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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
This book bridges the gap between sophomore and advanced / graduate level organic chemistry courses, providing students with a necessary background to begin research in either an industry or academic environment.
• Covers key concepts that include retrosynthesis, conformational analysis, and functional group transformations as well as presents the latest developments in organometallic chemistry and C–C bond formation
• Uses a concise and easy-to-read style, with many illustrated examples
• Updates material, examples, and references from the first edition
• Adds coverage of organocatalysts and organometallic reagents
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Seitenzahl: 618
Veröffentlichungsjahr: 2017
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Modern Organic Synthesis
An Introduction
Second Edition
George S. Zweifel
University of California, Davis
Dept of Chemistry
Davis, CA, US
Michael H. Nantz
University of Louisville
Dept of Chemistry
Louisville, KY, US
Peter Somfai
Lund University
Ctre for Analysis & Synthesis
Lund, SW
This edition first published 2017 © 2017 John Wiley & Sons, Inc.
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The right of George S. Zweifel, Michael H. Nantz and Peter Somfai to be identified as the author(s) of this work has been asserted in accordance with law.
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Library of Congress Cataloging-in-Publication Data
Names: Zweifel, George S. | Nantz, Michael H. | Somfai, Peter, 1960-- Title: Modern organic synthesis : an introduction / George S. Zweifel, Michael H. Nantz, Peter Somfai. Description: Second edition. | Hoboken, NJ : John Wiley & Sons, Inc., 2017. | Includes bibliographical references and index. Identifiers: LCCN 2016054037 (print) | LCCN 2016054265 (ebook) | ISBN 9781119086536 (pbk.) | ISBN 9781119086727 (pdf) | ISBN 9781119086765 (epub) Subjects: LCSH: Organic compounds--Synthesis. Classification: LCC QD262 .Z94 2017 (print) | LCC QD262 (ebook) | DDC 547/.2--dc23 LC record available at https://lccn.loc.gov/2016054037
