Lindberg Strategies and Tactics in Organic Synthesis

1. Auflage 2012
ISBN: 978-0-08-092430-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 3, 552 Seiten

Reihe: Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis, Volume 3 provides detailed accounts of interesting advances in the field of synthesis. This book discusses the tasks of multistep synthesis from finding the proper reagents, reaction, and conditions for individual steps to inventing new chemistry to fill gaps in existing synthetic methodology. Organized into 13 chapters, this volume begins with an overview of the development of redox glycosidation strategy through ester methylenation. This text then examines the development of computer-assisted molecular modeling with applications to a wide range of problems in biological and organic chemistry. Other chapters consider the medicinal significance of ginkgo tree, which has prompted systematic studies to correlate the claimed beneficial effects of its extracts to the active principles. This book discusses as well the biological potency of pentacyclic quassinoids. The final chapter deals with the economic synthesis of a penem antibacterial. This book is a valuable resource for chemists.

Autoren/Hrsg.

Lindberg, Thomas

Inhaltsverzeichnis

1;Front Cover;1
2;Strategies and Tactics in Organic Synthesis;4
3;Copyright Page;5
4;Table of Contents;6
5;CONTRIBUTORS;14
6;FOREWORD;16
7;PREFACE;18
8;GLOSSARY OF ABBREVIATIONS;20
9;CHAPTER 1. REDOX GLYCOSIDATION: A STEREOSELECTIVE SYNTHESIS OF SUCROSE;22
9.1;I. Prologue;22
9.2;II. Preparation of Selectively Protected and Hydroxy Acids;25
9.3;III. Development of a Redox Glycosidation Strategy via Ester Methylenation;31
9.4;IV. Redox Glycosidation via Thionoester Intermediates;42
9.5;V. The Synthesis of Sucrose;45
9.6;VI. Epilogue;52
9.7;References;53
10;CHAPTER 2. SOLUTION OF COMPLEX STEREOCHEMICAL PROBLEMS WITH THE AID OF MOLECULAR MECHANICS-BASED MODELING: AN APPLICATION TO THE TOTAL SYNTHESIS OF (± )-PLEUROMUTILIN;58
10.1;I. Introduction;58
10.2;II. Conformational Analysis of Pleuromutilin Derivatives;60
10.3;III. Retrosynthetic Analysis;63
10.4;IV. Synthesis of Keto-Olefin 9: Investigation of the Oxy-Cope Sequence;69
10.5;V. Functionalization of Ring A: Our First Encounter with Transannular Effects;81
10.6;VI. Installation of the Stereogenic Centers Present on the 8-Membered Ring;85
10.7;VII. Conversion of the Fully Functionalized Intermediate to (± )-Pleuromutilin (1);103
10.8;VIII. Summary;104
10.9;References;105
11;CHAPTER 3. TOTAL SYNTHESIS OF (± )-GINKGOLIDE B;110
11.1;I. Introduction;111
11.2;II. The Retrosynthetic Analysis;112
11.3;III. Synthesis of Spirocyclic Intermediate 11;115
11.4;IV. Synthesis of Carboxylic Acid 10;118
11.5;V. The [2 + 2] Ketene-Olefin Cycloaddition Reaction [10-9];120
11.6;VI. A Startling Outcome in the Photolysis Reaction: Confirmation of Stereochemistry;122
11.7;VII. Completion of Ring E: A Major Milestone Reached;126
11.8;VIII. Allylic Oxidation of 7: The Problem Resolved;129
