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Amino Acids, Peptides, and Proteins Volume 28

A Review of the Literature Published during 1995

The Royal Society of Chemistry

Amino Acids

BY GRAHAM C.BARRETT

1 Introduction

The literature of the amino acids for 1995 is reviewed in this Chapter, aiming particularly at thorough coverage of developments in chemical and analytical areas. Although the literature covering routine biological studies of common amino acids is excluded, the more innovative biological and pharmaceutical work is covered. Scrutiny of the hard copy literature (the major journals, and Chemical Abstracts from issue 11 of Vol 122 to issue 9 of Vol 124 inclusive) has provided the citations that make up the Chapter.

Continuity with preceding Volumes of this Specialist Periodical Report has been a prime consideration, so the Chapter has been sub-divided in the style used in all previous Volumes in this series. The device '(see p. XX, Vol YY)' that is used in this Chapter provides reference back to preceding Volumes, and helps the reader to keep track of important amino acid topics that have been developing over the years.

This Report has acknowledged in recent Volumes, that the term 'amino acids' has numerous meanings, but that the almost exclusive emphasis of this Chapter is on the α-aminoalkanoic acids. The reason for acknowledging this is the rising interest in the study of amino acids incorporating other oxyacid functions, particularly phosphorus analogues of the common aminoalkanoic acids. Short sections are included in this Chapter, on this topic, even though coverage must be selective in order that the literature of aminoalkanoic acids may receive thorough treatment. The unusually acidic 3-hydroxy-3-cyclobuten-1,2-dione grouping, established to be a bio-isostere of the carboxy group, has stimulated the synthesis of the corresponding amino acid analogues (1).

2 Textbooks and Reviews

Several recent textbooks give either partial or exclusive coverage of amino acid topics. A symposium report covers a wide range of recent studies on amino acids in higher plants.

Reviews have appeared covering derivatives of natural amino acids as radio-protectants, and industrial aspects of the uses of amino acids. The unusual amino acids hypusine [Nε -(4-amin0-2-hydroxybutyl)-L-lysine], ovothiols (mercaptohistidines), and the pyridinolines have been reviewed from the point of view of their occurrence; members of the last-mentioned family, particularly pyridinoline itself and deoxypyridinoline, that derive from collagen breakdown, are present in urine at levels related to bone resorption activity, and these levels may be used as an osteoporosis index for individual patients (see also Ref. 849). The occurrence in proteins of the fluorescent crosslinking amino acid, pentosidine, has been reviewed; its formation accompanies glycoxidation in vivo, and it accumulates at a greatly accelerated rate in uraemic patients; thus it is linked with the ageing process, and this suggests that its accumulation can be used as a diagnostic indicator. A review covers the extensive literature on the non-natural amino acid threo-dihydroxyphenylserine, whose importance lies with the fact that it undergoes L-aromatic amino acid decarboxylase-catalyzed decarboxylation to give neurally- active norepinephrine.

Other recent reviews are more appropriately located in later Sections of this Chapter.

3 Naturally Occurring Amino Acids

The work described in this Section concentrates mainly on new amino acids, and on the more unusual of the known amino acids discovered in previously-unknown natural compounds.

3.1 Isolation of Amino Acids from Natural Sources – If reliable results are to emerge from such endeavours, then reliable methods of isolation of individual amino acids from complex mixtures are needed. This section has been introduced into this Chapter in recent years as a collection point for citations on apparently routine current work that often includes salutary warnings of sources of error and contamination. Analytical and preparative scale purification of amino acids is covered in later sections of this Chapter.

