Kuiling Ding Chinese Academy of Sciences Shanghai Institute of Organic Chemistry 345 Ling Ling Road Shanghai 200032 China Prof.. Li-Xin Dai Chinese Academy of Science Shanghai Institute
Trang 1and Perspectives
Trang 2Hanessian, S., Giroux, S., Merner, B.L.
Design and Strategy in Organic
Classics in Total Synthesis III
Further Targets, Strategies, Methods
2011
ISBN: 978-3-527-32958-8
Carreira, E M., Kvaerno, L
Classics in Stereoselective Synthesis
2009 ISBN: 978-3-527-29966-9
Steinborn, D
Fundamentals of Organometallic Catalysis
2011 ISBN: 978-3-527-32716-4
Trang 3Edited by Kuiling Ding and Li-Xin Dai
Organic Chemistry –
Breakthroughs
and Perspectives
Trang 4The Editors
Prof Dr Kuiling Ding
Chinese Academy of Sciences
Shanghai Institute of Organic Chemistry
345 Ling Ling Road
Shanghai 200032
China
Prof Dr Li-Xin Dai
Chinese Academy of Science
Shanghai Institute of Organic Chemistry
345 Ling Ling Road
Shanghai 200032
China
All books published byWiley-VCH are
carefully produced Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at
<http://dnb.d-nb.de>.
© 2012 Wiley-VCH Verlag & Co.
KGaA, Boschstr 12, 69469 Weinheim, Germany
All rights reserved (including those of translation into other languages) No part
of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
ISBN Hardcover: 978-3-527-33377-6 ISBN Softcover: 978-3-527-32963-2 ISBN Online: 978-3-527-66480-1 Cover Design Formgeber, Eppelheim, Germany
Typesetting Laserwords Private Limited, Chennai, India
Printing and Binding Markono Print Media Pte Ltd, Singapore
Printed on acid-free paper
Trang 51.2 Diversity-Oriented Synthesis (DOS) 2
1.2.1 Diversity-Oriented Synthesis of Skeletally and Stereochemically Diverse
Small Molecules [10a] 3
1.2.2 Biomimetic Diversity-Oriented Synthesis of Galanthamine-Like
Molecules 3
1.3 Diverted Total Synthesis (DTS) 7
1.3.1 Diverted Total Synthesis of the Migrastatins 7
1.4 Function-Oriented Synthesis (FOS) 9
1.4.1 Syntheses of Novel and Highly Potent Analogs of Bryostatin 10
1.4.2 Discovery of Potent and Practical Antiangiogenic Agents Inspired
by Cortistatin A 11
1.5 Target-Oriented Synthesis (TOS) 11
1.5.1 Synthetic Studies and Biological Evaluation of
1.5.6 Total Synthesis of Diverse Carbogenic Complexity Within the Resveratrol
Class from a Common Building Block 23
Trang 61.6 Conclusion and Perspectives 24
2.2.2 Total Synthesis of Hirsutellone B 36
2.2.3 Total Synthesis of (±)-Minfiensine, (−)-Phalarine, and Aspidophytine 40
2.3 Multicomponent Reactions 43
2.3.1 Introduction 43
2.3.2 Total Synthesis of (−)-Spirotryprostatin B 46
2.3.3 Total Synthesis of Hirsutine 50
2.4 Oxidative Anion Coupling 52
2.4.1 Direct Coupling of Indole with Enolate, Total Synthesis of Hapalindoles,
Fischerindoles, and Welwitindolinones 52
2.4.2 Total Synthesis of (±)- and (−)-Actinophyllic Acid 54
2.4.3 Total Synthesis of (−)-Communesin F 56
2.5 Pattern Recognition 60
2.5.1 Introduction 60
2.5.2 Total Synthesis of (±)-Aplykurodinone-1 60
2.5.3 Total Synthesis of (±)-Vinigrol 63
2.6 Conformation-Directed Cyclization 65
2.6.1 Introduction 65
2.6.2 Cyclosporin and Ramoplanin A2 65
2.7 Conclusion and Perspectives 69
Trang 73.1 Chemical Biology: Historical and Philosophical Aspects 81
3.1.1 The Chemical Space and the Biological Space 81
3.1.2 Historical Aspects of Chemical Biology 83
3.1.3 Scope of Today’s Chemical Biology 85
3.1.4 Forward Chemical Genetics 88
3.2 Preparation of Chemical Libraries 90
3.2.1 Natural Product-Inspired Synthesis 90
3.3.4 Data Management and Informatics Analysis 102
3.3.5 Chemical Approaches to Stem Cell Biology 103
3.4 Target Elucidation and Validation 106
3.4.1 Strategies Employing Affinity Reagents 106
3.4.1.1 Methods Employing Affinity Chromatography 106
3.4.1.2 Methods Employing Biotinylated Probes 108
3.4.1.3 Methods Employing Radiolabeled/Fluorescent and Photoaffinity
Trang 84 Biosynthesis of Pharmaceutical Natural Products and Their Pathway
4.2.1.2 Modular Type I PKSs and Their Broken Colinearity Rule 129
4.2.1.3 New Enzymology Complementing the Established Type I PKS
Paradigms 129
4.2.1.4 Iterative Type I PKSs in Bacteria 134
4.2.1.5 ACP-Independent, Noniterative Type II PKSs 138
4.2.1.6 Archetypical NRPS Paradigms 139
4.2.1.7 Atypical NRPS Paradigms 139
4.2.1.8 Hybrid NRPS–PKS Paradigms 141
4.2.2 Ribosomal Paradigms of Peptide NPs 143
4.2.3 New Strategies for Peptide–Amide Bond Formation 146
4.3 New Approaches to NP Biosynthesis Research 147
4.3.1 Comparative Gene Cluster Analyses Facilitate Biochemical
Characterization 148
4.3.2 Unique Combinatorial Strategies for Different Pathways 151
4.3.3 Synthetic Metagenomics for Improved Methyl Halide Production 155
4.4 Better Understanding of the Scope and Diversity of NP Production 156
4.4.1 Genome Sequencing, Scanning, and Screening for Chemical
Potential 157
4.4.2 Genome Mining for Terpene Biosynthesis 160
4.4.3 Genomisotopic Approach for Orphan Gene Clusters 162
4.4.4 Awakening Cryptic Gene Clusters through Global Regulators 163
4.4.5 Activation of NP Pathways Through Mixed Culturing 164
Yi Yu and Zi-Xin Deng
Authors’ Response to the Commentaries 179
Response to Yi Tang 179
Response to Yi Yu and Zixin Deng 179
Trang 95 Carbohydrate Synthesis Towards Glycobiology 181
Biao Yu and Lai-Xi Wang
5.1 Introduction 181
5.2 Advances in Chemical Glycosylation 182
5.2.1 New Glycosyl Donors with Novel Leaving Groups 183
5.2.1.1 Glycosylation with PTFAI Donors 183
5.2.1.2 Glycosylation with 2-Carboxybenzyl Glycosides (CB Donors) 184
5.2.1.3 Glycosylation with Glycosyl o-Alkynylbenzoates 184
5.2.2 New Methods for Controlling the Stereochemistry in Glycosylation 186
5.3 New Strategies in Oligosaccharide Assembly 189
5.3.1 Automated Oligosaccharide Synthesis 189
5.3.2 One-Pot Sequential Glycosylations 192
5.4 Enzymatic and Chemoenzymatic Methods 193
5.5 Synthesis of Heparin and Heparan Sulfate Oligosaccharides 195
5.5.1 Chemical Synthesis of Heparin Oligosaccharides 196
5.5.2 Enzymatic Synthesis of Heparin Oligosaccharides 198
5.6 Synthesis of Homogeneous Glycoproteins 200
5.6.1 Convergent Glycopeptide Synthesis Coupled with Native Chemical
