Organic Synthesis E-Book

Paul Wyatt

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1317

Veröffentlichungsjahr: 2013

Beschreibung

Organic Synthesis: Strategy and Control is a sequel to Stuart Warren's bestseller Organic Synthesis: The Disconnection Approach. The 'Disconnection' book concentrated on the planning behind the synthesis of compounds.

The two themes of this new book are strategy and control: solving problems either by finding an alternative strategy or by controlling any established strategy to make it work.

The book is divided into five sections that deal with selectivity, carbon-carbon single bonds, carbon-carbon double bonds, stereochemistry and functional group strategy. Interpenetrating this structure, the 36 chapters start with classic methods and progress to modern methods and modern strategic considerations. Heterocyclic chemistry is treated throughout the book with full mechanistic explanations as part of organic chemistry rather than a separate mystery.

• A comprehensive, practical account of the key concepts involved in synthesising compounds.
• Takes a mechanistic approach, which explains reactions and gives guidelines on how reactions might behave in different situations.
• Focuses on reactions that really work rather than those with limited application.
• Extensive, up-to-date references in each chapter.

Students and professional chemists familiar with Organic Synthesis: The Disconnection Approach will enjoy the leap into a book designed for chemists at the coalface of organic synthesis.

Leseprobe

Contents

Preface

Section A: Introduction: Selectivity

1. Planning Organic Syntheses: Tactics, Strategy and Control

A Modern Synthesis: Fostriecin (CI-920)

References

2. Chemoselectivity

Definitions

Chemoselectivity by Reactivity and Protection: An anti-Malaria Drug

When Protection is not Needed

Chemoselectivity by Reagent: The Pinacol Rearrangement

Chemoselectivity in Enol and Enolate Formation

Examples of Chemoselective Reactions in Synthesis

References

3. Regioselectivity: Controlled Aldol Reactions

Definition

Specific Enol Equivalents

Regioselective Aldol Reactions

Reaction at Oxygen or Carbon? Silylation, Acylation and Alkylation

Acylation at Carbon

Reactions with Other Electrophiles

A Final Example

References

4. Stereoselectivity: Stereoselective Aldol Reactions

The Stereochemistry of the Aldol Reaction

Stereoselectivity outside the Aldol Relationship

References

A Note on Stereochemical Nomenclature

5. Alternative Strategies for Enone Synthesis

The Synthesis of Enones by Many Strategies

Strategy 4a: The Aldol Route to Enones

Strategy 4b: Acylation of a Vinyl Anion

Strategy 4c: Unsaturated Acyl Cations and Anions

References

6. Choosing a Strategy: The Synthesis of Cyclopentenones

Strategies Based on an Aldol Reaction

Using the Aliphatic Friedel-Crafts Reaction

The Nazarov Reaction

Cycloadditions of Fe(CO)4 Complexes of Oxyallyl cations

The Pauson-Khand Reaction

Recent Developments in the Pauson-Khand Reaction

Oxidative Rearrangement of Tertiary Allylic Alcohols

Other Methods

References

Section B: Making Carbon–Carbon Bonds

7. The Ortho Strategy for Aromatic Compounds

Introduction

PART I Friedel-Crafts Reaction and Fries Rearrangement

The Claisen Rearrangement

PART II Using Lithium

Ortho-lithiation

Multiple Directed Lithiations

Reactions of Fluoroanisoles

Several lithiations

Halogens

Benzyne Formation—A different aromatic strategy

α-Lithiation

Lateral Lithiation

Summary

Summary of Reagents

References

8. σ-Complexes of Metals

Introduction The structure of organo-Iithium compounds

Transition Metal Complexes

References

9. Controlling the Michael Reaction

Introduction: Conjugate, 1,4- or Michael addition vs direct or 1,2-addition

Using Copper (I) to Achieve Michael Addition

Michael Addition followed by Reaction with Electrophiles

A Double Nucleophile: An Interlude without Copper

A Michael Reaction Coupled to a Photochemical Cyclisation: Copper Again

Michael Additions of Heteroatom Nucleophiles

Michael Additions with and without Copper: Functionalised Michael Donors

References

10. Specific Enol Equivalents

Introduction: Equilibrium and Specific Enolates

Enolates from 1,3-di-Carbonyl Compounds

Enamines and Aza-Enolates

Lithium Enolates and Silyl Enol Ethers

Tables of Enol Equivalents and Specific Enolates

Modern Use of Specific Enolate Equivalents

References

11. Extended Enolates

Introduction: The extended enolate problem.

