Amino Acids and Peptides Volume 19

A Review of the Literature Published during 1986

By J. H. Jones

The Royal Society of Chemistry

Copyright © 1987 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-174-6

Contents

Chapter 1 Amino Acids By G. C. Barrett,
Chapter 2 Peptide Synthesis By I. J. Galpin, with Appendices compiled by C. M. Galpin,
Chapter 3 Analogue and Conformational studies on Peptide Hormones and Other Biologically Active Peptides By J. S. Davies,
Chapter 4 Cyclic, Modified, and Conjugated Peptides By P. M. Hardy,
Chapter 5 β-Lactam Antibiotic Chemistry By A. V. Stachulski,
Chapter 6 Metal Complexes of Amino Acids and Peptides By R. W. Hay and K. B. Nolan,

CHAPTER 1

Amino Acids

BY G. C. BARRETT

1 Introduction

The coverage is predominantly derived from the chemical literature, though much of the interest in the amino acids lies in their biological context. The list of references at the end of this Chapter (p.40) reveals many citations from biological journals and secondary sources, however. The “cut-off point1 as far as this Chapter is concerned is to exclude coverage of the distribution of amino acids and metabolic and biosynthetic aspects and biological roles.

2 Textbooks and Reviews

Reviews of a specialist nature are cited in the appropriate Sections of this Chapter. This Section lists more general references: a supplementary list of nomenclature recommendations (IUPAC-IUB) covers selenium-containing amino acids; N-hydroxyamino acids; L-proline and L-hydroxyproline as chiral auxiliary agents in asymmetric synthesis; historical account of the discovery of [??]-aminobutyric acid; and arginine with special emphasis on evolutionary and metabolic aspects. Monographs and compendia include a volume entitled ‘Glutamate; Glutamine, and Related Compounds’ that contains authoritative coverage of many other amino acids of similar functionality; Proceedings volumes; comprehensive analytical coverage; and more broadly based texts.

3 Naturally Occurring Amino Acids

3.1 Occurrence of Known Amino Acids.- This Section includes examples of unusual occurrence of simple, familiar amino acids, either in the free form or in a non-peptide coupling.

D-Leucine is found, not merely in trace amounts, in aerial parts of Coronilla varia and in seeds of Coronilla scorpioides. S-(β -Carboxyethyl) cysteine is the major free amino acid (up to 2.9% dry weight) in seeds of several Calliandra species, and survives in leaves of these plants at early stages of germination. Since this derivative is moderately insecticidal, young plants have chemical defence against at least some of their natural adversaries.

Culture media of Streptomyces cattleya contain (2S)-amino-(3R)-hydroxypent -4-ynoic acid (“β-ethynyl serine”). The detection of 1,2,3,4-tetrahydro β-carboline-3-carboxylic acid in beer and wine has been reported; it is accompanied by its 1-methyl homologue.

Argiopine, a fortuitously named ion-channel blocking agent from the spider Argiope iobata, contains arginine and asparagine linked through their carboxy groups by the polyamine moiety -NH(CH2)3 NH(CH2)3NH(CH2)5NH-, the side-chain amide being substituted by a 2,4-dihydr-oxyphenylacetic acid grouping.

3.2 Uncommon Amino Acids in Peptides and Proteins. – This would be a much larger section if it covered the title comprehensively; it is restricted to representative citations.

The aquatic fern Azolla caroliniana contqins(N-[??]-L-glutamyl-D-amino) phenylpropanoic acid. The modified nucleoside N-[9-(β-D-ribofuranosyl) purin-6-ylcarbamoyl]-L-threonine occurs in the urine of patients with certain types of breast cancer and may be of diagnostic value in this context.

Hydrolysis of the glycopeptide antibiotic aricidin A gives (2R,2’S)-actinoidinic acid (as a mixture of two atropisomers) and the phenylglycine derivative (1). More familiar but still uncommon amino acids reported as substituents of proteins are D-aspartic acid in myelin and myelin basic protein; [??]-N-methyl asparagine in allophycocyanin; and histidinoalanine, a crosslinking residue in a Macrocallista nimbosa protein. This crosslink is surmised to derive from non-enzymic condensation of phosphoserine and histidine residues, though since this protein also contains phosphothreonine this conclusion would be more plausible if analogous “histidinobutyrine” crosslinks could also be hunted for.

