Marco Alpegiani

The carbonyl-carbonyl coupling route to penems : a stepwise analysis

Abstract Preparation and reactivity of novel azetidinyl(phosphoranylidene)acetates implicated in penem synthesis is discussed

2-Selenacephems and 1-dethia-1-selenapenems

Abstract The first selena nuclear analogues of β-lactam antibiotics have been synthesized and compared with their sulphur counterparts.

Desulphurative approaches to penem antibiotics. III. Synthesis and desulphurisation of 3-methyl-2-thiacephem-4-carboxylates

Abstract Displacement of leaving groups from a number of 2-oxo-azetidin-4-ylthio derivatives with sulphide or hydrosulphide salts conveniently affords 2-thiacephem, whose desulphurisation gives penems.

2-(Heteroaroma-substituted)methyl Penems. III. Nitrogen Derivatives

Synthese dhydroxy-1 methyl-6 X-CH 2 -2 penemecarboxylates-3 (avec X=N-heteryl, pyrrolidinio, pyridinio, acylamino, ureido, guanidino). Etude de leur activite antibacterienne

Desulphurative approaches to penem antibiotics. IV. Bromination of 3-methyl-2-thiacephems, a novel entry in the synthesis of potent antimicrobial agents

Abstract The 3-methyl group in 2-thiacephem-4-carboxylates can be brominated in good yield, thus providing access to a series of highly active penem antibiotics.

Desulphurative approaches to penem antibiotics. VI: From penam methyl esters to penem acetonyl esters: a fully conservative conversion

Abstract A straightforward conversion of penam methyl esters into penem acetonyl esters entailing incorporation of all the elements of the former into the latter is described.

Desulphurative approaches to penem antibiotics. V. 2-(Functionalized methyl)penems from 3-methylenecepham-1-oxides

Abstract 3-Methylenecepham-1-oxides are converted into 3-(functionalized methyl)-2-thiacephems, direct precursors of a group of valuable penem antibiotics.

Penems: some recent advances

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 Woodwards 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 carbanionic 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).

Desulphurative approaches to penem antibiotics. I. 4-acyldithioazetidin-2-ones via thermolysis of penicillin-derived sulphoxides

Abstract Thermolysis of penicillin-derived sulphoxides in the presence of thioacids offers a simple route to 4-acyldithioazetidin-2-ones, whose desulphurisatio yields key intermediates for the synthesis of penem antibiotics.

Desulphurative approaches to penem antibiotics. II. 4-acyldithioazetidin-2-ones from penicillin derived sulphenimides, thiolsulphonates and disulphides.

Abstract Displacement of different leaving groups from a number of 2-oxo-azetidin-4-ylthio derivatives with thioacids, followed by sulphur extrusion, provides a facile access to β-lactam thioesters and hence to penems.