Wittig and Horner-Wadsworth-Emmons Reactions

Extended Aza-Enolates

Extended Lithium Enolates of Aldehydes

Summary: α-Alkylation of Extended Enolates

Reaction in the γ-Position

Extended Enolates from Unsaturated Ketones

Diels-Alder Reactions

Extended Enolates from Birch Reductions

The Baylis-Hillman Reaction

The Synthesis of Mniopetal F

A Synthesis of Vertinolide Using α′ and γ-Extended Enolates

Conclusion: Extended Enolate or Allyl Anion?

References

12. Allyl Anions

Introduction: Allyl Grignard Reagents

Allylic Lithiums and Grignard Reagents

Allyl Nickel Complexes

Allyl Silanes

An Allyl Dianion? The Role of Tin in Anion Formation

Halide Exchange with Chelation: Indium Allyls

Allyl Anions by Deprotonation

References

13. Homoenolates

Introduction: Homoenolisation and homoenolates

Three-Membered Ring Homoenolate Equivalents (The ‘Direct’ Strategy)

The Defensive Strategy: d3 Reagents with Protected Carbonyl Groups

The Offensive Strategy: Heteroatom-Substituted Allyl Anions

Allyl Carbamates

References

14. Acyl Anion Equivalents

Introduction: Acyl Anions?

Acyl Anion Equivalents: d1 Reagents

Modified Acetals as Acyl Anion Equivalents

Protected Cyanohydrins of Aldehydes

Methods Based on Vinyl (Enol) Ethers and Enamines

Oxidative Cleavage of Allenes

Vinyl Ethers and Enamines from Wittig-Style Reactions

Nitroalkanes

Catalytic Methods: The Stetter Reaction

References

Section C: Carbon–Carbon Double Bonds

15. Synthesis of Double Bonds of Defined Stereochemistry

Introduction: Alkenes: framework or functional groups?

Control of Alkene Geometry by Equilibrium Methods

A More Detailed Look at The Principles

The Wittig Reaction

Crossing the Stereochemical Divide in the Wittig Reaction

Stereocontrolled Reactions

Stereoselective Methods for E-alkenes: The Julia Reaction

Direct Coupling of Carbonyl Compounds and Alkenes

Stereoselective Methods for E-alkenes

Reduction of Alkynes

Stereospecific Methods for Z-Alkenes

Interconversion of E and Z Alkenes

Stereospecific Interconversion of E and Z-isomers

References

16. Stereo-Controlled Vinyl Anion Equivalents

Introduction: Reagents for the Vinyl Anion Synthon

Vinyl-Lithiums

Vinyl-Lithiums from Ketones: The Shapiro Reaction

The Aliphatic Friedel-Crafts Reaction

Hydrometallation of Alkynes

Hydroboration and Hydroalumination of Alkynes

Hydrosilylation

Hydrozirconation

Carbo-Metallation

Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles

References

17. Electrophilic Attack on Alkenes

Introduction: Chemo-, Regio-, and Stereoselectivity

Chemoselectivity

Controlling Chemoselectivity

Regioselectivity

‘Markovnikov’ Hydration

Hydroboration: ‘Anti-Markovnikov’ Hydration of Alkenes

Alternative Approaches to the Synthesis of Alcohols from Alkenes

Stereoselectivity

Selectivity by Intramolecular Interactions Halolactonisation

Sulfenyl- and Selenenyl-Lactonisation

The Prins Reaction

Hydroboration as a Way to Make Carbon-Carbon Bonds Carbonylation of Alkyl Boranes

