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LIST OF CONTRIBUTORS xiii
PREFACE xv
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
1.2.1 The Chemical Space of Natural Products 10
1.2.2 The Biosynthetic Pathways as an Inspiration for Synthetic Challenges 11
1.2.3 The Science of Total Synthesis 14
1.2.4 Conclusion: a Journey in the Future of Total Synthesis 16
References 16
SECTION I ACETATE BIOSYNTHETIC PATHWAY 19
2 Polyketides 21 Françoise Schaefers, Tobias A. M. Gulder, Cyril Bressy, Michael Smietana, Erica Benedetti, Stellios Arseniyadis, Markus Kalesse, and Martin Cordes
2.1 Polyketide Biosynthesis 21
2.1.1 Introduction 21
2.1.2 Assembly of Acetate/Malonate-Derived Metabolites 23
2.1.3 Classification of Polyketide Biosynthetic Machineries 23
2.1.4 Conclusion 39
References 40
2.2 Synthesis of Polyketides 44
2.2.1 Asymmetric Alkylation Reactions 44
2.2.2 Applications 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
2.3.4 Application 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 ¿-3 and ¿-6 Polyunsaturated Fatty Acids 135
3.3 Synthesis of ¿-3 and ¿-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
3.4 A pplications 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
4 Polyethers 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
4.2.3 A nnonaceous 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
4.4 A pplications to Total Synthesis 176
4.4.1 Acid-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
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
6.2.1 A cyclic Monoterpenes 197
6.2.2 Cyclic Monoterpenes 197
6.2.3 Iridoids 200
6.2.4 Irregular Monoterpenes 202
6.3 A symmetric 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 (Bronsted) Acids and H-Bonding Donors 213
6.3.4 Chiral Bronsted/Lewis Bases and Nucleophilic Catalysis 218
6.3.5 A symmetric Phase-Transfer Catalysis 220
6.4 O rganocatalysis 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
6.4.4 A lstoscholarine 229
6.4.5 (+)-Aspidospermidine and (+)-Vincadifformine 230
6.4.6 (+)-Yohimbine 230
6.5 Conclusion 231
References 231
7 Sesquiterpenes 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
7.3 Application of Cycloisomerizations in the Total Synthesis of Sesquiterpenoids 266
7.3.1 Picrotoxane Sesquiterpenes 266
7.3.2 A romadendrane 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
7.3.8 Diverse Sesquiterpenoids 276
7.4 Conclusion 276
References 276
8 Diterpenes 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
10.2 Auxiliary-Assisted C(sp3)-H Arylation Reactions in Organic Synthesis 336
10.3 Friedel-Crafts Reactions in Organic Synthesis 344
10.4 Total Synthesis of Lignans by C(sp3)-H Arylation Reactions 353
10.5 Total Synthesis of Lignans and Polymeric Resveratrol by Friedel-Crafts Reactions 357
10.6 Conclusion 375
References 376
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
11.2 The Asymmetric Mannich Reaction in Organic Synthesis 392
11.2.1 Chiral Amines as Catalysts in Asymmetric Mannich Reactions 394
11.2.2 Chiral Bronsted Bases as Catalysts in Asymmetric Mannich Reactions 398
11.2.3 Chiral Bronsted Acids as Catalysts in Asymmetric Mannich Reactions 404
11.2.4 Organometallic 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
12.2.5 Amaryllidaceae Alkaloids 438
12.2.6 Biosynthetic Overview of Tyrosine-Derived Alkaloids 442
12.3 Aryl-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
12.3.4 Transition 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
13.3 Atom Economy and Protecting-Group-Free Chemistry 480
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
INDEX 548
Bastien Nay1 and Xu-Wen Li2
1 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
The primary and secondary metabolisms are traditionally distinguished by their distribution and utility in the living organism network. Primary metabolites include carbohydrates, 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 pathways 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.
Figure 1.1 Primary versus secondary 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 complex that produces adenosine triphosphate (ATP) while electrons 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" ß-ketoacid. This is cleaved into two molecules of 3-phosphoglycerate (3-PGA), which is then reduced into 3-phosphoglyceraldehyde (3-PGAL, a "C3" triose phosphate) 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.
Scheme 1.1 The photosynthetic machinery (PS-I and PS-II, photosystems I and II).
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) (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 oligomerized 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 redirected toward methylerythritol-4-phosphate (MEP) in the 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.
Scheme 1.2 The building block chart, involving glycolysis, and the Krebs cycle.
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 methionine as a methyl supplier), and 2-oxoglutaric acid, precursor 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.
Most reactions occurring in the living cells are performed by specialized enzymes, which have been classified in an international nomenclature defined by an enzyme commission (EC) number. There are six classes of enzymes depending on the biochemical reaction they catalyze: EC-1, oxidoreductases (catalyzing oxidoreduction reactions); EC-2, transferases (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, isomerases (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 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 biosyntheses allows the construction of natural product frameworks, 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].
Scheme 1.3 (a) From building blocks to natural products and (b) the example of 10-deacetylbaccatin III.
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 CH 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.
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-ß-ketoacyl intermediate H(CH2CO)nOH 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 HCCH (by dehydratases (DH)), and as CH2CH2 (by enoyl reductases (ER)), leading to a...
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