Natural Compounds as Drugs, Volume II (Progress in Drug Research)

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#ONTENTS &OREWORD VII 'LOSSARY  IX !CTIVATIONOFFUNGALSILENTGENECLUSTERS!NNEWAVENUE TODRUGDISCOVERY  !XEL!"RAKHAGE *ULIA3CHUEMANN 3EBASTIAN"ERGMANN +IRSTIN3CHERLACH 6OLKER3CHROECKHAND#HRISTIAN(ERTWECK



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VI

&OREWORD 7ITHTHEBOOKS.ATURAL#OMPOUNDSAS$RUGS6OL)AND))WEAIMTOSHOW NOTONLYTHECOMPLEXTECHNOLOGYCATALOGUEAPPLICABLETONATURALPRODUCTS INDRUGDISCOVERYANDDEVELOPMENT RELATEDSCIENCE)MPORTANTADDITIONAL MOTIVATIONSFORTHECURRENTEDITIONHAVEBEENTODEMONSTRATEHOWNATURAL PRODUCTSRESEARCHCANSUCCESSFULLYBEINTEGRATEDINMOSTMODERNTECHNOLO GIESANDCONCEPTSOFDRUGDISCOVERY ANDTOILLUSTRATETHEPOTENTIALWHICH NATURAL PRODUCTS HAVE EVEN TODAY FOR INNOVATIVE TREATMENTS OF HUMAN DISEASES )NTHEPRESENTVOLUMEWEPUTANEMPHASISONNATURALPRODUCTS RELATED CHEMICALDIVERSITY TARGETIDENTIFICATION ANDMOSTRECENTEXAMPLESOFNATURAL PRODUCTS BASEDTHERAPIESINCLINICALRESEARCHANDBEYOND 4HE INCREASINGLY SYSTEMATIC SEARCH FOR NEW BIOSYNTHESIS GENE CLUSTERS OFMICROBIALORIGINORWHOLEGENOMESEQUENCINGAREPROMISINGCONCEPTS TO GET ACCESS TO NOVEL NATURAL PRODUCTS RELATED CHEMODIVERSITY INDEPEN DENT OF INITIAL PHYSIOLOGICAL LIMITATIONS 3OPHISTICATED TOTAL SYNTHESES OF COMPLEXSECONDARYMETABOLITES AHOMEDOMAINOFONLYAFEWREMAINING DISTINGUISHED ACADEMIC CHEMISTRY GROUPS CREATE INNOVATIVE AND ELEGANT METHODOLOGIES IN SYNTHETIC CHEMISTRY AND THEREBY EXPAND CONTINUOUSLY THEARMAMENTARIUMOFTHISKEYDISCIPLINEFORTHEBENEFITOFDRUGDISCOVERY AND ORGANIC CHEMISTRY IN GENERAL &URTHERMORE THE EXPLOITATION OF THOSE SYNTHETICROUTESPAIREDWITHTHEUNDERSTANDINGOFSTRUCTURALCHARACTERISTICS OF SECONDARY METABOLITES AND THEIR BIOLOGICAL ACTIVITY IS LEVERAGED IN THE DESIGNOFMOREANDNEWNATURALPRODUCTS LIKEMOLECULESPOTENTIALLYUSEFUL ASNOVELANDBETTERDRUGS 4HERELEVANCEOFRECENTNATURALPRODUCTSFORNEWMEDICALTREATMENTSAND ONCE INTRODUCED TO THE PHARMACEUTICAL MARKET THE CONSEQUENCES FOR THE UNDERLYINGSUPPLYCHAINMANAGEMENTOFPLANTMETABOLITES CONCLUDETHIS SECONDVOLUME 7EDOHOPETHATBOTHBOOKVOLUMESWILLCONTRIBUTETOADIFFERENTIATED VIEWOFCURRENTACTIVITIESANDMAYVITALIZECONSTRUCTIVEDISCUSSIONSONFUTURE DIRECTIONSOFNATURALPRODUCTSRESEARCHINACADEMIAANDTHEPHARMACEUTICAL INDUSTRY 7EAPPRECIATETHEKINDSUPPORTOF+LAUS-EMMERT 2OWAN-ORRIS AND 9ING7ANG

VII

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7E WARMLY THANK ALL AUTHORS FOR THEIR COMPREHENSIVE AND EXCELLENT REVIEWS GIVING AN IN DEPTH INSIGHT INTO THE FASCINATING WORLD OF NATURAL COMPOUNDS &RANK0ETERSEN 2ENÎ!MSTUTZ

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-OSTCONVENIENTLY THISSTRATEGYWOULDALLOWFORTHECONCERTEDEXPRESSION OFALLPATHWAYGENES2ECENTLY WECOULDSUCCESSFULLYAPPLYTHISSTRATEGY ;= 4HE CRYPTIC ! NIDULANS 0+3 .203 GENE CLUSTER CONTAINS A PUTATIVE ACTIVATORGENEDESIGNATEDAPD24HEDEDUCEDGENEPRODUCTISRELATEDTOA PUTATIVE#TRANSCRIPTIONFACTOROF!FUMIGATUSANDTOAPUTATIVEREGULATOR WITHA'!, TYPE:N#YSBINUCLEARCLUSTER$.! BINDINGDOMAINFROM !FLAVUS4OPROVETHECONCEPTTHATTHEHOMOLOGOUSOVEREXPRESSIONOFA REGULATORYGENECANLEADTOACTIVATIONOFASILENTGENECLUSTERTHEPUTATIVE ACTIVATOR GENE APD2 WAS AMPLIFIED FROM GENOMIC $.! AND CLONED INTO ANEXPRESSIONVECTORCARRYINGTHEPROMOTEROFTHEALCOHOLDEHYDROGENASE OF!NIDULANS&IG 4HISPROMOTERCANBEINDUCEDBYTHEADDITIONOF CYCLOPENTANONETOTHEMEDIUMANDREPRESSEDBYTHEUSEOFGLUCOSEASTHE CARBONSOURCE;=



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&IGURE !CTIVATIONOFASILENTGENECLUSTERIN!SPERGILLUSNIDULANSBYOVEREXPRESSIONOFTHETRANSCRIPTIONFACTOR GENEAPD2LEDTOTHEIDENTIFICATIONOFTHENOVELNATURALPRODUCTSASPYRIDONE!AND";=

4RANSFORMANTSOF!NIDULANSCARRYINGTHEALC!P APD2GENEFUSIONECTOP ICALLYINTEGRATEDINTOTHEGENOMEWERECHECKEDFORTRANSCRIPTIONOFGENES OF THE CLUSTER BY .ORTHERN BLOT ANALYSIS 7HEREAS THE TRANSCRIPTS WERE COMPLETELYABSENTINTHEWILDTYPEUNDERBOTHNON INDUCINGANDINDUCING CONDITIONS INTHETRANSFORMANTSTRAINUNDERINDUCINGCONDITIONSSTRONG M2.!SIGNALSWEREDETECTEDFORTHEGENESOFTHECLUSTERINCLUDINGTHE0+3 .203HYBRID4HISOBSERVATIONFURTHERCONFIRMEDTHATUNDERTHECONDI TIONSAPPLIEDTHISGENECLUSTERWASSILENTWITHOUTINDUCTION&URTHERMORE ITALSOHELPEDTOCONFINETHEBORDERSOFTHEGENECLUSTER;=



#HEMICALANALYSIS

(0,# COUPLED TO $!$ AND -3 DETECTORS REVEALED THAT UNDER INDUCING CONDITIONS THETRANSFORMANTSTRAINSPRODUCEDTWOMAINPRODUCTSASWELL ASTWOMINORCOMPOUNDS4HEMAINMETABOLITESWEREISOLATEDANDTHEIR STRUCTURESWEREELUCIDATEDBY$AND$.-2MEASUREMENTSASWELLASBY )2AND-3;=4HENOVELMETABOLITESPRODUCEDBYTHETRANSFORMANTSTRAIN WERENAMEDASPYRIDONES!AND"DUETOTHEIRPYRIDONEMOIETIES&IG  4HEYARESIMILAR BUTNOTIDENTICALTOAVARIETYOFOTHERPYRIDONESISOLATED FROMFUNGI SUCHASMILITARINONE$ANDTENELLIN; =)NABROADBIOAC TIVITYSCREENINGTHEYEXHIBITEDMODERATECYTOTOXICACTIVITIES4HEFUNCTION



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OFTHEASPYRIDONESINTHENATURALCONTEXTANDPOSSIBLETRIGGERSFORTHEONSET OFTHEIRBIOSYNTHESISREMAINTHESUBJECTOFONGOINGINVESTIGATIONS (OWEVER THERESULTSCITEDHEREPROVIDETHEPROOFOFPRINCIPLEFORASTRAT EGYTHATMAYBEGENERALLYAPPLICABLETOTHEACTIVATIONOFSILENTBIOSYNTHESIS GENECLUSTERS INPARTICULARINEUKARYOYTES



#ONCLUSION

4HEONGOINGEXPONENTIALGROWTHOF$.!SEQUENCEDATAWILLLEADTOTHEDIS COVERYOFMANYNATURAL PRODUCTBIOSYNTHESISPATHWAYSBYGENOMEMINING FORWHICHNOACTUALPRODUCTHASBEENCHARACTERISED4HEVASTAMOUNTOF $.!SEQUENCESINTHEPUBLICDATABASEREPRESENTSONLYTHEBEGINNINGOF THIS NEW GENOMICS ERA 4HE ACTIVATION OF THESE GENE CLUSTERS BY GENETIC ENGINEERINGWILLLEADTOTHEDISCOVERYOFMANYSOFARUNKNOWNPRODUCTS ANDTHEREFOREREPRESENTSANOVELAVENUETODRUGDISCOVERY

2EFERENCES    



  

 



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!BSTRACT 4HISCHAPTERDERIVESITSINSPIRATIONFROMTHECHALLENGESPRESENTEDTOTOTALSYNTHESISCHEM ISTS BYAPARTICULARGROUPOFMACROCYCLICPIPECOLICACIDNATURALPRODUCTS!LTHOUGHTHEREIS CONSIDERABLEEMPHASISONTHECOMPLETEDSYNTHESESOFTHEMAINCHARACTERS&+ THE ANTASCOMYCINSAND ANDRAPAMYCIN THEOVERALLCOMPLEXITYOFTHEMOLECULARPROB LEMHASSTIMULATEDAWEALTHOFNEWKNOWLEDGE INCLUDINGTHEDEVELOPMENTOFNOVELSTRATEGIES ANDTHEINVENTIONOFNEWSYNTHETICMETHODS4HEINGENIOUSANDINNOVATIVEAPPROACHESTO THESETARGETSHAVEENABLEDNEWGENERATIONSOFANALOGUES ANDPROVIDEDMATERIALTOFURTHER PROBE THE BIOLOGY OF THESE FASCINATING MOLECULES 7ITH PHARMACEUTICAL APPLICATION AS AN IMMUNOSUPPRESSANT ASWELLASPOTENTIALUSEFORTHETREATMENTOFCANCERANDNEURODEGENERA TIVEDISEASES THISFAMILYOFNATURALPRODUCTSCONTINUESTOINSPIRENEWANDINTERESTINGSCIENCE WHILEPROVIDINGSOLUTIONSTOHEALTHCAREPROBLEMSOFTHEWORLD



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#ONSIDERABLESTRUCTURALINSIGHTINTOTHENATUREOFINHIBITIONOFBOTH CALCINEURINANDM4/2VIATHE&+ ORRAPAMYCIN &+"0COMPLEXESHAS BEENPROVIDEDBY8 RAYANALYSISOFTHETERNARYCOMPLEX&IG ;n= !SDESCRIBEDPREVIOUSLY BOTH&+ ANDRAPAMYCIN BINDTIGHTLYTO &+"0THROUGHHYDROPHOBICINTERACTIONSUSINGTHETRICARBONYLPIPECOLIC PORTIONOFTHEIRARCHITECTURE WHILETHEREMAINDEROFTHEMOLECULEISSITU ATEDINASOLVENTACCESSIBLEREGION)TISNOWRECOGNISEDTHATITISTHISLATTER FEATUREWHICHISPRIMARILYRESPONSIBLEFORTHEDIFFERINGBIOLOGICALMODES OFACTIONOFTHESETWONATURALPRODUCTS ANDCONSEQUENTLYBOTHSTRUCTURES OFANDCANBEDESCRIBEDASHAVINGABINDINGDOMAIN;FORASSOCIATION WITH&+"0 !BLUE &IG=ANDANEFFECTORDOMAIN;FORDETERMINING SUBSEQUENTACTIVITY !RED &IG=)NTHECASEOF&+ THEDOMINANT SITEOFBINDINGOFTHEBINARYCOMPLEXTOCALCINEURININVOLVESHYDROPHOBIC INTERACTIONSWITHTHEEFFECTORREGIONOF# #AND#ALLYLGROUP )N ADDITION ASECONDARYRECOGNITIONSITEINVOLVINGSUBSTANTIALPROTEINnPRO TEIN &+"0 CALCINEURIN INTERACTION ALSO PLAYS A ROLE IN THE FORMATION OFTERNARYCOMPLEX)NCONTRAST THEAGGREGATECOMPOSITEOFRAPAMYCIN &+"0ANDM4/2EXHIBITSESSENTIALLYNOPROTEINnPROTEINCONTACTS AND IT APPEARS THAT RAPAMYCIN  ACTS AS A LINCHPIN INTERACTING SEPARATELY WITH THE TWO ENZYMES THROUGH HYDROPHOBIC INTERACTIONS )N THESE THE LARGERMACROCYCLERELATIVETO&+ ANDTHETRIENEPORTIONOFFULFILLAN ESPECIALLYIMPORTANTROLEFORBINDINGTOM4/2 ASROTATIONSLIGHTLYOUTOF CONJUGATIONINTHEFULLTERNARYCOMPLEXALLOWSFURTHERBURYINGOFTHE# METHYLGROUPINTOASMALLCREASEINTHESECONDARYTARGETM4/2  7HILETHEIMMUNOMODULATINGEFFECTSOFBOTH&+ ANDRAPAMYCIN  ARE OF TREMENDOUS IMPORTANCE THE TRICARBONYL MACROLIDES ALSO HOLD GREATPOTENTIALINAPPLICATIONTOAVARIETYOFOTHERHUMANMALIGNANCIES &OREXAMPLE THENON IMMUNOSUPPRESSIVEMEMBERSOFTHISFAMILYOFNATU RALPRODUCTS PARTICULARLYMERIDAMYCIN ANDTHEANTASCOMICINSAND  ;= AREOFCONSIDERABLEINTERESTFORTHETREATMENTOFNEURODEGENERATIVE DISEASE;n=4ODATE THEMODEOFACTIONOFTHESEMOLECULESHASNOT BEENFULLYELUCIDATEDHOWEVER ITAPPEARSTHATINHIBITIONOF&""0ANDOR DIFFERENTISOZYMESEG &+"0  ; =OFTHESAMEFAMILYISSOMEHOW INVOLVED;n=!LTHOUGHBOTH&+ ANDRAPAMYCIN ALSOSHARE THIS ACTIVITY THEIR IMMUNOSUPPRESSIVE PROPERTIES LIMITS CHRONIC USE IN PATIENTS(OWEVER SYNTHETICORENGINEEREDANALOGUESOF&+ ;n= HAVEBEENDEMONSTRATEDTOPROMOTENOTONLYREGROWTHOFDAMAGEDNERVES



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

&IGURE $OMAINAL ANALYSIS OF &+"0 LIGANDS ! &+  AND RAPAMYCIN  BINDING DOMAINS TO &+"0 SHOWN IN BLUE EFFECTOR DOMAINS SHOWN IN RED ;= " 2IBBON DIAGRAM OF &+;WHITE BALL AND STICK= &+"0;PURPLECALCINEURIN BLUEANDORANGESUBUNITSOFHETERODIMER=COMPLEX;=2EPRIN TEDBYPERMISSIONFROM-ACMILLAN0UBLISHERS,TD.ATURE COPYRIGHT# 2IBBONDIAGRAMOF RAPAMYCIN;GREENBALLANDSTICK= &+"0;BLUE=M4/2;RAPAMYCINBINDINGDOMAINOFM4/2INRED= COMPLEX&ROM;=2EPRINTEDWITHPERMISSIONFROM!!!3

INTHEPERIPHERALNERVOUSSYSTEM BUTALSOTHEREGENERATIONOFNEURONSIN THE CENTRAL NERVOUS SYSTEM 4HESE NOVEL DERIVATIVES ARE CURRENTLY BEING EVALUATEDFORTHETREATMENTOFSUCHDEBILITATINGAILMENTSAS0ARKINSONS ;=AND!LZHEIMERS;=DISEASESAMONGOTHERS;= 9ETANOTHERAREAOFPROFOUNDANDRECENTIMPORTANCERELATESTOTHEUSE OF THE TRICARBONYL PIPECOLIC ACID MACROLIDES SPECIFICALLY RAPAMYCIN  ANDDERIVATIVES ASANTICANCERAGENTS;n=)NTERESTINGLY RAPAMYCIN WASIDENTIFIEDBYTHE.ATIONAL#ANCER)NSTITUTE.#) SHORTLYAFTERITSDIS COVERY ASANON CYTOTOXICAGENTTHATHADCYTOSTATICACTIVITYAGAINST SEVERAL DIFFERENT HUMAN CANCERS BOTH IN VITRO AND IN VIVO (OWEVER THE DEVELOPMENTPROGRAMOFASAPOTENTIALANTICANCERAGENTRECEIVEDLITTLE ATTENTIONUNTILTHEENDOFTHESFOLLOWINGTHEDISCOVERYOFANALOGUES



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

WITH IMPROVED PHARMACOLOGICAL PROPERTIES ;= AND THE RECOGNITION OF THEIMPORTANCEOFM4/2ASACENTRALREGULATOROFBOTHCELLULARCATABOLISM ANDANABOLISM /F THE THREE MAJOR SIGNALLING PATHWAYS THAT HAVE BEEN IDENTIFIED AS IMPORTANTFORTHEDEVELOPMENTOFCANCERNAMELYTHE0)+ !+4KINASE ;= PROTEINKINASE#FAMILY; = AND-!0+2AS;=SIGNALLINGCAS CADES M4/2; =HASBEENIDENTIFIEDASAKEYDOWNSTREAMENZYME INTHEPHOSPHATIDYLINOSITOLKINASE0)+ PATHWAY4ODATE THEUNIQUE ABILITYOFTHERAPAMYCINRAPAMYCINDERIVATIVE &+"0AGGREGATECOMPLEX TOEFFECTIVELYINHIBITM4/2HASHADADEMONSTRATEDVALUEINAVARIETYOF HUMAN TUMOUR TYPES %SPECIALLY USEFUL IN CELL LINES WITH MALFUNCTION ING PHOSPHATASES AND TENSIN HOMOLOGUES DELETED ON CHROMOSOME  04%. NEGATIVE REGULATOR OF 0)+ ; = THREE CANDIDATES ##)  TEMSIROLIMUS 7YETH 0HASE))) 2!$  EVEROLIMUS .OVARTIS 0HASE)) AND!0!RIAD 0HASE)) ARECURRENTLYINADVANCEDCLINICALTRIALS!LL THREE OF THESE CANDIDATES ARE # /( RAPAMYCIN DERIVATIVES THAT OFFER IMPROVEDPHARMACOKINETICSANDWATERSOLUBILITYFORFORMULATIONPURPOSES /FNOTE NOIMMUNOSUPPRESSIVEEFFECTSWEREMANIFESTEDWHENANYOFTHE ABOVEDRUGCANDIDATESWEREADMINISTEREDINTERMITTENTLYINCLINICALSETTINGS ;= 4HEROLEOFCHEMICALSYNTHESIS INBOTHTARGETANDDIVERSITYORIENTATED CONTEXTS HASPLAYEDANINTEGRALROLEINTHEELUCIDATIONOFTHEFASCINATING BIOLOGICALPROFILEOFTHEMACROCYCLICPIPECOLICACIDNATURALPRODUCTSn ASOUTLINEDBRIEFLYABOVE4HEREMAINDEROFTHISCHAPTERWILLFOCUSONTHE PRINCIPLESYNTHETICEFFORTSDIRECTEDTOWARDSTHECONSTRUCTIONOF&+ ;n= ANTASCOMICINSAND ;n= ANDRAPAMYCINSAND ;n=



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!SDISCLOSEDINBYRESEARCHERSAT-ERCK3HARPAND$OHME &+ WASTHEFIRSTOFTHETRICARBONYLMACROLIDEFAMILYOFIMMUNOSUPPRESSANTS ORRELATEDNATURALPRODUCTS TOSUCCUMBTOATOTALSYNTHESISEFFORT; = 4HISLANDMARKACHIEVEMENTFOLLOWEDYEARSOFINTENSEINTERESTANDEFFORT AND PROVIDED A FOUNDATION WHICH FUTURE SYNTHESES WOULD BUILD UPON -OREOVER ITALSOAFFORDEDSYNTHETICMATERIALFORFURTHERINVESTIGATIONOF



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 2ETROSYNTHETICANALYSIS

THEINTRIGUINGBIOLOGICALACTIVITYOF&+ ASWELLASADVANCEDINTER MEDIATESFORDIVERTEDTOTALSYNTHESIS;=INTHESEARCHFORCOMPOUNDSWITH IMPROVEDPHARMACOLOGICALPROPERTIES %XTENSIVE STUDIES ON THE STABILITY AND POTENTIAL FORMATION OF THE MASKEDTRICARBONYLUNITOF&+ INDICATEDTHATTHISFUNCTIONALITYWAS EXTREMELYSENSITIVE ESPECIALLYTOBASEMEDIATEDBENZILICACIDREARRANGE MENT; =#ONSEQUENTLY AKEYRETROSYNTHETICSTRATEGYTHATENTAILED THELATEINTRODUCTIONOFTHISSYSTEMWASADOPTED-OREOVER CONCERNFOR EPIMERISATIONOFTHECHIRALCENTREIN3 PIPECOLICACIDDICTATEDTHECHOICE OFAMACROLACTAMISATIONAPPROACHFORRINGCLOSURE)NTHISFASHION THEESTER BONDAT#COULDBEGENERATEDUNDERHIGH CONCENTRATIONCONDITIONSEAR LIERINTHESYNTHESISINAMILDFASHION ANDHOPEFULLYAVOIDANYPOTENTIAL COMPLICATIONSDUETORACEMISATIONATTHISCENTRE3CHEME  &URTHERDISSECTIONACROSS# #WASENVISIONEDTOINSTALLTHETRICAR BONYL PRECURSOR IN A REDUCED AND SUITABLY PROTECTED FORM TO LEAVE THE # # ALDEHYDE  AS THE PRINCIPLE SYNTHETIC TARGET $ISCONNECTION AT THECHALLENGINGTRISUBSTITUTEDOLEFINICLINKAGE# # THROUGHA7ITTIG TYPEOLEFINATIONSTRATEGYFURTHERSIMPLIFIEDTHEPROBLEMTOTHEPREPARATION OFTWOMAJORFRAGMENTSAND OFSIMILARCOMPLEXITYWHICHWOULD RELYHEAVILYONASYMMETRICALDOLMETHODOLOGY; =FORTHEIRCON STRUCTION3CHEME  )NITIAL PREPARATION OF THE # # FRAGMENT  INCORPORATING THE CYCLOHEXANEMOIETYUTILISEDTHECHIRALPOOLASASOURCEOFTHESTEREOCHEMI CALARRAYOFFUNCTIONALITYABOUTTHISSIXMEMBEREDRING;=4HUSLACTONE  READILYAVAILABLEFROMn QUINICACIDINONESTEP WASCONVERTEDTOBIS



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

THIOCARBONYLLACTONEINPREPARATIONFORREDUCTIVECLEAVAGEOFTHEEXTRA NEOUSHYDROXYLFUNCTIONALITYUNDERRADICALCONDITIONS!TWOSTEPPROTO COLWASFOUNDTOBENECESSARY BUTPROCEEDEDSTEREOSPECIFICALLYANDWITH GOODREGIOSELECTIVITY TOFURNISHSIMPLIFIEDLACTONE3TANDARDFUNCTIONAL GROUPMANIPULATIONSTHENAFFORDEDTHEKEYCYCLOHEXANECARBOXALDEHYDE BUILDINGBLOCKASASINGLEDIASTEREOMER&ORSUBSEQUENTINTRODUCTION OFTHE# #TRISUBSTITUTEDOLEFINTHEHOMOLOGATIONPROTOCOLINITIALLY INTRODUCEDBY#OREYANDLATERMODIFIEDBY3CHLESSINGERWASINVESTIGATED ; = %ARLY ATTEMPTS UNDER THE REPORTED CONDITIONS USING α LITHI ATED TRIETHYLSILYL T BUTYLIMINEOFTENRETURNEDUNREACTEDSTARTINGMATERIAL  ANDMOREWORRYINGLYGAVECAPRICIOUSANDLOW%:SELECTIVITYFOR !TTHISJUNCTURE THE-ERCKTEAMMADEACRITICALOBSERVATIONTHATTREAT MENTOFTHECRUDEIMINEMIXTUREWITHANHYDROUSTRIFLUOROACETICACIDPRIOR TOTHEADDITIONOFWATERAFFORDSANOPPORTUNITYFORTHEBULKYPROTONATED IMINEINTERMEDIATE TOISOMERISEANDGREATLYIMPROVEDBOTHREACTION CONSISTENCYANDSELECTIVITY;=!N%VANSALDOLCONDENSATION;=OF THERESULTINGALDEHYDEANDBORONENOLATEOFIMIDEFURNISHEDTHEDESIRED ADDUCT WITHEXCEPTIONALSTEREOCONTROL 3UBSEQUENTMANIPULA TIONSGENERATEDASECONDELECTROPHILE WHICHWASCONDENSEDWITHTHE LITHIUMENOLATEOF3 n  ACETOXY    TRIPHENYLETHANOL ;n= TOAFFORDALCOHOLWITHMODESTSELECTIVITYFORTHEDESIRED3 CONFIGURATION AT# &URTHERSTANDARDFUNCTIONALGROUPMODIFICATIONS ANDYET ANOTHER%VANSALDOLCONDENSATIONTOSELECTIVELYINSTALLTHEALLYLSIDECHAIN AT#COMPLETEDTHEASYMMETRICSYNTHESISOFTHE# #FRAGMENT OF&+ INATOTALOFSTEPS3CHEME  5PON SCALING UP THE ABOVE ROUTE A NUMBER OF SUBSTANTIAL PROBLEMS WERE ENCOUNTERED ; = 0RINCIPLE AMONG THESE WAS THE EARLY TRIBU TYLTINHYDRIDEREDUCTIONOFQUINICACIDDERIVATIVE WHICHPROVEDVERY CUMBERSOMEONLARGE SCALE4REATMENTOFCOMMERCIALLYAVAILABLE CYCLO HEXENECARBOXYLICACID WITHM#0"!FOLLOWEDBYHIGH DILUTIONTHER MOLYSIS AFFORDED HYDROXYL LACTONE  AND ALTHOUGH BOTH LOW YIELDING ANDRACEMIC THISPROVEDTOBEMORECONVENIENTFORMATERIALTHROUGHPUT &URTHERELABORATIONINASIMILARFASHIONASPREVIOUSLYDISCUSSEDUNEVENT FULLYFURNISHEDENALWHICHWASTHENSUBJECTEDTOTHEBORONENOLATEOF IMIDETOGIVETHEALDOLADDUCT INCOMPARABLEYIELDANDSELECTIVITY 4RANSAMIDATIONOFTHE%VANSALDOLADDUCTDERIVEDFROMAND FOL LOWEDBY4%3PROTECTION AFFORDEDANINTERMEDIATE7EINREBAMIDEWHEREIN



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

S

OH HO

O 34

O

a

30

O

+

TIPSO

MeO

MeO

17

19

E-20

CHO

OH Ph Ph Ph

O

H N

Z-20

E-21

O

MeO

OH Ph Ph Ph 25

O

O

N

m

18

H2O

TIPSO

OH O TESO 26

30

R TFA

34

O

30

17

+ N

23

MeO

O

R

R

N Li

26

H

26

O

30

34

h

16

SiEt3

H

TIPSO

34

d,e,f,g

O

O S 15

14

R

Im

O

TIPSO

34 30

O

O

O

HO b,c

34

OH

30

R

O2CCF3

H

i

O 18

22

TIPSO

34

j,k,l 30

MeO

34

30

H

26

N

26

OH O

O

TESO 24

O

N

O

O

23

n,o,p,q TIPSO MeO

TIPSO

34

r

MeO

30 26

TESO

23

CHO OTIPS

O

O N

TIPSO

34

s,t,u 30 23

26

O

OTIPS OH O

TESO 29

27

20

O

N

O

MeO

34

30 26

TESO

23

20

CHO OTIPS OTBS

11

28

3CHEME A THIOCARBONYLDIIMIDAZOLE   $#% REFLUX B N"U3N( XYLENES  #C N"U3N( !)". XYLENES  #  OVER TWO STEPS D 4)03/4F   LUT #(#L  # E -E-E/ .!L#L-E 0H#( OVERTWOSTEPSF -E/4F   DI T BUTYL  METHYLPYRIDINE #(#L 24G $)"!, ( 4(& n # OVERTWOSTEPSH  LITHIO  TRIETHYLSILYLPROPANALT BUTYLIMINE 4(& n #→n # THEN 4(&  # THEN(/  #  %:I  N"U"/4F $)0%! 4(& THEN n #→ #J -E-E/ .!L#L-E #(#L n #→24K 4%3/4F   LUT #(#L  #L $)"!, ( 4(& n # OVERFOURSTEPSM 3 n  ACETOXY    TRIPHENYLETHANOL ,$! 4(& n # THEN  3 2 N .A/-E -E/(  #O 4)03/4F   LUT #(#L  #P $)"!, ( 4(&  # Q 3/q0Y %T. $-3/ #(#L 24 OVERFOURSTEPSR  N"U"/4F $)0%! 4(& THEN n #→ # S -E-E/ .!L#L-E #(#L n #→24T 4"3/4F   LUT #(#L  # U $)"!, ( 4(& n # OVERTHREESTEPS

THEDIASTEREOMERSARISINGORIGINALLYFROMRACEMICCOULDBECONVENIENTLY SEPARATED/THERSUBSTANTIALCHANGESINVOLVEDTHEUSEOFCHLOROIMIDE ;=ASACHIRALACETATESYNTHONINPLACEOF$ESPITEREQUIRINGANADDI TIONALSTEPTOREDUCTIVELYREMOVETHECHLORIDE BOTHTHEYIELDANDSELECTIV ITYWEREMUCHIMPROVED!LTHOUGHNOTEXPLICITLYCLEAR ADIFFERENTSERIES OFREACTIONSWEREEMPLOYEDTOCONVERTTO PRESUMABLYASTHISWAS HIGHERYIELDING ORMORECONVENIENTWITHREGARDSTOPRODUCTISOLATIONOR PURIFICATION3CHEME /VERALL THISMODIFIEDAPPROACHTOISSLIGHTLY LONGER ENCOMPASSINGSTEPSINTOTALANDDELIVERINGTHEDESIREDPRODUCT



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

HO

34

MeO

H

g

MeO

h 30

34

Bn 30

O

N

26

O

CHO

O

N

26

17

16

MeO

O

30

O

30

TIPSO

34

34

c,d,e,f

30

O

O

TIPSO

TIPSO

34

a,b

OH

30

O

OH O

18

O

32

Bn 31 i,j,k

TIPSO MeO

TIPSO

34

30 26

TESO 11

23

20

q,r,s,t,u,v O O

CHO OTIPS OTBS

N Bn 34

MeO

TIPSO

34

30 26

O

l,m,n,o,p O O

TESO 27

23

CHO OTIPS

Cl

N Bn 33

MeO

34

30

H

26

O

TESO

O

24

3CHEME A M#0"! #(#L  #B CHLOROBENZENE  # OVERTWOSTEPSC 4)03/4F   LUT #(#L  # D !L#(  (./#( #(q(#L 0H#(  # E -E/4F   DI T BUTYL  METHYLPYRIDINE #(#L  #F $)"!, ( 4(& n #G  LITHIO  TRIETHYLSILYL PROPANAL. CYCLOHEXYLIMINE 4(& n # THEN 4(&  # THEN (/  #  OVER FIVE STEPS H  %T. N"U"/4F n # THEN  n #  I !L#(  (./#( #(q(#L #(#L  # J 4%3/4F   LUT #(#L  # SEPARATEDIASTEREOMERS OVERTWOSTEPSK $)"!, ( 4(& n # L  %T. N"U"/4F n # THEN n # M ZINC !C/( 4(& ULTRASOUNDIRRADIATION  # N !L#(  (./#( #(q(#L #(#L  # O 4)03/4F   LUT #(#L  # P $)"!, ( 4(& n # Q  %T. N"U"/4F n # THEN n # R ,I/( (/ (/ 4(&  #S CARBONYLDIIMIDAZOLE #(#L  # THEN(./#( #( #(#L  #T ,I/( (/ (/ 4(&  # OVERTHREESTEPSU 4"3/4F   LUT #(#L  # V $)"!, ( 4(& n # 

INOVERALLYIELD(OWEVER ITISAVERYPRACTICALANDROBUSTSYNTHETIC SEQUENCEANDCLEARLYDEMONSTRATESTHEUTILITYOF%VANSALDOLTECHNOLOGY FORTHECONSTRUCTIONOFPOLYKETIDESUBUNITS3CHEME  4HEAPPROACHTOTHE# #FRAGMENT WASORIGINALLYDESIGNED TO HIGHLIGHT THE UTILITY OF # SYMMETRY IN BIDIRECTIONAL SYNTHESIS ; = (OWEVER TO AID IN PRODUCT STRUCTURE DETERMINATION AND TO AVOID ADDITIONAL TERMINUS DIFFERENTIATION METHODOLOGY NEAR THE END OF THE SEQUENCE THESTEREOCENTRESWERECREATEDSEQUENTIALLY;=-ONOEPOXY BENZYLALCOHOL READILYAVAILABLETHROUGHUSEOF3HARPLESSEPOXIDATION OF   PENTADIEN  OL ;= WAS ELABORATED TO FURNISH AN INTERMEDIATE BUTYROLACTONEINGOODOVERALLYIELD%NOLISATION FOLLOWEDBYALKYLATION WITH-E)AFFORDEDWITHREASONABLESELECTIVITY FORTHEDESIRED STEREOCHEMISTRYAT#)NCONTRASTTOALLYLICALCOHOLS SUBSTRATEORREAGENT CONTROLLED EPOXIDATIONOFHOMOALLYLICALCOHOLSNOTORIOUSLYOCCURSWITH SUBSTANTIALLYDIMINISHEDSELECTIVITY; =4OADDRESSTHIS THE-ERCK GROUPEMPLOYEDATHREESTEPPROCEDUREINVOLVINGTHEINTRAMOLECULARFOR



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME A ,I#(#. 4(& n #→24B .(#L -E/( REFLUX OVERTWOSTEPSC ,$! 4(& n # →n # THEN-E) n #  DRD ,I!L( 4(& 24E  T BUTOXYCARBONYLOXYIMINO  PHENYLACETONITRILE .A( 4(&  #F "R +#/ #(#L n # OVERTHREESTEPS DR G .A/-E -E/( 24H -E) .A( 4(& 24 OVERTWOSTEPSI ,I#(#. 4(& n #→24J .(#L -E/( REFLUXK 4"3#L )M $-& 24 OVERTHREESTEPSL ,$! 4(& n #→n # THEN-E) n #  DRM ,I!L( 4(& 24N -/-"R $)0%! #(#L  #O -E) .A( 4(& 24 OVERTHREESTEPSP 4"!& 4(& 24Q 0$# $-& 24R ( 0D/(  %T/( 24S !C/ #(#L REFLUX OVERFOURSTEPS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O 18

O

N

O

18

a,b,c

OH

15

d,e

H

OPMB

18

15

44

N OPMB

N

O

45

18 13

O

Ph

O

Bn 31

f,g

OBn

O

13

TBSO OBn + 10

h,i,j,k

12

HO

O

10

12

OCH3

OH 47

49

O

O

Br

48

l

46

S

OTBS 15

S

10

OMe OMe 13

19

O PPh2

S

v,w,x

OTBS 15

S

10

OMe OMe 52

OPiv 18

r,s,t,u

OTBS 10

OTBS 15

OMe OMe 51

OPiv 18

OPMB

OTBS m,n,o,p,q 10

15

18

OBn O

OH 50

3CHEME A .A(-$3 ALLYLIODIDE 4(& n # B ,I/( (/ (/ 4(&  #C ,I!L( %T/  #→24 D .A( "N"R 4(&$-& 24 OVERTHREESTEPSE /S/ .A)/ (/ ACETONE 24 F  N"U"/4F %T. #(#L n # THEN n # G !L#(  (./#( #(q(#L 4(&0H#(  # H 4"3#L )M $-&  #I $)"!, ( 4(&0H#( n #→24OVERTWOSTEPSJ -S#L %T. #(#L n #K 4"!" ACETONE REFLUX OVERTWOSTEPSL  ,I %T/  # THEN  4(& n # M #( ."(/!C  #(#. !C/( (/ n #  DRN .A( -E) 4(&  #→24 O ( 0D/(  %T/!C 24P 0IV#L 0Y  #Q 4"3/4F   LUT #(#L  # OVERTHREESTEPSR 4&! 4(&(/  # S #/#L  $-3/ #(#L n # THEN %T. n # → n #  T #(#(3(  "&q/%T #(#L  #  U 4"3/4F   LUT #(#L  # V ,I!L( %T/  #→24 W 0H3/#L 0Y  # X 0H0/ %T N"U,I 4(& n #→ # 

STEPSANDOVERALLYIELD3CHEME -OREIMPORTANTLY ESSENTIALLY ALLSTEREOISOMERSOFAREPOTENTIALLYAVAILABLETHROUGHSIMPLEMODIFICA TIONOFREAGENTSAGOALOFSIGNIFICANTIMPORTANCEFORTHE-ERCKGROUPWHO WEREUNDOUBTEDLYINTERESTEDINSUBSEQUENTSTRUCTUREACTIVITYEVALUATION #ONVERSION OF THE ADVANCED INTERMEDIATE  TO THE DITHIANE PHOSPHINE OXIDEWASINTENDEDTOINSTALLTWOCONVENIENTSITESFORFRAGMENTCOUPLING THROUGHANIONICADDITIONANDOLEFINFORMATIONRESPECTIVELYVIDEINFRA  #OUPLINGOFTHE# #AND# #FRAGMENTSWASACCOMPLISHED BYDEPROTONATIONOFPHOSPHINEOXIDEFOLLOWEDBYADDITIONOFTHEALDE HYDEELECTROPHILE ;n=4HERESULTINGDIASTEREOMERICMIXTUREOF HYDROXYLPHOSPHINEOXIDESCOULDBECHROMATOGRAPHICALLYSEPARATEDINTO TWO MAJOR ADDUCTS AND IN TURN CONVERTED TO THE CORRESPONDING OLEFINS % AND: RESPECTIVELY THROUGHEXPOSURETOPOTASSIUMHEXAMETHYL DISILAZANE+(-$3 4HISAPPROACHTOTHE# #TRISUBSTITUTEDALKENE ALTHOUGHOVERALLLOWYIELDING ALLOWEDISOLATIONOFGEOMETRICALLYPURE%  WHICHNOTABLYISINSEPARABLEFORM: 3CHEME  4HEDITHIANEMOIETYPRESENTIN% WASINITIALLYTOSERVEASANACYL ANIONEQUIVALENTFORREACTIONWITHDIETHYLOXALATEANDEVENTUALINTRODUC



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO MeO

TIPSO

OTBS

S

15

S

19

10

O PPh2

34

30

H

34

OTBS

26 22

+

MeO

O TESO TIPS

a,b,c

30 23

26

TESO

13

20

CHO OTIPS OTBS

OMe OMe

19

Z-53

11

OMe S S

15 10

OMe OTBS

E-53

1

N CO2H Boc 12 TIPSO MeO

TIPSO

34

30

MeO

H

TIPSO

34

30

MeO

H

OTBS

26

N H H O PMBO O O

1

i,j 19

OMe 10

H 22

15

OMe OTBS

O

O O TIPS

N O Boc PMB Bn O 10 N O

O

OH 54

OTBS

26

22

O O TIPS

OTES 55

34

30

OTBS

26

22

1

d,e,f,g

1

h

O OMe

O

O 19

N

OMe

OPMB

15

OMe OTBS

N Boc

O

19

O O TIPS

Bn 10

15

OHC 10

OMe OTBS

9

3CHEME A  N"U,I 4-%$! 4(& n # THENB SEPARATEADDUCTSC +(-$3 4(&  # OVERTHREE STEPS SIMILARLY: WASPREPAREDINYIELDOVERTHETHREESTEPS D 4&! (/ 4(&  #E  $## $-!0 #(#L n #F !G./ .#3   LUT #(/(4(&  #G GLYOXYLICACIDHYDRATE !C/( #(#L OVERFOURSTEPSH  N"U"/4F %T. 0H#( n # THEN n # I ,I/(q(/ (/ 4(&(/  #J 4%3/4F   LUT #(#L  #OVERTWOSTEPS

TIONOFTHETRICARBONYLREGIONOF&+(OWEVER MODELSTUDIESREVEALED FUNCTIONALITYPRESENTELSEWHEREINTHEMOLECULEDIDNOTTOLERATESTRONGLY BASIC NOR ACIDIC CONDITIONS CONSEQUENTLY AN ALTERNATIVE WAS SOUGHT !LTHOUGHTHESTEREOCHEMICALCONTROLAT#AND#ISULTIMATELYIMMATE RIAL ABORONALDOLCHIRALIMIDE ;=STRATEGYWASVIEWEDASADVAN TAGEOUS FOR ISOLATION AND CHARACTERISATION PURPOSES AS WELL AS THE MILD REACTIONCONDITIONSINVOLVEDINTHISMETHODOLOGY4HUS PRIORINTRODUC TIONOFTHEPIPECOLICACIDMOIETYUNDERCAREFULLYCONTROLLEDCONDITIONSTO AVOIDEPIMERISATIONAT# WASFOLLOWEDBYTWO STEPDEPROTECTION;= OFTHE  DITHIANETOALDEHYDE4HISVERSATILESYNTHETICINTERMEDIATEIS ALSOAVAILABLETHROUGHEFFICIENTDEGRADATIONSTEPS OVERALLYIELD OFTHENATURALPRODUCT ANDSUPPLEMENTEDMATERIALSUPPLIESFOREND GAME ANALYSISANDANALOGUEPREPARATION;=!SYMMETRICALDOLCONDENSATION



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TIPSO

TIPSO MeO

30

MeO

H

HO

34

34

30

MeO

H OTBS

26

OTBS

26

N H H O

O O TIPS

O TIPS O

O

O

H O

26 22

a,b,c,d,e

1

f,g,h,i 19

OH

O

O

1

19

19

N

N

PMBO O

30

22

22

1

34

OMe 10

OTES 55

15

OMe OTBS

8 8

O

O TBSO

15

OMe

O

O OH H O 10

15

OMe

10

OCH3

OCH3

O

56

FK506 1

3CHEME A  CHLORO  METHYLPYRIDINIUM IODIDE %T. #(#L  #  B $$1 (/ #(#L  # C 4&! (/ 4(&  # OVERTWOSTEPSD #/#L  $-3/ #(#L n # THEN%T. n # →24E #/#L  $-3/ #(#L n # THEN%T. n #→24 OVERTWOSTEPSF (&AQ #(#.  # G 4%3#L 0Y  # H $-0 0Y #(#L  # I (&AQ #(#.  # 

OFWITHTHEBORONENOLATEOF FURNISHEDINEXCELLENTYIELD; =!LTHOUGHNOTOBVIOUS THECHOICEOF0-"PROTECTINGGROUPINIMIDE EMBODIESASUBSTANTIALAMOUNTOFPRELIMINARYSTUDYANDWASCRITICAL FOR THE FUTURE INTRODUCTION OF THE TRICARBONYL REGION SPANNING # # #LEAVAGE OF THE IMIDE UNDER STANDARD CONDITIONS TO THE FREE CARBOXYLIC ACID FOLLOWEDBYGENERATIONOFTHEFREEAMINEVIATHEMETHODOF3HIOIRI AND/HFUNE4%3/4F   LUT ; =ANDSIMULTANEOUS4%3PROTECTION AT# SUCCESSFULLYGENERATEDTHEUNSTABLEMACROCYCLICPRECURSOR IN ALONGESTLINEARSEQUENCEOFSTEPSANDOVERALLYIELD3CHEME  )MMEDIATE APPLICATION OF -UKAIYAMA CONDITIONS ;= UNDER HIGH DILUTIONCONDITIONSRESULTEDINSMOOTHFORMATIONOFTHEDESIREDLACTAM MACROCYCLEINEXCELLENTYIELD3EQUENTIALDEPROTECTIONAT#AND#VIA EXPOSURETO$$1FOLLOWEDBYAQUEOUSACIDANDTWOSUCCESSIVEAPPLICA TIONSOF3WERNOXIDATIONCONDITIONSTHENFURNISHEDTHETRICARBONYLCOM POUND INAVERYPLEASINGYIELD3ELECTIVEDESILYLATIONOFPROVED IMPOSSIBLE THUS ALL SILICON PROTECTING GROUPS WERE REMOVED WITH (& IN ACETONITRILERESULTINGINSPONTANEOUSHEMI KETALFORMATION/FTHEREMAIN INGFREEHYDROXYLGROUPS THOSEAT#AND#EXHIBITEDHIGHERREACTIVITY ANDCOULDBESELECTIVELY4%3PROTECTEDTOALLOWOXIDATIONAT#TOTHE CORRESPONDING KETONE WITH THE $ESS -ARTIN PERIODINANE $-0 ;= &INALLY DESILYLATIONONCEAGAINWITH(&FURNISHED&+ IDENTICALIN ALLRESPECTSWITHTHENATURALPRODUCT3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 3UMMARYOFTHE-ERCKTOTALSYNTHESISOF&+

)NSUMMARY THETOTALSYNTHESISOF&+ BYTHE-ERCKGROUPWAS ACCOMPLISHEDINALONGESTLINEARSEQUENCEOFSTEPSANDOVERALL YIELD4HEFIRSTTOTALSYNTHESISOFANYOFTHETRICARBONYLMACROLIDEFAMILY OFNATURALPRODUCTSTHISACHIEVEMENTSTANDSASANIMPORTANTMILESTONEIN THEFIELDSETTINGTHESTAGEFORALLFUTURESYNTHESES(IGHLIGHTSINCLUDEDAN EFFICIENTUSEOFTHE%VANSALDOLREACTIONFORTHEPREPARATIONOFVARIOUSSUB UNITS CONSTRUCTIONOFTHE# #TRISUBSTITUTEDOLEFINTHROUGHANINTER MOLECULAR7ITTIGTYPEREACTION ANDEFFICIENTFORMATIONOFTHEMACROCYCLIC RINGTHROUGHMACROLACTAMISATION!LTHOUGHNOTTHESHORTESTNORHIGHEST YIELDINGAPPROACHVIDEINFRA OVERCOMINGTHEUNEXPECTEDCHALLENGESASSO CIATEDWITHTHEFIRSTSUCCESSFULSYNTHESISSHOULDNOTBEOVERLOOKED



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

HO MeO

34

30

TIPSO

H

MeO

O

26

34

30

O

1

N 8

O

O OH H O 10

TIPSO

MeO

H

C20-C34 aldehyde 59

34

30

H

OPMB

26

22

20

26

CHO O OPMB TIPS

22

OH

O

C10-C34 aldehyde 57

19

O

OMe 15

O

FK506 1

MeO

8

+

1

19

N Boc

O

O

+

OMe

9

OMe

OCH3

N 1 O Boc OMe

O O TIPS

15

OHC 10

OMe OTBS

58

S S

(Me2N)2P O MeO

19

15

OMe OTBS C10-C19 dithiane 60 10

3CHEME 2ETROSYNTHETICANALYSIS



4HE3CHREIBERTOTALSYNTHESISOF&+

3TUART3CHREIBERANDHISRESEARCHGROUPAT(ARVARD5NIVERSITYHAVEBEEN PROMINENTPLAYERSINTHEFIELDOFIMMUNOSUPPRESSANTSANDTHEIRASSOCI ATEDIMMUNOPHILINS BOTHWITHREGARDTOTOTALSYNTHESISEFFORTSASWELLAS INVESTIGATION OF THE BIOLOGICAL MODES OF ACTION 4HIS IS APTLY ILLUSTRATED BY THEIR DISCLOSURE IN  ;= SHORTLY AFTER THE -ERCK REPORT ON THE TOTALSYNTHESISOF&+ASWELLAS# # #RADIOLABELLED &+WHICH PROVEDUSEFULTODELINEATETHEMECHANISMBYWHICHTHEROTAMASEACTIVITY OF&+"0ISINHIBITED 2ETROSYNTHETICALLY THE3CHREIBERAPPROACHTO&+ISVERYSIMILARTO THATREPORTEDBY-ERCKANDENCOMPASSESTHEMAJORITYOFALLKEYSTRATEGIC DECISIONS NAMELYALATE STAGEINTRODUCTIONOFTHETRICARBONYLREGION MAC ROLACTAMISATION ANDAMODIFIED(ORNERREACTIONFORFRAGMENTCOUPLINGAND CONSTRUCTION OF THE # # TRISUBSTITUTED OLEFIN 3CHEME   (OWEVER THEREARECONSIDERABLEDIFFERENCESINTHEWAYTHATTHEINDIVIDUALFRAGMENTS AREPREPARED#OMPAREDWITHTHE-ERCKSYNTHESIS THEREISANOTICEABLELACK OFASYMMETRICALDOLREACTIONS ANDINDEEDAMORECONVERGENTAPPROACHTO FRAGMENTSYNTHESESRESULTSINASIGNIFICANTLYSHORTERAPPROACH 3CHREIBERSSYNTHESISOFTHE# #ALDEHYDEBEGINSSIMILARLYTOTHE INITIAL -ERCK SYNTHESIS OF THE # # FRAGMENT 3CHEME  ;= )N THISCASE 3HARPLESSEPOXIDATIONOFFOLLOWEDBYPROTECTIONOFTHEMONO EPOXYALCOHOLWITH0-""RUNDERCAREFULLYCONTROLLEDCONDITIONSTOAVOID THEFORMATIONOF0AYNEREARRANGEMENT;=PRODUCTSFURNISHEDINGOOD YIELD2EGIOSELECTIVERING OPENINGWITHTHEANIONOFETHOXYACETYLENEAS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

OEt OH 34

c,d

32

31

O

OH

28

g

31

34

O

31

34

34

OMe

OMe 64

OMe 63

62

61

EtO2C

e,f

OPMB

34

32

O

28

28

OPMB

a,b

65

h,i TBSO

HO

34

m

31 28

MeO

MeO

70

k,l 28

SO2Ph

OMe

HO

34 31

34

28

MeO

SO2Ph 69

OH 68

34

j

31

31

O

31

34

CO2H

MeO

28

28

TBSO

67

66

3CHEME A ,  $)04 4I/I0R  T"U//( ¯-3 #(#L B 0-""R .A( 4(&  # C ,I#≡#/%T "&q/%T n #D .A( -E) 4(&  #→24 OVERTWOSTEPSE (G#L %T/( 24F $$1 (/ #(#L 24 OVERTWOSTEPSG P4S/( ¯-3 0H( 24 H 4"3/4F %T. #(#L n # → #I 0H#(  # OVERTWOSTEPSJ "(q4(& 4(& n #→24 THEN(/ .A/( 24 K 0H0 0Y ) 0H(  # L .A3/0H $-&  #M 4"3#L %T. #(#L  #→24 OVERTWOSTEPS

ANALTERNATIVETOANACETICACIDDERIVEDANIONOCCURREDSMOOTHLYINTHE PRESENCEOF"&q/%TTOAFFORDANUNSTABLEALCOHOLWHICHWASIMMEDIATELY METHYLATEDTOALKYNYLETHER#ONSTRUCTIONOFTHECYCLOHEXYLRINGWAS ACCOMPLISHED VIA AN INTRIGUING )RELAND #LAISEN ;n= APPROACH FOR TRANSFEROFSTEREOCHEMICALINFORMATIONFROMTHEREADILYPREPAREDLACTONE 3UBJECTINGTHERESULTINGCARBOXYLICACID TOANEXCESSOF"(q4(& RESULTEDINBOTHREDUCTIONANDTHEREGIO ANDSTEREOSELECTIVEINTRODUCTION OF A HYDROXYL GROUP AT #  ;= #OMPARISON WITH A DEGRADATION PRODUCT;=FROM&+CONVENIENTLYCONFIRMEDTHECORRECTSTRUCTUREFOR PRIMARYALCOHOLWHICHWASFURTHERTRANSFORMEDTOSULFONEWITHOUT INCIDENT3CHEME  5NION OF SULFONE  WITH AN APPROPRIATE ELECTROPHILE WAS ORIGINALLY INTENDEDTOCONSTRUCTTHE# #TRISUBSTITUTEDOLEFINTHROUGHANEVEN TUALDEHYDRATIONPROTOCOL&ORTHISPURPOSE ALDEHYDEWASPREPAREDFROM THEREADILYAVAILABLEβ KETOESTERASDISPLAYEDINSCHEME!SYMMETRIC CATALYTICREDUCTIONUNDER.OYORISCONDITIONS;=PROVIDEDβ HYDROXY ESTERWITHEXCELLENTENANTIOCONTROLEE WHICHWASSUBJECTEDTO &RATER 3EEBACHALKYLATION; =WITHALLYLBROMIDETOFURNISHAS ASINGLEDIASTEREOMER!SERIESOFPROTECTINGGROUPMANIPULATIONSWHICH INCLUDEDMASKINGTHEALLYLGROUPASANIODOETHER ANDFINALLYOXIDATION FURNISHEDALDEHYDE/FTHENUMEROUSMETHODSTOEFFECTASYMMETRIC



