From biosynthesis to total synthesis strategies and tactics for natural products

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From Biosynthesis to Total Synthesis

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From Biosynthesis to
Total Synthesis
Strategies and Tactics for Natural Products
Edited by

Alexandros L. Zografos
Aristotle University of Thessaloniki, Greece

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Names: Zografos, Alexandros L., editor.
Title: From biosynthesis to total synthesis : strategies and tactics for natural products / edited by Alexandros L. Zografos.
Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2016] | Includes bibliographical references and index.
Identifiers: LCCN 2015037375 (print) | LCCN 2015047240 (ebook) | ISBN 9781118751732 (cloth) | ISBN 9781118753569 (Adobe PDF) |
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10 9 8 7 6 5 4 3 2 1

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Dedicated to my mother, father and wife

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Contents

LIST OF CONTRIBUTORS

xiii

PREFACExv
1 From Biosyntheses to Total Syntheses: An Introduction

1

Bastien Nay and Xu‐Wen Li

1.1 From Primary to Secondary Metabolism: the Key Building Blocks,  1
1.1.1 Definitions, 1
1.1.2 Energy Supply and Carbon Storing at the Early Stage
of Metabolisms,  1
1.1.3 Glucose as a Starting Material Toward Key Building Blocks
of the Secondary Metabolism,  1
1.1.4 Reactions Involved in the Construction of Secondary Metabolites,  3
1.1.5 Secondary Metabolisms,  4
1.2 From Biosynthesis to Total Synthesis: Strategies Toward the Natural
Product Chemical Space,  10
1.2.1The Chemical Space of Natural Products,  10
1.2.2The Biosynthetic Pathways as an Inspiration
for Synthetic Challenges,  11
1.2.3The Science of Total Synthesis,  14

1.2.4Conclusion: a Journey in the Future of Total Synthesis,  16
References, 16
SECTION I  ACETATE BIOSYNTHETIC PATHWAY

19

2Polyketides

21

Franỗoise Schaefers, Tobias A. M. Gulder, Cyril Bressy, Michael Smietana,
EricaBenedetti,Stellios Arseniyadis, Markus Kalesse, and Martin Cordes

2.1 Polyketide Biosynthesis,  21
2.1.1 Introduction, 21
2.1.2Assembly of Acetate/Malonate‐Derived Metabolites,  23
2.1.3 Classification of Polyketide Biosynthetic Machineries,  23
2.1.4 Conclusion, 39
References, 40

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Contents

2.2 Synthesis of Polyketides,  44
2.2.1Asymmetric Alkylation Reactions,  44
2.2.2Applications of Asymmetric Alkylation Reactions in Total Synthesis

of Polyketides and Macrolides,  60
References, 83
2.3 Synthesis of Polyketides‐Focus on Macrolides,  87
2.3.1 Introduction, 87
2.3.2 Stereoselective Synthesis of 1,3‐Diols: Asymmetric Aldol Reactions,  88
2.3.3 Stereoselective Synthesis of 1,3‐Diols: Asymmetric Reductions,  106
2.3.4Application of Stereoselective Synthesis of 1,3‐Diols in
the Total Synthesis of Macrolides,  117
2.3.5 Conclusion, 126
References, 126
3 Fatty Acids and their Derivatives

130

Anders Vik and Trond Vidar Hansen

3.1 Introduction, 130
3.2 Biosynthesis, 130
3.2.1 Fatty Acids and Lipids,  130
3.2.2 Polyunsaturated Fatty Acids,  134
3.2.3 Mediated Oxidations of ω‐3 and ω‐6 Polyunsaturated
Fatty Acids,  135
3.3 Synthesis of ω‐3 and ω‐6 All‐Z Polyunsaturated Fatty Acids,  140
3.3.1 Synthesis of Polyunsaturated Fatty Acids by the Wittig
Reaction or by the Polyyne Semihydrogenation,  140
3.3.2 Synthesis of Polyunsaturated Fatty Acids via
Cross Coupling Reactions,  143
3.4Applications in Total Synthesis of Polyunsaturated Fatty Acids,  145
3.4.1 Palladium‐Catalyzed Cross Coupling Reactions,  145
3.4.2 Biomimetic Transformations of Polyunsaturated Fatty Acids,  149

3.4.3 Landmark Total Syntheses,  153
3.4.4 Synthesis of Leukotriene B5, 158
3.5 Conclusion, 160
Acknowledgments, 160
References, 160
4Polyethers

162

Youwei Xie and Paul E. Floreancig

4.1 Introduction, 162
4.2 Biosynthesis, 162
4.2.1 Ionophore Antibiotics,  162
4.2.2 Marine Ladder Toxins,  165
4.2.3Annonaceous Acetogenins and Terpene Polyethers,  165
4.3 Epoxide Reactivity and Stereoselective Synthesis,  166
4.3.1 Regiocontrol in Epoxide‐Opening Reactions,  166
4.3.2 Stereoselective Epoxide Synthesis,  172
4.4Applications to Total Synthesis,  176
4.4.1Acid‐Mediated Transformations,  176
4.4.2 Cascades via Epoxonium Ion Formation,  179
4.4.3 Cyclizations under Basic Conditions,  181
4.4.4 Cyclization in Water,  182
4.5 Conclusions, 183
References, 184

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Contents

SECTION II  MEVALONATE BIOSYNTHETIC PATHWAY

187

5 From Acetate to Mevalonate and Deoxyxylulose Phosphate
Biosynthetic Pathways: an Introduction to Terpenoids

189

Alexandros L. Zografos and Elissavet E. Anagnostaki

5.1 Introduction, 189
5.2 Mevalonic Acid Pathway,  191
5.3 Mevalonate‐Independent Pathway,  192
5.4 Conclusion, 194
References, 194
6 Monoterpenes and Iridoids

