Methods of Non--Amino Acid Synthesis

385 Pages·1995·5.38 MB·English

by  Michael Smith

Methods of
Non-a-Amino Acid
Synthesis
Michael B. Smith
University of Connecticut
Storrs, Connecticut
Marcel Dekker, Inc. New York. Basel Hong Kong
Library of Congress Cataloging-in-PublicationD ata
Smith, Michael.
Methods of non-a-amino acid synthesis/ Michael B. Smith.
cpm . .
Includes bibliographical references.
ISBN 0-8247-9604-7
1. Aminoa cids-Synthesis.I .T itle.
QD431. S 6851 995
547.7’50459-dc20 95-11621
CIP
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Preface
Amino carboxylic acids(o r just amino acids) are. as a class of organic molecules,
among the most important and useful compounds knowTn.h e chemistry of amino
acids has been studiedf or well over a century. The importance of a-amino acids
[RCH(NH2)COOH] in mammalian biology anads synthetic intermediatesi s well
established and thereh ave been many reviews, several monographs and thousanodfs
individual research papers inth is area. The synthesis of a-amino acidsh as also been
the subject of many books and reviews. In addition toa -amino acids, there are many
other amino carboxylic acids where the amino griosu npo t on the carbon immediately
adjacent to the carboxyl group( the a position) but rather is attached to another carbon
'y.
in the chain( e.g.. the p, 6 carbon, etc.). These non-a-amino acids are also
components of biologically important moleculesa, re important in the pharmaceutical
industry, and are useful in materials science, particularly for polymer synthesis.
This monograph givesa representative overviewo f the synthesiso f non-a-amino
acids beginning with the year 1962. Wiath f ew exceptions,c itations prior to that date
are leading references taken from othecri tations. The work prior to 1962 is well
...
111
iv Preface
represented, however, in the synthetic approaches incorporatiendto this book since the
"early work is the basis of mosto f those approaches. Every attempt was made to
give the most common and useful methofodrs the synthesis ofn on-a-amino acids.
This monograph will focus attention on acyclic amino acidso f C3-Clo and includes
aminoalkanoic carboxylica cids, aminoalkenoic acids and aminoalkynoic acidsT. he
synthesis of amino carboxylic acids attachetdo or incorporated inr ings of three to ten
carbons is also presented, including amino cycloalkanoic and amino cycloalkenoic
acids. Although saturated heterocyclicd erivatives and aryl substituted amino acids are
discussed, aromatic amino carboxylic acids and heteroaromatic amino carboxylic acids
are not discussede, xcept where they ares ynthetic precursors to or related to aliphatic
amino carboxylica cids.
The primary goal oft his book is to summarize synthetic approachesto non-a-
amino acids, particularly those amino acids thaatr e key synthetic intermediates or
important compounds int heir own right. Achiral amino carboxylica cids are discussed
throughout ands pecial attention is focused on both chiral nonracemic andc hiral
racemic amino acids in chapter five. emphasizingd itahset ereoselectivitya ndor
enantioselectivity of each synthetic process. Having such synthetic information
collected in one placew ill, it is hoped, facilitate current research and stimulate new
research in this important area.
Saturated amino acids of all types are discussed,a s well as unsaturated, alkyl and
aryl substituted, and amino acids that bear a heteroatom functional groupI. n general,
four structural types of alkenyl amino acids are considered. In thfei rst type, the
double bond can be conjugatedt o the carbonyl group and the amine moiety bcea n
attached directly to the double bond. Secondly, the amino group canb e attached to the
saturated carbon chain. The third and fourth types focuso n the double bond, which
can be in or out of conjugation with the carboxyl, and the amine grcoaunp b e attached
Preface V
anywhere on the chain. Substituents can appear anywhere on the chain.L ess
formalism is required for discussing structural variations in alkynyl amino acids. The
triple bond is both conjugated and unconjugated and the amino grcoaunp a ppear at
almost any point in the carbon. Only odneer ivative has the amino attacheddi rectly to
the triple bond, however, andi t is 3-amino 2-propynoic acid.
Non-a-amino acids have been importanfto r over a century andth eir synthesis and
chemical transformationsc onstitute a rich and varied chapteirn organic chemistry.
Despite this, virtually no compilations exist that discuss these compounds. This
stands ins tark contrast to a-aminoa cids, for which thousands ofa rticles have
appeared, as well as numerous books, monographs and reviews.S ince parto f my
own research involves the used n oofn -a-amino acidsi n the development of synthetic