A commercial cation exchange resin has been found to be contaminated with several common amino acids (e.g. leucine: 260 pmol ml-1resin). It is a mixed blessing, that there is no satisfactory method of clearing this background, which could have serious consequences for the reliable quantitation of amino acids in at trace levels if released by the resin into analytical samples. Concentration of solutions of amino acids can be achieved using ion exchange membranes, and ion exchange chromatography has been used for large-scale purification of phenylalanine. Other purification procedures with a similar context, for phenyl-alanine (continuous emulsion liquid membrane separation), and for the separation of isoleucine from valine (kerosene – D2EHPA partition), rely on different physical principles. The extraction of phenylalanine and tyrosine from aqueous solutions, using hydrophilic solvents, has been precisely formulated, a resource that may help in the work-up of complex amino acid mixtures. Milligram scale preparative HPLC allows the isolation of pure (96-99%0) individual amino acids from mixtures, as their N-benzyloxycarbonyl derivatives. The recovery (68-89%) of amino acids from mixtures in this way should surely be capable of improvement.

3.2 Occurrence of Known Amino Acids – Selection for this section is limited by excluding routine work with common amino acids; but the identification of αα-dialkyl α-amino acids in geological samples (they are minor components), of common amino acids in resinous and other non-protein materials used by artists, and in amber-entombed insects, seem to be eminently worthy of mention. Samples for the last-mentioned study were aged from <100 y to 130 x 106y; the interpretation of amino acid racemization data determined for these samples would have given much younger ages; racemization rates for common amino acids must suffer retardation by the amber environment by a factor greater than lo4.

Streptomyces akiyoshiensis cultures accumulate N-acetyl-L-DoPA, which is shown in this study not to be involved in the biosynthesis of 5-hydroxy-4-oxo-L-norvaline (the major metabolite of this bacterium). Fungal and other plant sources shown to contain unusual amino acids include Tricoloma muscarium (ibotenic acid; the first report of this isoxazole derivative in a mushroom not belonging to the genus Amanita), Ateleia glazioviana Baillon, a tree that is insect-repellent and toxic to cattle (1-aminocyclobutane-1,3-dicarboxylic acid and δ-acetylornithine), and roots of Glycyrrhiza yunnanensis (NNN-trimethyl tryptophan betaine).

Rhizocticins A, B, and D contain (Z)-L-Zamino-5-phosphonopent-3-enoic acid, an α-amino acid already described to be a component of plumbemycins but thought to be of the D-configuration in these members of the latter family, whose structures are now in need of correction as far as absolute configuration is concerned. Structures have been established for new microcystins, which contain 2-aminobuten-2-oic acid. Cyanobacteria (blue-green algae) are already known to produce bioactive cyclic peptides, and new examples are: anabaenopeptins A and B (Anabaena flos-aquae NRC 525-17) that contain, together with other common L-amino acids, D-lysine, N-methyl-L-alanine and homo-L-tyrosine; and the cyclic depsipeptide oscillapeptin (Oscillatoria agardhii NIES-204) together with the cyclic hexapeptide oscillamide Y, which contain homotyrosine and N,O-dimethyl-L-tyrosine (in the former case) and N-methyl-L-alanine (in the latter case) amongst other constituents. The dioxopiperazine, flutimide (2) has been isolated from a new fungus Delitschia confertaspora.

The rapidly accumulating literature covering the discovery of D-enantiomers of the common amino acids in natural sources is illustrated for D-serine in rat brain and D-aspartic acid in peripheral organs (see Ref. 897 for the identification of D-amino acids in serum samples). The occurrence of D-aspartic acid in proteins, and the broader picture concerning in vivo racemization of amino acids, have been reviewed. D-Alanine occurs in free form in 15 out of 24 species of marine micro-algae.

3.3 New Naturally Occurring Amino Acids – New aliphatic α-amino acids include (2S,3S,4R)-β-hydroxy-γ-methyl glutamic acid and its (2S,3R,4R)-epimer (together with pipecolic acid and 5-hydroxypipecolic acid) in seeds of Gymnocladus dioicus (see also Ref. 828), (S)-cis-2-amino-5-chloropent-4-enoic acid in Amanita vergineoides, 2S)-2-amino-5-chloro-4-hydroxyhex-5-enoic acid from Amanita gymnopus fruit bodies (together with (2S)-2-aminohex-5-enoic acid a first natural occurrence of an amino acid already known in the laboratory and (2S)-2-aminohexa-4,5-dienoic acid and (2S)-2-aminohex-5-ynoic acid). The pyroglutamic acid relatives (3; R = OH, or H), found in Streptomyces sp. SA-3501, have been christened pyrostatins A and B, respectively; they have potential importance due to their role as inhibitors of N-acetyl β-glocosaminidase.

