Amino Acids, Peptides and Proteins Volume 32

A Review of the Literature Published during 1999

By J.S. Davies

The Royal Society of Chemistry

Copyright © 2001 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-232-6

Contents

Chapter 1 Amino Acids By Graham C. Barrett, 1,
Chapter 2 Peptide Synthesis By Donald T. Elmore, 107,
Chapter 3 Analogue and Conformational Studies on Peptides, Hormones and Other Biologically Active Peptides By Anand S. Dutta, 163,
Chapter 4 Cyclic, Modified and Conjugated Peptides By J.S. Davies, 287,
Chapter 5 Current Trends in Protein Research By Jennifer A. Littlechild, 342,

CHAPTER 1

Amino Acids

BY GRAHAM C. BARRETT

1 Introduction

The literature of 1999 is covered in this chapter, which aims to report and appraise newly-published chemistry of the amino acids, with some biological aspects covered to provide clarification of the chemical content of particular studies. A few references deal with literature appearing a little earlier (from late 1998)and also into the early part of 2000.

Literature citations forming the basis for this chapter have been found through Chemical Abstracts (Volume 130, Issue no. 11 to Volume 132, Issue no. 9 inclusive), and from searches of major journals that are favoured by authors of relevant material.

Excessive fragmention by authors and lax refereeing is responsible to a significant extent for the ever-increasing number of references for this chapter. This chapter’s policy for dealing with papers reporting obvious results, is to group such papers together without detailed comment on any of them. Conference proceedings are not covered in detail and the patent literature is excluded.

As usual, the carboxylic acid grouping is understood to be implied by the term ‘amino acid’ for the purposes of this chapter, though interest in boron and phosphorus oxyacid analogues, and also in sulfonic acid analogues, is continuing to grow. Methods applicable for the synthesis of α-aminoalkane-boronic acids, α-aminoalkanesulfonic acids, and α-aminoalkanephosphonic acids and other phosphorus oxyacids are usually extensions of standard methods in the amino carboxylic acid field, and representative examples of syntheses of amino oxyacid analogues are mixed in with corresponding methods for amino carboxylic acids in appropriate locations in this chapter.

2 Textbooks and Reviews

Most of the relevant material under this heading is mentioned in later sections of this chapter. The following sources are listed here where more general topics within amino acid science are reviewed.

Textbooks covering amino acids to a significant extent include protein reviews, plant amino acids, peptides, and metabolism.

Reviews have appeared, of roles for D-aspartic acid in animal tissues, glycine transport systems, biotransformations, PNA, and selenocysteine, the twenty-first coded amino acid. Recommended 1- and 3-letter abbreviations for selenocysteine are U and Sec, respectively (a website, http://www.chem.qmw.ac.uk/iupac/Amino Acid/, is available for all current IUPAC IUB amino acid and peptide nomenclature pronouncements).

Some interesting amino acid papers that do not fall naturally into a section in this chapter are located here. The seventh paper in an idiosyncratic series on orismology (the science of defining words)suggests that the trivial amino acid names have an effect in stimulating research. More important is an unexplained finding that amino acid infusion of a patient during general anaesthesia induces thermogenesis and prevents post-operative hypothermia and shivering, and hospitalization may thereby be shortened.

3 Naturally Occurring Amino Acids

3.1 Occurrence of Known Amino Acids. – This section reports unusual contexts in which known amino acids appear, and these reports can include the most familiar amino acids – glycine as its N-[3-(D-13′-methyltetradecanoyl-oxy)-15-methylhexadecanoyl] derivative constitutes more than 5% of the lipids of Cyclobacterium marinus, and serine appears in UK-2A (1) from Streptomyces sp. 517-02. Ethiin (alias S-ethyl-L-cysteine sulfoxide)has been found for the first time in alliin. Justiciamide (2), an amide of (2S,4S)-threo-γ-hydroxyglutamic acid found in Justicia ghiesbreghtiana, is in the same category of novel derivatives of known amino acids, as is N-acetyl aminomalonic semialdehyde AcNHCH(CHO)CO2H shown to be the acetyl derivative of the ‘lost C3 fragment’ that is a side-product in the biosynthesis of thyroxine (rather than dehydroalanine, as accepted for more than 50 years).

