Biomimetic Organic Synthesis E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1223

Veröffentlichungsjahr: 2011

Beschreibung

In this exciting 2 volume set, the approach and methodology of bio-inspired synthesis of complex natural products is laid out, backed by abundant practical examples from the authors' own work as well as from the published literature.

Volume 1 describes the biomimetic synthesis of alkaloids.

Volume 2 covers terpenes, polyketides, and polyphenols.

A discussion of the current challenges and frontiers in biomimetic synthesis concludes this comprehensive handbook.

Key features:

• Biomimetic Strategies have become an every-day tool not only for chemists but also for biologists. The synthetic applications are overwhelming, making this comprehensive 2 volume work a must-have for everyone working in the field.
• Unifying both synthetic and biosynthetic aspects, this book covers everything from organocatalysis and natural product synthesis to synthetic biology and even green chemistry.

Leseprobe

Table of Contents

Related Titles

Title Page

Copyright

Foreword

Preface

List of Contributors

Biomimetic Organic Synthesis: an Introduction

Part I: Biomimetic Total Synthesis of Alkaloids

Chapter 1: Biomimetic Synthesis of Ornithine/Arginine and Lysine-Derived Alkaloids: Selected Examples

1.1 Ornithine/Arginine and Lysine: Metabolism Overview1

1.2 Biomimetically Related Chemistry of Ornithine- and Lysine-Derived Reactive Units

1.3 Biomimetic Synthesis of Alkaloids Derived from Ornithine and Arginine

1.4 Biomimetic Synthesis of Alkaloids Derived from Lysine

1.5 Pelletierine-Based Metabolism

References

Chapter 2: Biomimetic Synthesis of Alkaloids Derived from Tyrosine: The Case of FR-901483 and TAN-1251 Compounds

2.1 Introduction

2.2 Biomimetic Total Syntheses of FR-901483 and TAN-1251 Compounds

2.3 Oxidative Amidation of Phenols

2.4 Biomimetic Syntheses of FR-901483 and TAN-1251 Compounds via Oxidative Amidation Chemistry and Related Processes

References

Chapter 3: Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Indolemonoterpene Alkaloids

3.1 Introduction

3.2 Biomimetic Synthesis of Indolomonoterpene Alkaloids with a Non-rearranged Monoterpene Unit: Aristotelia Alkaloids

3.3 Biomimetic Synthesis of Secologanin-Derived Indolomonoterpene Alkaloids

3.4 Biomimetic Synthesis of Secologanin-Derived Quinoline Alkaloids

3.5 Biomimetic Synthesis of Dimeric Indolomonoterpene Alkaloids

3.6 Conclusion

References

Chapter 4: Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Dioxopiperazine Alkaloids

4.1 Introduction

4.2 Prenylated Indole Alkaloids

4.3 Non-prenylated Indole Alkaloids

4.4 Conclusion

Acknowledgment

References

Chapter 5: Biomimetic Synthesis of Alkaloids with a Modified Indole Nucleus

5.1 Introduction

5.2 Individual Examples

5.3 Conclusion

References

Chapter 6: Biomimetic Synthesis of Manzamine Alkaloids

6.1 Introduction

6.2 Two Complementary Hypotheses: An “Acrolein Scenario” and a “Malondialdehyde Scenario”

6.3 Biomimetic Synthesis of Pyridinium Marine Sponge Alkaloids

6.4 Development of Baldwin's Hypothesis: From Cyclostellettamines to Keramaphidin-Type Alkaloids

6.5 “Malondialdehyde Scenario:” A Modified Hypothesis Placing Aminopentadienals as Possible Precursors of Manzamine Alkaloids

6.6 Testing the Modified Hypothesis in the Laboratory

6.7 Biomimetic Approaches toward Other Manzamine Alkaloids

6.8 A Biomimetic Tool-Box for the Synthesis of Manzamine Alkaloids: Glutaconaldehydes and Aminopentadienals

6.9 Biosynthesis of Manzamine Alkaloids: Towards a Universal Scenario

6.10 Total Syntheses of Manzamine-Type Alkaloids

6.11 Conclusion

References

Chapter 7: Biomimetic Synthesis of Marine Pyrrole-2-Aminoimidazole and Guanidinium Alkaloids

7.1 Introduction

7.2 Ground Work of George Büchi: Dibromophakellin (7) Synthesis from Dihydrooroidin (31)

7.3 Biomimetic Synthesis of P-2-AI Linear and Polycyclic Monomers

7.4 Biomimetic Synthesis of P-2-AIs Simple Dimers

7.5 Biomimetic Synthesis of Complex Dimers: Palau'amine and Related Congeners

7.6 New Challenging P-2-AI Synthetic Targets and Perspectives

References

Chapter 8: Biomimetic Syntheses of Alkaloids with a Non-Amino Acid Origin

8.1 Introduction

8.2 Galbulimima Alkaloids

8.3 Cyclic Imine Marine Alkaloids

8.4 Other Polyketide Derived Alkaloids

8.5 Alkaloids Derived from Terpene Precursors

8.6 Conclusion

References

Chapter 9: Biomimetic Synthesis of Azole- and Aryl-Peptide Alkaloids

9.1 Introduction

9.2 Azole-Containing Peptide Alkaloids

9.3 Peptide Alkaloids Cyclized by Oxidation of Aryl Side Chains

References

Chapter 10: Biomimetic Synthesis of Indole-Oxidized and Complex Peptide Alkaloids