Ligation 200
5.6.2 Site-Selective Glycosylation via a Protein ‘‘Tag and Modify’’ Strategy 202
5.6.3 Chemoenzymatic Glycosylation Remodeling of Glycoproteins 204
5.7 Synthesis of Carbohydrate-Containing Complex Natural Compounds 206
5.7.1 Total Synthesis of Carbohydrate Immune-Adjuvant QS-21Aapi 208
5.7.2 Total Synthesis of Lobatoside E 208
5.7.3 Total Synthesis of Moenomycin A 208
5.7.4 Total Synthesis of Lipoteichoic Acid 210
5.8 Conclusion and Perspectives 212
Trang 106.2.3 Total Synthesis of Insulin 223
6.2.4 Solid-Phase Peptide Synthesis 224
6.3.3 Overcome the Cys Limitation 231
6.3.4 Multiple Fragment Condensation 232
7.2 Azide–Alkyne Cycloaddition: the Basics 249
7.3 CuAAC: Catalysts and Ligands 251
7.4 Mechanistic Aspects of the CuAAC 258
7.5 Reactions of 1-Iodoalkynes 264
7.6 Examples of Application of the CuAAC Reaction 266
7.6.1 Synthesis of Compound Libraries for Biological Screening 266
7.6.2 Copper-Binding Adhesives 268
7.7 Reactions of Sulfonyl Azides 269
7.7.1 1-Sulfonyl Triazoles: Convenient Precursors of Azavinyl Carbenes 271
Trang 118 Transition Metal-Catalyzed C–H Functionalization: Synthetically Enabling
Reactions for Building Molecular Complexity 279
Keary M Engle and Jin-Quan Yu
8.1 Introduction 279
8.2 Background and Early Work 281
8.2.1 The Challenges of Functionalizing C–H Bonds 281
8.2.2 Mechanisms of C–H Cleavage by Transition Metals 282
8.2.3 Early Work in Metal-Mediated C(Aryl)–H Cleavage 285
8.2.4 C(aryl)–H Functionalization via Cyclometallation 288
8.2.5 Early Investigations of C(sp3)–H Cleavage 289
8.3 First Functionalization: Challenges in Hydrocarbon Chemistry 293
8.3.1 Selective Functionlization of Methane and Higher n-Alkanes 294
8.4.2 Steroid Functionalization Using Free Radical Chemistry 301
8.4.3 Building Molecular Complexity Using Transition Metal-Mediated
Reactions 303
8.5 Catalytic C–H Functionalization via Metal Insertion 303
8.6 Other Emerging Metal-Catalyzed Further Functionalization Methods 311
8.6.1 Biomimetic C–H Oxidation Methods 312
Trang 129.1 Introduction 335
9.2 Asymmetric Carbon–Carbon Bond Formation 336
9.2.1 Asymmetric Hydroformylations 336
9.2.2 Asymmetric Additions Involving Carbon Nucleophiles 337
9.2.2.1 Direct Aldol and Aldol Type 338
9.2.5 Asymmetric Catalysis Involving Coupling Processes 345
9.2.6 Asymmetric Catalysis Involving Metathesis 348
9.3 Asymmetric Reductions and Oxidations 348
9.3.1 Asymmetric Reductions 348
9.3.1.1 Asymmetric Hydrogenation (AH) 348
9.3.1.2 Asymmetric Transfer Hydrogenation 350
9.3.1.3 Other Asymmetric Reductions 351
Trang 13Domino Reactions by Amine Catalysis 378
Hydrogen Bonding Catalysis 378
Conclusion 379
Comment 3 379
Wen-Jing Xiao
References 382
11 Recent Topics in Cooperative Catalysis: Asymmetric Catalysis,
Polymerization, Hydrogen Activation, and Water Splitting 385
Motomu Kanai
11.1 Introduction 385
11.2 Cooperative Catalysis in Asymmetric Reactions 387
11.2.1 On the Shoulder of Giants in the Twentieth Century 387
11.2.2 Catalyst Higher Order Structure as a Determinant of Function: Catalytic
Enantioselective Strecker Reaction of Ketimines by Poly-Rare Earth MetalComplexes 389
11.2.3 Cooperative Asymmetric Catalysis Involving the Anion Binding
Concept 391
11.3 Cooperative Catalysis in Alkene Polymerization 393
11.4 Cooperative Catalysis in Hydrogen Activation/Generation 394
11.4.1 Ligand–Metal Cooperation 394
11.4.2 Frustrated Lewis Pairs 396
11.5 Conclusion and Perspectives 398
Trang 1412 Flourishing Frontiers in Organofluorine Chemistry 413
G K Surya Prakash and Fang Wang
12.1 Introduction 413
12.2 Synthetic Approaches for the Introduction of Fluorine-Containing
Functionalities and Related Chemistry 415
12.2.1 Novel Fluorinating Reagents and C–F Bond Formation Reactions 416
12.2.1.1 Nucleophilic Fluorinations 416
12.2.1.2 Electrophilic Fluorinations 423
12.2.2 Efficient Trifluoroalkylation Reactions 428
12.2.2.1 Nucleophilic Trifluoromethylating Reagents, Trifluoromethyl-Metal
Reagents, and Related Chemical Transformations 429
12.2.2.2 Electrophilic Trifluoromethylating Reagents and Reactions 433
12.2.2.3 Recent Developments in the Construction of CF3-C Bonds 437
12.2.3 Novel Methods for the Introduction of Difluoromethyl Motifs 445
12.2.3.1 Nucleophilic Difluoromethyl Building Blocks and Approaches 445
12.2.3.2 Electrophilic Difluoromethyl Reagents and Approaches 451
12.2.4 Catalytic Asymmetric Synthesis of Chiral Monofluoromethylated Organic
Molecules via Nucleophilic Fluoromethylating Reactions 452
12.3 Conclusion and Perspectives 459
Kuiling Ding and Li-Xin Dai
Authors’ Response to the Commentaries 472
Trang 1513.3.5.4 Flexible Arylamide Oligomers 492
13.3.5.5 Modified Arylamide Oligomers: Molecular Tweezers 494
Author’s Response to the Commentaries 532
Reply to Zhao and Wang’s Comments 532
Reply to Tung’s Comments 533
Reply to Stang’s Comments 533
References 533
Trang 1614 Novel Catalysis for Alkene Polymerization Mediated by Post-Metallocenes:
a Gateway to New Polyalkenes 537
Hiromu Kaneyoshi, Haruyuki Makio, and Terunori Fujita
14.1 Introduction 537
14.2 Late Transition Metal Complexes 538
14.2.1 Diimine-Ligated Ni and Pd Complexes 538
14.2.2 Pyridyldiimine-Ligated Fe and Co Complexes 540
14.2.3 Phenoxyimine-Ligated Ni Complexes 542
14.3 Early Transition Metal Complexes 544
14.3.1 Phenoxyimine-Ligated Group 4 Metal Complexes 544
14.3.1.1 High Activity for Ethylene Polymerization 544
14.3.1.2 Wide-Ranging Control over the Molecular Weight of the PE 545
14.3.1.3 Living Polymerization Mediated by Fluorinated Ti-FI Catalysts 546
14.3.1.4 Effect of Catalyst Activator 547
14.3.1.5 Stereospecific Polymerization of Propylene 547
14.3.1.6 Copolymerization of Ethylene with Cyclic Alkenes 548
14.3.1.7 Selective Production of 1-Hexene by Ethylene Trimerization 548
14.3.2 Chelating Bis(phenoxy)-Ligated Group 4 Metal Complexes 549
Early Work on Late Metals 556
Ligand Design Principles for Post-metallocenes 556
Comment 3 557
Eugene Y.-X Chen
Authors’ Response to the Commentaries 559
References 559
15 Chem Is Try Computationally and Experimentally: How Will Computational
