Cutting-Edge Organic Synthesis and Chemical Biology of Bioactive Molecules Yuichi Kobayashi Editor

Cutting-Edge Organic Synthesis and Chemical Biology of Bioactive Molecules The Shape of Organic Synthesis to Come Editor Yuichi Kobayashi Department of Biotechnology Tokyo Institute of Technology Yokohama, Japan

ISBN 978-981-13-6243-9 ISBN 978-981-13-6244-6 (eBook) https://doi.org/10.1007/978-981-13-6244-6

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This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface

The purpose of organic synthesis is to provide target compounds by selective methods with high optical purity. Many transition metal-catalyzed asymmetric reactions and reactions catalyzed by organocatalysts have been developed to efficiently reach the goals. Reducing and oxidizing reagents that are highly chemoselective and/or environmentally friendly are also indispensable tools toward the purpose. On the other hand, analytical techniques have advanced to allow swift determination of the efficiency of reactions and the structures. For example, LC-MS analysis equipped with a chiral column could determine the chirality of the structure. Such new reactions and the advances in analytical techniques produced new power for organic synthesis to foray into fields, which used to be considered out of organic synthesis. As a consequence, many interdisciplinary areas have emerged, attracted attention of chemists, and rapidly grown. This book was planned to grasp the latest and excellent achievements in organic synthesis, which are expected to be grown more in the future. On the other hand, the background of each chapter is explained. I hope that the chapters will be understood easily by researchers, especially young, and stimulate research in the future. Chapters “Microbial Fraction Library: A Screening Source for Drug Discovery”, “Efficient Total Synthesis ofŌ mura Natural Products”, “Enantioselective Total Synthesis of the Antitumor Polycyclic Natural Products FR182877 and Taxol”, “Synthetic Approaches on the Pluramycin-Class Antibiotics”, “Recent Progress Toward the Total Synthesis of Duocarmycins A and SA, Yatakemycin, and PDE-I and –II”, “Structure-Activity Relationship Studies of Maitotoxin Based on Chemical Synthesis”, “Substitution of Allylic Picolinates with Various Copper Reagents and Synthetic Applications”, “Total Synthesis of Ingenol” present isolation, elucidation, and organic syntheses of several compounds that are naturally occurring. Organic synthesis and biosynthesis of metabolites of polyunsaturated fatty acids are described in chapters “Strategies for the Synthesis of Anti-inflammatory Metabolites of Unsaturated Fatty Acids” and “Biosynthesis, Biological Functions, and Receptors of Leukotriene B4 and 12(S)-Hydroxyheptadecatrienoic Acid”, respectively. Chapter “Synthesis of Classical/Nonclassical Hybrid Cannabinoids and Related Compounds” deals with natural and unnatural cannabinoids and would be helpful to design new

v vi Preface medical cannabinoids. Chapters “Exploring Bioactive Marine Natural Products and Identification of Their Molecular Targets”, “Target Protein Chemical Modification”, “Target Identification of Bioactive Compounds by Photoaffinity Labeling Using Diazido Probes” explain chemical biology focusing on tools that are designed based on organic reaction and/or interaction with target proteins. The project of publishing this book began with an invitation of Mr. S. Koizumi, Springer Japan. I sincerely acknowledge Ms. A. Komada of Springer and Ms. M. Shimoda in our laboratory for checking the chapters carefully.

Yokohama, Japan Yuichi Kobayashi Contents

1 Microbial Fraction Library: A Screening Source for Drug Discovery �� 1 Toshihiko Nogawa, Julius Adam V. Lopez, and Hiroyuki Osada 2 Efficient Total Synthesis of Ōmura Natural Products �� 21 Toshiaki Sunazuka, Tomoyasu Hirose, and Satoshi Ōmura 3 Enantioselective Total Synthesis of the Antitumor Polycyclic Natural Products FR182877 and Taxol �� 49 Masahisa Nakada 4 Synthetic Approaches on the Pluramycin-Class Antibiotics �� 75 Yoshio Ando, Kei Kitamura, Takashi Matsumoto, and Keisuke Suzuki 5 Recent Progress on the Total Synthesis of Duocarmycins A and SA, Yatakemycin, and PDE-I and PDE-II �� 101 Juri Sakata and Hidetoshi Tokuyama 6 Structure-Activity Relationship Studies of Maitotoxin Based on Chemical Synthesis �� 125 Tohru Oishi 7 Substitution of Allylic Picolinates with Various Copper Reagents and Synthetic Applications �� 145 Yuichi Kobayashi and Miwa Shimoda 8 Total Synthesis of Ingenol �� 171 Tyler F. Higgins and Jeffrey D. Winkler 9 Strategies for the Synthesis of Anti-inflammatory Metabolites of Unsaturated Fatty Acids �� 193 Yuichi Kobayashi and Masao Morita

vii viii Contents

10 Biosynthesis, Biological Functions, and Receptors

of Leukotriene B4 and 12(S)-Hydroxyheptadecatrienoic Acid �� 233 Toshiaki Okuno and Takehiko Yokomizo 11 Synthesis of Classical/Nonclassical Hybrid Cannabinoids and Related Compounds �� 247 Thanh C. Ho and Marcus A. Tius 12 Exploring Bioactive Marine Natural Products and Identification of Their Molecular Targets �� 291 Masayoshi Arai 13 Target Protein Chemical Modification �� 305 Hiroyuki Nakamura 14 Target Identification of Bioactive Compounds by Photoaffinity Labeling Using Diazido Probes �� 335 Suguru Yoshida and Takamitsu Hosoya List of Figures

