Amino Acids, Peptides, and Proteins Volume 30

A Review of the Literature Published during 1997

By J.S. Davies

The Royal Society of Chemistry

Copyright © 1999 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-222-7

Contents

Chapter 1 Amino Acids By Graham C. Barrett, 1,
Chapter 2 Peptide Synthesis By Donald T. Elmore, 111,
Chapter 3 Analogue and Conformational Studies on Peptide Hormones and Other Biologically Active Peptides By Anand S. Dutta, 163,
Chapter 4 Cyclic, Modified and Conjugated Peptides By John. S. Davies, 285,
Chapter 5 β-Lactan Chemistry By Christopher J. Schofield and Magnus W. Walter, 335,

CHAPTER 1

Amino Acids

* * *

BY GRAHAM C. BARRETT

1 Introduction

The science of amino acids described here is based mainly on the literature of 1997. Criteria used for structuring this Chapter in all preceding Volumes of this Specialist Periodical Report have been used again for defining the papers chosen for citation here.

Thus, advances in the chemistry of the amino acids, and biological aspects impinging on their chemistry, have been the preoccupation for this Chapter, with routine aspects being excluded from consideration. Even so, the year-on-year increase in the number of papers eligible for inclusion here has continued, and has required a certain amount of restraint and retrenchment in the layout of this Chapter, with merging of some Sections.

Most of the papers cited here are the rewards of scanning the major Journals, and of scanning Chemical Abstracts (Issue 10 of Volume 126, up to and including Issue 9 of Volume 128).

2 Textbooks and Reviews

Monographs providing detailed coverage of enantioselective synthesis of βamino acids and protein sequence determination have appeared; the latter contains a range of chapters relevant to the analysis of amino acids. A text that is aimed at advanced undergraduate and postgraduate students will also assist those active in amino acid and peptide research in chemical, biochemical, pharmaceutical and related research areas.

The biochemistry of L-arginine, and the context of this amino acid in biology, has been reviewed. A survey of methods for the enantioselective synthesis of chiral drugs also covers amino acid synthesis protocols. The occurrence of D-amino acids in free form (particularly D-serine and D-aspartic acid in human brain) and in naturally-occurring peptide has been reviewed, and the literature dealing with hypusine (a post-translationally modified L-lysine derivative) has been surveyed.Other reviews cover the biosynthesis and metabolism of those amino acids (isoleucine, threonine, methionine and lysine) that derive from aspartic acid in higher plants, 10 the amino acid composition of bacterial and mammalian cells, and the natural provenance of dihydroxyprolines.

3 Naturally Occurring Amino Acids

3.1 Occurrence of Known Amino Acids – Leaving until later (Section 5.6) some citations that were traditionally placed here (e.g., papers describing unusual results from preparative-scale isolation of amino acids from mixtures), the non-routine literature describes three further N,G, NG-permethyl arginines in ribonucleoprotein, N-acetyl-L-aspartic acid and N-acetyl-L-histidine as components of the vertebrate nervous system and in the eye lens of goldfish and rats, N-(17-hydroxylinolenoyl)-L-glutamine, known as volicitin, in a secretion of the caterpillars of beet armyworm that attracts predators, four new N-acyl 2-methylene-α-alanine methyl esters (hurghamides A 7–D, from a Red Sea sponge Hippospongia), and five new bengamides (e.g. 1) from the New Caledonian sponge Jaspis carteri. Further information has been provided on S-methyl-L-methionine salts, with the suggestion that this widely-distributed cellular species (vitamin U) probably acts to diminish lipid peroxidation and monoamine oxidase activity. New data on the neurotoxicity of domoic acid have been reported.

Norvaline has been incorporated into leucine positions in recombinant human haemoglobin expressed in Escherichia coli, probably through mis-aminoacylation of tRNALeu (norleucine is misincorporated in similar circumstances in place of methionine). The tryptophan residue in the cardioexcitatory tripeptide amide H-Asn-Trp-Phe-NH2 from Aplysia kurodai heart tissue is of the D-configuration (the all-L tripeptide amide is much less physiologically active).

A continuing fascination is the occurrence of common amino acids in extraterrestrial samples, and the implications of the report 23 that small excesses of L-amino acids have been found in the Murchison meteorite have been considered. The result is confirmed independently, and stable isotope analysis indicates that the amino acids are not terrestrial contaminants. The amino acids involved include 2-amino-2,3-dimethylpentanoic acid (α-methylisoleucine; the ‘L-enantiomers’ among the four possible stereoisomers exist in 7.0 and 9.1% excess, respectively). However, other amino acids are present as racemates (aminoisobutyric acid, norvaline, isovaline and α-methylnorvaline). This might be interpreted to show that what Bada calls ‘asymmetric influences’ were at work on organic reactions occurring in prebiotic times.