Cover image: annuker/Getty Cover design by Wiley
CONTENTS
About the Authors
Preface to the Second Edition
Preface to the First Edition
1: Synthetic Design
1.1 Retrosynthetic Analysis
3
1.2 Reversal of the Carbonyl Group Polarity (Umpolung)
5
1.3 Steps in Planning a Synthesis
1.4 Choice of Synthetic Method
1.5 Domino Reactions (Cascade or Tandem Reactions)
26
1.6 Computer-Assisted Retrosynthetic Analysis
27
References
2: Stereochemical Considerations in Planning Syntheses
2.1 Conformational Analysis
1
2.2 Evaluation of Non-Bonded Interactions
2.3 Six-Membered Heterocyclic Systems
2.4 Polycyclic Ring Systems
2.5 Cyclohexyl Systems with sp
2
-Hybridized Atoms
2.6 Significant Energy Difference
25
2.7 Computer-Assisted Molecular Modeling
2.8 Reactivity and Product Determination as a Function of Conformation
Notes
References
3: The Concept of Protecting Functional Groups
3.1 Protection of N–H Groups
3
3.2 Protection of OH Groups
3.3 Protection of Diols as Acetals
3.4 Protection of Carbonyl Groups in Aldehydes and Ketones
3.5 Protection of the Carboxyl Group
3.6 Protection of Double Bonds
3.7 Protection of Triple Bonds
References
4: Functional Group Transformations
4.1 Oxidation of Alcohols to Aldehydes and Ketones
4.2 Reagents and Procedures for Alcohol Oxidation
4.3 Chemoselective Oxidizing Agents
4.4 Oxidation of Acyloins
4.5 Oxidation of Tertiary Allylic Alcohols (The Babler Oxidation)
47
4.6 Oxidative Procedures to Carboxylic Acids
4.7 Allylic Oxidation of Alkenes
4.8 Terminology for Reduction of Carbonyl Compounds
4.9 Nucleophilic Reducing Agents
4.10 Electrophilic Reducing Agents
4.11 Regio- and Chemoselective Reductions
4.12 Diastereoselective Reductions of Cyclic Ketones
124
4.13 Inversion of Secondary Alcohol Stereochemistry (The Mitsunobu Reaction)
132
4.14 Diastereofacial Selectivity in Acyclic Systems
4.15 Enantioselective Reductions
References
5: Functional Group Transformations
5.1 Reactions of Carbon–Carbon Double Bonds
5.2 Reactions of Carbon–Carbon Triple Bonds
References
6: Formation of Carbon–Carbon Single Bonds via Enolate Anions
6.1 1,3-Dicarbonyl Compounds
6.2 Direct Alkylation of Enolates
6.3 Cyclization Reactions—Baldwin's Rules for Ring Closure
72
6.4 Stereochemistry of Cyclic Ketone Alkylation
74
6.5 Imine and Hydrazone Anions
68
b
6.6 Enamines
82
,
83
6.7 The Aldol Reaction
89
6.8 Condensation Reactions of Enols and Enolates
6.9 Robinson Annulation
159
References
7: Formation of Carbon–Carbon Bonds via Organometallic Reagents
7.1 Organolithium Reagents
3
7.2 Organomagnesium Reagents
41
7.3 Organotitanium Reagents
53
7.4 Organocerium Reagents
60,61
7.5 Organocopper Reagents
65
7.6 Organochromium Reagents
101
7.7 Organozinc Reagents
107
7.8 Organoboron Reagents
135
7.9 Organosilicon Reagents
163
7.10 Organogold Chemistry
212
References
8: Palladium-Catalyzed Coupling Reactions
8.1 Palladium Oxidation State
8.2 Organic Synthesis with Palladium(0) Complexes
8.3 The Heck Reaction—Palladium(0)-Catalyzed Olefin Insertion Reactions.
1h,k,15
8.4 Palladium-Catalyzed Cross-Coupling with Organometallic Reagents
8.5 Cross-Coupling Reactions Involving sp-Carbons
8.6 The Trost–Tsuji Reaction
References
9: Formation of Carbon–Carbon π-Bonds
9.1 Formation of Carbon–Carbon Double Bonds
1
9.2 Formation of Carbon–Carbon Triple Bonds
139
References
10: Syntheses of Carbocyclic Systems
10.1 Intramolecular Free Radical Cyclizations
10.2 Cation–π Cyclizations
23
10.3 Pericyclic Reactions
36
10.4 Ring-Closing Olefin Metathesis
81
References
Index
EULA
List of Tables
Chapter 1
Table 1.1
Table 1.2
Table 1.3
Chapter 2
Table 2.1
Table 2.2
Table 2.3
Chapter 4
Table 4.1
Table 4.2
Table 4.3
Table 4.4
Table 4.5
Table 4.6
Table 4.7
Table 4.8
Table 4.9
Chapter 5
Table 5.1
Table 5.2
Chapter 6
Table 6.1
Table 6.2a
Table 6.2b
Table 6.3a
Table 6.3b
Chapter 7
Table 7.1
Table 7.2
Table 7.3
Table 7.4
Table 7.5
Table 7.6
Table 7.7
Chapter 8
Table 8.1
Table 8.2
Chapter 10
Table 10.1
Table 10.2
Table 10.3
Table 10.4
Guide
Cover
Table of Contents
Preface to the Second Edition
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e1
About the Authors
George S. Zweifel was born in Switzerland. He received his Dr. Sc. Techn. degree in 1955 from the Swiss Federal Institute of Technology (ETH Zürich, Switzerland, Professor H. Deuel), working in the area of carbohydrate chemistry. The award of a Swiss–British Exchange Fellowship in 1956 (University of Edinburgh, Scotland, Professor G. O. Aspinall) and a Research Fellowship in 1957 (University of Birmingham, England, Professors S. A. Barker and A. B. Forster) made it possible for him to study conformational problems in the carbohydrate field. In 1958, he became Professor H. C. Brown's personal research assistant at Purdue University, undertaking research in the new area of hydroboration chemistry. He joined the faculty at the University of California, Davis in 1963, where his research interest has been the exploration of organometallics as intermediates in organic synthesis, with emphasis on unsaturated organoboron, organoaluminum, and organosilicon compounds.
Michael H. Nantz earned a Bachelor of Science degree from Western Kentucky University in 1981. His interest in natural product synthesis led him to work with Professor Philip L. Fuchs at Purdue University, where he received a PhD degree in 1987. Over the next 2 years, he studied asymmetric synthesis with Professor Satoru Masamune at the Massachusetts Institute of Technology. In 1989, he joined the faculty at the University of California, Davis and established a research program in organic synthesis with emphasis on the development of gene delivery vectors. In 2006, he joined the faculty at the University of Louisville as Professor of Chemistry and Distinguished University Scholar.
Peter Somfai was born in Sweden and received his PhD in 1987 from the Chalmers University of Technology. After a 2-year post doc in the group of Professor S. Masamune at the Massachusetts Institute of Technology, he returned to Sweden. In 1999, he was appointed as Professor at the Royal Institute of Technology (KTH) in Stockholm. He joined the faculty at Lund University in 2012, where he is Professor in organic chemistry. He is interested in the development of new methodology for organic synthesis and its application to the synthesis of complex organic molecules.
Preface to the Second Edition
Organic synthesis is a dynamic subject under constant development. Much progress has been made since the first edition of this book was printed in 2007. Our aim for this edition was to update the many advances in the methodologies and interpretations already presented in Modern Organic Synthesis: An Introduction (MOS) as well as to introduce emerging technologies. As a result, many new examples and more than 500 literature references have been included to provide students an overview of contemporary organic synthesis. The content of the book is organized using the same thematic chapters as in the previous edition with one exception. During the last decade, palladium-catalyzed coupling reactions have evolved into a powerful technique for synthesis of organic molecules. A new chapter, Chapter 8, is now devoted to this chemistry. As with the previous edition, the present one is intended to enlighten senior undergraduate and beginning graduate students. Updating MOS has been stimulating and rewarding; we hope you will find this edition informative.
Preface to the First Edition
Modern Organic Synthesis: An Introduction is based on the lecture notes of a special topics course in synthesis designed for senior undergraduate and beginning graduate students who are well acquainted with the basic concepts of organic chemistry. Although a number of excellent textbooks covering advanced organic synthesis have been published, we saw a need for a book that would bridge the gap between these and the organic chemistry presented at the sophomore level. The goal is to provide the student with the necessary background to begin research in an academic or industrial environment. Our precept in selecting the topics for the book was to present in a concise manner the modern techniques and methods likely to be encountered in a synthetic project. Mechanisms of reactions are discussed only if they might be unfamiliar to the student. To acknowledge the scientists whose research formed the basis for this book and to provide the student access to the original work, we have included after each chapter the relevant literature references.
We wish to express our gratitude to the present and former Chemistry 131 students at the University of California at Davis and to the teaching assistants of the course, especially Hasan Palandoken, for their suggestions and contributions to the development of the lecture notes. We would also like to thank our colleague Professor Dean Tantillo for his helpful advice. Professors Edwin C. Friedrich (UC Davis) and Craig A. Merlic (UCLA) read the entire manuscript; their pertinent comments and constructive critiques greatly improved the quality of the book.
