Amino Acids and Peptides Volume 17

A Review of the Literature Published during 1984

By J. H. Jones

The Royal Society of Chemistry

Copyright © 1986 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-154-8

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 Conjugate Peptides By P. M. Hardy,
Chapter 5 β-Lactam Antibiotic Chemistry By J. Brennan,
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

Thorough coverage centred on the 1984 literature, though omitting routine biological applications and reports of the distribution of well-known amino acids, is the intention for this chapter. There is therefore continuity with preceding volumes of this Specialist Periodical Report(to which reference is occasionally made in order to help the reader put into context some recent progress reported here for an on-going topic of study).

2 Textbooks and Reviews

The 1983 recommendations for amino acid nomenclature are only a library distant, since the I.U.P.A.C.–I.U.B. Newsletter (1984) has been reproduced in major journals. The recommendations have been quickly followed by nomenclature for amino acid amides (1984).

Important compilations providing support of research work with amino acids represent the latest outputs from sources already well known for similar recent monographs. Other reviews, much less readily accessible, deal with various facers of medium- to large-scale production of amino acids.

3 Naturally Occurring Amino Acids

Occurrence of Known Amino Acids. — Points of interest to appeal to a cross-section of readers are found in the location of D-2-aminopimelic acid and its trans-3, 4-dehydro analogue in Asplenium unilaterale, of five γ-carboxyglutamic acid residues within a novel heptadecapeptide toxin in the venom of a fish-hunting cone snail, Conus geographus, and of the cross-linking amino acid residues lysinoalanine (in alkali-treated partial hydrolysates of β-casein and broad-bean protein) and 3-hydroxypyridinium-containing moieties (in cartilage). Other heteroaromatic and aromatic moieties of familiar types feature in a useful study of optimum conditions for protein hydrolysis in which tryptophan degradation is largely avoided (92% recovery using 3M mercaptoethane sulphonic acid at 166 °C for 25 min) and in structure elucidation of the common aglycone moiety of the actaplanin antibiotics (made up of hydroxylated phenylalanine and phenylglycine units condensed into a tetracyclic peptide array).

New Natural Amino Acids. — First findings reported in this section range from free amino acids [trans-4-hydroxy-N -methyl-L-proline in the red alga Chondria coerulescens and an intermediate (1) in the transformation of chorismic acid to anthranilic acid by anthranilate synthase I from Serratia marcescens] to simple derivatives histargin (a new carboxypeptidase B inhibitor from Strepto-myces roseoviridis, in which arginine and histidine are linked via carboxy groups by 1,2-diaminoethane), siderochelin C (2) from an Actinomycete, and an unusual deoxynucleotide, α-N-(9-β-D-2′-deoxyribofuranosylpurin-6-yl) glycin-amide, specified by bacteriophage Mu.

New Amino Acids from Hydrolysates. — This section continues to record unsuspected and unlikely (but real) protein amino acids, with a spectacular ‘first’, the location of aminomalonic acid, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], in Escherichia coli and atherosclerotic plaque proteins (the latter also contain β-carboxyaspartic and γ-carboxyglutamic acids).

Although both cis and trans isomers of 3- and 4-hydroxyproline appear in collagen hydrolysates, the cis isomers are formed during the hydrolysis procedure.

The presence of ε-(γ-glutamyl)lysine in protein hydrolysates has been established through sensitive h.p.l.c. methods.

4 Chemical Synthesis and Resolution of Amino Acids

General Methods of Synthesis. — Amination of simple substrates is represented in reactions of sodium chloroacetate with secondary amines in tetrahydrofuran and of aliphatic aldehydes with CHCl3 and NH3 in CH2Cl2-H2O containing a phase-transfer agent and in reductive amination of keto acids using sodium cyanoborohydride and an ammonium salt. Analogous carboxylation processes are represented in electroreduction of Schiff bases PhCR1=NCHR2Ph in the presence of CO2 and in hydrocarbonylation of N-vinyl- and -allyl-phthalimides catalysed by Rh or Pd complexes.

