Stereospecific synthesis of a chiral intermediate for the preparation of thienamycin, penems, and carbapenems: use of the nitro group as a hydroxy protecting group

Abstract

Atotal stereo- and enantio-controlled synthesis of (3S,4R)-4-acetoxy-3-[(R)-1-hydroxyethyl]azetidin-2-one (1) from ethyl (S)-3-hydroxybutyrate is reported. A simple method of inversion and concomitant protection of the hydroxy function in the side chain is achieved. The synthesis starts with the conversion of ethyl (S)-3-hydroxybutyrate into the azetidinone derivatives (4) and (5)via a stereospecific imine-ester enolate cycloaddition. The resulting azetidinones, with unnatural configuration at C-l′ of the ethyl group were converted into the mesylates (8) and (9); these were further elaborated into the nitrate esters (10) and (11) with the natural configuration at C-1′. Sequential treatments of these compounds, with ozone, Jones' reagent, lead tetra-acetate, and cerium ammonium nitrate afforded as a sole product, in 24.8% overall yield, the chiral azetidinone (17). Finally, smooth removal of the nitric protecting group of the hydroxy function afforded, quantitatively, the azetidinone (1), a key intermediate for the preparation of thienamycin and its biologically active analogues.