Amino Acids, Peptides and Proteins: Volume 27

Amino Acids, Peptides and Proteins: Volume 27

by J S Davies

Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 90 years The Royal

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Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 90 years The Royal Society of Chemistry and its predecessor, the Chemical Society, have been publishing reports charting developments in chemistry, which originally took the form of Annual Reports. However, by 1967 the whole spectrum of chemistry could no longer be contained within one volume and the series Specialist Periodical Reports was born. The Annual Reports themselves still existed but were divided into two, and subsequently three, volumes covering Inorganic, Organic, and Physical Chemistry. For more general coverage of the highlights in chemistry they remain a 'must'. Since that time the SPR series has altered according to the fluctuating degree of activity in various fields of chemistry. Some titles have remained unchanged, while others have altered their emphasis along with their titles; some have been combined under a new name whereas others have had to be discontinued. The current list of Specialist Periodical Reports can be seen on the inside flap of this volume.

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Amino Acids, Peptides, and Proteins Volume 27

A Review of the Literature Published During 1994

By J.S. Davies

The Royal Society of Chemistry

Copyright © 1996 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-207-4


Amino Acids


1 Introduction

The 1994 literature covering the amino acids, from the point of view of their chemistry and biochemistry, is dealt with in this Chapter. The approach adopted is identical to that used in all previous Volumes of this Specialist Periodical Report. The Chapter concentrates on the literature covering the natural occurrence, chemistry, and analysis methodology for amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded. Patent literature deals with material that also finds its way into the conventional literature, and is therefore excluded from this Chapter. It is easily reached through the appropriate sections of Chemical Abstracts (Section 34 in particular).

The flow of Journal papers and secondary literature continues to accelerate, as far as the amino acids are concerned, and papers have been collected for this Chapter from major Journals and from Chemical Abstracts [to Volume 122 (1995), issue 9]. Where it is helpful to refer to earlier Volumes of this Specialist Periodical Report, the formula '(see Vol. 23, p. 3)' is used.

Most of the papers cited are only briefly described, so that adequate commentary can be offered for particular papers presenting significant advances in synthetic and analytical methodology relating to the amino acids, with mechanistically-interesting chemistry being given prominence.

The coverage adopts the usual meaning of the term 'amino acids', i.e. aminoalkanoic acids H3N+(R1R2C) nCO2-. Many conceivable structural types (for example, benzene derivatives carrying amino and carboxy groups) are excluded. Representative citations are offered, of analogues in which the carboxy group is replaced by a phosphorus oxyacid equivalent, H3 N+(R1R2C)n-P(O)(OH)(O-), e.g. (1S,2S)-phosphothreonine have important research applications; even the boron analogue R3N·(BHR1)n-CO2 Rmay hold some similar promise.

2 Textbooks and Reviews

A substantial source of information on instrumental and analytical protocols includes material on the amino acids. A similarly thorough coverage of topics in the synthesis of amino acids has been published.

Several reviews will be found in appropriate sections of this Chapter, though others of a more general nature are collected here; these cover α-aminoisobutyric acid, carboranylalanine in neutron capture therapy cyclopropane-based amino acids, 1-aminocyclopropanecarboxylic acid synthesis, cyclobutane-based amino acids, synthesis of heterocyclic amino acids, uses of amino acid esters as chiral auxiliaries in organic synthesis, uses of α-amino acids in aminosugar synthesis, and stereochemical details of metabolic reactions of amino acids.

3 Naturally Occurring Amino Acids

3.1 Isolation of Amino Acids from Natural Sources – All fermentative processes for the production of amino acids require routine isolation of the product, and, like the production of amino acids through protein hydrolysis, the separation of mixtures is a common concluding stage to the process. This section is intended to select some less routine aspects of the isolation of amino acids, particularly those unexpected outcomes of otherwise straightforward procedures.

Protein hydrolysis is most commonly accomplished using hydrochloric or methanesulfonic acids, but several alternative protocols have been suggested; mercaptoethanesulfonic acid (160-180°) has been found to be effective.