Fig. 1.1 Screening strategy of interesting secondary metabolites...... 2 Fig. 1.2 Morphological profiles of HeLa and srcts-NRK cancer cells treated with pyrrolizilactone...... 5 Fig. 1.3 Concept of the fraction library...... 7 Fig. 1.4 Culture condition and preparation of crude extracts and fractions...... 8 Fig. 1.5 A basic concept of 2D separation for the preparation of fractions...... 9 Fig. 1.6 Mass distribution of fractions...... 9 Fig. 1.7 General activity profile of the fraction library evaluated at 100 μg/mL...... 10 Fig. 1.8 NPPlots and unusual alignments...... 11 Fig. 1.9 NPPlots and specific metabolite group of Streptomyces sp. RK88–1355...... 11 Fig. 1.10 Structure and putative biosynthetic pathway of verticilactam...... 12 Fig. 1.11 Structures and putative biosynthetic pathway of spirotoamides...... 13 Fig. 1.12 Structures of octaminomycins A and B...... 14 Fig. 1.13 NPPlot of Streptomyces sp. RK88–1355 and new antimycin-related metabolites...... 15 Fig. 1.14 Structural diversity of the antimycin class of metabolites...... 16 Fig. 1.15 Variety of the functional group at C-3 position...... 17 Fig. 2.1 Our strategy...... 22 Fig. 2.2 Structures of novel Ōmura natural products...... 23 Fig. 2.3 Structures of pyripyropenes...... 24 Fig. 2.4 Biosynthesis of pyripyropene A...... 24 Fig. 2.5 Structures of pyripyropene analogues...... 26 Fig. 2.6 Structure-activity relationships of pyripyropenes...... 27 Fig. 2.7 Structure of PP8201 (Afidopyropen)...... 27 Fig. 2.8 Structures of arisugacins...... 28 Fig. 2.9 Computer simulation of arisugacin A 8 docking with AChE...... 30 Fig. 2.10 Structures of lactacystin and salinosporamide A...... 31

ix x List of Figures

Fig. 2.11 Regulatory functions of the eukaryotic proteasome and target for lactacystin...... 31 Fig. 2.12 Structures of lactacystin analogues...... 32 Fig. 2.13 Inhibitory mode of macrosphelide A on cell adhesion...... 33 Fig. 2.14 Structures of macrosphelides A and B...... 34 Fig. 2.15 Structures of madindolines A 41 and B 42...... 36 Fig. 2.16 The mode of action of madindoline A...... 39 Fig. 2.17 Structures of neoxaline 59 and oxaline 60...... 40 Fig. 2.18 Collaboration between the natural products and the organic synthesis for drug discovery...... 44 Fig. 3.1 Structures of (−)-FR182877 (1) and (−)-FR182876...... 50 Fig. 3.2 X-ray crystal structure of 29...... 58 Fig. 3.3 Immunostaining images obtained using control (I), paclitaxel (10 nM) (II), and 31 (200 μM) (III) (left) and the mitotic indexes (right)...... 59 Fig. 3.4 Structure of (−)-taxol...... 60 Fig. 4.1 Pluramycins...... 77 Fig. 4.2 Hedamycin and conformation of α-C-glycosyl vancosamine...... 78 Fig. 4.3 Synthetic challenges and lability of the pluramycins...... 78 Fig. 4.4 Strategies for the skeletal construction of the pluramycin aglycon...... 79 Fig. 4.5 The rare deoxyamino sugars on pluramycins...... 84 Fig. 4.6 Platforms for installing bis-C-glycoside...... 90 Fig. 4.7 Further utilities of bis-C-glycosyl monocycles...... 92 Fig. 5.1 Structures of duocarmycins and the related compounds...... 103 Fig. 5.2 Proposed mechanism of DNA alkylation...... 103 Fig. 5.3 Structures of PDE-I (5) and PDE-II (6)...... 104 Fig. 5.4 Proposed structure of yatakemycin (40) by Igarashi and coworkers...... 109 Fig. 6.1 Structure of maitotoxin (MTX)...... 126 Fig. 6.2 Structure of brevetoxin B (BTXB)...... 126 Fig. 6.3 Hypothesis of mode of action...... 127 Fig. 6.4 Partial structures of MTX...... 127 Fig. 6.5 Structure of artificial ladder-shaped polyether ALP7B...... 139 Fig. 7.1 Synthetic targets using the allylic substitution...... 152 Fig. 7.2 Synthetic targets of the quaternary carbon-forming allylic substitution...... 159 Fig. 8.1 (a) Ingenol 1 alongside a 3-D model that highlights the highly contorted trans-intrabridgehead stereochemistry, (b) trans- and cis-intrabridgehead stereochemistry in bicyclo[4.4.1]undecanes, and (c) the Paquette ingenane analog with cis-intrabridgehead stereochemistry...... 172 List of Figures xi