196

Mario Waser and Uwe Rinner

6.1 Introduction, 196
6.2 Biosynthesis, 196
6.2.1Acyclic Monoterpenes,  197
6.2.2 Cyclic Monoterpenes,  197
6.2.3 Iridoids, 200
6.2.4 Irregular Monoterpenes,  202

6.3Asymmetric Organocatalysis,  203
6.3.1 Introduction and Historical Background,  204
6.3.2 Enamine, Iminium, and Singly Occupied Molecular
Orbital Activation,  207
6.3.3 Chiral (Brønsted) Acids and H‐Bonding Donors,  213
6.3.4 Chiral Brønsted/Lewis Bases and Nucleophilic Catalysis,  218
6.3.5Asymmetric Phase‐Transfer Catalysis,  220
6.4Organocatalysis in the Total Synthesis of Iridoids and
Monoterpenoid Indole Alkaloids,  225
6.4.1 (+)‐Geniposide and 7‐Deoxyloganin,  226
6.4.2 (–)‐Brasoside and (–)‐Littoralisone,  227
6.4.3 (+)‐Mitsugashiwalactone, 229
6.4.4Alstoscholarine, 229
6.4.5 (+)‐Aspidospermidine and (+)‐Vincadifformine,  230
6.4.6 (+)‐Yohimbine, 230
6.5 Conclusion, 231
References, 231
7Sesquiterpenes

236

Alexandros L. Zografos and Elissavet E. Anagnostaki

7.1 Biosynthesis, 236
7.2 Cycloisomerization Reactions in Organic Synthesis,  244
7.2.1 Enyne Cycloisomerization,  245
7.2.2 Diene Cycloisomerization,  257
7.3Application of Cycloisomerizations in the Total Synthesis of
Sesquiterpenoids, 266
7.3.1 Picrotoxane Sesquiterpenes,  266

7.3.2Aromadendrane Sesquiterpenes: Epiglobulol,  267
7.3.3 Cubebol–Cubebenes Sesquiterpenes,  267
7.3.4 Ventricos‐7(13)‐ene, 270
7.3.5 Englerins, 271
7.3.6 Echinopines, 271
7.3.7 Cyperolone, 273

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Contents

7.3.8 Diverse Sesquiterpenoids,  276
7.4 Conclusion, 276
References, 276
8Diterpenes

279

Louis Barriault

8.1 Introduction, 279
8.2 Biosynthesis of Diterpenes Based on Cationic Cyclizations,
1,2‐Shifts, and Transannular Processes,  279
8.3 Pericyclic Reactions and their Application in the Synthesis
of Selected Diterpenoids, 284

8.3.1 Diels–Alder Reaction and Its Application in the Total
Synthesis of Diterpenes,  284
8.3.2 Cascade Pericyclic Reactions and their Application in the Total
Synthesis of Diterpenes,  291
8.4 Conclusion, 293
References, 294
9 Higher Terpenes and Steroids

296

Kazuaki Ishihara

9.1 Introduction, 296
9.2 Biosynthesis, 296
9.3 Cascade Polyene Cyclizations,  303
9.3.1 Diastereoselective Polyene Cyclizations,  303
9.3.2 “Chiral proton (H+)”‐Induced Polyene Cyclizations,  304
9.3.3 “Chiral Metal Ion”‐Induced Polyene Cyclizations,  308
9.3.4 “Chiral Halonium Ion (X+)”‐Induced Polyene Cyclizations,  313
9.3.5 “Chiral Carbocation”‐Induced Polyene Cyclizations,  319
9.3.6 Stereoselective Cyclizations of Homo(polyprenyl)arene
Analogs, 319
9.4 Biomimetic Total Synthesis of Terpenes and Steroids through
Polyene Cyclization, 319
9.5 Conclusion, 328
References, 328
SECTION III  SHIKIMIC ACID BIOSYNTHETIC PATHWAY

331

10 Lignans, Lignins, and Resveratrols

333

Yu Peng

10.1 Biosynthesis, 333
10.1.1 Primary Metabolism of Shikimic Acid and Aromatic
Amino Acids,  333
10.1.2 Lignans and Lignin,  335
10.2Auxiliary‐Assisted C(sp3)–H Arylation Reactions in
Organic Synthesis,  336
10.3 Friedel–Crafts Reactions in Organic Synthesis,  344
10.4Total Synthesis of Lignans by C(sp3)─H Arylation Reactions,  353
10.5Total Synthesis of Lignans and Polymeric Resveratrol by
Friedel–Crafts Reactions,  357
10.6 Conclusion, 375
References, 375

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SECTION IV MIXED BIOSYNTHETIC PATHWAYS–
THE STORY OF ALKALOIDS

381

11 Ornithine and Lysine Alkaloids

383

Sebastian Brauch, Wouter S. Veldmate, and Floris P. J. T. Rutjes

11.1 Biosynthesis of l‐Ornithine and l‐Lysine Alkaloids,  383
11.1.1 Biosynthetic Formation of Alkaloids
Derived from l‐Ornithine, 383
11.1.2 Biosynthetic Formation of Alkaloids
Derived from l‐Lysine, 388
11.2The Asymmetric Mannich Reaction in Organic Synthesis,  392
11.2.1 Chiral Amines as Catalysts in Asymmetric Mannich Reactions,  394
11.2.2 Chiral Brønsted Bases as Catalysts in Asymmetric
Mannich Reactions,  398
11.2.3 Chiral Brønsted Acids as Catalysts in Asymmetric
Mannich Reactions,  404
11.2.4Organometallic Catalysts in Asymmetric Mannich Reactions,  408
11.2.5 Biocatalytic Asymmetric Mannich Reactions,  413
11.3 Mannich and Related Reactions in the Total Synthesis of
l‐Lysine‐ and l‐Ornithine‐Derived Alkaloids,  414
11.4 Conclusion, 426
References, 427
12 Tyrosine Alkaloids

