Amino Acids, Peptides and Proteins Volume 35

A Review of the Literature Published during 2002

By J.S. Davies

The Royal Society of Chemistry

Copyright © 2006 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-247-0

Contents

Amino Acids Weng C. Chan, Avril Higton and John S. Davies, 1,
Peptide Synthesis Donald T Elmore, 74,
Analogue and Conformational Studies on Peptides, Hormones and Other Biologically Active Peptides Botond Penke, Gábor Tóth and Györgyi Váradi, 129,
Cyclic, Modified and Conjugated Peptides John S. Davies, 272,
Metal Complexes of Amino Acids and Peptides E. Farkas and I. Sóvágó, 353,

CHAPTER 1

Amino Acids

BY WENG C. CHAN, AVRIL HIGTON AND JOHN S. DAVIES

1 Introduction

As the coverage of Amino Acids did not make it into Volume 34 of these Reports, this Chapter covers the years 2001 and 2002. This inevitably means that the authors this time needed to be a little more selective in the papers reviewed, due to space limitations. The main source of the citations was again Chemical Abstracts (Vols 134–136), CA Selects on Amino Acids Peptides and Proteins and the Web of Knowledge. No references to conference proceedings have been included, and the patent literature has not been scanned. With the addition of an extra author, the style of the Chapter might show minor changes, but in order to preserve continuity for those taking ‘year on year’ surveys within a field, the pattern of sub-headings have been retained.

2 Reviews

The main aim of this Report is to review the original refereed papers in this subject area, so reporting on reviews covering similar areas is included in ‘title-only’ format as a token of respect for all those that have similarly laboured through the literature to bring us highlights from specific areas of endeavour. Reviews cited during 2001–2002 were:-

New Strecker Synthesis-Asymmetric Synthesis and Chiral Catalysts

Methods for the Synthesis of Unnatural Amino Acids

Chiral Oxazinones and Pyrazinones as α-Amino Acid Templates

Amino Acid Derivatives by Multicomponent Reactions

Progress on the Asymmetric Synthesis of α-Amino Acids

Comparison of different Chemoenzymatic Process Routes to Enantiomerically Amino Acids

α-Imino Esters: Versatile Substrates for the Catalytic, Asymmetric Synthesis of α- and β-Amino Acids and Lactones

The Asymmetric Synthesis of Unnatural α-Amino Acids as building blocks for Complex Synthesis

Asymmetric Hydrogenation and other Methods for the Synthesis of Unnatural Amino Acids

Metabolic Engineering of Glutamate Production

Amino Acids Production Processes

Biotechnological Manufacture of Lysine

The Threonine Story

The Economic Aspects of Amino Acid Production

Synthesis of Enantiometrically pure Pipecolic Acid Derivatives via Bio- and Transition Metal Catalysis

A Journey from Unsaturated Amino Acid Synthesis to Cyclic Peptides

Side-chain modifications and Applications of Aliphatic Unsaturated α-Amino Acids

Fullerene-based Amino Acids and Peptides

Selenocysteine Derivatives for Chemoselective Ligations

Study on Resolution of Chiral Amino Acid Enantiomers

Highly Diastereoselective Michael Reactions between Nucleophilic Glycine Equivalents and β-Substituted] α,β-Unsaturated Acids: A General Approach to chi-Constrained Amino Acids

3 Naturally-Occurring Amino Acids

While interest continues in the synthesis of known naturally-occurring amino acids, it has not been a productive period in papers highlighting the existence of amino acids from new sources.

3.1 New Naturally Occurring Amino Acids. – Amongst the new nortropane alkaloids isolated from the fruit of Morus alba LINNE in Turkey, six new amino acids have been characterised. They have been allocated pyrrolidinyl do-decanoic and piperidinyl dodecanoic structures: (3R)-3-hydroxy-12-{(1S, 4S)-4-[(1-hydroxyethyl-pyrrolidin-1-yl}-dodecanoic acid-3-O-β-D-glucopyranoside; its free acid; (3R)-3-hydroxy-12-[(1R, 4R, 5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid-3-O-β-D-glucopyranoside; its free acid; (3R)-3-hydxoxy-12-[(1R, 4R, 5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-β-D-glucopyranoside and (3R)-3-hydroxy-12-[(1R, 4S, 5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid.

4 Chemical Synthesis and Resolution of Amino Acids

As in past years this remains the core section of the activity in the field, with some aspects already covered by the reviews listed in sub-section 2. Some subject matter also overlaps with material in subsequent sections of this Report.