Finally, without the support and encouragement of our wives, Hanni and Jody, Modern Organic Synthesis: An Introduction would not have been written.
George S. ZweifelMichael H. NantzOctober 27, 2005 Davis, California
1Synthetic Design
In character, in manners, in style, in all things, the supreme excellence is simplicity.
Henry Wadsworth Longfellow
Chemistry touches everyone's daily life, whether as a source of important drugs, polymers, detergents, or insecticides. Since the field of organic chemistry is intimately involved with the synthesis of these compounds, there is a strong incentive to invest large resources in synthesis. Our ability to predict the usefulness of new organic compounds before they are prepared is still rudimentary. Hence, both in academia and at many chemical companies, research directed toward the discovery of new types of organic compounds continues at an unabated pace. Also, natural products, with their enormous diversity in molecular structure and their possible medicinal use, have been and still are the object of intensive investigations by synthetic organic chemists.
Faced with the challenge to synthesize a new compound, how does the chemist approach the problem? Obviously, one has to know the tools of the trade, their potential and limitations. A synthetic project of any magnitude requires not only a thorough knowledge of available synthetic methods, but also of reaction mechanisms, commercial starting materials, analytical tools (IR, UV, NMR, MS) and isolation techniques. The ever-changing development of new tools and refinement of old ones makes it important to keep abreast of the current chemical literature.
What is an ideal or viable synthesis and how does one approach a synthetic project? The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps), selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). Furthermore, the experimental ease of the transformations and whether they are environmentally acceptable must be considered.
Synthesis of a molecule such as pumiliotoxin C involves careful planning and strategy. How would a chemist approach the synthesis of pumiliotoxin C?1 This chapter outlines strategies for the synthesis of such target molecules based on retrosynthetic analysis.
E. J. Corey (Nobel Prize, 1990) introduced and promoted the concept of retrosynthetic analysis, whereby a molecule is disconnected leading to logical precursors.2 Today, retrosynthetic analysis plays an integral and indispensable role in research.
1.1 Retrosynthetic Analysis3
The following discussion on retrosynthetic analysis covers topics similar to those in Warren's Organic Synthesis: The Disconnection Approach3a and Willis and Will's Organic Synthesis.3g For an advanced treatment of the subject matter, see Corey and Cheng's The Logic of Chemical Synthesis.3b
Basic Concepts
The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis. The symbol ⇒ signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C–C bonds, and functional group interconversions(FGI).
Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and FGI. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon–carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SEs). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs.
Synthetic design involves two distinct steps3a: (1) retrosynthetic analysis and (2) subsequent translation of the analysis into a “forward direction” synthesis. In the analysis, the chemist recognizes the functional groups in a molecule and disconnects proximally by methods corresponding to known and reliable reconnection reactions.
Chemical bonds can be cleaved heterolytically or homolytically, or through concerted transform (into two neutral, closed-shell fragments). The following discussion will focus on heterolytic and cyclic disconnections.
Donor and Acceptor Synthons3c,g
Heterolytic retrosynthetic disconnection of a carbon–carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, and into a donor synthon, a carbanion. In a formal sense, the reverse reaction—the formation of a C–C bond—then involves the union of an electrophilic acceptor synthon and a nucleophilic donor synthon. Tables 1.1 and 1.2 show some important acceptor and donor synthons and their synthetic equivalents.3c
Often, more than one disconnection is feasible, as depicted in retrosynthetic analyses A and B below. In the synthesis, a plan for the sequence of reactions is drafted according to the analysis by adding reagents and conditions.
Table 1.1 Common Acceptor Synthons
Table 1.2 Common Donor Synthons
Alternating Polarity Disconnections3g,4
The question of how one chooses appropriate carbon–carbon bond disconnections is related to functional group manipulations since the distribution of formal charges in the carbon skeleton is determined by the functional group(s) present. The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atoms of the molecule. The concept of alternating polarities or latent polarities (imaginary charges) often enables one to identify the best positions to make a disconnection within a complex molecule.
Functional groups may be classified as follows:4a
E Class:
Groups conferring electrophilic character to the attached carbon (+):
–OH, –OR, O, NR, –X (halogens)
G Class:
Groups conferring nucleophilic character to the attached carbon (-):
–Li, –MgX, –AlR
2
, –SiR
3
A Class:
Functional groups that exhibit ambivalent character (+ or -):
–BR
2
, CCR
2
, CCR, –NO
2
, N, –SR, –S(O)R, –SO
2
R
The positive charge (+) is placed at the carbon attached to an E class functional group (e.g., O, –OH, –Br) and the TM is then analyzed for consonant and dissonant patterns by assigning alternating polarities to the remaining carbons. In a consonant pattern, carbon atoms with the same class of functional groups have matching polarities, whereas in a dissonant pattern their polarities are unlike. If a consonant pattern is present in a molecule, a simple synthesis may often be achieved.
Examples of choosing reasonable disconnections of functionally substituted molecules based on the concept of alternating polarity are shown below.
One Functional Group
In the example shown above, there are two possible ways to disconnect the TM, 2-pentanol. Disconnection close to the functional group (path a) leads to substrates (SE) that are readily available. Moreover, reconnecting these reagents leads directly to the desired TM in high yield using well-known methodologies. Disconnection via path b also leads to readily accessible substrates. However, their reconnection to furnish the TM requires more steps and involves two critical reaction attributes: quantitative formation of the enolate ion and control of its monoalkylation by ethyl bromide.
Two Functional Groups in a 1,3-Relationship
The consonant charge pattern and the presence of a β-hydroxy ketone moiety in the TM suggest a retro-aldol transform. Either the hydroxy-bearing carbon or the carbonyl carbon of the TM may serve as an electrophilic site and the corresponding α-carbons as the nucleophilic sites. However, path b is preferable since it does not require a selective FGI (reduction).