Continuous concentration of amino acids using a liquid emulsion membrane with a cation extractant, di-2-ethylhexylphosphoric acid, has been described. Preparative chromatographic isolation (gel filtration and partition) of pyridino-line and of hydroxylysyl- and lysyl-pyridinolines from biological fluids, and preparative chromatography of benzyl esters of basic amino acids and N-benzyloxycarbonyl amino acids (Z-amino acids) illustrate standard methods.

3.2 Occurrence of Known Amino Acids – Where common amino acids are found in meteorites, and in ancient fossils, an obvious first question, but one only recently addressed in a rational scientific manner, is: is the amino acid indigenous or has it been introduced subsequently? Further studies (see Vol.25, p.3) based on sensitive GC-MS isotope-analytical techniques confirm the indigeneity of amino acids through identical δ13C and δ15N values for D- and L-enantiomers of a particular amino acid in thoroughly-cleaned 7000–105 y samples, and in Pleistocene fossils. Quaternary land snails given more detailed study confirm this diagnostic test as far as neutral amino acids are concerned, but differing δ13C values for D- and L-enantiomers of aspartic and glutamic acids introduce an element of doubt; presumably these amino acids as constituents of shell protein are subject to more complex diagenesis.

Contemporary natural sources that have been shown to contain unusually interesting, though known, amino acids include D-aspartic acid (supplied by intestinal bacteria) in appreciable quantities in Octopus vulgaris, the antimicrobial and antioxidant N-(p-coumaryl)pipecolic acid in rhizomes of Cirsium brevicaule. Both D- and L-tert-leucine appear, together with D-kynurenine, as constituents of discodermin E, from the marine sponge Discodermia kiiensis. α-Methylcysteine appears in condensed form in the cryoprotective agent thiazohalostatin (1) from Actinomadura. Another peptide from Verticillium coccosporum has been discovered to contain 2-amino-8oxo-9-hydroxydecanoic acid.

The presence of β-alanine in Clitocybe acromelalga, as its L-glutamide derivative adds another natural location to those already established for this β-amino acid. γ-Hydroxy-L-glutamic acid occurs in bulbs of Hemerocallis longituba in the form of the amide, longitubanine (2; R = OH).

Synthetic cis-4-methylproline is physically different from the compound located over the years in various natural sources, calling for some reconsideration of the structural assignments.

The assessment of crosslinks that develop in vivo in proteins of higher species, as a result of ageing or disease, has become an important diagnostic criterion, and pyridinium crosslinks and dityrosine crosslinks have been identified in bovine thyroglobulin.

3.3 New Naturally Occurring Amino Acids – Mycestericins from Mycelia sterilia are potent immunosuppressants that have been shown to be hydroxylated α-hydroxymethyl-α-aminoalkanoic acids (3–5) of extraordinary types. Another new acyclic aliphatic α-amino acid also owes its fascination to the functional group that it contains, the first natural azoxy-containing antifungal agent, L-azoxybacilin (6), from Bacillus cereus NR2991. Sphingofungins (7) are a new family of antifungal metabolites from Aspergillus fumigatus ATCC 20857. New opines (8) and piperidine 2,4,5-tricarboxylic acid (9), are further metabolites from Clitocybe acromelalga (see also Ref.30). Five new compounds (e.g., 10 and stereoisomers) related to domoic acid have been isolated from mussels.

3.4 New Amino Acids from Hydrolysates – γ-Hydroxy-tert -leucine is a constituent of polytheonamides A-C from the marine sponge Theonella swinhoei, and Zwittermicin A from Bacillus cereus is (11). The other new amino acids are mostly lactams condensed into more complex structures; the 2,5-dihydrofuryl-γ-lactams, fulvanines D and E (12), (13) from Hemerocallis fulva, anchinopeptolides B–D (14) from the sponge Anchinoe tenacior, the antibiotic magnesidin A (15) from Vibrio gazogenes, and the novel siderophore vibrioferrin (16) that develops in Vibrio parahuemolyticus in response to limitation of Fe in the culture fluid.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods for the Synthesis of α-Amino Acids – The term 'general methods' has been attached to a group of reactions that have become familiar through use for many years; these are covered in this Section as far as the α-amino acids are concerned.