3.2 New Natural Amino Acids.- Xylem sap of Pisum sativum contains an amino-chlorobut-anoic acid C4H8NO2Cl; while further structural studies can be expected for this compound, more complete assignments have been reported for Nδ -(1-carboxyethyl)-L-ornithine from Streptococcus lactis grown in ornithine-supplemented media. Synthesis of this compound from poly (L-ornithine) or Nα-benzyloxycarbonyl-L-ornithine gave a 1:1 mixture of diastereo-isomers, one of which was identical with the natural material.

Seven new amino acids have been found in the red alga Chondria armata, but the information from Chemical Abstracts is limited to domoilactone B (2) and two palitoxin analogues. The strongly insecticidal properties of these amino acids towards cockroach will ensure the availability of more complete information on this research. Ectothiorhodispira halochloris yields ectoine (3), shown by X-ray analysis to exist in the zwitterionic form.

An unusual type of derivative, D-β-lysylmethanediamine, occurs in Streptomyces nashvillensis.

The earlier finding that α-amino-[??], δ-dihydroxyadipic acid is a constituent of normal human urine is now corrected; it is an artefact from boiling urea and D-glucuronolactone with 6M hydrochloric acid.

3.3 New Amino Acids from Hydrolysates.- This Section covers new amino acids found in peptides and proteins and related condensation products. 2,2′-Bifyrosine has been detected in yeast acospore wall protein in previously unknown racemic and meso Forms. Hydrolysis of proteins that have been chemically modified through azo-coupling of lysine residues releases the modified residues unaltered when MeSO3H is used, but when aqueous HCI is used for the hydrolysis α-amino-ε -hydroxycaproic acid and α-amino-ε-chlorocaproic acid are formed.

2-Aminoethylphosphanic acid, claimed to have been found in hydrolysates of ruminate stomach contents, is thought to be a mis-interpretation.

Lipopurealins A (4; R = Me, n = 12) and homologues B (4; R = iPr, n = 11 ) and C (4; R = Me, n = 14) are novel bromotyrosine derivatives from the marine sponge Psammaplysilla purea. Nikkomycin from Streptomyces tendae.

releases three novel amino acids ( 5) on hydrolysis, whose structures have been confirmed by synthesis.

4 Chemical Synthesis and Resolution

4.1 General Methods of Synthesis of α-Amino Acids.- This Section collects together those papers that illustrate the use of standard methods (the objectives of these papers are mentioned elsewhere in this Chapter), and also the development of alternative methods. Several papers in the following Section on Asymmetric Synthesis describe the use of standard general methods.

Acylaminomalonates, Ac-or Z-NHCH(CO2Et)2, and other glycine derivatives, e.g. Ph2C=NCH2CO2Me, are alkylated by alkenes, alkyl halides, or αβ-unsaturated aldehydes (Michael addition leading to Z/E-3-ethylproline). Analogous alkylation of ‘azlactones’ continues in use; a new azlactone synthesis uses the glycine derivative t-butyl isocyanoacetate (6) in a condensation that is closely analogous to the standard use of (6) for the synthesis of αβ-dehydro amino acids through reaction with aldehydes or ketones.

Several methods exist for the amination of carboxylic acid derivatives, either employing ammonia with an α-halo-acid or amines with triflates of α-hydroxyacids. In the latter study based on (S)-lactic acid derivatives, decreasing reactivity of various leaving groups (MeCHRCO 2Et: R = CF3SO3 >> Br > MeSO3 > TolSO3 > Cl) is accompanied by increasing tendency towards racemizarion and elimination. Reductive amination of α-keto-acids using NADH and NADPH with NH3 has been given a novel aspect in the use of photoinduced regeneration of the reducing agent.

The use of nitrosobenzene for the introduction of a nitrogen functional group into a silyl enol ether, PhNO + (Me3S;O)2 C = CR1R2 [right arrow] PhNHCR1RCO 2H, involves LiAIH4 reduction of the intermediate adduct. Nitro-alkanoate esters are reduced by catalyzed hydrogen transfer (ammonium formate and Pd-C).

The hydrolysis of α-aminonitriles to corresponding amides is markedly catalyzed by thiols; for example 2-mercaptoerhanol leads to 90% conversion in 17 hours at room temperature in aqueous solution at pH 6.5.

Further study of the amidocarbonylation of allylic alcohols has led to improvement in details: R1R2C=CHCH2OH+ AcNH2 + CO + H2 [right arrow] R1 R2CHCH2CH(NHAc)CO2H under mild conditions through the use of the catalyst system HRh(CO)(PPh3)2 + Co2(CO)8.

