Amino Acids, Peptides and Proteins Volume 31

A Review of the Literature Published During 1998

By J.S. Davies

The Royal Society of Chemistry

Copyright © 2000 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-227-2

Contents

Chapter 1 Amino Acids By Graham C. Barrett, 1,
Chapter 2 Peptide Synthesis By Donald T. Elmore, 120,
Chapter 3 Analogue and Conformational Studies on Peptides, Hormones and Other Biologically Active Peptides Anand S. Dutta, 174,
Chapter 4 Cyclic, Modified and Conjugated Peptides John S. Davies, 285,
Chapter 5 Metal Complexes of Amino Acids and Peptides E. Farkas and I Sóvágó, 336,
Chapter 6 Current Tends in Protein Research By Jennifer A. Littlechild, 413,

CHAPTER 1

Amino Acids

BY GRAHAM C. BARRETT

1 Introduction

The literature of 1998 relating to the amino acids is covered in this Chapter, which is based on the chemistry literature mainly, and on related biological studies. The format used in all preceding Volumes of this Specialist Periodical Report is adopted. Some economies, introduced last year to save space, are continued. These do not affect the depth of coverage, but there are fewer subheadings so that some topics, previously grouped on their own, have been combined more economically with other material.

Literature coverage is based on information from Chemical Abstracts (Issue 10 of Volume 128 to Issue 9 of Volume 130 inclusive), and scanning the major Journals. The literature continues to expand. The accusation that much of the primary scientific literature is of declining quality could be recast in less provocative language so as to become more acceptable (in the context of the present Chapter: the accusation could be ‘too many fragmented reports, too many papers describing predictable outcomes of well-known reactions and obvious properties of amino acids’); but nevertheless, most of the new experimental detail published on amino acids is actually needed by researchers.

2 Textbooks and Reviews

A recent monograph deals with the synthesis of derivatives of amino acids. Reviews covering synthesis include: uses of L-amino acids in synthesis, uses of L-pyroglutamic acid for the synthesis of alkaloids and other natural products. Further reviews covering synthesis, reactions and properties of amino acids are located in appropriate sub-sections of this Chapter.

Mycosporins and excitatory amino acids, occurrence and physiological role of D-amino acids, and L-cysteine metabolism and toxicity have been reviewed.

The nomenclature of amino acids and their approved abbreviations have been surveyed.

3 Naturally Occurring Amino Acids

3.1 Occurrence of Known Amino Acids – Among the non-routine topics that this Section covers, is the location of amino acids in extra-terrestrial samples, bones and fossils. The significance of amino acids as biomarkers indicative of life early in the Earth’s history has been reviewed, and the uncertainty in the use of 14C data for dating bone samples through their γ-carboxyglutamic acid and α-carboxyglycine (alias aminomalonate) content has been emphasised.

The other main area under this heading, the identification of known amino acids in live organisms, is similarly restricted here to non-routine examples: the high levels of L-DOPA in seeds of Stizolobium aterrima and the presence of cis-3-hydroxy-N-methyl-L-proline in the South Australian marine sponge Dendrilla.

Unusual known amino acids condensed with other compounds to give representatives of the usual families of natural products include D-proline-containing dioxopiperazines in the sponge Calyx CF podatypa for which a correction has been published. Nε-[(R)-(1-Carboxyethyl)]-L-lysine in the form of its Nα-(D-glucuronoyl) derivative in Providencia alcalifaciens 023, γ-glutamyl-S-ethenylcysteine in seeds of the Narbon bean (Vicia narbonensis; breakdown products of this isopeptide are responsible for the repulsive odour associated with its germination), and 1-aminocyclopropanecarboxylic acid in the Streptomyces sp. metabolite cytotrienin A, provide further examples. Unusual modifications of common amino acids in peptides include D-tryptophan as a constituent of contryphans present in the venom of fish-hunting cone-snails Conus radiatus, and 6-chloro-N-methyl-L-tryptophan and N-methyl-L-tryptophan as constituents of keramamides K and L respectively, from Theonella sp. The novel indole alkaloid martefragin A (1) present in the red alga Martensia fragilis, is the result of an unusual in vivo elaboration process applied to Nα-L-isoleucyl-L-tryptophan.

