Amino Acids and Peptides Volume 21

A Review of the Literature Published during 1988

By J. H. Jones

The Royal Society of Chemistry

Copyright © 1990 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-194-4

Contents

Chapter 1 Amino Acids By G C Barrett, 1,
Chapter 2 Peptide Synthesis By D T Elmore, 74,
Chapter 3 Analogue and Conformational Studies on Peptide Hormones and other Biologically Active Peptides By J S Davies, 129,
Chapter 4 Cyclic, Modified, and Conjugated Peptides By P M Hardy, 174,
Chapter 5 β-Lactam Antibiotic Chemistry By A V Stachulski, 248,
Chapter 6 Metal Complexes of Amino Acids and Peptides By R W Hay and K B Nolan, 301,

CHAPTER 1

Amino Acids

BY G. C. BARRETT

1. Introduction

The literature on amino acids, taken as a whole, includes elegant lessons in biology for the chemist, and conversely provides insights for the biologist into relationships between molecular structure and properties. It will please this Reviewer if some sense of this duality continues to be conveyed in this Chapter, which has, as usual, been confined to the occurrence, chemistry and analysis of amino acids. The Chapter is arranged into sections as used in all previous Volumes of this Specialist Periodica. Report.

Access to the literature for creating this Chapter has been by way of Chemical Abstracts (to Volume 110, issue 9) and Biological Abstracts (to issue 8 of Volume 85), supplemented by scanning major journals so as to cover adequately the literature of 1988. The abstracts coverage also nets a few citations published in 1987, and these are included to give continuity for the topic over the years in this series of Specialist Periodical Reports.

2 Textbooks and Reviews

One of the Tetrahedron ‘Symposia-in-Print’ series (which comprise collections of original research papers), is devoted to α-amino acid synthesis, describing current themes and practice in this field.’ Reviews have appeared on methionine sulphoxide and cross-linking amino acids in proteins, the latter in a Volume of that covers other amino acids in the protein context. Further reviews are cited in the relevant sections later in this Chapter.

A Russian language text originates from a research group active in the amino acids field.

3. Naturally Occurring Amino Acids

3.1 Isolation of Amino Acids.- While this would be thought of as a routine topic, there is a salutary lesson in the comparison of five different extraction methods for locri mans; the amino acid profile determined for this fungus varies widely, depending on the extraction procedure.

The adsorption of N.-acetyl cysteine from solution on to activated carbon has been described.

3.2 Occurrence of Known Amino Acids..- There is a vast and continuing literature on f amiliar amino acids in familiar biological contexts, and this is almost entirely excluded from this Chapter. This Sect ion is restricted, as in previous Volumes of this Specialist Periodical Report , to the occurrence of unusual amino acids, and other significant relevant observations.

Amino acids present in carbonaceous chondrite meteorites have been reviewed. The content of ornithine in fossil bones increases with age; 8 in samples of known age (1 100 – 37 000 years), reasonable linearity of correlation of ornithine content with age has been established, which suggests a useful method for fossil dating, as an alternative to enantiomer-ratio age determinat ion (see Section 6. 1).

The simplest amino acids continue to be found as their betaines in natural sources. Glycine betaine occurs in Echinacea pyrpyrea and angustifolia, then finds its way into pharmaceutical preparations; L-alanine betaine occurs in the marine green alga Cladgphqra. Hydroxylated analogues of simple amino acids include β-hydroxy-L-valine in fruit ing bodies of Pleurqcybella porrigens, and β-hydroxyaspart ic acid and N[??]-hydroxyornithine (with homoserine and citrulline) in pyoverdins and azotobactins. The isolation of (S)-(+)-α -methylserine in Sphagnum palustre represents the first observation of the occurrence of this amino acid in plants. α-Hydroxymethylserine occurs (with L-citrulline) in “tianhuafen”, the root tuber of Trichosanthes kirilowii.

