Amino Acids, Peptides, and Proteins Volume 25

A Review of the Literature Published During 1992

By J.S. Davies

The Royal Society of Chemistry

Copyright © 1994 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-234-7

Contents

Chapter 1 Amino Acids By G. C. Barrett, 1,
Chapter 2 Peptide Synthesis By D. T. Emore, 97,
Chapter 3 Analogue and Conformational Studies on Peptide Hormones and Other Biologically Active Peptides By C. M. Bladon, 155,
Chapter 4 Cyclic, Modified, and Conjugated Peptides By J. S. Davies, 246,
Chapter 5 Current Trends in Protein Research By J. A. Littlechild, 296,
Chapter 6 Metal Complexes of Amino Acids and Peptides By K. B. Nolan, R. W. Hay, and A. A. Soudi, 359,

CHAPTER 1

Amino Acids

By G.C.BARRETT

1 Introduction

The chemistry and biochemistry of the amino acids as represented in the 1992 literature, is covered in this Chapter. The usual policy for this Specialist Periodical Report has been continued, with almost exclusive attention in this Chapter, to the literature covering the natural occurrence, chemistry, and analysis methodology for the amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded.

The discussion offered is brief for most of the papers cited, so that adequate commentary can be offered for papers describing significant advances in synthetic methodology and mechanistically-interesting chemistry. Patent literature is almost wholly excluded but this is easily reached through Section 34 of Chemical Abstracts. It is worth noting that the relative number of patents carried in Section 34 of Chemical Abstracts is increasing (e.g. Section 34 of Chem Abs., 1992, Vol. 116, Issue No. 11 contains 45 patent abstracts, 77 abstracts of papers and reviews), reflecting the perception that amino acids and peptides are capable of returning rich commercial rewards due to their important physiological roles and consequent pharmaceutical status. However, there is no slowing of the flow of journal papers and secondary literature, as far as the amino acids are concerned. The coverage in this Chapter is arranged into sections as used in all previous Volumes of this Specialist Periodical Report, and major Journals and Chemical Abstracts (to Volume 118, issue 11) have been scanned to provide the material surveyed here.

2 Textbooks and Reviews

Reviews cover the asymmetric synthesis of unusual amino acids starting from serine or cysteine’and the uses of amino acids as chiral synthons in synthesis. A review of selenocysteine, an amino acid that has leapt to prominence as a new addition (codon UGA) to the universal genetic code, has appeared. A plea for consistent representation on paper of chiral formulae, and details of a new method for doing so, has been published Several other reviews have appeared, and are listed at the start of appropriate Sections in this Chapter.

3 Naturally Occurring Amino Acids

3.1 Isolation of Amino Acids from Natural Sources.

This Section continues to hold a position early in this Chapter even though it would be thought of as a routine aspect of the literature. However, the validity of reports on the presence of amino acids in natural locations is only reliable if it is certain that artefacts are not introduced through extraction procedures. Although the extreme sensitivity of current analytical methods for amino acids enhances confidence in the results obtained for samples, at the same time it enhances the possibility that erroneous conclusions may be reached on the indigeneity of amino acids in natural sources.

Extraction of tyrosine from aqueous solutions using n-butanol is 87% complete after two partitions if the aqueous solution is saturated with an alkali -metal salt. Similar partition leading to separation of amino acid mixtures and enrichment of amino acids in liquid surfactant membranes using tri-n-octylmethylammonium chloride, has been described. After extraction of samples with water, acidic amino acids (aspartic and glutamic acids) may be adsorbed preferentially from the solutions on to acid-treated alumina. A similar principle has been applied to isolate glutamic acid, glycine and lysine sequentially from aqueous solutions using silica-magnesia mixtures, and histidine and lysine using silica-titania mixtures. Isolation of tryptophan from aqueous solutions using the MK-40 cation exchange membrane and the adsorption of this amino acid onto the gel matrix during gel chromatography of amino acid hydrolysates on Bio-Gel P-2 has been described.” Tryptophan is the most readily adsorbed from a mixture of amino acids [Gly

3.2 Occurrence of Known Amino Acids.

The unusual amino acids present in mushrooms’ and the distribution in plant gall tumours and the chemistry of N-(carboxyalkyl) amino acids, have been reviewed. The occurrence and identification of N-carbamyl-β-amino acids in urine has relevance in the monitoring of metabolic processes.

