and non-bonded i n t e r a c t i o n s (20) would r e q u i r e t h a t t h e l -> f r e e base f o r m , has t h e two amino groups i n v e r y c l o s e proximity. T h u s , p r o t o n a t i o n o f t h e amino groups w o u l d be e x p e c t e d t o produce a r e p u l s i o n between groups b o t h a s t h e r e s u l t o f e l e c t r o s t a t i c r e p u l s i o n between t h e c h a r g e d groups and an i n c r e a s e o f t h e e f f e c t i v e volumes o f t h e two groups because o f s t r o n g hydrogen b o n d i n g w i t h t h e w a t e r . T h u s , an a d j u s t m e n t o f t h e c o n f o r m a t i o n o f 17 would be e x p e c t e d , on i t s p a s s i n g from t h e f r e e base t o t h e s a l t f o r m , t h a t would a l l o w a g r e a t e r s e p a r a t i o n between t h e two amino g r o u p s . The abnormal 3 - s h i f t o b s e r v e d f o r t h e a g l y c o n i c C - 3 atom may be c o n s i d e r e d a m a n i f e s t a t i o n o f t h i s c o n f o r m a t i o n a l change. I f so, the fact that the 3 - s h i f t s were n o r m a l f o r t h e o t h e r t h r e e c a r b o n s w h i c h a r e 3 t o an amino group i n 17 would i n f e r t h a t t h e c o n f o r m a t i o n a l change w h i c h o c c u r r e d on p r o t o n a t i o n o f 17 was l a r g e l y r e s t r i c t e d t o a r o t a t i o n about t h e a g l y c o n i c C-3 t o oxygen b o n d , [change i n t h e ψ t o r s i o n a n g l e (20)]. T h i s c o n c l u s i o n would be i n l i n e w i t h t h e e x p e c t a t i o n based on t h e eχο-anomeric effect that the φ t o r s i o n angle tends t o remain constant (exo-anomeric e f f e c t ) (20) and t h e main a d j u s t m e n t t o e s t a b l i s h t h e most s t a b l e c o n f o r m a t i o n about a g l y c o s i d i c l i n k a g e i s by change o f t h e ψ a n g l e . The 2 - a c e t a m i d o - 2 - d e o x y - 3 - D - g a l a c t o p y r a n o s y l group o c c u r s a t t h e 4 - p o s i t i o n o f a D - g a l a c t o p y r a n o s y l group i n c e r t a i n g a n g l i o s i d e s (6,23). T h u s , i t was o f i n t e r e s t t o examine t h e e f f e c t i v e n e s s o f t h e method for the g l y c o s i d a t i o n of the r e a d i l y a v a i l a b l e methyl 2 , 3 , 6 - t r i - O - b e n z o y l - a - D - g a l a c t o p y r a n o s i d e (24). I n d e e d , r e a c t i o n w i t h 5 produced t h e d e s i r e d compound (26) i n e x c e l l e n t y i e l d (79%) and i t i s p l a n n e d t o u s e t h e method i n t h e c o u r s e o f an e f f o r t t o s y n t h e s i z e g a n g 1

1

1


6.

101

2-Αητίηο-2-ά6θχί^-β-Ό-βΙη€ορι^ταηο8ΐάβ8

LEMiEux E T A L .

13 lioside related structures. The C-NMR spectrum s u b s t a n t i a t e d the s t r u c t u r e of the derived methyl 4-0-(2-amino-2-deoxy-£-D-glucopyranosyl)-a-D-galactopyranoside (27). TABLE I I I

13

C-NMR P a r a m e t e r s To D i s p l a y β - S h i f t s Base Salt a a Compound 12 17 24 12 17 r Δ = 5.2 »

» . 4 . , - ί = ^

C-l

104.3

103.6

103.3

C-2

57.0

57.0

57.0

76.5

Δ = 4.3 76.6 76.5 72.2 i Λ = 4.5

99.4

7 2 ..11

C-4

98.9

98.1

55.2 5 6 ..11 56.3 — Δ = 4.4 a - . . . ——

•

C-3'

24 1

}

72.1

•

1

70.2

69.9

70.0

70.1

69.5

70.4

C-5'

76.0

76.1

75.3

76.9

76.4

75.2

C-6'

61.3

61.0

61.0

60.7

60.4

60.7

Δ = 4.7 103.9 4 56.6

C-l

-

103.6

C-2

-

55.9

C-3

-

85.7

C-4

-

68.2

Δ = 8.6 74 .4 * 78.9

C-5

-

76.1

C-6

-

61.0

It

98.9 Δ = 4.8 55.2

9.9.1 * 55.9

-

77.1 Δ = 4.3 67.2

70.1 * 77.1

76.0

-

76.4

76.3

60.6

-

60.4

60.5

Α

-

a ι

C - l i s denoted C - l f o r convenience of p r e s e n t a t i o n .


102

S Y N T H E T I C M E T H O D S FOR CARBOHYDRATES

Experimental

A l l s o l v e n t e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e p r i o r to s o l v e n t removal u s i n g a r o t a r y e v a p o r a t o r under the vacuum of a water a s p i r a t o r . The H-HMR s p e c t r a were measured a t 100 MHz ( V a r i a n HA-100) and C-NMR s p e c t r a a t 22.6 MHz (Bruker HFX-90). Un l e s s o t h e r w i s e s t a t e d , d e u t e r i o c h l o r o f o r m was used as a s o l v e n t and i n t e r n a l TMS as a s t a n d a r d . Thin layer chromatograms (TLC) were developed on a s i l i c a g e l G (Ε. Merck A.G., Darmstadt) u s i n g e t h y l a c e t a t e - S k e l l y s o l v e Β or e t h y l a c e t a t e - b e n z e n e and v i s u a l i z e d by s p r a y i n g w i t h 5% s u l f u r i c a c i d i n e t h a n o l f o l l o w e d by h e a t i n g a t 100°. Column chromatography was performed on s i l i c a g e l (CAMAG) or on Woelm Alumina ( n e u t r a l , A c t i v i t y I ) . The g l y c o s i d a t i o formed under a dry methane, 2 , 2 , 2 - t r i c h l o r o e t h a n o l and 2 , 4 , 6 - t r i m e t h y l p y r i d i n e ( c o l l i d i n e ) were d r i e d and f r e s h l y d i s t i l l e d p r i o r to u s e . A l l s o l i d reactants f o r glycosidation were d r i e d o v e r n i g h t over phosphorus p e n t o x i d e under h i g h vacuum p r i o r t o use. 1,3,4,6-Tetra-0-acetyl-2-deoxy-2-phthalimido-3-Dg l u c o p y r a n o s e (1). D-glucosamine h y d r o c h l o r i d e (21.6 g, 100 mmol) was added to a sodium methoxide s o l u t i o n (prepared from 2.3 g of sodium i n 100 ml of m e t h a n o l ) . A f t e r shaking f o r 10 min, the s e p a r a t e d sodium c h l o r i d e was removed by f i l t r a t i o n and washed w i t h methanol (50 m l ) . The combined f i l t r a t e s were t r e a t e d w i t h f i n e l y ground p h t h a l i c a n h y d r i d e (7.4 g, 50 mmol) and shaken f o r 10 min. T r i e t h y l a m i n e (10.1 g, 100 mmol) was then added and the c l e a r s o l u t i o n was t r e a t e d w i t h p h t h a l i c a n h y d r i d e (8.1 g, 55 mmol). A f t e r shaking f o r 10 min, a c r y s t a l l i n e s o l i d s t a r t e d to p r e c i p i t a t e . The m i x t u r e was then brought to 50° and s t i r r e d f o r 20 min. A f t e r being kept a t 0° f o r 1 h r , the s o l i d (20.5 g) was c o l l e c t e d by f i l t r a t i o n and d r i e d . H-NMR i n d i c a t e d the s o l i d to be the triethylammonium s a l t of 2-(2 -carboxybenzamido)-2-deoxy-D-glucopyranose (25^26). D r y i n g o v e r n i g h t i n a i r r e s u l t e d i n the l o s s of the triethylamine. E v a p o r a t i o n of the f i l t r a t e gave a y e l low s o l i d which was suspended i n d i e t h y l ether (200 ml) and c o l l e c t e d by f i l t r a t i o n . The H-NMR spectrum i n D2O showed t h i s f r a c t i o n to be contaminated w i t h a t r a c e of t h e unreacted glucosamine. The p r o d u c t s were combined (46.5 g) and t r e a t e d w i t h p y r i d i n e (200 ml) and a c e t i c a n h y d r i d e (100 m l ) , at room temperature f o r 16 h r . The s o l u t i o n was poured i n t o i c e - w a t e r and the aqueous m i x t u r e s u b s e q u e n t l y ex t r a c t e d w i t h c h l o r o f o r m (3 χ 100 ml). The combined ex13

1

1


6.

LEMiEux E T A L .

103

2-Α™ΐηο-2-άβοχΐ}-β-Ό-βΙηοορΐ}ταηο8ΐ(Ιβ8

t r a c t s were washed successively with cold water, 3% h y d r o c h l o r i c a c i d , saturated sodium bicarbonate s o l u t i o n and w a t e r . Solvent removal l e f t a yellow foam w h i c h was d i s s o l v e d i n d i e t h y l ether (500 ml) and treated with c h a r c o a l . C o n c e n t r a t i o n to a volume of 150 m l and s t o r a g e overnight a t 0° gave a c o l o r l e s s s o l i d (39.1 g, 82% y i e l d ) . The H - N M R s p e c t r u m of the product showed i t to be a 2:1 m i x t u r e of 3and a-anomers. A 3:1 m i x t u r e of t h e β- and α - a n o m e r s was ob t a i n e d on r e a c t i o n of the t r i e t h y l a m i n e s a l t with sod ium a c e t a t e and a c e t i c a n h y d r i d e a t 100° for 1 h r . However, the product was d a r k r e d and d i f f i c u l t to de c o l o r i z e . The pure 3-anomer ( 1 5 - 2 0 g) c a n be obtained by c r y s t a l l i z a t i o n from e t h a n o l and r e e r y s t a l l i z a t i o n from e t h y l acetate, mp 9 0 - 9 4 ° [ l i t . 199-200° (11) , 9 1 - 9 4 ° f:Z0J] , [a]g2 + •^H-NMR s p e c t r u m w a s t e d by H o r t o n and c o w o r k e r s (19). 1

1,3,4,6-Tetra-0-acetyl-2-deoxy-2-phthalimido-a-gglucopyranose ( 2 ) . A sample (6.6 g) of 2 - ( 2 - c a r b o x y 1

benzamido)-2-deoxy-ot-D-glucopyranose w h i c h had the same p h y s i c a l constants as r e p o r t e d i n the l i t e r a t u r e was obtained by f r a c t i o n a l c r y s t a l l i z a t i o n of a p r e p a r a t i o n of the 3-anomer f o l l o w i n g the procedure reported by Hirano (25). A c e t y l a t i o n of the m a t e r i a l as described b y H i r a n o (25) provided a 51% c r u d e y i e l d of a product w i t h mp 1 1 6 - 1 1 6 . 5 ° a n d [ a ] +114° (chloroform). A f t e r two r e c r y s t a l l i z a t i o n s f r o m m e t h a n o l , t h e mp w a s 126127° and [a]^ +119.2° (c 1, i n chloroform). Hirano (25) h a s r e p o r t e d mp 1 3 1 ° , [a]jjj + 98° whereas Akiya and Osawa (10) reported mp 1 2 4 - 1 2 6 ° , [a]g + 116.1°. T h e NMR s p e c t r a (see Table II) were i n agreement with the assigned s t r u c t u r e . 2

2

2

6

5

3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-glucopyranosyl C h l o r i d e (4). T h i s compound was prepared

from the 3-bromide (5, to be d e s c r i b e d below) under k i n e t i c conditions using the procedure of Lemieux and Hayami (15). Compound 5 (1.03 g) was d i s s o l v e d i n dry a c e t o n i t r i l e (10 ml) w h i c h c o n t a i n e d tetraethylammonium c h l o r ide (0.50 g). A f t e r 5 hr at room t e m p e r a t u r e , the p r o d u c t was i s o l a t e d i n t h e u s u a l manner and was r e c r y s t a l l i z e d from d i e t h y l e t h e r - S k e l l y s o l v e Β to a f f o r d an 80% y i e l d (0.72 g) of m a t e r i a l , mp 1 7 4 - 1 7 5 ° , [ C L ] ^ + 122.2° (c, 0.88 i n a c e t o n i t r i l e ) (see Table I I ) . Anal. C a l c d . for C 2 Ν, 3.09; C l , 7.80. Found: C l , 7.78. The 3-anomer (3) (see 3-tetraacetate (1) using al 2

0

H

0 C,

N

0

9 53.13; C

1

:

C

' H,

52.93; 4.59;

H, Ν,

4.44; 3.39;

Table II) was p r e p a r e d from uminum c h l o r i d e as described


104

SYNTHETIC

by A k i y a agreed.

and

Osawa

and

(10)

the

METHODS

p h y s i c a l

FOR

CARBOHYDRATES

constants

3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-3-Q-glucopyranosyl Bromide ( 5 ) . A s o l u t i o n o f t h e β - a c e t a t e 3 (9.54 g, 20 m m o l ) and a c e t i c a n h y d r i d e (5 m l ) i n a saturated hydrogen bromide s o l u t i o n of g l a c i a l a c e t i c acid (30 ml) was k e p t a t room t e m p e r a t u r e f o r 24 h r . A f t e r d i l u t i o n with chloroform (200 ml) and c h i l l i n g with ice, the s o l u t i o n was washed w i t h c o l d w a t e r (3 times) and s a t u r a t e d sodium bicarbonate s o l u t i o n . S o l vent removal a f t e r d r y i n g l e f t a foamy s o l i d w h i c h was c r y s t a l l i z e d from d i e t h y l ether (7.77 g, 78% y i e l d of a c o l o r l e s s s o l i d , s e e T a b l e I I ) , m p 122-123°, [α]ρ + 57.3° ( c , 1 i n c h l o r o f o r m ) . L i t . m p 120-121° (11).

3.4.5- Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-glucopyranosyl Bromid . above p r e p a r a t i o n o dryness and the r e s i d u for chromatography usi as d e v e l o p i n g phase. The second f r a c t i o n to t h i r d f r a c t i o n r e s i s t e tra r e q u i r e d a high st 1

3

yls), 123.9

C-4,

e a p ng b Four be d c r ate

p l i e d to a s i l i c a gel column enzene-diethyl ether (1:1) f r a c t i o n s were separated. e l u t e d w a s t h e ( 3 - f o r m 5. The y s t a l l i z a t i o n b u t NMR s p e c of p u r i t y .

C-NMR:

169.0, 169.9, 170.4 (3 a c e t y l c a r b o n p h t h a l o y l c a r b o n y l s ) , 134.5, 131.4 a n d (aromatic), 87.3 ( C - l ) , 72.6, 69.1, 67.8 (C-3,

167.3 C-5),

(2

61.1

(C-6),

56.4

(C-2),

20.6

(3

acetyl

methyls). H-NMR: δ 7.80 (m, H - l ) ; 6.52 (q, 9, 11 H - 4 ) ; 4.35 ( q , 4, 11 H z , 1

Hz,

4, p h t h a l i m i d o ) , 6.97 (d, 4 H z , H - 3 ) ; 5.18 (q, 9, 10 H z , H - 2 ) ; 4.2 ( m , H - 5 , H-6 a n d (s, 0-acetyl).

H - 6 ) ; 2.10, 2.08, 1.88 3.4.6- Tri-0-acetyl-2-deoxy-2-phthalimido-3-g-glucopyranosyl Iodide (7). A s o l u t i o n o f h y d r o g e n i o d i d e 1

in acetic a c i d was p r e p a r e d by a d d i t i o n of acetic a n hydride (14 ml) t o 47% hydroiodic a c i d (3 m l ) a t 0° i n a n i t r o g e n atmosphere. C o m p o u n d 1 (15.0 g) was added, t h e s o l u t i o n was s t i r r e d for 1 hr at room temperature and then poured into i c e - w a t e r . The c h l o r o f o r m ex t r a c t was f i r s t n e u t r a l i z e d with saturated aqueous sod ium b i c a r b o n a t e and t h e n w i t h aqueous sodium t h i o s u l f a t e p r i o r to d r y i n g over sodium s u l f a t e . The c h l o r o f o r m s o l u t i o n was e v a p o r a t e d to an o i l y r e s i d u e which c r y s t a l l i z e d from d i e t h y l ether. The from

y i e l d

ether

tot]

+ 38.2° H-NMR: H - l ) ; 5.73 1

Hz,

4.68

(t,

10

was

r a i s e d

50%, the

mp

91-92°.

m e l t i n g

point

R e c r y s t a l l i z a t i o n to

94-94.5°

(β, 1 in chloroform). 6 7.83 ( m , 4, p h t h a l i m i d o ) , 6.71 (q, 9, 10 H z , H - 3 ) ; 5.26 ( t , 10

H z , H - 2 ) ; 4.24

(m,H-6 a n d H-6 ); f

(dec.), (d, Hz,

3.94


10

H-4);

6.

LEMiEux E T A L .


(m,

105

H-5); 2.12,2.04, 1.86 ( s , O - a c e t y l ) . 3,4,6-Tri-0-acetyl-2-deoxy-2-phthalimido-a-g-gluc o p y r a n o s y l I o d i d e ( 8 ) . The mother l i q u o r from t h e c r y s t a l l i z a t i o n of 7 was l e f t a t room temperature. A f t er two days, a compound, mp 89.5-90°, [α]β +131.3° (c, 0.58 i n a c e t o n i t r i l e ) c r y s t a l l i z e d . The y i e l d was 15% (2.6 g ) . S i n c e the NMR s p e c t r a (see T a b l e I I ) i n d i c a t e d h i g h p u r i t y and, l i k e 7, the product was q u i t e u n s t a b l e , no f u r t h e r p u r i f i c a t i o n was attempted. H-NMR: 6 7 .80 (m, 4, p h t h a l i m i d o ) ; 6.97 (d, 4Hz, H - l ) ; 6.52 ( q , 10, 8 Hz, H-3); 5.18 ( t , 8 Hz, H-4); 4.35 (q, 4, 10 Hz, H-2); 4.60-4.10 (m, 3, H-5, H-6 and H - 6 ) ; 2.10, 2.08, 1.88 ( s , O - a c e t y l ) . 3,4,6-Tri-O-acetyl-l,2-dideoxy-2-phthalimido-gα:rα&^nσ-hex-l-enopyranose (9) . A s o l u t i o n o f the brom i d e 5 (996 mg, 2 mmol) 2 mmol) and 2 , 4 , 6 - t r i m e t h y l p y r i d i n i n nitromethane (20 ml) was s t i r r e d a t 90 f o r 48 h r . The s o l u t i o n was d i l u t e d w i t h c h l o r o f o r m (50 ml) and washed w i t h c o l d water and c o l d 10% h y d r o c h l o r i c a c i d . E v a p o r a t i o n of the s o l v e n t gave a syrup which was passed through a s h o r t alumina column u s i n g e t h y l a c e t a t e - d i e t h y l ether (1:1). Treatment of the e l u e n t w i t h c h a r c o a l , e v a p o r a t i o n and c r y s t a l l i z a t i o n from d i e t h y l e t h e r gave a c o l o r l e s s s o l i d (585 mg, 70% y i e l d ) , mp 117-118°, [ α ] £ - 34.2° {a, 0.5 i n c h l o r o form) . H-NMR: δ 7.98-7.68 (m, 4, p h t h a l i m i d o ) ; 6.78 ( s , H - l ) ; 5.61 ( d , 4 Hz, H-3); 5.32 ( t , 4 Hz, H-4); 4.664.25 (m, 3, H-5 and H-6); 2.16, 2.13, 1.94 ( s , O-ace tyl). Anal. C a l c d . f o r C H I Q N O : C,57.55; H, 4.59; N, 3.36. Found: C, 57 . 52 ; Η, 4 . 57 ; Ν, 3.29. 2,2,2-Trichloroethyl 3,4,6-Tri-0-acetyl-2-deoxy2 - p h t h a l i m i d o - p - D - g l u c o p y r a n o s i d e (10). A s o l u t i o n of the 3-bromide 5 7 9 . 9 6 g, 20 mmol) i n n i t r o m e t h a n e (20 ml) was added dropwise to a c o o l e d (-30°) s o l u t i o n of 2 , 2 , 2 - t r i c h l o r o e t h a n o l (3.30 g, 22 mmol), s i l v e r t r i f l a t e (5.66 g, 22 mmol) and c o l l i d i n e (2.66 g, 22 mmol) i n nitromethane (20 m l ) . A f t e r s t i r r i n g a t -30° f o r 2 hr and d i l u t i o n w i t h c h l o r o f o r m (100 m l ) , t h e s o l i d was removed by f i l t r a t i o n and washed w i t h c h l o r o form (20 m l ) . The combined f i l t r a t e s were washed w i t h c o l d water, 3% h y d r o c h l o r i c a c i d and water and d r i e d . S o l v e n t removal l e f t a y e l l o w foam which was passed through a s h o r t alumina column u s i n g d i e t h y l e t h e r e t h y l acetate (1:1). Treatment w i t h c h a r c o a l , s o l v e n t removal and c r y s t a l l i z a t i o n from d i e t h y l e t h e r gave a c o l o r l e s s s o l i d (9.74 g, 86% based on 5 ) , mp 176-177°, [a]£ + 4.4° (β, 0.5 i n c h l o r o f o r m ) . 1

1

4

1

2

0

q

3


106


H-NMR:

6

7.95-7.65

(m,

4,

p h t h a l i m i d o ) ;

10 H z , H - 3 ) ; 5 . 6 0 ( d , 8 H z , H - l ) ; 5 . 1 9 ( t , 10 2.12, 2.04, 1.88 (s, O - a c e t y l ) ; 4.52-3.82 (m, ing p r o t o n s ) . Anal. C a l c d . f o r Ν, 2.47; C l , 18.77. 2.34; C l , 18.84.

C22H22 OioCl3: C, Found: C , 46 . 6 8 ; N

2,2,2-Trichloroethyl glucopyranoside ( 1 1 ) . A

5.92

( t ,

H z , H-4); 6 remain

46.62; H , 3.91; H , 3 . 9 7 ; Ν,

2-Deoxy-2-phthalimido-

s o l u t i o n of the t r i a c e t a t e 10 (7.93 g, 15 mmol) i n acetone (200 m l ) , water (100 ml) and cone, h y d r o c h l o r i c a c i d (40 ml) was s t i r r e d a t 70° for 3 h r . Removal of acetone l e f t a white suspension w h i c h was e x t r a c t e d w i t h e t h y l acetate (3 χ 100 m l ) . The combined e x t r a c t s were washed w i t h cold water, saturated sodium bicarbonate s o l u t i o n and water and d r i e d . Solvent remova benzene-ethyl acetat (6.0 g, 91% y i e l d ) , mp 2 2 4 - 2 2 5 ° , [α]£° - 37.6° (e, 0.5 in acetone). iH-NMR ( a c e t o n e - d ) : δ 7.86 (s, 4, p h t h a l i m i d o ) ; 5.46 (d, 8 H z , H - l ) ; 4.31 (d, 5 H z , 2, CHoCCl-); 4.72 (d, 5 H z , 1, O H , D 0 e x c h a n g e a b l e ) ; 2.80 (d, 3 H z , 2, O H , D2O exchangeable); 4.80-3.45 (m, 6 r e m a i n i n g p r o tons) . 13C-NMR ( a c e t o n e - d ) : 99.9 ( C - l ) , 97.4 ( C C l o ) , 81.1 ( C H ) , 77.9 (C-5), 72.4 (C-3), 71.8 (C-4), 62.5 (C-6), 57.7 (C-2). Anal. C a l c d . f o r C-, Η N0 C l ο : C, 43.61; H , 3.66; Ν, 3.18; C l , 24.14. Found: C, 43.70; H , 3 . 6 5 ; N , 2.93; CI, 24.00. 6

2

6

2

6

Ί

2,2,2-Trichloroethyl ranoside ( 1 2 ) . A s o l u t i o n

fi

7

2-Amino-2-deoxy-3-Q-glucopy-

of the p h t h a l i m i d o compound 11 (2.20 g, 5 mmol) a n d 87% h y d r a z i n e h y d r a t e (1.0 g) in 95% e t h a n o l (50 m l ) was r e f l u x e d f o r 4 h r . The p r e c i p i t a t e was removed by f i l t r a t i o n and washed w i t h ethanol (10 m l ) . S o l v e n t removal l e f t a pale y e l l o w s o l i d which was a p p l i e d to an ion-exchange r e s i n (Dowex l x , hydroxide form) column and eluted w i t h water. F r e e z e - d r y i n g l e f t a c o l o r l e s s s o l i d w h i c h was d r i e d over P2O5 u n d e r h i g h v a c u u m ( 1 . 3 5 g , 8 7 % y i e l d ) , m p 167-168°, [a]£° - 44.2° (c 0.5 i n w a t e r ) . I H - N M R (ΓΓ20) : 6 5 .12 (d, 8 H z , H - l ) ; 4.88 (d, 5 H z , 2 , CH2CCI3); 4 . 4 6 - 3 . 0 4 (m, 6 r e m a i n i n g p r o t o n s ) . The C-NMR i s reported i n Table I I I . Anal. C a l c d . f o r C0H1ANOCCIO: C, 30.94; H , 4.54; Ν, 4 . 5 1 ; C l , 34.25. Found: C, 31.18; H , 4 . 5 4 ; Ν, 4 . 3 3 ; C l , 34.07. y

1

3

2,2,2-Trichloroethyl copyranoside ( 1 3 ) . A s o l

(1.25 g) methanol

2-Acetamido-2-deoxy-3-g-glu-

u t i o n of t h e amino compound and a c e t i c anhydride (6 m l ) i n 50% aqueous (20 ml) was s t i r r e d a t room t e m p e r a t u r e f o r


12 2

6.

107

2-Α™ϊηο-2-άβοχψβ-τ)-$ηοορψαηού(ΙβΒ

LEMiEux E T A L .

hr. Solvent removal and d r y i n g over P2O5 gave a c o l o r less s o l i d w h i c h was r e e r y s t a l l i z e d from benzene-ace tone (2:1) (1.34 g, 9 6 % y i e l d ) , mp 1 7 1 - 1 7 2 ° , [a]* 35.7° (tf, 0.6 i n w a t e r ) , (lit.(27) 170-171°). H-NMR ( D 0 ) : 6 5.24 (d, 8 Hz, H - l ) ; 4.83 (d, 5 Hz, CH2CCI3); 2.45 (s, tf-acetyl), 4.45-3.80 (m, 6 r e maining protons). 13C-NMR (D20): 102.9 ( C - l ) , 96.5 (CClo) , 80.9 (CH ), 76.4 (C-5), 73.7 (C-3), 70.3 (C-4), 61.2 (C-6), 55.8 (C-2). Anal. C a l c d . for 0, H , N0 Clo : C, 3 4 . 0 5 ; H, 4.57; Ν, 3.97; C l , 30.16. F o u n d : C, 3 4 . 4 6 ; H, 4.65; Ν, 4.21; C l , 29.77. 0

D

2

J

2

Λ

n

fi

fi

2,2,2-Trichloroethyl 4,6-0-Benzylidene-2-deoxy-2phthalimido-3-D-glucopyranoside (14). A s o l u t i o n of

the hydroxy compound 11 (6.61 g, 15 m m o l ) , α,α-dimethoxytoluene (9.10 g acid ( 1 0 0 mg) i n f r e s h l ml) was s t i r r e d at room t e m p e r a t u r e for 12 h r . T r e a t ment w i t h t r i e t h y l a m i n e (1 m l ) and s o l v e n t removal l e f t a s t i c k y s o l i d w h i c h was d i s s o l v e d i n chloroform (100 ml) and washed w i t h c o l d water and s a t u r a t e d sod ium b i c a r b o n a t e s o l u t i o n . Solvent removal a f t e r d r y ing, and c r y s t a l l i z a t i o n from e t h y l a c e t a t e - S k e l l y s o l v e Β gave a c o l o r l e s s s o l i d w h i c h was r e e r y s t a l l i z e d from 2-propanol (7.37 g, 9 3 % y i e l d ) , mp 1 9 6 - 1 9 7 ° , [α]£° 47.2° (c, 0.5 i n chloroform). H-NMR: δ 7.89-7.24 (m, 9, b e n z y l and p h t a l i m i d o ) ; 5.58 (s, 1, b e n z y l i d e n e ) ; 5.50 (d, 8 Hz, H - l ) ; 4.72-4.50 (m, 1, H-2); 2.98 (d, 3 H z , OH, D2O exchange a b l e ) ; 4.44-3.50 (m, 7 remaining protons). Anal. C a l c d . for C23H20NO7CI3: C, 52.24; H, 3.81; N, 2.65; C I , 20.11. F o u n d : C, 5 2 . 3 3 ; H, 3.85; N, 2.38; CI, 20.25.

2,2,2-Trichloroethyl 3-0-(3,4,6-Tri-0-acetyl-2deoxy-2-phthalimido-(S-D-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-2-phthalimido-3-g-glucopyranoside (15).

