Biomimetic Organic Synthesis Edited by Erwan Poupon and Bastien Nay
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Biomimetic Organic Synthesis Edited by Erwan Poupon and Bastien Nay
Related Titles Nicolaou, K. C., Chen, J. S.
Breslow, R. (ed.)
Classics in Total Synthesis III
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2003
Biomimetic Organic Synthesis
Volume 1 Alkaloids
Edited by Erwan Poupon and Bastien Nay
Biomimetic Organic Synthesis
Volume 2 Terpenoids, Polyketides, Polyphenols, Frontiers in Biomimetic Chemistry
Edited by Erwan Poupon and Bastien Nay
The Editors Prof. Dr. Erwan Poupon Universit´e Paris-Sud Facult´e du Pharmacie 5, rue Jean-Baptiste Cl´ement 92260 Chˆatenay-Malabry France Dr. Bastien Nay Museum National d’Histoire Naturelle, CNRS 57, rue Cuvier 75005 Paris France
All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany
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V
Foreword The beauty and diversity of the biochemical pathways developed by Nature to produce complex molecules is a good source of inspiration for chemists who want to guided in their synthetic approach by biomimetic strategies. The first biomimetic syntheses were reported at the beginning of the 20th century, with the famous examples of Collie’s and Robinson’s related to the synthesis of phenolics (orcinol) and alkaloids (tropinone). Since then, the number of reported biomimetic syntheses, especially in the last twenty years, has increased, demonstrating the power of these approaches in contemporary organic and bioorganic chemistry. Biomimetic strategies allow the construction of complex natural products in a minimum of steps which is in accordance with the ‘‘atom economy’’ principle of green chemistry and, in addition, simple reagents can be used to access the targets. Furthermore, the bioorganic consequences of such successful syntheses allow the comprehension of the biosynthetic origin of natural compounds and these processes can produce sufficient quantities of pure products to achieve biological investigations. The biomimetic synthesis field came to maturity thanks to interconnexions between biosynthetic studies and organic synthesis, especially in the total synthesis of complex molecules. Biomimetic syntheses could even be considered as the latest stage of biosynthetic studies, confirming or invalidating the intimate steps leading to natural product skeletons. For example, the Johnson’s polycyclization of squalene precursors is one of the most impressive achievements in this field. This is still organic synthesis as the reactions are taking place in the chemist’s flask under chemically controlled experimental conditions, while biosynthetic steps can involve enzymatic catalysis, at least to a certain extent. However, concerning complex biochemical transformations, the exact role of enzymes has not always been clear, and has even been questionned by synthetic chemists. The two book volumes ‘‘Biomimetic Organic Synthesis’’ fill the gap in the organic chemistry literature on complex natural products. These books gather 25 chapters from outstanding authors, not only dealing with the most important families of natural products (alkaloids, terpenoids, polyketides, polyphenols. . .), but also with biologically inspired reactions and concepts which are truly taking part in biomimetic processes. By assembling these books, the editors E. Poupon and B. Nay succeeded in gathering specialists in complex natural product chemistry
VI
Foreword
for the benefit of the synthetic chemist community. With an educational effort in discussions and schemes, and in comparing both the biosynthetic routes and the biomimetic achievements, the demonstration of the power of the biomimetic strategies will become obvious to the readers in both research and teaching areas. These books will be a great source of inspiration for organic chemists and will ensure the continued development in this exciting field. ESPCI-ParisTech Paris, France
Janine Cossy
VII
Contents to Volume 1 Preface XVII List of Contributors XIX Biomimetic Organic Synthesis: an Introduction XXIII Bastien Nay and Erwan Poupon Part I 1
1.1 1.1.1 1.1.2 1.1.2.1 1.1.2.2 1.1.3 1.1.4 1.1.5 1.2 1.2.1 1.2.1.1 1.2.1.2 1.2.2 1.2.2.1 1.2.2.2 1.2.2.3 1.2.3 1.2.3.1 1.2.3.2
Biomimetic Total Synthesis of Alkaloids 1
Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples 3 Erwan Poupon, Rim Salame, and Lok-Hang Yan Ornithine/Arginine and Lysine: Metabolism Overview 3 Introduction: Three Important Basic Amino Acids 3 From Primary Metabolism to Alkaloid Biosynthesis 5 l-Ornithine Entry into Secondary Metabolism 5 l-Lysine Entry into Secondary Metabolism 5 Closely Related Amino Acids 6 The Case of Polyamine Alkaloids 7 Biomimetic Synthesis of Alkaloids 8 Biomimetically Related Chemistry of Ornithine- and Lysine-Derived Reactive Units 9 Ornithine-Derived Reactive Units 9 Biomimetic Behavior of 4-Aminobutyraldehyde 9 Dimerization 10 Lysine-Derived Reactive Units 11 Oxidative Degradation of Free l-Lysine 11 Clemens Sch¨opf ’s Heritage: 50 Years of Endocyclic Enamines and Tetrahydroanabasine Chemistry 12 Spontaneous Formation of Alkaloid Skeletons from Glutaraldehyde 13 Biomimetic Access to Pipecolic Acids 15 Pipecolic Acids: Biosynthesis and Importance 15 Biomimetic Access to Pipecolic Acids 16
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Contents
1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.5.1 1.3.5.2 1.3.6 1.4 1.4.1 1.4.2 1.4.2.1 1.4.2.2 1.4.2.3 1.4.3 1.4.3.1 1.4.3.2 1.4.3.3 1.4.4 1.5 1.5.1 1.5.2 1.5.2.1 1.5.2.2 1.5.3 1.5.4 1.5.4.1 1.5.4.2 1.5.4.3 1.5.4.4 1.5.4.5 1.5.4.6 1.5.4.7 1.5.4.8
Biomimetic Synthesis of Alkaloids Derived from Ornithine and Arginine 18 Biomimetic Access to the Pyrrolizidine Ring 18 Biomimetic Syntheses of Elaeocarpus Alkaloids 19 Biomimetic Synthesis of Fissoldhimine 22 Biomimetic Synthesis of Ficuseptine, Juliprosine, and Juliprosopine 25 Biomimetic Synthesis of Arginine-Containing Alkaloids: Anchinopeptolides and Eusynstyelamide A 26 Natural Products Overview 26 Biomimetic Synthesis 26 A Century of Tropinone Chemistry 29 Biomimetic Synthesis of Alkaloids Derived from Lysine 30 Alkaloids Derived from Lysine: To What Extent? 30 Lupine Alkaloids 31 Overview and Biosynthesis Key Steps 31 Biomimetic Synthesis of Lupine Alkaloids 32 A Biomimetic Conversion of N-Methylcytisine into Kuraramine 33 Biomimetic Synthesis of Nitraria and Myrioneuron Alkaloids 34 Biomimetic Syntheses of Nitraramine 35 Biomimetic Syntheses of Tangutorine 37 Endocyclic Enamines Overview: Biomimetic Observations 39 Biomimetic Synthesis of Stenusine, the Spreading Agent of Stenus comma 39 Pelletierine-Based Metabolism 42 Pelletierine: A Small Alkaloid with a Long History 42 Biomimetic Synthesis of Pelletierine and Pseudopelletierine 43 Pelletierine (129) 43 Pseudopelletierine 44 Lobelia and Sedum Alkaloids 44 Lycopodium Alkaloids 44 Overview, Classification, and Biosynthesis 44 Biomimetic Rearrangement of Serratinine into Serratezomine A 47 Biomimetic Conversion of Serratinine into Lycoposerramine B 47 Biomimetic Interrelations within the Lycoposerramine and Phlegmariurine Series 49 When Chemical Predisposition Does Not Follow Biosynthetic Hypotheses: Unnatural ‘‘Lycopodium-Like’’ Alkaloids 50 Total Synthesis of Cermizine C and Senepodine G 51 Biomimetic Steps in the Total Synthesis of Fastigiatine 52 Biomimetic Steps in the Total Synthesis of Complanadine A 53 References 54
Contents
2
2.1 2.2 2.2.1 2.2.2 2.3 2.4 2.4.1 2.4.2 2.4.3
3
3.1 3.1.1 3.1.2 3.2 3.3 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.4 3.5 3.5.1 3.5.2 3.6
Biomimetic Synthesis of Alkaloids Derived from Tyrosine: The Case of FR-901483 and TAN-1251 Compounds 61 Huan Liang and Marco A. Ciufolini Introduction 61 Biomimetic Total Syntheses of FR-901483 and TAN-1251 Compounds 63 Snider Synthesis of FR-901483 64 Snider Synthesis of TAN-1251 Substances 67 Oxidative Amidation of Phenols 71 Biomimetic Syntheses of FR-901483 and TAN-1251 Compounds via Oxidative Amidation Chemistry and Related Processes 77 Sorensen Synthesis of FR-901483 78 Honda Synthesis of TAN-1251 Substances 79 Ciufolini Synthesis of FR-901483 and TAN-1251C 80 References 86 Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Indolemonoterpene Alkaloids 91 Sylvie Michel and Fran¸cois Tillequin Introduction 91 Indolemonoterpene Alkaloids 91 Classification and Botanical Distribution 91 Biomimetic Synthesis of Indolomonoterpene Alkaloids with a Non-rearranged Monoterpene Unit: Aristotelia Alkaloids 93 Biomimetic Synthesis of Secologanin-Derived Indolomonoterpene Alkaloids 96 Strictosidine, Vincoside, and Simple Corynanthe Alkaloids: Heteroyohimbines and Yohimbines 96 Antirhine Derivatives 99 Conversion of the Corynanthe Skeleton into the Strychnos Skeleton 99 Fragmentation and Rearrangements of Corynanthe Alkaloids: Ervitsine-, Ervatamine-, Olivacine-, and Ellipticine-Type Alkaloids 102 Iboga and Aspidosperma Alkaloids 106 Fragmentation and Rearrangements of Aspidosperma Alkaloids: Vinca Alkaloids and Rhazinilam 106 Biomimetic Synthesis of Secologanin-Derived Quinoline Alkaloids 109 Biomimetic Synthesis of Dimeric Indolomonoterpene Alkaloids 110 Anhydrovinblastine and the Anticancer Vinblastine Series 110 Strellidimine 113 Conclusion 113 References 114
