Read an Excerpt
Amino Acids and Peptides Volume 24
A Review of the Literature Published during 1991
By J.S. Davies The Royal Society of Chemistry
Copyright © 1993 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-224-8
CHAPTER 1
Amino Acids
BY G. C. BARRETT
1 Introduction
The chemistry and biochemistry of the amino acids, as featured in the 1991 literature, is reviewed in this Chapter. The targeted material could be categorized as the occurrence, chemistry, and analysis of the amino acids, and with the exclusion of routine literature covering the natural distribution of well-known amino acids. As before, the term 'amino acids' is taken to mean [ω]-amino-alkanoic acids, and there is therefore no coverage of amino-phosphonic, -sulphonic, -boronic acids and others of these types.
There continue to be themes in this literature that will be familiar to regular readers of this Specialist Periodical Report, and papers developing these long-running themes are usually given only brief coverage here. However, more thorough discussion is offered for papers where more significant synthetic work, and mechanistically-interesting results, are reported. Patent literature is almost wholly excluded, but this is easily reached through Section 34 of Chemical Abstracts, and other Sections (e.g. Section 16: Fermentations etc).
This Chapter is arranged into sections as used in all previous Volumes of this Specialist Periodical Report, and major Journals and Chemical Abstracts (to Volume 116, issue 11) have been scanned to reveal the material to be reviewed.
2 Textbooks and Reviews
Most of the citations of textbooks and reviews are located within appropriate Sections of this Chapter. Some books and monographs having broad relevance to several Sections of this Chapter, are collected here.
3 Naturally Occurring Amino Acids
3.1Methodology of Isolation of Amino Acids from Natural Sources
This Section covers a number of topics of increasing importance (though mostly simple in themselves). The generation of artefacts through extraction procedures applied to natural samples, and the ever more sensitive analytical methods used with amino acids, all factors that increase the scope for erroneous conclusions concerning the presence (or absence) of amino acids in natural sources.
Aqueous acidic hydrolysis of peptides can be accelerated by microwave irradiation, 3 and large-scale separation of amino acids from hydrolysates can be achieved using appropriately-designed ion-exchange columns or by reverse-phase flash chromatography. Large-scale crystallisation of L-asparagine from aqueous solutions has received detailed attention.
3.2Occurrence of Known Amino Acids
Topics in reviews include non-protein amino acids, the role of D-amino acids in the biosphere, and N-acylamino acids as components of bacterial lipids. An issue of Advances in Enzymology and Related Areas in Molecular Biology includes several reviews relevant to this Chapter [e.g. N5-(1-carboxyethyl)-L-ornithine and related opines in crown gall tumours, marine invertebrates, microorganisms, and ovothiols].
Perhaps the most spectacular example of the occurrence of a known amino acid is the presence of alanine in the Murchison meteorite – though known for many years, refined analytical methods now allow the additional, even more spectacular, knowledge to emerge, that the amount of the L-enantiomer exceeds that of D-alanine by about 18%. The result needs independent confirmation in another laboratory, but also needs independent proof that the amino acids in a meteorite (or in a fossil, for that matter) are indigenous; this is partly solved by stable isotope analysis, the 13C-content of the meteorite amino acid indicating extraterrestrial origin. The 15N-content of amino acids in fossil samples can be a useful monitor of indigeneity since this isotope is increasingly enriched up the food chain. These are welcome analytical checks on the authenticity of spectacular inferences made, based on the appearance of well-known amino acids in ancient samples – evolution of protein content being one such controversial topic – and another consideration is the chemical stability of the amino acids over such time-spans. The environmental decomposition of aspartic and glutamic acids, serine, alanine, and glycine in 1500y-old molluscan shells has been discussed.