11.9;IX. Construction of Ring C: An Inventive Solution to a Recalcitrant Problem;130
11.10;X. Completion of the Synthesis of Ginkgolide B;137
11.11;References;139
12;CHAPTER 4. SYNTHETIC STUDIES ON PENTACYCLIC QUASSINOIDS;142
12.1;I. Introduction;143
12.2;II. Synthetic Philosophy and Goals;144
12.3;III. Overall Synthetic Strategy;150
12.4;IV. The Diels-Alder Approach;153
12.5;V. The Conjugate Addition Approach;156
12.6;VI. Trouble at the Tricyclic Stage;159
12.7;VII. A Tetracyclic Route Triumphs;163
12.8;VIII. Onward to Pentacyclics;167
12.9;IX. Summary;181
12.10;References and Notes;182
13;CHAPTER 5. TOTAL SYNTHESIS OF TAXUSIN: AN INITIAL STEP TOWARD TAXOL SYNTHESIS;186
13.1;I. Background: The Taxane Diterpenes;186
13.2;II. Synthesis of the Taxane Skeleton;189
13.3;III. Synthesis of Taxusin;193
13.4;IV. Summary and Outlook;214
13.5;References and Notes;216
14;CHAPTER 6. THREE AND ONE-HALF APPROACHES TO THE SYNTHESIS OF PEDERIN;220
14.1;I. Introduction;220
14.2;II. Isolation and Structure Proof;222
14.3;III. Biological Activity;224
14.4;IV. Synthesis of Pederin;227
14.5;V. Conclusion;254
14.6;References;255
15;CHAPTER 7. THE CHAMPAGNE ROUTE TO AVERMECTINS AND MILBEMYCINS;258
15.1;I. Introduction;258
15.2;II. The Challenge;259
15.3;III. Initial Plans and Results;261
15.4;IV. The Next Stage;268
15.5;V. Synthesis of Model Compounds and Model Reactions;274
16;CHAPTER 8. THE TOTAL SYNTHESIS OF (± )-NEOLEMNANE AND (± )-14-DEOXYISOAMIJIOL: "THE REST OF THE STORY";316
16.1;I. Introduction;316
16.2;II. (±)-Neolemnane;317
16.3;III. (±)-14-Deoxyisoamijiol;335
16.4;IV. Summary;360
16.5;References;361
17;CHAPTER 9. SYNTHESIS OF CEMBRANOID NATURAL PRODUCTS BY INTRAMOLECULAR SE' ADDITIONS OF ALLYLIC STANNANES TO YNALS;368
17.1;I. Introduction;368
17.2;II. Preliminary Studies–SE' Additions and Horner- Emmons Condensations;370
17.3;III. a-(Alkoxy)allyl Stannanes–Efficient SE' Partners in Cyclizations Leading to Cembranoids;376
17.4;IV. Elaboration of the Cembranoid System–Synthesis of a Racemic Cembranolide;380
17.5;V. Optically Active a-(Alkoxy)allyl Stannanes– Preparation and SE' Chemistry;383
17.6;VI. A Stereorational and Highly Enantioselective Cembranolide Synthesis;387
17.7;VII. Extensions, Disappointments, and Pleasant Surprises;390
17.8;VIII. Summary;398
17.9;References;399
18;CHAPTER 10. SYNTHESIS OF A CANCER GROWTH-INHIBITING DITERPENE: SPATOL;402
18.1;I. Nature's Strategy;403
18.2;II. Prior Art;407
18.3;III. Pilot Studies;413
18.4;IV. A Structurally Selective Synthesis of C-Ring Precursor 44;414
18.5;V. First Synthesis of a Tricyclic Malonic Ester Intermediate;416
18.6;VI. Koga's Enantiospecific Synthesis of a Tricyclic Malonic Ester Intermediate;421
18.7;VII. Dauben's More Convergent Approach;424
18.8;VIII. The Allylic Diepoxide Spatol Side Chain;426
18.9;References;436
19;CHAPTER 11. TOTAL SYNTHESIS OF THE FK506/FKBP COMPLEX;438
19.1;I. Introduction;439
19.2;II. Retrosynthetic Analysis;440
