Amino Acids and Peptides Volume 18

A Review of the Literature Published during 1985

By J. H. Jones

The Royal Society of Chemistry

Copyright © 1987 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-164-7

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 Conjugated Peptides By P. M. Hardy,
Chapter 5 β-Lactam Antibiotic Chemistry By J. Brennan and A. Sheppard,
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

All major sub-divisions of amino acid science are represented in this Chapter as in previous Volumes of this Specialist Periodical Report (formerly named ‘Amino acids, Peptides, and Proteins), though with some waxing and waning as topic areas develop or become exhausted. The emphasis continues to reside in chemical studies but covers the biological literature to the extent that chemical and analytical studies are included there.

2 Textbooks and Reviews

Reference texts and compendia of data include the second supplementary list of amino acid derivatives that are useful in peptide synthesis (taking in the literature to the end of 1982). Other topics reviewed include 1-aminocyclopropanecarboxylic acid, synthesis of N-methylamino acids, applications of uncommon amino acids in natural-products synthesis, the role of S-adenosylhomocysteine and of L-ergothioneine, and boron analogues of amino acids including p-borono-L-phenylalanine.

3 Naturally Occurring Amino Acids

3.1 Occurrence of Known Amino Acids. – Close relatives of the common amino acids are covered here, and no attempt is mode to review the routine literature of the distribution of well-known amino acids.

The first natural appearance of methionine sulphoximine is reported; it is the toxic principle of Chestis glabra. L-DOPA-3-Sulphate has been located in the brown alga Ascophyllum nodosum, and α-hydroxymethylserine, not previously reported to be a natural product, has been found in Vicia pseudo-orobus.

N-Substituted amino acids continue to arise in a variety of systems: N-trimethyl-alanine at the N-terminus of myosin light chains, L-pyrrolidone-2,4-dicarboxylic acid in the muscle of the mollusc abalone Haliotis discus hannai, and 3R,4R-dihydroxy-L-proline (1), present in virotoxins. (1), like (+)-3,4,5-trihydroxypipecolic acid (2) from Baphia seeds, competitively inhibits cattle β-D-glucuronidase. Leucinopine one of a group of N-(1-carboxyalkyl)amino acids often categorized as ‘opines’, has been shown to possess the L-threo stereochemistry; in others words, this amino acid, N-(1-3-dicarboxy-propyl)leucine, has the ‘Lglu-, Lleu-‘ configuration and in this respect is unique amongst the other opines octopine (‘Dala-, Larg-‘), nopaline (‘Dglu-, Larg-‘), and succinamopine (‘Dglu-, Lasn’).

Plant, fungal, and microbial sources of less common amino acids: Asplenium unilaterale (4-hydroxy-L-2-aminopimelic acid as well as D-2-aminopimelic acid and trans-3,4-dehydro-D-2-aminopimelic acid), Dactylosporangium aurantiacum (L-threo-β-hydroxyaspartic acid, previously only found in Arthrinium and in various Streptomycetes), and Amanita pseudoporphyria (L2-aminopent-4-ynoic acid and L-2-aminopent-4-enoic acid, L-2-aminohex–4-ynoic acid and L-2-aminohept-4-en-6-ynoic acid, as well as L-2-amino-4-chloropent-4–4-enoic acid and L-2-aminohexa-4,5-dienoic acid as previously reported). Another cyclic tetrapeptide from Helminthosporium carbonum has been described, containing a 2-amino-8-oxo-9,10-epoxydecanoic acid residue. L-Phenylalanine and its 3S-methyl homologue (3) occur as their N-acetyl derivatives esterified with the unusual 8R-hydroxy-9S-methyl oxiranyl-2E,4Z,6E-decatrienoic acid as AK-toxins I and II from Alternaria alternata pear fungus (black spot disease).

Cross-linking amino acid residues in mammalian proteins continue to attract interest, a recent citation referring to the identification of pyridinoline in Type 1 collagen.

