Amino Acids and Peptides Volume 23

A Review of the Literature Published during 1990

By J.H. Jones

The Royal Society of Chemistry

Copyright © 1992 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85186-214-9

Contents

Chapter 1 Amino Acids By G C Barrett, 1,
Chapter 2 Peptide Synthesis By D T Elmore, 89,
Chapter 3 Analogue and Conformational Studies on Peptide Hormones and other Biologically Active Peptides By J S Davies, 156,
Chapter 4 Cyclic, Modified and Conjugated Peptides By J S Davies, 211,
Chapter 5 β-Lactam Antibiotic Chemistry By C H Frydrych, 249,
Chapter 6 Metal Complexes of Amino Acids and Peptides By R W Hay and K B Nolan, 297,

CHAPTER 1

Amino Acids

BY G.C. BARRETT

By G.C. Barrett

1 Introduction

This year’s literature on the chemistry and biochemistry of amino acids provides further proof of the ever-increasing rate of accumulation of new knowledge of these compounds. This expansion calls for increasing constraints on space allocated for the areas reviewed in this Chapter, which, as in earlier Volumes of this Specialist Periodical Report, emphasises papers covering the occurrence, chemistry and analysis of amino acids. Further narrowing is imposed within this context, only partial coverage being possible from what is judged to be routine literature. Biological areas such as the natural distribution and metabolism of well-known amino acids, for example, are not covered.

Patent literature is almost wholly excluded (but this is easily reached, mostly through Sections 16 and 34 of Chemical Abstracts). The Chapter is organised into a sequence of sections as used in all previous Volumes of this Specialist Periodical Report. Major Journals and Chemical Abstracts (to Volume 114, issue 11) have been scanned for the material to be reviewed.

2 Textbooks and Reviews

Textbook coverage of amino acids within plant biochemistry and biosynthesis- has appeared, as has a review of the taste properties (particularly sweetness) of amino acids. A clinical use for assay of 3-methylhistidine in urine, as a marker for skeletal muscle protein degradation, is discussed in a review of this amino acid. Reviews of γ-carboxyglutamic acid and selenocysteine have appeared, in the latter case giving the background to the claimed discovery of the gene for its tRNA. Cyclopropane-based amino acids (“2,3- and 3,4-methano-amino acids”) have been reviewed. Numerous other reviews of aspects of amino acid science have been published during the year under review, and references are located in the relevant sections of this Chapter,

A five-year retrospective survey on amino acids science has been published in the first issue of a new Journal “Amino Acids” (Springer Verlag, Vienna and New York) whose well-justified launch includes in its first Volume, abstracts of papers that were presented at the Second International Congress on Amino Acids and Analogues, Vienna, August 1991.

3 Naturally Occurring Amino Acids

3.1 Isolation of Amino Acids from Natural Sources. – Isolation of amino acids has a simple requirement, to be sustained by proper practice, that the integrity of the amino acid in the extract is preserved. The well-known problem – losses of certain amino acids during protein hydrolysis – has been controlled in many cases by improvements in protocols, Classical 6M-hydrochloric acid hydrolysis procedures can give good recovery of tryptophan if tryptamine is included in the hydrolysis cocktail, or if 3% phenol is added, However, comparisons with standards show that more than 20% destruction of tryptophan must still be expected even when using these additives, though there is some improvement in the recovery of methionine and carboxymethylcysteine in these methods. Microwave irradiation of hydrolysis mixtures helps, and vapour phase hydrolysis (7M-hydrochloric acid containing 10% trifluoroacetic acid, 20% thioglycol1ic acid, and indole) can give up to 75% recovery of tryptophan.

An extraordinary physical property – adsorption of the NαNe-bis(naphthalene-2,3-dicarboxaldehyde) derivative of lysine on to glass – is not shared by the Nα-mono-tagged amino acid, Thus, reductive alkylation of proteins (Ne-amino groups -> NN-dimethylamino) is recommended before acid hydrolysis, to avoid this “loss” of lysine residues in this increasingly popular derivatization method through this unexpected way.

Methanesulphonic acid (115°, 22h) continues to gain adherents for acid hydrolysis of proteins.

Care taken in preparative h.p.l.c, operations in processing aqueous extracts from fossil bones are described. Errors due to contamination are minimized if all collagen analyses are based on a single bone sample. An aqueous two-phase system (water – aqueous polyethyleneglycol) has been advocated for isolation of amino acids from fermentation broth.

