Enantiospecific synthesis of 4-alkoxyazetidin-2-ones

Abstract

4-Alkoxyazetidin-2-ones were obtained by thermolysis of N-unsubstituted 4-alkylsulphinyl- and 4-benzothiazolylthio-azetidin-2-ones in the presence of a primary, secondary, or tertiary alcohol. The configuration of the incoming alkoxy group is controlled by the stereochemistry of the substituent at position-3 and a trans relationship between the two groups results. Thus, the thermally induced substitution at position-4 of (3R,4R,5S)-4-(2-methoxycarbonylethyl)sulphinyl-3-phthalimidoazetidin-2-one (6) and (3R,4S)-4-benzothiazol-2-ylthio-3-phthalimidoazetidin-2-one (7) by ethanol and pentan-3-ol afforded stereospecifically the corresponding (3S,4S)-4-alkoxy-3-phthalimidoazetidin-2-ones (14) and (15). Similarly (3S,4R)-3-chloro-4-methylsulphinylazetidin-2-one (17) was substituted by 2-methylbut-3-yn-2-ol to give (3R,4R)-3-chloro-4-(2-methylbut-3-yn-2-yloxy) azetidin-2-one (21) and by pentan-3-ol to give mainly (3R,4R)-3-chloro-4-(1-ethylpropoxy) azetidin-2-one (22). Nitrogen protection followed by chlorine reduction of (22) afforded the enantiomerically pure (4R)-(1-ethylpropoxy) azetidin-2-one (27).