Amino-Acids, Peptides, and Proteins Volume 7

A Review of the Literature Published During 1974

By R. C. Sheppard

The Royal Society of Chemistry

Copyright © 1976 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-064-0

Contents

Chapter 1 Amino-acids By G. C. Barrett, 1,
Chapter 2 Structural Investigations of Peptides and Proteins, 31,
Chapter 3 Peptide Synthesis By D. J. Schafer, 247,
Chapter 4 Peptides with Structural Features not Typical of Proteins By B. W. Bycroff, 320,
Chapter 5 Chemical Structure and Biological Activity of Enzymes By A. R. Fersht, 352,
Chapter 6 Metal Derivatives of Amino-acids, Peptides, and Proteins By R. D. Gillard, R. W. Hay, and D. R. Williams, 381,
Author Index, 403,

CHAPTER 1

Amino-acids

BY G. C. BARRETT

1 Introduction

No substantial new emphasis on some aspect of amino-acid science has arisen in the recent literature, and the present Chapter, reviewing the literature of 1974, is subdivided as in previous Volumes of this series. As before, the coverage is intended to be thorough, but excludes most of the biological literature dealing with biosynthetic, metabolic, physiological, and microbiological aspects.

Textbooks and Reviews. — The laboratory synthesis and large-scale productions of amino-acids, and their technological applications, have been surveyed. Other more specific reviews are cited in the appropriate sections.

2 Naturally Occurring Amino-acids

Occurrence of Known Amino-acids. — Increasing attention is being given to the identification of organic compounds in geological samples, and the analysis of ancient cyanite schists from the Kola peninsula (six free amino-acids and seven in a bound form) uses routine techniques; more information can be inferred from the degree of racemization of amino-acids present in fossils (see p. 21).

Aspects of the distribution of non-protein amino-acids in plants have been reviewed. Among the more notable reports of the appearance of known amino-acids in plant sources are the presence of cis-4-hydroxy-L-proline in three genera (four species) of Santalaceae, suggesting a useful taxonomic index for the species; also, the isolation from Crotalaria juncea seeds of δ-hydroxy-norleucine (5-hydroxy-2-aminohexanoic acid), previously noted to be a constituent of the ilamycins. Partly racemized (R) -2-aminobut-3-enoic acid (‘D-vinylglycine’) isolated from Rhodophyllus nidorosus is shown to exist in the plant in optically impure form. Tissues of Medicago sativa contain several amino-acid betaines, including stachydrine and homostachydrine (NN-dimethylproline and NN-dimethylpipecolic acid betaines, respectively), and a careful study has established links between betaine content and growth rate.

Chirality at side-chain asymmetric centres may differ from species to species. The demonstration that enniatin A is a mixture of diastereoisomers containing both N-methyl-L-isoleucine and N-methyl-L-alloisoleucine residues is incorrectly claimed (see refs. 12, 31, 32) to be the first report of the co-occurrence of both epimers of an L-amino-acid with two chiral centres in the same group of natural products. γ-L-Glutamyl-S -(trans-prop-1-enyl)-L-cysteine sulphoxide isolated from Santalum album leaves has the opposite configuration at sulphur from that in the same dipeptide isolated from onion. The γ-hydroxyisoleucine residue in γ-amanatin is shown by X-ray analysis of its lactone hydrobromide to be (2S,3R,4S)-2-amino-3-methyl-4 -hydroxyvaleric acid (1), from which there follows a re-formulation of the absolute configuration of γδ-dihydroxyisoleucine present in the α- and β-amanatins to (2S, 3R, 4R) -2-amino-3-methyl-4,5-di-hydroxyvaleric acid on the basis of chemical correlation. Revision of the configurational assignments to the γ-hydroxyisoleucine diastereoisomers found recently (in unequal amounts) in plants, for the first time (see Volume 6, p. 2), may now be necessary. Alternariolide (2), a host-specific toxin produced by Alternaria mali (responsible for apple blotch), contains two non-protein amino-acids; structure (2) is assigned to the toxin on the basis of spectroscopic data, but no evidence for absolute configuration was obtained.