3.2 New Naturally Occurring Amino Acids – Previously-known (2RS)-2-amino-4,5-hexadienoic acid and (2S)-2-amino-4-hexynoic acid accompany new natural products (2R)-2-amino-6-hydroxy-4-hexynoic acid and (2S)-2-amino-5-chloro-5-hexenoic acid in fruit bodies of Amanita miculifera. A novel lysine relative (2) has been identified in the Micronesian marine sponge Axinyssa terpnis. Ascaulitoxin is an unusual phytotoxic bis(amino acid) N-glucoside (3) that has been isolated from Ascochyta caulina.

3.3 New Amino Acids from Hydrolysates – As usual, this section collects papers that describe reports of new amino acids condensed with other compounds: into dioxopiperazines, e.g. mollenines A and B (4) from the sclerotoid ascostromata of Eupenicillium molle, and into peptides: the potent trypsin inhibitor, dehydroradiosumin (5) from the freshwater cyanobacterium Anabaena cylindrica, eurypamide A and three related cyclic tripeptides in the Palauan sponge Microciona eurypa, containing iodotyrosine and (2S,3S,4R)-3,4-dihydroxyarginine, cyclolinopeptide CLX from linseed that contains N-methyl-4-aminoproline, 27 hibispeptin A (6) from the root bark of Hibiscus syriacus, that contains a novel homophenylalanine derivative (stereochemistry not yet defined), and 3-amino-6-hydroxystearic acid in nostofungicidine from the terrestrial blue-green alga Nostoc commune.

(2S,3R)-3-Hydroxy-3-methylproline is a new natural product, a component together with other unusual α-amino acids of the carcinoma apoptosis-inducing polyoxypeptin.

A novel protein crosslink found in bovine dentin, together with dihydroxy-lysinonorleucine and hydroxylysylpyridinoline, consists of a pyrroleninone carrying three amino groups and three carboxy groups.

4 Chemical Synthesis and Resolution of Amino Acids

This Section is subdivided so as to collect current papers describing new examples of applications of each of the major general amino acid synthesis approaches. These methods are mostly well-established, though many improvements are to be found in the small print of these papers. Some newly-introduced synthesis methods are described.

As in last year’s Volume, syntheses of isotopically-labelled coded amino acids are not collected in a separate subsection, but are spread throughout the Chapter: 2H, Refs. 98, 370, 599, 945, 946, 1034, 1097; 3H, Ref. 1105; 11C, Ref. 161; 13C, Refs. 122, 124, 126, 131, 599, 1098; 14C, Refs. 123, 1105; 15N, Refs. 122, 124, 131, 160, 235; 18O, Ref. 599; 18F, Refs. 1011, 1038; 128I, Ref. 1035.

General reviews of synthesis methods applied to α-amino acids have appeared: asymmetric synthesis, general strategies of synthesis of α-amino acids and α-methyl-α-amino acids, use of sulfinimines in asymmetric synthesis, 2-(α-aminoalkyl)thiazoles as masked α-aminoaldehydes, and use of the Mitsunobu reaction.

4.1 General Methods for the Synthesis of α-Amino Acids, Including Enantio-selective Synthesis – 4.1.1 Amination of Alkanoic Acid Derivatives by Amines and Amine-related Reagents – Descriptions of simple syntheses of common amino acids are to be found in the recent literature, and some of these emerge from the continuing fascination of prebiotic amino acid synthesis (Section 4.5). α-Phenylglycine, H3N+CHPhCO2-, is formed from the reaction of phenylacetic acid with Br2 and NH3, and 3,5-dihydroxy-4-methoxybenzaldehyde leads on to the correspondingly-substituted phenylglycine through reaction with ammonia and toluene-p-sulfonyl cyanide (Strecker synthesis, see also Section 4.1.6).

Palladium(O)-catalysed azidation of (2S)-1-ethoxycarbonylmethylidine-2-methylcyclopropanes is a notable feature of a route to (—)-(1R,2S)-norcoronamic acid (Scheme 1). Similar treatment of the ex-chloroester formed by m-chloroperbenzoic acid oxidation of sugar-derived dichloroalkenes (Scheme 2) makes use of a remarkably simple C = O [right arrow] >CHCO2Me procedure.