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O MeO

O

OPMB a

O MeO

24 20

OH OPMB

O b

MeO

24

c,d,e,f,g

24 20

SnPh3

Me

PMBO

OH OPMB

O H

20

O

24

H

20

TESO

72

26 24

I

73

74

76

i,j,k,l,m,n

PMB O O

20

OH

O

I 71 3 steps ~45%

PMBO 20

75 h

Ph s,t

CHO

24

PMBO

O

O

TESO

PMBO

r

20

O

HO

27

PMBO

o,p,q

O

20

OAc

24

27

Ph

Ph

Ph

O

O

20

OAc

24

O

O

CHO

24

27

27

I

TBSO u,v,w

34 31

MeO

70

TESO 20

PMB O O

28

SO2Ph

Ph

O

H

x,y

OMe 28

24

O H34 81

77

78

79

80

31

TESO

PMB O O

Ph

O 28

20

OMe

24

H 34

OTBS 82

O

z,aa 31

PMB O O

Ph

O 28

H

20

OMe

24

H 34

OTBS

31

OTBS

83

3CHEME A 2U#L;3 BINAP= %T. (PSI -E/( 24  EEB ,$! 4(& n # THEN ALLYLBROMIDE (-0! n #→24 C ,I!L( 4(&  #→24 D $$1 ¯-3 #(#L 24 E ) .A(#/ #(#.  #→24F $)"!, ( #(#L n # OVERTWOSTEPS MIXTUREOFIODOMETHYLDIASTEREOMERS G #/#L  $-3/ #(#L n # THEN%T. n #→24 H  "&q/%T #(#L n #  DRI 4"3/4F %T. J / #(#L THEN 0H0K VINYL'RIGNARD #(#L  DRL N"U.&M 0H#(/ P4S/(N / $-3 +#/ O .A"(P !C/ %T.Q :N .(#LR 4%3/4F %T.S +#/ -E/(T #/#L  $-3/ #(#L n # THEN%T. n #→24U  N"U,I 4(& n # THEN n #→ #V $-0 #(#L 24W .A(G .A(0/ 4(& -E/( n # OVERTWOSTEPSX -E-G"RY "URGESS REAGENTZ N"U.&AA #/#L  $-3/ #(#L n # THEN%T. n #→24

.OYIELDSORFURTHEREXPERIMENTALDETAILSREPORTED

CROTYLATIONOFCHIRALORACHIRALALDEHYDES 3CHREIBERENJOYEDMOSTSUCCESS WITHSTANNANEINTHEPRESENCEOF"&q/%TWHICHAFFORDEDTHEDESIRED ALCOHOL ASASINGLEIODOMETHYLDIASTEREOMER;=&URTHERELABORA TIONTOANDATTEMPTEDANIONICCOUPLINGWITHSULFONEFAILEDUNDER STANDARD CONDITIONS DUE TO THE PRESENCE OF THE IODOMETHYL GROUP .O SUITABLESOLUTIONCOULDBEFOUND ANDCONSEQUENTLYARATHERLENGTHYSERIES OFMANIPULATIONSCONVERTEDTOELECTROPHILE WHICHWHENCOMBINED WITHLITHIATEDAFFORDEDAFTEROXIDATIONANDDESULFONYLATIONTHEDESIRED KETONE!DDITIONOF-E-G"RTHENGENERATEDATERTIARYALCOHOLWHICH COULDBESUBSEQUENTLYDEHYDRATEDBYUSAGEOFTHE"URGESSREAGENTTOAFFORD TRISUBSTITUTEDALKENE;=.EITHERYIELDNORSELECTIVITYINTHISTRANS FORMATIONWASREPORTED ALTHOUGHEARLIERMODELSTUDIESHADREVEALEDTHAT



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

MeO2C

28

OMe

a,b

MeO2C

28

OMe 31

31 34

84

34

OTIPS

85

c,d

OHC

28

OMe 31

34

OTIPS

17

28

OMe

e,f

31 34

OTIPS

86

g

Br

28

OMe 31 34

OTIPS

87

3CHEME A "(q4(& 4(& n #→ # THEN.A/( (/  #→24 B 4)03/4F %T. #(#L  # →24 C ,I!L( 4(&  # D #/#L  $-3/ #(#L n # THEN%T. n #→24 E T"U/+ .#(0/ /-E  4(& n # THEN n #→n # F N"U,I 4(& n # →n # THEN-E) n # G #P:R( #L 0H(  # THEN. BROMOSUCCINIMIDE 24 

SUCHASTRATEGY ALTHOUGHSUCCESSFUL AFFORDSONLYMODERATESELECTIVITYIN FAVOUROFTHE% OLEFIN^ &URTHERELABORATIONTOTHEFULLYFUNCTIONALISED # #FRAGMENT WASREADILYACCOMPLISHEDUSINGSTANDARDMETHOD OLOGY3CHEME ALTHOUGHONCEAGAINNOYIELDSWEREREPORTED 4HIS ROUTE WAS ULTIMATELY ABANDONED DUE TO ITS LENGTH INABILITY TO DIFFERENTIATETHE#AND#HYDROXYLGROUPS ANDPERHAPSINEFFICIENT FORMATIONOFTHECRUCIALTRISUBSTITUTEDOLEFIN 4HE ALTERNATIVE APPROACH TO THE # # FRAGMENT  REPORTED BY 3CHREIBERWASBASEDUPONTHESTEREOSELECTIVEADDITIONOFAVINYLMETALSPE CIESTOA#ALDEHYDE FORMINGTHE# #BONDINSTEAD ANDTHUSALLOW INGPRIORREGIOSELECTIVEFORMATIONOFTHETRISUBSTITUTEDOLEFIN4OACHIEVE THIS 3CHREIBERFIRSTSOUGHTASYNTHESISOFTHE# #VINYLBROMIDE THROUGHANEXTENSIONTOHIS)RELAND #LAISENAPPROACHFORTHECYCLOHEXYL MOIETYOF&+;=!CCORDINGLY STRAIGHTFORWARDMANIPULATIONOF TOALDEHYDEWASFOLLOWEDBYEFFICIENT HIGH YIELDINGINSTALLATIONOFTHE TERMINAL ALKYNE USING THE 3EYFERTH DIAZOPHOSPHONATE REAGENT IN METH ODOLOGY DEVELOPED BY #OLVIN AND 'ILBERT ;= 3TANDARD METHYLATION OFTHEALKYNETHENALLOWEDFORMATIONOFTHEDESIRED% BROMOOLEFINVIA TREATMENTOFWITH3CHWARTZREAGENT; =ANDSUBSEQUENTTRAPPING OFTHEINTERMEDIATEVINYLZIRCONIUMSPECIESWITHANELECTROPHILICSOURCE OFBROMINE."3 TOAFFORDINATOTALOFSTEPSANDOVERALLYIELD 3CHEME  4HEDESIREDCOUPLINGPARTNERFORVINYLBROMIDE ALDEHYDE WAS EASILY PREPARED FROM ALLYLIC ALCOHOL  3CHEME   3ILYL PROTECTION OF THE#ALCOHOL FOLLOWEDBYCHEMOSELECTIVEOZONOLYSISLIBERATED4HE PRESENCE OF PYRIDINE IN THIS OZONOLYSIS WAS ESSENTIAL IN MODERATING THE REACTIVITYOFTHEOZONEANDPREVENTINGANYOXIDATIVEREMOVALOFTHE# 0-"ETHER BYOXIDISINGITSELFPREFERENTIALLYTOPYRIDINE . OXIDE!DDITION



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

I

a,b

24

20

Br

PMB TIPS O O O

PMB OH O

O 76

24

20

28

OMe

PMB TIPS O O OH

31

H 34

OTIPS

28

87

H

O

c

I

20

OMe

24

31

H 34

88

OTIPS

89

I

d

PMB TIPS O O O O

N Boc H O 28

H

20

OMe

24

31

H 34

59

PMB TIPS O O O

f

OTIPS

20

HO

N Boc H O

OMe 31

H 34

91

N Boc H O 28

28 24

PMB TIPS O O O

e

O

20

OMe

24

31

H 34

OTIPS

I

OTIPS

90

3CHEME A 4)03/4F %T. #(#LB / 0Y #(#L -E/( THEN-E3 24 OVERTWOSTEPSC  T"U,I 4(& n # THEN-G"R THEN n #→24 αβ D . "OC , PIP $##  PYRRO LIDINOPYRIDINE #(#L n # E :N .(#L %T/(AQ  # F #/#L  $-3/ #(#L n # THEN%T. n #→24 

TOACOLDSOLUTIONOFTHEVINYL'RIGNARDDERIVEDFROMVIAINITIALLITHIUM HALOGENEXCHANGEFOLLOWEDBYTRANSMETALLATIONWITH-G"R GAVEAREA SONABLEYIELDOFDIASTEREOMERICPRODUCTS0LEASINGLY THISSEPARABLEMIXTURE WASWEIGHTEDINFAVOUROFTHEDESIREDα CARBINOL^ ASPREDICTED INA#RAM SELECTIVEADDITION#RUCIALLY THISAPPROACHNOWALSOALLOWED DIFFERENTIATION OF THE # AND # ALCOHOLS WITH THE FORMER ALREADY PROTECTEDASTHE4)03ETHER7ITHTHISINPLACE THE#HYDROXYLCOULDBE SELECTIVELYACYLATEDUSINGREADILYAVAILABLE. "OCPROTECTED3 PIPECOLIC ACIDUNDERSTANDARDCONDITIONS&INALLY UNMASKINGTHEALLYLSIDECHAINON TREATMENTWITHZINCAND3WERNOXIDATIONOFTHERESULTANTPRIMARYALCOHOL  COMPLETEDAMUCHMOREEFFICIENTSYNTHESISOFTHE# #FRAGMENT  INATOTALOFSTEPSANDOVERALLYIELD3CHEME  4HECOUPLINGPARTNERFORTHE# #ALDEHYDEWASTHE# #PHOS PHONATE ANDITWASANTICIPATEDTHATTHESECONDTRISUBSTITUTEDOLEFIN BETWEEN#AND# WOULDBEINSTALLEDINA(ORNER TYPEOLEFINATION BETWEENTHESETWOFRAGMENTS&ORTHESYNTHESISOF 3CHREIBERCHOSETO APPLYATWODIRECTIONALSTRATEGY; = TAKINGADVANTAGEOFTHELATENT # SYMMETRYOFTHE#METHYLAND#METHOXYGROUPSABOUT#TO THOSEAT#AND# RESPECTIVELY4HEREFORE BYSTARTINGFROM# SYM METRIC ARABITOL  HE WAS ABLE TO RAPIDLY AND EFFICIENTLY BUILD UP  3CHEME ;=



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

O

O

OH OH

AcO

C(O)Cl 93

O

O 15

15

a,b,c

OH OH OH

O

d,e

O

O

OMe OMe

g,h,i

10

MeO2C

15

OTBS 95

94

O

O

f

10

15

OTBS

92

O

CO2Me

15

10

OBn

OTBS 96

97

j,k

(Me2N)2(O)P

10 19

15

n,o,p,q

10 15

O OTBS

60

S

OMe OMe

OMe OMe

OMe OMe OMe OMe

S

m

MeO2C

l

15

O

S

MeO2C

15

O

10

10

S

O

100

99

OH

98

O

3CHEME A α ACETOXYISOBUTYRIC ACID CHLORIDE #(#.  # → 24  B .A/-E 4(&  # → 24  C 4"3#L .A(  #→24 D (##/%T N"U,I 4(& n # THEN "&q/%TE (G#L P4S/( %T/( REFLUX OVERTWOSTEPSF I0R.( N"U,I 4(& n # THEN THEN-E) n #→n # G (& #(#.H "N4#! 4F/( #(#LCHEX OVERTWOSTEPSI .A/( -E/( 4(&.A( -E) $-&  #→24 J ( 0D/(  %T/!C K 0043 #(#L  BRSM L ,nSELECTRIDE 4(& n #M   PROPANEDITHIOL "&q/%T #(#L n #→24 OVER TWOSTEPSN ,I!L( 4(&  # O 0H0 ) 0Y 0H(  #→24 P 4"3/4F %T. #(#L  # Q #(#(0/ .-E  N"U,I 4(& n #→ # THENALKYLIODIDEDERIVEDFROM n #→ # 

"IS EPOXIDEREADILYAVAILABLEFROMCOMMERCIALLYAVAILABLEARABITOL BYTREATMENTWITHTHE-OFFATTREAGENT;=ANDTHENACETATEHYDROLYSIS WASOPENEDREGIOSELECTIVELYATBOTHOXIRANERINGSWITHANETHOXYACETYLIDE ANION GIVINGASPECIESTHATRECYCLISEDINSITUONWORKUPWITHWEAKACIDTO THECORRESPONDINGFIVE MEMBEREDLACTONE3CHEME -ETHYLATION OFTHELITHIUMENOLATEOFTHENOCCURREDTHROUGHSUBSTRATECONTROLTO INSTALLTHE#AND#METHYLGROUPSWITHHIGHDIASTEREOFACIALSELEC TIVITYWITHANUNIDENTIFIEDMINORISOMER !FTERPROTECTINGGROUP SWAPOFTHE#HYDROXYLGROUP METHANOLYSISOFTHEBIS LACTONEOCCURRED WITH CONCOMITANT METHYLATION OF THE # AND # HYDROXYLS GIVING  WHEREIN THE # SYMMETRY IS STILL PRESENT 4HIS WAS NOW EXPLOITED AFTERUNMASKINGTHE# /(USING0EARLMANSCATALYST TREATMENTWITH 0043 PROMOTED A SELECTIVE RECYCLISATION TO GIVE THE DESIRED LACTONE  7HEN  ADOPTS A CHAIR CONFORMATION ALL SUBSTITUENTS ARE EQUATORIAL GIVINGRISETOTHESELECTIVITY VERSUSTHESTEREOISOMERWHICHPLACESTHE BULKY# #SUBSTITUENTAXIAL;=(AVINGDIFFERENTIATEDTHETERMINI SUCCESSFULLY LACTONE  WAS CLEAVED VIA REDUCTION AND TRAPPING OF THE RESULTANT ALDEHYDE AS THE DITHIANE    PROPANEDITHIOL "&q/%T  &INALLY ASERIESOFSTANDARDTRANSFORMATIONSCONVERTEDLACTONETOTHE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TIPSO MeO

34

30

OPMB

26

N

OMe OMe (Me2N)2(O)P

10 19

15

OTBS

S

S

O +

60

PMB TIPS O O O

22

Boc a

O 28

H

20

O TIPS O

O 1

OMe

24

31 34

N Boc

OTIPS

59

19

TBSO 15

S 10 S 101

OMe

OMe

8

O MeO

HO MeO

MeO

30

30

O

N 8

O

O OH H O 10

O

e,f,g,h,i

1

19

O TIPS O

22

O 19

OMe

O

8

DMBO

1

d

N Boc

N

OMe FK506 1

OPMB

26

22

OH O

1 26

30

OPMB

26

22

O

34

34

MeO

b,c

58

TIPSO

TIPSO

34

OMe

CO2Me

TBSO 15

OMe

TESO 103

HO2C 8

19

TBSO 15

DMBO

10

OMe

O TIPS O

10

OMe

OMe

OH

102

3CHEME A  N"U,I n #→ # THEN(-0! n # THEN n #→ #0H-E REFLUX B  0H)/#/#&  -E/( #(#L(#/ #/( !C/( #(#L 24→ # C I0R.( N"U,I 4(& →n # THEN THENALDEHYDEDERIVEDFROM THEN,I/( n #→24D   LUT #(#L  # THEN 4%3/4F THEN 3I/ 24  . METHYL  CHLOROPYRIDINIUM IODIDE %T. #(#L E 4&! 4(& (/ F $-0 #(#LG $$1 T"U/( P(BUFFER OVERSIXSTEPSH $-0 #(#L I (& #(#. 

PRIMARYALKYLIODIDE WHICHWASDISPLACEDUSINGTHELITHIUMSALTOFETHYL BISDIMETHYLAMINO PHOSPHONAMIDETOGIVETHEDESIREDPHOSPHONAMIDE REAGENT3CHEME  7ITHTHETWOKEYFRAGMENTSOF&+NOWCOMPLETED 3CHREIBERSATTEN TIONTURNEDTOHISENDGAMESTRATEGY+EYTOTHISWASTHEINITIALCOUPLING OFANDTOFORMTHE# #TRISUBSTITUTEDOLEFIN(OWEVER ONADDI TIONOFTHELITHIUMANIONOFTOALDEHYDEANDSUBSEQUENTTHERMAL ELIMINATION OF THE MAJOR DIASTEREOMER PAIR 0H-E  # OLEFIN  COULDONLYBEOBTAINEDASTHEDESIREDISOMERINADISAPPOINTINGYIELD 3CHEME  4HEINITIALADDITIONALSOGAVERISETOASECONDPAIROFDIASTEROEOMERS WHICHONHEATINGGAVERISETOTHE: OLEFIN ALTHOUGHTHEIRQUANTITIES DO NOT ACCOUNT FOR THE BULK OF THE MATERIAL 4HIS WAS UNDOUBTEDLY A



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

SIGNIFICANT PROBLEM IN THE SYNTHESIS ALTHOUGH THIS RESULT SHOULD NOT HAVEBEENCOMPLETELYUNEXPECTEDTHE-ERCKGROUPHADSIMILARTROUBLES IN THE FIRST TOTAL SYNTHESIS OF &+  YIELD OF THE DESIRED OLEFIN ANDINDEEDFRAGMENTCOUPLINGSTOFORMTRISUBSTITUTEDOLEFINSWITHANY RESPECTABLE STEREOCONTROL OR YIELD ARE NOTORIOUSLY DIFFICULT IN NATURAL PRODUCTSSYNTHESES .EVERTHELESS THE UNION OF  AND  ALLOWED 3CHREIBER TO PROCEED TOWARDS&+5NMASKINGTHE#ALDEHYDEWASACHIEVEDINATWO STEP PROCEDURE VIA THE DIMETHYLACETAL IN  YIELD WITH STANDARD ONE STEP PROCEDURESGIVINGATBEST4HEFINALTWOCARBONSOFTHENATURALPROD UCTWERETHENINSTALLEDUSINGANALDOLREACTIONWITHTHELITHIUMENOLATE OF  TWO STEPS FROM COMMERCIALLY AVAILABLE α BROMOACETIC ACID AND THE ALDEHYDE DERIVED FROM  GIVING AN INCONSEQUENTIAL MIXTURE OF DIASTEREOMERS!TTHISSTAGETHE# # #RADIOLABELLEDANALOGUEWASALSO PREPAREDVIAINCORPORATIONTHROUGHUSEOFCOMMERCIALLYAVAILABLE#  α BROMOACETICACID3CHEME  (YDROLYSISOFTHEALDOLADDUCT FOLLOWEDBYSILYL MEDIATEDREMOVALOF THE. "OCPROTECTINGGROUPTHENENABLEDSTANDARD-UKAIYAMAMACROLAC TAMISATION;= TOGIVETHEPARENTMACROCYCLEOFTHEIMMUNOSUPPRESSANT &+INREASONABLEOVERALLYIELDFROMALDEHYDE&INALLY ADELICATE ANDORDER SENSITIVESERIESOFPROTECTINGGROUPMANIPULATIONSANDOXIDA TIONSWEREACHIEVED RETURNINGTHENATURALPRODUCTANDCOMPLETINGTHE SECONDTOTALSYNTHESISOF&+ )NCOMPLETINGHISTOTALSYNTHESISOF&+ 3CHREIBERUNVEILEDASTRAT EGYVERYSIMILARTOTHATSUCCESSFULLYACCOMPLISHEDBYTHE-ERCKGROUP )NDEED WITH THE SAME MAJOR DISCONNECTIONS OF THE NATURAL PRODUCT 3CHREIBERSAPPROACHONLYREALLYDIFFERSATTHEHIGHESTLEVELINWHATSTAGE THE PIPECOLATE MOIETY IS INSTALLED .EVERTHELESS THERE IS CONSIDERABLE DIFFERENCEINTHEINDIVIDUALPREPARATIONOFTHEKEYFRAGMENTSTHE-ERCK GROUP PLACED A STRONG EMPHASIS ON THE UBIQUITOUS AND RELIABLE ASYM METRIC ALDOL REACTION PARTICULARLY THAT OF %VANS ; = WHILE THIS IS NOTICEABLY ABSENT ABOVE !S A RESULT THE SECOND SYNTHESIS OF &+ FEATURESAGREATERVARIETYOFINTERESTINGMETHODOLOGY0ARTICULARLYNOTICE ABLEARETHEFIRSTUSEOFTHE)RELAND #LAISENREARRANGEMENTINTHESYNTHESIS OFTHISCLASSOFNATURALPRODUCTSFORTHECONSTRUCTIONOFTHECYCLOHEXYL MOIETY ANDTHEEXPLOITATIONOFTHELATENT# SYMMETRYAROUNDTHE# HYDROXYLGROUPINATWO DIRECTIONALSYNTHESISOFTHE# #PORTION



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME 3UMMARYOFTHE3CHREIBERTOTALSYNTHESISOF&+

OFTHEMOLECULE(OWEVER SUCHASTRATEGYWASINEVITABLYDISADVANTAGED FROMTHEOUTSET WITHTHEKEYDISCONNECTIONACROSSTHE# #TRISUB STITUTEDOLEFINALWAYSGOINGTOPROVEPROBLEMATICINTHEFORWARDSENSE 4HELOWYIELDFORTHISREACTIONnANDCRUCIALLYFOROTHERKEYSTEPSnISDIS APPOINTING ANDMARSTHESYNTHESISSOMEWHAT.EVERTHELESS 3CHREIBER HASREPORTEDACONSIDERABLYSHORTERAPPROACH ASWELLASAHIGHEROVERALL YIELD3CHEME  &URTHERMORE 3CHREIBERSACHIEVEMENTSINHISWORKON&+ARESIGNIFI CANT0ROBABLYMOSTIMPORTANTINHISSTRATEGYWASTHEABILITYTOINCORPORATE # LABELSAT#AND# ANDTHEPREPARATIONOFTHISRADIOLABELLEDANALOGUE OF &+ HAS LED TO A DRAMATIC IMPROVEMENT IN THE UNDERSTANDING OF THEMODEOFACTIONOFTHISIMMUNOSUPPRESSANT4HESIGNIFICANCEOFTHIS ADVANCEMENTSHOULDNOTBEUNDERESTIMATED



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS



4HE)RELANDTOTALSYNTHESESOF&+

)N THE LATE S 2OBERT )RELAND DISCLOSED DETAILS OF TWO SEPARATE TOTAL SYNTHESESOF&+ WITHINTWELVEMONTHS;n=4HESEPUBLICATIONS WERETHECULMINATIONOFMANYYEARSOFINVESTIGATIONINTOTHECHEMISTRYOF THISFORMIDABLEMOLECULEWITHINHISLABORATORIESATTHE5NIVERSITYOF6IR GINIA WHICHALSOGAVERISETOAFLEXIBLESYNTHESISOF&+ !.!, ANANALOGUE COMPRISINGTHE  ACETONIDEOF  DIHYDRO &+;= 7HILE)RELANDSTWOSYNTHESESOF&+ CANBEDIFFERENTIATEDSOME WHAT BY THEIR KEY DISCONNECTIONS AND THEIR ALTERNATIVE APPROACHES TO SOME OF THE FUNCTIONALITY WITHIN THE MOLECULE THERE IS UNSURPRISINGLY CONSIDERABLEOVERLAPACROSSBOTHSTRATEGIES5BIQUITOUSISASTRONGEMPHA SISONTHEUSEOFSPIROENONES ANDTHECORRESPONDINGFUNCTIONALISEDSPIRO KETALS ASPRECURSORSTOTHEα ALLYLALDOLSYSTEM# # VIAFRAGMENTA TION METHODOLOGYDEVELOPEDPREVIOUSLYBY)RELAND!SEXPECTED SOME OFTHEKEYFRAGMENTSAREALSOPREPAREDINASIMILARFASHION ASISTHECASE ACROSSMANYOFTHEPUBLISHEDSYNTHESESOFTHESERELATEDNATURALPRODUCTS .EVERTHELESS TOREALISETWOSEPARATEANDCOMPLETEROUTESTOAMOLECULE SUCHAS&+ ISAFANTASTICACHIEVEMENTWITHINTHEFIELDOFNATURAL PRODUCTSSYNTHESES &ORTHEPURPOSEOFTHISREVIEW THEFOCUSWILLBEPREDOMINANTLYONTHE SECONDOF)RELANDSTOTALSYNTHESES ARGUABLYTHEMOREEXCITINGANDTHOR OUGHOFTHETWO(OWEVER DETAILSOFHISOTHERWORKAREPRESENTEDAFTER THIS

 )RELANDTOTALSYNTHESESOF&+0ART/NE 4HUS IN )RELANDDISCLOSEDDETAILSOFTHEFOURTHANDHISSECOND TOTAL SYNTHESISOF&+ ; =4HESYNTHETICSTRATEGYWASANATTRACTIVE COMBINATION BORN OUT OF METHODOLOGIES DEVELOPED WITHIN THE )RELAND GROUP ANDBENEFITINGFROMPREVIOUSDISCOVERIESBYTHE-ERCKGROUP AND OTHERS INTHEIREFFORTSTOSYNTHESISETHISPOTENTIMMUNOSUPPRESSANT 3PECIFICALLY THEREWEREANUMBEROFKEYCONCERNSIDENTIFIEDBY)RELAND THATDICTATEDTHERETROSYNTHESIS!FINALMACROCYCLISATIONWASENVISAGEDVIA AMIDEBONDFORMATION THUSAVOIDINGTHEPUBLISHEDDIFFICULTIESINATTEMPT INGMACROLACTONISATION; = ANDCRUCIALLYTHECONFIGURATIONALLYLABILE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

HO MeO

34

TBDPSO 30

TBDPSO

34

34

H O

24

1

22

O

CO2H N Boc + 12

OH 1

MeO

O

OTES 30

H

8

O

O OH H O 10

O

OMe OMe

FK506 1

O

26

CO2Et H O

O O

15

OMe

H

105

O O PMB

CHO

MeO

21 8

N

26

21 16

CO2Et H 15 O CHO

O

OMe

C8-C34 spiroketal 104

Br +

8

O

O O

27

+

OTBS

O O PMB 107

OMe

106

3CHEME 2ETROSYNTHETICANALYSIS

#STEREOCENTREWITHIN&+ NECESSITATEDLATE STAGEINTRODUCTIONOF THEPIPECOLATEMOIETY 3CHEME  &URTHERMORE THEMASKEDTRICARBONYLUNITWASBYTHISPOINTKNOWNTO BEEXTREMELYSENSITIVEWITHAPROPENSITYFOR# #BONDCLEAVAGE;   = ANDASARESULT)RELANDCHOSEINSTEADTOPURSUEALESSELECTROPHILIC # /(ANALOGUE"YANALOGYWITHTHENATURALPRODUCTPEDERIN THE GROUPSOUGHTTOAPPLYANDEXTENDMETHODOLOGYDEVELOPEDBY-EINWALD FORTHEIRSYNTHESISOFTHETOXICVESICANT;= WHEREINHYDROLYSISOFSPIRO KETALACETONIDEREVEALSAFTERMANIPULATIONANα HYDROXY β KETOAMIDE ACETAL SIMILARTOTHATIN&+3CHEME  4HE # # β HYDROXY KETONE ALSO IMPARTS INSTABILITY BOTH UNDER ACIDIC AND BASIC CONDITIONS ;= !S DISCUSSED )RELAND LOOKED TO TAKE ADVANTAGEOFTHEα ALLYLGROUP# BYINCORPORATINGITINTOTHEPROTECT INGGROUPSTRATEGY USINGMETHODOLOGYTHATHADBEENDEVELOPEDPREVIOUSLY INTHEGROUPANDTHATWASBASEDONTHATOF&ßRSTNER4HEREIN FRAGMENTA TIONOFFUNCTIONALISEDSPIROKETALSOFTHETYPEINDIRECTLYDELIVEREDTHE α ALLYLALDOLSYSTEMINTHECORRECTOXIDATIONSTATE;= 4HUS DECONSTRUCTION OF  REVEALED COMMERCIALLY AVAILABLE 3 PIPE COLICACIDAND THELATTEROFWHICHWASDISCONNECTEDFURTHERACROSS # #AND# #VIAANTICIPATEDCARBANIONICCOUPLINGS GIVINGTHREE IMMEDIATETARGETS AND 4HESYNTHESISOF# #TRICARBONYLPRECURSORBEGANWITHSTANDARD CARBOHYDRATECHEMISTRYTOCONVERTMETHYLα $ GLUCOSIDE TOALCOHOL  IN  STEPS  ;n= TAKING ADVANTAGE OF THE INEXPENSIVE READILYAVAILABLESOURCEOFCHIRALITYTHATSUGARSAFFORD$EOXYGENATIONOF THEFREEALCOHOLWASACHIEVEDVIAPREPARATIONOFTHEUNUSUAL# PHOS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

O

O

O

O

OH

a,b

OH

O

CO2Et

CO2Et

OMe

O

OMe O

CONH2

c,d

OH

OH

ArSe

HO

O

OMe OMe

OH

109

108

OMe N H

110

pederin 111

3CHEME A O NITROPHENYLSELENOCYANATE N"U0 4(&  # B !C#L -E/( C (/ 4(&  #→24 D SEPARATION.( -E/( → # 

O

MeO

H

10

HO

15

OH OH 112

O

MeO

OH

H

6 steps 56%

O

15

O

10

O

10

H

O

MeO 15

a,b Ph

Ph

O O

O

O

MeO

c

15

OH

OH

P Me2N NMe2

OH 113

H

10

115

114 d,e,f,g 8

8

CO2Et O H 15 CHO O O 10

k,l

CO2Et O H O O 10

i,j

15

OBn

THPO HO

CO2Me 15 O H 10

118

h

O

O

H

15

OBn

10

OBn

OMe OMe

OMe

OMe 106

8

117

116

3CHEME A N"U,I $-% 4-%$!  # THEN#L0/.-E  #→24B (.-EC ,I %T/( %T.( 4(&  # OVERTHREESTEPSD .A( "N"R 4(&  # E .A( -E) 4(& F !C/( (3/ (/  #G !C/ $-3/ OVERTWOSTEPSH ,$! 4(& 4(0/#(#/#( n #I 0043 4(& (/  #J #(#/#( 0/ OVERTWOSTEPSK ( 0D/(  %T/( L $-0 #(#L 

PHORODIAMIDATE  USING A MODIFIED PROCEDURE ; = FOLLOWED BYDISSOLVINGMETALREDUCTION,I%T.( THATOCCURREDWITHCONCOMITANT CLEAVAGEOFTHEBENZYLIDENEACETAL FURNISHINGDIOL!FTERINSTALLATION OF THE BENZYL AND METHYL ETHERS HYDROLYSIS OF THE METHYL ACETAL AND !LBRIGHT 'OODMANOXIDATION;=COMPLETEDASIMPLE SCALABLEAPPROACH TOLACTONE3CHEME  )NTRODUCTION OF A KETAL ESTER INTO LACTONE  PROVED UNEXPECTEDLY PROBLEMATICDUETOSTERICHINDRANCE!FTERCONSIDERABLEEXPERIMENTATION THE ADDITION OF TETRAHYDROPYRANYL ETHYL GLYCOLATE WAS ACHIEVED TO GIVE ADDUCT THATCOULDBEPROTECTEDASTHEACETONIDEANDOXIDISEDTOGIVE THEDESIREDINTERMEDIATESTEPSANDYIELD INAREASONABLE YIELDOVERTHREESTEPS3CHEME 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

26

24

d

OH

BnO TBSO

OH

122 26

BnO

CHO

+

(Ipc)2B

a,b

25

BnO

c

26

26

+

25

26

119

120

e,f,g

24

BnO TBSO

121

24

BnO TBSO

OTBS OH

O

124

OH

123

3CHEME A  4(& n # THEN"&q/%T THEN %T/ THEN.A/( (/ REFLUXB 4"3#L $-!0CAT $-& OVERTWOSTEPSC /S/ .-/ ACETONE (/ 0H(  D .A( 4(&  # THEN4S)M  #→24 E "Z#L $-!0CAT 0YF -S#L $-!0CAT 0YG .A/-E -E/(  # OVERTHREESTEPS

BnO

BnO 26

O

OMe

a

26

O

OH

O

125 6 steps ~47%

OMe 24

24

126

b,c

SEt 26

BnO TBSO

127

24

OH

SEt

d,e

26

BnO TBSO

122

24

OH

f OH

26

BnO TBSO

24

O

124

3CHEME A -E-G#L #U"Rq3-E 4(& nB %T3( (#LC 4"3#L )M $-!0CAT $-& OVERTWO STEPSD (G#L #A#/ #(#.E .A"( 4(& (/  #→24 OVERTWOSTEPSF .A( 4(&  # THEN4S)M  #→24 

&ORTHESYNTHESISOFKEY# #SPIROKETALFRAGMENT )RELANDIDEN TIFIEDTHREEKEYSTRUCTURESA@LINKERDOMAIN CORRESPONDINGTO# #  3CHEME THESPIROKETALITSELF # # 3CHEME ANDA @  DIOL # # 3CHEMES  (OWEVER DESPITETHISOBSERVA TION THESTRATEGYTOREMAINEDALARGELYLINEARSEQUENCE 4HEFIRSTPARTOFTHISSTRATEGYENTAILEDTHECONSTRUCTIONOFTHE  DIOL MOTIF INITIALLYVIAANENANTIOSELECTIVE"ROWNSCROTYLATION; =OF BENZYLOXYACETALDEHYDE USING: CROTYLDIISOPINOCAMPHEYLBORANE  TOINSTALLTHEABSOLUTESTEREOCHEMISTRYAT#AND#WITHDR ANDEE(OWEVER ELABORATIONOFHOMOALLYLICALCOHOLTOEPOXIDE PROVEDPROBLEMATIC$IHYDROXYLATIONOFTHEDOUBLEBONDGAVEA MIXTUREOFDIOLSAND ATBEST ANDWHILSTBOTHOFTHESECOULDBE EASILY TRANSFORMED INTO THE DESIRED EPOXIDE ENANTIOMER THIS REQUIRED SEPARATIONOFTHEDIOLISOMERShTEDIOUSAND ONLARGESCALES≥G EVEN FORMIDABLEv $IRECTED EPOXIDATION OF THE HOMOALLYLIC ALCOHOL  PRO



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

HO(CH2)n

O

R OH

128

[O]

O HO(CH2)n

O

e.g. mCPBA

OH 129

H+

HO(CH2)n HO 130

O

R

O

O

O R

+

(CH2)n-2

O 131

O

R

(CH2)n-2

O 132

O

R

3CHEME $E3HONGSSPIROKETALISATIONMETHODOLOGY

CEEDEDWITHEVENWORSESELECTIVITY FURNISHINGAMIXTUREOFEPOXIDES USING6/ACAC  4"(0;=SEEPAGE  !SANALTERNATIVETOTHISLABORIOUSPROBLEM )RELANDTURNEDHISATTEN TIONTOREPORTSINTHELITERATURETHATREADILYAVAILABLE  ANHYDRO β RIBO FURANOSIDE  SIX STEPS FROM $ XYLOFURANOSE ;= REACTS REGIO AND STEREOSELECTIVELYWITH-E-G#LATTHE POSITION# TOFURNISHALCOHOL ;= WHICHBARESANIDENTICALSTEREOCHEMICALRELATIONSHIPTO  DIOL  7HILST THE ORIGINAL CONDITIONS REPORTED %T/ REFLUX WERE LARGELY UNSUCCESSFUL FOR BENZYL ETHER  IN THE PRESENCE OF #U"Rq3-E IN TET RAHYDROFURAN 4(& THE REACTION GAVE CONSISTENTLY GOOD YIELDS AT ROOM TEMPERATURE3CHEME ;= !FTERRINGCLEAVAGEOFBYTHIOACETALFORMATION SELECTIVEPROTECTION OFTHELESSHINDEREDALCOHOLASTHESILYLETHERGAVE#AREFULDEPROT ECTION OF THE DITHIOACETAL USING (G#L AFFORDED AN ALDEHYDE WHICH WAS IMMEDIATELYREDUCEDTO  DIOLWITHOUTISOLATIONTOAVOIDEPIMERISA TION&INALLY FORMATIONOFTHEEPOXIDEASPREVIOUSLYCOMPLETEDACCESSTO  ASASINGLEDIASTEREOMERANDINMULTI GRAMQUANTITY3CHEME  STEPS   )TWASHOPEDTHATTHESPIROKETALMOIETYCOULDBEINTRODUCEDUSINGA VARIANTOF$E3HONGSMETHODOLOGY;= WHEREINASUBSTITUTEDFURFUROL DERIVATIVEOFTHETYPEISOXIDISEDTOAFFORDPYRANONE WHICHSUBSE QUENTLYUNDERGOESINTRAMOLECULARKETALISATIONTOFURNISHASPIROKETAL AND CARRYINGTHE  ANTIRELATIONSHIPUNDEREQUILIBRATINGCONDITIONS 3CHEME  !CCORDINGLY THE FURFURYL GROUP WAS INTRODUCED BY TREATING EPOXIDE WITHLITHIATEDFURFURYLALCOHOLINTHEPRESENCEOF"&q/%T!CIDIC REMOVALOFTHEMETHOXYISOPROPYL-)0 PROTECTINGGROUPUSINGCATALYTIC AMOUNTSOF0043IN4(& (/GAVEALCOHOL READYFORTHECRUCIALSPIRO KETALISATION!FTEROXIDATIONWITHM#0"! INSITUTRAPPINGOFTHEENEDIONE DIOL ACETAL WITH  METHOXYPROPENE IN THE PRESENCE OF (#L GRATIFYINGLY



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

21

R 23

BnO TBSO 124

O

133

OMIP

a,b

BnO TBSO

23

OH 134

O

OH

c

23

OH

21 27

O

OH OH

21

O OH

21

OMe

R

23

O 27

135

OTBS

BnO 137

26

O

136

O O

21

O

O O 138

3CHEME A  N"U,I 4(& n #→n # THEN "&q/%T n #B 0043 4(& (/ OVER TWOSTEPSC  M#0"! #(#L  # THEN (#L 

GAVETHESPIROKETALPRODUCTINYIELD ASAMIXTUREINFAVOUROF THEDESIREDPRODUCT)NTERMOLECULARTRAPPINGOFTHEREACTIVEINTERMEDIATE INTHISCASEWITH METHOXYPROPENE ATTHETIMEREPRESENTEDANIMPORTANT EXTENSION OF $E3HONGS WORK )MPRESSIVELY THE REACTION SEQUENCE FROM EPOXIDETOSPIROKETALWASACHIEVEDCONSISTENTLYINOVERALL YIELDONSCALESUPTOG3CHEME  4HE ENONE FUNCTIONALITY IN  PROVIDED A HANDLE FOR THE INTRODUC TIONOFTHE# #LINKERDOMAINVIACONJUGATEADDITIONAT#!LKYNE  EASILYPREPAREDFROM2OCHEESTERDERIVATIVE;= PROVIDEDTHE PRECURSORFORTHE# #OLEFINWHICHWASOBTAINEDASTHEDESIRED% ISO MERUSING.EGISHICARBOALUMINATION; =!FTERTRANSMETALLATIONOF THEALUMINIUMSPECIESWITHAMIXEDHIGHER ORDERCUPRATE;= ADDITION OFENONETOTHEREACTIONFURNISHEDTHEELONGATEDFRAGMENTASA SINGLEGEOMETRICANDSTEREOISOMERINANEXCELLENTYIELD3TEREOSELEC TIVEREDUCTIONOFTHECYCLICKETONEUSING, SELECTRIDE;=VIAEQUATORIAL ATTACKTHENESTABLISHEDTHE# /(SOLELYASTHEDESIREDCONFORMERVIDE INFRA !FTERMUCHEXPERIMENTATION THISWASPROTECTEDASTHE0-"ETHER  USING0-"TRICHLOROACETIMIDATEANDTRITYLTETRAFLUOROBORATEAT # ;= AVOIDINGTHEDESTRUCTIVEPATHWAYSTHATOCCURREDINTHEPRESENCEOF THESTANDARDACIDCATALYSTSFORTHISREAGENT4F/( "&q/%T 3CHEME  4HE0-"ETHERWASUSEDIN)RELANDSSUCCESSFULSYNTHESIS ALTHOUGHFOR SOMEOFHISEARLIERSTUDIESTHE#HYDROXYLWASPROTECTEDASTHEETHOXY ETHYL%% ETHER VIDEINFRA 4HEORTHOGONALHYDROXYLPROTECTINGGROUPSAT#AND#INWERE CRUCIAL FOR ENABLING FURTHER SELECTIVE HOMOLOGATION 7ITH THIS IN MIND )RELAND INVESTIGATED TWO ALTERNATIVE PATHWAYS FOR ELABORATION AT # TO INSTALLTHEOXYGENATEDCYCLOHEXYLMOIETY )NITIALATTEMPTSWERECENTREDABOUTTHECONSTRUCTIONOFTHE# # OLEFINBONDVIATHEADDITIONOFA# ANIONTOA# KETONEMODEL FOL



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

OTBS

BnO

26

O O

21

O 16

THPO

OTs

a,b

16

TBSO

19

O

BnO

OTBS O O

138

140

OTBS

O O 21

O O 141

OTBS 26

d,e

21

c 16

139 3 steps 94%

BnO

26

16

OTBS

O O PMB 142

3CHEME A (#≡#,Iq%$! $-3/ n # B 4S/( -E/(  #4"3/4F %T. %T/ C I #P:R#L -E!L #L#(#(#L THEN 24II(#→##( N"U,I 4(& n # THEN#U#. n→ n #III %T/ n # D ,nSELECTRIDE 4(& n #→ # BRSM E 0-"n4#! 0H#"&CAT 4(&  # 

LOWEDTHENBYDEHYDRATION-ODELSTUDIESDEMONSTRATEDTHATANUNSUB STITUTEDCYCLOHEXYLMETHYLANION GENERATEDBYLITHIUM HALOGENEXCHANGE OFCYCLOHEXYLMETHYLBROMIDEFOLLOWEDBYTRANSMETALLATIONWITHCERIUM )) CHLORIDE COULDBESUCCESSFULLYADDEDTOANα HYDROXY METHYLKETONE ANALOGUEOF INGOODYIELDS(OWEVER THISREACTIONWASUNSUCCESSFUL WITHFUNCTIONALISEDCYCLOHEXANEEASILYPREPAREDFROMKNOWNESTER  ;= BOTHASTHEORGANOCERIUMREAGENTORASANYOFANUMBEROF OTHERORGANOMETALLICDERIVATIVES4HESENEGATIVERESULTSWEREATTRIBUTEDTO THERELATIVELYLOWREACTIVITYOFTHEMETHYLKETONE ANDINDEEDMOREPOSI TIVERESULTSWEREPROMPTLYOBTAINEDFORTHEADDITIONOFTHEORGANOCERIUM SPECIES DERIVED FROM  INTO THE MORE REACTIVE # ALDEHYDE MODEL 3CHEME  #ONSEQUENTLY CAREFULCLEAVAGEOFTHEBENZYLETHERINTHEREALSYSTEM  WITH7 2ANEYNICKELAND(;=AVOIDEDPROBLEMSASSOCIATED WITH THE MIGRATION OF SILYL GROUPS AND REDUCTION OF THE TRISUBSTITUTED ALKENE3UBSEQUENTOXIDATIONFURNISHEDTHEKEYALDEHYDE!DDITIONOF LITHIATEDALKYLIODIDETOASOLUTIONOFTHISALDEHYDEATn #GRATIFY INGLYRETURNEDTHEDESIRED# #BACKBONE INREASONABLEYIELDAS AMIXTUREOFDIASTEREOMERSTHATWASDIRECTLYOXIDISEDTOKETONEUSING $ESS -ARTINPERIODINANE3UCCESSFULADDITIONSWEREALSOACHIEVEDWITHTHE CORRESPONDING ORGANOCERIUM AND 'RIGNARD REAGENTS ALTHOUGH FOR COM PARABLEPRODUCTYIELDSTHESEREQUIREDASIGNIFICANTEXCESSOFNUCLEOPHILE $UETOCONCERNSABOUTTHEDIFFICULTYOFLATE STAGECLEAVAGEOFTHE# /4"3 GROUP BOTHTHE# AND# /4"3GROUPSWEREREPLACEDATTHISPOINT WITHTHEMORELABILE4%3PROTECTINGGROUP ALBEITSOMEWHATPROBLEMATI



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBDPSO

a,b

34 28

MeO

CO2Me

143 8 steps 26.2% c.f. Scheme 27

TBDPSO

I

MeO

28

144

TBDPSO

O

34

+

c,d

H

MeO OTBS 145

34

H 146

O 28

OTBS

3CHEME A ,I!L( %T/  #  B %T. -S#L 4(&  #  ,I) 4(& →  #  C  T"U,I HEXANE %T/ n # THEN#E#L THEN 4(& n # THEN-E/( n #→24D $-0 #(#L 24 OVERTWOSTEPS

CALLYDUETOCOMPETITIVEDEPROTECTIONOFTHE%%ETHER !TTENTIONNOW TURNEDTOTHEFORMATIONOFTHETRISUBSTITUTEDOLEFIN ALLTHATREMAINEDTO COMPLETETHERIGHTHANDSIDEOF&+ 4HEINSTALLATIONOFTHEMISS ING# METHYLGROUPWASENVISAGEDVIACOUPLINGOFANENOLTRIFLATEWITH METHYLCUPRATEASDEVELOPEDBY-C-URRY;=7HILSTENOLISATIONOF WITHLITHIUMDIISOPROPYLAMIDE,$! WASUNSUCCESSFUL TREATMENTWITH EQUIVALENTSOFLITHIUMDIETHYLAMIDEFOLLOWEDBY$-05AND. PHENYLTRI FLIMIDEGAVETHEDESIRED: ENOLTRIFLATEASASINGLEGEOMETRICISOMERBY& .-2&RUSTRATINGLY REACTIONWITH-E#U,IORHIGHERORDERORGANOCUPRATES DIDNOTOCCURTOANYUSEFULLEVEL INSTEADRETURNINGTHEKETONE%VEN TUALLY COUPLINGWASFINALLYPROMOTEDBYSONICATINGTHEREACTIONMIXTURE ;= BUTDESPITETHEREACTIVENATUREOF-E#U,ITHISREQUIREDSONICATION FORUPTOH RESULTINGPRACTICALLYINASEVEREBOTTLENECKFORTHEPREPARATION OFONANYAPPRECIABLESCALE3CHEME  7ITHTHISINMIND THESTRATEGYTOINCORPORATETHECYCLOHEXYLMOIETY WASADAPTED4HENEWAPPROACHWASNOWBASEDONFORMATIONOFTHE# # BOND VIA COUPLING OF A CYCLOHEXYL VINYL ANION DERIVED FROM VINYL BROMIDEWITH#ALDEHYDE4HEFORMEROFTHESETWOFRAGMENTS  WASREADILYAVAILABLEINSIGNIFICANTQUANTITIESTHROUGHTHESEQUENCE OFREACTIONSSHOWNIN3CHEME;=$IELS !LDERCYCLOADDITIONBETWEEN BUTADIENE AND THE ACRYLOYL ESTER OF 3 . METHYL  HYDROXYSUCCINIMIDE  GAVEASACRYSTALLINEADDUCT;=3UBSEQUENTOXYGENATIONAT #AND#WASACHIEVEDVIAINTRAMOLECULARRING OPENINGOFINTERMEDIATE OXIRANEFORMEDINHIGHSTEREOSELECTIVITYBYTREATMENTOFWITHM#0"! TOGIVELACTONE!SERIESOFSTANDARDFUNCTIONALGROUPMANIPULATIONS GENERATEDAMETHYLSUBSTITUTEDALKYNE THATAFTERHYDROZIRCONATION AND TRAPPING WITH AN ELECTROPHILIC SOURCE OF BROMINE ."3 AS A SINGLE OLEFINISOMERINATOTALOFSTEPSANDYIELD3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TBDPSO

34

TBDPSO

a,b

34

28

MeO

CO2Me

I

MeO

TBDPSO

28

34

144

143 8 steps 26.2% c.f. Scheme 27

TBDPSO

OH

OTBS

MeO

30

H

O O

e

34

O OTBS

MeO

26

28

30

H

f

26

28

O O

21

BnO

O

OTBS 26

H

O O

O EE

OTBS

147

MeO

149

150 OEE =

O

TBDPSO

OTES

34

30

H

28

34

O O

O OTES

MeO

26

21

30

i

H

26

28

O O 21

21

O

O

O 16

16

O EE

OTES

TBDPSO

OTf

OTES

MeO

j

O O

O

g,h

26

H

O

O EE 148

34

30

O EE

OTBS

21 16

TBDPSO

16

O EE

OTBS

O O

O

OTBS

O

16

OTBS 26

c,d

21 16

21

O

O EE

OTES

153

O EE

OTES

151

152

3CHEME A ,I!L( %T/  # B %T. -S#L 4(&  #,I) 4(& → # C 7 2ANEY .I ( %T/( D $-0 #(#L E  T"U,I HEXANE %T/ n # THEN %T/ n # BRSM F $-0 #(#L G 4"!& ¯-3 4(&H 4%3#L )M $-&  OVERTWOSTEPSI %T.( N"U,I HEXANE  # THENCONCENTRATEINVACUO THEN4(&  n # THEN $-05 THEN0H.4F n #→24 J #U) -E,I 4(&  # THEN ULTRASOUND 

34

34

O

O

a

NMe

O

O b

NMe

O

154 2 steps 52%

TBDPSO

O

155

TBDPSO

34

30 27

O O

30

156

MeO

TBDPSO

34

30

TBDPSO

34

i,j 27

MeO

H 30

34

g,h

MeO

OMe 30

O

Br 105

30

O

O

34

c,d

OH 30

e,f

k

MeO

TBDPSO

34

O 30

158

157

O 143

3CHEME A   BUTADIENE 4I#L #(#L  # B ,I/( (/ 4(&  # C M#0"! ##L  #→ 24 THEN%T. 3I/  # D 4"$03#L )M $-& E -E/( .A(#/F -E/4F   DI T BUTYLPYRIDINE #(#L OVERTWOSTEPSG ,I!L( %T/  # H #/#L  $-3/ #(#L n # THEN%T. n #→24 I .A( .#(0/ /-E  4(& n # J N"U,I -E) 4(& n # K #P:R( #L 4(&  # THEN."3 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

BnO

OTBS

OH

BnO

26

O O

O O

a,b

21

O O

c

O PMB

OTBS

142

O O 21

O

16

O PMB

159

O

16

O PMB

OTBS

CHO

d

21

O

16

OTBS

26

26

21

O

16

OH

HO

26

O PMB

OTBS

160

107

TBDPSO

g

34

e

MeO 27

105 TBDPSO

MeO

TBDPSO

34

O 30

MeO

26

H

O O

OH H

O O

34

OH 30

O PMB

162

O O

+ 21

O

O OTBS

26

H

21

O

163

MeO

26

f

21

OTBS

TBDPSO

34

30

Br

O PMB

OTBS

O PMB

161

3CHEME A 4"!& ¯-3 4(& B 4"3#L %T. $-!0 4(& C 7 2ANEY .I ( %T/(  D .A)/ 4(& (/ E  T"U,I 4(& n # THEN-G"Rq/%T THEN 4(&  F $-0 #(#L G ,I!L( ,I) %T/ n # 

&ORTHELATTER#ALDEHYDE ASERIESOFPROTECTINGGROUPMANIPU LATIONSESTABLISHEDA  DIOLFROMTHE0-"PROTECTEDSUBSTRATE WHICHWASTHENOXIDATIVELYCLEAVEDUSINGSODIUMPERIODATETOAFFORD 7HILETHISDESTROYEDTHECHIRALITYAT# ITWASRE ESTABLISHEDINTHENEXT STEPWHENWASADDEDTOACOOLEDSOLUTIONOFTHEVINYL'RIGNARDOF FORMEDVIATHEVINYLLITHIUMBYTRANSMETALLATIONWITH-G"Rq/%T 4HE REACTION PROCEEDED SMOOTHLY TO GIVE AN EXCELLENT  YIELD OF ADDUCTS AND ALTHOUGHASAMIXTUREOFSEPARABLEDIASTEREOMERSATBEST 3CHEME  5NFORTUNATELY ATTEMPTSTOIMPROVETHISBYOXIDISINGTHISMIXTUREAND THENREDUCINGTHEENONESTEREOSELECTIVELYTOTHEDESIREDα ISOMER GAVEEVENLESS SELECTIVITY)NDEED ALLATTEMPTSTOINCREASEDIASTEREO ISOMERRATIODR WEREMETWITHFRUSTRATION BUTNEVERTHELESSTHISMODIFIED ROUTEENABLEDTHERAPIDPREPARATIONOFMULTI GRAMQUANTITIESOFTHERIGHT HANDSIDEOF&+  (AVINGESTABLISHEDRELIABLESYNTHESESOFBOTHMAJORFRAGMENTSOF&+  WORKWITHINTHEGROUPTHENTURNEDTOTHEIRUNIONANDTHEELABORATION TOTHENATURALPRODUCT4HESENSITIVENATUREOFTHE# STEREOCENTREDICTATED THATTHEPIPECOLATEMOIETYBEINTRODUCEDASLATEASPOSSIBLE ANDSOPROGRESS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

8

O

TBDPSO MeO

TBDPSO

34

OH 30

MeO

26

H

O O

34

21

OTBS

O

O O 21

8

O

O PMB

SO2Ph

161

26

H

106 e,f,g

21

O

O PMB

OTES 30

OMe

O O

a,b,c,d

34

MeO

26

H

TBDPSO

O

OTES 30

CO2Et H 15 CHO O

CO2Et H O 15

O

O O PMB

O

OMe

164

165

TBDPSO

OTES

MeO

30

h

TBDPSO

34

O O

OTES

MeO

26

H

34

30

O O

CO2Et H O 15

8

O OMe

OMe

104

O O

Me H O 13

21

21 8

26

H

i

O PMB

O O

CO2Et H O 15

O OH

O PMB

Ce

O

15

O

O 8

O 16

CO2Et

R

166

OMe

167

3CHEME A 4"!& 4(& B 4S#L 0Y $-!0 #(#L THEN # 4%3#LC ,I) 4(&  #D 0H3/.A $-&  # OVERTHREESTEPSE  N"U,I 4(& n # THEN BRSM F $-0 0Y #(#L G "U3N( !)". 0H-E  # H #E#Lq(/ -E/( %T/ THENn # .A"( I 0ROTON3PONGE¤ -E/"& ¯-3 #(#L 

WASFIRSTFOCUSEDONCOMBININGAND4HISWASTOBEACHIEVEDVIA ADDITIONOFA#ANION DERIVEDFROMTHESULFONE TOTHE#ALDEHYDE 3CHEME  !CCORDINGLY BOTH TERT BUTYLDIMETHYLSILYL 4"3 ETHERS IN  WERE REMOVED FOLLOWED BY FORMATION OF THE PRIMARY TOSYLATE AND REPROTEC TIONOFTHE# /(ASITSTRIETHYLSILYL4%3 ETHERINONEPOT3CHEME  3EQUENTIALNUCLEOPHILICSUBSTITUTIONOFTHETOSYLATEWITHIODIDEANDTHEN BENZENESULFINATEGAVE# ANIONPRECURSORINGOODYIELD WHICHWAS AZEOTROPED REPEATEDLY WITH TOLUENE PRIOR TO THE KEY COUPLING REACTION )NTHIS ADDITIONOFEQUIVALENTOFN"U,ITOATn #GENERATEDTHE DESIREDYELLOWANIONTHATREACTEDCLEANLYWITHFRESHLY PREPAREDALDEHYDE TOAFFORDAMIXTUREOFTHEDIASTEREOMERICSULFONEALCOHOLSINAPLEAS INGYIELDESSENTIALLYQUANTITATIVEBASEDONRECOVEREDSTARTINGMATE RIAL 4HISMIXTUREWASOXIDISEDUSINGTHE$ESS -ARTINREAGENT;= AND THESULFONEGROUPCLEAVEDRADICALLYONTREATMENTWITHEXCESS"U3N(AND !)".INBOILINGTOLUENE TOAFFORD#KETONEINEXCELLENTYIELDAFTER CAREFUL CHROMATOGRAPHY TO AVOID SILYL ETHER CLEAVAGE 4HIS WAS REDUCED



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

CHEMOSELECTIVELYINTHEPRESENCEOFTHE#ETHYLESTERUSING,UCHECONDI TIONS; =TOESTABLISHTHELASTSTEREOCENTREIN&+ ASASINGLE DIASTEREOMER INQUANTITATIVEYIELD4HE# /(WASASSIGNEDASTHE α ISOMERBASEDONPRECEDENTINSIMILARSYSTEMS ANDWASBELIEVEDTOOCCUR VIAFORMATIONOFASIX MEMBEREDCERIUM))) CHELATEFOLLOWEDBYHYDRIDE ATTACKATTHELESSHINDEREDβ FACE ;= 3UBSEQUENT METHYLATION OF THIS ALCOHOL PROVED UNEXPECTEDLY PROB LEMATIC WITHBASICCONDITIONSRESULTINGINDECOMPOSITIONANDCOMMON ALTERNATIVESSUCHAS#(.OR!G/ -E)GIVINGONLYTRACESOFPRODUCT4HE USEOF-EERWEINSSALT-E/"& AND0ROTON3PONGE¤WASMOREENCOURAG ING;= ALTHOUGHTHEREACTIONWOULDNOTGOBEYOND^CONVERSION ANDLONGERREACTIONTIMESLEDTO,EWISACID CATALYSEDDESTRUCTIONOFTHE SPIROKETAL MOIETY (OWEVER SOMEWHAT SURPRISINGLY IN THE PRESENCE OF ¯MOLECULARSIEVES THEREACTIONWENTTOCOMPLETIONINONLYMININ NEAR QUANTITATIVEYIELDANDFURNISHEDTHEDESIRED# #SPIROKETAL 3CHEME  7ITHTHEASSEMBLYOF&+ NEARINGCOMPLETION )RELANDTURNEDHIS ATTENTIONTOTHE; = SPIROKETALSUBUNITANDITSUSEASAPRECURSORFORTHE TRICARBONYLFUNCTIONALITY4HISWASANTICIPATEDTHROUGHCLEAVAGEOFTHE# #ACETONIDE FOLLOWEDBYOXIDATIONATTHERESULTING# /((OWEVER EARLY INDICATIONS IN MODEL SYSTEMS SUGGESTED THAT THE INITIAL ACETONIDE HYDROLYSISWOULDREQUIREREFLUXINGINAMIXTUREOFACETICANDSULFURICACID CONDITIONSTHATWEREOBVIOUSLYPROHIBITIVEFORAMOLECULESUCHASWITH ARANGEOFSENSITIVEFUNCTIONALITIES !SANALTERNATIVE WORKTHENFOCUSEDONAPOTENTIALANIONICFRAGMENTA TIONOFTHESAMESPIROKETAL4HEORETICALLY DEPROTONATIONAT#WOULDBE FOLLOWED BY β ELIMINATION TO CLEAVE THE SPIROKETAL IN A SELECTIVE FASHION ASITWASANTICIPATEDTHATONLYONEOFTHETWOOXYGENSAT#WOULDBE ABLETOADOPTTHENECESSARYORIENTATIONFORTHISPROCESS'RATIFYINGLY THIS PROVEDTOBETHECASEINMODELSYSTEMSANDTHUSONTREATMENTWITH,I(-$3 IN4(& (-0! β ELIMINATIONOCCURREDINTOGIVEENEDIOLACETAL WHICHWASIMMEDIATELYSILYLATEDTOTOIMPROVESTABILITYINANIMPRES SIVEYIELDOVERTWOSTEPS!FTERINSTALLATIONOFTHEPIPECOLATEMOIETY FURTHERENCOURAGEMENTWASPROVIDEDWHENTREATMENTOFWITHDIMETHYL DIOXIRANE$-$/ RESULTEDINSELECTIVEOXIDATIONOFTHEENEDIOLACETAL4HIS SUCCESSFULLYINSTALLEDTHEDESIREDVICINALTRICARBONYL THEREBYJUSTIFY ING)RELANDSNOVELAPPROACHTOTHISSENSITIVEPROBLEM3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

O

O

a 14

9

O

EtO2C H

R

O

Li

OMe

O 9

O

14

O

R

O

H

OMe

O

HO

EtO2C

H

OEt

168

9

169

b

14

R

O TBS 14 O R

O 9

OMe

H

EtO2C

OMe

H

170

171 c,d

O

OH

O

9

O

14

R

N O CO2Me 174

H

OMe

f

9

O TBS 14 O R

N O CO2Me 173

H

O OMe

e

9

O TBS 14 O R

N O CO2Me 172

OMe

H

3CHEME A ,I(-$3 4(& (-0!  n # →  # B 4"3#L )M $-!0 $-&  OVER TWO STEPS C ,I/(q(/ -E/(D -ETHYLPIPECOLATEHYDROCHLORIDE %T.  CHLORO . METHYLPYRIDINIUMIODIDE $-!0CAT #(#L OVERTWOSTEPSE $-$/ #(#L n→n # F (& -E#. 