4.1 General Methods for the Synthesis of α-Amino Acids, including Enantiose-lective Synthesis. – The development of benzophenone imines of glycine derivatives for the synthesis of α-amino acids has been outlined. Substituted phenylalanines have been prepared using UV photolysis of protected glycines in the presence of di-t-butylperoxide, substituted toluenes and the photo-sensitiser, benzophenone. After removal of the chiral auxiliary by lithium hydroperoxide, N-acetyl-D-serine methyl ester was the final product of the rearrangement summarised in Scheme 1.

Reaction of 5-oxazolidinones such as (1), with alcohols in bicarbonate solution, and with PLE and HLE has led to good yields of amino acid derivatives. A chiral copper catalyst can catalyse an enantioselective Mannich type reaction as summarised in Scheme 2. Catalysis by L-proline has enabled a general reaction between ketones and PMP-protected α-imino ethyl glyoxy-late (Scheme 3) to be made highly stereoselective. Its simplicity would make it an attractive proposal regarding prebiotic synthesis. Either enantiomer of both α- or (β-amino acids have been made available if this reaction includes an aldehyde instead of a ketone.

A broad-based methodology for the synthesis of non-natural amino acids has used catalytic enantioselective alkylation of α-imino esters and acetals with enol silanes, allyl silanes and olefins using chiral Cu(I) phosphine complexes. With suitable substitution (using 4-methoxybenzylidene) the pathway of Pd-cata-lysed acrylation can be guided to amino acid esters as summarised in Scheme 4. A novel method, via a radical pathway for the asymmetric synthesis of α-amino acids has been reported. Starting from the pantolactone (2) and using the conditions summarised in Scheme 5, it was shown that the absolute configuration of the stereogenic centre was dependent on the nature of the added radical. Rhodium-catalysed conjugated addition of α-aminoacrylates, with organotin and organobismuth reagents have yielded amino acids under ambient conditions of air and water. Similar conditions have been used by the same authors for the zinc-mediated conjugate addition of alkyl halides to α-phthalimidoacrylate.

α- and β-Substituted alanine derivatives have been efficiently produced by α-amidoacrylation or Michael addition reactions using microwave irradiation and catalysis by silica-supported Lewis acids. Diverse functionalities, such as chlorides, nitriles, azides, acetates, thioacetates, thioethers and amines have been inserted at varying chain lengths away from the α-centre, if amino acids (Ala or Phe), attached to a Wang resin, and derivatised with 3,4-dichlorobenz-aldehyde were subjected to alkylation by α-bromo-co-ω-chloroelectrophiles. The one-step conversion of azetidine-2,3-diones (3) to amino acids in the presence of cadmium/wet methanol has been explained by chelation of the ketone and amide groups to the metal, which allows for attack of the keto group by methanol followed by CO extrusion. The demands of the chemical libraries fraternity for a fast throughput of synthons, has brought the Ugi 4-component condensation into mainstream activity, and the formation of chiral products has now been made easier through better access to chiral 1-amino carbohydrates. The reductive amination of ketones has been adapted for the synthesis of racemic amino acids from α-keto acids, as shown by the synthesis of phenylglycine, and its 3-indolyl or 2-thienyl analogues.

4.1.1 Use of Chiral Synthons in Amino Acid Synthesis. This still represents a booming area of interest and justifies its own sub-section. The Oxford school continues its productivity in this area as exemplified by the chiral glycine enolate, (S)-N, N’-bis-(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione. This was able to discriminate between enantiomers of 2-bromopropionate esters in forming (4), which on further manipulation resulted in the synthesis of chiral 3-methylaspartates. A more detailed examination of the same chiral synthesis has also been carried out. Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to α,β-unsaturated esters followed by enolate hydroxylation, reduction and oxidative cleavage has been shown to be a route to α-amino acids in high enantiomeric excess. (S)-α-Amino acids in high chiral yields have been obtained from (S)-N-N’-bis(p-methoxybenzyl)-3-methylene-6-isopropylpiperazine by reaction with a range of organocuprates.