New natural aromatic and heteroaromatic a-amino acids include purealidins J – R [nine new bromotyrosine derivatives, e.g. (4) and (5), from Psammaplusilla purea, an Okinawan marine sponge], and the cysteine derivative (6) from Streptomyces SB212305. A new mycosporin-like amino acid (7) from the reef-building corals Pocillopora damicornis and Stylophora pistillata contains methylamine in place of the glycine moiety usually seen in the mycosporins.

The novel β-amino acid (S)-3-amino-5-mercatopropionic acid (8) occurs in caledonin (from the marine tunicate Didemnun rodriguesi), while the higher homologue (9) is one of four new piperidine alkaloids from leaf extracts of Cassia leptophylla.

3.4 New Amino Acids from Hydrolysates – The title of this Section, though cumbersome, adequately accommodates details of work through which the presence of new amino acids bound up into amides of varying structures, and esters and close analogues, has been revealed.

The dipeptide (10) incorporating a novel adenine derivative has been isolated from the fungus Taloromyces NK 374200. 2-Oxohistidine has been established to be a constituent of oxidatively-modified proteins, and β-hydroxyhistidine is only one extraordinary feature of exochelin MN (11), the extracellular siderophore from Mycobacterium neoaurun that transports iron into Mycobacterium lerae. Phosphocysteine is a constituent of a PTS-protein from Staphyllococcus carnosus. A β-hydroxy-γ-chloroproline residue is a notable feature of the cyclic pentapeptide astin I (from Aster tataricus roots), while trans-2,3-cis-3,4-dihy-droxyproline (12) occurs repeatedly in the sequence of the byssus protein from the marine mussel Mytilus edulis. The trichlorovaline subunit present in dysidenin (13) from the marine sponge Dysidea herbacea is also represented in a novel chlorinated ketide amino acid, herbamide A (14), from the same source.

A new metabolite of the cyclosporin-producing fungus Tolypocludium terricola is identical with cyclosporin D except for the presence in this cyclic peptide, of hydroperoxy-MeBmt (i.e. 3-hydroxy-7-hydroperoxy-4-methyl-2-methylamino-SE-octenoic acid).

Dioxopiperazine-2,s-diones (alias cyclic dipeptides) have featured in this section over the years, and have continued to show increasingly surprising structures, and they often have useful medicinal properties. Recent examples range from the dehydrotyrosine derivative (15) (together with new pipecolic acid derivatives) from the sponge Anthosigmellua aff: raromicrosclera, the tryptophan derivatives maremycins A and B (16) from a marine Streptomyces sp., leptosins K, K1, and K1, and tryprostatins A and B (17; R = H, OMe, respectively) from Aspergillus fumigutus BM939. Dehydrogenated derivatives macrophominol (18) from Macrophomina phuseolina, terezines A – D (19) from Sporormiella teretispora,58 and the morpholin-2,5-dione bassiatin (20) from Beauveria bassiana K-717 are notable new naturally-occurring amino acid derivatives.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods for the Synthesis of α-Amino Acids – The methods that have been used for many years are well trusted, and sufficiently broad in their scope to accommodate new and current needs. However, innovation in organic synthesis continues at its usual rapid pace within the amino acids field, as elsewhere, and some new ideas (as well as fresh-looking results that are in fact extensions of existing knowledge) have been a feature of this Section over recent years. The elaboration of side-chains of the readily available α-amino acids is increasingly being chosen for the synthesis of other amino acids, and this literature is covered in a later Section (Section 6.3; Specific Reactions of Amino Acids).

Advances in methodology are more noticeable in aspects of asymmetric synthesis (see next Section), and in some cases these can also be considered to be advances in general methods of synthesis.

