Methods of Non-α-Amino Acid Synthesis, Second Edition

226 Pages·2013·18.89 MB·English

by  Michael Bryant Smith

Organic Chemistry
Methods of
Second
Although less common than α-amino acids, non-α-amino acids— Edition
where the amino group is not on the carbon immediately adjacent
to the carboxyl group but is attached to another carbon in the chain
M Non-α-Amino Acid
(for example, the β, γ, δ carbon)—are components of biologically
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important molecules, are significant in the pharmaceutical industry,
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and are useful starting materials for many areas of organic chemistry. h
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Since the publication of the first edition of this book nearly 20 years
Synthesis
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ago, synthetic work devoted to the preparation of non-α-amino
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acids has expanded greatly.
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Methods of Non-α-Amino Acid Synthesis, Second Edition has
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S e c o n d E d i t i o n
been extensively rewritten and reorganized, providing an up-to-date o
review of strategies and methods for non-α-amino acid synthesis, n
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particularly those amino acids that are key synthetic intermediates α
or important compounds in their own right. It focuses on acyclic -
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amino acids of C –C , but also aminoalkanoic carboxylic acids,
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aminoalkenoic acids, and aminoalkynoic acids. The new edition
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contains many updated references and has a greater emphasis on n
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the biological importance of non-α-amino acids. In addition to an

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array of synthetic methods, the book offers discussions on why
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The book covers synthetic methods that rely on substituent
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refunctionalization, the conversion of cyclic precursors to acyclic y
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amino acids, conjugate addition reactions, and enolate anion
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reactions and condensation reactions that lead to non-α-amino h
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acids. It also examines reactions and strategies that lead to good
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diastereoselectivity and enantioselectivity during synthesis. A
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chapter devoted to biologically important amino acids includes
separate sections on GABA, GABOB, carnitine, DAVA, statine, and
other significant amino acids as well as a new section on peptides
and proteins that contain non-α-amino acids. The final chapter
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addresses aminocyclic and heterocyclic amino acids.
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K16816
Michael Bryant Smith
K16816_Cover.indd 1 9/27/13 3:02 PM
Methods of
Non-a-Amino Acid
Synthesis
Second Edition

Methods of
Non-a-Amino Acid
Synthesis
S e c o n d E d i t i o n
Michael Bryant Smith
University of Connectitcut
Storrs, USA
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2014 by Taylor & Francis Group, LLC
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Version Date: 20130719
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Contents
Preface to the Second Edition ...................................................................................ix
Preface to the First Edition .......................................................................................xi
Common Abbreviations ...........................................................................................xv
Introduction .............................................................................................................xix
Chapter 1 Functional Group Exchanges ...............................................................1
1.1 Reactions with Ammonia, Amines, or Amine Surrogates ........1
1.1.1 Reaction with Ammonia ..............................................1
1.1.2 Reaction with Amines ..................................................3
1.1.3 Reaction with Amine Surrogates .................................3
1.2 Conversion of Carbonyl Compounds to Amines .....................10
1.2.1 From β-Keto-Acids or β-Diketones ...........................10
1.2.2 From Other Keto-Acids or Aldehyde Acids ...............12
1.3 Refunctionalization to Generate Carboxyl Groups .................15
1.3.1 Carboxyl Equivalents .................................................15
1.3.2 Carboxyl-Bearing Carbanions and Ylids ...................19
1.3.3 Oxidative Methods .....................................................21
1.4 Refunctionalization of Amino Acids .......................................23
1.4.1 From α-Amino Acids .................................................23
1.4.2 From Other Non-α-Amino Acids ..............................29
1.4.3 N-Alkylation or N-Arylation ......................................31
1.5 Specialized Methods ...............................................................35
1.5.1 Oxidation and Reduction ............................................35
1.5.2 Rearrangement Reactions ...........................................38
Chapter 2 Cyclic Precursors ...............................................................................41
2.1 From Lactams or Imides .........................................................41
2.1.1 From β-Lactams .........................................................41
2.1.2 From Other Lactams ..................................................44
2.1.3 From Imides ...............................................................48
2.2 From Ketones ..........................................................................48
2.2.1 Direct Cleavage of Cyclic Ketones ............................49
2.2.2 Via Rearrangement Reactions ....................................50
2.3 From Lactones and Anhydrides ..............................................51
2.3.1 From Lactones ............................................................52
2.3.2 From Anhydrides........................................................53
2.4 From Heterocycles ...................................................................54
2.4.1 Isoxazolidines, Isoxazoles, Oxazolidines,
and Oxazine Derivatives ............................................54
v
© 2010 Taylor & Francis Group, LLC
vi Contents
2.4.2 Pyrazole Derivatives ..................................................58
2.4.3 Pyridine, Hydropyridine, and Pyridone Derivatives.....59
2.4.4 From Uracil Derivatives and Cyclic Carbamates .......61
2.4.5 From Thiophene, Thiazolidine, and Oxathiolone
Derivatives ..................................................................62
2.5 Diels-Alder Strategies ..............................................................62
Chapter 3 Conjugate Addition Reactions ............................................................65
3.1 Ammonia and Amine Nucleophiles ........................................65
3.2 Carbon Nucleophiles ...............................................................70
3.2.1 Nitro Enolates and Nitrile Enolates ............................70
3.2.2 Addition to Conjugated Nitro Derivatives ..................72
3.2.3 Addition of Enamines ................................................73
Chapter 4 Enolate Anion and Related Reactions ................................................75
4.1 Acid, Ester, and Malonate Enolate Anion Reactions ..............75
4.2 Nitrile Enolate Anions .............................................................81
4.3 Nitroalkane Enolate Anions ....................................................83
4.4 Mukaiyama Type Condensations ............................................85
4.5 Condensation Reactions Involving Organozinc
Intermediates ...........................................................................87
4.6 Ylid Reactions .........................................................................88
Chapter 5 Diastereoselective and Enantioselective Syntheses............................91
5.1 α-Amino Acid Templates ........................................................91
5.2 Non-α-Amino Acid Templates ..............................................102
5.3 Synthesis from Other Starting Materials ..............................105
5.4 Transformations Using Carbohydrates as Chiral Templates ....113
5.5 Enzymatic Transformations ..................................................114
Chapter 6 Biologically Important Amino Acids ...............................................119
6.1 Peptides and Proteins ............................................................119
6.1.1 As Residues in Peptides and Proteins ......................119
6.1.2 As Substrates for Peptides and Proteins ...................124
6.1.3 As Residues in Cyclic Peptides ................................129
6.2 β-Alanine and Aminopropanoic Acid Compounds ..............131
6.3 GABA and Related Compounds ............................................135
6.4 GABOB and Carnitine ..........................................................145
6.5 DAVA (Ava) and Ahx ............................................................153
6.6 Statine and Related Compounds ...........................................156
6.7 Other Biologically Important Amino Acid Derivatives ........167
6.8 Non-α-Amino Acids in Catalysis ..........................................172
© 2010 Taylor & Francis Group, LLC
Contents vii
Chapter 7 Aminocyclic and Heterocyclic Amino Acids...................................175
7.1 Aminocycloalkylcarboxylic Acids from Cyclic Precursors .....176
7.1.1 Lactam-Based Syntheses ..........................................176
7.1.2 Dicarboxylic Acids and Related Precursors .............178
7.2 From Aromatic Precursors ....................................................184
7.3 From Cyclic Ketones .............................................................187
7.4 Cycloaddition Strategies ........................................................191
7.5 Heterocyclic Amino Acids ....................................................195
© 2010 Taylor & Francis Group, LLC