Substantial studies over the years, of cross-linking amino acids in proteins, continue unabated, a representative review this year being the identification of cross-links in cattle hide after maturation. These cross-links are predominantly between histidine and hydroxylysinonorleucine, but the discovery of proteoglycans as a source of bridging sites, is notable.

Other studies identifying the presence of known, but unusual, amino acids in hydrolysates, include alloisoleucine, allothreonine, N-methylphenylalanine, and p-methoxyphenylglycine from the antibiotic xanthostatin, and O-methylserine and αβ-dehydrotryptophan from the cyclic peptide keramamide F from the marine sponge Theonella. Herbaceamide (1), from the marine sponge Dysidea herbacea, is an N-acylated (2S,4S)-5,5,5-trichloroleucine, adding to the lengthening list of halogenated amino acids found in such organisms.’ Careful studies have established the presence of D-enantiomers of alanine, serine, and proline in the mouse kidney.” Similarly careful studies are obligatory in assessing the common amino acids present in meteorites, and the problem of ensuring the indigeneity of protein amino acids in such sources was recently considered solved, since in test cases, the stable isotope distribution of organic constituents differed from the terrestrial distribution (see Vol. 24, p.2). A salutary warning arises from independent studies, that hydrolysis and derivatization reactions performed on fossils and meteorites can be accompanied by kinetic fractionation, influencing the stable isotope signatures.’ In a particular context as a dipeptide is progressively hydro1ysed the residual unhydrolysed dipeptide is increasingly enriched in 13C and 15N.

3.3 New Naturally Occurring Amino Acids.

Close relatives of protein amino acids that have been newly-discovered, are the novel immunomodulator metacyclofilin (2), from Metarhizium sp.TA2759 (the structure assigned lacks details of absolute configuration)and the potent insecticide ulosantoin (3) from the marine sponge Ulosa ruetzleri. New α-amino acids with heterocyclic side-chains are two analogues (4) and (5) of acromelic acid, from Clitocybe acromelalga. Full details have been published of the characteristics of the new amino acids from Clitocybe acromelalga L-3-(2-pyrrolyl)alanine (see Vo1.24, p.3) and L-3-(2-oxo-05-pyridyl)alanine, as well as their biosynthetic precursor, the already-known stizolobic acid (6). Also from the poisonous mushroom Clitocybe acromelalga, another neuroexcitatory α-amino acid L-3-(6-carboxy-2-oxo-4-pyridyl)alanine (7) has been identified. The isoxazolinone (8) from Streptomyces platensis A-136 shows antifungal activity against Candida albicans and low toxicity against mice.

Greater separation between the amino and carboxy functions is shown in the herbicidal γ-amino acid cis-2-amino-l-hydroxycyclobutane-l-acetic acid (9) from Streptomyces rochei, and the new spermine macrocyclic alkaloid budmunchiamine (10) present in seeds of Albizia amara.

3.4 New Amino Acids from Hydrolysates.

The flow continues unabated, of new discoveries of peptides and related derivatives comprising new amino acids that can be formally considered to be obtained from them by hydrolysis. In the protein cross-linking category, “cyclopentensine” has joined other elastin cross-links and is a condensate of three allysine residues to generate a cyclopentene moiety, unprecedented in crosslinking amino acids. Lysine residues in proteins can provide the amino group required for the Maillard reaction. There is a growing realization that crosslinking may result from an in vivo version of this reaction between proteins and carbohydrates (see Vol. 22, p.49), and a model reaction between α-N-acetyl-L-lysine and glucose has been shown to lead to fluorescent compounds [11; R = -(CH2)4CH (NHAc)CO2H] that have properties similar to age- and diabetes-related cross-linking moieties in proteins. Simpler analogues (11; R = n-pentyl) were also made in this study, and, like the lysine analogues, the configuration at one chiral centre is still to be determined.