Organic Chemistry Impact Organic Theories, Mechanisms, and Synthesis in the Twenty-First Century? 561
Zhi-Xiang Yu and Yong Liang
Trang 1715.2.2 Computational Prediction of Carbon Tunneling 566
15.2.3 Predictions of Contra-Steric Stereochemistry in Cyclobutene Ring-Opening
Reactions by the Theory of Torquoselectivity 568
15.3 Understanding Reaction Mechanisms 571
15.3.1 Mechanism of Phosphine-Catalyzed [3+ 2]-Reactions of Allenoates and
Electron-Deficient Alkenes: Discovery of Water-Catalyzed [1, 2]-Proton
Shift 574
15.3.2 Mechanism of Metal Carbenoid O–H Insertion into Water: Why Is a
Copper(I) Complex More Competent Than a Dirhodium(II) Complex in
Catalytic Asymmetric O–H Insertion Reactions? 577
15.3.3 Mechanism of the Nazarov Cyclization of Aryl Dienyl Ketones: Pronounced
Steric Effects of Substituents 580
15.4 Computation-Guided Development of New Catalysts, New Reactions, and
Synthesis Planning for Ideal Synthesis 583
15.4.1 Discovery of Catalysts for 6π Electrocyclizations 586
15.4.2 Computational Design of a Chiral Organocatalyst for Asymmetric
Anti-Mannich Reactions 588
15.4.3 Computation-Guided Development of Gold-Catalyzed Cycloisomerizations
Proceeding via 1,2-Si Migrations 590
15.4.4 A Computationally Designed Rh (I)-Catalyzed [(5+ 2) + 1] Cycloaddition for
the Synthesis of Cyclooctenones 593
16 Case Study of Mechanisms in Synthetic Reactions 603
Ai-Wen Lei and Li-Qun Jin
16.1 Introduction 603
16.2 Mechanistic Study of Coupling Reactions 604
16.2.1 Oxidative Addition 605
16.2.1.1 Influence of Ligands on Oxidative Addition 605
16.2.1.2 Oxidative Addition of Haloarenes to Trialkylphosphine–Pd(0)
Complexes 608
16.2.2 Transmetallation 615
16.2.2.1 General Aspects of the Transmetallation Step 615
16.2.2.2 Investigation of the Transmetallation Step in Coupling Reactions 617
16.2.3 Reductive Elimination 624
16.2.3.1 General Aspects of Reductive Elimination 624
Trang 1816.2.3.2 Case Study of the Reductive Elimination Step of the Oxidative Coupling
Reaction 626
16.3 Mechanistic Study of Aerobic Oxidation 627
16.3.1 Recent Progress in Aerobic Oxidation 627
16.3.2 Mechanistic Characterization of Aerobic Oxidation 629
Comment 2 640 Yoshinori Yamamoto
Authors’ Response to the Commentaries 640
References 640
17 Organic Materials and Chemistry for Bulk Heterojunction Solar
Cells 643 Chun-Hui Duan, Fei Huang, and Yong Cao
17.1 Introduction 643
17.2 Molecular Design and Engineering of Donor Materials 645
17.2.1 Molecular Design and Engineering of Conjugated Polymers 645
17.2.1.1 Homopolymers 645
17.2.1.2 Push–Pull Copolymers 650
17.2.1.3 Conjugated Polymers with Pendant Conjugated Side Chains 655
17.2.1.4 Block Conjugated Copolymers 656
17.2.2 Solution-Processed Small-Molecule Donor Materials 660
17.3 Molecular Design and Engineering of Acceptor Materials 662
Comment 2 677 Yongfang Li
Comment 3 681 Guillermo C Bazan
Trang 19Comment 4 682
Xiong Gong
Authors’ Response to the Commentaries 682
References 682
18 Catalytic Utilization of Carbon Dioxide: Actual Status and Perspectives 685
Albert Boddien, Felix G¨artner, Christopher Federsel, Irene Piras, Henrik Junge, Ralf Jackstell, and Matthias Beller
18.3 CO2as a C1-Building Block in C–C Coupling Reactions 702
18.4 Catalytic C–O Bond Formation Utilizing Carbon Dioxide 703
18.4.1 Synthesis of Linear Carbonates 704
18.4.2 Synthesis of Cyclic Carbonates 707
18.5 Current Industrial Processes Using CO2 710
19 Synthetic Chemistry with an Eye on Future Sustainability 725
Guo-Jun Deng and Chao-Jun Li
Trang 2019.2.1 CDC Reaction of theα-C–H Bond of Nitrogen in Amines 730
19.2.1.1 Alkynylation (sp3–sp Coupling) 730
19.2.1.2 Arylation (sp3–sp2Coupling) 732
19.2.1.3 Alkylation (sp3–sp3) 732
19.2.2 CDC Reaction ofα-C–H Bond of Oxygen in Ethers (sp3–sp3) 734
19.2.3 CDC Reaction of Allylic and Benzylic C–H Bonds 735
19.2.5 CDC Reaction of Aryl C–H Bonds 739
19.3 Nucleophilic Addition of Terminal Alkynes in Water 741
19.3.1 Direct Nucleophilic Addition of Terminal Alkynes to Aldehydes 741
19.3.2 Direct Addition of Terminal Alkynes to Ketones in Water 743
19.3.3 Addition of Terminal Alkynes to Imines, Tosylimines, Iminium Ions, and
Acyliminium Ions 744
19.3.3.1 Imines 744
19.3.3.2 Iminium Ions 744
19.3.3.3 Acylimine and Acyliminium Ions 747
19.3.3.4 Multiple and Tandem Addition of Terminal Alkynes to C=N Bonds 747
19.3.4 Direct Conjugate Addition of Terminal Alkynes in Water 748
19.4 Conclusion and Perspectives 749
20.2 Conjugated Molecules for p-Type Organic Semiconductors 760
20.3 Conjugated Molecules for n-Type Organic Semiconductors 766
20.4 Conjugated Molecules for Photovoltaic Materials 769
20.5 Conclusion and Outlook 773
References 774
Trang 21Commentary Part 777
Comment 1 777
Seth R Marder
Comment 2 777
Tien Yau Luh
Authors’ Response to the Commentaries 779
Trang 22Tak Hang Chan
McGill UniversityDepartment of Chemistry
801 Sherbrooke Street WestMontreal, QC H3A 2K6Canada
Eugene Y.-X Chen
Colorado State UniversityDepartment of Chemistry
1301 Centre Av
Fort Collins, CO 80523-1872USA
David Crich
Centre de Recherche de Gif CNRSInstitut de Chimie des SubstratesNaturelles
Avenue de la Terrasse
91198 Gif-sur-YvetteFrance
Trang 23Li-Xin Dai
Chinese Academy of Sciences
Shanghai Institute of Organic
Shanghai Jiaotong University
School of Life Sciences and
345 Ling Ling RoadShanghai 20032China
Christopher Federsel
Universit¨at RostockLeibniz-Institut f¨ur KatalyseAlbert Einstein Strasse 29a
18059 RostockGermany
Michael Foley
Broad Institute of MIT and Harvard
301 Binney StreetCambridge, MA 02142USA
Trang 24Terunori Fujita
Mitsui Chemicals Singapore R&D
Center Pte, Ltd
50 Science Park Road
#06-08 The Kendall Singapore
Hefei National Laboratory for
Physical Sciences at the Microscale
and Department of Chemistry
Goodyear Polymer Center
185 East Mill Street
Akron, OH 44325
USA
Robert Grubbs
California Institute of Technology
Division of Chemistry and Chemical
345 Ling Ling RoadShanghai 200032China
K N Houk
University of California Los AngelesDepartment of Chemistry andBiochemistry
Los Angeles, CA 90095-1569USA
Jinbo Hu