7ITHTHESERESULTSINHAND ASSEMBLYOFTHEMACROCYCLEENSUED3CHEME  !GAIN WORKFOCUSEDONELABORATIONOFRATHERTHANINSTALLATION OFTHESENSITIVEPIPECOLATEGROUP WHICHWASTOBELEFTTOTHELATESTPOS SIBLE STAGES !S PREVIOUSLY SPIROKETAL  WAS TREATED WITH ,I(-$3 IN 4(& (-0! ALTHOUGHFRUSTRATINGLYFRAGMENTATIONTOTHE#ALCOHOLPRE CURSORTO WASNOWMUCHSLOWERANDACCOMPANIEDBYCONSIDERABLE DECOMPOSITIONOFTHESTARTINGMATERIAL&URTHERMORE RECYCLISATIONOFTHE GENERATEDLITHIUMALKOXIDETOTHE# EPIMEROFTHESTARTINGMATERIAL WASOBSERVEDUPONPROLONGEDREACTIONTIME4HISPROCESSWASREPORTEDLY SO FAVOURABLE THAT hWHEN A REACTION MIXTURE CONSISTING ^ STARTING MATERIALANDTHEPRODUCT WASLETSTANDATn #OVERNIGHT THEPRODUCT DISAPPEAREDCOMPLETELYv )NORDERTOINFLUENCETHEEQUILIBRIUMINPLACEANDFAVOURTHEELIMINA TIONPRODUCT )RELANDINVESTIGATEDTHEUSEOF,EWISACIDSINSTABILISINGTHE RING OPENED PRODUCT VIA THE FORMATION OF STRONG OXYGEN CHELATES !FTER EXTENSIVE SYSTEMATIC STUDIES OPTIMISED CONDITIONS WERE ACHIEVED ,I( -$3^EQUIV -G(-$3 ^EQUIV (-0! $-%  # MIN WHICHCONSISTENTLYGAVETHEINTERMEDIATE#ALCOHOLINnISOLATED YIELD 4HE PROPENSITY OF THIS INTERMEDIATE TO REVERT TO  ALSO PROVED PROBLEMATICFORTHESUBSEQUENTSILYLATIONOFTHE# /( ALTHOUGHBYTHE SAMERATIONALEOPTIMALCONVERSIONWASACHIEVEDWHENUSING4"3/4FIN THEPRESENCEOF-G3/ 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBDPSO

TBDPSO

34

34

OTES

MeO

30

30

26

H

O O

TBDPSO

CO2Et H O 15

O O

H

MeO

O O

a,b

30

O O

O PMB

O

EtO2C

OMe

TBS O

H

15

OMe OMe

O

O

EtO2C

TBS O

175

15

OMe OMe H

f,g,h

TBDPSO

34

O O

26

21 1

O

8

O

176 e

34

TBDPSO

34 1

I

OMe OMe H 179

O O

26

21

k,l

1

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NH O

O TBSO H

O PMB

MeO

MeO

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O O O

O PMB

H

TBDPSO

O O

8

O

MeO

30

O PMB OMe OMe H

178

26

H

N Boc H O

O O

i,j

O

N HO

O TBSO H

O

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21

H

104

26

H

c,d

21

O OMe

1

O

26

21 8

34

OTES

MeO

21

O O HO2C

O

TBS O

H

15

OMe OMe H

O PMB

177

3CHEME A ,I(-$3 -E-G"R $-% (-0!  # B 4"3/4F   DI T BUTYLPYRIDINE $-!0 -G3/ #(#L C 4&! 4(& (/ D . "OC , PIP $## $-!0CAT #(#L n #  E ..A/( DIOXANE (/  # F ..A/( DIOXANE (/  #G 4&! 4(& (/  H . "OC , PIP $## $-!0 #(#L n # THEN.A/( 4(& (/ OVERTHREESTEPSI 4%3/4F   LUT #(#L  # THEN3I/J METHYL  CHLOROPYRIDINIUMIODIDE %T. #(#L OVERTWO STEPSK $$1 #(#L (/ L 0H0 )M 0H-E  # THEN) 

3ELECTIVECLEAVAGEOFTHESECONDARY4%3ETHERTHENLIBERATEDTHE# HYDROXYLINQUANTITATIVELY ALLOWINGINSTALLATIONOFTHEPIPECOLATEESTER UNDER STANDARD CONDITIONS -UKAIYAMA MACROLACTAMISATION WAS ANTICI PATEDUSINGTHE-ERCKPROTOCOL; = HOWEVERPRELIMINARYHYDROLYSIS OFTHEETHYLESTERTOREQUIREDHEATINGAT #WITHEQUIVALENTS OF.A/(INAQUEOUSDIOXANEFORH7HILETHEREACTIONAPPEAREDTOPRO CEEDCLEANLYANDWITHOUTHYDROLYSISOFTHELABILEPIPECOLATEESTER ITCOULD NOTBEDETERMINEDCONCLUSIVELYWHETHERORNOTEPIMERISATIONATTHE# STEREOCENTREHADOCCURREDBECAUSEOFAMBIGUITIESINTHENUCLEARMAGNETIC RESONANCE.-2 SPECTRA ARISINGFROMTHEPRESENCEOFROTAMERSABOUTTHE . "OCBOND4HISUNCERTAINTYWASACCENTUATEDAFTERINVESTIGATINGTHESAME HYDROLYSISOFWITH.A/$ $/ AREACTIONTHATGAVEAPRODUCTWITHOUT THECHARACTERISTICSIGNALFORTHE#PROTONINTHE(.-24HISINDICATION THATENOLISATIONWASOCCURRINGLED)RELANDTOPURSUEADIFFERENTENDGAME STRATEGYF G Hn3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

4HEALTERNATIVEWASTOHYDROLYSEESTERFIRST FOLLOWEDTHENBY# /4%3DEPROTECTIONANDESTERIFICATION4HISLATTERESTERIFICATIONAFFORDEDTHE PRODUCT ASAMIXEDANHYDRIDEWITHTHE# CARBOXYLICACID WHICH COULDBESELECTIVELYHYDROLYSEDTOTHROUGHBRIEFEXPOSURETO.A/( IN4(& (/7HILESPECTROSCOPICANALYSISREMAINEDINCONCLUSIVE THE# STEREOCENTREHADNOTBEENEXPOSEDTOSTRONGLYBASICCONDITIONS ANDASA RESULTITWASBELIEVEDTHATTHESTEREOCHEMICALINTEGRITYOFTHEPIPECOLATE MOIETYSHOULDHAVEREMAINEDINTACT4HUS REMOVALOFTHE"OCGROUPUSING 4%3/4FFOLLOWEDBYSILICAGEL; = ANDFINALLY-UKAIYAMAMACROLAC TAMISATIONFURNISHEDINREASONABLEYIELDANDCOMPLETEDTHECARBON SKELETONOF&+ 3CHEME  4OUNMASKTHE# #ALDOLMOTIF THE# 0-"ETHERWASFIRSTCLEAVED USINGSTANDARDCONDITIONS BEFORECAREFULCONVERSIONOFTHE# /(TOTHE CORRESPONDINGIODIDE3CHEME 7HILESTANDARDCONDITIONSPROVED UNRELIABLEFORTHISTRANSFORMATION THISWASEVENTUALLYACHIEVEDTHROUGHA MODIFIEDLITERATUREPROCEDURE;=THATINVOLVEDMETICULOUSTITRATIONOF SOLUTIONSOFINTOLUENEAT # WITHANIODINESOLUTIONINTHEPRESENCE OFEXCESS0H0ANDIMIDAZOLE 7ITH THE SUBSTRATE FOR THE CRUCIAL SPIROKETAL FRAGMENTATION IN HAND ADDITION TO A SUSPENSION OF FRESHLY PREPARED ZINCSILVER GRAPHITE ;= EFFECTED DEALKOXYDEHALOGENATIVE CLEAVAGE TO FURNISH THE DESIRED α ALLYL ALDOL  IN A VERY IMPRESSIVE NEARLY QUANTITATIVE YIELD 4HE USE OF A HIGHLY REACTIVEMETAL GRAPHITECOMBINATIONTOAFFECTTHISTRANSFORMATION ALLOWED EXTREMELY MILD REACTION CONDITIONS SUPPRESSING ANY SIDE REAC TIONS MORE COMMON WHEN USING 2EIKE ZINC FOR EXAMPLE SUCH AS THE DEGRADATIVEPATHWAYSTHATAREPREVALENTIN&+ ANDITSANALOGUES ASDISCUSSEDPREVIOUSLY4HISREAGENTALSOOFFERSPRACTICALADVANTAGES WITH SIMPLEWORKUPSOLELYBYTHEFILTRATIONOFINSOLUBLES-ECHANISTICALLY THE REAGENTISNOTCOMPLETELYUNDERSTOOD#+ISKNOWNTOBEBOTHANEFFECTIVE ONE ANDTWO ELECTRONDONOR YETINTHEPRESENCEZINCOROTHERMETALS THIS ISSOMEWHATAMBIGUOUS 7ITHTHEFRAMEWORKOF&+NOWUNMASKED TREATMENTOFWITH $-$/PROCEEDEDASINMODELSTUDIESANDWITHOUTINCIDENTTOREVEALTHE VICINALTRICARBONYLINQUANTITATIVEYIELD ANDWITHNOTRACEOFEPOXIDATION &INALLY ALLTHATREMAINEDWASDESILYLATION WHICHOCCURREDWITHSPONTA NEOUSLACTOLFORMATIONTOCOMPLETE)RELANDSTOTALSYNTHESISOF&+ 3CHEME 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

HO TBDPSO

HO

34

MeO

MeO

H

MeO

O O

21

1

O

NHO

O

a

OMe OMe

OH

b,c

8

OH

TBS O

O

H

8

OMe OMe

O

O OH H O 10

OMe OMe

H

180

21

O

1

N

O

O

24

O

H O O

H 179

H

21

1

N I

O TBSO

O

O

8

H

O

24 26

O

34

34

FK506 1

3CHEME A #  # THEN+  # THEN:N#L !G/!C 4(& 24→ #→ # THENB $-$/ #( #/ n→n #C (& #(#. OVERTHREESTEPS

3CHEME 3UMMARYOF)RELANDSTOTALSYNTHESESOF&+ 0ART/NE

)RELANDS SECOND TOTAL SYNTHESIS OF &+  REPRESENTS AN INVENTIVE STRATEGYTOTWOOFTHESIGNIFICANTPROBLEMSPOSEDBYTHESYNTHESISOFTHIS NATURALPRODUCT"YMASKINGBOTHTHETRICARBONYLANDβ HYDROXYKETONE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

HO MeO

30

TBDPSO

TBDPSO

34

OH

1

O

1

8

O

O OH H O 10

8

OMe

H

H

O O

+

OH 10

OMe

O

10

O

O 182

OH H O H

20

183

H

H

15

16

181

OMe OMe FK-506 1

N Boc H O

22

I

OMe OMe

26

H 21

O

O

O

OMe

O

NH O

TESO

N

O O

26

22

O

30

30

O

24

1

O

MeO

MeO

H

34

34

H

OMe O 184 +

I

20

TMS 185

3CHEME 2ETROSYNTHETICANALYSIS

MOIETIESWITHINSPIROKETALS HEHASAVOIDEDTHELATENTINSTABILITYASSOCI ATEDWITHTHESEREGIONSANDBEENABLETODEVELOPAFASCINATINGAPPROACH TO&+ 4HISISCOMBINEDWITHGREATEFFICIENCYINGENERATINGSOMEOF THEOTHERFUNCTIONALITYFOREXAMPLE BOTHTRISUBSTITUTEDOLEFINSASSINGLE GEOMETRICISOMERS ANDAHIGHLYEFFECTIVE STEREOCONTROLLEDCOUPLINGSTRAT EGYTOMAKETHISARGUABLYTHEMOSTCOMPLETEOFTHE&+ SYNTHESES REQUIRING A LONGEST LINEAR SEQUENCE OF  STEPS IN  OVERALL YIELD 3CHEME 

 )RELANDTOTALSYNTHESESOF&+0ART4WO )RELANDS ALTERNATIVE TOTAL SYNTHESIS OF &+ ACTUALLY RELEASED ONE YEAR PREVIOUSLY;= WASACHIEVEDUSINGMUCHOFTHESAMEMETHODOLOGYASTHAT ALREADYDISCUSSED WITHBOTHSTRATEGIESUNDOUBTEDLYBENEFITINGFROMTHE EXPERIENCESANDSUCCESSESOFTHEOTHER)NTHISAPPROACH FINALCYCLISATION WAS AGAIN ANTICIPATED VIA MACROLACTAMISATION # . AND THE # # α ALLYL ALDOL FUNCTIONALITY REMAINED EMBEDDED WITHIN THE INITIAL FRAG MENTTARGETSASASPIROKETAL(OWEVER KEYDIFFERENCESINCLUDEDTHEMASKED VICINALTRICARBONYLFUNCTIONALITYNOWPLANNEDFROMASILYLENEDIOL ASWELLASTHEGENERALRETROSYNTHESISWHICHAFTERFURTHER# #DISCON NECTIONGAVELARGEKEY@TOP AND@BOTTOM HALVESINANARGUABLY AMORECONVERGENTAPPROACH3CHEME  2ATHERIRONICALLY THEFIRSTAPPROACHTOTOPHALFWASALENGTHYLINEAR SEQUENCE4HISBEGANFROMPROTECTEDLACTONE;= ACOMMONINTER



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBDPSO

TBDPSO a,b MeO

34

28

O

TBDPSO

TBDPSO

OMTM

g,h

MeO

MeO

MeO

26

26

O

186

34

34

e,f

O

156 6 steps 25.3% (c.f. Scheme 27)

26

34

c,d 28

O

TBDPSO

TBDPSO

34

CHO

187

188

189

24

TBSO

i,j

34

TBDPSO

OTBS

MeO

30

34

TBDPSO

HO

26

H

o

O O

21

O

MeO

m,n

22

TBDPSO

34

k,l

MeO

26

O

26

TBSO

OH

TBSO

192

O 193

34

BzO

MeO

24

26

O

24

TBSO

191

OH

190

TBDPSO

X

34

MeO

30 27

TBDPSO

TBDPSO N Boc H MeO O bb,cc,dd

34

O

MeO

30

26

H

TBDPSO

34

OH 30

H

O O

21

O O

21

200

O 182

OH 30

26

H

O O

+ 21

O

TBSO

O

MeO

26

199

26

O H 198

H

x

201

26

26

H

24

OBn

p,q

24 26

O 119

OH 194

OH

r,s,t

24

22

26

O

OH

u

195

O O

21

OH

O O

21

TBSO

aa

z

O

H

y

O

TBSO

H

Br 105 13 steps 13.7% (c.f. Scheme 27)

34

O O

196

v,w

O O

21

O TBSO

H 197

3CHEME A %T-G"R %T. 0H-E → # B -E/4F   DI TERT BUTYL  METHYLPYRIDINE #(#L  C +(-$3 (-0! 4(& n→ # THEN(#/%T n #→24 D +#/ -4-#L 4(&  E #E#Lq(/ .A"( -E/(  #F P4S/( 4(& OVERTWOSTEPSG : CROTYLDIISOPINOCAMPH EYLBORANE "&q/%T %T/ n # THEN(/ .A/(H 4"3/4F   LUT #(#L OVERTWOSTEPS I /S/ .-/ 4(&  #→24 J "Z#L 0Y $-!0CAT K -S#L 0Y $-!0CAT  # L .A/-E -E/(  # OVERTWOSTEPSM  LITHIOFURFURYLMETHOXYISOPROPYLETHER "&q/%T 4(& n #N #3! 4(& (/ OVERTWOSTEPSO M#0"! #(#L  # THEN METHOXY PROPENE P4S/( P : CROTYLDIISOPINOCAMPHEYLBORANE 4(& n # THEN(/ .A/(Q ,I .( n # OVERTWOSTEPSR 4S#L 0YS .A( %T/  #T  LITHIOFURFURYLMETHOXYISOPROPYL ETHER "&q/%T 4(& n # OVERTHREESTEPSU M#0"! #(#L  # THEN METHOXYPROPENE (#L → # V ,nSELECTRIDE 4(& n # W 4"3#L )M $-& X /S/ .-/ 4(& (/ THEN.A)/ (/ Y  T"U,I %T/ n # THEN   Z $-0 #(#L AA #E#Lq(/ .A"( -E/( n # BB . "OC , PIP $## $-!0 CAT #(#L n # CC 4"!& 4(&  # DD $-0 #(#L 

MEDIATEINTHESYNTHESISOFTHECYCLOHEXYLMOIETYOFTHISCLASSOFNATURAL PRODUCTS AND EASILY AVAILABLE ON SCALE USING ROBUST $IELS !LDER CHEMIS TRY!FTERFORMATIONOFETHYLKETONEWITHETHYLMAGNESIUMBROMIDE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

HOMOLOGATIONVIACONDENSATIONWITHETHYLFORMATEANDMETHYLTHIOMETHYL -4- PROTECTIONGAVE WHICHAFTER,UCHEREDUCTION; =UNDER WENT ACID CATALYSED REARRANGEMENT TO GIVE THE DESIRED TRANS SUBSTITUTED ALDEHYDEPREFERENTIALLY ALTHOUGHNOTEXCLUSIVELY!FTER"ROWNSCROT YLATION; =TOSET#AND#WITHADROF THEOLEFININ COULDBEREADILYTRANSFORMEDTOEPOXIDE&URTHERFUNCTIONALISATIONVIA RING OPENINGWITH LITHIOFURFURYLMETHOXYISOPROPYLETHER ANDELABORA TIONTOTHESPIROENONEMOIETYASDISCUSSEDPREVIOUSLYGAVEWITHOUT COMPLICATION3CHEME  &RUSTRATINGLY SELECTIVEDEPROTECTIONOFTHE#4"3INWASELUSIVE ATTHISPOINT"IS DESILYLATIONCOULDBEACHIEVED BUTONLYINYIELDAT BESTPOLYMERIC(&q0Y ANDSELECTIVEREPROTECTIONOFTHE#HYDROXYL WHILSTPOSSIBLE MADETHISAPPROACHCUMBERSOMEANDUNATTRACTIVE#ON SEQUENTLY)RELANDPURSUEDAMORECONVERGENTAPPROACHTOTHETOPHALFOF &+3CHEME  !DDITIONOFTHEORGANOLITHIUMSPECIESOFVINYLBROMIDESEE3CHEME  TO ALDEHYDE  EASILY PREPARED FROM  ALBEIT IN NINE STEPS AS WASUSEDIN)RELANDSAPPROACHTO&+ !.!, ;= GAVEDIRECTLYTHEFREE # /( AS A  DIASTEREOMERIC MIXTURE IN FAVOUR OF THE DESIRED α /(  5NFORTUNATELY ANYATTEMPTSTOIMPROVETHISRATIOBYANOXIDA TION REDUCTIONSEQUENCEWEREUNSUCCESSFUL GIVINGTHEUNDESIREDISOMER EXCLUSIVELYUNDERAVARIETYOFCONDITIONS.EVERTHELESSTHEDESIREDDIASTE REOMERCOULDBESEPARATED ANDSUBSEQUENTINSTALLATIONOFTHEPIPECOLATE MOIETYWASSTRAIGHTFORWARD ALLOWINGRAPIDCONVERGENTACCESSTOTOPHALF  OF&+ 3CHEME  4HESYNTHESISOFTHEBOTTOMHALFBEGANFROMDIOL;=3ELECTIVE METHYLATIONANDOXIDATIONGAVEALDEHYDE WHICHWASADDEDINTOA SOLUTIONOFTHE# #'RIGNARDDERIVEDFROMVIALITHIUMHALOGEN EXCHANGEANDTRANSMETALLATIONWITH-G"R ATn #TOGIVEASASINGLE DETECTABLEDIASTEREOMERVIACHELATIONCONTROL3CHEME ; = 3TRAIGHTFORWARDELABORATIONTOLACTOLFOLLOWEDBY7ITTIGOLEFINATION INSTALLED#AND# ASANINSEPARABLEMIXTUREINFAVOUROFTHEDESIRED TRANS OLEFIN ^ WHICH WAS SUBSEQUENTLY REDUCED TO ALLYLIC ALCOHOL WITH$)"!, (5SEOFTHESTOICHIOMETRIC3HARPLESSEPOXIDATION;= CONDITIONS THEN PROCEEDED ONLY UPON THE TRANS OLEFIN ALLOWING SEPARA TIONOFTHE7ITTIGBY PRODUCT ANDTHEEPOXIDETHATFORMEDWASCONVERTED SPONTANEOUSLYINSITUTOREFORMTHETETRAHYDROPYRANRINGINGOODYIELD



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

OMe

OMe

O

H

O

a,b,c,d

H

H

O

16

I 115 9 steps 42% (cf. Scheme 19) OTBS OTBS H 10 O H

206

16

H 15

16

TMS

OMe OH

OMe OMe

202

203 h,i

Me Al

O m 10 20

I

OMe OMe

O

20

185 7 steps 44.6%

184

20

10

15

OMe O

OH OH

f,g H

TMS

OH

20

10

e

15

15

TMS

OMe

10

10

O H O

OH

l H

10

OH H O H

CH2OH

H

TMS 20

20

j,k

10

OH 16 15

20

AlRn

OMe OMe 205

OMe OMe 183

OMe OMe 204

3CHEME A 4R#L 0YB .A( -E) 4(&C (#L -E/( OVERTHREESTEPSD $-0 #(#L E  T"U,I %T/ n # THEN -G"R n # →  # THEN   F .A( -E) 4(&  #  G !C/( (/  # H 0H0#(#/%T %T. 0H( REFLUX I $)"!, ( 4(& n #→ # J 4I/I0R   $%4 4"(0 ¯-3 #(#L n # THEN K 4"!& 4(&  #  L #P:R#L -E!L #(#L THEN THENn # ) M 4"3#L )M $-!0CAT $-& 

&INALLY REMOVALOFTHETERMINAL4-3GROUPCOMPLETEDTHESYNTHESISOFKEY ALKYNEINTERMEDIATE)TWASENVISAGEDTHATUNIONOFTHETWOHALVES AND COULDBEACHIEVEDVIATHE# #BONDINACARBOALUMI NATIONTRANSMETALLATIONPROCEDURETHATHADBEENUSEDSUCCESSFULLYBY)RE LANDPREVIOUSLY4OTHISEND CARBOALUMINATION#P:R#L -E!L OCCURRED CLEANLY ALBEITSLOWLY GIVINGVINYLALANEINTERMEDIATE5NFORTUNATELY ALLATTEMPTSTOACHIEVETRANSMETALLATIONTOTHEDESIREDVINYLCUPRATEGAVE NOREACTION ASJUDGEDBYTHELACKOFPRODUCTSONQUENCHINGWITHSIMPLE SPIROENONES )NSTEAD ADDITION OF IODINE GAVE A VINYL IODIDE AS A SINGLE GEOMETRICISOMERINPLEASINGYIELD ANDITWASANTICIPATEDTHATAFTERBIS 4"3 PROTECTION THISIODIDE COULDBEUSEDASAPRECURSORFORTHEDESIRED VINYLCUPRATE3CHEME  !CCORDINGLY AFTERLITHIUMHALOGENEXCHANGE TRANSMETALLATIONWITHA RANGEOFCYANOCUPRATESWASINVESTIGATED;=$ESPITEINITIALDISAPPOINT INGRESULTS REQUIRINGEXCESSOFVINYLLITHIUMANDGIVINGONLYPOORYIELDS ANEFFECTIVEPROTOCOLWASEVENTUALLYACHIEVED)NTHIS ADDITIONOFHEXYNYL COPPERASITSBIS (-0!COMPLEX;=TOTHEORGANOLITHIUMSPECIESDERIVED FROM FOLLOWEDTHENBYSPIROENONE GAVETHEDESIREDKETONE INCONSISTENTYIELDSASASINGLEDIASTEREOMERANDTHETRISUBSTITUTED# # OLEFINEXCLUSIVELYINTHETRANS CONFIGURATION3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TBDPSO

TBDPSO

N Boc H O

34

1

MeO

O 30

26

H

O O

21

MeO

OTBS OTBS H 10 O H

+

30

1

H

TBSO

O TBSO

206

O O

16

10

22

O

NHO Boc

20

OMe OMe

O 182

O O

26

a I

O

34

OMe OMe

H

H

207 g,h

b,c

TBDPSO

TBDPSO

34

MeO

MeO

30

O O

26 1

8

H

O

H

O

O

16

OMe OMe H 210

O O

26

f

1

8

H

O H

O

22

O

O O

26 1

O

16

30

d,e

O

NHO

HO

34

MeO

30

O

NH O

O

22

O

TBDPSO

34

NH O Boc

OMe H

22

O

16

O O

10

OMe OMe H 209

O

O

HO

H

OMe OMe H 208

3CHEME A  T"U,I %T/ n # THEN#(###Uq(-0! n #→n # THEN 4-3#L(#L 4(& B 4"!& 4(& C .A(#/ +"R #(#L THEN4%-0/  # THEN.A/#L.A#L/ .A(0/  METHYLBUTENE T"U/(#(. %T/ D ,I/(q(/ 4(&4%3/4F   LUT #(#L  # THEN !C/( 4(&  #   CHLORO  METHYLPYRIDINIUM IODIDE %T. #(#L REFLUX E %T. %T/( OVERTWOSTEPSF $-0 #(#L G $-0 #(#LH ,I/(q(/ 4(& 4%3/4F   LUT #(#L  # THEN!C/( 4(&  # CHLORO  METHYLPYRIDINIUMIODIDE %T. #(#L REFLUX FROM

%LABORATION OF  TO THE &+ MACROCYCLE STARTED WITH SELECTIVE OXIDATIONOFTHE  DIOLTOANα HYDROXYALDEHYDE USINGTHEHINDERED CHLOROOXAMMONIUMSALTDERIVEDFROM METHOXY 4%-0/INTHEPRES ENCE OF .A/#L ;= FOLLOWED BY FURTHER OXIDATION TO THE RESULTING CARBOXYLICACID4HISWASESTERIFIEDWITHDIAZOMETHANETOFACILITATEPURI FICATION!FTERHYDROLYSISOFTHISESTERANDREMOVALOFTHE"OCGROUPWITH 4%3/4F MACROLACTAMISATION WAS ACHIEVED UNDER STANDARD CONDITIONS 5NFORTUNATELYANUMBEROFPROBLEMS INCLUDINGISOLATIONOFTHECYCLISED HYDROXYLACTAM RESULTEDINAVERYLOWYIELDFORTHISSEQUENCEnAMERE OFDIKETONEFROMHYDROXYESTER(OWEVER BYREARRANGING THESE TRANSFORMATIONS )RELAND MANAGED TO IMPROVE THIS TO  FROM 3CHEME 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBDPSO

TBDPSO

34

MeO

30

O O

26 1

8

H

O

a,b

1

O

O

16

O

OMe OMe

O O O

O

I

16

O

O O

NH O

TESO

8

I

O

O

OMe OMe H 181

H

H 211

H

O O

26 22 1

OMe OMe

210

30

c

22

O

NHO 8

H

H

H

30

O

NHO

O

34

MeO 26

22

O

TBDPSO

34

MeO

d

HO MeO

TBDPSO

34

30

MeO

H

TBDPSO

34

30

MeO

H

O

24

8

O

O OH H O 10

f

22

N 8

OMe

O

e

O

1

O OR H O 10

213

O

1

O

N 8

OMe

TESO

O 10

H

OMe OMe

OMe

OMe FK-506 1

O

24

OH

O

OH

O

O

N

H

22

OH

1

30

O

24

22

O

34

212

3CHEME A , SELECTRIDE 4(& n # B ) 0H0 0H-E THEN)M THENALCOHOLDERIVEDFROM  # C +(-$3 4(& n # THEN4%3#L D #  # THEN+  # THEN:N#L !G/!C 4(& 24→REFLUX→24 THEN E $-$/ #(#L n→ #F (& -E#. OVERTWO STEPS

3ELECTIVEREDUCTIONOFTHEKETONEINUSING, SELECTRIDE;= AND TRANSFORMATIONTOEQUATORIALIODIDEINSTALLEDTHENECESSARYFUNCTION ALITY FOR DEALKOXYDEHALOGENATIVE FRAGMENTATION OF THE SPIROKETAL 4HUS AFTERCHEMOSELECTIVEENOLISATIONOFTHE#KETONEWITHPOTASSIUMHEXA METHYLDISILAZIDE+(-$3 WHICHHASBEENSHOWNNOTTOENOLISEESTERS ATLOWTEMPERATUREINTHEABSENCEOFPOLARCOSOLVENTSSUCHASHEXAMETH YLPHOSPHORAMIDE (-0! THUS RETAINING THE STEREOCHEMICAL INTEGRITY AT # ;= AND TRAPPING WITH TRIETHYLCHLOROSILANE 4%3#L GAVE  4REATMENTWITHTHESAME:N !GALLOY;=DISCUSSEDPREVIOUSLYAFFORDED  WITH THE α ALLYL ALDOL FUNCTIONALITY IN PLACE #OMPARED WITH OTHER EXAMPLESOFTHISMETHODOLOGY THEYIELD WASSOMEWHATDISAPPOINT ING WITHDEHYDRATIONOFTHEDESIREDALDOLPRODUCTPREVALENT.EVERTHE LESS THEBACKBONEOF&+WASNOWINPLACE ANDALLTHATREMAINEDWAS OXIDATIVEANDPROTECTINGGROUPMANIPULATIONS!CCORDINGLY OXIDATIONOF THESILYLENEDIOL WASACHIEVEDUSING$-$/INTHESAMEWAYASTHE CYCLICACETONIDEENEDIOLPREVIOUSLY ANDTHERESULTINGMIXTUREOFSILYLATED



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 3UMMARYOF)RELANDSTOTALSYNTHESESOF&+ 0ART4WO

ANDDESILYLATEDTRICARBONYLHEMIKETALS WASTREATEDWITHHYDROGEN FLUORIDE (& TO COMPLETE )RELANDS SECOND TOTAL SYNTHESIS OF &+  3CHEME  )RELANDSALTERNATIVESTRATEGYTO&+ ISAMORECONVERGENTAPPROACH RELYINGONTHEEFFICIENTSYNTHESISOFTOPANDBOTTOMHALVES!LTHOUGHSUB STANTIALLYMORECONCISEWHENVIEWEDASAWHOLE THISAPPROACHOVERALLIS THREE FOLDLOWERYIELDING3CHEME  .ONETHELESS RELEASED AS THE FIRST OF HIS TWO TRIUMPHS OVER THIS MOL ECULE IT SUCCESSFULLY AVOIDED SOME OF THE EARLY PROBLEMS ENCOUNTERED WITHTHEUSEOFTHESPIROKETAL PROTECTEDTRICARBONYLUNITWHILEMANAGING TO MAINTAIN SOME OF THE INVENTIVE APPROACHES SO ATTRACTIVE IN HIS FIRST DISCUSSEDWORK



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TIPSO

TBSO MeO

34

34

H

TIPSO

20

26

30

PMBO

MeO

23 CHO O OTBS TBS

34

OTBS

26

216

22

HO O TIPS

O

H

+ 19

SO2Ph 19

OMe 15

OMe

OMe OTBS

OHC 10

OMe OTBS

13 Sih (& Merck)

O

PMP

19

15 10

OTBS

26

O

30

+

S S

H 22

MeO

215

Ph2P O MeO

30

S

Merck intermediate 214

I TBDPSO MeO

15 10

S

OTBS 22

OMe OTBS

217 Danishefsky

34

+

30

PMBO

19

S

26

S

OMe 15

MeO

10

OMe 218

Smith III

OMe OTBS 219

3CHEME 2ETROSYNTHETICANALYSES



&ORMALSYNTHESESOF&+

!MONG THE PLETHORA OF SYNTHETIC INVESTIGATION CARRIED OUT SURROUNDING &+ THREEFORMALSYNTHESESHAVEBEENREPORTED3CHEME ;n =%ACHOFTHESEWASCENTREDAROUNDANIMPROVEDSYNTHESISOFTHEKEY INTERMEDIATEORCLOSEANALOGUE REPORTEDINASPARTOFTHEFIRST TOTALSYNTHESISOF&+ BY-ERCK 4HEANALOGIESWITHTHEORIGINALSUCCESSAREVARIEDINEACHWORKTHAT BY3IHWASCONCERNEDPREDOMINANTLYWITHANIMPROVEDSYNTHESISOFTHE SAMEINDIVIDUALBUILDINGBLOCKS  ANDFEATURESCOUPLINGREACTIONS UNDERTHESAMECONDITIONSASPREVIOUSLYREPORTED$ANISHEFSKYTOOKTHIS ONESTEPFURTHER USINGTHESAMEKEYDISCONNECTIONOFTHE-ERCKINTER MEDIATEACROSSTHE# #OLEFINBONDBUTVARYINGBOTHTHEIMMEDIATE TARGETS  ANDTHEMETHODOFCONSTRUCTIONOFTHETRISUBSTITUTED ALKENE 3MITH HOWEVER PURSUED A COMPLETELY DIFFERENT DISCONNECTION CHOOSING DISCONNECTION ACROSS THE # # BOND AND ANTICIPATING ITS RECONSTRUCTIONVIACOUPLINGOFA# #DITHIANEWITHAPRIMARY IODIDE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS



4HE3IHSYNTHESISOFTHE-ERCKINTERMEDIATE

#HARLES3IH FORMERLYOFTHE5NIVERSITYOF7ISCONSINS3CHOOLOF0HARMACY TOOK AN UNORTHODOX APPROACH TO THE # # SEGMENT OF &+ THAT RELIEDHEAVILYONBIOSYNTHETICMETHODOLOGY;=7ITHTHESAMEKEYOLE FINICDISCONNECTIONASTHESUCCESSFULGROUPAT-ERCK HISGROUPWASMORE INTERESTEDINTHEAPPLICATIONOFENZYMESFORCHEMOSELECTIVEHYDROLYSESOR ENANTIOSELECTIVEREDUCTIONS;= 3UCHMETHODOLOGYCANBEDEMONSTRATEDINTHEIRAPPROACHTOTHECYCLO HEXYLMOIETYOF&+ 3CHEME 7HILEINITIALATTEMPTSTOHYDROLYSE ›;=ENANTIOSELECTIVELYWEREUNSUCCESSFUL AFTERASEQUENCEOFMETH ANOLYSIS ALKENEREDUCTIONANDMETHYLATION ATTEMPTSON›PROCEEDED QUITEDIFFERENTLY)NTHISCASE BIOCATALYTICHYDROLYSISOFTHE# /!CWAS ACHIEVED WITH COMPLETE ENANTIOSELECTIVITY USING LIPASE !+ !MANO IN P(BUFFERTOGIVEALCOHOLINTHEMAXIMUMYIELD!SERIESOF STANDARDFUNCTIONALGROUPTRANSFORMATIONSCONVERTEDTOELECTROPHILE THATAFTERFIVEFURTHERSTEPSFURNISHEDENAL2EFORMATSKYREACTION WITHRACEMICMETHYL  BROMOPROPIONATEGAVEAMIXTUREOFALLFOURPOS SIBLEDIASTEREOMERSOFWHICHWASMOSTUSEFULFORCONVERSIONTOASA SINGLEANTIPODEALTHOUGHSTILLREQUIRINGTEDIOUSSEPARATIONANDFIVEFURTHER REACTIONS3OMEMATERIAL WASALSOSALVAGEABLETHROUGHANEIGHT STEP SEQUENCEEMPLOYINGTHEMIXTUREOFSYNDIASTEREOMERSAND THAT FEATURESANENZYMATICACETATEHYDROLYSISTOREMOVETHEOFFENDINGDIASTE REOMER!LTHOUGHNOTSPECIFIED ITISUNLIKELYTHATALLCOMBINEDMATERIAL REPRESENTEDGREATERTHENCHEMICALYIELDFROM#ONDENSATIONOF WITHTHELITHIUMENOLATEOFALSOPREPAREDVIAENZYMATICMEANS ;= GAVE YET ANOTHER DIASTEREOMERIC MIXTURE IN REASONABLE YIELD BUT FAVOURING THE UNDESIRED # EPIMER   3EPARATION AND FOUR FURTHER SYNTHETIC MANIPULATIONS UPON THE DESIRED ISOMER  THEN FURNISHED ALDEHYDE INAMINIMUMOFSTEPSANDAPPROXIMATELYOVERALL YIELD 4HEOTHERMAJORFRAGMENTREQUIREDFORCONSTRUCTIONOFTHE-ERCK INTERMEDIATE WASPHOSPHINEOXIDEWHOSESYNTHESISONCEAGAIN FEATUREDTHEAPPLICATIONOFENZYMESTOPREPAREOPTICALLYPUREMATERIALS 3CHEME ;=!DDITIONOFTHEDIANIONOFTOALDEHYDEFUR NISHEDTHEDESIREDCOUPLEDMATERIAL ASAMIXTUREOFEPIMERS AT # 3EQUENTIAL BENZOYLATION AND BENZYLATION AFFORDED AN INTER



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

AcO

AcO

a,b,c

34

O

MeO

30

220 5 steps 56.9%

34

30

221

MeO

30

6 steps ~20% from 225

CHO OPMB

H 230

26 30

H

CO2Me

34

TBSO

e,f,g

30

MeO

26 30

H

CO2Me

OH TBSO

227

MeO

30

TBSO

H

OTBS

CO2Me

34 26

MeO

30

OH 228

i

34

h MeO

20

CHO

5 steps 60%

34

OH

34

30

224

+ TBSO

34

MeO

CO2Me

223

226

26

O 23

MeO

TBSO

34

variety 26

30

CO2Me

222

MeO 34

HO

34

+ MeO

TBSO

TBSO

AcO

d CO2Me

H

H 30

H

O

225

CO2Me

OH 229

231 7 steps 23.7% TBSO TBSO

TBSO

34 26

MeO

30

H

OTBS

23 20

PMBO 232

OH O

26

MeO

30

H

34

j,k,l,m

34

+

OTBS

23 20

PMBO 233

26

MeO

30

H

PMBO

OH O

20 23 CHO O OTBS TBS

215

3CHEME A +#/ -E/(  #B 0D# ( %T/!CC #(. ("& #(#L OVERTHREESTEPSD ,IPASE !+!MANO P(  # ANDE 4"3/4F %T. #(#L  #F ,I!L( 4(&  # → 24 G $-0 #(#L  OVER THREE STEPS H › METHYL  BROMOPROPIONATE :N 0H( REFLUX  AND AND  CONVERSION→INMAXIMUMI  ,$! %T/ n # THEN:N#L THEN  J -E.("/!C  !C/( #(#. n # K 4"3/4F %T. #(#L 24L 4&! 4(& (/M $-0 #(#L OVERFOURSTEPS

MEDIATE WHICH ALLOWED CONVENIENT SEPARATION OF THE DIASTEREOMERS BOTH OF WHICH COULD BE ELABORATED TO THE DESIRED PHOSPHINE OXIDE  ALTHOUGHTHROUGHSLIGHTLYDIFFERENTREACTIONSEQUENCES3CHEME  CONVERSION OF THE UNDESIRED EPIMER NOT SHOWN  ! NUMBER OF UNSPECIFIED YIELDS MAKES AN ESTIMATION OF OVERALL EFFICIENCY IMPOS SIBLEALTHOUGHITCANBESAIDTHESHORTESTSEQUENCETOREQUIREDATA MINIMUMOFFOURSTEPS #ONDITIONSFORTHESUCCESSFULUNIONOFMAJORFRAGMENTSAND WERE REPORTED ALTHOUGH NO YIELD WAS GIVEN !SSUMING SIMILAR SUCCESS TOTHATOFTHE-ERCKGROUPANESTIMATEFORTHEPROJECTEDOVERALLUTILITY OFTHEAPPROACHTO&+ CANBEMADEANDSUGGESTSATOTALYIELDOF THROUGHSTEPS!NUMBEROFTEDIOUSSEPARATIONSOFDIASTEREO MERS LONGSYNTHETICSEQUENCES ANDSOMETIMESLOWYIELDSDETRACTFROM THEOVERALLAPPROACH(OWEVER 3IHHASMANAGEDTOUSETHEPLATFORMOF



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

18

18

CO2Et

CO2H

a

CO2Et

CO2Et

15

15

234

S

b,c,d,e

O

18 15

S

CO2tBu

18

f,g,h,i

15

H MEMO

OH

OTBS OH

237

10

n

+

CO2Et

S

OH +

Ph2P O

15

OMe OTBS

10

13

10

OEt

m

OTBS

S S

S 10

S 240

242

OH

241

o,p,q,r,s

OBn 18

10

BzO 7 steps

O MEM

S

OTBS

19

MeO S S

S

S 239

238

HO

O

O j,k,l 10

18

15

236

235

15

t,u

OTBS

OMe OMe 244

18

10 15

BzO O

OTBS

OH 243

3CHEME A # CYLINDRACEA LIPASE /& -EITO 3ANGYO P(   B .A( 4(& n # C N"U,I (3#( 3( 4(& n # → n # THEN SODIUM SALT OF  D ISOBUTYLENE (3/ #(#L 24 OVERTHREESTEPSE "AKERSYEAST2ED3TAR TAPWATER  # F -%-#L $)0%! #(#L 24G ,I!L( %T/  #→24H 4"3#L 0Y 24I -E) #A#/ ACETONE (/  # OVERFOUR STEPSJ / #(#L n #THEN0H0 n #→24K (3#( 3( "&q/%T #(#L n #  OVERTWOSTEPSL 00,3IGMA P(M ,I!L( 4(&  #→24N  N"U,I n #→ #→ n # THEN  DRO "Z#L 4(& 0Y  #P .A( .A) 4(& "N"R OVERTWO STEPS SEPARATEDIASTEREOMERSQ 4I#L #(#L HEXANE n #R 4L./ q(/ -E/( %T/ 24 S 4"3#L 0Y #(#LT -E.("/!C  ACETONE !C/( n #U #(. #(#L ("& 24  OVERTWOSTEPS .OYIELDSREPORTED

3CHEME %ND GAMEANDSUMMARYOF3IHSFORMALSYNTHESISOF&+

AFORMIDABLEMOLECULETODEMONSTRATETHEUTILITYOFENZYMESINNATURAL PRODUCTSSYNTHESIS



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

PMP

OAc

OH

26

a,b,c

OAc

26

24

OAc

O

MeO

O

OH

HO

d,e

24

26

OTBS MeO

O

f,g,h

26

OTBS

O

MeO 246

247

O

24

248

24

I

O 249 i,j

TIPSO

34

TBSO MeO

30

H OTBS

26

11 steps 23.4%

MeO

34

22

O

216 PMP 27 steps 1.7%

O

O

H

O

TBSO 26

24

O

O

30

OHC

34

k,l,m

MeO

+ 30

SO2Ph 251

PMP

70 16 steps 7.1%

26

24

O

O

PMP 250 10 steps 23.8%

3CHEME A -E/( 3N#L   $#% B .A/-E -E/( C 4"3#L %T. #(#L  OVER THREE STEPS D M#0"!   THIOBIS TERT BUTYL  METHYLPHENOL #(#L REFLUX  E #U#. -E,I %T/ n #→ # THENEPOXIDEFROM n #→ #F P ANISALDEHYDEDIMETHYLACETAL #3! 0H( REFLUX $EAN 3TARKG 4"!& 4(& OVERTHREESTEPSH 0H0 ) 0Y 0H(  # I :N 0Y %T/( REFLUXJ 0043 #(#L OVERTWOSTEPSK  N"U,I 4(& n # THENL  "". 4(&  # THEN.A/( (/M $-0 0Y #(#L 24 OVERTHREESTEPS



4HE$ANISHEFSKYSYNTHESISOFTHE-ERCKINTERMEDIATE

)NTHECOURSEOFEXTENSIVEINVESTIGATIONSINTOTHESYNTHESISOF&+ $AN ISHEFSKYARRIVEDATANALTERNATIVESTRATEGYTOTHE# #PORTIONOFTHE MOLECULE;=!SISOFTENTHECASEINSYNTHESESOFSUCHELABORATETARGETS $ANISHEFSKY HAD ENVISAGED THE SAME KEY DISCONNECTIONS AS THE -ERCK GROUP WITHMACROCYCLISATIONVIALACTAMBONDFORMATIONANDFURTHERCLEAV AGEOFACROSSTHE# #ISOLATEDTRISUBSTITUTEDALKENE(OWEVER THE LATTERWASANTICIPATEDVIAADDITIONOFTHELITHIOANIONOFSULFONETO ALDEHYDE COMPAREDTOTHE7ITTIG TYPEAPPROACHALREADYREPORTED !LDEHYDEWASPREPAREDINCOMMERCIALLYAVAILABLEGALACTOSEDERIVA TIVE  IN  STEPS  YIELD ;= )NITIAL INSTALLATION OF THE # METHOXYGROUPUSINGMETHANOLINTHEPRESENCEOF3N#LGAVE WHICH AFTERPROTECTINGGROUPMANIPULATIONSUNDERWENTDIRECTEDEPOXIDATIONTO GIVEPREDOMINANTLYβ OXIRANE ;=2EGIOSELECTIVEORGANOCUPRATE ATTACK THEN INSTALLED THE # METHYL GROUP BEFORE A SERIES OF STANDARD TRANSFORMATIONS LED TO IODIDE  4HE SYNTHESIS OF THIS FRAGMENT WAS COMPLETEDONTREATMENTWITHZINC0Y %T/( REFLUX WHEREIN6ASELLA TYPE FRAGMENTATION;=OFTHEPYRANOSERINGAFFORDEDINOVERTWO



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

HO OH O HO OMe 14 OH 252

a,b,c,d

MeO OH O OH BnO 14 OMe 253

O

e,f,g,h

OBn

O

14

18

19

MeO

S

15

10

OMe OTBS

S

217

OEt

O

OH

10

14

MeO

OMe

258

o,p,q,r

BF4 PPh2

O

OBz 18

18

OMe

255

Rh

MeO

OH

14

MeO

OMe 254

Ph2P

t,u,v,w,x,y z,aa,bb

OH

O O

SO2Ph

OMe

i,j,k,l,m,n

O

257 s

MeO

OH

OBz

14

10

MeO

18

OMe

256

3CHEME A 4"3#L %T. $-!0 #(#L 24 B N"U3N / 0H#( REFLUX THEN"N"R 4"!)  #  C .A( -E) 4(& 24 D -(#L 4(& REFLUX E .A"( %T/( 24 F ACETONE P4S/( ¯-3 24 G #/#L  $-3/ #(#L n # THEN%T. n #→24H 0H0#-E #/-E #(#L  #→24 OVERTWOSTEPSI ,I%T"( 4(& n #→n # J -S#L ,I#L S COLLI DINE $-&  # K .A#. $-& 24 L $)"!, ( #(#L n #M .A"( %T/( 24  OVERTWOSTEPSN .A .(LIQ n # n # O !C/( (/ 4(& REFLUXP .A)/ 4(& (/ 24Q 0H0#-E #/-E #(#L  #→24"Z#L 0Y 4(& 24 OVERFOURSTEPSS  ( PSI #(#L 24 T 4S/( ¯-3 #(#L U ,IS"U "( 4(& n # V (3#( 3( "&q/%T #(#L n #→ # W 4"3/4F   LUT #(#L 24 X +#/ -E/( 24 Y -S#L %T. #(#L  # Z .A) ACETONE REFLUX AA 0H3/.A $-& 24  BB N"U,I -E) 4(& n # 

STEPS AFTER EPIMERISATION OF THE AXIAL BENZYLIDENE ACETAL TO THE DESIRED EQUATORIALCONFORMER4HISWASTHENCOUPLEDWITHTHESULFONE STABILISED ANIONOF PREPAREDUSINGSTANDARDMETHODOLOGYSTEPS  ;= ANDTHERESULTINGDIASTEREOMERICMIXTUREELABORATEDTOKEY# #ALDE HYDEWITHOUTMAJORINCIDENTSTEPS YIELD 3CHEME  7ORTHYOFPARTICULARNOTEIN$ANISHEFSKYSWORKISHISAPPROACHTOTHE # #FRAGMENT OF&+ ;=#ONTAINEDWITHINTHESEVEN CARBONSFROM#TO#ISDUPLICATIONOFTHESYNMETHYL METHOXYRELA TIONSHIPAROUNDTHECENTRAL#SECONDARYHYDROXYLGROUP2ECOGNITION THATTHISSTEREOCENTRECOULDBEEXPLOITEDTOESTABLISHBOTHRELATIONSHIPS BYCONCURRENTHYDROGENATIONOFADIOLEFIN REPRESENTSANINTERESTING APPROACHTOSETTINGTHESESTEREOCENTRES3CHEME  !LTHOUGHTWOROUTESWEREDEVELOPED THEONEWHICHFEATUREDDIFFEREN TIATEDTERMINIASINPROVEDMOREAPPLICABLETOMATERIALTHROUGHPUT 4HUS BEGINNINGFROMCOMMERCIALLYAVAILABLEANDINEXPENSIVEβ $ GALAC TOPYRANOSIDE ASANINITIALSOURCEOFCHIRALITY ASERIESOFRELIABLEAND HIGHYIELDINGTRANSFORMATIONSFURNISHED4HISWASFURTHERELABORATED