Standard procedures are employed in alkylationof diethylacetamidomalonate (e.g. 2,6-dihalotyrosines), formation of α-aminonitriles (RCHO + Me3SiCN catalysed by Znl2 -> NCCHROSiMe3, which is reacted with a secondary amine in MeOH), more conventional Strecker synthesis of alicyclic α-amino acids from corresponding ketones and PhCH2NH2 with KCN, aziactone synthesis, alkylation of isocyanoacetic esters and glycine derivatives [e.g. the Schiff base Ph2C=NCH2 CO2Et and PhSCH2NMeCH2CO2Et, the latter with NaH undergoing cycloaddition with PhCH=C(CO2Me) in HMPA–dimethoxy-ethane to yield N-methylproline derivatives], and an example of the Ugi four-component condensation, leading to compound (3).

A new synthesis has been reported, based on the rearrangement of acetimidates R1CH=CHCHR2OC(=NH)CCl3 derived from allylic alcohols. Overnight refluxing in xylene followed by treatment of the resulting amide CCl3CONH-CHR2CH=CHR1 with NaIO4-RuO3 then hydrolysis in aqueous HCl gives the amino acid [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]. The potential of this method is limited by both the accessibility of the allylic alcohol and the compatibility of the eventual amino acid side chain R2 with the reaction conditions (the conversion of an alcohol into the acetimidate requires NaH and CCl3CN as reagents).

Asymmetric Synthesis. — Many of the recent papers on this topic cover what could be described as established general methods, since many of them extend studies that have featured in this section in preceding volumes. One of the longest-established of these, the asymmetric hydrogenation of amino-acrylates, azlactones, and Schiff bases, is represented in familiar forms, employing chiral phosphine-Rh or -Co catalysis or the incorporation of a chiral moiety into the substrate. The protonation of amino-acrylic acid itself occurs with modest (15–20%) enantiomeric excess during its conversion into alanine catalysed by the Pseudomonas striata amino acid racemase.

The reason for the continuing flow of papers is the incomplete understanding of the relationship between stereoselectivity and structure in this area of asymmetric synthesis. This uncertainty also applies to asymmetric transaminations of α-keto acids using a chiral pyridoxamine and aminolysis of azlactones by chiral amines. The crop of papers in which asymmetric alkylation processes are extended generally describe high stereoselectivity, however; a synthesis of α-methylated (S)-amino acid esters H2NCRMeCO2Me through alkylation of the Schiff base of methyl L-alaninate with an alkyl bromide RBr after lithiation with LiNPri2, where the Schiff base is formed with the aldehyde formed from 1,2,3,4-protected D-galactose (cf. precedent work, Vol. 14, p. 11), gives enantiomeric excesses of 44–85%. L-Serine undergoes α-alkylation with retention of its configuration through reaction of the derived lithium enolate (4) with electrophiles. The same principle also applies to the asymmetric alkylation of nickel(II) complexes of (N-benzyl-L-prolyl)-o-aminobenzaldehyde with acetaldehyde, leading to L-threonine and its allo isomer in enantiomeric yields of 86 and 76%, respectively. Amides formed between DL-amino acids and (S)-prolinol methyl ether can be lithiated and re-protonated with up to 92% diastereoselectivity; much less selectivity is seen in the alkylation of DL-amino acids esterified either with (S)-prolinol or with (-)-menthol, since diastereoisomeric excesses range from 5 to 46%.

Continuing studies with alkylation of lithiated 2,5-dimethoxy-3,6-dihydro-pyrazines (see also refs. 42 and 76) confirm the high levels of enantiomer purity that can be achieved (see Vol. 16, p. 6; for a review see ref. 45). For example, condensation of the (S)-3-isopropyl compound with Me3CSiMe2CR1R2CHO after lithiation gives [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] in better than 95% enantiomer excess.

