Amino-acids, Peptides, and Proteins Volume 15

A Review of the Literature Published During 1982

By J H Jones

The Royal Society of Chemistry

Copyright © 1984 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-134-0

Contents

Chapter 1 Amino-acids By G. C. Barrett,
Chapter 2 Structural Investigations of Peptides and Proteins,
Chapter 3 Peptide Synthesis By I. J. Galpin, with Appendices compiled by C. M. Galpin,
Chapter 4 Peptides with Structural Features not Typical of Proteins By P. M. Hardy,
Chapter 5 Metal Complexes of Amino-acids, Peptides, and Proteins By R. W. Hay and K. B. Nolan,

CHAPTER 1

Amino-acids

BY G. C. BARRETT

1 Introduction

The coverage given in this chapter draws mainly on the chemical literature, but also on the biochemical and biological literature where material relevant to the chemistry, occurrence, and analysis of amino-acids can be found. However, only brief coverage is given, as in previous years, of the distribution and biological roles of well known amino-acids.

Textbooks and Reviews. — Important new textbooks and symposium proceedings cover non-protein amino- and imino-acids, ammonia assimilation and amino-acid metabolism in plants and recent developments in amino-acid chemistry in the context of peptide and protein synthesis. Reviews cover physiological roles for γ-aminobutyric acid (GABA) and its β-hydroxy analogue, crosslinking amino-acid residues in collagen, and the history of the discovery of the existence of asparagine and glutamine residues in proteins. Fowden has reviewed the recent literature for non-protein amino-acids.

2 Naturally Occurring Amino-acids

Occurrence of Known Amino-acids. — This section is particularly concerned with the location of well-known amino-acids in unusual situations and of unusual amino-acids in a variety of sources.

Methods for the isolation of proline and hydroxyproline from fossil bone have been described. L-Canavanine isolated from Canavalia gladiata may be purified as its flavianic acid salt; the pentacyanoammonioferrate positive spot seen in cellulose t.l.c. of extracts of alfalfa is histidine, not canavanine as claimed earlier.

The simplest non-protein amino-acid, 2-aminobutanoic acid, has been located in mixed rumen ciliate protozoal culture media. Other aliphatic α-amino-acids uncovered recently include L-threo-γ-hydroxycitrulline and Nδ-benzoyl-γ-hydroxy-L-ornithine from seeds of Vicia pseudo-orubus, N[varies]-(γ-glutamyl) -histidine, -ornithine, and -lysine from Shiitake mushroom (Lentinus edodes; the first report of the occurrence of these derivatives in mushrooms),L-β-(1,4-cyclohexadienyl)-L-alanine from Pseudomonas 1–30, and another 1,4-cyclohexadiene derivative, arogenic acid (1) from Pseudomonas aureofa-ciens as an intermediate in the biosynthesis of phenylalanine and tyrosine.

The methionine adduct of dopa o-quinone, which forms during work-up of solutions of these amino-acids and therefore may appear in biological extracts, is proposed to possess structure (2). The natural occurrence of S-methyl-L-cysteine and its sulphoxide has been reviewed.

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The possibilities for the existence of amino-acids and other important biochemicals on other planets have been reviewed.

The archetypal β-amino-acid β-alanine has been found in mycelial cell walls of mature Morchella esculenta.

New Natural Amino-acids. — E-2S-Amino-3-methyl-3-pentenoic acid is a new natural amino-acid, found in Coniogramme intermedia. The β-lactam (3) and the γ-lactone (4) are cyclized N-acetyl-α-amino-acid derivatives isolated from bacterial cultures; (4) has little biological potency.

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Re-investigation of agropine from crown-gall tumours (see also Vol. 10, p. 2) shows it to be N2-(1′-deoxy-D-mannitol-1′-yl)-L-glutamine-1, 2′-lactone (5). The amino-glyconic acids as a class would be as well located among amino-acids as among amino-sugars. A compound of this type (6) occurs in Pseudomonas aeruginosa 170 005.