3.2 New Natural Amino Acids. – Derivatives of protein amino acids that owe their exceptional biological activity to the overall structure of the derivative, with the amino acid moiety being merely the passive “carrier” of the derivatizing group, are not unusual, Amphikeumin (1) is an example of this class; it is a synomone, since it mediates partner-recognition between sea anemones and anemone-fish (and the fact that these words end in “-mone” is purely coincidental – synomone and pheromone, for example, have the same etymological base). The range of extraordinary natural thioamides present in roots of radish (takuan) has grown, one of the new ones being the tryptophan derivative (2), presumed to be formed from L-tryptophan and 4-methylthiobut-3-enyl isothiocyanate. The vinyl sulphide =CH-SMe in place of the tryptophanyl moiety and the corresponding vinyl ether are further examples.

A more complex heterocyclic system, though with equally suggestive biosynthetic origins, is represented in L-lupinic acid (3), isolated from the racemic amide through use of the aminopeptidase from Pseudomonas putida.

A new antifungal antibiotic (4) has had all its structural features verified through X-ray analysis of its N-CN-phenylthiocarbamoyl-L-phenylalanyl) derivative. “Pyrrolams” (5) and (6) are new simple pyrrolizidine alkaloids (from Streptomyces olivaceus) that can be recognized as cyclized proline homologues [but the absolute configuration in one case is (R), which might imply that proline itself is not on the biosynthetic pathway]. Amino alcohols are near relatives of amino acids, and as such, deserve brief mention in this section of this Chapter; xestoaminols A – C [B is (2S)-aminotetradeca-11, 13-dien-(3R)-ol, and A and C are its dihydro- and tetrahydro-derivatives, respectively) have been isolated from a Fijian sponge Xestospongia sp., and are positional isomers of compounds reported from similar sources in 1989.

3.3 New Amino Acids from Hydrolyzates. – The meaning intended to be conveyed by the title of this section, is the discovery of new groupings in larger structures that would, in principle, be released as a new amino acid by hydrolysis (in principle rather than necessarily in practice). A new penta-functional crosslinking amino acid, allodesmosine, has been identified in bovine ligamentum nuchae elastin. It is a pyridinium salt like its well-known near-relative crosslinking amino acid, desmosine, and arises by further processing of the reduced aldol condensation product of two allysine, and one lysine, residues in the protein. Pulcherosine (7) is a new trifunctional crosslinking amino acid from the fertilization envelope of the sea urchin embryo. It occurs alongside the other major tyrosine-derived crosslinks, dityrosine and tri-tyrosine, β-Aminoglutaric acid (“β-Glu”) is a constituent of marine methanogenic bacteria.

4 Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods for the Synthesis of α-Amino Acids. – The reworking of a promising reaction through time, until it becomes established to be more generally applicable, is recorded in several papers relevant to this Section. Also, the well-known general methods are shown to continue to hold their own through further examples of non-routine character, many of these examples being mentioned elsewhere in this Chapter – particularly in the next section ‘Asymmetric Synthesis’.

An α-halogenoglycine in a protected form is a useful synthon for α-amino acid synthesis, nucleophilic substitution by alkynyltin reagents Bu-SnC[equivalent to]CR giving βγ-alkynylglycines. The free alkynyl amino acids formed by deprotection were found in this study to be very labile but trapping experiments demonstrated that they had indeed been formed. N-Benzoyl-α-bromoglycine methyl ester readily undergoes nucleophilic substitution by side-chain functional groups in protected cysteines, serines, and threonines to give novel “cross-linking amino acids” (by which is meant, compounds with the potential for synthesizing peptides as models for cross-linked proteins). The N,O- and N,S-acetal structures formed in this way are relatively easily hydrolyzed, though the cysteine derivatives seem to show stability sufficient for some applications. N-Acetyl bromoglycine methyl ester has been used for a synthesis of L-2-amino-4-methoxy-cis-but-3-enoic acid by reaction with MeO. CH=CHLi. An alternative diethyl acetamidomalonate synthesis was reported later by the same workers [via the dimethylacetal of HCO.CH22. C(CO2Et)2NHAc -> (E)-MeOCH=CH.CH(NH2)CO2H, or -> MeOCH(OCOMe). CH2. CH(NH2)CO2H -> (Z)-MeOCH=CH.CH(NH2)CO2H].

