Harmata Strategies and Tactics in Organic Synthesis

1. Auflage 2004
ISBN: 978-0-08-051796-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 436 Seiten

A classic in the area of organic synthesis, Strategies and Tactics in Organic Synthesis provides a forum for investigators to discuss their approach to the science and art of organic synthesis. Rather than a simple presentation of data or a second-hand analysis, we are given stories that vividly demonstrate the power of the human endeavour known as organic synthesis and the creativity and tenacity of its practitioners. First hand accounts of each project tell of the excitement of conception, the frustration of failure and the joy experienced when either rational thought and/or good fortune give rise to successful completion of a project.
In this book we learn how synthesis is really done and are educated, challenged and inspired by these stories, which portray the idea that triumphs do not come without challenges. We also learn that we can meet challenges to further advance the science and art of organic synthesis, driving it forward to meet the demands of society, in discovering new reactions, creating new designs and building molecules with atom and step economies that provide solutions through function to create a better world.
- Personal accounts of research in organic chemistry.
- Written by internationally renowned scientists.
- Details state of the art organic synthesis.

Autoren/Hrsg.

Harmata, Michael

Inhaltsverzeichnis

1;COVER;1
2;TOC$CONTENTS;6
3;CONTRIBUTORS;14
4;FOREWORD;16
5;PREFACE;18
6;DEDICATION;20
7;CH$CHAPTER 1. METHODOLOGY VALIDATION AND STRUCTURE CORRECTION BY TOTAL SYNTHESIS: THE CASE OF THE CLERODANE DITERPENOID, SACACARIN;22
7.1;I. Introduction;22
7.2;II. The Search for a Synthetic Target for Double Annulation;23
7.3;III. Retrosynthetic Analysis and Synthetic Design;25
7.4;IV. First-Generation Approach: Synthesis of Tethered Diacid;26
7.5;V. First-Generation Approach: Diastereoselectivity Problem in Double Michael Reaction;27
7.6;VI. Second-Generation Approach: The Double Michael, Pinner, and Dieckmann Reactions;29
7.7;VII. Methylation, Reduction, and Lactonization;31
7.8;VIII. Introduction of the Side Chain;33
7.9;IX. Revision of the Target Structure;35
7.10;X. Proof of the Revised Structure;36
7.11;XI. Conclusion;37
7.12;Acknowledgements;38
7.13;References;38
8;CH$CHAPTER 2. TOTAL SYNTHESIS OF (±)-CYLINDROSPERMOPSIN;40
8.1;I. Introduction;40
8.2;II. Retrosynthetic Analysis;41
8.3;III. Model Study for Closure of the B Ring;42
8.4;IV. Preparation of Acetylene;46
8.5;V. Unsuccessful Approaches to Ketone;49
8.6;VI. Synthesis of Ketone;51
8.7;VII. Completion of the Synthesis of Cylindrospermopsin (1);53
8.8;VIII. Conclusion;57
8.9;References and Footnotes;58
9;CH$CHAPTER 3. THE TOTAL SYNTHESIS OF (-)-ARISUGACIN A.;62
9.1;I. Introduction;62
9.2;II. Retrosynthetic Analysis;65
9.3;III. A Diels-Alder Approach;69
9.4;IV. A Formal [3+3] Cycloaddition Approach;71
9.5;V. The Epoxy Diol Route;72
9.6;VI. Problems with the Epoxy Diol Route;75
9.7;VII. The Triol Route;77
9.8;VIII. Commencement of the Synthesis of (±)-Arisugacin A;81
9.9;IX. An Enantioselective Synthesis of (-)-Arisugacin A;83