IX
X
Contents
4
4.1 4.2 4.2.1 4.2.2 4.2.3 4.3 4.3.1 4.4
5 5.1 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6 5.2.7 5.2.8 5.2.9 5.2.10 5.3
6 6.1 6.2 6.2.1 6.2.2 6.2.3 6.3
Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Dioxopiperazine Alkaloids 117 Timothy R. Welch and Robert M. Williams Introduction 117 Prenylated Indole Alkaloids 117 Dioxopiperazines Derived from Tryptophan and Proline 119 Dioxopiperazine Derived from Tryptophan and Amino Acids other than Proline 122 Bicyclo[2.2.2]diazaoctanes 126 Non-prenylated Indole Alkaloids 141 Epidithiodioxopiperazines 141 Conclusion 146 Acknowledgment 147 References 147 Biomimetic Synthesis of Alkaloids with a Modified Indole Nucleus 149 Tanja Gaich and Johann Mulzer Introduction 149 Individual Examples 150 (±)-Camptothecin 150 (±)-Discorhabdins C and E 154 (±)-Brevianamides, Paraherquamides, VM55599, and Marcfortines 155 (+)-Stephacidin A and (−)-Stephacidin B 158 (±)-Chartelline C 160 (+)-Welwitindolinone A and (−)-Fischerindole I 164 (−)-Gelselegine 166 Communesin, Calycanthines, and Chimonanthines 168 (+)-11,11 -Dideoxyverticillin A 171 (±)-Borreverine and (±)-Isoborreverine 173 Conclusion 175 References 175 Biomimetic Synthesis of Manzamine Alkaloids 181 Romain Duval and Erwan Poupon Introduction 181 Two Complementary Hypotheses: An ‘‘Acrolein Scenario’’ and a ‘‘Malondialdehyde Scenario’’ 182 From Fatty Aldehydes Precursors to Simple 3-Alkyl-Pyridine Alkaloids 182 Biomimetic Synthesis of Dihydropyridines and Dihydropyridinium Salts 188 A Tool Box of Biomimetic C5 Reactive Units from the ‘‘Old’’ Zincke Reaction 189 Biomimetic Synthesis of Pyridinium Marine Sponge Alkaloids 191
Contents
6.3.1 6.3.2 6.3.3 6.3.4 6.3.4.1 6.3.4.2 6.4 6.4.1 6.4.2 6.4.2.1 6.4.2.2 6.4.3 6.4.3.1 6.4.3.2 6.4.3.3 6.5
6.5.1 6.5.2 6.6 6.6.1 6.6.2 6.7 6.7.1 6.7.2 6.7.3 6.8 6.9 6.9.1 6.9.2 6.9.3 6.9.4 6.9.5 6.9.6 6.9.7
Biomimetic Total Synthesis of Cyclostellettamine B and Related 3-Alkylpyridiniums 191 Biomimetic Synthesis of Xestospongins and Related Structures 191 Is the Zincke-Type Pyridine Ring-Opening Biomimetic? 193 Alkylpyridines with Unusual Linking Patterns 194 Biomimetic Synthesis of Pyrinodemin A 194 Biomimetic Synthesis of Pyrinadine A 195 Development of Baldwin’s Hypothesis: From Cyclostellettamines to Keramaphidin-Type Alkaloids 195 Linking Pyridinium Alkaloids and Manzamine A-Type Alkaloids 195 Biomimetic Total Synthesis of Keramaphidin B 197 Model Studies (1994) 197 Total Synthesis of Keramaphidin B (1998) 197 Drawbacks of the ‘‘Acrolein’’ Scenario 198 Very Low Yield of the Endo-Intramolecular Diels–Alder Reaction 198 Undesirable Transannular Hydride Transfers 199 Conversion of a ‘‘Keramaphidin’’ Skeleton into an ‘‘Ircinal/Manzamine’’ Skeleton Was Not Experimentally Possible 200 ‘‘Malondialdehyde Scenario:’’ A Modified Hypothesis Placing Aminopentadienals as Possible Precursors of Manzamine Alkaloids 200 Keramaphidin/Ircinal Connection 200 Halicyclamine Connection 201 Testing the Modified Hypothesis in the Laboratory 203 Biomimetic Models toward Manzamine A 203 Biomimetic Models toward Halicyclamines 205 Biomimetic Approaches toward Other Manzamine Alkaloids 208 Biomimetic Models of Madangamine Alkaloids 208 Biomimetic Model of Nakadomarine A 210 Biomimetic Models of Sarains: A Side Branch of the Manzamine Tree 211 A Biomimetic Tool-Box for the Synthesis of Manzamine Alkaloids: Glutaconaldehydes and Aminopentadienals 213 Biosynthesis of Manzamine Alkaloids: Towards a Universal Scenario 215 From Fatty Acids to Long-Chain Aminoaldehydes and Sarain Alkaloids 215 Pyridine Alkaloids: Theonelladine, Cyclostellettamine, and Xestospongin-Type Alkaloids 215 From Cyclostellettamines to Keramaphidin and Halicyclamine/Haliclonamine Alkaloids 218 Spinal Cord of Manzamine Metabolism: The Ircinal Pathway 218 From Ircinal and Pro-ircinals to Manzamine A Alkaloids 218 From Pro-ircinals to Madangamine Alkaloids 218 From Pro-ircinals to Manadomanzamine Alkaloids 219
XI
XII
Contents
6.9.8 6.10 6.11
From Ircinals and Pro-ircinals to Nakadomarine Alkaloids 219 Total Syntheses of Manzamine-Type Alkaloids 219 Conclusion 220 References 221
7
Biomimetic Synthesis of Marine Pyrrole-2-Aminoimidazole and Guanidinium Alkaloids 225 J´erˆome Appenzeller and Ali Al-Mourabit Introduction 225 Introduction to Pyrrole-2-Aminoimidazole (P-2-AI) Marine Alkaloids 226 Proposed Biogenetic Hypothesis for Clathrodin (1) and Related Monomers Starting from α-Amino Acids 229 Ground Work of George B¨uchi: Dibromophakellin (7) Synthesis from Dihydrooroidin (31) 233 Biomimetic Synthesis of P-2-AI Linear and Polycyclic Monomers 234 Biomimetic Synthesis of Linear Monomers 237 Debromodispacamides B (18) and D (39) and Dispacamide A (4) 237 Clathrodin (1) and Its Brominated Derivative Oroidin (3) 237 Biomimetic Synthesis of Cyclized Monomers 238 Cyclooroidin (48) 238 Dibromoagelaspongin (6) 238 Dibromophakellin (7) and Dibromophakellstatin (69) 243 Hymenialdisines (91) 247 Agelastatins 250 Biomimetic Synthesis of P-2-AIs Simple Dimers 253 Mauritiamine 253 Sceptrins, Ageliferins, and Oxysceptrins 254 Biomimetic Synthesis of Complex Dimers: Palau’amine and Related Congeners 255 Common Chemical Pathway for P-2-AI Biosynthesis 256 First Proposal Based on a Diels–Alder Key Step 257 Universal Chemical Pathway 257 Intramolecular Aziridinium Mediated Mechanism for the Formation of Massadine (141) from Massadine Chloride (155) 259 Aziridinium Mechanism for the Formation of the Tetramer Stylissadine A 259 Synthetic Achievements 261 Axinellamines A/B 262 Massadine Chloride (149) and Massadine (135) 263 Palau’amine (11) 265 New Challenging P-2-AI Synthetic Targets and Perspectives 266 References 267
7.1 7.1.1 7.1.2 7.2 7.3 7.3.1 7.3.1.1 7.3.1.2 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.4 7.4.1 7.4.2 7.5 7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.5.6 7.5.6.1 7.5.6.2 7.5.6.3 7.6
Contents
8 8.1 8.2 8.2.1 8.2.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.5 8.5.1 8.5.2 8.6
9
9.1 9.1.1 9.1.2 9.1.3 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.2.5 9.2.6 9.3 9.3.1 9.3.2 9.3.3 9.3.4
Biomimetic Syntheses of Alkaloids with a Non-Amino Acid Origin Edmond Gravel Introduction 271 Galbulimima Alkaloids 271 Alkaloids of Class I 272 Alkaloids of Class II and Class III 273 Cyclic Imine Marine Alkaloids 275 Symbioimine and Neosymbioimine 276 Pinnatoxins and Pteriatoxins 279 Gymnodimine and Derivatives 282 Other Polyketide Derived Alkaloids 284 Cassiarins A and B 284 Decahydroquinoline Alkaloids 285 Zoanthamine Alkaloids 288 Azaspiracids 291 Alkaloids Derived from Terpene Precursors 293 Cephalostatins and Ritterazines 294 Daphniphyllum Alkaloids 298 Conclusion 305 References 307 Biomimetic Synthesis of Azole- and Aryl-Peptide Alkaloids 317 Hans-Dieter Arndt, Roman Lichtenecker, Patrick Loos, and Lech-Gustav Milroy Introduction 317 Peptide Alkaloids: An Overview 317 Sources of Peptide Alkaloids 318 Key Features of Biosynthesis 319 Azole-Containing Peptide Alkaloids 321 Structural Features 321 Biomimetic Elements in Azole-Containing Peptide Alkaloids 323 Thiangazole 324 Lissoclinamide 7 326 Thiostrepton 328 GE2270A 334 Peptide Alkaloids Cyclized by Oxidation of Aryl Side Chains 336 Cyclic Peptides Containing Aryl-Alkyl Ethers 336 Cyclic Peptides Containing Biaryl Ethers 339 Cyclopeptides Containing Biaryls 344 Vancomycin 345 References 350
271
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XIV
Contents
10
10.1 10.1.1 10.1.2 10.1.2.1 10.1.2.2 10.1.2.3 10.1.3 10.1.3.1 10.1.3.2 10.1.3.3 10.1.4 10.1.4.1 10.1.4.2 10.1.4.3 10.1.5 10.1.5.1 10.1.5.2 10.1.5.3 10.1.5.4 10.1.5.5 10.1.5.6 10.2 10.2.1 10.2.2 10.2.3 10.2.4 10.3
Biomimetic Synthesis of Indole-Oxidized and Complex Peptide Alkaloids 357 Hans-Dieter Arndt, Lech-Gustav Milroy, and Stefano Rizzo Indole-Oxidized Cyclopeptides 357 Introduction 357 TMC-95A–D 358 Formation of the Trp-Tyr Biaryl Bond by Metal-Catalyzed Cross Coupling 361 Stereocontrolled Oxidation of the Oxindole Fragment 361 Late-Stage Stereoselective (Z)-Enamide Formation 362 Celogentin C 363 Intramolecular Knoevenagel Condensation/Radical Conjugate Addition 366 C–H Activation–Indolylation 367 NCS-Mediated Oxidative Coupling 368 Himastatin and Chloptosin 369 Synthesis of the Himastatin Pyrroloindole Core 372 Synthesis of the Chloptosin Pyrroloindole Core 373 Macrolactamization 373 Diazonamide 375 Late-Stage Aromatic Chlorination 378 Bisoxazole Ring System via Oxidative Dehydrative Cyclization 379 Oxidative Annulation 379 Sequential Nucleophilic 1,2-Addition, Electrophilic Aromatic Substitution 380 Reductive Aminal Formation 380 Indole–Indole Coupling 381 A Complex Peptide Alkaloid: Ecteinascidine 743 (ET 743) 382 Biosynthesis and Biomimetic Strategy 383 Pentacycle Formation 385 Bridge Formation 389 Endgame 390 Outlook 391 References 392