Two Functional Groups in a 1,4-Relationship
The dissonant charge pattern for 2,5-hexanedione exhibits a positive (+) polarity at one of the α-carbons, as indicated in the acceptor synthon above. Thus, the α-carbon in this synthon requires an inversion of polarity (Umpolung in German) from the negative (−) polarity normally associated with a ketone α-carbon. An appropriate substrate (SE) for the acceptor synthon is the electrophilic α-bromo ketone. It should be noted that an enolate ion might act as a base resulting in deprotonation of an α-halo ketone, a reaction that could lead to the formation of an epoxy ketone (Darzens condensation). To circumvent this problem, a weakly basic enamine is used instead of the enolate.
In the case of 5-hydroxy-2-hexanone shown below, Umpolung of the polarity in the acceptor synthon is accomplished by using the electrophilic epoxide as the corresponding SE.
The presence of a C–C–OH moiety adjacent to a potential nucleophilic site in a TM, as exemplified below, points to a reaction of an epoxide with a nucleophilic reagent in the forward synthesis. The facile, regioselective opening of epoxides by nucleophilic reagents provides for efficient two-carbon homologation reactions.
1.2 Reversal of the Carbonyl Group Polarity (Umpolung)5
In organic synthesis, the carbonyl group is intimately involved in many reactions that create new carbon–carbon bonds. The carbonyl group is electrophilic at the carbon atom and hence is susceptible to attack by nucleophilic reagents. Thus, the carbonyl group reacts as a formyl or as an acyl cation. A reversal of the positive polarity of the carbonyl group so it acts as a formyl or as an acyl anion would be synthetically very attractive. To achieve this, the carbonyl group is converted to a derivative whose carbon atom has negative polarity. After its reaction with an electrophilic reagent, the carbonyl is regenerated. Reversal of polarity of a carbonyl group has been explored and systematized by Seebach.5b,c
Umpolung in a synthesis usually requires extra steps. Thus, one should strive to take maximum advantage of the functionality already present in a molecule.
The following example illustrates the normal disconnection pattern of a carboxylic acid with a Grignard reagent and carbon dioxide as SEs (path a), and a disconnection leading to a carboxyl synthon with an “unnatural” negative charge (path b). Cyanide ion can act as an SE of a negatively charged carboxyl synthon. Its reaction with R–Br furnishes the corresponding nitrile, which on hydrolysis produces the desired TM.
Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions. There are several reagents that are synthetically equivalent to formyl or acyl anions, permitting the Umpolung of carbonyl reactivity.
Formyl and Acyl Anions Derived from 1,3-Dithianes5b,c,f
The most utilized Umpolung strategy is based on formyl and acyl anion equivalents derived from 2-lithio-1,3-dithiane species. These are readily generated from 1,3-dithianes (thioacetals) because the hydrogens at C(2) are relatively acidic (pKa ∼31).6 In this connection it should be noted that thiols (EtSH, pKa 11) are stronger acids compared to alcohols (EtOH, pKa 16). Also, the lower ionization potential and the greater polarizability of the valence electrons in sulfur as compared to oxygen makes the divalent sulfur compounds more nucleophilic in SN2 reactions. The polarizability factor may also be responsible for the stabilization of carbanions α to sulfur.6
The anions derived from dithianes react with alkyl halides to give the corresponding alkylated dithianes. Their treatment with HgCl2–HgO regenerates aldehydes or ketones, respectively, as depicted below. In addition to Hg(II)-mediated methods for dithiane deprotection, other methods,7 such as oxidative7b,c and photoremoval7d approaches, have been developed to unmask the carbonyl group.
Dithiane-derived carbanions can be hydroxyalkylated or acylated to produce, after removal of the propylenedithiol appendage, a variety of difunctional compounds, as shown below. In the presence of HMPA (hexamethylphosphoramide, [(Me2N)3PO]), dithiane-derived carbanions may serve as Michael donors.8 However, in the absence of HMPA, 1,2-addition to the carbonyl group prevails.
An instructive example of using a dithiane Umpolung approach to synthesize a complex natural product is the one-pot preparation of the multifunctional intermediate shown below, which ultimately was elaborated to prepare the antibiotic vermiculin.9
Acyl Anions Derived from Nitroalkanes10
The α-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, pKa 10.2; CH3CH2NO2, pKa 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (Henry–Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine–HMPA complex of molybdenum (VI) peroxide.9b Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions.
An example of an α-nitro anion Umpolung in the synthesis of jasmone (TM) is depicted below.9a
Acyl Anions Derived from Cyanohydrins11
O-Protected cyanohydrins contain a masked carbonyl group with inverted polarity. The α-carbon of an O-protected cyanohydrin is sufficiently activated by the nitrile moiety [CH3CH2CN, pKa 30.9]12 so that addition of a strong base such as LDA generates the corresponding anion. Its alkylation, followed by hydrolysis of the resultant alkylated cyanohydrin, furnishes the ketone. The overall reaction represents alkylation of an acyl anion equivalent, as exemplified for the synthesis of methyl cyclopentyl ketone.11a
An attractive alternative to the above protocol is the nucleophilic acylation of alkylating agents with aromatic and heteroaromatic aldehydes via trimethylsilyl-protected cyanohydrins.11b
Acyl anion synthons derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction.11c–e However, further reaction with electrophiles is confined to carbonyl compounds and Michael acceptors.
Acyl Anions Derived from Enol Ethers
The α-hydrogens of enol ethers may be deprotonated with tert-BuLi.13 Alkylation of the resultant vinyl anion followed by acidic hydrolysis provides an efficient route for the preparation of methyl ketones.
