Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 80 years the Royal Society of Chemistry and its predecessor, the Chemical Society, have been publishing reports charting developments in chemistry, which originally took the form of Annual Reports. However, by 1967 the whole spectrum of chemistry could no longer be contained within one volume and the series Specialist Periodical Reports was born. The Annual Reports themselves still existed but were divided into two, and subsequently three, volumes covering Inorganic, Organic and Physical Chemistry. For more general coverage of the highlights in chemistry they remain a 'must'. Since that time the SPR series has altered according to the fluctuating degree of activity in various fields of chemistry. Some titles have remained unchanged, while others have altered their emphasis along with their titles; some have been combined under a new name whereas others have had to be discontinued. The current list of Specialist Periodical Reports can be seen on the inside flap of this volume.
Read an Excerpt
Amino-Acids, Peptides, and Proteins Volume 4
A Review of the Literature Published During 1971
By G. T. Young
The Royal Society of ChemistryCopyright © 1972 The Chemical Society
All rights reserved.
BY B. W. BYCROFT
The past twelve months have witnessed interesting developments in amino-acid chemistry, but pride of place must be taken by the isolation, characterization, and synthesis of the amino-acid derivative from phenyl-alanine t-RNA. This work also reflects the growing sophistication in the application of physical methods in general. The interesting advances reported last year on asymmetric synthesis have been extended, and a staggering number of new amino-acids continues to be synthesized for a variety of reasons. The established pattern of coverage for this chapter is maintained, attention being focused on a broad selection of topics with the significant developments highlighted where necessary.
1 Naturally Occurring Amino-acids
A. Occurrence of Known Amino-acids. — A large number of papers which are concerned with the free amino-acid content of a wide variety of living organisms is published annually. Since the emphasis for the majority of this work is on biological aspects, it is not considered appropriate to cover them in this section and only those amino-acids which are rarely encountered or are interesting from the chemical viewpoint have been included.
The presence of amino-acids in extra-terrestrial material as well as their synthesis under simulated prebiotic conditions (see Section 2B) has attracted a considerable amount of attention. Examination of samples from the Apollo 11 and Apollo 12 missions has revealed extremely low concentrations of amino-acids (ca. 20–70p.p.b.); ultra-sensitive analytical techniques were employed for these investigations and, because of the presence of a considerable number of non-protein amino-acids, the investigators maintain that they are not due to terrestial contamination. Similar conclusions have been made concerning the presence of amino-acids in the Murray and Murchinson meteorites. In the case of the Murray meteorite, seventeen amino-acids were identified of which seven were conclusively shown to be racemic and eleven to be non-protein in origin. An earlier report that the amino-acid content of the Orgueil meteorite was due solely to terrestrial contamination has been questioned, and it is now suggested that there are amino-acids indigenous to the meteorite in addition to those present as contaminants.
The presence of amino-acids in the North Atlantic ocean has been the subject of a detailed examination and the distribution appears to be non-uniform and varies qualitatively with depth. In marine sediments the degree of racemization of free amino-acids shows a progressive increase with the age of the sediment,' and the ratio of allo-isoleucine to leucine is a reliable indicator of age for samples less than 400 000 years old. In samples older than about 15 x 106 years the amino-acids are completely racemic.
The stereochemistry of the α-hydroxy-analogue of cysteine present in the urine of certain mentally retarded patients has been established by comparison with synthetic material. The work reported initially last year on the isolation of the methylated derivatives of arginine and lysine has been extended and it has been noted that, in patients with malignant tumours, the relative urinary level of guanidino-NN-dimethylarginine to that of arginine is markedly increased. Bovine and rat brain tissue has been shown to contain appreciable amounts of NG-monomethylarginine as well as NGN'G-dimethylarginine.
Further spectral evidence on the aldol condensation product isolated on alkaline hydrolysis of elastin provides strong support for the previously assigned structure (1).