A s o l u t i o n of the (S-bromide 5 (800 mg, 1.5 mmol) i n nitromethane (5 m l ) was a d d e d to a cooled (-30°) s o l u t i o n of the 3-hydroxy compound 14 (670 mg, 1.27 mmol), s i l v e r t r i f l a t e (385 mg, 1.5 mmol) and c o l l i d i n e (182 mg, 1.5 mmol) i n nitromethane (10 m l ) . A f t e r s t i r r i n g at -30° for 3 h r , then at room t e m p e r a t u r e for 1 h r , the m i x t u r e was d i l u t e d w i t h c h l o r o f o r m (50 m l ) . The s o l i d was removed by f i l t r a t i o n and washed w i t h chloro form (20 m l ) . The combined f i l t r a t e s were washed suc c e s s i v e l y with cold water, 3% h y d r o c h l o r i c a c i d and wa t e r . Solvent removal l e f t a yellow foam w h i c h was ap p l i e d to a s i l i c a g e l column and e l u t e d w i t h e t h y l ace t a t e - S k e l l y s o l v e Β ( 1 : 1 ) . Solvent removal and c r y s t a l l i z a t i o n from d i e t h y l ether gave a c o l o r l e s s s o l i d (980


108


mg, (Cj

82% y i e 0.5 i n H-NMR: i d o ) ; 5.60 5.49 (d, 8 Hz, H - 4 ' ) ; a c e t y l ) ; 4.

l d based on 1 4 ) , mp 1 6 7 - 1 6 8 ° , [a]g 0.6 c h l o r o f o r m ) . δ 7.76-7.28 (m, 1 3 , b e n z y l a n d 2 p h t h a l (s, 1, b e n z y l i d e n e ) ; 5.52 (t, 10 H z , H - 3 H z , H - l ) ; 5.24 (d, 8 Hz, H - l ) ; 5.07 (t, 4.96 (q, 9 Hz, H - 3 ) ; 2.02, 1.92, 1.71 (s, 45-3.50 (m, 11 r e m a i n i n g p r o t o n s ) . u

f

1

Anal. C a l c d . for N, 2.96; C I , 11.24. CI, 11.11.

0 Η Ν Found: 4

3

3

9

2

° i m ) ; 10 0-

0 0 1 : C,54.59; H, 4.15; C, 53.99; H, 4.06; N , 2.88; 1

6

3

2,2,2-Trichloroethyl 3-0-(2-Deoxy-2-phthalimido-3D-glucopyranosyl)-2-deoxy-2-phthalimido-3-D-glucopyranoside ( 1 6 ) . A s o l u t i o n of compound 15 (550 mg, 0.58 mmol) i n 10% t r i f l u o r o a c e t i c a c i d (90%) i n d i c h l o r o m e thane (10 ml) was s t i r r e d for 10 m i n a t room tempera t u r e . Solvent remova i n a m i x t u r e of aceton h y d r o c h l o r i c a c i d (4 m l ) . The s o l u t i o n was s t i r r e d at 70° for 3 h r . E v a p o r a t i o n of acetone gave a suspension w h i c h was c o l l e c t e d by f i l t r a t i o n and washed w i t h cold water. R e c r y s t a l l i z a t i o n from a c e t o n e - e t h y l acetate gave a c o l o r l e s s s o l i d ( 4 0 0 m g , 94% y i e l d ) , m p , 263.5264°, [a]g - 0.86° (c, 0.35 i n acetone). 3

!H-NMR ( a c e t o n e - d j : δ 8.0-7.10 (m, 8, p h t h a l i m i do); 5.23, 5.21 (d, 8 H z , H - l and H - l ) ; 4.72-4.38 (m, H-2 and H - 2 ) . !3c-NMR ( a c e t o n e - d j : 99.4 ( C - l , C - l ) , 97.1 (CC1 ), 82.3 (CH ), 80?5 (C-3), 78.3, 77.9 (C-5, C - 5 ) , 72.1 ( C - 3 ) , 71.4 ( C - 4 ) , 70.7 (C-4), 62.0 (C-6, C - 6 ) , 57.9 (C-2), 55.6 ( C - 2 ) . Anal. C a l c d . for C o H N O i 0 C I 0 : C, 4 9 . 2 3 ; H, 3.99; N, 3.83. Found: C , 4 9 T 4 8 ; H7 4.02 ; Ν , 3.75. 1

1

f

3

f

2

1

f

f

f

n

9

q

?

2,2,2-Trichloroethyl 2-Amino-2-deoxy-3-0-(2-amino2-deoxy-3-D-glucopyranosyl)-β-g-glucopyranoside ( 1 7 ) .

A s o l u t i o n of the p h t 85% h y d r a z i n e h y d r a t e r e f l u x e d for 2 hr and s o l i d was removed by ethanol (5 m l ) . The to a foam w h i c h was d p l i e d to a column of F r e e z e - d r y i n g of the m g , 8 8 % y i e l d ) , mp 2 0 0 . 2 5 - i n w a t e r ) .

h a l i m i d o compound 16 (366 mg), and (2 m l ) i n 95% e t h a n o l (20 ml) was the s o l u t i o n cooled to 0°. The f i l t r a t i o n and washed w i t h cold combined f i l t r a t e s were evaporated i s s o l v e d i n water (10 ml) and ap Dowex 1x8 r e s i n (hydroxide form). e l u e n t gave a c o l o r l e s s s o l i d (208 2-204° ( d e c ) , [α]£ - 33.6° (c, 5

H-NMR ( D 0 ) : δ 5.22, 5.19 (d, 8 Hz, H - l and The ^C-NMR i s r e p o r t e d i n T a b l e I I I . Anal. C a l c d . for C H N 0 C l o : C, 35.65; H , 5.94. Found: C, 3 5 . 8 2 ; H, 5.23; N, 5.78. 2

1

N,

4

2

5

2

9

H - l ) . f

5.34;

2,2,2-Trichloroethyl 2-Acetamido-2-deoxy-3-0-(2acetamido-2-deoxy-3-D-glucopyranosyl)-3-D-glucopyranoside ( 1 8 ) . A s o l u t i o n of t h e a m i n o c o m p o u n d 17 (161


mg,

6.

0.34 with s t i r r l e f t treat mesh, f i l t r ( d e c

mmol) i n 50% a q u e o u s m e t h a n o l ( 1 0 m l ) w a s t r e a t e d acetic a n h y d r i d e (1.0 ml) and t h e s o l u t i o n was e d f o r 2 h r a t room t e m p e r a t u r e . Solvent removal a foam w h i c h was d i s s o l v e d i n w a t e r (10 ml) and ed with Ion R e t a r d a t i o n Resin, AG 11A8 (50-100 B i o - R a d ) . F i l t r a t i o n and f r e e z e - d r y i n g of the a t e g a v e a s o l i d ( 1 7 0 m g , 9 0 % y i e l d ) , mp 222-224° ) , [a]g - 26.6° (c, 0.5 i n water). H-NMR(D 0): δ 5.12 (d, 8 H z , H - l ) ; 4.92 (d, 8 H - l ) ; 2 . 3 3 , 2 .39 (s, tf-acetyl) . 5

1

Hz,

109

2-Α™ϊηο-2-άβοχψβ-τ>-φιοορνταηούάβ$

LEMiEux E T A L .

2

f

C-NMR (D 0): 103.9 ( C - l (C-3), 7 5 . 8 , 75.5 ( C - 5 , C - 5 ) , 68.6 ( C - 4 ' ) , 60.7 ( C - 6 , C - 6 ) , Anal. Calcd. for C H αΝ 0 5.26; N , 5.04. Found: C, 38.54 1

3

2

1

f

n

ft

2

2

Ί

) , 101.3 ( C - l ) , 81.5 73.3 ( C - 3 ) , 69.9 (C-4), 5 5 . 7 , 54.3 ( C - 2 , C - 2 ) . -, C l o : C , 3 8 . 9 0 ; H , ; Η , 5 . 2 6 ; Ν, 5 . 2 3 . 1

f

1

2,2,2-Trichloroethyl 3-0-Acetyl-4,6-O-benzylidene2-deoxy-2-phthalimido-3-g-glucopyranosid i c a n h y d r i d e (8 m l ) w a s a d d e d t o a c o o l e d s o l u t i o n of t h e 3 - h y d r o x y compound 14 ( 3 . 7 0 g) i n d r y p y r i d i n e (16 m l ) . The s o l u t i o n was kept o v e r n i g h t a t room tem perature and poured into crushed i c e . C o l l e c t i o n of the separated s o l i d by f i l t r a t i o n and r e e r y s t a l l i z a t i o n from ethyl a c e t a t e - e t h a n o l (1:4) gave a c o l o r l e s s s o l i d ( 3 . 5 8 g , 9 0 % y i e l d ) , mp 2 0 8 ° " , [a]^° - 29.8° (ο, 0.5 i n chloroform). H-NMR: δ 7.90-722 (m, 9, b e n z y l and p h t h a l i m i d o ) ; 6.00 (t, 9 H z , H - 3 ) ; 5.64 (d, 8 H z , H - l ) ; 5.53 (s, 1, b e n z y l i d e n e ) ; 1.90 (s, 0 - a c e t y l ) ; 4.52-3.64 (m, 7 remaining protons). 1

Anal. Calcd. f o r C H N 0 C 1 : C, Ν, 2 . 4 5 ; C l , 1 8 . 6 3 . Found: C , 52 . 8 9 ; 2.31; C I , 18.72. 2

5

2

2,2,2-Trichloroethyl limido-B-D-glucopyranoside

2

8

3

52.60; H , 3.88; H , 3.97; N ,

3-0-Acetyl-2-deoxy-2-phtha-

(20). A s o l u t i o n of the above b e n z y l i d e n e compound 19 ( 2 . 8 5 g) i n 60% a q u e o u s a c e t i c a c i d (150 ml) was s t i r r e d a t 100° f o r 30 m i n . Solvent removal l e f t a y e l l o w s o l i d w h i c h was s l i g h t l y contaminated by the s t a r t i n g compound. The crude mix t u r e was a p p l i e d to a s i l i c a - g e l column and e l u t e d with ethyl acetate-benzene. Solvent removal of the second f r a c t i o n gave a c o l o r l e s s s o l i d ( 2 . 1 5 g , 89% y i e l d ) , mp 1 9 0 - 1 9 1 ° , [a]^° - 29.2° (c , 1 i n acetone). H-NMR ( a c e t o n e - d ) : δ 7.86 (s, 4, p h t h a l i m i d o ) ; 5.70 ( t , 10 H z , H - 3 ) ; 5.67 (d, 8 H z , H - l ) ; 4.88 (d, 5 Hz, 1, OH, D 0 e x c h a n g e a b l e ) ; 4.36 (d, 4 H z , 2, CH2CCI3); 2.91 ( s , 1, OH, D 0 e x c h a n g e a b l e ) ; 1.86 (s, 0 - a c e t y l ) ; 4.50-3.55 (m, 5 r e m a i n i n g protons). Anal. Calcd. for C Η 0NO0CI0: C, 44.79; H , 3.74; N, 2.90; C I , 22.03. Found: C, 44.93; H , 3.82; N , 2.81; C I , 22.06. 6

2

2

n 8

η


110


2,2,2-Trichloroethyl 3,6-Di-0-acetyl-2-deoxy-2phthalimido-3-g-glucopyranoside (21). A c e t i c anhydride ( 0 . 3 0 6 g , 3 mmol) was added to a cooled s o l u t i o n of compound 20 ( 1 . 4 6 6 g , 3 mmol) i n d r y p y r i d i n e (4 m l ) . After s t i r r i n g a t room t e m p e r a t u r e f o r 2 h r , t h e s o l u t i o n was c o o l e d t o 0° a n d t r e a t e d w i t h m e t h a n o l (5 m l ) . Solvent removal l e f t a foamy s o l i d w h i c h was shown to be a m i x t u r e o f 1 0 , 2 0 , a n d 21 b y T L C . T h e c r u d e m i x t u r e was a p p l i e d t o a s i l i c a g e l column and eluted with benzene-ethyl acetate (4:1). Solvent removal of the second f r a c t i o n gave a c o l o r l e s s s o l i d (0.86 g, 54.5% y i e l d ) , mp 1 3 9 - 1 4 0 ° [a]^ -36.7° (c, 0.9 i n chloroform).

exchangeable); 2.16, 1.96 7 remaining protons) Anal. C a l c d . f o N, 2.67; C I , 20.27. 2.70; C I , 20.11.

(s,

Found:

0 - a c e t y l ) ;

C,

45.83;

4.55-3.60

H ,

3.94;

(m,

N ,

2,2,2-Trichloroethyl 4-0-(3,4,6-Tri-0-acetyl-2deoxy-2-phthalimido-£-D-glucopyranosyl)-3,6-di-Oacetyl-2-deoxy-2-phthaIimido-3-D-glucopyranosidë ( 2 2 ) . A s o l u t i o n o f t h e β - b r o m i d e 5 ( 1 . 1 0 g , 22 mmol) i n nitromethane (15 m l ) was added to a cooled (-30°) s o l u t i o n of the 4-hydroxy compound 21 ( 1 . 0 5 g , 2 . 0 mmol) and c o l l i d i n e (266 m g , 2 . 2 mmol) i n nitromethane (15 m l ) . A f t e r s t i r r i n g a t - 3 0 ° f o r 4 h r , 1 mmol each of 5, the s i l v e r s a l t and c o l l i d i n e were added. The m i x t u r e was s t i r r e d f o r an a d d i t i o n a l 2 hr a t -30° and then l e f t overnight a t room t e m p e r a t u r e . Chloroform (50 m l ) was added a n d t h e s o l i d s were removed by f i l t r a t i o n and washed w i t h chloroform (20 m l ) . The com bined f i l t r a t e s were washed w i t h cold w a t e r , 3% h y d r o c h l o r i c acid and water and d r i e d . Solvent removal l e f t a y e l l o w foam w h i c h was a p p l i e d to a s i l i c a g e l column and e l u t e d w i t h b e n z e n e - e t h y l acetate (4:1). Removal of the solvent from the second f r a c t i o n and c r y s t a l l i z a t i o n from d i e t h y l ether gave a c o l o r l e s s s o l i d (1.28 g, 68% y i e l d b a s e d o n 2 1 ) , mp 1 3 3 - 1 3 4 ° , [α]£ +1.6° (ο 0.5 i n chloroform). H-NMR: δ 8.0-7.62 (m, 8, 2 p h t h a l i m i d o ) ; 5.87 (q, 9 H z , H - 3 ) ; 5 . 7 4 ( t , 10 H z , H - 3 ) ; 5.51 (d, 8 H z , H - l ) ; 5.48 (d, 8 H z , H - l ) ; 5 . 1 5 ( t , 10 H z , H - 4 ) ; 2.11, 2 . 0 1 , 1.99, 1.94, 1.84 (s, 0 - a c e t y l ) ; 4.60-3.62 (m, 11 r e m a i n i n g p r o t o n s ) . Anal. C a l c d . f o r 0 Η Ν 0 0 1 : C, 51.00; H , 4.17; Ν, 2 . 9 7 ; C l , 1 1 . 2 9 . Found: C, 50.85; H , 4.27; Ν, 3.10; C l , 11.36. 4

9

1

1

f

4

0

1

3

9

2

1

8

3


6.

111

2'Αχηιηο-2'άβοχψβ-τ>-φιοο'ρψαηούάβ8

LEMIEUX ET AL.

2,2,2-Trichloroethyl 2-Deoxy-2-phthalimido-4-0-(2deoxy-2-phthalimido-β-Q-glucopyranosyl)-£-|)-gluco-~ pyranoside (23). A s o l u t i o n o f t h e c o m p o u n d 2 2 ( 3 4 6 mg, 0.5 mmol) i n a m i x t u r e of acetone (20 m l ) , water (10 ml) and cone, h y d r o c h l o r i c a c i d (4 m l ) was s t i r r e d at 70° for 6 h r . E v a p o r a t i o n of acetone l e f t a white s u s p e n s i o n w h i c h was c o l l e c t e d by f i l t r a t i o n and washed with water. R e c r y s t a l l i z a t i o n from e t h y l a c e t a t e benzene gave a c o l o r l e s s s o l i d ( 2 2 0 m g , 82% y i e l d ) , mp 221-223° ( d e c ) , [a]£ -20.8° {β, 0.25 i n acetone). 5

H-NMR (acetone-d ): δ 7.88, 7.86 (m, 8, 2 p h t h a l i m i d o ) ; 5.38, 5.36 (d, 8 Hz, H - l , H - l ) ; 5.862.80 ( m , r e m a i n i n g 19 protons). C-NMR (acetone-d ): 100.6, 100.4 ( C - l , C - l ) , 81.5 (C-4), 78.4 ( C - 5 ) , 76.6 (C-5), 72.8, 72.5 (C-3, C - 3 ) , 70.7 ( C - 4 ) , 62.8, 61.7 (C-6, C - 6 ) , 58.5, 57.1 (C-2, C - 2 ) . 1

6

1

1

3

1

6

1

1

1

1

Anal. Ν,

3.99;

Calcd. for C 3.83. Found:

3

H C, 0

2

N 0 C 1 : C, 49.23; H, 49.84; H, 4.12; Ν, 3.54.

9

2

1

3

3

2,2,2-Trichloroethyl 2-Amino-2-deoxy-4-0-(2-amino2-deoxy-(3-D~glucopyranosyl) -3-Q-glucopyranoside (24) . C o m p o u n d 2 4 , mp 1 6 0 - 1 6 2 ° ( d e c ) , [a]g water), w a s o b t a i n e d i n 87% y i e l d from the method used for the p r e p a r a t i o n of H-NMR (D 0): δ 5.26 (d, 8 Hz, H Hz, H - l ) : 4.69 (d, 3.5 H z , 2, C H C C 1 4

1

2

f

N,

The Anal. 5.94.

2

3

-7.8° (ο, 2 i n compound 23 by the compound 17. - l ) ; 5.02 (d, 8 ) .

1 C-NMR i s reported i n Table I I I . Calcd. for C ^ H ^ N ^ g C ^ : C , 35 . 65 ; Found: C, 35.63; H, 5.17; N, 5.99. 3

H,

5.34;

2,2,2-Trichloroethyl 2-Acetamido-2-deoxy-4-0-(2acetamido-2-deoxy-3-D-glucopyranosyl)-3-g-glucopyranoside ( 2 5 ) . C o m p o u n d 2 5 , mp 2 1 8 - 2 1 9 ° ( d e c ) , [a]]} -22.4° (c 0.25 i n w a t e r ) , was y i e l d from compound 24 b y t h e m e t h o d p a r a t i o n of the compound 18. 3

y

H-NMR (D 0): δ H - l ) ; 2.22, 2.18 1

Hz,

2

f

4.98 (d, 8 Hz, (s, N - a c e t y l ) .

prepared used for H - l ) ;

i n 80% the p r e

4.74

(d,

8

C-NMR (D 0): 102.8, 102.0 ( C - l , C - l ' ) , 79.8 (C-4), 76.3 ( C - 5 ) , 75.0 (C-5), 74.2, 73.8 (C-3, C - 3 ) , 72.4 ( C - 4 ) , 61.0, 60.6 (C-6, C - 6 ) , 56.0, 55.1 (C-2, C-2 ) . Anal. Calcd. for C H N 0 C 1 : C, 38.90; H, 5.26; Ν, 5.04. Found: C , 38 . 3 5 ; H , 5 . 2 0 ; Ν, 5.12. 1

3

2

1

T

1

?

f

1

8

2

9

2

1

1

3

Methyl 4 - 0 - ( 3 , 4 , 6 - T r i - 0 - a c e t y l - 2 - d e o x y - 2 - p h t h a l i mido-3-D-glucopyranosyl)-2,3,6-tri-O-benzoyl-a-Dgalactopyranoside ( 2 6 ) . A s o l u t i o n of the β-bromide 5 (1.99 g, 4 mmol) i n n i t r o m e t h a n e (10 cooled (-30°) s o l u t i o n of m e t h y l 2 , 3 D-galactopyranoside (24) , mp 1 3 5 . 5 ° , in chloroform), (1.52 g, 3 mmol), s i l

ml) was added to a , 6 - t r i - 0 - b e n z o y 1 - a [a]g -120° (c, 1 v e r t r i f l a t e 2


112


(1.03

g,

4

mmol),

nitromethane and

at

room

d i l u t e d by

(20

chloroform

(70

m l ) .

and washed

f i l t r a t e s a c i d

foam

was

d i e t h y l

153-154°,

passed

f

) ;

5.47

4

1.93,

1.52.

through

the

m i x t u r e

was

The

s o l i d

a

short

(c,

1

i n

a

hr

removed The

3%

l e f t

a

alumina

gave

3

m l ) .

w a t e r ,

Solvent

ether

i n

was

(20

cold

a c e t a t e .

d i e t h y l

(q,

12

h y

y e l l o w

column

removal

s o l i d ,

c h l o r o f o r m ) ,

and

mp

2.19

g

(79%

(m,

9

19,

H z , H - 3

H z , H - 2 ) ;

f

3

benzoyl

) ;

5.19

5.52 (d,

4

and

(d,

1

8 H z ,

H z , H - 3 ) ;

4.97

(s

. C a l c d .

Anal. N,

f o r

w i t h

mmol)

4.7

1.80

protons)

-30°

C o n c e n t r a t i o n

8.12-7.12

(q,

4

g a l a c t o p y r a n o s i d e ) .

5.80

H z , H - 4 ) ;

2.03, ing

the δ

-••H-NMR:

(t,

+no°

on

p h t h a l i m i d o ) ; H - l

from

g, at

chloroform

washed

e t h e r - e t h y l

[a]22

based

were

h r ,

w i t h

and water.

c r y s t a l l i z a t i o n y i e l d

(0.48

s t i r r i n g 1

w i t h

which

A f t e r f o r

d r o c h l o r i c using

c o l l i d i n e

temperature

f i l t r a t i o n

combined

and m l ) .

f o r

Found:

C ^ H ^ N O - ^ :

C,

62.61;

H ,

C,

5.02;

62.40; N ,

H ,

4 . 9 1 ;

1.58.

Methyl 4 - 0 - ( 2 - A m i n o - 2 - d e o x y - 3 - D - g l u c o p y r a n o s y l ) a-D-galactopyranoside ( 2 7 ) . A s o l u t i o n of the d i s a c c h a r i d e

26

(40

m l ) ,

ml)

was

(1.02

water the

acetate

(2

χ

at

70°

f o r

3

s t i c k y

r e s i d u e

50

and

ml)

bonate

s o l u t i o n .

t i o n

of

t h i s

r e l f u x e d a

the

by

e t h a n o l 1

(302

) ;

1

3

100.0,

61.5

( C - 6

3.94.

w i t h

a

a

The

which

was

A ml)

was

was

evaporated

of

Dowex

1x8

F r e e z e - d r y i n g

c r y s t a l l i z e d 210-212°

mg)

s o l u

a n d 85%

(10

was

b i c a r

(890

s o l i d

column

w a t e r . mp

s o l i d

product

f i l t r a t e to

were

compound.

0 ° .

of

e t h y l

sodium

e t h a n o l

u s i n g

(d,

OCH3);

r e m a i n i n g

from

( d e c ) ,

of 98%

[ α ] £

( C - l

7 0 . 6 , 1

70.1

) ,

and

68.9 70.1

5 7 . 5 ,

( C - 4

f

2

H z , H - l ) ; 4.86

2.96

( t ,

8

H z ,

(d,

8

H - 2 ' ) ;

5.0

(C-5),

56.9

) ,

r e s p e c t i v e l y ) :

(C-2),

7 0 . 4 , 6 1 . 5 ,

( C - 2 ) ,

7 6 . 5 ,

f

7 6 . 5 ,

76.4

69.7 60.9

( C - 5 ' ) ,

(C-3), (C-6),

72.6 6 1 . 5 ,

) . C a l c d .

Found:

4

p r o t o n s ) .

pH 9.5 6 9 . 2 ,

(C-4),

1

the

5.15

3,

0 ,

(C-I),

7 0 . 4 ,

and

95% to

a p p l i e d

δ

(s,

2

l e f t

(8

removal

w a t e r ) .

11 ( D

100.1

) , Anal.

N,

(m,

79.1

105.0,

cooled

acetone a c i d

e x t r a c t s

c o n t a i n i n g i n

of

the

s a t u r a t e d

removal

77% y i e l d ) ,

i n 2

C-NMR

combined

ml)

foam

(D 0):

99.9

78.9,

a

A f t e r

d e a c e t y l a t e d

form)

3.70

4.60-3.56

1

was

m i x t u r e

e x t r a c t e d

cold

group

and

mg,

0.5

H-NMR ?

a

(3.0

hr

gave

(c,

H - l

( C - 3

3

(hydroxide

+102°

be

benzoyl

which

eluent

Hz,

to

a

h y d r o c h l o r i c

h r . was

the and

Solvent

f i l t r a t i o n

syrup

r e s i n

water

hydrate f o r

removed to

cold

appeared

i n

cone,

w i t h

h y d r a z i n e

mmol) and

washed which

1.1 ml)

s t i r r e d

acetone,

g,

(20

f o r C,

C

1

3

H

43.32;

2

5

N 0 H ,

1

0

:

C,

6 . 9 6 ;

43.94; N ,

H ,

3 . 9 0 .


7.09;

6. LEMiEux ET AL.

2-Ατηΐηο-2-άβοχί^-β'Ό^Ιη€ορί^ΐαηο8ΐάβ8

113

Methyl 4-0-(2-Acetamido-2-deoxy-g-D-glucopyranos y l ) - α - g - g a l a c t o p y r a n o s i d e (28). The compound, mp 160162° ( d e c ) , [a]g5 +83.3 (c, 0.5 in water), was obtained in 94% yield from compound 27 by the method used for the preparation of the compound 18. 1 H-NMR (D 2 0): 6 5.12 (d, 2.5 Hz, H-l); 4.94 (d, 8 Hz, H - l 1 ) ; 3.72 (s, 0CH 3 ); 2.38 (s, N-acetyl). 13 C-NMR (D 2 0): 102.2 ( C - l ? ) , 99.5 (C-l), 77.2 (C-4), 75.6 (C-5 f ), 73.9 (C-3'), 70.9 (C-5), 70.2 (C-3), 69.4 (C-2), 68.5 (C-4 1 ), 61.0 (C-6, C-6 f ), 55.8 (C-2 f ). Anal. Calcd. for C 1 5 H 2 7 N 0 1 1 : C, 45.34; H, 6.85; N, 3.53. Found: C, 44.98; H, 6.80; Ν, 4.02. Acknowledgements The authors are indebted to the National Research Council of Canada fo to R. U. Lemieux (A-172). The NMR and microanalyses were provided by the service laboratories of this Department. Abstract The chemical properties of the anomeric t r i - 0 acetyl-2-deoxy-2-phthalimido-D-glucopyranosyl halides were examined. With the halogen C1, Br and I, the anomerization equilibrium constants are 3.2, 1.2 and 3.0, respectively, in accord with earlier evidence (S. Akiya and T. Osawa, 1960) for destabilization of the α-forms by the phthalimido group. The α-anomers undergo replacement of the halogen with inversion whereas extensive retention of configuration occurs using the β-forms and therefore a cationic inter mediate is indicated. Reaction of the β - h a l i d e s with 2-propanol in nitromethane containing mercuric cyanide provided the β - g l y c o s i d e s in high yield. However, with 2,2,2-trichloroethanol, glycosyl cyanide formation was extensive. Using silver triflate-collidine (1:1) as the halogen acceptor, 2,2,2-trichloroethyl t r i - 0 acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside was formed in 86% yield. Under these conditions, the t r i 0-acetyl-2-deoxy-2-phthalimido-β-g-glucopyranosyl derivatives of 2,2,2-trichloroethyl 4,6-0-benzylidene2- deoxy-2-phthalimido-3-g-glucopyranoside, 2,2,2trichloroethyl 3,6-di-0-acetyl-2-deoxy-2-phthalimidoβ- D-glucopyranoside and methyl 2,3,6-tri-0-benzoyl-αg-galactopyranoside were synthesized in 82, 68 and 79% yields, respectively.


114


Literature 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

Cited

Schmitt, F. and Sinaÿ, P., Carbohyd. Res., (1973), 29, 99. Wulff, G. and Röhle, G., Angew. Chemie, Internat. Edit., (1974), 13, 157. Meyer zu Reckendorf, W. and Wassiliadou-Micheli, Ν., Chem. Ber., (1970), 103, 1792. Heyns, K., Harrison, R. and Paulsen, H., Chem. Ber., (1967), 100, 271. Heyns, Κ., Propp, Κ., Harrison, R. and Paulsen, H . , Chem. Ber., (1967), 100, 2655. Shapiro, D., Acher, A. J. and Rachaman, E. S., J . Org. Chem., (1967), 32, 3767. Matta, K. L., Johnson E A and Barlow J J., Carbohyd. Res. Zurabyan, S. E . A. Ya., Carbohyd. Res., (1970), 15, 21. Jacquinet, J . - C . and Sinaÿ, P., Carbohyd. Res., (1976), 46, 138. Akiya, S. and Osawa, T., Chem. Pharm. Bull. (Tokyo), (1960), 8, 583. Baker, R. B., Joseph, J . P., Schaub, R. E. and Williams, J. H . , J. Org. Chem., (1954), 19, 1786. Helferich, B. and Zirner, J., Chem. Ber., (1962), 95, 2604. Igarashi, K., Irisawa, J . and Honma, T., Carbohyd. Res., (1975), 39, 213. Kronzer, F. J. and Schuerch, C., Carbohyd. Res., (1973), 27, 379. Lemieux, R. U. and Hayami, J., Can. J. Chem., (1965), 43, 2162. Lemieux, R. U., Hendriks, Κ. B., Stick, R. V. and James, Κ., J . Am. Chem. Soc., (1975), 97, 4056. Lemieux, R. U. and Chu, Ν. J., Abstr. of Papers, Am. Chem. Soc., (1958), 133, 31N. Lemieux, R. U. and Stevens, J. D., Can. J. Chem., (1965), 43, 2059. Horton, D., Hughes, J . B., Jewell, J . S., Philips, K. D. and Turner, W. N., J. Org. Chem., (1967), 32, 1073. Lemieux, R. U. and Koto, S., Tetrahedron, (1974), 30, 1933. Bundle, D. R. and Lemieux, R. U., Methods in Carbohydrate Chemistry, (1976), VII, 79. Lemieux, R. U. and Koto, S., Abstr. of Papers, Am. Chem. Soc., (1973), 165, Medi 022. McKibbin, J . Μ., "The Carbohydrates Chemistry and Biochemistry," Vol IIB, p. 711, Editors, Pigman, W. and Horton, D., Academic Press, New York (1970).