Acyl Anions Derived from Lithium Acetylide
Treatment of lithium acetylide with a primary alkyl halide (bromide or iodide) or with aldehydes or ketones produces the corresponding monosubstituted acetylenes or propargylic alcohols. Mercuric ion-catalyzed hydration of these furnishes methyl ketones and methyl α-hydroxy ketones, respectively.
The sensitivity of some propargylic alcohols toward acid conditions has led to the development of milder, acid-free conditions using gold catalysis for hydration of the derived propargylic acetates, as illustrated below.14
1.3 Steps in Planning a Synthesis
In planning an organic synthesis, the following key interrelated factors may be involved:
Construction of the carbon skeleton
Control of relative stereochemistry
Functional group interconversions
Control of enantioselectivity
Construction of the Carbon Skeleton
Reactions that result in formation of new carbon–carbon bonds are of paramount importance in organic chemistry because they allow the construction of complex structures from smaller starting materials. Important carbon–carbon bond-forming reactions encountered in organic syntheses are summarized in Table 1.3 and include:
Reactions of organolithium and Grignard reagents, such as RLi, RC≡CLi, RMgX, and RC≡CMgX, with aldehydes, ketones, esters, epoxides, acid halides, and nitriles
Reactions of 1° alkyl halides with NaCN (or KCN) to extend the carbon chain by one carbon
Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis)
Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann
Michael additions, organocuprate additions (1,4-additions)
Friedel–Crafts alkylation and acylation reactions of aromatic substrates
Wittig reactions, Horner—Wadsworth–Emmons olefination
Diels–Alder reactions to access to cyclohexenes and 1,4-cyclohexadienes
Ring-closing olefin metathesis
Table 1.3 Summary of Important Disconnections3c
Below are summarized some important guidelines for choosing disconnections of bonds. At the initial stage of the retrosynthetic analysis, key fragments must be recognized that can be recombined in the forward synthetic step in an efficient way.3
Disconnections of bonds should be carried out only if the resultant fragments can be reconnected by known and reliable reactions.
Disconnection via path a leads to synthons whose SEs can be reconnected by a nucleophilic attack of the phenoxide on the propyl bromide to furnish the desired TM. On the other hand, disconnection via path b would require either attack of n-PrO− on bromobenzene to reconstruct the TM, a reaction that is not feasible, or displacement of a benzenediazonium salt by n-PrO−M+.
Aim for the
fewest
number of disconnections. Adding large fragments in a single reaction is more productive than adding several smaller fragments sequentially.
Choose disconnections in which functional groups are close to the C–C bonds to be formed since the presence of functional groups often facilitates bond-making by a substitution reaction.
It is often advantageous to disconnect at a branching point since this may lead to linear fragments that are generally more readily accessible, either by synthesis or from a commercial source.
A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic acids or amino-carboxylic acids as targets. Many macrocyclic natural products contain these functional groups and their syntheses often include a macrocyclization reaction.
Functional groups in the TM may be obtained by
FGI
.
Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for obtaining the TM.
Introduction of an
activating
(auxiliary) functional group may facilitate carbon–carbon bond formation. This strategy works well for the synthesis of compounds exhibiting a dissonant charge pattern. After accomplishing its role, the auxiliary group is removed.
There is no simple way to disconnect the TM shown below (dissonant charge pattern). However, the presence of a 1,6-dioxygenated compound suggests a ring opening of a six-membered ring. A variety of cyclohexene precursors are readily available
via
condensation and Diels–Alder reactions or
via
Birch reductions of aromatic compounds.
Disconnection of an internal (
E
)- or (
Z
)-double bond, or a side chain of an alkene, suggests a Wittig-type reaction or an alkylation of a vinylcuprate, for example, respectively.
The presence of a six-membered ring, especially a cyclohexene derivative, implies a Diels–Alder reaction.
The structural feature of an α, β-unsaturated ketone or a β-hydroxy ketone in a six-membered ring suggests a
double disconnection
coupled with FGI [Michael addition followed by intramolecular aldol condensation (
Robinson annulation
)].
Disconnection of 5–30-member cycloalkenes via a non-heterolytic path suggests the use of ring-closing metathesis (RCM, see Chapter 10) to prepare the alkene by, ideally, the combination of tethered, terminal alkenes, as illustrated below.
15
The
E/Z
-selectivity in the cyclization step depends on the ring strain. The ruthenium catalysts used to catalyze RCM tolerate a wide variety of functional groups. This mode of cycloalkene synthesis has gained widespread application as versatile Ru catalysts have become commercially available.
Functional Group Interconversions (FGI)
Functional groups are the keys to organic synthesis.16 They can be converted into other functional groups by a wide variety of transformations, such as by substitution, displacement, oxidation, and reduction reactions. Also, they may be used to join smaller molecular fragments to form large molecules or to produce two smaller molecules from a large one. Developing expertise with FGIs is crucial for the beginning chemist to expand options for synthetic design. Consider the exercise below in transforming propanal to butyric acid using two distinct routes and vice versa. As one engages such synthetic exercises, the need to master FGIs as well as be familiar with name reactions becomes clear. Along these lines, the texts by Larock,17 on functional group preparation, and by Kürti and Czakó,18 on name reactions, are highly recommended resources for aspiring synthetic chemists.