3.2 New Natural Amino acids. – New aliphatic α-amino acids include 2S-aminohex-5-ynoic acid (from Cortinarius claricolor var. tennipes), Ds-erythro-2-amino-4-ethoxy-butanoic acid (from the edible mushroom Lyophyllum ulmarium), erythro-[??]-hydroxyhomo-L-arginine (from the seed of Lonchocarpus costaricaensis; the threo diastereoisomer is already known to be a natural product), and the sulphate ester of trans-4-hydroxypipecolic acid (seeds of Peltophorum africanum). This is the first naturally occurring sulphate ester of a non-protein amino acid to be reported. The bulgecins contain Q-glycosylated 5-hydroxy-methyl-4-hydroxyproline amides (4; R = glycosyl residue). ‘Dealanylalahopcin’ (5), found with alahopcin in Streptomyces albulus cultures, is (2S, 3R)-2-amino-4-formyl-3-(hydroxyamino-carbonyl)butyric acid (wrongly named as the 4-(hydroxyaminocarbonyl)acid in the original paper). A high level of interest in N(1-carboxyalkyl)amino acids (the ‘opines’; see listing in preceding Section) is reflected in three new examples from the 1985 literature: crown-gall tumours incited by Agrobacterium tumefaciens produce agropine and related mannityl opines and leucinopine and in addition large amounts of a new member of the family N-{(1S)-1-carboxy-2-carbamoylethyl}-{S)-glutamic acid (‘LL-succinamopine’). The D,L-diastereo-isomer having been isolated previously from the same source, this is the first example of the natural occurrence of epimeric opines. The other two new opines are N-(1-carboxyethyl)-L-methionine and a phosphorylated example (agrocinopine A) secreted by heal thy crown-gall cells induced by the same bacterium.

3.3 New Amino acids from Hydrolysates. – This section specifically refers to natural products that in principle or in practice can release new amino acids on hydrolysis.

Lavendomycin from Streptomyces lavendulae is an unusual peptide (7) containing some close analogues of common amino acids.

Carzinophilin contains (2S,3S)-4-amino-2,3-dihydroxy-3-methylbutanoic acid.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods of Synthesis. – The major standard methods, mostly of many years’ standing, continue to be fully used. It is not necessary to do more than cite most of these with literature references (recent review coverage is available), and some further details of the synthetic objectives are given in later sections of this Chapter. The alkylation methods in which the side chain of the α-amino acid is put in place include alkylation of acetylaminomalonates and other glycine derivatives (MeS)2C=NCH2CO2Et, Ph2C=NCH2CO2Et, PhCH=NCH2CO2Et, CNCH2CO2Et, and azlactones.

Alkylation of methyl 2-acetamidoacrylate with a Grignard reagent in the presence of copper(I) iodide gives moderate yields of 3-substituted alanines, and N-alkylamino acid esters, benzaldehyde, and alkenes react in refluxing toluene to give prolines. The latter process involves cycloaddition to intermediate azomethine ylides.

Strecker synthesis of α-amino nitriles involving reaction of an aldehyde, a secondary amine, and Me3SiCN in MeOH can be accomplished within less than 5 minutes, thus providing some assistance in the synthesis of α-amino acids labelled with short-lived radioactive isotopes. Dehydrogenation of aliphatic secondary amines by phenylseleninic acid (or its anhydride), under mild conditions in the presence of NaCN or Me3SiCN, is a new route to α-amino nitriles.

A full paper has been published on the synthesis of N-acyl α-amino acids through the isomerization – amidocarbonylation of allylic alcohols by primary amides and H2 with carbon monoxide, using a homogeneous binary catalyst system HRh(CO)(PPh3)3 with Co(CO)8 or [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII].

A new amino acid synthesis adding to the group of methods in which the amino function is introduced into an alkanoic acid (or a precursor of it) has been reported. Ethanolysis of the pyrroline formed after reaction of the corresponding N-oxide (8) with N-phenylbenz-imidoyl chloride yields an N-phenyl-N-benzylamino acid ethyl ester, from which the various N and C substituents can be removed by standard methods.

4.2 Asymmetric Synthesis. – Further examples have accumulated in the literature during 1985 to extend established methods in the amino acid area. The already voluminous output of Schöllkopf and co-workers, based on the alkylation of bis-lactim ethers (9) derived from piperazine-2,5-diones, has been augmented to include syntheses of D-tryptophan methyl ester and (R)-α-methyltryptophan methyl ester, other alkylation processes in which very high diastereoselectivity is achieved. One of these deals with asymmetric synthesis of D-threonine through reaction of acetaldehyde with the Ti(NMe2)3 complex of the bis-lactim ether. Another is concerned with the synthesis of chiral deuteriated α-aminoisobutyric acid through reaction of the bis-lactim ether(10) with C2H3I.