431

Uwe Rinner and Mario Waser

12.1 Introduction, 431
12.2 Biosynthesis of Tyrosine‐Derived Alkaloids,  431

12.2.1 Phenylethylamines, 431
12.2.2 Simple Tetrahydroisoquinoline Alkaloids,  433
12.2.3 Modified Benzyltetrahydroisoquinoline Alkaloids,  433
12.2.4 Phenethylisoquinoline Alkaloids,  436
12.2.5Amaryllidaceae Alkaloids,  438
12.2.6 Biosynthetic Overview of Tyrosine‐Derived Alkaloids,  442
12.3Aryl–Aryl Coupling Reactions,  442
12.3.1 Copper‐Mediated Aryl–Aryl Bond Forming Reactions,  443
12.3.2 Nickel‐Mediated Aryl–Aryl Bond Forming Reactions,  446
12.3.3 Palladium‐Mediated Aryl–Aryl Bond Forming Reactions,  447
12.3.4Transition Metal‐Catalyzed Couplings of Nonactivated
Aryl Compounds,  450
12.4 Synthesis of Tyrosine‐Derived Alkaloids,  456
12.4.1 Synthesis of Modified Benzyltetrahydroisoquinoline Alkaloids,  456
12.4.2 Synthesis of Phenethylisoquinoline Alkaloids,  460
12.4.3 Synthesis of Amaryllidaceae Alkaloids,  462
12.5 Conclusion, 468
References, 469
13 Histidine and Histidine‐Like Alkaloids

473

Ian S. Young

13.1 Introduction, 473
13.2 Biosynthesis, 473
13.3Atom Economy and Protecting‐Group‐Free Chemistry,  480

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Contents

13.4 Challenging the Boundaries of Synthesis: Pias, 488
13.5 Conclusion, 497
References, 499
14 Anthranilic Acid–Tryptophan Alkaloids

502

Zhen‐Yu Tang

14.1 Biosynthesis, 502
14.2 Divergent Synthesis–Collective Total Synthesis,  508
14.3 Collective Total Synthesis of Tryptophan‐Derived Alkaloids,  510
14.3.1 Monoterpene Indole Alkaloids,  510
14.3.2 Bisindole Alkaloids,  512
References, 517
15 Future Directions of Modern Organic Synthesis

519

Jakob Pletz and Rolf Breinbauer

15.1 Introduction, 519
15.2 Enzymes in Organic Synthesis: Merging Total

Synthesis with Biosynthesis,  520
15.3 Engineered Biosynthesis,  526
15.4 Diversity‐Oriented Synthesis, Biology‐Oriented Synthesis,
and Diverted Total Synthesis,  533
15.4.1 Diversity‐oriented Synthesis,  535
15.4.2 Biology‐oriented Synthesis,  536
15.4.3 Diverted Total Synthesis,  539
15.5 Conclusion, 541
References, 545
INDEX548

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List of Contributors

Elissavet E. Anagnostaki, Department of Chemistry,
Laboratory of Organic Chemistry, Aristotle University
of  Thessaloniki, Thessaloniki, Greece and Research
and  Development Department, Pharmathen S.A.,
Thessaloniki, Greece
Stellios Arseniyadis, School of Biological and Chemical
Sciences, Queen Mary University of London, London,
United Kingdom
Louis Barriault,  Department of Chemistry, University of
Ottawa, Ottawa, Ontario, Canada
Erica Benedetti, Laboratoire de Chimie et Biochimie
et  Pharmacologiques et Toxicologiques, CNRSUniversité Paris Descartes Faculté des Sciences
Fondamentales et Biomédicales, Paris, France
Sebastian Brauch,  Institute for Molecules and Materials,

Radboud University Nijmegen, Nijmegen, The
Netherlands
Institute of Organic
Rolf Breinbauer, 
Technische Universität Graz, Graz, Austria

Chemistry,

Cyril Bressy,  Aix Marseille Université, Centrale Marseille,
CNRS, Marseille, France
Martin Cordes,  Institute for Organic Chemistry and Center
of Biomolecular Drug Research (BMWZ), Leibniz
Universität Hannover, Hannover, Germany and Helmholtz
Center for Infection Research (HZI), Hannover,
Germany
Paul E. Floreancig, Department of Chemistry, Chevron
Science Center, University of Pittsburgh, Pittsburgh,
PA, USA

Tobias A. M. Gulder,  Department of Chemistry and Center
for Integrated Protein Science Munich (CIPSM),
Biosystems Chemistry, Technische Universität München,
Munich, Germany
Trond Vidar Hansen,  School of Pharmacy, University of
Oslo, Oslo, Norway
Kazuaki Ishihara,  Department of Biotechnology, Graduate
School of Engineering, Nagoya University, Nagoya, Japan
Markus Kalesse, Institute for Organic Chemistry and
Center of Biomolecular Drug Research (BMWZ),
Leibniz Universität Hannover, Hannover, Germany

and Helmholtz Center for Infection Research (HZI),
Hannover, Germany
Xu‐Wen Li,  Shanghai Institute of Material Medica, Chinese
Academy of Science, Shanghai, China
Bastien Nay, Muséum National d’Histoire Naturelle and
CNRS (UMR 7245), Unité Molécules de Communication
et Adaptation des Microorganismes, Paris, France
Yu Peng, State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou, China
Jakob Pletz, Institute of Organic Chemistry, Technische
Universität Graz, Graz, Austria
Uwe Rinner, Institute of Organic Chemistry, Johannes
Kepler University Linz, Linz, Austria and Department
of Chemistry, College of Science, Sultan Qaboos
University, Muscat, Oman
Floris P. J. T. Rutjes,  Institute for Molecules and Materials,
Radboud University Nijmegen, Nijmegen, The Netherlands

