Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

Abstract

A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates was developed involving amination, bromination and base-induced cyclization of alkyl 2-(bromomethyl)acrylates. The aziridines are the kinetically favored cyclization products and could be transformed into 3-bromoazetidine-3-carboxylic acid derivatives via thermal isomerization. The new small-membered azaheterocyclic α-and β-amino acid derivatives contain a bromo-substituted carbon center as a useful moiety for functionalization.Transformation of these functionalized azaheterocycles via nucleophilic substitution with carbon, sulfur, oxygen and nitrogen nucleophiles and via elaboration of the amino and carboxyl group provided a broad range of new conformationally constrained aziridine-2-and azetidine-3-carboxylic acid derivatives which are of interest from a biological point-of-view as well as for applications in the field of foldamers.

Selective Elaboration of Aminodiols towards Small Ring α‐ and β‐Amino Acid Derivatives that Incorporate an Aziridine, Azetidine, or Epoxide Scaffold

“…To demonstrate the usefulness of the synthesized constrained C α ‐tetrasubstituted amino acid derivative 20 as a possible building block for the synthesis of peptides, it was subjected to hydrogenolysis and hydrolysis reactions 1c,21. The hydrogenolysis of 3‐azidoazetidine 20 by using 10 wt.‐% palladium on carbon in ethanol at room temperature for 30 min afforded ethyl 1‐tosyl‐3‐aminoazetidine‐3‐carboxylate ( 22 ) in 83 % yield.…”

“…Recently, our research group reported the synthesis of azetidines 5 , which are heterocyclic analogues of amino acid 4 and have an electron‐donating alkyl group at the azetidine nitrogen atom (Figure 3). 1c A subsequent investigation of the conformational features of these amino acid analogues in model peptides 6 and 7 led us to conclude that such a 3‐aminoazetidine‐3‐carboxylic acid moiety is a β‐turn inducer 21…”

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

“…Additional support for the occurrence of different isomeric cations has been provided by the ring expansion of 2‐(bromomethyl)aziridines 42 to the corresponding 3‐substituted azetidines 46 . In that study, the isomerization reaction of alkyl aziridine‐2‐carboxylates 42 to alkyl azetidine‐3‐carboxylates 45 has been investigated (Scheme ).…”

Recent advances in synthetic facets of immensely reactive azetidines

“…Best results in terms of yield was obtained via dropwise addition of Tf 2 O to a premixed solution of (R)-1,3-butanediol 14 and Hunig's base at À35 C followed by treatment with benzhydrylamine resulted in the formation of 18 which upon hydrogenolysis in the presence of palladium hydroxide to afford (S)-2-methylazetidine(R)-(À)-camphorsulfonate (CSA) 17 (Scheme 5). 10 De Kimpe and co-workers 11 have developed thermal isomerization of aziridines for the synthesis of 3-bromoazetidine-3-carboxylic acid derivatives. The key step involved the base promoted cyclization of dibromo amino esters 21 to yield the desired aziridines 22 and/or azetidines 23.…”

“…with Pd/C yielded the corresponding 3-aminoazetidine-3carboxylate 26 (Scheme 6). 11 The above methodology was further extended by De Kimpe and co-workers 14 to afford a facile access to 1-t-butyl-and 1-(4methylbenzyl)-3-bromo-3-methylazetidines as shown in Scheme 7. The synthetic approach followed a sequence of synthetic events with the key step involving the thermal isomerisation of aziridine 30 in acetonitrile to afford 3-bromoazetidine 31 (Path A).…”