The continuing fascination of phycobiliproteins (see Vol. 20, p. 1) from cyanobacterium Mastigocladus laminosus is expressed in the report that these contain three N[??]-methylasparagine residues. Occurrences of other relatively simple α-amino acids and analogues include 1-(malonylamino) cyclopropane-1-carboxylic acid in soya bean (Glycine sola)) seedlings, Nα-malonyl-D-tryptophan as the only D-amino acid that accumulates during wilting of tomato leaves, (S)-4-chloro-tryptophan in seed protein of the pea plant (Pisum sativum), and 4-amino-anthranilic acid in Streptomyces flocculus. The last-mentioned ‘β-amino acid’, not previously observed in Nature, is an important discovery as a part of a new shikimate pathway. Another “first observation” is of 2-acetylamino-3-hydroxy-4 -methyloct-6-enoic acid in Neocosmospora vasinfecta E. F. Smith; the amino acid itself is well known as a constituent of the peptide cyclosporin A (which is also produced by this fungus).

A careful study has established the absence (contrary to previous reports) of β-leucine in human blood.

The report of the presence of 1-amino-2-propanol in Onopordum acanthium (ca 400 mg g-1 fresh weight) and 11 other Compost tae is worth recording in this Chapter (it is not an amino acid, but is at least, close relative).

3.3 New Natural Amino Acids.– The L-ornithine-based α-amino acid ( 1 ) is a new antifungal agent (from Streptomyces violaceoniger griseofuscus Tü 2557. It is the first pyridazine discovered among microbial secondary metabolites. A compound from the mushroom Lactarius piperatus that is, at first sight, similar to ( 1 ) is, however, on closer inspection, clearly shown to be an N-alkylated L-glutamic acid (2 in Scheme 1). The n.m.r. structure determination of ( 2 ) has been verified through its straightforward synthesis from [??]-t-butyl-L-glutamic acid.

Further new amino acids showing similarities with ( 1 ), on the basis of their betaine or mixed zwitterion structures, are the hydroxyproline relative ( 3 ) and the L-methionine derivative ( 4 ). Both ( 3 ) and ( 4 ) are from marine algae; (3 ) from Grateloupia proteus, and ( 4 ) from marine Lophocladia lallemandi.

Making comparisons between amino acids on this superficial basis is not intended to indicate similarities in biosynthetic pathways, but the link between ( 2 ) and the opines [N-(α-carboxyalkyl)- α-amino acids] is less tenuous. New opines continue to be reported more frequently than many other types of α-amino acid; can a rational explanation for the ubiquity of this class of compound be the subject of much longer gestation? In addition to the recently-discovered ornithine analogue ( 5a ) produced by Streptococcus lactus cultured on an arginine-deficient medium, (2S, 8S) -N6 -(1-carboxyethyl) lysine ( 5b ) has now been detected. Among further new opines are β-alanopine, N-[(R)-1-carboxyethyl]-β-alanine ( 6 ), from the adductor muscle of the blood shell Scarpharca broughtonii; and vitopine (details absent from Chemical Abstracts source of this citation.

Full details are available for galantinamic acid ( 7 ), a component of galantin, shown to be (2R,3S,5S,6R)-6,10-diamino-2,3,5-trihydroxydecanoic acid.

3.4 New Amino Acids from Hydrolysates. – New amino acids that have been discovered as residues in peptides and proteins are described in this Section, whether or not they are actually liberated as such by hydrolysis . Even so, the section would be substantial if it attempted to cover thoroughly, for example, newly-discovered compounds with amino acid side-chain – carbohydrate covalent links (as in glycoproteins); and no such comprehensiveness is intended. An example is asparagine, glycosidically-linked to rhamnose through the side-chain amide nitrogen atom, this moiety being released on hydrolysis of the surface glycoprotein of Bacillus stearothermophilus NRS 2004/3a.