6. LEMIEUX ET AL.

2-Amino-2-deoxy-β-D-glucopyranosides

115

24. Reist, Ε. J., Spencer, R. R., Calkins, D. F., Baker, B. R. and Goodman, L., J. Org. Chem., (1965), 30, 2312. 25. Inouye, Y . , Onodera, K., Kitaoka, S. and Hirano, S., J. Am. Chem. Soc., (1956), 78, 4722. 26. Hirano, S., Carbohyd. Res., (1971), 16, 229. 27. Lemieux, R. U. and Driguez, H . , J. Am. Chem. Soc., (1975), 97, 4063.


7 Some Aspects of the Chemistry of D-Glucal I. D. BLACKBURNE, A. I. R. BURFITT, P. F. FREDERICKS, and R. D. GUTHRIE School of Science, Griffith University, Nathan, Q.4111, Australia

D-Glucal (Fig. 1) is a well known unsaturated sugar (1) in the words of Fraser-Rei much study of the chemistr -isomers, D-galactal etc., as witnessed by work described in the excellent reviews in Advances in Carbohydrate Chemistry by Ferrier (3,4) and its continuing mention in the Specialist Periodical Reports on Carbohydrate Chemistry. Not unexpectedly much of the research on D-glucal has involved addition of a wide variety of molecules to the 1,2-double bond (3,4). Little work has been done to exploit the other feature of D-glucal, namely that it has three different types of hydroxyl group, primary, secondary, and allylic. (Fig. 1) Those few derivatives at the 3,4 or 6 position that have been made have been prepared from the appropriate D-glucose compound then finally putting the 1,2-double bond in place. No studies have been made, as far as we are aware, of the selectivity of reaction amongst the three hydroxyl groups. This exploitation of D-glucal chemistry has "relevance" as a l l our work is nowadays supposed to have. Amino-glycoside antibiotics (5) are now important chemotherapeutic substances. The nitrosyl chloride based synthesis devised by Lemieux (Fig. 2) is of particular interest here as it utilises glucals in the synthesis of α-linked glycosides with an amino or an hydroxyl group at C-2. Thus one could envisage a semi-synthetic route to modified kanamycins. (Figs. 3 and 4) These suppose that D-glucal derivatives with required modification at C-3 or C-6 (Fig. 5) are available: such compounds are our targets. We decided f i r s t to investigate the synthesis of 6-deoxy-6-fluoro derivatives. 3,4-Di-0-benzoyl-6-0-tosyl-D-glucal (Fig. 6) is probably the most readily available (7) potential starting material. Reaction with fluoride ion in protic solvents such as ethylene glycol led to products that were difficult to separate. Caesium fluoride in DMF, in contrast gave a beautifully crystalline compound, (92%) which was identified as the novel 116


7.

BLACKBURNE E T A L .

Chemistry

of

Ό-Glucal

Figure 1. Ό-Glucal, showing, from top to bottom, a pri mary, secondary, and an allylic hydroxyl group


117

118

SYNTHETIC

METHODS

FOR

CARBOHYDRATES

NHR'

Figure 4

Figure 5

HO

TsO—ν

/ \

0coo- -
that

t h e

that

i n enzyme

i s

not a i s

for

large

ber

o f

highly

o f

500

the

close

membered to

give

isomers

furanose

i s

2

This

w i l l

o f >

r i n g

n u c l e o p h i l i -

-NH > -0H> 2

a

a

s o l u

present

prevalent

p r o c l e v i t y

f a i r

(5)

with

are

the

shown

with

o f

H

i n

have

t h e sugar

forms

furanoid

isomers

p

are

w i l l

i n 5-thio-D-glucose

amount

also

t o

o f

appears

β-D-fructofuranose

Lewis

a c i d

c a t a l y s t

i s

t h e a c y l i c

analogs

containing

i n t e r e s t i n g

a

heteroatom

biochemically

analog,

analogs

(UDPTG)

as

u r i d i n e

have

shown

reactions.

acts

agent

c o n t r o l l i n g

nor a

t o x i c

substance

continuously

a

Since

r e v e r s i b l e

examined

i t s present

new s i m p l i f i e d A unique

increases

a

Most

f i r s t

hormone

as

with

under

5 - t h i o -

the a c t i v i t y

o f o f

other pathway

5 ( 5 - t h i o - a unusually

c o n t r o l male

(6).

UDPTG

use

o f

male

f e r t i l i t y This

sugar

a n t i c i p a t e d

o f

than

5 - t h i o - D -

s i g n i f i c a n t l y

synthesis

synthesis

feature

i s

i t s g l y c o l y t i c

such

alone

desirable. i t

-SH>-

t h e main product

c o n t r o l l e d

amounts.

percent

occur. with

i s t h e

being

steps,

amounts,

w i l l

always

i n t h e presence

sugar

5-thio-D-glucose

analog

o f

have

monosaccharide

I t

and

may r e a c t

The order

i s

D-glucopyranosyl)pyrophosphate

f e r t i l i t y .

to

carbon

than oxygen

isomers

i n s o l u t i o n

and i t s nucleotide

fulness

carbon

the rings

5-Thio-D-fructose

f a r t h e most This

analogs

and

normal

pentaacetate.

a l l the

oxygen,

o f

show

(4)

mixture

conditions

keto-D-fructose Of

group

opening

p o r t i o n

ketosesT

present.

toward

i n

The various

n u c l e o p h i l i c

r i n g

substituents

only

a

o r

size

and s i x

be

produce

carbonyl

hydroxyl ring.

to

pyranose

may o p e n

five

ring

i t w i l l

While

the

the r i n g

carbonyl

population

tions

form

been

aldose

on the

epsilon

attack

proper

that

stable

o r

an

carbon

depend

t h e p a r t i c u l a r nucleophile.

a

so

the heteroatom.

membered

Experimental r e s u l t s

form.

sugar

moderately

a

have

e x i s

with

reactive

NHCOR.

C-5 o f

carbony1

a c y c l i c ando f

seven

heteroatoms

react

t o

ketose

on the d e l t a

o f

s t a b i l i t y and less

r i s e

o f

and, on occasion,

p o r t i o n

l i t i e s . higher

i n a

carbon.

the monosaccharide

carbon

on the

hemiketal,

portions

o f

o r

s t a b i l i t y w i l l

t h e oxygen

hemiacetal

forms

part

a

o f

procedures

discussed.

can n u c l e o p h i l i c a l l y

various

minute

a

attack

c h a r a c t e r i s t i c s

group

i n v e r s i o n

be

C-4,

C-6 of

hemiketal

monosaccharides

giving

w i l l

become

The r i n g

by

introductory

carbon

C-5 o r

ring.

carbonyl

to on


hemiacetal

furanose

to

these

heteroatom

normally

sugar

form

number

a n d some

The is

a

demand

involves

a

num

5-thio-D-glucose i s

glycogen

that,

i s

i n

s m a l l

synthetase

some

(7).


8.

Heteroatoms

WHISTLER A N D A N i s u z z A M A N

Sugar

Rings 1.

Containing

N u c l e o p h i l i c

Nucleophilic most

widely

with

a t h i o a k y l

as

used

charide

xide,

thiocyanate

reduced group

(1)

with

sodium

y i e l d s

a n d require

primary, of

a

good

a p r o t i c

anions

allowed

carbon,

following

s u l f u r .

used

by

Among

a r e b e n z y l t h i o -

b u t these

groups

d e r i v a t i v e s

ammonia

such

monosac-

t h e sugar

containing agents

oxygen

t o remove

require

a r e u s u a l l y t h e benzyl

Hence

a n d t h i o s u l f a t e

reduction

these

i n

nucleophiles

i n displacements positions Best

times

give

have

been

a r e more

d i f f i c u l t

conditions

require

as N,N-dimethylformamide been

displaced

i n t h e synthesis

5-thio-D-ribopyranose (11), 5-thio-D-glucose

(13,14),

4-thio-D-xylose

(JL6) s t r u c t u r e s .

parative

sequences

a n d i s easy

were t o

used

(9,10), (12),

6.

t h e f o l l o w i n g

a t

(DMF).

thiobenzyl, o f

5 - t h i o -

6-deoxy-44 - t h i o - ^ -

(15), a n d 6 - t h i o - D -

The method

5-thio-g-fructofuranose,

r e a c t i o n

with

A l l

than

t h e use

such

anions

most

a t primary carbons.

have

(1-3),

poor

displacements

groups

D-ribofuranose t o prepare

form

o r i s

t h i o l a c y l

solvent

thio-D-glucofuranose

(15 )

long

o r t h i o l b e n z o y l

galactoseptanose

deblock

ester

a

blocked

t h e carbonyl

Thiocyanate

rather

a t secondary

p-Tolylsulfonyloxy

and

w i l l

(tosyloxy)

nucleophile

b

a p p l i e d

D-xylopyranose

Commonly

Thiobenzyl

a s may be expected.

t h i o l a c e t y l

s u l f u r

i n a properly

i n l i q u i d

(2).

carbons.

displacements

Groups.

and 1,2-diphenylethane

a r e cleaved

secondary

by a

d i s p l a c i n g

t h e t h i o l .

borohydride

s a t i s f a c t o r i l y

ring

Sulfonyloxy

monosaccharide

o r t h i o s u l f a t e

form

sodium on

a

t o attack

containing

as toluene

s u l f a t e

group

acetolysis

t h e stable

s u l f u r t o

o f

p - t o l y l s u l f o n y l o x y

because,

s u l f u r

other

reduction

a

f o r r e p l a c i n g

d e r i v a t i v e , o f

o f

(mesyloxy)

i s used

introduced

a c e t y l a t i o n

Displacement

o r t h i o l a c y l group.

t h i o l a c e t y l

the

Sulfur

displacement

methylsulfonyloxy

135

into Sugar Rings

was recently

While

s e v e r a l

i l l u s t r a t e s t h e

conduct.


used

p r e -

136


Here (40%) at

1,2-£-isopropylidene-|j-sorbopyranose,

with

0°

to

an

equimolar

produce

the

y i e l d s

the

a c e t y l

d e r i v a t i v e ,

q u a n t i t y

t o s y l

di-O-acetate, 4

N , N - d i m e t h y I f o r mamicfe fluoroacetic

a c i d

fructopyranose,

at

80°.

y i e l d s

5,

on

methoxidej" produces

t i v e l y

methyl

t i v e l y

tosylated

indicated

i s

w i t h

2,

which on

3~~is

high

above,

but

chloride


converted

potassium

Hydrolysis of

4

to

the

t h i o -

t h i o l a c e t a t e w i t h

i n

aqueous

deacetylation,

i n

methanol

5-thio-D-fructofuranose,

1,3-0-benzylidene-L-sorbofuranoside i n

tosylated

t r i -

3,4-di-0-acetyl-5-S-acetyl-5-thio-P-D-

which

sodium

as

Compound

r e a c t i o n

1,

p-toluenesuïïonyl


3.

by

of

y i e l d the

at

C-5

number

of

and

the

containing

6.

A l t e r n a -

may

be

selec-

reactions

synthetic

steps

continued i s

increased. 5-Thio-P-D-fructofuranose, α-D-is

also

produces sugar

obtained.

the

thiophene

d e r i v a t i v e s

r a t i o n

to

mineral

by

a c i d

very

where

a

easy.

Mineral

excellent

compound

d e r i v a t i v e

that

subsequent

ribofuranose degradation i n

the

less

be

at

i s

room or

but

the

temperatures

i s

s i m i l a r

from

more

thiophene,

degradation

also

convert

degree

than

i n

to

the

mono-

and

r e a d i l y of

than

s t a b i l i z e d 5 - t h i o - D -

4-thioaldoses the

5-thioketose

groups

to

the

converted

to

of

I t the

nucleophile

forms

the

at by

i n

can

glycosides

displacement

the

preparation

and

be

but

r e a d i l y

d i r e c t l y being

sugar or

Displacement

groups

cold

methyl

2,3-di-O-isopropylidene

0-4.

the

acetate

acetochloro

i s

t h i o l a c e t a t e

blocking

temperatures

base.

p-tolysulfonyloxy s t a r t i n g m a t e r i a l i s

t o s y l a t e d

stable

i n p y r i d i n e ;

converted

of

The

e a s i l y

hydrolysis

which

a c i d

anhydride further

anomer high

compounds

decompose obtaining

s u l f u r

(20).

which can

a

4-0-p-toluenesulfonyloxy

be

or

r e a c t i o n

furan

acids

example

containing

j-lyxopyranoside

phene

of

makes

somewhat

4-thio-D-ribofuranose

and

The

ketoses

energy,

to

major

acids

(19).

Another by

formation

(17)

but

the

d e r i v a t i v e

The~~possibility of

thiophene

r e a c t i o n

i s

strong

th

induced

(18).

6

of

d e r i v a t i v e s .

higher"resonance

fructose to

of

thiophene

polysaccharides aldoses

Use

gives

the

the

slow

dehydrates

acetylated

s u l f u r

4 - t h i o - D -

undergoes

stable.

using

of

introduces

to

by

t h i o a c e t i c i t

can

normal reactions

and

nucleosides

Further (13,21,22).


8.

WHISTLER

Heteroatoms

AND A N i s u z z A M A N

137

into Sugar Rings

OAc

• CH OAc 2

Although

displacemen

ion

normally

ous

rearrangement

t i o n

o f

proceeds

methyl

2,3-

rhamnopyranoside, expected

wit

and i n v e r s i o n

c a n also

occur.

Thus,

t h e

reac

0-isοpropy1idene-4-0-p-1οlyIsu1fοny1-a-L-

8 with

potassium

6-deoxy-4^thio-Ir-talose

thiolbenzoate


gives

n o t t h e

9 b u t methyl 5 - S -

benzoyl-6-deoxy-2,3-0-isôprypylidene-5-thio-O^L-talofuranoside, 10 y s i s

(2'3).

Reaction

talopyranose, size

o f

10 w i t h

a n d deacetylation^gives 11.

contraction

I n general under

a

sodium

methoxide

c r y s t a l l i n e L-rhamnose

number

o f

followed

by

a c e t o l -

6-deoxy-5-thio-£tends

conditions

t o

undergo

(24,25).

CH„ H-OSBZ OMe

C(CH3)

2

10


ring

138


Reaction

of

Qxirane

Terminal hexoses,

and

r e a c t i o n

with

for

s u l f u r

s i s

of

Rings

oxirane are

r i n g s

are

convertable

thiourea.

i n t r o d u c t i o n

e a s i l y

i n

good

produced,

y i e l d

A

good

example

of

i s

that

used

one

5-thio-D-glucose

(26).

i n

Here i s

produce

t o s y l a t e d

A l k a l i

C-6

saponifies

a l l o w i n g

the the

0-6

t i o n

of

urea

produces

Acetoxy

the

to

produces

and

the

then

benzoyl

oxygen

t e r m i n a l

attack

conditions s i s

ester

to

group

epoxide,

expected

12.

t h i r a n e

p r e f e r e n t i a l at 13

which

with

the

C-6

at

to

the

the

i n

r i n g s

of

t h i s

f o r

the

the

cold

the

C-5

primary

This

on

r i n g

w i t h

i n

i n

form

t o s y l

gives

sodium

use

route

benzoylated

displace

e s p e c i a l l y

t h i r a n e

by method

synthe-

3 - 0 - b e n z y l - l , 2 - 0 -

isopropylidene-D-glucofuranose the

to

p o s i t i o n

group

w i t h

treatment

forma-

w i t h

i n v e r s i o n of

r i s e

l i q u i d

to ester.

under

t h i o C-5.

a c e t y l a t i n g

ammonia

and

h y d r o l y -

5Êhio-D-glucose

form.

~

~ ÇH OA ζ c 0

C ( C H

The p r i a t e

oxirane

potassium


t o l y l s u l f o n a t e methoxide the

s t r u c t u r e

can

be

obtained

5 , 6 - d i - 0 - p - t o l y l s u l f o n y l d e r i v a t i v e d e r i v a t i v e

forms

t h i r a n e

r i n g

CH OTs 0

ι ^

H-CO-TS

to

a

produce that

on

5 , 6 - e p i s u l f i d e can

proceed

i n

CH SAc 2

H-COTS

the

the

by

from

the

)

2

an

appro

a c t i o n

of

6 - S - a c e t y l - 6 - t h i o - 5 - 0 - p -

treatment r i n g

also

3

(27).

normal

w i t h

cold

Further

sodium opening

ways. CH„

CH


of

8.

Heteroatoms

WHISTLER AND A N i s u z z A M A N

into Sugar

Rings

139

Another way of forming thirane rings from terminal oxirane rings i s by treatment with thiocyanate anion (28). H2

Î> âss>

H-C'

HÇ-S

H C-S-CN

1

N

© CN

H-C-0

v

H-C-O

CH„ H-C-O-CN

7

N

+

CH

®OCN

I S t i l l another route to an appropriate terminal thirane ring is from the 5,6-dideoxy-5,6-dichloro sugar derivative produced, for example, from 3-0-benzoyl-l,2-0-isopropylidene-a-D glucofuranose by reactio and triphenylphosphine (29). Thiolacetate easily displaces the primary chlorine anion and subsequent treatment with potassium hydroxide causes the S-6 sulfur to displace the secondary chlorine to form the expected thirane ring with normal inversion at carbon C-5. CH_OH H.CC1 2ι H

C

S

A

c

A possible mechanism for the halogenation reaction is shown. Ph P:

CCI.

3

Ph PO 3

Ph PClCCl 3

RC1

ROE 3

®

Θ

Ph FORCI 3

CHC1„

Direct opening of an oxirane ring by a nucleophilic sulfur compound may also be easily effected. Thus 5,6-anhydro-l,2-0isopropylidene-a-D-glucofuranose on treatment with sodium Cfrtoluene thioxide produces the 6-S-benzyl-6-thio compound (16). Treatment of 1,6:3,4-dianhydro-P-D-galactopyranose, 15 (4) with a-toluenethioxide produces preferential attack at C-4 with forma tion of the D-glucose derivative, 16. The 1,6-anhydro ring i s not


140


opened

under

Reductive a c e t o l y s i s the

the

conditions

removal gives

of

the

forms

glucopyranose to

pyranose

of

the

Oxetane

Ring

Oxetane the

same

r i n g

i n

way

analog

s o l u t i o n ,

forms, r i n g

is

i n

rings as

can

are

be

carbohydrates with

D-xylopyranose

the

and

compound

by

for

rings

i n

from

allows

on

group.

the

0-3

a c e t y l

oxygen

of

the

s u l f u r

C-5

treatment

displacement

to

and

produce

the

p-tolysulfonyloxy

at

dimethylformamide major

of

furanose s t a b i l i t y

and

with

at of

s i m i l a r

displacement

5-azido

d e r i v a t i v e

reagents

example s u l f u r

i n

oxetane

and

also

of

1,2-0-isopropylidene-a-

or

sodium

a

The

to

the

oxetane

oxetane group. the

s t e r i c oxygen

the

6-0sodium

n u c l e o p h i l i c r i n g

by

azido

the

i n

group

at to

on

ensuing

of

the

ring

configuration

hinderance occurs

metho-

attack

Opening D-gluco

QKtoluenethioxide

Due with

without

methanol w i t h

r e e s t a b l i s h

150°, occurs

much

of

3-0-acetyl-l,2-0-isopropylidene-5-0~

group

occurs

r a t i o

greater

1,2-0-isopropylidene-P-^-idofuranose.

made

i n

i n s e r t

7:3

i n t r o d u c t i o n of

with

displacement

a

only

Treatment

to

other

4-thio-D-

n u c l e o p h i l i c The

triphenylmethyl the

or

Since

e q u i l i b r i u m w i t h

p-tolylsulfonyl-a-D-glucofuranose

by

hydrolysis

acetate.

comparative

rings.

3,5-anhydro

i n

i s

opened

oxirane

i s

C-5

i t s

Opening

i n

removes

s t a b i l i t y .

by

forms.

use

xide

great

or

produces

i n d i c a t i n g the

nitrogen l a t t e r

i t s

followed

p r i n c i p a l l y the


acetates

s u l f u r

of

group

4-thio-D-glucofuranose

underivatized sugar

isomeric

because

benzyl

CARBOHYDRATES

N, N at

C-5

C-3 (30).

give

(31).


the

the A

8.

Heteroatoms

WHISTLER AND ANisuzzAMAN

A l t e r a t i o n I t s u l f u r

of

i s at

E x i s t i n g

sometimes an

p a r t i c i p a t e

Sulfur

i n

the

sought

is

often

be

isomerized

or

caused

ing

reactions

to

produce

the

preparation of

i n s e r t

the

find

good

i n

monosaccharide

a

ring.

s u l f u r

undergo

the

methods

Therefore

i n t o

a

chain

structure

4-thio-D-arabinose

sugar

methyl

intermediate

serve

desired. and

s t a r t i n g material.

the

excise

carbon

i n the

and

the

isopropylidene

benzyl

ammonium t o by

a

groups

Thus,

group

free

group

displaced

r i z e d

Raney

n i c k e l

and

to

i s

then

This

opened

by

to

This

This

introduce

w i t h

a l k a l i benzyl

product

t h i o l a c e t a t e This

i s

sugar.

of

the

a c e t y l

remains

then

i s

a

i s

t r e a t e d

and the

the

to

to

to

i s

a may

hydrolyzed

to

o x i d i z e d

to

prepared

i n

good

1 , 2 : 5 , 6 - d i - 0 -

i s

t o s y l a t e d

and

the

a t

0-3,

sugar

the

d e s u l f u -

the

group

and

the

the

w i t h i s

less not

Under a c i d i c

benzoylated

group

to

displaced by

excise

oxidized

by

to

conditions

with

carbon

one

oxide

but

methanol

the

methyl

5-0-benzyl-2-deoxy-4-thio-D-erythropentofuranoside

i s

formed

and

i n

l i q u i d

ammonia.

One

the

of

containing

the

treated

with

d e r i v a t i v e

with

However,

most

s u l f u r ,

fructopyranose i s

benzyl

while

major and

loss

from

s u l f u r

i s

is

not

i n

i s

can r i n g

and

the

the

removed

by

up due

and

a

part

i s

hence

a

N i c e l y isolated.

to

the

high

l i m i t e d

the

i s

for no

to

r i n g

(33).

isomerase e q u i l i b r i u m

q u a n t i t a t i v e

the

s t a b i l i t y

tendency

compound

pyranose

lack

sugar,

D-fructose

i s w i t h

6-thio-D-glucose

c r y s t a l l i n e The

of of

6-thio-P-D-

l a t e r

nearly from

one

of

the

e s s e n t i a l l y

be

i t s

of

to

substrate

formation

loss.

e a s i l y

When t h e

sodium

of

formation

isomerized

conversion

d i s u l f i d e

work

probably

fructopyranose

i t

becoming

r a t h e r

being

i s

6-thio-D-glucose.

6-thio-D-glucose

general

reversion

another

isomerase

but

fructopyranose

r e d u c t i v e l y

i n t e r e s t i n g transformations

into

from

6-thio-D-fructose established

group

i s

hydrolysis.

attachment

the

i n

which

d e r i v a t i v e .

removed

negative

i n

tosylated.

5,6-epoxide,

tosyloxy

periodate i s

i s then

6-0-benzyl

isopropylidene

s u l f u r

3-deoxy-l,2-0-

product

produce

and

the

the

The

o b t a i n

s u l f u r

uneffected.

(32)

This

6-0-benzoyl

o x i d i z e d

group

(12)

5-thio-D-glucose

periodate


converted

tosylated

Since

are

3 - d e o x y - l , 2 : 5 , 6 - d i - 0 - i s o p r o p y l i d e n e - a -

is

anion

anion

product

the

examples

2-deoxy-4-thio-D-ribose

s t a r t i n g w i t h

isopropylidene-a-D-glucofuranose. cold

then

shorten-

5 - S - a c e t y l - 3 , 6 - d i - 0 - b e n z y l -

isopropylidene-a-D-glucofuranose.

the

can

or

D-arabinofuranos ide.

route

tosyloxy by

may

r e d u c t i v e l

the

long

D-glucofuranose.

which Two

i t

expedient

4-thio-D-arabinoside

synthesis

2-deoxy-4-thio-D-riboside r a t h e r

the

Th

produce

Methyl y i e l d

one.

i n s e r t i n g

that

lengthening

1,2-0-isopropylidene-5-thio-D-glucofuranose remove

for

structures.

preparation of

possible as

sugar

the

to

(C-4-thio-g-deoxyribose) In

to

p o s i t i o n

intended

to

Containing Structure

d i f f i c u l t

appropriate

141

into Sugar Rings

6-thio~-P-D-

of of

s i g n i f i c a n t the

open

to

6 - t h i o - D provide


142


the It

a c y c l i c is

form

necessary

e s p e c i a l l y

fructopyranose than

for

i n t e r e s t i n g

i s

the

enzyme

to

sweetest

note

binding that

sugar

and

isomerization.

6-thio-P-D-

known

being

some

30%

sweeter

D-fructose.

Selenium

i n

There nium

as

routes

the i s

the

only

r i n g

Ring

one

example

heteroatom

to

similar

paration

Sugar

those

proceeds

for

from

α- D - x y l o f u r a n o s e

which

α-tolueneselenol

to

with

sodium

is

methanolic

sugar

analog

The

compound

the

s u l f u r

containing i s

s e l e

prepared

sugar

by

analog.

Pre

with

the

sodium

s a l t

of

5-Se-benzyl-l,2-0-isopropylidene-5Removal

l i q u i d

hydrogen

making

reacted

give

i n

a

1,2-0-isopropylidene-5-£-p-tolylsulfonyΙ

seleno-a-D-xylofuranose. t i o n

of

(34).

of

ammonia

the

and

benzyl

group

subsequent

by

reduc

reaction

with

chlorid

deoxy-a-D-xylofuranosid-5-yl)-5,5'-diselenid diastereomers

of

D-threo-3,

phene-2-dimethyl from

nmr

and

Nitrogen An

i n

j o i n i n g

the

with

group

s t a r t

containing

chain. ment

i n

a

carbonyl

positioned r i n g

a

of

nitrogen

Displacement Thus,

of

a

desired

often

i s

a

to

sugar. to

along

often S h i f f

group

Szarek

bases

by

ammonia

reacted

(35)

h y d r o l y t i c

isopropylidene

group.

group

before

The r e s u l t i n g s u g a r

5-acetamido-5-deoxy-D-xylopyranose xylofuranose water i n

i n

solution,

methanolic

methyl In

the

i t

of

4:1.

and When

e q u i l i b r a t e s

hydrogen

above

forms

containing

r i n g

group.

can by

Thus

(benzyloxycarbonyl) favor

r a t i o

5-[

the

monosaccharide by

i n

d i s p l a c e

the

w i t h

form

chloride

the

produces

an

of

early

i n

methanol

removing

c y c l i z e s

to

the

produce

5-acetamido-5-deoxy-D-

e i t h e r the

was

ammonia

form

other the

of

the

compounds be an i f

the

a l t e r e d

is

heated

form.

two

i n

Treatment

r i n g

increase the

amino

pyranose

e q u i l i b r i u m between

i n

favor

i n

the

acetamido group,

form.

Thus

of

forms

as

isopropylidene,

almost

pyranose

l a r g e r

and

n u c l e o p h i l i c i t y

group

the

the is

replaced

e q u i l i b r i u m is

of by

and

nitrogen the

N -

the

s h i f t e d

i n

5-[(benzyloxycarbony1)amino]-5-

deoxy-1,2-0-isopropylidene-a-g-xylofuranose of

a

a l l

n i t r o

D-xylosides.

furanose a c y l

a

u s e f u l

1,2-0-isopropylidene-

with

amino

a

occurs

and

the

n u c l e o p h i l i c Consequently

locate

location of

monosaccharide

due

5-0-p-toluenesulfoyl-a-D-xylofuranose acetylated

established

employed.

tosyloxy

and

the

most

reduction

are

Jones

of

designed

at

although

i n

compound

carbon

reactions

hydrazones

which

Ring

properly

with

of

information.

group

or

method.

structure

Introduction

reactions

oximes

Sugar

the

4-dihydroxy-2,3,4,5-tetrahydroseleno-

the

spectroscopic

p a r t i c i p a t e s

syntheses gen

mass

amino

structure

acetal,

e x c l u s i v e l y

gives,

the

on

hydrolysis

c r y s t a l l i n e

(benzyloxycarbonyl)amino]-5-deoxy-Q5-g-xylopyranose

(36)


and

8.

the

six-membered

Amide

I I band For

of

Heteroatoms


r i n g

s t r u c t u r e

i n t h e i r

follows

form

i s

l i k e w i s e

acetamido-5-deoxy-D-xylose. y i e l d s

syrupy

o f a n proportion

compared

w i t h

i n favor

o f

with

o r

a n a c i d

ion-exchange

i n t h e r a t i o

L)-arabinose,

t h e furanose

5 -

5-benzamido-5-deoxy-

c r y s t a l l i n e 5-benzamido-5-deoxy-D-xylopyranose

5-acetamido-5-deoxy-(D

displaced

as

Hydrolysis o f

5-benzamido-5-deoxy-D-xylofuranose

For is

t h e absence

t h e e q u i l i b r i u m

increased,

1,2-0-isopropylidene-a-D-xylofuranose r e s i n

from

143

Rings

spectrum.