Chinese Academy of SciencesShanghai Institute of OrganicChemistry
345 Ling Ling RoadShanghai 20032China
Takao Ikariya
Tokyo Institute of TechnologyGraduate School of Science andEngineering
Department of Applied Chemistry2-12-1 Ookayama
Meguro-kuTokyo 152-8550Japan
Trang 25Molecular Catalysis Unit
Catalysis Science Laboratory
10015 LausanneSwitzerland
Ai-Wen Lei
Wuhan UniversityCollege of Chemistry andMolecular SciencesLuo-jia-shan, WuchangWuhan
Hubei Province 430072China
Chao-Jun Li
McGill UniversityDepartment of Chemistry
801 Sherbrooke Street WestMontreal, QC H3A2K6Canada
Wei-Dong Li
Nankai UniversityState Key Laboratory and Institute ofElemento-Organic Chemistry
94 Weijin RoadTianjin 300071China
Yongfang Li
Chinese Academy of SciencesInstitute of ChemistryCAS Key Laboratory ofOrganic SolidsZhongguancunBeijing 100190China
Trang 26Chinese Academy of Sciences
Shanghai Institute of Organic
China
Wen Liu
Chinese Academy of SciencesShanghai Institute of OrganicChemistry
State Key Laboratory of Bioorganicand Natural Products Chemistry
345 Ling Ling RoadShanghai 200032China
Tien Yau Luh
National Taiwan UniversityDepartment of ChemistryRoosevelt Road
Taipei 10617Taiwan (Republic of China)
Da-Wei Ma
Chinese Academy of SciencesShanghai Institute of OrganicChemistry
345 Ling Ling RoadShanghai 200032China
Haruyuki Makio
Mitsui Chemicals Singapore R&DCentre Pte, Ltd
50 Science Park Road
#06-08 The Kendall SingaporeScience Park II
Singapore 117406Singapore
Seth R Marder
Georgia Institute of Technology
901 Atlantic DriveAtlanta, GA 30332USA
Trang 27Weizmann Institute of Science
Department of Organic Chemistry
Rehovot 76100
Israel
Xin Mu
Chinese Academy of Sciences
Shanghai Institute of Organic
Furo-choChikusa-kuNagoya 464-8601Japan
David O’Hagan
University of St AndrewsCentre for Biomolecular SciencesNorth Haugh
St AndrewsFife KY16 9STUK
Jun Okuda
RWTH Aachen UniversityInstitut f¨ur Anorganische ChemieLandoltweg 1
52074 AachenGermany
Takashi Ooi
Nagoya UniversityGraduate School of EngineeringDepartment of Applied ChemistryChikusa
Nagoya 464-8603Japan
Jian Pei
Peking UniversityCollege of Chemistry and MolecularEngineering
202 Chengfu RoadBeijing 100871China
Trang 28University of Southern California
Loker Hydrocarbon Research
Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
State Key Laboratory of Bioorganic
and Natural Products Chemistry
345 Ling Ling Road
Shanghai 200032
China
Christian A Sandoval
Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
345 Ling Ling Road
Shanghai 200032
China
Niyazi Serdar Sariciftci
Johannes Kepler University of LinzLinz Institute for Organic SolarCells (LIOS)
Altenberger Strasse 69
4040 LinzAustria
Roger A Sheldon
Delft University of TechnologyFaculty of Applied SciencesLorentzweg 1
2628 CJ DelftThe Netherlands
Ben Shen
University of Wisconsin-MadisonMicrobiology Doctoral TrainingProgram
777 Highland AvenueMadison, WI 53705USA
and
University of Wisconsin-MadisonSchool of Pharmacy
Division of Pharmaceutical Sciences
777 Highland AvenueMadison, WI 53705USA
130 Scripps Way, #3A1Jupiter, FL 33458USA
Trang 29Qi-Long Shen
Chinese Academy of Sciences
Shanghai Institute of Organic
Chinese Academy of Sciences
Shanghai Institute of Organic
315 South 1400 EastSalt Lake City, UT 84112USA
Yi Tang
University of California, Los Angeles
420 Westwood PlazaLos Angeles, CA 90096USA
Chen-Ho Tung
Chinese Academy of SciencesTechnical Institute of Physics andChemistry
2 Beiyitiao StreetZhongguancunHaidian DistrictBeijing 100190China
Fang Wang
University of Southern CaliforniaLoker Hydrocarbon ResearchInstitute
Department of ChemistryUniversity Park
Los Angeles, CA 90089USA
Lai-Xi Wang
University of MarylandInstitute of Human VirologyDepartment of Biochemistry andMolecular Biology
725 West Lombard StreetBaltimore, MD 21201USA
Trang 30Mei-Xiang Wang
Tsinghua University
Department of Chemistry
MOE Key Laboratory of Bioorganic
Phosphorus Chemistry and
Chinese Academy of Sciences
Shanghai Institute of Organic
Chemistry
State Key Laboratory of Bioorganic
and Natural Products Chemistry
345 Ling Ling Road
Yun-Dong Wu
Peking UniversityShenzhen Graduate SchoolLaboratory of Chemical Genomics
Li Shui RoadShenzhen 518055China
Zhenfeng Xi
Peking UniversityCollege of Chemistry and MolecularEngineering
202 Chengfu RoadBeijing 100871China
Wen-Jing Xiao
Central China Normal UniversityCollege of Chemistry
152 Luoyu RoadWuhan
Hubei 430079China
Ling-Min Xu
Peking UniversityShenzhen Graduate SchoolDepartment of Chemistry
Li Shui RoadShenzhen 518055China
Trang 31Dalian University of Technology
The State Key Laboratory of
Shenzhen Graduate School
Laboratory of Chemical Genomics
Chinese Academy of Sciences
Shanghai Institute of Organic
State Key Laboratory of Bioorganicand Natural Products Chemistry
345 Ling Ling RoadShanghai 200032China
Yi Yu
Wuhan UniversitySchool of Pharmaceutical Sciences
185 East Lake RoadWuhan 430071China
Zhi-Xiang Yu
Peking UniversityCollege of Chemistry and MolecularEngineering
202 Chengfu RoadBeijing 100871China
Jun-Ying Yuan
Harvard UniversityDepartment of Cell Biology
240 Longwood AvenueBoston, MA 02115USA
Trang 32Shenzhen Graduate School
Laboratory of Chemical Genomics
China
Qi-Lin Zhou
Nankai UniversityState Key Laboratory ofElemento-Organic Chemistry
94 Weijin RoadTianjin 300071China
Jie-Ping Zhu
Swiss Federal Institute ofTechnology
EPFL SB ISIC LSPNBCH 5304 (Bˆatiment de ChimieUNIL)
1015 LausanneSwitzerland
Dao-Ben Zhu
Chinese Academy of SciencesInstitute of ChemistryCAS Key Laboratory ofOrganic SolidsZhongguancun North First Street 2Beijing 100190
China
Trang 33Kuiling Ding and Li-Xin Dai
From the 1950s to the Second Decade of the Twenty-First Century
About half a century ago, two books were published The first, entitled Perspectives in Organic Chemistry, 1956 [1], was dedicated to Sir Robert Robinson on the occasion of his
70th birthday Twenty-two years later, another book, with the same theme as the first, with
the title Further Perspectives in Organic Chemistry, 1978 [2], appeared This book contains