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New Amino-acids from Hydrolysates. — Unusual components of polypeptides and proteins are collected under this heading. The occurrence of N-trimethylalanine at the N-terminus of histone 2B from Tetrahymena pyriformis constitutes the first example of N-terminal blocking through methylation in the histone field. Muscle myosin subfragment I has been shown by H n.m.r. to carry the same N-terminal residue.

Crosslinking opportunities other than the disulphide grouping of cystine continue to stimulate a considerable amount of research effort, because of the importance of irreversible inter-chain reactions in the ageing process. The structure of pyridinoline (7), a crosslinking diamino-diacid from collagen (see also Vol. 13, p, 2), has been confirmed by f.a.b. mass spectrometry, and the existence of deoxypyridinoline (the analogue of pyridinoline with H in place of the aliphatic hydroxy group) as a new crosslinking residue in collagen has been established by two research groups.

‘Isodityrosine’, an oxidatively coupled dimer of tyrosine involving a diphenyl ether linkage, is a new phenolic crosslinking diamino-diacid found in hydrolysates of cell walls of many higher plants.

3 Synthesis of Amino-acids

General Methods. — Standard methods have been used for the synthesis of β-(3-pyrrolin-N-oxyly1)alanine (8) proposed as a paramagnetic amino-acid for use in peptide synthesis. Alkylation of dimethyl acetylaminomalonate, di-phenylmethylideneglycine ethyl ester, or diethyl malonate (followed by treatment with diphenylphosphoryl aide and benzyl alcohol to give the N-benzyloxycarbonyl amino-acid) was fully studied in this context. Alkylation of acylamidomalonates continues to be widely used for the synthesis of α-amino-acids [homologues of 2-amino-5-(p-methoxyhenyl)pentanoic acid and other examples mentioned later in this chapter, refs. 113, 115, 130, 131,133, and 147]. Improvements have been achieved in the Schiff-base alkylation route, where 73 – 94% yields of monoalkylation products were obtained in most cases using ion-pair extraction or catalytic liquid–liquid or solid–liquid phase-transfer techniques with ethyl p-chloro-benzylideneglycinate. Yields of a-methyl-α-amino-acids were equally good in corresponding alkylation reactions of the alanine analogue.

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Alternative methods for the introduction of a nitrogen function adjacent to a carboxy group include amido-alkylation (for β-amino-acid synthesis R1·CO·NH·CHR2·SO2Tol has been proposed), a racemization-free synthesis of NN-dialkylamino-acids (9) [right arrow] and development of the biogenetically modelled amination of α-keto-acids in aqueous media, which has led to the discovery of the novel reaction in which low yields (1–20%) of the corresponding N-(2-oxoalkanoyl) amino-acid amide (11) [right arrow] (12) are formed. The α-amino-acids are easily obtained from these intermediates by acid hydrolysis.

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Further exploration of amidocarbonylation routes to α-amino-acids (see Vol. 13, p. 4) has established that allylic alcohols react with acetamide in the presence of Co2(CO)8 and HRh(CO) (PPh3)3, reductive carbonylation with a 1:1 mixture of H2 and CO at 100 atm at 110°C in dioxane, giving good yields of N-acetylamino-acids (the allylic moiety is hydrogenated in this process). Electrochemical reductive carboxylation of N-arylideneamines RN=CHAr and RN=CMeAr with CO2 at a mercury cathode gives predominantly C-carboxylation products, and competing reduction of the double bond can be suppressed by increasing the water content of the medium.

Synthesis of amino-acids and peptides exploiting 1,4-opening of β-lactams (see Vol. 13, p. 4) has been reviewed. A forthcoming textbook includes an exhaustive coverage of the synthesis of amino-acids.

A full account has been published of the synthesis of β-amino-acids from N-acetyl thioamides and Ph3P=CHCO2Me followed by reduction of the resulting β-acetylaminoacrylate. A total synthesis of iturinic acid, Me2CH(CH2)8CH ([??]H3)CH2CO2-, as its ethyl ester was included as an example of this efficient route. The Reformatzky route to β-amino-acids employing α-bromoalkanoic acids and Schiff bases gives moderate yields.