Polyene Cyclisations

Looking Forwards

References

18. Vinyl Cations: Palladium-Catalysed C–C Coupling

Introduction: Nucleophilic Substitution at sp2 Carbon does NOT Occur

Towards Carbon Nucleophiles and Vinyl Cation Equivalents

Conjugate Substitution

Conjugate Addition to Alkynes

The Diels-Alder Reaction on β-Bromo and β-Sulfonyl Alkynes

Modified Conjugate Addition

The Heck Reaction

Sp2–sp2 Cross-Coupling Reactions by Transmetallation

Summary

References

19. Allyl Alcohols: Allyl Cation Equivalents (and More)

PART I – INTRODUCTION

The Problem of the [1,3]-Shift

PART II – PREPARATION OF ALLYLIC ALCOHOLS

Traditional Methods

Allylic Alcohols by [2,3] Sigmatropic Shifts

PART III - REACTIONS OF ALLYLIC ALCOHOLS

[2,3] Sigmatropic Rearrangements

Reactions with Electrophiles

Regio- and Stereocontrolled Reactions with Nucleophiles

Summary

References

Section D: Stereochemistry

20. Control of Stereochemistry – Introduction

Introduction

The Words We Use

The Structures We Draw

The Fundamentals of Stereochemical Drawings

Stereochemical Descriptors

The Next Ten Chapters

Stereochemical Analysis

Some Principles

Popular Misconceptions

References

21. Controlling Relative Stereochemistry

Introduction

PART I – NO CHIRALITY IN PLACE AT THE START

Formation of Cyclic Compounds via Cyclic Transition States

Formation of Acyclic Compounds via Cyclic Transition States

Reactions of Cyclic Compounds

PART II – CHIRALITY IN PLACE FROM THE START

Reactions of Cyclic Compounds: Conformational Control

Formation of a Cyclic Intermediate

Formation of an Acyclic Compound via a Cyclic Transition State

Stereoselective Reduction of β-Hydroxy Ketones

Open Chain Chemistry - with Chelation Control

Open Chain Chemistry - in its Most Genuine Form

References

22. Resolution

Resolution

Choice and Preparation of a Resolving Agent

Advantages and Disadvantages of the Resolution Strategy

When to Resolve

Resolution of Diastereoisomers

Physical Separation of Enantiomers

Differential Crystallisation or Entrainment of Racemates

Resolution with Racemisation

Kinetic Resolution with Enzymes

Asymmetric Synthesis of Prostaglandins with many Chiral Centres

References

23. The Chiral Pool — Asymmetric Synthesis with Natural Products as Starting Materials —

Introduction: The Chiral Pool

PART I – A SURVEY OF THE CHIRAL POOL

The Amino Acids

Hydroxy Acids

Amino Alcohols

Terpenes

Carbohydrates – the Sugars

The Alkaloids

PART II – ASYMMETRIC SYNTHESES FROM THE CHIRAL POOL

Amino Acids

Hydroxy-Acids

Amino Alcohols

The New Chiral Pool

Conclusion: Syntheses from the Chiral Pool

PART III–THE CHIRAL POOL

References

24. Asymmetric Induction I Reagent-Based Strategy

Introduction to Reagent-Based Strategy

Asymmetric Reduction of Unsymmetrical Ketones

Asymmetric Electrophiles

Asymmetric Nucleophilic Attack

Transfer of Allylic Groups from Boron to Carbon

Asymmetric Addition of Carbon Nucleophiles to Ketones

Asymmetric Nucleophilic Attack by Chiral Alcohols

Asymmetric Conjugate Addition of Nitrogen Nucleophiles

Asymmetric Protonation

Asymmetric Deprotonation with Chiral Bases

Asymmetric Oxidation

References

25. Asymmetric Induction II Asymmetric Catalysis: Formation of C–0 and C–N Bonds

Introduction: Catalytic methods of asymmetric induction

PART I – SHARPLESS ASYMMETRIC EPOXIDATION

The AE method

Modification after Sharpless Epoxidation

Asymmetric Induction at the Allylic Alcohol Centre: AE is anti-Selective

No Asymmetric Induction from Remote Allylic Alcohol Centre: Reagent Control

Asymmetric Synthesis of Diltiazem

Summary of Sharpless Epoxidation

PART II – SHARPLESS ASYMMETRIC DIHYDROXYLATION

The AD Method

Substrate Dependence and the Mnemonic Device

Applications of the Sharpless AD Reaction

Dihydroxylating Compounds with More than One Double Bond I—Regioselectivity

Dihydroxylating Compounds with More than One Double Bond II—Diastereoselectivity

Scaling Up the Asymmetric Dihydroxylation

PART III – AMINOHYDROXYLATION

PART IV – CONVERTING 1,2-DIOLS INTO EPOXIDES

PART V – JACOBSEN EPOXIDATION

PART VI – DESYMMETRISATION REACTIONS

PART VII – HETERO DIELS-ALDER REACTIONS

References

26. Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds

Introduction: Formation of C–H and C–C Bonds

PART I – ASYMMETRIC FORMATION OF C–H BONDS

Introduction: Catalytic hydrogenation with soluble catalysts