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xiv

List of Contributors

Franỗoise Schaefers, Department of Chemistry and Center
for Integrated Protein Science Munich (CIPSM),
Biosystems Chemistry, Technische Universität München,
Munich, Germany
Michael Smietana,  Institut des Biomolécules Max Mousseron,

CNRS, Université de Montpellier, ENSCM, France

Anders Vik,  School of Pharmacy, University of Oslo, Oslo,
Norway
Mario Waser, Institute of Organic Chemistry, Johannes
Kepler University Linz, Linz, Austria
Youwei Xie, Max‐Planck‐Institut für Kohlenforschung,
Mülheim, Germany

Zhen‐Yu Tang,  Department of Pharmaceutical Engineering,
College of Chemistry and Chemical Engineering, Central
South University, Changsha, China

Ian S. Young,  Bristol‐Myers Squibb Company, Chemical
Development, New Brunswick, NJ, USA

Wouter S. Veldmate, Institute for Molecules and
Materials,  Radboud University Nijmegen, Nijmegen,
The Netherlands

Alexandros L. Zografos, Department of Chemistry,
Laboratory of Organic Chemistry, Aristotle University of
Thessaloniki, Thessaloniki, Greece

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Preface

There is pleasure in the pathless woods,

there is rapture in the lonely shore,
there is society where none intrudes,
by the deep sea, and music in its roar;
I love not Man the less, but Nature more.
Lord Byron

The first time I came across with the idea of editing a book
that merges selected chapters of biosynthesis and total
synthesis was when I was teaching postgraduate courses
of  natural product synthesis at Aristotle University of
Thessaloniki. This period, I realized that the best way to
teach youngsters synthesis was to start from the very origin
of inspiration, nature and its tools: biosynthesis.
Over the last decades, biosynthesis is filling our gaps of
understanding the complex mechanisms of nature and provides useful sources of inspiration not only in the way natural
products can be synthesized but also by directing synthetic
chemists in developing atom‐economical, efficient synthetic
methods. Several are the examples that mimic biosynthetic
guidelines, from modern iterative alkylations and aldol
reactions to C─H oxidations that compile nowadays the
modern toolbox of organic synthesis.
The handed book is constructed in the logic of presenting
the parallel development of biosynthesis and organic methodology and how these can be applied in efficient syntheses
of natural products. The book is divided into four sections
each representing the four major biosynthetic pathways of
natural products, namely, acetate, mevalonate, shikimate
biosynthetic pathways, and the mixed biosynthetic pathways

of alkaloids. These sections are divided into chapters that
represent selected classes of natural products, for example,

lipids, sesquiterpenoids, lignans, etc. Each of these chapters
is further divided into three distinct subchapters: (a) biosynthesis, (b) methodological section, and (c) application of
the  described methodology in the total synthesis of the
described family of natural products. By this way, the readers
can be focused in the direct comparison between biosyntheses and the developed methodologies to construct the
crucial for each class of natural product carbon bonds.
Although the book, as it develops, is focused on presenting
the power of biosynthesis and how this power can be applied
in providing inspiration for the efficient synthesis of natural
products, it was not the authors will to present only biomimetic total syntheses but rather to exploit the modern
synthetic methodologies and recognize their disabilities
for further improvement.
Of course this book will not have been realized without
the excellent work of renowned scientists worldwide
working either in the field of biosynthesis or total synthesis,
who collected the existing knowledge on biosynthesis,
­analyzed the existing modern methodologies, and presented
a  bouquet of selected total syntheses. Throughout our

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xvi

Preface

endeavor to complete this book, I learned many things from
their expertise but I also realized that only with tight collaborations you can build long‐lasting friendships. I would like
to thank them all once again for their trust and effort to
complete this book. We all hope that the current work will

contribute to a better understanding of the current status of

organic chemistry and to the discovery of novel strategies
and tactics for the synthesis of natural products.

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Alexandros L. Zografos
September 2015
Thessaloniki, Greece


1
From Biosyntheses to Total Syntheses:
An Introduction
Bastien Nay1 and Xu‐Wen Li2
 Muséum National d’Histoire Naturelle and CNRS (UMR 7245), Unité Molécules de Communication et Adaptation des
Microorganismes, Paris, France
2
 Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, China
1

1.1  FROM PRIMARY TO SECONDARY
METABOLISM: THE KEY BUILDING BLOCKS
1.1.1 Definitions
The primary and secondary metabolisms are traditionally
distinguished by their distribution and utility in the living
organism network. Primary metabolites include carbohy­
drates, lipids, nucleic acids, and proteins (or their amino
acid constituents) and are shared by all living organisms on

Earth. They are transformed by common pathways, which
are studied by biochemistry (Fig. 1.1). Secondary metabolites are structurally diverse compounds usually produced
by a limited number of organisms, which synthesize them
for a special purpose, like defense or signaling, through
specific biosynthetic pathways. They are studied by natural
product chemistry. This distinction is not always so obvious
and some compounds can be studied in the context of both
primary and secondary metabolisms. This is especially
true nowadays with the use of genetic and biomolecular
tools, which tend to make natural product sciences more
and more integrative. However, an important point to
remember is that the primary metabolism furnishes key
building blocks to the secondary metabolism. It would be
difficult to describe in detail the full biosynthetic path­
ways in this section. We tried to organize the discussion as
a vade mecum, synthetically gathering information from
extremely useful sources, which will be cited at the end of
this chapter.