Contents to Volume 2 Part II Biomimetic Synthesis of Terpenoids and Polyprenylated Natural Compounds 395 11
Biomimetic Rearrangements of Complex Terpenoids 397 Bastien Nay and Laurent Evanno
Contents
12
Polyprenylated Phloroglucinols and Xanthones 433 Marianna Dakanali and Emmanuel A. Theodorakis Part III
Biomimetic Synthesis of Polyketides
469
13
Polyketide Assembly Mimics and Biomimetic Access to Aromatic Rings 471 Gr´egory Genta-Jouve, Sylvain Antoniotti, and Olivier P. Thomas
14
Biomimetic Synthesis of Non-Aromatic Polycyclic Polyketides 503 Bastien Nay and Nassima Riache
15
Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening 537 Ivan Vilotijevic and Timothy F. Jamison
16
Biomimetic Electrocyclization Reactions toward Polyketide-Derived Natural Products 591 James Burnley, Michael Ralph, Pallavi Sharma, and John E. Moses Part IV
Biomimetic Synthesis of Polyphenols 637
17
Biomimetic Synthesis and Related Reactions of Ellagitannins 639 Takashi Tanaka, Isao Kouno, and Gen-ichiro Nonaka
18
Biomimetic Synthesis of Lignans 677 Craig W. Lindsley, Corey R. Hopkins, and Gary A. Sulikowski
19
Synthetic Approaches to the Resveratrol-Based Family of Oligomeric Natural Products 695 Scott A. Snyder
20
Sequential Reactions Initiated by Oxidative Dearomatization. Biomimicry or Artifact? 723 Stephen K. Jackson, Kun-Liang Wu, and Thomas R.R. Pettus Part V Frontiers in Biomimetic Chemistry: From Biological to Bio-inspired Processes 751
21
The Diels–Alderase Never Ending Story Atsushi Minami and Hideaki Oikawa
753
22
Bio-Inspired Transfer Hydrogenations 787 Magnus Rueping, Fenja R. Schoepke, Iuliana Atodiresei, and Erli Sugiono
XV
XVI
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23
Life’s Single Chirality: Origin of Symmetry Breaking in Biomolecules 823 Michael Mauksch and Svetlana B. Tsogoeva Part VI
24
Conclusion: From Natural Facts to Chemical Fictions 847
Artifacts and Natural Substances Formed Spontaneously 849 Pierre Champy Index 935
XVII
Preface When we decided to start this project, at the end of 2008, we were perfectly aware that the amount of work to provide on it, the Biomimetic Organic Synthesis saga, would be very important. In fact, we were far from reality since the field not only concerns the huge universe of natural product chemistry, but also tends to embrace many fields beyond. We tried to design this book according to natural product chemistry principles, mainly by compound classes, and hope that few of them slipped our notice. Hopefully, the contributors who were asked to write a chapter in their respective field have welcomed this project with a great enthusiasm and worked hard to finish their chapter on time. Our editing adventure is now ending and we want now to warmly thank all of them for their outstanding contribution to this lengthy book. We also want to pay tribute to Professor Franc¸ois Tillequin, so happy with natural product chemistry, who recently passed away. Special thanks are also due to the staff of Wiley-VCH especially to Dr Gudrun Walter and Lesley Belfit for excellent collaboration. Biomimetic synthesis is the construction of natural products by chemical means using Nature’s hypothetical or established strategies, i.e. starting from synthetic mimicry of Nature’s biosynthetic precursors, ideally by way of biologically compatible reactions. In theory, this principle can be applied to all natural product classes, from the simplest to the most complex compounds. Yet the activation methods in the laboratory can be far from Nature’s enzymatic environment, and the biomimetic step can then be more difficult than expected at first glance. The way may therefore be tricky, even for a skilled chemist. We hope this book will delight readers by materializing most of organic synthesis concepts built from biochemical (biosynthetic) inspirations. Fortunately, readers may find solutions to synthetic problems or, at least, find a new way to improve their knowledge, as we did. Enjoy reading. March 2011
Erwan Poupon Universit´e Paris-Sud, Chˆatenay-Malabry, France Bastien Nay Mus´eum National d’Histoire Naturelle, Paris, France
XIX
List of Contributors Ali Al-Mourabit Centre de Recherche de Gif-sur-Yvette Institut de Chimie des Substances Naturelles UPR 2301 CNRS Avenue de la Terrasse 91198 Gif-sur-Yvette France J´erˆome Appenzeller Centre de Recherche de Gif-sur-Yvette Institut de Chimie des Substances Naturelles UPR 2301 CNRS Avenue de la Terrasse 91198 Gif-sur-Yvette France Hans-Dieter Arndt Technische Universit¨at Dortmund Fakult¨at Chemie Otto-Hahn-Strasse 6 44221 Dortmund Germany and
Max-Planck Institut f¨ur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Marco A. Ciufolini The University of British Columbia Department of Chemistry 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada Romain Duval Institut de Recherche pour le D´evelopement UMR 152 Facult´e des Sciences Pharmaceutiques 118 Route de Narbonne 31062 Toulouse France Tanja Gaich Leibniz Universit¨at Hannover Institute of Organic Chemistry Schneiderberg 1 30167 Hannover Germany
XX
List of Contributors
Edmond Gravel CEA, iBiTecS Service de Chimie Bioorganique et de Marquage 91191 Gif-sur-Yvette France Huan Liang The University of British Columbia Department of Chemistry 2036 Main Mall Vancouver British Columbia V6T 1Z1 Canada Roman Lichtenecker Technische Universit¨at Dortmund Fakult¨at Chemie Otto-Hahn-Strasse 6 44221 Dortmund Germany
Max-Planck Institut f¨ur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Sylvie Michel Universit´e Paris Descartes Facult´e de Pharmacie Laboratoire de Pharmacognosie U.M.R.-C.N.R.S. n◦ 8638 4 Avenue de l’Observatoire 75006 Paris France Lech-Gustav Milroy Technische Universit¨at Dortmund Fakult¨at Chemie Otto-Hahn-Strasse 6 44221 Dortmund Germany and
and Max-Planck Institut f¨ur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Patrick Loos Technische Universit¨at Dortmund Fakult¨at Chemie Otto-Hahn-Strasse 6 44221 Dortmund Germany and
Max-Planck Institut f¨ur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Johann Mulzer University of Vienna Institute of Organic Chemistry W¨ahringer Strasse 38 1090 Vienna Austria Erwan Poupon Universit´e Paris-Sud 11 Facult´e de Pharmacie 5 rue Jean-Baptiste Cl´ement 92260 Chˆatenay-Malabry France
List of Contributors
Stefano Rizzo Technische Universit¨at Dortmund Fakult¨at Chemie Otto-Hahn-Strasse 6 44221 Dortmund Germany and Max-Planck Institut f¨ur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Rim Salame Universit´e Paris-Sud 11 Facult´e de Pharmacie 5 rue Jean-Baptiste Cl´ement 92260 Chˆatenay-Malabry France Franc¸ois Tillequin Universit´e Paris Descartes Facult´e de Pharmacie Laboratoire de Pharmacognosie U.M.R.-C.N.R.S. n◦ 8638 4 Avenue de l’Observatoire 75006 Paris France
Timothy R. Welch Colorado State University Department of Chemistry Fort Collins, CO 80523-1872 USA Robert M. Williams Colorado State University Department of Chemistry Fort Collins, CO 80523-1872 USA Lok-Hang Yan Universit´e Paris-Sud 11 Facult´e de Pharmacie 5 rue Jean-Baptiste Cl´ement 92260 Chˆatenay-Malabry France
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List of Contributors Sylvain Antoniotti Universit´e de Nice-Sophia Antipolis Facult´e des Sciences D´epartment de Chimie 28 AvenueValrose 06108 Nice Cedex 2 France Iuliana Atodiresei RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52074 Aachen Germany James Burnley University of Nottingham Faculty of Science School of Chemistry University Park Nottingham NG7 2RD United Kingdom
Pierre Champy Universit´e Paris-Sud 11 Chimie des Substances Naturelles CNRS UMR 8076 BioCIS Facult´e de Pharmacie 5 rue Jean-Baptiste Cl´ement 92296 Chˆatenay-Malabry France Marianna Dakanali University of California San Diego Department of Chemistry and Biochemistry 9500 Gilman Drive La Jolla San Diego, CA 92093-0358 USA Laurent Evanno Mus´eum National d’Histoire Naturelle Unit´e Mol´ecules de Communication et Adaptation des Micro-organismes associ´ee au CNRS (UMR 7245) 57 rue Cuvier 75005 Paris France
XX
List of Contributors
Gr´egory Genta-Jouve Universit´e de Nice-Sophia Antipolis Facult´e des Sciences D´epartment de Chimie 28 AvenueValrose 06108 Nice Cedex 2 France Corey R. Hopkins Vanderbilt University Medical Center Department of Chemistry Department of Pharmacology Vanderbilt Program in Drug Discovery Nashville, TN 37272-6600 USA Stephen K. Jackson University of California Department of Chemistry and Biochemistry Santa Barbara, CA 93106-9510 USA Timothy F. Jamison Massachusetts Institute of Technology Department of Chemistry 77 Massachusetts Avenue Cambridge, MA 02139 USA
Isao Kouno Nagasaki University Graduate School of Biomedical Sciences Department of Molecular Medicinal Sciences 1-14 Bunkyo-machi Nagasaki 852-8521 Japan Craig W. Lindsley Vanderbilt University Medical Center Department of Chemistry Department of Pharmacology Vanderbilt Program in Drug Discovery Nashville, TN 37272-6600 USA Michael Mauksch University of Erlangen- Nuremberg Department of Chemistry and Pharmacy Henkestrasse 42 91054 Erlangen Germany Atsushi Minami Hokkaido University Graduate School of Science Division of Chemistry Sapporo 060-0810 Japan
