Acylenamino Acid Derivatives

Assignments of the configuration of acylenamino acid derivatives depend mainly on H-NMR spectroscopic measurements, in particular because the influence of the carboxy and acylamino substituents on the chemical shifts of P-alkyl and vinyl protons. Thus Brown and Smale (75) have shown that the vinyl proton in 2-benzamido- and 2-phthalimido-crotonic acid esters absorbs at lower field when it and the acylamino group are mutually cis E isomer). The configurational assignments deduced in this study from the chemical shifts of the P-methyl protons must however be corrected (see below). 

IV. Synthesis of Dehydroamino Acid Derivatives A. Acylenamino Acid Derivatives... 

One of the earliest known syntheses of acylenamino acid derivatives (11) consists of the ring opening of 4-alkylidene-(aralkylidene-)-A -oxazolin-5-ones (10) by attack of a nucleophile HY on the carbonyl group. As nucleophiles also readily add to the exocyclic double bond of... 

Riordan and Stammer (335, 336) employed o-chloranil to oxidize saturated A -oxazolinones, and obtained dioxinones. Treatment of the latter with nucleophiles such as CH3O", PhNH2 or PhCH2SH afforded a-substituted amino acid derivatives, possibly by addition to the acylimine in equilibrium with the quinone adduct. Use of a non-nucleophilic base coupled with scavenging of the phenolic hydroxy groups by etherification made possible the isolation of acylenamino acid derivatives. 

O, D) A hypothetical pathway is the formation of an acylimino acid unit by N-hydroxylation of the amino acid within the peptide chain followed by loss of water. a-Acylimino carboxylic acid derivatives readily rearrange to acylenamino carboxylic acid derivatives 314). N-Hydroxy compounds, such as mycelianamide and pulcherrimic acid [for a review on cyclic hydroxamic acids see ref. (26)], have been found within the class of dehydrocyclopeptides. Although N-hydroxypyra-zinones are common, it is not known whether these compounds are biogenetically linked with the piperazinediones. It is appropriate to point out that N-hydroxylation of amides is a familiar degradative pathway in the metabolic processes of higher organisms 412). The facile elimination of water from N-acylhydroxylamino acids to form acylenamino acids 377) should also be noted in this context. 

A synthesis of acylenamino carboxylic acids from acylamino acids has been described by Poisel and Schmidt 310,312,313). Acylamino acid esters are N-chlorinated with t-butylhypochlorite in the presence of catalytic quantities of base. A full equivalent of base can then be used to eliminate HCl, with the initial formation of acylimino esters as unstable primary products which then either add solvent (alcohol) to form a-acylamino-a-alkoxy acid derivatives (22), or (in the absence of protic solvents) rearrange to the acylenamino acid esters (21). The a-acylamino-a-methoxy carboxylic acid (22) esters can also be converted... 

Acylenamino Carboxylic Acid Derivatives From N-Hydroxyamino Acid... 

Acylenamino Carboxylic Acid Derivatives by Chain Lengthening of -Halo-a-acylaminoacrylic Acid Derivatives... 

This reaction has been studied in some detail by H. Poisel and U. Schmidt 310, 312, 314), using several acylamino acid esters, a-Methoxy derivatives (22) were obtained from the N-chloro compounds on elimination of HCl with CHaO /CHaOH, while treatment with non-nucleophilic bases in aprotic solvents afforded acylenamino acid esters (21). Acylimino acids were undoubtedly primary elimination products, although it proved impossible to detect them. 

The double bond of N-acylenamino acids and their esters represents the locus minoris resistentiae . As a result of conjugation with the carboxyl group, the double bond is a good acceptor for nucleophilic addends under basic catalysis. The acylamino group makes electrophilic additions possible. It is thus possible to obtain a- or P-mercapto a-amino acid derivatives by selecting the appropriate reaction conditions for the addition of mercaptans. 

Acylenamino Derivatives by N-ChlorinationjDehydrochlorination of Acyl Amino Acid Esters... 

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