(2S,3R,5S)-3-Amino-2,5,9-trihydroxy-10-phenyldecanoic acid ( 8 ) is found (with other unusual amino acids) in hydrolysates of scytonemin A1, a novel calcium antagonist from the blue-green alga Scytonema. It is interesting to note the structural similarity between this new amino acid and 3-amino-9-methoxy-2, 6,8 -trimethyl-10-phenyldeca-4, 6-dienoic acid ( 9 ), present in cyanoginosin-LA, a cyclic heptapeptide toxin from Microcystis aeruginosa.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods for α-Amino Acid Synthesis.- The full range of standard methods of α-amino acid synthesis continues to be gainfully employed, and in some cases, usefully developed. Later sections of this Chapter, particularly the next one (4.2 ‘Asymmetric Synthesis’) and that (6.3) covering modifications of amino acid side chains

The hydroformylation – amidoalkylation procedure bas been reviewed, and has been given a thorough mechanistic study using C6F5CH=CH2 and Co2

α-Alkylation of glycine derivatives services most of the routine syntheses, diethyl 2-acetamidomalonate continuing to be favoured; among these is a notable study describing phase transfer-catalyzed alkylation ‘without solvent’

Alkylation of 2-(1-pyrrolyl>acetates ( 10 ) using an alkyl halide and lithium di-isopropylamide is a new glycine alkylation approach; however, the alkyl group introduced in this way needs to be ozone-friendly if it is to survive ‘deprotection’. The ‘other-way-round’ imines, e.g. Me3SiCH2N=CHCO2Me, are the source of azometbine ylides suitable for 1,3-dipolar cycloaddition reactions

The classical route based on alkylation of 2-pbenyloxazol-5(4H)-one (formed in situ from hippuric acid) is widely useful (e.g. in synthesis of β-di- and – trifluoromethylphenylalanines by condensation with corresponding phenyl fluoromethyl ketones, followed by reduction and hydrolysis).

α-Alkylation of an alkyl α-nitroacetate, in the various ways described above for analogous glycine derivatives, is the starting point for another general amino acid synthesis. Reduction using H2-Pt or Zn-AcOH completes the process, which, in the latter case, is part of an overall route to [??]-substituted N-acetylbutyrines through nucleophilic ring-opening of aryl 1-nitrocyclopropane-1 -carboxylates (Scheme 3).

Substitution of the halogen atom of N-benzoyl-α-bromoglycine methyl ester (see also ref.72) and the corresponding reaction with an α-methoxy amino acid, illustrate other general methods . Radical conditions with 2-functionalized allylstannanes are used in the former example, leading to [??]δ-unsaturated a-amino acids

A non-routine variant is employed in a single-step Strecker synthesis of methionine hydantoin (acrolein, ammonium carbonate, MeSH, HCN), and a classical version (a ketone R1 COR2, ammonium hydroxide or chloride, NaCN; then methacryloyl chloride, NaOH; then 12N-sulphuric acid) has been reported for the synthesis of (methacryloyl)amino acids CH2=CH2CMeCONHR1 R2CO2H.

4.2. Asymmetric Synthesis of α-Amino Acids. – Most of the methods employed are developments of standard general routes, though there seems to be no end to novelties of planning and execution. A review, with title identical with that of this Section, has appeared. Later sections of this Chapter feature specific asymmetric syntheses, using both routine and novel methods.

A rare example, amounting to asymmetric α-carboxylation of an amine, involves anodic α-methoxylation (cf. Vol. 20,p. 18) of an N-protected (S)-phenylethylamine, followed by substitution by Me3SiCN and hydrolysis, to give a mixture of L-isoleucine and D-alloisoleucine in modest optical yield. Poly[(R)-3 -hydroxybutanoate], -(CHMeCH2COO)n-, is an inexpensive starting material to which a recently-introduced amination procedure (di-tert-butyl azodicarboxylate) has been applied. This leads to D-allothreonine and L-threonine with only moderate diastereoselectivity, but conformational restriction (conversion of the starting material into a dioxanone analogue) raises this to 99. lot too distantly related, and capable of very high diastereoselectivity, are asymmetric Ugi and Strecker syntheses, employing 2,3,4,6-tetra-Q-pivaloyl-β-D-galactopyranoeyl -amine as chiral auxiliary (Scheme 5). The former route can yield enantiomerically pure D-amino acids. So does the Strecker route when the Lewis acid is ZnCl2 in propan-2-ol, or SnCl4 in THF, but the bias is towards L-amino acids using ZnCl2 in CHCl3.