Fig. 8.2 (a) Taxol and (b) retrosynthetic approach to AB system of taxol...... 173 Fig. 8.3 Taxol AB ring system retrosynthetic analysis via intramolecular dioxenone photocycloaddition-fragmentation...... 174 Fig. 8.4 (a) Ingenol in which the tricyclic core is highlighted in blue and (b) retrosynthetic analysis for the synthesis of the tricyclic core 19...... 175 Fig. 8.5 (a) Oxygen functionality and unsaturation previously installed. (b) Oxygen functionality and unsaturation yet to be installed...... 177 Fig. 8.6 Models depicting rationale for stereochemistry of (a) 1,2-addition and (b) cyclization...... 185 Fig. 9.1 ω-3 Fatty acids and their metabolites...... 194 Fig. 9.2 Metabolites of arachidonic acid...... 195 Fig. 9.3 The substructure of the metabolites in this section...... 198 Fig. 9.4 RvE1 analogues synthesized by Kobayashi/Ogawa...... 203 Fig. 9.5 Structural difference of the aspirin-triggered (AT) and endogenous metabolites...... 203 Fig. 9.6 The substructure of the metabolites in this section...... 211 Fig. 9.7 Naturally occurring RvE3...... 213 Fig. 9.8 The substructure of the metabolites in this section...... 216 Fig. 9.9 The substructure of the metabolites in this section...... 217 Fig. 9.10 Structural similarity between 5,18-DiHETE and resolvin E2...... 226 Fig. 9.11 Purification of compounds by using a recycle HPLC: YMC, LC-forte/R, normal phase (silica gel) column with eluents specified...... 228

Fig. 10.1 Biosynthesis pathways of leukotriene B4 (LTB4) and LTC4 ...... 235 Fig. 10.2 LTB4 inactivation pathways...... 236 Fig. 10.3 Structure of LTB4 and related fatty acids...... 238 Fig. 10.4 PGH2 biosynthesis pathway...... 240 Fig. 10.5 Biosynthesis and metabolism pathway

of 12-HHT and TxA2 ...... 242 Fig. 11.1 Structural classification of cannabinoids with representative compounds...... 249 Fig. 11.2 Three pharmacophores and retrosynthetic analysis of classical tricyclic cannabinoids...... 250 Fig. 11.3 By-products detected in the condensation of olivetol with (+)-p-mentha-2,8-dien-1-ol...... 252 Fig. 11.4 Structures of optically active monoterpenes commonly used in cannabinoid synthesis...... 253 xii List of Figures

Fig. 11.5 Examples of a classical cannabinoid, a nonclassical cannabinoid, and a hybrid cannabinoid...... 263 Fig. 11.6 Structure of some fused multicyclic cannabinoids...... 272 Fig. 11.7 Structure of some heterocyclic cannabinoids and a phenanthrene-derived cannabinoid...... 277 Fig. 12.1 Chemical structures of previously discovered bioactive marine natural products...... 294 Fig. 12.2 Inhibition of protein complex formation by furospinosulin-1 (A) and structure of nucleotide probe (B)...... 296 Fig. 12.3 Chemical structures of furospinosulin-1 probe and dummy probe...... 297 Fig. 12.4 Expected mechanism of action of furospinosulin-1...... 298 Fig. 12.5 Summary of the phage display method...... 299 Fig. 12.6 Chemical structure (A) and activity (B) of the dictyoceratin probes...... 300 Fig. 12.7 Strategy of target identification usingM. smegmatis transformed with genomic DNA library...... 302 Fig. 13.1 (a) Pre-translational protein modifications that require genetic manipulation and (b) posttranslational protein modification with small chemicals...... 306 Fig. 13.2 The photoaffinity functional groups and their reactive intermediates...... 308 Fig. 13.3 A series of α-D-mannoside photoaffinity probes conjugated with an azide (1), a diazirine (2), and a benzophenone (3)...... 309 Fig. 13.4 Typical chemical modification reactions of proteins at lysine residues...... 310 Fig. 13.5 Typical chemical modification reactions of proteins at cysteine residues...... 311 Fig. 13.6 Typical chemical modification reactions of proteins at tyrosine residues...... 312 Fig. 13.7 Other amino acid residue-specific chemical modifications...... 317 Fig. 13.8 Typical trifunctional chemical probes for target identification...... 318 Fig. 13.9 The photoaffinity labeling/photo-cross-linking process from the non-covalent binding to the detection and identification of the tagged proteins...... 318 Fig. 13.10 Post-photoaffinity labeling modification of a saccharide-binding protein, concanavalin A (ConA)...... 319 Fig. 13.11 The affinity labeling modification followed by the hydrazone/oxime exchange reaction...... 320 Fig. 13.12 Schematic illustration of LDT chemistry for labeling endogenous proteins in living native cells...... 321 List of Figures xiii

Fig. 13.13 Schematic illustration of the strategy for the quenched ligand-directed tosylate (Q-LDT)-mediated construction of turn-on fluorescent biosensors...... 321 Fig. 13.14 A fluorescent dye transfer strategy for identifying the target protein of marinopyrrole A...... 322 Fig. 13.15 Schematic illustration of ligand-directed acyl imidazole (LDAI) chemistry for selective protein modification. Lg ligand, Nu nucleophilic amino acid...... 322 Fig. 13.16 Schematic of “turn-on” fluorescent labeling of a target protein by the O-NBD method. A small bifunctional O-NBD unit is contained in the ligand. Lg ligand...... 323 Fig. 13.17 Ligand-tethered-DMAP-catalyzed acyl transfer reaction for lectin...... 324 Fig. 13.18 Acyl transfer reaction for lectin catalyzed by DMAP...... 324 Fig. 13.19 Catalytic covalent modification of a specific side chain of a substrate peptide using coiled-coil assembly to drive localization of a dirhodium metallopeptide. Label subscripts represent the position, on a helical-wheel model, of key residues that deviate from the parent E3 or K3 sequences...... 325 Fig. 13.20 Covalent modifications of various E3gX peptides with the styryl-diazo reagent 8 by dirhodium metallopeptide