Control of Relative Stereochemistry
Use stereoselective and stereospecific reactions (where applicable), such as:
S
N
2 displacement reactions; E2 elimination reactions
Catalytic hydrogenation of alkynes (
cis
product)
Metal ammonia reduction of alkynes (
trans
product)
Oxidation of alkenes with osmium tetroxide
Addition of halogens, interhalogens (e.g., BrI) or halogen-like species (e.g., PhSCl, BrOH) to double bonds
Hydroboration reactions
Epoxidation of alkenes; ring opening of epoxides
Cyclopropanation
Control of Enantioselectivity
Control of enantioselectivity will be discussed in the corresponding sections on carbonyl reduction (Chapter 4); alkene hydrogenation, epoxidation, and dihydroxylation (Chapter 5); aldol condensation (Chapter 6); allylation and crotylation (Chapter 7); Claisen rearrangement (Chapter 9); and the Diels–Alder reaction (Chapter 10).
1.4 Choice of Synthetic Method
The choice of a method for synthesizing a compound derived from a retrosynthetic analysis should be based on the following criteria:
Regiochemistry
, the preferential addition of the reagent at only one of the two possible regions or directions, exemplified in the Robinson annulation by the preferential alkylation of 2-methylcyclohexanone by the derived enolate at C(2) and not at C(6).
Chemoselectivity
, selective reaction of one functional group in the presence of other functional groups, exemplified by the preferential reaction of an aldehyde in the presence of a keto group.
Stereoselectivity
, the exclusive or predominant formation of one of the several possible stereoisomeric products, exemplified by the preferential formation of
cis
-3-methylcyclohexanol on reduction of 3-methylcyclohexanone with lithium aluminum hydride in THF or Et
2
O.
Efficiency
, fewest number of steps.
High yields
in each step, of paramount concern in any chemical reaction is the yield.
Availability
and
costs of starting materials.
Most
environmentally friendly route
. Ideally, the atoms of the substrate and any additional reagents used for the reaction should appear in the final product, called “
atom economy”
19
—no by-products are formed, isolation of desired product is facilitated, and waste disposal is minimized (e.g., Diels–Alder reaction, metal-catalyzed reactions such as the example below
20
):
Simplicity
of selected procedures. Over the years, a large number of reagents have been developed that require special techniques for handling. If possible, one should use procedures that are less demanding in their execution.
Isolation and purification of reaction products
.
21
Despite recent advances in methodologies for the synthesis of very complex molecules, one important aspect of synthesis has not been affected much over the last decades: isolation and purification. An excellent review entitled “Strategy-Level Separations in Organic Synthesis: From Planning to Practice” discusses various techniques for the separation of reaction mixtures.
22
The yield and hence the utility of every reaction is limited by the ability to separate and recover the reaction product from other materials.
Possibility of a
convergent synthesis
or a “
one-pot process
” (cascade or tandem reactions).
Linear Synthesis versus Convergent Synthesis3h,j,23
The overall yield in a multistep step synthesis is the product of the yields for each separate step. In a linear synthetic scheme, the hypothetical TM is assembled in a stepwise manner. For the seven-step synthesis of the hypothetical TM below, if the yield of the intermediate at each step is 80%, the overall yield will be 21% (0.87 × 100); for a 70% yield at each step, the overall yield would be only 8%.
Since the overall yield of the TM decreases as the number of individual step increases, a convergent synthesis should be considered in which two or more fragments of the TM are prepared separately and then joined together at the latest-possible stage of the synthesis. The overall yield in a convergent synthesis is the product of yields of the longest linear sequence. For the synthesis of the above TM, only three stages are involved in the convergent strategy shown below, with an overall yield of 51% (0.83 × 100).
It should be noted, however, that the simple overall yield calculation is somewhat misleading since it is computed on one starting material whereas several are used and the number of reactions is the same! Nevertheless, the increased efficiency of a convergent synthesis as compared to the linear approach is derived from the fact that the preparation of a certain amount of a product can be carried out on a smaller scale.
Another important consideration in choosing a convergent protocol is that failure of a single step in a multistep synthesis does not nullify the chosen synthetic approach as a whole, whereas a failure of a single step in a linear scheme may require a revision of the whole plan. An example of a triply convergent protocol is the synthesis of the prostaglandin PGE2 derivative shown below, where the three fragments were prepared separately. The two side chains were then coupled sequentially with the cyclopentenone.24 Introduction of the first fragment involved the conjugate addition of the nucleophilic vinylic organocopper reagent to the enone, followed by trapping of the resulting enolate with the electrophilic side chain.
Convergent syntheses involve consecutive reactions, where the reagents or catalysts are added into the “one pot” sequentially, as illustrated in the example below.25
1.5 Domino Reactions (Cascade or Tandem Reactions)26
Domino-type reactions involve careful design of a multistep reaction in a “one-pot” sequence in which the first step creates the functionality to trigger the second reaction and so on, making this approach economical and environmental friendly. A classical example of a tandem reaction is the Robinson annulation (a Michael reaction followed by aldol condensation and dehydration).
1.6 Computer-Assisted Retrosynthetic Analysis27
Compter programs are available that suggest possible disconnections and retrosynthetic pathways.28 Such programs utilize the sort of systematic analysis outlined above to identify key bond2 for disconnection and plausible FGI. In doing so, “retrosynthetic trees” of possible pathways that connect a synthetic target to simple (and/or commercially available) starting materials are generated. The strength of such programs is their thoroughness—in principle, all possible disconnections for any target molecule can be considered. For any molecule of even moderate complexity, however, this process would lead to a plethora of possible synthetic routes too large for any synthetic chemist to analyze in a reasonable amount of time. Fortunately, synthesis programs generally also include routines that rank the synthetic pathways they produce based on well-defined criteria such as fewest number of synthetic steps (efficiency), thus allowing chemists to focus their energy on evaluating the viability and aesthetic appeal of key disconnections. Still, each program is limited by the synthetic strategies (transforms and FGI) contained in its library of possible reactions. Synthetic programs are unlikely to ever replace creative chemists, but this is generally not the intent of those who have created them.
