Amino-Acids, Peptides, and Proteins Volume 8

A Review of the Literature Published During 1975

By R. C. Sheppard

The Royal Society of Chemistry

Copyright © 1976 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-074-9

Contents

Chapter 1 Amino-acids By G. C. Barrett, 1,
Chapter 2 Structural Investigations of Peptides and Proteins, 29,
Chapter 3 Peptide Synthesis By E. Atherton and R. C. Sheppard, with Appendices compiled by G. A. Fletcher and J. H. Jones, 248,
Chapter 4 Peptides with Structural Features not Typical of Proteins By B. W. Bycroft and C. M. Wels, 310,
Chapter 5 Chemical Structure and Biological Activity of Hormones and Related Compounds By D. J. Schafer and M. Szelke, 339,
Chapter 6 Further extracts from the Rules and Tentative Rules of the I.U.P.A.C.-I.U.B. Commission on Biochemical Nomenclature, 438,
Author Index, 473,

CHAPTER 1

Amino-acids

BY G. C. BARRETT

1 Introduction

The layout for this chapter follows that used in previous volumes. Coverage is intended to be thorough as far as the chemistry of the amino-acids is concerned, but excludes most of the biological literature. The patent literature is also excluded, but this is felt to be not a serious omission in a continuous series; the Sections 16 (Fermentations) and 34 (Amino-acids, Peptides, and Proteins) of Chemical Abstracts provide easy access to this aspect of the literature.

Nomenclature. — IUPAC-IUB Recommendations (1974) on the nomenclature of amino-acids (reproduced in Chapter 6) include no drastic revision of current usage, but some opportunities have been taken to decide between rival systems. In particular, the imidazole nitrogen atoms of histidine should be distinguished as π and τ (pros and tele; the N atom closest to the side-chain CH2 group, and that farthest from the side-chain CH2 group, respectively).

Textbooks and Reviews. — Synthetic methods and other specific topics are covered in recent textbooks. Reviews are cited elsewhere in this chapter.

2 Naturally Occurring Amino-acids

Occurrence of Known Amino-acids. — Implications of the occurrence of non-protein amino-acids in plants have been discussed.

Sensitive g.l.c. assay techniques permit the identification of amino-acids in marine sediments and in meteorites; the NASA Viking programme leading to exploration on Mars will involve the use of these techniques for assessing the existence of life in former times, in case no evidence for surviving life forms is found. At least 23 amino-acids are present in the Murchison meteorite, as shown using g.l.c.-m.s. techniques, and are thought to arise through extra-terrestrial abiotic synthesis since they are racemic; a clinching argument for their abiotic origin is the demonstration that isovaline from this source is also racemic.

Seeds of Combretum zeyheri contain N-methyl-L-tyrosine, while branches of Limonium vulgare contain 2-trimethylaminopropionic acid and 2-trimethyl-amino-6-oxoheptanoic acid (as the choline ester). L-Dopa found in Hygrocybe conica and H. ovina is responsible for the formation of red and black colours in these toadstools after bruising.

Unusual amino-acids from microbial sources include 3-cyclohexenylglycine from Streptomyces tendae, and δ-aminovaleric acid from rumen ciliate protozoa. Elastatinal, a microbial elastase inhibitor, releases (2RS),(3S)-α-[2-iminohexahydro-4-pyrimidyl]glycine on acid hydrolysis, and is similar in this respect to the chymostatins (Vol. 6, p. 7). The literature on microbial synthesis and production of amino-acids can only be represented generally here; recent reviews are available and papers describing the fermentative production of L-proline or L-tryptophan by auxotrophs of Corynebacterium glutamicum are typical of a substantial amount of current literature in this area.

New Natural Free Amino-acids. — L-3-(3-Carboxyfuran-4-yl)alanine (1) exists in the free state in Phyllotopsis nidulans and in Tricholomopsis rutilans fruiting bodies. Simultaneous independent investigation of the same species has occurred with Pentaclethra macrophylla, seeds of which contain penmacric acid whose structure has been elucidated in full detail as 3(R)-[1′(S)-amino-carboxymethyl]-2-pyrrolidone-5(S)-carboxylic acid (2). X-Ray and n.m.r. studies indicate a Cs-envelope conformation for (2) both in crystal and solution states.