Reviews have appeared covering α-cation equivalents of amino acids and the 1994 literature on the synthesis of amino acids, amides, and peptides. Synthesis of α-amino acids from higher fatty acids, and synthesis through photolysis of chromium(II)-carbene complexes in the presence of nucleophiles (see Vol 27, p. 15, and Ref. 118 for further examples), have been reviewed.

Standard routes illustrated in the 1995 literature are the Bucherer-Bergs synthesis (αα-disubstituted α-amino acids from 3-substituted cyclopentanones; see also Ref. 718) and its near relative seen in the preparation of phenylglycine from PhCHO/CHCl3/NH3in aqueous NaOH containing Bu4/NBr. The Ugi

synthesis continues to provide a direct approach in suitable cases (Refs. 258, 295). The Strecker synthesis has been used for the preparation of 3,5-dimethoxyphe-nylglycine constituents of vancomycins. α-Bromo-substitution (CBr4) of the 2-methoxycarbonylpyran α-proton can be readily achieved after anion formation using lithium bis(trimethylsilyl)amide, if substituents elsewhere in the ring place this proton in the equatorial plane; ensuing azidolysis and reduction to the αα-disubstituted glycine proceeds normally. Substitution of triflate by azide, and elaboration into α-substituted α-amino acids, has also been used in this study of the preparation of glucofuranose- and glucopyranose-based hydantoins and related dioxopiperazines as analogues of the potent herbicide, hydantocidin.

Conversion of chiral α-hydroxy acid derivatives into amino acid analogues can be accomplished by the Mitsunobu protocol, illustrated this year for N-alkylation of 2-(trichloroethyloxycarbonylamino)thiazole by ethyl (S-lactate.

There are numerous examples elsewhere in this Chapter, of applications of classical rearrangements that deliver a nitrogen grouping to carbon, in a manner appropriate for amino acid synthesis [Curtius (e.g. Refs. 183, 207, 287), Hofmann (Ref. 265), Beckmann (Ref. 423) and Schmidt rearrangements among others], and a further example of the aza-Claisen rearrangement of an ally1 trichloroacetimidate has offered a new entry to 1-amino cyclopropanecarboxylic acids (Scheme 1).

Examples of alkylation of familiar glycine synthons illustrating general routes are found in the phase-transfer catalyzed alkylation of diethyl acetamidomalonate with weakly electrophilic alkyl halides [see also Ref. 296; diethyl formamidomalonate (Ref. 286) and ethyl acetamidocyanoacetate (Ref. 285) have also been used for similar purposes], phase transfer-catalyzed Michael anti-addition of (MeS)2C=NCH2CO2R1 to αβ-unsaturated esters (see also Ref. 132), and alkylation of Ph2C=NCH2CO2R with cyclohexadienyliron π-complexes (Scheme 2) and with 1, ω-dichloroalkanes [giving bis(α-amino acids)]. Condensation of diazoacetylglycine methyl ester with an aldehyde, and Bu4NF cyclization of the resulting β-keto-amides, gives a 3-acyltetramic acid (21; these can be categorized in other ways, as cyclized δ-amino acids for example). Alkylation of the α-bromoglycine derivative R1R2NCHBrCO2R3 by alkyl nitronates gives α-halogeno-, β-nitro-, and αβP-dehydro-amino acid derivatives. Ammonia reacts with methyl N-benzoyl-2-bromoglycinate to yield trimethyl 2,2',2"-nitrilotris[2-(benzoylamino)acetate] as a 6:1-mixture of diastereoisomers, which can be separated by crystallization. α-Methoxyglycine derivatives (alias glyoxylic acid – amine adducts) continue to reappear in different applications, e.g. the 2-pyrrolidinone adduct (22) or its pyroglutamic acid analogue, that is susceptible to arylation via its N-acyliminium ion (Scheme 3). An example of an unfamiliar glycine synthon is carbethoxyformonitrile oxide, used as Michael donor to alkylate a vinyl ester in a synthesis of the racemic form of the natural sweetener, monatin (Scheme 4).

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Excerpted from Amino Acids, Peptides, and Proteins Volume 28 by J.S. Davies. Copyright © 1997 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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