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Synthesis of 3,3-dimethylazetidine-2-carboxylic acid and some derivatives

par De Kimpe, Norbert;Boeykens, Marc;Tourwe, Dirk
Référence Tetrahedron, 54, 11, page (2619-2630)
Publication Publié, 1998-03

Article révisé par les pairs

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Résumé :

γ-Chloro-α-(N-alkylimino)esters were reduced by sodium cyanoborohydride in methanol in the presence of acetic acid with complete selectivity to give rise to either γ-chloro-α-(N-alkylamino)esters (reaction at 0°C) or 1-alkyl-3,3-dimethylazetidine-2-carboxylic esters (reaction at reflux). The isolable γ-chloro-α-(N-alkylamino)esters are suitable sources for I-(N-alkylamino)-2,2-dimethylcyclopropane-1-carboxylic esters via base-induced 1,3-dehydrochlorination, while the former substrates as transient species undergo 1,4-dehydrochlorination to the corresponding azetidines. The latter process was used for the synthesis of 3,3-dimethylazetidine-2-carboxylic acid, a new non-proteinogenic sterically hindered α-amino acid, via hydrogenolysis of methyl 1-benzyl-3,3-dimethylazetidine-1-carboxylate and subsequent acidic hydrolysis. Reduction of alkyl 4-chloro-3,3-dimethyl-α-(N-alkylimino)butanoates with lithiumaluminiumhydride in diethyl ether afforded 1-alkyl-3,3-dimethyl-2-(hydroxymethyl)-azetidines.