Of three unusual amino-acids found in Mycena pura, viz. γ-methylene-, γ-ethylidene-, and γ-propylidene-L-glutamic acids, the third has not been found previously in Nature. A similar situation occurs for Combretum zeyheri, seeds of which contain L-3-(3-aminomethylphenyl)alanine in addition to the 3-hydroxy-methylphenyl and 3-carboxyphenyl analogues previously reported. New amino-acids have been isolated from fruit bodies of Lactarius quietus (L-2-amino-4-methylpimelic acid), and from seeds of Aleurites fordii (L-3-carboxy-1,2,3,4-tetrahydro-β-carboline). In addition to 13 known non-protein amino-acids, marine red algae contain pyrrolidine-2,5-dicarboxylic acid and N-methyl-methionine sulphoxide.

Lupinic acid (3), β-[6-(4-hydroxy-3-methylbut-trans-2-enylamino)purin-9-yl]-alanine, is the first reported example of a naturally occurring purine derivative linked through one of its ring nitrogen atoms to an amino-acid moiety (although compounds of this type have been synthesized). It is a novel zeatin metabolite, isolated from Lupinus angustifolius seedlings; the available 40 µg was insufficient to allow determination of its absolute configuration.

The structure β-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)-L-alanine (4) assigned to quisqualic acid (from Quisqualis fructus) has been confirmed by synthesis; hydrolysis by alkali gives the novel 2-amino-3-(1-hydroxyureido)propionic acid (5), which might be expected to accompany quisqualic acid in the natural source.

New microbial metabolites include the anti-tumour agent (6) from Streptomyces sviceus; the homologue (6; H in place of OH) was recently found in the same culture (Vol. 6, p. 6). L-threo-β-Hydroxyaspartic acid, L-β-(5-hydroxy-2-pyridyl)alanine and L-β-(3-hydroxyureido)alanine, L-trans-2,3-dicarboxyaziridine (7), and the urea (8) derived from L-phenylalanine and L-arginine have also been isolated from Streptomyces cultures. Cultures of Claviceps fusiformis deprived of oxygen accumulate Nα-methyl-4-dimethylallyl-L-tryptophan; the non-methylated amino-acid was itself isolated from the same source previously.

Novel amino-acids isolated from higher organisms are 2,5-S, S-dicysteinyldopa (9) from the eye of the alligator Lepisosteus spatula, and cystathionine sulphoxide and perhydro-1,4-thiazepine-3,5-dicarboxylic acid from the urine of a cystathioninuric patient.

Although formally outside the scope of this chapter, the report of the isolation of the tyrosine analogue (10) from the marine sponge Hymeniacidon sanguinea deserves mention.

New Amino-acids from Hydrolysates. — The outstanding new example under this heading is the discovery of γ-carboxy-L-glutamic acid in several locations in Vitamin K-dependent prothrombin and in mineralized tissue proteins. It survives alkaline hydrolysis, but is quantitatively decarboxylated in 0.05M-HCl at 100 °c.

The presence of an α-aminoadipic acid δ-semialdehyde residue in myelin basic protein from bovine brain has been established through reduction with NaB3H4 and isolation of 3H-labelled ε-hydroxynorleucine from alkaline hydrolysates. Further fascinating work on collagen cross-links has been reported, leading to structure assignment to a new hydroxy-aldolhistidine trifunctional cross-link from cow skin collagen.

Peptide antibiotics and related compounds providing new derivatives of the protein amino-acids on acid hydrolysis are cerexins A and B (first appearance of L-threo-γ-hydroxylysine) and actinomycin Z1 (3-hydroxy-5-methylproline). More complicated phenylglycine derivatives are released from ristocetin A, actinoidin, ristomycin, and vancomycin; the derivative (11; R1 = Me, R2 = OH, R3 = R4 = H) is present in hydrolysates of ristocetin A, and structure (11; R1 = R2 = H, R3 = R4 = OH) is established for actinoidinic acid, present in hydrolysates of the other antibiotics. Substantial progress towards elucidation of structure of vancomycin has been made; it is thought to include three oxygenated phenylglycine units and two chloro-β-hydroxytyrosine units.

3 Chemical Synthesis and Resolution of Amino-acids

Asymmetric Synthesis. — Further development of asymmetric hydrogenation using ruthenium(II) chiral phosphine catalysts has been reported, leading to moderate optical yields for synthesis of 2-aminoalkanoic acids from α-acylamido-acrylic acids.