10.1 Indole-Oxidized Cyclopeptides

10.2 A Complex Peptide Alkaloid: Ecteinascidin 743 (ET 743)

10.3 Outlook

References

Part II: Biomimetic Synthesis of Terpenoids and Polyprenylated Natural Compounds

Chapter 11: Biomimetic Rearrangements of Complex Terpenoids

11.1 Introduction

11.2 Beginning with Monoterpene Rearrangements

11.3 Biomimetic Rearrangements of Sesquiterpenes

11.4 Diterpene Rearrangements

11.5 Triterpene Rearrangements

11.6 Some Examples of the Biomimetic Synthesis of Meroterpenoids

11.7 Conclusion

References

Chapter 12: Polyprenylated Phloroglucinols and Xanthones

12.1 Introduction

12.2 Polycyclic Polyprenylated Phloroglucinols

12.3 Polyprenylated Xanthones

References

Chapter 13: Polyketide Assembly Mimics and Biomimetic Access to Aromatic Rings

13.1 Introduction

13.2 Polyketide Assembly Mimics

13.3 Biomimetic Access to Aromatic Rings

13.4 Conclusion

References

Chapter 14: Biomimetic Synthesis of Non-Aromatic Polycyclic Polyketides

14.1 Introduction

14.2 Biomimetic Studies in the Nonadride Series

14.3 Biomimetic Syntheses Involving the Diels–Alder Reaction

14.4 Biomimetic Cascade Reactions

14.5 Conclusion

References

Chapter 15: Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

15.1 Introduction

15.2 Synthetic Considerations: Baldwin's Rules

15.3 Polycyclic Polyethers: Structure and Biosynthesis

15.4 Epoxide-Opening Cascades in the Synthesis of Polycyclic Polyethers

15.5 Summary and Outlook

References

Chapter 16: Biomimetic Electrocyclization Reactions toward Polyketide-Derived Natural Products

16.1 Introduction

16.2 Electrocyclic Reactions

16.3 Polyketides

16.4 Fatty Acid Biosynthesis

16.5 Biomimetic Analysis

16.6 6π Electrocyclizations

16.7 8π Systems and the Black 8π –6π Electrocyclic Cascade

16.8 Biological Electrocyclizations and Enzyme Catalysis

16.9 Conclusion

Acknowledgments

References

Chapter 17: Biomimetic Synthesis and Related Reactions of Ellagitannins

17.1 Introduction

17.2 Biosynthesis of Ellagitannins

17.3 Biomimetic Total Synthesis of Ellagitannins

17.4 Conversion of Dehydroellagitannins into Related Ellagitannins

17.5 Reactions of C-Glycosidic Ellagitannins

17.6 Conclusions and Perspectives

References

Chapter 18: Biomimetic Synthesis of Lignans

18.1 Introduction to Lignans

18.2 Conclusion

References

Chapter 19: Synthetic Approaches to the Resveratrol-Based Family of Oligomeric Natural Products

19.1 Introduction

19.2 Biosynthetic Approaches

19.3 Stepwise Synthetic Approaches

19.4 Conclusions

Acknowledgments

References

Chapter 20: Sequential Reactions Initiated by Oxidative Dearomatization. Biomimicry or Artifact?