5-benzamido-5-deoxy-D-xylose,

t h e pyranose

into Sugar

form.

t h e

Thus,

o f

and 3 : 1 (37).

e q u i l i b r i u m

1,2-0-

isopropylidene-5-0-tolylsulfonyl-P-L-arabinofuranose,

o n

ment

5-acetamido-

with

ammonia

and subsequent

a c e t y l a t i o n ,

y i e l d s

5-deoxy-1,2-0-isopropylidene-P-L-arabinofuranose s i s

o f

t h i s

compound

w i t h

a c i d

gives

(38).

a mixture o f

5-acetamido-5-deoxy-]>arabinopyranose

a n d syrupy

t r e a t Hydroly

c r y s t a l l i n e 5-acetamido-5-

deoxy-L-arabinofuranose A

s i m i l a r

Azido group

such

r e a c t i o

i s a good

nucleophile

t h a t

as p-toluenesulfonyloxy,

a p p l i c a t i o n .

A n example

i s

found

r e a d i l y

displaces

and t h e r e a c t i o n

i n t h e preparation

1,2,3,5-tetra-£-acetyl-4-deoxy-D-xylofuranose,

17.

a

leaving

has had wide 4-acetamidoReaction

o f

2 , 3 - d i - 0 - b e n z o y l - 4 - (p-tolylsulfonyl) - β - ^ a r a b i n o p y r a n o s i d e , 1 8 w i t h sodium azide g i v e s m e t h y l 4-azido-4-deoxy-a-g-xylopyranoTide, 19

which o n c a t a l y t i c

hydrogénation

3eoxy-a-D-xylopyranoside, a c e t o l y s i s form,

y i e l d s

20.

produces

methyl

N - a c e t y l a t i o n o f

17 a n d p o s s i b l y

a

small

4-amino-4-

19 followed

anount'~~of

i t s

21. ( 4 0 ) .

21

by

pyranose

OAc


144

SYNTHETIC METHODS FOR CARBOHYDRATES The

but

i r spectra

there

i s

no

o f

absorption

a t

rable

t h e furanose

w i t h

Another for

6.5μ.

These

example

absorption

due t o

NH a b s o r p t i o n

a t

and t h e nmr spectra

t h e use o f sugars

o f

amide

17 a r e

displacement nitrogen

r e a c t i o n

as t h e

r i n g

t h e c r y s t a l l i n e

5-acetamido-5-deoxy-a-D-lyxopyranose

22 f r o m

benzyl

2, 3 - £ - i s o p r o p y l i d e n e - 5 - 0 - m e t h y l s u l f o n y l - a - D - l y x o f u r a n o s i d e In (

J

t h e nmr spectrum o f l

22

2

=

2

·

5

Η ) 2

i s t h e a

Tne

o r i g i n o f

r o t a t i o n

a t

and i s a

r o t a t i o n a l

around

Azide

22 t h e 1 - H s i g n a l s

centered

anomer

o f

has been

i s due t o

also

used

(39),

This

dideoxy-D-xylofuranose L)-arabinofuranose

(42,43), (44),

23

(41).

doublets

indicates

that

22a and22b.

r e s t r i c t i o n o f resonance

o f

t h e

type

f o r t h e preparation

o f

5-benzamido-5-deoxy-D-

(37), 5-acetamido-5-deoxy-D-ribopyranose

5-acetamido-5-deoxy-L-arabinopyranose (and

as

i t s rotamers

r e s u l t i n g from

5-acetamido-5-deoxy-D-xylopyranose xylopyranose

appear

4.09 a n d 4.52.

mixture

isomerism

t £ e C-N b o n d

displacement

τ

I I

compa

~ " azide

containing

i s t h e p r e p a r a t i o n o f

OAc and NAc

3 . Ομ o r

s t r u c t u r e .

o f

t h e p r e p a r a t i o n o f

heteroatom

17 s h o w s

evidenceT"for

(39),

(39)

9

4-acetamido-4,5-

4-acetamido-4-deoxy-D 4-acetamido-4-deoxy-L-xylofuranose


8.

WHISTLER

(45),

Heteroatoms

AND A N i s u z z A M A N

into Sugar

145

Rings

1,2:3,5-di-^-isopropylidene^4-acetamide-4^deoxy-a-L-

xylofuranose

(45) a n d 4 - a c e t a m i d o - l , 2 , 3 ,5 - t e t r a - i O - a c e t y l - D -

ribofuranose

(46).

The

presence

acetamido

group

c o n f i g u r a t i o n

o f

a

i n a

sulfonate

sugar

through

ester

molecule

neighboring

group

i n a d d i t i o n

c a n r e s u l t

group

i n a

t o a n

change

p a r t i c i p a t i o n .

o f

Thus

5-acetamido-5-deoxy--l,2-0-isopropylidene-3-0-methylsulfonyl-Darabinofuranose,

obtained

0-isopropylidene

D-arabinofuranose,~~24,

benzoate

from

5 - 0 - p - t o l y l s u l f o n y l - 5 - d e o x y - l , 2 -

i n N,N-dimethylformamide gives

O-isopropylidene-D-lyxofuranose^25. presumably (47).

proceeds

through

when

heated

w i t h

sodium

5-acetamido~5-deoxy-l,2-

The conversion

t h e o x a z o l i n i u m

o f

24 t o 25

ion-oxazoline

,


system

146

SYNTHETIC

Acid

h y d r o l y s i s o f

5-acetamide

Hydrazine the

o f

i s

The

o f

f i r s t

a

u s e f u l

into

step

involves

a

d i s p l a c i n g agent A convenient


group

f o r

method

i n t r o -

(48)

compound neighboring

which

group

with

s u b s t i t u t i o n o f

by hydrazine t o

form

converts

t h e

t o

f o r i s

the

hydrazine.

the

primary

6-hydrazino-5-

a

three-membered

p a r t i c i p a t i o n .

CH OMs

I

5-acetamido-5-

1:TT

a n N - a m i n o a z i r i d i n e compound o f hexoses

0-(methylsulfonyl) through

as

sugars.

CARBOHYDRATES

c r y s t a l l i n e

5, 6 - d i - 0 - ( m e t h y l s u l f o n y l ) a l d o h e x o s e

methylsulfonyloxy r i n g

mixture o f

i n t h e r a t i o

aTio

n i t r o g e n

p r e p a r a t i o n o f

r e a c t i o n

a

FOR

5-deoxy-a-D-Tyxopyranose, 2 6 a n d s y r u p y

deoxy-lyxofuranose,27 duction

25 g i v e s

METHODS

CH -NHNEL

2

H NNH

\£y

MSO-C-H

J,NHNH

I

2

->

MsO-C-H

H

-

C

^

2

R Reduction 5,6-dideoxy d e r i v a t i v e

with

hydrazine

d e r i v a t i v e s which (49).

Thus,

i n presence c a n be

o f

n i c k e l

c y c l i z e d

1, 2 - 0 - i s o p r o p y l i d e n e - 3 , 5 , 6 - t r i - 0 on

r e a c t i o n

t h e isopropylidene

with

group

dideoxy-P-L-idopyranose, form

rated

chromatography

by

t o

pyridine spectra the

o f

29

yield

Reduction a t

o f

i n d i c a t e w i t h

followed

e x i s t s

4 : 1 .

by

h y d r o l y s i s

i n e q u i l i b r i u m

The compound

reacts

w i t h

a c e t i c


t h a t

both

these

s u b s t i t u e n t s

aluminium


to

a t

28

with

i s

sepa-

ariKydride a n d

30.

The nmr

compounds

prefer

C - l and C-5 being

32 a n d a

Hydrolysis

oT^these

from

free

which

hydroxy1

1:1

used

t o

i n

amine,

mixture o f

The nmr spectra

s u l f u r

w i t h

t h e free

amino

t h e

k e t o -

d i m e t h y l sulfoxide and i s

a

dioxide

a r e obtained o f

produce Thus

2 , 3 : 5 , 6 - d i - O - i s o p r o p y l i d e n e - D reduced

gives

l i t h i u m

sugars

derivative^33.

b i s u l f i t e

by r e a c t i o n

t h e p y r r o l i n e

w i t h

4-amino-4-deoxy-D-glucose

4-amino-4-deoxy-D^-galactose w i t h

sugars

i n e q u i l i b r i u m

from

be

molecules.

by o x i d a t i o n with

with a

can a l s o

i n sugar

31 obtained

r e a c t i o n hydride

(50)

l o c a t i o n

dimethyl aceta1

subsequent

e x i s t

and i t

oximes

s p e c i f i c


glucose

xide.

This o f

from

position

groups oxime

28.

prepared

5-(benzyloxycarbonylamino)-5,6-

i t s t r i - O - a c e t y l

C l ( L ) conformation

a x i a l

gives

i n t h e raîfio

28 a n d 3 0

5-amino-

amino-pyranose

(methylsulfonyl-a-D-glucofuranose

benzyloxyformyl c h l o r i d e

furanose

gives

a n

5 - a m i n o - l , 2 - 0 - i s o p r o p y l i d e n e - 3 - 0 -

(methylsulfonyl)-5,6-dideoxy-P-£-idofuranose

of

t o

with

i n d i c a t e

form

and a

adduces

barium

t h a t

hydro-

these

dimeric


form.

8.

WHISTLER AND A N i s u z z A M A N

Heteroatoms

into Sugar Rings

American Chemical Society Library 1155 16th St. N. w. Washington, C. 20036 El Khadem, H.; In Synthetic Methods D. for Carbohydrates; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

147

148

SYNTHETIC

ÇH(0Me)

.

0

'

\

_

FOR

CARBOHYDRATES

ÇH(OMe),

?

1.

Me S0-Ac

2.

Η N-OH

2

_

^

-C(CH ) 3

01

METHODS

Ο

L i A l H ^

3 ( C

0 1

2

C H

3

>2

É-N-0H

i

i-o

C ( C H

3

)

> ( C H

2

)

C H / C

H

2 ° 31

CH(OMe)

h^x:(CH ) 3

^ C ( C H

2

)

3

2

O•NH

H N2

> C ( C H

)

C H . O ^ 33

Z

CH OH n

I

2

HO-C-H

H-C-OH

OH

1

CH OH 2

-Cj!-OH CH„OH


8.


Heteroatoms

into Sugar

149

Rings

An example o f t h e use o f a hydrazone d e r i v a t i v e t o i n t r o d u c e nitrogen i n t h e sugar r i n g i s t h e preparation 5-acetamido-5-deoxyD - x y l o p y r a n o s e , 34 f r o m 1,2-cyclohexylidene-a-D-xylopentodialdo1 , 4 - f u r a n o s e p h e n y l h y d r a z o n e , 35 ( 5 1 ) . H y d r o g é n a t i o n o f 35 a f f o r d s t h e a m i n o c o m p o u n d , 3 6 w K i c h o n N - a c e t y l a t i o n gives*** 5-acetamido 1,2-p-cyclohexyli3ene-5-deoxy-D-xylofuranose 37. A 2 : 1 m i x t u r e o f 34 a n d i t s f u r a n o s e i s o m e r 38 i s o b t a i n e d b y ^ t h e a c i d hydro lys i s ~ f 37. B o t h 34 a n d 38 a r e a t a b l e i n n e u t r a l solution but readilyêquilibraEe i n acid a t 70°. A benzyl glycos i d e o f 34 consumes two m o l e s o f s o d i u m p e r i o d a t e w i t h t h e l i b e r a t i o n οίΓεΓ m o l e o f f o r m i c a c i d a n d t h i s r e s u l t i s c o m p a t i b l e w i t h a pyranose s t r u c t u r e . >

OH

5 - A m i n o - 5 - d e o x y - I r - i d u r o n i c 3'9 a c i d r e l a t e d t o t h e c a r b o h y d r a t e component o f p o l y o x i n s h a s ^ e e n s y n t h e s i z e d r e c e n t l y (52). The r e a c t i o n o f 1,2-0-isopropylidene-5-aldo-D-xylopentodialdofuranose w i t h b e n z y l amine a n d hydrogen cyanide" g i v e s 5 - b e n z y l a m i n o 5-deoxy-l, 2-0-isopropylidene^-L-idofuranonitrile, 40, which on hydrolysis with water y i e l d s 5-benzylamino S"-deoxy-l, 2fr-isopropylidene-L-iduronic acid, 41. Hydrogenolysis o f 41 leads t o t h e f o r m a t i o n o f 5-amino-5-deoxy~"compound, 42 from w h i c h t h e f r e e 5 - a m i n o - 5 - d e o x y - L - i d u r o n i c a c i d 39 i s p r e p a r e d by way o f t h e b e n z y l o x y c a r b o n y l compound, 4 3 . TheT"free a c i d 39 e x i s t s i n a e q u i l i b r i u m o f t h e f u r a n o s e "form a n d p i p e r i d i n e H E b r m a n d t h e l a t t e r s i x membered f o r m p r e d o m i n a t e s . : :


150

SYNTHETIC

METHODS

FOR

CARBOHYDRATES

OH Phosphorus i n the Sugar Ring As an exercise i n chemistry and to show the further general i t y of producing sugar rings containing various heteroatoms we undertook the replacement of oxygen by phosphorus i n the six member g-xylose ring (53). i n this sequence, 1,2-0-isopropylidene3-0-methy1-5-0-(p-toluenesulfonyl) c^D-xylofuranose or 5-bromo-5deoxy-1, 2-£-isopropylidene-3-0-methyI-a-D-xylofuranose i s reacted with triethylphosphite to produce the 5-deoxy-5-(diethylphosphinyl) derivative. Reduction with lithium aluminium hydride followed by hydrolytic removal of the isopropylidene group produces i n the one case 5-deoxy-3-jO-methyl-5-phosphinyl-D-xylopyranose, 44 and 5-deoxy-3-£-methyl-5-(phosphinic acid)-D-xylopryanose, 45?~ Formation of 44 and 45 presumably proceed through intermediates 46 and 47. Comûnd 4T"does not mutarotate and i s stable toward a i r oxidation. However, with bromine i t i s oxidized to the phosphinic acid 45. The i r spectrum of 44 shows absorption due to the B-H groupT


8.


Heteroatoms

into Sugar

Rings

151

45 Inokawa and associates recently synthesized a D-ribose deri vative containing phosphorus i n the ring (54). They undertake nucleophilic displacement of the iodo group i n methyl 5-deoxy-5iodo-2, 3-£-isopropylidene-P-g-ribofuranoside with ethyldiethoxyphosphine to produce methyl 5-deoxy-5-(ethoxyethylphosphinyl)-2,3O-isopropylidene-P-D-ribofuranoside 48. Reduction of 48 with sodium dihydro-bis72-methoxyethoxy)'âluminate i n THF gTves methyl 5-deoxy-(ethylphosphinyl)-2,3-0-isopropylidene-P-D-ribofuranoside 49, acid hydrolysis of which yields 5-deoxy-5-(ethylphospinyl)-DrTbopyranose 50. Evidence for the pyranose structure of 50 i s derived from ΈΚβ absence of characteristic PH peaks i n i~Esf nmr and i r spectra. The reaction of 50 with a mixture of acetic anhy dride and pyridine gives i t s 1, 2,3^~4-tetra-0-acetyl derivative, 51 which reverts to 50 on deacetylation with sodium methoxide i n "~ methanol. By using reactions similar to those described above, 5-(alkylphosphinyl)-5-deoxy-3-0-methyl-(and benzyl)-D-xylopyranoses were also prepared (55 56). 5


152

SYNTHETIC METHODS

Ο

FOR CARBOHYDRATES

E t

Literature Cited 1. Ingle, D. L. and Whistler, R. L., J. Org. Chem. (1962) 27, 3896. 2. Schwarz, J. C. S. P. and Yule, K. C., Proc. Chem. Soc. (1961) 417. 3. Adley, T. J. and Owen, L. Ν., Proc. Chem. Soc. (1961) 418. 4. Vegh, L. and Hardegger, E., Helv. Chim. Acta (1973) 56, 2020. 5. Chmielewski, M. and Whistler, R. L., J. Org. Chem. (1975) 40, 639. 6. Zysk, J. R., Bushway, Α. Α., Whistler, R. L. and Carlton, W. W., J. Reprod. Fert. (1975) 45, 69. 7. Graham,T.L. and Whistler, R. L. Biochemistry, (1976) 15, 1189. 8. Gross, B. and Driez, F. X., Carbohyd. Res. (1974) 36, 385. 9. Clayton, C. J. and Hughes, Ν. Α., Chem. Ind. (London) (1962) 1975. 10. Clayton, C. J. and Hughes, Ν. Α., Carbohyd. Res. (1967) 4, 32. 11. Owen, L. N. and Ragg, P. L., J. Chem. Soc. (C) (1966) 1291. 12. Whistler, R. L., Nayak, U. G. and Perkins, A. W., Jr., J. Org. Chem. (1970) 35, 519. 13. Reist, E. J . , Gueffroy, D. E. and Goodman, L., J. Am. Chem. Soc. (1963) 85, 3717.


8. WHISTLER AND ANISUZZAMAN

Heteroatoms into Sugar Rings

14. Reist, E. J . , Gueffroy, D. E. and Goodman, L., J. Am. Chem. Soc. (1964) 86, 5658. 15. Reist, E. J., Fisher, L. V. and Goodman, L., J. Org. Chem. (1968) 33, 189. 16. Cox, J. M. and Owen, L. N., J. Chem. Soc. (C) (1967) 1121. 17. Newth, F. Μ., Advan. Carbohyd. Chem. (1951) 6, 83; Feather, M.S. and Harris, J. F., Advan. Carbohyd. Chem. (1973) 28, 161. 18. Haworth, W. N. and Jones, W. G. M., J. Chem. Soc. (1944) 667. 19. Whistler, R. L. and Hoffman, D. J . , Carbohyd. Res. (1969) 11, 137. 20. Whistler, R. L., Dick, W. E., Ingles, T. R., Rowell, R. M. and Urbas, B., J. Org. Chem. (1964) 29, 3723. 21. Whistler, R. L., Bobek, M. and Bloch, Α., J. Med. Chem. (1970) 13, 411. 22. Ototani, N. and Whistler 535. 23. Stevens, C. L., Glinsky, R. P., Gutowski, G. E. and Dicker son, J. P., Tetrahedron Lett. (1967) 649. 24. Stevens, C. L., Glinski, R. P., Taylor, K. G., Blumbergs, P. and Sirokoman, F., J. Am. Chem. Soc. (1967) 88, 2073. 25. Kefurt, K., Jary, J. and Samek, Z., Chem. Commun. (1969) 213. 26. Nayak, U. G. and Whistler, R. L., J. Org. Chem. (1969) 34, 97. 27. Creighton, A. M. and Owen, L. N., J. Chem. Soc. (1960) 1024. 28. Hall, L. D., Hough, L. and Pritchard, R. Α., J. Chem. Soc. (1961) 1537. 29. Chiu, C-W. and Whistler, R. L., J. Org. Chem. (1973) 38, 832. 30. Whistler, R. L., Luttenegger, T. J. and Rowell, R. M., J. Org. Chem. (1968) 33, 396. 31. Nayak, U. G. and Whistler, R. L., J. Org. Chem. (1968) 33, 3482. 32. Nayak, U. G. and Whistler, R. L., Chem. Commun. (1969) 434. 33. Chmielewski, Μ., Chen, M. S. and Whistler, R. L., Carbohyd. Res., 000. 34. van Es, T. and Whistler, R. L., Tetrahedron (1967) 23, 2849. 35. Jones, J. Κ. N. and Szarek, W. Α., Can. J. Chem. (1963) 41, 636. 36. Paulsen, H., Leupold, F. and Ίodt, Κ., Ann. (1966) 692, 2001. 37. Patel, M. S., Jones, J. Κ. N., Can. J. Chem. (1965) 43, 3105. 38. Jones, J. Κ. N. and Turner, J. C., J. Chem. Soc. (1962) 4699. 39. Hanessian, S. and Haskell, T. H., J. Org. Chem. (1963) 28, 2604. 40. Reist, E. J . , Fisher, L. V. andGoodman, L., J. Org. Chem. (1967) 32, 2541. 41. Brimacombe, J. S., Hunedy, F. and Stacy, M., J. Chem. Soc. (C) (1968) 1811.


153

154 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

SYNTHETIC METHODS FOR CARBOHYDRATES Brimacombe, J. S. and Bryan, J. G. Η., J. Chem. Soc. (1966) 1724. Hanessian, S., Carbohyd. Res. (1965) 1, 178. Dick, A. J. and Jones, J. Κ. Ν., Can. J. Chem. (1968) 46, 425. Dick, A. J. and Jones, J. Κ. Ν., Can. J. Chem. (1965) 43, 977. Reist, E. J., Gueffroy, D. E., Blackford, R. W. and Goodman, L., J. Org. Chem. (1966) 31, 4025. Hanessian, S., J. Org. Chem. (1967) 32, 163. Paulsen, H. and Stoye, D., Chem. Ber. (1969) 102, 820. Paulsen, H. and Friedmann, Μ., Chem. Ber. (1972) 105, 731. Paulsen, Η., Propp, K. and Heynes, Κ., Tettrahedron Lett. (1969) 683. Paulsen, H., Ann. (1963) 670, 121. Paulsen, H. and Mä Whistler, R. L. an 4455. Inokawa, S., Kitagawa, H., Seo, K., Yoshida, Y. and Ogata, T., Carbohyd. Res. (1973) 30, 127. Inokawa, S., Ysuyoshi, Υ., Seo, K. and Ogata, T., Bull. Chem. Soc., Japan, (1971) 44, 2279. Seo, K. and Inokawa, S., Bull. Chim. Soc., Japan (1973) 46, 3301.


9 Stereoselective Synthesis and Properties of 1-0-AcylD-Glucopyranoses PHILIP E. PFEFFER, GORDON G. MOORE, PETER D. HOAGLAND, and EDWARD S. ROTHMAN Eastern Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Philadelphia, Pa. 19118 In general, 1-0-acylaldoses, and in particular the derivatives with a cis accessible substances found in nature, e.g., 1-0-benzoyl-β-D-glucopyranose (peri -planetin) in insects (1), stevioside in Stevia Rebaudiana Bertoni (2), asiaticoside from Cantella asiatica (3) and 1-0galloyl-β-D-glucopyranose in Chinese rhubarb (4). Over the years there have been numerous attempts at preparing anomerically pure H

H

I c=o I R

Ια

\β

1-α and β-D-glucopyranose esters 1α and 1β using various reactions aimed at controlling the anomerism of the C-1 acylation site. Schmidt (5) prepared the sterically hindered 1-0-galloyl-α-D— glucopyranose 2a in 5% yield through a lengthy five-step synthesis.

2a

OH

155


156

SYNTHETIC METHODS

F O R CARBOHYDRATES

The key steps in this scheme involved a BF isomerization for five days of the more accessible 2,3,4,6-tetra-0-acety1-1-0(triacetyl-galloy1)-ß-D-glucopyranose followed by preferential deacylation of the more labile acetyl protecting groups. This work represented the first reported preparation of a 1-0-acyl-αD-glucopyranose 1α. In later studies Fletcher (6) questioned the positional assignment of the ester grouping of Schmidt's compound 2a and took another approach to solve the problem. In his attempt using a silver benzoate displacement reaction on D-glucose diethyl dithioacetal, Fletcher prepared in very low conversions 2-0-benzoyl-ß-D-glucose, which was isolated as its tetraacetate. A similar treatment of ethyl-1-thio-ß-D-glucopyranoside gave after acetylation both 1,3,4,6-tetra-0-acetyl-2-0-benzoyl-α-Dglucopyranose and 2,3,4,6-tetra-0-acetyl-1-0-benzoyl-α-Dglucopyranose (6). Although, the 1-α-D-glucosyl ester was apparently an initially formed product migratio th 2-position evidently too preparation of a stable 1-0-α-D-glucosyl ester, which did not undergo migration, was finally realized in the synthesis of the hindered mesitoate derivative 2b in 17% yield (6). 3

Although 2b was stable to neutral conditions, i t could be induced to undergo C- to C« ester migration under basic conditions (7). I t was concluded (6) that 2b would be "the only example of a cis-l-O-acylaldose that could be prepared and isolated" without rapid rearrangement. Preparation of the 1-0-acyl-p-D-glucopyranoses 1β i s less complex because of the i n a b i l i t y of the trans


9.

oriented

157

1-O-Acyl-O-glucopyranoses

PFEFFER E T A L .

1-0-acylaldose

to undergo

Acylation of p a r t i a l l y protected glucopyranose 3 yielded l b a f t e r

analogous

ester

shifting.

4,6-O-benzylidine-l-O-sodio-Dd e b l o c k i n g (8). Nevertheless,

o v e r a l l conversions of the anomerically pure product ester l b based on g l u c o s e were o n l y 30-40% due t o t h e l o w and v a r i a b l e results

obtained

for

the i s o l a t i o n and p u r i f i c a t i o n of

benzylidine-D-glucopyranose In to

this

report

we w i l l

the preparation of

their acyl

spectral

which

We w i l l

are important

achieved

describe

glucosyl

properties

migration.

4 and i t s corresponding

Stereoselective

esters

3. approaches

l a and l b , and examine

discuss

reactivity including the mechanistic

i n explaining the stereochemical

i n the key acylation

glycopyranose

some new s y n t h e t i c

and chemical also

4,6-0-

salt

implications control

reaction.

Acylation of 2,3,4,6-tetra-O-benzyl-l-O-lithio-D(TBG L i

+

One o f t h e m o s t e l e g a n t m e t h o d s f o r a c h i e v i n g stereoselective g l y c o s i d a t i o n has r e c e n t l y been demonstrated by Schuerch (10), e q u a t i o n 1, and Lemieux ( 1 1 ) , e q u a t i o n 2. Utilizing 2,3,4,6tetra-O-benzyl-l-bromo-a-D-glucopyranose (TBGB), these workers c a r r i e d out double i n v e r s i o n displacement reactions i n which the f i n a l glycoside linkage had the desired configuration. Equation 1

.

C ]

«»0

v

u

«*0v

N(Et)s

- o

Ihl3u

wc'f"

*CH CI 2

w

2

0

V

^ C

M

+,_..

ROH

^0

B r

^VH

H

**C

0

(ID R

d e p i c t s s t e r e o c h e m i c a l c o n t r o l through t h e agency of the " r e v e r s e anomeric" effect exhibited by the e q u a t o r i a l preference of ammonium s a l t i n t e r m e d i a t e ( 1 0 ) , w h i l e e q u a t i o n 2 d e m o n s t r a t e s the approach through e q u i l i b r a t i o n effected by s o l u b i l i z e d bromide i o n . I n each case a h i g h s e l e c t i v i t y f o r α - g l y c o s i d e l i n k a g e f o r m a t i o n was shown. l a t t e r r e a c t i o n ( e q u a t i o n 2)

However, i n the e a r l y stages a p r e f e r e n c e f o r t h e β-anomer

of the could

be r e a l i z e d , b u t o v e r a l l c o n v e r s i o n t o t h i s s p e c i e s was l o w . F o r t h e s t u d y o f t h e a c y l a t i o n o f t h e a n o m e r i c OH o f g l u c o s e , w e e x a m i n e d t h e r e a c t i o n s <j>f 2 , 3 , 4 , 6 - t e t r a - O - b e n z y l - l - O - l i t h i o - D g l u c o p y r a n o s e 5 (TBG L i ) b e c a u s e o f at the position. Furthermore, i f could be c a r r i e d out d i r e c t l y on 5, i prepare the unstable bromide d e r i v a t i displacement reaction. (10

i t s n o n p a r t i c i p a t i n g group stereoselective acylation t would o b v i a t e t h e need t o v e TBGB ( 1 1 ) f o r a n i n d i r e c t

Metalation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (TBG) 6 mmol) i n 1 2 5 m l o f t e t r a h y d r o f u r a n (THF) a t - 3 0 t o - 4 0 ° w i t h


158


1.1 equivalents of η-butyl lithium (1.6 M i n hexane) followed by acylation with 1.1 equivalents of acyl halides, (20 minutes) produced a mixture of 2,3,4,6-tetra-O-benzyl-l-O-acyl-D-glucopyranose esters (TBG esters) 7a and 0 i n 90-95% yield with a Η

π Bu Li THF or Benzene

1

B 0^CH^ N

ρ V^0B^^0Li n

"

5

decided preference for the α-configuration 7α. Often the isolated products were o i l s which could not be crystallized; however, the anomeric composition was easily determined by evaluation of the proton nmr spectrum of the characteristic anomeric hydrogens. Table I l i s t s the physical properties of esters prepared by this procedure. For each member i n this series, the anomeric composi tion of the isolated product esters was always at least 90% α and 10% 3 by nmr analysis. However, selectivity for the a-anomer diminished (70% a, 30% 0) with acylation temperature elevation to 60°. Metalation of 6 i n benzene at 0-5°C followed by acylation at this temperature produced a mixture of esters 7a and 70, con taining equal amounts of both a- and 0-anomeric forms. At higher temperatures, ^60°, we observed unexpectedly high selectivity for the production of the 0-anomeric ester 70. In a l l cases studied at ^60° we obtained products with a 0/a ratio of 9/1, a complete reversal of the selectivity shown i n THF at -30°. Table II contains physical properties of ester products obtained from acylation of 5 i n benzene at 60°. This stereoselectivity i s much greater than previously reported. For example, the direct acylation of 6 i n methylene chloride-pyridine over a wide range of temperatures gives only slight selectivity for formation of the a-anomer (60-70% a, 30-40% 0) (12) as does the dehydrationacylation reaction with the N-acylamino acid f a c i l i t a t e d by dicyclohexylcarbodiimide (13). To establish the mechanism responsible for the stereoselective control of this reaction we studied the products as a function of solvents and temperature using a single acylating agent. Table III shows the results obtained through acylation of 5 with hexadecanoyl chloride i n benzene and i n THF at temperatures from -40° to +62°C. As previously noted i n the THF, the α-glycosyl ester 7a i s the predominant product over the temperature range of -40° to +60°. However, selectivity for the α-anomer decreased (70% a, 30% 0) when the reaction temperature was raised to 25°, and



H

H

C

b

17

33

b

6.70(d,3.3)

e

1740

6.60 (d,3.3) 6.66(d,2.7)

e

e

1737

1740

5.90 (m)

f

+73.7

+72.0

f

5.90(m)

+73.5

+42.8

f

5.90(m)

5.85(d,6.8)

+45.9

5.85(d,6.8)

6.65(d,2.6) 6.65(d,2.6)

C

2

2

(CH C1 , l c ) +39.2

5

5.85(d,6.8)

M p

6.65 (d,2.6)

1

<S (ppm) C --H,J (Hz) a-anomer β-anomer

1750°

1745

1745°

i r , C=0, cm ^

a

Neat films.