N-Methyl amino-acids of various types are represented for this Section by N-methyl-L-methionine-S-sulphoxide which is found, together with the corresponding primary amino-acid, in the red alga Grateloupia turuturu the proposal that promine and retine, from calf liver and thymus, are Nε-trimethyl-lysine and NG-dimethyl-arginine respectively is not borne out by the physical and chemical properties of the compounds.

Where appropriate, mention is made in this Chapter of β- and γ-amino-acids, although most amino-acids mentioned in the literature are of the α-series. γ-Amino-L-α-hydroxybutyric acid has been established as a component of 4′-deoxy-butirosins.

Microbial synthesis of amino-acids continues to provide an expanding literature, and only representative papers can be cited here. L-Amino-acids produced through biosynthesis include isoleucine and cyclo-isoleucylisoleucine, threonine, O-alkyl-homoserines, arginine and citrulline, indole-substituted tryptophans, phenylalanine, histidine, dopa and N-Z, N-Boc, and N-formyl derivatives of dopa, and azetidine-2-carboxylic acid.

New Natural Free Amino-acids. — Further details have been provided of the acetylenic amino-acids present in Tricholomopsis rutilans. Both threo and erythro diastereoisomers of L-2-amino-3-hydroxyhex-4-ynoic acid are present, adding a further example to those reported in the past two years of the occurrence of epimeric amino-acids in the same species. A number of other unsaturated amino-acids have been isolated from plant sources, and from bacterial and fungal cultures, and reported during the year under review. (2S,3S) -3-Hydroxy-4-methylene-glutamic acid is present in seeds of Gleditsia caspica [the known amino-acids (2S,4R)-4-methyl-glutamic acid and its (2S,3S,4R)-3-hydroxy analogue are also present], and L-2-amino-4-chloropent-4-enoic acid (from Amanita pseudoporphyria) and L-2-amino-4-(2-aminoethoxy)-trans-but-3-enoic acid (3) (from an unidentified Streptomycete) are further acyclic examples, with an unusual alicyclic derivative, L-2-amino-4-(4′-amino -2′,5′-cyclohexadienyl)butyric acid (4), being a new amino-acid antibiotic. The stereochemistry of the cyclohexadienyl moiety in (4) is not yet established.

α-Amino-γ-(isoxazolin-5-on-2-yl)butyric acid has been isolated from Lathyrus odoratus, together with β-(isoxazolin-5-on-2-yl) alanine and β-(2-β-D-gluco-pyranosyl-isoxazolin-5-on-4-yl)alanine which were previously found in Pisum sativum seedlings. 4-(4-Hydroxy -3-methyl-Δ2-butenyl)tryptophan has been isolated from cultures of Claviceps purpurea, the structural assignment resting on mass spectrometric study of its N-trifluoroacetyl methyl ester so that no configurational assignment could be made. A further new heterocyclic amino-acid, of particular interest, is 3-(3-amino-3-carboxypropyl)uridine (5), a novel modified nucleoside from E. coli tRNA representing the site of reaction with phenoxy-acetic acid.

N-(3-Aminopropyl)-4-aminobutyric acid, NH2(CH2), 3NH(CH2)3CO2H, appears in rabbit urine as a metabolite of bleomycin A5.

New Amino-acids from Hydrolysates. — Peptide antibiotics continue to provide novel amino-acids, often closely related in structure to the protein amino-acids. Hydrolysates of longicatenamycin contain 5-chloro-D-tryptophan, and antibiotic SF-1293 contains an L-2-amino-4 -(methylphosphino)butyric acid residue (6). The structure of SF-1293, the tripeptide (6)-L-Ala-L-Ala, has an extraordinary similarity with an L-glutamine antimetabolite, (X)-L-Ala-L-Ala[where (X) = L-(N5-phosphono) methonine-S-sulphoximine residue], mentioned in last year’s review (Volume 6, p. 7). Antibiotic LL-AV 290 contains 3-Chloro-4-hydroxyphenylglycine and p-hydroxyphenylsarcosine residues.

New β-amino-acids and higher homologues have been reported. γ-Hydroxy-β-lysine is a new basic amino-acid from hydrolysates of tuberactinomycins A and N; a metabolite from an unclassified Streptomycate is a dipeptide (7) containing a 2-aminocyclobutane-1-acetic acid moiety. The novel amino-acid detoxinine (8; R1 = R2 = R3 = H) is a constituent of a group of depsipeptide antibiotics, the detoxins.