4.2 Asymmetric Synthesis of α-Amino Acids. Electrophilic amination by BocN=NBoc of chiral silylketene acetals and of camphane esters leads to α-hydrazino acids. These are readily reduced (H2/Pt) to α-amino acids and provide valuable new routes as alternatives to well established methodology. In the latter category, the ‘asymmetric Strecker synthesis’ in which (S)-1-phenylethylamine is condensed with NaCN and PhCH2COMe to give (R)-α-methyl phenylalanine, numerous examples of alkylation of glycine derivatives (Ph2 C=NCH2CO>2Me) and allyl acetate catalyzed by a chiral Pd catalyst, (MeS)2C=NCH2CONR1 R2 where -Nr1R2 is a chiral 2,5-bis (methoxymethyl)pyrrolidine, and the D-camphor imine of t-butyl glycinate), and analogous Schiff bases (RCH=NCHMePh + BrCN [right arrow] RCH(CN) NBrCHMePh, and PhCON=CHC02R + enamines (7)) provide a range of optical efficiency. While modest enantioselectivity (up to 57%) is frequently obtained, some of these methods are exceedingly enantio- and diastereoselective (better than 97%, 100%), alkylation by enamines being postulated to proceed via a Diels-Alder-like transition state.

Amination processes of a conventional type are involved in the reaction of α-halogeno-10-sulphonamido-isobornylesters(8) with NaN3 and of D(-keto-acids mediated by polymer-bound NADH and leucine dehydrogenase. Both lead to nearly 100% enantioselective syntheses of a variety of simple aliphatic L-α-amino acids including L-alloisoleucine and L-t-leucine. Other examples of chiral auxiliaries are D-mannitol (conversion into diaziridiiws, thence to N-toluene-p-sulphonyl-L-α-aminobutyric acid, or conversion into (R)-phthalimido-aldehydes and D-amino acids: Scheme 1). (R,R)-Tartaric acid has been used for the preparation of N-Boc-L-erytrrro-β -benzyloxyaspartate through partial debeniylation, then conventional stages. Enantioselective profanation of lithium enolates by chiral acids alters the optical purity of an amino acid, the extent determined by the lithium counter-ion.

Chiral heterocyclic compounds are being worked hard for the present purpose, with the bislactim ethers (e.g. 9) derived from L-valylglycine di-oxopiperazine having been in use by Schollkopf’s group for several years. Chlorination by Cl3CCCl3 followed by reaction with a malonic ester gives β-carboxy-D-aspartic acid diesters, while more conventional alkylation methods lead to [??]-diethoxyphosphinyl-L-butyrine. The oxazinone (10) from erythro-αβ-diphenyl-β-hydroxyethylamine enantiomers is a useful electrophilic glycine synthon when R = Br (prepared from 10; R = H by reaction with N-bromosuccinimide) that reacts with carbon nucleophiles. The (-) isomer after alkylation in this way gives L-α-amino acids through hydrolysis and hydrogenolysis; one example in which displacement of the bromine substituent is brought about by 2H2 has been described, leading to (S)-chiral glycine.

Seebach’s exploitation of the enantioselectivity accompanying alkylation of lithium enolates of imidazolidines (11; see also Vol. 18, p. 5) has been extended to other examples, including analogous oxazolidinones. Condensation of pivalaldehyde with glycin-amide gives (11), which can be resolved in the conventional way using (5)-PhCH(OH)CO2H, while use of an L-amino acid in the condensation gives the oxazolidinone corresponding to (11) with a cis relationship between the 2-t-butyl group and the 4-substituent. Use of an N-alkanoyl ossazolidinone (12) as a chiral glycine synthon for the synthesis of N-methyl-β-hydroxy amino acids through syn-diastereoselective aldol addition of the stannous enolate of (12; R2 = nBu) has been illustrated for N-methyl-3-hydroxy-4-methyloct-6-enoic acid, an unusual α-amino acid in cyclosporin. The novel aminating agents BocN=NBoc and RO2 CN=NCO2R react with near-100% stereoselectivity with (12) in the form of its Li enolate, the resulting (S)-hydrazino acids being hydrolysed (LiOH), deblocked, and hydrogen-olyzed (H2/Ni) to give the amino acids. N-Isocyanoacetyl-L-prolinol derivatives (13) have served the corresponding purpose in syntheses of enantiomers of α-disubstituted amino acids.