Chloroform solution.

g

ABX multiplet. mp of recrystallized product 124.2-125.0 (EtOH),

f

mp of recrystallized product 84-85 (EtOH).

d

^Noncrystallizable glasses, c

A l l products are 90% a-anomer, 10% β except where otherwise indicated, rotations are for pure α-anomers when recrystallization was possible.

2,4,6-trimethylphenyl

p-nitrophenyl^

phenyl^

çis-9,C H

15 31

17 35

C

R

+

Table I. Acylation Products of TBG""Li i n THF at -30 to -40°C


1 5

C

H

H

3 1

3 5

1735

d

1737

6.60(d,3.3)

6.66(d,2.8)

6.70(d,3.3)

6.65(d,2.6)

6.65(d,2.6)

a-anomer

5.90(m)

d

5.90(m)

d

e

5.90(m)

5.85(d,6.8)

5.85(d,6.8)

β-anomer

6, (ppm) C.-H,J (Hz) 2

-27.0

+1.6

-23.0

+ 9.1

+10.7

D

^(Dioxane, 6 c ) reference 12.

mp of recrystallized product 96-98, see reference 12.

mp of recrystallized product 131.0-1.5 (EtOH).

f

ABX multiplet.

e

mp of recrystallized product 96.0-97.2 (cyclohexane).

d

°mp of recrystallized product 52-53 (EtOH).

^Noncrystallizable glass.

2

h

25 [ a ] (CH Cl ,lc)

A l l products were 90% β, 10% α, rotations are for pure β-anomers when recrystallization was possible.

a

p-nitrophenyl

g


1740

1750

C

f

1750

b

phenyl

1 7

C

i r , C=0, cm

1

Table II. Acylation Products of TBG LI i n Benzene at 60°


"

II

If

a

Derived

from

10% 30 30 30 50 74 89 30

0

the i n t e g r a t i o n of

90% 70 70 70 50 26 11 70

α

the anomeric

protons.

-30 to 40° 25° 45° 60° 0 t o 5° 40 t o 45° 62° 62°

Temperature [a]* 5

+36.0 +27.8 +20.6 +14.9 +35.0

+45.9 +39.2

2

2

(CH C1 , lc)

Stereochemical D i s t r i b u t i o n of Anomeric 1-0-Hexadecanoyl-D-TBG as a F u n c t i o n o f Temperature and S o l v e n t

+ 4% HMPA

Benzene

ff

II

It

THF

III.

Solvent

Table

162


CARBOHYDRATES

seemed t o r e m a i n c o n s t a n t a b o v e t h i s t e m p e r a t u r e . Overall con v e r s i o n s t e n d t o d r o p f r o m 95% t o 8 5 % w i t h p r o l o n g e d h e a t i n g . In b e n z e n e , a c y l a t i o n s e l e c t i v i t y e x h i b i t s more s e n s i t i v i t y to t e m perature change. T h e h i g h s e l e c t i v i t y f o r 7β f o r m a t i o n a t elevated temperature (62°), decreases with decreasing temperature ( l i m i t i n g temperature i s the f r e e z i n g point of benzene). Addition o f 4% o f a h i g h l y p o l a r a p r o t i c s o l v e n t , h e x a m e t h y l p h o s p h o r a m i d e (HMPA), r e v e r s e d t h e p r o d u c t d i s t r i b u t i o n i n b e n z e n e a t 62°C t o g i v e t h e same p r o d u c t d i s t r i b u t i o n o b s e r v e d i n THF a t 2 5 ° . F i g u r e 1 d e p i c t s the r o t a t i o n of 1-0-hexadecanoyl-D-TBG e s t e r s as a f u n c t i o n of the α/β r a t i o . A l t h o u g h we h a v e b e e n u n a b l e t o i s o l a t e the 1-0-hexadecanoyl-a-D-TBG i n h i g h p u r i t y owing to the n o n c r y s t a l l i n e nature of the r e a c t i o n product, by e x t r a p o l a t i o n o f t h e d a t a o f F i g u r e 1 we o b t a i n a r o t a t i o n v a l u e o f + 5 1 . 0 for the pure α m a t e r i a l . Concerning

the

Structur

Acylation T h a t T B G 6 mp 1 5 2 - 1 5 3 ° e x i s t s i n t h e α - c o n f i g u r a t i o n i s w e l l documented (11, 12, 14, 1 5 ) . However, t h i s f a c t i s i n c o n s i s t e n t w i t h the observations that the stereochemistry of i t s a c y l a t i o n p r o d u c t s v a r y so w i d e l y . F o r t h i s r e a s o n o u r f i r s t t a s k was t o reexamine the stereochemistry of TBG. In s t u d y i n g the proton s p e c t r u m o f T B G , e a r l i e r w o r k e r s (14) h a d f a i l e d t o o b s e r v e t h a t the α-anomeric p r o t o n resonance does not account f o r a s i n g l e proton r e l a t i v e to the other protons i n the molecule. We o b s e r v e d t h a t the measured i n t e n s i t y of t h i s resonance r e l a t i v e to a l l o t h e r p r o t o n r e s o n a n c e s i n TBG r e f l e c t s o n l y a f r a c t i o n o f t h e anomeric composition. T h i s m i x e d a n o m e r i c c o m p o s i t i o n may a l s o b e v e r i f i e d b y m e a s u r e m e n t o f t h e a n o m e r i c OH r e s o n a n c e i n a s l o w OH e x c h a n g i n g e t h e r s o l v e n t s u c h a s T H F - d g . E x a m i n a t i o n o f TBG i n v a r i o u s a p r o t i c s o l v e n t s b y 220 MHz p r o t o n nmr spectroscopy c o n f i r m e d t h a t TBG i s a n a n o m e r i c m i x t u r e . Table IV l i s t s the a n o m e r i c c o m p o s i t i o n o f TBG i n f o u r a p r o t i c s o l v e n t s . I n each solvent except for chloroform, the anomeric composition appeared t o be v e r y s i m i l a r . This i s also borne out by the r o t a t i o n a l data (Table I V ) . These d a t a support the i d e a t h a t c r y s t a l l i n e TBG a p p a r e n t l y e x i s t s a s a e u t e c t i c m i x t u r e o r s o l i d s o l u t i o n o f α and β forms, s i n c e instantaneous m u t a r o t a t i o n i n a p r o t i c media would be h i g h l y u n l i k e l y . In a d d i t i o n , the e q u i l i b r i u m concentra t i o n s o f TBG f o u n d i n THF a n d b e n z e n e do n o t r e f l e c t t h e a c y l a t e d p r o d u c t d i s t r i b u t i o n s o f 7a a n d 7β i n t h e s e r e s p e c t i v e s o l v e n t s . An a p r i o r i e x p l a n a t i o n for the a c y l a t i o n product d i s t r i b u t i o n might be based on a s o l v e n t dependent e q u i l i b r a t i o n between the anomeric m e t a l a t e d s p e c i e s 5a and 5β. T h u s , we m i g h t e x p e c t a p r e d o m i n a n c e o f a n o m e r 5 a i n THF a n d a p r e d o m i n a n c e o f 5β i n benzene i n accord w i t h the observed a c y l a t i o n product d i s t r i b u t i o n . However t h i s does not t u r n out to be the c a s e . To e x a m i n e t h i s



+55.0 +46.8 +53.6 +19.1

5.89 5.20 5.23 5.12 e

e

5.45 5.0 -

d,11.0 d,10.5

%

^Fraction estimated from comparison of the area of the anomeric proton resonance with the area of the remaining protons i n molecules.

Could not be observed.

^Measurement made at 55°.

Composition was confirmed by comparison of the α and β-ΟΗ resonances observed at 5.9 6 and 5.38 6, respectively.

52 50^, 67 59^ 65*

β-anomer fraction 6 C -H ppm,J(Hz) α

^Spectra taken at 17° except where indicated otherwise.

d,3.0 brs d,3.0 d,3.0

a-anomer 6 C -H ppm,J(Hz)

0.100 g/10 ml of solvent.

a

g

pyridine d THF d Benzene d, Chloroform d,

Solvent

Table IV. Anomeric Composition of TBG by 220 MHz H'NMR and Rotational Measurements

164

SYNTHETIC M E T H O D S FOR CARBOHYDRATES

60

0

r

I

I

0

0.

I

I

L

I

.4

Figure 1. Plot of the α,β composition of 1Όhexadecanoyl-O-TBG against observed rotation [a] (CH Cl , lc) 2 5 D

Figure 2.

2

2

Pathway for the reaction of a- and β-TBG zene and THF

Li uAth acid chlorides in ben +


9.

hypothesis 5β

i n the

we m e a s u r e d two

reaction

An attempt

165


PFEFFER E T A L .

to

the

equilibrium concentrations

of

5a

and

solvents.

evaluate

the

composition

of

5 i n both

THF-dg

and b e n z e n e - d ^ b y p r o t o n nmr met w i t h f a i l u r e due t o i n o r d i n a t e l y broad resonances. However s p e c t r u m showed n a r r o w l i n e s w h i c h w e r e r e a d i l y a s s i g n a b l e t o the respective anomeric carbons. Samples were p r e p a r e d by the a d d i t i o n o f one e q u i v a l e n t o f η - b u t y l l i t h i u m i n h e x a n e t o a d r i e d d e g a s s e d s o l u t i o n ( 2 m l ) , c o n t a i n i n g 1 5 0 mg o f 6 J n a 1 0 mm nmr t u b e . T h e s p e c t r a w e r e r e c o r d e d a t 2 2 . 6 3 MHz o n a C FT spectrometer. Ten second d e l a y times were u t i l i z e d between scans t o a l l o w f o r d i f f e r e n c e s i n T- r e l a x a t i o n t i m e s and t o a s s u r e q u a n t i t a t i o n resonance absorption responses, ( r e l a x a t i o n times (T^) h a v e b e e n o b s e r v e d t o b e n e v e r m o r e t h a n 1 . 5 s e c o n d s ) (16). Taule V gives the C c h e m i c a l s h i f t s and i n t e n s i t i e s of the anomeric carbons f o r 6 and 5 i n b e n z e n e - d . and THF-dg. The C c a r b o n o f t h e β - a n o m e r 6β i s o b s e r v e d a t l o w e r f i e l d t h a n t h e o f t h e α - a n o m e r 6a ( 1 7 ) . The α / β r a t i o a g r e e d w e l l w i t h the 1

d a t a o b t a i n e d b y p r o t o n nmr ( s e e T a b l e I V ) . Upon m e t a l a t i o n each o f t h e r e s p e c t i v e C - c a r b o n s u n d e r w e n t a 3 ppm u p f i e l d s h i f t d u e to the s h i e l d i n g e f f e c t of the n e g a t i v e charge on oxygen (18). O n l y a s m a l l change i n t h e anomer d i s t r i b u t i o n was o b s e r v e d , i . e . , t h e α a n o m e r c o n t r i b u t i o n d e c r e a s e d f r o m 6 1 % a n d 67% i n b e n z e n e a n d T H F , r e s p e c t i v e l y , t o 50% a n d 52% i n t h e m e t a l a t e d f o r m s . A p p a r e n t l y t h e r e a r e no s i g n i f i c a n t d i f f e r e n c e s i ç t h e e q u i l i b r i u m c o n c e n t r a t i o n s o f e i t h e r a n o m e r i c f o r m s o f TBG L i , 5 a o r 5 β , i n either reaction solvent. The s t e r e o c h e m i c a l s e l e c t i v i t y of t h i s r e a c t i o n must, t h e r e f o r e , be c o n t r o l l e d by the r e l a t i v e v e l o c i t y w i t h w h i c h e i t h e r o f t h e s e two s p e c i e s 5 a a n d 5β a r e a c y l a t e d . F i g u r e 2 shows p o s t u l a t e d r e l a t i v e e n e r g i e s of t h e v a r i o u s s o l v a t e d a c t i v a t e d complexes t h a t might account f o r the observed

13 Table V.

Anomeric Composition and δ Benzene α β

TBG_ TBG L i

91.3 89.1

98.2 95.9

C Chemical Shifts

6 THF α 91.6 88.8

β 98.6 96.1

% α Benzene

% α THF

61 50


67 52

166


product outcome. I n THF s o l u t i o n , t h e l o w e r e n e r g y p a t h w a y p r o v i d e d by s o l v e n t - s o l v a t e d A r e l a t i v e to the h i g h e r energy pathway g i v e n by i n t e r n a l l y s o l v a t e d Β leads to a predominance of product 7a. C o n v e r s e l y , i n benzene i n t r a m o l e c u l a r c o o r d i n a t i o n of Β i s favored since i t offers gjeater s t a b i l i z a t i o n r e l a t i v e to the s t a b i l i z a t i o n imparted to A by the r e l a t i v e l y nonpolar, poorly s o l v a t i n g benzene. T h e r e f o r e , i n b e n z e n e , p r o d u c t 73 predominates. Increase i n the p o l a r i t y of the benzene s o l u t i o n w i t h a s l i t t l e a s 4% ν / ν H M P A , ( T a b l e I I I ) p e r m i t s t h e f o r m a t i o n o | a l o w e n e r g y HMPA i n t e r m o l e c u l a r l y s o l v a t e d t r a n s i t i o n s t a t e A leading to product 7a. I n t h e a b s e n c e o f k i n e t i c d a t a we c a n o n l y s p e c u l a t e o n t h e e f f e c t o f t e m p e r a t u r e o n p r o d u c t d i s t r i b u t i o n . H o w e v e r , we c a n see t h a t i n b o t h s o l v e n t s , i n c r e a s e d temperature i g a s s o c i a t e d w i t h an i n c r e a s e i n the r e a c t i o n through pathway Β to produce more 7β. /This temperatur a h i g h AS for transitio l a t t e r * s ordering of solvent molecule. Thus,/as the temperature i s i n c r e a s e d i n b o t h s o l v e n t s y s t e m s , t h e TAS t e r m c o u l d become d o m i n a n t (more p o s i t i v e ) , e f f e c t i v e l y l o w e r i n g / e v e n f u r t h e r t h e AG f o r the pathway through t r a n s i t i o n s t a t e Β r e l a t i v e to pathway through A . 1-0-Acyl^D-Glucopyranoses

l a and

1β

B o t h p r o d u c t s 7a a n d 7β f r o m a c y l a t i o n i n THF a n d b e n z e n e , r e s p e c t i v e l y , underwent f i n a l p u r i f i c a t i o n by e l u t i o n from a column of F l o r i s i l w i t h methylene c h l o r i d e - p e t r o l e u m e t h e r . ( R e f e r e n c e t o b r a n d o r f i r m name d o e s n o t c o n s t i t u t e endorsement by the U . S . Department of A g r i c u l t u r e over others of a s i m i l a r nature not mentioned.) E a c h was t h e n h y d r o g e n a t e d (40 p s i ) i n

ethanol with palladium black for eight hours. I n m o s t c a s e s we found p r i o r chromatographic p u r i f i c a t i o n e s s e n t i a l for successful deblocking. On some o c c a s i o n s , a d d i t i o n o f a f e w d r o p s o f acetic a c i d was n e c e s s a r y to c a t a l y z e t h e h y d r o g e n o l y s i s . Although the p r o t e c t e d e s t e r s 7a a n d 7β w e r e 9 0 : 1 0 a n o m e r i c m i x t u r e s w h i c h i n m o s t c a s e s w e r e n o t s e p a r a b l e , t h e d e b l o c k e d e s t e r s l a a n d 1β c o u l d e a s i l y be r e c r y s t a l l i z e d to produce b o t h pure a - and βforms i n 70-85% y i e l d . In contrast to the f i n d i n g of previous r e p o r t s ( 6 , 7 ) , we o b s e r v e d t h e Ι - α - D - g l u c o s y l e s t e r s l a t o b e



H

16 31

H

H

C

C

H

H

C

1 7

3 1

β

b

d

d

3

c

d

153-9 c

166-9

c

192-3

c

112-121

(CHCl )

1725

1725

1729

1725

e

e

d, 3.0 m

6.40 5.75

d,3.0

6.27

5.90 m

1712

d,3.0

2

+51.0 (MeOH, 0.9c)

+59.0 (MeOH 0.9c)

-

+102 (H 0, 0.50c)

-

-27 (HO, 0.45c)

2

+85.2 (H 0, 0.36c)

+72.9 (MeOH, l c )

d,3.0

6.55

6.48

1742

-1.17 (MeOH, 1.2c)

d,6.8

1720

5.65

1725

2 5

66.9 (MeOH, 0.9c)

[a]

r ι D

d,3.0

J (Hz) 6.48

1740

a

6 C^-H ppm ,

1742

C=0, cm"

ir,

d

a

chloroform-hexane.

Anomeric proton resonance coincided with the double bond proton resonances.

Recrystallized from EtOH.

Unable to crystallize these derivatives.

Recrystallized from

Spectra obtained at 60 MHz i n CD 0D (sealed tubes at 76°)because of the insolubility of the derivatives.

c i s , cis-9,11 C H

3 3

β

1 7

β

cis-9, C

H

α

α


3

β

α

α

108, 170-5

β

b

98-108

α b

mp

2,4,6-1r ime thylpheny1

CH

6 5

6 5

C

18 35

16 31

C

R

Configu ration

Table VI. Physical Properties of 1-Glucosyl Esters Ια, 1β

168


r e l a t i v e l y s t a b l e , g i v i n g r i s e to rearrangement only a f t e r p r o longed heating. F u r t h e r d e t a i l s of t h i s a c y l m i g r a t i o n w i l l be e l a b o r a t e d on i n the l a s t s e c t i o n . Table V I l i s t s the p h y s i c a l p r o p e r t i e s o f t h e i s o l a t e d l a a n d 1β e s t e r s . T h e ^ c o n f i g i g a t i o n o f e a c h o f t h e s e m a t e r i a l s was e s t a b l i s h e d l g both Η and C nmr e x c e p t f o r t h e u n s a t u r a t e d e s t e r s w h e r e C c o u l d o n l y be used b e c a u s e of o v e r l a p p i n g resonance signals Jn the p r o t o n s p e c t r a . F i g u r e s 3A a n d 3B i l l u s t r a t e t y p i c a l C s p e c t r a o f l a a n d 13 d e r i v e d f r o m l o n g c h a i n s a t u r a t e d carboxylic acids. As i s observed f o r the p a r e n t g l u c o s e m o l e c u l e , the α-anomeric carbon C a b s o r b s a t a h i g h e r f i e l d t h a n t h e β-C^ carbon (17), yet the d i f f e r e n c e i n chemical s h i f t between a-C^ a n d β - C . i s o n l y 2 ppm c o m p a r e d t o t h e 4 p p m n o t e d f o r g l u c o s e (17). The s m a l l e r d i f f e r e n c e i n f i e l d p o s i t i o n s i s l i k e l y due t o i n d u c e d u p f i e l d s h i e l d i n g o f t h e 3-C^ r e l a t i v e t o t h e α - C ^ b y the ester carbonyl. S h i e l d i n g o f 2 . 2 ppm i s a l s o e v i d e n t i n t h e resonance of l a , presumabl respect to the c a r b o n y l whereas

lb

is

deshielded

by

1.6

ppm.

A comparison of the hexose r i n g C s h i f t s f o r l a a n d 1β a n d glucose i s given i n Table V I I . The a n o m e r i c p u r i t y of each com pound was v e r i f i e d by g l c a n a l y s i s o f t h e c o r r e s p o n d i n g trimethyls i l y l d e r i v a t i v e s on a 6 1 / 4 " O . D . g l a s s c o l u m n p a c k e d w i t h 3% SP2100 and programmed from 180-250° a t 6 ° / m i n u t e . Under these c o n d i t i o n s each of the i s o m e r i c a - and β - p a i r s c o u l d be r e a d i l y s e p a r a t e d , t h e β-anomer h a v i n g t h e l o n g e r r e t e n t i o n t i m e . T y p i c a l r e t e n t i o n times f o r the a - and β-hexadecanoate e s t e r s were 12.0 and 12.5 m i n u t e s , the a - and β - m e s i t o a t e s , 8 and 8.2 minutes, respectively. f

Table V I I .

13 Hexose R i n g C S h i f t s f o r α and β-D-Glucose Corresponding 1-Hexadecanoyl E s t e r s Carbon C

6-D-Glucose? β-D-Glucose l-a-D-Glucosylhexadecanoate Ι-β-D-Glucosylhexadecanoate

C

All

shifts

Spectra °Spectra

relative

0

to

l

92.8 96.7 92.2 94.3 TMS a s

C

2

C

72.3 74.9 73.9 72.7

Shifts

3

C

73.6 76.7 74.2 76.8

internal

4

70.4 70.4 69.7 69.9

(ppm) C

5

72.3 76.5 71.0 76.8

and a

°6 61.6 61.6 61.4 61.7

standard.

t a k e n i n DÔ. taken i n 50/50

v/v

CDC1 , 3

CD 0D. 3

A l t e r n a t e Routes to 1-0-Acyl-D-glucopyranoses Unsaturated Carboxylic Acids

Derived

from

To p r e p a r e 1 - D - g l u c o s y l e s t e r s d e r i v e d f r o m u n s a t u r a t e d c a r b o x y l i c a c i d s , a s e c o n d pathway was needed s i n c e t h e method m e n t i o n e d above r e q u i r e d a f i n a l r e d u c t i v e s t e p t o remove a l l


PFEFFER E T A L .


c=o

92.2

I80~

160

140

120

80

100

60

—1— 40

20

60

40

20

PPM

c,c

Ic 3

c=o

180

5

:

160

140

120

80

100 PPM

Figure 3. C spectra of (A) l-a-O-glucosyl hexadecanoate and (Β) 1-β-Όglucosyl hexadecanoate were taken at 22.63 Hz using 150 mg of sample in 2 ml of 50/50 ν/υ CD OD-CDCl at 50°C. The spectra were obtained on a Fourier Transform nmr spectrometer after 700 transients with a 5 sec delay time. All shifts are relative to internal TMS. 13

3

s


170


CARBOHYDRATES

blocking groups. Our f i r s t a p p r o a c h a t s o l v i n g t h i s p r o b l e m was the p r e p a r a t i o n of 2,3,4,6-tetra-O-acetyl-l-O-acyl-0-D-glucopyranose 8 through displacement of the corresponding bromide 9 (19). T h i s was e a s i l y a c c o m p l i s h e d by r e a c t i o n o f 9 w i t h t h e b e n z y l - t r i m e t h y l ammonium s a l t o f e i t h e r o c t a d e c a n o i c or c i s - 9 octadecenoic a c i d i n 65:35 DMS0-CH Cl a t 5 0 ° f o r 24 h o u r s . o

o

60-65%

A f t e r workup and chromatographic p u r i f i c a t i o n of the r e a c t i o n m i x t u r e t h r o u g h a F l o r i s i l c o l u m n w i t h CH C l - p e t r o l e u m e t h e r , we o b t a i n e d 6 0 - 6 5 % o f p u r e e s t e r 8 w i t h t n e p - c o n f i g u r a t i o n . Nmr i n C D C 1 ~ s h o w e d t h e c h a r a c t e r i s t i c a n o m e r i c p r o t o n resonance a t 6.06 d , J = 6.5 H z , i r , C = 0 1750 cm" , r o t a t i o n - 1 . 5 (MeOH), 1 C). The m e l t i n g p o i n t o f the o c t a d e c a n o a t e was 6 9 - 7 0 ° , (lit. mp 7 7 ° ( 2 0 ) ) , w h e r e a s t h e o c t a d e c e n o a t e w a s a v i s c o u s o i l . Both compounds p r o v i d e d t h e c o r r e c t e l e m e n t a l a n a l y s e s . Attempted d e a c e t y l a t i o n o f t h e s e compounds w i t h e i t h e r b a r i u m h y d r o x i d e (21) o r s o d i u m h y d r o x i d e i n m e t h a n o l a t t e m p e r a t u r e s as l o w as - 4 0 ° f a i l e d t o show p r e f e r e n t i a l r e m o v a l o f a c e t a t e o v e r t h e long chain a c y l group. E v e n t h e ammonia i n m e t h a n o l d e a c e t y l a t i o n d e s c r i b e d b y R o b e r t (22) f o r t h e p r e p a r a t i o n Ι - β - D - g l u c o s y l anthranilate resulted i n unselective deacylation. The l a t t e r p r o c e d u r e appears t o be a p p l i c a b l e to the r e m o v a l of acetate only i n the presence of l e s s r e a c t i v e aromatic e s t e r s . ?

The pathway s e l e c t e d f o r t h e p r e p a r a t i o n of the u n s a t u r a t e d g l u c o s y l e s t e r s 1 employs 4 , 6 - 0 - b e n z y l i d i n e - D - g l u c o s e 4 (23). P r e p a r a t i o n and i s o l a t i o n of the d r i e d sodium s a l t of 4,6-0b e n z y l i d i n e - D - g l u c o s e 3 from e t h a n o l s o l u t i o n f o l l o w e d by

10 In Synthetic Methods for Carbohydrates; El Khadem, H.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

9.

171

10-Acyl-O-glucopyranoses

PFEFFER E T A L .

acylation i n CH^Cl^, (heterogeneous mixture) led to 4,6-0benzylidine-l-O-acyl-D-glucopyranose 10 i n 40-50% isolated yield based on 4 (8) (overall yields based on glucose were more variable because the yields i n preparing 4 ranged from 20-80%). ^ The^stereochemistry of these derivatives was studied by both H and C nmr. Figure 4 shows how the anomeric proton resonance which coincides with the chemical shift of the benzyl hydrogen i n 10 i s shifted downfield with the incremental additions of Eu(fod)^ pseudocontact shift reagent. Judging from the i n i t i a l chemical shift of the anomeric proton (5.86) and coupling constant, 7.5 Hz, the hexadecanoate ester has the β-configuration. In studying this acylation reaction, we observed that as the acylation reagent became more unsaturated the reaction became less stereo selective, e.g., acylation of 3 with hexadecanoyl chloride or octadecanoyl chloride gave effectively 100% of the β-isomer while cis-9-octadecenoy decadienoyl chloride, 85 decatrienoyl chloride, 60% β (Table V I I I Measurement of the isomer ratio was routinely performed by C nmr because of the d i f f i c u l t y i n directly observing the β-anomeric proton i n the absence of shift reagent as mentioned above. Comparison of the C^ anomeric carbon resonances at 92.26 (a) and 94.16 (β) provided a direct analysis of the stereoselectivity of the reaction. The isomer ratios were also confirmed by glc analyses of the corres ponding TMS derivatives. Table VIII. Stereoselectivity of Acylation of l-O-Sodio-4,6-0 Benzylidine Glucose as a Function of the Degree of Unsaturation i n the Acylating Agent R

anomeric % α

a

mp

composition %β

C H 1 ?

3 5

132-3

0

100

C H

3 1

131-131.8

0

100

1 5

-

C

10

90

cis,cis-9,12, C ^ H ^

-

C

15

85

cis,cis,cis-9,12,14, C ^ H ^

-

C

40

60

cis-9,10 C H 1 ?

3 3

a -1 A l l esters had C=0 absorption at 1755 cm (CHCO. b 13 A l l compositions determined by C nmr comparison of the anomeric carbon resonances prior to recrystallization. Viscous glass.



Figure 4. Low field 60 MHz proton spectrum of l-Ohexadecanoyl-4fiO-benzylidine-/3-O-glucopyranose (0.04 g in 0.400 ml of CDCl ). (a) Spectrum in the absence of Eu(fod) solution; (b) after addition of 15 ml of 0.30 M Eu(fod)s solution in CCl^ (c) after addition of 20 ml of 0.30 M Eu(fod) solution in CCl . s

n

n

h


9.