Further examples given later (Section 6.1: Racemization) describe studies of protein amino acids in fossils, but several recent papers report the presence of some uncommon, but known, amino acids in contemporary natural sources. These include L-aminobutyric acid as C-terminal residue in nazumamide A, a thrombin-inhibitory peptide from the marine sponge Theonella sp., L-thiazolidine-5-carboxylic acid combined with L-proline in a new di-oxopiperazine (1) found in the Bermudan sponge Tedania ignis, another new di-oxopiperazine (2), a germacranolide – valine condensation product (the first of its type) from aerial parts of Centaurea aspera, and α-methyl-L-serine as a constituent of conagenin (3) from Streptomyces roseosporus. Lactacystin (4) is a new microbial metabolite that induces differentiation of neuroblastoma cells.
Further bromotyrosine – cysteine condensation products have been found in a marine sponge already shown to be rich in such psammaplins. Far-reaching revision has been necessary for structure assignments made to radish hypocotyl constituents, the raphanusins, thought to be piperidine-2-thiones (see Vol.23, p.3). Raphanusin B is now established to be the pyrrolidinethione (5).
3.3New Natural Amino Acids
Relatively simple aliphatic amino acids emerging for the first time include trans-4-methoxypipecolic acid (6) from the tropical legume, Inga Paterno, and trans-4-hydroxy-β-proline (7) from the red marine alga Furcinellaria lumbricalis. Phenol ring-opening (at C-2 – C-3, and at C-4 – C-5) of L-DOPA by an enzyme from the red peel of Amanita muscaria yields two (hitherto hypothetical) intermediates 2,3-secodopa and 4,5-secodopa (8) and (9) respectively. They must be regarded as still elusive since their existence was proved in this study on the basis of the isolation of reaction products muscaflavin and betalamic acid.
A novel addition to the natural biphenyl family is the aldose reductase inhibitor (10) from the fungus Humicola grisea, while the similarly-expanding bromotyrosine family has gained two new derivatives (11; R = H) and its ethyl ester.
Heterocyclic systems are represented by L-3-(2-carboxy-4-pyrrolyl) alanine (12) from the poisonous mushroom Clytocybe acromelalga, and near relatives (13), a novel fungal antibiotic (TAN-950A) [with (14) as minor component; structural proof supplied by synthesis from L-glutamic acid], and (15), the oxidative adduct from N-acetyl-L-histidine and N-acetyldopamine, but from very different sources. TAN-950A was isolated from Streptomyces platensis A-136, while (15) was formed in vitro through the action of the cuticle of silkmoth larvae as an enzyme source [(15) is suggested to be widespread in Nature though as yet not recognized to be a natural product]. S-[2-Carboxy-1-(1 H-imidazol-4-yl)ethyl]cysteine (16) has been located in normal human urine. It is suggested to be the precursor of its reductive de-amination product, recently discovered also in normal urine.
3.4New Amino Acids from Hydrolysates
As in previous Volumes, this Section is intended to include new amino acids that would be released from condensed structures (i.e. peptides and proteins, mostly) by hydrolysis (in principle if not readily achievable in practice).
Full details are available (cf Vol.23, p.3) of the new protein crosslink allodesmosine (from bovine lung, aorta and skin hydrolysates, as well as from elastin). As the name implies, this pentafunctional amino acid is structurally related to well-known crosslinking amino acid residues, and, like desmosine, contains a pyridinium moiety, being formed from one lysine and four allysine residues in the proteins.
Another reference back to earlier-published material is a correction of the structure of the antibiotic FR900148, revised from the pyrrolone isomer to (17). The opportunity was also taken to establish additional stereochemical details for (17), including the L-configuration shown).
The marine sponge Theonella (see also, preceding Section 3.2) bio-synthesizes thrombin-inhibitory factors cyclotheonamides A and B made up of proline, phenylalanine 2,3-diaminoptropionic acid, as well as a modified arginine residue (-CO- between the a-methine and COOH groupings) and a modified tyrosine residue (-CH=CH-between the α-methine and COOH groupings). 35 The sea urchin Tripneustes gratilla produces o-, m- and p-bromophenylalanine-containing peptides, the p-isomer being the only previously-known isomer.