While enzymic synthesis of L-amino-acids from DL-α-hydroxy-acids and synthesis of L-aspartic acid derivatives from addition of (S)-PhCHMeNH2 to dimethyl fumarate or maleate illustrate familiar principles, asymmetric induction in the synthesis of N-benzoyl-N[(R)-α-ferrocenylisobutyl]-L- and -D-valine t-butylamide via a four-component condensation involving benzoic acid, (R)-α-ferrocenylamine, Me2CHCHO, and ButNc is particularly interesting because of its extremely high stereoselectivity. Another highly selective example is the general synthesis of L-amino-acids and their N-methyl derivatives from corresponding α-keto-acids using L-proline as chiral agent (Scheme 1).

Asymmetric synthesis of threonine and allo-threonine from optically active N-salicylideneglycine cobalt(III) complexes has been reported.

General Methods of Synthesis. — Isocyanides continue to appeal as starting materials in general syntheses of α-amino-acids. α-Isocyano-alkanoate esters CNCHR1CO2R2 yield N-formylamino-acid esters on hydrolysis; they may be prepared by alkylation of alkyl isocyanoacetates (R1 = H) after metallation, though the nature of R2 influences ratios of mono- and di-alkylated products. Alkylation with a ketone gives β-branched amino-acids when reaction conditions causing dehydration of the β-hydroxyalkanoate are employed, or threonine analogues when aldehydes are used. t-Alkylglycines are obtained by addition of a Grignard reagent to an α-isocyanoacrylate [R1R2C=C(NC)CO2Et + R3MgBr [right arrow] R1R2R3CCH(NHCHO)CO2Et]. Good yields of phenylglycines are obtained by successive lithiation, carboxylation, and hydrolysis of PhCH2NC.

Ogura and Tsuchihashi’s extraordinary new synthesis (Vol. 7, p. 6) has been exemplified further in a synthesis of N-lauroylvaline methyl ester from MeSOCH2SMe and Bu1CN.

Methods employing Schiff bases as starting materials involve either metallation followed by alkylation [use of dithioacetals (RS)2C=NCH2CO2Et is noteworthy], or more novel procedures, e.g. Cl3CCH=NCO2Et + RMgX [right arrow] Cl3CCHRNHCO2Et [right arrow] -O2CCHRNH3+, and MeCH=NCHMePh + Me3Si-CN [right arrow] MeCH(CN)N(SiMe3)CHMePh [right arrow] DL-alanine in 37% yield.

α-Hydroxy-, α-methoxy-, or α-alkanethio-hippuric acids may be employed in new α-amino-acid syntheses since they are amido-alkylating agents towards aromatic compounds (e.g. PhCONHCH(OH)CO2H + ArH [right arrow] PhCONHCHArCO2H), active methylene compounds, and alkenes.

Classical procedures of amino-acid synthesis continue to be methods of first choice in many areas. The hydantoin synthesis, Strecker synthesis, acetamidomalonate synthesis, use of ethyl α-nitroacetate, and extension of a side-chain through functionalized amino-acids (e.g. β-ch1oro-L-a1anine and trans-4-bromoproline) and through αβ-dehydro-α-amino-acids, are representative examples of methods used for synthetic objectives described in later sections of this chapter. Use of 2-phenylimidazol-5-ones in synthesis of N-benzoylamino-acids (a relative of the azlactone synthesis) has been described.

A new synthesis of amino-acids is general in the sense that an excellent reagent (RuO2) is available for oxidizing the aryl moiety of an aralkylamine to a carboxy-group, e.g. ArCHR(CH2)nNH2 [right arrow] – O2CCHR(CH2)nNH3+; tyrosine can be oxidized to aspartic acid by this method. A classical method for converting an α-amino-acid into its β-homologue is illustrated for the conversion of Z-L-Pro-OH into ‘α-L-homoproline’ by treatment with diazomethane (Wolff rearrangement) followed by de-protection.