The

173

ΙΌ-Acyl-O-glucopyranoses

PFEFFER E T A L . C spectrum

of

the

isomeric

m i x t u r e of

1-0-cis,cis-9,12-

octadecadienoyl-4,6-0-benzylidine-D-glucopyranose Figure 5a. Assignments at a l l r i n g carbons could made

owing

to

the

unpredictable

changes

i s shown i n n o t be r e a d i l y

i n chemical

shifts

imposed by the a c e t a l b r i d g i n g . Nevertheless the α/β r a t i o at t h e a n o m e r i c c e n t e r as w e l l as t h e c i s / t r a n s r a t i o was e a s i l y determined. Because of the a l k a l i n i t y of the r e a c t i o n medium, we o b s e r v e d a s much a s 5-7% t r a n s p r o d u c t a t a c y l a t i o n t e m p e r a t u r e s of -30 to - 4 0 ° . C o m p a r i s o n o f t h e Cg and C ^ resonances, (external a l l y l i c carbons associated w i t h an adjacent c i s double bond) a t 27.36 w i t h the C and C - , resonances a t 32.66, associated f t

with

the

trans

double

bonds,

yielded

the

cis/trans

ratio

directly.

A t p r e s e n t we c a n n o t e x p l a i n why a n i n c r e a s e i n t h e d e g r e e of u n s a t u r a t i o n of the a c i d c h l o r i d e caused a decrease i n s t e r e o selectivity. H o w e v e r , o n e p o s s i b l e c a u s e may b e s o l u b i l i t y changes t a k i n g p l a c e i m i x t u r e due t o s t r u c t u r a rated acid chlorides used. A c y l a t i o n of b o t h sodium and l i t h i u m s a l t s 3 generated i n s i t u homogeneously from e i t h e r sodium or n b u t y l l i t h i u m i n THF a t - 3 0 ° g a v e v a r y i n g p r o d u c t d i s t r i b u t i o n s , i . e . , e s t e r m i x t u r e s composed of 50-60% 9b, 20-25% 9 a , and 1 5 20% a c y l m i g r a t e d c o m p o u n d s 1 2 . P r e s u m a b l y , 3 when i s o l a t e d i n c r y s t a l l i n e f o r m , a s s u m e s t h e β - c o n f i g u r a t i o n 3β w h i c h w h e n a c y l a t e d i n a n o n s o l u b i l i z e d form y i e l d s 10β. However, as the s o l u b i l i t y of 3 i s i n c r e a s e d , e i t h e r by s o l u b i l i z i n g agents, i . e . , p o l y u n s a t u r a t e d a c i d c h l o r i d e s or by g e n e r a t i o n i n s o l u b l e f o r m i n s i t u , e q u i l i b r a t i o n o f t h e a n o m e r i c s a l t s 3 a a n d 3β c a n occur. Unlike TBG~Li 5, no change i n t h e d i s t r i b u t i o n o f i s o m e r i c a c y l a t i o n p r o d u c t s i s n o t i c e d when benzene i s s u b s t i t u t e d for THF. This difference i n behavior i s probably a r e f l e c t i o n o f p a r t i c i p a t i o n b y f r e e C ^ - O H w h i c h i s made u n a v a i l a b l e i n TBG through ether p r o t e c t i o n . +

β-Glucosyl

esters

lb

derived

from unsaturated

carboxylic

a c i d s w e r e r e a d i l y g e n e r a t e d f r o m 9 b b y h y d r o l y s i s i n 75% a c e t i c a c i d - w a t e r a t 60° f o r one h o u r ( 2 4 ) . Y i e l d s of i s o l a t e d and p u r i f i e d ( s i l i c a g e l chromatographed) e s t e r s 9β w e r e i n t h e range of 40-50% based on g l u c o s e . The C spectrum of 1-0c i s , c i s - 9 , 11-octadecadienoyl-D-glucopyranose (85% a , 15% β ) seen i n F i g u r e 5b. Other p h y s i c a l properties esters are given i n Table V I . Stability In la,

i t

(6,

7).

of

several has

attempts

to

reported

that

the

derivative

unmigrated (through

been

Only when

mesitoate

groups)

1-0-Acyl-a-D-Glucopyranose

state.

deblocking were

prepare

ester

2a,

The p r e v i o u s

c a r r i e d out

compound

attempts

compounds

i n basic

is

unsaturated

1-0-acyl-a-D-glucopyranose not

was h i g h l y h i n d e r e d , the

the

Derivatives

i s o l a t i o n could

could

precursor

of

to

be

be

accomplished

e.g.,

isolated

generate

l a and

containing acyl

solution.

the in

the 1β

protecting

This caused


acyl

SYNTHETIC

METHODS

FOR

CARBOHYDRATES

(A)

HO

0H^~0-CC

1

7

H | 3

^ C i s 8,14

T r a n s 8,14 C=0

o-C,

180

160

140

120

60

80

100

40

20

PPM

(B)

HO HCH, H^^VO-IR X

-Cis 8,14

Trans 8,14

C=

C

0-C,

0

4

C

6

a-C,

—r~ 180

160

140

120

80

100

60

40

PPM

Figure 5. (A) C spectrum of 0.150 g of cis,cis-9,12-octadecadienoyl-afi4,6-0-benzylidine glucose in CDCl . Chemical shifts rehtive to internal 23 TMS. (B/ C spectrum of 0.150 g of cis,cis-9,12-octadecadienoyl-O-glucopyranose(85% /?, 15% a). 13

3


9.

migration

and s a p o n f i c a t i o n .

hydrogenolysis mitted

us

to

175

l-O-Acyl-O-glucopyranoses

PFEFFER E T A L .

i n neutral

isolated pure,

α-D-glucopyranoses

l a are

We h a v e

or

successfuly

slightly

a c i d medium.

unrearranged l a .

stable

i n the

deblocked

7α

T h i s has

Although

by

per

1-0-acyl-

crystalline state,

they

s l o w l y r e a r r a n g e upon prolonge upon m e l t i n g on a g l a s s s u r f a c e . R e a r r a n g e m e n t o f l a was s t u d i e d i n methanol and p y r i d i n e by p r o t o n nmr. The p r o g r e s s of a c y l m i g r a t i o n o f t h e h e x a d e c a n o a t e d e r i v a t i v e i n CDÔD a t 7 6 ° i s i l l u s t r a t e d i n t h e s p e c t r u m shown i n F i g u r e 6. Appearance of the anomeric p r o t o n resonances a t the h i g h p o s i t i o n s of 5.56 and 4.76 i s i n d i c a t i v e of the formation of the i s o m e r i c m i x t u r e of free C - O H g l u c o p y r a n o s e s 1 2 a a n d 1 2 β e s t e r i f i e d a t C^. The d e t a i l e d 220 MHz p r o t o n s p e c t r u m o f 1 2 a a n d 12β i n p y r i d i n e - d ^ , ( F i g u r e 7) i d e n t i f i e s the m i g r a t i o n p r o d u c t s as the C - 0 H e s t e r i f i e d product ?

by

its

characteristic H-C-O-acyl

Table

IX.

Migration Rates

Rotations

of

shift

of

k

a

6

χ

lO^nin"

field

position

1-0-Acyl-a-D-glucopyranoses

the Product

and

2-0-Acyl-D-glucopyranoses

Methanol R

p a t t e r n and

Pyridine 1

k

a

6

χ

l O ^ i n "

[a]^

1

5

0 C

1

5

H

3

1

C

2.8

1.0

+34.6

(MeOH,

3.0

-

+41.5

(H 0,

0.6c)

0 C H C 6

5

CH

C H j < ( _ ) >~C CH

No r e a c t i o n

No r e a c t i o n

+44.5

2

b

(H 0, 2

0.96c)

0.4c)

3

M e a s u r e d by f o l l o w i n g the disappearance of the anomeric p r o t o n of the 1 - 0 - a c y l - a - D - g l u c o p y r a n o s e and the appearance of the α and β anomeric protons of 2 - 0 - a c y l - D - g l u c o p y r a n o s e products. ^Reference

7.



PPM Figure 6. 60-MHz nmr spectrum of 1-O-hexadecanoyl-a-O-glucopyranose in CD OD during acyl migration at 76° C. All shifts are refotive to internal TMS. 3

Figure 7. 220-MHz nmr spectrum of 2-O-hexadecanoyl-O-glucopyranose (region from 4.5-6.28) in pyridine-d . All shifts are relative to internal TMS. 5


9.

177


PFEFFER E T A L .

(25). I n t e g r a t i o n o f t h e α and β a n o m e r i c p r o t o n s shows t h i s m i x t u r e t o b e 5 5 % 1 2 a a n d 45% 1 2 β . Rearrangement r a t e s at 76°, given i n Table IX, p y r i d i n e , the rate aliphatic

a r e f i r s t o r d e r i n e s t e r l a i n methanol and i n t h e f o r m e r b e i n g somewhat f a s t e r . Both

and u n s u b s t i t u t e d a r o m a t i c

esters

migrate

at

rate. The m e s i t o a t e d e r i v a t i v e i s s t a b l e under t h e s e Significantly, although migration readily occurred at

the

same

conditions. 76° i n m e t h

a n o l and p y r i d i n e , no a c y l m i g r a t i o n was o b s e r v e d i n t h e p r e s e n c e o f 8 . 0 m o l e % a c e t i c a c i d a t 7 6 ° a f t e r 24 h o u r s . Reaction rates i n b o t h t e f l o n a s w e l l a s q u a r t z nmr t u b e s w e r e t h e same a s those observed i n pyrex, i n d i c a t i n g t h a t a c t i v e s i t e s i n the g l a s s were not responsible for c a t a l y z i n g t h i s process. Summary The s t e r e o s e l e c t i v i t c o n t r o l l e d by a l t e r i n g th b l o c k i n g b e n z y l e t h e r groups were removed by h y d r o g e n o l y s i s to produce b o t h s t a b l e 1-a and l - β g l u c o s y l e s t e r s d e r i v e d from saturated carboxylic acids. TBG a n d i t s s a l t T B G ~ L i were found b y nmr t o b e a n e q u i l i b r i u m m i x t u r e o f b o t h α a n d β - a n o m e r i c forms. A mechanism c o n c e r n i n g the s t e r e o c h e m i c a l c o n t r o l of TBG L i a c y l a t i o n i s d i s c u s s e d i n terms of i n t e r and i n t r a molecular l y solvated transition states. Glucosyl esters of unsaturated c a r b o x y l i c a c i d s were prepared through the a c y l a t i o n of 4 , 6 - 0 - b e n z y l i d i n e - l - 0 - s o d i o glucopyranose. Stereoselectivity of a c y l a t i o n dropped off w i t h an increase i n the degree of u n s a t u r a t i o n i n the a c y l a t i n g agent. A c y l a t i o n of b o t h 1 - 0 - l i t h i u m and sodium s a l t s o f 4 , 6 - 0 - b e n z y l i d i n e g l u c o s e g e n e r a t e d i n homogeneous s o l u t i o n y i e l d e d m i x t u r e s of 1 - a - and 0 - g l u c o s y l e s t e r s and a c y l migration products. The s t a b i l i t y , k i n e t i c s , and p r o d u c t s a c y l m i g r a t i o n of Ι - α - g l u c o s y l e s t e r s were examined.

of

Acknowledgment We t h a n k J . J . U n r u h s p e c t r a were which

is

taken at

supported

for

his

able

assistance.

the Middle A t l a n t i c

b y N I H g r a n t RR542 a t

220 MHz nmr

R e g i o n a l NMR f a c i l i t y the U n i v e r s i t y

of

Pennsylvania.

Literature Cited 1. 2. 3. 4. 5.

Quilico, Α., Piozzi, F., Pavan, M., and Mantica, E. Tetrahedron (1959) 5, 10. Wood, Η. B., Jr., Allerton, R., Diehl, H. W., and Fletcher, H. G., Jr. J. Org. Chem. (1955) 20, 875. Polonsky, J., Sach, E., and Lederer, E. Bull. Soc. Chim. France (1959) 880. Fischer, E., and Bergmann, M. Ber. (1918) 51, 1760. Schmidt, O. Th., and Herok, J. Ann. (1954) 587, 63.


178


6.

Pedersen, C., and Fletcher, H. G., Jr. J . Amer. Chem. Soc. (1960) 82, 3215. Wood, H. B . , and Fletcher, H. G., Jr. J . Amer. Chem. Soc. (1956) 78, 2849. Fletcher, H. G., Jr. In "Methods in Carbohydrate Chemistry" VI, 231, Academic Press, New York, 1972. A preliminary report of this acylation method has been reported by Pfeffer, P. E . , Rothman, E. S., and Moore, G. G. J . Org. Chem. (1976) in press. West, A. C., and Schuerch, C. J . Amer. Chem. Soc. (1973) 95, 1333. Lemieux, R. U., Hendriks, Κ. B . , Stick, R. V . , and James, K. J . Amer. Chem. Soc. (1975) 97, 4056. Glaudemans, C. P. J., and Fletcher, H. G., Jr. In "Methods in Carbohydrate Chemistry" VI 373 Academic Press New York, 1972. Valentekovic', S. 47, 35. Volkova, L. V . , Luchinskaya, Karimoua, Ν. M., and Evstigneeva, R. P. Zh. obs. Khim. (1972) 42, 1405. Schmidt, O. Th., Traute, Α., and Schmadl, H. Chem. Ber. (1960) 93, 556. Boock, K . , and Hall, L. D. Carbohydrate Res. (1975) 40, C3. Dorman, D. E . , and Roberts, J . D. J . Amer. Chem. Soc. (1970) 92, 1356. deWit, G., Kieboom, A. P. G., and van Bekkum, H. Tetrahedron Lett. (1975) 45, 3943. Scheurer, P. G., and Smith, F. J . Amer. Chem. Soc. (1954) 76, 3224. Nishikawa, Y . , Yoshimoto, K . , Kurono, G., and Michishita, K. Chem. Pharm. Bull. (1975) 23, 597. Isbell, H. S. Bur. Stand. J. Res. (1930) 5, 1179. Robert, D., Tabone, J. Bull. Chim. Soc. France (1953) 206. Fletcher, H. G., Jr. In "Methods in Carbohydrate Chemistry" II, 307, Academic Press, New York, 1963. Jeanloz, R. W. In "Methods in Carbohydrate Chemistry" I, 214, Academic Press, New York, 1962. Kaiser, C., Hillges, B . , and Becker, F. Liebigs Ann. Chem. (1969) 725, 196.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.


10

Preparation and Characterization of 1,6-Anhydro-3,4dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose FRED SHAFIZADEH and PETER P. S. CHIN Wood Chemistry Laboratory, University of Montana, Missoula, Mont. 59801

Pyrolysis of carbohydrates results in transglycosylation (1,2), dehydration (3) reactions (4). These reaction which can be used as intermediates for synthesis of carbohydrate derivatives. 1,6-Anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (levoglucosenone) has recently teen detected in several labora tories (5-8) from the pyrolysis of cellulose containing an acidic catalyst and has been assigned the structures, namely 1,5-anhy dro-2,3-deoxy-β-D-pent-2-eno-furanose (a) and cis-4,5-epoxy-2pentenal (b) as well as the levoglucosenone structure (c) shown in Figure 1. The correct structure of this compound was con firmed in our laboratory by making crystalline derivatives (8), and by investigating the reaction of the isolated compound. These investigations revealed that levoglucosenone can be produced in comparable yields from the pyrolysis of various materials, such as acid-treated starch and waste papers, in addition to pure cellulose (Table I). These yields were deter mined by pyrolysis gas chromatography of small samples, using a pyrolysis temperature of 350°. The crude pyrolyzate contained, in addition to levoglucosenone, 2-furaldehyde as the major im purity. It was also found that levoglucosenone is unstable at high temperatures and could further pyrolyze, especially in the presence of zinc chloride (8). In previous studies, levoglucosenone was purified by pre parative gas chromatography, which was a time consuming method only suitable for small-scale preparation. In the current in vestigation, the following procedure was developed for a larger scale preparation. Waste Kraft paper bags were shredded, treated with dilute phosphoric acid and dried. Eight-gram batches of the treated paper containing 5% phosphoric acid were pyrolyzed under nitrogen in a tube furnace. To minimize the ex cessive decomposition of the products on the hot furnace tube, a reduced temperature of 275° was used. After 208 g of the raw material was pyrolyzed, the accumulated pyrolyzate was extracted 179


180

SYNTHETIC METHODS

FOR CARBOHYDRATES

H

Figure 1. Structures of (a) l,5-anhydro-2,3-deoxy-fi-O-pent-2-enofuranose; (b) cis4,5-epoxy-2-pentenal; and (c) l 6-anhydro-3 4-diaeoxy^-O-glycero-hex-3-enopyranos-2-ulose }

TABLE I.

f

YIELDS OF LEVOGLUCOSENONE FROM THE PYROLYSIS OF DIF FERENT MATERIALS AT 3 5 0 . o a

Material

Neat

(%)

5% H P 0 - t r e a t e d 3

4

Cellulose

1.2

11.1

Starch

0.3

9.0

T*

9.1

News-print with

ink

K r a f t shopping bags

Determined by p y r o l y z i n g the v o l a t i l e s by GLC.

Τ

(%)

10.2

5 mg samples and d i r e c t l y

analyzing

Τ = t r a c e amount.


10.

S H A F i z A D E H AND CHIN

Preparation

of

181

Levoglucosenone

with chloroforrn and the chloroform solution was dried, filtered and evaporated. The gas-liquid chromatography (GLC) analysis of this mixture gave chromatogram A in Figure 2, showing the levo glucosenone and 2-furaldehyde as the major components with the ratio of 4:1, respectively. 2-Furaldehyde and other aldehydo impurities were removed from the pyrolyzate by reaction with 5,5-dimethyl-l,3-cyclohexane-dione (dimethone) in 50% aqueous ethanol solution at 100°. Upon cooling, the bismethone derivatives of aldehydo compounds precipitated from the solution and were removed by f i l tration. Ethanol was removed from the filtrate under vacuum and the remaining aqueous solution was again extracted with chloro form, dried, filtered, and evaporated. The resulting mixture gave chromatogram Β in Figure 2, which shows the complete re moval of 2-furaldehyde along with other aldehydo impurities. This aldehyde-free pyrolyzate was then vacuum distilled at 1.5 mm Hg. The fraction collected between 55-60° as shown in chroma togram C in Figure 2, contained 96% levoglucosenone, pure enough for synthetic purposes. The yield of purified product weighed 6.8 g, amounting to an overall yield of 3.3% based on the weight of waste paper. 26 The product was a light-yellow colored liquid with [a] 458°, compared with the -460° reported before (7). This product was further characterized as the crystalline 2,4-dinitrophenylhydrazone (DNPH) reported before (8) and semicarbazone which is a new derivative. Levoglucosenone possesses an interesting α,3-unsaturated keto structure, which can be used to synthesize branched-chain, keto and amino sugar derivatives. In this study, we have ex plored some of these possibilities. Table II shows some of the derivatives prepared by modifying the functional groups of this compound. Selective reduction of the keto group by lithium aluminum hydride in ether gave a mixture containing 84% of 1,6-anhydroD

3,4-dideo^-e-D-erythro-hex-3-enopyranose (d) and 8% of its C-2

epimer. The major product formed in 75% yield, and was charac terized by i t s 3,5-dinitrobenzoate derivative. The nuclear mag netic resonance (NMR) spectrum of this compound showed that there was no spin-spin coupling between the CI and C2 protons, con firming the assigned configuration. The second derivative was prepared by hydrogénation of the double bond using Pd/BaSÛ4 as a catalyst. This gave 1,6-anhydro3,4-dideoxy-6-D-giycero-hexopyranos-2-ulose (e) as an oil in 85% yield. This compound was characterized by i€s DNPH derivative. The reduction of both keto and double bond functional groups gave 1,6-anhydro-3,4-dideoxy-3-D-erythro-hexopyranose (f) as an o i l , that was characterized by I t s 3,5-dinitrobenzoate derivative. The same product-, 3,5-dinitrobenzoate derivative, was obtained by both hydrogénation of d or reduction of e; indicating that the saturation of the double bond on the sugar ring did not change


182

SYNTHETIC

M E T H O D S FOR CARBOHYDRATES

c

Figure 2. Gas-liquid chromatograms of (A) crude prolyzate; (B) crude pyrolyzate after removing aldehydo impurities; and (C) final product. Peak a is 2-furaldehyde and peak b is levoglucosenone.

50

82

114

146

178

2li>

ISOTHERMAL



(s)

• ο «

•o

OH

(SÎ

(£)

-o

Ether

LiAlH, 4

Pd/BaSO,

Pd/BaSO,

Ether

L i AT Hy,

(i)

(1)

(·)

(i)

OH

•o

70

84

85

75

Yield

{%) by

3,5-DNB derivative

derivative

3,5-DNB

derivative

DNPH

derivative

3,5-DNB

Characterized

Note

DERIVATIVES OF LEVOGLUCOSENONE PREPARED BY MODIFYING ITS FUNCTIONAL GROUPS.

Reaction & Product

TABLE II.

184

SYNTHETIC METHODS

FOR CARBOHYDRATES

the stereospecific nature of the lithium aluminum hydride reaction and also confirming the assigned configuration. The former reaction gave 84% yield and the latter reaction gave 70% yield of the major product and 7% of the corresponding isomer. In addition to modifying the functional groups of levoglucosenone, different branched-chain sugar derivatives could also be prepared by the reaction of levoglucosenone with Grignard reagent under controlled conditions as shown in Table I I I . At room temperature, levoglucosenone reacted with methylmagnesium iodide to give mainly the 1,2 addition product, 1,6anhydro-3,4-dideo)^"2-c-methyl^-p-erythro-hex-3-enopyranose (g) in 56% yield. The reaction mixture also contained 6% of the C-2 epimer and 6% of the 1,4-addition product. The major product was separated by column chromatography (CC), reduced by hydrogénation to 1,6-anhydro-3,4-dideoxy-2-c-methyl -3 -D-erythro-hexopyranose (h), and characterized as the 3,5-dinitrobenzoate derivative. At -78° and in th phosphine) copper (I)], however, the reaction of levoglucosenone with methyl magnesium iodide gave mainly the 1,4-addition product, 1,6-anhydro-3,4-dideoxy-4-c-methyl-6 -D-erythro-hexopyranos-2ulose, (i) in 64% yield. This compound was characterized as the DNPH derivative. The configuration of compound 2 was assigned by ΝMR spectroscopy which showed that there was no spin-spin coupling between the C4 and C5 protons. The reaction of e with methylmagnesium iodide at room temp erature was not stereospecific. It gave nearly equal amounts of compound h and 1,6-anhydro-3,4-dideoxy-2-c-methyl-β-J-threohexopyranose"(j) as an o i l which could not be clearly separated by CC. However, these two compounds were characterized by their 3,5-dinitrobenzoate derivatives from the early and late fractions. The configurations of compounds g,h and j were determined by NMR spectroscopy with the aid of europium III [Eu (fod)o] shift reagent. The NMR of the product mixture containing h and j in CDClj shown in spectrum A in Figure 3, contains two equal sized hydroxyl signals at 2.5 and 2.8 ppm due to the equal con centrations of the two compounds. There was only one sharp signal at 5 ppm for the anomeric protons. In order to increase the concentration of one of the two isomers, compound g was hydrogenated to h and added to the solution. This increased the size of the hydroxy! signal at 2.5 ppm as shown in spectrum Β in Figure 3. Upon gradual addition of Eu (fod)3, as shown in spectra C and D, the larger hydroxyl signal at 2.5 ppm shifted significantly to a lower field while the other one remained re latively unchanged. Also, the common signal for the anomeric protons at 5 ppm was gradually separated into two peaks. The peak which shifted to a lower field was larger in size than the one remaining relatively unchanged. Therefore, the isomer pre pared by hydrogénation of compound g should have the structure h that contains the more accessible~hydroxyl group.



;°,

(·)

(£)

(£)

(

-78°

Room Temp.

3

CH MgI

3

n-Bu PCuI

3

CH MgI

Room Temp.

CH~MgI

->

(J)CHl

(fe)

M

\ *

(i)

(s)

31

31

64

56

Yield GLC Analysis

[%)

44

51

Isolated

3,5-DNB derivative

3,5-DNB derivative

DNPH derivative

Characterized

by

J

4,5

Note

0 cps

DERIVATIVES OF LEVOGLUCOSENONE PREPARED BY GRIGNARD REACTIONS UNDER DIFFERENT CONDITIONS.

Reaction & Product

TABLE III.

186


J 6

5

1

4

1

•

8

2

'

1

OPPM

'

6

'

5

'

4

I

8

I

2

I

1

0 PPM

Figure 3. Gradual change in nmr spectra; (A) Grignard reaction products of compound e; (B) after adding the hydrogénation product of compound e; (C) after adding Eu(fod) ; and (D)at the end of the addition of Eu(fod) s

s


10. SHAFIZADEH AND CHIN

Preparation of Levoglucosenone

187

Literature Cited 1. Shafizadeh, F., Adv. Carbohyd. Chem., (1968), 23, 419-474. 2. Shafizadeh, F. and Fu, Y. L., Carbohyd. Res., (1973), 29, 113-122. 3. Shafizadeh, F. and Lai, Y. Z.,Carbohyd.Res., (1975), 40, 263-274. 4. Lai, Y. Z. and Shafizadeh, F.,Carbohyd.Res.,(1974), 38, 177-187. 5. Lipska, A. E. and McCasland, G. E., J. Appl. Polym. Sci., (1971), 15, 419-435. 6. Lam, L. Κ. Μ., Fung, D. P. C., Tsuchiya, Y., and Sumi, K., J. Appl. Polym. Sci., (1973), 17, 391-399. 7. Halpern, Y., Riffer, R., and Broido, Α.,J.Org.Chem., (1973), 38, 204-209. 8. Shafizadeh, F. and Chin, P. P. S., Carbohyd. Res., (1976), 46, 149-154.


11 Formation and Conversion of Phenylhydrazones and Osazones of Carbohydrates HELMUT SIMON and ADOLF KRAUS Technische Universität München, Organisch-Chemisches Institut, D-8000 Munich, West Germany

Since their discovery b E Fische (1,2) phenylhydrazone and sugar osazones hav different reasons (3-7) a) At first, the hydrazones and osazones were used for the identification and to some extent, the estimation and separation of saccharides. b) Then, chemists were interested in the mechanism of osa zone formation and the structure of phenylhydrazones and osazones. c) Later, chemists wanted to know why the reaction between phenylhydrazine and sugars usually stopped at the bishydrazone stage, and why disubstituted hydrazines such as N-methyl-N-phe nylhydrazine could "oxidize" sugars beyond the bishydrazone level as shown by Chapman et al. (8,9). It was also interesting to know why the formation of osazones from different monosaccharides pro ceeded in such widely varied yields and rates. d) Sugar osazones have been used as starting materials for numerous interesting heterocycles (10-13). We have carried out some work in area "b", especially on the mechanism of osazone formation and in areas "c" and "d". For a long time efforts to solve problems "b" and "c" did not lead to decisive results for two reasons. Chemists have often tried to get information about the structure of phenylosazones or phenylhydrazones from their reaction products and it was not realized that certain isomers present only in small concentra tions in the equilibrium mixture could be the reacting species. Although the structures of some hydrazones and osazones in the crystalline state are well known (4), the structures of most of the species present in solution are not. This means that many of the kinetically controlled intermediates and the products of the reactions of aldoses and ketoses with phenyl hydrazine are not known. Further, our knowledge of the reaction mechanism was ham pered by our not knowing for certain what a l l the reactions taking place are. This does not mean that we do not know what the predominant forms are, but rather that the starting materials for certain reactions could be present in concentrations not detect188


11.

SIMON AND KRAUS

Phenylhydrazones

and

189

Osazones

able by the physico-chemical methods available. Further, the occurance of a given reaction does not prove the presence of only one structure. For more details see a review by Mester et al. (14) and a paper by Blair et al. (15) on the structure of phenyl hydrazones of different hexoses. The structure of osazones has been discussed in detail. A careful analysis of a l l the available information suggests that the structure originally proposed by Fieser and Fieser (16) is still valid (17,18). It explains reasonably well why the two phenylhydrazone groups of osazones behave differently in most of their reactions. These structures, however, do not explain satis factorily why the reaction of saccharides with phenyl hydrazines stops at the second carbon atom. We (7,19) and others (20,21) studied a series of model compounds and reactions of phenylhydrazones of a-hydroxyaldehydes, α-hydroxyketones and monoses as well as reactions of osazones under the influence of aci more insight into the behaviour of sugar phenylhydrazones and osazones under the conditions of their formation. Phenylhydrazones The problems of formation of peroxides and the equilibrium between different isomers are of current interest. The mutarotation of 3,4,5,6-tetra-O-benzoyl-JD-glucose phenylhydrazone pre viously attributed (22) to a phenyl hydrazone^ phenylazo tautomerism has been shown to be due to the formation of a phenylazohydroperoxide equilibrium (23)* Further, phenylhydrazones under the influence of acids and "bases exist in equilibrium with different isomers (24) and may react in different ways, as can be seen in Figure 1. "For simplicity the equilibria between the different cyclic and acyclic isomers which may exist for sugar derivatives were omitted (for a discussion of these forms see ref. 25). Usually form 1 is by far the most predominant form but tïïere are examples such as that of D-xylo-4,5,6-trihydroxy-2-oxo-l,3-bis (phenylhydrazono)-cyclohexane where both forms 1 and 4 are known (26). In such cases where X = OH 6 is an intermediate in a rather general reaction which in the f i e l d of carbohydrates has been f i r s t described by Amadari (27). It may be summarized by the following tautomerizations: H

H R—C—C


R

190

SYNTHETIC

METHODS FOR

CARBOHYDRATES

X = H orOH X«OH

Ί

V

Γ V V®

V?

