合成路线1

An alternative procedure for the preparation of the carbapenem system was based on the desulfurative ring contraction of a 1-aza-3-thiabicyclo[4.2.0]octane. The required diethyl (mercaptomethyl)malonate (XXI) was prepared by condensation of diethyl malonate (XVIII) with paraformaldehyde to give methylene malonate (XIX). Conjugate addition of thioacetic acid to (XIX) afforded thioester (XX) and subsequent acid hydrolysis yielded the desired mercaptomethyl derivative (XXI). Coupling of (XXI) with azetidinonepropionic acid (XXII) via activation with CDI generated thioester (XXIII). Oxalic acid chloride isobutyryloxymethyl ester (XXV) was obtained from isobutyryl chloride (XXIV) by condensation with paraformaldehyde, followed by reaction of the resulting chloromethylbutyrate with monobenzyl oxalate tetrabutylammonium salt, hydrogenolysis of the benzyl group and chlorination with oxalyl chloride. Coupling of this acid chloride (XXV) with azetidinone (XXIII) gave imide (XXVI), which was reduced to the hydroxy derivative (XXVII) with Zn and AcOH. After chlorination of (XXVII) with SOCl2 and pyridine, cleavage of the methylenemalonate group, followed by cyclization in the presence of Et3N gave rise to the bicyclic system (XXIX).