Efficient route to (S)-azetidine-2-carboxylic acid.
A new and efficient route to (S)-azetidine-2-carboxylic acid (>99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1'-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1'S)-1-(1'-methyl)benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1'S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1'S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent re-protonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1'S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1'S)- and (2R,1'S)-isomers.
Futamura
Yasuhiko
Y
Department of Chemistry, Keio University, Hiyoshi, Yokohama, Japan.
Kurokawa
Masayuki
M
Obata
Rika
R
Nishiyama
Shigeru
S
Sugai
Takeshi
T
D000598:Amino Acids, Cyclic / Q000138:chemical synthesis; D001383:Azetidinecarboxylic Acid / Q000138:chemical synthesis*; D003500:Cyclization; D013237:Stereoisomerism
D000598:Amino Acids, Cyclic; D001383:Azetidinecarboxylic Acid