Η Ι|< R-CX-N=N- Z) take place. When R = CH the azo form 4 cannot be formeS and consequently no hydrogen exchange can be oBserved (24). With the phenylhydrazones of glycol aldehyde 9a and 2-hydroxy-cyclohexanone §b (Figure 2) as model compounds ancTthe phenylhydrazones of mannose and glucose in 0.12 m KOH in ethanol labeled with tritium in the OH-group the following was observed (30): Within 15 min at 80° 10.3 % of the hydrogen atom attached to "C^l of glycol aldehyde phenylhydrazone was exchanged with protons of the medium. This can be explained by an equilibrium between 1 ^ 4 . Acetaldehyde phenylhydrazone shows hydrogen exchange at C-l and C-2 in a ratio of 1.0 : 1.7 (30). This probably occurs via 1 ^ 2^-Ç and 1^ | respectively. Tn contrast to acetaldehyde phenylRydrazone and other aldehyde phenylhydrazones with no OH-group in the 2-position there is no exchange at C-2 of the phenylhydrazones of glycolaldehyde (3a), mannose and 2-hydroxy-cyclohexanone (9b). That means that the~"hydroxy group at C-2 prevents the equilibrium 1 ^ 6 . The reason is very probably the fast consecutive reaction | - * Z - In agreement with this conclusion, we observed that aniline was eliminated during the reaction. The ratio of exchange rates at C-l of the phenylhydrazones of acetaldehyde, glycol aldehyde and mannose were found to be 1.0 : 3.5 : 7.0. 2-Hydroxy-cyclohexanone phenylhydrazone exchanged in 120 min 22.5 % of its hydrogen atoms presumably at C-6, and was finally transformed to phenylhydrazono-cyclohexene ]2§ via 9^—»lia —H2. This corresponds to in the general Figure I."Glycolaldehyde phenylhydrazone however eliminated some aniline presumably via 1

1

1

3

3

Aldose phenylhydrazones 13 show some additional reactions and yield other products, sucFas N-phenyl-pyrazole 1§ which is


192


formed under strictly identical conditions in yields of 35 % from mannose phenylhydrazone and in 20 % from glucose phenylhydrazone. The reaction sequence may be represented according to Figure 3. Intermediate 1| which corresponds to compound 5 in Figure 1 is l-phenylazo-D-arabino-3,4,5,6-tetraacetoxyhexene-(l) which is formed from 13 in pyridine-aceticanhydride according to Wolfrom et a l . (31,32). The formation of such alkene-azoaryl structures TuTsTeen also observed by Caglioti e_t al_. (33). They described the formation of 1-phenyl azo-cyclohexene-(iy~ll from 2-acetoxycyclohexanone phenylhydrazone by treating this"with lithiumhydride in benzene and the 1.4-addition of phenyl hydrazine to the alkene-azoaryl system discussed later.

Reactions of Hydrazones in Dilute Acid Solutions. The elimination of aniline is an important reaction of a-hydroxyaldehydes in acetic acid-methanol as can be seen from Table I. Table I Aniline Elimination from Phenylhydrazones and Formation of Bis(phenylhydrazones) During 6 h Heating in CH 0H-CH C00H (1:1) at 40° 3

Starting Material Glycol aldehydephenyl hydrazone Glucosephenylhydrazone Mannosephenylhydrazone 2-Deoxy-2-phenylhydrazi noglycolaldehyde phenylhydrazone

3

Aniline/Mole n

Λ 9

Bisphenylhydrazone/ n

9

o

U e

0.07

Q.23 0

1 8

0.63

"

0

0 3

0.44

Besides aniline, bis(phenylhydrazones) are formed. However, there is no stoichiometric relationship between aniline and osazone formation. This aniline elimination is comparable to the amine elimination which occurs during the formation of nitrogen con taining reductones from N-glycosides (34,35).


11.

SIMON AND KRAUS

Phenylhydrazones

and

193

Osazones

H-Y

I

c —

+

HNC

C=0 17

18

When Υ = Ν we have an amine elimination from the l-amino-3-hydroxy-azaallyl system and when Y = CH we observe the amine e l i mination from the l-amino-3-hydroxy-allyl system. Erythrose re acts with an amine such as N-methyl-benzylamine to give the Ncontaining reductone 23 in 45 % yield (Figure 4). [1-' C]Erythro se forms this reductone with 97 % of the carbon-14 in the methyl group and 3 % in the amino methylene group (34). A reasonable explanation of this woul the Amadori product 2Q which enolizes to 21· This can eliminate in two directions. If the amine is eliminated C-l of the ery throse becomes the methyl group in 22· If the OH-group is e l i minated C-4 of the erythrose becomes the methyl group in 24. The ratio is about 30 : 1 in favor of the amine elimination. TRe fast elimination of a structure such as 21 with Υ = Ν can also be seen from the fact that [3- H]-l-deoxy-l Benzylamino-D-fructose does not lose H even when 50 % of the starting material has reacted via amine elimination (34). That means that the step correspond ing to 2Q-> 21 is irreversible since i t is followed by a fast eliminaÏTon." Another important reaction is the formation of alkeneazoaryl systems such as 5 which can lead to addition products. Heating hydrazone 9£ witR 0.02 η hydrochloric acid in methanol for a few minutes Teads quantitatively to phenylhydrazone 1Q§ as shown in Figure 2 (30). Very probably 11 is the interme3Tate since 1Q§ is formed from 11 about three times faster than from 9J2 under identical conditions. We studied this phenomenon with several model compounds (36-38) but also with carbohydrate deri vatives (19,39). The isomerization 9£-» 12a occurs in acid as well as in basic solutions. In acidic an3 Basic media a competi tion exists also between the addition of nucleophiles of the type HX and the isomerization to a Δ^-enephenyl-hydrazone such as 12a. In acidic media the isomerization §b->12a with different suBstituents Y in the para position of tRe pRenylhydrazine resi due shows a strong dependence on Y. The reaction rate constants (sec χ 10" ) for the conversion l l - > 12a are shown for different Y groups in Figure 2. In 0.55 η HC1 tetrahydrofuran at 25° the rates are as follows (37): -NO? = 1.7; -CO0C2H5 = 22; Η = 507; CHo = 1810; OCH3 = 2SW. The Tatter value was calculated by using the Hammett equation. In acidic media the group Y has only l i t t l e influence on the rate of addition of compounds such as methanol. Besides alcohols the alkene-azoaryl system adds sodium 4

3

z

3

5


194


HON-NC H 6

HC-N=NC H

5

6

AcOCH

HON-pC H

5

6

H Î

HC m AcOÇH

AcO^H HÇOAc

5

H

HÏOAC

HÇOAc

•

R

R

HÇ=0

13

ϋ

R

J5

j£ —

Figure 3

U

I

, J

H-N.

HCOH HCOH I HjCOH

H^CH C6H5

C=0

2

COH

HC-N"

H^C Ο H

2g

H Ç-NC

HJVNC

3

OO

C=0

97% Ic=0 Hb=0

ÇH

3

i l

2

C-OH I C-OH I

-

HCOH

I

H COH 2

u

H COH 2

21 3%

_

ι

C=0 I

H C-NC 2

_

I

C-OH I

00

c=o

1

CH3

CH

3

24 Figure 4


I

23

11.

Phenylhydrazones

SIMON AND KRAUS

and

195

Osazones

hydrogen s u l f i t e , acetic acid and compounds with activated C-H bonds. Examples are diethyl malonate, malonodinitril, 2-acetaminodiethyl malonate, ethyl cyanoacetate etc. (38). Overend et a l . (40-42) have used arylazo-glycenosides for preparative work in the carbohydrate field taking advantage of the 1,4-additions that occured in a highly stereoselective fashion. We found that 1phenylazo-3,4,5,6-tetra-0-acetyl-Q-arabino-transhexene-(1) adds methanol, acetic acid or 2,4-dinitrothiophenol. Only in the lat ter case was i t possible to isolate the expected glucose and mannose derivative (39). Phenylosazones Some of the reactions which are observed with the phenyl hydrazones of sugars occur also with the bis(phenylhydrazones). However, the presence of two phenylhydrazone groups in the latter compounds causes osazone zones in most of their reactions. Reactions of Bis(hydrazones)in Dilute Alkaline Solution. In s 1ightly alkaline media the hydrogen atoms bound to carbon exchange with protons of the medium to varying degrees (Figure 5) (29). In the case of glucose phenylosazone this exchange occurs rriiTnly at C-l and to a small extent at C-3 as can be seen in Table II. Table II

Hydrogen Exchange*^ of Osazones (29).

Substance Glucose phenylosazone 2-Phenyl-l ,2,3-triazole(4)-carboxylic acid '

30 min. 45.0

60 min. 51.8

b)

4 1

Q

b)

4

8

4

90 min. 60.4 b)

5 5 e 5

L

Glyoxal bis(phenylhydrazone) Methylglyoxal bis(phenylhydrazone) Glucose methyl phenylosazone Glyoxal bis (methyl phenylSly iyd hydrazone)

_

_

56.7 ^

_

_

28.0

-

-

"1-0 -,

d

Q

a) Conditions: 0.1 m Κ0Η in ethanol, 80 under nitrogen. The molar radioactivity of C H 0 H corresponds to 100 %. b) ô 'Measured in form of the phenylosotriazole. Ôbtained from the phenylosotriazole by periodate treatment. The difference of the molar specific radioactivity of phenyl osotriazole and 2-phenyl-l,2,3-triazole-(4)-carboxylic acid 9

c

3


196

SYNTHETIC

H C-N=NC H 2

6

HCsNNHCeHs

5

Ç=N-NHC5H

Ζ

5

C=N-NHC H 6

METHODS

FOR CARBOHYDRATES

HC=N-NHC H 6

Qnlvtoq small extern

5

5

0-NHNHC H5 6

R 24

HC=N-NHC H 6

5

Ç=N-NHCgH

HC=N-NHC H

HC=N-NHC6Hd 5

C-N=NC H II HC I HCOH I HCOH I ^ C O H 6

HC I HCOH I

HCOH

6

5

CsN-NHCeHs

5

HC=N-NHC6H

5

HC=N-NHC H 6

5

I—CH COOH

HC=0

LOCH

2

HCOH

4

H£OH 27

21

Figure 5

HON-NHC H 6

CsN-NHCgHs

d j N ^ C .HCj

HCOAc

H-ÎÇxOAc

HjCOAc

e

H

HC=N-N HCgHs

HCrN-N-CgHg

C - l î ^ N HC5H5

5

0—1EH

HCOAc

HCOAc

fc

HOjr^NCeHç

5

— »

n h / COA c

HCOfe""'

H-COAc HjCOAc

H COAc 34 2

(AçJjO C§g).~ Only reaction d leads to an intermediate which would be able to react further with phenylhydrazine to give a t r i s(phenylhydrazone) and reactions a and c should not be possible with bis(methylphenyl hydrazones ). Addition of alcohols to the intermediate alkene-azoaryl compound 4jjj is very probable because [3- H]phenylglucosazone is converted to 2Z and ZÎ without any loss of tritium. That means that enolizatiofis between C-2 and C-3 can be excluded (19). This mechanism explains also the observation of Diels et aK (43) that alkyl phenyl osazones of glucose can not be convertêïï to anTiydroosazones. The anhydro-osazones 27 and 29 are obtained from glucose phenylosazone in a ratio 3 : 2."This ralio corresponds to the thermodynamic equilibrium. Under the conditions of its formation pure 2Z is converted again to a 3 : 2 mixture of Zl and £|. This result contradicts the rule that in anhydro-osazones the carbon atom in position three always seeks to acquire the configuration of the subsequent carbon not involved in ring formation (5J). Consequently starting with 8 hexose phenylosazones there could be 8 anhydro-osazones of the Diels type and not only 4 as predicted (51). In the case of pentose-phenylosazones, 4§a and 4Z| 3


200


CARBOHYDRATES

are formed. Heating Q-arabinosephenylosazone in a solution of ethanol or isopropanol with a trace of sulfuric acid leads to mixtures corresponding to 4|a and 47a with a yield of about 80 %. The mixtures can be separated by thin layer or column chromato graphy. These products are identical with those erroneously de scribed by Diels et al (43) as anhydro-osazones containing crystal alcohol. T F iTso these compounds are formed via an e l i mination-addition mechanism one could expect again a reversible conversion from 4§§ to |Zi under the conditions of their forma tion. That is the case. The configuration of 4§a was determined by preparing i t s osotriazole and comparing the fully 0-methylated product with that of the osotriazole of D-arabinose phenylosazone after O-methylation (]9). Unlike the anhydro-osazone formation which yields two isomers with glucose phenylosazone we could detect only one dehydroosazone. This product was f i r s t de scribed by Diels et aK (52) who obtained i t by oxidation of glu cosazone in alkaline solutio 53) i t is a dehydro-allose osazone §Ζ· We have evidence that âTkene-azophenyl intermediates play an important role in its formation and transformations (19,39). We were interested to see how the inversion at C-3 occurs. We found that [3- H]glucose phenylosazone lost no tritium during i t s conversion to §Z (19). This means that no enolization took place during the inversion of the configuration at C-3. Therefore, we suggest again an e l i mination-addition mechanism via a bis(phenylhydrazone) of structure §3 which would give an alkene-azophenyl intermediate 55 which Ts converted to §§. The latter is in equilibrium with §Z (Figure 10). If this is correct i t should be possible to get other elimination-addition products as well. We could show that heating of 5Z in 0.03 η H2S0 /methanol leads to an 0-methylproduct whicfi probably is best described by structure 5§. Chroma tographic runs in 7 different solvent systems always showed only one reaction product. We measured CD spectra from 18 different phenylhydrazones, phenylosazones and their derivatives which were obtained during these studies. In every case the sign of the Cotton effect de pended upon the configuration of that carbon atom which follows the chromophore (19). Mester et a l . (51) observed a positive Cotton effect in tKe region of^2"3u-30TTnm or 340 nm for osazones and osotriazoles respectively in those derivatives having the 0H-group or the linkage to a cyclic ether on the right in the Fischer projection. This rule can now be expanded to 3-0 methylderivatives of phenylosazones and osotriazoles. 3

4

The Key Reaction of the Osazone Formation and the Differ ences Between Phenylhydrazine and Methyl phenyl hydrazine. Phenylhydrazones of α-hydroxy carbonyl compounds eliminate aniline under conditions of osazone formation at a rate comparable with that observed during osazone formation (35). Therefore, i t is reasonable to assume that the elimination 7T-*§ ->7) i s


11.

SIMON

AND

Phenylhydrazones

KRAUS

HON-NHC H 6

6

201

Osazones

HC-N-NHCeHc]

5

C=N-NHC H

and

C-N-NCg^

Ο^ΟΗ/Η^

5

HCOH

al R-CHOHCÔH

RKCHOH^CHjOH

O^NHCçHç

Ç-N-NHCgHs HC

CH3OÇH

OCHj

R

R

il jfeand^ft: R-CHOHCH2OH

HON-NHC H 6

5

C-NH-NHCeHs HC-OH

H ÇsN-NHC H 6

à—

H ^ - lN=NC6H

5

H OO ΗέθΗ

21

HCsN-NHCçHs C-NH-NHCeH COH

HON-NHCeHs HON-NHCeHç

5

HCOH I HCOH I. R

Λ

r Jft

HCsN-NHCeHs 5

C"NH I

CeHçNHj

00 1 R

2L Figure 9


202

SYNTHETIC

METHODS

FOR

CARBOHYDRATES


11.

SIMON

AND

KRAUS

Phenylhydrazones

and

203

Osazones

usually the key reaction in osazone formation. Unlike other suggested mechanisms, this elimination reaction can be proved and measured. The formation of an intermediate § with a side equilibrium to §a can be made detected by the incorporating hydrogen isotopes from the medium when the osazone formation is conducted in labeled water/alcohol (54). But since 6§ is the product of a side equilibrium the amount of proton excRange at C-l of glucose during osazone formation varies widely with the conditions (55). Hydrogen exchange via 1# 4 cannot be excluded, but i t shoulcTbe rather low in solutions with weak acids. In special cases another elimination may occur. Osazone formation of 2-methoxycyclo-hexanone runs slower than that of 2-hydroxycyclohexanone. Presumably an elimination 1Q-»11 takes place followed by addition of phenylhydrazine according to Caglioti et a l . (33). This addition product can then eliminate aniline. Anotïïêr elimination takes place during the formation of 3-deoxy-bis-(benzoylhydrazones) in the presence of p-toluidine. This reactio (56). In this special case two moles of benzoyl hydrazine ?RbuTd be sufficient to transform the sugar to the osazone according to the following mechanism:

I

NH

2

x

2

CH I

HC-OH

>

CH 0H 2

CH 0

2

CH

2

I XXXVII

XXXVI method o f s y n t h e s i s f o l l o i n g the scheme: (58) N CH-C00R

NH

CH C00R

2

ι

2

C= ι

+ CH=0

—

CH3S-C HC—0

I

HC—0

X

NHp w h i c h m a y

from

the

is

racemization

hydrogénation,

five-membered

freed

splitting

side

purpuricene

reactions, of

occurring closure hydrogen

during the

between atoms

to

the

however,

C eliminated assume

to

involve

similar

1,2-dihydroxyethyl

step

earlier.

are

the

a helical

formation of

ring

to

a series

those

and

by

the

atoms

with

a

needed

dehydrogenations

C i n purpuricene.

also

of

occurring

1,2,3-trihydro-

The hydrogen

generated

r i n g Ε and F occurs

loss

of

Ring two

each.

Dihydropurpuricene benzene

seems

probably

chain mentioned

the hydrogénation

other

ρlane.

azulene

form.

The

for

in

DDQ.

the

form 3 epoxy

c a n be

with

steric

the

dihydro derivative,

racemic.

follow

system contains

Upon c a t a l y t i c

The d i h y d r o p r o d u c t

purpuricene

to

of

column chromatography,

T h i s was

to

ο

140

azulene

by dehydrogenation of

to

possible

The

acid.

a colorless

separated

i n one

due

molecule. .

Upon h e a t i n g

probably

solution

loses

i n an i n e r t

two h y d r o g e n atmosphere,

u n i d e n t i f i e l d compounds.

It

atoms to

s h o u l d be

upon keeping

form purpuricene noted

further


a and

that

238


R=CH :m.p.176°C 3

R=C H5:m.p.180°C 2

Figure 19

purpuricene possesses an acidic proton, thus reacts with potassium t-butylate in dimethylsuIfoxide giving a dark green salt. This is accompanied by an increase in the specific rotation from -k60 to -6^0 , and upon acidification, purpuricene is obtained unchanged (figure 21)· The chiral a l i c y c l i c aromatic hydrocarbons described here have not been isolated from natural sources, like their a l i c y c l i c analogs, the terpenes and steroid which are widely distributed in nature. Although the mode of formation of a l i c y c l i c aromatic hydrocarbons bears no relation to the biosynthesis of terpenes and steroids, i t might bear some relation to the processes i n volved in the formation of coal from the components of wood (cellulose, mannans, xylans and lignin). The presently accepted view, is that coal is formed from lignin and that the polysaccharide components of wood mysteriously disappear. We believe that our studies have shown that the carbohydrates of wood may play an important role in the coalification. The conditions of coal formation are somwhat similar to the condition we described for the interaction of carbohydrates and aromatic systems. The medium in both is acidic, although in coal formation i t i s weaker than in the hydrogen fluoride use. However, the temperature is much higher and the reaction time is considerably longer. Lignin is a macromolecule composed of monomuclear aromatic residues linked through three atomic aliphatic residue, Hydroxyl, methoxyl, and ether linkages are abundant. We have treated


13. LOUIS ET AL.

Chiral Hydrocarbons

239

Figure 20

glucose with lignin obtained from woods, under the conditions described earlier for 1 3 C-labelled D-glucose, and obtained lignin derivative containing 6-17$ of the radioactivity calculated as a D-glucose. The D-glucose residue or their fragments were found in the form of the carbon-carbon bound lignins. It is certainly possible that the aldoses liberated from polysaccharides would link to lignins in an analogous manner. We believe, therefore, that our discovery may have a great significance in understanding the processes involved in coal coalification. Literature Cited 1. Micheel, F. and Rensmann, L . , Makromol. Chem. (1963) 65,26. 2. Haines, A. H. and Micheel, F . , Makromol. Chem. (1964) 80, 74. 3. Micheel, F. and Staněk Jr., J., Tetrahedron Lett. (1970) 1609. 4. Micheel, F. and Staněk Jr., J., Tetrahedron Lett. (1971) 1605. 5. Micheel, F. and Sobitzkat, Η., Tetrahedron Lett. (1970) 1605. 6. Micheel, F. and Staněk Jr., J., Ann. Chem. (1972) 759, 37. 7. Micheel, F. and Schleifstein, Ζ. Η., Chem. Ber. (1972) 105, 8.

650.

Micheel, F . , Pesenacker, Μ., Killing, E. O. and Louis, G., Carbohydr. Res. (1973) 26, 278. 9. Micheel, F. and Sobitzkat, Η., Carbohydr. Res. (1973) 30, 71. 10. Micheel, F. and Schleifstein, Ζ. Η., Tetrahedron Lett. (1970) 1613. 11.

Walker, D. and Hiebert, J. D., Chem. Rev.

(1967) 67,


153.

14 Synthesis of N e w Sugar Derivatives of Biogenic Amines LASZLO MESTER and MADELEINE MESTER Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91190 Gif sur Yvette, France

Many s p e c i f i c r o l e s have been proposed for the biogenic amines i n p h y s i o l o g i c a (1) i s a powerful agen neurotransmitter and its r o l e i n the i n t r o d u c t i o n of sleep i s w e l l e s t a b l i s h e d . Catecholamines (2,3) are im portant regulators for many basic b i o l o g i c a l processes and involved i n diseases, such as manic depressive psy c h o s i s , Parkinsonism and e s s e t i a l hypertension. The po lyamines (4) spermine, spermidine and putrescine have a r o l e i n the b a c t e r i a l cell d i v i s i o n and in the growth of aminal cells. Sugar D e r i v a t i v e s of Serotonin and of Catecholamines In s p i t e of the impressive number of studies on serotonin i n the l a s t two decades, our knowledge on the mode of a c t i o n of t h i s biogenic amine i s h i g h l y specula tive (5). In 1971 we have reported (6) the enzymically cata lysed i n c o r p o r a t i o n of C l a b e l l e d N-acetyl-neuraminic acid i n t o the p l a t e l e t membrane (Figure 1). The higher sialic acid content increased the serotonin induced ag gregation of blood p l a t e l e t (7). The i n c o r p o r a t i o n of N-acetylneuraminic acid accelerated the uptake of sero tonin by the p l a t e l e t s (8) and also the serotonin cata lysed transport of potassium ions through the p l a t e l e t membrane (9). These effects suggest that sialic acid i s a component of the primary receptor for serotonin on the p l a t e l e t membrane. However, serotonin can react i n other b i o l o g i c a l processes i n a d i f f e r e n t way. Alivisatos and coworkers (10) suggested a Schiff-base type i n t e r a c t i o n to explain the mode of a c t i o n of serotonin i n the c e n t r a l nervous system (Figure 2 ) . The presence of a Shiff-base s t r u c ture has been demonstrated by chemical methods. 14

240


14.

MESTER

A N D MESTER

Sugar Derivatives

of Biogenic

241

Amines

SIALOTRANSFERASE (homogenized rat liver)

of the normal sialic acid content

Figure I. Incorporation membrane using CMP-N-( C)-acetyl neuraminic acid and rat liver sialyltransf erase 14

Science

Figure 2.

Mode of action of serotonin in the central nervous system ( 10)


242


CARBOHYDRATES

The S c h i f f - b a s e s t r u c t u r e advanced by A l i v i s a t o s to e x p l a i n t h e mode of a c t i o n of t h i s biogenic amine, i n c i t e d us to i n v e s t i g a t e the i n t e r a c t i o n of reducing sugars w i t h the p r i m a r y amino group of serotonin (11) (Figure 3). Between a l a r g e number of s u b s t i t u t e d serotonin d e r i v a t i v e s , prepared i n order to u n d e r s t a n d the role of 5-HT i n h e a l t h and d i s e a s e (J_2^ , o n l y t w o sugar d e r i v a t i v e s of serotonin (J_3,J^4) h a v e s o f a r b e e n r e ported. However, the presence of h y d r o p h i l i c groups may have a d e c i s i v e effect on the t r a n s p o r t and metabolism of t h e a m i n e . One o f these sugar d e r i v a t i v e s i s the 0(3-D-glycopyranosy1)-serotonin (1) showing an i n c r e a sed h y d r o s o l u b i l i t y , but h a v i n g p r o p e r t i e s very close to the w e l l s t u d i e d group of O - e t h e r s of serotonin. The s e c o n d one i s the N - g l u c o s i d i n t e r e s t b e c a u s e of i t s easy h y d r o l y s i s i n t o 5-HT and D-glucose i n aqueous s o l u t i o n even at room temperature. Thus, the p r e p a r a t i o n of a stable N - s u b s t i t u t e d sugar d e r i v a t i v e of s e r o t o n i n i s of b i o l o g i c i n t e r e s t . O n l y v e r y few a t t e m p s h a v e b e e n mad to prepare (_1J5,JM6) 1 - d e s o x y - 1 - a m i n o - D - f r u c t o s e d e r i v a t i v e s (Amador i c o m p o u n d s ) (J_7) a r i s i n g from s u b s t i t u t e d phenylethyl a m i n e . The p r e p a r a t i o n of t h i s type of compounds from 5-HT i s r e n d e r e d even more d i f f i c u l t b e c a u s e of the for m a t i o n of t e t r a h y d r o - n o r h a r m a n (3) d e r i v a t i v e s (J_8) . T o overcome these d i f f i c u l t i e s , the oxalate s a l t of serot o n i n e was u s e d f o r the r e a c t i o n with sugar, to obtain the corresponding Amadori compound, the 1-desoxy-l(5-hydroxy-tryptamino)-D-fruetose (4). Oxalic acid is o f t e n used to i s o l a t e A m a d o r i compounds a f t e r the reac t i o n between the sugar and the amine. S t a r t i n g w i t h the oxalate s a l t of serotonin, the 1-desoxy-1-amino-D-fruc tose d e r i v a t i v e is s t a b i l i z e d i n _ s i t u , preventing sero tonin from undergoing other r e a c t i o n s . The r e s u l t i n g p r o d u c t is a pale yellow m i c r o c r y s t a l l i n e powder, e a s i l y soluble i n water, slowly i n ethanol, i n s o l u b l e i n ethyl acetic ester, e t h y l ether or acetone. The o x a l a t e s a l t of 1-desoxy-1 -(5-hydroxyt r y p t a m i n o - ) - D - f r u c t o s e is stable i n aqueous s o l u t i o n and does not show m u t a r o t a t i o n . As f o r a l l Amadori com pounds prepared from D-glucose, the o p t i c a l rotatory power is negative ( 1 9 ) . N M R s p e c t r u m i n D2O c l e a r l y shows that the 5 - h y d r o x y - i n d o l e fragment of the molecu le, c h a r a c t e r i z e d by f o u r t y p i c a l proton signals i n the r e g i o n from 6.5 to 7.5 ppm, i s u n c h a n g e d a n d no trace of any other condensed s y s t e m c o u l d be d e t e c t e d . Carbon13 NMR s p e c t r o s c o p y s h o w s the A m a d o r i compound to exist i n D2O m a i n l y a s t h e β - p y r a n o s e s t r u c t u r e i n t h e Reeves 1C c o n f o r m a t i o n (20). The s i g n a l of C-2 i s l o c a t e d at


14.

MESTER

AND

MESTER

Sugar Derivatives

of Biogenic

Amines

243

DF-5 HT

Time (Min.)

Figure 4. Metabolism of serotonin (5-HT) and desoxy-fructo-serotonin (DF-5-HT) by rat brain MAO expressed by the rate of oxygen uptake in conventional Warburg manometric technique


In Synthetic Methods for Carbohydrates; El Khadem, H.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977. o

tryptaraino)-D-fructose

1-Desoxy-l-(5-methoxy-

tryptamino)-D-fructose

1-Desoxy-l-(5-hydroxy-

COMPOUND l

C

2

96.3

96.3

C

a

70.9

70. 9

c= secondary carbon

b= t e r t i a r y carbon

a= quaternary carbon

53.8

53.8

C

b b

5

69.9

69. 9

C

b

confirmed by o f f resonance decoupling

70.4

70.4

SUGAR CARBONS 6

64.9

64. 8

C

C

CARBON-13 N.M.R. DATA OF AMADORI TYPE SUGAR DERIVATIVES OF TRYPTAMINE IN D 0

TABLE I.

14.