Hydrogenation with C2-Symmetrical bis-Phosphine Rhodium Complexes

Hydrogenation with C2-Symmetrical BINAP Rh and Ru Complexes

Asymmetric Hydrogenation of Carbonyl Groups

A Commercial Synthesis of Menthol

Corey’s CBS Reduction of Ketones

PART II – ASYMMETRIC FORMATION OF C–C BONDS

Organic Catalysis

Catalysed Asymmetric Diels-Alder Reactions

Cyclopropanation

Asymmetric Alkene Metathesis

Asymmetric Pericyclic Additions to Carbonyl Groups

Nucleophilic Additions to Carbonyl Groups

Palladium Allyl Cation Complexes with Chiral Ligands

Summary

References

27. Asymmetric Induction IV Substrate-Based Strategy

Introduction to Substrate-Based Strategy

Chiral Carbonyl Groups

Chiral Enolates from Imines of Aldehydes: SAMP and RAMP

Chiral Enolates from Amino Acids

Chiral Enolates from Hydroxy Acids

Chiral Enolates from Evans Oxazolidinones

Aldol Reactions with Evans Oxazolidinones

Chiral Auxiliaries

The Asymmetric Diels-Alder Reaction

Improved Oxazolidinones: SuperQuats

Asymmetric Michael (Conjugate) Additions

Other Chiral Auxiliaries in Conjugate Addition

Asymmetric Birch Reduction

References

28. Kinetic Resolution

Types of Reactivity

The Water Wheel

S Values, Equations & Yields

Standard Kinetic Resolution Reactions

Dynamic Kinetic Resolutions

Parallel Kinetic Resolutions

Regiodivergent resolutions

Double Methods

References

29. Enzymes: Biological Methods in Asymmetric Synthesis

Introduction: Enzymes and Organisms

Organisms: Reduction of Ketones by Baker’s Yeast

Ester Formation and Hydrolysis by Lipases and Esterases

Enzymatic Oxidation

Nucleophilic Addition to Carbonyl Groups

Practical Asymmetric Synthesis with Enzymes

References

30. New Chiral Centres from Old — Enantiomerically Pure Compounds & Sophisticated Syntheses —

The Purpose of this Chapter

New Chiral Centres from Old

Creating New Chiral Centres with Cyclic Compounds

Stereochemical Transmission by Cyclic Transition States: Sigmatropic Rearrangements

Control of Open Chain Stereochemistry

Introduction to 1,4-1,5- and Remote Induction

The Asymmetric Synthesis of (+)-Discodermolide

Conclusion

References

31. Strategy of Asymmetric Synthesis

Introduction: Strategy of Asymmetric Synthesis

PART I – (R) AND (S)-2-AMINO-1-PHENYLETHANOL

PART II – (2S,4R)-4-HYDROXYPIPECOLIC ACID

PART III – GRANDISOL AND SOME BICYCLO[3.2.0] HEPTAN-2-OLS

Chiral Pool Syntheses from Other Terpenes

Asymmetric Synthesis

A Disappointment and a Resolution

PART IV – METALLOPROTEINASE INHIBITORS

PART V – CONFORMATIONAL CONTROL AND RESOLUTION: KINETIC OR NOT?

PART VI – ASYMMETRIC DESYMMETRISATION OF A DIELS-ALDER ADDUCT

PART VII – ASYMMETRIC SYNTHESIS OF A BICYCLIC β-LACTONE

References

Section E: Functional Group Strategy

32. Functionalisation of Pyridine

Introduction

PART I – THE PROBLEM

N-Nitro Heterocycles as Nitrating Agents

PART II – TRADITIONAL SOLUTIONS: ADDITION OF ELECTRON-DONATING SUBSTITUENTS

Regioselectivity in Electrophilic Substitution with Electron-Donating Groups

The Anti-Tumour Antibiotic Kedarcidin

Halogenatìon and Metallation

Pyridine N- Oxides in Electrophilic Substitution

Ortho-Lithiation of Pyridines

Diazines

The Halogen Dance

Tandem Double Lithiation: The asymmetric synthesis of camptothecin

Tandem Lithiation of Pyridine N- Oxides and Nucleophilic Substitution

PART III – SURPRISINGLY SUCCESSFUL DIRECT ELECTROPHILIC SUBSTITUTIONS

PART IV – SUCCESSFUL NITRATION OF PYRIDINE

Sulfonation of Pyridines

Extension by Vicarious Nucleophilic Aromatic Substitution

Synthesis of Imidazo[4,5-c]pyridines

PART V – APPLICATIONS

References

33. Oxidation of Aromatic Compounds, Enols and Enolates

Introduction

PART I – ELECTROPHILIC SUBSTITUTION BY OXYGEN ON BENZENE RINGS

The Diazotisation Approach

The Friedel-Crafts and Baeyer-Villiger Route

Oxidation through Lithiation and Ortho-Lithiation

Hydroxylation of Pyridines by ortho-Lithiation

Synthesis of Atpenin B

Introducing OH by Nucleophilic Substitution

PART II – OXIDATION OF ENOLS AND ENOLATES

Direct Oxidation without Formation of a Specific Enol

Indirect Oxidation with Formation of a Specific Enol: Enone Formation

Asymmetric Synthesis of Cannabispirenones

Oxidation of Enones: Epoxides and the Eschenmoser Fragmentation

PART III – ELECTROPHILIC ATTACK ON ENOL(ATE)S BY OXYGEN

The Problem

Unexpected Success with the “Obvious” Reagents

First Successful Method: Epoxidation of Silyl Enol Ethers (Rubottom Oxidation)