Immunosuppressive lipopeptides, microcolins A and B, from Lyngba majuscula, contain N-methylvaline, O-acetyl-D-threonine, N-methylleucine, proline (or hydroxyproline, in the case of microcolin B), and 2-methylpyrrolidin-5-one condensed in that order from the N-terminus. The microcolins carry an N-terminal 2,4 dimethyloctanoyl moiety. Botanical interest predominates in the case of BZR-cotoxin II, the cause of Leaf Spot disease in corn and produced by Bipolaris zeicola race 3 (the factor is a cyclic nonapeptide containing N-methyl δ-hydroxyleucine, 1-aminocyclopropane-1-carboxylic acid, and of γ-methylproline, together with some common amino acids), and in the case of the antimitotic tetrapeptide ustiloxin (12) produced by Ustilaginoidea vireus growing on rice plant panicles. The latter compound is related to Phomopsin A, but contains a novel di-amino di-acid carrying a sulphinyl function.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods of Synthesis of α-Amino Acids.

Named preparative methods are as widely used as ever, almost literally “as ever”, since they were established many decades ago. Many of the methods described in the next, and later, Sections are also general methods. The Ploechl-Erlenmeyer process based on Ph2C = NMe for alkylation of 2-phenyloxazol-5(4H)-one has been illustrated and an interesting in situ generation of a triose aldehyde for the process using Pb(OAC)4 to cleave a protected hexose derivative (Scheme 1) has been described. The customary concluding step for the process is reduction of the C = C bond but the latter example is designed to lead to β-bromo-αβ-dehydro-amino acids. A related procedure employing 2,5-di-oxopi-perazine has been exemplified for a synthesis of phenylalanine, through alkylation with benzaldehyde followed by Zn-acid reduction.

More fundamental processes are at work in carbonylation reactions illustrated for perfluoroalkyl α-amino acids (Scheme 2). A yield of 64% obtained in this study for the preparation of 3,3,3-trifluoro-alanine, compares well with a figure (12%) through the best previous route for this compound. The Strecker synthesis applied to N-alkyl α-amino acids uses a primary amine, HCN, and an aldehyde. The similarly-oriented hydantoin synthesis but using (NH4)2CO3, has been used to provide a series of phenylalanine analogues with two substituents in the phenyl moiety.

Alkylation of glycine derivatives has expanded in scope from the time-honoured acetamidomalonate synthesis to the more recent processes based on the alkylation of glycine Schiff bases, e.g. Ph2C = NCH2CO2Me [right arrow] Ph2C = NCHRCO2Me. Schiff base alkylation can be achieved by various strategies after carbanion generation, illustrated by Michael addition to ArCH = CRCO2 Et giving 3-arylglutamates, and by the use of nitro-aldols formed from RCH2NO2 + HCHO [right arrow] RCH(NO2)CH2OH (R = D-xylopyranosyl). The purpose of the last-mentioned study, synthesis of C-glycosyl serines, was achieved after reductive de-nitration of the alkylated Schiff base with Bu3SnH/AIBN. More conventional alkylation protocols, using alkyl halides, are represented in the synthesis of phenylalanine analogues including α-dialkylation after NaHDMS de-protonation, leading to the remarkable αα-dialkylated glycines (13; such crowded structures are difficult to prepare through the classical Bucherer-Bergs method) An improved synthesis of α-amino phosphoric acids follows this strategy with Ph2C = NCH2P(O)(BUiO)2. αα-Disubstituted amino acid amides can be prepared by phase-transfer alkylation of benzylidene-amino acid amides PhCH = NCHRCONH2.

The most obvious short cut for this alkylation approach for some applications, is to use an N-acylated or N-carbamylated amino acid, i.e. not an ester; thus, Boc-glycine gives the tri-anion with LDA/THF which gives 40-80% yields on alkylation without di-alkylation side-products. Contrary to earlier reports, only two equivalents of strong base (rather than one, which results in N-alkylation) are needed for C-alkylation of methyl hippurate, though it should be noted that the choice of additive (TMEDA versus HMPA) influences the product composition. The carbanion formed with LDA from Boc-sarcosine ethyl ester, undergoes aldol condensation with acrolein to give predominantly (85%) the anti-isomer.

The special opportunities offered by proline as a synthon are often grasped for the synthesis of substituted prolines (and indeed, in alkaloid synthesis), and a circuitous approach giving 3-substituted prolines through γ-alkylation of 2-aminoketene S,S-acetals after carbanion formation LDA (Scheme 3). Intramolecular azide cycloaddition can provide the pyrrolidinone S,S-acetals and higher homologues (also in Scheme 3).