catalysts (K3a,eRh2)...... 326 Fig. 13.21 LDRP system for target-selective (A) modification and (B) oxidative inactivation...... 327 Fig. 13.22 EGFR knockdown using Ru-gefitinib in A431 cells...... 327 2+ Fig. 13.23 Structures of [Ru(bpy)3] -conjugated with the GU40C peptoid (RuGU40C) and RIP1 (RuRIP1) for CALI targeting to VEGF and the 26S proteasome, respectively...... 328 Fig. 13.24 Selective isolation and modification of target proteins...... 330 Fig. 14.1 Chemical methods for target identification...... 337 Fig. 14.2 Typical photoreactive groups used for PAL probes...... 338 Fig. 14.3 Typical detectable groups used for PAL probes...... 339 Fig. 14.4 Diazido probe method...... 340 Fig. 14.5 Diazido PAL probes developed by other groups...... 341 Fig. 14.6 Photoreaction of an equimolar mixture of azides 1a and 1b...... 342 Fig. 14.7 Cerivastatin (4) and diazido probe photovastatin CAA1 (5)...... 343 Fig. 14.8 1BnTIQ (10) and diazido probe 11...... 344 Fig. 14.9 Dantrolene (18) and PAL probes 19 and 20...... 346 Fig. 14.10 Synthesis of biaryl-type diazido compounds using borylated building block 21...... 347 Fig. 14.11 Synthesis of aryl azides 24 by the formal C–H azidation...... 348 Fig. 14.12 Diazido building blocks prepared from diazido compounds 14, 27, and 28...... 350 xiv List of Figures

Fig. 14.13 Other bifunctional PAL probe candidates of dantrolene...... 351 Fig. 14.14 Bifunctional PAL probe and unit bearing (ethynyldifluoromethyl)diazirinyl group...... 352 Fig. 14.15 Bifunctional PAL probe library...... 353 Fig. 14.16 Bifunctional PAL probe 53 of palmitic acid (54)...... 353 Fig. 14.17 Minimalist photo-crosslinkers...... 354 Fig. 14.18 Minimal all-in-one PAL unit...... 354 Fig. 14.19 Commercially available building blocks for bifunctional PAL probe synthesis...... 354 List of Schemes

Scheme 2.1 Retrosynthetic analysis of pyripyropene A �� 25 Scheme 2.2 Total synthesis of pyripyropene A �� 26 Scheme 2.3 Total synthesis of arisugacin A (part 1) �� 28 Scheme 2.4 Total synthesis of arisugacin A (part 2) �� 29 Scheme 2.5 Total synthesis of lactacystin �� 32 Scheme 2.6 Total synthesis of macrosphelide A �� 35 Scheme 2.7 Strategy for a combinatorial synthesis of macrosphelide analogues �� 35 Scheme 2.8 Asymmetric oxidative ring closure of tryptophol �� 36 Scheme 2.9 First-generation strategy for total synthesis of madindolines �� 37 Scheme 2.10 Second-generation strategy for total synthesis of madindolines �� 38 Scheme 2.11 The synthesis of the indoline spiroaminal framework of neoxaline (part 1) �� 41 Scheme 2.12 The synthesis of the indoline spiroaminal framework of neoxaline (part 2) �� 41 Scheme 2.13 Synthesis of cyclization precursor �� 42 Scheme 2.14 Construction of indoline spiroaminal �� 43 Scheme 2.15 Total synthesis of neoxaline �� 44 Scheme 3.1 Sorensen’s and Evans’ total syntheses of (−)- FR182877 (1) �� 51 Scheme 3.2 Construction of the AB-ring moiety by the stereoselective IMDA reaction �� 51 Scheme 3.3 Construction of the CD-ring moiety by the stereoselective IMHDA reaction �� 52 Scheme 3.4 Transformation of 2 to 7 via the stereoselective IMDA-IMHDA reaction cascade �� 52 Scheme 3.5 Stereoselective reduction of 7 (Table 3.1) �� 53 Scheme 3.6 Preparation of 10 �� 53 Scheme 3.7 The palladium-catalyzed 7-exo-trig cyclization of 10a and 10b (Table 3.2) �� 54