20.1 Overview

20.2 Oxidative Dearomatization Sequences and the Initial Intermediate

20.3 Intermolecular Dimerizations

20.4 Successive Intermolecular Reactions

20.5 Intramolecular Cycloadditions

20.6 Other Successive Intramolecular Cascade Sequences

20.7 Successive Tautomerizations and Rearrangements

20.8 Sequential Ring Rupture and Contraction

20.9 Sequential Ring Rupture and Expansion

20.10 Successive Intramolecular and Intermolecular Reactions

20.11 Natural Products Hypothesized to Conclude Phenol Oxidative Cascades

20.12 Conclusion

References

Chapter 21: The Diels–Alderase Never Ending Story

21.1 Introduction

21.2 Diels–Alderases Found in Nature

21.3 Intramolecular Diels–Alder Reactions Possibly Catalyzed by Dehydratase or DH-Red-Domain of PKS or Hybrid PKS-NRPS

21.4 Diels–Alder Reactions after Formation of Reactive Substrates by Oxidation Enzymes

21.5 Summary

References

Chapter 22: Bio-Inspired Transfer Hydrogenations

22.1 Introduction

22.2 Nature's Reductions: Dehydrogenases as a Role Model

22.3 Brønsted Acid Catalyzed Transfer Hydrogenation of Imines, Imino Esters, and Enamines

22.4 Asymmetric Organocatalytic Reduction of N-Heterocycles

22.5 Asymmetric Organocatalytic Reductions in Cascade Sequences

22.6 Conclusion

References

Chapter 23: Life's Single Chirality: Origin of Symmetry Breaking in Biomolecules

23.1 Introduction

23.2 Autocatalytic Enantioselective Reactions

23.3 Autocatalysis and Self-replication

23.4 Polymerization and Aggregation Models of Enantioenrichment

23.5 Phase Equilibria

23.6 Adsorption on Chiral Surfaces

23.7 Spontaneous Symmetry Breaking in Conglomerate Crystallizations

23.8 Symmetry Breaking in Reaction–Diffusion Models, Collision Kinetics, and Membrane Diffusion

23.9 Concluding Remarks and Outlook

References

Chapter 24: Artifacts and Natural Substances Formed Spontaneously

24.1 Introduction

24.2 Glucosidases as Triggers for Formation of By-products

24.3 Oxidation Processes

24.4 Exposure to Light

24.5 Heat and Pressure

24.6 Alkaline Media

24.7 Acidic Conditions during Purifications

24.8 Protic Solvents

24.9 Acetone-Derived Artifacts

24.10 Halogenated Solvents

24.11 Protoberberines, a “Cabinet de Curiosités”

24.12 Conclusion

References

Index

Related Titles

Nicolaou, K. C., Chen, J. S.

Classics in Total Synthesis III

Further Targets, Strategies, Methods

2011

978-3-527-32958-8

Dewick, P. M.

Medicinal Natural Products

A Biosynthetic Approach

Third Edition

2009

ISBN: 978-0-470-74168-9

Dalko, P. I. (ed.)

Enantioselective

Organocatalysis

Reactions and Experimental Procedures

2007

ISBN: 978-3-527-31522-2

Breslow, R. (ed.)

Artificial Enzymes

2005

ISBN: 978-3-527-31165-1

Berkessel, A., Gröger, H.

Asymmetric Organocatalysis

From Biomimetic Concepts to Applications

in Asymmetric Synthesis

2005

ISBN: 978-3-527-30517-9

Nicolaou, K. C., Snyder, S. A.

Classics in Total Synthesis II

More Targets, Strategies, Methods

2003

ISBN: 978-3-527-30684-8

The Editors

Prof. Dr. Erwan Poupon

Université Paris-Sud

Faculté du Pharmacie

5, rue Jean-Baptiste Clément

92260 Châtenay-Malabry

France

Dr. Bastien Nay

Museum National d'Histoire

Naturelle, CNRS

57, rue Cuvier

75005 Paris

France

Cover

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© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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ISBN: 978-3-527-32580-1

ePDF: 978-3-527-63477-4

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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 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

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 François 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

Université Paris-Sud, Châtenay-Malabry, France

Bastien Nay

Muséum National d'Histoire Naturelle, Paris, France

List of Contributors

Part on Alkaloids

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

Jérôme 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 Universität Dortmund

Fakultät Chemie

Otto-Hahn-Strasse 6

44221 Dortmund

Germany

and

Max-Planck Institut für 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 Dévelopement

UMR 152

Faculté des Sciences Pharmaceutiques

118 Route de Narbonne

31062 Toulouse

France

Tanja Gaich

Leibniz Universität Hannover

Institute of Organic Chemistry

Schneiderberg 1

30167 Hannover

Germany

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 Universität Dortmund

Fakultät Chemie

Otto-Hahn-Strasse 6

44221 Dortmund

Germany

and

Max-Planck Institut für Molekulare Physiologie

Otto-Hahn-Strasse 11

44227 Dortmund

Germany

Patrick Loos

Technische Universität Dortmund

Fakultät Chemie

Otto-Hahn-Strasse 6

44221 Dortmund

Germany

and

Max-Planck Institut für Molekulare Physiologie

Otto-Hahn-Strasse 11

44227 Dortmund

Germany

Sylvie Michel

Université Paris Descartes

Faculté 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 Universität Dortmund

Fakultät Chemie

Otto-Hahn-Strasse 6

44221 Dortmund

Germany

and

Max-Planck Institut für Molekulare Physiologie

Otto-Hahn-Strasse 11

44227 Dortmund

Germany

Johann Mulzer

University of Vienna

Institute of Organic Chemistry

Währinger Strasse 38

1090 Vienna

Austria

Erwan Poupon

Université Paris-Sud 11

Faculté de Pharmacie

5 rue Jean-Baptiste Clément

92260 Châtenay-Malabry

France

Stefano Rizzo

Technische Universität Dortmund

Fakultät Chemie

Otto-Hahn-Strasse 6

44221 Dortmund

Germany

and

Max-Planck Institut für Molekulare Physiologie

Otto-Hahn-Strasse 11

44227 Dortmund

Germany

Rim Salame

Université Paris-Sud 11

Faculté de Pharmacie

5 rue Jean-Baptiste Clément

92260 Châtenay-Malabry

France

François Tillequin

Université Paris Descartes

Faculté 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

Université Paris-Sud 11

Faculté de Pharmacie

5 rue Jean-Baptiste Clément

92260 Châtenay-Malabry

France

Part on Terpenoids, Polyketides, Polyphenols, Frontiers in Biomimetic Chemistry

Sylvain Antoniotti

Université de

Nice-Sophia Antipolis

Faculté des Sciences

Départment 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

Université Paris-Sud 11

Chimie des Substances

Naturelles CNRS

UMR 8076 BioCIS

Faculté de Pharmacie

5 rue Jean-Baptiste Clément

92296 Châtenay-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

Muséum National

d'Histoire Naturelle

Unité Molécules de

Communication et Adaptation

des Micro-organismes associée au

CNRS (UMR 7245)