9.10;X. Conclusions;85
9.11;References and Footnotes;86
10;CH$CHAPTER 4. TOTAL SYNTHESIS OF KAINOIDS BY DEAROMATIZING ANIONIC CYCLIZATION;92
10.1;I. Introduction the discovery of the dearomatising cyclisation;92
10.2;II. Establishing the cyclisation as a viable synthetic reaction;94
10.3;III. The strategy: conversion of cyclisation products to kainoids;95
10.4;IV. Structural and mechanistic features of the cyclisation;96
10.5;V. Cumyl as a protecting group;97
10.6;VI. Functionalised benzamides: enones as products;98
10.7;VII. Avoiding HMPA: LDA as a cyclisation promoter;99
10.8;VIII. Asymmetric cyclisation with chiral lithium amides;100
10.9;IX. Stereospecific cyclisation of chiral benzamides;102
10.10;X. Synthesis of the acromelic analogue 2;103
10.11;XI. Synthesis of kainic acid 1;109
10.12;XII. Synthesis of a novel methylkainoid 117;113
10.13;XIII. Future prospects: the domoic/isodomoic acid family;115
10.14;References and Footnotes ;116
11;CH$CHAPTER 5. TOTAL SYNTHESIS OF JATROPHATRIONE, AN UNPRECEDENTED [5.9.5] TRICYCLIC ANTILEUKEMIC DITERPENE;118
11.1;I. Introduction;118
11.2;II. Retrosynthetic Analysis;121
11.3;III. Preparation of the Diquinane Building Block;124
11.4;IV. Acquisition of the Brominated Cyclopentadiene ;126
11.5;V. Defining the Nonserviceability of Bromo Acetal 12;128
11.6;VI. Arrival at the Carbotricyclic Framework;130
11.7;VII. More Advanced Functionalization of Potential 9-Epi Precursors;133
11.8;VIII. Elaboration of 8,9-Dehydro Precursors;138
11.9;IX. Setting the Natural Configuration at C9;140
11.10;X. Responding to a Siren Call;141
11.11;XI. Preferred Means for Functionalizing the Northern Rim;143
11.12;XII. Relevance of the Treibs Reaction to the End Game;144
11.13;XIII. The Ultimate Characterization of Jatrophatrionev;148
11.14;XIV. Conclusion;149
11.15;References and Footnotes;149
12;CH$CHAPTER 6. ALKYNYLIODONIUM SALTS IN ORGANIC SYNTHESIS;154
12.1;I. Introduction to Alkynyliodonium Salts and Alkylidenecarbene Chemistry;154
12.2;II. The Synthesis Targets: Scope of the Problem;159
12.3;III. Early Studies on the Synthesis of Agelastatin A;161
12.4;IV. Completion of the Syntheses of (-)-Agelastatin A and (-)-Agelastatin B;166
12.5;V. Synthesis Studies of Halichlorine;174
12.6;VI. Synthesis of Pareitropone;180
12.7;VII. Conclusions;188
12.8;References;188
13;CH$CHAPTER 7. HOW TO THREAD A STRING THROUGH THE EYE OF A MOLECULAR NEEDLE: TEMPLATE SYNTHESIS OF INTERLOCKED MOLECULES;192
13.1;I. Mechanically Interlocked Molecules: A Historical Perspective;192
13.2;II. A Primer to Templated Organic Synthesis;196
13.3;III. Template Effects for the Syntheses of Rotaxanes, Catenanes, and Knots;198
13.4;IV. A Surprising Formation of Catenanes through a Network of Hydrogen Bonds;203
13.5;V. Extending the Amide-Based Template Synthesis to Rotaxanes;208
13.6;VI. Molecular Topology and Topological Chirality;210
13.7;VII. A Trefoil Knot;214
13.8;VIII. The Next Surprise: Rotaxane Synthesis Mediated by a Template Based on Hydrogen-Bonded Anions;218
13.9;IX. Problems and Solutions: A Synthetic Approach to Rotaxanes with Functional Groups in the Axle Centerpiece;223
13.10;X. Conclusions and Future Perspectives;226