Relatively few novel ideas have been introduced under this heading in recent years, and those that have, have been concerned with the burgeoning area of 'Asymmetric Synthesis'. Although given a Section of their own in this Chapter (Section 4.2) asymmetric synthesis methods are nearly always 'general methods of synthesis' too. Other general reactions by which one amino acid is used as starting material for the synthesis of another, are mostly covered in the later Section 6.3 (Specific Reactions of Amino Acids).

Long-established methods continue to be revisited as reliable routes, and many of these are used in syntheses of labelled amino acids (see Section 4.15). The alkylation of diethyl phthalimidomalonate (see Refs. 166,256) and diethyl acetamidomalonate (see also Refs.254,258), e.g. for a synthesis of 2-amino-7, 7-dimethyloctanoic and 2-amino-8,8-dimethylnonanoic acids, and the alkylation of oxazolones, e.g. in an aspartic acid synthesis (17 [right arrow] 18), in a synthesis of α-amino-β-phosphonopropionic acid, and in an arylglycine synthesis (Scheme 1) and corresponding vinylglycine synthesis, are typical long-established methods. Rearranged dimers that are well-known (usually unwanted) side-products from oxazolone alkylation, can be hydrolysed to give α-alkyl-α-amino acids. Addition of a thiol to 4-benzylidene-2-methyloxazolone, followed by routine work-up, gives a threo/erythro-mixture of N-acetyl S-(p-methylbenzy1) -β-phenylcysteine methyl ester. A novel variant of the oxazolone procedure is represented in the conversion of a 4,4-bis(isopropylthio) oxazolone into amides or peptides, and its chlorinolysis (SO2Cl2) to give halogenoglycine derivatives that are easily converted into other amino acids through halogen substitution.

These two general methods are essentially glycine alkylation procedures; other routes in this category include alkylation of glycine Schiff bases (phase-transfer catalysed alkylation of PhCH = NCH2CO2Me [right arrow] phenylalanine, mediated by microwave energy), and corresponding syntheses of leucine, serine and aspartic acid, Michael additions, of (RlO)2P(O)CH = CH2 and a two-step alkylation (by R1CH = CRCH2Br then γ-elimination of Br) to give α-cyclopropylglycines. Similar approaches employing N-phenacyl-N-benzylglycine and N-(ω-chloro-alkyl)-N-Boc-glycine as starting materials lead to azetidinecarboxylic acids and higher homologues. The corresponding use of N-oxides of glycine Schiff bases to prepare α-(N-hydroxyamino) acids, and of α-amidinoalkanoates (Scheme 2) have a good deal in common, mechanistically.

The [3,3]-rearrangement of N-protected glycine ally1 esters (19 [right arrow] 20) exemplifies an alternative glycine alkylation process that has been well studied from the 1960's.

Alkylation of α-halogenoglycine synthons (Scheme 3) is significantly facilitated by ZnC12, indicating a radical mechanism where the catalyst is both a radical initiator and chelates the substrate. Copper(I)-catalysed Cl-transfer radical cyclization of N-(alk-3-enyl)-α-chloroglycines gives prolines via 2-aza-5-alken-l-yl radicals. A similar study of the generation of the glycine α-radical formed by stannanes from α-bromo-, -benzyloxycarbonyloxy-, and -methoxy-glycine derivatives, and its alkanesulfenylation with disulfides, has been described. Xanthates MeO2CNHCH(S2COEt) CO2Me similarly yield radicals that add to alkenes to offer a valuable new general amino acid synthesis. N-Protected α-hydroxyglycine esters are readily substituted, illustrated this year in a preparation of (p-vinylphenyl)glycine. α-Acetoxy analogues have been employed in syntheses of vinylglycine and propargyl homologues.

Isocyanoacetates CNCH2CO2R (see also Ref.255) perform well in aldol additions that show high diastereoselectivity to provide β-hydroxy-α-amino acids. α-Nitroacetates are readily alkylated, Michael addition of ally1 acrylate followed by reductive cyclization giving N-hydroxy-pyroglutamate derivatives.