Most syntheses of amino-acids yield salts from which they may be recovered by passage through columns of crosslinked poly(4-vinylpyridine). Basic amino-acids, however, elute as their mono-acid salts.

Asymmetric Synthesis. — All the papers encountered in the 1982 literature describe extensions of previously established principles. The general topic has been reviewed.

Representative papers concerned with asymmetric hydrogenation continue the use of chiral rhodium–phosphine complexes. Reductive amination of 4-isopropylidene-2-methyloxazolin-5-ones using (S)-phenylethylamine gives N-acetyl-L-valine phenylethylamide in 44% enantiomeric excess.

The asymmetric-alkylation approach also offers several alternative methodologies. Schiff bases Ph2C=NCH2CO2R (R = Me or Et) give up to 40% enantiorneric excess of the S-alanine derivatives after carbanion formation with Pri2NLi and methylation with a 1,2,5,6-di-isopropylidene-D-gluco-furanose 3-methanesulphonate. N-Benzylidene DL-phenylalanine methyl ester similarly underwent asymmetric methylation with methyl iodide in the presence of chiral lithium (S)-2-alkylpyrrolidines. The chiral heterocycles (13) are masked Schiff bases and have been extensively studied (see also Vol. 13, p. 5) in the context of asymmetric synthesis of α-amino-acids and their α-methyl analogues. Better than 95% stereoselectivity can be achieved through anion formation with BuLi, followed by alkylation with an alkyl or benzyl bromide.

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Alkylation of chiral Schiff bases RCMe==NCH2CO2-, where R is the (S)-0-N-(N-benzylpropy1amino)phenyl grouping complexed to Cu2+, gives predominantly (95%) threo-threonine in at least 97% optical purity when acetaldehyde is the other reactant.

(-)-Menthyl isocyanoacetate CNCH2CO2 Men gives H2N (CH2)3CR([??]H3)-CO2- through successive alkylation with an alkyl iodide RI and acrylonitrile after anion formation with NaH, followed by acid hydrolysis. Higher homologous amino-acids such as (3S,4S)- and (3R,4S)-Me2CHCH2CH (NH3)-CH(OH)CO2- were prepared in several steps from N-phthaloyl-L-leucyl chloride through condensation with (-)-menthyl t-butyl malonate and NaBH4 reduction of the resulting β-oxo-ester.

Full details of the enantioselective protonation of phenylglycine Schiff bases with a chiral acid leading to enantiomer excesses up to 70% have been published. The preliminary communication describing this approach was discussed in Vol. 11, p. 16.

Prebiotic Synthesis of Amino-acids. — A number of papers mentioned elsewhere in this chapter have described new possibilities for the synthesis of amino-acids from simple starting materials under ambient conditions. Ammonia and glyoxylic acid yield N-oxalylglycine in aqueous solutions, and u.v. irradiation of these solutions in the presence of an alkene with acetone as sensitizer gives aspartic acid, norvaline, valine, leucine, phenylalanine, and tyrosine.

Simpler reactants such as CO2 or methane can be caused to react with nitrogen to yield amino-acids, using u.v. light or electric discharges as energy sources, suggesting that the frozen surface of Titan, with its HCN-CH4-N2 atmosphere, could indeed have accumulated amino-acids.

Glycine is converted into a mixture of seven aliphatic α-amino-acids at 200°C in contact with N2 and granite, basalt, or bentonite with or without MnCO3 or Al2O3. An entertaining abstract for a paper describing the formation of amino-acids ‘in systems not containing any source of N, utilizing compounds with antiseptic properties such as PhOH, resorcinol, etc.’ hides the fact that the nitrogen molecule is the source of the amino groups in the products. The reaction is light-driven and not a bacterial process; the phenols are oxidized and water is cleaved by photolysis, to provide the energy to drive the (unlikely) reactions.

Aqueous solutions of ammonium salts of dicarboxylic acids irradiated with ultra-short (picosecond) laser u.v. pulses gave the corresponding amino-dicarboxylic acids.