14;CH$CHAPTER 8. TOTAL SYNTHESIS OF SPONGISTATIN 1 (ALTOHYRTIN A): A TALE OF TEN ALDOLS;232
14.1;I. Introduction;232
14.2;II. Retrosynthetic Analysis;235
14.3;III. The AB-Spiroacetal Subunit;236
14.4;IV. The CD-Spiroacetal Subunit;240
14.5;V. The Northern Hemisphere;245
14.6;VI. The Southern Hemisphere;247
14.7;VII. Wittig Coupling of the Northern and Southern Hemispheres;257
14.8;VIII. Final Steps and Structure-Activity Relationships;260
14.9;IX. Conclusions;264
14.10;References;264
15;CH$CHAPTER 9. THE RING-CLOSING METATHESIS APPROACH TO FUMAGILLOL;268
15.1;I. Introduction;268
15.2;II. The Synthesis of Fumagillol;269
15.3;References;287
16;CH$CHAPTER 10. DEVISING AN ESPECIALLY EFFICIENT ROUTE TO THE 'MIRACLE' NUTRIENT COENZYME Qio;290
16.1;I. What's "CoQ10"?;290
16.2;II. Why Bother to Synthesize CoQ10?;294
16.3;III. Putting Good Ideas to;295
16.4;IV. The Synthesis: Few Steps, High Yields,... and No Excuses!;299
16.5;V. The Final Oxidation... It's All About the Ligand;303
16.6;VI. Final Thoughts;309
16.7;References;311
17;CH$CHAPTER 11. TOTAL SYNTHESIS OF LIPID I AND LIPID II: LATESTAGE INTERMEDIATES UTILIZED IN BACTERIAL CELL WALL BIOSYNTHESIS;314
17.1;I. Introduction to Bacterial Cell Wall Biosynthesis;11
17.2;II. Retrosynthetic Analysis for Lipid I;317
17.3;III. Synthesis of Phosphomuramyl Pentapeptide;319
17.4;IV. Lipid I Endgame;323
17.5;V. Retrosynthetic Analysis for Lipid II;326
17.6;VI. Assembly of an Orthogonally Protected NAG-NAM Disaccharide;328
17.7;VII. Total Synthesis of Lipid II;330
17.8;VIII. Concluding Remarks;332
17.9;References and Footnotes;332
18;CH$CHAPTER 12. RING REARRANGEMENT METATHESIS (RRM) - A NEW CONCEPT IN PIPERIDINE AND PYRROLIDINE SYNTHESIS;336
18.1;I. Introduction;336
18.2;II. Olefin Metathesis;337
18.3;III. Domino Reactions - Ring Rearrangement Metathesis (RRM);337
18.4;IV. Heterocyclic Systems;338
18.5;V. ROM-RCM;340
18.6;VI. RCM-ROM-RCM - establishing alkaloids containing two rings;350
18.7;VII RCM-ROM-RCM - strategical formation of cyclic silylethers;360
18.8;VIII. Conclusions;364
18.9;Acknowledgements;364
18.10;References;364
19;CH$CHAPTER 13. CATALYTIC ASYMMETRIC TOTAL SYNTHESIS OF (-)-STRYCHNINE AND FOSTRIECIN;368
19.1;I. Introduction;368
19.2;II. Catalytic Asymmetric Total Synthesis of (-)-Strychnine;368
19.3;III. Catalytic Asymmetric Total Synthesis of Fostriecin;374
19.4;IV. Closing Remarks;381
19.5;References and Footnotes;381
20;CH$CHAPTER 14. THE SYNTHESIS OF (±)-STRYCHNINE VIA A COBALT-MEDIATED [2 + 2 + 2]CYCLOADDITION;386
20.1;I. Introduction - The Objectives of Organic Synthesis;386
20.2;II. Target Strychnine;388
20.3;III. The Cobalt Way to Strychnine;389
20.4;IV. Unsuccessful Approaches to Strychnine From ABCD Intermediates;392
20.5;V. Successful Approach to Strychnine: Part 1 - A "Simpler" Plan Hits Snags;398
20.6;VI. Successful Approach to Strychnine: Part 2 - An Unprecedented [2 + 2 + 2]Cyclization;401
20.7;VII. Successful Approach to Strychnine: Part 3 - Formation of the E Ring by Oxidative Demetalation/Intramolecular Conjugate Addition;405
20.8;VIII. Successful Approach to Strychnine: Part 4 - The Battle for the F Ring;407
20.9;IX. Conclusions;421
20.10;References and Footnotes;422
21;IDX$Index;428