List of Contributors
John E. Moses University of Nottingham Faculty of Science School of Chemistry University Park Nottingham NG7 2RD United Kingdom
Michael Ralph University of Nottingham Faculty of Science School of Chemistry University Park Nottingham NG7 2RD United Kingdom
Bastien Nay Mus´eum National d’Histoire Naturelle Unit´e Mol´ecules de Communication et Adaptation des Micro-organismes associ´ee au CNRS (UMR 7245) 57 rue Cuvier 75005 Paris France
Nassima Riache Mus´eum National d’Histoire Naturelle Unit´e Mol´ecules de Communication et Adaptation des Micro-organismes associ´ee au CNRS (UMR 7245) 57 rue Cuvier 75005 Paris France
Gen-ichiro Nonaka Usaien Pharmaceutical Company Ltd. 1-4-6 Zaimoku Saga 840-0055 Japan
Magnus Rueping RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52074 Aachen Germany
Hideaki Oikawa Hokkaido University Graduate School of Science Division of Chemistry Sapporo 060-0810 Japan Thomas R.R. Pettus University of California Department of Chemistry and Biochemistry Santa Barbara, CA 93106-9510 USA
Fenja R. Schoepke RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52074 Aachen Germany Pallavi Sharma University of Nottingham Faculty of Science School of Chemistry University Park Nottingham NG7 2RD United Kingdom
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List of Contributors
Scott A. Snyder Columbia University Department of Chemistry Havemeyer Hall 3000 Broadway New York, NY 10027 USA Erli Sugiono RWTH Aachen University Institute of Organic Chemistry Landoltweg 1 52074 Aachen Germany Gary A. Sulikowski Vanderbilt University Medical Center Department of Chemistry Department of Pharmacology Vanderbilt Program in Drug Discovery Nashville, TN 37272-6600 USA Takashi Tanaka Nagasaki University Graduate School of Biomedical Sciences Department of Molecular Medicinal Sciences 1-14 Bunkyo-machi Nagasaki 852-8521 Japan Emmanuel A. Theodorakis University of California San Diego Department of Chemistry and Biochemistry 9500 Gilman Drive La Jolla San Diego, CA 92093-0358 USA
Olivier P. Thomas Universit´e de Nice-Sophia Antipolis Facult´e des Sciences D´epartment de Chimie 28 AvenueValrose 06108 Nice Cedex 2 France Svetlana B. Tsogoeva University of Erlangen-Nuremberg Department of Chemistry and Pharmacy Henkestrasse 42 91054 Erlangen Germany Ivan Vilotijevic Massachusetts Institute of Technology Department of Chemistry 77 Massachusetts Avenue Cambridge, MA 02139 USA Kun-Liang Wu University of California Department of Chemistry and Biochemistry Santa Barbara, CA 93106-9510 USA
XXIII
Biomimetic Organic Synthesis: an Introduction Bastien Nay and Erwan Poupon
Nature always makes the best of possible things Aristotle 1 General remarks
‘‘Biomimetic’’, ‘‘biomimicry’’ and ‘‘biologically inspired’’ are terms that can be used whenever Nature symphonic processes inspire human creation. This will encompass science, arts, architecture and so on. In this book, we will focus our attention on organic chemistry. To assemble these two volumes, we were spoiled for choice. A selection of topics was made to give a wide perspective on biomimetic synthesis, especially when dedicated to natural product chemistry and total synthesis which will constitute the major part and a guiding principle all along this book. We are of course conscious that entire fields are left aside such as material chemistry or supramolecular chemistry. Yet we wish that this book will convince most readers that applying biomimetic strategies to organic synthesis can provide a shortcut toward efficiency, beauty and originality, in a wide scope of fields (Figure 1).
2 Natural products as a vital lead
For many decades, the question why living organisms of all kingdoms produce secondary metabolites (‘‘natural products’’) has been the subject of many debates. As soon as the first structures were determined, chemists also started thinking about the possible origin of the molecules [1]. Natural products are at the center of chemical ecology and have been forged in the crucible of Darwinian evolution. Many theories have tried to explain the incredible diversity of natural substances, including appealing views concluding that the living organisms that may be selected by evolution are the ones that favor chemical diversity [2], which may be the product of biochemical combinatorial processes. It is needless to remind here the importance of secondary metabolites
XXIV
Biomimetic Organic Synthesis: an Introduction
state of the art tools for bioorganic chemistry e.g.:
natural product chemistry, e.g.: - state of the art strategies for total synthesis - biosynthetic pathways understanding - chemical interrelations state of the art tools for organic chemistry e.g.: - cascade reactions, multicomponent reactions - organocatalysis - Diversity Oriented Synthesis - green chemistry
- Diversity Oriented Synthesis - chemical biology applications - prebiotic chemistry domains of organic synthesis that can benefit from biomimetic strategies
Figure 1
Tentacular influence of biomimetic strategies.
for Humanity notably as a source of drug candidates, pharmaceuticals, flavours, fragrances, food supplements. This aspect has been widely covered over the years. Back to the biological functions, activities of natural substances may be explain because they interact with and modulate almost all type of biological targets including proteins (enzymes, receptors, and cytoskeleton), membranes, or nucleic acids. Here again, important notions such as the conservation of protein domains in living organisms or the selection of privileged scaffolds have been discussed and should not be ignored by chemists interested in natural substances [3].
3 Biomimetic synthesis
Biomimetic synthesis is the construction of natural products by chemical means using Nature’s hypothetical or established strategy. It therefore stands in close relation with biosynthetic studies. Engaged in biomimetic strategies, the chemists 30 25 20 15 10 5
10
08
20
06
20
04
20
20
02
00
Figure 2 Analysis of bibliographical search in SciFinder with the terms ‘‘biomimetic total synthesis’’ from 1960 to 2010, leading to 339 references (30/10/2010).
20
98
20
96
19
94
19
92
19
90
19
88
19
86
19
84
19
82
19
80
19
78
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0
Biomimetic Organic Synthesis: an Introduction
will face pragmatic issues for planning their synthesis but will undoubtedly wonder about the exact role of enzymes in nature’s way to construct sometimes highly complex structures. From highly evolved biosynthetic pathways involving enzymes with very high selectivity to less evolved routes or less specific enzymic catalysis, secondary metabolism pathways embrace a wide range of chemical efficiency. Biomimetic strategies will often, usually unintentionally, point out this aspect. An increasing number of total syntheses have been termed ‘‘biomimetic’’ or ‘‘biosynthetically inspired’’ and so on, especially during the last decade. Basically a quick search in SciFinder, using the term ‘‘biomimetic total synthesis’’ over the period 1960–2010, afforded 339 occurrences, beginning in 1976. As illustrated in Figure 2, the last ten years have shown an increasing number of publications in this field. Different situations and ‘‘degree of biomimicry’’ can then be instinctively distinguished when closely analyzing the final total synthesis including: • a total synthesis featuring a biomimetic crucial step after a multistep total synthesis of the natural product precursor; • a total synthesis featuring a biomimetic cascade reaction from more or less simple precursors. Many examples in both situations will be found in this book. Simple parameters can at first sight help defining the relevance of the biomimetic step especially in terms of complexity generation. These include among others: the number of new carbon-carbon bonds and cycles formed, the number of changes in hybridization state of carbon atoms, the global oxidation state and also the stereochemical changes. The chemical reactions borrowed from Nature tool box for building carbon-carbon bonds that will emerge will particularly stand out century-old reactions such as aldolization, Claisen condensation, Mannich reaction and Diels-Alder and other cycloadditions. Situations where self-assembly relies merely on inherent reactivity of the precursors are probably situations that will be most likely mimicked successfully in the laboratory [4]. Beautiful examples will be presented in this book. Since simplicity should be the hallmark of total syntheses approaching the perfect or ideal total synthesis [5], the use of biomimetic strategies can advantageously bring solutions to intricate synthetic problems [6]. Let us finally add that by many aspects we will not debate here, biomimetic strategies may fulfill the criteria of ‘‘green chemistry’’ and ‘‘atom economy’’ when exploiting for example multicomponent strategies [7].