Interest in plants containing L-Dopa continues, and a widespread investigation has shown that several Mucuna species contain up to 5% of this important amino-acid. The neurotoxin α-amino-β-oxalylaminopropionic acid has been isolated from Lathyrus sativus and the major alkaloid of Aotus subgzauca has been identified as S-(+)-Nα-methyltryptophan methyl ester. The previously unidentified amino-acid from Peganum harmala is established as L-4-hydroxypipecolic acid D-Pipecolic acid, as well as and D-erythro-αβ-diaminobutyric acid, has been isolated on acid hydrolysis of the antibiotic amphomycin, and griselimycin afforded, inter alia, 4-trans-4-methyl-L -proline and N-methyl-D-leucine on hydrolysis.
B. New Natural Free Amino-acids. — The novel azirine amino-acid (2) isolated from a strain of Stregtomyces aureus, and appropriately named azirinomycin, exhibits broad-spectrum activity in vitro against both Gram positive and negative bacteria. It is unstable especially in concentrated form and was identified by spectral analysis and by conversion on catalytic hydrogenation into L-α-aminobutyric acid. L-2,5-Dihydrophenylalanine (3), which had previously been synthesized by a Birch reduction of L-phenylalanine, is an antimetabolite of L-phenylalanine produced by an unidentified stregtomyces. A related compound, anticapsin (4), is produced by a strain of Streptomyces griseoplanus and is presumably derived from L-tyrosine by a similar reduction with subsequent epoxidation.
The increasing application of mass spectrometry as a valuable tool for characterization is apparent and has been employed for many of the amino-acids described in this section. Trimethylsilylation is still the most commonly employed procedure for enhancing the volatility of amino-acids containing a number of polar substituents and has been successfully applied in characterizing L-threo-α -amino-βγ-dihydroxybutyric acid. The new compound (5), which has been isolated from the common mushroom, affords on oxidation an unstable quinone, also present in the organism.
Glutamic acid derivatives have also been isolated from a number of plant sources. Pinnatanine (6), a new amino-acid isolated from the European bladder nut (Staphylea pinnata), affords on acid hydrolysis L-allo-γ-hydroxyglutamic acid, ammonia, and compound (7), the structure of which has been confirmed by synthesis. It is suggested that (7) arises via a Diels-Alder dimerization of the transient 2-methylenebut-3-enal initially formed in the hydrolysis. In the course of an investigation on nitrogen metabolism in tobacco plants a new amino-acid, nicotianamine, was isolated and the structure (8) was assigned on the basis of extensive chemical degradation and spectral analysis. Azetidine-2-carboxylic acid had previously been obtained from a considerable number of plant species.
The isoquinoline derivative (9) has been isolated from the plant Mucuna mutisianal which also contains appreciable amounts of L-Dopa, and it appears likely that (9) is derived from L-Dopa by condensation with formaldehyde. The corresponding derivative (10), formed from L-Dopa and acetaldehyde, had previously been isolated.
The urine of homocystinuric patients has been shown to contain S-(3-hydroxy-3-carboxy-n-propylthio)- and S(2-hydroxy-2-carboxyethyl-thio)-homocystine in addition to the α-hydroxy-analogue of cystine. Further work on the phaemelanin pigments has been reported, and an isomer of trichosiderin C has been isolated and characterized.
C. New Amino-acids from Hydro1ysates. — The most notable achievement in this field is undoubtedly the characterization and subsequent synthesis (see Section 2C) of the fluorescent Y base present in phenylalanine t-RNA derived from yeast, wheat germ, and rat liver. It represents a significant triumph for the application of physical methods; the structure (11) was established on 300 µg of material mainly on the interpretation of the results obtained from high-resolution mass spectrometry and n.m.r. spectroscopy.
Full details on the structures of the novel piperazic acid derivatives from the antibiotic monamycin and the guanidine amino-acid viomycidine from viomycin have been reported. β-Hydroxyhistidine has been isolated on the acid hydrolysis of the antibiotic bleomycin.
2 Chemical Synthesis and Resolution of Amino-acids
A. Introduction and General Methods. — The interest in asymmetric syntheses of amino-acids continues unabated and a valuable article covering the literature up to 1969 has been published. In addition those syntheses which involve enantioselective catalytic hydrogenation have also been reviewed. In this respect it is of considerable interest to note that this year has seen the first significant application of homogeneous asymmetric catalysis to amino-acid synthesis. The rhodium complex of the chiral diphosphine (12) readily reduces N-acyldehydroamino-acids (13) to the corresponding (R)-N-acylamino-acids in high yield and with an optical efficiency of about 70%. The relatively high stereoselectivity is ascribed to the conformational rigidity of the diphosphine chelating the rhodium, together with the participation of the acid function of the substrate.