The delivery of amino acids and other extraterrestrial compounds was an incidental feature of the catastrophe that wiped out the dinosaurs and most other species in the Cretaceous – Tertiary era. The same result is implied in the theory that is increasingly gaining support: the encounter of Earth with a giant molecular cloud (which better explains the lowered oxygen levels seen in amber-entombed contemporary air samples and lack of amino acids carrying oxygenated functional groups).

3.2 New Naturally Occurring Amino Acids – The cis-fused hexahydro[3,2- b]pyran (2) that is reminiscent of domoic acid in its neurotoxic effects is a new dysherbaine from the Micronesian sponge Dysidea herbacea. One of two palythines (3 and homologue CHMeOH in place of CH2OH), new UV-B absorbing amino acids of the mycosporin family extracted from a reef-building coral Stylophora pistillata, is the sulfate ester of one of the compounds present in Pocillopora eydouxi. New mycosporin-like amino acids have been found in the Antarctic sea urchin Sterechinus neumayeri. The first report of pyrazoles as natural products (4; and its 4-methyl homologue) concerns the sponge Tedania anhelans.

4-Methylaeruginoic acid (5) is a new cytotoxic imino acid from StreptomycesKCTC 9303. Eupenicillium shearii PF1191 produces kaitocephalin (6; information on stereochemical features not yet available), a novel glutamate receptor antagonist that is a potent suppressor of kainate toxicity. 1-Amino-3-methylcy-clobutanecarboxylic acid has been identified in seeds of Atelia glazioviana Baillon, though without information on its stereochemistry.

Cycasindene (7; see also Ref. 974) and cycasthioamide (8) have been found, together with eight known ‘non-protein amino acids’, in seeds of Cycas revoluta Thunb. Fruiting bodies of Clavulinopsis helvola contain cis-DL-2-amino-3(cis), 5-hexadienoic acid. Root bark of Calotropis gigantea produces giganticine (9) which functions as an insect antifeedant.

3.3 New Amino Acids from Hydrolysates – Dysidea herbacea contains (10), composed of two unusual α-amino acids, and is accompanied by a closely related

dioxopiperazine (CHC12 in place of CC13), also found as the bis-N-methyl homologue dysamide D (10, NMe in place of NH, >CHCH2- in place of >C=CH-), in Dysidea fragilis. (-)-Phenylahistin, (11), from Aspergillus ustus, is a prenylated dehydrohistidine derivative. A review covers the identification of P-(methylthio)aspartic acid as a novel post-translationally modified amino acid in ribosomal protein S12 from E. coli.

Oscillaginin B, a tetrapeptide from the freshwater toxic cyanobacterium Oscillatoria agardhii contains the new amino acid, 3-amino-10-chloro-2-hydroxydecanoic acid. Fischerellin B [(3R,5S)-3-methyl-5(E)-pentadec-5-ene-7, 9-diynyl)pyrrolidin-2-one], a new algicide from the cyanobacterium Fischerella muscicola, is the lactam of a δ-amino acid.

4 Chemical Synthesis and Resolution of Amino Acids

General reviews of amino acid synthesis are located in the appropriate subsections of this Chapter. More specific reviews relate to preparations of coded α-amino acids labelled with stable isotopes (2H, 13C, 15N, and 18O). Examples throughout this Chapter describe preparations and uses of amino acids labelled with 2H (Refs. 51, 221, 539, 543, 553, 566, 576, 584, 586, 806, 967), 11C (Refs.113, 162, 805, 839), 13C (Refs. 219, 221, 229, 442, 443, 538, 586, 781), 15N (Refs. 228, 229, 442, 444, 547, 966), 17O (Ref. 586), 18F (Refs. 162, 260, 261, 913), 35S (Ref. 893), 77Se (Ref. 832) and iodine isotopes (Ref. 910). Preparations of amino- boronic and aminophosphonic acids are likewise scattered through Section 4, rather than grouped together as in recent previous Volumes.