4 On the organization of the book, in close relation with secondary metabolism biochemistry
The chief purpose of this book is not to give a full coverage of the main biosynthetic pathways of secondary metabolites. Yet a particular care has been brought by
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XXVI
Biomimetic Organic Synthesis: an Introduction
authors in providing basic key elements of biosynthesis in the different chapters, to make them as comprehensive as possible to readers. If more has to be known about biosynthetic elements, we suggest referring to excellent books that have already covered the subject [8]. 4.1 Alkaloids
An alkaloid is a cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms. This is a modern definition for a heterogeneous class of natural substances given by S. W. Pelletier in the first volume of the series of famous periodical books Alkaloids [9]. In our Biomimetic Organic Synthesis, all chapters related to alkaloids have been gathered in the first volume of this edition. Many classifications were proposed for this class of compounds. They could be based on the biogenesis, structure, biological origin, spectroscopic properties or also biological properties. The great lack of general principles towards a unified classification is obvious and the borderline between alkaloids sensu stricto and other natural nitrogen-containing secondary metabolites (such as peptides or nucleosidic compounds) is often unclear. A classification based on the nitrogen source of the alkaloid will guide
Chapter 2.1 by R.Salame, L.-Y. Yan and E. Poupon
Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples O Me H H HO H H2 N N N H H N CO2H HO H2 N H L-ornithine NH N O NH2 "C4N" units H N H2N NH O H H NH O CO2H NH (+)-cycloanchinopeptolide C H2 N N L-arginine H NH2 O OH O O N L-lysine H2N CO2H "C5N" units CH3 N H N NH2 OH nitraramine serratezomine A Chapter 2.2 by H. Liang and M. A. Ciufolini
Biomimetic synthesis of alkaloids derived from tyrosine: the case of FR-901483 and TAN 1251 compounds OMe NH2
HOOC
NMe
2×
HO
HO
N
H
N
O
H
NHMe O
L-tyrosine
OP
Scheme 1
FR-901483
TAN-1251A
Alkaloids derived from ornithine/arginine, lysine and tyrosine.
OH
Biomimetic Organic Synthesis: an Introduction
our choice of topics tackled in this book. This has the advantage of linking the biosynthetic origin (and thereby the biomimetic approach) and the chemical structure of the secondary metabolites. Accordingly, chapters will be devoted to alkaloids primarily deriving from ornithine, arginine, lysine, tyrosine (Scheme 1) and of course tryptophan (which highly diverse chemistry will be envisaged in three chapters, Scheme 2). Particularly, we thought that the important class of indolomonoterpenic alkaloids, despite largely discussed along the years, deserved an overview chapter putting forward crucial ideas and challenges when approaching their chemistry. A large array of natural substances isolated from microorganisms displays a diketopiperazine ring system in more or less rearranged form. Because of constant efforts towards the comprehension of their biosynthesis and their total synthesis, a chapter is dedicated to these alkaloids. In fact, they are probably among the secondary metabolites that have largely benefited from biomimetic strategies
Chapter 2.3 by S. Michel and F. Tillequin
Biomimetic synthesis of alkaloids derived from tryptophan: indolemonoterpene alkaloids H NH
N H H
NH H
H H3COOC
O
H
H N
Glc
N
N
O
H
O
H strychnine
aristoteline
strictosidine Chapter 2.4 by T. R. Welch and R. M. Williams
Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Dioxopiperazine Alkaloids
O
H N
N N H
O N
O
O
N
Me
HN O
N H
H
HN
Me Me H N
O
N
Me
OH O
brevianamide A
H
okaramine N
Chapter 2.5 by T. Gaich and J. Mulzer
Biomimetic synthesis of alkaloids with a modified indole nucleus O N
O N N
Br O OH O
camptothecin
Scheme 2
N N Br N H chartelline C
Alkaloids derived from tryptophan.
Cl Me
Cl
CN
H Me Me O
N H welwitindolinne A
H O
XXVII
Biomimetic Organic Synthesis: an Introduction
XXVIII
Chapter 2.6 by R. Duval and E. Poupon
Biomimetic synthesis of manzamine alkaloids
N H
N H
O
O
OH
N
O
N
N
O
N
NH2
HO N
HO
H
manzamine A
sarain A
Chapter 2.7 by J. Appenzeller and A. Al Mourabit
Biomimetic synthesis of marine pyrrole-2-aminoimidazole and guanidium alkaloids Cl
H2 N
H H N O
NH2 N
O
NH
pyrrole-2-amino-imidazole (P-2-AI)
H OH NH2 N N NH
Br NH
Br Br N H
H N O oroidine
N N H
NH2
Br
palau'amine
Scheme 3
H N N H
O
NH2
NH HN
NH NH2 sceptrine
Focus on two classes of complex marine alkaloids.
with undeniable success. Also of special interest in biomimetic chemistry, several alkaloids are derived in nature by profound modifications of the indole nucleus itself giving rise to secondary metabolites for which the biosynthetic origin is not obvious at first glance. The examples of quinine and camptothecin were among the first structures where such phenomena were suspected. Up to now, such biomimetic syntheses imply an initial oxidation step of the indole nucleus, which selected examples are disclosed in a proper chapter. Two chapters will also cover the biomimetic synthesis of two classes of important marine alkaloids: the manzamine type alkaloids and the pyrrole-2-aminoimidazole alkaloids (Scheme 3). Alkaloids encompass also secondary metabolites obviously deriving from terpenes/steroids or polyketides, they will be considered as well in an individualized chapter (Scheme 4). Despite more related to polyketides in terms of biosynthetic machinery (see below), peptides alkaloids will be covered by two chapters in this section (Scheme 5). 4.2 Terpenes and terpenoids
Terpenes and terpenoids will be covered by chapters of the second volume of Biomimetic Organic Synthesis. They are made by terpene cyclases which catalyze
Biomimetic Organic Synthesis: an Introduction
XXIX
Chapter 2.8 by E. Gravel
Biomimetic synthesis of alkaloids with a non amino-acid origin polyketide alkaloids Me O
O
MeMe
HH
O
O
O
Me AcO
Me
Me
Me
Galbulimima alkaloid 13
zoanthamine
Scheme 4
daphniphylline
NH Me H H O H
Me O
O
HO
N Me
Me O
terpenoid alkaloids
Me
N
Polyketide and terpenoid alkaloids.
Chapter 2.9 by H.-D. Arndt, R. Lichtenecker, P. Loos and L.-G. Milroy
Biomimetic synthesis of azole- and aryl-peptide alkaloids HO H
HO H N
H2 N
OH OH H N
O
N H
NH2
NH
N
S
H O
N
HN
NH2
HS OH Me
HO thiostrepton
O
H
Me
N Me S O
S HN N
H N H Me
S O
OH N
O
O
H N
N H
O
H N
N H
N
N
O
OH O NH
HN biphenomycin C
O NH
Me
OH
O
N H H OH O
O
Me
O
O
HN
H N
Me O
H Me Me
Me
OH
Chapter 2.10 by H.-D. Arndt, L.-G. Milroy, S. Rizzo
Biomimetic synthesis of indole-oxidized and complex peptide alkaloids Me
O HO H
Me HO NH O H
Me H N O O
O
Me N HO
N N
O
N H
diazonamide A
Scheme 5
NH
HO
Cl
O
Cl
O
H
NH
NH O N H
HO NH
MeO O CONH2 Me
O AcO
Me
OMe
HO O
S
Me
H N
Me
Me
N O
O
TMC-95A-D
N
Me
O
OH
ecteinascidin 743
H
Complex peptide alkaloids.
highly efficient reactions at the origin of such a rich chemistry. The cationic cascade aspect of terpene biosynthesis from oligomers of activated forms of isoprene is very appealing for many biomimetic endeavors. Current aspects of terpene biosynthesis include the interesting notion of accuracy of terpene cyclases, an issue that is closely
O NH2
XXX
Biomimetic Organic Synthesis: an Introduction
n
two possible biosynthetic outcomes of prenyl cation terpene synthases = terpenes cyclases
aromatic prenyl transferases
terpenes sensu stricto Chapter 3.2 by M. Dakanali and E. Theodorakis
Chapter 3.1 by B. Nay and L. Evanno
Biomimetic rearrangements of complex terpenoids HO O
H
H
O
hyperforine HO
H O CO2H
antheridic acid
Scheme 6
O
O
CO HO
O
Polyprenylated xanthones and phloroglucinol O
O
O intricarene
O
O O
O O
O
O
OH
lateriflorone
Biomimetic synthesis of terpenes and terpenoids.
related to the quest for selectivity in biomimetic synthesis of such compounds. Leading review articles have already been published elsewhere about cationic cascade cyclizations [10]. A chapter will focus on the post-polycyclization events, dealing with biomimetic rearrangements of already complex terpene structures. Polyprenylated secondary metabolites resulting primarily from the transfer of prenyl units to aromatic rings by aromatic prenyl transferases, and sometimes followed by rearrangements, will be covered by another chapter in the second volume (Scheme 6). Other aspects of terpene alkaloids have been developed in the first volume of Biomimetic Organic Synthesis (especially, the reader can refer to chapters 2.3 and 2.8). 4.3 Polyketides
Manipulations of polyketide gene clusters have contributed to a revolution in the comprehension of polyketides (PK), and also of non-ribosomal peptides (NRP), biosynthesis. The genome sequencing of numerous PK and NRP producing microorganisms has revealed a large number of cryptic metabolites mostly unknown. Current challenges include the discovery of such natural compounds by allowing the expression of the corresponding genes (‘‘turn them on’’) and the programming/reprogramming of fungal PKS. Not to be forgotten is the implication of the PK pathways in aromagenesis in nature via the biosynthesis of phenols. We therefore
Biomimetic Organic Synthesis: an Introduction O H3C
O SCoA
O
O
O
H3C
poly-β-ketoester
SCoA
n
assembly mimic aliphatic polyketides aromatic polyketides
Chapter 4.2 by B. Nay and N. Riache
Chapter 4.1 by G. Genta-Jouve, S. Antoniotti, O. P. Thomas
Biomimetic synthesis of non-aromatic polycyclic polyketides
Polyketide assembly mimics and biomimetic access to aromatic rings
Me
KS AT ACP
Me
O H3C
CH3
SCoA SCoA O O
O
O
O O
O
O O
O
O O
O
O O
O Me
SCoA
OH abyssomycine C
O H
Chapter 4.3 by I. Vilotijevica and T. F. Jamison
CO2H phomoidride B
HO H
Polyketide assembly mimics and biomimetic access to aromatic rings Me Me O O O O O O O
O O
O
O O O O
O
Me Chapter 4.4 by J. Burnley, M. Ralph, P. Sharma and J. E. Moses
Biomimetic Electrocyclisation Reactions Towards Polyketide-derived Natural Products O O
H Me O
Me Me
H
elysiapyrone B
Scheme 7
O
HO2C O O
O
HO2C
O
O H O O
O
H
O
H H
torreyanic acid
Biomimetic synthesis of polyketides.