The equivalent α-acetoxyglycines, e.g, Ph2C=NCH(OAc).CO2R, on condensation with malonate anions give protected β-carboxyaspartates, α-Keto-acid methyl esters can be condensed with benzyl carbamate to give protected αβ-unsaturated α-amino acids available also through Wittig condensation of aldehydes with α-phosphono-glycines (e.g. RCHO + ZNHCH(PO3Et2). CH(NH2)CO2Me) or from base-catalyzed eliminations from B-halogeno- or β-acetoxy-α-amino acids. An alternative amination procedure is illustrated in the condensation of diethyl azodicarboxylate with lithium dienolates; full details in support of the preliminary communication of this work (Vol. 22, p.7) stress the importance of choice of catalyst, tin salts giving α-amination products while germanium salts yield γ-amino acids.

Oxalic acid mono-amide, H2N.CO.CO2H, should be an α-cationic glycine equivalent suitable for Wittig olefination, and the preparation of a suitably protected form of it has been described, starting from oxalyl chloride, through reaction with t-butanol and collidine – benzophenone imine.

Further details (see Vol. 22, p.7) are available of the preparation of α-acylamino nitriles from Mannich-type condensation of benzotriazole with an aldehyde and an amide to give the substituted benzotriazole R1CONH.CHR2.Bt which gives the α-acylaminonitrile with an alkali metal cyanide. Conditions are used that should permit a variety of functions within the aldehyde component to survive the reaction and subsequent hydrolysis of the nitrile to an a-amino acid. The same intermediate is involved in a preparation of α-substituted acyl aminals when NH2 is used in place of cyanide.

The Ugi four-component condensation has been used in an extraordinary “high-pressure mode” in which highly-hindered amino acids are constructed in the form of their N-(Z-L-valyl) derivatives CZ-L-Val-OH + Ph.CH2.NH2 + R12CO + CN.CH2.CO2R2 -> Z-L-Val.N(CH2Ph).CR12.CO-Gly-OR2.

Alkylation of diethyl acetamidomalonate, using N-ferrocenylmethyl trimethylammonium iodide and NaOEt (reflux 45h to give N-acetyl β-ferrocenylalanine ethyl ester after work-up), or using long-chain halogenoalkanes, illustrate standard malonate applications. Improved routes to cis- and trans-3-substituted prolines (condensation of diethyl acetamidomalonate with an αβ-unsaturated aldehyde, and routine elaboration of the resulting 3-substituted 5-hydroxyproline) have been described. A similar approach provides 4-hydroxyproline and proline itself in a route involving reduction of the Michael adduct and cyclization of the derived toluene-p-sulphonate. A new 3-substituted proline synthesis (Scheme 1) depends on the propensity of ketene dithioacetals for carbanion formation and has been developed further for its potential in asymmetric synthesis (next Section, 4.2).

Similar alkylation procedures underpin other general methods, for example the phase-transfer catalyzed alkylation of Phi2C=N.CHR.CN with variously-substituted benzyl bromides followed by routine work-up. A chiral phase transfer catalyst has been used with little success (as far as enantiomeric discrimination is concerned) in catalyzed alkylation of Ph2C=N.CH2.CO2Et. The other type of Schiff base, e.g. R1N=CH.CO2R, gives C-alkylation products with Reformatzky reagents RZnBr. A different alkylation principle is involved in the conversion of the isocyanide CN.C(CO2Et)=CMe2 into 1-amino-2,2-dimethylcyclopropane carboxylic acid using trimethylsulphonium iodide and sodium hydride.

Exploitation of side-chain functionalized amino acids as synthons for preparing other amino acids has continued to develop into useful general methods in some cases, and many new examples could be created from efficient reactions performed on amino acid side-chains (see Section 6.3), N-Benzyloxycarbonyl-L-vinylglycine methyl ester, for which there are now reliable methods of synthesis not anticipated in the early days, is open to use in this way, [CH2=CH.CH(NHZ)CO2Me -> R1CH2CHR2CH(NHZ)CO2Me] and so, also, are N-protected aspartic and glutamic anhydrides, proposed as synthons for alanines from an observation that oxidative addition and decarbonylation processes result from heating in THF with nickel complexes (Scheme 2). Alkylation of the protected aspartic acid β-ester enolate and their condensation with aldehydes so as to give βγ-unsaturated α-amino acids, is fully described. A route from a protected L-aspartic acid to 2,3-diamino-4-phenylbutanoic acid via Curtius degradation of (8) involves benzylation of the β-carbanion with benzyl bromide, a process that is said to show higher diastereoselectivity than some analogous processes. Organocuprates react with DL-4-iodo-2-(t-butyloxcarbonylamino)-butanoates to give heterocyclic side-chain analogues, while the corresponding use of chiral imines (9) leads to a satisfactory excess of the L-enantiomer.