The imine moiety of (5S)-3-([2-methoxycarbonyl]ethyl)-5 -phenyl-5,6-dihy-dro-2H-1,4-oxazin-2-one has been shown to undergo highly diastereocon-trolled reduction followed by Lewis-acid-mediated nucleophilic addition of Grignard reagents to give enantiomerically pure glutamic acid analogues. The same authors have also shown that iminium ions derived from (S)-5-phenyl-morpholine-2-one undergo diastereoselective Strecker reactions using copper(I) cyanide/anhydrous hydrochloric acid, which lead eventually to D-α-amino acids. An inexpensive chiral auxiliary, the imino lactone (5), from (1R)-(+)-camphor on alkylation afforded good yields of monosubstituted products at the Hendo position, which on hydrolysis yielded D-α-amino acids. Using camphor of the opposite configuration, or by switching the OH group of the auxiliary from C2 to C3, gave the L-enantiomer. N-Methyl pseudoephedrine has also been used as a chiral auxiliary, by mediating a dynamic resolution of α-bromo-α-alkyl esters in nucleophilic substitution. Enantiomeric ratios of 98: 2 were achieved in the a-amino acids finally produced.

A variety of α-amino acids have been produced diastereoselectively using indium-mediated allylation and alkylation of the Oppolzer camphorsultam derivative of glyoxylic oxime ether. A new chiral auxiliary (S)-N-(2-benzoyl-phenyl)-1-(3,4-dichlorobenzyl)-D-pyrrolidine-2-carboxamide, and related halogen-containing auxiliaries as their Ni(II) complexes have been shown to give an increased chiral bias in the formation of (N)-α-amino acids, due possibly to the halogen substitution in the N-benzyl group. A 5-step asymmetric synthesis of the (2R, 4R) 4-hydroxy-D-pyroglutamic acid involved the 1,3-dipolar cyclo-addition of a chiral nitrone (from glyoxylic and protected D-ribosyl hydroxylamine) with the acrylamide of Oppolzer’s sultam. The scope of this reaction using other analogues has also been studied experimentally and theoretically for the formation of the (2S, 4S)-isomer.

By association with substrates, chiral catalysts can also be considered under the heading ‘chiral auxiliaries’, and recently together with phase-transfer reagents constitute a popular means of asymmetric synthesis. A novel substrate/ catalytic pair under phase-transfer conditions turned out to be based on complex (6) which reacted quickly with 2-amino-2′-hydroxy-1,1-binaphthyl (NOBIN) as the phase transfer catalyst and could then be alkylated asymmetrically to give purifiable complexes for further processing to amino acids.

Stereoselective alkylation reactions of N’ [(S)-1′-phenylethyl]-N-(diphenylmeth-ylene)glycinamide using 18-crown-6 as catalyst, gave a series of enantioen-riched (83:17 ratio) unnatural amino acids. Structures based on the chirality of cinchona alkaloids have a noble track record in this area, and when polymer-supported cinchona alkaloid salts with different spacers were used as catalysts in the C-alkylation of N-diphenylmethylene glycine t-butyl esters, it was found that the best result (81 % ee) came from the polymer bearing a 4-carbon spacer. When dimeric cinchonidine- and cinchonine-derived ammonium salts incorporating a dimethylanthracenyl bridge were studied in the same type of asymmetric alkylations, 90% ee was achieved. In the enantioselective synthesissummarised in Scheme 6 cinchonidine is used to control the stereochemistry of the α-carbon when side-chains are introduced using β-alkyl-9-BBN organobo-rane reagents. In 12 examples studied 54-95% ee’s were recorded. A new class of naphthalene-based dimeric cinchona alkaloids have been developed which show excellent enantioselectivity in the alkylation of glycine derivatives and seem good prospects for adoption by industry. Cinchonidinium salts bearing a 3,5-dialkoxybenzyl have been shown to be efficient catalysts for the alkylation of N-diphenylmethylene)glycine Pri ester with benzyl bromide, but surprisingly give the (S)-enantiomer when KOH is used as base and the (R)-enantiomer when NaOH was used. A cinchonidine-based phase-transfer catalyst in the presence of KOD/D2O, provided the means to incorporate deuterium into the a-position of benzophenone-derived glycine imine to produce α-deuterated α-amino acids.

4.1.2 Synthesis via Rearrangements. γ-Amino acids were produced via the hydrogen-mediated ring-opening of (7) to the carboxy nitrile, followed by hydrogenation of the nitrile group. N-Benzyl-4-acetylproline has been prepared from N(2-hydroxy-2-methyl)but-2-enyl-N-benzylamine and glyoxylic acid via a tandem cationic aza-Cope rearrangement and Mannich reaction under mild conditions. A TEMPO-mediated ring expansion to the α-keto-β-lactam (8) resulted in the formation of N-carboxyanhydrides which could be hydrolysed without loss of chirality to the α-amino acid derivatives as summarised in Scheme 7. N-Protected allylic amines produced from allylic alcohols via Overman’s [3,3] sigmatropic rearrangement of trichloroacetimidates have been converted to N-protected amino acids by using NaIO4 with catalytic amounts of RuCl3. 3H2O or by ozonolysis, without loss of chirality.

