Amino-Acids, Peptides, and Proteins Volume 13

A Review of the Literature Published During 1980

By R. C. Sheppard

The Royal Society of Chemistry

Copyright © 1982 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-114-2

Contents

Chapter 1 Amino-acids By G. C. Barrett,
Chapter 2 Structural Investigation of Peptides and Proteins,
Chapter 3 Peptide Synthesis By I. J. Galpin,
Chapter 4 Peptides with Structural Features not Typical of Proteins By P. M. Hardy,
Chapter 5 Chemical Structure and Biological Activity of Hormones and Related Compounds,
Chapter 6 Metal Complexes of Amino-acids, Peptides, and Proteins By R. W. Hay and D. R. Williams,
Author Index, 441,

CHAPTER 1

Amino-acids

BY G. C. BARRETT

1 Introduction

This chapter continues to offer detailed coverage of the chemical and biochemical literature on the amino-acids, but with only superficial treatment of biological aspects (distribution of the common amino-acids, metabolism, and biosynthesis).

Textbooks and Reviews. — Several sources of up-to-date information have become available, dealing with biosynthesis, stereochemical studies of metabolism, toxic and other amino-acids with plant-defensive roles, and a broader review of non-protein amino-acids. Electrochemical synthesis of amino-acids has been surveyed.

2 Naturally Occurring Amino-acids

Occurrence of Known Amino-acids. — Identification of four previously undetected leucine isomers (2-amino-2-ethylbutyric acid, both diastereoisomers of 2-methyl-norvaline, C-t-butylglycine, and 2-amino-2,3-dimethylbutyric acid) in the Murchison meteorite contributes further support to the hypothesis that a single one-carbon precursor can account for all amino-acids so far found in this sample.

A review of amino-acids present in marine algae has appeared. Other α-amino-acids found in new locations are diaminopimelic acid from the cell wall of Legionnaires’ disease bacterium, L-2-amino-4, 5-hexadienoic acid from Amanita neooroidea, cyclopentenylglycine in Flacourtiaceae, and 3-(2-furoyl)alanine from roots of Rumex obtusifolius (this compound is now believed to be formed from ascorbalamic acid during isolation from the plant). An improved isolation procedure (3-hydroxyproline from seeds) gives an excellent account of modern methodology which is generally applicable.

γ-Carboxyglutamic acid is a constituent of ovocalcin (hen eggshell), and bovine teeth phosphoprotein contains α-aminoadipic acid, probably derived from a lysine residue via the corresponding aldehyde (‘allysine’). Several papers dwell on the possibility that crosslinking amino-acids previously located in proteins may be artifacts of the isolation procedures; although pyridinoline (see Vol. 11, p. 3), now structurally revised to (1; probably n = 1, m = 2), has been established to be an in vivo component of collagen, this has been disputed. The tetrafunctional collagen crosslink, dehydrohistidinohydroxymerodesmosine, has also been shown not to be an artifact.

Simple derivatives of the common protein amino-acids continue to be found, either in an uncombined form [N-methyl-L-alanine and N-methyl-L-serine in high concentrations in Dichapetalum cymosumN-(γ-L-glutamyl)ethanolamine in mushrooms; N–p-coumarylglutamic acid in black tea; and H·Leu·NHNMeP(O)(OH)OMe, as antibiotic FR-900137 from Streptomyces un-zenensis] or as protein constituents (NNN-trimethyl-L-alanine and trimethyl-L-lysine in ribosomal protein L11 from E. coli, and NN-dimethyl-proline at the N-terminus of a cytochrome).

New Natural Free Amino-acids. — Plant sources and new free amino-acids are: Caylusea abyssinica (2 diastereoisomers of 4-carboxy-4-hydroxy-2-amino-adipic acid, with the (S)-configuration at C-2 assumed, as well as two diastereoisomers of 4-hydroxy-4-methylglutamic acid); further information on mugineic acid (see Vol. 12, p. 3) from root-washings of Gramineae, Avena sativa root washings as source of avenic acid A, (2), a new amino-acid with iron-chelating ability; seeds of Ateleia herbert smithii Pittier are the source of the remarkable new cyclobutanes 2,4-methanoproline and 2,4-methanoglutamic acids [(3) and (4) respectively; antibiotic SF-1836 (17) is a homologue of the former]; and sargassumlactam, (5), a new βγ-unsaturated γ-lactam from the marine alga Sargassum kjellmanianum. Shinorine, claimed as a new amino-acid (from the red alga Chondrus yendoi), is identical with mytilin A (see Vol. 12, p. 4), a member of the palythine family (Vol. 11, p. 3).