Hydroxylation of Amino-ketones via Silyl Enol Ethers

Second Successful Method: Hydroxylation with MoOPH

Third Successful Method: Hydroxylation with N-Sulfonyl Oxaziridines

Summary

References

34. Functionality and Pericyclic Reactions: Nitrogen Heterocycles by Cycloadditions and Sigmatropic Rearrangements

PART I – INTRODUCTION

The Effects of Functionality on Pericyclic Reactions

PART II– CYCLOADDITIONS TO MAKE NITROGEN HETEROCYCLES

Diels-Alder Reactions with Azadienes

Diels-Alder Reactions with Imines

Intramolecular Diels-Alder Reactions with Azadienes

Intramolecular Diels-Alder Reactions with Imines

Intramolecular Diels-Alder Reactions with a Nitrogen Tether

PART III – ‘ENE’ REACTIONS TO MAKE NITROGEN HETEROCYCLES

Intramolecular Alder ‘Ene’ Reactions with a Nitrogen Tether

Intermolecular ‘Ene’-style Reactions with Oximes

PART IV – [3,3] SIGMATROPIC REARRANGEMENTS

The Aza-Cope’ Rearrangement

The Anionic ‘Aza-Cope’ Rearrangement

PART V – OTHER REACTIONS

Electrocyclic Reactions

Ring Closing Olefin Metathesis

The Pauson-Khand Reaction

Metal-Catalysed Alkyne Trimerisation

References

35. Synthesis and Chemistry of Azoles and other Heterocycles with Two or more Heteroatoms

PART I – INTRODUCTION

Azoles: Heterocyclic Compounds with More than One Nitrogen Atom

PART II – BUILDING THE RING

a. The Simplest Disconnections

b. Routes to Isoxazoles

c. Tetrazoles

PART III – DISCONNECTIONS OUTSIDE THE RING

a. N–C Disconnections: Azole Anions

b. C–X Disconnections

c. C-C Disconnections

d. Examples: an Anti-Ulcer Drug and Pentostatin

A Designed Enzyme Inhibitor

References

36. Tandem Organic Reactions

PART I – INTRODUCTION

What are Tandem Reactions?

Tandem Reactions We Shall Not Discuss

PART II – CONJUGATE ADDITION AS THE FIRST STEP

Simple Enolate Capture by Electrophiles

Tandem Michael-Michael Reactions: One Conjugate Addition Follows Another

Tandem Reactions as Polymerisation Terminated by Cyclisation

Heterocycles by Tandem Conjugate Additions

Tandem Conjugate Addition and Aldol Reaction

PART III – INTERMEDIATE IS UNSTABLE IMINE OR ENAMINE

Intermediate Would Be Formed by Amide Condensation

Asymmetric Tandem Methods Involving Unstable Imines etc.

An Asymmetric Synthesis of (+)-Pumiliotoxin B

PART IV – TANDEM PERICYCLIC REACTIONS

Electrocyclic Formation of a Diene for Diels-Alder Reaction

Tandem Ene Reactions

Tandem [3,3]-Sigmatropic Rearrangements

Tandem Aza-Diels-Alder and Aza-Ene Reactions

Tandem Reactions Involving 1,3-Dipolar Cycloaddition

PART IV – OTHER TANDEM REACTIONS LEADING TO HETEROCYCLES

A Tandem Metallation Route to the Ellipticine Skeleton

Tandem Aza-Diels-Alder and Allyl Boronate Reactions

Tandem Beckmann Rearrangement and Allyl Silane Cyclisation

PART V – TANDEM ORGANOMETALLIC REACTIONS

Tandem Asymmetric Heck and Pd-Allyl Cation Reactions

Tandem Ring-Closing and Ring-Opening Metathesis

A Ru-Catalysed Four-Component Coupling

References

General References

Index

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Library of Congress Cataloging-in-Publication Data

Wyatt, Paul.

Organic synthesis: strategy and control / Paul Wyatt and Stuart Warren.

p. cm.

Includes bibliographical references.

ISBN: 978-0-470-48940-5

ISBN: 978-0-471-92963-5

1. Organic compounds – Synthesis. 2. Stereochemistry. I. Warren, Stuart

G. II. Title.

QD262.W89 2007

547′.2–dc22      2006034932

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-471-48940-5 (HB)

ISBN: 978-0-471-92963-5 (PB)

Preface

We would like to thank those who have had the greatest influence on this book, namely the undergraduates at the Universities of Bristol and Cambridge. But, particularly we would like to thank the organic chemists at Organon (Oss), AstraZeneca (Alderley Park, Avlon Works, Mölndal and Macclesfield), Lilly (Windlesham), Solvay (Weesp) and Novartis (Basel) who contributed to the way the book was written more than they might realise. These chemists will recognise material from our courses on The Disconnection Approach, Advanced Heterocyclic Chemistry, New Synthetic Methods and Asymmetric Synthesis. Additionally we would like to thank the participants at the SCI courses organised by the Young Chemists Panel. All these industrial chemists participated in our courses and allowed us to find the best way to explain concepts that are difficult to grasp. This book has changed greatly over the ten years it was being written as we became more informed over what was really needed. The book is intended for that very audience – final year undergraduates, graduate students and professional chemists in industry.