19.3;III. Early Success: The Application of the Class C Two-Directional Chain Synthesis Strategy to the C10–C19 Portion;441
19.4;IV. Preparation of the Cyclohexyl Portion and Model Sulfone Couplings: The First Generation Approach to the C27–C28 Trisubstituted Olefin;445
19.5;V. Preparation of the C20–C27 Portion: Acyclic Stereocontrol via Substrate-Controlled Reactions;449
19.6;VI. The Burgess Elimination Route to the C20–C34 Portion: A Tedious Coupling Procedure;453
19.7;VII. The Vinyl Bromide Coupling: A More Efficient Second Generation Approach to the C27–C28 Olefin;455
19.8;VIII. The Phosphonamide Coupling: Preparation of the C1–N7/C10–C34 Dithiane;460
19.9;IX. Macrolactamization and Challenging Protecting Group Removal: The Total Synthesis ofFK506;464
19.10;X. Discovery of a FK506 and Rapamycin Binding Protein (FKBP);469
19.11;XI. Molecular Cloning and Overexpression of FKBP;471
19.12;XII. (8,9-13C)FK506 and Its Application to Investigations of the FK506/FKBP Complex;472
19.13;XIII. Conclusion;478
19.14;References and Footnotes;479
20;CHAPTER 12. TOTAL SYNTHESIS OF ( – )FK506;484
20.1;I. Introduction;484
20.2;II. The General Plan;486
20.3;III. The C20–C34 Northern Hemisphere: Strategy;487
20.4;IV. The C20–C34 Northern Hemisphere: Synthesis of the Cyclohexanecarboxaldehyde;488
20.5;V. The C20–C34 Northern Hemisphere: Homologation to the C26 Aldehyde;490
20.6;VI. The C20–C34 Northern Hemisphere: Homologation to C20/Aldol Sequence;492
20.7;VII. The C10–C19 Southern Hemisphere: Strategy;494
20.8;VIII. The C10–C19 Southern Hemisphere: Synthesis;495
20.9;IX. The C10–C19 Southern Hemisphere: The Propionamide Enolate–Epoxide Approach;497
20.10;X. Coupling/The C19–C20 Trisubstituted Olefin;500
20.11;XI. Tricarbonyl Introduction: The Dithiane Approach;502
20.12;XII. Tricarbonyl Introduction: C10 as an Electrophile;504
20.13;XIII. Degradation and Rearrangement of FK506;506
20.14;XIV. Pipecolate Chemistry and Macrocyclization;508
20.15;XV. Completion of the Synthesis;509
20.16;References;513
21;CHAPTER 13. AN INDUSTRIAL PERSPECTIVE ON TOTAL SYNTHESIS; PENEM ANTIBACTERIAL CP-70,429;516
21.1;I. Introduction: Discovery of Penem Antibacterial CP-65,207(7);516
21.2;II. Retrosynthetic Analysis: Identification of a General Strategy for Penem Synthesis;519
21.3;III. Background: The Original Synthesis of CP-65,207 (7);519
21.4;IV. The Azetidinone Problem: A Penicillin-Based Approach;522
21.5;V. Problems in Penem Synthesis: The Oxalyl Fluoride Solution;527
21.6;VI. Problems in the Clinic: A Call for Both Penem Diastereomers;531
21.7;VII. Sweet Smell of Success: The Emergence of CP-70,429 (82);534
21.8;VIII. A Convergent Approach to Side-Chain Addition: The Dithiolactone (84) Connection;535
21.9;IX. Some Confusion about Sulfur Extrusion: A Synthesis of Dithiolactone (84);537
21.10;X. Trithiocarbonate Ring Contraction: An Interesting Synthetic Excursion;541
21.11;XI. Michael Addition-Elimination: The Triflate Process;545
21.12;XII. Concluding Remarks;552
21.13;References;552
22;Index;556