1.1.2  Energy Supply and Carbon Storing at the
Early Stage of Metabolisms
The sunlight is essential to life except in some part of the
deep oceans. It provides energy for plant photosynthesis that
splits molecules of water into protons and electrons and
releases O2 (Scheme 1.1). A proton gradient inside the plant
chloroplasts then drags a transmembrane ATP synthase com­
plex that produces adenosine triphosphate (ATP) while elec­
trons released from water are transferred to the coenzyme
reducer nicotinamide adenine dinucleotide phosphate
hydride (NADPH). A major function of chloroplasts is to fix

CO2 as a combination to ribulose‐1,5‐bisphosphate (RuBP)
performed by RuBP carboxylase (rubisco), forming an
instable “C6” β‐ketoacid. This is cleaved into two molecules
of 3‐phosphoglycerate (3‐PGA), which is then reduced into
3‐phosphoglyceraldehyde (3‐PGAL, a “C3” triose phos­
phate) during the Calvin cycle. This is one of the major
metabolites in the biosynthesis of carbohydrates like glucose
and a biochemical mean for storing and retaining carbon
atoms in the living cells.
1.1.3  Glucose as a Starting Material Toward Key
Building Blocks of the Secondary Metabolism
Glucose‐6‐phosphate arises from the phosphorylation of
glucose. It is the starting material of glycolysis, an important
process of the primary metabolism, which consists in
eight  enzymatic reactions leading to pyruvic acid (PA)

From Biosynthesis to Total Synthesis: Strategies and Tactics for Natural Products, First Edition. Edited by Alexandros L. Zografos.
© 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc.

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2

From Biosyntheses to Total Syntheses: An Introduction

Biosynthetic
pathways

The field of

biochemistry

The field of
natural product
chemistry

Primary metabolism

Secondary metabolism

Essential to
living organisms

Essential to the
producer organisms
under particular
conditions

Biological effects
(defense, signaling)

Nucleic acids (DNA,
RNA), carbohydrates,
lipids, amino acids,
peptides, and proteins

Alkaloids, terpenes,
polyketides,
polyphenols, and
their heterosidic form

Main compound
classes

Figure 1.1  Primary versus secondary metabolisms.

(a) Light dependent process
H+ and O2

H2O

hν

Thylakoid
compartment

H+ (gradient)

PS-II
e–

Thylakoid
membrane

NADP reductase
e–

PS-I

NADPH,H+

NADP+
H+

Chloroplast
stroma

ATP synthase
ADP + Pi

H+

ATP

(b) Light independent process
CH2OPO32–
O
OH

Rubisco

HO

2–

CH2OPO3
RuBP

CO2

HO2C

HO
HO

CH2OPO32–

CO2H
HO

O

CH2OPO32– ADP
2–

CH2OPO3
Unstable β-ketoacid

CO2PO32– NADPH,H+

ATP

3-PGA

HO

CHO
HO

CH2OPO32– NADP+
1,3-diPGA

CH2OPO32–
3-PGAL

(Calvin cycle)

trioses, tetroses, pentoses, hexoses (e.g., glucose), heptoses

Chloroplast
stroma
Cytosol

Scheme 1.1  The photosynthetic machinery (PS‐I and PS‐II, photosystems I and II).

(Scheme  1.2). Important intermediates for the secondary
metabolism are produced during glycolysis. Glucose,
glucose‐6‐phosphate, and fructose‐6‐phosphate can be
­converted to other hexoses and pentoses that can be oligo­
merized and enter in the composition of heterosides.
Additionally, fructose‐6‐phosphate connects the pentose

phosphate pathway, leading to erythrose‐4‐phosphate toward
shikimic acid, which is a key metabolite in the biosynthesis
of aromatic amino acids (phenylalanine, tyrosine, or C6C3
units) and C6C1 phenolic compounds. The next important
intermediate in glycolysis is 3‐PGAL, which can be redi­
rected toward methylerythritol‐4‐phosphate (MEP) in the

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FROM PRIMARY TO SECONDARY METABOLISM: THE KEY BUILDING BLOCKS
Alkaloids
C6C2N

Alkaloids

Phenolics
C6C3

CO2H C6C1
CO2H

TYR
PHE

HO

(Indole)C2N

NH2

OH

TRP

CYS

GLY

MET

OH
HO

SER

CH2OPO32–
Erythrose-4-phosphate
HOH2C

Glucose6-phosphate

HO

ORN

ARG

ASP

GLU

PRO

CO2H
2-Oxoglutaric
acid
CO2H

Amino

acids
Peptides,
proteins

VAL, ALA, ILE, LEU

O

CHO

OH

THR LYS

Alkaloids

CO2H
O
Oxaloacetic O
acid
“CH3”
HO2C Krebs
cycle
(citric
acid)

OHC

Glycolysis

C4N

C1

OH
Shikimic acid
Pentose
phosphate
pathway

C5N

Alkaloids

3

HO

HO

CH2OPO32–
Fructose-6-phosphate

CH2OPO32–
3-PGAL

HO

CO2H

OPO32–

CH2OPO32–
3-PGA

CO2H

CO2H
O

C2
O

PA

PEP

SCoA
AcCoA

Polyketides

3x
HOH2C
HO

OH

Chloroplasts

CH2OPO32–
MEP

C5
3–

IPP
C10, C20, and C40 terpenes

HO2C

Cytosol

OP2O6

Chloroplasts

3–

OP2O6
DMAPP
Cytosol

OH
CH2OH
MVA

C15 and C30 terpenes

Scheme 1.2  The building block chart, involving glycolysis, and the Krebs cycle.