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2Stereochemical Considerations in Planning Syntheses
2.1 Conformational Analysis1
Molecules that differ from each other by rotation about single bonds are called conformational isomers or conformers. Derek H. R. Barton (Nobel Prize, jointly with Odd Hassel, 1969) showed that the chemical and physical properties of complicated molecules can be interpreted in terms of their specific or preferred rotational arrangements and that a knowledge of the conformations of molecules is crucial to understanding the stereochemical basis of many reactions.2
Acyclic Systems3
Ethane
The eclipsed conformation of ethane is ∼3 kcal/mol less stable than the staggered conformation (∼1 kcal/mol for each eclipsed H/H pair).* Any conformation between staggered and eclipsed is referred to as a skew conformation.
The instability of the eclipsed form of ethane was postulated to result from repulsion of filled hydrogen orbitals. However, state-of-the-art quantum chemical calculations indicate that two main factors contribute to the preference for the staggered conformation of ethane.4 First, the eclipsed form is selectively destabilized by unfavorable 4-electron interactions between the filled C–H bonding orbitals of each pair of eclipsed bonds. Second, the staggered conformer is selectively stabilized by favorable orbital interactions between filled C–H bonding orbitals and unfilled C–H antibonding orbitals of antiperiplanar C–H bonds (hyperconjugation5).
The energy required to rotate the ethane molecule about the C–C bond is called its torsional energy. Torsional strain is the repulsion between neighboring bonds (electron clouds) that are in an eclipsed relationship.
Propane
The CH3–H eclipsed interaction imposes 1.4 kcal/mol of strain on top of the 2.0 kcal/mol H–H torsional strains in the eclipsed conformation of propane. The 0.4 kcal/mol of additional strain is referred to as steric strain, the repulsion between non-bonded atoms or groups.
Butane
A potential energy plot for rotation about the C2–C3 bond in butane shows unique maxima and minima. There are two kinds of staggered conformations, gauche (steric strain) and anti, and two distinct eclipsed conformations (torsional and steric strain).
At room temperature, n-butane is a mixture of 70% anti and 30% gauche conformations. To separate these two species, one would have to slow down the interconversion by working at –230°C!
Ring Systems
In addition to torsional strain (eclipsing interaction) and steric strain (non-bonded interaction), the compression of internal bond angles in ring systems leads to an additional type of strain: angle strain.
Cyclopropane
Compression of the ideal 109.5° Csp3 bond angle to an internal bond angle of 60° in cyclopropane results in considerable angle strain, which is manifested by “bent bonds.” Six pairs of eclipsed hydrogens add an additional ∼6 kcal/mol of torsional strain. Total strain is ∼27 kcal/mol.
The poor orbital overlap in cyclopropane leads to C–C bond cleavage under conditions where typical Csp3–Csp3 bonds are stable. For example, cyclopropanes undergo hydrogenolysis, affording synthetic pathways to geminal dimethyl6 or isopropyl groups.7 Activated cyclopropanes (i.e., bonded to an electron-withdrawing group) are cleaved by nucleophiles, as illustrated below.8
Cyclobutane
Spectroscopic measurements indicate that cyclobutane is slightly bent (puckered), so that one carbon atom lies about 25° above the plane of the other three. This slightly increases the angle strain (∼88° internal bond angle) but decreases the torsional strain (<8 kcal/mol) until a minimum energy balance between the two opposing effects is reached. Total strain is ∼26 kcal/mol.9
Cyclopentane
There would be no angle strain in cyclopentane if it were planar (108° internal bond angle); however, if planar, there would be ∼10 kcal/mol torsional strain. Consequently, cyclopentane adopts a puckered, out-of-plane conformation that strikes a balance between increased angle strain and decreased torsional strain. Four of the carbons are in approximately the same plane, and the hydrogens of the out-of-plane methylene group are nearly staggered with respect to their neighbors. In this conformation, the hydrogens at three of the five carbons can adopt quasi-equatorial or quasi-axial positions. The cyclopentane ring is not static but is in constant motion in such a way that each carbon alternates as the point of the envelope. Total strain, after puckering, is 6 kcal/mol.
Cyclohexane
Cyclohexane is the most important of the carbocycles; its structural unit is widely encountered in various natural products. It can adopt a chair conformation that is essentially strain free.10 The chair form of cyclohexane has two distinct types of hydrogens: equatorial and axial.
Cyclohexane is a dynamic structure, and the chair conformations rapidly flip. Its room temperature 1H-NMR spectrum displays a broad singlet at δ 1.43 ppm (spin averaging), which resolves at –106°C into absorptions at δ 1.20 (axial H's) and at δ 1.66 (equatorial H's) ppm. The interconversion of the two conformations has an enthalpy of activation of 10.8 kcal/mol.
The boat form is an alternate conformation of cyclohexane. Actually, by a slight twist, the non-bonded interactions in the boat form can be reduced (twist boat conformation).
Although the chair form of cyclohexane is the preferred conformation, other conformations are known and in some systems are required.
The lactone moiety acts as a stereochemical bridge, maintaining the hydroxyl and carboxylic acid groups in a cis relationship.