2-Amino-3-cyclopropylbutanoic acid accompanies the known 2-amino-5-chloropent-4-enoic acid in the toxic fungus Amanita castanopsidis. (R)-β-DOPA (3)constitutes 2i of the dry weight of the mushroom Cortinarius violaceus in the form of its iron(III)complex.

The betaine solorinine (4) previously located in the Canadian lichen Solorine crocea, is now shown to be widespread in Pettigeraceae, accompanied in Pettigera praetextata by its homologue (NMe2 instead of NMe3+).

Dehydrotryptophan appears in the form of its dioxopiperazine, dipodazine, in Penicillium dipodomyis and Penicillium nalgiovense. The easy formation of the 2,2′-bi-indole grouping established for the reaction of tryptophan with an aldehyde is seen in the ditryptophan crosslink, a prominent feature of the fascaplysins. Cysteine sulfenic acid occurs in proteins and provides an unusually stable example of this fleeting sulfur functional group.

3.2 New Naturally Occurring Amino Acids. – The claim to have isolated (2,5-dioxo-4-imidazolidinyl)carbamic acid (5) from Cistanche deserticola Y. C. Ma requires some reconsideration for the predictable instability of this structure (carbamic acids are recognized to be artefacts created during isolation procedures and α-aminoglycine derivatives are easily hydrolysed). Uncertainty should not however surround the claims for dysibetaine (6), a new α,α-disubstituted α-amino acid from the marine sponge Dysidea herbacea, and (—)-dysiherbaine (7; see also ref. 268) from the same source. The Caribbean sponge Plakortis simplex produces (S)-2-amino-4-ethylpent-4-enoic acid.

Novel bromotyrosine derivatives (8, 9) from the sponge Aplysina cauliformis possess cytotoxic properties.

3.3 New Amino Acids from Hydrolysates. – Acylated or amidated versions of new amino acids are covered in this section, whether or not the reported work actually included hydrolysis of the derivatives to the parent compounds. Peptides and depsipeptides are the usual source of these new amino acids, and polyoxypeptins A and B from a Streptomyces sp. (which show potent apoptosis-inducing properties)are notable not only in containing (2S,3R)-3-hydroxy-3-methylproline in the former compound, but other unusual amino acids also (3-hydroxyleucine, N-hydroxyvaline, N-hydroxyalanine, piperazic acid, 5-hydroxyhexahydropiperazine-3-carboxylic acid). The cyclic dipeptide (—)-indolactam (10) from Streptomyces blastmyceticum has been characterized.

Higher homologous amino acids are well represented. Five ψ-cyclotheon-amides (new cyclic peptides from the marine sponge Theonella swinhoei), contain α-ketohomoarginine and vinylogous tyrosine moieties, and are effective as serine protease inhibitors. Zelkovamycin from Streptomyces sp. 1454-19 is a cyclic peptide containing several unusual features. Aeshynomate (11) is a derivative of a new γ-amino acid from Aeshynomene indica L.; calvine (12) with its 2-epimer (13) derives from the ladybird beetle (Calvia); and the 11-membered ring (14) is a component of the alga Sargassum vachellianum.

Cyclopentenosine (a new trifunctional crosslinking amino acid from elastin hydrolysates)is a cyclopent-2-en-1-one and αβ,γδ-unsaturated aldehyde, and its imine-enamine tautomers and enantiomers, formed from three allysine residues.

4 Chemical Synthesis and Resolution of Amino Acids

Sections 4 and 6.3 of this chapter should be consulted by readers seeking syntheses of particular amino acids, but a considerable degree of cross-referencing has been included to aid searches.

Several reviews of standard syntheses, most of them lacking depth and critical appraisal, have been published: general surveys, synthesis of aspartic acid β-semi-aldehyde, uses of β-lactams in syntheses of α- and β-amino acids, synthesis of pipecolic acids and derivatives, synthesis of lipidic amino acids, large-scale synthesis of non-natural amino acids employing enzymes, and syntheses of γ-aminobutyric acid analogues.

Discussion of isotopically-labelled amino acids is distributed throughout this chapter: syntheses of [2H]-, [11C]-, [13C]-, [15N]-, [18F]-, [99mTc]-, and [128I]-isotopomers are represented.

Syntheses of phosphorus oxyacids and sulfur oxyacids are located in sections determined by the underlying functional group chemistry.