Leseproben

Chapter 1 Methodology Validation and Structure Correction by Total Synthesis: The Case of the Clerodane Diterpenoid, Sacacarin
Robert B. Grossman and Ravindra M. Rasne,     Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506 I Introduction II The Search for a Synthetic Target for Double Annulation III Retrosynthetic Analysis and Synthetic Design IV First-Generation Approach: Synthesis of Tethered Diacid V First-Generation Approach: Diastereoselectivity Problem in Double Michael Reaction VI Second-Generation Approach: The Double Michael, Pinner, and Dieckmann Reactions VII Methylation, Reduction, and Lactonization VIII Introduction of the Side Chain IX Revision of the Target Structure X Proof of the Revised Structure XI Conclusion Acknowledgements References I. Introduction
Scientists who pursue the total synthesis of natural products may choose a target compound for several reasons. The target may be chosen because it has potentially useful properties in biological systems (antibiotic, anticancer, etc.); because of unique structural elements that make its synthesis particularly challenging, so that its structure can be confirmed; or because it has structural elements that make it particularly amenable to synthesis by a newly developed synthetic methodology. The total synthesis described in the following account was a product of the last motivation. Our group had developed a synthetic methodology, a suite of reactions that we called double annulation, and we sought to apply it to the synthesis of a naturally-occurring compound. The target that we chose was sacacarin, whose structure was reported to be 1 (Figure 1).1 We chose this compound simply because, among all the natural products we found when we sifted through the literature, its structure was best suited to our methodology. However, the achievement of the synthesis resulted in a correction of the structure of the natural product to 2,2 showing that, despite all the powerful spectroscopic methods available to chemists today, total synthesis is sometimes still the ultimate structural proof. Figure 1 The originally reported structure of sacacarin (1) and its corrected structure (2). II. The Search for a Synthetic Target for Double Annulation
Our story begins in 1999, when our group had completed several projects showing that the double annulation sequence provided a convenient, stereoselective route to trans-decalins, 3, featuring two quaternary centers decorated with three functionalized, one-carbon substituents (Scheme 1).3,4 The double annulation was originally conceived as a potential route to the insect antifeedant, azadirachtin (Figure 2), which features just such a trans-decalin moiety.5 However, it was clear to us that azadirachtin’s very complex structure would make it a poor choice for our first total synthesis effort. In fact, despite the efforts of some large and very talented synthetic groups across the world,6 azadirachtin has yet to succumb to total synthesis. Figure 2 Azadirachtin, the inspiration for the double annulation. Scheme 1 Azadirachtin is a tetranortriterpenoid; i.e., it has a C26 skeleton that is built up from six isoprene units (C5 × 6) followed by the removal of four C atoms. Many other terpenoids are known whose skeletons, like azadirachtin, contain trans-decalin moieties similar to the one present in 3 (Figure 3). These terpenoids include sesquiterpenoids such as the drimanes, diterpenoids such as the labdanes, clerodanes, kauranes, atisanes, and abietanes, and higher terpenoids such as the lanostanes. Because of their simpler structures, we chose to focus our search among the drimane, labdane, and clerodane terpenoids. Specifically, we sought terpenoids in these classes in which as many of the C(4) and C(10) substituents [C(5) and C(9) in clerodanes] as possible were functionalized, because we wanted to incorporate as much as possible of the functionality that was present in 3 into the final target. We also preferred to see functionalization at C(7) [C(2) in clerodanes] and none at C(1–3) [C(6–8) in clerodanes]. Finally, we preferred that our target had biological activity. Figure 3 Skeletons of some terpenoids that contain trans-decalin moieties. The strictures that we placed on our search eliminated most natural products from consideration. The most suitable compound, 1, was the one recently reported to be the structure of the clerodane, sacacarin (Figure 4).1 With respect to the C(5) and C(9) substituents, 1 was functionalized at both C(19) and C(20), and, although it was not functionalized at C(11), we could easily imagine attaching C(12–16) to a synthetic precursor via a functionalized C(11). Furthermore, 1 was functionalized at C(2) and was unfunctionalized at C(6–8). Finally, although sacacarin had not been tested for biological activity, most of the clerodanes isolated from natural sources have been shown to have insect antifeedant and other biological activities.7 Sacacarin itself was isolated from the bark of a Brazilian tree, known locally as sacaca, that was used for various medicinal purposes,8 although it constituted only about 0.0015% by weight of the dry bark. Figure 4 Compound 1 and its numbering system. III. Retrosynthetic Analysis and Synthetic Design
With a target chosen, the next task was a retrosynthetic analysis (Scheme 2). We envisioned attaching the C(12–16) side chain of 1 via a Wittig reaction of tricyclic aldehyde 4. We envisioned the lactone of 4 as being prepared by cyclization of a cyano alcohol, which could be prepared from diester 5. Finally, we presumed that the C(18) Me group of 5 could be installed by addition of MeLi to the ß-ethoxyenone group of 6. Our retrosynthetic analysis ended at this point, because 6 was very similar to 3c, a compound we had already prepared in our previous work.3 Following that precedent, 6 would be prepared from 7 by a regioselective Dieckmann reaction, 7 would be prepared from 8 by a diastereoselective double Michael reaction, and 8 would be prepared from 9 by alkylation of diethyl malonate and ethyl cyanoacetate with 1,3-dibromobutane. Scheme 2 We wanted to incorporate several features into our synthetic design. First, like all clerodanes, 1 had four contiguous stereocenters, and we wanted our synthesis to be highly diastereoselective and amenable to enantioselective modification. Second, we wanted to avoid protecting group manipulations wherever possible. Protecting groups must sometimes be used in a synthesis, but they are the bane of organic synthesis. Many a synthetic effort has foundered on the shoals of an injudicious or merely unlucky choice of protecting group. Protecting groups also introduce extra steps into a synthesis, entailing costs of material loss and consumption of time and effort. We wanted to show that seemingly identical functional groups within densely functionalized intermediates such as 5, 6, and 7 could be differentiated without resorting to protecting group manipulations. Third, we wanted to use simple, inexpensive, off-the-shelf reagents to carry out these manipulations. Fourth, we wanted to maximize the proportion of C–C bond-forming steps in the total synthesis, keeping the overall synthesis as short as possible. Fifth, we wanted our synthetic approach to differ significantly from previous synthetic approaches to the clerodane diterpenoids.9 IV. First-Generation Approach: Synthesis of Tethered Diacid
The starting materials for double annulation are compounds that we have dubbed “tethered diacids.” They consist of two carbon acids (malonate derivatives, nitro compounds, and the like) connected by a tether. Tethered diacid 8 was easily prepared by the methodology we had previously reported for preparing such compounds (Scheme 3).10 Knoevenagel adduct 10 was deprotonated with NaH and...