57 rue Cuvier

75005 Paris

France

Grégory Genta-Jouve

Université de

Nice-Sophia Antipolis

Faculté des Sciences

Départment 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

John E. Moses

University of Nottingham

Faculty of Science

School of Chemistry

University Park

Nottingham NG7 2RD

United Kingdom

Bastien Nay

Muséum National

d'Histoire Naturelle

Unité Molécules de

Communication et Adaptation

des Micro-organismes associée 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

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

Michael Ralph

University of Nottingham

Faculty of Science

School of Chemistry

University Park

Nottingham NG7 2RD

United Kingdom

Nassima Riache

Muséum National

d'Histoire Naturelle

Unité Molécules de

Communication et Adaptation

des Micro-organismes associée au

CNRS (UMR 7245)

57 rue Cuvier

75005 Paris

France

Magnus Rueping

RWTH Aachen University

Institute of Organic Chemistry

Landoltweg 1

52074 Aachen

Germany

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

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

Université de

Nice-Sophia Antipolis

Faculté des Sciences

Départment 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

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).

Figure 1 Tentacular influence of biomimetic strategies.

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 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 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.

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).

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 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 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 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.

Scheme 1 Alkaloids derived from ornithine/arginine, lysine and tyrosine.

Scheme 2 Alkaloids derived from tryptophan.

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).

Scheme 3 Focus on two classes of complex marine alkaloids.

Scheme 4 Polyketide and terpenoid alkaloids.

Scheme 5 Complex peptide alkaloids.

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 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 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).

Scheme 6 Biomimetic synthesis of terpenes and terpenoids.

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 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).

Scheme 7 Biomimetic synthesis of polyketides.

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 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 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.

Scheme 8 Biomimetic synthesis of polyphenolic natural substances.

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 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.

Scheme 9 Frontiers in biomimetic organic synthesis.

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.

Scheme 10 Artifacts as a matter of debate for the conclusion.

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. Touré, B.B. and Hall, D.G. (2009) Chem. Rev., 109, 4439–4486.

8. (a) Dewick, P.M. (2009) Medicinal natural products: a biosynthetic approach, 3rd Edition, Wiley, Chichester (UK); (b) Bruneton, J. (2009) Pharmacognosie, phytochimie et plantes médicinales, 4th Edition, Tec et Doc, Paris; (c) see also the book series: Barton, D., Nakanishi, K., Meth-Cohn, O. (Eds) (1999) Comprehensive Natural Products Chemistry, 1–9, Elsevier Science Ltd, Oxford; (d) Mander, L. and Liu, H.-W. (Eds) (2010) Comprehensive Natural Products Chemistry II, 1–10, Elsevier Science Ltd, Oxford; (d) See also the monthly issues of Nat. Prod. Rep.

9. Pelletier, S.W. (1983) The nature and definition of an alkaloid in Alkaloids: Chemical and Biological Perspectives, Vol. 1 (ed. Pelletier, S.W.) Wiley-Interscience, New York, pp. 1–32.

10. For example, see the following early and late reviews: (a) Johnson, W.S. (1976) Bioorg. Chem., 5, 51–98; (b) Yoder, R.A. and Johnston, J.N. (2005) Chem. Rev., 105, 4730–4756.

11. Andersen, Ø. M. and Markham, K.R. (Eds) (2006) Flavonoids: chemistry, biochemistry, and applications, CRC Taylor and Francis, Boca Raton.

12. (a) Berkessel, A. and Groger, H. (2005) Asymmetric organocatalysis: from Biomimetic Concepts To Applications In Asymmetric Synthesis, Wiley-VCH, Weinheim; (b) Reetz, M.T., List, B., Jaroch, S., and Weinmann, H. (eds) (2008) Organocatalysis, Springer Verlag, Berlin; (c) with specific applications in total synthesis, see for example: Marquéz-López, E., Herrera, R.P., and Christmann, M. (2010) Nat. Prod. Rep., 27, 1138–1167.

Part I

BIOMIMETIC TOTAL SYNTHESIS OF ALKALOIDS

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.

Figure 1.1 Structure of the amino acids.

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.

Scheme 1.1 Place of the three amino acids in primary metabolism.

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-Δ1-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.

Scheme 1.2 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 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).

Scheme 1.3 Key elements of lysine metabolism toward alkaloids.

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

1.1.4 The Case of Polyamine Alkaloids

Cases where a C4N2 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).

Scheme 1.4 Main polyamine backbones encountered in polyamine alkaloids.

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

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 1H 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.

Scheme 1.5 Biomimetic reactions from 4-aminobutyraldehyde (27).

With substituted nitrogen atom, for example, with a biosynthetically relevant aminobutyl side chain (Scheme 1.6), the formation of the pyrrolidinium ring is nearly exclusive, with 36 predominant among several other entities [15]. Notably, aminal 37 is a bicyclic compound that is formed spontaneously at basic pH.9

Scheme 1.6 Biomimetic behavior of a substituted pyrrolidinium ion.