PJWSGWJuly 2006

Section A: Introduction: Selectivity

1. Planning Organic Syntheses: Tactics, Strategy and Control

2. Chemoselectivity

3. Regioselectivity: Controlled Aldol Reactions

4. Stereoselectivity: Stereoselective Aldol Reactions

5. Alternative Strategies for Enone Synthesis

6. Choosing a Strategy: The Synthesis of Cyclopentenones

1

Planning Organic Syntheses: Tactics, Strategy and Control

The roll of honour inscribed with successful modern organic syntheses is remarkable for the number, size, and complexity of the molecules made in the last few decades. Woodward and Eschenmoser’s vitamin B12 synthesis,1 completed in the 1970s, is rightly regarded as a pinnacle of achievement, but since then Kishi2 has completed the even more complex palytoxin. The smaller erythromycin and its precursors the erythronolides31, and the remarkably economical syntheses of the possible stereoisomers of the cockroach pheromones 2 by Still4 deal with a greater concentration of problems.

Less applauded, but equally significant, is the general advance in synthetic methods and their industrial applications. AstraZeneca confess that it took them nearly a century to bring Victor Grignard’s methods into use, but are proud that Corey’s sulfur ylid chemistry made it in a decade. Both are used in the manufacture of the fungicide flutriafol53.

Optically active and biodegradable deltamethrin64 has taken a large share of the insecticide market, and asymmetric hydrogenation is used in the commercial synthesis of DOPA 5 used to treat Parkinson’s disease.7 These achievements depend both on the development of new methods and on strategic planning:8 the twin themes of this book.

To make any progress in this advanced area, we have to assume that you have mastered the basics of planning organic synthesis by the disconnection approach, roughly the material covered in our previous books.9 There, inspecting the target molecule, identifying the functional groups, and counting up the relationships between them usually gave reliable guidelines for a logical synthesis. All enones were tackled by some version of the aldol reaction; thus 6 would require the attack of enolate 7 on acetone. We hope you already have the critical judgement to recognise that this would need chemoselectmty in enolising 7 rather than acetone or 6, and regioselectivity in enolising 7 on the correct side.

In this book we shall explore two new approaches to such a problem. We shall see how to make specific enol equivalents for just about any enolate you might need, and we shall see that alternative disconnections such as 6a, the acylation of a vinyl anion 8, can be put into practice. Another way to express the twin themes of this book is strategy and control: we solve problems either by finding an alternative strategy or by controlling any given strategy to make it work. This will require the introduction of many new methods - a whole chapter will be devoted to reagents for vinyl anions such as 8, and this will mean exploring modern organometallic chemistry.

We shall also extend the scope of established reactions. We hope you would recognise the aldol disconnection in TM 10, but the necessary stereochemical control might defeat you. An early section of this book describes how to control every aspect of the aldol reaction: how to select which partner, i.e. 11 or 12, becomes an enolate (chemoselectivity), how to control which enolate of the ketone 12 is formed (regioselectivity), and how to control the stereochemistry of the product 10 (stereoselectivity). As we develop strategy, we shall repeatedly examine these three aspects of control.

The target molecules we shall tackle in this book are undoubtedly more difficult in several ways than this simple example 10. They are more complex quantitatively in that they combine functional groups, rings, double bonds, and chiral centres in the same target, and qualitatively in that they may have features like large rings, double bonds of fixed configuration, or relationships between functional groups or chiral centres which no standard chemistry seems to produce. Molecules 1 to 5 are examples: a quite different one is flexibilene 13, a compound from Indonesian soft coral. It has a fifteen-membered ring, one di- and three tri-substituted double bonds, all E but none conjugated, and a quaternary centre. Mercifully there are no functional groups or chiral centres. How on earth would you tackle its synthesis? One published synthesis is by McMurry.10

This short synthesis uses seven metals (Li, Cr, Zr, Pd, Ti, Zn, and Cu), only one protecting group, achieves total control over double bond geometry, remarkable regioselectivity in the Zr-Pd coupling reaction, and a very satisfactory large ring synthesis. The yield in the final step (52%) may not look very good, but this is a price worth paying for such a short synthesis. Only the first two steps use chemistry from the previous books: all the other methods were unknown only ten years before this synthesis was carried out but we shall meet them all in this book.