New cyclic anti-tumour peptides trapoxins A and B (18) contain the surprising α-amino 6-epoxyacylhexanoic acid residue. These differ in the adjacent prolyl or pipecolyl residue.
More complex aliphatic amino acids (often heavily disguised) are represented in the newly-studied pyoverdin-type peptide siderophores (19) from Pseudomonas fluorescens E2.
4 Chemical Synthesis and Resolution of Amino Acids
4.1General Methods of Synthesis of α-Amino Acids
This Section offers representative examples from the 1991 literature of mostly well-established general methods. Later sections often reinforce the merits of some of these methods, by giving further examples, and no attempt is made to rank them here; but over the years reviewed in this Specialist Periodical Report, readers will have noticed the growing distinctions between the perennials and the annuals.
Amination reactions, e.g. the reaction of 2-bromopropanamide enantiomers with amines to give alanine amides, and conceptually-related azidation (3-fluoro-alanine from BrCH2CHBrCO2Me by BrF3, then NaN3 followed by catalytic hydrogenation) a similar approach to all isomeric 3-phenyl-serines and -iso-serines; and a very useful, long sought – but extremely hazardous! – regiospecific SN2 ring-opening of an alkoxycarbonyl epoxide using HN3-di-isopropylethylamine at room temperature (20 [right arrow] 21) are conventional ways of introducing a nitrogen functional group into an aliphatic substrate. They are joined by a new reagent, p-Me-C6H4-SO2-O-NHBoc, that may be converted into the N-lithio-derivative so as to offer a Boc-NH+ equivalent for α-amino acid synthesis; thus, reaction with the zinc enolate PhCH=C(OiPr)ZnMe gives isopropyl N-Boc-phenylglycinate but in only 35% yield. Time will tell whether the methodology can be improved (and simplified) so as to turn this promising method into a generally useful procedure.
A new α-amination method for aliphatic carboxylic acids, would be a suitable way of describing the rearrangement of N-acyl-N-methyl-hydroxylamine O-carbamates to α-amino acid N-methylamides under basic conditions. Yields are in the range 34 – 76% in the cases so far tried for this anionic hetero[3,3]-rearrangement (Scheme 1). Mercury-catalyzed cyclization of chiral amidals is also a new α-amination method, applied to αβ-unsaturated aliphatic carboxylic acids (Scheme 2).
Cobalt-catalyzed aminocarbonylation processes using Co2(CO)8 with CO and aldehydes, or equivalent gem-dihalogenoalkanes, continue to provide effective entry to α-amino acids. Use of acetamide as substrate leads to N-acetyl β-cyclopropylalanines and its β-methyl homologue, and use of diethylamine gives NN-diethylamino acid NN-diethylamides.
Alkylation of glycine derivatives is as popular as ever as a route to target α-amino acids. Diethyl acetamidomalonate has been employed in many laboratoriese.g.,221 including use in the synthesis of cis- and trans-pyrrolidine-2,4-dicarboxylic acid. These targets are viewed as cyclic analogues of glutamic acid, and similar objectives and methods are involved in the synthesis of all stereoisomers of related substituted prolines. Alkylation of diethyl acetamidomalonate has yielded 4,4-difluoro-threonine, and similar methodology has been applied, to syntheses of 3,6-dimethyldioxopiperazines (from dioxopiperazine and methyl magnesium carbonate), to ethyl α-azidoacetate [aldol reaction with 4-{(bis-t-butoxy)phosphonylmethyl}benzaldehyde and reduction of the resulting cinnamate], and to α-aminonitriles (readily alkylated by epibromhydrin, in contrast with acylated glycine esters, to give 2,3-methanoserines).