3 Chemical Synthesis and Resolution of Amino-acids

Asymmetric Synthesis. — Decarboxylation of α-amino-α-methylmalonic acid after binding to Λ(-) 436-α-[(2S,9S)-2,9-diamino-4, 7-diazadecanecobalt(III) dichloride] cation leads to the corresponding (R,S)-alanine complex in which the (S)-enantiomer is present in 30% excess. This is the first example of the absolute chiral recognition of a prochiral centre by a small molecule – the process is otherwise well illustrated in enzymic reactions. The crystal structure of Λ(-)436-β2-[(2S,9S)-2, 9-diamino-4,7-diazadecanecobalt(III) α-amino-α-methyl-malonate] perchlorate monohydrate shows that a Λ-β-R-conformation is adopted, with the pro-S-carboxy-group of the malonate moiety co-ordinated to cobalt, rather than the pro-R-carboxy-group, and the considerable asymmetric induction caused by the dissymmetric cobalt centre in favour of inversion accompanying decarboxylation (Scheme 1) is due to a less obstructed pathway for the incoming proton in this direction. A late stage in the classical malonic ester synthesis of α-amino-acids is represented in these decarboxylation studies, and the opportunity has now been created for developing a new asymmetric synthesis based on otherwise well-established reactions.

Treatment of a Schiff base derived from (-)-(S)-1-(4-pyridyl)ethylamine and an α-keto-ester with base in ButOH solution gives the rearranged (S)-α-amino-acid ester Schiff base (see Scheme 6, p. 23). This stereospecific (suprafacial) proton transfer depends on the presence of bulky substituents to sustain the geometry of the starting material through the transition state. In ButOD, the α-deuteriated (S)-α-amino-acid is formed. Efficient asymmetric hydrogenation of α-acetamidocinnamic acids is catalysed by chiral phosphine–rhodium complexes; in a partial asymmetric synthesis, chiral isocyanides are converted into their lithium aldimine homologues, e.g. PhCMe(Et)N=CRLi, followed by carboxylation or ethoxycarbonylation.

A novel procedure favouring the formation of D-amino-acids based on N-amino-L-proline and an isocyanide is displayed in Scheme 2.

General Methods of Synthesis. — Further examples of the Ugi reaction have been provided, illustrating a synthesis of L-prolyl-D-amino-acids and a synthesis of 1,4-dihydrophenylalanine, for which a conventional Strecker synthesis was inappropriate. A review has appeared of the uses of α-metallated isocyanides in organic synthesis, including the synthesis of β-functional α-amino-acids (see Volume 6, p. 9). An outstanding new synthesis of α-amino-acids from nitriles (Scheme 3) involves a rearrangement step whose characteristics are not yet fully understood.

Full details of the use of malonic acid half-esters in a modified Curtius reaction (diphenylphosphoryl azide) for amino-acid synthesis are available, supplementing the preliminary communication mentioned in Volume 6 (p. 11). The use of the α-acylamino-malonic ester route is exemplified in many papers, as usual, for the synthesis of specific α-amino-acids, and the hydantoin synthesis and azlactone synthesis, Strecker synthesis, and the α-halogeno-acid amination procedure, have been employed.

Schiff bases are already counted among the more valuable starting materials for amino-acid synthesis, and further such applications have been devised. Electroreductive coupling with an alkyl halide using constant potential electrolysis can give 38–86% yields of α-methyl-α-amino-acids from a pyruvate ester Schiff base (9; see Scheme 4). β-Amino-acid amides R1NHCHR2CH2CONR32, and corresponding esters may be prepared from Schiff bases through the Reformatzky reaction.

General methods for the synthesis of β-carboxy-α-aminosulphonic acids and αβ-unsaturated α-amino-acids have been reported; N-trimethylsilyImethyl-glycinamide, Me3SiCH2 NHCH2CONH2 has been synthesized from Me3 SiCH2-NH2 and ClCH2 CONH2 in a method suitable for general application.

