Workbook for Organic Synthesis: The Disconnection Approach E-Book

Stuart Warren

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

Seitenzahl: 311

Veröffentlichungsjahr: 2011

Beschreibung

One approach to organic synthesis is retrosynthetic analysis. With this approach chemists start with the structures of their target molecules and progressively cut bonds to create simpler molecules. Reversing this process gives a synthetic route to the target molecule from simpler starting materials. This “disconnection” approach to synthesis is now a fundamental part of every organic synthesis course.

Workbook for Organic Synthesis: The Disconnection Approach, 2^nd Edition

This workbook provides a comprehensive graded set of problems to illustrate and develop the themes of each of the chapters in the textbook Organic Synthesis: The Disconnection Approach, 2^nd Edition. Each problem is followed by a fully explained solution and discussion. The examples extend the student’s experience of the types of molecules being synthesised by organic chemists, and the strategies they employ to control their syntheses. By working through these examples students will develop their skills in analysing synthetic challenges, and build a toolkit of strategies for planning new syntheses. Examples are drawn from pharmaceuticals, agrochemicals, natural products, pheromones, perfumery and flavouring compounds, dyestuffs, monomers, and intermediates used in more advanced synthetic work. Reasons for wishing to synthesise each compound are given. Together the workbook and textbook provide a complete course in retrosynthetic analysis.

Organic Synthesis: The Disconnection Approach, 2^nd Edition

There are forty chapters in Organic Synthesis: The Disconnection Approach, 2^nd Edition: those on the synthesis of given types of molecules alternate with strategy chapters in which the methods just learnt are placed in a wider context. The synthesis chapters cover many ways of making each type of molecule starting with simple aromatic and aliphatic compounds with one functional group and progressing to molecules with many functional groups. The strategy chapters cover questions of selectivity, protection, stereochemistry, and develop more advanced thinking via reagents specifically designed for difficult problems. In its second edition updated examples and techniques are included and illustrated additional material has been added to take the student to the level required by the sequel, Organic Synthesis: Strategy and Control. Several chapters contain extensive new material based on courses that the authors give to chemists in the pharmaceutical industry.

Workbook for Organic Synthesis: The Disconnection Approach, 2^nd edition, combined with the main textbook, provides a full course in retrosynthetic analysis for chemistry and biochemistry students, and a refresher course for organic chemists working in industry and academia.

Leseprobe

Contents

Preface

General References

1 The Disconnection Approach

A Synthesis of Multistriatin

References

2 Basic Principles: Synthons and Reagents: Synthesis of Aromatic Compounds

A Problem from the Textbook

References

3 Strategy I: The Order of Events

References

4 One-Group C–X Disconnections

References

5 Strategy II: Chemoselectivity

Using Disconnections to Solve Structural and Mechanistic Problems

References

6 Two-Group C–X Disconnections

Counting Relationships between Functional Groups

Synthesis of a Heterocycle

References

7 Strategy III: Reversal of Polarity, Cyclisations, Summary of Strategy

Regioselective Attack on Epoxides

References

8 Amine Synthesis

An Example of a Triamine

Strategic Bond Disconnection

A New Generation Pfizer anti-HIV Drug Maraviroc

References

9 Strategy IV: Protecting Groups

Synthesis without Protection

Protection

An HIV-Protease Inhibitor as an anti-AIDS Drug

Example: Synthesis of Statins (Cholesterol-Lowering Drugs)

References

10 One-Group C–C Disconnections I: Alcohols

An Example of Simple Alkylation

References

11 General Strategy A: Choosing a Disconnection

Summary of Guidelines for Good Disconnections

The Synthesis of an Unusual Amino Acid

Strategy in the Synthesis of Sildenafil (Viagra®)