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME %ND GAMEANDSUMMARYOF$ANISHEFSKYSFORMALSYNTHESISOF&+ A  N"U,I 4(& n # THEN B #&#/ / 0Y $-!0 #(#LC LITHIUMNAPHTHALENIDE 4(& n # OVERTWO STEPS %: INSEPARABLED 0043  PROPANOL #(#.  # E 4)03/4F   LUT 

TO THE BISOLEFINIC REDUCTION SUBSTRATE  THROUGH PROTECTING GROUP MANIPULATIONSANDSEQUENTIALHOMOLOGATIONAT#WITHCYANIDEFOLLOWED BY#VIAA(ORNER 7ADSWORTH %MMONS(7% REACTION;=$IRECTED HYDROGENATION OF THE ALKENE GROUPS WITHIN  WAS ACHIEVED USING ( AT PSIINTHEPRESENCEOF%VANSRHODIUMCATALYST;=)NTHIS CASEITISBELIEVEDTHATTHEALLYLICMETHOXYGROUPSSTRONGLYFAVOURPRODUCT ;= ANDINDEEDTHISWASISOLATEDINANIMPRESSIVEYIELDOF! VARIETYOFSTANDARDFUNCTIONALGROUPMANIPULATIONSWERETHENEMPLOYED TOCONVERTTOTHEFULLYELABORATEDSULFONEINATOTALOFSTEPSAND OVERALLYIELD3CHEME  )NTHEEVENTOFTHEKEY# #COUPLINGREACTION LITHIATIONOF N"U,I 4(& n # PROCEEDEDSMOOTHLYANDUPONADDITIONOFALDEHYDE  ADIASTEREOMERICMIXTUREOFβ HYDROXYSULFONESWASPRODUCEDINGOOD YIELD5NFORTUNATELY ATTEMPTSTODIRECTLYINSTALLTHEUNSATURATIONBYREDUC TIVEELIMINATIONOFTHEVICINALPHENYLSULFONEANDHYDROXYLGROUPSPROVED PROBLEMATIC ASNODESIREDPRODUCTWASISOLATEDANDANALYSISINSTEADSUG GESTEDLOSSOFTHE#ALLYLGROUP!FTERMUCHEXPERIMENTATION$ANISHEF SKYWASABLETOOVERCOMETHISTHROUGHMODIFICATIONOFTHELEAVINGGROUPAT #VIAFORMATIONTHEMORELABILETRIFLUOROACETATE!SARESULT ELIMINATION WASREADILYACHIEVEDUSINGLITHIUMNAPHTHALENIDE4(& n # GIVINGA YIELDOFFORTHESELASTTWOSTEPS3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

$ESPITE THE PRESENCE OF THE COMPLETE BACKBONE OF THE -ERCK INTER MEDIATE FURTHERPROBLEMSWEREENCOUNTEREDTHATMARREDTHEENDOFTHE STRATEGY5NFORTUNATELY THE# #ALKENEWASFORMEDASANINSEPARABLE MIXTUREOFGEOMETRICISOMERS%VENMOREFRUSTRATINGLY SUBSEQUENT CLEAVAGE OF THE PARA METHOXYBENZYLIDENE ACETAL PROVED ELUSIVE GIVING OFTHECORRESPONDINGDIOLATBEST0043  PROPANOL ACETONITRILE  # ALTHOUGH SEPARATION OF THE GEOMETRIC OLEFIN ISOMERS WAS AT LEAST POSSIBLE,ATE STAGEDIFFICULTIESWITHPROTECTINGGROUPSTRATEGIESARESOOFTEN APITFALLINNATURALPRODUCTSSYNTHESIS ANDWHILEINTHISCASEITISUNDOUBT EDLYDISAPPOINTING $ANISHEFSKYWASNEVERTHELESSABLETOFURTHERELABORATE TOASUITABLE-ERCKINTERMEDIATEANDCOMPLETETHEFORMALSYNTHESISOF &+ /VERALLTHEPROJECTEDTOTALSYNTHESISOF&+ ASSUMINGTHE SAMEEND GAMEASPREVIOUSLYEMPLOYEDBYTHE-ERCKGROUPAFFORDSIN ATOTALOFSTEPSANDOVERALLYIELDSUBSTANTIALLYLONGERANDLOWER YIELDINGTHENTHEORIGINALREPORT3CHEME 



4HE3MITHSYNTHESISOFTHE-ERCKINTERMEDIATE

/FTHEFORMALSYNTHESESACHIEVED !MOS3MITH)))HASREPORTEDTHEONLY APPROACHTHATDIFFERSINITSMAINDISCONNECTIONOFTHE-ERCKINTERMEDIATE ;=7HILE-ERCK 3IHAND$ANISHEFSKYALLATTEMPTEDFRAGMENTUNION THROUGHTHE# #OLEFIN 3MITHSAWTHISASAMISJUDGEMENT"YCHOOS ING AN ALTERNATE STRATEGY HE THOUGHT IT WAS POSSIBLE TO DEVELOP A MORE EFFECTIVE AND STEREOCONTROLLED GENERATION OF THE TRISUBSTITUTED OLEFIN AS WELLASANIMPROVEDFRAGMENTCOUPLING4OTHISEND HEENVISAGEDFORMA TIONOFTHE# #BONDTHROUGHCOUPLINGOFA# #DITHIANE ;=WITHA# #PRIMARYALKYLIODIDE;= 3MITHSAPPROACHTOTHETRISUBSTITUTEDALKENEDERIVESFROMTHEREADILY PREPAREDALKYNE3UBSEQUENTTREATMENTWITH-E!LINTHEPRESENCEOF CATALYTIC #P:R#L EFFECTED CARBOALUMINATION TO GIVE THE CORRESPONDING VINYLALANEASASINGLEGEOMETRICISOMER!FTERFORMATIONOFTHEATECOMPLEX WITHN"U,I ADDITIONOFSYMMETRICALTRANS SUBSTITUTEDEPOXIDE;= GAVEALCOHOLINPLEASINGYIELD EVENONLARGE SCALE7HILETHEUSEOF THIS SYMMETRICAL EPOXIDE NECESSITATED SUBSEQUENT DIFFERENTIATION OF THE TWOPRIMARYBENZYLETHERS ITAVOIDEDPROBLEMSWITHALACKOFCHEMOSELEC TIVITYENCOUNTEREDWHENUSINGALTERNATIVEASYMMETRICEPOXIDES4HUS 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

22 19

+

O

BnO

TBDPSO

OBn

a

OBn OH

OBn OBn

22

22

b,c,d,e

BnO

f

19

TBDPSO

261 5 steps 65.5%

22

BnO

BnO

19

260 7 steps 68.6%

OBn OBn

MeO

O 10

PhO2S

262

263

19

CO2Me 15

OTBS

PhO2S H MeO O

264 13 steps

265

22

BnO

OMe 19

OBn

10

10 steps

O

22

H OMe 15

OMe OTBS

OMe

219

O

OTBS

OBn OBn

22

10

15

10

OTBS

I

MeO

H

MeO

19 15

HO

h,i 19

OBn OBn

MeO

267

O

H

10

266

15

O

OTBS

3CHEME A -E!L #P:R#L #L#(#(#LN"U,I HEXANES  # THEN 0H( B .A( "N"R 4"!) 4(& C 4"!& 4(& D 0H3  "U0 $-& E /XONE¤ 4(& -E/( (/ F N"U,I 4(& n # THEN n #→ # G "U3N( !)". 0H-E REFLUX H (&q0Y 4(&  I -E."(/!C  !C/( #(#. n # 

WASREADILYELABORATEDTOSULFONE WHICHCOULDBEDEPROTONATEDUNDER STANDARDCONDITIONS ANDONSUBSEQUENTADDITIONOFESTERRESULTEDIN OFANEPIMERICMIXTUREOFβ KETOSULFONES $ESULFONATIONOFTHE PRODUCT MIXTURE PROVED UNEXPECTEDLY TROUBLESOME BUT WAS EVENTUALLY ACHIEVEDWITHTHENOVELUSEOFN"U3N(ANDAZOBISISOBUTYLONITRILE!)". INREFLUXINGTOLUENE GIVINGKETONE$ESILYLATIONANDDIRECTEDREDUC TION USING TETRAMETHYLAMMONIUM TRIACETOXYBOROHYDRIDE FURNISHED THE DESIREDANTI   DIOLASTHEMAJORPRODUCT 4HISWASELABORATED THROUGHTOKEYα SILOXYIODIDEUSINGASTANDARDSEQUENCEINVOLVING FUNCTIONALGROUPMANIPULATIONSWHICHPROCEEDEDWITHOUTINCIDENTTO FURNISHTHEDESIREDFRAGMENTINATOTALOFSTEPSANDOVERALLYIELD 3CHEME  4HECOUPLINGPARTNERFORIODIDEWASDITHIANE DERIVEDFROMSUL FONEPREPAREDINANEAR IDENTICALSEQUENCETOTHATOF$ANISHEFSKY AND ALDEHYDE;=4HELATTERWASACHIEVEDINASEQUENCEOFSEVENSTEPS FROMCROTYLALCOHOLAFTERINITIAL3HARPLESSASYMMETRICEPOXIDATION ANDPROTECTIONOFTHEPRIMARYALCOHOL ADDITIONOFTHELITHIOANIONOF  DITHIANEINTHEPRESENCEOF  DIMETHYL     TETRAHYDRO ( PYRIM



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

O

a,b

26

TBDPSO

HO

268

c

26

S

26

TBDPSO

O

d,e,f,g

OH S

269

270

MeO

TBDPSO

34

30

l

H

S

26 24

PMBO

218

S

MeO

i,j,k

H 26 TfO PMBO 273

34

SO2Ph

S 24

S

h

30

TBDPSO

34

30

24

S

271 TBSO 70 14 steps MeO

TBDPSO

S

26

H PMBO

24

MeO

34

SO2Ph 30

S

26

HO PMBO

24

S

272

3CHEME A 3HARPLESS!% $ n $%4 #(#LB 4"$03#L %T. $-!0CAT $-& OVERTWOSTEPSC  LITHIO   DITHIANE $-05 4(&  # D 4"!& 4(&E P ANISALDEHYDEDIMETHYLACETAL P4S/( $-&  # OVERTWOSTEPSF $)"!, ( #(#L n # G 3/q0Y $-3/ %T. #(#L  #H  N"U,I 4(& n # THEN OVERTWOSTEPSI 4&!! $-3/ #(#L n # THEN %T. J !L(G 4(&AQ REFLUX K ,$! . PHENYLTRIFLIMIDE $-% $-05 n #TO24 L -E#U,I 4(&  # 

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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O

3CHEME 2ETROSYNTHETICANALYSIS

4HECHIRALAUXILIARYWASREMOVEDUSINGSODIUMBOROHYDRIDETOGIVEDIOL WHICHWASSUBJECTEDTOPROTECTINGGROUPMANIPULATIONSANDATWO STEP3WERN 0INNICKOXIDATIONPROTOCOLTOFURNISHACID!FTERFORMATION OFTHEMIXEDANHYDRIDEOF ADDITIONOFCHIRALAUXILIARYRESULTEDIN . ACYLATIONTOGIVEAMIDE WHICHCOULDBEMETHYLATEDAT#VIATHE SODIUM ENOLATE WITH COMPLETE DIASTEREOSELECTIVITY ALBEIT IN DISAPPOINT ING YIELD &URTHER REDUCTIVE REMOVAL OF THE OXAZOLIDINONE WAS FOLLOWED BY3WERNOXIDATIONANDHOMOLOGATIONWITHTHELITHIUM ENOLATEOFETHYL ACETATE GIVINGβ HYDROXYESTERASAMIXTUREOFDIASTEREOMERS !FTERHYDROLYSISOFUSING,I/( THEPIPECOLATEMOIETYWASINTRO DUCEDASTHEMETHYLESTERWITH%$#)AND(/"T GIVINGINMODERATE YIELD OVERTWOSTEPS/XIDATIONOFβ HYDROXYAMIDEWITH$ESS -ARTIN PERIODINANE INSTALLED THE    TRICARBONYL FUNCTIONALITY ;= ANDONDESILYLATIONTHISRESULTEDINSPONTANEOUSLACTOLFORMATION  )THASBEENDEMONSTRATEDTHATNATURALPRODUCTSOFTHISTYPETHATFEATURE THE   TRICARBONYLFUNCTIONALITYMASKEDASASIX MEMBEREDLACTOLCAN ACTUALLYEXISTASISOMERICMIXTURESWITHTHESEVEN MEMBEREDLACTOL;= ANDCONSEQUENTLYTOAVOIDANYCOMPLICATIONSASSOCIATEDWITHTHIS THE # HYDROXYLGROUPWASPROTECTEDASTHE4-3ETHER THROUGHABIS PROTECTIONMONO DEPROTECTION STRATEGY &INALLY 0ARIKH $OERING OXIDA TIONOFTHEPRIMARYALCOHOLGAVETHEDESIREDALDEHYDEELECTROPHILE 3CHEME  4HISSENSITIVEINTERMEDIATEWASUSEDWITHOUTPURIFICATIONINA.OZAKI (IYAMA +ISHI.(+ ;n=COUPLINGWITHVINYLIODIDEPREPARED INASERIESOFSEVENSTRAIGHTFORWARDREACTIONSFROMTHEMONO TERT BUTYLDI METHYLSILYL MONO 4"3 ETHER OF PENTANE   DIOL   4HIS COUPLING



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

Bn

N

O S

Bn H

16

14

10

O

OBn

+

O 316

a

N

O S

16

14

O

OH

317

b

10

c,d

14

16

318

14

16

10

10

OH

OTBS

TBSO

OBn

OH

HO

OBn

319

320

Bn

HN

Bn 16

TBSO

OEt

14

10

OTBS

OH O

j,k

16

TBSO

325

l,m

6

h,i

14

10

OTBS

OH

16

TBSO

324

N

14

10

OTBS

O

e,f

O

O 322 g

O

16

TBSO

O

10

OTBS

O

323

321

1

N H 326

CO2Me 1

6 6

6

16

TBSO

OH

14

14

10

OTBS

OH O

n,o

N 1

CO2Me

1

N O

10

O

N

1

6

CO2Me p,q

O HO

N

O TMSO

CO2Me r

O

O TMSO 10

10

O

O 14

327

14

328

16

OH

14

329

16

CO2Me

O

OH 330

16

H

O

3CHEME A  4I#L $)0%! #(#L n # THEN n #→ # B .A"( %T/(  #  C 4"3#L )M $-!0CAT $-&  #→24D ( 0D# %T/!C OVERTWOSTEPSE #/#L  $-3/ #(#L n # THEN%T. n #→24F .A#L/ .A(0/  METHYL  BUTENE T"U/(  # →24 OVERTWOSTEPSG 0IV#L %T. 4(& THEN ,I#L n #→24 H .A(-$3 4(& THEN-E) n #I ,I"( %T/ (/  # OVERTWOSTEPSJ #/#L  $-3/ #(#L n # THEN%T. n #→24K ,$! #(#/%T 4(& n #→ # OVERTWOSTEPSL ,I/( 4(& -E/( (/  #→24M , 0IP /-E %$#) (/"T $)0%! #(#L  #→24 OVER TWOSTEPSN $-0 0Y #(#L 24O (& #(#. OVERTWOSTEPSP 4-3/4F   LUT #(#L  #→24Q .(#L 24 OVERTWOSTEPSR 3/q0Y $-3/ %T. #(#L  # 

GAVEANALLYLICALCOHOLINYIELDASANUNSPECIFIEDMIXTUREOFDIASTEREO MERSTHATWASDIRECTLYOXIDISEDUSING$-0TOCOMPLETETHESYNTHESISTHE FIRSTOFTWOKEYINTERMEDIATES 3CHEME  4HE SYNTHESIS OF THE # # FRAGMENT  BEGAN WITH CHEMISTRY DEVELOPEDINTHE#HAKRABORTYGROUPFORTHEIRSYNTHESISOFTHETOPHALFOF &+ )NTHIS THEYDEVELOPEDASCALABLEROUTETOTHECYCLOHEXYLFRAG MENTOFTHEIMMUNOSUPPRESSANTTHATPROCEEDSVIACYCLOHEXYLMETHYLESTER 3CHEME ;=3TARTINGFROMCOMMERCIALLYAVAILABLE$ n QUINIC ACID  TREATMENT WITH BENZALDEHYDE IN THE PRESENCE OF ACID CATALYST FORMED BOTH THE BENZYLIDENE ACETAL AND FIVE MEMBERED LACTONE IN ONE STEP!FTER"ARTON -C#OMBIEDEOXYGENATION; =TO AFURTHER SERIESOFRADICALREACTIONSFIRSTOPENEDTHEACETAL."3 !)". 0H(  # TOGIVEANDTHENAFFECTEDDEBROMINATIONN"U3N( !)". 0H(  # 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

1

N OTBS

OH

a,b,c,d,e

SePh

I 22

22

331

f,g

22

I 17

17

332

333

+

O TMSO

1

h,i

O 10

N

CO2Me

O

O 10

16

CO2Me 22

O TMSO O

16

H

17

O

O 330

315

3CHEME A #/#L  $-3/ #(#L n # THEN%T. n #→24B #() #R#L 4(&  #→24 OVER TWOSTEPSC #3! #(#L -E/(  # D 4S#L %T. $-!0 #(#L  #→24E 0H3E3E0H .A"( %T/( 4(&  #→24 OVERTWOSTEPSF M#0"! #(#L n #G $)0%! ##L REFLUX OVERTWOSTEPSH #R#L .I#L $-3/ 24 I $-0 0Y #(#L 24 

&INALLY METHANOLYSISOFTHELACTONEACHIEVEDTHEDIFFERENTIATED   TRI SUBSTITUTEDCYCLOHEXYLMOIETYPREVALENTINTHESENATURALPRODUCTS!SERIES OF OXIDATION STATE ADJUSTMENTS AND PROTECTING GROUP MANIPULATIONS LED EVENTUALLYTOALDEHYDE WHICHUNDERWENT(7%OLEFINATION;=WITH KETO PHOSPONATEDERIVEDFROM3 2  NOREPHEDRINE ;=  (YDROGENATIONOFTHERESULTINGDOUBLEBONDUNDERSTANDARDCONDITIONS GAVE. ACYLATEDINYIELDOVERTWOSTEPS "ORONALDOLCONDENSATIONBETWEENTHEENOLATEOFANDCHIRALALDE HYDE DERIVEDINSIXSTRAIGHTFORWARDSTEPSFROM2 2OCHEESTER GAVE THEEXPECTEDANTI ALDOLADDUCTASASINGLEDIASTEREOMER0ROTECTIONOFTHE # HYDROXYLGROUPASTHE4%3ETHER FOLLOWEDBYREDUCTIVECLEAVAGEOF THECHIRALAUXILIARYAFFORDEDWHICHWASDEOXYGENATEDVIATHETOSYLATE USINGSUPERHYDRIDE)NSTALLATIONOFTHETERMINALALKENEWASACHIEVEDUSING 7ITTIGMETHYLENATIONAFTERLIBERATIONOFTHEPRIMARYALCOHOLAND0ARIKH $OERINGOXIDATION ANDFINALSELECTIVEDESILYLATIONUSINGn CAMPHORSUL FONICACID#3! COMPLETEDTHESYNTHESISOFTHESECONDFRAGMENT AND UNMASKEDTHE# /(READYTOCOUPLETHISWITH3CHEME  $ESPITESYNTHESISINGBOTHOFTHEKEYFRAGMENTSINTHEIRRETROSYNTHESIS THROUGHRELIABLEANDPROVENCHEMISTRY THE#HAKRABORTYGROUPHAVENOT REPORTEDTHECONCLUSIONSOFTHEIREFFORTSINTHETIMESINCE4HEIRENDGAME STRATEGYWOULDSEEMPREDICTABLEANDEFFECTIVE HOWEVERTHEREISTHEPOS SIBILITYTHATBYINTRODUCINGTHEPIPECOLATEMOIETYATARELATIVELYEARLYSTAGE OFTHEIRSYNTHESIS THEYMAYHAVEENCOUNTEREDPROBLEMSASSOCIATEDWITH THE CONFIGURATIONALLY LABILE # STEREOCENTRE AS SEEN WHEN ATTEMPTING MACROLACTONISATION IN PREVIOUS SYNTHESES OF THE RELATED &+  VIDE SUPRA )NTHEIRAPPROACH SCRAMBLINGOFTHISCENTREWOULDBEPARTICULARLY



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

Ph

OH

HO

Br

O

O

a

OH OH

32

Ph

O

HO

d

32

32

28 28

O

334

32

e,f

32

335

O

28

O

O

28

HO

OH

O

BzO

BzO

O

b,c

OMe

O

O

O

336

28

337

338

Ph (EtO)2(O)P

g,h

O

N

O

Ph

TBSO 32

N

TBSO

O

H

O

l

HO i,j,k

32

OH

TBSO

28

H 341

32

OH

TBSO

28

O

343 o,p,q

TBSO

32

TBSO

m,n

28

O

TBSO

342

O

340

28

339

OBn

26 22

O

TBSO

344

TBSO

HO 32

TBSO

OBn

26 22

28

OTES 345

TBSO 32

r,s

TBSO

OBn

26 22

28

32

t,u,v,w

TBSO

OTES 346

26 22

28

OH 314

3CHEME A 0H#(/ P4S/( 0H-E B +( #3 -E) 4(& C N"U3N( !)". 0H-E D ."3 !)". 0H(  # E N"U3N( !)". 0H(  # F +#/ -E/(  # G 4"3/4F   LUT #(#L  #H $)"!, ( #(#L n #→ # H OVERTWOSTEPSI !C#L    COL LIDINE #(#L n #J 4"3/4F   LUT #(#L  #K +#/ -E/(  #→24 OVERTHREE STEPSL #/#L  $-3/ #(#L n # THEN%T. n #→24 M  ,I#L $)0%! #(#. 24N ( 0D# %T/!C 24 OVERTWOSTEPSO "U"/4F %T. #(#L n # THEN n # →24P 4%3/4F   LUT #(#L  #Q ,I%T"( %T/  # OVERTHREESTEPSR 4S#L %T. $-!0 #(#L  #→24S ,I%T"( 4(& nTO # OVERTWOSTEPST ( 0D# %T/!C 24 U 3/q0Y %T. $-3/ #(#L  #V 0H0#() .A.( %T/  #W #3! -E/( #(#L  # OVERFOURSTEPS

PROBLEMATICTODETECTSPECTROSCOPICALLY DUETOTHEPRESENCEOF. CENTRED ROTAMERSINANUMBEROFSTEPS-ORELIKELY RING CLOSINGMETATHESISMAYBE PROVINGASTUMBLINGBLOCKWITHEITHERSELECTIVEFORMATIONOFTHE# # OLEFINGEOMETRYPROBLEMATIC ORPERHAPSDIRECTDIFFICULTYINFORMINGTHE POTENTIALLYSTRAINEDMACROCYCLEITSELF;=

 4HE.ICOLAOUTOTALSYNTHESISOFRAPAMYCIN !LTHOUGH ORIGINALLY ISOLATED IN THE MID S BY 6ÎZINA AND CO WORKERS ; = RAPAMYCIN DIDNOTATTRACTSERIOUSATTENTIONFROMTHESYNTHETIC ORGANICCOMMUNITYUNTILAPPROXIMATELYYEARSLATER FOLLOWINGTHEDISCLO SUREOF&+ BYTHE&UJISAWAPHARMACEUTICALCOMPANY; =4HEOBVI



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBDPSO

HO

TBDPSO

42

MeO

MeO

38

38

H

H

O HO

9

10

O

O

Ph

Me

MeO

38

H

N

35

+

MeO

CHO

OPMB 26

O

32

32

N H1 O O

28

42

C21-C42 iodide 347

42

O

N H H

OH O

MeO

OMe

O O

OTIPS

O TES

MeO

+

16

(-)-rapamycin 7

HO HO

8

22

1

+ TBSO

N CO2H Boc 12

I

+ O Bu3Sn TIPS 10 SnBu3 O OMe + 348

O

351

OH 22

O

350

OTES 26

34

PMBO

I

352

22

10

16

29

OMe

I HO

O

C8-C18 acid 349 353

OPMB + O

+

8

OMe 16

13

I

354

SiMe3

355

3CHEME 2ETROSYNTHETICANALYSIS

OUSSTRUCTURALHOMOLOGYBETWEENTHESETWOMOLECULES COMBINEDWITHTHE IMPORTANCEOFTHEIRIMMUNOMODULATINGEFFECTS INITIATEDMASSIVERESEARCH EFFORTSACROSSABROADSPECTRUMOFSCIENTIFICDISCIPLINESINCLUDINGNUMEROUS TOTALSYNTHESISEFFORTS.ICOLAOUSAPPROACH SUCCESSFULLYCOMPLETEDIN ; = WASTHEFIRSTTODELIVERSYNTHETICMATERIALANDPAVEDTHEWAYFOR ANALOGUEPREPARATIONASWELLASIMPROVEDUNDERSTANDINGOFTHEDRUGSMODE OFACTIONTHROUGHDELINEATIONOFFUNDAMENTALCELLSIGNALLINGPATHWAYS )N A BOLD END GAME STRATEGY .ICOLAOU INTENDED TO CONSTRUCT A FULLY DEPROTECTEDACYCLICPRECURSORTHROUGHAMIDEBONDFORMATIONBETWEENTHE # #VINYLIODIDE ;=ANDTHE# #TRICARBONYLPRECURSOR  WHICHWOULDTHENLACKONLYTHE# #OLEFINICUNIT4HISLASTTWO CARBONBRIDGEWASENVISIONEDTOBEINTRODUCEDVIAAFINALMACROCYCLISATION USINGDISTANNYLETHENEINADOUBLE@STITCHING3TILLEREACTION3CHEME  ;n= !LTHOUGHTHEREHADBEENPREVIOUSREPORTSOF3TILLEMACROCYCLISATIONS IN THE LITERATURE ; = .ICOLAOUS INTER INTRAMOLECULAR COUPLING APPROACH WAS UNPRECEDENTED AND IF SUCCESSFUL WOULD REPRESENT A NEW METHODFORTHECONSTRUCTIONOFPOLYENEMACROLIDES&URTHERMORE THEMILD REACTIONCONDITIONSANDBROADFUNCTIONALGROUPTOLERANCEOFTHE3TILLEREAC TIONWASANTICIPATEDTOALLOWDIRECTPRODUCTIONOFRAPAMYCIN ANDAVOID PROTECTINGGROUPMANIPULATIONSANDOXIDATIONSTATEADJUSTMENTSNEARTHE ENDOFTHESYNTHESIS&INALLY THELATESTAGEINTRODUCTIONOFTHETRIENEINTHIS FASHIONISSTRATEGICALLYSOUNDANDWOULDMINIMISEANYPOTENTIALPROBLEMS WITHTHISSENSITIVEPORTIONOFTHEMOLECULE3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

"OTH MAJOR COMPONENTS  AND  OF THE EVENTUAL MACROCYCLE PRECURSORWERESUFFICIENTLYCOMPLEXTOREQUIREFURTHERRETROSYNTHETICANAL YSIS2ECOGNISINGTHATTHESTEREOCHEMISTRYAT#AND#OFISULTI MATELYINCONSEQUENTIALASTHESEPOSITIONSWILLLATERBEARTRIGONALCARBONYL GROUPS DISCONNECTIONACROSSTHISBONDTHROUGHARACEMICALDOLREACTION OFMETHYLGLYCOLATE ANDASUITABLE# #ELECTROPHILESHOULDCON VENIENTLYINTRODUCETHEOXYGENFUNCTIONALITYOFTHETRICARBONYLPORTION OFTHEMOLECULE!2OCHEESTERDERIVATIVE WASTHEPLANNEDSOURCE OFTHE#METHYLSTEREOCENTRE ASTHEMETALLATEDPRIMARYIODIDE OUGHTTOATTACKTHELESSHINDEREDTERMINALCARBONATOMOFEPOXIDE FORMINGTHE# #CARBON CARBONBOND.OTEWORTHYINTHEDESIGNOF THISLATTERFRAGMENT ISTHETRISUBSTITUTEDVINYLSILANEWHICHEVENTU ALLYWILLSERVETOINTRODUCETHEREQUISITEVINYLIODIDEAT#VIDEINFRA  4HISFUNCTIONALITYMAYBECONVERTEDWITHRETENTIONOFOLEFINGEOMETRY UPONTREATMENTWITHVARIOUSSOURCESOFELECTROPHILICIODIDE; = ANDTHUSTHISAPPROACHAVOIDSCARRYINGASENSITIVEVINYLIODIDETHROUGHA LONGSYNTHETICSEQUENCE &ORTHELARGE# #VINYLIODIDEFRAGMENT THREEDISCONNEC TIONS LEAD TO THE FOUR FRAGMENTS  AND n AS POTENTIAL BUILDING BLOCKS 4HE INDICATED DISASSEMBLY AT # # THROUGH AN ASYMMETRIC %VANSALDOLCONDENSATION; =ISESPECIALLYINTERESTING ASTHECHIRAL OXAZOLIDINONEOFISTOFUNCTIONASBOTHACONTROLELEMENTINSETTING THEABSOLUTESTEREOCHEMISTRYAT#AND#ASWELLASANEVENTUALPRECUR SORTOTHEMETHYLSUBSTITUTIONAT#3UBSEQUENTDISCONNECTIONBETWEEN #AND#THROUGHA.(+COUPLING;n= HOPEFULLYOCCURRINGWITH HIGHDIASTEREOSELECTIVITY WASPLANNEDASTHESECONDMAJORFRAGMENTCOU PLINGREACTIONLEAVINGANDASSIMPLIFIEDTARGETS4HEPREPARATION OFTHEVARIOUSFRAGMENTSANDMAJORCOUPLINGREACTIONSCOMPRISINGTHEFIRST SYNTHESISOFRAPAMYCIN AREDISCUSSEDBELOW 3YNTHESIS OF THE # # DIHYDROXY ACID  COMMENCED WITH THE CONSTRUCTIONOFASUITABLYFUNCTIONALISEDDERIVATIVEOF, ASCORBICACID THATCOMPRISES# #OFRAPAMYCIN !LTHOUGHTHESEQUENCETOPRE PARE7EINREBAMIDE ISSOMEWHATLENGTHY THESTARTINGMATERIALIS INEXPENSIVEANDEMPLOYSACOMBINATIONOFWELLESTABLISHEDLITERATUREPRO TOCOLSTOAFFORDINSEVENSTEPSANDOVERALLYIELD;n=#ON DENSATIONOFWITHTHELITHIO ANIONOFVINYLIODIDE AVAILABLEFROM COMMERCIAL TRIMETHYLSILYLPROPYNE VIAAREGIO ANDSTEREOSELECTIVE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

OH

OH

O

O

OH H

HO

16

a,b,c

MeO

16

f,g

O

O

N

16

O

O

O

13

357

358

359 h,i

Me3Si

OH

MeO2C

O 13

O

13

356

16

O

O

OH

MeO

d,e

O

13

j

Me3Si

18

p,q,r

I

18

360

301

363 10

I

Me3Si

16

10

OMe OH

OPMB

OPMB Me3Si 354 s

m,n,o

O

I Me3Si H

bond 60o + Me rotation R

10

OMe OTIPS

OPMB

O

I

v,w

I

k,l

16

O

O

O

13

O

361

+ Me

H

R

Me3Si

O

X 16

10

OMe OTIPS

O

H

8

353 x

OH

OMe

OMe

HO HO

8

O TIPS 10 O OMe 16

366

Me3Si

362

HO 16

16

OMe

355

365

I

Me3Si

13

364

t,u

13

16

OMe

367

368

y

I

HO HO

8

10

O

O TIPS OMe 16

I

C8-C18 acid 349

3CHEME A   DIMETHOXYPROPANE (#L G ACETONE 24  B #A#/ (/ (/  # →  # THEN CHARCOAL 0D# STEAMBATH C .A(#/ -E) $-! 24 D O PHENYLCARBONOCHLORI DOTHIOATE 0Y #(#L  #→24 E N"U3N( !)". 0H#(  # F .A/( ACETONE (/ G -E/ -E.(q(#L $## %T. #(#L 24 H N"U3N( -OALLYL "R#/ #(#.  CAT 4(& 24I ) #(#L 24 OVERTWOSTEPSJ  T"U,I %T/ n # THEN n #  K ,I!L( ,I) %T/ n #  L .A( -E) $-& 24  M #3! -E/( 24  N #&3/#L %T. #(#L  # O +#/ -E/( 24  OVER TWO STEPS P 0-" 4#! #3! #(#L 24 Q ,I!L( %T/ 24 R ) )M 0H0 0H( 24 S  T"U,I %T/ n # THEN THIENYL#U#. ,I n #→ # THEN n #→ # T 4)03/4F   LUT #(#L  # U .)3 4(& 24 V $$1 #(#L (/ 24 W #/#L  $-3/ #(#L n # THEN%T. n #→ # X  ,$! 4(& n #→24 THEN(-0!  n # Y ,I/( 4(& -E/( (/  # 

MOLYBDENUM CATALYSEDCIS HYDROSTANNYLATIONFOLLOWEDBYCHEMOSELECTIVE REACTIONWITHIODINE AFFORDEDENONE3CHEME  /FPARAMOUNTIMPORTANCEWASTHESUBSEQUENTSTEREOSELECTIVEREDUCTION OFTHEKETONEAT#OF'ENERALLY THEDIASTEREOSELECTIVEREDUCTIONOF β HYDROXYKETONESTOEITHERTHESYN ORANTI   DIOLISAWELLESTABLISHED ANDVALUABLESYNTHETICTRANSFORMATION;n=(OWEVER OFTHEVARIETY OFCONDITIONSWHICHEXIST MOSTAREBYANDLARGEAPPLICABLEONLYTOUNPRO TECTED ALCOHOLS &ORTUNATELY REDUCTION OF  WITH LITHIUM ALUMINUM HYDRIDEATLOWTEMPERATUREINTHEPRESENCEOFLITHIUMIODIDEASACOORDI NATING,EWISACIDWASFOUNDTODELIVERASINGLEALLYLICALCOHOLDIASTEREOMER



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

;n=-ETHYLATIONOFTHENEWLYFORMEDSECONDARYALCOHOLAT#UNDER STANDARDCONDITIONS FOLLOWEDBYACUSTOMARYTHREESTEPSEQUENCETOCON VERTISOPROPYLIDENEKETALTOTHECORRESPONDINGOXIRANE CREATEDTHE ELECTROPHILICCENTRE# NECESSARYFORCHAINEXTENSION&ORTHISPURPOSE AREADILYAVAILABLEDERIVATIVEOFTHE2OCHEESTER ;=WASLITHIATEDBY TREATMENTWITHT"U,IAND FOLLOWINGFORMATIONOFTHEMIXEDHIGHERORDER CUPRATE;= SMOOTHLYFORMEDTHEDESIRED# #BONDOFRAPAMYCIN UPONREACTIONWITH!TTHISPOINT THEVINYLIODIDEFUNCTIONMASKEDAS THECORRESPONDINGSILANEWASREVEALEDBYTREATMENTOF4)03PROTECTED WITH .)3 TO AFFORD  IN EXCELLENT YIELD AND WITH RETENTION OF THE OLEFIN GEOMETRY4HEWELLKNOWNABILITYOFSILICONTOSTABILISEAβ DISPOSEDPOSITIVE CHARGETHEβ EFFECT ;=THROUGHOVERLAPOFACARBON SILICONσBONDWITH AVACANTORDEFICIENT PORBITALONTHEADJACENTCENTREHYPERCONJUGATION ISCRITICALFORTHISREACTIONOUTCOME&ORMAXIMALSTABILISATIONOFTHERESULT INGPOSITIVECHARGE A BONDROTATIONOCCURSTOPLACETHECARBON SILICONσ BONDANDTHEEMPTYP ORBITALINTHESAMEPLANE!LTHOUGHROTATIONINTHE OTHERSENSEIE THROUGHANANGLEOF  WOULDALSOACHIEVETHEOPTIMAL ORIENTATION THISWOULDREQUIREPASSINGTHROUGHAPERPENDICULARGEOMETRY WHEREINALLBENEFICIALINTERACTIONSARELOSTANDTHUSDOESNOTOCCUR#ON SEQUENTLY CLEAVAGEOFTHECARBON SILICONBONDTOREGENERATETHEπ SYSTEM OCCURS FROM A DEFINED CONFIGURATION AND RETENTION OF OLEFIN GEOMETRY IS OBSERVEDSEE 3CHEME 0ROTECTINGGROUPMANIPULATIONAND3WERN OXIDATIONTHENPROVIDEDALDEHYDEREADYFORINTRODUCTIONOFTHEREMAIN INGCARBONFRAMEWORKOFTHE# #CARBOXYLICACID &ORTHISPURPOSE ANINTERMOLECULARALDOLREACTIONBETWEENTHEDIANIONOFMETHYLGLYCOLATE  SERVEDTOINTRODUCETHENECESSARYOXYGENATIONAT#AND# WITHTHE RESULTINGDIASTEREOMERICMIXTUREOFNOCONSEQUENCEDUETOLATEROXIDATION ATTHESECENTRES&INALLY HYDROLYSISOFTHEMETHYLESTEROFUNDERBASIC CONDITIONSCOMPLETEDTHESYNTHESISOFTHE# #FRAGMENTWITHALONGEST LINEARSEQUENCEOFSTEPSANDANOVERALLYIELD 4HEFIRSTKEYCOMPONENTOFTHE# #VINYLIODIDEISALDEHYDE DERIVEDULTIMATELYFROMTHECHIRALPOOL#OMMERCIALLYAVAILABLE    DI / BENZYLIDENE $ MANNITOL WASRECOGNISEDASANINEXPENSIVEAND CONVENIENT SOURCE OF α METHOXY ALDEHYDE  AND FOLLOWING PROTECT ING GROUP MANIPULATIONS LEAD TETRAACETATE CLEAVAGE OF VICINAL DIOL  EFFICIENTLYGENERATEDTWOMOLAREQUIVALENTSOFTHISINITIALBUILDINGBLOCK 3CHEME 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

Ph OH O

28

a,b,c

28

26

O

O

OH OTBDPS

MeO

O

26

28

TBDPSO

OH

26

O d

28

H

26

OH OMe

OH OTBDPS

22

O Ph

22

OH

N O

O

O

OMe

O

22

374 25

372

25

N

376

O

i

373

Ph

375

k,l,m

CHO

Ph

OPMB q

OPMB 22

p

28

OH

26

O 22

O 28

n,o

OH OTBDPS 22

28 26

26

OMe

OMe OMe

22

351

26

Ph

O

N

O

e,f,g,h 25

26

28

j

O Li

28

22

371

369

MeO

OTBDPS OMe

370

Ph

28

26

379

378

377

3CHEME A .A( -E) $-& 24 B 0D# (G %T/( %T/!C 24 C 4"$03#L )M $-& 24 D 0B/!C  .A#/ #(#L  #→24 E M#0"! #(#L 24F (#L/ (/ 4(& 24 G .A)/ (/ 4(& 24H #R/ (3/AQ ACETONE OVERFOURSTEPSI #( ##/ #L %T. %T/ n #→ # THEN n #→ # J  N"U"/4F %T. #(#L n #→ # THEN  n #→n # THEN(/AQ K ,I"( (/ %T/  #→24 L 4S#L %T. $-!0 #(#L  # M ,I%T"( 4(&  #→24 N 4"!& 4(& 24 O P ANISALDEHYDE DIMETHYLACETAL #3! #(#L 24 P $)"!, ( #(#L n #→24 Q #/#L  $-3/ #(#L n # THEN%T. n #→ # 

4HEREMAININGCARBONATOMSOFTHE# #ELECTROPHILEREQUIREDCON STRUCTIONOF. ACYLOXYAZOLIDINONEWHOSEPREPARATIONBEGINSFROM β CITRONELLENE 3ELECTIVEOXIDATION;=OFTHEMOREELECTRONRICHTRI SUBSTITUTEDOLEFINBYTREATMENTWITHM#0"! FOLLOWEDBYACIDICHYDROLYSIS OFTHERESULTINGEPOXIDE FURNISHEDA  DIOLWHICHWASSUBSEQUENTLYCON VERTEDTOCARBOXYLICACIDTHROUGHSODIUMPERIODATEINDUCEDOXIDATIVE CLEAVAGEAND*ONESOXIDATIONOFTHEINTERMEDIATEALDEHYDE!NAPPEALING ASPECTOFTHISFOURSTEPSEQUENCEISTHEABSENCEOFANYCHROMATOGRAPHIC PURIFICATIONSnIDEALINTHEEARLYSTAGEOFASYNTHETICPROCESS ASTHEYMUST BE PERFORMED ON A SUBSTANTIAL SCALE )NTRODUCTION OF THE OXAZOLIDINONE ;=DERIVEDFROM3 2 NOREPHEDRINEVIAAMIXEDANHYDRIDECOMPLETED THEPREPARATIONOF3CHEME  !RECURRINGSTRATEGICOPERATIONWITHINTHE.ICOLAOUAPPROACHTORAPA MYCIN ISTHEUSEOFANOXAZOLIDINONEAUXILIARYBOTHTOCONTROLFACIAL



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

SELECTIVITYANDTOSERVEEVENTUALLYASASURROGATETOAMETHYLSUBSTITUENT 4HIS IS APTLY DEMONSTRATED IN THE SYNTHESIS OF THE # # ALDEHYDE WHEREINFRAGMENTCOUPLINGBETWEENTHEBORONENOLATEOFANDSETS BOTHTHE#AND#STEREOCHEMISTRY4HECHIRALAUXILIARYISSUBSEQUENTLY CONVERTED THROUGHASHORTSEQUENCECULMINATINGWITHTHEREDUCTIONOFA PRIMARYTOSYLATEWITH3UPER(YDRIDE4-TOTHEREQUISITE#METHYLGROUP !LTHOUGHREQUIRINGTHREESYNTHETICOPERATIONSTOACCOMPLISH THESEADDI TIONAL STEPS WERE OFFSET BY THE EXCEPTIONAL SUBSTRATE CONTROL OBSERVED TYPICALOFAN%VANSALDOLCONDENSATION$ESILYLATIONOFFOLLOWEDBY SUBSEQUENT BENZYLIDENE ACETAL FORMATION VIA ADDITION OF PARA ANISALDE HYDEDIMETHYLACETALUNDERACIDICCONDITIONSGENERATED!REDUCTIVE CLEAVAGEWASTHENREGIOSELECTIVELYACCOMPLISHEDBYTREATMENTOFWITH $)"!, ( TO RELEASE THE # PRIMARY ALCOHOL  REPRESENTING A USEFUL METHOD TO SELECTIVELY PROTECT THE MORE HINDERED ALCOHOL OF A   DIOL &INALLY 3WERNOXIDATIONCOMPLETEDTHESYNTHESISOFINALONGESTLINEAR SEQUENCEOFSTEPSANDANOVERALLYIELDOF 4HESYNTHESISOFTHESECONDMAJORELEMENT OFTHE# #VINYL IODIDE  BEGAN WITH THE GENERATION OF ACHIRAL ALDEHYDE  FROM PROPANE   DIOL;=4HETWOCONTIGUOUSSTEREOCENTRESAT#AND# OFWEREINTRODUCEDSIMULTANEOUSLYVIATHE"ROWNASYMMETRICCROT YLATIONPROTOCOLWITHEXCELLENTSELECTIVITY; =!SERIESOFSTANDARD FUNCTIONALGROUPMANIPULATIONS INCLUDINGMETHYLATIONOFANINTERMEDI ATELITHIUMACETYLIDEDURING#OREY &UCHSHOMOLOGATION;= PROVIDED ANINTERNALALKYNE INPREPARATIONFORTRANSFORMATIONTOTHECRITICAL TRANS VINYLIODIDE 4HISWASREADILYACHIEVEDVIAHYDROZIRCONATIONOF THETRIPLEBONDWITH#P:R( #LFOLLOWEDBYTRAPPINGWITHIODINE7HILE TERMINALALKYNESAREALWAYSHYDROZIRCONATEDTOTHETERMINALALKENYLZIRCO NIUMPRODUCTANINTERNALALKYNECANATTIMESGIVEREGIOISOMERICMIXTURES )NGENERAL ZIRCONIUMADDSPREFERENTIALLYTOTHECARBONATOMBEARINGTHE STERICALLYSMALLERSUBSTITUENT(OWEVER TOACHIEVEGOODSELECTIVITY ASLIGHT EXCESS OF #P:R( #L AND PROLONGED REACTIONS TIMES IS CRITICAL TO ALLOW EQUILIBRATIONOFTHEINITIALKINETICMIXTUREVIAAPROPOSEDDOUBLYHYDRO ZIRCONATEDINTERMEDIATE;='RATIFYINGLY INTHECASEINQUESTIONONLY THEDESIREDISOMERWASOBSERVED COMPLETINGTHESYNTHESISOFTHISFRAG MENTINEIGHTOVERALLSTEPSANDYIELD3CHEME  4HESYNTHESISOFTHEREMAININGCOMPONENTOF BEARINGTHETRISUB STITUTEDCYCLOHEXANEMOIETY REQUIREDEFFICIENTACCESSTOOPTICALLYACTIVE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

32

O

a,b

34

OH OH

H

OH OTBS

c

34

30

H

OTBS

32

380

381

PMB OTBS O

O

d,e

34

34 30

382

383

f

RL

Zr(Cp)2Cl

RS

H

RL

H

RS

Zr(Cp)2Cl

+

TBSO

34

h

E-elimination

PMBO 352

29

I

Cp2Zr(H)Cl

Cp2Zr(H)Cl

RL RS

H

H

Zr(Cp)2Cl

TBSO

g

34 29

PMBO

385

PMB OTBS O

Br

29

34

Br 384

Zr(Cp)2Cl

3CHEME A 4"3#L %T. #(#L 24B 0## .A/!C #(#L 24 OVERTWOSTEPSC TRANS  BUTENE N"U,I +/T"U  )PC"/-E THEN"&q/%T THEN n #→24 THEN..A/(AQ (/ 24  EED .A(-$3 0-""R 4(& $-&  # E / 0Y -E/( #(#L n # THEN -E3 n #→24 F #"R 0H0 :NDUST #(#L  #G N"U,I 4(& n #→n # THEN -E) n #→ # H #P:R( #L 24 THEN)  # 

2  CYCLOHEXEN  OL &ORTHISPURPOSETHEPOWERFUL#OREY "AKSHI 3HIBATA#"3 REDUCTIONOFPROCHIRALKETONESDEVELOPEDBY#OREYANDCO WORKERSWASSELECTED; =4HISMETHODOLOGYHASANUMBEROFADVAN TAGES WIDESCOPE READYAVAILABILITYOFEITHERENANTIOMERICFORMOF THECATALYST PREDICTABLESTEREOCHEMICALOUTCOME HIGHYIELDSAND EXPERIMENTALSIMPLICITYAND EASYANDEFFICIENTRECOVERYOFTHEAMINO ALCOHOLCATALYSTPRECURSOR (OWEVER THE#"3REDUCTIONREQUIRESSUBSTAN TIALSTERICBIASINTHESUBSTRATE ANDTHUSTHEUSEOFATEMPORARYBROMINE ATOMINISACLEVERMETHODTOACHIEVEHIGHSELECTIVITY!PPLICATIONOF STANDARDCONDITIONSFORASYMMETRICREDUCTIONOF BROMOCYCLOHEXENONE  ; =GAVETHEENANTIOMERICALLYENRICHEDALLYLICALCOHOL IN NEARQUANTITATIVEYIELDANDWITHHIGHENANTIOCONTROLEE 0RACTICAL ACCESSTOTHECRITICALENANTIOENRICHEDBUILDINGBLOCK2  CYCLOHEXEN  OLWASTHENESTABLISHEDFOLLOWINGREDUCTIVECLEAVAGEOFTHE# "RBONDIN WITHLITHIUMMETAL4HEFREESECONDARYALCOHOLPRESENTINWAS PRODUCTIVELYUSEDTOSUBSEQUENTLYDIRECTOXIDATIONOFTHERESULTANTADJA CENTOLEFINTHROUGHTREATMENTWITHM#0"!INAPROCESSTERMEDTHE(EN BESTEPOXIDATION;=!FTERBENZYLATION STEREOSPECIFICRING OPENINGOF WITHMETHANOLUNDERACIDICCATALYSISOCCURREDREGIOSELECTIVELYATTHE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

Ph

O

N B

O Br

a

42

38

Ph

O

Ph

O

388 b

42

OH

Me

Br

42

O

B

38

386

B

N

OBn c,d,e

42

42

Ph

O

38 38

H

387

38

391

390

Br

389 f,g

NMe2 TBSO

42

O

O

MeO

42

MeO MeO

TBSO

j,k

42

TBSO

OBn 42

TBSO

h,i

42

MeO

38

MeO

38

MeO

38

38

38

396

397

l

42

NMe2

38

TBSO

O

O

OH m

TBSO

n,o

392

393

394

395

Ph

Me

(EtO)2(O)P N

TBSO MeO

42

38

OH

p,q

TBSO

MeO

42

38

CHO

O 342 r

O

TBSO

TBDPSO

42

O 38

H

N

35

O 398

224

Ph

Me

MeO

399

O

s,t,u

42

Ph

Me

MeO

38

H

N

35

O

O

O

O

350

3CHEME A 0H3E"R 0Y #(#L  # B  "(q$-3 4(& n #  EEC ,I 4(& T"U/( REFLUX D M#0"! #(#L 24E .A( "N"R 4"!) 4(&  # OVERTWOSTEPSF #3! -E/( 24  G 4"3/4F   LUT #(#L  #  H (  0D# %T/( 24  I #/#L  $-3/ #(#L n # THEN%T. n #→n # J ,$! 4(& n # THEN4-3#L n #→ 24K 0D/!C  #(#.  # OVERTWOSTEPSL ,I"( #E#Lq(/ 4(& -E/( n #  M . . DIMETHYLACETAMIDEDIMETHYLACETAL XYLENES REFLUX N ,I%T"( 4(&  #O (  0D# %T/( 24 OVERTWOSTEPSP O ./#(3E#. N"U0 4(& 24 THEN(/ 4(& 24 Q / -E/( #(#L n # THEN-E3 n #→24 R  ,I#L I0R.%T #(#. 24 S %T3I(NEAT 0H0 2H#L  #T (&AQ #(#. 24U 4"$03#L )M $-& 24  OVERTHREESTEPS

MORESTERICALLYACCESSIBLEPOSITIONOFTHEOXIRANETOFURNISHFOLLOWING SILYLATION3CHEME  4HERECOGNITIONTHAT  TRANSFEROFSTEREOCHEMISTRYFROM#TO# VIA A ; = SIGMATROPIC REARRANGEMENT COULD INTRODUCE THE REQUISITE CAR BONSIDECHAINOFTHECYCLOHEXANESECTOROFRAPAMYCIN DICTATEDTHE NEXTCHEMICALTRANSFORMATIONS&OLLOWINGTHEDEBENZYLATIONAND3WERN OXIDATIONOF INTRODUCTIONOFTHENECESSARYUNSATURATIONWASACCOM PLISHEDVIAIMPLEMENTATIONOFTHE3AEGUSAPROTOCOL;=WITHTHEKINETIC TRIMETHYLSILYL4-3 SILYLENOLETHEROF7ITHENONEINHAND AXIAL DELIVERY OF HYDRIDE IN A   FASHION UNDER ,UCHE CONDITIONS ; = ESTABLISHED WITHEXCELLENTDIASTEREOSELECTIVITY ALLYLICALCOHOLINTHE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

DESIREDSTEREOCHEMICALARRANGEMENTFORTHEPLANNED%SCHENMOSER #LAISEN REARRANGEMENT ;= )N THE EVENT THE INTERMEDIATE KETENE . / ACETAL  FORMED FROM . . DIMETHYLACETAMIDE DIMETHYL ACETAL AND  IN REFLUXINGXYLENES STEREOSPECIFICALLYREARRANGEDTOTHECORRESPONDINGγ δ UNSATURATEDAMIDEINHIGHYIELD2EDUCTIONTOTHEPRIMARYALCOHOL WITH3UPER(YDRIDE4- FOLLOWEDBYHYDROGENATIONOFTHE# #ALKENE AFFORDED2EMOVALOFTHEEXTRANEOUSCARBONATOMATTACHEDAT#WAS ACHIEVEDTHROUGHOZONOLYSISOFTHEALKENERESULTINGFROMOXIDATIVESYN ELIMINATION OF THE 'RIECO ORTHO NITROPHENYLSELENYLATION PRODUCT OF  ;=4HERESULTINGALDEHYDEWASTHENEMPLOYEDASTHEELECTROPHILIC PARTNERINA(7%REACTION;= WITHREADILYAVAILABLEANDENANTIOMERI CALLY PURE PHOSPHONATE  ;= UNDER MILD -ASAMUNE 2OUSH CONDI TIONS;=THATOCCURREDWITHOUTRACEMISATIONANDOROTHERDESTRUCTIVE REACTIONPROCESSES&INALLY REDUCTIONOFTHEDOUBLEBONDINWITHTRI ETHYLSILANEUNDERRHODIUMCATALYSIS ANDPROTECTINGGROUPMANIPULATIONS TOINSTALLTHEMOREROBUSTTERT BUTYLDIMETHYLSILYL4"$03 GROUPCOMPLETED THESYNTHESISOFTHELASTMAJORFRAGMENTOFTHE# #VINYLIODIDE INALONGESTLINEARSEQUENCEOFSTEPSANDOVERALLYIELD3CHEME   7ITHVIABLEROUTESAVAILABLETOALLMAJORFRAGMENTSOFTHERAPAMYCIN  SKELETON ATTENTIONWASTHENFOCUSEDONTHEIREFFICIENTUNIONREQUIR INGFIRSTCONSTRUCTIONOFTHEFULLYELABORATEDVINYLIODIDE#ATALYSED BYTRACEAMOUNTSOFNICKEL THEBROADFUNCTIONALGROUPTOLERANCEINBOTH PARTNERS AND MILD REACTION CONDITIONS ARE SOME OF THE CHARACTERISTICS WHICHMAKETHEVENERABLE.(+; =REACTIONIDEALFORAPPLICATION INCOMPLEXMOLECULESYNTHESIS4HUS TREATMENTOFAMIXTUREOFAND INDIMETHYLSULFOXIDE$-3/ WITH#R#LANDTRACEAMOUNTSOF.I#L SMOOTHLYEFFECTEDTHEIRUNIONFORMINGTHEDESIRED# #CARBONBOND INHIGHYIELD&ORTUNATELY THEPOOROBSERVEDDIASTEREOSELECTIVITYALBEITIN FAVOUROFTHEDESIRED#EPIMER WASMITIGATEDBYSEPARATIONVIA CHROMATOGRAPHY ANDRECYCLINGTHROUGHANOXIDATIONREDUCTIONSEQUENCE OFTHEUNDESIREDSTEREOISOMER )NTERESTINGLY FORTHESTEREOSELECTIVE REDUCTIONOFENONE $)"!, (WASEMPLOYEDRATIOOFTO OBSERVED RATHERTHEN:N"( WHICHISKNOWNTOWORKWELLFOR  ANTI REDUCTIONS; =OFα METHOXYKETONESSEEFOREXAMPLETHE3CHREIBER AND,EYSYNTHESESOFRAPAMYCIN VIDEINFRA )NSTALLATIONOFABULKYTRIISO PROPYLSILYL 4)03 PROTECTING GROUP ON THE # HYDROXYL GROUP OF 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