decided to ask for a contribution on biomimetic mimics of the fundamental steps of PK assembly and phenol ring formation. Turning our attention to more complex structures, beautiful examples of biomimetic synthesis of complex non aromatic polycyclic-PKs will be presented. The two following chapters will deal with two specific classes of natural substances characterized by their seminal mechanism of formation: i.e. polyepoxide ring opening and electrocyclization (Scheme 7). 4.4 Polyphenolic compounds
Another important biosynthetic route to aromatic rings in nature is provided by the shikimate/chorismate pathway. Simple phenolic acids enter the biosynthesis
XXXI
Biomimetic Organic Synthesis: an Introduction
XXXII
Chapter 5.1 by T. Tanaka, I. Kouno, G.-i. Nonaka
Biomimetic synthesis and related reactions of ellagitannins OH HO OH OH CO2H HO HO HO
OH
OH OH O
O O O O
OH HO
OH gallic acid
O
HO
OH OH OH
HO accutissimine B
OH
O
O
HO
OH
O
O O
HO OH
Chapter 5.2 by C. W. Lindsley, C. R. Hopkins and G. A. Sulikowski
Biomimetic synthesis of lignans
OH
MeO HO
Me
OMe
O
Me
H
OH
H
H
coniferylic alcohol
O
H O O
O pinoresinol
HO
O
O
OMe
O
carpanone
Chapter 5.3 by S. A. Snyder
Synthetic approaches to the resveratrol-based family of oligomeric natural products HO
OH
HO
HO
OH
OH
resveratrol OH
Scheme 8
HO
O OH OMe hopeanol
OH
H
O
HO
OH
H H HO
O O HO
H
H O
OH
OH
vaticanol C
HO
Biomimetic synthesis of polyphenolic natural substances.
of sometimes highly complex ellagitannins, a class of hydrolysable tannins widely studied for their health benefits (Scheme 8). Among phenylpropanoids natural substances directly derived from chorismate are the lignans that are discussed in the following chapter. Typical extended phenylpropanoids include compounds such as flavonoids and stilbenes. The chemistry of flavonoids has been widely studied and reviewed over the years [11]. This is not the case for natural substances deriving from resveratrol which hold center stage in the last few years because of the growing importance of resveratrol itself in human health, and because of new developments
Biomimetic Organic Synthesis: an Introduction
in the total synthesis of this very interesting class of polycyclic molecules. For these last three classes of molecules (ellagitannins, lignans, resveratrol derived), radical phenolic couplings plays a center role as the main source of carbon-carbon bonds. 4.5 Frontiers in biomimetic synthesis
At the cross-roads of methodology and total synthesis, a few topics will show how nature observation, especially enzymic mechanisms, can lead to new discoveries in organic chemistry (Scheme 9). A discussion on the engaging issue of occurrence of the Diels-Alder reaction in nature will be conducted in a chapter. The exponential impact of organocatalysis in organic chemistry will be illustrated by the challenging problem of transfer hydrogenations in a bio-inspired manner. Once again a plethora of review articles and books deals with the other aspects of organocatalysis [12]. Finally, by many aspects, biomimetic organic chemistry may be closely linked Chapter 6.1 by A. Minami and H. Oikawa
The Diels-Alderase never ending story Mg2+
−
O
O
−
Tyr169
O
NH
H2N
R
1
Arg101 O
NH2
O R2
O
macrophomate synthase mechanism Chapter 6.2 by M. Rueping, F. R. Schoepke, I. Atodiresei and E. Sugiono
Bio-inspired Transfer Hydrogenations O H H O
2 N R
R
EtO
OEt
R1 N H
conditions O
2 HN R
R
H H O
EtO
R1
OEt N H
Chapter 6.3 by M. Mauksch and S. B. Tsogoeva
Life's single chirality: symmetry-breaking reactions OMe
OMe autocatalysis
N EtO2C
Scheme 9
O HN H
O
CO2Et
Frontiers in biomimetic organic synthesis.
XXXIII
XXXIV
Biomimetic Organic Synthesis: an Introduction Chapter 7.1 by P. Champy
Artifacts and natural substances formed spontaneously artifactual ? alkaline media air heat light acidic media silica gel solvent reactivity
O O
artifactual ? O
H
artifactual? H O
O
O
cis-Anethole
Desmosine
O H
OGlc
N N
O
O
air oxidation?
O H3CO H3CO
O
O OH
Korolkoside
artifactual light-induced isomerization?
O
O O HO
O H
H
NH2
N
Vasicolinone
from NH4OH?
Scheme 10
Artifacts as a matter of debate for the conclusion.
to prebiotic chemistry. Key-words such as spontaneous evolution, molecular and supramolecular self-organization of organic molecules can indeed refer to both domains. A chapter will be devoted to the emergence of life single chirality on earth in a manner, once again, understandable to a broad readership. Eventually, we thought that a chapter about artifacts in natural product chemistry might provide the matter of debate for an open conclusion, just to spin out the discussion (Scheme 10). May the readers enjoy their trip in the fascinating science of Biomimetic Organic Synthesis.
References 1. See, this article of great interest:
Thomas, R. (2004) Nat. Prod. Rep., 21, 224–248. 2. See among others: (a) Firn, R.D. and Jones, C.G. (2009) J. Exp. Bot., 60, 719–726 and references cited therein; (b) Jenke-Kodama, H. and Dittmann, E. (2009) Phytochemistry, 70, 1858–1866. 3. See among others: (a) Breinbauer, R., Vetter, I.R., and Waldmann, H. (2002) Angew. Chem. Int. Ed., 41, 2878–2890; (b) Bon, R.S. and Waldmann H. (2010) Acc. Chem. Res., 43, 1103–1114 and references cited therein; (c) Dobson, C.M. (2004) Nature, 432, 824–828 and references cited therein; (d) Welsch, M.E., Snyder, S.A., and Stockwell, B.R. (2010) Curr. Opin. Chem. Biol., 14, 347–361. 4. (a) Gravel, E. and Poupon, E. (2008) Eur. J. Org. Chem., 27–42; (b) E.J.
Sorensen (2003) Bioorg. Med. Chem., 11, 3225–3228. 5. (a) Wender, P.A., Handy, S.T., and Wright, D.L. (1997) Chemistry & Industry, 765; (b) Wender, P.A. and Miller, B.L. (2009) Nature, 460, 197–20; (c) Gaich, T. and Baran, P.S. (2010) J. Org. Chem., 75, 4657–4673. 6. Among other review articles, interesting thoughts and historical perspectives are discussed in: (a) Scholz, U. and Winterfeldt, E. (2000) Nat. Prod. Rep., 17, 349–366; (b) de la Torre, M.C. and Sierra, M.A. (2004) Angew. Chem. Int. Ed., 43, 160–181; (c) Heathcock, C.H. (1996) Proc. Natl. Acad. Sci. USA, 93, 14323–14327. 7. Tour´e, B.B. and Hall, D.G. (2009) Chem. Rev., 109, 4439–4486.
Biomimetic Organic Synthesis: an Introduction 8. (a) Dewick, P.M. (2009) Medicinal nat-
Bioorg. Chem., 5, 51–98; (b) Yoder, ural products: a biosynthetic approach, R.A. and Johnston, J.N. (2005) Chem. 3rd Edition, Wiley, Chichester (UK); Rev., 105, 4730–4756. 11. Andersen, Ø. M. and Markham, K.R. (b) Bruneton, J. (2009) Pharmacognosie, (Eds) (2006) Flavonoids: chemistry, biophytochimie et plantes m´edicinales, 4th chemistry, and applications, CRC Taylor Edition, Tec et Doc, Paris; (c) see also and Francis, Boca Raton. the book series: Barton, D., Nakanishi, 12. (a) Berkessel, A. and Groger, H. K., Meth-Cohn, O. (Eds) (1999) Com(2005) Asymmetric organocatalyprehensive Natural Products Chemistry, sis: from Biomimetic Concepts To 1–9, Elsevier Science Ltd, Oxford; (d) Applications In Asymmetric SyntheMander, L. and Liu, H.-W. (Eds) (2010) sis, Wiley-VCH, Weinheim; (b) Comprehensive Natural Products ChemReetz, M.T., List, B., Jaroch, S., istry II, 1–10, Elsevier Science Ltd, and Weinmann, H. (eds) (2008) Oxford; (d) See also the monthly issues Organocatalysis, Springer Verlag, Berlin; of Nat. Prod. Rep. 9. Pelletier, S.W. (1983) The nature (c) with specific applications in total synand definition of an alkaloid in thesis, see for example: Marqu´ez-L´opez, Alkaloids: Chemical and Biological PerE., Herrera, R.P., and Christmann, spectives, Vol. 1 (ed. Pelletier, S.W.) M. (2010) Nat. Prod. Rep., 27, Wiley-Interscience, New York, pp. 1138–1167. 1–32. 10. For example, see the following early and late reviews: (a) Johnson, W.S. (1976)
XXXV
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Part I Biomimetic Total Synthesis of Alkaloids
Biomimetic Organic Synthesis, First Edition. Edited by Erwan Poupon and Bastien Nay. 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.
