ChemInform Abstract: Penems: Some Recent Advances

Abstract

Recent advances in penem synthesis are presented, with particular attention to the 2-CH2X derivatives. Two main approaches to the thiazoline ring of penems are discussed, the desulphurization or desulphonylation of their six-membered sulphur analogues and a double—bond forming strategy based on a new type of reductive carbonyl condensation. Generation of the appropriate azetidinone thioester intermediates from penicillins has become the discriminating step for the selection of the manufacturing procedure of our clinical candidate, FCE 22101. The penems are not found in nature. They were created as a nuclear hybrid by combining in a single molecule both structural elements essential for the chemical reactivity and biological activity of penicillins and cephalosporins: namely, the hindered amide resonance imposed by the nonplanar skeleton of the former and the competing enamine resonance operative in the latter (ref. 1). Beside the nucleus, a second combination of structural elements appeared appropriate for the side chains. Today, the structure of many remarkable penems reveals something that I venture to call a double hybrid nature: a first group of biologically promising products are inspired by thienamycin at C6 and cephalosporins at C2, and a second one by thiena— mycin alone for both substituents (Fig. 1). CEPHALOSPOR INS R-C-NH,5 THIENAMYCIN OH N / X=OCONH,.R=Na FCE 22101 0 X=ocoNH,, H C0,H R=CH,OCOCH, FCE 22891 Fig. 1. Remarkable penems from RcNHss THIENAMYCIN double hybridization. CO,H XH Sch 29482 X=OCONH, Sch 34343 We focused our research in the former direction, in the effort of reproducing the enhancement of antibacterial activity that in cephalosporins is associated with the inductive effect and leaving group ability of the C3' substituent (ref. 2). The carbamate FCE 22101 is the most advanced product along this line, together with its orally adsorbed acetoxymethyl ester pro— drug FCE 22891 (ref. 3), and newer products are being actively examined. In ten years, some advances over the pioneering Woodward's work have been achieved. Nonetheless, the chemical ways by which this highly strained skeleton can be assembled remain very limited in number. If we arrange them according to the bond which is made last (Fig. 2), we are left with only two main approaches: the 2,3 and the 1,5 bond—forming strategies. The latter suffers from obvious problems of stereocontrol and we shall marginally discuss it when dealing with the 2—thiacephem ring contraction. The former can be divided into Wittig—type reactions (the phosphorane—thioester approach originally devised by Woodward) and routes, where the active N—acetate methylene acts as a nucleophile on a trigonal carbon centre. The thienamycin—inspired penems are conveniently prepared from 2—thioxopenams (ref. 4) arising through carbanionic routes (Fig. 2, X= S, X'= OPh), but this is not the case for other types of 2—substituted penems, and the products object of our interest had to wait for the inventiveness of Prof. Hanessian before being accessible by this strategy (ref. 5).