Aldol reactions (CNCH2CO2Me + RCHO) and hydrogenations of 2-acylaminocrotonates show a wide range of enantio- and diastereoselectivities with the influence of chiral catalysts. Bis(cyclohexylisocyanide)gold(I) tetrafluoroborate and an (R)-ferrocenylphosphine are very effective in this respect for the aldol reaction, while a range of chiral Rh(I) phosphines of familiar types has shown mixed ability (less than 26%, 100%). ‘Asymmetric hydrogenation (H2 can be replaced by 80% aqueous HCC2H) has been reviewed in relation to the commercial synthesis of L-dopa. Closely related studies have been described for the hydrogenation of alkylidene derivatives of glycyl-L-alanine dioxopiperazine, leading to L-amino acids in better than 94% e.e., and α-nitrocaprolactam catalyzed by PdCl2-(S)-phenyl-ethylamine (giving L-lysine in only 11% e.e.); aminotysis of 2-methyl-4-(4-acetylamino-butyl)oxazolin-5-one with (S)-phenylethylamine gives mainly the L-lysine-containing diastereoisomer.

A review has appeared concerning applications of enzymes in asymmetric synthesis.

4.3 Synthesis of β – and Higher Homologous Amino Acids.- These systems can be made available through standard methods of introduction of amine and carboxy functional groups, and there are few characteristic routes.

Addition of ammonia to αβ-unsaturated acids at 15-30 Kbar yields β-amino acids. An alternative conventional approach to these compounds, exemplified in the synthesis of 3-amino-3-(2-nitrophenyl)propionic acid from o-nitrobenzaldehyde, malonic acid, and NH4OAC in AcOH, offers a ‘one-pot’ procedure. Asymmetric synthesis is illustrated in the threo-selective condensation of Z-(O-vinyloxy)boranes with imines (14)[right arrow](15). The addition of a chirat primary amine to an αβ-unsaturated ester at 5-15 Kbar is generally highly enantio-selective, especially so in the case of 8-(2-naphthyl)menthylamine (better than 99%).

Seebach has taken up the procedure for decarboxylative electrochemical methoxylatlon of amino acids (see Vol. 17, [p26) to provide a conversion of (2S,4R)-hydroxyproline into (R)- 3 -amino-3-hydroxybutanoic acid (“GABOB”), as shown in Scheme 2.

Proline isomers (16) can be prepared by cyclization of azomethine ylides formed between alkenes, amines, and formaldehyde.

4.4 Prebiotic Synthesis Models for Amino Acids.- A number of enterprising experiments have been described under this heading in recent Volumes of this Report. These are joined by an account of the formation of the polymer “Titan tholin” by continuous d.c. discharge through N2 and CH4 (9:1) at 0.2 mbar pressure. This mixture and energy source simulates the turbulent cloud-top atmosphere of Jupiter’s moon; hydrolysis of the polymer with 6M-hydrochloric acid leads to glycine, aspartic acid, alanine, and β-alanine, with 12 other amino acids in lesser proportions. A review has appeared covering HCN polymers as a potential prebiotic source of amino acids.

An efficient system for the synthesis of amino acids that may be relevant to the primordial scene is the ammonolysis of keto-acids in aqueous ammonia, mediated by visible light and dyes.

Conventional experiments, repeating the earliest laboratory demonstrations, have been described for photolysis of CH4 with HCN, CO2, and other simple compounds; of HCHO with aqueous K4Fe(CN)6; and electric discharge studies with CH4, N2, H2O, NH4+ and metal salts; and similar mixtures also including PH3. Amino acids are formed in all these cases.

4.5 Synthesis of Protein Amino Acids and Other Naturally Occurring α-Amino Acids.- As in previous Volumes, there is insufficient space here for the ever more voluminous literature concerning enzymic synthesis of protein amino acids. This important area can only be acknowledged through representative citations here, but it is well served with reviews and is accessible through Section 16 (Fermentation and Bio-industrial Chemistry) of Chenuccd Abstract.

Selected papers and a compendium describe the use of immobilized cells of Alcali-genes metalcaligenes for the synthesis of L-aspartic acid from ammonium fumarate; mixed enzymes (serine hydroxymethyltransferase with β-tyrosinase) for the synthesis of L-tyrosine from glycine and phenol; and individual treatment of the microbiological production of each of the protein amino acids.

Several of the papers discussed in other sections (synthesis and reactions of amino acids) lead incidentally to the synthesis of natural amino acids, and a full appraisal of syntheses achieved should take in these other Sections.

(Continues…)Excerpted from Amino Acids and Peptides Volume 19 by J. H. Jones. Copyright © 1987 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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