The inherent problem of conformational mobility of the substrate in all asymmetric syntheses which was referred to in last year's Report is probably the cause of the relatively low optical efficiency of the new synthesis outlined in Scheme 1 and of the asymmetric reduction of dehydroamino-acid peptides. Unfortunately, the ingenious synthesis of amino-acids by the insertion of a carbene into an N–H bond of an optically active amine (Scheme 2) also gives low optical efficiency, presumably for the same reason.
A general synthesis has been reported which employs a carbonylation reaction and is essentially a variation of the hydroformylation reaction and the Oxo process (Scheme 3). Although the products are completely racemic the yields are reasonable and it is claimed that the reaction has a wide application to amino-acid synthesis. The starting materials are readily available and the synthesis reflects the growing commercial interest in the large-scale chemical production of amino-acids.
B. Synthesis under Simulated Prebiotic Conditions. — It is now well established that amino-acids are formed when a simulated primitive atmosphere is subjected to high temperature, u.v. irradiation, or high-frequency discharge, or any combination of these conditions. Recent work has centred on more rigorous analysis of the reaction mixtures and identification of amino-acids with functional groups in the side-chain. Irradiation of mixtures of methane, ammonia, hydrogen sulphide, and water produces mixtures which contain either cysteine or cystine depending on the reaction conditions and similar experiments using high-frequency discharge produce mixtures in which histidine has been conclusively identified. The preferential adsorption of the L-isomer of racemic amino-acids on Kaolinite templates has been demonstrated and is of particular interest in connection with the natural predominance of L-amino-acids.
C. Protein and Other Naturally Occurring Amino-acids. — Many of the syntheses described in this section have been achieved by standard procedures, and therefore only the salient features of the more important will be presented.
The various methods for the synthesis of glycine have been reviewed and a large-scale preparation of ornithine from glutamic acid has been reported. A new synthesis of threonine from the glycine copper complex and acetaldehyde has been described together with a detailed investigation of the course of this reaction. Interest in the synthesis of L-Dopa and related compounds (Section 2F) continues, and two further syntheses are now available.
The full details of the syntheses of capreomycidines indospicine, and the piperazic acid derivatives from the antibiotic monamycin, initially reported in preliminary form, have now been published.
The structure of the Y base from phenylalanine t-RNA, as well as the stereochemistry at the single asymmetric centre, has been conclusively established by the synthesis outlined in Scheme 4. The novel cyclopropyl amino-acid (14) from horse chestnuts has been synthesized by carbene addition to 3, 4-dehydroproline. The reaction gives rise to a mixture of the cis- and trans-isomers (14) and (15) in the ratio 1 : 3.5. The stereochemistry of the natural amino-acid (14) was established by X-ray crystallographic analysis.
D. C-Alkyl- and Substituted C-Alkyl-α-amino -acids. — An improved method is claimed for the preparation of unsaturated α-amino-acids by reduction with aluminium amalgam of the unsaturated α-hydroxyimino intermediate (16) derived by the normal malonate route. A convenient method for direct conversion of N-acyl -α-amino-acids into the N-acyl-αβ-dehydro -amino-acids has been reported. ((S)-α-Methyl -α-amino-acids have been obtained in high yield by a modified Strecker synthesis and new syntheses of α -aminosuberic and α-aminosebacic acids have been described.
Considerable interest exists in cyanoamino-acids because of the strong neurotoxic properties of the naturally occurring β-cyano-L-alanine. Dehydration of N-o-nitrophenylsulphenyl (Nps) asparagine and glutamine with dicyclohexylcarbodi-imide affords the corresponding protected ω-cyanoamino-acid. The free amino-acids were obtained by removing the Nps group under mild conditions which did not effect the cyano-group. α-Cyanoglycine has been prepared by enzymic deacetylation of the readily available acetamidocyanoacetic acid. Attempts to prepare it by chemical hydrolysis were unsuccessful because it undergoes rapid decarboxylation in hot aqueous solution.