Fungal and bacterial sources of new amino-acids are: Streptomyces catenulae (antibiotic FR-900130 is L-2-amino-3-butynoic acid); unspecified Actinomyces [source of forphenicine, (6)]; Streptomyces filamentosus [antibiotic SF-1961, (7)]; 2-(3-alanyl)clavam, (8), from Streptomyces clavuligerus; arogenic acid, (9), a biosynthetic precursor of phenylalanine and tyrosine (from a Neurospora crassa mutant).

New Amino-acids from Hydrolysates. — One of the four possible stereoisomers of 3,4-dihydroxy-L-proline, the 2,3-trans-3,4 –trans isomer, is a component of the virotoxins, toxic peptides of Amanita virosa. Additional information on the chlorotyrosine derivatives from vancomycin (see Vol. 12, p. 5) has been published.

3 Chemical Synthesis and Resolution of Amino-acids

General Methods of Synthesis of Amino-acids. — Standard syntheses of amino-acids have been applied to the synthesis of analogues of ibotenic acid, including alkylation of diethyl acetamidomalonate (used in other laboratories;’ see also refs. 75, 78, and 117). Alkylation of the potassium enolate of the Schiff base (RS)2C=NCH2CO2Et with alkyl halides illustrates a general synthesis of α-amino-acids from glycine derivatives which is of increasing importance. As in other examples of this approach, di-alkylation is feasible. The Bucherer-Bergs hydantoin synthesis (see refs. 120 and 121) and Strecker synthesis (see ref. 94) have been useful general procedures.

Yields of 21–84% have been claimed for the conversion of a primary amide into an α-acylamino-acid (R1CHO + CO + R2CONH2 [right arrow] R2CONHCHR 1CO2H), catalysed by Co2(CO)8. Effects of electron or radical scavengers on the amination of carboxylic acids induced by γ-irradiation have been studied. Hydrogenolysis of 1-aryl-3-azido-azetidinones has been explored as a route to β-amino-acid amides.

Examples of the applications of standard synthetic approaches to β- and higher homologous amino-acids are included later in this chapter.

Asymmetric Synthesis of Amino-acids. — Further development of previously established methods is illustrated in a synthesis of 2-t-butylglycine (‘t-leucine’) based on the asymmetric addition of HCN to the Schiff base derived from pivalic aldehyde and (S)-1-phenylethylamine, followed by hydrolysis and hydrogenolysis (see also Scheme 1); asymmetric addition of PhCH2SH to α-phthalimidoacrylate catalysed by acrylonitrile–cinchona alkaloid co-polymers [to give an enantiomeric excess of the (S)-isomer of N-phthaloyl-S-benzylcysteine when quinine or cincho-nidine are used]; asymmetric hydroformylation and hydrocarboxylation of enamides catalysed by hydridorhodium(II) carbonyl–chiral phosphine complexes (use of a chiral aldehyde in the distantly related α-acylamino-acid synthesis described in the preceding section led to no enantiomeric excess); and asymmetric hydrogenation processes of various types {alkylidene-oxazolinones with rhodium–chiral phosphine complexes or with common hydrogenation catalysts in the presence of (S)-l-phenylethylamine or Al-Hg, or H2-Raney Ni hydrogenation of chiral 6-phenyl-2-alkylidene-oxazinones [(10) gives L-aspartic acid in 14–17% optical yield] and chiral dioxazepinones}. The latter is an example of hydrogenation of a chiral Schiff base, related to the asymmetric synthesis of β-amino-acids by hydrogenation of (Z)-3-[(R)-l-phenylethylamino]-αβ-unsaturated esters.

Enantioselective alkylation of the mono-anion of the L-alanine dioxopiperazine derivative (11) provides a route to α-methyl-α-amino-acids involving moderately high (41–74%) asymmetric induction. The advantage of enclosing a chiral signal-centre in a ring in this area of asymmetric synthesis is further illustrated in a use of chiral 4-phenyl-5-alkylamino-1,3-dioxans (Scheme 1) leading to C-arylglycines.