OPMB

O

OPMB

22

34

29

TBSO

26

28

OMe b

TBSO

O

OPMB

28

26

+ H

29

PMBO

I

22 29

TBSO

26

28

OMe

OMe

351

TBDPSO

+

26

28

OH OPMB

34

29

TBSO

OMe

352

MeO

22

34

a

OPMB

OH OPMB

OPMB 22

34

c

402

400

401

d,e,f

42

38

H O

TBDPSO

42

32

OH O N O Me PMB O MeO Ph

Me

g

OTIPS

MeO

38

N

35

OPMB

Ph

O

TIPS OPMB O

OPMB

22

+

H

O

H

29

OMe

O

O

350

404

26

28

34

26

403

22

h,i,j

TBDPSO

MeO

TBDPSO

42

38

1

H 32

OH O PMB

OTIPS MeO

OPMB

N CO2H Boc 12 k

MeO

TBDPSO

42

38

MeO

H

38

H

32

N H O Boc

O

32

OTIPS

O PMB

OPMB

MeO

26

405

42

l,m,n,o,p

N H H

O O

OTIPS

O TES

26

406

OTES

MeO

26

347

I 22

22

22

3CHEME A #R#L .I#L $-3/ 24  B $-0 #(#L 24 C $)"!, ( 4(& n #    D 4)03/4F   LUT #(#L  #  E (&q0Y 4(& 24  F #/#L  $-3/ #(#L n # THEN%T. n #→n # G  N"U"/4F %T. #(#L n #→ # THEN n #→n # THEN(/AQ H ,I"( (/ %T/  #→24 I 4S#L %T. $-!0 #(#L 24 J ,I%T"( 4(&  #→24 K  $## I0R.%T  PYRROLIDINOPYRIDINE #(#L n # L /S/ .-/ ACETONE (/ 24M 0B/!C  .A#/ 0H(  #→24 OVERTWOSTEPSN #() #R#L 4(& DIOXANE 24  %:O $$1 #(#L (/ 24 4%3/4F   LUT #(#L  #THEN3I/ #(#L 24 

FOLLOWEDBYSELECTIVECLEAVAGEOFTHEMORELABILE4"3GROUPAT#AND SUBSEQUENT3WERNOXIDATIONGENERATED SUITABLYADORNEDFORCOUPLING WITH3CHEME  %MPLOYINGTHESAMESTRATEGYASDISCUSSEDPREVIOUSLYSEE3CHEME ADDITION OF THE BORON ENOLATE OF  TO ELECTROPHILE  FORMED WITH EXCELLENTDIASTEREOSELECTIVITY THELASTCARBON LINKAGEOFTHE# #VINYL IODIDE !FTERCONVERSIONOFTHE%VANSAUXILIARYINTOACORRE SPONDING#METHYLSUBSTITUENT DICYCLOHEXYLCARBODIIMIDE$## COU



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

PLINGOFWITH. T "OC , PIPECOLICACID ATLOWTEMPERATURETOAVOID POTENTIALEPIMERISATIONOFTHE#STEREOCENTRE GAVE4HELESSHINDERED TERMINALOLEFINOFWASTHENSELECTIVELYDIHYDROXYLATEDVIATHE5PJOHN PROCEDURE;= ANDTHEINTERMEDIATEDIOLCLEAVEDTOTHECORRESPONDING ALDEHYDEWITHLEADTETRAACETATE3UBJECTIONOFTHISELECTROPHILETO4AKAIS #R#L MEDIATEDIODOOLEFINATIONPROCESS;n=GAVETHEDESIREDTRANS VINYL IODIDE IN BOTH EXCELLENT SELECTIVITY %: AND YIELD &INALLY DICHLORODICYANOQUINONE $$1 INDUCED PARA METHOXYBENZYL 0-" ETHERDEPROTECTIONATBOTH#AND#HYDROXYLBEARINGCARBONATOMS FOLLOWEDBYFORMATIONOFTRIETHYLSILYLETHERSATTHESESAMETWOCENTRESWITH CONCOMITANTLOSSOFTHETERT BUTOXYCARBONYL"OC GROUPONNITROGENWITH TREATMENTWITHTRIETHYLSILYLTRIFLUOROMETHANESULFONATE4%3/4F FURNISHED /VERALL COMPLETIONOFTHEFULLYFUNCTIONALISED# #FRAGMENTOF RAPAMYCIN REQUIREDSTEPSINALONGESTLINEARSEQUENCE ANDWAS ACCOMPLISHEDINANEFFICIENTYIELD3CHEME  7ITHINHAND THESTAGEWASNOWSETFORTHEFINALSTAGESOFTHESYN THESISAND@STITCHINGCYCLISATIONLEADINGTOTHECOMPLETIONOF.ICOLAOUS RAPAMYCIN EFFORT5NIONOFTHE# #VINYLIODIDE AND# # CARBOXYLICACID WASACCOMPLISHEDVIATHEACTIVEESTERFORMEDBYTREAT MENTOFWITH$##AND(/"4FOLLOWEDBYADDITIONOFTHEAMINETO AFFORDAMIDEINGOODYIELD3CHEME  "ISOXIDATIONAT#AND#OFTHEISOMERICMIXTURE THROUGHTHE 3WERNPROTOCOLINSTALLEDTHECHARACTERISTICTRICARBONYLREGIONOFRAPAMY CIN 4HISWASFOLLOWEDBYSELECTIVEDEPROTECTIONOFTHE4%3ETHERS AT # AND # AND YET A SECOND APPLICATION OF THE SAME OXIDATIVE CONDITIONSPRODUCEDTETRAKETONE!TTHISSTAGE REMOVALOFTHEMORE ROBUSTREMAININGSILYLPROTECTINGGROUPSAT# # AND#RESULTED INSPONTANEOUSHEMIKETALFORMATIONASAMIXTUREOFLACTOLEPIMERS IN GOOD OVERALL YIELD FOR FOUR SYNTHETIC OPERATIONS $ELIGHTFULLY WHEN THERESULTINGFULLYDEPROTECTEDMACROCYCLICPRECURSORWASCOMBINED WITHENEDISTANNANE;=ANDSUBJECTEDTO3TILLECROSS COUPLINGCON DITIONS FORMATION OF THE DESIRED MACROCYCLE WAS ACHIEVED COMPLETING THELANDMARKFIRSTTOTALSYNTHESISOFRAPAMYCIN 7HILSTTHISNOVELLAST SYNTHETICOPERATIONWASNOTEXCEPTIONALLYHIGHYIELDING BOTHUNREACTED STARTINGMATERIAL  ANDAMONOCROSS COUPLEDVINYLIODIDEVINYL STANNANEINTERMEDIATE WERERECOVEREDANDBOTHCOULDBEREADILY RECYCLED3CHEME 



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TBDPSO

TBDPSO

42

TBDPSO

42

42

C21-C42 iodide 347 MeO

38

MeO

H

38

MeO

H

N H H

HO HO

8

O + TIPS 10 OMe O

O

O

O TES

a

OTIPS MeO

HO HO

OTES 26

O

N

H O O TIPS 10 OMe O 8

I

I

16

H 32

32

32

OH

38

O TES

OTIPS

N

OTES

MeO

26

I

I

16

O O TES H O O 8 MeO O O TIPS 10 OMe O

b

OH 26

I

I

16

22

22

22

408

407

C8-C18 acid 349

OTIPS

c,d

HO

HO

42

MeO

38

H 32

O HO

9

10

N H1 O O O

O

nBu3Sn

O

OH O

MeO

OMe 16

TBDPSO

42

MeO

38

MeO

H

H

32

SnnBu3

348 f

42

38

N 8

O HO

O

H

O 10

O

32

O

O

OH

MeO

O 26

OMe

22

I

16

I

e

O H O O 8 O O TIPS 10 OMe O

N

410

OTIPS

MeO

I

16

22

(-)-rapamycin 7

O

O 26

I 22

409

3CHEME A  $## (/"4 #(#L  # THEN  # B #/#L  $-3/ #(#L n # THEN%T. n #→ # C (&q0Y 4(&  #→24D #/#L  $-3/ #(#L n # THEN%T. n # → # E (&AQ #(#. 24 YIELDOVERFOURSTEPSF AND 0D#(#. #L MOL I0R.%T $-&4(& - 24 

)NSUMMARY THEIMPRESSIVESYNTHETICEFFORTBYTHE.ICOLAOUGROUPIN COMPLETINGTHETOTALSYNTHESISOFRAPAMYCIN STANDSASAMONUMENTAL ACHIEVEMENTINTHEFIELDOFNATURALPRODUCTSYNTHESIS)NGENERAL ALTHOUGH THEAPPROACHWASRELATIVELYCONSERVATIVE THEEFFICIENCYINWHICHTHEFRAG MENTS WERE CONSTRUCTED AND COUPLED IN A HIGHLY CONVERGENT MANOR IS MANIFESTINTHEOBSERVEDOVERALLYIELDOFTHROUGHALONGESTLINEAR SEQUENCEOFSTEPS3CHEME )NFACT DESPITEBEINGTHEFIRSTSUCCESSFUL SYNTHETICENTRYTOTHISNATURALPRODUCTANDTHEEMERGENCEOFFOURSUBSE QUENTSUCCESSFULSYNTHESESOFRAPAMYCIN THEOVERALLYIELDREMAINSTHE HIGHEST OBTAINED TO DATE -OREOVER THE CORNERSTONE DOUBLE INTERINTRA MOLECULAR3TILLEMACROCYCLISATIONONAFULLYDEPROTECTEDANDHIGHLYFUNC TIONALISEDPRECURSOR DEVELOPEDFOR ANDSUCCESSFULLYIMPLEMENTEDIN STITCHINGTOGETHERTHEFORMIDABLERAPAMYCIN MACROCYCLEISINTRIGUING ANDFINDINGUSEINOTHERCONTEXTS;n=



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME 3UMMARYOF.ICOLAOUSTOTALSYNTHESISOFRAPAMYCIN

 4HE3CHREIBERTOTALSYNTHESESOFRAPAMYCIN )N CONTINUATION OF AN ALREADY IMPRESSIVE LIST OF CONTRIBUTIONS DIRECTED TOWARDS IMPROVED SYNTHETIC AND BIOLOGICAL UNDERSTANDING OF THE TRICAR BONYL FAMILY OF IMMUNOMODULATING NATURAL PRODUCTS 3TUART 3CHREIBER DISCLOSEDHISTOTALSYNTHESISOFRAPAMYCIN IN;=WITHINMONTHS OFTHEFIRSTPUBLISHEDREPORTBY+#.ICOLAOU 2ETROSYNTHETICALLY IT IS CLEAR THAT EXPERIENCE GAINED IN HIS RECENTLY COMPLETEDSYNTHESISOF&+ WASINSTRUMENTALINMANYOFTHESTRA TEGICDECISIONSINTHEPROPOSEDSYNTHETICAPPROACH)NPARTICULAR THEFIRST MAJOR SIMPLIFICATION IDENTIFIED THE . # AMIDE BOND AS SUITABLE FOR FORMATIONOFTHEMEMBEREDMACROCYCLEINRAPAMYCIN VIAAMAC ROLACTAMISATION PROTOCOL )NTERESTINGLY OF ALL THE RAPAMYCIN SYNTHESES ONLY3CHREIBERCHOSETOPURSUEAMORECONVENTIONALMEANSOFMACROLIDE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO HO

42

C22-C42 aldehyde 411

42

MeO MeO

38

38

H

O HO

9

10

O

O

42

MeO

H

38

H

O

OH O

MeO

OMe

OLi

N Boc H O +

O

O Alloc

ODEIPS

N

28

35

O O 9 412 + MeO OMe TBS 10 OMe O

22

16

(-)-rapamycin 7

414

26

O

8

26

OTBS

415

PhS

+

1

CHO N Boc 416

22

22

OMe O

OAlloc

MeO

OPMB

O

O

+

32

32

N H1 O O

TIPSO

29

Br 417

H

16

21

Ph3P=CHCO2Et O 21 20 P Ph Ph

OH O 10

PMBO

16

418 C10-C21 phospine oxide 413

N

O

+

Br

OTBS

17 19

419

3CHEME 2ETROSYNTHETICANALYSIS

FORMATION&URTHERDISCONNECTIONINTHETRICARBONYL# # ANDTRIENE # # REGIONS REVEAL MAJOR FRAGMENTS  ;= AND  ;= AS PRINCIPLESYNTHETICTARGETS4HEPLANNEDUSEOFPHOSPHINEOXIDETO EFFECTTHEUNIONOFTHESEFRAGMENTS AND REPRESENTSTHEFIRST ANDONLY 7ITTIGTYPEAPPROACHTOWARDSTHEMERGEROFMAJORSUBUNITSIN THERAPAMYCINSERIES !N INTRIGUING ASPECT OF THE PLANNED SYNTHESIS OF THE # # ALDE HYDE  INVOLVES THE USE OF A PIPECOLATE UNIT CONTAINING A # ALDE HYDE)TSADDITIONTOTHEMAINCARBONBACKBONEOFWASENVISIONEDTO OCCURUNDER%VANS 4ISHCHENKO;n=REDUCTIVECONDITIONSTHATWOULD SIMULTANEOUSLYALSOACCOMPLISHTHESTEREOSELECTIVEANTI REDUCTIONOFTHE #KETOFUNCTION&URTHERDISSECTIONOFIDENTIFIEDn AND ASADVANCEDTARGETS/FPARTICULARIMPORT BOTHDISCONNECTIONAT# # AND # # VIA SEQUENTIAL CARBANIONIC COUPLINGS WITH FORMAL DIANION EQUIVALENTORVARIANTSTHEREOF ANDTHEUSEOFASTEREODEFINEDEPOXIDE TODEFINETHE#HYDROXYSTEREOCENTREPRIORTO# #BONDFORMATIONHAVE SUBSEQUENTLY BECOME POPULAR STRATEGIES ADOPTED IN A NUMBER OF OTHER SYNTHESESOFRAPAMYCIN VIDEINFRA  3CHREIBERSSYNTHESISBEGINSWITHACOMMERCIALLYAVAILABLE2OCHEESTER DERIVATIVE PREPAREDTHROUGHTHESHORTSYNTHETICSEQUENCESHOWNIN 3CHEMEUSINGSTANDARDLITERATUREPROTOCOLS 7ITHELECTROPHILEINHAND ALKYLATIONOFTHEDIANIONOFACETOAC ETATE  OCCURRED REGIOSELECTIVELY AND IN HIGH YIELD AT THE γ POSITION ;=3UBSEQUENTCONVERSIONOFTOITS7EINREBAMIDEANALOGUE



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O O MeO

a,b,c,d,e OH

10

O 422

Br

PMBO

f

420

O

OMe

10

O 16

421

OH O

g,h

10

PMBO

OMe

10

PMBO

16

423

N

O

418

17

i,j,k,l

19

Br

OTBS

17 19

m

OH 424

MeO

O

H

OMe OTBS

10

16

OH OH

p,q

OH O

10

OTBS

HO

19

419

16

427

n,o

10

OTBS

PMBO

19

16

19

425

426

r,s,t

S S

TBSO

OMe OH

10

16

19

u,v,w MeO

OMe TBSO

OMe

10

16

x,y,z,aa CO2Et 21

MeO OMe TBS 10 O OMe 16 21

428

429

O P Ph Ph

413

3CHEME A $(0 P4S/( %T/  #→24B ,I!L( %T/C .A( 0-""R 4(& 24D P4S/( -E/( 24  OVERFOURSTEPSE ."3 0H0 #(#L  #→24 F  .A( N"U,I (-0! 4(&  # THEN  # G 2U#L;3 BINAP=%T.MOL (PSI -E/(  # H -E.(/-Eq(#L -E!L I ,I!L(   $-% J "R ##L n #K ,$! (-0! 4(& n # OVER TWOSTEPSL 4"3#L )M 4(& M  T"U,I 4(& n # THENPREMIXEDWITHN"U,I 4(& n # n # N $$1 P(BUFFER #(#L O %T"/-E 4(& -E/( n # THEN .A"( n # THEN!C/( P 2U#L00H  0H( AIR 24Q .A( -E) 4(&  #→24  OVERTWOSTEPSR (3#( 3( 4I#L n #→ #S 4"3/4F   LUT T (&q0Y 0Y 4(& 24 U 0H)/#/#&  -E/( V "A-N/ CELITE #(#LW 0H0##(#/%T #(#L 24 OVERTWOSTEPS %:X $)"!, ( Y HEXACHLOROACETONE 0H0   DI T BUTYLPYRIDINE n #Z ,I00H 4(& n #AA AIR 4(& 24 OVERTHREESTEPS

WASREADILYACCOMPLISHED ASWASCONSTRUCTIONOFTHESTEREODEFINEDVINYL BROMIDE   'IVEN THE WELL KNOWN INCREASED STABILITY OF TETRAHEDRAL INTERMEDIATESOF7EINREBAMIDES;= LITHIATIONOFTHELATTERSPECIES ANDADDITIONTOSMOOTHLYFORMEDENONEWITHOUTANYCOMPLICA TIONSOFOVERADDITION4HISσ BONDFORMINGAPPROACHTOTHEGENERATION OF GEOMETRICALLY DEFINED TRISUBSTITUTED OLEFINS IS A VERY USEFUL ONE AS IT CIRCUMVENTSTHESOMETIMESPROBLEMATIC%: SELECTIVITYISSUESASSOCIATED WITHDIRECTπ BONDINSTALLATIONSEE3MITHSSYNTHESIS VIDEINFRA !LSOOF INTERESTISTHEFREEHYDROXYLGROUPPRESENTINWHICH TOAVOIDUNPRO DUCTIVE CONSUMPTION OF LITHIATED  MUST BE DEPROTONATED PRIOR TO REACTION!LTHOUGHONASMALLSCALETHISPROTOCOLWORKEDWELL WITHMATE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

RIALINEXCESSOFONEGRAMSIGNIFICANTAMOUNTSOFA# BUTYLADDUCTWERE OBSERVED.EVERTHELESS WITHAVAILABLE TREATMENTWITH$$1FOLLOWED BYBORONMEDIATEDANDSYN STEREOSELECTIVEREDUCTIONUNDER%VANS 0RASAD ;  =CONDITIONSFURNISHEDASASINGLEDIASTEREOMER4ODIF FERENTIATETHETHREERESULTINGHYDROXYLGROUPSTHE#ALCOHOLWASUSEDTO TRANSIENTLYPROTECTTHE#ALCOHOLVIAOXIDATION;=ANDINTRAMOLECULAR HEMIACETAL FORMATION ALLOWING SELECTIVE FORMATION OF THE METHYL ETHER AT# 2INGOPENINGOFTHELACTOL PROVEDESPECIALLYDIFFICULT (OWEVER EVENTUALSUCCESSWASACHIEVEDVIAFORMATIONOFTHEDITHIOLANE UNDER,EWISACIDICCONDITIONS3TANDARDFUNCTIONALGROUPMANIPULATIONS INCLUDINGALLYLICOXIDATIONANDHOMOLOGATION GAVETHEDIENEESTER WITHGOOD%: SELECTIVITY&INALLY INTRODUCTIONOFTHEPHOSPHINEOXIDEVIA DISPLACEMENTOFANINTERMEDIATEALLYLICCHLORIDEWITH,I00HANDEXPOSURE TOAIRCOMPLETEDTHESYNTHESISOFTHE# #FRAGMENTINSTEPSAND OVERALLYIELD !SSEMBLY OF THE # # ALDEHYDE  BEGAN BY EXPLOITING SOME PREVIOUSLY DEVELOPED CHEMISTRY FOR THE PREPARATION OF &+ WHEREIN   PENTADIEN  OL  WAS MANIPULATED TO PRIMARY ALCOHOL  #ON VERSIONTOTHECORRESPONDINGIODIDEANDSUBSEQUENTALKYLATIONWITHTHE LITHIATEDALLYLICSULFIDE ;=GENERATEDANα SUBSTITUTEDALLYLICTHIO ETHER  WITH EXCELLENT REGIOSELECTIVITY /XIDATION ; = SIGMATROPIC REARRANGEMENT; =OFTHERESULTINGSULFOXIDE ANDINSITUCLEAVAGE OFTHESULFENATEESTER%T.( -E/( THENFURNISHEDEXCLUSIVELYAS THE TRANS ISOMER 3UBJECTING THIS ALLYLIC ALCOHOL TO 3HARPLESS ASYMMETRIC EPOXIDATIONCONDITIONSAFFORDEDEPOXYALCOHOL WHICHWHENTREATED WITH TRIMETHYLALUMINIUM UNDERWENT REGIOSELECTIVE RING OPENING WITH INVERSIONOFCONFIGURATIONAT#;=3UBSEQUENTCONVERSIONOFVICINAL DIOL  TO THE CORRESPONDING OXIRANE EMPLOYED A CUSTOMARY TWO STEP SEQUENCE TO COMPLETE THE SYNTHESIS OF THE CYCLOHEXYL BEARING # # EPOXIDEINATOTALOFSTEPSANDYIELD3CHEME  3TANDARD CHEMISTRY WAS USED TO PREPARE THE CENTRAL FORMAL DIANION EQUIVALENTFROMCOMMERCIALLYAVAILABLEMATERIALS!LLSTEPSLEADING TO  WERE REASONABLY EFFICIENT AND ALLOWED PROCESSING OF SUBSTANTIAL QUANTITIESOFMATERIAL5NFORTUNATELY THEHYDROZIRCONATION BROMINATION SEQUENCEWHICHCULMINATEDTHESYNTHESISOFOCCURREDINPOORYIELD 3CHEME   "OTH A REGIOISOMERIC PRODUCT OF   AND AN OVER REDUCEDBY PRODUCTWERENOTED BUTFORTUITOUSLYTHEINSEPARABLEREGIOISO



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TIPSO

13 steps 14.0%

OH

MeO

cf. Schemes 10 and 12

42

61

TIPSO

38

OH

42

MeO

H

S

42

38

H

MeO

36

33

MeO

33

38

42

O 38

OH

H

36

H

434

433

d

431 N

TIPSO

TIPSO

42

MeO

38

H

O

MeO

OH OH

437

38

TIPSO

Al

42

33

35

TIPSO

N

TIPSO

N

O

414

c

N

432

f,g 38

S

33

430

33

MeO

42

36

S

TIPSO

N

N

42

a,b

40

O

MeO

33

H

42

e

O AlMe3

AlMe2

436

38

33

OH

H 435

3CHEME A ) 0H0 )M B  ,$! 4(& n #→n # THENIODIDEDERIVEDFROM 4(& n # C M#0"! #(#L  #→24 THEN%T.( -E/( D 4I/I0R  ,  $%4 T"U//( ¯ -3 E -E!L HEXANES  # F 4S#L 0YG +#/ -E/( OVERTWOSTEPS

O

OH 29

MeO

OTBS a,b,c

Br

32

29

OTBS

32

d

SPh

32

e,f

29

29

g

PhS 32

Br 363

29

Br 438

439

440

417

3CHEME A 4"3#L )M $-&  #→24 B $)"!, ( #(#L n #C #"R 0H0 :N #(#L  #→ 24 OVERTWOSTEPSD N"U,I 4(& n # THEN-E) n #→24 E 4&! (/ 4(&F 0H3 "U0 0H( 24 OVERTWOSTEPSG #P:R( #L 0H#( 24→ # THEN"R n # 

MERICPRODUCTWASUNREACTIVEAFTERLITHIATIONINTHESUBSEQUENTCOUPLING STEPSEE3CHEME  4HEFINALSUB FRAGMENTREQUIREDFORTHEPREPARATIONOFWAS7EINREB AMIDESYNTHESISEDASSHOWNIN3CHEME/NCEAGAINA2OCHEESTER WASUSEDASACONVENIENTSTARTINGMATERIALANDINITIALSOURCEOFCHIRALITY !FTERCONVERSIONTO3  BENZYLOXY  METHYLPROPANAL HOMOLOGA TIONGAVEENOATEWITHEXCELLENT%:SELECTIVITY3TANDARDFUNCTIONAL GROUP MANIPULATIONS THEN GENERATED PRIMARY ALCOHOL  WHICH WAS HYDROGENATEDEMPLOYINGTHECATIONICRHODIUM) SYSTEMOF%VANS;= TOGENERATEINHIGHDE )NTHEFORMERTRANSFORMATION SUBSTANTIAL !  ALLYLICSTRAINHASBEENPOSTULATEDTORESTRICTTHEHYDROXYLMOIETYTO THEVICINITYOFONEOLEFINICFACEGIVINGRISETOTHEOBSERVEDFACIALSELECTIVITY ;=3WERNOXIDATIONOFANDCONDENSATIONOFTHERESULTINGALDEHYDE WITHTHEBORONENOLATEOF3  METHOXYACETYL  PHENYLMETHYL  OXA



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

Rh

Ph2P O

O

OH

OBn

a,b

26

MeO

26

H

EtO

441

363

TBSO

OBn

O c

TBSO

OH

d,e,f

26

22

BF4 PPh2

22

26

444

443

442

O

O 28

22

PMBO 26

O 28

N

O

k

TBSO 22

OMe 415

TBSO

OH O 26

28

N

O

j

22

O

OH O 26

28

N

OMe Bn

OMe 448

26

g

MeO

TBSO

OH

257 22

447

N

Bn

O

h O TBSO

O

446

i

22

26

H

445

3CHEME A "N4#! 4F/( CYCLOHEXANE #(#L  B $)"!, ( #(#L n # C 0H0#-E #/%T #(#L 24 OVERTWOSTEPSD $)"!, ( #(#L n #→ # E 4"3#L %T. $-!0 #(#L 24F .A .( n # OVERTWOSTEPSG WT (PSI #(#L  DE H #/#L  $-3/ #(#L n # THEN%T. n #→24I  "U"/4F I0R.%T 0H#( n # THEN n #→ # OVERTWOSTEPSJ -E.(/-Eq(#L !L-E #(#L  #→24 K 0-"4#! 4F/( 

ZOLIDINONE ;  =GAVETHEDESIREDSYN %VANSALDOLADDUCT INAMODESTYIELDOF!MAJORADVANTAGEOFTHISTRANSFORMATIONISTHE DIRECTINTRODUCTIONOFTHE# HYDROXYLGROUPASITSREQUISITEMETHYLETHER  ANDTHUSAVOIDSANYPOTENTIALCOMPLICATIONSWITHPROTECTINGGROUP MANIPULATIONSAT#5SEFULREMOVALOFTHECHIRALAUXILIARYINVIA DIRECTTRANSAMIDATION;=TO7EINREBAMIDE AND0-"PROTECTIONOF THEREMAININGFREESECONDARYHYDROXYLGROUPFURNISHEDINALONGEST LINEARSEQUENCEOFSTEPSANDOVERALLYIELD 7ITH ALL THREE OF THE MAJOR COMPONENTS OF  IN HAND FOCUS WAS SHIFTEDTOEFFECTINGTHEKEYCARBON CARBONBONDFRAGMENTCOUPLINGREAC TIONSTOCONSTRUCTTHE# #ALDEHYDE4OTHISEND VINYLBROMIDE WASLITHIATEDANDINTRODUCEDTOGIVEENONEINGOODOVERALL YIELDALTHOUGHMOLAREQUIVALENTSOFTHENUCLEOPHILEWHEREREQUIRED4O SET THE REQUIRED STEREOCHEMISTRY AT # A   ANTI CHELATION CONTROLLED  ZINCBOROHYDRIDEREDUCTION; =OFWASSELECTEDANDPLEAS INGLYFURNISHEDWITHSUBSTANTIALLYIMPROVEDSELECTIVITY THAN OBSERVEDINTHE.ICOLAOUSYNTHESIS3CHEME  &URTHERPROTECTINGGROUPMANIPULATIONSANDSULFIDEOXIDATIONGENER ATED THE FULLY ELABORATED # # SULFOXIDE  THAT UPON α DEPROT



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBSO

PhS

+

32

PMBO

O

26

28

22

29

TBSO N

O

a

29

417

b

32

OMe

415

MeO

32

OMe

Me O

449

451 ZnX O

R 450

TIPSO

TIPSO

29 26

H

R

SPh

OH

PMBO

22

26

OMe

Br

TBSO

SPh

O

PMBO

22

c

42

42

MeO 38

H

38

H

35

35 32

OH SPh O O 454 MeO

ODEIPS

TBSO

O

415

ODEIPS

PMBO

29

22

SO2Ph

d

TBSO

32

29

26

SPh 32

26

OMe 453

OPMB

ODEIPS

PMBO

22

26

e

OMe 452

22

TBSO

f or g,h,i TIPSO MeO

TIPSO

42

38

H

35

CHO N 1 Boc

32

OH O

416 j

ODEIPS

MeO

455

R' O H

42

38

H

35

34

H

32

32

N

R

O

OPMB

O Sm

26

TBSO

MeO

H

N H Boc O

Boc

457

L 456

22

OH

O

ODEIPS

MeO

TBSO

OPMB 26

22

k

TIPSO MeO

42

38

H

TIPSO MeO

35

32

N Boc

O

H

O

O Alloc

ODEIPS

OAlloc

MeO

26

TIPSO

42

38

H

MeO 35 32

m,n N H Boc O

O O Alloc 459

411

O

ODEIPS

MeO

OAlloc 26

42

38

H

35 32

l N H Boc O

O

458

OH

ODEIPS

MeO

OH 26

22

TBSO

22

TBSO

22

H

3CHEME A  T"U,I 4(& n # THEN  n #  B :N"(  %T/ n #  DR   C $%)03/4F   LUT #(#L  # → 24  D M#0"! 0Y n # → 24  E  N"U,I n # THEN THEN"&q/%T  DR SEPARABLEBY(0,# MAJORISOMERISOLATEDIN YIELDF N"U,I n #THEN4-3/  RECOVERED3- G N"U,I 4(& n # THEN#() I0R-G#L n # AFTERRECYCLEOFRECOVEREDSULFONE H /S/ 0Y THEN.A(3/I .A)/ 3I/ 4RIS (#LP(BUFFER OVERTWOSTEPSJ  4(&  # THEN0H#(/ 3M) 3M)MOL  DRK $$1 .A(#/L !LLOC#L 0Y   LUT 4(& OVERTWOSTEPSM 0043 P4S/( 4(& (/ RECOVEREDSTARTINGMATERIAL N #/#L  $-3/ #(#L n # THEN%T. n #→24 

ONATIONWITHN"U,ISMOOTHLYEFFECTEDRING OPENINGOFTHEELECTROPHILIC EPOXIDE INTHEPRESENCEOF"&q/%T; =3OMEDIFFICULTYWAS ENCOUNTEREDINATTEMPTINGTHEOXIDATIVEDESULFONYLATION;=OFTHE DIASTEREOMERICMIXTUREOFβ HYDROXYSULFONES )NITIALSUCCESSWAS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

ACHIEVED AFTER SCREENING A MYRIAD OF CONDITIONS AND INVOLVED METALLA TIONWITHN"U,IFOLLOWEDBYTREATMENTWITHBISTRIMETHYLSILYL PEROXIDE 5NFORTUNATELY ONLY A  ISOLATED YIELD WAS ACHIEVED EVEN AFTER ONE RECYCLEOFRECOVEREDSTARTINGMATERIAL-OREOVER THISTRANSFORMATIONWAS ONLYSUCCESSFULONTHEMAJORDIASTEREOMERANDNECESSITATEDSEPARATIONBY (0,#3OMEIMPROVEMENTWASREALISEDBYREACTIONOFTHEα LITHIOCARB ANIONOFANDACARBENOIDELECTROPHILE#() I0R-G#L TOPRODUCEAN INTERMEDIATEOLEFINTHATWASSUBSEQUENTLYDIHYDROXYLATEDANDOXIDATIVELY CLEAVED !LTHOUGH REQUIRING THREE SYNTHETIC MANIPULATIONS THE OVERALL YIELD ISANIMPROVEMENTFROMTHEEARLIERPROCEDUREANDTHESUCCESS ISFURTHERNOTABLEGIVENTHATASIMILARINTERMEDIATEINTHE,EYSYNTHESISOF RAPAMYCIN COULDNOTBEADVANCEDVIDEINFRA 7ITHβ HYDROXYKETONE  IN HAND STEPS WERE TAKEN TO INTRODUCE THE PIPECOLIC SUBUNIT AND SIMULTANEOUSLYPROTECTAGAINSTITSELIMINATIONTHROUGHREDUCTIONOFTHE #KETONE&ORTHISPURPOSE THE3CHREIBERGROUPEMPLOYEDAVERYINTER ESTING FRAGMENT UNION%VANS 4ISHCHENKO ;= REDUCTION STRATEGY WITH 3 "OC PIPECOLAL;=)NTHEEVENT MIXINGANDFOLLOWEDBYTHE ADDITIONOFPREFORMED0H#(/ 3M) 3M)PROVIDEDTHECOUPLEDPRODUCT  INBOTHEXCEPTIONALYIELDANDSELECTIVITY WITHNODETECTABLE RACEMISATIONAT#0ROTECTINGGROUPMANIPULATIONSANDOXIDATIONCOM PLETED THE SYNTHESIS OF THE SECOND MAJOR TARGET  IN THE 3CHREIBER SYNTHESISOFRAPAMYCIN INATOTALOFSTEPSANDOVERALLYIELD 3CHEME  4HESTAGEWASNOWSETFORTHELASTMAJORFRAGMENTCOUPLINGREACTION VIAANINTERMOLECULAR7ITTIGREACTIONBETWEENPHOSPHINEOXIDEAND ALDEHYDE'RATIFYINGLY REACTIONOFTHELITHIUMSALTOFTHEFORMERWITH ELECTROPHILEGENERATEDTHECRUCIALOLEFINICLINKAGEINYIELDASA MIXTUREOF%:ISOMERS3CHEME )NADDITION SUBSTANTIALAMOUNTS  OFβ HYDROXYPHOSPHINEOXIDEADDUCTSWEREISOLATEDWHICHCOULD BESALVAGEDBYTREATMENTWITHLITHIUMHEXAMETHYLDISILAZIDE,I(-$3 TO EFFECTCONVERSIONTOTHETRIENEINGOODYIELD THUSFURTHERIMPROV INGMATERIALTHROUGHPUTOFTHISADVANCEDINTERMEDIATE(YDROLYSISOFTHE ACETALAT#WITHPYRIDINIUMPARA TOLUENESULFONATETHENFURNISHED ALBEIT IN MODERATE YIELD PERHAPS AS A CONSEQUENCE OF OTHER ACID LABILE FUNCTIONALITIESINTHEMOLECULE3CHEME  )NSTALLATIONOFTHETRICARBONYLREGIONANDEVENTUALMACROCYCLEFORMA TIONOFRAPAMYCIN REQUIREDPRIORCHAINEXTENSIONAT# WHICHWAS



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TIPSO

TIPSO

42

MeO

38

42

MeO

H

38

35

N H O Boc

ODEIPS

O Alloc

+

OAlloc

MeO

16

26

21

411

a,b

O P Ph Ph

O

ODEIPS

O Alloc

N H1 Boc O O TBS 10 O OMe

413

O

H 32

MeO OMe TBS 10 O OMe

32

O

OAlloc

MeO 22

22 16

H 460

O O

c

O 461

TIPSO

TIPSO

42

MeO

38

H

TIPSO

42

MeO

AllocO 10

O Alloc

N H1 O O TBS O OMe

H

38

32

32

32

O

42

MeO

H

38

ODEIPS

e

N H1 H O

Alloc OH O

OAlloc

MeO

O

22

O

O Alloc

ODEIPS

10

Alloc OEE O

OAlloc

MeO

TBS O OMe

d

O

22

N H1 Boc O

ODEIPS

10

OAllo c

MeO 22

16

463

464

O Alloc

TBS O OMe

16

16

O

OEE =

462

O

f

TIPSO

TIPSO

42

MeO

38

MeO

H

HO

42

38

H

32

N H HO 10

O

OH

16

ODEIPS

O

H 32

OH

MeO

O O 10

22

N H1 O O TBS O OMe

O

ODEIPS O

MeO

h

N H O HO

10 22

O

9

O

O

O

OH

1

O

O

MeO

OMe

22

16

16

465

38

32

g

1

O O TBS O OMe

42

MeO

466

(-)-rapamycin 7

3CHEME A  N"U,I 4(& (-0! n # THEN %: B 0043 ACETONE  #  RECOVEREDSM C ETHOXYETHYLACETATE ,$! 4(& n # THEN THEN!LLOC#L   LUT n # → 24 D 4%3/4F   LUT #(#L  # THEN 3I/ E  CHLORO  METHYLPYRIDINIUM IODIDE %T. #(#L- OVERTHREESTEPS MIXTUREOFDIASTEREOMERSF 0D00H  (#/.( 4(&G $-0 #(#LH (&q0Y 0Y 4(& OVERTHREESTEPS

ACCOMPLISHED THROUGH CONDENSATION OF  WITH THE LITHIUM ANION OF  ETHOXYETHYL ACETATE   !DDITION OF !LLOC#L AND WARMING AFFECTED ANINSITUQUENCHOFTHELITHIUMALKOXIDEAT#TOAFFORDTHEPROTECTED CARBOXYLICACIDDERIVATIVE4REATMENTWITH4%3/4FTOREMOVETHE"OC PROTECTINGGROUP; =FURNISHEDTHEREQUISITEAMINOACIDTHATWAS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 3UMMARYOFTHE3CHREIBERSYNTHESISOFRAPAMYCIN

DIRECTLY SUBJECTED TO -UKAIYAMA MACROCYCLISATION CONDITIONS ;= TO EFFECTRINGCLOSUREGIVINGAMIXTUREOFTWODIASTEREOMERS# OFTHE DESIRED MACROCYCLE   0ALLADIUM CATALYSED DEPROTECTION OF ALL THREE ALLYLCARBONATESAT# # AND#FOLLOWEDBYTREATMENTWITH$-0 USINGTHE'OLECPROTOCOL;=EFFECTEDOXIDATIONOFALLTHREERELEASEDALCO HOLSALONGWITHGENERATINGTHETRICARBONYLMOTIFVIAOXIDATIONOFTHE# METHYLENETOYIELD&INALLYGLOBALDEPROTECTIONOFALLREMAININGSILYL GROUPSWITH(&q0YRESULTEDINSPONTANEOUSHEMIACETALFORMATIONAT# GIVINGMATERIALIDENTICALINALLRESPECTSWITHNATURALRAPAMYCIN  )N SUMMARY THE 3CHREIBER APPROACH TO RAPAMYCIN  FEATURES SOME INTRIGUINGCHEMICALTRANSFORMATIONSTOCONSTRUCTTHISNATURALPRODUCTINA LONGESTLINEARSEQUENCEOFSTEPSANDOVERALLYIELD3CHEME  .OTABLEAMONGTHESEISTHEUSEOFA# #SPACERASAFORMALDIANION



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

EQUIVALENTTOADDSEQUENTIALLYTWOELECTROPHILESINBUILDINGTHE# # PORTIONOFTHEMOLECULE!VARIETYOFSTEREOSELECTIVEπ BONDCONSTRUCTIONS THROUGHAσ BONDFORMINGSTRATEGY THEFORMATIONOFTHETRIENEUNITVIAA 7ITTIGOLEFINATION AFASCINATING%VANS 4ISHCHENKOFRAGMENTUNION AND AMACROLACTAMISATIONAPPROACHTOMACROCYCLEFORMATIONREPRESENTOTHER ASPECTSSTRATEGIESOFCONSIDERABLEINTERESTANDUSE)NISOLATION THECON TRIBUTIONOFTHE3CHREIBERGROUPTOTHEFAMILYOFTRICARBONYLNATURALPROD UCTSTHROUGHTOTALSYNTHESIS&+ RAPAMYCIN ANDANALOGUES IS IMPRESSIVE ANDALTHOUGHTHISREVIEWISCENTREDPRIMARILYUPONSYNTHETIC ASPECTSITMUSTBEHIGHLIGHTEDTHATARGUABLYNORESEARCHGROUPHASCON TRIBUTEDMORETOTHEBIOLOGICALUNDERSTANDINGOFTHISFASCINATINGFAMILY OFNATURALPRODUCTS

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO

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C28-C42 aldehyde 468

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42

MeO

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38

38

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32

10

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10

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C1-C27 acid 469

30

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23

475

473

3CHEME 2ETROSYNTHETICANALYSIS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

 FEATURESOMEINTRIGUINGTRANSFORMATIONSANDUNIQUEAPPROACHESAS DISCUSSEDBELOW 5NDOUBTEDLY THEOVERALLSTRATEGYADOPTEDBYTHE$ANISHEFSKYRESEARCH TEAMWASBASEDSUBSTANTIALLYUPONEXTENSIVEDEGRADATIONWORKPERFORMED ONRAPAMYCIN ITSELF;  n=3UCHINVESTIGATIONSAREOFOBVI OUSVALUEWHENREASONABLESUPPLIESOFTHENATURALPRODUCTAREAVAILABLEAS THEYALLOWINVESTIGATIONOFTHECRITICALEND GAMEOFSYNTHESESWHENSYN THETICMATERIALISEXTREMELYPRECIOUS-OREOVER INSOMECASESLARGEINTACT ADVANCEDFRAGMENTSCANBERECOVEREDWHICHCANSERVEASVALIDATIONOFSYN THETICINTERMEDIATESASWELLASSUPPLEMENTMATERIAL4HISWASCERTAINLYTHE CASEFOR$ANISHEFSKYWITHRAPAMYCIN ASILLUSTRATEDIN3CHEME 3ELECTIVEANDSEQUENTIALPROTECTIONOFTHE#AND#HYDROXYLFUNC TIONSOFFOLLOWEDBYTREATMENTWITHLEADTETRAACETATEIN-E/(RESULTED IN OXIDATIVE CLEAVAGE AT # # TO GIVE  IN EXCELLENT YIELD 0RESUM ABLYTHISLATTERTRANSFORMATIONEXPLOITSTHEPROPENSITYOFTHEELECTROPHILIC #CARBONYLTOFORMTETRAHEDRALINTERMEDIATESANDISBASEDUPONSTUDIES PERFORMEDUPON&+ INARELATEDCONTEXT;=4REATMENTOFKETONE WITH,I!L(/T"U GIVES INAHIGHLYSELECTIVEFASHION WHATWASLATER CONFIRMEDTOBETHE2 #HYDROXYCOMPOUNDTHATAFTERSELECTIVEDESI LYLATIONAT#GAVE0REVIOUSSTUDIESHADSHOWNTHATTHE# # BONDISVERYSUSCEPTIBLETOARETROALDOLPROCESSUNDERBASICOR,EWISACIDIC CONDITIONS; = ANDINDEEDREACTIONOFWITH,$!ATLOWTEM PERATUREFURNISHEDBOTHANDINGOODOVERALLYIELD3CHEME  !FTER4"3PROTECTIONOF REDUCTIVEREMOVALOFTHEPIPECOLATESUBUNIT ANDALLYLICOXIDATION THEFIRSTOFTWOMAJORSUBUNITS INTEGRALTOTHE TOTALSYNTHESISEFFORTOF$ANISHEFSKYWASOBTAINED ALBEITOFOPPOSITECON FIGURATIONAT#RELATIVETOSYNTHETICMATERIAL,ACTONE WASCORRE SPONDINGLYCONVERTEDINSHORTORDERVIASTANDARDFUNCTIONALGROUPMANIP ULATIONSTOALDEHYDEWHICHCORRESPONDSIDENTICALLYTOMATERIALMADE INTHEFORWARDDIRECTIONVIDEINFRA 4HESAMELACTONE COULDALSOBE PREPAREDTHROUGHASHORTERDEGRADATIVEPROTOCOLBYOMITTINGPROTECTING GROUPMANIPULATIONS(OWEVER INTHISCASEOXIDATIVECLEAVAGEWITHLEAD TETRAACETATEFOLLOWEDBYEXPOSURETO,$!PRODUCEDUNBENEFICIALLYENONE FORMEDVIAβ ELIMINATION INADDITIONTODESIRED%FFICIENT DIRECT ROUTESTOBOTHAND ANDTHEOBSERVATIONOFFACILERETROALDOLPRO CESSESABOUTTHELINKAGEBETWEEN# # WITHOUTQUESTIONINFLUENCEDIN THESYNTHETICAPPROACHUNDERTAKENBY$ANISHEFSKYANDCO WORKERS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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32

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10

22

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42

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38

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9

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42

32

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16

476

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28

k

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478

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480

481

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484

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38

H

32

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

Ph

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42

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485

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487

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38

488

HgX

BnO

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489

OH

f,g

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42

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470

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

HO

30

OH

a

O

30

O

b,c

O

d,e

32 30

H

32 30

f

34

O

OBn

491

O

492

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493

32

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30 34

O

490

g,h

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32

32

494

30

OBn

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496 O

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32 30

36

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471

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m,n

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HO

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32 30

TBSO 499

OTBS

l

34

TBSO

OBn

32 30

36

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498

j,k

34

OBn

32 30

36

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O OH BnO

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32

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30

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32

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O

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o,p,q,r

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H

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32 30

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H

507

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

OH

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22

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22

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511

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26

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517

518

23

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H

520

3CHEME A "N"R !G/ %T/ REFLUXB ,I!L( %T/  # OVERTWOSTEPSC #/#L  $-3/ #(#L n # THEN%T. n #→24 D (#/%T .A( 0H(  #→24 THEN(#L E P4S/( -E/( 0H( REFLUX F 4-3/4F 4%! %T/  # G  -G"R 4(& 24 THEN THEN !C/( (/ H $)"!, ( 0H( 24I P4S/( I0R/( 24 OVERTWOSTEPSJ 0D!L/ ( PSI %T/!C 24K 0D# (PSI %T/!C 24 OVERTWOSTEPSL (3#( 3( "&q/%T #(#L n #→n # M 0B/!C  +/!C #(#. n # N METHYLTRIPHENYLPHOS PHORANYLIDENE ACETATE #(#L 24 O $)"!, ( 0H#( n #→24 P #/#L  $-3/ #(#L n # THEN%T. n #→24 

4HEADDITIONOFHYDROGENIODIDETOTETROLICACIDCANFURNISHEITHERTHE% OR: IODOCROTONICACIDPRODUCTDEPENDINGUPONTHECONDITIONSEMPLOYED ; = ANDFUNCTIONSASEFFICIENTENTRYTOTHECENTRALSPACERDIANION EQUIVALENT OF  )N THIS CASE ISOMERISATION OF THE INITIALLY FORMED : ADDITIONPRODUCTGAVEAND AFTERASERIESOFSTANDARDMANIPULATIONS TOINSTALLTHESULFONEAT# FURNISHEDASACRYSTALLINESOLIDINOVERALL FIVESTEPSANDOVERALLYIELD3CHEME  $ANISHEFSKYSUSEOFSUGARDERIVATIVESASACONVENIENTSOURCEOFSTARTING MATERIALCHIRALITYCONTINUESINHISPREPARATIONOFFRAGMENT3CHEME   $ 'LUCAL WASREADILYCONVERTEDTOα METHYL DEOXYGLYCOSIDE  THROUGHASHORTREACTIONSEQUENCEFEATURINGASTEREOSELECTIVEIODO METHOXYLATIONREDUCTIONSEQUENCE&URTHERFUNCTIONALGROUPMANIPULA TIONSANDASTANDARD(7%;=THENLEDTOALLYLICMESYLATE !LTERNATIVELY $ GALACTALTRIACETATE WASANEXPEDIENTENTRYPOINTTO INAREACTIONSEQUENCESIMILARTOTHATEMPLOYEDFORTHE% ISOMER



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

CO2H

a

17

b

c

17

I

I

I

I

I 17

17

d

17

e

17

19

19

526

CO2H

527

19

CO2Me

528

19

19

19

X

OH

529

530

SO2Ph 474

3CHEME A ()AQ  # SEALEDTUBE THENNEAT  #B #(. %T/  # THEN!C/( C $)"!, ( 0H#(  # D -S#L %T. $-!0 #(#L  # 8#LOR-SMIXTUREEMPLOYED E SODIUM BENZENESULFINICACID $-& 24 OVERTWOSTEPS

BUTEMPLOYINGTHEMODIFIED3TILL 'ENNARI;=PROCEDURETOINTRODUCETHE : OLEFIN3CHEME "ASEDUPONTHEWORKOF)BUKAAND9AMAMOTO;= EITHERORSHOULDGIVERISETOTHEDESIRED# METHYLSTEREOCHEM ISTRYFOLLOWINGMETHYLCUPRATE3.DISPLACEMENTOFTHEACTIVATEDALCOHOL )N THESE REACTIONS THE ADDITION OF "&q/%T IS CRITICAL TO EFFECTING CLEAN   CHIRALITYTRANSFER!LSOOFNOTE THE% DOUBLEBONDINTHEPRODUCTISNOT DEPENDENTONTHATOFTHESTARTINGMATERIAL)NDEED UPONAPPLICATIONOF THEDESCRIBEDOPTIMISEDCONDITIONSFORCUPRATEDISPLACEMENTTHECLOSELY RELATEDESTERS2%T AND2-E  WEREISOLATEDASSINGLEDIASTEREO MERS3TANDARDFUNCTIONALGROUPTRANSFORMATIONSSUCCESSFULLYCONVERTED EITHERORTOTHESAME# #ALDEHYDEINASHORTESTLINEAR SEQUENCEOFSTEPSANDYIELD 4HEFIRSTATTEMPTATCOUPLINGTHETHREEADVANCEDFRAGMENTS   TOWARDSTHECOMPLETIONOFTHE# #CARBONSKELETONOFRAPAMY CIN ISSHOWNIN3CHEME 5NIONOFALDEHYDE ANDVINYLIODIDE UNDER.(+CONDITIONS ;n= GAVE A REASONABLE YIELD OF THE COUPLED PRODUCTS n BUT WITH NO SELECTIVITY AT THE NEWLY FORMED # HYDROXY STEREOCENTRE !LTHOUGHSOMEMATERIALCOULDBESALVAGEDTHROUGHANOXIDATIONREDUC TIONSEQUENCEOFTHEUNWANTEDEPIMER THELATTERREACTIONONCEAGAIN OCCURREDWITHNODIASTEREOSELECTIVITYGIVINGAMIXTUREOFAND -ETHYLATIONOFTHEDESIRED#ISOMER FOLLOWEDBYDEPROTONATIONOF ANDADDITIONOFTHERESULTINGα LITHIOSULFONYLANIONINTODITHIANEENAL GAVEAMIXTUREOFSTEREOISOMERS FOLLOWINGACETYLATIONINGOOD YIELD!TTEMPTEDDIRECTFORMATIONOFTHEDESIRED# #TRIENEBYTREAT MENTOFWITHSODIUMAMALGAMIN4(&WASSUCCESSFUL HOW EVERTHECENTRAL# #OLEFINWASFORMEDASAINSEPARABLEMIXTURE OF% AND: ISOMERSANDTHEPRODUCTWASNOTSUFFICIENTLYSTABLETOALLOW



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

HO

TBSO a,b,c

HO 12

O

HO

TBSO d,e

MsO 12

BnO

16

531

HO O

12

HO

16

16

OBn S

f

MsO

O

BnO

O

g,h

OBn S

EtO 10

S

14

533

S

OMs

OMs

OMe

532

16 12

535

534

i AcO

TBSO j,k,l,m

AcO 12

12

HO

HO

q,r 14

S

12

10

OMs

OMe

246

OBn S

OBn S 16

O 16

16

AcO

HO n,o,p

HO

O

538

MeO

O

S

OBn S

RO 10

OMs

14

S

R = Et, 536; R = Me, 537

540

539

O

s

t

OBn O w

10

TBDPSO

14

545

H

TBDPSO

OBn S

10

14

544

v

S

HO 10

OBn S 14

543

u

S

RO

O

OBn S

10

14

S

R = Et, 541; R = Me, 542

3CHEME A 4"3#L $-& 24 B "U3N/ 0H#( $EAN 3TARK THEN"N"R N"U."R 0H#(  #  C -S#L 0Y  #→24 D .)3 #(#. -E/( 24 E N"U3N( !)". 0H( REFLUX  F (3#( 3( "&q/%T #(#L  #→24 G 0B/!C  0H( 24 H CARBOETHOXYME THYLENE TRIPHENYLPHOSPHORANE #(#L  # I -E#U#. ,Iq,I"R "&q/%T 4(& n #  J .)3 -E/( #(#. 24 K N"U3N( !)". 0H#( REFLUX L .A/-E -E/( 24M 4"3#L )M $-& 24 OVERTWOSTEPS MIXTUREOFαβANOMERSN "U3N/ 0H#( $EAN 3TARK THEN"N"R N"U."R 0H#(  # O -S#L 0Y $-!0 #(#L 24 P (3#( 3( "&q/%T #(#L  #→24 Q 0B/!C  0H( 24 R #&#(/ 0/ #(#/#(  #  +(-$3 4(& n # S -E#U#. ,Iq,I"R "&q/%T 4(& n # T 0H0 2H#L ( 0H( 24 FOR FORU $)"!, ( 0H#(  # FORANDV 4"$03#L )M $-& 24 W ."3 ACETONE (/ n # 