Amination processes leading to amino acids constitute an established group of general methods that have been exemplified this year by some of the oldest variants: reductive amination of α-ketocarboxylic acids using NH3/Raney nickel, and of methyl (1S,2R,3R)-3-hydroxy-2-methoxycyclohexanecarboxy-late; ammonolysis or methylaminolysis of t-butyl bromoacetate, and the corresponding process with diethyl bis(2-methylthioethyl)malonate. Addition of ammonia, primary amines, or hydroxylamine to substituted fumaric acids leads to corresponding aspartic acid analogues, and corresponding Michael addition of N-acylisoureas (formed from a carbodi-imide and a carboxylic acid) to methyl hydrogen maleate to give N-carbamylaspartic acids. Further examples (see Vol. 26) of the formation of cyclic hydrazino-acids through cycloaddition of dienes to azodicarboxylates, have been published (see also Ref. 199). Condensation of a primary amine (TiCl4) with a γ-chloro-α-ketoester to give a γ-chloro-α-iminoester is followed by cyclization to give a 1-amino-2,2-dialkylcyclopropanecarboxylic acid.

Several examples of azidation, of enolates and of α-methoxyacrylonitriles (giving α-azidonitrates), have been described as stages in α-amino acid syntheses. Diazonium salts are electrophilic α-aminating agents towards esters in the form of their ketene silyl ketals, yielding α-azo- or -hydrazono-esters which on hydrogenation yield α-amino acid esters. Use of an alkyl sulfenimine R2S = NH as aminating agent towards a latent nucleophilic carboxy group equivalent has been given a preliminary assessment.

Amination through Stevens rearrangement of transient ammonium ylides formed between amines and diazoketones or diazoesters gives α-aminoketones or α-amino esters, respectively, in one step.

Amidocarbonylation – the introduction of both amino and carboxy groups in a one-pot process – has been illustrated in an N-acetylglycine synthesis (paraformaldehyde, CO, and H2, with a cobalt-phosphine catalyst), and the distantly-related equivalent process from aldehydes and CHCl3 continues to be studied.

Introduction of the carboxy function into a protected amine, to lead to the corresponding α-amino acid, can be accomplished in certain cases, e.g. by the oxidation of a phenyl group (C6H5- [right arrow] -CO2H) using RuO4.

'Modifications to an amino acid side-chain' could be described as a general method of amino acid synthesis, although examples of this approach constitute a somewhat miscellaneous collection and are mostly located later in this Chapter (Section 6.3). However, an interesting set of procedures for the alkylation of the dehydro-alanine derivative methyl 2-acetamidoacrylate)tricarbonyliron(0), has been described, leading to βββ-tri-alkyl amino acids through successive treatment with 2 eq MeLi and an alkyl halide (see also Vol.25, p.9).

Contraction of a β-amino acid backbone could also be described as a general synthesis method for α-amino acids, and further examples (see Vo1. 24, p.8) of the conversion of α-keto-β-lactams into α-amino acid N-carboxylic acid anhydrides have been accomplished by Baeyer-Villiger oxidation, a process that is applicable to homochiral substrates, leading to β-alkylserine N-carboxylic anhydrides. The method has been also been illustrated in a synthesis of (R)-α,β-diamino-γ-hydroxyacid N-carboxylic anhydrides from β-lactams.

4.2 Asymmetric Synthesis of α-Amino Acids – Activity in this area continues to increase, both in the provision of new methodology and in the development of established methods, including well-known standard general methods of synthesis, some of which are described in the preceding section, and revisited here in 'asymmetric versions'.

Two thorough reviews cover the overall topic and another review deals with asymmetric synthesis of '2,3-methano'-amino acids (i.e., 1-aminocyclopro-panecarboxylic acids).

Modifications of standard general methods of α-amino acid synthesis are represented in a Strecker procedure employing a chiral ketone as catalyst for the equilibration of aminonitriles R1R2 C(CN)NHCHRCN, and in an equivalent process using homochiral sulfinimines (illustrated for the (Ss)-configuration in Scheme 4).


Excerpted from Amino Acids, Peptides, and Proteins Volume 27 by J.S. Davies. Copyright © 1996 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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