N-Trifluoroacetylphenylglycine (17) has been converted by an interesting and unusual series of thermal rearrangements into trifluoroalanine (18). The proposed reaction sequence is outlined in Scheme 5. The overall yield is acceptable and it is probable that this novel synthesis could be extended to other fluorinated amino-acids.
E. α-Amino-acids with Aliphatic Hydroxy-groups in the Side-chain. — The considerable interest in β-hydroxyvaline in relation to penicillin chemistry is reflected in the large number of syntheses already available for this compound. A further synthesis involves the addition of ethoxycarbonyl-nitrene to ethyl ββ-dimethylacrylate to give the aziridine intermediate (19). Ring opening of (19) with acetic acid and subsequent base hydrolysis affords (20) in good yield.
Both erythro- and threo-β-hydroxyleucine have been synthesized from β-isopropylglycidic acid, and a detailed account of a number of unsuccessful routes to α-hydroxyamino-acids has appeared.
F. Aromatic and Heterocyclic α-Amino-acids. — Aromatic amino-acids continue to be synthesized as potential enzyme inhibitors. A series of 6-alkyl-Dopa derivatives and 3-(2,5-dimethoxy-4-methyl)phenylalanine have been prepared by standard routes, and an improved synthesis of 6-hydroxy-Dopa is claimed. A variety of tyrosine derivatives 3p and 2-aminoindan-2-carboxylic acids have been prepared as possible inhibitors of tyrosine hydroxylase. A novel method for the synthesis of α-hydrazino-acids related to L-Dopa has been reported. The key intermediate was the hydantoic acid (21) (prepared from the amino-acid and potassium cyanate) which on treatment with sodium hypochlorite afforded the hydrazino-acid (22) in good yield. The stereochemistry at the α-centre was retained, but in all the cases so far investigated the [alpha-centre was fully substituted. It is possible that this method may have a broader application to the synthesis of α-hydrazino-acids.
A number of fluoro- and amino-phenylalanines, as well as p-azidophenylalanine, designed as a photoaffinity probe in synthetic peptides, has been reported. Interest continues in structural analogues of thyroxine; the stilbene derivative (23) has been synthesized by means of a Wittig reaction.
A wide range of pyridyl, pyridimyl,and purinyl amino-acids have been synthesized mainly by well-established routes for a variety of specific reasons too diverse to enumerate. The first example of a ring-fluorinated histidine derivative has been obtained by a new route involving the photochemical decomposition of diazonium fluoroborates, and the method promises to offer a general route to aromatic and hetero-cyclic fluorination.
G. N-Substituted α-Amino-acids. — A further method for the preparation of N-methylamino-acids, which is also claimed to give high yields and optical purity, has been reported. The reaction of the L-bromo-acid (24) with anti-benzaldoxime afforded the N-oxide (25) which, on hydrogenation and hydrolysis, gave D-phenylalanine, thus demonstrating that the reaction had proceeded with inversion of configuration at the α-centre. A novel route to α-hydrazino-acids from the corresponding amino-acid has been described in the foregoing section.
An interesting variation of the Favorski reaction has been employed to synthesize a series of ring homologues of proline. α-Halogenation of the readily available ω-aminolactams (26) afforded the α-halogeno-compounds (27) which underwent ring contraction on treatment with base to give the α-imino-acids (28). The already extensive programme on the synthesis of N-bis-2-halogenoethyl derivatives of amino-acids as potential antimeta-bolites has been extended.
Excerpted from Amino-Acids, Peptides, and Proteins Volume 4 by G. T. Young. Copyright © 1972 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.
Table of Contents
Front matter; Preface; Contents; Abbreviations; Amino-acids; Structural investigation of peptides and proteins Part I: Primary structure and chemical modification; Part II: Secondary structure; Part III: X-Ray analysis; Peptide synthesis; Peptides of abnormal structure; The relationship between the structure and biological activity of some peptides and proteins (excluding enzymes); Metal derivatives of amino-acids peptides and proteins; Author index