REMOVAL OF THE DITHIANE MOIETY 2EVERSING THE ORDER OF EVENTS THROUGH TREATMENTWITH.#3AND!G./REVEALEDTHEALDEHYDEFUNCTIONAT# WHICHWASSUBSEQUENTLYREDUCEDWITH.A"(3UBJECTINGTHERESULTINGPRI MARYALCOHOLTOTHEACTIONOFSODIUMAMALGAMFURNISHEDTHEDESIRED UNPROTECTED TRIENE  UNFORTUNATELY ONCE AGAIN AS A  MIXTURE OF OLEFINISOMERS3CHEME  )NTERESTINGLY ASOLUTIONTOBOTHSELECTIVITYINFORMATION ANDSTABILITY UPONUSEOFTHETRIENEWASACHIEVEDVIAANINTERMEDIATEPHENYLSULFONYL ALKENE FORMEDINEXCELLENTYIELDANDSELECTIVITYBYDIAZABICYCLOUN DECANE $"5 INDUCED ELIMINATION OF ACETATE &ROM THIS SPECIES  THEALDEHYDEWASEASILYREVEALEDANDSUBSEQUENTDESULFONYLATIONUNDER STANDARD CONDITIONS FURNISHED THE CENTRAL # # OLEFIN AS A SINGLE % GEOMETRY ALTHOUGHSOMEEPIMERISATIONAT#HADOCCURRED



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

OBn O 10

TBDPSO

SO2Ph

14 19

548 b

I

OBn O

17

10

TBDPSO

H

14

c

OBn OH

OBn OH 10

a

+

TBDPSO

19

+

19

TBDPSO

SO2Ph

14 19

SO2Ph 547

546

474

545

10

SO2Ph

14

d OBn OMe

OAc

10 14

S

20

S

20

OBn OMe

S

H

e,f

26

19

TBDPSO

23

26

+

S

O

10

TBDPSO

SO2Ph

14 19

SO2Ph

525

550

549

g,h,i

OBn OMe

H

10

j

TBDPSO

551

OBn OMe

H

OBn OMe

S

10

TBDPSO

26

OH

14

19

14

S

O

10

k,l

26

TBDPSO

14 19

26

H

SO2Ph 552

553

3CHEME A #R#L.I#L $-3/ 24   SEPARABLEB $-0 0Y #(#L 24  C ,I"( #E#Lq(/ -E/( 4(& n #   SEPARABLED -E/4F   DI T BUTYL PYRIDINE #(#L REFLUX E  S"U,I 4(& n # THEN n #F !C/ %T. $-!0 #(#L 24  MIXTUREOFDIASTEREOMERSG .#3 !G./ (/ #(#. 24  MIXTUREOFDIAS TEREOMERSH .A"( #(#L %T/(  #I +(0/ 4(& -E/( n # THEN.A(G OVER TWOSTEPS MIXTUREOF%:OLEFINISOMERSJ $"5 4(& 24 K .#3 !G./ (/ #(#. 24 L +(0/ 4(& -E/( n # THEN.A(G  MIXTUREOF#EPIMERS

4HECOMPLETELACKOFCONTROLOFTHE# STEREOCENTER3CHEME NECES SITATEDASUBTLEREDESIGNOFTHEREACTIONSEQUENCE3CHEME HOWEVERTHE LESSONSLEARNEDINTHEPREVIOUSSTUDYWERECRITICALTOTHEULTIMATEDESIGNOF AVIABLESYNTHESISOF)NANAPPROACHSIMILARTOTHATTAKENTOADDRESS PROTECTING GROUP DIFFICULTIES IN FRAGMENT  3CHEME  $ANISHEFSKY ANDCO WORKERSELECTEDTOPURSUEALACTONEFORMATIONSTRATEGYASAMEANS TOOVERCOME INTHISCASE SELECTIVITYISSUES.(+COUPLINGOFVINYLIODIDE ANDMODIFIEDALDEHYDECOUPLINGPARTNER AGAINOCCURREDWITHNO SELECTIVITYGIVINGAMIXTUREOFDIASTEREOMERICCOMPOUNDSWHICHWERE CONVERTEDTOTHESAMEβ HYDROXYKETONE BYOXIDATIONANDREMOVAL OFTHEBENZYLPROTECTINGGROUP3CHEME  !TTHISPOINT THERESULTINGFREEALCOHOLAT# WASEXPLOITEDINA SUBSTRATECONTROLLEDREDUCTIONUNDER%VANS 0RASAD;  =CONDI



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O EtO

OBn S

EtO

S

14

10

I

OBn O

O

a

10

16

541

17

H

O

OH O

10

14

b,c,d

+ 19

EtO

474

473

SO2Ph 19

SO2Ph 554

e O TBSO TESO

OMe

i,j,k,l

SO2Ph

14

10

10

O

19

26

H

OH OH

10

14

26

23

555

CHO

26

TBSO

x,y,z

19

OPiv

14

26

23

S

20

524

OMe

10

O

558

559

S

OCH3

m,n,o,p

23

TBDPSO

TBDPSO

475

26

q,r 20

23

SO2Ph 19

19

OPiv s,t 20

20

O

TBSO

O

556 OPiv

TESO

EtO

SO2Ph

14

557

u,v,w

f,g,h

OMe

OMe

O

10

TESO

14

26

19

H

SO2Ph 560

561

aa,bb

H

O

TBSO

10

14

OMe

O

TBSO

cc,dd

26

O

OMe

10

19

OMe

TESO

14

26 19

OMe

484

562

3CHEME A B #R#L.I#L $-3/ 24 OF#EPIMERSC $-0 #(#L 24 OVERTWOSTEPS D "#L #(#L n # E .A"( %T"/-E 0H#( n # F ,I/( 4(& -E/( (/  #G %$#) #(#L 24 OVERTWOSTEPSH -E) !G/ 24I +#/ -E/( 24J 4"3/4F   LUT #(#L  # OVERTHREESTEPSK $)"!, ( 4(&  # L 4%3#L %T. #(#L OVER TWOSTEPSM $)"!, ( 0H#( n #→24 N 4"$03#L %T. #(#LO .#3 !G./ 4(& -E/( P GLYOXYLIC ACID !C/( #(#L  OVER THREE STEPS Q .A"( %T/( R 0IV#L %T. #(#LS (&AQ (/ #(#.T $-0 #(#L OVERFOURSTEPSU  ,$! 4(& n # THEN V !C/ %T. $-!0 #(#L 24W $"5 4(& 24 OVERTHREESTEPSX $)"!, ( 0H#(  #Y +(0/ 4(& -E/( n # THEN.A(G Z $-0 0Y 24  OVERTHREESTEPSAA ,I#(/#( %T/ n #BB $-0 0Y #(#L 24 OVERTWOSTEPSCC !C/( (/ 4(& 24DD $-0 0Y #(#L OVERTWOSTEPS

.OYIELDOREXPERIMENTALDETAILSREPORTED

TIONSWHICHGAVEASASINGLEDIASTEREOMER0RODUCTIVELACTONEFORMA TIONBETWEENTHE# ALCOHOLAND# ESTERALLOWEDFORINSTALLATIONOF THE METHYL ETHER AT # AND THEN DIFFERENTIATED PROTECTING GROUPS AT BOTH#AND# 0RIORTOCOUPLINGWITH THEENALELECTRO PHILE ALSOUNDERWENTMODIFICATIONSEQUENCEM→ NIN3CHEME



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TOAVOIDPOTENTIALISSUESWITHLATESTAGEREMOVALOFTHEDITHIANEMOIETY WHICHHADPREVIOUSLYBEENPROBLEMATIC)NTHEEVENT FORMATIONOFTHE LITHIOANIONOFSULFONE ADDITIONTO ANDELIMINATIONTOTHEPHE NYLSULFONYLTRIENE GRATIFYINGLYOCCURREDINEXCELLENTYIELDOVERTHE THREESTEPS!SEXPECTED REDUCTIVEREMOVALOFTHEPIVALATETHROUGHTREAT MENTOFWITH$)"!, ( ANDDESULFONYLATIONYIELDEDASASINGLE # #ALKENE&URTHERELABORATIONTOTHE# #ALDEHYDEOCCURRED WITHOUTINCIDENTAFFORDINGINALONGESTLINEARSEQUENCEOFSTEPS ANDOVERALLYIELDOF 4HEFINALSTAGESOF$ANISHEFSKYSSYNTHESISOFRAPAMYCIN REQUIRED INCORPORATIONOFTHE   TRICARBONYLMOIETYUPONTHETRIENEFRAGMENT  JUST DISCUSSED &OR THIS PURPOSE THE ADDITION OF THE ANION OF α PHENYLTHIOAMIDES TO A SUITABLE ALDEHYDE FOLLOWED BY OXIDATION WITH $ESS -ARTINPERIODINANEHADBEENDEVELOPEDPREVIOUSLYTOACCESSSIMPLE VICINALTRICARBONYLSYSTEMS;=!PPLICATIONTOTHEREALSYSTEM3CHEME  WITHTHEREADILYPREPARED, PIPECOLICSULFOXIDEDERIVATIVEPLEAS INGLYGAVETHEDESIREDTRICARBONYLSYSTEMAFTEROXIDATION4REATMENTOF THISINTERMEDIATEWITH(&q0YRESULTEDINDESILYLATIONANDSPONTANEOUS HEMIACETALFORMATIONAT#-ODELSTUDIES;=HADINDICATEDTHATA FREEHEMIKETALHYDROXYLGROUPAT#WOULDINTERRUPTANYATTEMPTSTO COUPLETHEPIPECOLATEGROUPWITH# #FRAGMENTUNDERSTANDARDACTI VATINGCONDITIONSSEEINSERT 3CHEME !CCORDINGLY AFTEREXCHANGING THE ACID LABILE TERT BUTYL ESTER FOR THE ALLYL ESTER THE TERTIARY HEMIKETAL HYDROXYLGROUPINWASPROTECTEDASITSTRIMETHYLSILYLETHER4REATMENT WITHPALLADIUMNOWEFFECTEDCLEAVAGEOFTHEALLYLESTERUNDERMILDCON DITIONS ANDCRUCIALLYRETAINEDTHE4-3GROUPTOFURNISHCARBOXYLICACID  3UBSEQUENT ESTERIFICATION OF  WITH THE FREE SECONDARY ALCOHOL PRESENTAT#OFUNDERSTANDARDCONDITIONS SELECTIVEDESILYLATION OF THE # AND # HYDROXYL GROUPS AND OXIDATION GAVE THE CRUCIAL PRECURSOR  PRECURSOR FOR THE INTENDED MACROALDOLISATION PROCESS 3CHEME )TISSOMEWHATCURIOUSTHATTHELATTERDESILYLATIONOXIDATION SEQUENCE WAS PERFORMED PRIOR TO ATTEMPTING THE INTRAMOLECULAR ALDOL REACTIONESPECIALLYGIVENTHEPROPENSITYFORELIMINATIONOFTHEPIPECOLATE UNIT 7ITHCOMPOUNDINHANDEXTENSIVEINVESTIGATIONSDIRECTEDTOWARDS SUCCESSFULGENERATIONOFTHEDESIREDENOLATEANDSTEREOSELECTIVERING CLO SUREWEREINVESTIGATED4HISTRANSFORMATIONPROVEDEXCEPTIONALLYDIFFICULT



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

O 1

N H

OtBu

OtBu +

1

a,b

N O

9

O

O

TBS O OMe

10

OMe

14

1 OtBu H O O 9 TBS 10 O OMe

N

PhS(O) HO

c

26

19

O 26

PhS(O)

OMe

14

563

472

19

484

564 H

O

N

1

O

O

carboxyl activation (X) absence of TMS at C10-OH

9 10

O

O HO

O

O

9

X

O d,e,f,g

O

10 14

1

N

R

R 566 14

567

TIPSO

42

38

OH

1

N MeO

H

32

+

O TMSO

9

10

OH O TBS

CHO

1

N

H O O

O

O

OMe

O HO

9

10

26

OMe

14

28

h,i

O

H O O

O

O

OMe

OMe 19

19

565

469

468

26

14

j,k,l

TIPSO

TIPSO

42

MeO

38

H

HO

42

MeO

38

H

32

N H1 O O 9

O HO 10

O

O

16

O

m

CHO O

22

isomer 570 (22%)

O HO

9

10

N H1 O O O

O

H 32

OH

O

O

MeO

OMe

n

O HO

9

10 22

N H1 O O O

O

O

OH O

MeO

OMe

22

16

16

568

38

32

MeO

OMe

42

MeO

569

(-)-rapamycin 7

3CHEME A PHENYLTHIO ACETICACID %$#) #(#L 24 B .A)/ (/ -E/( 24 C  ,$! 4(& n # THEN n # D $-0 0Y #(#L 24E (&q0Y 4(& 24 OVERTWOSTEPS F (#/( #(#L 24 G ALLYL BROMIDE +#/ 4"!) $-& 24  OVER TWO STEPS H 4-3 )M $-!0 $-& 24 I 0D00H MOL 0H0 #(#L 24 J $## $-!0 #(#L n # K 4"!& !C/( 4(&  # L $-0 0Y #(#L 24 M 4I#L/I0R #(#L %T. n # N (&q0Y 4(& 24 

ANDESSENTIALLYALLSTANDARDREACTIONCONDITIONSINVESTIGATEDFAILEDTOPRO VIDEEVENATRACEOFTHEDESIREDPRODUCT&INALLY USEOF4I#LINTHEPRESENCE OF%T.WASSUCCESSFULININDUCINGTHEDESIREDBONDFORMINGEVENTALBEITIN LOWYIELD3LIGHTLYIMPROVEDRESULTSWEREACHIEVEDBYUSEISOPROPOXYTITA NIUMTRICHLORIDEASTHEPROMOTER BUTUNFORTUNATELYWASNEVERISOLATED INMORETHEN5NREACTEDSTARTINGMATERIAL DEGRADATIONPRODUCTS AND



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 3UMMARYOF$ANISHEFSKYSTOTALSYNTHESISOFRAPAMYCIN

THECONSISTENTPRESENCEOFANAPPARENTSTEREOISOMEROFACCOUNTEDFOR THEREMAINDEROFTHEMASSBALANCE&INALLYDESILYLATIONOFWITH(&q0Y YIELDEDRAPAMYCIN IDENTICALINALLREGARDSWITHSAMPLESOFTHENATURAL MATERIAL )NSUMMARY THE$ANISHEFSKYSYNTHESISOFRAPAMYCINREQUIREDALONGEST LINEARSEQUENCEOFSTEPSANDANOVERALLYIELDOF3CHEME  !LTHOUGHTHELONGESTOFTHEVARIOUSAPPROACHES THISTOTALSYNTHESISEFFORT INCLUDEDNUMEROUSINTRIGUINGANDUNCONVENTIONALSTRATEGIES MOSTNOTA BLYANOVELMACROALDOLISATION/THERHIGHLIGHTSINCLUDEIMPLEMENTATION OFANUMBEROFGROUP DEVELOPEDMETHODOLOGIESEG HETERO $IELS !LDER CYCLOADDITION CONSTRUCTIONOFTHETRICARBONYLREGION ELEGANTDEGRADATION STUDIES ANEFFICIENTUSEOFCARBOHYDRATESTARTINGMATERIALSINCOMBINATION WITHREARRANGEMENTPROCESSESTOACCESSAVARIETYOFFRAGMENTS ANDANUM BEROFCLEVERSOLUTIONSTOUNEXPECTEDDIFFICULTIESENCOUNTEREDDURINGTHE COURSEOFSYNTHESIS



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

 4HE3MITHTOTALSYNTHESESOFRAPAMYCINAND  DEMETHOXYRAPAMYCIN )N !MOS"3MITH)))DISCLOSEDTHELASTOFTHESUCCESSFULAPPROACHES TORAPAMYCIN OFTHATDECADE WITHFULLEXPERIMENTALDETAILSFOLLOWING TWOYEARSLATER;n=4HESYNTHESISHIGHLIGHTSBOTHσ BONDFORMA TIONFORTHECONSTRUCTIONOFSTEREODEFINEDOLEFINS ANDDITHIANECHEMISTRY FORTHEUNIONOFCOMPLEXFRAGMENTS; =-OREOVER ITISAHIGHLY MODULARANDCONVERGENTAPPROACH ANDWASSUCCESSFULINDELIVERINGNOT ONLY RAPAMYCIN  BUT ALSO ITS NATURALLY OCCURRING CONGENER  DEME THOXYRAPAMYCIN ; = 2ETROSYNTHETICALLY CLEAVAGE OF THE # ESTER LINKAGE AND THE CENTRAL OLEFIN # # OF THE TRIENE AFFORDS THE TWO LARGE FRAGMENTS  AND 4HISSTRATEGYWASDESIGNEDTOALLOWMAXIMUMFLEXIBILITYINTHEFINAL MACROCYCLISATIONASEITHERA3TILLECOUPLINGORMACROLACTAMISATIONCOULDBE EMPLOYEDDEPENDINGUPONTHEORDERINGOFEVENTS&URTHERCONSIDERATION OFANDREVEALSBUILDINGBLOCKSnASINITIALSYNTHETICTARGETS 3CHEME  4HESYNTHESISOF# #STANNANE WASENVISIONEDTORELYHEAV ILYONANIONICCOUPLINGSOFSUBSTITUTED  DITHIANESWITHSUITABLEELECTRO PHILESTOBUILDTHE# #AND# #SIGMABONDS)NCONTRASTTOMUCH OF THE EARLY WORK INVOLVING TRANSFORMATIONS OF THIS TYPE ; = THE STRUCTURALCOMPLEXITYOFISSUBSTANTIALANDWOULDPROVEANEXCELLENT TESTINGGROUNDFORDEMONSTRATIONANDADVANCEMENTOFTHISMETHODOLOGY 4HEDISCONNECTIONACROSSTHE# #LINKAGEINTHISFASHIONISESPECIALLY INTERESTING ASITAFFORDSANEXCELLENTPOINTOFDIVERGENCETOWARDSTHETWO NATURALPRODUCTTARGETSAND (OWEVER THISISALSOAPOTENTIALLYPROB LEMATICSTRATEGYASCONTROLOFTHERESULTINGSTEREOCHEMISTRYAT#ISCRUCIAL ANDFARFROMASSURED4HECHALLENGINGTRISUBSTITUTEDOLEFINICLINKAGEWITH FLANKINGSTEREOCENTRESONEITHERSIDEWASTOBECONSTRUCTEDUSINGAσ BOND FORMATIONEVENT; =)NTHISFASHION THEUNACCEPTABLEISOMERICMIX TURESOFTENOBTAINEDFROMα α DISUBSTITUTEDYLIDESMIGHTBEAVOIDED !STHESTEREOCHEMISTRYWITHINTHE# #REGIONISULTIMATELYUNIM PORTANT ADDITIONOFTHEDIANIONOF , . ACETYLPIPECOLICACID; =TO ALDEHYDE FOLLOWEDBYOXIDATIONUNDERTHE'OLECPROTOCOL;=AS MENTIONEDPREVIOUSLYSEE3CHEME PAGE SHOULDRAPIDLYGENERATE THETRICARBONYLREGIONOF4HESILYLTERMINATEDENYNEOFWASENVI



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO

42

MeO

HO

38

42

C21-C42 stannane (R = OMe) 571; (R = H) 572

TIPSO

42

H

38

H

38

OH O

H

OTBS

32

R

O HO

9

N H1 O O

O

O

OH

I OPMB

O

OMe

OPMB

S

26

+

+

(MeO)2HC 22

575

32

S

OTBS 27

1

CO2H

N 10

574

O

R 22

16

O TESO

(-)-rapamycin (R = OMe) 7 (-)-27-demethoxyrapamycin (R = H) 8

Bu3Sn

576

22

O 10

S 26

33

32

MeO

S

+

MeO

CHO

O 10

O

OMe 16

H C1-C20 acid 573

1

20

N

I

CO2H

8

+

OTBS OMe 16

O 577

20

TMS 578

3CHEME 2ETROSYNTHETICANALYSIS

SIONEDTOSERVEASTHEPRECURSORTOASECONDσ BONDCONSTRUCTIONTHROUGH HYDROMETALLATIONIODINATION )N THE FORWARD DIRECTION THE SYNTHESIS OF THE # # SULFONE BOR ROWSFROMCHEMISTRYEMPLOYEDIN3MITHSFORMALTOTALSYNTHESISOF&+  3CHEME  ; = !N ASYMMETRIC $IELS !LDER REACTION OF   BUTADIENEWITHHOMOCHIRALSULTAM;=UNDER,EWIS ACIDCATALYSIS EFFICIENTLYGENERATEDCARBOXYLICACIDINGOODOVERALLYIELDANDENANTIO MERICEXCESS FOLLOWINGBASE PROMOTEDHYDROLYSISOFTHECHIRALAUXIL IARY!LTHOUGHCERTAINLYSUITABLEFORTHEPRODUCTIONOFREASONABLEAMOUNTS OF THEREAREANUMBEROFDRAWBACKSTOTHISAPPROACHINCLUDING MOST SIGNIFICANTLY THEMULTI STEPSYNTHESISOFASTOICHIOMETRICASYMMETRICCON TROLLER5NFORTUNATELY TODATEDIRECTCATALYTICASYMMETRIC$IELS ALDERREAC TIONSOFUNSUBSTITUTED  BUTADIENESANDSIMPLEDIENOPHILESREMAINSAN UNRESOLVEDPROBLEMFORTHEORGANICCHEMISTRYCOMMUNITY; = 7ITHINHAND IODOLACTONISATIONINSTALLEDTHENECESSARYOXYGENATION AT#ANDSUBSEQUENTDEHYDROHALOGENATIONWITH$"5GENERATEDANOLE FINICHANDLEFORFURTHERMANIPULATION!FTERREDUCTIONOFTHELACTONE WITH,I!L( THERESULTINGPRIMARYALCOHOLWASSELECTIVELYTRANSFORMEDTO THECORRESPONDINGSULFIDE BYTREATMENTWITHTRI N BUTYLPHOSPHINE ANDDIPHENYLDISULFIDE3TANDARDSYNTHETICMANIPULATIONSTHENPRODUCED SULFONE  SUITABLY ADORNED FOR THE CRUCIAL REGIO AND STEREOSELECTIVE INTRODUCTIONOFTHELASTREMAININGHYDROXYLFUNCTION0REVIOUSLYITHAD BEENSHOWNTHATHYDROBORATIONOXIDATIONOF ALKOXYCYCLOHEXENEDERIVA TIVES IS SUITABLE FOR THE TRANS INSTALLATION OF A VICINAL HYDROXYL GROUP TO



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O2 S N

O

O2 S N

a,b

O 42

42

c,d

R

42

e,f

38

H

CO2H

38

HO

O

42

g,h

SPh

MeO

38

SO2Ph 38

O

579

30

580

581

583

582

i TIPSO

MeO

TIPSO

42

o,p 38

H

574

TIPSO

33

I OPMB

MeO

m,n 38

H

33

MeO

O

42

42

HO

TIPSO 42

585 38

H

33

OTBDPS O

414

OTBDPS

586

k,l

MeO

42

j

MeO

38

38

SO2Ph

SO2Ph

OH 584

69

3CHEME A   BUTADIENE %T!L#L #(#L n #  B ,I/( 4(&(/ 24  C ) +) .A(#/ (/  #  D $"5 4(& REFLUX  E ,I!L( %T/  #  F "U0 0H3  $-& 24  G #(. "&q/%T %T/  #  H /XONE¤ 4(&-E/((/  #  I "(q4(& .A/( T"U/( n #→24 J 4)03#L )M $-& 24 ^K  N"U,I 4(& n # THEN  "&q/%TL .A(G .A(0/ -E/( 24 OVERTWOSTEPSM -S#L %T. #(#L  N .A( (-0!  #→24 O ,I) "&q/%T %T/ n # P 0-" 4#! "&q/%T #(#L n # 

ANEIGHBOURINGALKOXYGROUP; =)NTHEEVENT TREATMENTOF WITH"(q4(&ATLOWTEMPERATUREGAVETHEDESIREDPRODUCTINGOODOVER ALL YIELD 3ILYLATION ;= FOLLOWED BY "&q/%T PROMOTED REGIOSELECTIVE RING OPENINGOFTHEREADILYAVAILABLEEPOXIDE;=BYTHEANIONOF  EFFICIENTLY COMPLETED THE CARBON FRAMEWORK AND INSTALLED THE LAST TWO STEREOCENTRES OF  )NTERESTINGLY THE INCORRECT ANTIPODE AT # WASINSTALLEDPURPOSEFULLYTOALLOW AFTERDESULFONYLATIONANDMESYLATION INVERSIONOFTHISCENTRETHROUGHINTRAMOLECULAREPOXIDEFORMATIONOFTHE LIBERATED#HYDROXYLGROUPUPONDEPROTECTIONUNDERBASICCONDITIONS ;n=&INALLY RING OPENINGOFTHEOXIRANE WITHLITHIUMIODIDE AND"&q/%TGAVEANINTERMEDIATEIODOHYDRINWHICHWASSUBSEQUENTLY PROTECTEDASITS0-"ETHERUNDERTHEACIDICCONDITIONSOF"UNDLE;=TO COMPLETETHESYNTHESISOFTHE# #FRAGMENT /VERALL THISWAS PREPAREDINTOTALSTEPSANDYIELDFROMTHECHIRALDIENOPHILE STEPS YIELDFROMBASICSTARTINGMATERIALS 3CHEME  4HESYNTHESISOFTHE# #CENTRALDITHIANEFRAGMENT BEGAN WITHASERIESOFSTANDARDTRANSFORMATIONS WHICHCONVERTED2  HYDROXY  METHYLPROPIONATE TODITHIANEINOVERTHEFOURSTEPS$ESI LYLATION OF  TOSYLATION AND &INKELSTEIN TREATMENT AFFORDED PRIMARY IODIDETHATUNDERWENTCLEANDISPLACEMENTWHENTREATEDWITHSODIUM



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

MeO

a,b

OH

32

O

S

c,d

OTBDPS

32

e,f,g

OTBDPS

32

S

S

OH

420

587

h

I

32

S

S 588

SO2Ph

32

S

589

590

OHC

O

O

i

591

o,p,q,r

32

H OTBS

S

27

32

OH

27

S 576

S

OH 595

m,n

S

27

32

O O

S 594

OH

O

OTf

O

S

l

S

27

32

O O

S 593

j,k

S

27

32

O

S O2SPh O 592

3CHEME A 4"$03#L )MB ,I"( %T/ OVERTWOSTEPSC #/#L  $-3/ #(#L n # THEN%T. n #→24D (3#( 3( "&q/%T OVERTWOSTEPSE 4"!& 4(&F 4S#L %T. OVER TWOSTEPSG .A) ACETONEH 0H3/.Aq(/ $-& OVERTWOSTEPSI  N"U,I 4(& n # → n # THEN  J #/#L  $-3/ #(#L n # THEN %T. n # → 24  OVER TWO STEPSK !L(G 4(&(/ REFLUX L ,I(-$3 (-0!4(& n # THEN4F.0H M -E#U,I %T/ n # N #3! -E/( 24 O 0IV#L $-!0 P 4"3/4F   LUT  Q $)"!, ( R #/#L  $-3/ #(#L n # THEN%T. n #→24 

BENZENESULFINATETOGIVETHECORRESPONDINGSULFONE α ,ITHIATIONAND CONDENSATIONWITHISOPROPYLIDENE , GYLCERALDEHYDEGAVEASINGLEKETONE  FOLLOWINGOXIDATIONANDDESULFONYLATION4HESTEREOSELECTIVEGENERA TIONOF% OR: ENOLATESISAWELLSTUDIEDPROCESS;= ASISTHEABILITYTO TRAPTHEMWITHGEOMETRICALINTEGRITYASEITHERSILYLENOLETHERSORVINYLTRI FLATES4HEFINDINGTHATTHELATTERUNDERGOSMOOTHCOUPLING;=WITHLITH IUMDIMETHYLCUPRATESPROVIDESANELEGANTSOLUTIONTOTHESTEREOSELECTIVE GENERATIONOFMETHYLATEDTRI SUBSTITUTEDOLEFINSPRESENTINALARGENUMBER OFNATURALPRODUCTS;n=4HISWASEXPLOITEDBY3MITHINHIS&+ SYNTHESIS ANDHASFOUNDAPPLICATIONFORTHECONSTRUCTIONOFTHE# # OLEFINICLINKAGEPRESENTINRAPAMYCIN#ONSIDERABLEEXPERIMENTATIONWAS REQUIREDTODETERMINETHEOPTIMUMENOLISATIONCONDITIONSFOR;= (OWEVER WITHTHESEINHAND TRAPPINGWITH. PHENYLTRIFLUOROMETHANE SULFONIMIDE;=ANDCOUPLINGWITH-E#U,IGAVEEXCLUSIVELYTHEDESIRED :OLEFINISOMER INRESPECTABLEYIELD0ROTECTINGGROUPMANIPULATIONS ANDAFINAL3WERNOXIDATIONGAVETHEα SILOXYALDEHYDE FORWHICH ACRYSTALSTRUCTUREWASOBTAINEDCONFIRMINGBOTHTHESTEREOCHEMISTRYAND OLEFINGEOMETRY3CHEME ;=/VERALL FROMTHECOMMERCIALLYAVAIL ABLE2OCHEESTER ALDEHYDEREQUIREDSYNTHETICMANIPULATIONSAND WASPREPAREDINAYIELDOF



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

O

O

OEt

EtO

+

O

b,c

O

O

d,e

598

597

CO2Me

MeO2C

EtO2C

Br 596

CO2Et

EtO2C

a OEt

599

600

f

S S 26

m,n

HO

26

S

22

OMe

S

j,k,l

g,h,i

OH

TBDPSO

22

MeO

603

26

22

602

CO2Me

HO2C

26

22

601

575

3CHEME A .A %T/( REFLUX B (#L REFLUX C !C/ REFLUXTHENRECRYSTALLISEFROM%T/!C  D -E/( REFLUX E -E/(0H( (3/ REFLUX F α CHYMOTRYPSIN -PHOSPHATEBUF FERP( 24 H G "/-E  "(q$-3 4(&  # H 4"$03#L )M I $)"!, ( J #/#L  $-3/ #(#L n # THEN%T. n #→24 K (3#( 3( "&q/%T L 4"!& M #/#L  $-3/ #(#L n # THEN%T. n #→24N -E/ #( 4S/( -E/( OVERTWOSTEPS

7ITH ROUTES TO BOTH THE # # AND # # FRAGMENTS IN HAND ATTENTION WAS THEN FOCUSED ON THE SYNTHESIS OF THE REMAINING MOIETY REQUIREDTOCONSTRUCT NAMELYTHE# #DITHIANE &OR THIS 3MITHELECTEDTOPURSUEENZYMATICDESYMMETRISATION;=OFMESO DIESTERWITHα CHYMOTRYPSINTOAFFORDTHEHALFESTERINGOODYIELD ANDENANTIOSELECTIVITY !TTHETIMEOFPUBLICATION THISWASPROBABLY THEMOSTRELIABLEOFTHEENZYMATICMETHODSAVAILABLE ALTHOUGHCURRENTLY MOREEFFICIENTALTERNATIVESEXIST/NEOTHERSALIENTPOINT NOTIMMEDIATELY APPARENT ISTHATSTARTINGMATERIALREQUIRESFIVESTEPSTOPREPARE;= OFWHICHACCESSTOTHEMESOANHYDRIDEWASPARTICULARLYLOWYIELDING 4HISHASRECENTLYBEENADDRESSEDBY-AIERTHROUGHADYNAMICRECRYSTAL LISATION;= ANDTHISIMPROVEMENTHASBEENEMPLOYEDIN,EYSSYNTHESIS OFRAPAMYCINVIDEINFRA !SERIESOFROUTINEFUNCTIONALGROUPCONVERSIONS ANDOXIDATIONSTATEADJUSTMENTSWASTHENEMPLOYEDTOPREPARETHEFULLY ELABORATED# #DITHIANEINANOVERALLYIELDANDSTEPS4O AVOID OXIDATIVE METHODOLOGY LIMITATIONS DUE TO THE PRESENCE OF SULFUR ANDPOTENTIALEPIMERISATIONOFTHE#METHYLSTEREOCENTREINADVANCED INTERMEDIATES THE#ALDEHYDEWASMASKEDINTHECORRECTOXIDATIONSTATE ASITSDIMETHYLACETAL3CHEME  4HEIMPORTANCEOFFLEXIBLYINALARGESYNTHETICENDEAVOURISAPTLYDEM ONSTRATEDBYTHEFACTTHAT  ANDOF3CHEMEALLPROVEDTOBE



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO

S

a

OTBDPS

32

TIPSO

S 588

MeO

38

H

33

b,c

OTBDPS

MeO S

H

OMs 30

605

d

TIPSO

MeO

H

33

TIPSO

42

I

38

H

PMBO

SS

PMBO 607

MeO

33

30

decomposition (MeO)2HC

33

604

I OPMB

26

?

H

Nuc

33

42

38

38

PMBO S S

OMs

S

42

PMBO S S

574

TIPSO

38

MeO

30

42

MeO

TIPSO

42

S

S

42

38

H

33

PMBO

S

S

OMs

606

608

22

575

3CHEME A  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTIONIN(-0!4(&  B .A( (-0!  #→24 C -S#L %T. D .A) ACETONE  # DECOMPOSITION

IMPORTANTFORTHEELUCIDATIONOFAVIABLEROUTETOTHEFULLYELABORATED# #CARBONFRAMEWORK!LTHOUGHNOTPREVIOUSLYDISCUSSED 3MITHSINITIAL SYNTHETICTARGETWAS FORMEDEFFICIENTLYBYIMMEDIATEADDITIONOFPRI MARYIODIDETOTHEPREFORMED ALKYL   DITHIANEANIONT"U,I OF INACOLDn # (-0!4(&MIXTURE3CHEME 4HISPROTOCOLAND SLIGHTMODIFICATIONSTHEREOF HASPROVENREMARKABLYGENERALINAWIDEVARI ETYOFCOMPLEXFRAGMENTCOUPLINGSANDREPRESENTSAVERYIMPORTANTADVANCE FORAPPLICATIONOFDITHIANEMETHODOLOGY;=4HEKEYOBSERVATIONWAS THENEARINSTANTANEOUSGENERATIONMIN OFTHEDITHIANEANIONUNDER THESECONDITIONS WHICHGRADUALLYLOSESITSREACTIVITYWITHTIME; = NECESSITATINGEITHERTHEINITIALPRESENCEOFTHEELECTROPHILEEG EPOXIDE OR ITSRAPIDADDITIONTOACHIEVEHIGHYIELDS7ITHREADYACCESSTOSECURED THEPLANWASSUBSEQUENTCONVERSIONTOELECTROPHILEANDCOUPLINGOFA SECONDDITHIANEANIONSUCHAS5NFORTUNATELYALLATTEMPTSTOPREPARE PRIMARYIODIDEFAILEDUNDERTHECONDITIONSEXPLOREDANDREVEALEDAN INTERESTINGFEATUREOF  DISUBSTITUTED  DITHIANESWITHPROXIMALLEAVING GROUPSTOREARRANGEDECOMPOSEUNPRODUCTIVELY; =4HEDIFFERENCE BETWEEN MONOSUBSTITUTED  DITHIANES WHERESIMILARREARRANGEMENTS ARE GENERALLY NOT PROBLEMATIC AND THEIR DISUBSTITUTED COUNTERPARTS HAS BEENATTRIBUTEDTOTHECONFORMATIONALCHANGESANDSTERICCONGESTIONABOUT THEDITHIANE; =)NANYREGARD ANINABILITYTOACCESSREQUIREDA



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

S

27

32

O O

S

594 TIPSO a

TIPSO MeO

42

MeO

38

33

I OPMB

574

42

38

H

H

33

27

O

PMBO S S

O

609

b,c TIPSO

TIPSO

42

MeO

38

H

33

SS

PMBO

27

d,e

MeO

38

H

I OTBS

PMBO

SS

OH

610 TIPSO

S

g

27

33

MeO

42

38

H

27

33

OTs

611

S

TIPSO

42

O

SS

PMBO

613

42

S

S

26

26

f

MeO

38

h,i

H 32

(MeO)2HC

PMBO S S

22

OTBS

575

(MeO)2HC 22

575 26

S S

+ elmination products (41%) (MeO)2HC

612

22

3CHEME A  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTIONIN(-0!4(& B #3! -E/( 24 C 4S#L %T. $-!0 #(#L  #→24 D .A) ACETONE  E 4"3/4F   LUT F  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTION IN(-0!4(& G +#/ -E/( 24H  T"U,I (-0!4(& n #THENPRE COOLED n # SOLUTIONIN(-0!4(& OVERTWOSTEPSI 4"3/4F   LUT n # 

REDESIGNOFTHESYNTHETICAPPROACHWHICHWASREADILYACHIEVEDDUETOTHE MODULARNATUREOFTHEOVERALLSTRATEGYVIDEINFRA  &OR DEMETHOXYRAPAMYCIN ALKYLATIONOFTHELITHIO ANIONOF INPLACEOF WITHIODIDE UNDERTHECONDITIONSDISCUSSEDPREVI OUSLYAFFORDEDTHEDESIREDPRODUCT INANIMPRESSIVEYIELDOF 3UBSEQUENTFUNCTIONALGROUPTRANSFORMATIONSCONVERTEDTOTHECORRE SPONDINGPRIMARYIODIDE 5NFORTUNATELY UPONATTEMPTEDCOUPLING WITHTHEFINAL# #FRAGMENT ANUNACCEPTABLYLOWYIELDOF WASOBTAINEDDUETOTHEFORMATIONOFSUBSTANTIALAMOUNTSOFIODO ELIMI



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO

MeO

TIPSO

42

38

H

33

a,b,c,d

27

MeO

TIPSO

42

38

[O]

H

33

O

PMBO

SS

O

PMBO

609

SS

MeO

27

OH OTBS

38

O

H

33

PMBO

614

SS

27

H OTBS

615

S

S 26

e,f

TIPSO

42

(MeO)2HC

42

22

MeO

38

H

O

575

33

PMBO O 616

27 H OTBS

g

multiple products

3CHEME A #3! -E/( 24 B 0IV#L $-!0 #(#L C 4"3/4F   LUT #(#L D $)"!, ( 0H#( E -E) #A#/ -E#.4(&(/  # F #/#L  $-3/ #(#L n # THEN %T. n #→24 G  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTION IN(-0!4(& MULTIPLEPRODUCTS

NATIONPRODUCTS4OAVOIDTHISISSUE WASCONVERTEDTOEPOXIDE WHICHWASSMOOTHLYRING OPENEDATTHEOXIRANETERMINUSBYMETALLATED  !FTER SILYLATION COMPLETION OF THE DEMETHOXYRAPAMYCIN # # BACKBONEREQUIRESONLYTHEINSTALLATIONOFTHEVINYLSTANNANEMOIETYVIDE INFRA /VERALL WASPREPAREDINALONGESTLINEARSEQUENCEOFSTEPS ANDOVERALLYIELD )NCONTRASTTO DEMETHOXYRAPAMYCIN FORPREPARATIONOFRAPAMY CIN #MUSTBEAROXYGENATION"OTH&ELKIN !NHANALYSIS;n= STERIC AND STEREOELECTRONIC ARGUMENTS CAN BE MADE TO PLACE THE /4"3 MOIETY PERPENDICULAR TO THE CARBONYL AND LITERATURE PRECEDENT FOR THE ADDITIONOFMETALLATEDDITHIANESTO$ ISOPROPYLIDENEGLYCERALDEHYDE; =SEEMEDTOSUGGESTTHEDESIREDSTEREOCHEMISTRYOFTHENEWCHIRALCENTRE WOULDPREDOMINATE)NITIALLYTHESAMECOUPLINGSEQUENCEASUSEDSUCCESS FULLYABOVEFOR DEMETHOXYRAPAMYCIN 3CHEME WASENVISIONED TOSERVEASANEFFICIENTENTRYTO4HUS AFTERHYDROLYSISOFACETONIDE ASPREVIOUSLYDESCRIBED THERESULTINGDIOLWASSELECTIVELYPROTECTEDAT THEPRIMARYPOSITION ANDFURTHERFUNCTIONALGROUPTRANSFORMATIONSTHEN AFFORDED THE OXIDATION PRECURSOR  3CHEME   (OWEVER ALL OXIDA TIONPROTOCOLSFAILEDTODELIVERTHEDESIREDALDEHYDE ANDTHROUGHA SERIESOFCONTROLEXPERIMENTSANUNFAVOURABLECONFORMATIONIMPARTEDBY THEPRESENCEOFTHE  DISUBSTITUTED  DITHIANESEEMEDTHEMOSTPROB



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

S

O

S

a

26

O S

(MeO)2HC

H OTBS

S

575

S

32

H

H

Nuc

617 Observed

32

S

TBSO

(MeO)2HC

(MeO)2HC

618

619

22

576

S S

27

+

TBSO

S

OH

S

S S

27

32 27

22

OH

OTBS

R

22

b TIPSO

TIPSO

MeO

42

42

MeO 38

H

38

H

32

PMBO S S

OTBS 27

S S

MeO

574

33

I OPMB

OMe

S

32

S S

27

S

TBSO

c

(MeO)2HC 22

620 (MeO)2HC 22

621

3CHEME A  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTIONIN(-0!4(&   B -E) .A(  #  4(& 24 C  T"U,I (-0!4(& n #THEN PRECOOLED n # SOLUTIONIN(-0!4(& 

ABLECAUSE.OTSURPRISINGLY THEMULTIPLEELECTROPHILICSITESINKETO ALDE HYDEMADEFURTHERELABORATIONTHROUGHANIONICCHEMISTRYUNSUITABLE 3CHEME  )NANATTEMPTTORESOLVETHISISSUE ANALTERNATIVEFRAGMENTASSEMBLY ORDERWASINVESTIGATED ANDPROVEDTOAFFORD3MITHSFIRSTSUCCESSFULROUTE TOTHE# #CARBONFRAMEWORKOFRAPAMYCIN !SBOTHAND CONTAIN SIMILAR FUNCTIONALITY THEIR UNION WAS COMPLICATED BY COMPETI TIVEPROTONTRANSFER4HISDIFFICULTYCOULDBERESOLVEDBYADDITIONOFTHE PRE COOLEDALDEHYDE TOANEXCESSFIVEEQUIVALENTS OFTHEPREFORMED DITHIANEANIONOFATn #!LTHOUGHNOTIDEAL THEMAJORITY OFUNREACTEDCOUPLINGPARTNERCOULDBERECOVEREDANDAFFORDEDTHE ADDITIONPRODUCTASAMIXTUREOF#EPIMERSINOVERALLYIELD !SDISCUSSEDPREVIOUSLY ANDASSUMING&ELKIN !NHCONTROL ITWASEXPECTED THAT THE MAJOR COMPONENT OF THIS MIXTURE WOULD BE THE DESIRED # 2 ALCOHOL 3URPRISINGLY 8 RAY ANALYSIS OF A DERIVATIVE OF  REVEALED THATUNDESIRED# 3 ALCOHOL WASTHEDOMINANTPRODUCT SUGGEST INGADDITIONOFTHEMETALLATEDDITHIANETOACONFORMATIONINWHICHTHE VINYLSIDECHAINWASPERPENDICULARTOTHECARBONYL4HISWASSUPPORTED BYAPREVIOUSLYOBTAINEDCRYSTALSTRUCTUREOFTHEELECTROPHILICPARTNER



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO O S

S

576

S

a

32 27 H OTBS

CH(OMe)2

32

MeO

b

27

S

42

38

H

574 TIPSO MeO

TIPSO

42

38

H

MeO

OTBS 27

R

38

+

OTBS

33

623

I OPMB

TIPSO

H

42

32

PMBO S S

MeO

d

OTBS

38

O

H

33

27

S S

S S

HO

(MeO)2HC

22

22

PMBO

S S

e

CH(OMe)2

SS

c

(MeO)2HC R = OH, 625

33

42

32

PMBO S S

H PMBO

622 MeO

38

27

TIPSO

OTBS

42

SS

27 H OTBS

CH(OMe)2

26

22

615 575

624

R = OMe, 621

3CHEME A -E/ #( -E/( 4S/( B  T"U,I (-0!4(& n #THENPRECOOLED n # SOLUTION IN  (-0!4(&  C #L##/( ACETONE  D  T"U,I  (-0!4(& n # THEN  PRE COOLED n # SOLUTION IN  (-0!4(&     E -E) .A(  #  4(& 

)N THIS THE SOLID STATE CONFIGURATION CLEARLY DEMONSTRATES THAT THE STERIC INFLUENCEOFTHETRISUBSTITUTEDOLEFINOVERRIDESTHATOFTHESTEREOELECTRONIC EFFECTOFTHEα ALKOXYSUBSTITUENT.OMENTIONOFEFFORTSTOINVERTTHE# STEREOCHEMISTRYWASMADE ALTHOUGHBYVIRTUEOFITSα DISPOSITIONTOTHE BULKY  DISUBSTITUTEDDITHIANESUCHATRANSFORMATIONMIGHTBEDIFFICULT )NANYREGARD SEPARATIONOFTHEDIASTEREOMERSWASPOSSIBLE ANDALLOWED UNEVENTFULTRANSFORMATIONTOTHE# #ADVANCEDFRAGMENTAFTERASEC ONDALKYLATIONWITHPRIMARYIODIDE3CHEME  !LTHOUGHSUCCESSFULINDELIVERINGDESIREDTARGET THEPOORSELECTIV ITY ANDTHUSOVERALLSTEPYIELD ALONGWITHITSTEDIOUSPURIFICA TIONRADIALCHROMATOGRAPHY NECESSITATEDANALTERNATIVESTRATEGY3MITH HADACCURATELYNOTEDTHEDRAMATICEFFECTTHATA  DISUBSTITUTEDDITHIANE CANHAVEONREACTIVITYONNUMEROUSOCCASIONSVIDESUPRA ANDCORRECTLY SPECULATEDTHATTHESAMEMIGHTHOLDTRUEWITHREGARDTOSTEREOCHEMICAL OUTCOMES #ONSEQUENTLY THE # # FRAGMENT WAS MODIFIED TO ALLOW ACCESS TO THE PREVIOUSLY INACCESSIBLE ALDEHYDE  !LKYLATION OF THE METALLATEDDITHIANEDIMETHYLACETAL WITHFOLLOWEDBYHYDRO LYSIS REVEALED THE ALDEHYDE FUNCTION WITHOUT COMPLICATION 3UBSEQUENT ADDITIONTOASOLUTIONOFTHEPREFORMEDANIONOFTHENGENERATEDA



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

MIXTUREOF#αANDβEPIMERS BUTINMUCHIMPROVEDSELECTIVITYFORTHE DESIREDCONFIGURATIONVERSUS ONCEAGAINSEPARATEDBYRADIALCHRO MATOGRAPHY 4HISIMPORTANTMODIFICATIONGREATLYIMPROVEDTHEMATERIAL THROUGHPUTFORTHEADVANCED# #CARBONBACKBONE ANDOVERALL WASPREPAREDINALONGESTLINEARSEQUENCEOFSTEPSANDOVERALL YIELD3CHEME  !LL THAT REMAINED TO COMPLETE THE # # STANNANE  FOR THE SYNTHESIS OF BOTH RAPAMYCIN  AND  DEMETHOXYRAPAMYCIN  WASAONECARBONHOMOLOGATION TOINSTALLTHEEVENTUALVINYLSTANNANEAT # ANDASERIESOFPROTECTINGGROUPMANIPULATIONS4HERECENTDEVELOP MENTOFTHE3TORK :HAOBISTRIFLUOROACETOXY IODOBENZENEPROTOCOL;= HAS PROVED VERY VALUABLE FOR REVEALING KETONE FUNCTIONALITY IN COMPLEX MOLECULES ASEXEMPLIFIEDBYTHESMOOTHCONVERSIONOFTOAND TO0ALLADIUMCATALYSEDHYDROSTANNATIONOFTHERESULTINGBIS KETO INTERMEDIATESANDCOMPLETEDTHESYNTHESISOFTHE# #VINYL STANNANEFORBOTHRAPAMYCIN ANDITSANALOGUE INEXCELLENTYIELD AND WITH HIGH REGIO AND STEREOSELECTIVITY /VERALL THE SYNTHESIS OF  2( AND2/-E REQUIREDATOTALOFANDSTEPS INAND YIELDSRESPECTIVELY3CHEME  #ONSTRUCTION OF THE REMAINING # # CARBOXYLIC ACID ONCE AGAIN UTILISED IN PART PREVIOUSLY DEVELOPED CHEMISTRY EMPLOYED IN 3MITHS SYNTHESISOFTHELATRUNCULINS; ="AEYER 6ILLIGEROXIDATIONOFREAD ILY AVAILABLE ›  ALLYLCYCLOPENTANONE  GENERATED RACEMIC LACTONE  WHICHWASTHENENOLISEDUNDERSTANDARDCONDITIONSANDTRAPPEDWITH -E)TOINSTALLTHE# α METHYLGROUP!LTHOUGHINITIALLYAMIXTUREOF DIASTEREOMERS ORTHOESTERFORMATIONWITH 2 2   BUTANEDIOLEFFECTED BOTHRESOLUTIONANDEQUILIBRATIONIMPROVINGTHETRANSCISRATIOTO4HIS UNEXPECTED YETFORTUITOUSRESULTPRESUMABLYAROSEDUETOAMOREBIASED CONFORMATIONALPREFERENCEFORTHEORTHO ESTERSn VERSUSTHESTART INGLACTONE 4HEISOMERSCOULDTHENBESEPARATEDBYPREPARATIVEHIGH PERFORMANCELIQUIDCHROMATOGRAPHY(0,# TOAFFORDBOTHAND INnYIELDS7HILEWASEMPLOYEDINTHELATRUNCULINPROJECT ITS DIASTEREOMER WASSUITABLEFORFURTHERELABORATIONFORTHERAPAMYCIN SYNTHESIS3CHEME  /ZONOLYSISOFTHETERMINALALKENEFURNISHEDALDEHYDEWHICHWAS SUBSEQUENTLY CONDENSED WITH THE LITHIO ANION OF ENYNES  OR  PREPAREDFROMTHEKNOWNSILYLDIYNE;=BYSTANNYLATION; =



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO MeO

TIPSO

42

38

MeO

H

38

32

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OTBS 27

R

TIPSO

42

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H

38

32

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a

42

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H

32

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27

S S

27

S S

R

S S

R

22

(MeO)2HC 22 R = H, 612 R = OMe, 621

OHC 22

R = H, 626 R = OMe, 627

R = H, 628 R = OMe, 629

d

TIPSO

MeO

TIPSO

42

38

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H 32

HO

TIPSO

42

38

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27

R

f

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38

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27

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42

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e

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22

22

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O

22

R = H, 632 R = OMe, 633

R = H, 630 R = OMe, 631

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

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16

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634

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d

O

O

O

16

635

636

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O

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637

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638

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639

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639

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20

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f

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640

641

O

642

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+ 20

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O 10

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O

o,p

m,n

OH

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16

20

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640

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O

20

OH

+

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O 10

O

20

OH 16

TMS 643

645

i,j

646 k,l

O

O 10

O

OMe

20

SnBu3

16

647

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

ERABLEIMPORTANCEINTHEEVENTUAL3TILLECOUPLINGREACTION MODELSTUDIES WERE FIRST PERFORMED ! SIMPLE VINYL IODIDE  READILY PREPARED FROM 3CHEME SERVEDASTHETESTFRAGMENTALONGWITHDIENYLSTANNANE !TTEMPTEDCOUPLINGOFTHESETWOSPECIESUNDERSTANDARDCONDITIONS FURNISHEDTHEDESIREDTRIENE INONLYLOWYIELD ANDOMINOUSLYASA MIXTURE OF% AND: ISOMERS4HEFORMATIONOFSIGNIFICANTQUANTITIES  OFATETRAENEFROMHOMOCOUPLINGOFWASALSOOBSERVEDSUGGESTING THATSLOWOXIDATIVEADDITIONOFTHEVINYLIODIDE TOPALLADIUMMIGHTBE THECAUSE-ODIFICATIONOFVARIOUSREACTIONPARAMETERSCATALYST LIGAND SOL VENT ETC AFFORDEDNOMEANINGFULIMPROVEMENTINTHEREACTIONOUTCOME )TISKNOWNTHATVINYLIODIDESWITHNEARBY,EWISBASICFUNCTIONALITY SUCH ASESTERSORAMIDES CANPERFORMPOORLYIN0D CATALYSED3TILLECROSS COU PLINGS; =/NEINTERPRETATIONOFTHISBEHAVIOURISINHIBITIONTHROUGH LIGATIONOFTHEPROXIMAL,EWISBASE ANDTHISISCERTAINLYAPOSSIBILITYWITH SUBSTRATESSUCHASWHICHBEARADITHIANEGROUPRELATIVELYCLOSETOTHE VINYL IODIDE #ONSEQUENTLY THE NUCLEOPHILIC AND ELECTROPHILIC PARTNERS WHERE INVERTED THROUGH USE OF STANDARD FUNCTIONAL GROUP MANIPULATION ANDRESUBJECTEDTO3TILLECONDITIONS3CHEME !DRAMATICIMPROVEMENT IN BOTH YIELD AND ISOMERIC PURITY OF THE DESIRED TRIENE COUPLING PARTNER % WASOBSERVED ANDASSUCHTHEDECISIONTOPREPARETHE# #VINYL IODIDERATHERTHENTHECORRESPONDINGSTANNANEWASMADE4HESEOBSERVA TIONSALSOAIDEDTHE,EYGROUPVIDEINFRA INTHEIRSYNTHESISOFRAPAMYCIN 7ITHTHESUCCESSFULISOMERISATIONOFTHE: ENYNE TOTHE% % DIE NYLSTANNANE DURINGRADICALSTANNATION3CHEME BOTHAND WEREFURTHERELABORATEDTOTHEFULLYFUNCTIONALISED# #CARBOXYLIC ACID &ORTHEFORMER / METHYLATIONOFUNDERCONDITIONSWHICH RETAINEDTHE4-3GROUPONTHETERMINALALKYNE FOLLOWEDBYADDITIONAL STANDARDFUNCTIONALGROUPTRANSFORMATIONSFURNISHEDALDEHYDEREADY FORALDOLCONDENSATIONWITHTHEDIANIONOF. ACETYL , PIPECOLICACID  $OUBLEDEPROTONATIONOFWITH,I(-$3ANDADDITIONOFFURNISHED THEDESIREDADDUCT ASANINCONSEQUENTIALMIXTUREOFDIASTEREOMERS WHICHAFTERMETHYLESTERFORMATIONANDOXIDATIONWITH$ESS -ARTINPERI ODINANE GAVE THE INTERMEDIATE TRICARBONYL IN GOOD YIELD $ESILYLATION WITH(&INACETONITRILEREMOVEDBOTH4"3AND4%3PROTECTINGGROUPSAND ALSO INDUCED SPONTANEOUS LACTOL FORMATION AS A SINGLE ISOMER /BSERVA TIONSBY3MITH ASWELLAS$ANISHEFSKY;= HADINDICATEDTHENECESSITY OFPROTECTIONOFTHE#HEMIKETAL&URTHERMORE EVALUATIONOFENDGAME



