Practical preparation of enantiopure 2-methyl-azetidine-2-carboxylic acid; a γ-turn promoter

A robust and practical synthesis of each enantiomer of 2-methyl-azetidine-2-carboxylic acid, based on the use of (S)-phenylglycinol as resolving agent, is described. This synthesis affords practical quantities of this quaternary amino acid suitably N- and C-protected for use in further peptide coupling. Synthetic highlights include the formation of the azetidine ring by intramolecular alkylation and the facile separation of the diastereoisomeric amides derived from phenylglycinol.

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(S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) esterC20H19NO4[α]D25=-82 (c 1, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (2S)

(S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-benzyl esterC21H24NO4[α]D25=-88 (c 1.1, CHCl3)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (2S)

(S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl esterC12H17NO4[α]D25=-126 (c 0.5, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (2S)

(S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-tert butyl ester 2-methyl esterC11H19NO2[α]D25=+36 (c 3.3, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (2S)

(S)-1-Benzyl-2-methyl-azetidine-2-carboxylic acid methyl esterC13H17NO2[α]D25=+47 (c 1.1, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (2S)

(1S,2S)-1-(2-tert-Butoxycarbonylamino-propionyl)-2-methyl-azetidine-2-carboxylic acid methyl esterC12H24N2O5[α]D25=-64 (c 1.5, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (1S,2S)

(1S,2R)-1-(2-tert-Butoxycarbonylamino-propionyl)-2-methyl-azetidine-2-carboxylic acid methyl esterC12H24N2O5[α]D25=+27 (c 1.6, CH2Cl2)Source of chirality: (S)-phenyl glycinolAbsolute configuration: (1S,2R)