all the lectures given at a Symposium in memory of the late Sir Robert Robinson Thesetwo books share a similar relationship with the great organic chemist, Sir Robert, andrecorded the progress of organic chemistry at that time Now we are in a new century
and living in a rapidly changing world The stimulus for us to edit this book, Organic Chemistry – Breakthroughs and Perspectives, is the tremendous achievements of organic
chemistry in the last two decades After the Second World War, we had experiencedbasically a sufficiently long peaceful and stable period that engendered the steady growth
of chemistry A relatively good financial situation to support the efforts of talentedchemists, and also mutual interactions with neighboring sciences, all contributed tothe tremendous achievements of organic chemistry Organic chemistry is thus endowedwith vital forces The emergence of many new disciplines marks the vigorous newfaces of organic chemistry These disciplines include chemical biology, organocatalysis,supramolecular chemistry, green or sustainable chemistry, combinatorial chemistry, andflow chemistry, to name just a few
The renaming of the Department of Chemistry as the Department of Chemistry andChemical Biology by Harvard University at the end of the last century marked theemergence of chemical biology, an interface of chemistry and life sciences To manifest
the maturity of this new discipline, several new journals, namely Nature Chemical Biology, ChemBioChem, Chemical Biology, BMC Chemical Biology, Chemical Biology and Drug Design, and Chemistry and Biology, with the sole aim of reporting developments in
chemical biology, were launched in the last couple of years Chemical biology is now adistinct discipline in understanding science at the intersections of chemistry and biology.Chemical biologists believe that they are standing at the doorstep of an exciting era [3]
Similarly, green chemistry or sustainable chemistry is another new discipline, and assuch also has its specialized new journals Sixteen years ago, the establishment of the
Trang 34Green Chemistry Award at the Presidential level in the United States demonstrated to
us the importance of green chemistry In 1998, Paul T Anastas coined the term ‘‘green
chemistry’’ in his book Green Chemistry, Theory and Practice [4], and therefore defined
this new discipline Some new research areas are involved in green chemistry, such asionic liquid chemistry, fluorous chemistry, and synthetic reactions in aqueous medium.Supramolecular chemistry and organocatalysis are further examples Organocatalysiscan really be regarded as the chemistry of this century In the last century, we usuallysaid that there were two ways to carry out an asymmetric catalytic reaction, that is,metal-catalyzed asymmetric reaction and enzymatic asymmetric reaction Now, in thetwenty-first century, we should add a third: organocatalysis
As can be seen, the emergence in a not too long period of so many new disciplines andnew research areas has evidenced the rapid and exciting growth of organic chemistry.Thus, organic chemistry has become a matured as well as a dynamic science From thisstatus of organic chemistry, probably it is a good time to survey the breakthroughs in thissubject and to make a perspective view of this dynamic science To speak frankly, neither
of the Editors is in a perfect position to do this job However, fortunately, many of ourfriends and colleagues promised to support this project, and with their great support thisproject is now realized Furthermore, the publisher has also shown great interest andlasting support, which were indeed a strong motivation behind this project
It has been a great privilege and an honor for us to assemble a magnificent internationalteam of outstanding organic chemists – over 100 organic chemists from around 10nations They have made great efforts to write excellent reviews and to present insightfulcomments during their very busy hours between two important holidays, Christmas andthe Chinese New Year We owe them a great deal and thank them wholeheartedly
In this book, there are 21 chapters in total and an introduction The last chapter gives usoverall remarks on the perspectives if organic chemistry in this new century Not only isthe last not the least, we would also say that the last chapter is of the utmost importance
We are extremely grateful to Professor Ronald Breslow: without his agreement to writethat chapter, we would not have been confident to undertake such an ambitious task as
to edit this book The other chapters may be divided into four groups First, Chapters1–7 deal with total synthesis of natural products and chemical biology The second groupcovers synthetic methodology, encompassing Chapters 8–12 Chapters 13, 15, and 16involve physical organic chemistry The last group, preceding Prof Breslow’s essay inChapter 21, comprises Chapters 14 and 17–20 and is dedicated to chemistry in meetingthe urgent needs of human beings
Total Synthesis of Natural Products and Chemical Biology
Total syntheses of natural products have long been regarded as a mainstream of organicchemistry The milestones in this area often represent the advancement of organicchemistry to a certain extent Friedrich W¨ohler’s synthesis of urea from inorganiccompounds is frequently cited because it is regarded as the first example of totalsynthesis The total synthesis of vitamin B12, palytoxin, brevetoxin, and many others aremilestones in total syntheses The total synthesis of vitamin B12by Robert Woodwardand Albert Eschenmoser not only has manifested a chemical synthesis of an important
Trang 35naturally occurring and structurally complex cobalt-containing chemical compound, butalso bestowed on our scientific community the beautiful Woodward–Hoffmann rules onconservation of molecular orbital symmetry [5].
N N
H P O O N N
O
H H
H H
N N N
O
OH H H H
H O
O O O
O O
C D
O
H Me Me H H Me H H
H H
O OH
OH OH
HO O HO
OH
OH Me
O OH
OH HO
OH O HO
OH
Me OH Me
OH
O N N
HO OH
OH
OH OH OH
OH
Me Me
OH OH O
HO