1.2.1.2 Dimerization

Whereas dimerization of six-membered ring enamines is a major outcome (as we will discuss in detail when dealing with lysine-derived units), the dimerization of the corresponding five-membered ring systems such as 29 is by far less described in the literature. The chemistry of these molecules is, correspondingly, simpler than that of lysine, probably because of a lesser propensity to react as an enamine (Scheme 1.7).

Scheme 1.7 Dimerization in the pyrrolidine series.

The dimer type 35 has never been described, although it has been postulated in some biosynthesis (Section 1.3.3). In the case of N-methyl substituted 13,10 dimerization has been observed and dimer 38 characterized. Notably, the corresponding reduced dimer 39 has been detected as a mixture of diastereomers from the root system of Nicotiana tabacum, as well as monomeric 13 [18]. In fact, at physiological pH (around 7.2 in a growing tobacco plant), the coexistence of imine and enamine forms of 13 should provide the opportunity for more or less spontaneous condensations.

In the laboratory (Scheme 1.8), starting from N-methyl-4-aminobutanal diethyl acetal (40) in acidic conditions, deprotection affords 12, which cyclizes into biosynthetic intermediate 13, which in turn can dimerize into 38. The product of a retro-Michael reaction, 41, has also been fully characterized; it was usually observed as an impurity in the course of the synthesis of monomers 13 [19]. Alternative procedures toward 13 consist of the oxidation (e.g., with mercuric diacetate [20]) of N-methylpyrrolidine (42) or the reduction of lactam 43 with aluminum hydrides [21].

Scheme 1.8 Biomimetic dimerization in the pyrrolidine series.

1.2.2 Lysine-Derived Reactive Units

1.2.2.1 Oxidative Degradation of Free L-Lysine

Despite a seemingly simple pathway, mimicking the fundamental L-lysine (and L-ornithine) catabolism pathways in the laboratory is far from trivial. Only a few publications report on the direct oxidation of L-lysine. In 1966, B. Franck and colleagues oxidized L-lysine with alkaline NaOCl in water (Scheme 1.9) [22]. Cyclic oxidation products were identified and compared with authentic samples. Scheme 1.9 highlights the possible pathways toward the isolated compounds; it may be assumed that the cyclic oxidation products arise from L-lysine by one (intermediates 46, 47), two (intermediate 48) or three oxidation steps (15, 16, 44, 45). Despite an incomplete conversion of L-lysine and the complex mixtures obtained, this simple reaction is of great interest as a totally biomimetic reaction that mimics (i) the decarboxylation/oxidative deamination steps and (ii) the spontaneous evolution of the resulting reactive species (15, dimer 16, lactam 44).

Scheme 1.9 Cyclic oxidative products of L-lysine.

1.2.2.2 Clemens Schöpf's Heritage: 50 Years of Endocyclic Enamines and Tetrahydroanabasine Chemistry

Numerous compounds resulting from the self-condensations of endocyclic enamines, which are closely related to metabolic pathways, have been described, especially in the pioneering work of Schöpf, starting from the late 1930s.

The simplest compound, that is, Δ1-piperideine (15), does not exist in monomeric forms but, instead, trimeric assemblies of types α- and β-49 and 50 have been isolated (Scheme 1.10).11 Structures 16, 49, and 50 were characterized by Schöpf in 1948 [23] and the configurations and conformations studied by the Kessler group in 1977 by 13C NMR [24]. At neutral or slightly basic pH (∼8), and as in nature, monomers 15 dimerize into tetrahydroanabasine (16) (which can be isolated as a dihydrobromide crystalline salt in the laboratory [25]). As early as 1956, Schöpf and colleagues clearly demonstrated the importance of pH on the kinetic and yield of conversion of 15 into 16. Studies were conducted with pioneering and clear-sighted biosynthetic considerations (zellmöglichen Bedingungen, see Scheme 1.11) [26]. Tetrahydroanabasine also reacts in solution at pH 9 with imine 15 and gives in almost quantitative yield trimer 50, also called isotripiperideine [23]. Consequently, trimer 50 is, in turn, in equilibrium with tetrahydroanabasine 16 and free Δ1-piperideine 15 [27] and can, therefore, be considered as a stable, protected form of tetrahydroanabasine with interesting synthetic potential.

Scheme 1.10 Evolution of tetrahydropyridine.

Scheme 1.11 Schöpf's pioneering works.

Aldotripiperideine (aldo-49) is another trimer that results from a rearrangement of α-tripiperideine in acidic conditions or in basic conditions at pH 9.2 at 100 °C. Interestingly, aldo-49 was isolated from Haloxylon salicornicum as a natural substance [28].