Photolysis of Cr-carbene complexes ( 11 ) containing a chiral, optically-active amino -alcohol moiety, gives lactones in high yields and with high diastereo-selectivity (Scheme 6). Hydrolysis of the products gives D-amino acids with return of the chiral auxiliary.

Ammonolysis of α-keto-acids in the presence of β-cyclodextrin-functionalized pyridoxamines mimics the in vivo transaminase-catalyzed process with moderate success.

Synthesis of (S)-(-)-α-methylDOPA through an asymmetric Strecker route, and of (R)-(-)-α-methylserine and of D-serine by the ‘bis-lactim ether’ method, have been reviewed. The latter method, amounting to the asymmetric alkylation of an enolized glycine moiety, has featured in every one of the last ten or more Volumes of this Specialist Periodical Report. It is featured again this year, in a showcase of papers from the research group that invented it. Two of these reports are selected for display here, since they are both representative of the method and interesting (in different ways) in mechanistic terms (Scheme 7). In one project, (R)-N-Boc-amino-2-arylcyclopropene-1-carboxylates are formed through an asymmetric cycloaddition of a carbene to an alkyne; in the other, a bis-lactim ether-derived cuprate is added to a-unsaturated carbonyl compounds.

Further examples of diastereoselective substitution of glycine derivatives, the area in which most effort is being directed for asymmetric α-amino acid synthesis, have been reported. A paper that appeared at the end of 198865 describes a new chiral glycine enolate synthon derived from (R)-2-phenyl-2-aminoethanol (“D-2 -phenylglycinol) for asymmetric syntheses (Scheme 8). This approach is modelled on an earlier classic study which has been extended further (Scheme 9). The chiral auxiliary used for this route ( 12 ) is commercially available, and can be recycled after recovery at the end of the synthesis.

There are puzzling aspects as far as diastereoselectivity is concerned, in these studies. In the ‘asymmetric nucleophilic glycine’ approach, the N-protecting group determines the bias as shown in Scheme 8; solvent and counterion, X-, are also crucial. Similar results in the ‘asymmetric electrophilic glycine’ approach (Scheme 9) indicates that either retention or inversion accompanies substitution of the halogen atom, the anti-relationship resulting from substitution with inversion, being associated with easily crystallised products.

Alkynylstannanes Bu3SnC [equivalent to] CR1 have been used with the I-benzyloxycarbonyl analogue of ( 12 ) in an extension of the route in Scheme 9, the resulting α -alkynylglycine derivatives being susceptible to hydrogenation/hydrogenolysis (H2/Pd) to give γ-substituted D-butyrines.

The basis of these routes is not new-found, but the natural conserva ism that has made some workers reluctant to take up some of the earlier methods will be overcome by the thoroughness of studies such as these, and there should be much to report on them in future Volumes of this Report. A thoroughly-studied route with a longer history is based on the alkylation of chiral imidazolidinones (e.g. 13), and further resu 1ts have been reported, for the asymmetric synthesis of α -alkylated ornithines, lysines, and tryptophans.

An analogous approach using the N-acylated α-hydroxyglycine ( 14 ) is flawed by the requirement of an indirect cleavage method for the acyl group at the end of the synthesis if racemization is to be avoided. The use of Steglich’s α-bromo-N -Boc-glycine tert-butyl ester approach [but using the corresponding (-) -phenylmenthyl ester], represents another chiral electrophilic glycine equivalent, and has been developed further (photolysis of N-bromosuccinimide in CCl4. for introduction of the bromine atom; substitution by Grignard reagents).

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