4.1 General Methods for the Synthesis of α-Amino Acids, including Enantioselective Synthesis – 4.1.1 Amination of Alkanoic Acid Derivatives by Amines and Amine-related Reagents. – These processes provide reliable routes to α-amino acids in many cases. They are illustrated in their simplest form in the conversion of chiral α-bromoacrylates into cis- and trans-1H-aziridinecarboxylates (12) through Michael-type reactions with ammonia, and in the synthesis of methyl aziridine-2-carboxylate from methyl 3-(2,2,2-trimethylhydrazino) propionate bromide through N-N-bond cleavage; in the reaction of dehydroascorbic acid with cyanate to give the amino acid carbamate (13) present in Solanum tuberosum; and for the rhodium(II) acetate-catalysed decomposition of diazoacetates in the presence of compounds containing N-H groups [α-phenyl diazoacetate or PhC(N2)P(O)(OMe)2 giving N-substituted phenylglycines or corresponding phosphonates respectively]. 2-(N-Trifluoroacetylamino)alkanoic acids are formed from trifluoroacetamide and a 2-bromoalkanoate in the presence of a base, using phase-transfer catalysis.

Some simple nitrogen species that are suitable for the task are indicated in these preceding examples. Azidolysis is also convenient, an interesting example starting with α-alkenyl N-Boc oxazolidines and leading via an epoxy-bromocyclo-carbocation (formed by reaction with NBS) to β-aminoalkanols through azidolysis, and completed through routine elaboration. Epoxidation of E-but-2-en-1-o1 with tert-BuO2H using L-(+)-di-isopropyl tartrate – titanium isopropoxide, followed by C2H3Li-LiI opening, mesylation, and azidolysis are the main steps in a synthesis of (2S,3S)-4,4,4-[2H3]valine, and mesylate displacement by azide is also featured in a route to (2S, 1’S,2’S)-2-(carboxycyclopropyl)glycine (see also Ref 271). The L-lysine keto-amide derivative BocNH(CH2) 4CH(NH2)CO-CONHPh has been prepared similarly by oxirane ring-opening azidolysis, and nucleophilic opening of the epoxide formed from 4-TBSO-C6H4 CH(OH)-CH=CH2 is the crucial step in a synthesis of (2S,3R)-β-hydroxytyrosine. A new procedure for the reductive transformation of azido esters into N-Boc-amino acid derivatives using Pd(OH)2-C, EtSi3H and Boc2O in ethanol has been outlined. Mitsunobu azidolysis of the homochiral secondary alcohol TolS(O)CH-2CH(OH)CH2F followed by sulfoxide cleavage through non-oxidative Pummerer rearrangement gives 3-fluoro-D-alanine.

(Ethoxycarbonyl)nitrene, produced through photolysis in situ of ethyl azido- formate, reacts with β-silylated silyl ketene acetals RCH(SiMe2Ph)CH=C-(OMe)OSiMe2 But to give preferentially anti-β-silylated α-N-(ethoxycarbonyl-amino) esters. Full details are available 58 describing the preparation of N-substituted 3-alkyl-aspartic acids (Vol. 29, p. 13) through conjugate addition of amines to fumaric acid under catalysis by β-methylaspartase.

Enantioselective electrophilic amination by di-tert-butyl azodicarboxylate (S:R-ratios ranging from 90:10 to 95:5) of an achiral N-acyloxazolidin-2-one ( cf Scheme 5; H in place of Ph and R), is efficiently catalysed by (14), prepared from the bis-sulfonamide and dimethylmagnesium. The use of this amination reagent, applied to preparation of α-amino-β-hydroxy acids from β-hydroxyester enolates, has been reviewed. Palladium(0)-catalysed allylic amination of homochiral allyl acetates by simple amines, followed by oxidation, gives arylglycines and glutamic acid derivatives.

Oxime ethers of 2-furyl ketones Bz1ON=CR 1R2 (R2 = 2-furyl) undergo enantioselective alkylation with a homochiral boron complex, the furan moiety providing the carboxy group in the final stage of a novel α-amino acid synthesis (a route whose expense may be justified in certain circumstances). A more straightforward method (see also Ref. 879) uses an O-benzyloxime (α-alkylation using an organolithium compound leading to αα-dialkylglycines; Scheme 1). The (R)-O-(1-phenylbutyl) ether of cinnamaldoxime has provided the substrate for alkylation using an organolithium compound in a diastereoselective synthesis of α-amino acids. A proton shift induced by NEt3 in the homochiral imine (15) starts a route to βββ -trifluoro-L-alanine. Nitrones formed from aldoximes (e.g. from the protected L-gulose oxime, 16 in Scheme 2) have served in a synthesis of the N-terminal component ofNikkomycin Bz.