Preface to the Second Edition
The first edition of this book was published just under 20 years ago. During this
time, many new publications have appeared that expand the synthetic work devoted
to the preparation of non-α-amino acids. This new edition continues the work of
the first edition to give a representative overview of the synthesis of non-α-amino
acids beginning with the year 1962. New literature references expand this work to
include literature after 1995 through 2012. As with the first edition, this edition will
focus on acyclic amino acids of C –C , but also aminoalkanoic carboxylic acids,
3 10
aminoalkenoic acids, and aminoalkynoic acids. The syntheses of amino carboxylic
acids attached to or incorporated in rings of 3 to 10 carbons are also presented,
including amino cycloalkanoic and amino cycloalkenoic acids. Saturated heterocy-
clic derivatives and aryl-substituted amino acids are discussed once again, but aro-
matic amino carboxylic acids and heteroaromatic amino carboxylic acids are not
discussed, except where they are synthetic precursors to or related to aliphatic amino
carboxylic acids. The first five chapters not only illustrate different synthetic strate-
gies to prepare non-α-amino acids, but also serve as a useful review of a variety of
synthetic methodology.
There are significant differences in this new edition. It has been extensively
rewritten and reorganized. Apart from many updated references, there is a greater
emphasis on the biological importance of non-α-amino acids, and a serious attempt
to limit redundancies. The first edition was more or less a litany of synthetic meth-
ods, but there were few discussions that concerned why non-α-amino acids are
important. Throughout the new edition there are many brief statements to illustrate
the biological activity of important non-α-amino acids. Further, Chapter 6 in the
new edition is greatly expanded to include several specific classes of non-α-amino
acids with a focus on the biological importance as well as syntheses. The goal is to
push this new edition away from a simple recitation of syntheses and methods toward
a comprehensive discussion of both synthesis and the biological importance of this
class of compounds.
As with the first edition, synthetic approaches to saturated amino acids of all
types are discussed, as well as unsaturated, alkyl, and aryl-substituted derivatives,
and amino acids that bear a heteroatom functional group. In general, four structural
types of alkenyl amino acids are considered. In the first type, the double bond can
be conjugated to the carbonyl group and the amine moiety can be attached directly
to the double bond. Second, the amino group can be attached to the saturated carbon
chain. The third and fourth types focus on the double bond, which can be in or out
of conjugation with the carboxyl, and the amine group can be attached anywhere on
the chain. Substituents can appear anywhere on the chain. For alkynyl amino acids,
both conjugated and unconjugated are discussed.
As in the first edition, this new monograph is divided into seven chapters. However,
the organization and content of these seven chapters are significantly different. The
first chapter discusses synthetic methods that rely on substituent refunctionalization.
ix
© 2010 Taylor & Francis Group, LLC