1.2.2.3 Spontaneous Formation of Alkaloid Skeletons from Glutaraldehyde

Glutaraldehyde (51) is a well-known crosslinking agent in biochemistry or histology and is used as a biocide.12 It can also be advantageously seen as a convenient surrogate of lysine by considering a hypothetical oxidative deamination on aminopentanal 14.13

Simple reactions (Scheme 1.12) were recently disclosed, highlighting an impressive propensity of 51 to mimic several lysine metabolism elements [29]. Whereas 51 was known to polymerize14 according to different mechanisms and kinetics (Scheme 1.12) depending, for example, on the pH, very few studies previously described compounds resulting from self-condensations into small molecules. Products formed during the treatment of 51 in an aqueous solution at pH 8.5 and 60 °C were investigated. A double homoaldolization followed by crotonization of one of the aldol adducts can easily explain the formation of bicyclic 52. This compound was previously described but no information was available concerning its stereochemistry [30]. Oxidation of 52 with Dess–Martin periodinane permitted crystallization of the major diastereomer 53. Compound 52 is, interestingly, related to a biosynthetic intermediate postulated in the course of the biosynthesis of Nitraria alkaloids (Section 1.4.3). From the same mixture, a crystalline compound 54 that displayed a tricyclic structure with a spiranic quaternary carbon and contiguous acetal and hemiacetal functions was isolated. This intriguing molecule has a striking analogy with known simple spiroalkaloids such as nitramine also isolated from different species of the Nitraria genus and its plausible mechanism of formation totally parallels the postulated biosynthesis of such natural substances [31]. Diethoxypentanal 55, which is easily available from monoprotection of 51, has been treated in a boiling sodium hydroxide solution to furnish quantitatively compound 56 by aldolization/crotonization as a single (E)-stereoisomer. Deprotection in acidic conditions gave 57, an interesting oxidized analog of tetrahydroanabasine.

Scheme 1.12 Various condensations of glutaraldehyde.

Glutaraldehyde (51) has been widely used for the synthesis of various heterocycles through the formation of dihydropyridine-type intermediates. The most powerful applications are probably the so-called “CN(R,S)”15 method (Scheme 1.13) with the use of the chiral non-racemic N-cyanomethyloxazolidine ring system integrated in a piperidine structure as an ideal way to stabilize dihydropyridine 58 into compound 59 [prepared in a single step from glutaraldehyde 51, (R)-(−)-phenylglycinol (60) and a source of cyanide ions in water]. This strategy, developed by the Husson and Royer groups, permitted the total synthesis of many alkaloids in a diastereoselective manner. Some of them are closely related to biomimetic strategies. This strategy has been extensively reviewed over the years [32]. As, interestingly, naturally occurring piperidine alkaloids bearing α − side chains are either in the (R) or (S) configuration, the possibility of using building blocks such as 59 to modulate the stereochemistry at α or α′ positions constituted a real breakthrough in piperidine total synthesis.

Scheme 1.13 Cyanophenyloxazolopiperidine: a convenient building block.

1.2.3 Biomimetic Access to Pipecolic Acids

1.2.3.1 Pipecolic Acids: Biosynthesis and Importance

L-Pipecolic acid (L-9) was first identified in 1952 as a constituent of leguminous plants [33]. It is now recognized as a universal lysine-derived entity present in plants, animals, and microorganisms [34]. In natural substances, L-9 is a key element in molecules as diverse as swainsonine (61) or castanospermine (62) (small indolizidine alkaloids known for their glycosidase-inhibiting properties, Scheme 1.14) or FK 506/tacrolimus (63) (a polyketide/non-ribosomal peptide hybrid clinically approved as an immunosuppressant). Over the years, many studies have sought to establish the biosynthetic routes to L-9. Different metabolic pathways (with different proposed mechanisms [35]) are involved in the formation of L-9 (Scheme 1.15). Chemically speaking, these basic routes are distinguishable at the loss of the amino group of lysine 3. The reality of immediate precursors, that is, piperideine carboxylic acids 64 (known as P2C) and 65 (P6C), has been demonstrated by many feeding experiments and will not be further developed in the present chapter as many research and review articles are available [33]. The reverse pathways converting L-pipecolic acid (L-9) into (P6C 65) [36] or lysine (3) [37] are also known. D-Pipecolic acid (D-9) was also reported and derives from D-lysine (whereas L-9 can be biosynthesized from both L- and D-lysine (3) [38]) and was found as a constituent of a few natural substances.

Scheme 1.14 Selected example of pipecolic acid derived alkaloids and pipecolic acid containing secondary metabolites.

Scheme 1.15 Biosynthesis of pipecolic acid.

1.2.3.2 Biomimetic Access to Pipecolic Acids

The chemical synthesis of pipecolic acid has been a subject of great interest. Powerful methods of asymmetric piperidine synthesis have been developed toward this aim [39] and have been reviewed [40]. We only outline, in this section, reactions directly involving L-lysine (3) (or protected L-3) to access 9 in a somewhat biomimetic way. In the 1970s, a first conversion of L-lysine (3) into optically active pipecolic acids was disclosed by Yamada and colleagues (Scheme 1.16) [41]. Sodium nitrite–hydrochloric acid was used as a deaminating agent of L-lysine, followed by barium or sodium hydroxide treatment to afford D-pipecolic acid (D-9) with more than 90% optical purity and satisfactory overall yield. Net retention of configuration was explained by the formation of lactonic intermediate 66 followed by halogeno-acid 67. On the other hand, L-lysine could be converted directly into natural L-pipecolic acid starting from ε − tosyl − l − lysine (68) but in very low yield (∼1%) in strong acidic conditions. This work by Yamada and colleagues is not “truly” biomimetic, but is worth mentioning as it converts in a single step the acyclic skeleton of L-3 into the piperidine ring of 9.