4.1 General Methods for the Synthesis of α-Amino Acids, Including Enantio-selective Synthesis. – The various approaches are grouped into conventional categories as in preceding Volumes, and most of the papers are merely listed or given only brief comment where no new methodology is involved.

4.1.1. Amination of Alkanoic Acid Derivatives by Amines and Amine-related Reagents The standard Gabriel reaction protocol applied to the reaction of fluoroarylamines and methyl α-bromoisovalerate under phase-transfer catalysis conditions yields corresponding N-arylvalines. Another down-to-earth study describes continuous production of glycine from monochloroacetic acid through catalysed ammonolysis. α-Halogeno-α-phenylselenoesters give 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid esters through Lewis acid-catalysed reaction with N-toluene-p-sulfonyl-β-phenylethylamines.

Further examples of aminolysis by benzylamine of α-halogeno-esters Br(CH2)3CHBrCHRCO2Et exploiting kinetic dynamic resolution (Volume 31, p. 7) achieve diastereoisomeric excesses of 98i (and no less than 85%). Reaction of ammonia with chloroform and an aldehyde [RCHO [right arrow] H3N+ CHRCO2-] can be guided to favour one enantiomer when β-cyclodextrin is present.

More roundabout, but still simple, amination procedures start with ketones via oximes (leading to β-alkoxy-α-amino acids) and insertion of a carbene into an N-H bond (Scheme 1). Diethyl azodicarboxylate as aminating agent for enolates of (S,S)-(+)-pseudoephedrine amides ArCH2CONHCHMe CH(OH)Ph gives good stereoselectivity.

A review has appeared of amination of silyl enol ethers and glycal derivatives by a nitridomanganese complex. Cyanate as aminating species is featured in conversion of dehydroascorbic acid into (15), an unusual reaction product that releases cyanate when in alkaline solution (this corrects the information in an earlier abstract used to obtain material in Volume 30, p. 5). Prochiral malonates subjected to pig liver esterase-catalysed hydrolysis give half-esters from which an α-hydroxymethyl α-amino acid (e g. the myriocin precursor in Scheme 2)may be obtained using cyanate. Analogous treatment of diisopropyl α-chloroacetoxyphosphonates prepared from aliphatic aldehydes and lipase resolution gives phosphonic acid analogues of coded L-amino acids (valine, leucine, isoleucine, methionine)and α-amino-butyric acid. 1-Amino-2-hydroxypropanephosphonic acid and 1-amino-2-hydroxy-2-phenylethanephosphonic acid have been prepared.

Conversion of methyl α-bromo-esters into corresponding azides en route to α-amino acids continues to be a popular approach, radical bromination of carbohydrate C-glycosides giving tetrahydrofuran-based α-amino acids. Preparation of α-azido-esters through epoxide opening (Scheme 3), also applicable to the preparation of α-azidovinyl esters, e g. PrnCH=CH(N3)CO2Et when using diphenyl phosphoroazidate, emphasizes the favoured regio-selectivity for the process. α-Azido-β-ketoesters (16 in Scheme 4) undergo Schmidt rearrangement accompanying Bu3SnH reduction, unusually involving radical intermediates.

Asymmetric aminohydroxylation of alkenes gives β-aminoalkanols (eg. the synthesis of the Abbott aminodiol)from which corresponding α-amino acids may be obtained, illustrated in preparations of phenylglycines and phenylalanines (17 and 18 respectively)designed as conformationally restricted L-arginine analogues. The enantioselectivity of the (DHQ)2-AQN amino-hydroxylation system is dependent on the structure of the αβ-unsaturated aryl esters which the methodology has been applied. Uses of the reaction have been reviewed.

Aldols from chiral aldehydes and (4-methylphenylthio)nitromethane give oxiranes through oxidation with a metal alkyl peroxide, aminolysis giving α-amino acid thiolesters, also obtainable from N,N-disubstituted 2-amino-alken-2-als R1CR2=C(NR32)CHO through addition of a thiol through an unusual 1,3-shift of the initial 1,2-adduct.