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O

O

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S S

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20

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648

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d

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16

20

O

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650

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O 10

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16

OMe

649

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20

651

E-649

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TMS , R2 = H, 653 TMS , R1 = H, 654

g,h,i,j

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TIPSO MeO

38

1

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O

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27

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c

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME 3UMMARYOF3MITHSTOTALSYNTHESISOFRAPAMYCIN

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

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4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TBSO HO MeO

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673

3CHEME 2ETROSYNTHETICANALYSIS

 AND UNDERTAKE INSTRUCTIVE DEGRADATIVE STUDIES ; = %ND GAME PROTECTINGGROUPSTUDIESHADSUGGESTEDTHATDIFFERENTIATEDSILYLGROUPSAT #4"3 AND#4%3 WEREDESIREDANDCONDITIONSWEREOPTIMISEDTO INSTALLTHESESEQUENTIALLYANDINHIGHYIELDTOAFFORD3CHEME  %XCISIONOFTHEPIPECOLATEANDTRICARBONYLREGIONSFROMUNDERTHE CONDITIONSDEVELOPEDBY,UENGO;=MINIMISEDFORMATIONOFTHEENONE BY PRODUCTFORMED^OBSERVED FROMβ ELIMINATIONACROSSTHE# #ALDOLLINKAGEANDGAVEINGOODYIELD3UBSEQUENTREINSTALLATION OFAPIPECOLATEFRAGMENTINITS"OCPROTECTEDFORMVIASTANDARDCONDITIONS FURNISHED  AND EXTENSIVE STUDIES WERE INITIATED TO SELECTIVELY CLEAVE THE# #TRIENEPORTIONOFTHEMOLECULE)NACCORDWITHOURPREVIOUS SUCCESSWITHSELECTIVEOZONOLYSISINTHEAVERMECTIN"AANDINDANOMYCIN TOTALSYNTHESISPROJECTS; =TREATMENTWITHOZONEUNDERCAREFULLY CONTROLLEDCONDITIONSGAVEENALANDALDEHYDEASMAJORFRAGMENTS ALONGWITHANINSEPARABLEMIXTUREOFLACTONEDERIVATIVESAND  !LLATTEMPTSTOCONVERTTOWEREULTIMATELYUNSUCCESSFUL NEVERTHE LESSTHETWOPRODUCTSWEREPARTIALLYSEPARABLEANDISOLATEDALDEHYDE WOULDPROVEVERYUSEFULINLATERVALIDATIONOFSYNTHETICINTERMEDIATES)N ADDITION FURTHEROZONOLYSISOFTHEMIXTUREOFLACTONESGAVEPUREENAL WHICHWASSIMILARLYCONSTRUCTIVEINDEVISINGTHEFORWARDSYNTHESIS&INALLY THEREADILYAVAILABLETRIENEDERIVATIVEALSOINTERSECTEDMATERIALINTHE FORWARD DIRECTION AND GIVEN THE COMPLEXITY OF .-2 ANALYSIS PROVIDED ANOTHERIMPORTANTCHECKPOINT )NTHEFORWARDDIRECTION TWOSYNTHESESOFTHELACTONEPORTIONOFRAPA MYCIN WEREINFACTDEVELOPED BOTHOFWHICHCOMMENCEWITH CIS 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

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682

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BENZYLOXY  BUTEN  OL  3CHEMES  AND  ;= )N THE FIRST APPROACH APPLICATIONOFTHEVENERABLE3HARPLESSASYMMETRICEPOXIDATION FOLLOWED BY 0ARIKH $OERING OXIDATION AND HOMOLOGATION VIA THE -ASA MUNE 2OUSHPROTOCOL;=GAVE3UBSEQUENTTREATMENTWITH$)"!, (EFFECTEDREDUCTIONOFTHEESTERANDOXIRANEFUNCTIONALITIES THELATTERINA REGIOSELECTIVEFASHIONAFFORDINGONLYTHEPRODUCTFROMHYDRIDEADDITIONAT THEMOREELECTROPHILICCARBONCENTRE7ITHINHANDSTANDARDPROTECT INGGROUPMANIPULATION ASECOND3HARPLESSEPOXIDATIONOFALLYLICALCOHOL



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME A 4I/I0R   DIETHYLTARTRATE T"U//( n #  EEB 3/q0Y %T. $-3/ #(#L  #→24 C ,I#L %T/ 0/ #(#/#( $"5 #(#. 24 D $)"!, ( #(#L n # E 0IV#L 0Y #(#L  #  OVERTWOSTEPSF .A( -E)  # G $)"!, ( #(#L n # H 4I/I0R  n DIETHYLTARTRATE T"U//( ¯-3 #(#L n # I 40!0 .-/ #(#L #(#. ¯-3 J 0H0#("R +(-$3 4(&  #→24 K &E#/  4(& L #/ ATM 0H(  # M 0T/ (ATM %T/!C 24 N ,$! 4(& n #   O ,$! 4(& n # THEN(/ 

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME A 4I/I0R   DIETHYLTARTRATE T"U//( n #  EEB 3/q0Y %T. $-3/ #(#L  #→24C 0H0#("R +(-$3 4(&  #→24D $)"!, ( 0H#( n # OVERTHREESTEPSE N"U,I %T/ 24 THEN"OC /. 4(& 24 F )"R 0H#( #(#L n #  DRG +#/ -E/( 24 H -E) !G/ $-& 24 I $(0 0043 #(#L 24 J ,I!L( %T/ n # K 0-"#L .A( $-& 24 L ACIDACTIVATEDAMBERLITE¤)2 -E/( 24 M 4S#L 0Y  #→24 N 0H3( +#/ 4(& 24 THEN REFLUX O M#0"! #(#L  #→ 24 P  N"U,I 4(& n # THEN THEN"&q/%T n #→24 Q -LITHIUM NAPHTHALENIDE 4(& n # R $$1 (/ #(#L 24 S 40!0 .-/ #(#L ¯-3 T $)"!, ( 0H#( n #U 4"3#L )M $-!0 $-& 24 OVERTWOSTEPSV 0D/(  (ATM %T/!C 24 W 40!0 .-/ ¯-3 #(#L #(#. X -E-G"R 4(& n #  DRY 40!0 .-/ ¯-3 #(#L #(#. 24 Z  .A(-$3 4(&  # THEN n #  %:AA $)"!, ( 0H#( n # BB 4"!& !C/( (/ 4(& 24CC 40!0 .-/ ¯-3 #(#L OVERTWOSTEPSDD #R#L #() 4(& DIOXANE  #  %:

!S A CONSEQUENCE OF THE HIGH TOXICITY OF &E#/  HIGH PRESSURE OF CARBON MONOXIDE AND POOR SELECTIVITY EXHIBITED IN INTRODUCTION OF THE NECESSARY METHYL GROUP AT # AN ALTERNATIVE ROUTE WAS DEVELOPED 3CHEME )NMUCHTHESAMEMANNERASDISCUSSEDPREVIOUSLY WAS ELABORATEDTOVINYLOXIRANEWHICHWASTHENREGIOSELECTIVELYREDUCED WITH $)"!, ( AND CONVERTED TO IODOCARBONATE  FOLLOWING 3MITHS )"R ELECTROPHILIC CYCLISATION PROCEDURE ;= 3YNTHESIS OF THE FIRST SUB UNIT OFTHEEVENTUALLACTONE WASTHENACCOMPLISHEDTHROUGH EPOXIDEFORMATIONAND0URDIEMETHYLATION;=INATOTALOFEIGHTSTEPS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

ANDYIELD3UBSEQUENTRING OPENINGOFWITHTHEα LITHIOANION OFSULFONEREADILYAVAILABLEFROMTHE2OCHEESTER INSEVENSTEPS  YIELD PROCEEDED SMOOTHLY TO PROVIDE  IN QUANTITATIVE YIELD &OLLOWINGREDUCTIVEDESULFONYLATIONAND0-"ETHERCLEAVAGE TREATMENT OFTHEENSUINGDIOLWITHTETRAPROPYLAMMONIUMPERRUTHENATE40!0 ;= GENERATEDTHEDESIREDLACTONE VIAANINTERMEDIATEHEMIACETAL4HIS WASIDENTICALINALLREGARDSWITHMATERIALPREVIOUSLYPREPAREDINASHORTER STEPS ANDHIGHERYIELDING SEQUENCE THATPROVEDMOREAME NABLETOLARGE SCALE3CHEME  &URTHERELABORATIONTOTHEEVENTUAL3TILLECROSS COUPLINGPARTNER COMMENCEDWITHANECESSARYREDUCTIONPROTECTIONPROTOCOLTOFORM AND PREVENT EPIMERISATION OF THE # METHYL STEREOCENTRE IN ENSUING STEPS ! STANDARD SEQUENCE WAS THEN EMPLOYED TO CONVERT THE PRIMARY BENZYLETHERAT#TOTHECORRESPONDINGMETHYLKETONE!TTHISPOINT AVARIETYOFATTEMPTSTOINSTALLTHEDESIRED% % DIENYLIODIDE CONCISELY VIAANENYNEHYDROSTANNYLATIONAPPROACHWEREULTIMATELYUNSUCCESSFUL !LTHOUGH INTRODUCTION OF THE ENYNE WAS NOT PROBLEMATIC HYDROSTAN NYLATION IN OUR SYSTEM GAVE VERY LOW YIELDS IN CONTRAST TO THE SUCCESS ENJOYEDINTHE3MITHSYNTHESISVIDESUPRA ;=#ONSEQUENTLYASEQUEN TIALHOMOLOGATIONAPPROACHWASADOPTEDTHATFEATUREDFIRSTREACTIONWITH DIETHYLCYANOMETHYL PHOSPHONATE WHICHATLOWTEMPERATUREGAVE GOODLEVELSOF%:OLEFINGEOMETRY FORTHECONJUGATEDPRODUCT ASESTABLISHEDBY.UCLEAR/VERHAUSER%FFECT./% STUDIES&URTHERFUNC TIONALGROUPMANIPULATIONCONVERTEDTHECYANOGROUPTOTHECORRESPOND INGALDEHYDEANDREGENERATEDTHELACTONEWHICHUPONAPPLICATIONOFTHE %VANS "LACK MODIFICATION ;= OF THE 4AKAI OLEFINATION ;n= GAVE ASAMIXTUREOFOLEFINISOMERSINOVERALLSTEPSANDYIELD )NTERESTINGLY ALTHOUGHINSEPARABLETHISMIXTUREWASULTIMATELYOFNODETRI MENTINCOUPLINGOFTHEADVANCEDFRAGMENTSAND 4HE CONSTRUCTION OF THE # # VINYL STANNANE  COMMENCED WITHPREPARATIONOFTHECYCLOHEXYLPORTIONOFRAPAMYCIN ; = &OR THIS PURPOSE THE READILY PREPARED BUILDING BLOCK  TRIMETHYLSILYL METHYL  PROPEN  OL WASSUBJECTEDTOANACIDCATALYSED*OHNSON ORTHOESTER#LAISENREARRANGEMENT; =WITHTRIETHYLORTHOACETATETO FURNISHINGOODYIELD3UBSEQUENTMONO ADDITIONOFTHELITHIOANION OFSULFONEGENERATEDARACEMICMIXTUREOFβ KETOSULFONES4HESEWERE THENSUBJECTEDTOASYMMETRICREDUCTIONWITHTHE#"3SYSTEM; =



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

3CHEME A N"U,I 4-%$! %T/ 4(& THEN #→24 THEN4-3#L n #→24 B .(3/ 4(& 24 C -E#/%T  %T#/(  # D  T"U,I $-% n # THEN n #→24 E "(q$-3 #"3 4(&   EE F 0$# #(#L  #→ 24 UNOPTIMISED G 4"3/4F 0Y $-!0 #(#L  # H 3N#L #(#L n #  CIS  TRANS  I 4"3/4F 0Y $-!0 #(#L  # J 3N#L #(#L n #  TRANS  CIS  K  "". 4(&  #→24 THEN.A/(AQ (/ L #/#L  $-3/ #(#L n # THEN%T. n #→24 M n % CROTYL")PC  4(& %T/ n # THEN ..A/( (/ n #→24 N 6/ACAC  T"U//( #(#L  DR ISOLATED O N"U,I 4(& n # THEN#L#3 /0H P N"U3N( !)". 0H( REFLUX 

TOAFFORDSYNANDANTIISOMERS WITHMODESTENANTIOSELEC TIVITY )NTERESTINGLY ALTHOUGH THE SAME INTERMEDIATE OXONIUM ION WAS EXPECTEDTOFORMFROMEITHERSILYLATEDSUBSTRATEUPONTREATMENTWITHTIN TETRACHLORIDE INTRAMOLECULARCOLLAPSEOFTHEPENDENTALLYLSILANEBEGIN NING FROM THE SYN ISOMER  GAVE PREDOMINATELY THE CIS METHYLENE CYCLOHEXANE WHEREASTHEANTIISOMER RESULTEDINAMIXTURE INFAVOUROFTHETRANSSIXMEMBEREDRING )THASBEENHYPOTHESISED THAT THE UNEXPECTED STEREO OUTCOME OF THE REACTION IS A CONSEQUENCE RAPIDINTRAMOLECULARCAPTUREBYTHEALLYLSILANEATSUFFICIENTRATETHATTHE INITIALLYFORMEDOXONIUMIONSDONOTHAVETIMETOEQUILIBRATE; = 4HUS THEANTICONFIGUREDSTARTINGMATERIALAFFORDSTHE% OXONIUMION WHILETHESYNANALOGUEFURNISHESINITIALLYTHE: COUNTERPART)NTHEFORMER CASE THEFAVOURABLEPSEUDOEQUATORIALPOSITIONISNATURALLYACHIEVED GIVINGRISEPREFERENTIALLYTOTHEDESIREDTRANS PRODUCT /NTHEOTHER



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

TBSO

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42

38

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722

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32

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363

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29

29

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32

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32

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725

726

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3CHEME A $(0 P4S/( 4(& 24B ,I!L( %T/ 24 OVERTWOSTEPSC #/#L  $-3/ #(#L n # THEN%T. n #→24D #"R 0H0 #(#L  # OVERTWOSTEPSE N"U,I 4(& n # THEN -E) n #→24 F #P:R( #L 4(& 24 THEN) 

HAND TOAVOIDUNFAVOURABLESTERICINTERACTIONSWITHTHESILYLETHER THE : OXONIUM ION MAY PREFER TO ADOPT A PSEUDOAXIAL POSITION  ANDTHUSFAVOURTHEFORMATIONOFTHECIS PRODUCT4HEABOVERATIONALFOR THEDISPARATESTEREOCHEMICALOUTCOMEHASBEENSUPPORTEDBYTHEORETICAL CALCULATIONSATTHE--LEVEL ALTHOUGHTODATETHEPOSSIBILITYOFCOM PETITIONBETWEEN3.AND3.REACTIONMANIFOLDSHASNOTBEENRULEDOUT 3CHEME  !S ONLY THE ANTI CONFIGURED α METHOXYSULFONE  FAVOURED THE DESIREDPRODUCT ATWOSTEPOXIDATIONREDUCTIONSEQUENCEUPONTHE SYN ISOMERWASDEVISEDTOSALVAGEMATERIAL2EGARDLESS WITHTHEROUTETO  ESTABLISHED FURTHER ELABORATION TO THE # # EPOXIDE  WAS RELATIVELYSTRAIGHTFORWARD2EGIOSELECTIVE ANDSTEREOSELECTIVE HYDROBORA TION WITH  "". FOLLOWED BY STANDARD OXIDATIVE WORK UP FURNISHED THE CORRESPONDINGPRIMARYALCOHOLANDALLOWEDFORCONVENIENTSEPARATIONOF THEMINORCIS DIASTEREOMERDERIVEDPRODUCTFROMTHECYCLISATION&URTHER OXIDATIONVIATHE3WERNPROTOCOLAND"ROWNCROTYLATION; =OFTHE RESULTINGALDEHYDEGAVEASTHEMAJORPRODUCT READILYSEPARABLEFROM TRACESOFOTHERDIASTEREOMERSBYFLASHCHROMATOGRAPHY4HERESULTINGFREE HYDROXYLGROUPAT#WASTHENUTILISEDTODIRECT6/ACAC INAHOMOAL LYLICEPOXIDATION;=WHICHPROCEEDEDWITHREASONABLESELECTIVITY;= FORTHEDESIREDISOMER  )TSFUNCTIONCOMPLETED ASTANDARDTWO STEP"ARTONDEOXYGENATIONPROTOCOL;  =REMOVEDTHESUPERFLU



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

OUS#HYDROXYLGROUPPROVIDINGACCESSTOTHEDESIREDEPOXIDEIN STEPSANDOVERALLYIELD /RIGINALLY THE PLANNED CONSTRUCTION OF THE # # VINYL STANNANE  INVOLVEDTHECOUPLINGOFTHESAMEOXIRANE WITHANEVENTUAL ACYL ANION EQUIVALENT  3CHEME   4HE CYCLIC ACETAL COMPRISING MUCHOFTHE# #REGIONWASINTENDEDTOPROTECTBOTHTHE# ALDE HYDEANDTHE# KETONEINITSREDUCEDFORM!LSO ITWASANTICIPATEDTHAT THERINGSYSTEMWOULDCONFERSTEREOCONTROLWHENEXTENDINGTHE# # CHAIN BY INFLUENCING FACIAL SELECTIVITY ON A PENDANT # ALDEHYDE 4HE SYNTHESISOFTHEFIRSTOFTHEREQUISITEFRAGMENTS FORBEGANFROM THE2OCHEESTERANDEMPLOYSASTANDARDSEQUENCEOFREACTIONSTOEVENTUALLY AFFORDVINYLIODIDE 4HEKEYBUILDINGBLOCKFORTHE# #ELECTROPHILES INOURSYNTHESIS IS MESO ANHYDRIDE  WHICH ALSO FOUND USE IN 3MITHS TOTAL SYNTHESIS OFRAPAMYCIN VIDESUPRA /RIGINALLYAVAILABLEINONLYMODERATEYIELD USINGLITERATUREPROTOCOLS;= RECENTIMPROVEMENTSVIAADYNAMICCRYS TALLISATIONOFTHENORMALMIXTUREOFMESO ANDDL ISOMERSHASMADEACCESS TOVERYPRACTICAL;=2EDUCTIONOFTHEANHYDRIDETOTHECORRESPOND INGDIOLWITH,I!L( ANDDESYMMETRISATION; =WITHCOMMERCIALLY AVAILABLEANDINEXPENSIVE,IPASE03 GAVETHEMONOACETYLATEDPRODUCT INCONSISTENTLYHIGHENANTIOSELECTIVITY!SIMPLETHREESTEPPROCEDURE ACCOMPLISHEDCONVERSIONTOTHEHYDROXYLALKENE FROMWHICHTWO STEP OXIDATION TO THE CORRESPONDING ACID AND SELENO CYCLISATION UNDER KNOWNCONDITIONS;=AFFORDEDLACTONEINGOODYIELD!SEXPECTED FORAPRESUMEDCHAIR LIKETRANSITION WHEREINBOTH#METHYLGROUPS ADOPT AN EQUATORIAL TRANSITION STATE THIS CYCLISATION OCCURRED WITH GOOD STEREOCONTROLANDONLYTRACEAMOUNTSOFAMINORDIASTEREOMERWERENOTED /XIDATIVEELIMINATIONOFTHEPHENYLSELENENYLMOIETYGAVEASINGLEDIASTE REOMEROFTHECORRESPONDINGALKENE WHICHWASCONVERTEDVIAAMIXTUREOF ANOMERICACETALSTOTHEDESIREDALDEHYDE!LTHOUGHEITHEROFTHE# EPIMERSCOULDINPRINCIPLEBEEMPLOYEDFORFURTHERELABORATIONATTHISSTAGE THE ANOMERS WERE SEPARATED BY FLASH CHROMATOGRAPHY FOR CONVENIENCE 3CHEME  !MOREDIRECTANDHIGHERYIELDINGROUTETOTHESAMEINTERMEDIATE WASLATERDEVELOPED WHEREBYOXIDATIONOFTOTHECORRESPONDINGALDE HYDERATHERTHENACID ANDSELENIUM MEDIATEDACETALISATIONGAVEASA MIXTUREOFANOMERS;=3EPARATIONATTHISPOINT FOLLOWEDBYOXIDA



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

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-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

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741

3CHEME A #R#L.I#L $-3/   SEPARABLEB 40!0 .-/ ¯-3 #(#L C :N"(  %T/  # D .A( 0-"#L .A) 4(&  #→24 E -E/( !MBERLYST  F "U0 . PHENYLTHIOSUCCINIMIDE 0H( G /XONE¤ P(BUFFER 4(& -E/( H T"U,I 4(& n #THEN-E3  I  T"U,I 4(& n # THEN THEN"&q/%T n #→24  J  PENTEN  OL 0043   $#%  #  MIXTUREOF#ANOMERS SEPARABLEK /XONE¤ 4(& -E/( P(BUFFER  # L T"U,I 4(& n # THEN-E3  M  T"U,I 4(& n # THEN THEN"&q/%T n #→ # 

PERATUREFOLLOWEDBYSEQUENTIALADDITIONOFAND"&q/%TANDWARMING GAVETHECOUPLEDPRODUCTINANUNOPTIMISEDYIELDOF!LTHOUGH +OTAKEHASOBSERVEDTHATHYDROLYSISOFDITHIOKETALMONOSULFONESUSUALLY REQUIRESMOREFORCINGANDLONGERREACTIONSTIMES#U#L 3I/ ORANODIC HYDROLYSIS WEWEREVERYPLEASEDTODIRECTLYOBTAINTHEDEPROTECTEDKETONE  AFTERWORK UP)NTHISINSTANCE WESPECULATEDTHATHYDROLYSISWAS FACILITATEDBYTHEPRESENCEOFEXCESS,EWISACIDEXPLAININGTHENEEDFOR MOLAREQUIVALENTSOF"&q/%T7ITHTHEPRODUCTIONOFAPRECURSOR



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

WHICHCONTAINEDMOSTOFTHEFRAMEWORKOFVINYLSTANNANE SYNTHESIS OF THIS IMPORTANT FRAGMENT SEEMED IMMINENT 4O OUR GREAT DISAPPOINT MENT ALL EFFORTS TO CONVERT THE SIX MEMBERED CYCLIC ACETAL DESIGNED TO UNMASK THE # ALCOHOL AND # ALDEHYDE TO AN ACYCLIC FORM FAILED AFFORDINGONLYSTARTINGMATERIALORDECOMPOSITIONPRODUCTSINACIDICMEDIA 3CHEME  ! POTENTIAL SOLUTION FOLLOWED FROM REPORTS OF THE USE OF  PENTENYL ACETALSBY&RASER 2EID; =THATSUGGESTEDDEPROTECTIONUNDERNEUTRAL CONDITIONS."3 (/ MIGHTPROVIDEACCESSTOANINTERMEDIATELACTOL AND THUSHOPEFULLYARING OPENEDFORM UNDERMILDERCONDITIONSTHANPREVI OUSLYACCESSIBLE4HUS THEMETHYLACETALINTHIOETHERWASEXCHANGED FORTHEPENTENYLEQUIVALENT3UBSEQUENTFUNCTIONALGROUPMANIPULATION AND COUPLING WITH  AS DESCRIBED PREVIOUSLY GAVE A SECOND # # ADVANCEDINTERMEDIATE5NFORTUNATELY ALTHOUGHTHEANOMERICSUB STITUENTSCOULDBEINTERCHANGEDAT# INNOINSTANCEWERECONDITIONS FOUNDTHATGENERATEDTHERING OPENEDPRODUCT0RESUMABLY THERINGSUB STITUTION PATTERN GREATLY STABILISES THE CLOSED STRUCTURE MAKING FURTHER ADVANCEMENTWITHTHISSTRATEGYUNWORKABLEINOURHANDS3CHEME  )NORDERTOCONVERTTHESTUBBORNCYCLICACETALINTOAUSEFULINTERMEDIATE WERETURNEDOURATTENTIONTOTHIOETHER(YDROLYSISOFTHEACETALUNDER ACIDIC CONDITIONS AND REDUCTION WITH $)"!, ( THEN GAVE  &URTHER STANDARDFUNCTIONALGROUPMANIPULATIONSGAVETHELINEARSULFENYLSULFONE WITHOUTDIFFICULTYBUTNOWPROGRESSWASTHWARTEDBYEXTREMELYPOOR REACTIVITY IN THE CRUCIAL COUPLING REACTIONS $ESPITE EXPLORING A VARIETY OFPROTECTINGGROUPSFORBOTHTHE#AND#HYDROXYLGROUPS INNO INSTANCEWASUNIONOFTHETWOMAJORFRAGMENTSANDORDERIVA TIVES EFFECTEDINGREATERTHENYIELD$EPROTONATIONOFTHEMORENUCLEO PHILICANDLESSHINDEREDSULFONEFOLLOWEDBYTREATMENTWITHEPOXIDE DIDAFFORDTHEALKYLATEDSULFONEINGOODYIELDASASINGLEISOMER OFUNDETERMINEDCONFIGURATION(OWEVER INTHISCASEWEWEREUNABLETO EFFECTOXIDATIVEDESULFONYLATIONTOAFFORD3CHEME  4HE LESSONS LEARNED WITH THE ADVANCED FRAGMENTS ABOVE DICTATED A NUMBEROFKEYSTRATEGICREVISIONS&IRSTANDFOREMOST FORTHECENTRAL# #FORMALDIANIONEQUIVALENT WEELECTEDTOPURSUEADITHIANESTRATEGY INPLACEOFTHECOMPROMISEDSULFONYLORSULFENYLSULFONEAPPROACH GIVEN THEIRSUCCESSINCOMPLICATEDFRAGMENTCOUPLINGREACTIONSSEE3MITHSSYN THESISOFRAPAMYCIN VIDESUPRA ANDPOTENTIALDEPROTECTIONUNDERAVARIETY



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

PhS

PhS 32

PhS 32

28

MeO

OPMB H OMe O

28

MeO

22

738 TBSO MeO

PhO2S 32

a

OPMB H O OH

32

OPMB H OH OH

b 28

MeO

22

743

28

MeO

22

744

22

745 d

42

38

OPMB H OH OH

c

H

TBSO

32

HO

PhO2S

42

OPMB

O

OH

MeO

X

MeO

38

+

H

PhO2S

32

28

MeO

O

748

OPMB H OH OMTM

MeS

32

e

OPMB H OH OMTM

28

MeO

22

22

669 MTMO

746 747

22

X

f

TBSO

42

TBSO

MeO

38

42

H MeO

32

HO PhSO2 749

38

H

OPMB O

OH

MeO

669

MTMO 22

3CHEME A !C/( (/B $)"!, ( 4(& OVERTWOSTEPSC /XONE¤ 4(& -E/( P(BUFFER  D -E3 "Z/  #(#. E  T"U,I 4(& n # THEN-E3  F  T"U,I 4(& (-0! n # THEN 

OF CONDITIONS )N ADDITION NEW ROUTES TO LINEAR # # ELECTROPHILES WEREDESIGNEDTOACHIEVEMOREEFFICIENTACCESSANDGREATERFLEXIBILITYWITH REGARDSTOBOTHSTEREOCHEMISTRYANDPROTECTINGGROUPSSHOULDDIFFICULTIES ARISE "EGINNINGWITHTHE2OCHEESTER STANDARDFUNCTIONALGROUPMANIPULA TION AFFORDED DITHIANE ALCOHOL  AS A SINGLE ENANTIOMER !TTEMPTS TO INTRODUCETHEDESIREDHALOGENATEDOLEFINFAILEDWHENATTEMPTINGAPPLICA TIONOF3CHWARTZHYDROZIRCONATIONCONDITIONSUPON0ARTIALSUCCESS WASREALISEDVIAPALLADIUMCATALYSEDHYDROSTANNYLATIONFOLLOWEDBYTRAP PINGWITHIODINEUNFORTUNATELYASANUNSUITABLEMIXTUREOF%:ISOMERS  4ORESOLVETHISSELECTIVITYISSUE ANINTERESTINGVARIATION;n= OF3TILL 'ENNARIPHOSPHONATE;=WASEMPLOYEDWHEREINPRIORBROMINA TIONOFTHEREAGENTANDREACTIONWITHFRESHLYPREPAREDALDEHYDEFROM GAVETHEKINETICTRISUBSTITUTEDBROMOALKENE ASONLYONEDETECTABLE OLEFINISOMER2EMOVALOFTHEEXTRANEOUSMETHYLESTERFUNCTIONALITYWAS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

MeO

OH

32

a,b

OTr

32

c,d

S

30

CO2Me S

S

750

420

e,f

32

29

30

OH

O

OH

32

30

S

S

751

Cp2Zr(H)Cl

OH

g

Br

32

29

753

752

e,j,k

X

h

I2 or Br2 S

32 29

S

I

l

Br

S

32 29

S

756

Br

S

S

i

32

29

S

755

Br

S

32 29

Br

S

670

754

3CHEME A 4R#L 0Y #(#L  #→24B ,I!L( 4(&  # OVERTWOSTEPSC #/#L  $-3/ #(#L n # THEN$)0%! n #→ #D (3#( 3( "&q/%T #(#L n #→24 OVERTWOSTEPS E 3/q0Y $)0%! $-3/ #(#L 24 F #&#(/ 0/ #(#/-E +(-$3 4(& THEN"R THEN #  +(-$3 THENALDEHYDEFROM 4(& n # G $)"!, ( #(#L n #  H -S#L %T. $-!0 #(#L  # THEN,I"R $-& nI ,I%T"( 4(&  # J #"R 0H0 #(#L  # K N"U,I 4(& n # THEN-E) n #→24 L "U3N( 0H0 0D#L 4(& n # THEN)  %: INSEPARABLE

BESTACCOMPLISHEDTHROUGHTHEALLYLICBROMIDE VIAREDUCTIONWITH 3UPER(YDRIDE4-TOAFFORDINNINESTEPSINANEFFICIENTOVERALL YIELD3CHEME  'IVENTHATTHESTEREOCHEMISTRYOFTHE#ALCOHOLISULTIMATELYOFNO CONSEQUENCE TWOCONCURRENTAPPROACHESFORANEWSYNTHESISOFALINEAR # #ELECTROPHILEWEREPURSUED"OTHOFTHESEUTILISEDTHEKEYENANTIO ENRICHED  DIMETHYLATEDALCOHOL PREPAREDASDISCUSSEDPREVIOUSLY 3CHEME )NTHEFIRSTAPPROACH REACTIONOFREADILYPREPAREDALDEHYDE  WITH A γ METHOXYALLYLZINC REAGENT DERIVED FROM TRANSMETALLATION OF ZINC ONTO THE LITHIO ANION OF ALLYL METHYL ETHER WAS HIGH YIELDING BUTPOORLYSELECTIVE SLIGHTLYFAVOURINGTHEUNDESIREDDIASTEREOMER  !LTHOUGHSEPARABLE OBTAININGCLEANBYPURIFICATIONWASTEDIOUSAND INTHEENDIMPRACTICAL#ONSEQUENTLY ASYMMETRIC"ROWNALKOXYALLYLATION ;=OFTHESAMEALDEHYDEFOLLOWEDBYCLEAVAGEOFTHEACETATEPROTECTING GROUP TO FACILITATE PURIFICATION FURNISHED  AS A SINGLE DIASTEREOMER !LTHOUGHTHEYIELDFORTHESETWOSTEPSWASLOWERTHENDESIRED THEREACTION UTILISEDTHEPRODUCTOFENZYMATICDESYMMETRISATIONDIRECTLY ANDCOULDBE PERFORMEDONLARGE SCALE-OREOVER BYMASKINGTHE#CARBONYLASAN OLEFIN PROTECTIONOFTHE#ALCOHOLASITS0-"ETHERWASFACILEANDUPON APPLICATION OF STANDARD CONDITIONS  WAS ISOLATED IN EXCELLENT YIELD $IRECTOZONOLYSISOFPROVEDPROBLEMATIC THUS ATWO STEPDIHYDROXYL



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

OH

OH

OAc 22

+

22

OMe

OMe O

22

HO

OAc

b

a

OAc c,d

728 5 steps 42%

759

758

22

H

OAc

28

28

757

OH

OH

28 22

OMe 760

OPMB e

OPMB

28 22

O

f,g H

OMe

OPMB

OPMB 22

28

OMe 761

762

3CHEME A 3/q0Y $)0%! $-3/ #(#L 24 B ALLYLMETHYLETHER S"U,I :N#L n #→n # THEN    SEPARABLEC ALLYLMETHYLETHER S"U,I 4(& n # THENn -E/ ")PC THEN"&q/%T THEN THEN..A/( (/ n #→24D +#/ -E/( 24 OVER TWOSTEPSE .A( 0-"#L 4"!) $-& 24 F /S/ .-/ ACETONE (/ 24 G 0B/!C  0H( 24 

ATIONCLEAVAGEPROTOCOLWASUSEDTOAFFORDTHEDESIREDELECTROPHILE  .OTABLY CLEAVAGEOFTHEINTERMEDIATEDIOLRESULTINGFROMDIHYDROXYLATION WITH0B/!C WASCLEANANDHIGHYIELDING ANDPURIFICATIONOFTHISSENSI TIVECOUPLINGPARTNER COULDBEOMITTED3CHEME  !SECOND HIGHER YIELDINGCONSTRUCTIONOFTHE# #CARBONBOND INVOLVED APPLICATION OF OUR RECENTLY DEVELOPED "$! VARIANT OF GLYCOLIC ACID TOEFFECTAHIGHLYSELECTIVEALDOLCONDENSATIONWITHEITHER OR;=4HE0-"PROTECTEDDERIVATIVE PROVEDMOREPRACTICAL FORADVANCEMENTINLATERTRANSFORMATIONS ALTHOUGHASEXPECTED PROTEC TIONOFTHESECONDARYALCOHOLAT#WASEXTREMELYDIFFICULTASARESULTOF THEβ DISPOSITIONOFESTERCARBONYLFUNCTIONANDNUMEROUSACETALMOIETIES PRESENTWITHIN%VENTUALLY TREATMENTWITH0-" 4#!WITHACATALYTIC AMOUNTOF4R"&WEREIDENTIFIEDASSUITABLECONDITIONSFORPRODUCTIONOF ;  = ANDALTHOUGHTHISREACTIONWOULDNOTGOTOCOMPLETION THESTARTINGMATERIALCOULDBERECOVEREDANDRECYCLED&URTHERTRANSFORMA TIONTOTHEDESIREDELECTROPHILE INTHISCASEA7EINREBAMIDE WASSTRAIGHT FORWARDANDWASPREPAREDINANOVERALLYIELDOFTHROUGHSTEPS 3CHEME  4HEFIRSTMAJORFRAGMENTUNIONINVOLVEDREACTIONOFTWOEQUIVALENTS OFLITHIATEDWITHEITHERORTOCONSTRUCTTHEDESIRED# # BONDINGOODYIELDS&ORTHEFORMER APARTIALLYSEPARABLEMIXTUREOFDIASTE REOMERS WASOBTAINEDINFAVOUROFTHEUNDESIREDCONFIGU RATIONOFTHE#CARBINOL!LLMATERIALCOULDBEREADILYSALVAGEDTHROUGH ANOXIDATIONREDUCTIONSEQUENCEOFTHEMIXTUREWHICHOCCURREDWITHHIGH



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME A 4"3#L )M #(#L  #→24B +#/ -E/( 24C .A( 0-"#L 4"!) 4(&  #→24D 4"!& 4(&  # OVERFOURSTEPSE 3/q0Y $)0%! $-3/ #(#L 24 F  ,I(-$3 4(& n # THEN THEN!C/( n #→24 G 0-" 4#! 4R"&MOL 4(& 24 H #3! -E/( 24 I !G/ -E) #(#L  # J ,I(-$3 -E/-E .(q(#L 4(& n # THEN  n #→n # K  ,I(-$3 4(& n # THEN THEN!C/( n #→24 

ANTI  SELECTIVITYEMPLOYINGETHEREALSOLUTIONSOFZINCBOROHYDRIDE AND AFTER 4%3 PROTECTION  WAS ISOLATED AS A SINGLE DIASTEREOMER READY FOR COUPLINGTOTHE# #EPOXIDE !LTERNATIVELY UNIONOFAND GAVEASUBSTANTIALLYIMPROVEDYIELDOFDIRECTLYWITHOUTTHEPROB LEMSASSOCIATEDWITHTHEPREVIOUSDIASTEREOMERICMIXTURE2EDUCTIONAND 4%3 PROTECTION AS BEFORE UNDER SLIGHTLY MODIFIED CONDITIONS PROVIDED A SECONDCOMPLETED# #FRAGMENT READYFORCOUPLINGTOEPOXIDE ANDDIFFERINGONLYINTHEABSOLUTECONFIGURATIONOFTHE#0-"ETHER 3CHEME  0LEASINGLY LITHIATIONOFEITHERORWITHT"U,IINTHEPRESENCE OFANDIMMEDIATEWARMINGRESULTEDINSMOOTHEPOXIDERING OPENING ANDCONSTRUCTIONOFTHEFULL# #CARBONFRAMEWORKAFFORDINGAND 4HISPROCEDURE BASEDUPONREPORTSBY3MITH;= WASIMPORTANTTO ACHIEVEGOODYIELDSASα METHYL   DITHIANESOFTHISTYPEAREKNOWNTO FORMLITHIO ANIONSALMOSTINSTANTANEOUSLYINAMIXTUREOF4(&(-0!BUT THENRAPIDLYLOSETHEIRREACTIVITY PRESUMABLYTHROUGHAGGREGATION)NBOTH SERIESAND REMOVALOFTHEDITHIANEMOIETYUSINGTHEBISTRIFLUO ROACETOXY IODOBENZENEPROTOCOLOF3TORKAND:HAO;=WASNECESSARYTO



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

O O

N

32

28

S

O

OPMB

O H

S

22

OMe S

770 a

22

OPMB

OMe

OPMB

32 29

S

32

28

S

OH OPMB 775 + OMe

22

28

OMe

OPMB

OPMB

22

OMe S

OPMB

28

762

Br

i

670

S

32

28

S

OH OPMB 776

OPMB

22

772 b,c

OPMB

j,k,l OMe S

32

28

S

TESO

OMe S

22

OPMB

OPMB

32

28

S

TESO

773

777

TBSO d

MeO

TBSO

42

MeO

38

TBSO MeO

H

OTES

e,f,g,h

38

MeO

H

N H Boc O

OPMB

MeO

O

O

OTES

PMBO 22

12

38

H

32

HO S S

n,o,p,q

28

OTES 28

O

MeO

OPMB

MeO

1

N CO2H H Boc

O 42

32

1

28

774

m

H

TBSO

42

32

HO S S

38

669

O

42

38

42

MeO

H

669 TBSO

22

OPMB

OPMB

1

N CO2H H Boc

681 OHC 22

12

778 PMBO 22

3CHEME A  T"U,I 4(& n # THEN n #→n # B :N"(  %T/ n # H  C 4%3#L )M $-&  #  D  AND  T"U,I 4(&(-0!  n # → n #  E 0H)/#/#&  (/ -E/( 4(& 24 F  $## $-!0 #(#L n # G $$1 P( BUFFER #(#L 24 Q #/#L  $-3/ #(#L n # THEN%T. n #→24 I  T"U,I 4(& n # THEN n #→n #  J 3/q0Y $)0%! $-3/ #(#L  # K :N"(  %T/ n # DAYS L 4%3/4F   LUT #(#L n # M  AND T"U,I 4(&(-0! n #→n # N 0H)/#/#&  (/ -E/( 4(& 24  O  $## $-!0 #(#L n # P $$1 P(BUFFER #(#L 24 Q #/#L  $-3/ #(#L n # THEN%T. n #→24 

PERMITESTERIFICATIONOFTHE#ALCOHOLWITH3 "OC PIPECOLICACID0-" DEPROTECTIONWITHBUFFERED$$1 FOLLOWEDBYDOUBLEOXIDATIONAT# AND # EMPLOYING 3WERN CONDITIONS CONCLUDED TWO VIABLE ROUTES TO THESAMEINTERMEDIATE IDENTICALINALLRESPECTSSTARTINGFROMEITHER   STEPS  OVERALL YIELD OR   STEPS  OVERALL YIELD ANDALSOMATCHINGMATERIALOBTAINEDTHROUGHDEGRADATIONSEE3CHEME  4HEPARTICULARUSEOFTHE3WERNOXIDATIONINTHISINSTANCEWASCRITI CALTOAVOIDSPONTANEOUSFORMATIONOFTHEUNDESIREDLACTOLBETWEEN# AND# /(3CHEME ;n=4HEFINALSTAGESOFTHESYNTHESIS



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

REQUIREDCONVERSIONOFALDEHYDETOVINYLSTANNANEWHICHWAS READILYACCOMPLISHEDVIA4AKAIOLEFINATIONANDPALLADIUMCROSS COUPLING OFTHEINTERMEDIATE% VINYLIODIDEWITHHEXAMETHYLTINANDFRESHLYPRE PARED0D0&UR #L;=3UBSEQUENTUNIONWITHMAJORFRAGMENTDIENYL IODIDEEMPLOYINGTHESAMECATALYSTSYSTEMRESULTEDINSMOOTHFORMA TIONOFTHEDESIREDTRIENE WITHNOEVIDENCEOFMINORGEOMETRICAL ISOMERSDESPITEEMPLOYINGAN%:MIXTUREOF/NEEXPLANATIONOF THISFORTUITOUSRESULTISTHATTHEMINOR:COMPONENTOFMIGHTHAVE EQUILIBRATED UNDER THE REACTION CONDITIONS OR PERHAPS MAY REACT MORE SLOWLY THEN THE % ISOMER 4O GUARD AGAINST RECURRING PROBLEMS WITH β ELIMINATIONACROSS# #LATERINTHESYNTHESIS THE#CARBONYLWAS SELECTIVELYREDUCEDANDPROTECTEDTOFURNISH&URTHERMANIPULATIONTO α BROMOAMIDEWASACHIEVEDVIAHYDROLYSISOFTHELACTONE PROTECTION OFTHELIBERATEDSECONDARYHYDROXYLGROUPWITHCONCOMITANTLIBERATION OFTHEAMINE ANDFINALLYAMIDEFORMATIONWITHα BROMOACETYLBROMIDE 4HESEQUENCEOFEVENTSINTHEABOVETHREEREACTIONSWASCRITICALTOAVOID EPIMERISATION OF THE # METHYL STEREOCENTRE 7ITH  IN HAND THE STAGEWASSETFORINTRODUCTIONOFTHECATECHOLTEMPLATINGMOIETYANDCRITI CAL INTRAMOLECULAR MACROCYCLE FORMATION 4O ACCOMPLISH THIS STANDARD $##COUPLINGOFCATECHOLWITHTHEFREECARBOXYLICACID FOLLOWED BYALKYLATIVERINGCLOSUREAFFORDEDMACROCYCLICETHERINGOODYIELD )N CONTRAST TO THE PREVIOUS USE OF THE CATECHOL STRATEGY FOR MACROCYCLE FORMATIONANTASCOMICIN VIDESUPRA WEWEREESPECIALLYPLEASEDTODEM ONSTRATETHEFEASIBILITYOFITSINTRODUCTIONVIAAMACROETHERIFICATION; =PROTOCOLRATHERTHANTHEMORECOMMONMACROESTERIFICATION4REAT MENT OF  WITH ,I(-$3 UNDER THE PREVIOUSLY OPTIMISED CONDITIONS EFFECTEDTHETEMPLATED$IECKMANN LIKECONDENSATIONTOGIVETHENATIVE RAPAMYCINMACROCYCLE INANEXCELLENTYIELDOF/FALLTHEVARI OUSAPPROACHESTOCONSTRUCTIONOFTHISMOTIFINTHERAPAMYCINSERIESTHIS STRATEGYISTHEHIGHESTYIELDINGMOREOVERDIRECTCOMPARISONTOTHEOTHER EXAMPLE OF MACROCYCLE FORMATION VIA A CARBON CARBON BOND FORMING STRATEGY $ANISHEFSKY n  SERVES BEST TO ILLUSTRATE THE UTILITY OF THIS METHODOLOGY#OMPLETIONOFTHETOTALSYNTHESISOFWASSUBSEQUENTLY ACCOMPLISHEDVIATHEFOURSTEPSEQUENCEOF!LLOCDEPROTECTION CATECHOL CLEAVAGE OXIDATIONOFTHE#AND#ALCOHOLS ANDGLOBALDEPROTECTION WITH (&q0Y YIELDING MATERIAL IDENTICAL IN ALL REGARDS WITH AN AUTHENTIC SAMPLEOFTHENATURALPRODUCT3CHEME 



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

TBSO

TBSO

42

MeO

38

10

MeO

H

38

32

O

O

1

N H Boc O

a,b

OTES

H

O

N H Boc O

O

O

MeO

32

I

668 c

OTES

1

O 10

Me3Sn

OHC 22

H

38

20

16

O

42

MeO

OMe

32

1

O

MeO

TBSO

O

42

N H Boc O O

O

OTES O

MeO

OMe

22

16 22

666

681

O

679 d

TBSO

TBSO MeO

MeO

H

38

TBSO

42

42

38

H

N H O

O

O

O

O Alloc

OTES

Br

O

O

O

32

OTES

O Alloc

HO2C

1

f,g,h O

MeO

OMe

10

22

10

O

1

N H

i,j

O

MeO

OMe

O

H

38

32

32

1

42

MeO

O 10

22

N H Boc O O

OTES O

MeO 22

16

OTES 781

OTES 782

OR

OMe

16

16

O

779 R = H 780 R = Alloc

e

k,l TBSO MeO

TBSO

42

38

MeO

H

HO

42

38

H

42

MeO

32

38

32

H 32

OH N H O 10

1

O HO

O O TES O OMe O 16

OTES O

MeO

m,n

N H O 10

22

1

O

O O TES O OMe O

O

OTES O

MeO 22

o

N H O HO

O 10

O

1

O

O

OH

O

O

MeO

OMe

22

16 16

783

784

(-)-rapamycin 7

3CHEME A #R#L #() 4(&  #→24 B 0D0&UR #L -E3N  .-0 DARK 24 C 0D0&UR #L  .-0 DARK 24  D ,I!L(/T"U  4(& n #  E !LLOC#L  PYRROLIDINOPYRIDINE #(#L F -,I/(IN(/ 4(&  # G 4%3/4F   LUT #(#L n #→24  H "R#(#/ "R   LUT #(#L n # I CATECHOL $## $-!0 #(#L  #→24  J +#/ $-& 24 K ,I(-$3 4(& n #→n # L 0D00H  DIMEDONE 4(& 24 M 0H)/!C  #(#.(/  #N $-0 0Y #(#L 24OVERTWOSTEPSO (&q0Y 4(&  # 

)NSUMMARY THEFIFTHANDLATESTSYNTHESISOFRAPAMYCIN WASCOM PLETEDINALONGESTLINEARSEQUENCEOFSTEPSANDOVERALLYIELD3TA TISTICALLY ITISNEITHERTHESHORTEST NORHIGHESTYIELDINGOFTHEAPPROACHES TODATE ANDTHEREISUNDOUBTEDLYPOTENTIALFORIMPROVEMENT PARTICULARLY INASOMEWHATLENGTHYANDOUTDATEDSYNTHESISOFTHE# #FRAGMENT



4OTALSYNTHESISSTUDIESONMACROCYCLICPIPECOLICACIDNATURALPRODUCTS

3CHEME 3UMMARYOF,EYSTOTALSYNTHESISOFRAPAMYCIN

 (OWEVER INOURSYNTHESISOFRAPAMYCIN WEHAVEDEMONSTRATED THEEFFICIENTAPPLICATIONOFAWIDEVARIETYOFGROUP DEVELOPEDMETHODOLO GIES INCLUDING IRON CARBONYL CHEMISTRY THE INTRAMOLECULAR ADDITION OF ALLYLSILANESTOOXONIUMIONS A"$! CONTROLLEDALDOLCONDENSATION AND MOSTNOTABLYACATECHOL TEMPLATEDINTRAMOLECULARMACROCYCLECONSTRUC TION)NCONCERTWITHTHEHIGHLYEFFECTIVEUNIONOFMAJORFRAGMENTS THIS MAKES THE MOST RECENT SYNTHESIS A VERY ENGAGING ADDITION TO A FIELD OF ENDURINGINTEREST



-ATTHEW,-ADDESS -ILES.4ACKETTAND3TEVEN6,EY

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,ISA!-ARCAURELLEAND#HARLES7*OHANNES

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,ISA!-ARCAURELLEAND#HARLES7*OHANNES

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,ISA!-ARCAURELLEAND#HARLES7*OHANNES

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,ISA!-ARCAURELLEAND#HARLES7*OHANNES

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,ISA!-ARCAURELLEAND#HARLES7*OHANNES

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!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

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 ,IBRARIESCONTAININGFEATURESCOMMONTONATURAL PRODUCTSINGENERAL )N AN EFFORT TO MIMIC NATURAL PRODUCTS IN A MORE GENERAL SENSE THERE HAVEBEENMANYREPORTSONLIBRARIESINCORPORATINGDENSESTEREOCHEMICAL ANDFUNCTIONALDIVERSITYAROUNDONEORMORENOVELMOLECULARSKELETONS !N APPROACH SUCH AS THIS PROVIDES INCREASED OPPORTUNITY TO GENERATE TRULY NOVEL PHARMACOPHORES FOR ADDRESSING DIFFICULT BIOLOGICAL TARGETS !NEARLYEXAMPLEOFA$/3LIBRARYWHICHCONTAINSCHARACTERISTICSREMI NISCENT OF NATURAL PRODUCTS IS THAT SHOWN IN &IGURE  3CHREIBER AND CO WORKERSSYNTHESIZEDALIBRARYOFOVERMILLIONDENSELYFUNCTIONALIZED COMPOUNDSSTARTINGFROMSHIKIMICACID DERIVEDEPOXYCYCLOHEXENOL; = ! CONVERGENT TANDEM ACYLATION  DIPOLAR CYCLOADDITION OF BOTH ENANTIOMERS OF EPOXYCYCLOHEXENOL WITH SUBSTITUTED NITRONE CARBOXYLIC ACIDS PROVIDED PRODUCTS WITH STEREOCHEMICAL DIVERSITY AND HANDLES FOR APPENDAGE DIVERSITY 4HESE RIGID POLYCYCLIC SCAFFOLDS THEN UNDERWENT A VARIETYOFAPPENDAGEANDSKELETALDIVERSITYGENERATINGREACTIONSTOGEN ERATE BICYCLIC AND TRICYCLIC CORES &ROM THIS LIBRARY SEVERAL COMPOUNDS WERE DISCOVERED WHICH ACTIVATE THE 4'& β RESPONSIVE REPORTER GENE IN MAMMALIANCELLSINACHEMICALGENETICSASSAYWITHTHE%#OFTHEMOST ACTIVEBEINGμ- 



,ISA!-ARCAURELLEAND#HARLES7*OHANNES

R1 N

N

Ar O

R2 = H R

N Ar

CO2Me

R2 = N3

O

N

Ar

R

O

O

O Ph

R2

R1 = H

R1 = CH2N3

R2 = CH2N3

Bn N

Bn N

R1 = H

R1 = N3

O

R2 = H R1 = H

R

R2 = H

N

Ar

N

O

Ar Bn

N

Ar O

O

N R O Ph

CONHR

Ph

&IGURE !LIBRARYOFSPIRO ANDBICYCLICLACTAMSWASGENERATEDFROMAZIDOESTERINTERMEDIATESVIAFOURBRANCHING PATHWAYS WHILEMONOCYCLICAMIDESWEREOBTAINEDVIAAMIDATIONOFTHEUNSUBSTITUTEDESTERCORE

2ECENTLY -ITCHELLAND3HAWEMPLOYED$/3FORACCESSINGSKELETALDIVER SITYFROMASINGLESOLID PHASESTARTINGMATERIALBYEXPLOITINGONLYASINGLE FUNCTIONALGROUPMANIPULATION;=%MPLOYINGACLEVERDESIGNSTRATEGY SKELETALDIVERSITYWASINTRODUCEDATALATESTAGETHROUGHADIVERGENTCYCLIZA TIONTOPROVIDESPIROCYCLICORTRICYCLICCOMPOUNDSOF AND MEMBERED RINGS &IG   !PPENDAGE DIVERSITY WAS INTRODUCED THROUGH . ALKYLA TIONAND. ACYLATIONOFTHERESULTINGLACTAMSINASPLITPOOLMANNERTO AFFORDTHEFINALPRODUCTS&URTHERSTRUCTURALDIVERSITYWASACCOMPLISHEDBY DIRECTLYCONVERTINGTHEACYCLICMETHYLESTERPRECURSORTOVARIOUSAMIDES TOPROVIDEMONOCYCLICSTRUCTURES4HEINCORPORATIONOFMONOCYCLIC FUSED ANDSPIROCYCLICPRODUCTSINTHIS MEMBEREDLIBRARYALLOWEDFORTHECOV ERAGEOFAWIDERANGEOFTHREE DIMENSIONALSPACE0RELIMINARYSCREENINGOF THISPILOTLIBRARYLEDTOTHEDISCOVERYOFCOMPOUNDSWHICHMODULATETHE CELLULARPROCESSOFBOTHYEASTANDHUMANCANCER(E,A CELLS 0ORCOETALHAVERECENTLYAPPLIEDTHECONCEPTOFDOMAINSHUFFLINGTO SMALLMOLECULESINPURSUITOFCOMPOUNDSWITHINCREASEDBIOLOGICALACTIVITY ;=4HISSTRATEGYHARNESSESKEYSTRUCTURALDOMAINSOFBIOLOGICALLYACTIVE COMPOUNDSANDTHENSHUFFLESTHEMTOPREPARECOMPLEXHYBRIDSTRUCTURES INACONVERGENTMANNER;=4HISSTRATEGYISREMINISCENTOFTHATUSEDBY NATUREFORPOLYKETIDEBIOSYNTHESIS APROCESSWHICHHASBEENEXPLOITEDFOR THECOMBINATORIALBIOSYNTHESISOF@UNNATURALNATURALPRODUCTS;=)NTHIS STUDYALIBRARYOFHYBRIDOXIMESWASCONSTRUCTEDBYTHESHUFFLINGOFCOM