References

12 Strategy V: Stereoselectivity A

References

13 One-Group C–C Disconnections II: Carbonyl Compounds

References

14 Strategy VI: Regioselectivity

Other Examples of Regioselectivity

A Heterocyclic Example

References

15 Alkene Synthesis

A Pharmaceutical Example

The Importance of Experimental Work

References

16 Strategy VII: Use of Acetylenes (Alkynes)

Examples from the Textbook Chapter

Synthesis of a Cyclic Ketone by Hydration of an Acetylene

An Interesting Mechanism and a Useful Separation

Electrophilic Acetylenes

Alkynes in Synthesis

References

17 Two-Group C–C Disconnections I: Diels-Alder Reactions

References

18 Strategy VIII: Introduction to Carbonyl Condensations

References

19 Two-Group C–C Disconnections II: 1,3-Difunctionalised Compounds

A Synthesis of the Enzyme Inhibitor Elasnin

References

20 Strategy IX: Control in Carbonyl Condensations

Three Examples

References

21 Two-Group C–C Disconnections III: 1,5-Difunctionalised Compounds Conjugate (Michael) Addition and Robinson Annelation

References

22 Strategy X: Aliphatic Nitro Compounds in Synthesis

The Synthesis of an ACE Inhibitor

References

23 Two-Group Disconnections IV: 1,2-Difunctionalised Compounds

Acyl Anion Equivalents

Some Problems

α-Functionalisation of Carbonyl Compounds

References

24 Strategy XI: Radical Reactions in Synthesis

The Mechanism of Allylic Bromination with NBS

Application of NBS in Synthesis

Carbon–Carbon Bond-Forming Reactions

A Pharmaceutical Example

References

25 Two-Group Disconnections V: 1,4-Difunctionalised Compounds

Buying the 1,4-diCO Relationship

Troubles and Triumphs with Homoenolates

A General Synthesis of Partly Protected Succinic Acids

A Remarkable Reaction from the Textbook

References

26 Strategy XII: Reconnection

Synthesis of 1,2-and 1,4-diCO Compounds by Oxidative C=C Cleavage

Oxidative Cleavage of Aldol Products

Cleavage of Aldol Products by Retro-Aldol Reaction

References

27 Two-Group C–C Disconnections VI: 1,6-diCarbonyl Compounds

Problems from the Textbook

The Synthesis of Acorenone B

The Synthesis of a Symmetrical Keto-di-Acid

Oxidative Cleavage by the Baeyer-Villiger Rearrangement

References

28 General Strategy B: Strategy of Carbonyl Disconnections

The Synthesis of Long Chain Fatty Acids

The Synthesis of a Furan

The Synthesis of a Modern Drug Candidate

References

29 Strategy XIII: Introduction to Ring Synthesis: Saturated Heterocycles

Cyclisation Reactions

A Bicyclic Amine

References

30 Three-Membered Rings

Cyclisation and Carbene Strategies Compared

Cyclopropanes from Electrophilic Alkenes

The Synthesis of Halicholactone

References

31 Strategy XIV: Rearrangements in Synthesis

Diazoalkanes

The Pinacol Rearrangement

The Favorskii Rearrangement

References

32 Four-Membered Rings: Photochemistry in Synthesis

An Example from Chapter 31

Development of Material from the Textbook

Photochemical Cycloadditions

Four-Membered Rings by Ionic Reactions

References

33 Strategy XV: The Use of Ketenes in Synthesis

Do Ketenes Exist?

The Synthesis of α-Lactones

Ketenes as Intermediates

[2 + 2] Thermal Cycloadditions of Ketenes

References

34 Five-Membered Rings

An Intermediate in the Synthesis of Coriolin

Asymmetric Synthesis from Terpenes

Cyclisation of Alkyl Lithiums onto Alkenes

References

35 Strategy XVI: Pericyclic Reactions in Synthesis: Special Methods for Five-Membered Rings

Electrocyclic Reactions

Sigmatropic Rearrangements

References

36 Six-Membered Rings

A Synthesis from the Textbook Chapter

The Diels-Alder Route

The Birch Reduction Route

References

37 General Strategy C: Strategy of Ring Synthesis

Development of Some Chemistry from the Textbook

References

38 Strategy XVII: Stereoselectivity B

The Prelog-Djerassi Lactone

A Pharmaceutical Example

The Synthesis of a Cage Molecule

Conformational Control

References

39 Aromatic Heterocycles

The Mechanism of the Stetter Synthesis of 1,4-diCarbonyl Compounds

The Synthesis of Five-Membered Heterocycles

Mechanisms in Heterocyclic Chemistry

Pyrazole, Imidazole and Quinoline

References

40 General Strategy D: Advanced Strategy

The Synthesis of Methoxatin

The Key Reaction Strategy: Diels-Alder Reactions

References

Index

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Library of Congress Cataloging-in-Publication Data

Warren, Stuart.Workbook for organic synthesis: the disconnection approach/Stuart Warren and Paul Wyatt. – 2nd ed.p. cm.Includes bibliographical references and index.ISBN 978-0-470-71227-6 – ISBN 978-0-470-71226-91. Organic compounds – Synthesis – Textbooks. I. Wyatt, Paul. II. Title.QD262.W93 2009547'.2 – dc222009030810

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

ISBN 978-0-470-7-12276 (h/b) 978-0-470-7-12269 (p/b)

Preface

In the 26 years since Wiley published Organic Synthesis: The Disconnection Approach and the accompanying Workbook, this approach to the learning of synthesis has become widespread while the books themselves are now dated in content and appearance. In 2008, Wiley published the second edition of Organic Synthesis: The Disconnection Approach by Stuart Warren and Paul Wyatt for which this is the accompanying Workbook.

