Unnatural amino acids. 3. Aziridinyl ketones from esters and amides of aziridine-2-carboxylic acids

Abstract

A series of N-substituted amides and esters of aziridine-2-carboxylic acids have been prepared and have been subjected to deprotonation with lithium diisopropylamide. The intermediate carbanions reacted more readily with the carbonyl groups of the substrates than with methyl iodide. So, in place of the expected amides or esters of methylaziridine-2-carboxylic acids, amides or esters of 2-aziridinylcarbonylaziridine-2-carboxylic acids were isolated.Keywords: aziridinyl ketones, esters and amides of aziridin-2-carboxylic acids, deprotonation.Esters and amides of aziridine-2-carboxylic acids are suitable starting materials for the preparation of derivatives of α-and β-amino acids after opening the aziridine ring [2,3]. Unlike other esters of α-amino acids, aziridine-2-carboxylates do not have a tendency to dimerize to form diketopiperazines. Our interest in esters and amides of aziridine-2-carboxylic acids is connected with the study of the conditions for deprotonation of the α-center of the aziridine ring to prepare sterically hindered cyclic unnatural α-amino acids, required for the synthesis of different derivatives of α-and β-amino acids.Deprotonation of esters of aziridine-2-carboxylic acid was first carried out by Seebach [4,5]. However isolation of the reaction products was unsuccessful. Only after moving to thiol esters was isolation of the products from the reactions with electrophiles successful [4]. In this paper [4]it was first postulated that carbanions were configurationally stable at low temperatures. In 1997 Vedejs published a paper on lithiated complexes of aziridines with BH 3 [6]. It was shown that the increased s-character of the CH bonds in the aziridine ring accelerated lithiation in position 2 of the aziridine ring, facilitating the reaction with electrophiles.The stability of carbanions in a series of esters of aziridine-2-carboxylic acids has been demonstrated recently [7,8]. A methoxymethyl protecting group on the aziridine nitrogen atom stabilizes the intermediate carbanion and permits the preparation of a series of 2-substituted esters of aziridine-2-carboxylic acids [8]. Alkylation of 3-substituted esters of 1-(diphenylmethyl)aziridine-2-carboxylic acids gave a mixture of 2-alkylated aziridines and diaziridinyl ketones [9].We have studied the deprotonation of derivatives of aziridine-2-carboxylic with different substituents in the aziridine ring to determine the limits of use of this reaction. As substituents we chose well known protecting groups which are readily removed after the reaction was completed. We have developed a method for synthesis of the 1-substituted dimethylamides of the aziridine-2-carboxylic acids 2a-c (scheme 1) required for this study.

An Easy Route to Aziridine Ketones and Carbinols

“…Hydroxylamines 3b–f were synthesized from corresponding esters 1 as described in [ 12 ] or from activated bis-Boc amides 2 according to the published procedure [ 24 ]. Aziridine-2-carboxylic acid amides 4a and 4b were obtained from the aziridine-2-carboxylic acid dimethylamide in accordance with the previous reports [ 8 ]. All reactions involving organolithium compounds were carried out under an argon atmosphere.…”

“…From our previous work [ 8 ], we knew that dimethyl amides 4a ( Scheme 2 ) and 4b (Scheme 4) were more readily available in comparison with Weinreb amides through direct aminolysis of corresponding methyl esters. In the synthesis of 2-aziridinylketones from N -protected N,N -dimethyl aziridine-2-carboxamides 4a,b as substrates, we have demonstrated comparable results in chemical yields and regioselectivity with the Weinreb amides described in the literature [ 11 , 12 , 13 ].…”

“…The unusual bond angles and shorter than normal sp 3 carbon bond in aziridines, combined with the strain in the three-membered ring and the electronegativity of the nitrogen atom, make these molecules interesting and powerful building blocks. Aziridines are excellent substrates for the selective synthesis of unnatural amino acids, amino alcohols and different heterocycles of biomedical interest [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. For this reason, easy access to 2-aziridinyl ketones and corresponding carbinols is highly necessary.…”