Resin-tethered N-chloroacetyl arylamides and bromoacetates have been converted into N-alkyl glycines (for use in the synthesis of ‘peptoids’) through successive reaction with an amine and an acylating agent.

Nitrenes are seldom used in routine synthesis for amination, potential hazards possibly being a deterrent, but low yields are another factor, seen in the FeCl2-catalysed amination of ketene acetals by Boc-azide.

Amination of aldehydes to give imines has long been a reliable method of introducing a nitrogen function as a substituent on a carbon chain, and in the special case of glyoxylic acid some useful amino acid syntheses have been established. One-pot processes starting with this step can be developed in a number of ways depending on other reagents; the formation of a ternary iminium salt (Scheme 3) from the intermediate aminal is a key step in the synthesis of syn,anti- or anti,syn-δ-hydroxy-α-amino acids. Some inspired reasoning in mechanistic organic chemistry is needed to explain how cis-2-butenedial held at 435 K for 6 h in aqueous ammonia is converted into aspartic acid.

Homochiral bis(sulfinyl)oxiranes (7) are masked forms of ketones that can be aminated to give α-amino acid amides, announced as a new asymmetric synthesis.

Amination of 3-nosyloxy-2-ketoesters with methyl carbamate and reduction of the resulting 4-alkoxycarbonyloxazolin-2-ones gives α-amino acid esters, but hydrogenation is sluggish. Reductive amination of α-ketoesters represents a one-pot introduction of an alkylamino group without isolation of the intermediate imine, and treatment of simple pyruvates with Na(OAc)3BH and phenylethylamine, and similar treatment of structurally complex homologues (protected α-D-galactohexodialdo-1,5-pyranoses [right arrow] 8) has been described. The trifluoroalanine analogue CF3CH(NHR1)P(O)(OR2)2 has been prepared in this way. (p-Methoxybenzoyl)acrylic acid PhCH2COCH=CHCO2H adds (S)-phenylethylamine to give the L-homophenylalanine derivative in poor diastereoisomeric excess (ca 10%), but gives enantiomerically pure product through equilibration, presumably involving dynamic resolution.

β-Keto-esters undergoing α-oximation and reduction to the α-amino-β-ketoester stage, and then asymmetric hydrogenation, have been converted into syn- and or anti-β-hydroxy α-amino acids, e.g. Pht(CH2)3CH(OH)CH(NH2)-CO2H. Exploitation of dynamic kinetic resolution in the last step led to a quantitative yield of the syn-isomer, (2S,3R)-3-hydroxylysine, after deprotection.

‘Intramolecular amination’ gives a title to the phenylselenium-induced lactamization of Nalpha-(alk-2-enoyl) L-prolinamides (9) to give both α- and β-amino acids with modest stereoselection.

Introduction of the azido group into (2S,RS)-1-(p-tolylsulfinyl)-butan-2-ol (NaN3, PPh3, CBr4) and the equivalent Mitsunobu reaction with diethyl azodicarboxylate (see also Ref. 911), gives enantiomerically pure β-amino-alkanols after routine functional group changes. Serine C-glucoside analogues that have an α-azido group masquerading as a protected amino group have been prepared from l-vinyl-D-glucosides by stereoselective [2,3] Wittig rearrangement (Vol. 30, p. 12).

The Evans approach to amino acids via amination procedures applied to N-acyloxazolidinones is illustrated in a synthesis of synthetically-useful ω-bromo-(2S)-azido acids (Scheme 4), and a further example of the same approach, used many times by Hruby’s group (Vol. 30, p. 10), giving four 2-amino-3,3-diarylpropanoic acids. C-Linked isosteres of α- and β-glycocon-jugates carrying the serine moiety have been prepared by electrophilic amination of the enolate of the Evans chiral oxazolidinone. A study of the conversion of the azido function into the Boc-amino group using the Staudinger reaction (PBu3 in the presence of Boc2O) has concentrated particularly on the side-reaction leading to ureas. The work of Evans and Nelson (1997, Vol. 30, p. 6) based on magnesium bis(sulfonamide) complexes as catalysts for merged enolization and amination of N-acyloxazolidinones has been surveyed, and a new cleavage method has been introduced that exchanges the chiral auxiliary for an alcohol moiety using lanthanum(III) iodide in an alcohol at room temperature. New data on dynamic kinetic resolution of α-haloacyl imidazolidinones accompanying amination have been collected.