The Strecker synthesis, applied to 11-amino-2,2-dialkylcyclopropane-carboxylic acids, depends on the survival of the halogeno-alkyl moiety at the stage of preparation of the α-aminonitrile from the aldehyde ClCH2.CR1R2.CHO. An analogous route involves cyclopropane ring-closure of an α-chloro-imine CICR1R2.C(=NR)R3, A one-carbon homologation of aldehydes using (phenylthio)nitromethane is analogous to the Strecker synthesis but is claimed to be superior, especially for sensitive multifunctional synthesis targets such as the glycosylamino acid, polyoxin C (Scheme 3). A quite different route to this compound uses the “penaldic acid equivalent”, viz, 5-formyl N-butoxycarbonyl 2,2-dimethyl oxazolidinone (from L-serine) as protected amino acid moiety on which the glycoside moiety is constructed.

Bucherer-Bergs synthesis of 1-aminocyclohex-2-ene-1,3-dicarboxylic acid from the corresponding cyclohexenone has been reported, and this hydantoin alkylation route has also been used in a large-scale synthesis of phenylalanine (hydantoin is condensed with PhCHO). No “General Methods” section on amino acids would be complete without mention of the azlactone synthesis, in which alkylation of 2-phenyloxazolin-5(4H)-one, generated in situ from hippuric acid, has led to “the 1- and 2-naphthol analogues of tyrosine”, i.e. β-(4- and 6-hydroxy-l-naphthyl)alanines.

4.22 Asymmetric Synthesis of α-Amino Acids. – Following on the ‘General Methods’ approach of the preceding Section, there are many well-developed general asymmetric synthesis routes to a-amino acids. These include direct extensions of some of those methods mentioned in the preceding Section – e.g. the Strecker synthesis of cyanohydrins catalyzed by the dioxopiperazine derived from L-phenylalanyl-L-histidine – while other methods are more distantly related. Some of these have become fully explored, as seems to be the case with the Schöllkopf bis-lactim ether approach (exemplified in Scheme 4 for a synthesis, from the bis-lactim ether derived from L-alanyl-L-valine, of (2R)- and (2S)-[1-13C]-2-amino-2-methylmalonic acid) and they require less space this year since they have been illustrated often in this Section in preceding Volumes.

Good yields of homochiral α-amino acid esters are routinely formed by photolysis of chiral chromium aminocarbene complexes (formed from a tertiary amide and Na2Cr(CO)6 with TMSC1) in solution in an appropriate alkanol. Homochiral β-lactams are formed similarly through reaction of these complexes with imines. The topic continues to be well-reviewed (see also Vol. 22, p.8).

Chiral saturated heterocycles have occupied a firm niche in this Section, as vehicles for asymmetric synthesis of α-amino acids. Evans’ methodology based on lithiated (4R,5S)-4-methyl-S-phenyloxazolidinone has been used for a synthesis of (+)-(2S,3S)-ethynyltyrosine (Scheme 5) and an analogous oxazolidinone underpins the asymmetric double alkylation of the glycine derivative (10) en route to homochiral N-(L-phenylalanyl)amino acids. L-Serine gives the same chiral heterocyclic system carrying a 4-methoxycarbonyl grouping, christened a nucleophilic L-alaninol synthon since conversion into the Wittig reagent and condensation with aldehydes [CO2Me -> -CH2P-Ph3 I- -> HOCH2CH(NHBoc)CH=CHR as a result of ring-opening] occurs readily and with high stereoselectivity. Bromination (N-bromosuccinimide) of dibenzylboron enolates (11) derived from N-alkanoyl 4-benzyloxazolidin-2-ones, followed by electrophilic azidation (tetramethylguanidinium azide) gives (R)- or (S)-α-azidoalkanoic acids. The more convenient potassium enolate reacting with 2,4,6-tri-isopropylphenylsulphonyl azide is better than 90% diastereoselective (but dependent on the nature of the acylating grouping).

(Continues…)Excerpted from Amino Acids and Peptides Volume 23 by J.H. Jones. Copyright © 1992 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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