Schiff base alkylation is much used, especially in asymmetric synthesis (next Section), notable examples being based on Ph2C = NCH2CO2Et [synthesis of a "-CH=CH- for -S-S- replacement", viz. 6,6-pentamethylene-2-amino-Δ4,5M-suberic acid (22) in a cystine analogue], or on PhCH=NCH2CO2Et (alkylation in an aqueous organic medium). The imidate PhC(OEt) = NCH2CO2Et and the corresponding nitrile PhC(OEt)=NCH2CN undergo aldol condensation with an aldehyde, elaboration of the resulting oxazoline in conventional ways giving β-hydroxy-α-amino acids and α-hydroxymethylserines.
Interesting applications of the ring expansion of azetidin-2,3-diones to N-carboxyanhydrides, which amounts to a general synthesis of α-amino acids from β-amino acids, have perhaps been slow in coming. The example in Scheme 3 (see also Scheme 30) is representative of the method.
4.2Asymmetric Synthesis of α-Amino Acids
Many of the methods that are familiar to regular readers are found again here. They have, in their own way, become an aspect of general methods of synthesis of α-amino acids, and the text of this Section could be combined with that of the preceding section for readers seeking information on the broader overall current situation.
Numerous reviews have appeared: the use of carbohydrates as chiral auxiliaries in asymmetric synthesis of α-amino acids including synthesis of prolines and pipecolic acids and β- and γ-amino acids (including polyoxins); amino acids from chiral lithiated amides; and asymmetric hydroformylation. A brief general review of asymmetric synthesis of amino acids is available, accompanied by a review of asymmetric synthesis of statine.
Standard methods are being exercised in a number of laboratories. Alkylation of the bislactim ether illustrated in Scheme 4, and its enantiomer, for the synthesis of (2R)- and (2S)-2-amino-2-methylmalonic acid (chiral on account of 13C-isotopic substitution at one of the carboxyl carbon atoms), has been fully described following last year's preliminary account (Scheme displayed in Vol.23, pp.9,10). The method has also been used in syntheses of (2R,3S)-3-hydroxy-3-(2',3'-substituted-cyclopropyl)alanines through diastereoselective Simmons-Smith cyclo-propanation of the appropriate l -hydroxy-2-alkenyl bis-lactim ether (Scheme 4). Corresponding (2R,3S)-3-substituted serines have been obtained similarly, exploiting the CITi(NEt23-catalyzed addition of the bis-lactim ether (via) to a ketone. Both enantiomers of each member of a series of 2-alkyl-2,3-diaminopropanoic acids, and substituted phenylglycines, have been prepared by bis-lactim ether alkylation, the latter case involving arene-Mn complexes as nucleophiles.
Asymmetric alkylation of Schiff bases also features in several recent papers. The prodigious output continues, of examples based on alkylation of the Ni(II) complex of the (S)-2-[N(N '-benzylprolyl)aminobenz-aldehyde] Schiff base of glycine or alanine ethyl ester (cf. Vol.23, p. 15). Phenylalanine or α-methylphenylalanine obtained in this way through (S)-(2-aminomethyl)pyrrolidine catalysis of benzylation, are obtained in 33-87% yields but only 3-21% optical purity. Hydroxyalkylation using benzaldehydes gives (2S,3R) and (2R,3R)-β-phenylserines from isomeric starting materials. Curiously, while (2S,3S)-perfluoralkylserines are obtained in this way with perfluoroalkanals, the (2R,3S)-alkylserines are obtained when non-fluorinated alkanals are used under otherwise identical conditions with the same starting material. Fluorine-substituted benzaldehydes give a range of (2R,3S)-phenylserines carrying F-, F2CHO-, F3CO-, and F3C-substituents when used in this process. α-Methylserine has been obtained from the process based on the alanine Schiff base, similarly applied to the asymmetric synthesis of α-methyl-valine and α-methylglutamic acid through conventional alkyl halide alkylation; however, although aspartic acid and its α-methyl analogue were prepared analogously using ethyl bromoacetate as alkylation agent, the latter target could not be obtained from α-allylalanine.
(Continues...)
Excerpted from Amino Acids and Peptides Volume 24 by J.S. Davies. Copyright © 1993 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.