Trang 36The total synthesis of palytoxin had once been regarded as the Mount Everest of totalsynthesis owing to its molecular weight of 2860 Da and 64 stereogenic centers [6] Thiswas true in the past, but on terms of the molecular complexity, this molecule is really notcomplex enough! In this regard, brevetoxin is more complex, with many fused alicyclicrings, ranging from six- to nine-membered, and the associated stereochemistry stemsfrom this polycyclic structure [7].
These molecules are just a very few examples among the vast array of importantnatural products that have been synthesized in recent decades In a way, the totalsyntheses of these molecules may help us to answer the question ‘‘Can we make it?’’This question, however, is now not worth posing any longer And then comes thesecond question, as addressed in Chapter 2, written by Qian Wang and Jieping Zhu,which has now shifted to ‘‘Why should we make it?’’ The answer to this questionmay be taken from the first sentence of Chapter 1, written by Zhen Yang and hisco-authors: ‘‘Natural products have proven to be valuable sources for the identification
of new drug candidates.’’ Christopher T Walsh and Michael A Fischbach recentlyanswered the question ‘‘Why do natural products still matter?’’ with four rationales: theycontinue to inspire synthetic and analytical chemists; they remain a major source ofhuman medicines; they have led to important biological insights; and there are manymore natural products to discover [8a] In addition, Alexander Todd once urged organicchemists ‘‘to devote much thought to the function of natural products’’ [2] When we turnour attention to the function of natural products, ‘‘diversity-oriented synthesis’’ (DOS)would emerge Chapter 1 talks about diversity-oriented synthesis and also diverted totalsynthesis (DTS) and function-oriented synthesis (FOS) Although ‘‘Can we make it?’’ is
no longer a valid question, ‘‘Can we make it efficiently?’’ still remains a real problem.Chapter 2 also addresses the synergy of synthetic methodology with the total synthesis ofnatural products Samuel Danishefsky once said, ‘‘the opportunities for total synthesisare realizable only in the context of continuing advances in the allied field of syntheticmethodology’’ [8b]
Scott Snyder, in concluding his commentary on Chapter 1, inspiringly raises threethought-provoking queries: (i) the reluctance to invest in natural products isolationefforts by major pharmaceutical companies, (ii) the reduction in the ease of federalfunding, and (iii) the increasing complexity of natural products isolated The reduction ininvestment by pharmaceutical companies probably is a reflection of the global economiccrisis With the increasing fruitful results from natural products, it is believed thatpharmaceutical companies will regain their interest in natural products The recentlaunch of two highly potent (at the sub-nanomolar level) anti-cancer drugs, ET-743 orYondelis® by Elias Corey and E7389 or Halaven® by Yoshito Kishi (see Chapters 1 and 2)are good examples to reconstruct their confidence Scott Snyder also pointed out the richhistory of traditional Chinese medicine The recent award to You-You Tu, the inventor ofanti-malaria compound artemisinin, of the Lasker–Debakey Clinical Medical ResearchAward, is a response to Scott Snyder’s observation Traditional Chinese medicine is thewealth of the whole world, and it is gratifying that the language barrier associated withthe use of this wealth may be somewhat alleviated by the publishing of several Englishversions of relevant literature [9]
Trang 37When chemists care more about the physiological functions in our bodies, they arecoming very close to chemical biology Ren-Xiao Wang wrote Chapter 3, delineating theinterplay between the chemical space and the biological space with special emphasis ondrug discovery Chapter 4, entitled ‘‘Biosynthesis of Pharmaceutical Natural Products andTheir Pathway Engineering,’’ was written by Ben Shen, Wen Liu and their co-authors.Despite the fact that research in biosynthesis is a field with a long and rich history, modernbiosyntheses and especially those in the post-genome era have shown a wholly differentnew facet Nowadays, the genome sequence of a microorganism can be determined within
a fairly short time and at acceptable cost The whole gene sequence of 1891 bio-specieshas already been determined and 11 446 targets are currently being determined Hencethis rich genomic information may facilitate the understanding of the metabolic pathway,the modification of the pathway or the engineering of a brand new pathway In thissense, synthetic biology will probably initially blossom in the area of microorganisms
It is now clear that the gene sequence will boost this field to a new height This chapterwholly reflects this new facet in gene cluster analysis, genome sequencing, scanning,and mining so as to allow us to understand and to reconstruct the biosynthetic pathway
at the molecular level
In addition to proteins and nucleic acids, carbohydrates are recognized as one ofthe three principal biomolecular materials Carbohydrates are not simply molecularstructural materials or means for energy storage, but also play important functions incellular communication Chapter 5, written by Biao Yu and Lai-Xi Wang, presents anoverview of the synthesis of this important class of compounds Although the empiricalformula of carbohydrates is extremely simple, Cn(H2O)n, that is, hydrates of carbon,the synthesis of these molecules is of tremendous complexity We can synthesizepeptide chains and deoxynucleic acids routinely with an automated machine, but theautomated synthesis of oligosaccharides has only recently been realized and still withsome limitations This may be explained by a paper by Hans Paulsen, who observed in
1982 [10] that ‘‘ it should be emphasized that each oligosaccharide synthesis remains
an independent problem, whose resolution requires considerable systematic research and
a good deal of know-how There are no universal reaction conditions for oligosaccharidesyntheses.’’ Indeed, through systematic research, two major breakthroughs in this fieldare elegantly addressed in this chapter They both involve chemistry belonging to thiscentury Now, a branched dodecasaccharide of the phytoalexin elicitorβ-glucan can be