An important reason for studying alternative strategies (other than just making the compound!) is the need to find short cheap large scale routes in the development of research lab methods into production. All possible routes must be explored, at least on paper, to find the best production method and for patent coverage. Many molecules suffer this exhaustive process each year, and some sophisticated molecules, such as Merck’s HIV protease inhibitor 20, a vital drug in the fight against AIDS, are in current production on a large scale because a good synthesis was found by this process.11

You might think that, say organometallic chemistry using Zr or Pd would never be used in manufacture. This is far from true as many of these methods are catalytic and the development of polymer-supported reagents for flow systems means that organo-metallic reagents or enzymes may be better than conventional organic reagents in solution with all the problems of by-product disposal and solvent recovery. We shall explore the chemistry of B, Si, P, S, and Se, and of metals such as Fe, Co, Ni, Pd, Cu, Ti, Sn, Ru and Zr because of the unique contribution each makes to synthetic methods.

In the twenty years since McMurry’s flexibilene synthesis major developments have changed the face of organic synthesis. Chiral drugs must now be used as optically pure compounds and catalytic asymmetric reactions (chapters 25 and chapters 26) have come to dominate this area, an achievement crowned by the award of the 2001 Nobel prize for Chemistry to Sharpless, Noyori and Knowles. Olefin metathesis (chapter 15) is superseding the Wittig reaction. Palladium-catalysed coupling of aromatic rings to other aromatic rings, to alkenes, and to heteroatoms (chapter 18) makes previously impossible disconnections highly favourable. These and many more important new methods make a profound impact on the strategic planning of a modern synthesis and find their place in this book.

A Modern Synthesis: Fostriecin (CI-920)

The anti-cancer compound Fostriecin 21 was discovered in 1983 and its stereochemistry elucidated in 1997. Not until 2001 was it synthesised and then by two separate groups.12 Fostriecin is very different from flexibilene. It still has alkene geometry but it has the more challenging three-dimensional chirality as well. It has plenty of functionality including a delicate monophosphate salt. A successful synthesis must get the structure right, the geometry of the alkenes right, the relative stereochemistry right, and it must be made as a single enantiomer.

The brief report of Jacobsen’s total synthesis starts with a detailed retrosynthetic analysis. The compound was broken into four pieces 21a after removal of the phosphate. The unsaturated lactone 24 (M is a metal) could be made by an asymmetric oxo-Diels-Alder reaction from diene 22 and ynal 23. The epoxide 25 provides a second source of asymmetry. One cis alkene comes from an alkyne 26 and the rest from a dienyl tin derivative 27.

The synthesis is a catalogue of modern asymmetric catalytic methods. The epoxide 25 was resolved by a hydrolytic kinetic resolution (chapter 28) using a synthetic asymmetric cobalt complex. The asymmetric Diels-Alder reaction (chapter 26) was catalysed by a synthetic chromium complex. The vinyl metal derivative 24 was made by hydrozirconation of an alkyne (this at least is similar to the flexibilene synthesis) and the secondary alcohol chiral centre was derived from the dithian 26 by hydrolysis to a ketone and asymmetric reduction with a synthetic ruthenium complex (chapter 24). The dienyl tin unit 27 was coupled to the rest of the molecule using catalytic palladium chemistry (chapter 18). Almost none of these catalytic methods was available in 1983 when flexibilene was made and such methods are a prominent feature of this book. Organic synthesis nowadays can tackle almost any problem.13

Please do not imagine that we are abandoning the systematic approach or the simpler reagents of the previous books. They are more essential than ever as new strategy can be seen for what it is only in the context of what it replaces. Anyway, no-one in his or her right mind would use an expensive, toxic, or unstable reagent unless a friendlier one fails. Who would use pyrophoric tertiary butyl-lithium in strictly dry conditions when aqueous sodium hydroxide works just as well? In most cases we shall consider the simple strategy first to see how it must be modified. The McMurry flexibilene synthesis is unusual in deploying exotic reagents in almost every step. A more common situation is a synthesis with one exotic reagent and six familiar ones. The logic of the previous books is always our point of departure.

The organisation of the book

The book has five sections:

A: Introduction, selectivity, and strategy

B: Making Carbon-Carbon bonds

C: Carbon-Carbon double bonds

D: Stereochemistry

E: Functional Group Strategy

The introductory section uses aldol chemistry to present the main themes in more detail and gives an account of the three types of selectivity: chemo-, regio-, and stereo-selectivity. We shall explore alternative strategies using enones as our targets, and discuss how to choose a good route using cyclopentenones as a special case among enones. Each chapter develops strategy, new reagents, and control side-by-side. To keep the book as short as possible (like a good synthesis), each chapter in the book has a corresponding chapter in the workbook with further examples, problems, and answers. You may find that you learn more efficiently if you solve some problems as you go along.