3
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples Erwan Poupon, Rim Salame, and Lok-Hang Yan
1.1 Ornithine/Arginine and Lysine: Metabolism Overview1) 1.1.1 Introduction: Three Important Basic Amino Acids
• l-Ornithine (l-1) (l-Orn, Figure 1.1) is a non-proteinogenic amino acid produced from l-glutamic acid (4) in plants and from l-arginine (2) in animals. l-Ornithine plays a central role in the urea cycle in terrestrial vertebrates [1]. • l-Arginine: With its guanidine residue, l-Arginine (l-2) (l-Arg, R) is a highly basic amino acid. It is encoded by DNA and is the direct precursor of l-ornithine (l-1), urea, and also nitric oxide. It is also be encountered in some natural products (see below) [1, 2]. • l-Lysine (l-3) (l-Lys, K): is the only amino acid to have two different biosynthetic pathways. One is the aspartate (5) pathway present in bacteria, plants, and algae. The other starts from α-ketoglutarate (6) and is present in fungi [3, 4]. Lysine is an essential amino acid for humans. Scheme 1.1 reflects some of the biochemical relations between l-ornithine (l-1)/l-arginine (l-2) and l-lysine (l-3). It is of course not the aim of this chapter to provide further details concerning their respective biosynthesis.2) Only important metabolic intermediates, helpful for a better comprehension of the following sections, have been stressed. 1) These three amino acids (Figure 1.1) share
common chemical reactivity and are implicated in more or less similar biosynthetic pathways. We thus decided, in an effort to establish useful comparisons, to garner
lysine and arginine/ornithine derived natural substances in a single chapter. 2) The interested reader is referred to classical biochemistry textbooks.
Biomimetic Organic Synthesis, First Edition. Edited by Erwan Poupon and Bastien Nay. 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.
4
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples
pKa 13.2
NH
H2N
CO2H
N H
L-arginine
"C4N" units
pKa 1.8
NH2 pKa 9
2 (R)
(encoded by DNA)
a CO2H pKa 1.7
pKa 10.7 H N d 2 L-ornithine
NH2
1
pKa 8.7
(not encoded by DNA)
nitrogen of the derived alkaloids
pKa 10.5 H N e 2
"C5N" units
L-lysine
a CO H pKa 2.2 2
NH2 pK 8.9 a
3 (K)
(encoded by DNA)
Figure 1.1
Structure of the amino acids.
CO2H
HO2C oxaloacetic acid
CO2H
HO2C
O
CO2H
NH2 NH2
Asp 5
NH2 L-Lys L-3
citric acid cycle (Krebs cycle)
HO2C
L-pipecolic acid L-9
NH HO2C
CO2H
H2N
O 2-ketoglutarate 6
CO2H L-Arg L-2
N H
NH2 H 2N
urea cycle (animals) HO2C L-Glutamic acid
CO2H NH2
NH2 L-Ornithine 1
(Glu) 4
HO2C
Scheme 1.1
NH H2N urea CO2H
H2N
H N
H 2N L-proline L-8
Place of the three amino acids in primary metabolism.
H N
NH2 putrescine 7
1.1 Ornithine/Arginine and Lysine: Metabolism Overview
5
1.1.2 From Primary Metabolism to Alkaloid Biosynthesis
The parallel between l-ornithine (l-1) and l-lysine (l-3) metabolism concerning their catabolism/biotransformation and subsequent chemical reactivity to form alkaloids is obvious (even if the incorporated nitrogen atom is different, that is, incorporation of the α-amino group for ornithine and ε-amino group for lysine). Mainly, both amino acids will be able to undergo decarboxylation to the corresponding diamine [putrescine 7 (C4 ) and cadaverine 10 (C5 ), respectively] and then oxidative deamination into aminoaldehydes (see below). Thereby, rather stable amino acids are turned into highly reactive units suitable for natural organic chemistry. 1.1.2.1 L-Ornithine Entry into Secondary Metabolism3) The diamine putrescine (7) can be formed directly from the decarboxylation of l-ornithine (1) (Scheme 1.2); it can also be derived from l-arginine (2) [6] after decarboxylation and transformation of the guanidine functional group. Putrescine (7) is then mono-N-methylated4) by putrescine N-methyltransferase (PMT). This reaction is the first purely ‘‘secondary metabolite’’ step and 11 is the first specific metabolite towards alkaloids. N-Methylputrescine (11) may then be oxidatively deaminated by diamine oxidase to 4-methylaminobutanal (12), which generates the N-methyl-1 -pyrrolinium cation 13, a cornerstone electrophilic intermediate and a central precursor of numerous alkaloids belonging to the pyrrolidine or tropane groups when the reaction with an appropriate nucleophile occurs. CO2H
H2N
decarboxylation H2N
NH2 L-ornithine L-1
pyrrolidine alkaloids
Me N
13 Nu Me
Scheme 1.2
putrescine 7
–CO2 CH3 +N
NH2 N-methylation
− Nu
Me NH
H2N 11
–H2O
Me NH
O
oxidative deamination
12 N
tropane alkaloids
Key elements of ornithine metabolism towards alkaloids.
1.1.2.2 L-Lysine Entry into Secondary Metabolism5) Decarboxylation of l-lysine (l-3) into the diamine cadaverine (10) (Scheme 1.3) followed by oxidative deamination leads to aminopentanal 14, which can cyclize into tetrahydropyridine 15.6) This latter is most likely the universal intermediate 3) The fundamental first steps of ornithine (or
lysine) catabolism towards alkaloids now constitute a classic in biosynthesis textbooks. See, among others, Reference [5]. 4) This important step has been widely studied. PMT is closely related to spermidine synthase. See Reference [7] for a valuable review.
5) The interested reader is referred to classical
biochemistry textbooks. 6) Synonymous terms: 2,3,4,5-tetrahydropyri-
dine = 1 -piperideine (imine form); 1,2,3, 4-tetrahydropyridine = 2 -piperideine (enamine form).
6
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples O HO
NH2
–CO2
oxidative deamination
NH2 NH2
O
cadaverine 10
5-aminopentanal 14
NH2 L-lysine
3
H N
H N
Nu
−
H N H lupine alkaloids
NH2
N
–H2O
15
tetrahydroanabasine 16 Nu
H N piperidine alkaloids
Scheme 1.3
Key elements of lysine metabolism toward alkaloids.
to lysine-derived piperidine alkaloids. This imine is too unstable and reactive to be isolated as such from plant material. Nucleophilic addition reactions at the imine function with suitable nucleophiles help stabilize 15 and are at the origin of various piperidine alkaloids. Dimerization into tetrahydroanabasine (16) is an important alternative in the lysine metabolism (the enamine form of 15 being the nucleophile). This latter reaction is spontaneous at physiological pH (vide infra) though stereospecific coupling involves an appropriate enzymic intervention in plants [8]. Tetrahydroanabasine (16) (which is probably also quite unstable as such in vivo) can then undergo various transformations and is at the origin of a class of alkaloids known as ‘‘lupine alkaloids’’ (Section 1.4.2). 1.1.3 Closely Related Amino Acids
• l-Proline: (l-8) (l-Pro, P, Scheme 1.1) is one of the 20 amino acids of the genetic code but the only one with a secondary amine function. It is biosynthesized from l-glutamic acid [9]. l-Proline recently increased in importance with the successful development of organocatalysis. • l-Pipecolic acid: Unlike l-proline (l-8), l-pipecolic acid (l-9) (Scheme 1.1) is a non-proteogenic amino acid. It derives from l-lysine and is at the origin of several classes of secondary metabolites. Biosynthetic and biomimetic aspects of pipecolic acid are discussed below.7) 7) Other close amino acids exist; of particular
interest are piperazic acids (structure shown here). Their biosynthesis from lysine is discussed in Chapter 10 (Indole-Oxidized and Complex Peptide
Alkaloids); see H HO2C N NH
also
Reference
[10].
1.1 Ornithine/Arginine and Lysine: Metabolism Overview
7
1.1.4 The Case of Polyamine Alkaloids
Cases where a C4 N2 building block is incorporated [i.e., the polyamine putrescine (7)] include ‘‘polyamine alkaloids’’ (Scheme 1.4). Comprehensive review articles, especially by M. Hesse and colleagues, have appeared detailing the massive amount of work done in the field of these secondary metabolites during the last 20 years [11, 12]. Essentially, six basic backbone components, namely, putrescine (7), spermidines (17, 18), homospermidines (19, 20), spermine (21), and homospermine (22), participate in the skeleton of polyamine alkaloids. Figure 1.2 gives examples of cyclic polyamine alkaloids [piriferine (23), celacinnine (24), aphelandrine (25), and lipogrammistin A (26)], organized according to the classification of M. Hesse and colleagues (see Reference [11]). Interestingly, cadaverine units are very rarely present in such cyclic molecules. Despite interesting biomimetic syntheses [13], polyamine alkaloids will not be covered in this chapter (except for the biosynthesis of pyrrolidine alkaloids; see Section 1.3.1).
CO2H H2 N L-ornithine
CH3
H N
H2N
R
S
H2N N
Adenosyl H3C
or L-arginine
H2N C3 putrescine 7
H2N N H
H2N
H2N H2N
H2N Scheme 1.4
H2N H N
C3
O
HO CO2H
N
OH
H N
NH2
H N
NH2
H N
NH2
sym -Nor - spermidine 18
H N
NH2
homospermidine 19
H N H N
N
S -adenosylmethionine
NH2
H2N
spermidine 17 spermine 21
C4
S
N
NH2 NH2
sym -homospermidine 20 sym -homospermine 22
Main polyamine backbones encountered in polyamine alkaloids.