Useful asymmetric transformations are illustrated by the conversion (71.7%) of the (R)-1-phenylethylammonium salt of (R,S)-N-benzoyl –C-phenylglycine into the corresponding salt of the (S)-acid (overall 77% yield) by boiling in toluene solution, and a related use of optically active cobalt(III)tetrammine-N-methyl-L-alanine complexes (and see ref. 234). (R)-Alanine results from the hydrolysis of the imidazoline (12) formed from either (R)- or (S)-N -benzyloxycarbonylalanine imidate and (S)-2-(aminoethyl)pyrrolidine, as a result of auto-epimerization.

Prebiotic Synthesis; Model Reactions. — A general review and specific survey of results from studies of the formation of amino-acids from sugars and NH3 in a model sea medium indicate the broad scope of this topic. Most of the recent papers continue the themes established in earlier years [Co-γ-irradiation of O2-free aqueous NH4CN; photolysis of NH3 in propionic acid gives α- and β-alanines through NH(1Δ) insertion of C-H bonds, whereas atomic nitrogen attacks acetic or succinic acids in aqueous media, leading to glycine, aspartic acid, glutamic acid, serine, and threonine; 254 nm irradiation of simple hydrocarbons, water, and NH3 in the presence or absence of H2S; carboxylation of primary amines in aqueous solutions at various pH values; and conversions of β-amino-acids into α-amino-acids under contact glow discharge electrolysis conditions]. The increasing emphasis on the involvement of hydrogen cyanide in putative mechanisms for abiogenic synthesis of amino-acids is further justified by the demonstration that this compound is the principal product of i.r.-laser photolysis of a methane–ammonia mixture. Amino-acids are formed in aqueous KCN in the presence of montmorillonite or graphite oxide at 70 °C.

The common feature of these model reactions is the involvement of an energy source to drive thermodynamically unfavourable processes. Matatov has shown that iron(III)-catalysed decomposition of H2O2 can facilitate the production of glycine, serine, threonine, and proline from formaldehyde and hydroxylamine hydrochloride in aqueous solutions.

Protein Amino-acids and Other Naturally Occurring Amino-acids. — Little scope exists for thorough coverage of biosynthetic production of amino-acids, important though this topic has become in both commercial and mechanistic terms. The general field can be represented by selected references (reviews of enzymic synthesis; fermentative production of L-glutamine by a Flavobacterium rigense mutant; microbial conversion of glycine into L-serine, and accumulation of O-methyl-L-homoserine in culture media of methanol-utilizing bacteria; and conversion of trans-4-hydroxy-L-proline into L-proline via the 4,5-dehydro-analogue).

A synthesis of L-α-aminoadipic acid from L-lysine involves treatment of the Nα-benzyloxycarbonyl derivative with NaOCl, elimination with DABCO, and hydrolysis of the resulting nitrile in refluxing 4M-HCl. Cyclization of ornithine, lysine, or 5-hydroxylysine with nitrosylpentacyanoiron(II) gives proline, pipecolic acid, and 5-hydroxypipecolic acid, respectively. Further new syntheses of γ-carboxy-L-glutamic acid involve either alkylation of diethyl benzyloxycarbonylamino-malonate with the Mannich reaction product of di-t-butyl malonate, or carboxylation of N-trityl dibenzyl L-glutamate with benzyl chloroformate after carbanion formation with LiNPri2, followed by de-protection with H2-Pd. Full details have been published of the novel synthesis of kainic acid reported in Vol. 11 (p. 10). γ-Oxo -DL-homotyrossine has been prepared from p-methoxyphenacyl bromide and diethyl acetamidomalonate.

Syntheses of β-amino-acids reported in 1980 include (2S,3R) -3-amino-2-hydroxy-5-methylhexanoic acid (present in amastatin), prepared from N-benzyloxycarbonyl-D-leucine methyl ester via LiA1HBui2 reduction into the aldehyde, thence into the cyanohydrin, and an alternative route to the same series of compounds from chiral oxiranes. threo-γ-Hydroxy-L-β-lysine has been prepared by Arndt-Eistert extension of the corresponding lysine derivative. A useful synthetic route to δ-amino-acids has been illustrated with a synthesis of δ-aminolaevulinic acid.