References

General references are given on page 893

1. R. B. Woodward, Pure Appl. Chem., 1973, 33, 145; A. Eschenmoser and C. E. Wintner, Science, 1977, 196, 1410; A. Eschenmoser, Angew. Chem., Int. Ed. Engl., 1988, 27, 5.

2. Y. Kishi, Tetrahedron. 2002, 58, 6239.

3. E. J. Corey, K. C. Nicolaou, and L. S. Melvin, J. Am. Chem. Soc., 1975, 97, 654; G. Stork and S. D. Rychnovsky, J. Am. Chem. Soc., 1987, 109, 1565; Pure Appl. Chem., 1987, 59, 345; A. F. Sviridov, M. S. Ermolenko, D. V. Yashunsky, V. S. Borodkin and N. K. Kochetkov, Tetrahedron Lett., 1987, 28, 3835, and references therein.

4. W. C. Still, J. Am. Chem. Soc., 1979, 101, 2493. See also S. L. Schreiber and C. Santini, J. Am. Chem. Soc., 1984, 106, 4038; T. Takahashi, Y. Kanda, H. Nemoto, K. Kitamura, J. Tsuji and Y. Fukazawa, J. Org. Chem., 1984, 51, 3393; H. Hauptmann, G. Mühlbauer and N. R C. Walker, Tetrahedron Lett., 1986, 27, 1315; T. Kitahara, M. Mori and K. Mori, Tetrahedron, 1987, 43, 2689.

5. P. A. Worthington, ACS Symposium 355, Synthesis and Chemistry of Agrochemicals, eds D. R. Baker, J. G. Fenyes, W. K. Moberg, and B. Cross, ACS, Washington, 1987, p 302.

6. M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pullman, Nature, 1974, 248, 710; M. Elliott, Pestic. Sci., 1980, 11, 119.

7. J. Halpern, H. B. Kagan, and K. E. Koenig, Morrison, vol 5, pp 1–101.

8. Corey, Logic; Nicolaou and Sorensen.

9. Designing Syntheses, Disconnection Textbook, and Disconnection Workbook.

10. J. McMurry, Acc. Chem. Res., 1983, 16, 405.

11. D. Askin, K. K. Eng, K. Rossen, R. M. Purick, K. M. Wells, R. P. Volante and P. J. Reider, Tetrahedron Lett., 1994, 35, 673; B. D. Dorsey, R. B. Levin, S. L. McDaniel, J. P. Vacca, J. P. Guare, P. L. Darke, J. A. Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J. H. Lin, I.-W. Chen, M. K. Holloway, P. M. D. Fitzgerald, M. G. Axel, D. Ostovic, P. S. Anderson and J. R. Huff, J. Med. Chem., 1994, 37, 3443.

12. D. L. Boger, S. Ichikawa and W. Zhong, J. Am. Chem. Soc., 2001, 123, 4161; D. E. Chavez and E. N. Jacobsen, Angew. Chem., Int. Ed., 2001, 40, 3667.

13. D. Seebach, Angew. Chem. Int. Ed., 1990, 29, 1320; K. C. Nicolaou, E. J. Sorensen and N. Winssinger, J. Chem. Ed., 1998, 75, 1225.

2

Chemoselectivity

Definitions

Introduction: three types of control

Chemoselectivity: simple examples and rules

Chemoselectivity by Reactivity and Protection: An anti-Malaria Drug

Protection to allow a less reactive group to react

When Protection is not Needed

Dianions: wasting reagent to achieve selectivity

Chemoselectivity by Reagent: The Pinacol Rearrangement

Selectivity between secondary and tertiary alcohols by reagent

Corey’s longifolene synthesis

Chemoselectivity in Enol and Enolate Formation

General discussion of enols and enolates

Formation of specific enol equivalents

Lithium enolates, enamines and silyl enol ethers

Enamines

Silyl enol ethers

Synthesis of the ant alarm pheromone mannicone

Examples of Chemoselectivity in Synthesis

Synthesis of lip statin, rubrynolide and hirsutene

Definitions

Introduction: three types of control

Behind all grand strategic designs in organic synthesis must lie the confidence that molecules can be compelled to combine in the ways that we require. We shall call this control and divide it into three sections by mechanistic arguments. These sections are so important that we shall devote the next three chapters to the more detailed explanation of just what the divisions mean. If you can recognise what might go wrong you are in a better position to anticipate the problem and perhaps avoid it altogether. Our three types of control are over chemoselectivity (selectivity between different functional groups), regioselectivity (control between different aspects of the same functional group), and stereoselectivity (control over stereochemistry). Examples of selectivity of all three kinds are given in Chemoselectivity in chapter 5, Regioselectivity in chapter 14, and Stereoselectivity in chapters 12 and 38. These aspects will not be addressed again in the present book.