synthesized by an automated synthesizer The other breakthrough is one-pot sequentialglycosylation A computer database recording the relative reactivities of a large number ofdiversely protected sugars has been established by Chi-Huey Wong that allows the choice
of appropriate reactants for a sequential glycosylation in one pot By this methodology,several hexa- and dodecaoligosaccharides were synthesized It has been claimed thatover 90% of human proteins are predicted to be glycosylated [11] Hence the chemicalsynthesis of glycoprotein is highly needed in SAR (structure–activity relationship)studies Furthermore, carbohydrate synthesis is highly relevant to vaccine research Inthis connection, we have more reasons to expect further breakthroughs in this field inthe coming decades
In Chapter 6, Lei Liu elegantly addresses the chemical synthesis of proteins and recalledthe total synthesis of crystalline bovine insulin in 1965, a great event of science at that
Trang 38time in China Insulin was then the only protein whose structure had been established(by Frederick Sanger), which contains 51 amino acid residues with two disulfide linkages.The realization of bovine insulin was the first synthesis of a protein, and inevitably ittook an exceedingly long time and much effort to achieve the goal Later, thanks to theinvention and elaboration of solid-phase peptide synthesis by Robert Merrifield, and tothe invention of native chemical ligation by Stephen Kent for the efficient coupling ofunprotected peptide segments, the chemical synthesis of proteins has now reached anew height The list of authors on the paper that announced the total synthesis of bovineinsulin is a very long one, whereas only two authors were included in the phenomenal
2011 paper reporting the synthesis of the covalent dimer of HIV-1 protease enzyme thatfeatures 203 amino acid residues The advancement of science in these 50 years is trulyamazing
Lei Liu also describes several applications of chemical synthesis in biological scienceand pharmaceutical discovery With the advancement of proteomics and structural bi-ology, the number of crystalline structures of proteins revealed has boomed to 70 209.This huge number of protein structures is apparently a great challenge to organicchemists Although native chemical ligation (NCL), invented by Stephen Kent, is agreat breakthrough in the last 20 years, the development of more efficient methods
is still needed In this chapter, Lei Liu reports the efforts in overcoming the cyslimitation of NCL A recent paper by Lei Liu in tackling this problem with a pep-tide hydrazide is yet another efficient complement to the current NCL In meetingthis grand challenge, further improvement of NCL and other protocols will certainlyappear
There is an obvious direction at present and will be in the future that syntheticchemistry should combine continuously with other subjects in order to create moreinterdisciplinary sciences From this point of view, synthetic chemistry requires anextremely high level of scientific creativity and insight to explore its limitless possibilities
In 2001, Barry Sharpless introduced a chemical philosophy termed ‘‘click chemistry,’’emphasizing that synthetic chemical reactions must strive for a high reaction rate, highselectivity, and excellent tolerance to various functional groups and reaction conditions
in order to generate substances quickly and reliably by joining two units together Asone of the frontier concepts in synthetic chemistry, click chemistry has provided a brandnew idea, methodology, and substance basis for the life and materials sciences, andhas been widely used in the development of new medicines and new materials and
in the research areas of molecular biology, chemical biology, and related disciplines[12], including modification of peptides, DNA and nucleotides, natural products, andpharmaceuticals, and also carbohydrate clusters and bioconjugates Chapter 7, written byValery Fokin, highlights the concept of click chemistry and its applications in numerousareas Clearly, be it in biology, polymers, or materials science, click chemistry is starting
to click [13a] As a further elaboration of click chemistry, two very recent papers areworth mentioning here Carolyn Bertozzi developed a copper-free AAC (azide–alkynecycloaddition) reaction [13b] in order to alleviate the copper ion effect in living systems,and another paper reports the use of mechano-chemistry to unclick this reaction back[13c]
Trang 39Chemistry Is a Central Science and Synthesis Plays an Essential Role in Chemistry
Chemistry has a central role in science, and organic synthesis plays an essential role
in chemistry [14] As a ‘‘central, useful, and creative’’ science, chemistry has playedand will continue to play an immense and irreplaceable role to improve the quality
of life and health condition of human, and also to promote the development of otherdisciplines and solve the problems of our society [15] Synthetic substances and materialshave demonstrated a significant impact in determining the quality of our life in thelast century Although chemical synthesis has now reached an extraordinary level ofsophistication, there is still vast room for improvement In this century, to be moretightly interlinked with other fields such as materials and life sciences, and to generatemore interdisciplinary areas, are two inevitable trends that synthetic chemistry mustfollow Nowadays, synthetic chemistry should pursue ‘‘green’’ processes In this context,the atom economy, the E-factor, and 3Rs (reduction, recycling, and reuse) of resourcesmust be taken into account in industrial synthetic processes In Chapter 19, entitled
‘‘Synthetic Chemistry with an Eye on Future Sustainability,’’ Guo-Jun Deng and Chao-Jun
Li present a general introduction to green chemistry and in particular instruct us how
to make a synthetically useful reaction, namely the cross-dehydrogenative couplingreaction, greener and greener They also address the catalytic nucleophilic additions