Prebiotic Synthesis; Model Reactions. — Reports of the synthesis of amino-acids from simple molecules under simulated prebiotic conditions now usually promote a feeling of indifference, but a report that no amino-acids are formed by low0pressure Hg lamp irradiation of a CH4-N2-H2O mixture (1:1:1) catches us in mid-yawn. Reviews of more productive experiments of this type are available, and further results on direct carboxylation of aliphatic amines by formic acid under glow discharge electrolysis conditions, and on the accumulation of urea, amino-acids, and u.v.-absorbing substances on alumino-silicates saturated with Ca2+, NH4+, and Fe3+ salts when heated in an atmosphere of CO + NH3, have been published. Specific factors (metal ion catalysis) favouring formation of cystine in irradiated mixtures of NH4SCN, HCHO, KH2PO4, and Ca(OAc)2 have been studied (other amino-acids are also formed under such conditions).

More evidence that α-aminonitriles are the primary condensation products in these processes, e.g. their formation behind shock waves in CH4-C2-H6-NH3-H2O mixtures, is provided indirectly by the link between the difficulty of hydrolysis of α-alkyl-α-aminonitriles and the fact that α-alkyl-α-amino-acids are not formed in simulated prebiotic reaction mixtures. Experiments with poly(α-cyanoglycine) and HCN suggest that the presence of α-amino-acids was not necessarily a prerequisite for the chance synthesis of the first proteins.

Protein and Other Naturally Occurring Amino-acids. — Although general synthetic methods outlined in the preceding section are represented here in reports of new syntheses of natural amino-acids, another common approach, the use of the protein amino-acids as starting materials for the synthesis of related compounds, is also illustrated.

Several syntheses have been described for α-carboxyglutamic acid, some yielding the γγ’-di-t-butyl ester α-methyl ester suitable for use in peptide synthesis. The pyroglutamic acid homologue 3,5-di(methoxycarbonyl)-pyrrolid-2-one has also been prepared.

Longicatenamycin constituents threo-β-hydroxy-L-glutamic acid, L-2-amino-5-methylhexanoic acid, L-2-amino-6-methylheptanoic acid, L-2-amino-7-methyl-octanoic acid, and DL-5-chlorotryptophan, DL-furanomycin, an antibiotic α-amino-acid containing a 2,5-dihydrofuran moiety, have been synthesized.

Examples of the use of protein amino-acids in the synthesis of other natural amino-acids involve β-chloro-L-alanine in syntheses of S-trans-propenyl-L-cysteine and of quisqualic acid (4), use of O-tosyl-L-serine methyl ester in the synthesis of γ-carboxy-L-glutamic acid, and use of D-serine and L-homoserine in the synthesis of rhizobitoxine [(12) in Scheme 2]. L-Histidine is used for the synthesis of enduracididine (13), a component amino-acid of enduracidin; Bamberger cleavage of L-histidine methyl ester, followed by catalytic hydrogenation, gives a mixture of (2S,4R)- and (2S,4S)-2,4,5-triaminopentanoic acid methyl esters, from which both natural (2S,4R) and allo-enduracididines were prepared by de-protection and guanidination. 2,5-S,S-Dicysteinyldopa (9) is synthesized from L-cysteine, L-dopa, and O2 using mushroom tyrosinase.

Synthesis of higher homologous amino-acids of natural origin is represented by (-)-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, present in pepstatins, and for tabtoxinine-δ-lactam (14).

α-Alkyl- and αα-Dialkyl-amino-acids. — Further details of routes reported last year (Vol. 7, p. 10) leading to α-alkyl-substituted ornithines and to 2-amino-4-chloroalkanoic acids have been published. Chlorinolysis of methionine derivatives yields 2-amino-3,4,4,4-tetrachlorobutanoic acid derivatives in addition to the 4,4,4-trichloro analogues previously reported; N-aryl substituents are not cleaved. Electrochemical reduction of 2-amino-4,4,4-trichlorobutanoic acid gives the 4,4-dichloro-analogue, alias armentomycin, a powerful anti-bacterial agent isolated in 1967 from Streptomyces armentosus. Electrochemical reduction of N-benzyloxycarbonyl 2-amino-3,4,4,4-tetrachlorobutanoic acid methyl ester gives the armentomycin analogue Cl2C=CHCH(NH3+)CO2- – after removal of protecting groups.

(Continues…)Excerpted from Amino-Acids, Peptides, and Proteins Volume 8 by R. C. Sheppard. Copyright © 1976 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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