!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

O N

Me

Me 12 Alkoxyamines

H2 N O

Me

Me

Me

O H N 168 hybrid domains Monomers have no activity

O

N N

N H O HO

O N

Me

Me

Me

O

H O

O

IC50 6.2 PM antiproliferative activity of A549 cells

N N

N H O HO

O 14 Aldehydes & ketones

&IGURE !LIBRARYOFHYBRIDOXIMESOBTAINEDVIADOMAINSHUFFLINGLEDTOTHEDISCOVERYOFACOMPOUNDWITH ANTIPROLIFERATIVEACTIVITY

PLEXALKOXYAMINEANDCARBONYLDOMAINS&IG /NLYCOMPOUNDS WERESYNTHESIZEDANDNOADDITIONALELABORATIONOFTHERESULTINGHYBRIDS THROUGHAPPENDAGEORSKELETALDIVERSITYREACTIONSWASPERFORMED 3CREENING OF THIS OXIME LIBRARY AGAINST HUMAN SMALL CELL LUNG CARCI NOMA! CELLSREVEALEDACOMPOUNDWITHAN)#OFμ-3CREENING OFTHEMONOMERICDOMAINSLEDTONOANTIPROLIFERATIVEACTIVITYHIGHLIGHTING THEIMPORTANCEOFTHELIGATIONOFTWODISCRETECHEMICALDOMAINSGENERAT INGAMORECOMPLEXSTRUCTUREWITHBIOLOGICALACTIVITY )N A RECENT PAPER 3CHREIBER TAKES ADVANTAGE OF EACH OF THE DIVERSITY PATHWAYS&IG 0ATH!n# BYUSINGBOTHCONVERGENTANDDIVERGENTDESIGN STRATEGIES ;= )N A CONVERGENT MANNER TWO SETS OF CAREFULLY DESIGNED CHIRALAMINOALCOHOLSWERESYNTHESIZEDANDTHENCOMBINEDTOPROVIDE DISTINCTACYCLICCORESTHROUGHBISANDTRIS COUPLINGOFTHEINDIVIDUALAMINO ALCOHOLS&IG )NADDITIONTOTHESTEREOISOMERICCORES THELIBRARY DESIGNINCLUDEDDIFFERENTIATEDHANDLESFORFURTHERSKELETALANDAPPENDAGE DIVERSITY)NADIVERGENTFASHION THEBISANDTRIS COUPLEDCORESUSEDTHE SAMEREACTION2#- TOGENERATEDIFFERENTPRODUCTSONEDIYNECOREWAS UNREACTIVE WITHFIVETYPESOFSKELETONS!DDITIONALLY THERESULTINGDIENES WEREFURTHERELABORATEDUSINGA;=CYCLOADDITIONTOPROVIDEACCESSTO FOURDISTINCTBI ANDTRICYCLICCORES4HEAPPENDAGEDIVERSITYANDADDITIONAL CASCADEREACTIONSTOGENERATEMORESKELETALDIVERSITYHAVENOTBEENFULLY EXPLORED



,ISA!-ARCAURELLEAND#HARLES7*OHANNES

Ns Bs BzO

2 diastereomers

Bs

H HO

NHBoc

HO

(S)

HO

NHBoc

BzO

H H N N

BzO

O

H NHBoc

Libraries from libraries

H NHBoc O

N Me

Me N O O Ns N N N

NHBoc

BzO

Convergent

N

BocHN

3 tri-coupled cores 12 functionalized acyclic cores

Ns

Divergent Bs

9 bis-coupled cores

H NHBs BzO

(S)

H NHBoc

H

(R)

H BzO

N

N

Bs

Ns N

H BzO

H

Ns

N

N

H

H

NHBoc

N H

BzO

NHBs

H N N Bs

(R) BzO

NHBs Bs

H N

NHBoc

H

NHBoc

N

plus enantiomer

O

Libraries from libraries

N Me Me N

O

BzO H 4 diastereomers

BzO

NHBoc H N Bs plus enantiomer

O

N

N

BzO

O H

NHBoc H

N Bs

&IGURE !NOLIGOMER BASEDAPPROACHFORGENERATINGSKELETALDIVERSITYVIACONVERGENTANDDIVERGENTSYNTHESIS

 #HEMISTRY DRIVENAPPROACHTO$/3AT)NFINITY 0ARTOFTHECHALLENGEOF$/3WITHINTHECONTEXTOFDRUGDISCOVERYISTO LIMITTHELIABILITIESOFACOMPOUNDCOLLECTIONUNDERTRADITIONALPARAMETERS SUCHAS,IPINSKISRULEOFFIVE;=AND6EBERSROTATABLEBONDS;= WHILE ATTHESAMETIMEHAVINGACOLLECTIONOFMOLECULESTHATAREDIVERSEANDSTILL REPRESENTNEWCHEMICALSPACE!T)NFINITY WEFEELTHATTHEREARESUFFICIENT REASONSTOEXTENDBEYONDTHEMOLECULARWEIGHTRANGEOFDALTONS SUCH ASTARGETINGSMALLMOLECULESWHICHPERTURBPROTEINnPROTEININTERACTIONS (OWEVER WEREMAINMINDFULOFKEYCHEMICALPROPERTIESSUCHASSOLUBIL ITYISSUES!LOG0 ANDTHEEXCLUSIONOFPOTENTIALLYREACTIVEMOIETIESSUCH AS -ICHAEL ACCEPTORS AND PRIMARY HALIDES !DDITIONALLY THE NUMBER OF AMIDESISLIMITEDTOTHREEORFEWERWITHINALIBRARYPATHWAY 4HE$/3EXAMPLESABOVEPROVIDEAGOODOVERVIEWOFTHEDIFFERENTSTRAT EGIESUSEDTOACCESSCOMPOUNDLIBRARIESFORTHEDISCOVERYOFNEWBIOLOGI CALLYACTIVECHEMICALENTITIESANDHIGHLIGHTTHEINFLUENCEOFNATURALPROD



!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

Stage 1: Idea Evaluation Scaffold Idea

Solution-Phase Feasibility

Stage 2: Diversity Establishment

Chemotype Diversity

Building Block Testing New Scaffold Direction

Stage 3: Process Chemistry Scale up of Scaffold(s)

Optimization

Stage 4: Library Production Solid-phase synthesis, cleavage & formatting

&IGURE /VERVIEWOFTHECHEMISTRYDRIVENPROCESSEMPLOYEDFORTHEGENERATIONOF$/3LIBRARIES

UCTSANDNATURALPRODUCT LIKEFEATURESONLIBRARYDESIGN)NMOSTCASES THE BIOLOGYWASNOTCONSIDEREDAPRIORI THUSHIGHLIGHTINGTHAT$/3ISAVALU ABLEAPPROACHTOGENERATECHEMICALMATTERWITHOUTSTRUCTURALKNOWLEDGE OFTHETARGETRECEPTOR)NEACHCASE THECIRCUMSTANCESTOREALIZETHELIBRARIES WEREDIFFERENTBUTINTHEENDWEREALLDICTATEDBYCHEMICALFEASIBILITY/NE OFTHECHALLENGESOF$/3ISHOWTOPRIORITIZETHEPOTENTIALNOVELSTRUCTURES THATMIGHTBESYNTHESIZEDANDTAKEADVANTAGEOFDIVERSITYOPPORTUNITIES !TTHEVERYEARLYSTAGESOFLIBRARYDESIGNTHEEXACTSTRUCTURESOFTHEFINAL COMPOUNDS ARE DIFFICULT TO CONCEPTUALIZE UNLESS A NATURAL PRODUCT TEM PLATEISBEINGCONSIDERED4HEFOURSTEPPROCESSWEHAVEIMPLEMENTEDTO OPTIMIZETHISDIFFICULTPROCESSISOUTLINEDIN&IGURE



,ISA!-ARCAURELLEAND#HARLES7*OHANNES

 3TAGE)DEAEVALUATION 0RIOR TO EMBARKING ON THE PRODUCTION OF A LIBRARY THE EFFORT IT TAKES TO DEFINE AND PRIORITIZE WHICH SCAFFOLDS TO SYNTHESIZE COMPUTATIONALLY OR OTHERWISE CAN BE RATHER CHALLENGING !T )NFINITY WE EMPLOY A PROCESS WHICHMAINTAINSAFOCUSONCHEMICALFEASIBILITYWHILEGENERATINGMOLECU LAR COMPLEXITY IN THE FORM OF NOVEL CORES CONTAINING HANDLES FOR THE INTRODUCTION OF DIVERSITY .ATURAL PRODUCT SCAFFOLDS SERVE AS INSPIRATION NOTONLYBECAUSETHEYHAVEAPROVENTRACKRECORDOFACCESSINGBIOLOGICAL TARGETS BUTALSOBECAUSEMANYREACTIONMETHODOLOGIESHAVEBEENDEVEL OPEDINTHECONTEXTOFTHENATURALPRODUCTTOTALSYNTHESIS4HEDIVERSITYOF AGIVENLIBRARYISDETERMINEDULTIMATELYBYCHEMICALFEASIBILITYWITHOUTA SPECIFICTARGETINMINDSINCEITISDIFFICULTTOPREDICTBIOLOGICALRELEVANCYOF NOVELCOMPOUNDS7EREFERTOTHISPROCESSASCHEMISTRY DRIVENANDBELIEVE THATITOFFERSTHEPATHOFLEASTRESISTANCETODIVERSITYINTHECONTEXTOFALL POTENTIALLYRELEVANTBIOLOGICALSPACE)NESSENCE WEAPPLYA@CHEMICALSUR VIVALOFTHEFITTESTAPPROACHTODIVERSITYINTHECONTEXTOFTHESTRUCTURAL CHARACTERISTICSOFTHEFINALCOMPOUNDS 4HE BRAINSTORMING AND FEASIBILITY PORTION OF THE PROCESS IS PERHAPS THEMOSTCRUCIALFORTHEINITIATIONOFALIBRARYIDEA$URINGTHISTIME KEY EXPERIMENTSARERUNWHICHWILLDETERMINEIFTHECHEMISTRYWILLENABLEA PARTICULARSCAFFOLDTOBEPURSUEDFURTHER4HEPRIORITIZATIONFORTHEDIREC TIONOFEACHLIBRARYDEPENDSONTHEROBUSTNESSOFTHEDIVERSITYOPTIONS!T )NFINITY WEGENERATEOURLIBRARIESUSINGACOMBINATIONOFSOLUTION AND SOLID PHASECHEMISTRYTECHNIQUES)NGENERALWEBUILDUPSCAFFOLDDIVERSITY USINGSOLUTION PHASEMETHODS WHILESOLID PHASEMETHODSARERESERVEDFOR THE INTRODUCTION OF VARIOUS TYPES OF APPENDAGE DIVERSITY !LTHOUGH FEA SIBLE WEHAVEFOUNDITMORERELIABLEANDCOST EFFECTIVETOPERFORMSOPHIS TICATED TRANSFORMATIONS SUCH AS ENANTIOSELECTIVE CATALYSIS IN SOLUTION ASOPPOSEDTOONSOLID SUPPORT4HISAVOIDSATTEMPTINGTOOPTIMIZEVERY SENSITIVECHEMISTRYONHUNDREDSORTHOUSANDSOFSUBSTRATESIMMOBILIZED ONSOLIDPHASEWHEREITISNOTPOSSIBLETOEASILYMONITORTHEPROGRESSOFA REACTION



!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

 3TAGE$IVERSITYESTABLISHMENT /NCEAVAILABLEAREPRESENTATIVESETOFSCAFFOLDSISLOADEDONTOSOLID SUPPORT -IMOTOPE¤ LANTERNS FOR BUILDING BLOCK TESTING AND FEASIBILITY STUDIES 4HECOREISLOADEDTHROUGHANALCOHOLFUNCTIONALGROUP WHICHPROVIDES ANADDITIONALOPPORTUNITYFORAPPENDAGEDIVERSITYDURINGSUBSEQUENTHIT FOLLOWUP&ORTHEINTRODUCTIONOFAPPENDAGEDIVERSITY WEGENERALLYUSE ROBUST WELL ESTABLISHED REACTIONS SUCH AS . ACYLATION REDUCTIVE ALKYLA TION @CLICK CHEMISTRY   CONJUGATE ADDITION OXIME FORMATION -ITSU NOBU SUBSTITUTION AND PALLADIUM MEDIATED CROSS COUPLINGS )N ORDER TO TAKEADVANTAGEOFTHESEREACTIONSTHEAPPROPRIATEORTHOGONALLYPROTECTED FUNCTIONALGROUPSONTHESCAFFOLDAREREQUIRED/CCASIONALLY DURINGSOLID PHASE STUDIES IT MAY BE FOUND THAT ACCESSING THE DESIRED DIVERSITY FOR A LIBRARYREQUIRESREVISITINGTHESYNTHESISOFTHESCAFFOLDSUCHTHATAPPROPRI ATEPROTECTINGGROUPCHANGESCANBEMADEORALTERNATEDIVERSITYLOADING SITESINTRODUCED4HISITERATIVEPROCESSOFMODIFYINGSCAFFOLDSANDOPTIMIZ INGSOLID PHASECHEMISTRYEVENTUALLYPROVIDESTHEFRAMEWORKFORLIBRARY DIVERSITY

 3TAGE0ROCESSCHEMISTRY (AVING ESTABLISHED THE POTENTIAL DIVERSITY FOR A LIBRARY THE FOCUS THEN SHIFTSTOWARDSPROCESSCHEMISTRYWHERESCALABILITYISSUESBECOMECRITICAL TODRIVINGTHEPROCESS5PONSCALEUP THEINITIALSYNTHETICROUTETOASCAF FOLDOCCASIONALLYREQUIRESUNFORESEENOPTIMIZATION WHICHMAYAFFECTTHE DIVERSITY GENERATINGREACTIONSTHATHAVEBEENESTABLISHEDINTHEPREVIOUS STAGEOFTHEPROCESS4HUS ITISNECESSARYTOBEMINDFULOFSCALABILITYISSUES ATTHEOUTSETOFTHEPROCESS4HEAMOUNTOFEACHCOREREQUIREDCANRANGE FROMSEVERALGRAMSTOGRAMSDEPENDINGUPONAVARIETYOFFACTORS SUCH ASTHESIZEOFALIBRARY THENUMBEROFCORESANDTYPESOFDIVERSITY

 3TAGE,IBRARYPRODUCTIONANDANALYSIS /NCE THE SCAFFOLDS HAVE BEEN SYNTHESIZED THE PRODUCTION STAGE OF THE PROCESSCANBEREALIZED!TTHISPOINTTHEINVOLVEMENTOFINFORMATICS ANA



,ISA!-ARCAURELLEAND#HARLES7*OHANNES

LYTICALCHEMISTRYANDCOMPOUNDMANAGEMENTARECRUCIALTOTHEOVERALL SUCCESSOFTHEPROJECT/FMAJORIMPORTANCEISTHEENCODINGPROCESSUSING 4RAN3TEMS4-RADIOFREQUENCYIDENTIFICATIONTAGS 2&)$TAGS 4HEDIVERSITY PATHWAYSTHATWEREGENERATEDAREREVIEWEDANDALLPOSSIBLEPRODUCTDETER MININGPATHWAYSAREIDENTIFIED4HISINFORMATIONISTHENENUMERATEDTO GENERATETHEFINALSTRUCTURESOFEACHCOMPOUNDBEINGSYNTHESIZED4HIS PROCESSISPARTICULARLYEFFECTIVEBECAUSETHE2&)$TAGISPHYSICALLYATTACHED TOTHESOLIDSUPPORTANDTHEIDENTITYOFANYLANTERNCANBEDETERMINED BYSCANNINGTHELANTERNANDACCESSINGTHEINFORMATIONINTHEDATABASE 4HISPROVIDESAMEANSTOIMPLEMENTAWELLDESIGNEDQUALITYCONTROL1# PROCESSDURINGPRODUCTIONBASEDONTHEFEASIBILITYSTUDIESFROM3TAGE  "Y PRE ENCODING THE LIBRARY THE DATA MANAGEMENT SYSTEMS CAN BE SYN CHRONIZEDWITHANALYTICALANDCOMPOUNDMANAGEMENTTOENSUREACCURATE TRACKINGOFEACHINDIVIDUALCOMPOUND

 %XAMPLEOFAN)NFINITY$/3LIBRARY /NEOFTHEINITIALLIBRARIESGENERATEDAT)NFINITYWASINSPIREDBYTHESTE REOCHEMICALDIVERSITYOFNATURALPRODUCTS7EUTILIZEDACHEMISTRY DRIVEN PROCESS BY TAKING ADVANTAGE OF A WELL ESTABLISHED TANDEM   DIPOLAR CYCLOADDITIONACYLATION BETWEEN NITRONE CARBOXYLIC ACIDS AND CHIRAL ALLYLICALCOHOLS&IG TOPROVIDEDISTINCTBICYCLICCORESREPRESENTING AHIGHDEGREEOFSTEREOCHEMICALDIVERSITYINTHEFORMOFCONSTITUTIONAL ISOMERS )T IS IMPORTANT TO NOTE THAT THIS STEREOCHEMICAL DIVERSITY WAS INTRODUCEDINSOLUTIONTHEREBYENSURINGAHIGHDEGREEOFPURITYFORTHE LIBRARY&URTHERAPPENDAGEANDSKELETALDIVERSITYWASINTRODUCEDONSOLID PHASE 4OACCOMPLISHTHESETRANSFORMATIONS EACHOFTHECORESWASLOADED ONTO-IMOTOPE¤LANTERNSVIAAPRIMARYORSECONDARYALCOHOLBYWAYOFA SILYLETHERLINKER&IG ;=4OINTRODUCEAPPENDAGEDIVERSITY EACHSCAF FOLDWASSUBJECTEDTO3ONOGASHIRAREACTIONCONDITIONSTOPROVIDETHEO M ORP ALKYNE SUBSTITUTEDPRODUCTS!DDITIONALSKELETALDIVERSITYWASINTRO DUCEDINADIVERGENTMANNERBYCONVERSIONTOTHEMONOCYCLICAMIDESVIA AMINOLYSISORRESERVEDFOR. /BONDCLEAVAGE!SETOF@SKIPCOMPOUNDS WASALSOGENERATEDSUCHTHATTHEBICYCLICLACTONEINTERMEDIATESCOULDBE INCLUDEDINSCREENING



!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

R1O *

OR2 Me

R or S

R1, R2 = Fmoc, H or H, TBS

HO H O

1) 1,3-dipolar cycloaddition 2) TBS or Fmoc removal

R1 H

O

O

I

OR3

N+ O

R2 O

H

O I

O

o,m,p

o,m,p

R-cores

S-cores

I

R1 H

N

N H

_

HO H O

R2

2 enantiomers X 2 allylic alcohols X 3 Nitrones = 12 cores R1, R2 = Me, H or H, Me

R3 = Me or H

&IGURE 3OLUTION PHASESYNTHESISOFTHEISOXAZOLIDINECORESUSINGATANDEMACYLATION  DIPOLARCYCLOAD DITIONASTHEKEYSTEP

12 cores

Sonogashira

R1 H

O H

O

O H

R2

R4

R2

OH

O

O

NHR3

N

N H

R1

O

O

Bicyclic lactone

R4 Monocyclic amide Aminolysis

N-O bond cleavage

O R1 H

O HO

R1

R2

HO R2

OH NHR3

HN O

O

HN H

O R4

R4 Monocyclic lactone

Acyclic amide

(only one enantiomer shown)

&IGURE 3OLID PHASEDIVERSIFICATIONOFTHEISOXAZOLIDINECORESONLYONEENANTIOMERSHOWN

&OLLOWING.n/BONDCLEAVAGE THEMONOCYCLICLACTONEINTERMEDIATES WERE SUBJECTED TO AMINOLYSIS CONDITIONS TO PROVIDE THE ACYCLIC AMIDES ANDADDAPPENDAGEDIVERSITY)NTOTAL^ ISOXAZOLIDINEANDα AMINO AMIDECOMPOUNDSWEREPREPARED 3CREENINGOFTHEISOXAZOLIDINELIBRARYINVARIOUSASSAYSLEDTOTHEDIS COVERYOFSEVERALINHIBITORSOFTHEANTI APOPTOTICPROTEINS"CL X,AND"CL  nμ- ; =ANDSEVERALINHIBITORSOFBACTERIALCELLGROWTHWITHAN



,ISA!-ARCAURELLEAND#HARLES7*OHANNES

Me

HO

HO

OH H N

O N

N

Me

(R)-core

H N

O

MW = 549 Bcl-xL inhibitor

OH

N

Me

O

H2 N

Me

H O

NH

MW = 538

Anti-bacterial compound (S)-core

&IGURE 4WOBIOLOGICALLYACTIVE$/3COMPOUNDSWHICHWEREIDENTIFIEDINPRIMARYSCREENING

-)#OFμGM,;=&IG )TISINTERESTINGTONOTETHATONELIBRARYOF RELATEDYETSTRUCTURALLYDIVERSECOMPOUNDSPROVIDEDACTIVECOMPOUNDSIN TWOVERYDIFFERENTASSAYS AGAINREINFORCINGTHEPOTENTIALOF$/3FORIDEN TIFYINGMOLECULESWITHDIVERSEBIOLOGICALTARGETS-OREOVER THEIDENTIFICA TIONOFμ-INHIBITORSOF"CL X,AND"CL DIRECTLYFROMPRIMARYSCREENING EFFORTS IS SIGNIFICANT CONSIDERING THE DIFFICULT NATURE OF DISRUPTING SUCH PROTEINnPROTEININTERACTIONS; =3TRUCTURALLY THEACTIVECOMPOUNDS FORTHE"CLFAMILYANDTHEANTIBACTERIALCOMPOUNDSDIFFERINTHESTEREO CHEMISTRYOFTHECORESCAFFOLDSENANTIOMERIC ASWELLASINTHEPOSITION OF A SINGLE METHYL GROUP AND APPENDAGE DIVERSITY AMINE AND ALKYNE COMPONENT 4HESEDIFFERENCESREFLECTTHEIMPORTANCEOFSUBSTITUTIONAND STEREOCHEMISTRYONTHEOVERALLTHREE DIMENSIONALSTRUCTUREOFINDIVIDUAL COMPOUNDSANDHOWTHEYCORRELATETOBIOLOGICALACTIVITY4HISOBSERVATION ALSOSUPPORTSTHEPREVIOUSCONCLUSIONOFPRIVILEGEDSTRUCTUREMOTIFSTHAT ARERELEVANTTODIFFERENTBIOLOGICALPROCESSES 4HE ADDITIONAL BENEFIT OF $/3 THAT IS INHERENT IN THE DESIGN OF THE LIBRARYISBUILTIN3!2DATA WHICHFACILITATESTHEEVALUATIONOFHITSOFINTER EST&URTHERMORE CORESANDINTERMEDIATESAREREADILYACCESSIBLEFROMTHE SCALE UP PROCESS ENABLING RAPID OPTIMIZATION STUDIES )N THIS EXAMPLE MEDICINALCHEMISTRYEFFORTSAROUNDTHEACTIVEISOXAZOLIDINECOMPOUNDS HAVELEDTO"CLFAMILYINHIBITORSWITHSUB NANOMOLARACTIVITYANDACOM POUNDTHATWASACTIVEAGAINSTMETHICILLINRESISTANT3AUREUS-23! WITH -)#SμGM,)NITIALINVIVOPROOFOFCONCEPTINAMOUSETHIGHINJEC TION MODEL SHOWED EFFICACY AND NO OVERT TOXICITY FOR THE ANTI BACTERIAL COMPOUND



!PPLICATIONOFNATURALPRODUCT INSPIREDDIVERSITY ORIENTEDSYNTHESISTODRUGDISCOVERY

 3UMMARY !S DEMONSTRATED BY THE EXAMPLES HIGHLIGHTED IN THIS CHAPTER THERE IS SIGNIFICANT POTENTIAL FOR $/3 LIBRARIES TO GENERATE NOVEL LEADS FOR DRUG DISCOVERY $/3 IS COMPLEMENTARY TO MORE TRADITIONAL METHODS SUCH AS STRUCTURE BASEDDESIGNWHERETHECRYSTALSTRUCTUREOFTHEBINDINGPOCKET IS KNOWN AND A SPECIFIC COMPOUNDS OR A LIBRARY OF COMPOUNDS CAN BE DESIGNED7HENSUCHANAPPROACHISNOTPOSSIBLE $/3ISVERYADVANTA GEOUS PROVIDINGAMEANSTOGENERATENOVELCHEMICALMATTERWITHTHEAIM OFACCESSINGMULTIPLEBIOLOGICALPATHWAYS ORDIFFERENTALLOSTERICBINDING SITESOFKNOWNTARGETS)NORDERTOREALIZETHEFULLPOTENTIALOF$/3 THE SCREENINGOF$/3COMPOUNDSAGAINSTMULTIPLEBIOLOGICALTARGETSISNECES SARY)NESSENCE THESCREENINGOF$/3COMPOUNDCOLLECTIONSISMUCHLIKE SCREENING A COLLECTION OF NATURAL PRODUCTS IN THAT IT SERVES AS A STARTING POINTFORDIVERSEANDCOMPLEXMOLECULESWHICHMAYPOSSESSINTERESTING BIOLOGICALACTIVITY

2EFERENCES 

   

  

 

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0ETER%RTLAND!NSGAR3CHUFFENHAUER

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0ETER%RTLAND!NSGAR3CHUFFENHAUER

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0ETER%RTLAND!NSGAR3CHUFFENHAUER

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#HEMINFORMATICSANALYSISOFNATURALPRODUCTS

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0ETER%RTLAND!NSGAR3CHUFFENHAUER

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&IGURE 4YPICALSCAFFOLDSOFNATURALPRODUCTSPRODUCEDBYANIMALS



#HEMINFORMATICSANALYSISOFNATURALPRODUCTS

&IGURE 4YPICALSCAFFOLDSOFNATURALPRODUCTSPRODUCEDBYBACTERIA

&IGURE 4YPICALSCAFFOLDSOFNATURALPRODUCTSPRODUCEDBYFUNGI



0ETER%RTLAND!NSGAR3CHUFFENHAUER

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!CKNOWLEDGEMENTS #" WAS SUPPORTED BY GRANTS FROM THE #ANADIAN )NSTITUTES OF (EALTH 2ESEARCH#)(2 AND'ENOME#ANADAAND'ENOME/NTARIO#.AND'' ARESUPPORTEDBYGRANTSFROM4HE.)(.('2) ANDTHE#)(2

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Epothilones as lead structures for new anticancer drugs

plexity (which is reflected in synthetic accessibility) between epothilonetype structures and taxol, for which an industrial scale synthesis is clearly out of reach. The chemistry, biology, and SAR (structure-activity-relationship) of epothilones have been extensively discussed in recent review articles [22, 25, 26, 29, 32–36] and it is not the goal of this chapter to recite all these different facets of epothilone-related research. Rather, this article will focus on some selected aspects of the fermentation, chemistry, biology, and clinical evaluation of natural epothilones and their synthetic and semisynthetic analogs, with particular emphasis on SAR work performed in our own laboratories. While this does not include any detailed discussion of the organic chemistry of epothilones, Section 3 provides an outline of the fermentation process that has been developed at Novartis for the production of Epo B, which will also be compared with processes established by other groups. In this context, some of the impressive advances in the elucidation of epothilone biosynthesis and the development of heterologous expression systems will also be briefly highlighted. However, for a more detailed discussion of this subject the reader is referred to two recent review articles [16, 38].

2

Biology and biochemistry of Epo B

2.1 Effects in vitro The basic biology and pharmacology of Epo B, which is the most potent (and, therefore, most extensively studied natural epothilone) have been reviewed in a number of previous accounts [16, 22, 25, 32, 34, 35, 39, 40]. As indicated above, the biological effects of the compound are based on its ability to bind to microtubules, thereby altering the intrinsic stability and dynamic properties of these supramolecular structures. In cell-free in vitro systems this is demonstrated by the prevention of Ca2+- or cold-induced depolymerization of preformed microtubule polymers [21] as well as the promotion of tubulin polymerization (to form microtubule-like polymers) in the absence of either microtubule associated proteins (MAPs) and/or guanosine triphosphate (GTP), at temperatures significantly below 37°C, and in the presence of Ca2+ [18, 21]. The latter phenomenon, i.e., the

279

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ET AL UNPUBLISHED AS A THIAZOLE REPLACEMENT BENZOTHIAZOLE ANALOG  &IG WASDESIGNEDANDSYNTHESIZED;=!SFORA THISCOMPOUND WASFOUNDTOBEMOREPOTENTTHAN%PO"UPTOFOUR FOLD 4AKENTOGETHER THESEFINDINGSSUGGESTTHATTHESIDECHAINBINDINGPOCKETONTUBULINCAN ACCOMMODATESIGNIFICANTLYEXPANDEDHETEROCYCLES IFTHEADDITIONALSTERIC BULKISLOCATEDINTHENORTH EASTERNQUADRANTOFTHESTRUCTURE)TISWORTH NOTINGTHATTHISISCONTRARYTOTHEEFFECTSTHATHAVEBEENOBSERVEDFORTHE INCORPORATIONOFBULKYSUBSTITUENTSATTHE POSITIONOFTHETHIAZOLERING IN%PO" WHICHHAVEBEENREPORTEDTOCAUSEASUBSTANTIALLOSSINBIOLOGICAL POTENCY; = )N ADDITION TO ANALOGS INCORPORATING AN OLEFINIC DOUBLE BOND AS A LINKERBETWEENTHEMACROLACTONERINGANDDIFFERENTTYPESOFHETEROCYCLES WE HAVE ALSO STUDIED A NEW FAMILY OF SIDE CHAIN MODIFIED STRUCTURES WHICHARECHARACTERIZEDBYRIGIDIFICATIONOFTHEENTIRESIDECHAINMANIFOLD EXEMPLIFIEDFORQUINOLINE BASEDANALOGSAND &IG ;=SEE ALSO;= 4HEDESIGNOFTHESEANALOGSWASGUIDEDBYTHERESULTSOF.-2 STUDIES ON THE BIOACTIVE TUBULIN BOUND CONFORMATION OF EPOTHILONES WHICHINDICATEDTHATTHE##DOUBLEBONDANDTHEAROMATIC# . BONDWEREPRESENTINATRANSOIDARRANGEMENTCORRESPONDINGTOA^  # # # . TORSION ANGLE ;= )N GENERAL ANALOGS OF THIS TYPE ARE MORE POTENT INHIBITORS OF HUMAN CANCER CELL PROLIFERATION THAN THE RESPECTIVEPARENTCOMPOUNDS%PO$AND%PO";  =&OREXAMPLE COMPOUNDSANDINHIBITTHEGROWTHOFTHEHUMANCERVIXCARCINOMA CELL LINE +"  WITH )# VALUES OF  N- AND  N- RESPECTIVELY VERSUSN-ANDN-FOR%PO"AND%PO$!SOBSERVEDFOROTHER ANALOGSOFTHISTYPEINCORPORATINGBENZOTHIAZOLE BENZOXAZOLE ORBENZ IMIDAZOLE TYPE SIDE CHAINS THE ACTIVITY DIFFERENCE IS MORE PRONOUNCED



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%POTHILONESASLEADSTRUCTURESFORNEWANTICANCERDRUGS

BE HIGHLY RELEVANT FOR CELLULAR POTENCY BUT NOT FOR THE INTERACTIONS OF THESEANALOGSWITHTHETUBULINMICROTUBULESYSTEM/NTHEOTHERHAND VIRTUALLYNOEFFECTOFTHELOCATIONOFTHE. ATOMONBIOLOGICALACTIVITYWAS OBSERVED BETWEEN EPOXIDE CONTAINING ANALOGS  AND A EITHER AT THE LEVELOFTUBULINPOLYMERIZATIONINVITROORATTHELEVELOFCANCERCELLGROWTH INHIBITION;=7HATSEEMSTOBECLEARFROMTHESEDATAISTHATFACTORS OTHERTHANTUBULIN POLYMERIZINGACTIVITYINVITROMUSTHAVEAPRONOUNCED IMPACT ON THE CELLULAR ACTIVITY OF EPOTHILONE ANALOGS A A  AND A(OWEVER FURTHEREXPERIMENTSWILLBEREQUIREDINORDERTOESTABLISHA MECHANISTICUNDERSTANDINGOFTHEOBSERVEDDIFFERENCESINCELLULARPOTENCY ANDOFTHEIRVIRTUALDISAPPEARANCEUPONCONVERSIONOFANDATOTHE CORRESPONDINGEPOXIDES

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+ARL (EINZ!LTMANNAND+LAUS-EMMERT

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%POTHILONESASLEADSTRUCTURESFORNEWANTICANCERDRUGS

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+ARL (EINZ!LTMANNAND+LAUS-EMMERT

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+ARL (EINZ!LTMANNAND+LAUS-EMMERT

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%POTHILONESASLEADSTRUCTURESFORNEWANTICANCERDRUGS

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%POTHILONESASLEADSTRUCTURESFORNEWANTICANCERDRUGS

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(ISTONEDEACETYLASEINHIBITORSFROMMICROORGANISMSTHE!STELLASEXPERIENCE

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9UHTA-ASUOKA .OBUAKI3HINDOHAND.ORIAKI)NAMURA

 #ONCLUSION ($!#ISANOVELANDPROMISINGMOLECULARTARGETFORHEMATOLOGICALAND SOLIDTUMORTHERAPEUTICS7EHAVEDISCOVERED&+AND9- POTENT ($!#INHIBITORS AMONGMICROBIALMETABOLITES4HEYHAVEUNUSUALBICY CLICSTRUCTURESANDREPRESENTANOTHERNOVELSTRUCTURALCLASSOF($!#INHIBI TORS &+ISTHEFIRSTPOTENT($!#INHIBITORTOUNDERGOCLINICALDEVELOP MENTASAPOTENTIALTREATMENTFORSOLIDANDHEMATOLOGICALCANCERS$UE TOITSDRAMATICEFFECTINPATIENTSWITHREFRACTORY#4#, IN/CTOBER THE 53 &$! GRANTED FAST TRACK STATUS TO &+ AS MONOTHERAPY FOR THE TREATMENTOF#4#,INPATIENTSWHOHAVERELAPSEDFOLLOWING ORBECOME REFRACTORYTO ANOTHERSYSTEMICTHERAPY&+HASALSORECEIVED/RPHAN $RUGDESIGNATIONBYBOTHTHE&$!ANDTHE%UROPEAN!GENCYFORTHE%VALU ATIONOF-EDICINAL0RODUCTS%-%! ASMONOTHERAPYFORTHETREATMENTOF #4#, ($!#INHIBITORSISOLATEDFROMMICROORGANISMS SUCHASTRICHOSTATIN! TRAPOXINAND&+ ARECONTRIBUTINGGREATLYTOTHEIDENTIFICATIONOF($!# ENZYMES AND THE DEVELOPMENT OF BASIC SCIENCE IN CHROMATIN RESEARCH -OREOVER &+ALSOHASTHEPOTENTIALTOBEAHIGHLYPOTENTTHERAPEUTIC DRUG IN CANCER PATIENTS )T IS NOTEWORTHY THAT THEIR STRUCTURES AND PRO DUCING ORGANISMS ARE QUITE DIFFERENT INDICATING THE DIVERSITY OF MICRO BIAL BIOSYNTHETIC ABILITY IN PROVIDING MULTIPLE TEMPLATES THAT CAN BIND TOMOLECULARTARGETSANDINHIBITENZYMEACTIVITYWITHGREATPOTENCYAND SELECTIVITY -ICROORGANISMS ARE SMALL BUT HIGHLY SKILLED @CHEMISTS AND HAVETREMENDOUSPOTENTIALFORMAKINGEXCELLENTDRUGSTHATARECOMPARABLE OREVENSUPERIORTOSYNTHETICCHEMICALCOMPOUNDS )T IS WELL KNOWN THAT NATURAL PRODUCTS ARE AN UNPARALLELED SOURCE OF MOLECULARDIVERSITYFORDRUGDISCOVERY%SPECIALLYTHEDISCOVERYOFANTITU MORAGENTSHASBEENVERYDEPENDENTUPONSCREENINGOFNATURALPRODUCTS $ISCOVERIESOFTHESEPHARMACOLOGICALAGENTSHAVEBEENLARGELYSUPPORTED BY*APANESEMICROBIOLOGY WHICHHASMADEGREATPROGRESSINASSOCIATION WITHTHEUNIQUEDIETARYCULTUREOF*APAN)TISOURFIRMINTENTIONTOCON TINUE TO CONTRIBUTE TO THE FUTURE DEVELOPMENT OF NEW PHARMACEUTICAL AGENTSBYAPPLICATIONOFOURWORLD CLASSMICROBIOLOGICALKNOWLEDGEAND TECHNOLOGIES WHICHHAVEBEENESTABLISHEDBYOURPREDECESSORS



(ISTONEDEACETYLASEINHIBITORSFROMMICROORGANISMSTHE!STELLASEXPERIENCE

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$UKE3 6AUGHN+ #ROOM*R% %LSOHLY( !RTEMISININ ACONSTITUENTOFANNUAL WORMWOOD!ANNUA ISASELECTIVEPHYTOTOXIN7EED3CIn #HEN0 ,EATHER' +LAYMAN$ !LLELOPATHICEFFECTOFARTEMISININANDITSRELATED COMPOUNDSFROM!ANNUA0LANT0HYSIOL .AMDEO! -AHADIK+ +ADAM3 !NTIMALARIADRUGn!RTEMISIAANNUA0HARMACOG NOSY-AGAZINE n 2OTH2 !CTON. !SIMPLECONVERSIONOFARTEMISINICACIDINTOARTEMISININ*.AT 0ROD n *UNG- %L3OHLY( #ROOM*R% 0RACTICALCONVERSIONOFARTEMISINICACIDINTODES OXYARTEMISININ*/RG#HEMn #OVELLO0 4EOH+ 0OLICHUK$ 2EED$ .OWAK' &UNCTIONALGENOMICSANDTHE BIOSYNTHESISOFARTEMISININ0HYTOCHEMISTRY n WWWWHOINTMEDICINESPUBLICATIONSPHARMACOPOEIAOVERVIEWENINDEXHTML WWWBUNDESRECHTJURISDEAFLATOXINVERBOTSV 2O$ 0ARADISE% /UELLET- &ISHER+ .EWMAN+ .DUNGU* (O+ %ACHUS2 (AM2 +IRBY*ETAL 0RODUCTIONOFTHEANTIMALARIALDRUGPRECURSORARTEMISINICACIDIN ENGINEEREDYEAST.ATUREn "OEHM- &ßNFSCHILLING0 +RIEGER- +UESTERS% 3TRUBER& !NIMPROVEDMANUFAC TURINGPROCESSFORTHEANTIMALARIADRUG#OARTEM 0ART/RG0ROCESS2$n "EUTLER5 &ßNFSCHILLING0 3TEINKEMPER! !NIMPROVEDMANUFACTURINGPROCESS FORTHEANTIMALARIADRUG#OARTEM 0ART/RG0ROCESS2$n

)NDEX

)NDEX !"*    ACETOACETATE γALKYLATION  3 n  ACETOXY    TRIPHENYLETHANOL  ACTIVATORGENE  ADSORBERRESINS  AFLATOXIN  ALAMETHICIN  !LBRIGHT 'OODMANOXIDATION  η π ALLYLTRICARBONYLIRONLACTONE COMPLEX  !LZHEIMERSDISEASE  AMINOPHOSPHOLIPIDTRANSLOCASE  ANTASCOMICIN     ANTASCOMICIN ADVANCEDSYNTHESIS n ANTASCOMICIN TOTALSYNTHESIS n !0  APICIDIN  APOPTOSIS  !PPELREACTION  APPENDAGEDIVERSITY  ARTEMETHER  !RTEMISIAANNUA   !ANNUA BIOMASS   !ANNUA PLANTATION  ARTEMISINICACID   ARTEMISININ n ARTEMISININ BIOSYNTHESIS  ARTEMISININ MARKETDEVELOPMENT  ARTEMISININ PURIFICATION  ARTEMISININ SUPPLYCHAIN  ARTEMISININ BASED#OMBINATION4HERAPY !#4   ASCOMYCIN  ASPYRIDONE!AND"  ATROPISOMER  AZA EPOTHILONE n AZATHILONE n β EFFECT  BAKERSYEAST  BARCODEMICROARRAYANALYSIS  "ARTONDEOXYGENATION 

"ARTON LIKEFREE RADICALDECARBOXYLATION  "ARTON -C#OMBIEDEOXYGENATION  BENZILICACIDREARRANGEMENT  BENZO; =DIOXIN  ONE  BIDIRECTIONALSYNTHESIS  BIOMASSMANAGER   BIOSYNTHETICGENECLUSTER  BIOSYNTHETICMETHODOLOGY  BIS THIOLDERIVATIVE  BLOOD BRAIN BARRIER  "-3  SEEIXABEPILONE "-3      BORONENOLATE  "ROWNALKOXYALLYLATION  "ROWNSCROTYLATION      "URGESSREAGENT  BUTANEDIACETAL"$!    CALCINEURIN  CARBOALUMINATION  CARPANONE  CATECHOLPINNINGTECHNIQUE   ##)   +" CELLLINE      +" CELLLINE    CELLULARREDUCTION  #HAKRABORTYSYNTHESIS n CHELATIONCONTROL  CHEMICALGENETICS   CHEMICAL GENETICANALYSIS  CHEMINFORMATICS n CHEMISTRYSPACE n #HINESE0HARMACOPOEIA  CHLOROQUINE  #HROMOBACTERIUMVIOLACEUM  α CHYMOTRYPSIN  CINNAMYCIN  #OARTEM¤  COMBINATORIALCHEMISTRY  COMBINATORIALLIBRARY  CONVERGENTSYNTHESIS 



)NDEX

#OREY "AKSHI 3HIBATA#"3 REDUCTION   #OREY &UCHSHOMOLOGATION  CUPRATE HIGHER ORDER  CUTANEOUS4 CELLLYMPHOMA#4#,  CYCLODEXTRIN  CYCLOPHILIN#Y0  CYCLOSPORINE!#S!   CYTISINE  $ANISHEFSKYSYNTHESIS  DEGLYCOSYLATION   DEHYDRO ARTEMISININ   DEMETHOXYRAPAMYCIN  DEMYELINATION    DEOXYDERIVATIVEOF%PO!AND"  DEOXY%PO&  DEPSIPEPTIDE  SEEALSO&+  DESMETHYL  METHYLSULFANYL %PO" SEE !"* DESYMMETRISATION  $IECKMANNCONDENSATION   $IECKMANN LIKEREACTION   $IELS !LDERCYCLOADDITION  $IELS !LDERREACTION ASYMMETRIC  DIHYDROARTEMISININ  DIIMIDEREDUCTION  DIMETHYLCUPRATE  DIMETHYLDIOXIRANE$-$/    DIMETHYL BENZIMIDAZOLEGROUP   DIRECTEDEPOXIDATION  DISCOVERY GENOMIC GUIDED  DISULFIDEBOND  DITHIANEMETHODOLOGY  DIVERGENTSYNTHESIS  DIVERSITY ORIENTEDSYNTHESIS  DOCETAXEL  DRUGDESIGN n DRUGDISCOVERY n DYNAMICRECRYSTALLISATION  % AND: ENOLATES STEREOSELECTIVEGENERATION  ENZYMATICDESYMMETRISATION  EPOTHILONES n EPOTHILONES AZIRIDINE BASED  EPOTHILONES CYCLOPROPANE BASED 



EPOTHILONES SIDECHAINMODIFICATION  EPOTHILONE!%PO!   %PO! TUBULIN BOUNDCONFORMATION  β TUBULIN%PO!COMPLEX  TRANS EPO!  EPOTHILONEANALOGS AMIDE BASED   EPOTHILONEANALOGS DIMETHYL BENZIMIDA ZOLE BASED EPOTHILONEANALOGS PYRAZOLE BASED  EPOTHILONEANALOGS QUINOLINE BASED  EPOTHILONE"%PO"     %PO"ANALOGS PYRIDINE BASED   DEOXYDERIVATIVEOF%PO!AND"  # DESMETHYL %PO"  # !MINO %PO" SEE"-3  # FLUORO %PO"  EPOTHILONE#%PO#    %PO#$MONOOXYGENASE  EPOTHILONE$%PO$      %PO+0EPOXIDASE   %0/ SEE0ATUPILONE TRANS   DIDEHYDROEPOTHILONE  TRANS EPO!  EPOXIDES REGIOSELECTIVERING OPENING  %SCHENMOSER #LAISENREARRANGEMENT  %SCHERICHIACOLI   ESSENTIALOILS  %VANSALDOLCONDENSATION  %VANSASYMMETRICALDOLREACTION   %VANS 0RASADSYN   REDUCTION   %VANS 4ISHCHENKOANTI   REDUCTION   EVEROLIMUS  EVOKEDPOTENTIAL  EXPERIMENTALAUTOIMMUNEENCEPHALO MYELITIS%!%   &ARINA 3COTTCATALYSTSYSTEM  &ELKIN !NHANALYSIS  &ERRIERREARRANGEMENT TYPE)  &ERRIERREARRANGEMENT TYPE))  FINGOLIMOD SEE&49 &INKELSTEINREACTION  &+  n  &+ REDUCED FORM  &+   

)NDEX

&+    &+ !.!,  &+"0   FLUDELONE  &2 SEE&+ &RATER 3EEBACHALKYLATION  &49 n FUNGI GENOMES  '-ARREST  GALANTHAMINE  GENECLUSTER BIOSYNTHESIS  GENECLUSTER CRYPTIC  GENOMICMINING  GEOGRAPHICALSPLIT  'LOBAL&UNDTO&IGHT!IDS4UBERCULOSISAND -ALARIA'!&4-  GLYCOLICACID "$!VARIANT  'OLECOXIDATION  'OLECPROTOCOL  GROWTHINHIBITION BY%PO"  HAPLOIDMUTANTSTRAIN  HAPLOINSUFFICIENCY   (ENBESTEPOXIDATION  HETERO $IELS !LDERCYCLOADDITION  HIERARCHICALCLUSTERING  HISTONEDEACETYLASE($!# n ($!# CLASS) )6  HOMOALLYLICEPOXIDATION  (ORNER 7ADSWORTH %MMONS(7% REACTION      HYBRIDPRODUCTS INBACTERIA  HYDROSTANNATION PALLADIUMCATALYSED  HYDROSTANNYLATION   HYDROXAMICACID   HYDROXYASCOMYCIN  HYDROZIRCONATION      HYPERCONJUGATION  )"RELECTROPHILICCYCLISATION  IMMUNOSUPPRESSANTS  )NSTITUTEOF-ICROBIOLOGYAND%PIDEMIOLOGY OFTHE!CADEMYOF-ILITARY-EDICAL 3CIENCES  INTERLEUKIN ),   IODOLACTONISATION 

)RELAND #LAISENREARRANGEMENT   IXABEPILONE     *OHNSON #LAISENREARRANGEMENT  *ONESOXIDATION  *ULIAOLEFINATION  +" CELLLINE      +" CELLLINE    03KINASE  +/3  SEEEPOTHILONE$ ,    LIPASE!+  LIPASE03   ,IPINSKISRULEOFFIVE  ,UCHEREDUCTION     LUMEFANTRINE  MACROALDOLISATION   MACROETHERIFICATION  MACROLACTAMRING  MACROLACTAMISATION     MACROLACTONISATION  MAGNETICRESONANCEIMAGING  MAJORHISTOCOMPATIBILITYCOMPLEX -(#  MALARIA  MAMMALIANTARGETOFRAPAMYCIN M4/2    M4/2 ACRONYMSOF  MARINESPONGE  -ASAMUNE 2OUSHCONDITION  -ASAMUNE 2OUSHPROTOCOL  -C-URRYCOUPLINGFORTHESYNTHESISOF TRISUBSTITUTEDOLEFINS   -EERWEINSSALT  MERIDAMYCIN   METABOLICPATHWAY SILENT  METABOLITES SECONDARY  α METHYL   DITHIANES  MICROTUBULE  MICROTUBULEBUNDLING  MICROTUBULEDYNAMIC  MICROTUBULEINHIBITOR  MICROTUBULESTABILIZER  -OFFATTREAGENT 



)NDEX

MOLECULARBARCODE  MOLECULARPROPERTIES   -UKAIYAMAMACROLACTAMISATION    MULTICOMPONENTREACTION  MULTIPLESCLEROSIS    MUTAGENESIS  -YXOCOCCUSXANTHUS   NATURALPRODUCTS MARINE  NATURALPRODUCTS MICROBIAL  NATURALPRODUCTS ORIGINOF  .EGISHICARBOALUMINATION  .EURAL4-  NEURODEGENERATIVEDISEASE  .ICOLAOUSYNTHESIS   NON %VANSALDOLREACTION  NON NATURALNATURALPRODUCTS  NONRIBOSOMALPEPTIDESYNTHETASE.20  .OYORIASYMMETRICREDUCTIONOFβ KETO ESTER  .OZAKI (IYAMA +ISHI.(+ COUPLING       .3#  SEE&+ NUCLEARFACTOROFACTIVATED4 CELLS.&!4C  OCTANOL WATERPARTITIONCOEFFICIENTLOG0  ORGANOMETALLICCOMPLEX  OZONOLYSIS SELECTIVE  PACLITAXEL  PAPUAMIDE"  PARALLELFITNESSTEST  0ARIKH $OERINGOXIDATION    0ARKINSONSDISEASE  PATHWAY SPECIFICREGULATORYGENES EXPRESSIONOF   PATUPILONE   0AYNEREARRANGEMENT   PENTENYLACETALS  PEPTIDE NONRIBOSOMAL  PEPTIDYLPROLYLCIS TRANSISOMERASE 00)ASE  0 GLYCOPROTEIN   PHARMACOPHOREMODELING n PHOSPHATIDYLINOSITOLKINASE0)+ 



PHOSPHATIDYLSERINE  0INNICKOXIDATION   PLASMASTABILITY  0LASMODIUM  POLARSURFACEAREA  POLYKETIDES  POLYKETIDESYNTHASE0+3  0+3MODULE  0+3 .203HYBRIDMETABOLITE  0+3 .203HYBRIDSYNTHASE  PRIVILEGEDSTRUCTURE  PROBABILISTICSPARSEMATRIXFACTORIZATION 03-&  PRODRUG NATURAL  PRODUCTINHIBITION  0ROGRAF4-  0SEUDOMONAS  PTEROCARYANIN#   0URDIEMETHYLATION  R!$   2APAMUNE4-  RAPAMYCIN  n n RAPAMYCIN DEGRADATIONSTUDY  RAPAMYCIN DEGRADATIVEWORK  RAPAMYCIN TOTALSYNTHESIS n 2EFORMATSKYREACTION  REGULATOROFGENECLUSTEREXPRESSION  RETROALDOL  RINGSYSTEM   RING CLOSINGMETATHESIS     ROMIDEPSIN SEE&+ 2OUSHCROTYLATION  30  30RECEPTOR    3ACCHAROMYCESCEREVISIAE  3ACCHAROMYCESCEREVISIAEGENEDELETION MUTANTCOLLECTION  3AEGUSAOXIDATION  SAGOPILONE   3ANDIMMUNE4-  SCAFFOLD    3CHREIBERSYNTHESIS  3CHWARTZREAGENT  SECONDARYMETABOLITES  SELENO CYCLISATION 

)NDEX

3EYFERTHDIAZOPHOSPHONATEREAGENT  3HARPLESSASYMMETRICEPOXIDATION       SHORT CHAINFATTYACID  SIGMATROPICREARRANGEMENT  SKELETALDIVERSITY  3MITHSYNTHESIS    SODIUMARTESUNATE  SOLID PHASEMETHOD INTRODUCTIONOF APPENDAGEDIVERSITY  3ORRANGIUMCOELICOLOR  3ORRANGIUMCELLULOSUM3OCE    SOURCEORGANISM  SPHINGOSINE PHOSPHATE  SPIROTRYPROSTATIN"  SPIRUCHOSTATIN! SEE9- STAUROSPORINE   STICHLOROSIDE#  3TILLECROSS COUPLING  3TILLEREACTION    3TILL 'ENNARIOLEFINATION  3TILL 'ENNARIPHOSPHONATE  3TORK :HAOBISTRIFLUOROACETOXY IODOBENZENE PROTOCOL   3TREPTOMYCESCOELICOLOR  3UÇREZOXIDATIVECLEAVAGE  SUBSTITUENT   SUBSTRUCTURALANALYSIS  SULFENYLSULFONE  SWEETWORMWOOD  3WERNOXIDATION  SYNTENY  SYNTHASE NONRIBOSOMAL  SYNTHASE POLYKETIDE  3YNTHETIC'ENETIC!RRAY3'! ANALYSIS  SYNTHETICGENETICINTERACTION  SYNTHETICLETHALGENETICANALYSIS  SYNTHETICLETHALGENETICNETWORK  TACROLIMUS  4AKAIOLEFINATION   TAXOL SEEPACLITAXEL

4AXOTERE¤  TEMSIROLIMUS  TETRAMETHYLAMMONIUMTRIACETOXYBORO HYDRIDE  TETRAPROPYLAMMONIUMPERRUTHENATE 40!0  THEOPALAUAMIDE  TOTALSYNTHESIS UNIONOFCOMPLEXFRAGMENTS  4RADITIONAL#HINESE-EDICINE4#-  TRAPOXIN  TRICHOSTATIN!  TRIMETHYLALUMINIUM  TUBULINMUTATION  TUBULINPOLYMERIZATIONINHIBITORS  β TUBULIN%PO!COMPLEX  TWODIRECTIONALSTRATEGY  5PJOHNPROCEDURE  VANCOMYCIN  6ASELLA TYPEFRAGMENTATION  6EBERSROTATABLEBONDS  WAXES  7EINREBAMIDES  7ORLD(EALTH/RGANIZATION7(/      7(/@%SSENTIAL-EDICINES,IST   7(/@2OLLBACK-ALARIAINITIATIVE  7(/MONOGRAPHONGOODAGRICULTURAL ANDCOLLECTIONPRACTICES'!#/ FOR !RTEMISIAANNUA,  XENOGRAFTMODEL  9-   ZINCBOROHYDRIDE    ZINCSILVER GRAPHITE  :+ %0/ SEESAGOPILONE :N"( ANTI   REDUCTION