methods, I was particularly interested in this type of reference book.T his wast he
impetus for preparing this monograph. whichi s a compilationo f synthetic methods
that can be usedt o prepare non-a-amino acids.
This monograph is a comprehensive review of synthetic methods ustoed p repare
non-a-amino acids. The source material surveyed inth is book formally begins with
literature after 1962, butt here are many citations and examples taken fromli terature
published prior to 1962. Virtually all of these early references were taken from
literature citations in later articles. I am confident that the "older" literature is well
represented. particularly in its survey of the synthesis of and the synthetic methods
applied to non-a-amino acids.
This monograph is divided into seven chapters. In the first chapter, methods for
synthesizing the fundamentasl tructural types found ina cyclic amino acidsa re
presented. In this chapter, the synthetic methods rely on substituenret functionaliza-
tion. In chapter two, refunctionalizationa gain plays a prominent role.T he major
difference is that cyclic precursorsa re used to prepare acyclic amino acids. Chapter
vi Preface
three discusses those methods tharet ly on conjugate additionr eactions. Chapter four
brings together those synthetisct rategies that rely on condensation reactions involving
a nucleophilic species with a carbonyl compounodr, a carbonyl surrogate. This
technique is particularly useful for incorporating heteroatoms ubstituents such as
hydroxyl, oxo, or amino into an amino acid. Chapter five collects a variety of
synthetic methods together under the umbreollfa s tereoselectivity. Those reactions
and strategies that lead to good diastereoselectivitya ndor enantioselectivityd uring the
synthesis are discussed. Chapter six again collects several different strategic
approaches for the synthesis of amino acidsT. he unifying themeo f this chapter is the
preparation of biologically important aminoa cids, with particular emphasis givent o
GABOB and carnitine as well as statine and its derivatives. Chapter seven concludes
the book and discusses amino acitdhsa t have a carboxyl group attachetdo a ring.
Those derivatives for which the amino groupi s attached to the ring and those in which
the nitrogeni s part of the ring (heterocyclic derivatives) are discussed.
This monograph will be particularly useful to those of us engaged in synthesis and
synthetic manipulations involving amino acidsI.t s utility is not limited to that
audience, however. Those involved in developing synthetic methods and those
pursuing the total synthesis of natural products will also find the book useful because
it contains a useful review ostfr ategies and reaction types found in nitrogen-containing
molecules. This monograph will be a useful reference to quickly find what synthetic
methods have been used, and in what systems. With such a backgrounidt ,i s my
hop that new areas of research in this important area will be discoveredm ore quickly.
I believe this work will be a valuable contributionto the ever-growingf ield of non-a-
amino acids.
Where there are errors, Ita ke completer esponsibility. Every effort has been made
to keep the manuscripet rror-free but if emrsa re found please contacmt e and I will try
Preface vii
to answer any questionst hat may be raised.
This manuscript was prepared with a MacintoIsIhc i computer using Microsoft
Word, version 5.1. All drawings int his book were prepared usingC SC ChemDraw
Plus, from Cambridge Scientific Computing, Inc., Cambridge, MA.
I want to thank Dr. Maurits Dekker, who made ainn triguing suggestion several
years ago concerning one of my papers. This suggestion for a book led tot he
preparation of this manuscript andI thank Dr. Dekkerf or inspiring this work. I want
to thank Mr. Joe Stubenrauch and Ms. Anita Lekhwani of Marcel Dekker f oInrc .,
editing this manuscript and providing thcea re and knowledge requiredt o convert it
into a book. I particularly want to thank the independent revieweros f this manuscript,
with whom I must share credit for the final form of this monograph. Their reviews
were insightful, very helpful. and I thank them very much. Most ofa ll I want to thank
my wife Sarah and my son Steven for their patience and understanding during the
research for, and preparation oft his manuscript
Michael B. Smith
This Page Intentionally Left Blank
Contents
Prejiie iii
Abbreviations xiii
Chapter 1
FUNCTIONAL GROUP EXCHANGE STRATEGIES 1
1.1. Functional Group Transformations that Generate Amines 1
1.2. Functionalization to Form Carboxyl Groups 30
1.3. Functionalization of Amino Acids 38
1.4. Specialized Methods 46
References 54
Chapter 2
CYCLIC PRECURSORS 63
2.1. From Ketones 63
2.2. From Lactones and Anhydrides 67
2.3. From Lactams and Imides 71
2.4. From p-Lactams 78
2.5. From Heterocycles 83