Further results from Seebach’s group on the alkylation of chiral enolates with what has been called ‘self-reproduction of the centre of chirality’ – i.e. the incoming group takes the place of the proton that is substituted – confirm the high (> 90%) diastereoselectivity that accompanies this approach. Enantiomerically pure pivalaldehyde aminals (11) derived from N-benzyl-L-alanine can be alkylated and elaborated into (R)- or (S)-α-methylDOPA, depending on the cis or trans orientation, respectively, of the aminal. Other α-methyl analogues prepared in this study in high optical purity include α-methyl-L-methionine and α-methyl-L-valine. Pivalaldehyde N,O-acetals (12) from O-acyl-4-hydroxy-L-proline and the corresponding compound from L-thiazolidine-4-carboxylic acid have also been studied in what is clearly the start of a programme seeking to understand the relationship of structure to carbanion stereochemical integrity, in which the alkylating agent no doubt plays a role.

Highest optical purity was observed in the stereoselective synthesis of L-aspartic acid through alkylation of a di-alkyl malonate with N-benzyloxycarbonyl-L-alanyl-2-chloro-glycine methyl ester, followed by hydrolysis, when the malanate carried bulky alkyl groups.

Other studies based on recent pioneering work include alkylation of chiral nickel(II) complexes, to yield either D-serine in better than 80% enantiomeric excess, using 0.2M NaOMe as base, but L-serine in 80-98% enantiomeric excess, using NEt3: when the complex (13) formed between N-benzyl-L-proline N-arylamide and the contiguous glycine Schiff base is alkylated with formaldehyde. A less puzzling result is seen for the corresponding alanine complex, used for the preparation of α-methyl amino acids in optically pure form after separation of diastereoisomers over silica gel.

Alternative asymmetric synthesis of α-methyl amino acids has been established but in much lower enantiomeric excess (31.7% for the R-enantiomer) when the alanine-based isonitrile (14) participates in Michael addition to acrylonitrile. Variable results (10-45% enantiomeric excess of the R-enantiomer) were obtained in the corresponding reaction with methyl acrylate, in relation to the asymmetric synthesis of α-methyl-D-glutamic acid and α-methyl-D-ornithine.

The chiral-template approach employed in these examples underpins other examples, based on initial explorations already familiar to readers of earlier volumes of this Specialist Periodical Report. Weinges and co-workers have provided further examples of the use of the chiral 5-amino-1,3-dioxan (15) as a component for asymmetric Strecker synthesis of α-amino nitriles. (2S,4S)-(-)- and (2S,4R)-(+)-5,5,5-trifluoroleucine have been prepared in this way, the latter from [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] prepared from [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] through successive Pd-catalyzed hydrogenation, LiAIH4 reduction, and resolution. D- and L-2-(2-thienyl)- and -2-(3-thienyl)glycines were prepared in an analogous fashion; in both cases the α-amino nitriles were converted into the α-amino acids and the chiral dioxan moiety removed by HIO4 cleavage. ‘Chiral glycine’, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]., has been prepared from the (R)-toluene-p-sulphonyl ribofuranoside (16) through aminolysis with N3- followed by reduction; aminolysis with potassium phthalimide gave the N-phthaloyl derivative in better than 93% enantiomeric purity, after oxidative cleavage (KMnO4).

Fewer research groups are studying asymmetric hydrogenation methodology for the introduction of a chiral centre into an αβ-unsaturated α-amino acid. Stille has described the use of a catalyst system with a chiral phosphine attached to polystyrene in combination with a Rh(I) salt.

4.3 Prebiotic Synthesis Models. – Interest in this topic covers broader areas than synthesis alone, and later sections cover models for chiral discrimination.