4.1.3 Synthesis from Dehydroamino Acids and by Carbohydroamination. Secondary phosphanes have proved to be useful ligands for the asymmetric hydrogenation of acetamidocinnamic and itaconic acids using [rhodium (cyclo-octa-1,5-diene)2]BF4 as catalyst. Enantiomeric excesses of up to 97% were found for both the bidentate and monodentate ligands. The asymmetric hydrogenation of dehydroaminoacid precursors was the key step in the synthesis of S) (–)-acromelobic acid (9) and S- (–)-acromelobonic acid (10). An ee of > 98% was achieved at the key stage in the synthesis of (9) through the use of (R, R)-Rh(DIPAAMP)(COD)]BF4, while (S,S)-[Rh(Et-DuPHOS) (COD)]BF4 was used for (10) and gave >96% ee. In the hydrogenation of (Z)-acetamido-3-arylacrylic acid methyl esters it has been discovered that the introduction of N for O into the binaphthyl chiral ligands allows catalysts such as [Rh(H8-BINAPO)] and [Rh(H8-BDPAB)] to give improved ee values. (2S, 6S)- and meso-Diaminopimelic acids have been synthesised by the asymmetric hydrogenation (95% ee) of their dehydroamino acid precursor under catalysis by [Rh(I))COD)-(S,S) or (R,R)-Et-DuPHOS]OTf.

No asymmetric bias, but good yields (up to 86%) have been claimed for the interesting formation of PhCH(NHR)CONHR, when various iodoarenes, primary amines and carbon monoxide were condensed together in a Pd-catalysed one-pot double carbonylation reaction.

4.2 Synthesis of Protein Amino Acids and Other Naturally Occurring Amino Acids. – The use of enzymes to carry out key conversions in the synthesis of amino acids has been a useful part of the armoury for many years. During this period, examples come from: the formation of L-[411-C]-aspartate and L-[511-C]-glutamate by enzymatic catalysis of 11C-hydrogen cyanide into O-acetyl-serine and -homoserine respectively; phenylalanine ammonia lyase was used to produce [1-14C] and [2-14C]-phenylalanine from corresponding cin-namic acids, and these isotopomers converted further to [1-14C]- and [2-14C]-tyrosine using L-phenylalanine hydroxylase; tyrosine phenol lyase from Citrobacter freundii can catalyse conversion of 2-aza-1- and 3-aza-1-tyrosine from 3-hydroxy- and 2-hydroxypyridine respectively and ammonium pyruvate; four tritium-labelled isotopomers of L-phenylalanine (2-3H-, 2′,6′-3H, 3R-3H and 3S-3H-phenylalanine) have been made and converted into [2-3H]-, [2′,6′-3H]-, [3R-3H] – and [3S-3H]-tyrosine using phenylalanine-4′-mon-ooxygenase; reductive animation of pyruvate to form L-alanine using alanine dehydrogenase from the hyperthermophilic archeon, Archaeoglobus fulgidus; the biotransformation of p-hydroxyphenylpyruvic acid to L-tyrosine using L-aspartate amino transferase from E. coli.

The chemical synthesis of well known amino acids and derivatives still commands a great deal of attention. Thus glutamic acid analogues have been prepared from PEG-supported intermediates using a Heck reaction as summarised in Scheme 8, followed by further processing to the amino acid derivatives. Starting from the same Schiff base, conjugative addition of Michael acceptors, either in solution or on solid phase, in the presence of quaternary salts from cinchona alkaloids have also given glutamic acid derivatives. Asymmetric synthesis of β-substituted aspartic acid derivatives has been secured via a catalysed [2+2] cycloaddition of ketenes and imines to form acyl-β-lactams, which ring-open under catalysis by benzoylquinine with high enantio- and diastereo-selectivity. Aziridines, such as (11) and cyclic sulfates based on (12) were the basis of the asymmetric synthesis of syn and anti forms of (β-substituted cysteines and serines, and reductive animation of phenylpyruvic acid over Pd/C catalyst yielded DL-phenylalanine. Oxazolidinones (13) and (14) have been shown to be efficient synthons on the pathway to α-amino-aldehydes and α-amino acids respectively.

(Continues…)Excerpted from Amino Acids, Peptides and Proteins Volume 35 by J.S. Davies. Copyright © 2006 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.