Leseproben

Chapter 2 Solution of Complex Stereochemical Problems with the AID of Molecular Mechanics-Based Modeling: An Application to the Total Synthesis of (±)-Pleuromutilin
Robert K. Boeckman, Jr.    Department of Chemistry, University of Rochester, Rochester, New York I. Introduction    37 II. Conformational Analysis of Pleuromutilin Derivatives   39 III. Retrosynthetic Analysis    42 IV. Synthesis of Keto-Olefin 9 Investigation of the Oxy-Cope Sequence    48 V. Functionalization of Ring A: Our First Encounter with Transannular Effects   60 VI. Installation of the Stereogenic Centers Present on the 8-Membered Ring   64 A. Introduction of the C11 and C14 Oxygen Functions   64 B. Creation of the C12 Quaternary Carbon    78 VII. Conversion of the Fully Functionalized Intermediate to (±)-Pleuromutilin (1)   82 VIII. Summary    83 References    84 I Introduction
The development of computer-assisted molecular modeling with applications to a wide array of problems in organic and biological chemistry has been rapid since the early work of Westheimer1 some 40 years ago and subsequent studies of Hendrickson2 and Allinger.3 The molecular mechanics method has become a well-established tool with the development of accurately parameterized computer-based MM2 and other force field methods by Allinger as well as a number of other groups.4–6 The method has proven quite useful as a means to evaluate the ground state energies and geometries of the various conformations in complex organic molecules, permitting the comparison of ground state properties and prediction of the equilibria between configurational isomers. The technique has now been extended with some modifications to the evaluation of transition state energies.7 In 1980, at the inception of our work on (±)-Pleuromutilin (1), we were interested in determining the applicability and usefulness of the molecular modeling technique as an apriori assistance to strategic and tactical planning of a synthetic route to a stereochemically complex system. An ideal choice of a target appeared to be (±)-Pleuromutilin (1), a diterpene antibiotic whose derivative Tiamulin (2) has some commercial importance as an animal health product.8 The structure of 1 had been known since the 1960’s,9,10 and 1 had been shown to exhibit a remarkable spectrum of unusual chemical transformations.Those transformations are principally the result of the chemical (and probably conformational) properties of the 8-membered ring containing 7 stereogenic centers which is the centerpiece of the unique 5-8-6 ring system present in 1.9–12 Since 8-membered rings are among the most conformationally complex of the medium rings, an approach to 1 appeared to pose a formidable challenge in synthetic planning. Although 1 has attracted the interest of a number of research groups,12,13 at the beginning of our work, little was known regarding the accessibility of the tricyclic ring system since most chemistry which had been conducted upon 1 and its derivatives involved degradation and semisynthesis.9–13 However, in 1982, Gibbons (working with Woodward at the time of his passing) described the first successful synthetic approach to 1 involving a typically elegant “Woodwardian” strategy of conformational restriction by rigidification via construction of a sterically strongly-biased ring system in the precursor(s). Using this template, the required stereogenic centers were installed prior to deconvolution to the pleuromutilin ring system (Scheme 1).14,15 This type of strategy has, as its major drawback, an inherently lower efficiency since a more lengthy sequence must be employed as the result of the steps required for assembly and deconvolution of the rigid system on which the stereochemical control is based. Scheme 1 II Conformational Analysis of Pleuromutilin Derivatives
Using MM2, we examined in detail the conformational properties of mutilin (3), the logical precursor of 1, in order to determine the level of complexity of the problem. We were encouraged to find that a conformational search led to only two conformers, 4 and 5, which were local energy minima (Scheme 2). Although it is possible that “twist” conformations may exist which involve C11–C13 (Scheme 2), the conformational search suggested that if these “twist” conformations are populated, they maintain the overall ring topography of the 8-membered ring in the local minimum energy conformations 4 and 5.16 These findings were supported by the analysis of Hendrickson and later Still who found that even-membered medium and macrocyclic rings tend to exist in a few well-defined symmetrical conformations whereas odd-membered rings tend to have more complexitineraries of conformations of often similar energies available to them.17–19 The further conformational restriction imposed by bridging C5 and C9 in 1 eliminates the chair–chair (cc) conformation. As the energy difference (?E = 13.1 kcal/mol) indicates (Scheme 2), the boat–boat (bb) conformation is quite significantly destabilized by the prow interaction between the methyl group at C12 and the hydrogen at C4 as well as by the necessity that the C11 hydroxyl group reside in an axial-like environment. Further analysis of the conformational properties of other related structures such as diketone 6, olefin 7, and keto olefin 8 was done based upon the expectation that the introduction of sp2 centers at C4 and C12 would lower the energy of the bb conformation relative to the boat–chair (bc) conformation. Still Scheme 2 had observed such an effect in his studies.19 The results shown in Scheme 3 indicated that the bb conformation would likely need to be considered only for early intermediates which are relatively unfunctionalized and possess sp2 centers at both C3 and/or C4, and C12. Scheme 3 Thus, the results of our conformational analysis led us to the conclusion that the 8-membered ring could be expected to adopt a well-defined low energy be conformation in most intermediates whose local topography in the region of C10–C14 could be expected to mimic the topography found in 6-membered rings (excepting systems which possess an endocyclic olefin). As a result, the substitution energies (A values) should roughly reflect those found in similar 6-membered ring structures. Therefore, it appeared one could employ a direct functionalization strategy which should result in significantly increased efficiency relative to other conceivable strategies, with the expectation that a reasonable level of stereoselection would be observed. With this background, we developed the two retrosynthetic schemes discussed below. III Retrosynthetic Analysis
Examination of the relative stereochemistry of the substituents in the low energy be conformation of 1 shows that only the vinyl group at C12 exists in an axial or axial-like environment. Therefore, use of thermodynamic control to establish the relative stereochemistry of the other stereogenic centers appeared potentially feasible. Further analysis suggested two potential dissections to arrive at a key keto olefin 9, both of which were intended to systematically remove the functionality in the 8-membered ring. Rather than remove all the substituents, it was deemed desirable to retain one substituent (the methyl group at C10 was selected) to impart additional conformational bias to the 8-membered ring. The first of these dissections is outlined in Scheme 4. Detailed evaluation of this route revealed several potential difficulties especially as the conformational properties of the projected intermediates were determined via MM2 calculations. After initial functional group manipulations to arrive at a differentially protected C14 alcohol, the substituents were envisioned to be removed successively from C12, C11 and C14(C13). Particularly noteworthy among these transformations is the need to reduce the C14 ketone in 10 from the a face. Hydride reduction was known to occur from the undesired ß face in C14 keto pleuromutilin derivatives.10,11A thermodynamically...