MESTER

AND

MESTER

Sugar Derivatives

of Biogenic

Amines

245

96,3 p p m , t h e C - 3 , C«-4 a n d C - 5 s i g n a l s a p p e a r as three peaks a t 7 0 . 9 , 70.4 and 69.9 ppm. The s i g n a l s at 64.8 and 53.8 ppm c o r r e s p o n d to the C-6 and C - l carbons r e s p e c t i v e l y (ppm r e l a t i v e to TMS=0). (Table I ) . I n 0.1 Ν NaOH s o l u t i o n a t pH = 1 1 , 2 4 ° C , 1-desoxy-1-(5-hydroxytryptamino)-D-fuctose reduced 1.5 moles of T i l l m a n s reagent (2J_) . 1-Desoxy-1 -(5-methoxy-tryρtamino)-D-fruetose been prepared i n a s i m i l a r way and c a r b o n - 1 3 NMR troscopy shows a very s i m i l a r s t r u c t u r e .

has spec

Due to t h e i r s t r o n g r e d u c i n g power and h i g h s t a b i l i t y , these new s u g a r d e r i v a t i v e s of serotonin show i n t e r e s t i n g b i o l o g i c a l p r o p e r t i e s . _^ At a f i n a l concentration of 1x10 mol, 1-Desoxy1- ( 5 - h y d r o x y - t r y p t a m i n o ) - D - f r u c t o s e i n d u c e d an aggrega t i o n of human p l a t e l e t p l a t e l e t ) , w h i c h was s i m i l a by s e r o t o n i n i t s e l f (22) , but the i n c o r p o r a t i o n of the l^C l a b e l e d (spec.act. 0.1 mC/mM) s u g a r d e r i v a t i v e into the p l a t e l e t s d u r i n g 1 hour of i n c u b a t i o n (_23) was very l i m i t e d . Tested on r a t u t e r u s , the minus l o g a r i t m i c dose response for serotonin (5-HT) was h i g h e r t h a n f o r 1-desoxy-1(5-hydroxy-tryptamino)-D-fructose (DF-5-HT). However, b o t h are i n h i b i t e d by M e t h y l s e r g i d e , showing b o t h a c t i v i t i e s to be of t h e same n a t u r e (_24) . Serotonin is r a p i d l y metabolised, w h i l e 1-desoxy1(5-hydroxy-tryptamino ) D-fructose i s only slowly o x i d i z e d by monoamine oxidase (MAO). T h i s was demonstra ted by the r a t e of uptake of oxygen at v a r i o u s i n t e r v a l s as a n i n d e x of m e t a b o l i s m of r a t b r a i n m i t o c h o n d r i a l MAO, using serotonin and i t s s u g a r d e r i v a t i v e as substrates in conventional Warburg manometric technique (2_5) ( F i g u r e 4) . Using various concentrations of DF-5HT and 5-HT, the s u b s t r a t e a c t i v i t y curves show t h a t desoxyfructoserotonine has much l e s s substrate a f f i n i t y t o w a r d s MAO than serotonine i t s e l f . When L i n e w e a v e r - B u r k p l o t s were drawn, the M i c h a e l i s constant for d e s o x y f r u c t o - s e r o t o n i ne was found to be two and h a l f time higher than for serotonine ( F i g u r e s 5 and 6). An o sugar d e r g i v e n by lamines) r a t e d by and c o u l d

ther f i i v a t i v e the cat becames Barton be tra

e l d , where the s y n t h e s i s of Amadori type s i s of great b i o l o g i c a l i n t e r e s t , i s e c h ο l a m i n e s . A new t y p e of b i s - ( c a t e c h o a v a i l a b l e through the s y n t h e s i s , elabo and h i s coworkers (2_6) for the alcaloïde, nsformed i n sugar d e r i v a t i v e s (Figure 7).


SYNTHETIC METHODS

30

-

25

-

20

-

FOR CARBOHYDRATES

_ -L =_L 0-07

Km

Km = 19-28 Χ

10" ϋ 3

15

10

5

J*

_ J_

Φ

.

i

ul

CO

l

l

QO

Figure 5.

^ d

ι

ι

(J3

3)β-NAcgal (1->3)Gal - p o r t i o n of the molecule.

253


254

SYNTHETIC

(Vl)a-Gluc(l-»2)a-G1uc(H2)a-Gluc(l^3)

METHODS

FOR

CARBOHYDRATES

1,2-Di-o-acyl-L-g1ycerol

T h e b l o o d g r o u p s u b s t a n c e s o f human e r y t h r o c y t e s a r e g l y c o l i p i d s w i t h perhaps a small c o n t r i b u t i o n from g l y c o p r o t e i n s (Z>8) . T h e c l a s s i c a l w o r k (9 J 0 ) on t h e s t r u c t u r e o f t h e immunoc h e m i c a l l y a c t i v e p o r t i o n s o f t h e b l o o d g r o u p s u b s t a n c e s was c a r r i e d o u t on g l y c o p r o t e i n b l o o d g r o u p a c t i v e s u b s t a n c e s w h i c h w e r e r e a d i l y i s o l a t e d and p u r i f i e d f r o m body f l u i d s . However t h e g l y c o l i p i d type blood group substances present in the e r y t h r o cytes (e.g. I I , I I I S- I V ) h a v e b e e n s h o w n ( 8 ) t o p o s s e s s i d e n t i c a l terminal o l i g o s a c c h a r i d e p o r t i o n s to those of the g l y c o p r o t e i n s a n d some o f t h e s e t e r m i n a l d i - a n d t r i s a c c h a r i d e s h a v e b e e n synthesised (JJ) . The s t r u c t u r e s of s e v e r a l g l y c o l i p i d s from microorganisms h a v e been e s t a b l i s h e d ( 1 2 - 1 4 ) and t h e s e r o l o g i c a l a c t i v i t i e s o f some o f t h e s e h a v e been d e m o n s t r a t e d . The r e a l i s a t i o n of the v a r i e t y of s t r u c t u r a l (an can be i n c o r p o r a t e d i n t o a t r i s a c c h a r i d e u n i t and o f t h e t e n d e n c y o f g l y c o l i p i d s t o a s s o c i a t e w i t h o t h e r membranous s t r u c t u r e s l e d t h e a u t h o r (15) t o f o r m u l a t e a h y p o t h e s i s , r e l a t i n g t h e g l y c o l i p i d s of microorganisms w i t h p o s s i b l e îmmunopathologîcal p h e n o m e n a , w h i c h may b e s t a t e d b r i e f l y a s f o l l o w s . G l y c o l i p i d s o r i g i n a t i n g from microorganisms i n v a d i n g the h o s t may b e c o m e i n s e r t e d i n t o t h e c e l l u l a r m e m b r a n e s o f host tissues. A n t i b o d i e s , r a i s e d against these " f o r e i g n " g l y c o l i p i d s present in the macromolecular environment of the microorganism, may t h e n a t t a c k t h e h o s t t i s s u e c o n t a i n i n g t h e " f o r e i g n " g l y c o l i p i d l e a d i n g ( i n the p r e s e n c e of complement) t o "immune l y s i s " (16) o f t h e h o s t c e l l s i . e . t o a t y p e o f a u t o i m m u n e a t t a c k on t h e host t i s s u e s . One o f t h e m i c r o o r g a n i s m s f o r w h i c h t h e p r e s e n c e o f serol o g i c a l l y a c t i v e g l y c o l i p i d s has been e s t a b l i s h e d ( 1 7 - 2 0 ) is Mycoplasma pneumoniae, the c a u s a t i v e agent of primary a t y p i c a l pneumonia. The s t r u c t u r e s of t h e a c t i v e g l y c o l i p i d s have been t e n t a t i v e l y r e l a t e d (19) by s e r o l o g i c a l r e a c t i o n s t o t h e g a l a c t o s y l d i g l y c e r i d e s o f p l a n t l i p i d s t h e s t r u c t u r e s ( e . g . V) o f w h i c h have been e s t a b l i s h e d (21-25) . The s t r u c t u r e s ( e . g . V I ) of g l y c o l i p i d s i s o l a t e d f r o m S t r e p t o c o c c i have been fully d e t e r m i n e d (26-28) and the s e r o l o g i c a l a c t i v i t i e s of t h e s e have been e s t a b l i s h e d ( 2 9 , 3 0 ) . W i t h some o f t h e s e g l y c o l i p i d s t r u c t u r e s e s t a b l i s h e d we c o n s i d e r e d i t p e r t i n e n t t o a t t e m p t t h e i r s y n t h e s i s , f i r s t l y to prove that these s t r u c t u r e s were in f a c t t h e a c t i v e components and s e c o n d l y t o make t h e m a t e r i a l s more r e a d i l y a v a i l a b l e for t e s t i n g our h y p o t h e s i s . A t t h e o u t s e t i t was r e a l i s e d t h a t t h e s y n t h e t i c m e t h o d s to prepare the types of g l y c o s i d i c linkages present in these molec u l e s were not f u l l y e s t a b l i s h e d . In p a r t i c u l a r r o u t e s t o 1,2c i s - 1 i n k e d n e u t r a l and 2 - a m i n o s u g a r s were not a v a i l a b l e w i t h any degree of c e r t a i n t y ( a l t h o u g h the methods f o r the p r e p a r a t i o n of 1 . 2 - t r a n s - l i n k e d n e u t r a l and 2 - a m i n o - 2 - d e o x y s u g a r s were w e l l


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documented) and moreover t h e p r o b l e m o f t h e p r o t e c t i o n o f h y d r o x y l g r o u p s had a l s o t o be c o n s i d e r e d . We had p r e v i o u s l y i n t r o d u c e d (31-35) t h e a11 y1 e t h e r p r o t e c t i n g group i n t o c a r b o h y d r a t e c h e m i s t r y and had shown i t s p a r t i c u l a r v a l u e in the p r e p a r a t i o n o f benzyl ethers o f carbo h y d r a t e s . Awareness o f e a r l i e r work (36-38) on t h e p r e v a l e n c e o f 1 , 2 - c j _ s - g l y c o s i d e f o r m a t i o n when n o n - p a r t i c i p a t i n g g r o u p s w e r e p r e s e n t on t h e 2 - h y d r o x y l g r o u p , l e d u s t o c o n s i d e r (39) a general type of o l i g o s a c c h a r i d e s y n t h e s i s using benzyl ethers f o r ' p e r s i s t e n t ' p r o t e c t i o n and a 11 y1 e t h e r s f o r ' t e m p o r a r y ' p r o t e c t i o n f hydroxyl groups. It is therefore relevant at this s t a g e t o r e v i e w o u r d e v e l o p m e n t o f t h e a l l y l e t h e r s as p r o t e c t ing groups. Q

Allyl

Ethers as P r o t e c t i n

In t h e c o u r s e o f s t u d i e s on t h e c h e m i c a l s y n t h e s i s (40-42) o f t h e p h o s p h o l i p i d s known a s t h e p l a s m a l o g e n s ( e . g . V I I ) i t was n e c e s s a r y t o i n v e s t i g a t e new methods f o r t h e s y n t h e s i s o f v i n y l ethers. P r i o r t o t h i s w o r k , two p a p e r s (42»Μ) appeared d e s c r i b i n g the rearrangement of a l l y l ethers ( V I I I ) t o c i s - p r o p 1-enyl e t h e r s ( I X ) u n d e r b a s i c c o n d i t i o n s and t h e r e a r r a n g e m e n t was shown (44) t o be p a r t i c u l a r l y r a p i d and q u a n t i t a t i v e w i t h p o t a s s i u m t , - b u t o x i d e i n d i m e t h y l s u l p h o x i d e . For o u r work on t h e p l a s m a l o g e n s we a t t e m p t e d a s i m i l a r r e a r r a n g e m e n t w i t h a y - s u b s t i t u t e d a l l y l e t h e r and a s a model compound we c h o s e t h e hept a d e c - 2 - e n y l e t h e r ( X ) . We f o u n d h o w e v e r , t h a t w i t h p o t a s s i u m ' t . - b u t o x i d e i n d i m e t h y l s u l p h o x i d e , t h i s compound was r a p i d l y de graded t o heptadecadiene (XI) and i t s isomers. A t t h i s t i m e we w e r e a l s o i n t e r e s t e d i n t h e s y n t h e s e s o f t h e p h o s p h o l i p i d known as p h o s p h a t i d y l i n o s i t o l (45) and o f t h e l o n g - c h a i n s p i n g o l i p i d b a s e s , p h y t o s p h i n g o s i n e (46.47) and sphingosine (48,4^) ^ carbo h y d r a t e p r e c u r s o r s and t h i s work r e q u i r e d t h e e x t e n s i v e u s e o f carbohydrate p r o t e c t i n g groups. I t o c c u r r e d t o us t h a t t h e ready e l i m i n a t i o n o f d i e n e s f r o m γ-substituted a l l y l e t h e r s c o u l d f o r m t h e b a s i s o f a new p r o t e c t i n g g r o u p and we f o u n d (33) f o r e x a m p l e , t h a t t h e r e a d i l y p r e p a r e d b u t - 2 - e n y l e t h e r o f 1,2:5, 6-di-0-isopropylîdene-D" g l u c o f u r a n o s e was r a p i d l y c o n v e r t e d i n t o 1,2:5,6-di-0-isopropylidene-D-glucofuranose by p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a t room t e m p e r a t u r e . A t t h e same t i m e we r e a l i s e d t h a t t h e a l l y l e t h e r i t s e l f was p e r h a p s a p o t e n t i a l l y more u s e f u l p r o t e c t i n g g r o u p i n t h e c a r b o h y d r a t e s e r i e s than t h e b u t - 2 - e n y l g r o u p . The a l l y l g r o u p was s t a b l e t o aqueous a c i d and b a s e and was r a p i d l y i s o m e r i s e d t o t h e p r o p - l - e n y l g r o u p w i t h p o t a s s i u m t,-butoxide i n dimethyl s u l p h o x i d e w i t h o u t a f f e c t i n g o t h e r conv e n t i o n a l base-stable p r o t e c t i n g groups. The p r o p - l - e n y l g r o u p was s t a b l e t o b a s e but was v e r y a c i d l a b i l e and c o u l d a l s o be removed by o x i d a t i o n w i t h a l k a l i n e p e r m a n g a n a t e , by o z o n o l y s i s n

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f o l l o w e d by a l k a l i n e h y d r o l y s i s (31 .32) o r by t h e a c t i o n o f m e r c u r i c c h l o r i d e (33) . T h u s , b o t h t h e a l l y l and p r o p - 1 - e n y l groups c o u l d be u s e d u n d e r t h e a p p r o p r i a t e c o n d i t i o n s as p r o t e c t i n g groups. T h e i n s t a n t a n e o u s h y d r o l y s i s o f t h e p r o p - l - e n y l g r o u p by m e r c u r i c c h l o r i d e (33) was p a r t i c u l a r l y u s e f u l s i n c e by t h e a d d i t i o n of m e r c u r i c o x i d e t o t h e r e a c t i o n m i x t u r e the h y d r o l y s i s c o u l d be c a r r i e d o u t u n d e r n e u t r a l c o n d i t i o n s t h u s p r e s e r v i n g other a c i d - l a b i l e p r o t e c t i n g groups in the m o l e c u l e . Moreover m e r c u r i c c h l o r i d e was f o u n d t o r e a c t o n l y v e r y s l o w l y w i t h a l l y l e t h e r s and t h u s p r o p - l - e n y l g r o u p s c o u l d be removed i n t h e p r e s e n c e o f a l l y l g r o u p s by t h i s m e t h o d . Amido groups were a l s o s t a b l e (33)to t h e a c t i o n o f p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e and t h u s t h e a l l y l e t h e r s c o u l d be u s e d f o r t h e p r o t e c t i o n of 2-acylamino sugars Mono p r o p - l - e n y l e t h e r s o f v i c i n a l g l y c o l s a r e a l s o c o n v e r t ed i n t o p r o p y l i d e n e a c e t a l s (33) by a c i d c a t a l y s t s a n d t h u s t h e a l l y l e t h e r s c o u l d be u s e d f o r t h e p r e p a r a t i o n o f t h i s t y p e o f protecting group. S u b s e q u e n t work by o t h e r g r o u p s has shown t h a t a l l y l e t h e r s can be removed by o x i d a t i o n w i t h s e l e n i u m d i o x i d e (50) and t h a t t h e a l l y l g r o u p c a n be i s o m e r i s e d t o t h e p r o p - l - e n y l g r o u p by t r i s t r i p h e n y l p h o s p h i n e r h o d i u m c h l o r i d e u n d e r c o n d i t i o n s suff i c e n t l y m i l d t o p r e s e r v e a l k a l î - 1 a b i 1 e g r o u p s s u c h as e s t e r s (51). A l s o in the presence of d i e t h y l d i a z o d i c a r b o x y l a t e the a l l y l e t h e r g i v e s an a d d i t i o n p r o d u c t w h i c h i s a v i n y l e t h e r and i s t h u s r e a d i l y h y d r o l y s e d (j>2, jj£) · We h a v e a l s o shown (54) t h a t t h e a c t i o n o f N - b r o m o s u c c i n î m i d e on a l l y l e t h e r s ( e . g . XII) g i v e s a m i x t u r e o f t h e bromo e t h e r (XI I l ) and t h e s u c c i n i m i d e d e r i v a t i v e (XIV) b o t h o f w h i c h can be h y d r o l y s e d by aqueous b a s e r e s u l t i n g i n t h e removal o f t h e a l l y l g r o u p . Thus v a r i o u s o t h e r methods f o r t h e removal o f t h e a l l y l g r o u p a r e a v a i l a b l e f o r u s e i n c i r c u m s t a n c e s where t h e v e r y b a s i c c o n d i t i o n s of p o t a s s i u m t _ - b u t o x i d e i n d i m e t h y l s u l p h o x i d e a r e not acceptable. Some o f t h e s e o t h e r methods f o r t h e removal o f t h e a l l y l g r o u p s u f f e r from d i s a d v a n t a g e s e . g . t h e r h o d i u m c a t a l y s t i s e x p e n s i v e , has t o be s e p a r a t e d f r o m t h e p r o d u c t and does n o t e f f e c t complete i s o m e r i s a t i o n of the a l l y l g r o u p . We h a v e f o u n d o n l y a few c a s e s w h e r e t h e s t r o n g l y b a s i c c o n d i t i o n s of potassium t - b u t o x i d e in dimethyl s u l p h o x i d e cause other rearrangements in the carbohydrate m o l e c u l e . The r e a c t i o n w i t h t h e p h e n y l o x a z o l î n e (XV) l e d r a p i d l y (33) to the f o r m a t i o n o f t h e o x a z o l e (XVI) a l t h o u g h t h e p h e n y l o x a z o l î n e g r o u p i n c o m pound (XVI I ) was c o n s i d e r a b l y more s t a b l e t o t h e s e c o n d i t i o n s and compound ( X V I l ) was r e a d i l y c o n v e r t e d (49) i n t o the p r o p - l e n y l g l y c o s i d e ( X V I l l ) u n d e r m i l d c o n d i t i o n s a l t h o u g h i t was d e g r a d e d t o o t h e r p r o d u c t s ( e . g . XIX) u n d e r more v i g o r o u s c o n d i t i o n s (55) . T h e o x a z o l i n e g r o u p i s however s t a b l e i n t h e


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Glycolipids

259

p r e s e n c e o f t h e r h o d i u m c a t a l y s t (56) . The a l l y l d e r i v a t i v e (XX) o f 1 . 2 - 0 - i s o p r o p y l i d e n e - m y o i n o s i t o l was a l s o d e g r a d e d by t h e a c t i o n o f p o t a s s i u m _ t - b u t o x i d e in dimethyl s u l p h o x i d e t o g i v e t h e h y d r o x y h y d r o q u i n o n e d e r i v a t i v e (XXIII) . T h i s b e h a v i o u r was a l s o shown by t h e b e n z y l e t h e r (XXI). Compound ( X X I l ) was i s o l a t e d as an i n t e r m e d i a t e i n t h e c o n v e r s i o n o f t h e b e n z y l e t h e r (XXI) i n t o t h e a r o m a t i c e t h e r (XXIV) (57) . I s o p r o p y l i d e n e groups i n p y r a n o s i d e s and f u r a n o s i d e s a r e however, s t a b l e t o these c o n d i t i o n s . We have r e c e n t l y (58) observed that the v i c i n a l b i s p r o p - l e n y l e t h e r (XXV) i s f u r t h e r d e g r a d e d by t h e a c t i o n o f p o t a s s i u m t . - b u t o x î d e i n d i m e t h y l s u l p h o x i d e and t h e n a t u r e o f t h e p r o d u c t s is being i n v e s t i g a t e d . Having thus e s t a b l i s h e d t h e a l l y l and p r c p - l - e n y l groups as u s e f u l p r o t e c t i n g group i n v e s t i g a t e d (34) the removed much more r a p i d l y t h a n t h e a l l y l g r o u p i s i s o m e r i s e d and i t i s t h e r e f o r e p o s s i b l e t o remove a b u t - 2 - e n y l g r o u p w i t h o n l y p a r t i a l î s o m e r i s a t i o n o f an a l l y l g r o u p when b o t h a r e p r e s e n t i n t h e same m o l e c u l e (34). Thus t h e a l l y l e t h e r (XXVII) was o b t a i n e d (59) f r o m t h e b u t - 2 - e n y l e t h e r (XXVI) i n a b o u t 40% y i e l d by t h i s p r o c e d u r e . One o f t h e main u s e s t h a t we h a v e f o u n d f o r t h e b u t - 2 e n y l g r o u p i s as a t e m p o r a r y p r o t e c t i n g g r o u p d u r i n g t h e p r e paration of other a l l y l ethers. Thus t h e a l l y l glycoside (XXVIII) g a v e (£2) t h e p r o p - 1 - e n y 1 g l y c o s i d e (XXIX) on t r e a t m e n t with potassiurn Jt-butoxide in dimethyl s u l p h o x i d e . A l l y l a t i o n of compound (XXIX) t o g i v e (XXX) and s u b s e q u e n t h y d r o l y s i s o f t h e p r o p - 1 - e n y î group gave 2 - 0 - a l l y l - 3 , 4 , 6 - t r i - 0 - b e n z y l - D - g l u c o p y r a n o s e (XXXI ) . A f u r t h e r e x t e n s i o n o f t h e u s e o f a l l y l e t h e r s came when we i n v e s t i g a t e d t h e c o m p a r a t i v e r a t e s o f i s o m e r i s a t ion o f o t h e r methyl s u b s t i t u t e d a l l y l e t h e r s . Both 1-methyl-(34) a n d 2 m e t h y l a l l y l (33.35) e t h e r s were i s o m e r i s e d a t a c o n s i d e r a b l y lower r a t e t h a n t h e a l l y l e t h e r s by p o t a s s i u m _ t - b u t o x i d e i n d i m e t h y l s u l p h o x i d e and t h e 2 - m e t h y l a l 1 y l e t h e r s (35) w h i c h a r e r e a d i l y prepared a r e convenient p r o t e c t i n g groups i n the presence o f b u t - 2 - e n y l g r o u p s s i n c e t h e l a t t e r c a n be removed c o m p l e t e l y (35) w i t h o u t i s o m e r i s a t i o n o f 2-methy1 a l 1yl g r o u p . We a l s o showed t h a t t h e b u t - 2 - e n y l g r o u p i s i s o m e r i s e d much more s l o w l y t h a n t h e a l l y l g r o u p by t h e r h o d i u m c a t a l y s t and t h i s a l l o w e d (£6, 60) t h e removal o f t h e a l l y l g r o u p i n t h e presence of the but-2-enyl group. Thus t h e a l l y l g a l a c t o p y r a n o s i d e d e r i v a t i v e (XXXIl) gave p r e d o m i n a n t l y t h e p r o p - l - e n y l g l y c o s i d e (XXXIV) on t r e a t m e n t w i t h t h e r h o d i u m c a t a l y s t a n d compound (XXXIV) was t h e n h y d r o l y s e d t o t h e f r e e s u g a r (XXXV) (60). T h i s t r a n s f o r m a t i o n o f compound (XXXI I) i n t o t h e p r o p - l e n y l g l y c o s i d e (XXXIV) was however a c c o m p l i s h e d i n h i g h e r y i e l d and w i t h fewer b y p r o d u c t s by f i r s t t r e a t i n g compound (XXXI I) w i t h


SYNTHETIC

260

fafya

METHODS

FOR CARBOHYDRATES

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(XXXVII)

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15.

GiGG

Serologically Active

Glycolipids

261

butoxide, to isomerîse the a l l y l group and remove the b u t - 2 - e n y l group, g i v i n g the p r o p - l - e n y l g l y c o s i d e (XXXI Il) which was then treated with ' c r o t y l bromide and sodium hydride to give the but2-enyl ether (XXXIV) (6l_) . In a l l of our e a r l y work on the use of potassium Jt-butoxide in dimethyl sulphoxide f o r the rearrangement of a l l y l ethers we used laboratory prepared potassium _t-butoxide. Recently t h i s material has become commercially a v a i l a b l e in the U.K. and the commercial material i s considerably more a c t i v e than our own p r e p a r a t i o n . A l l y l ethers are r a p i d l y isomerised at 20 by the commercial material whereas we r o u t i n e l y used higher temperatures in our e a r l y work. Many other groups (62-75) have found the a l l y l ethers useful as p r o t e c t i n g groups in the preparation of carbohydrate d e r i v a t i v e s and other compounds. 1

1 , 2 - C i s - G l y c o s i d e Synthesi The long standing problem of 1.2-ci s - q l y c o s i d e synthesis has been f u l l y reviewed (36-38) and at the outset of our work on the synthesis of the g l y c o l i p i d s t h i s was our major concern s i n c e many of these compounds contained t h i s g l y c o s i d i c l i n k a g e . When considering our projected general o l i g o s a c c h a r i d e synthesis using benzyl ethers f o r ' p e r s i s t e n t ' p r o t e c t i o n and a l l y l ethers f o r 'temporary' p r o t e c t i o n we were encouraged by e a r l i e r work which showed higher y i e l d s of 1 . 2 - c i s - q l y c o s i d e s when n o n - p a r t i c i p a t i n g groups were present on the 2 - p o s i t i o n (36-38) and by the work of Ishikawa and F l e t c h e r (76).on the r e l a t i v e rates of reaction of f u l l y benzylated a - and β - glycosyl h a l i d e s . We adopted these ideas in our i n i t i a l work and developed (39) simultaneously, a s i m i l a r route to 1.2-ci s-g1ycosi des as that used by Lemieux and his co-workers (11.77.78) and termed by him " h a l i d e c a t a l y s e d g l y c o s i d a t i o n r e a c t i o n s " . However, s i n c e we intended to use a l l y l ethers as p r o t e c t i n g groups in the glycosyl h a l i d e s , we decided to avoid using the g l y c o s y l bromides s i n c e t h e i r preparation could lead to problems with the unsaturated centres of the a l l y l groups and we therefore concentrated on the reactions of the g l y c o s y l chlorides. Our other concern at t h i s stage was the f e a s i b i l i t y of using perbenzylated intermediates; the degree of s t e r i c hindrance that might r e s u l t from t h e i r use and a l s o the physical p r o p e r t i e s of the p r o d u c t s . Our i n i t i a l experiments (39) were c a r r i e d out with f u l l y benzylated glucosyl c h l o r i d e s and some of the t r i - 0 benzyl ethers of benzyl α - D - g a l a c t o p y r a n o s i d e . Using d i c h l o r o methane as a s o l v e n t , tetraethylammonium c h l o r i d e as a c h l o r i d e source and t r i e t h y l ami ne as a base, to remove the hydrogen c h l o r i d e l i b e r a t e d , we showed that the f u l l y benzylated glucosyl c h l o r i d e (XXXVI) gave high y i e l d s of g l y c o s i d e s when condensed with benzyl 2 , 3 , 4 - t r i - 0 - b e n z y l - α - D - g a l a c t o p y r a n o s i d e (XXXVIl) and the product was moreover c r y s t a l l i n e . N.m.r. spectroscopy of the crude d i s a c c h a r i d e d e r i v a t i v e a l s o showed a high proportion of the


262

SYNTHETIC METHODS

^

.to. oft

CHjOH

Synthetic methods for carbohydrates

Carbohydrates (Best Synthetic Methods)

Carbohydrates (Best Synthetic Methods) (Best Synthetic Methods)

New Synthetic Methods

Hydrogenation Methods (Best Synthetic Methods)

General and synthetic methods

Indoles (Best Synthetic Methods)

General and synthetic methods

New Synthetic Methods

Best Synthetic Methods: Acetylenes, Allenes and Cumulenes (Best Synthetic Methods)

Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods

Organolithium Methods (Best Synthetic Methods Series)

Compendium of Organic Synthetic Methods,

Synthetic Methods in Step-Growth Polymers

Imidazole and Benzimidazole Synthesis (Best Synthetic Methods)

Compendium of Organic Synthetic Methods Volume 1

Synthetic Methods in Step-Growth Polymers

General and synthetic methods., Volume 3

Compendium of Organic Synthetic Methods (Volume 12)

Compendium of Organic Synthetic Methods Volume 5

Compendium of Organic Synthetic Methods Volume 8

General and synthetic methods, Volume 12

Synthetic methods in step-growth polymers

Compendium of Organic Synthetic Methods Volume 3

Compendium of Organic Synthetic Methods Volume 11

Volume 7, Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods Volume 6

Synthetic methods for carbohydrates

Carbohydrates (Best Synthetic Methods)

Carbohydrates (Best Synthetic Methods) (Best Synthetic Methods)

New Synthetic Methods

Hydrogenation Methods (Best Synthetic Methods)

General and synthetic methods

Indoles (Best Synthetic Methods)

General and synthetic methods

New Synthetic Methods

Best Synthetic Methods: Acetylenes, Allenes and Cumulenes (Best Synthetic Methods)

Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods

Organolithium Methods (Best Synthetic Methods Series)

Compendium of Organic Synthetic Methods,

Synthetic Methods in Step-Growth Polymers

Imidazole and Benzimidazole Synthesis (Best Synthetic Methods)

Compendium of Organic Synthetic Methods Volume 1

Synthetic Methods in Step-Growth Polymers

General and synthetic methods., Volume 3

Compendium of Organic Synthetic Methods (Volume 12)

Compendium of Organic Synthetic Methods Volume 5

Compendium of Organic Synthetic Methods Volume 8

General and synthetic methods, Volume 12

Synthetic methods in step-growth polymers

Compendium of Organic Synthetic Methods Volume 3

Compendium of Organic Synthetic Methods Volume 11

Volume 7, Compendium of Organic Synthetic Methods

Compendium of Organic Synthetic Methods Volume 6

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