Scheme 1.16 Yamada's biomimetic access to pipecolic acids.

In 2004, the fully protected L-lysine 69 was converted into aminal 70 by selective oxidation of the side chain using a Mn(OAc)2/peracetic acid system by the Rossen group (Scheme 1.17) [42]. No epimerization occurred under the buffered oxidation conditions. Treatment under mild acidic conditions gave enamide 71, which could be reduced to L-pipecolate 72. This study constitutes one of the rare examples of biomimetic conversion of a side chain amino group into an aldehyde oxidation state (obtained as the cyclic N,N-acetal 70).

Scheme 1.17 Rossen's biomimetic synthesis of pipecolate derivatives.

But one of the most interesting examples was probably the work disclosed by the Ohtani group (Scheme 1.18). The photocatalytic redox synthesis of pipecolic acid was achieved in a one-step procedure directly from unprotected L-lysine [43]. Several catalytic systems [various TiO2/co-catalyst (Pt, Rh, Pd)] were investigated to define the best conditions in terms of selectivity (oxidation of ε − amino versus α − amino – which influences the final optical purity of pipecolic acid), yields, and rates. The mechanism was proved to proceed via (i) oxidation of L-lysine with positive holes, leading to P2C (64) and P6C (65), depending on the oxidized nitrogen and (ii) reduction of the imines with electron, with both steps taking place at the surface of the catalyst. Titanium oxides were shown to predominantly oxidize the ε − amino group, permitting enantiomeric excess up to 90%. The ins and outs of the multiple combinations of catalysts/co-catalysts were studied; the interested reader is referred to the original article for details. With the recourse to catalysis and the release of ammonia as the only by-product of the reaction, this synthesis is indubitably a green chemistry process and a beautiful achievement.16

Scheme 1.18 Totally biomimetic synthesis of pipecolic acid by photocatalysis.

1.3 Biomimetic Synthesis of Alkaloids Derived from Ornithine and Arginine

1.3.1 Biomimetic Access to the Pyrrolizidine Ring

The pyrrolizidine nucleus consists of two fused pyrrolidine cycles; similarities between both biosyntheses may therefore be expected. These alkaloids are biosynthesized from homospermidine, which comes from putrescine (7) (Scheme 1.19). Oxidative deamination and subsequent formation of a first five-membered cycle (74) through dehydration is followed by an intramolecular Mannich reaction exploiting the enolization capacity of the remaining aldehyde of 75. Biosyntheses of such alkaloids have been reviewed, as well as their structure elucidation, chemistry, and pharmacology [44].

Scheme 1.19 Pyrrolizidine ring biosynthesis.

The direct conversion of an acyclic precursor into a pyrrolizidine-type bicyclic structure was accomplished by the Marson group in 2000 (Scheme 1.20) [45]. Treatment of compound 76 in acidic conditions permitted the deprotection of the masked aldehyde, formation of the Δ1-pyrrolidine, and subsequent formation of bicyclic 77 by an aza-Prins type cyclization. Such a cationic cyclization (radical cyclizations to pyrrolizidine are known) is closely related to biosynthetic pathways and was the first example of a non-enzymic synthesis of the pyrrolizidine ring from an acyclic precursor. The relative configuration of 77, which was the sole diastereomer isolated, was ascertained by X-ray crystallography.

Scheme 1.20 Biomimetic access to the pyrrolizidine ring.

1.3.2 Biomimetic Syntheses of Elaeocarpus Alkaloids

Homologous to intermediate 75 derived from homospermidine and implicated in the biosynthesis of indolizidine alkaloids, intermediate 78 (Scheme 1.21) has been postulated to be at the origin of interesting natural substances. Biomimetically speaking, aldehydic intermediate 78 was prepared in the laboratory by the Gribble group in the 1980s (Scheme 1.22) [46]. Bis-acetal 79 was prepared in three steps from chloroacetal 80 in 47% overall yield. It constitutes a stable protected equivalent of intermediate 81, which under acidic conditions can be deprotected to give in situ78. In fact, non-isolated 81 when buffered at pH 5.5 presumably generates pyrrolinium aldehyde 78. This latter was reduced to pyrrolidine 82 or more interestingly trapped by various nucleophiles in a biomimetic manner, thus giving a very interesting unified access to a group of alkaloids isolated from different species of Elaeocarpus and Peripentadiena (commonly known as Elaeocarpus alkaloids [47], see examples on Scheme 1.21, 83–86). Most of them share a common indolizidine backbone functionalized at positions 7 and 8. Onaka, in the early 1970s, suggested intermediate 78 as the universal precursor of these natural substances [48]. The isolation some years after of alkaloids such as peripentadenine (86) [49] ascertained a spermidine (17) metabolism pathway. Although numerous syntheses of Elaeocarpus alkaloids have been reported [47], we deliberately delineate herein syntheses based on the in situ generation of intermediate 78.

Scheme 1.21Elaeocarpus alkaloids.