Chiral 4-substituted-5,5-diaryloxazolidin-2-ones and benzosultams are readily N-acylated and can be used in the Evans way, azidation occurring with better than 95% diastereoselectivity and, no doubt, capable of improvement. For further applications of Evans methodology in the amino acids context see Refs. 142, 206, 335, 461, and 819.

A protected cyanohydrin, ROCH2CN, has appeared to be an attractive starting point for αα-disubstituted glycine synthesis for many years, through double nucleophilic addition to the triple bond, and this reaction with Grignard reagents has now been found to be promoted by titanium isopropoxide.

The enantioselective aminohydroxylation procedure improved recently by Sharpless has been shown to be a valuable stage on a route from alkenes to α-amino acids, e.g. conversion of styrenes into (R)- and (S)-N-benzyloxycarbonyl- or tert-butoxycarbonyl-arylglycinols, and the use of other alkyl carbamates in this way, and oxidation of the products to the corresponding arylglycine derivatives. Regioselection in aminohydroxylation of cinnamate esters can be reversed to give phenylserines if Cinchona alkaloid ligands with an anthraquinone core are used, or to give isoserines if the usual phthalazine ligands are used; adenine N-chloro-N-sodio salts are also suitable. The classic alternative route for aminohydroxylation of alkenes, via epoxides, is illustrated with aluminium azide as reagent. Oxidation of homochiral α-amino-β-hydroxyalkanes with CrO3 does not cause racemization. Oxazolines, readily prepared from α-amino-β-hydroxyalkanes, have uses in enantio-selective α-amino acid synthesis, and these uses have been reviewed. Alkyl carbamates have been employed for aminohydroxylation of styrenes. Conjugated dienes can be aminated through cycloaddition to diethyl azodicarboxylate, a particular example studied this year being 1,3-cyclo-octadiene; much interest in this study lies in the development of the resulting adduct into α-amino aldehydes and other useful products (Scheme 5). The bis(α-amino acid)s formed through pinacol formation are particularly notable.

Nitroalkenes are also valuable sources of α-amino acids through nucleophilic addition routes, rendered enantioselective when attached to a homochiral grouping; a (+)-camphorsulfonamide gives (10) through addition to a nitronate, and this is easily converted into the α-amino acid thiolester by ozonolysis. Further work has been reported, on addition of the potassium salt of (R)- or (S)-4-phenyl-2-oxazolidinone to nitroalkenes, followed by oxidative conversion into nitromethyl into carboxyl and oxazolidinone cleavage, giving D- and L-amino acids respectively.

α-Ethoxycarbonylaziridines are conveniently prepared from αβ-unsaturated esters, e.g. using Phl=NSO2Ar, and syntheses of α-amino acid develop from these intermediates through a variety of ways; for example through nucleophilic ring opening as in the preparation of D-α-(3-phenylpropyl)glycine and D-homophenylalanine using the aziridine (11) prepared from D-mannitol; preparation of α-hydroxymethylserine derivatives (12) and (13); and D-phenylalaninol by hydrogenolysis.

4.1.2 Carboxylation of Alkylamines and Imines, and Related Methods – Processing of N-TMS-N-aryl enamines (14; Scheme 6) gives αβ-dehydroamino acids and α-carboxyimines. The insertion of imines into acyl-palladium bonds was achieved (Scheme 7), but the intended outcome, a new synthesis of amino acid amides, was not realized.

α-Amino acid thiolesters R1NHCHR2COSPh can be obtained by triftuoro-acetic anhydride-induced Pummerer rearrangement of 3,N-disubstituted 4-phenylsulfinyl-β-sultams. Homochiral toluene-p-sulfinylaziridines (15) have been carboxylated with ethyl chloroformate, the products being further developed, e.g. into N-phenyl S-α-methylphenylalaninate.

(Continues…)Excerpted from Amino Acids, Peptides and Proteins Volume 31 by J.S. Davies. Copyright © 2000 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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