A novel transfer-of-chirality operation applied to the synthesis of N-benzyl-oxycarbonyl-D-amino acids in 78–84% enantiomer excess is based on [2,3]-sigmatropic rearrangement of a vinyl selenide (Scheme 1).

Prebiotic Synthesis Models. — The ripples continue to spread out from the original ‘electric discharge-CH4/H2O/ N2 or NH3’ experiment, and as in recent years (see Vol. 16, p. 6) one of the original authors has again reappeared on the expanding wavefront with a comparison of relative yields of C3-C6 amino acids in such a system when the NH3 concentration varies and when other simple alkanes are used in place of methane. Shock-wave compression (amplitude 10 GPa) converts ammonium salts of acrylic, crotonic, cinnamic, and fumaric acids into β-alanine, β-aminobutyric acid, phenylalanine, and aspartic acid, respectively, in yields of up to 10%.

Extended reaction times convert glycine–formaldehyde or –acetaldehyde mixtures at pH 3.5 and at 60–80 °C not only into the expected serine and threonine but also into alanine, glutamic acid, aspartic acid, norvaline, iso-leucine, and four other protein amino acids.

Synthesis of Protein Amino Acids and Other Naturally Occurring Amino Acids. — It would be inappropriate to ignore the burgeoning literature, but necessary to give representative citations, only, of fermentative production of amino acids. Enzymic synthesis of amino acids from β-chloroalanine has been reviewed biosynthetic studies include formation of L-isoleucine by methanogenic bacteria, enhanced L-proline production from L-glutamic acid by a barley mutant, and conversion of L-aspartic acid into L-alanine. The production of L-dopa (Mucuna pruriens) and L-tryptophan has been given detailed attention.

Protein amino acids are frequently the objective of exploratory studies with new or modified general syntheses, and examples of this type appear elsewhere in this chapter. The protein amino acids themselves are starting points for the synthesis of other natural products (see Section 6) including amino acids. The starting protein L-amino acid may appear as such in the synthetic target, as in the synthesis of histopine (5) via reductive alkylation of L-histidine with pyruvic acid in the presence of NaBH3CN and separation of the resulting mixture of diastereoisomers. An alternative synthesis based on the established route to this general class of crown-gall tumour metabolites, in this case using L-histidine and (R)- or (S)-α-bromopropionic acid, was also explored in this study.

L-Glutamic acid was the starting point for differently conceived syntheses of Nδ-hydroxy-L-ornithine, both sketched in Scheme 2. In one of these studies alternative approaches were thwarted by the propensity of the urethane nitrogen atom in Nα-Boc-L-glutamic semialdehyde to undergo intramolecular reaction and also by transamidation rearrangements that occurred on attempted reduction of the side-chain carboxy group in certain glutamic acid α-hydroxamate derivatives. However, when the nitrogen atom is enclosed in an oxazolidone ring, this problem is avoided. L-Serine has been used for the synthesis of L-2,3-diaminopimelic acid through application of the Mitsunobo reaction (Z-Ser-OMe with Ph3P and diethyl or di-isopropyl azodicarboxylate to give the corresponding α-azido-alanine, subjected to H2S-py reduction). The conversion of L-serine into D-α-amino acids involves N-benzenesulphonyl-L-serine lithium salt for aminoacylation of a Grignard reagent, the resulting side-chain carbonyl group being converted into a methylene group through Raney nickel reduction of the derived dithioketal; oxidation (-CH2OH -> -CO2H) was achieved using O2/PtO2, leading to excellent yields of D-amino acids [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] after cleavage of the N-protecting group with 48% HBr.

Another example in which a chiral natural product, this time (R,R)-tartaric acid, serves as starting material for a natural amino acid is the 25-stage synthesis of (2S,3R,4R,6E)-3-hydroxy-4-methylamino-6-octenoic acid (a constituent of cyclosporin A).

trans-α-(Carboxycyclopropyl)glycine, a constituent of ackee seed, has been prepared through cyclopropanation of (E)-EtO2CCH=CHCH (OEt)2, conventional amino acid synthesis through the masked aldehyde group involving the Strecker route. Stammer’s group (see Vol. 15, p. 12) continue their studies on synthesis of cyclopropane-based amino acids by diazoalkane cyclopropanation of amino-acrylates with examples including coronamic acid.