A common feature of many of the preceding examples is their dependence on a supply of αhalogeno-acids and analogues, and a route to ex-halogeno-amides from cm-dicyanoepoxides by reaction with a tertiary amine hydrohalide is notable. Mitsunobu condensation of Me3Si(CH2) 2SO2 NHCO2But and a chiral cyano-hydrin provides protected α-amino nitriles that are readily converted into aamino acids.

Electrophilic amination of chiral amide cuprates [from RCH2COX (X = chiral amide moiety) with nBuLi/CuCN] by lithium tert-butyl N-tosyloxycarbamate illustrates further the improving prospects for carbamates as amination reagents in amino acid synthesis. Benzyl carbamate serves in a route to 1-(Z-amino)-2-arylmethyl phosphinates ZNHCHArP(O(Ph)R through condensation with ArCHO and dichlorophenylphosphine with acetyl chloride, and in an equivalent route to phosphonates using an alkoxydichlorophosphine; phenylα(Z-amino)benzyl phosphonates ZNHCHArP(O)(OH)OPh are obtained similarly.

N-(Arene- or methanesulfonyl)aziridinecarboxylates formed as above (see also Refs. 281, 282) can undergo PdL4-catalysed isomerization (L = ligand) as detailed in a study of five sets of four stereoisomers. The expected higher stability of chiral alkyl (2E)-4,5-cis-(2E)-products, compared with their isomers, was established in this study. β-Erythro-substituted aspartic acids can be obtained through stereospecific nucleophilic ring-opening of dimethyl aziridine-2,3-dicarboxylates, and hydrogenolysis of an aziridine to give (2S,3S)-(-)-3-methylphenylalanine has been described (Ref. 281). tert-Butyl (2R,3R)-2-cyano-3-formylaziridine-1-carboxylate has been obtained from the glyceraldehyde acetonide (17). Further examples of ring-opening of 2H-azirin-3-amines (18; formed from N-methylanilides using LiNPri22/DPPCI), e.g. with PhCOSH, leading to heterocyclic α-amino acid derivatives, have been reported (cf Vol. 29, pp. 6, 22).

Both syn- and anti-β-methyl-L-phenylalanines have been prepared starting from (2S,3S)-2,3-epoxy-3-phenylpropan-1-o1, ring-opening with Me2CuCNLi2, then mesylation and azidolysis being followed by routine functional group development.

The classical Strecker and Bucherer-Bergs syntheses are also amination processes, illustrated for the former in preparations of (R)-N-Boc-3,5-dichloro-4-methoxyphenylglycine, and for the latter with syntheses of ‘3-phosphonocyclobutyl amino acids’ (i.e. 1-amino-3-diethylphosphonocyclobutane-1-carboxylates) from the corresponding cyclobutanone. (+)-2-Aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (a potent and selective Group 2 mGluR agonist) has been prepared by cyclopropanation of cyclopentenone (19) and Bucherer-Bergs synthesis. 4-Aminocyclohexanones have been converted into N,N’-Boc-hydantoins by the Bucherer-Bergs procedure followed by treatment with Boc2O, also the basis of preparations of 1-aminocycloalkanecarboxylic acids (see also Section 4.4) and α-methyl-(4-carboxyphenyl)glycine.

The asymmetric Strecker synthesis has been illustrated in an intramolecular version for syntheses of both enantiomers of α-benzyl and α-carboxymethyl-serine, and for an improved synthesis of ‘L-cyclopentylaspartic acid’ [(S)-1-(2α-aminocarboxymethyl)-l-carboxycyclopentane] via the (S)-cr-methylbenzylamino nitrile (20) on a large scale.

The amination by pyridoxamine of an cr-keto acid is a classical biogenetic route to amino acids, a fact that has stimulated a search for a laboratory equivalent, seen in the generation of glutamic acid using the pyridine reagent (21) covalently bound to the cysteine residue (Cys-60) of intestinal fatty acid-binding protein IFABP (cf Vol. 29, p.13). The amination rate is 62 times faster than that effected by pyridoxamine itself. Amination of α-keto-acids has also been illustrated for tert-leucine with an adaptation of the Leuckart reaction (Scheme 3), and for syntheses of vinylglycines using a modified Mannich reaction (Scheme 4) and α-aryl and α-heteroarylglycines.

(Continues…)Excerpted from Amino Acids, Peptides, and Proteins Volume 30 by J.S. Davies. Copyright © 1999 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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