chloroplast. MEP is a starting block in the biosynthesis of
terpenes through C5 isoprene units (isopentenyl diphosphate
(IPP) and dimethylallyl diphosphate (DMAPP)), especially
those in C10, C20, and C40 terpenes. 3‐PGA is a precursor of
serine and other amino acids, while phosphoenolpyruvate
(PEP), the precursor of PA, is also an intermediate toward
the previously mentioned shikimic acid. Lastly, PA is not
only a precursor of the fundamental “C2” acetyl coenzyme A
(AcCoA) unit but also an intermediate toward aliphatic
amino acids and MEP.
AcCoA is the building block of fatty acids, polyketides,
and mevalonic acid (MVA), a cytosolic precursor of the
C5 isoprene units for the biosynthesis of terpenes in the
C15 and C30 series (mind it is different from the MEP
pathway, in product, and in cell location). Finally, AcCoA
enters the citric acid or Krebs cycle, which leads to several
­precursors of amino acids. These are oxaloacetic acid,
precursor of aspartic acid through transamination (thus
toward lysine as a nitrogenated C5N linear unit and methi­
onine as a methyl supplier), and 2‐oxoglutaric acid, pre­
cursor of glutamic acid (and subsequent derivatives such
as ornithine as a nitrogenated C4N linear unit). All these
amino acids are key precursors in the biosynthesis of
many alkaloids.

1.1.4  Reactions Involved in the Construction
of Secondary Metabolites
Most reactions occurring in the living cells are performed by
specialized enzymes, which have been classified in an inter­

national nomenclature defined by an enzyme commission
(EC) number. There are six classes of enzymes depending on
the biochemical reaction they catalyze: EC‐1, oxidoreduc­
tases (catalyzing oxidoreduction reactions); EC‐2, transfer­
ases (catalyzing the transfer of functional groups); EC‐3,
hydrolases (catalyzing hydrolysis); EC‐4, lyases (breaking
bonds through another process than hydrolysis or oxidation,
leading to a new double bond or a new cycle); EC‐5, isomer­
ases (catalyzing the isomerization of a molecule); and EC‐6,
ligases (forming a covalent bond between two molecules).
Many subclasses of these enzymes have been described,
depending on the type of atoms and functional groups
involved in the reaction and, if any, on the cofactor used in
this reaction. For example, several cofactors can be used by
dehydrogenases like NAD(P)/NAD(P)H, FAD/FADH2, or
FMN/FMNH2. For a description of this classification, the
reader can refer to specialized Internet websites like
ExplorEnz [1]. What is important to realize is that most
enzymes are substrate specific and have been selected during

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4

From Biosyntheses to Total Syntheses: An Introduction

(a)

Construction

reactions

Building
blocks

(b)

Natural product
frameworks

Decoration reaction
(functionalization)

Natural
products

3×

OP2O63– P450 P450 P450
IPP
and electrophilic
cyclizations

OP2O63–
DMAPP

P450

Oxidative
auxiliary

enzymes
P450

H
?

H

P450
Taxadiene

?

HO

HO

O OH

O
H
OAc
OH OBz
10-Deacetylbaccatin III

Scheme 1.3  (a) From building blocks to natural products and (b) the example of 10‐deacetylbaccatin III.

evolution to perform specific transformations, making
natural products with often and yet unknown functions.
Secondary metabolites arise from specific biosynthetic

pathways, which use the previously defined building blocks.
The bunch of organic reactions involved in these biosyn­
theses allows the construction of natural product frame­
works, which are finally diversified through “decoration”
steps (Scheme 1.3). It is not the purpose of this introductive
chapter to describe in detail all biosynthetic pathways and
the reader can refer to excellent books and articles, which
have been published elsewhere [2, 3].
The reactions involved in the construction of natural
product skeletons will be described later for representative
classes of compounds. The identification of the building
block footprint in the natural product skeleton will be
emphasized as much as possible, sometimes referring to
biogenetic speculations [4]. After the framework
construction, the decoration steps will involve as diverse
reactions as aliphatic C─H oxidations (e.g., involving a
cytochrome P450 oxygenase) occasionally triggering a
rearrangement, heteroatom alkylations (e.g., methylation
by  S‐adenosylmethionine) or allylation (by DMAPP),
esterifications, heteroatom or C‐glycosylations (leading to
heterosides), radical couplings (especially for phenols),
alcohol oxidations or ketone r­eductions, amine/ketone
transaminations, alkene dihydroxylations or epoxidations,
oxidative halogenations, Baeyer–Villiger oxidations, and
further oxygenation steps. At the end of the biosynthesis,
such transformations may totally hide the primary building
block origin of natural products.
1.1.5  Secondary Metabolisms
1.1.5.1 Polyketides  Polyketides (or polyacetates) are
issued from the oligomerization of C2 acetate units performed

by polyketide synthases (PKS) and leading to (C2)n linear
intermediates [5, 6]. If the (C2)n intermediates arise from
successive Claisen reactions performed by ketosynthase