Scheme 1.22Elaeocarpus alkaloids: biomimetic synthesis.

Trapping of intermediate 78 with tryptamine gave a straightforward isohypsic synthesis of (±)-elaeocarpidine (85) in a stereoselective cascade of reaction from acetal 79 by just adjusting the pH of the solutions (Scheme 1.22) [46]. The elaeocarpidine aminal function was then reduced with sodium cyanoborohydride to give tarennine (87). In turn, trapping of intermediate 78 with β − keto ester 88, thus engaged in a tandem Mannich/aldol condensation, gave 89 as a mixture of two major diastereomers (axial and equatorial hydroxyl at C7) in 62% overall yield. Compound 89 appeared to be a common intermediate for the synthesis of both (±)-elaeokanine A (90) and C (84). Decarboalkoxylation in strong acidic conditions was accompanied with dehydration at position 7 and gave rise to (±)-elaeokanine A (90) in 91% yield. Milder conditions were necessary to carry out the synthesis of (±)-elaeokanine C (84). The conditions were carefully studied by the authors, who finally chose catalytic transfer hydrogenation with ammonium formate and palladium in methanol to afford the desired reaction. Although some degree of selectivity was expected, the outcome of the reaction clearly showed a preference for the wrong isomer, with a predominance of (±)-7-epi-elaeokanine C (91) over (±)-elaeokanine C (84) despite a good overall yield of 60% from bis-acetal 79. This experiment and its outcome in terms of stereochemistry can be rationalized when considering transition state 92 in which an equatorial hydroxyl is to be expected. This supposition was compared to a similar case studied by Tufariello and Ali [50] a few years before with the intramolecular kinetic aldol reaction of a ketone instead of a β − ketoester. In the latter, a stereocontrol, totally in favor of the axial configuration, could have been governed by transition state 93. Returning to a biosynthesis hypothesis and taking into account these findings, one can suggest that should such a pathway occur in Nature the decarboxylation step has to be prior to the aldol reaction.

Starting from readily accessible acetal 79, it is worth noting how simple starting materials (tryptamine, ketoesters) and reaction conditions (aqueous solutions at various pH) enabled the design of a divergent pathway to Elaeocarpus alkaloids following, and thereby reinforcing, previously proposed biosynthetic hypotheses.

Concomitant with Gribble's work, the Hortmann group used α − cyanopyrrolidine 94 as a surrogate of 79 (Scheme 1.23) [51]. It was prepared by oxidative cyanation of the corresponding pyrrolidine 95 with chlorine dioxide (as an alternative to classical mercury acetate oxidation or modified Polonovski reaction). Compound 94 was used in a total synthesis of (±)-elaeocarpidine (85). Lactam 96 was prepared by Lévy and colleagues for the synthesis of 85 [52]. It was engaged in a reductive Pictet–Spengler reaction under catalytic hydrogenation conditions. The recourse to trivalent functional groups (lactam of 96) where divalent ones (imine) are needed places this former approach at the borderline of biomimetic synthesis.

Scheme 1.23Elaeocarpus alkaloids: alternative biomimetic synthesis.

The Elaeocarpus alkaloid group gained constant interest with the discovery of new structures (see examples 97–99 in Figure 1.3) along with interesting biological properties (such as selective γ − opioid receptor affinity for grandisine-type alkaloids) [53]. These complex structures also stimulated state of the art total syntheses [54].

Figure 1.3 Other Elaeocarpus alkaloids.

1.3.3 Biomimetic Synthesis of Fissoldhimine

Fissoldhimine (100) was isolated in 1994 by Sankawa et al. [55] from fresh stems of Fissistigma oldhamii (Annonaceae), a shrub mainly found in Southern China and Taiwan (Scheme 1.24). Its structure was unambiguously confirmed by X-ray analysis. Since n-butanol was used to extract this basic molecule from an alkaline solution, it was suggested that fissoldhimine was an artifact resulting from the aminoacetalization of compound 101 (which may therefore be the “true” natural product) with a molecule of n-butanal presumably present in n-butanol.17 The authors proposed a biosynthetic pathway (Scheme 1.25) to fissoldhimine (100/101) from two molecules of cyclic enamine 29 that came from L-ornithine via a dimerization (see above). R. A. Batey and colleagues revisited the hypotheses in 2007 when disclosing the first biomimetic investigations toward fissoldhimine [56].

Scheme 1.24 Fissoldhimine: possible structures.

Scheme 1.25 Biosynthetic hypotheses.

Benzyl- or para-methoxybenzyl-protected urea 103 (Scheme 1.26) was used as biomimetic equivalent of biosynthetic intermediate 102 postulated in Scheme 1.25. The best conditions, the authors found, for the formation of the desired exo-dimer 104b were the use of trifluoroacetic anhydride in THF (endo/exo: 2 : 1 ratio) but separation of the two diastereomers was impossible. In addition, final deprotection of the urea nitrogens was also problematic (removal of the benzyl group was unsuccessful and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)-mediated deprotection of PMB groups resulted in the deprotection of only one of the nitrogens). Despite obtaining an endo relative stereochemistry that contrasts with the exo stereochemistry of natural fissoldhimine 100/101