2.2 Evaluation of Non-Bonded Interactions
Monosubstituted Cyclohexane
Stereoanalysis of monosubstituted cyclohexanes involves two distinct stages11:
Determination of the topology of the molecule
Assessment of the topology and its effects on the course of a reaction
Because of the 5.5 kcal/mol difference between the chair and the higher energy twist form of cyclohexane, the vast majority of compounds containing a six-membered ring exist almost entirely in the chair form. If a six-member ring system can be said to be in one chair conformation, then for the purpose of synthetic planning, stereochemical predictions can, in many instances, be made with considerable confidence. The factor that contributes to the instability of a monosubstituted cyclohexane is the presence of an axial substituent. The destabilization caused by an axial substituent (e.g., CH3) is due to its 1,3-diaxial interaction with the two hydrogens on the ring (n-butane gauche-type interactions).
The equilibrium population of any conformer is given by
Therefore, we can compute the equilibrium composition of the two methylcyclohexane conformers as shown below.
Table 2.1 shows the population dependence of the favored conformation on Keq and −ΔG°.
Table 2.1 Population of the Favored Conformation at 25°C
K
eq (25°C)
1
2
4
10
100
–Δ
G
° (kcal/mol)
0
0.41
0.82
1.4
2.7
Population (%)
50
67
80
91
99
Often interaction energy values of conformations are reported as potential energies E by assuming that the difference in free energy ΔG° between isomers is equal to E, and that ΔE may be equated with ΔH° and ΔS° ∼ 0, which is probably true for methylcyclohexane.
It should be noted that ΔS may not be equal to zero in some di- and polysubstituted cyclohexanes. However, since the entropy term ΔS° (in cal) will be relatively small as compared to ΔH° (in kcal), we assume that ΔS° ∼ 0 and hence ΔG° ∼ ΔH°.
Conformational energies for axial–equatorial interconversion for a number of monosubstituted cyclohexanes have been reported. These are often referred to as A-values and allow us to estimate steric effects in reactions.
The strong preference of the tert-butyl group to occupy the equatorial position makes it a highly useful group to investigate conformational equilibria. Thus, a tert-butyl group will ensure that the equilibrium lies on the side in which the tert-butyl group occupies the equatorial position. Note, however, that a tert-butyl group does not “lock” a system in a single conformation; conformational inversion still takes place, although with a high energy barrier.
Disubstituted Cyclohexanes
Depending on the substitution pattern, three principal interactions dictate the conformational equilibrium:
The presence of a single axial substituent (butane-type gauche interaction)
The interaction of a pair of 1,2-diequatorial substituents (butane-type gauche interaction)
The interaction of a pair of
cis
-1,3-diaxial substituents (1,3-diaxial interaction;
Table 2.2
)
trans
-
1,2-dimethylcyclohexane
cis
-
1,2-dimethylcyclohexane
Large steric interactions result when two groups are situated syn-axially (Table 2.2), as in cis-1,3-dimethylcyclohexane.
Table 2.2 1,2-Diequatorial and 1,3-Diaxial Interaction Energies (kcal/mol)11
Evaluation of Destabilization Energies (ED)
Corey and Feiner11 have developed a computer program (LHASA) for conformational analysis and for determining the destabilization energies (ED) in substituted cyclohexane derivatives. In the following discussion, we will adopt their A, G, and U designations and use the corresponding EDvalues for evaluating steric interactions.
Each substituent R has associated with it three appendage interaction values (Table 2.3):
An
A
R
value for R–H 1,3-diaxial interactions
A
G
R
value for gauche R–R′ 1,2-diequatorial interactions
A
U
R
value for R–R′ 1,3-diaxial interactions
Table 2.3 A, G, and U-Values of Cyclohexane Derivatives11
It is assumed that conformational effects are additive, that is, the destabilizing interactions operate independently of each other. However, this is not always the case. The magnitude of the
ED values for polar substituents may be affected by the polarity of the solvent, hydrogen bonding, and dipole–dipole interactions.
Atypical Disubstituted Cyclohexanes
Dipole–Dipole Interactions
The preferred conformations of 2-bromo- and 2-chloro-cyclohexanones depend on the polarity of the solvent.12 In the diequatorial conformer there is considerable electrostatic repulsion. Parallel dipoles are disfavored in a non-polar solvent.
Hydrogen Bonding
Intramolecular hydrogen bonding between 1,3-diaxial OH groups in non-polar solvents confers appreciable stability to a conformer. In polar solvents, however, the solvent competes for intermolecular H-bond formation, resulting in normal steric effects dominating the equilibrium.
2.3 Six-Membered Heterocyclic Systems
Tetrahydropyrans
The steric interaction between any axial substituent and a β-situated heteroatom is counted as zero.11 Thus, in 3-substituted tetrahydropyrans, the destabilization due to an axial R substituent is computed as half of the AR.
Because of the shorter C–O bond distance (C–O 1.43 Å), the 1,3 R ••• H interaction is expected to increase. This is especially evident when two heteroatoms are present in the cyclohexane ring, as in 1,3-dioxanes. For example, the conformational equilibrium in the following example favors the axial t-butyl group! It should be noted that interference by bonded atoms or groups is more severe than by non-bonding (lone pairs) electrons.
Anomeric Effect13
The anomeric effect refers to the tendency of a group X at C(1) of a pyranose ring to assume the axial rather than the equatorial orientation.14 This phenomenon is important in carbohydrate chemistry, since it influences the composition of isomeric mixtures and hence their reactivities. It has been suggested that the effect is caused mainly by a stabilizing interaction between the axial lone pair of electrons on the ring oxygen atom and the antiperiplanar, antibonding σ* orbital of the C–X bond.15 This leads to a shortening of the bond between the ring oxygen and the anomeric carbon and a lengthening of the C–X bond.
Alternatively, electrostatic repulsive forces between the dipoles due to the ring oxygen lone pairs and the exocyclic oxygen or halogen may account in part for the observed axial preferences.