domains (KS, in nonreducing PKS), a highly reactive poly‐
β‐ketoacyl intermediate H─(CH2C═O)n─OH is formed,
leading to phenolic and aromatic products through further
intramolecular Claisen condensations. Furthermore, highly
reducing PKSs are made of specialized enzymatic subunits
working in line or iteratively to functionalize each C2 linker
bond as CH(OH)CH2 (by ketoreductases (KR)), then as
HC═CH (by dehydratases (DH)), and as CH2CH2 (by enoyl
reductases (ER)), leading to a high degree of functionalization
of the final product (Fig. 1.2). By these iterative sequences,
highly reduced polyketides, which can be either linear,
macrocyclized, or polycyclized depending on the reactivity
of the biosynthetic intermediates, can be formed [7]. With
the same logic, fatty acids are also biosynthesized by fatty
acid synthases.
Moreover, the PKS enzyme can be hybridized with non­
ribosomal peptide synthetase (NRPS) domains (see also
“NRPS metabolites and peptides” in the “Alkaloids” sec­
tion), leading to the acylation of an amino acid by the (C2)n
acyl intermediate. As previously, the functionalization of the
acyl chain depends on the PKS enzyme, and the PKS/NRPS
products are also extremely diversified (e.g., hirsutellone B;
Fig. 1.2) [8].
1.1.5.2 Terpenes  Terpenes are derived from the oligo­
merization of the C5 isoprene units DMAPP and IPP. Both
precursors are prompt to generate either an allylic cation

(the  diphosphate is a good leaving group) or a tertiary
carbocation, respectively, which makes the IPP easy to react
with DMAPP (Scheme  1.4). This reaction happens in the
active site of a terpene synthase, which activates the depar­
ture of the diphosphate group from DMAPP, thanks to Lewis
acid activation (a metal like Mg2+, Mn2+, or Co2+ is present
in  the enzyme active site [9]). This leads to geranyl (C10,
monoterpene precursor) or farnesyl (C15, sesquiterpene
precursor) diphosphate, depending on the location of the
enzyme (chloroplast for the MEP pathway or cytosol for
the  MVA pathway). Geranylgeranyl (C20, diterpene) and

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FROM PRIMARY TO SECONDARY METABOLISM: THE KEY BUILDING BLOCKS

O
R

S-MAT

+

O
HO

S-ACP

KS Claisen condensation (–CO2)

O

R incremented by two carbons

R

HO

From a
hexanoyl
starting
block

OH
O
Norsolorinic acid

O

S-ACP
KR reduction (NADPH)
No
Yes

O H
O
HO

O

NH

O
H

HH

O

HO
H H
Hirsutellone B
(mixed PKS/NRPS
product)

HO OH
Erythronolide A

S-ACP
reduction
(NADPH)
ER
No
Yes

HO
OH

S-ACP
TE hydrolysis (H2O)

No
Yes
Release
R

1C lost from
decarboxylation

O

H

O

New cycle

O

H

O

New cycle
or
R
release

OH

From

tyrosine

OH

New cycle
OH O
or
R
S -ACP
release
DH dehydration (–H2O)
No
Yes
New cycle
or
R
release

OH O

OH O

O

5

H

O

H

H OH
CHO
H

O

H

Hemibrevetoxin B
OH

O

HO
Panaxytriol

OH

OH

Figure 1.2  Chemical logic of polyketide construction leading to variable functionalization of the elongated acyl chain and examples of
resulting chemical diversity. ACP, acyl carrier protein; DH, dehydratase; ER, enoyl reductase; KR, ketoreductase; KS, ketosynthase; MAT,
malonyl acyl transferase; TE, thioesterase.

IPP

OP2O63–
DMAPP

OP2O63–
HH

OP2O63–
Geranyl diphosphate (GPP)

2 × IPP
Examples:
labdane,
pimarane,
kaurane,
abietane,
aphidicolane,
gibberellane...

OP2O63–

OP2O63–
OP2O63–

Examples:
verticillane,
casbane,
taxane,
phorbol...

Geranylgeranyl diphosphate (GGPP)

Scheme 1.4  Early assembly of C5 units in terpene biosynthesis, leading to diterpenes (C20).

farnesylfarnesyl (C30, triterpene precursor) diphosphates can
also be obtained by further additions of IPP, leading to longer
linear intermediates.
The cyclization of linear precursors is achieved by spe­
cialized cyclases, which generate a poorly functionalized
natural product framework [10, 11]. Auxiliary enzymes such
as oxygenases then increase the complexity and the diversity

of compounds by further functionalization (Scheme  1.3b)
[12]. A high degree of oxidation can be observed in com­
pounds like thapsigargin, paclitaxel, or bilobalide (Fig. 1.3).
The biosynthesis of this last compound, for example,
involves a high oxygenation pattern, two Wagner–Meerwein
rearrangements, and several oxidative cleavages leading to
the loss of five carbons. The resulting natural products can

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6

From Biosyntheses to Total Syntheses: An Introduction

H

C10

C15

Menthol
HO H
H
C10

OGlc
H
O
MeO2C
Loganin (iridoid)
C10
H

CO2H
H

Chrysanthemic acid
C30

H

O

O

Ph
From PHE

O
Thapsigargin O

H H
C15
O
H
OO

H H

C30 - 3

nC3H7
C20 - 5

O

O
OH
OH

Bilobalide
(highly rearranged
and missing 5 C)
H

OHC
H
O

H

H
WM

O
H
HO OBz OAc
Paclitaxel
O H Cleavage
O WM
O

High O
oxidative H
cleavages

C25

Cleavage

O

O
OH

O
OH
OH

O
Artemisinin

C40

BzNH O

O O
Parthenolide O
C15 O
nC7H15 O H OAc O

OH

H

AcO O OH

C20

O
H
H
OH Ophiobolin A

H

H
H
H

H

Hopene

HO

H

Cholesterol
(missing 3 C, WM)

β-Carotene

Figure 1.3  Chemical diversity in the terpene series (WM, Wagner–Meerwein shifts; ●, lost carbons; bold bonds are remnant of primary
building blocks).

