Aziridine-2-carboxylic acids, synthesis

Only one report is concerned with the synthesis, molecular structure, and X-ray analysis of this ring system as 2 (86KGS477). The synthesis of 2 was achieved by the cyclization of 2-aziridine carboxylic acid hydrazide with acetone as shown in Scheme 2. 

Very recently, an asymmetric synthesis of enantiomerically pure aziridine carboxylic acid derivatives has been published based on a similar reaction type starting from the corresponding a-bromo acrylic acid derivatives135. 

Scheme 2 Synthesis of Aziridine-2-carboxylic Acids via the Serine and Threonine C-Sulfonates 41 44 47 65"671...

The Gabriel-Cromwell reaction of amines with chiral c/., 3-unsaturated a-bromo carbonyl compounds was exploited for the synthesis of aziridine-2-carboxylic acid derivatives. 79 This procedure was optimized for a solid support synthesis in which the peptide resin was acylated with 2,3-dibromopropanoic acid active ester in the presence of 3 equivalents of NMM to produce directly on resin the a-bromoacrylamide for the addition of amines to produce the aziridine ring. 80 ... 

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of c/s-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559. 

Biotransformation can serve as an alternative route towards enantiopure aziridines. (1R,25)-1 -Benzyl- and l-arylaziridine-2-carboxamides were obtained in enantiomerically pure form via kinetic resolution of their racemates by Rhodococcus rhodochrous IFO 15564 catalyzed hydrolysis <07OF521>. Rhodococcus erythropolis AJ270 was reported as an efficient whole cell catalyst for the synthesis of highly enantiopure 5,-l-arylaziridine-2-carboxamides and A-l-arylaziridine-2-carboxylic acids <07JOC2040>. Enantiopure 2-... 

Many methods have been developed for p-lactam synthesis, including cyclisation of the corresponding amino acids. The most widely used methods are two-component couplings, which occur via concerted cycloaddition or two-step mechanisms. Another simple route to 3-functionalised azetidinones is the reaction of aziridine-2-carboxylic acid sodium salt with oxalyl chloride or thionyl chloride. ... 

Preparation.- 4.1.1. Cyclisation. Dehydrohalogenation of (228) in aqueous LiOH at roan tenperature gives (229) (95 ) . This method has been applied to the synthesis of a number of aziridine-2-carboxylic acid... 

Carboxylic acids also add to the C=N double bond and the products rearrange to more stable compounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions [15] ... 

In a similar vein, Davis and co-workers have found the p-toluenesulf nyl group to be useful for such purposes. Aziridine-2-carboxylic acid derivatives 138 are prepared in high diastereomeric purity by a Darzens-type reaction of the lithium enolate of methyl bromoacetate (137) with enantiopure sulfrnimines (e.g., 136) [94JOC3243]. These compounds have been employed as intermediates in the asymmetric synthesis of the antibiotic (+)-thiamphenicol (139) [94TL7525]. 

An asymmetric s)mthesis of 5-isopropyloxazoline-4-carboxylic acid methyl ester (164) was performed through the ring expansion on N-acylaziridine (163). The synthesis started from 4-methylpentenoyl imidate 161 that underwent 1,4-addition of 0-benzylhydroxylamine. Ring closure, activation of the aziridine and final ring expansion catalysed by BF3.Et20 afforded the desired compound <01TA563>. 

In one of the earliest attempts, Henery-Logan and Limburg reported the synthesis of A -phenylaceturylaziridine-2-carboxylic acid from benzyl a,0-dibromo-proprionate [255]. Due to its aziridine ring, this compound may be considered... 

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