Prebiotic Synthesis; Model Reactions. — Electrical discharge studies with CH4-CO2-NH3 and CH4-NH3-H2O mixtures continue to demonstrate the formation of amino-acid mixtures, and the synthesis of amino-acids and high molecular weight proteins under radiofrequency cold plasma conditions has been reported. Polymeric material obtained from aqueous methylammonium bicarbonate after n,γ-irradiation gave glycine, alanine, and lysine on hydrolysis trimethylammonium bicarbonate gave in addition γ-aminobutyric acid and valine, and n-pentylammonium bicarbonate gave norleucine, γ-aminobutyric acid, alanine, and 6-aminohexanoic acid, on similar treatment. A related study, but with some preparative value, has shown that aliphatic carboxylic acids subjected to contact glow discharge electrolysis in concentrated aqueous ammonia give a wide variety of amino-acids in yields up to 13%. Propionic acid, for example, under these conditions (75 mA at 15 °C for 3h) gives 6.9% alanine, 5.3% β-alanine, and 1% glycine.

Exposure to sunlight of solutions of formaldehyde, ammonium molybdate, ammonium phosphate, and mineral salts gives appreciable amounts of amino-acids after 80 h, with some dependence of relative proportions of the different amino-acids upon the concentrations of formaldehyde and ammonium molybdate.

Hydrogen cyanide oligomers have been shown earlier to be a source of amino-acids on hydrolysis, even though the oligomers themselves do not appear to be closely related to polypeptides. Fractionation of the oligomers into acidic, neutral, and basic components, followed by hydrolysis and analysis by g.l.c. and mass spectrometry, shows that a wider range of protein amino-acids is available from this source than previously supposed. Glutamic acid is obtained by hydrolysis of the neutral oligomers, but not from the acidic and basic fractions which give glycine, aspartic acid, and meso– and DL-diaminosuccinic acids, with smaller amounts of alanine, isoleucine, and α-aminoisobutyric acid. In comparison with the somewhat disappointing earlier evidence that only the more esoteric amino-acids could be generated by hydrolysis of hydrogen cyanide oligomers, these results will enliven the arguments of those who advocate the origin of life within the chemistry of hydrogen cyanide.

Protein and Other Naturally Occurring Amino-acids. — New syntheses described in the preceding sections have employed some of the well-known protein amino-acids as synthetic objectives. This section reports specific syntheses which are interesting in their own right, and also capable of being developed into routes to close analogues of natural products.

A synthesis of lysine from butadiene involves conversion with nitrogen pentoxide into 1-nitrobuta-1,3-diene followed by addition to ethyl nitroacetate or diethyl 2-nitromalonate, and hydrogenation and acid hydrolysis.

A simple synthesis of L-proline from L-pyroglutamic acid (2-oxopyrrolidine -5S-carboxylic acid) employs the method used by the same author in a cucurbitine synthesis described in Volume 6 (p. 15), in which the amide grouping is converted into an imidate ester with triethyloxonium fluoroborate [-CO-NH- [right arrow]-C(OEt)=N-], which on reduction (NaBH4) gives the secondary amine -CH2-NH-. D-Glutamic acid gives a mixture of L-hydroxyproline and D-allohydroxyproline through a route involving the butyrolactone (10) amination of (10) followed by hydrolysis of the resulting amide gives a mixture of the diastereoisomeric hydroxyprolines from which an enhanced yield of L-hydroxyproline may be obtained by equilibration of the cyclic dipeptide of the D-allo-isomer, followed by acid hydrolysis.

Specific examples of syntheses of less-common naturally occurring amino-acids, using well-established methods, are αα-diaminopimelic acid, 3-(3-amino-3-carboxypropyl)uridine, and 4-methylphosphino-L-butyrine.

Elegant syntheses of roseonine [(11) alias streptolidine or geamine] starting from D-ribose have been reported, involving the lactone (12) as intermediate.

Mention has already been made (p. 3) of microbiological syntheses of natural amino-acids and close relatives, and the possibilities are intriguing when the continuous production implicit in the use of E. coli cells immobilized in poly-acrylamide gel is taken into account; the feasibility of this has been demonstrated for the synthesis of L-aspartic acid from ammonium fumarate.

(Continues…)Excerpted from Amino-Acids, Peptides, and Proteins Volume 7 by R. C. Sheppard. Copyright © 1976 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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