xv xvi List of Schemes

Scheme 3.8 Possible pathway from 11 to 13a and energetic difference between 13a and 13b calculated by the PM3 method �� 55 Scheme 3.9 Isomerization of allylic alcohol 11 to α-methyl ketone 13a (Table 3.3) �� 55 Scheme 3.10 Enantioselective total synthesis of (−)-FR182877 �� 56 Scheme 3.11 Structures of (−)-FR182877 (1) and 17, and retrosynthetic analysis of 17 �� 57 Scheme 3.12 Preparation of 19 �� 57 Scheme 3.13 Preparation of 18 �� 58 Scheme 3.14 Preparation of 17 and 29–32 �� 58 Scheme 3.15 Formation of the eight-membered ring of taxol in the convergent synthesis �� 61 Scheme 3.16 Intramolecular B-alkyl Suzuki-Miyaura coupling reactions of 33 and 34 �� 62 Scheme 3.17 Retrosynthetic analysis of (−)-taxol �� 63 Scheme 3.18 Preparation of the A-ring fragment 41-I from 43 �� 63 Scheme 3.19 Enantioselective preparation of 47-I from 46-I via organocatalysis �� 63 Scheme 3.20 The SAD of 49-I, 50-I, and 50-Br �� 64 Scheme 3.21 Transformation of 51-Br to 41-Br via 52 �� 65 Scheme 3.22 Attempted aldol reaction and Nozaki-Hiyama-type reaction and envisioned reliable stereoselective coupling of 41 and 54 to afford 55 �� 65 Scheme 3.23 Preparation of 54 via the baker’s yeast reduction of 56 �� 65 Scheme 3.24 Assembly of the A- and C-ring fragments and the intramolecular B-alkyl Suzuki-Miyaura coupling reaction of 60 �� 66 Scheme 3.25 Formation of 63 by palladium-catalyzed alkenylation of methyl ketone 62 �� 67 Scheme 3.26 Preparation of methyl ketone 68 via 1,5-hydride shift �� 68 Scheme 3.27 Formal total synthesis of (−)-taxol via the palladium-catalyzed alkenylation of 68 �� 68 Scheme 3.28 Kuwajima successful epimerization of 75 and our failed example �� 69 Scheme 3.29 Transformation of 73 to Nicolaou’s advanced synthetic intermediate 79 �� 70 Scheme 4.1 Synthesis of O-methyl kidamycinone �� 80 Scheme 4.2 Total synthesis of γ-indomycinone �� 80 Scheme 4.3 Total synthesis of (S)-espicufolin �� 80 Scheme 4.4 Friedel–Crafts cyclization in the synthetic study of kidamycin �� 81 Scheme 4.5 Total synthesis of γ-indomycinone �� 82 Scheme 4.6 Total synthesis of AH-1763 IIa �� 82 Scheme 4.7 Total synthesis of BE-26554A and heraclemycin B �� 82 List of Schemes xvii

Scheme 4.8 Total synthesis of (R)-espicufolin �� 83 Scheme 4.9 Synthesis of pluraflavin A aglycon �� 84 Scheme 4.10 Total synthesis of γ-indomycinone �� 84 Scheme 4.11 Baer and Georges synthesis �� 85 Scheme 4.12 Brimble synthesis �� 85 Scheme 4.13 McDonald synthesis �� 86 Scheme 4.14 Suzuki synthesis �� 86 Scheme 4.15 Kahne degradation �� 87 Scheme 4.16 Giuliano synthesis �� 87 Scheme 4.17 Nicolaou synthesis �� 88 Scheme 4.18 McDonald synthesis �� 89 Scheme 4.19 Parker synthesis �� 89 Scheme 4.20 Doi and Takahashi synthesis �� 89 Scheme 4.21 Suzuki synthesis �� 90 Scheme 4.22 O→C-Glycoside rearrangement �� 91 Scheme 4.23 Bis-C-glycosidation of monocyclic platforms �� 92 Scheme 4.24 Reverse polarity strategy for construction of bis-C-glycoside �� 93 Scheme 4.25 Synthetic study of kidamycin �� 94 Scheme 4.26 Synthetic study of pluraflavin A �� 94 Scheme 4.27 Total synthesis of isokidamycin �� 95 Scheme 4.28 Total synthesis of isokidamycin �� 96 Scheme 4.29 Total synthesis of saptomycin B �� 98 Scheme 5.1 Copper-mediated intramolecular aryl amination �� 105 Scheme 5.2 Synthesis of indoline 13 �� 105 Scheme 5.3 Preparation of left-hand segment 18 �� 106 Scheme 5.4 Terashima’s synthesis of right-hand segment 22 �� 106 Scheme 5.5 Preparation of right-hand segment 28 �� 107 Scheme 5.6 Fukuyama’s total synthesis of (+)-duocarmycin A (1) �� 107 Scheme 5.7 Fukuyama’s total synthesis of (+)-duocarmycin SA (2) �� 108 Scheme 5.8 Synthesis of the left-hand segment of the putative yatakemycin (40) �� 110 Scheme 5.9 Boger’s synthesis of proposed yatakemycin (40) �� 111 Scheme 5.10 Initial structural revision of yatakemycin �� 111 Scheme 5.11 Boger’s synthesis of revised left-hand segment 60 �� 112 Scheme 5.12 The second structural revision of yatakemycin �� 112 Scheme 5.13 Boger’s total synthesis of (+)-yatakemycin (4) �� 113 Scheme 5.14 Synthesis of the middle segment 73 �� 114 Scheme 5.15 Synthesis of left-hand segment 60 �� 114 Scheme 5.16 Boger’s second-generation total synthesis of (+)-yatakemycin (4) �� 115 Scheme 5.17 Synthesis of middle segment 87 �� 116 Scheme 5.18 Synthesis of amino alcohol 93 �� 116 Scheme 5.19 Synthesis of left-hand segment 100 �� 117 xviii List of Schemes