of terminal alkynes in water and metal-catalyzed A3 coupling Different from otherdisciplines, the most remarkable feature of synthetic chemistry is its powerful creativity.The synthetic chemist is able not only to realize the synthesis of substances that alreadyexist in Nature, but is also ready to create new materials with predicted properties andfunctions By serving satisfactorily the primary mission for creating novel substanceswith new structures and new functions, synthetic chemistry lies in the central positionand is situated at the frontier of chemical science By integrating with other disciplines,more and more cutting-edge interdisciplinary areas will emerge, thereby providingmore and more new opportunities for the further development of synthetic chemistry.Enriched by extensive research targets, complicated chemical processes, and diversedemands on structures and properties, synthetic chemistry is provided with morespace and higher requirements in respect of methods and theory developments Inaddition, the development of synthetic chemistry provides possibilities for elucidatingthe structure–function relationship and for the synthesis of new materials with structuraldiversity and excellent properties Synthetic chemistry therefore has provided us with
an avenue to explore its infinite possibilities by tapping into its extremely high level ofscientific creativity
The 2010 Nobel Prize in Chemistry was awarded to Richard Heck, Ei-ichi Negishi, andAkira Suzuki for their contribution to palladium-catalyzed cross-coupling reactions used
in organic synthesis These reactions represent one of the most important methods forthe construction of C–C bonds in modern synthetic organic chemistry These methodshave had a significant impact on the development of new drugs and materials, and havebeen widely used in the industrial production of agrochemicals, pharmaceuticals, andorganic materials The new generation of chemical transformations based on transitionmetal-catalyzed C–H bond activation and functionalization is obviously one of the mostfundamental and challenging issues to impart molecular complexity, and is currently
Trang 40undergoing rapid development in the area of chemical synthesis This thematic researcharea was recognized as one of the ‘‘Holy Grails’’ in chemistry [16] In Chapter 8, Keary En-gle and Jin-Quan Yu highlight the history, the state-of-art research, and future challenges
of this exciting area in synthetic organic chemistry Direct conversion of hydrocarbons tovalue-added chemicals (first functionalization) and further transformations of moleculeswith chemical functionality (including precursors of drugs, agrochemicals, and finechemicals) to realize higher level molecular complexity by the rapid construction ofnew stereocenters and functional group patterns (further functionalization) throughtransition metal-catalyzed C–H activation and functionalization are the main topics ofthis chapter For both the first and further functionalizations, metal complexes play acritically important role The authors emphasize that future efforts will focus on thediscovery of (i) new reactivities of transition metal complexes, (ii) new reaction patterns
to achieve high levels of efficiency (including chemo-, regio-, and enantioselectivity) forthe catalysis of C–H functionalization, and (iii) cost-effective processes
The 2001 Nobel Prize in Chemistry was awarded to William S Knowles, Ryoji Noyori,and Barry Sharpless for their great contributions to the area of asymmetric catalysis Afterthat, asymmetric catalysis experienced rapid development in the last decade Numerousnew chiral catalysts and reactions have been developed by chemists As highlighted
by Christian Sandoval and Ryoji Noyori in Chapter 9, metal-catalyzed asymmetrictransformations are still the mainstream of this research area In comparison with therelative maturity of asymmetric hydrogenation and oxidation, the past decade witnessedmany breakthroughs in catalytic asymmetric carbon–carbon and carbon–heteroatombond formation processes, although many challenges, including selectivity, activity, andapplicability, still remain to be overcome In comparison with metal-catalyzed asymmetrictransformations, organocatalysis, on the other hand, has emerged as one of the mostactive and fascinating areas of asymmetric catalysis since the beginning of this century[17] Chapter 10, by Benjamin List and Sai-Hu Liao, in combination with the commentary
by Keiji Maruoka, Liu-Zhu Gong, and Wen-Jing Xiao, highlights the significant advances
in this fantastic research area The concepts of enamine catalysis, iminium catalysis,amine catalysis, hydrogen-bonding catalysis, singly occupied molecular orbital (SOMO)activation, ketone catalysis, phase-transfer catalysis, nucleophilic catalysis, base catalysis,cooperative multifunctional catalysis, and multicomponent domino or cascade catalysishave been the lodestar for new catalyst and new reaction design In particular, themethodology of organocatalysis has provided an efficient and convenient approach
to access molecular complexity with diverse chemical functionality through one-potmulticomponent reaction patterns, which is expected to have significant impacts onthe generation of molecular diversity for drug discovery [17] (see also Chapters 1 and2) and process development for drug production Two recent examples have beenreported concerning the development of an efficient process for the synthesis of Tamiflu(oseltamivir phosphate), a neuraminidase inhibitor for the treatment of human influenza.Yujiro Hayashi used β-nitro acrylate as a Michael receptor through three ‘‘one-pot’’operations (nine steps) and realized the synthesis of the target molecule [18a] A similar
strategy was employed by Da-Wei Ma [18b], but he started from (Z)-2-nitroethenamine
and completed the process in only four steps (three steps in one pot) Organocatalysis wasused in these two processes The development of new activation modes, understanding