Synthesis of β- and Higher Homologous Amino Acids. — The large range of examples, many of them represented in natural products, that are covered by the title of this section is matched by a constant stream of papers. There are relatively few general methods specific to each class of ω-amino acid, and textbook methods of synthesis of amines are used, needing little particular discussion.

3-Ketoglutaric acid is converted through some conventional steps but including a notable use of Arthrobacter for stereoselective formation of ethyl (S)-3-hydroxyglutarate, into either L-carnitine, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], or the 4-amino-3-hydroxybutanoic acid itself. Other γ-amino acids reached through enantiospecific synthesis are (3S,4S)-statine, as its N-Boc ester, Me2CH CH2CH(NHBoc)CH(OH)CH2CO2Me, starting with N-Boc-L-leucinal, and (-)gabaculine (6), starting with benzoic acid and including a notable role for the Fe(CO)3 moiety in enabling enantiospecific introduction of 2H as well as the correct location of the amino group. Detoxinine has been synthesized from [FORMULA NOT REPRODUCIBLE IN ASCII] through a stereoselective route that competes with an alternative route described in Vol. 16 p. 10. The synthesis of (+)-galan-tinic acid (7) starting with (R)-CH2=CHCH(NH3)CO-2 mimics the detoxinine synthesis in some respects, involving stereospecific epoxidation and regiospecific ring cleavage with Li2(CN)Cu(CH=CH CH2OSiMe2CMe3)2, L-Glutamic acid serves as starting material for (S)-4-amino-4,5-dihydrofuran-2-carboxylic acid, found to be a potent γ-aminobutyric acid transaminase inhibitor; so also is (S)-4-amino-5-hexenoic acid, prepared from (S)-5-vinyl-2-pyrrollidone, available from L-glutamic acid through straightforward elaboration.

Synthesis of α-Alkyl Analogues of Protein Amino Acids. — Alkylation reactions continue to gain favour for this purpose as reaction procedures become optimized, in comparison with total synthesis by standard general methods employing ketones. In addition to examples described elsewhere in this chapter, alkylation of Schiff bases R1R2 C=NCHR3CO2R4 is easily accomplished using an alkyl halide in refluxing MeCN in the presence of K2CO3 and Bu4N+B-. α-Alkylated L-leucines are accessible through the use of lithiated 2,5-dimethoxy-3,6-di-isobutyl-3 6-dihydropyrazine (see also refs. 44 and 45) as chiral substrate; alkylation is followed by hydrolysis to give the α-alkyl-leucine methyl ester. Similar use of the chiral oxazinone formed between DL-2-(2-furyl)glycine and (S)-PriCH(OAc)COCl or (S)-ButCH(OAc) COCl after conversion into its potassium salt leads to (S)-α-alkyl-α-(2-furyl)glycines with asymmetric induction levels of 50-95%.

Synthesis of Other Aliphatic, Alicyclic, and Saturated Heterocyclic α-Amino Acids. — The use of 1,2-diaminoethane in the Strecker synthesis yields ‘bis-α-amino acids’ via the amino nitrile:

EtCHO + KCN + H2NCH2CH2NH2 -> NCCHEtNHCH2CH2NHCHEtCN

Hydrolysis to the amino acid succeeded only after benzoylation of both secondary amino groups. No such problem arose in the hydrolysis of the nitrile groups in alkylation products of the Schiff base Ph2C=NCH2CN in a study of bis-alkylation by 1,ω-dibromoalkanes Br(CH2),Br leading to 1-amino cyclopropane-1-carboxylic acid and ‘cycloleucine’ (n = 4) and to 2,6-diaminopimelic acid (n = 3).

(Continues…)Excerpted from Amino Acids and Peptides Volume 17 by J. H. Jones. Copyright © 1986 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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