Scheme 5.20 Synthesis of right-hand segment 105 �� 118 Scheme 5.21 Fukuyama’s total synthesis of (+)-yatakemycin (4) �� 118 Scheme 5.22 Tokuyama’s synthetic strategy based on their copper-mediated double amination �� 119 Scheme 5.23 Preparation of the substrate for the double amination reaction �� 120 Scheme 5.24 Result of the initial trial of the double arylamination �� 120 Scheme 5.25 Proposed reaction pathway �� 121 Scheme 5.26 Tokuyama’s first-generation synthesis of PDE-II (6) �� 121 Scheme 5.27 Tokuyama’s synthesis of PDE-I (5) �� 122 Scheme 5.28 Tokuyama’s second-generation synthesis of PDE-II (6) �� 122 Scheme 6.1 Convergent method via two-rings construction (1): α-cyano ether method �� 128 Scheme 6.2 Convergent method via two-rings construction (2) �� 129 Scheme 6.3 Synthetic methods of 6/6/6-tricyclic ether systems based on Achmatowicz reaction �� 130 Scheme 6.4 Convergent synthesis of the WXYZ ring (1) �� 130 Scheme 6.5 Convergent synthesis of the WXYZ ring (2) �� 131 Scheme 6.6 Convergent synthesis of the WXYZA′B′C′ ring �� 133 Scheme 6.7 Synthesis of the QRS ring �� 134 Scheme 6.8 Synthesis of the C′D′E′F′ ring �� 135 Scheme 6.9 Synthesis of the LMNO and ent-LMNO rings �� 136 Scheme 6.10 Synthesis of the NOPQR(S) ring �� 138 Scheme 7.1 Allylic substitutions using prim- and sec-allylic esters �� 146 Scheme 7.2 Allylic substitution of secondary allylic esters published by 2007 �� 147 Scheme 7.3 Picolinoxy (Pic) leaving group for allylic substitution �� 148 Scheme 7.4 A double activation of the Pic group �� 149 Scheme 7.5 Preliminary results using various secondary allylic esters with phenylmetal reagents: Table 7.1 �� 149 Scheme 7.6 Allylic substitution of enantioenriched picolinates with Grignard-based copper reagents �� 150 Scheme 7.7 Substitution with PhLi-based copper reagents: Table 7.2 �� 150 Scheme 7.8 Allylic substitution with RLi-based copper reagents �� 151 Scheme 7.9 1,4-Addition reactions of classical copper reagents to enone �� 152 Scheme 7.10 Synthesis of sesquichamaenol �� 152 Scheme 7.11 Synthesis of equol �� 153 Scheme 7.12 Synthesis of the inhibitor of ACAT �� 154 Scheme 7.13 Synthesis of the bioactive form of loxoprofen �� 155 List of Schemes xix

Scheme 7.14 Synthesis of trans-2,6-disubstituted cyclohexanones �� 156 Scheme 7.15 Allylic substitution with alkynyl reagents �� 157 Scheme 7.16 Synthesis of the Stork’s prostaglandin intermediate 61 �� 158 Scheme 7.17 Quaternary carbon-forming allylic substitution with Ph and n-Bu copper reagents: Table 7.3 �� 158 Scheme 7.18 Formation of enantioenriched quaternary carbons with Ph copper reagents derived from PhMgBr or PhLi �� 159 Scheme 7.19 Synthesis of mesembrine �� 160 Scheme 7.20 Synthesis of the verapamil intermediate �� 161 Scheme 7.21 Synthesis of LY426965 �� 162 Scheme 7.22 Construction of a quaternary carbon on a cyclohexane and possible targets �� 162 Scheme 7.23 Construction of a quaternary carbon: Table 7.4 �� 163 Scheme 7.24 Conformation-controlled allylic substitution �� 164 Scheme 7.25 Synthesis of cyclobakuchiols A and B �� 165 Scheme 7.26 Synthesis of anastrephin �� 166 Scheme 7.27 Synthesis of axenol �� 167 Scheme 8.1 Baldwin’s dioxenone intermolecular photocycloaddition-fragmentation �� 173 Scheme 8.2 Synthesis of trans-bicyclo[5.3.1]undecane �� 174 Scheme 8.3 Synthesis of the tricyclic core of the ingenane ring system �� 175 Scheme 8.4 Synthesis of 3-oxygenated ingenane diterpenes �� 176 Scheme 8.5 Synthesis of the first biologically active ingenane analog �� 177 Scheme 8.6 Elaboration of the A and B rings of the ingenane skeleton �� 178 Scheme 8.7 Retrosynthetic analysis for D ring incorporation �� 179 Scheme 8.8 Attempted elimination of the mesylate of the C-14 hydroxyl produced an unexpected transannular aldol reaction �� 180 Scheme 8.9 Incorporation of the D ring cyclopropane of ingenol �� 181 Scheme 8.10 First total synthesis of ingenol �� 181 Scheme 8.11 Completion of the first total synthesis of ingenol �� 182 Scheme 8.12 Tanino and Kuwajima’s original approach to ingenane synthesis �� 184 Scheme 8.13 Synthesis of ingenane skeleton 79 via key

Me3Al-mediated rearrangement �� 184 Scheme 8.14 Functionalization of A and B rings of ingenol �� 185 Scheme 8.15 Completion of Tanino and Kuwajima’s ingenol synthesis �� 186 Scheme 8.16 Ring-closing metathesis approach to the synthesis of ingenol �� 187 Scheme 8.17 Improved ring-closing metathesis toward the synthesis of ingenol �� 187 Scheme 8.18 Functionalization of the A ring of ingenol �� 188 xx List of Schemes

