Synthesis of γ,δ‐Aziridino α‐Amino Acid Derivatives and their Stereoselective Ring Transformation to 2‐(Aminomethyl)‐1‐aminocyclopropanecarboxylic Acid Derivatives

Abstract

1‐Benzyl‐2‐(bromomethyl)aziridine was successfully substituted with protected glycine esters to afford alkyl 3‐(N‐benzylaziridin‐2‐yl)‐2‐aminopropanoates, as constrained heterocyclic diamino acid derivatives, in good isolated yields. These new aziridines proved to be excellent building blocks for ring transformation to the corresponding stereochemically defined 2‐(aminomethyl)‐1‐aminocyclopropanecarboxylic acid derivatives, including methyl esters, piperidyl amides, and free carboxylic acids.

Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic Acid Carnosadines via Inter-intramolecular Double Alkylation with Optically Active 2-Methylaziridine Derivatives

“…The filtrate was concentrated in vacuo, and the resulting residue was purified by column chromatography on silica gel (eluted with hexane/acetone = 9:1) to afford the N-Alloc amine 3a (732 mg, 2.14 mmol, 77%) as a colorless oil. [ Ethyl (1S,5S)-3-tert-Butoxycarbonyl-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylate (11). Compound 11 was prepared from the carboxylic acid 10b (48.0 mg, 167 μmol) according to the procedure described above for 3a and was obtained in a 63% yield (28.3 mg, 105 μmol) as a colorless oil after purification by column chromatography on silica gel (eluted with hexane/EtOAc = 6:1).…”

“…10 However, there are no reports demonstrating the double alkylation using 2-substituted "aziridine" derivatives in one step. 11 Thus, tuning a protecting group on the aziridine nitrogen and a leaving group in 5 would be necessary to control the alkylation mode, providing 4 without losing the optical purity because routes A and B would give enantiomers. We initially surveyed stereo-controlled cyclopropane formation using optically active aziridines 5, and the details are summarized in Table 1.…”

“…Stereoselective formation of cyclopropane with malonate anion and optically active 2-substituted “epoxide” derivatives has been accomplished by both routes . However, there are no reports demonstrating the double alkylation using 2-substituted “aziridine” derivatives in one step . Thus, tuning a protecting group on the aziridine nitrogen and a leaving group in 5 would be necessary to control the alkylation mode, providing 4 without losing the optical purity because routes A and B would give enantiomers.…”