Protein and Other Naturally Occurring Amino-aciils. — There is space only for representative papers on production of protein α-amino-acids by fermentation (the formation of L-tryptophan in culture media of azaserine-resistant Bre-vibacterium flavum mutant and of Escherichia coli offered L-serine and indole, and L-lysine by Brevibacterium lactofermentum mutants). The topic has been reviewed, ref. 70 being taken from a volume containing numerous papers on the subject, and ref. 72 being narrower in its scope (L-dopa, L-cysteine, and D-p-hydroxyphenylglycine).

Methionine is biosynthesized from 5′-methylthioadenosine via 2-oxo-4-methylthiobutyric acid in rat liver.

Coverage of the biosynthesis of the non-protein α-amino-acids is similarly selective. β-Pyrazolyl-L-alanine has 1,3-diaminopropane as precursor for the pyrazole moiety in cucumber seeds. Biosynthesis of L-canavanine in jack bean (Canavalia ensifomis) has received further detailed study.

Laboratory syntheses of amino-acids that occur in proteins or in other natural sources continue to attract the interest of academic and industrial research groups. Full details of the synthesis of glycine by ammonolysis of trichloroethylene (Vol. 11, p. 9) and of DL-alanine by ammonolysis of 2-chloropropanoic acid in aqueous solution under pressure (Vol. 14, p. 5) have now been published. By-products in the preparation of MeS-CH2CH2CHO from acrolein and methanethiol, for use in the Strecker synthesis of DL-methionine, have been shown to be oligomers HO[CH(CH2CH2SMe)O]n and aldol condensation products of the target aldehyde.

Alternative syntheses have been reported for 4-hydroxy-DL-proline (Scheme 1), L-α-amino-adipic acid from N-Boc-L-aspartic acid α-t-butyl ester (Scheme 2), and L-dopa from L-glutamic acid (Scheme 3).

As in two of the three preceding syntheses, cycloaddition offers increasingly attractive possibilities in synthesis; the approach has already been used in syntheses of the anti-tumour compound AT-125 (‘acivicin’), and a further synthesis of this amino-acid (14) uses (S)-vinylglycine and chlorofulminic acid, CINCO, from dichloroformaldoxime, Cl2C=NOH, and AgNO3.

Aliphatic α-amino-acids for which syntheses have been reported recently include β-carboxy-L-aspartic acid. This is prepared by the reaction of [(NH3)CoO2CCHO]2+ with H2C(CO2Et)2 in DMSO, then dehydration, giving [(NH3)5CoO2CCH=C (CO2Et)2]2+ ; the addition of NH3 [through dissolution of the cobalt (III) complex in liquid ammonia] gives the malonate from which the target molecule is obtained through hydrolysis and resolution. Stereoselective synthesis of δγ-dihydroxyisoleucine starts with Boc-glycine and MeC[equivalent to]CCH2OH, proceeds via stereoselective Claisen rearrangement of the Z-2-butenyl ester obtained from these reactants, and then via elaboration into the appropriate stereoisomer of CH2=CHCHMeCH(NHBoc)CO2H and iodolactonization to give the lactone of the synthetic objective.

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Synthesis of hypusine from Nα-benzyloxycarbonyl-L-lysine benzyl ester, through treatment with (R)-ZNHCH2 CH2CH(OH)CH2Br and deprotection, gave material identical in all respects with the natural compound, thus verifying its absolute configuration. Synthesis of epimers of HO2 CCHMe-(S)-Arg-OH from D- or L-alanine and 5-acetylamino-2-bromopentanoic acid followed by conventional conversion of the resulting octopinic acids with H2NC(=NH)SMe into the octopines confirms the D-configuration of the alanine moiety of the natural (+)-octopine. Similar approaches have verified the L,D-configuration for nopaline (from the crown-gall tumour of Helianthus annus) through synthesis from L-arginine and 2-oxoglutaric acid, separation, and assignments of configuration by enzymic methods.

(Continues…)Excerpted from Amino-acids, Peptides, and Proteins Volume 15 by J H Jones. Copyright © 1984 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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