(R)-2-Methylglycidol is the starting point for a synthesis of (S)- and (R)-N-Boc-α-methyl serinal acetonides (Scheme 5), which can be used to prepare (R)- and (S)-α-methyl-α-amino acids respectively without racemization, through Wittig reaction with Ph3P+Me Br- and hydrogenation. Related ring-opening syntheses include conversion of 2-methylaziridine-2-phosphonic acid esters into α-amino-α-methylphosphonic acids (including α-methyl-‘phosphono-phenyl-alanine’), and corresponding use of homochiral N-toluene-p-sulfinylaziridine-2-phosphonates, and reductive opening of homochiral substituted aziridine-2-carboxylates (polymethylhydrosiloxane-Pd/C). A route from β-enamino esters to α-amino-β-esters through reaction with ethyl N-[(4-nitrobenzene-sulfonyl)oxy]carbamate is thought to involve an aziridine intermediate. Conversion of N-Boc-oxaziridines into α-aminoketones proceeds with moderate enantiomeric purity through reaction with α-silyl ketones (Scheme 6).

4.1.2 Carboxylation of Alkylamines and Imines, and Related Methods Control by the N-protecting group permits (—)-sparteine-catalyzed reaction of BzlN(SiR3)CO2Me with EtMeCHLi and carboxylation with CO2 to give either enantiomer of phenylglycine. Direct asymmetric α-carbalkoxylation of an amine, using an enantiopure carbonate as a chiral CO2 synthon for ring-opening an achiral zircona-aziridine derived from Cp2ZrCl2, exploits the dynamic kinetic resolution principle, and leads to α-amino acid esters in good enantiomeric purity (Volume 29, p. 7).

Reaction of an N-benzylimine with methyl chloroformate gives the corresponding amino acid ester, used for preparation of 9-aminofluorene-9-carboxylic acid and the 4,5-diaza-analogue. Analogous use of a chiral sulfur imine (19 or 20) with a metal phosphite leads to α-amino phosphonic acids. Alkylation at a methylene group adjacent to imine and chiral sulfoxide groupings in R1OCH2C(=NR2)CH2S(O)Tol offers the opportunity for general α-amino acid synthesis, illustrated for 4-substituted 2-aminoadipic acids.

Alkylation of amines by nitromethane and alkaline permanganate oxidation of the nitromethyl derivative is an indirect carboxylation process that is clearly limited to substrates that can withstand these conditions.

4.1.3. Use of Chiral Synthons in Amino Acid Synthesis Whereas chiral auxiliaries feature frequently in syntheses of α-amino acids, and are also covered in other sections, some have become identified with routes to amino acids through the names of their creators, and are covered here. Although these synthons are usually glycine derivatives, their use is covered here because papers describing the use of simple glycine derivatives in amino acid synthesis are covered in section 4.1.7.

The standard Schollkopf route employing a cyclized L-valylglycine [an ‘R)- or (S)-2-isopropyldiketopiperazine’] or a 3,6-dialkoxy-dihydropiperazine (a ‘bislactim ether’) derived from it by O-alkylation is illustrated for syntheses of 5-hydroxylysine, 3-(R)- and (S)-carboxyphenyl-(S)-prolines, 2-(3′-alkyl-2′-carboxycyclopropyl)glycine, the biphenylene analogue (21) of phenylalanine and its benzocyclobutane analogue, (2S)-2-amino-3-(1H-indol-4-yl) propanoic acid, the β-hydroxy-α-amino acid obtained from (22) using the lithium azaenolate of the bislactim ether, en route to 1-deoxygalactostatin, (2S,3R)-β- hydroxy-3′-isopropenyltyrosine, (—)-sparteine-catalysed aldolization of ethyl 3,6-diethoxy-2,5-dihydropyrazine-2-carboxylate in highly enantioselective fashion, use of a 2-(3-trimethylsilylethyn-1-yl) bislactim ether for substituted tryptophan synthesis. Variants of the process are represented in aldolization of the N-[(S)-2-phenylethyl] synthon (23) to give β-hydroxy-α-amino acids and in conjugate addition of organocuprates to the dehydroalanine homologue (3S)-N,N’-bis(p-methoxybenzyl)-3-isopropyl-6-methylenepiperazine-2,5-dione (24). A particularly interesting use of the latter approach establishes moderate to high diastereoselectivity in addition reactions of carbon radical species. The leaving group of the electrophile used in Schollkopf bislactim ether alkylation affects the diastereoselectivity of the process, with diphenyl phosphate best in this context, compared with tosylate and bromide.

(Continues…)Excerpted from Amino Acids, Peptides and Proteins Volume 32 by J.S. Davies. Copyright © 2001 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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