Synthesis of α-amino acids from simple compounds and elements, with energy input of the sort that might be available in Nature, has been a long-running topic. 60Co-δ-Irradiation of oxygen-free aqueous HCN and NH4CN gives mixtures of amino acids, and some of these arise by further reactions involving glycine, which is a major initial product. Aqueous KCN irradiated with u.v. light yields amino acids (but mainly oligoglycines), through a HO*-initiated chain reaction. U.v. irradiation of solutions of bisglycinato-nickel(II) dihydrate and an aldehyde yields mixtures of amino acids. Formaldehyde gives mainly glycine, alanine, aspartic acid, and serine, acetaldehyde gives glycine, aspartic acid, threonine, and allothreonine, while benzaldehyde somewhat surprisingly also gives glycine, serine, and aspartic acid (with two) unidentified products). Glyceraldehyde reacts with ammonia in phosphate buffer at pH 7 to give alanine. Seventeen amino acids, with glycine, alanine, serine, aspartic acid, and glutamic acid predominating, are formed in a radiofrequency plasma of H2 and N2 with cellulose as carbon source placed between the electrodes of the reaction cell.

4.4 Synthesis of Protein Amino Acids and Other Naturally Occurringα(-Amino Acids. – The literature supporting this Section can only be described as expansive and expanding, judging by the literature of the 1980’s and particularly 1985. Frequently, the authors’ primary interest is in an application of a novel synthetic procedure rather than in the establishment of a route to an amino acid for which efficient methods of synthesis already exist.

Reviews of large-scale production of protein amino acids, and peptides have appeared. This topic and its fine details as represented in the biosynthesis literature can only be hinted at here, with representative citations (production of L-tryptophan and 5-hydroxy-L-tryptophan by Escherischia coli, pilot-scale production of L-phenylalanine from D-glucose, and L-aspartic acid production by Brevibacterium flavum), with special reference to the conversion of one amino acid into another in this way (L-tyrosine and its N-formyl derivative into L-DOPA and its N-formyl derivative by Mucuna pruriens, hydroxytion of phenylalanine by hypoxanthine and xanthine oxidase via H2O2 and the superoxide anion to give o-, m-, and p-tyrosines, aid DL-methionine into Q-α-aminobutyric acid through the action of methlonine δ-lyase and D-amino acid amiotransferase).

Most of the syntheses to be described in this Section are side-chain hydroxylated amino acids; some are similarly close analogues of familiar amino acids. Few of these studies have contributed to generally applicable methodology, except the introduction of the phosphonium salt (17) as a generally useful chiral building block for β-substituted alanines. It is easily prepared from L-serine methyl ester and has been used in a synthesis of S-(-)-wybutine (18), a fluorescent minor base from yeast phenylalanine tRNA through Wittig condensation with the corresponding formylpurine.

Relatively simple operations are involved in the non-enzymatic and glutamate dehydrogenase – catalyzed reduction of Δ1-pyrroline-2-carboxylic acid, as part of a mechanistic study involving NAD(P)H and 2H isotope effects, and diborane reduction of N-benzyloxycarbonyl-α-methyl-L-glutamate to give N-benzyloxycarbonyl-L-proline methyl ester (40% yield after a 6 hour reaction in THF). A much more extensive-procedure is involved in the synthesis of bulgecinine(4), a constituent of the bulgecins (from Pseudomonas acidophila), that employs D-glucose as chiral synthon. The other hydroxylated amino acids that have received attention are:(2S,3R,4R)-3,4-dihydroxyproline (stereoselective synthesis from the erythro-β-hydroxy-α-amino acid, 19) and its 2S,3S,4S-diastereoisomer (the 2S, 3R, 4R-diastereoisomer has been prepare through the separation of the mixture of stereoisomers formed through a long-established route); erythro-β-hydroxy-L-aspartic acid and erythro-β-hydroxymethyl-L-serine through the common intermediate (20), formed from L-tartaric acid by oxirane ring opening and selective reduction of the resulting azido-ester; and 2-amino-4-hydroxy-4-(p-hydroxyphenyl)-3-methylbutanoic acid as a mixture of stereoisomers formed through 1,3-dipolar cyclo-addition of ethoxycarbonylmetham nitrile oxide to (E)-(4-methoxyphenyl)propene.

(Continues…)Excerpted from Amino Acids and Peptides Volume 18 by J. H. Jones. Copyright © 1987 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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