Aliphatic Amino-acids. — C-t-Butylglycine (‘t-leucine’) is accessible through addition of MeMgI to 2-phenyl-4-isopropylidene -oxazolinone or to Me2C=C(CO2Et)2 followed by hydrolysis or Curtius rearrangement, respectively. Unsaturated analogues of D-a-amino-adipic acid and of 3-halo-4-aminobutanoic acids have been prepared by alkylation of Ph2C=NCH2CO2Et with EtO2CCH=CHCH2Br, and from ClCH2 C[equivalent to]CCO2H, respectively, followed by straightforward elaboration. Kolbe reactions with mixtures of differently protected glutamic acids lead to 2,4-di-aminosuberates.

Proline derivatives and analogues feature as synthetic objectives for several laboratories, A 90:10 cis: trans-mixture of 1-benzyl-2-methylazetidine-carboxylates emerges from condensation of methyl 2,4-dibromopentanoate with benzylamine; an improved preparation of (S) -3,4-dehydroproline based on H3PO2-HI reduction of pyrrole-2-carboxylic acid involves resolution with (+)-tartaric acid, which is not necessary in the apparently easier route from L-hydroxyproline involving protection and Chugaev elimination of the xanthate (formed with CS2 and Bun4 N+HSO4); 1,2-dehydroproline gives the 3-phenoxy-analogue through allylic bromination followed by treatment with thallium phenoxide, easily reduced to cis: trans-3-phenoxyproline. Conversion of kainic acid into the strongly neuro-excitatory proline derivative (13) is achieved by ozonolysis of the N-boc-derivative.”

α-Alkyl Analogues of Protein Amino-acids. — Asymmetric synthesis of α-methyl-α-amino-acids has been illustrated earlier in the chapter, and the same general objective, formation of the α-carbanion of a protected amino-acid followed by alkylation, has been used in a synthesis of α-methyltryptophan. Synthesis of α-hydroxymethylserine from the reaction of formaldehyde with cobalt(III), copper(II), or nickel (II) complexed glycine Schiff bases, and the synthesis of α-(hydroxymethyl) aspartic acid through the Strecker synthesis with AcOCH2COCH2 CO2Et illustrate previously used routes. α-Vinyl analogues can be prepared through Michael addition of a 2-phenyloxazolin-5-one to PhSO2,C[equivalent to]CH followed by sulphone cleavage, or by alkylation of a Schiff base with (E)- or (Z)-RCH=CHBr after carbanion formation with LiNPri2.

α-Heteroatom-substituted α-Amino-acids. — Good yields of α-methoxy-N-acetyl amino-acids are obtained through the reaction of an N-acetyl-N-benzyloxy-amino-acid ester with potassium t-butoxide and MeOH. α-Bromination (NBS) and treatment with potassium thiolacetate places an acetylthio-grouping at the α-position of an N-acylamino-acid ester.

Aliphatic Amino-acids Carrying Halogen Substituents in Side-chains. — Further examples of the use of aziridinecarboxylates for the preparation of β-fluoro-α-amino-acids, by treatment with HF–pyridine, have been reported (see Vol. 12, p. 8) The relative stereochemistry of the products has been defined by chemical correlations and X-ray analysis.

Aliphatic Amino-acids Carrying Hydroxy-groups in Side-chains. — Free-radical chlorination of L-valine, and hydrolysis, gives a mixture of stereoisomers from which (2S,3S)- and (2S,3R) -4-hydroxyvaline have been isolated by crystallization and hydrolysis. A 34:66 erythro: threo-mixture of γ-hydroxy-DL-ornithine formed through hydrolysis of 2,5-di-amino-4-pentanolide isomers has been separated and converted into corresponding γ-hydroxyarginines.

α-Amino-acids with Unsaturated Side-chains. — A new synthesis of L-vinylglycine [(S)-2-amino-but-3-enoic acid] from L-methionine involves conversion into the sulphoxide, followed by pyrolytic elimination of methanesulphenic acid. Another example of the dehydration of N-benzyloxycarbonylserine or threonine into the corresponding αβ-dehydro-amino-acids employing DCCI has been reported.

(Continues…)Excerpted from Amino-Acids, Peptides, and Proteins Volume 13 by R. C. Sheppard. Copyright © 1982 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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