Scheme 8.19 Completion of Wood’s ingenol synthesis �� 189 Scheme 8.20 Baran’s retrosynthetic analysis of ingenol �� 190 Scheme 8.21 Cyclase phase for the Baran synthesis of ingenol �� 190 Scheme 8.22 Oxidase phase and completion of Baran’s ingenol synthesis �� 191 Scheme 9.1 Construction of conjugated olefins �� 196 Scheme 9.2 Synthesis of E-iodo olefins �� 197 Scheme 9.3 Synthesis of RvE1 methyl ester by Petasis/Serhan �� 199 Scheme 9.4 Improved synthesis of RvE1 by Schwartz �� 199 Scheme 9.5 Synthesis of key intermediates �� 200 Scheme 9.6 Synthesis of the three intermediates 36, 40, and 45 �� 201 Scheme 9.7 Synthesis of RvE1 by Kobayashi/Ogawa �� 202 Scheme 9.8 Improved synthesis of RvD3 by Petasis/Serhan �� 204 Scheme 9.9 Synthesis of PD1 and (18R)-PD1 (AT-PD1) by Petasis/Serhan �� 205 Scheme 9.10 Preparation of intermediates 60 and 61 �� 205 Scheme 9.11 Synthesis of PD1 by Kobayashi/Ogawa �� 206 Scheme 9.12 Preparation of intermediates 70 and 72 �� 206 Scheme 9.13 Synthesis of the PD1 intermediates by Spur �� 207 Scheme 9.14 Synthesis of PD1 by Hansen �� 207 Scheme 9.15 Synthesis of 10-epi-PD1 methyl ester by Balas �� 208 Scheme 9.16 Synthesis of MaR1 and (7S)-isomer by Inoue/Arita using Julia-Kocienski coupling �� 209 Scheme 9.17 Synthesis of MaR1 by Kobayashi/Ogawa via Suzuki-Miyaura coupling �� 210 Scheme 9.18 Synthesis of MaR1 by Spur via Sonogashira coupling �� 210 Scheme 9.19 Synthesis of MaR1 by Hansen via Sonogashira coupling �� 211 Scheme 9.20 Three approaches to RvD4 �� 212 Scheme 9.21 Synthesis of RvD4 intermediates 127 and 129 �� 212 Scheme 9.22 Synthesis of RvD4 by Kobayashi/Morita �� 213 Scheme 9.23 Kinetic stability of a dihydroxy acid �� 213 Scheme 9.24 Synthesis of RvE3 by Inoue/Arita �� 214 Scheme 9.25 Synthesis of RvE3 by Kobayashi �� 215 Scheme 9.26 Synthesis of MaR2 by Spur �� 215 Scheme 9.27 Synthesis of RvD1 and RvD2 by Spur �� 216 Scheme 9.28 Synthesis of RvD2 by Rizzacasa �� 216 Scheme 9.29 Synthesis of RvD1 by Kobayashi/Morita �� 217 Scheme 9.30 Approaches to RvE2 �� 218 Scheme 9.31 Synthesis of the intermediates for synthesis of RvE2 �� 219 Scheme 9.32 Synthesis of RvE2 by Inoue/Arita �� 219 Scheme 9.33 Synthesis of RvE2 by Kobayashi/Ogawa �� 220 Scheme 9.34 Ozonolysis of E- and Z-allylic alcohol derivatives

(R = Et, i-Pr, C5H11) �� 220 Scheme 9.35 Synthesis of (14R,15S)-diHETE by Kobayashi �� 221 List of Schemes xxi

Scheme 9.36 Synthesis of RvE2 by Spur �� 221 Scheme 9.37 Synthesis of RvE2 by Shuto �� 221 Scheme 9.38 Synthesis of RvD6 by Spur �� 222 Scheme 9.39 Approaches to RvD5 �� 222 Scheme 9.40 Synthesis of RvD5 by Spur �� 223 Scheme 9.41 Synthesis of RvD5 by Kobayashi/Ogawa/Morita �� 223 Scheme 9.42 Synthesis of (14S,20R)-dihydroxy-DHA by Inoue/Arita �� 224 Scheme 9.43 Synthesis of (17R,18S)-epoxy-(12S)-hydroxy-EPA by Inoue/Arita �� 224 Scheme 9.44 Synthesis of (14S,21R)-DiHDHA by Kobayashi/ Morita/Hong �� 225 Scheme 9.45 Synthesis of Maresin-like 1 by Kobayashi et al. �� 226 Scheme 9.46 Retrosynthesis of (5S,18R)-DiHETE �� 226 Scheme 9.47 Synthesis of HHTE and 12S-HHT �� 227 Scheme 11.1 Synthesis of (−)-Δ8- and (−)-Δ9-THCs from (−)-verbenol �� 251 Scheme 11.2 Synthesis of (−)-Δ8- and (−)-Δ9-THCs from (+)-p-mentha-2,8-dien-1-ol �� 251 Scheme 11.3 Synthesis of AM-411 �� 253 Scheme 11.4 Synthesis of AMG-3 �� 253 Scheme 11.5 Synthesis of HU-210 �� 254 Scheme 11.6 Synthesis of AM-708 �� 254 Scheme 11.7 Synthesis of ajulemic acid �� 255 Scheme 11.8 Synthesis of nabilone �� 255 Scheme 11.9 Condensation of resorcinols with diacetates 40 and 41 �� 256 Scheme 11.10 Synthesis of AM-993 and AM-994 �� 257 Scheme 11.11 Synthesis of AM-2389 and canbisol �� 257 Scheme 11.12 Synthesis of 9β-hydroxymethyl-HHC from HU-210 �� 257 Scheme 11.13 Synthesis of AM-7499 �� 258 Scheme 11.14 Synthesis of a 9-ketocannabinoid bearing a non-bulky C3 side chain �� 259 Scheme 11.15 Synthesis of a series of hexahydrocannabinols via a common intermediate �� 259 Scheme 11.16 Structures of (−)-CP-47,497 and (−)-CP-55,244 and the synthesis of (−)-CP-55,940 �� 260 Scheme 11.17 Synthesis of KLS-13019 �� 261 Scheme 11.18 Synthesis of PRS-211,375 �� 261 Scheme 11.19 Synthesis of HU-308 �� 261 Scheme 11.20 Synthesis of HU-910 �� 262 Scheme 11.21 Synthesis of (−)-6β-hydroxymethyl-Δ9-THC �� 263 Scheme 11.22 C6-diastereoselective synthesis of hybrid cannabinoids �� 264 Scheme 11.23 Total synthesis of hybrid cannabinoid AM-919 and derivatives �� 265 xxii List of Schemes

