Methods of Non-a-Amino Acid Synthesis, 2nd Edition

xix

Introduction

The chemistry of amino carboxylic acids, or just amino acids, has been studied

for well over a century. The importance of α-amino acids [RCH(NH

2

)COOH] in

mammalian biology and as synthetic intermediates is well established, and there

have been many reviews, several monographs, and thousands of individual research

papers in this area. Indeed, amino acids are among the most important and useful

compounds known, particularly α-amino acids. However, there are many other

amino carboxylic acids with a structure that has the amino group on a carbon

that is not immediately adjacent to the carboxyl group (the α position), but rather

attached to another carbon in the chain (the β, γ, δ carbon, etc.). These non-α-

amino acids are components of biologically important molecules, are important

in the pharmaceutical industry, and are useful starting materials for many areas of

organic chemistry.

This book focuses attention primarily on acyclic non-α-amino acids of C

3

–C

10

and

will include aminoalkanoic carboxylic acids, aminoalkenoic acids, and aminoalky-

noic acids. The synthesis of amino carboxylic acids attached to or incorporated in

rings of 3 to 10 carbons is also presented, including amino cycloalkanoic and amino

cycloalkenoic acids. Although saturated heterocyclic derivatives and aryl-substituted

amino acids are discussed in a limited manner, aromatic 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 goal of this book is to illustrate the synthetic approaches to and the impor-

tance of non-α-amino acids, particularly those amino acids that are key synthetic

intermediates or important compounds in their own right. Achiral as well as chi-

ral amino carboxylic acids will be discussed throughout, and special attention is

focused on both chiral nonracemic and chiral amino acids (see Chapter 5), empha-

sizing the diastereoselectivity and enantioselectivity of synthetic processes. Having

such synthetic information collected in one place will hopefully facilitate further

research and stimulate new research in this important area.

H

2

N(CH

2

)

n

CO

2

H

13

CO

2

H

H

2

N

R

2

CO

2

H

H

2

N

Glycine (H

2

N-CH

2

-COOH) is arguably the prototype α-amino acid, and the

formal name is 2-aminoethanoic acid. An ω-aminoalkanoic acid is dened as an

amino acid in which the amino group is on the carbon farthest removed from (distal

to) the carboxyl group (see 1). 3-Aminopropanoic acid (2) is the simplest ω-amino

carboxylic acid, and it has the common name of β-alanine (β-Ala). There are many

non-α-amino acids that have the amine moiety at positions other than the α-carbon

proximal to the carboxyl group. Derivatives of 3 that have alkyl substituents at C3

xx Introduction

and also an amino group at C3 (see 3) are referred to as β-amino acids.

*

As with 2

and 3, it is often useful to view an ω-amino acid as the parent structure for non-α-

amino acids, particularly functionalized and substituted amino acids.

Apart from 2, important amino acids include 1 (n = 3–9), and they appear

quite often in synthesis and in biologically important systems. These amino acids

1 include 4-aminobutanoic acid (n = 3), also known as γ-aminobutyric acid and

given the abbreviation GABA (γ-Abu).

†

5-Aminopentanoic acid (n = 4) is known as

δ-aminovaleric acid and given the abbreviation DAVA, but the three-letter code is

5-Ava. 6-Aminohexanoic acid (n = 5) is known as Amicar, ε-aminocaproic acid, and

has the three-letter code ε-Ahx. 7-Aminoheptanoic acid (n = 5) is known as 7-ami-

noenanthic acid, ζ-aminoenanthic acid, or ω-aminoenanthic acid. 8-Aminooctanoic

acid (n = 7), 9-aminononanoic acid (n = 8), and 10-aminodecanoic acid (n = 9),

which is also known as aminocapric acid, complete the straight-chain non-α-amino

carboxylic acids in this series.

There are several synthetic routes to these structurally simple yet important classes

of compounds, including functional group transformations that generate either the

amino group or the carboxyl group. In some cases, both groups are incorporated in a

single synthetic step. Biological aspects of these amino acids will be presented when

available, but in the context of the specic compound that is synthesized, although

Chapter 6 contains more detailed discussions of biological importance.

*

For a review on stereoselective syntheses of β-amino acids, see Liu, M.; Sibi, M.P. Tetrahedron 2002,

58, 7991. Also see Juaristi, E.; Soloshonok, V.A., eds. Enantioselective Synthesis of β-Amino Acids,

2nd ed. Wiley Interscience, Hoboken, NJ, 2005. For a discussion of chiral stationary phases in the

high-performance liquid chromatographic enantioseparation of unusual β-amino acids, see Ilisz, I.;

Berkecz, R.; Forró, E.; Fülöp, F.; Armstrong, D.W.; Antal Péter, A. Chirality 2009, 21, 339.

†

For a review on stereoselective syntheses of γ-amino acids, see Ordóñez, M.; Cativiela, C. Tetrahedron

Asym. 2007, 18, 3.