8
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples cyclic putrescine alkaloids: O N H
N
O piriferine 23
Ph
cyclic spermidine alkaloids: O H Ph
[Aglaia pirifera]
cyclic spermine alkaloids:
O
N H N H
N Ph
celacinnine 24
[Maytenus heterophylla...]
cyclic sym-homospermine alkaloids: (rare)
aphelandrine 25
O
O
[Aphelandra aurantiaca...]
O
H O
N H N
N H
H O N H
H
N N
O lipogrammistin A 26 NH
[Diploprion bifasciatum]
HN
Figure 1.2
Representative polyamine alkaloids.
1.1.5 Biomimetic Synthesis of Alkaloids
Ionic iminium/enamine reactions are central to the construction of the title alkaloids, especially the Mannich reaction. This is probably one reason why biomimetic strategies have been particularly efficient in this class of secondary metabolites. We will, of course, approach in this chapter only some of the multifaceted aspects of the biomimetic chemistry of l-lysine or l-ornithine/arginine derived secondary metabolites. We will select topics and examples that are not covered (or not with the scrutiny we think opportune) in other review articles. This is especially the case when dealing with the manipulation of small reactive C4 and C5 units derived from the three amino acids. Some selected examples are presented in the following sections and organized as follows:
• biomimetic syntheses from l-lysine and l-ornithine/l-arginine or C4 , C5 reactive units presumably derived from the amino acids; • selected examples of biomimetic syntheses of more complex structures.8)
8) For the implementation of highly complex
metabolisms within marine sponges and involving, according to biosynthetic proposals, l-lysine, l-arginine, and l-proline
see Chapter 7 (Biomimetic Synthesis of Marine Pyrrole-2-aminoimidazole and Guanidinium Alkaloids).
1.2 Biomimetically Related Chemistry of Ornithine- and Lysine-Derived Reactive Units
1.2 Biomimetically Related Chemistry of Ornithine- and Lysine-Derived Reactive Units 1.2.1 Ornithine-Derived Reactive Units 1.2.1.1 Biomimetic Behavior of 4-Aminobutyraldehyde The Christophersen group studied the evolution of aqueous solutions of 4-aminobutyraldehyde (27) [prepared from aminobutyraldehyde dimethyl acetal (28), Scheme 1.5] by 1 H NMR over a wide pH range (1–12) [14]. Entropic factors explain the rapid formation of cyclic imine 29, which can trimerize into 30. When in aqueous solution, different species are in equilibrium and are depicted in Scheme 1.5. Along with aminobutanal 27, two neutral (pyrrolidine 29 and trimer 30), and four protonated entities (31–34) were detected and tracked as a function of pH. Around physiological pH, the four protonated species predominate. Owing to the rapid emergence of acid-catalyzed aldol condensation products, the authors cautiously avoided concentrated solution. As we will detail in a coming section, no dimeric structure such as 35 has been characterized from the mixtures.
H3N
+
33
10% at pH 1-4 O +
OMe H2N
2 M HCl
H3N
H2N
OMe
28
HO OH
O 27
N N
50% at pH 1-6
29 100% at pH 9
20% at pH 13
H N
+
OH
32 H + N
N 30
H
31 ± H2O
N
20% at pH 1-7
N
34 20% at pH 1-7
H N 35 not found
% indicate the highest yield of the entities and the corresponding pH +
695/5 (73%) >95/5 (84%) >95/5 65/35
endo/exo
H
N
HN H N H N H2N H natural skeleton 100/101 O
O
24
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples
1.3 Biomimetic Synthesis of Alkaloids Derived from Ornithine and Arginine
25
correlation with the critical difficulty of dimerization of imine 29 as already evoked (see above, Scheme 1.5). 1.3.4 Biomimetic Synthesis of Ficuseptine, Juliprosine, and Juliprosopine
As we will now discuss, imine 29 was successfully engaged by the Snider group [57] in a biomimetic synthesis of two dihydroindolizinium alkaloids: ficuseptine (105) [58] and juliprosine (106) [59] (Scheme 1.27). Biosynthetic considerations led to the postulation of a Chichibabin pyridine synthesis type reaction as a cornerstone convergent step for both 105 and 106. Mixing aldehyde 107 (which is presumably a tyrosine metabolite in Nature) with imine 29, generated in situ from 108, in acetic acid provided ficuseptine (105) in a single step in 52% yield (Scheme 1.28). OMe R
R ficuseptine 105 [Ficus septica]
N Cl
N OH MeO
Scheme 1.27
O
OH NH Me
NH Me
juliprosine 106 [Ficus septica]
R
N
R
N 29
OMe
+
MeO 107
OMe MeO H2N
AcOH 95 °C, via imine 29
ficuseptine 105
(52%)
N
108
Cl MeO
Scheme 1.28
1
O biosynthetic Chichibabin synthesis of pyridines
Ficuseptine (105) and juliprosine structures (106), and plausible biogenesis.
O
L-ornithine
Ficuseptine: biomimetic synthesis.
This strategy appeared to be as effective (Scheme 1.29) when dealing with more complex juliprosine (106) in terms of side chains engaged in the pyridine formation (probably of polyketide origin in Nature). Aldehyde 109 was prepared in six steps from bromopyridinol 110 and reacted with preformed imine 29 at room temperature in acetic acid to give Troc-106, from which juliprosine 106 was liberated by protecting group removal. Juliprosopine (111) [60], a reduced tetrahydropyridine counterpart of juliprosine was then targeted by the authors as a final destination. Exposure of Troc-106 to sodium borohydride gave a separable 1 : 1 mixture of diastereomers. Prior to this last step, model studies concluded that the natural stereochemistry of 111 should be trans. Therefore, the trans isomer was deprotected to afford juliprosopine (111), for which the stereochemistry was in consequence clarified 25 years after its isolation. It is striking in terms of
26
Br
N
110
Troc-106
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples
Me
6 steps (32%)
9
OH
NTroc+ Me 109
OH
1-NaBH4, EtOH, 2-KOH, H2O, i-PrOH,
H
N
(36%)
NH Me
N 9
OH H
+
Troc=2,2,2-trichloroethoxycarbonyl
5
OH
(35%)
29
H N
Scheme 1.29
1-AcOH, 25°C, 2-Zn, HCl, MeOH, 65°C
O
NH juliprosine 106 Me
H N
juliprosopine 111
(36%)
Juliprosine (106) and juliprosopine (111) biomimetic synthesis.
evolutionary convergence that a pivotal biosynthetic (and synthetic!) reaction can give rise to different natural substances in different plants. These examples once again raise questions about the intervention of enzymes in such biosyntheses. 1.3.5 Biomimetic Synthesis of Arginine-Containing Alkaloids: Anchinopeptolides and Eusynstyelamide A 1.3.5.1 Natural Products Overview Original dihydroxybutyrolactams were isolated from marine ascidian Eusynstyela latericius collected in the Australian Great Reef and named eusynstyelamides A–C (112–114, Figure 1.4) by the Tapiolas group in 2009 [61]. They are in fact closely related to other natural substances, namely, anchinopeptolides A–D (115–118) and surprisingly cycloanchinopeptolide C (119) (with its central core consisting in a tricyclic 5-12-4 ring system) isolated earlier from a marine sponge [62]. Biosynthetically, they might all arise from dimerization of monomeric modified α-ketoacid-containing peptides (dipeptides or tripeptides in the case of eusynstyelamides and anchinopeptolides, respectively) by an aldol reaction (formation of the carbon–carbon bond) and an addition to the amide (Figure 1.4, box). Biomimetic syntheses of these two classes of alkaloids have been performed by the Snider group. 1.3.5.2 Biomimetic Synthesis (±)-Anchinopeptolide D (118) The aldol dimerization of protected modified tripeptide 120 (synthesis not described herein) was undertaken (Scheme 1.30) [63]. Treatment of 120 with potassium hydroxide in MeOH afforded a mixture of three isomeric compounds (Boc-118, Boc-121, 122), two of which were deprotected to afford 118 (anchinopeptolide D) and 121 (epi-anchinopeptolide D). Equilibration studies clearly demonstrated epimerization at the hemiaminal center: heating pure Boc-118 or Boc-121 for 1 h resulted in a 2 : 1 mixture of Boc-118 and Boc-121. Equilibration of the aldol stereocenter occurred more slowly (from pure Boc-118
NH
OH
H
HO
O N OH NH
NH2
NH
NH2 NH
HN
O
OH NH
H N
[Eusynstyela latericius]
N
N
NH O
O
Br
H
OH
O
H N
N H HO
N
O
O OH NH
N
O
O
N OH NH
OH NH
O not found
HO H
O
H 2N
H2N
(–)-eusynstyelamide A 112
Eusynstyelamides and anchinopeptolides.
O
O
O
HO H
O O eusynstyelamide B 113 (+)-eusynstyelamide C 114
H
HO
N H
Figure 1.4
Br
H N
HO O
O
O
N
H HO N H R1 O
R2
HO
N
O
O
N H
H N
H
H N H H O N H H
Me
relative stereochemistry
O
H HO
[Anchinoe tenacior]
(+)-cycloanchinopeptolide C 119
NH
NH
NH
NH
NH
NH
H N
OH
OH
OH (–)-anchinopeptolide A 115: R1=R2=Me (–)-anchinopeptolide B 116: R1=Me, R2=H (–)-anchinopeptolide C 117: R1=H, R2=Me (+)-anchinopeptolide D 118: R1=R2=H
H 2N
H 2N
OH
1.3 Biomimetic Synthesis of Alkaloids Derived from Ornithine and Arginine 27
1 Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples
28
Boc H
N
O
N N H Boc
O
O H HO HO
O 120
O H HO N H
N
H N
N H
HO
N
N H
O
O
121 (17%)
anchinopeptolide D 118 (52%)
H2N
O H HO
H N NH
H2N
1-KOH, MeOH, THF, 0 °C 2-TFA, CH2Cl2, 25 °C
OAc
HO
NH
N O
H HO
H N
N H
HO
N
N H
O O
O
OH
122 (Boc-protected) step 2 was not conducted (