thus be extremely modified, with structures whose biogenetic
origin is far from being obvious at first sight and cannot be
determined without further experiments such as isotopic
labeling.
1.1.5.3  Flavonoids, Resveratrols, Gallic Acids, and
Further Polyphenolics  We have previously discussed the
polyketide origin of some phenolic compounds based on the
(C2)n motif. Other polyphenols like gallic acids are directly
derived by the aromatization of shikimic acid (C6C1 building
block; Scheme 1.2) [13]. The C6C3 building blocks are avail­
able from the conversion of phenylalanine and tyrosine into
cinnamic and p‐coumaric acids, respectively, and then by
further hydroxylation steps (Scheme 1.5). These can dimerize
into lignans (e.g., podophyllotoxin) [14, 15] through radical
processes or converted to low molecular weight compounds
like eugenol, coumarins, or vanillin [16]. The coenzyme A

thioesters of these C6C3 acids can be used as initiator units
by specialized ketosynthases for an elongation by two acetyl
units, leading to aromatic polyketides like styrylpyrones
or  diarylheptanoids (e.g., curcumin) [17]. Important com­
pounds from this metabolism are flavonoids (C6C3C6) [18]
and stilbenoids (C6C2C6) (a decarboxylation occurs during
the aryl cyclization) [19], which are synthesized by chalcone
synthase and stilbene synthase, respectively. Flavonoids
(e.g., catechin) and stilbenes (e.g., resveratrol) are present in
large amounts in fruits and vegetables and may exert their
radical scavenging properties in vivo.

1.1.5.4 Alkaloids Alkaloids are nitrogen‐containing
compounds. The nitrogen(s) can be involved in an amine
function, conferring basicity to the natural product (like
“alkali”), or in less or nonbasic functions such as an amide,
a nitrile, an isonitrile, or an ammonium salt (quaternary
amines). For amines, protonation often occurs at
physiological pH and may condition their biological activity.
In many cases, the nitrogen is biogenetically derived from an
amino acid. We will thus discuss alkaloids according to their
amino acid origin.
Alkaloids Derived from the Krebs Cycle (Lysine and
Ornithine Derived)  As shown previously (Scheme  1.2),
the Krebs cycle is a crucial metabolic process, which leads
to α‐ketoacids (oxaloacetic and 2‐oxoglutaric acids). Their
enzymatic transamination affords the two amino acids—
aspartic acid and glutamic acid—which are the direct
biosynthetic precursors of amino acids lysine and ornithine,
respectively. These in turn produce cadaverine, a “C5N” unit,

and putrescine, a “C4N” unit, which are major components
for the biosynthesis of important alkaloids, as will be
discussed later (Scheme  1.6). Additionally, ornithine is a
precursor of arginine, another important amino acid.
ornithine‐derived alkaloids (incorporating the c4n
unit)  Putrescine is derived from the decarboxylation of
ornithine and is a precursor of linear polyamines like sperm­
ine. After enzymatic methylation of one amine of putrescine

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FROM PRIMARY TO SECONDARY METABOLISM: THE KEY BUILDING BLOCKS

CO2H

PHE
TYR
After E Z
isomerization

C6C3
R
Cinnamic acid (R=H)
p-Coumaric acid (R=OH)

[O]

From AcCoA

then
cyclization

O

n = 3, flavonoids
(from chalcone synthase)
From AcCoA

C — C and/or C — O
radical couplings
lignans

HO

OH

O

OH

H
OH

for example, Podophyllotoxin:
OH
H
O
O
O

H
H O

O
O
RO
Furocoumarins
(e.g., psoralen)

O

Yangonin

MeO
OH

RO

O
O
Coumarins
(e.g., scopoletin)
Prenylation
cyclization
cleavage[O]

OMe

n = 2, styrylpyrones

[H], [O]

RO

O

n
Acetyl-CoA

7

Catechin
OH
n = 3, stilbenoids
(from stilbene synthase)
From AcCoA OH From
AcCoA
(–CO )
2

OH
MeO

OMe

Resveratrol

HO

OMe

Scheme 1.5  The phenylpropanoid biosynthetic pathways.
OH MeN
OH

HN
HO

OH
Calystegine B2

OH

ARG

HO
O
Atropine

CO2H

ORN

Ph
O

LYS

CO2

HO

MeN

OH

O
O

NHMe

CO2

Tropinone

O

NH2

NH2
Putrescine

[O]
H

N
Me
Hygrine

NH2

( )n H
N
N
Me
n = 1: spermidine
N-Methylpyrrolinium n = 2: homospermidine

CO2

CO2

O

H2O

Pseudopelletierine

H
NH

H
N

N
Retronecine

H
O (–)-Cytisine

H

N

N
H
Pelletierine
H
N
H H

N
H

HO
HO

CO2

δ–

H
N

O

AcAcCoA

NH2

O

H

N
N
Me Cuscohygrine Me

O

Ph

N δ+
H
Piperideine
iminium

NH2 O

n=2
N
Me

H

N

NH2

2×
AcCoA

O

N
H
Lobeline

NH2 NH2 Ph
Cadaverine

OH

N
HO
Castanos permine

NH
Pipecolic acid

CO2

H

N
OH

H
N

H
H

(+)-Sparteine

H

H

N
Lupinine

Scheme 1.6  Lysine‐ and ornithine‐derived alkaloid biosynthetic pathways (mind the structural similarities).

in the presence of S‐adenosylmethionine, transamination of
the other affords γ‐(N‐methylamino)aldehyde [20]. The
resulting cyclic iminium is a key intermediate in the
formation of many medicinally important alkaloids such as

the plant‐derived compounds cocaine, atropine, or the calys­
tegines [21, 22]. Indeed, this iminium is a Mannich acceptor,
which can react with various nucleophiles, the first of those
being the carbanion of acetyl‐CoA. Thus, after a stepwise

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