The alternative approach in which α-hetero-atom-substituted glycines act as cation equivalents continues to be usefully explored. α-Methoxyglycines of various types (14) undergo BF3-catalysed addition to ester enolates so as to give ββ-disubstituted aspartates, and α-(trimethylsilyl)oxy alanines can be alkylated by allylsilanes with TMSOTf to give γδ-unsaturated α-methyl-α-amino acids. Some dehydro-alanine is formed as side-product in the latter study, and further clarification of reaction conditions will be needed if this is to be avoided. A new electrophilic sarcosine synthon (15) has been advocated, and employed in Michaelis-Arbuzov-type synthesis of sarcosines carrying phosphorus-containing side-chains.

αβ-Dehydroamino acids are becoming more attractive synthons for use in α-amino acid synthesis, though of course, as is the case for a number of outcomes of other alkylation methods, they yield racemic products when used for Lewis-acid catalysed α-acylamidoalkylation of furans and anisole. A most promising route, in which N-acetyl dehydro-alanine methyl ester complexed with Fe(CO)3 [alias (methyl 2-acetamido acry1ate)tricarbonyl iron(0)], treated with MeLi and a tertiary alkyl halide, gives t-leucine and new amino acids with β-branched alkyl side-chains (2-amino-3,3-dimethyl-pentanoic and -hexanoic acids).

Amination of a range of substrates has long been a favoured approach to α-amino acids, and is exemplified in its classical form using phase-transfer catalysed amination of α-halogeno-esters by Cl3CONH2 or by F3C(CF2) nCH2CH2NH2. Reductive amination of α-keto-acids is also represented in the recent literature. Synthesis of N,N-bis(carbamy1ated) amino acids can be accomplished using potassium iminodicarboxylates (readers will recognize the formula Boc2N-K+ more readily!) with 2-bromo-alkanoates or through a Mitsunobu reaction involving ethyl lactate (cf. also Ref. 78). New-style Hofmann rearrangement leading to amination employs Pb(OAc)4 and ButOH, and is illustrated (Scheme 4) in a synthesis of sterically-constrained surrogates for ornithine and arginine starting from a homochiral glycidyl triflate and di-t-butyl malonate. The same approach leads to all four stereoisomers of a constrained methionine [16; CH2SMe in place of (CH2)n NH2). Palladium(II)-catalysed Overman rearrangement of homochiral trichloroacetimidates Cl3CC(= NH)OCHRCH = CHCH2OTBDPS, yields (E)-[beta[γ-unsaturated α-amino acids via optically-pure mono-protected allyldiols Cl3CCONHCH(OTBDPS)CH = CHR in this particular case. Amination of trichloromethyl carbinols, formed from trichloromethyl ketones, provides the basis of a new enantioselective synthesis of α-amino acids, illustrated (Scheme 5) for t-butylglycine (alias t-leucine). A convenient synthesis of trichloromethyl ketones needed for this purpose, has been published. Phthalimides yield Boc-α-amino-organostannanes (Scheme 6), formed by Sn-Li exchange with BuLi, that are configurationally stable at very low temperatures (— 95%/ 10 minutes) but suffer significant racemization at — 78° and — 55°. An amino acid synthesis emerges from this work on the basis of carboxylation (CO2) after carbanion formation. Ring-opening of aziridines, e.g. those formed from electron-rich alkenes (such as MeCH = CHCO2Me) and HN(OMe)2/TMSOTf, from which the N-methoxy group can be reductively removed with Na/NH3, give correspondingly-substituted amino acids. For example, 3-arylaziridine-2carboxylic esters (17) give 3-chloro- and 3-benzenethio-phenylalanines when treated with HCl and with PhSH respectively, and the trans-3-hexyl analogue reacts similarly, as well as being shown to undergo ring-expansion with MeCN to give the corresponding cis-imidazoline-2-carboxylic acid (essentially a 3-aza-proline).

(Continues…)Excerpted from Amino Acids, Peptides, and Proteins Volume 25 by J.S. Davies. Copyright © 1994 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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