This workbook contains further examples, problems (and answers) to help you understand the material in each chapter of the textbook. The structure of this second edition of the workbook is the same as that of the textbook. The 40 chapters have the same titles as before but all chapters have undergone a thorough revision with some new material. The emphasis is on helpful examples and problems rather than novelty. Many of the problems are drawn from the courses we have given in industry on ‘The Disconnection Approach’ where they have stimulated discussion leading to deeper understanding. It makes sense for you to have the relevant chapter of the textbook available while you are working on the problems. We have usually devised new problems but some of the problems in the first edition seemed to do such a good job that we have kept them. Usually, the answers are presented in a different and, we hope, more helpful style.

It is not possible to learn how to design organic syntheses just from lectures or from reading a textbook. Only by tackling problems and checking your answers against published material can you develop this skill. We should warn you that there is no single ‘right answer’ to a synthesis problem. Successful published syntheses give some answers that work, but you may well be able to design others that have a good chance of success. The style of this second edition is to give more discussion of alternative routes.

Stuart Warren and Paul Wyatt2009

General References

Full details of important books referred to by abbreviated titles in the chapters to avoid repetition.

Clayden Organic Chemistry: J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry, Oxford University Press, Oxford, 2000.

Disconnection Textbook: S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach, Second Edition, Wiley, Chichester, 2008.

Drug Synthesis: D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, Wiley, New York, seven volumes, from 1977.

Fieser, Reagents: L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 20 volumes, 1967–2000, later volumes by T.-L. Ho.

Fleming, Orbitals: Ian Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London, 1976.

Vogel: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, and A. R. Tatchell, Vogel’s Textbook of Practical Organic Chemistry, Fifth Edition, Longman, Harlow, 1989.

1

The Disconnection Approach

We start with a few simple problems to set you at ease with disconnections. Problem 1.1: Here is a two-step synthesis of the benzofuran 3. Draw out the retrosynthetic analysis for the synthesis of 2 from 1 showing the disconnections and the synthons.

Answer 1.1: As this is a simple SN2 reaction, the disconnection is of the C–O bond 2a and the synthons are nucleophilic phenolate anion 4, which happens to be an intermediate in the reaction, and the cation 5, which happens not be an intermediate in the reaction but is represented by the α-bromoketone 6.

Problem 1.2: Draw the mechanism of the cyclisation of 2 to 3. This is an unusual reaction and it helps to know what is going on before we analyse the synthesis. Answer 1.2: The first step is an acid-catalysed cyclisation of the aromatic ring onto the protonated ketone 7. Loss of a proton 8 completes the electrophilic aromatic substitution giving the alcohol 9.

Now protonation of the alcohol leads to loss of water 10 to give a stabilised cation that loses aproton 11 to give the new aromatic system 3. Problem 1.3: Now you should be in a position to draw the disconnections for this step.

Answer 1.3: We hope you might have drawn the intermediate alcohol 9. Changing 3 into 9 is not a disconnection but a Functional Group Interconversion (FGI) – changing one functional group into another. Now we can draw the disconnection revealing the synthons 12 represented in real life by 2.

A Synthesis of Multistriatin

In the textbook we gave one synthesis of multistriatin 17 and here is a shorter but inferior synthesis as the yields are lower and there is little control over stereochemistry.1Problem 1.4: Which atoms in the final product 17 come from which starting material and which bonds are made in the synthesis? Hint: Arbitrarily number the atoms in multistriatin and try to trace each atom back through the intermediates. Do not be concerned over mechanistic details, especially of the step at 290°C.

Answer 1.4: However you numbered multistriatin, the ethyl group (7 and 8 in 17a) finds the same atoms in the last intermediate 16a and the rest falls into place. It then follows which atoms come from 14 and which from 15. Finally, you might have said that C-4 in our diagrams comes from formaldehyde.

So the disconnections also fall into place. Just one C–O bond was disconnected at first 17b then one C–O and one C–C 16b and finally the alkene was disconnected 14b in what you may recognise as an aldol reaction with formaldehyde. If you practise analysing published syntheses like this, you will increase your understanding of good bonds to disconnect.

References

1. W. E. Gore, G. T. Pearce and R. M. Silverstein, J. Org. Chem., 1975, 40, 1705.

2

Basic Principles: Synthons and Reagents: Synthesis of Aromatic Compounds

This chapter concerns the synthesis of aromatic compounds by electrophilic and nucleophilic aromatic substitution. All the disconnections will therefore be of bonds joining the aromatic rings to the sidechains. We hope you will be thinking mechanistically, particularly when choosing which compounds can undergo nucleophilic aromatic substitution and the orientation of electrophilic aromatic substitution. Any textbook of organic chemistry will give you the help you need.