Scheme 11.24 Synthesis of hybrid cannabinoid 130 via hetero- Diels−Alder reaction �� 267 Scheme 11.25 Preparation of the aliphatic aldehyde 125 �� 267 Scheme 11.26 Preparation of resorcinol 31 �� 268 Scheme 11.27 Synthesis of AM-4030 �� 269 Scheme 11.28 Synthesis of aliphatic aldehyde 140 �� 269 Scheme 11.29 Synthesis of acetophenone 141 �� 270 Scheme 11.30 Synthesis of AM-960 �� 271 Scheme 11.31 Synthesis of C3-adamantyl hybrid cannabinoids via oxymercuration-demercuration �� 271 Scheme 11.32 Synthesis of C3-adamantyl hybrid cannabinoids via hetero-Diels−Alder cyclization �� 271 Scheme 11.33 Synthesis of tetracyclic analogs of Δ8-THC �� 272 Scheme 11.34 Synthesis of rotationally restricted tetrahydrocannabinol ethers �� 273 Scheme 11.35 Synthesis of some cannabinoid quinones �� 274 Scheme 11.36 Synthesis of cannabinoid quinones via photooxygenation �� 274 Scheme 11.37 Synthesis of cannabinol via von Pechmann condensation �� 275 Scheme 11.38 Synthesis of cannabilactones via Suzuki coupling reaction �� 275 Scheme 11.39 Synthesis of C-ring cannabinoid lactones �� 276 Scheme 11.40 Asymmetric synthesis of levonantradol �� 277 Scheme 11.41 Synthesis of a pentacyclic hybrid cannabinoid �� 278 Scheme 11.42 Structure of rimonabant and the synthesis of chromenopyrazoles �� 279 Scheme 11.43 Synthesis of chromenopyrazolediones �� 280 Scheme 11.44 Synthesis of chromenoisoxazoles �� 281 Scheme 11.45 Structures of resorcinol−AEA hybrids and the synthesis of representative compound CB-25 �� 281 Scheme 11.46 Synthesis of O-2220 �� 282 Scheme 11.47 Structures of 2-AG and the synthesis of a resorcinol−2- AG hybrid �� 282 Scheme 13.1 The photoredox mechanism of the tyrosine residue-specific modification reaction catalyzed by ruthenium complex 2+ ([Ru(bpy)3] ) �� 313 Scheme 13.2 PTAD-based chemical modification �� 314 Scheme 13.3 Luminol-based tyrosine residue-specific chemical modification �� 315 Scheme 13.4 MAUra-based tyrosine residue-specific chemical modification �� 315 Scheme 13.5 Strain-promoted cycloaddition of 1,2-quinones converted from tyrosine residues specifically oxidized by mushroom tyrosinase �� 316 Scheme 14.1 Photoreaction of triazido compound 2 �� 342 List of Schemes xxiii

Scheme 14.2 Synthesis of photovastatin CAA1 (5) �� 343 Scheme 14.3 PAL experiment using photovastatin CAA1 (5) and recombinant HMGR �� 344 Scheme 14.4 Synthesis of diazido PAL probe 11 �� 345 Scheme 14.5 PAL experiment using diazido probe 11 in subcellular fractions of rat whole brain homogenates �� 345 Scheme 14.6 Facile synthesis of various diazido building blocks bearing connecting groups (CGs) �� 348 Scheme 14.7 Synthesis of diazido compounds 14 and 25 �� 349 Scheme 14.8 Synthesis of diazido compounds 27 and 28 �� 349 Scheme 14.9 Photoreaction of diazirine 40a �� 351 Scheme 14.10 Photoreaction of diazirine 40b �� 351 Scheme 14.11 Synthesis of 3-aryl-3-(azidodifluoromethyl)diazirine unit 48 �� 352 Scheme 14.12 Photoreactions of aryl(azidodifluoromethyl)diazirine48 �� 352 List of Tables

Table 1.1 Pros/cons of biological and chemical screenings �� 2 Table 1.2 Pros/cons of natural products and synthetic compound �� 3 Table 3.1 Stereoselective reduction of 7 (Scheme 3.5) �� 53 Table 3.2 The palladium-catalyzed 7-exo-trig cyclization of 10a and 10b (Scheme 3.7) �� 54 Table 3.3 Isomerization of allylic alcohol 11 to α-methyl ketone 13a (Scheme 3.9) �� 55 Table 6.1 Inhibitory activity of the synthetic specimens against Ca2+ influx induced by MTX �� 138 Table 7.1 Results of Scheme 7.5: Preliminary results using various secondary allylic esters with phenylmetal reagents �� 149 Table 7.2 Results of Scheme 7.7: Substitution of rac-12a with PhLi-based copper reagents �� 150 Table 7.3 Results of Scheme 7.17: Quaternary carbon-forming allylic substitution �� 158 Table 7.4 Results of Scheme 7.23: Feasibility study of the quaternary carbon construction �� 163

xxv