A new class of penems, the 2-heterocyclyl(thio)methyl derivatives.

Sir: Within our primary program specifically oriented to the synthesis of new "2-CH2-X" penem compounds'), we have been engaged in an extensive work=.3> directed towards the simultaneous insertion of the thienamycin and cephalosporin side chains into the penem nucleus. In practice, the conceptual operation of incorporating the heterocyclyl(thio)methyl groups characterizing the most important cephalosporins into the 6-hydroxyethylpenem framework gave rise to a novel class of ji-lactam antibiotics 1 of remarkable antibacterial action'). According to WOODWARD'S strategy'), compounds of formula 1 were first approached from a 4-acetoxyazetidinone and the suitable heterocyclic thioethanthioic acids. More recently, however, we devised a straightforward and general route exploiting the pivotal hydroxymethylpenems 2a-c-•3> as common intermediates. For instance, reaction of 2c with mesyl chloride (CH,C1z, triethylamine, -40°C, few minutes), followed by aqueous NaHCO, work-up, afforded the mesyl derivative 2d; IR (CHCI3) cm-1 1795, 1705, 1590, 1360, 1175; UV nm (_) 328 (6,250). Sequential displacement with the heterocyclylthiol 38> (THF, triethylamine, 0°C, 3 hours), desilylation (Bu4NF • 3H50 3 mol equiv, AcOH 9 mol equiv, THF, 25'C, 20 hours) and Pd-mediated transallylation71 with sodium 2-ethylhexanoate gave 1t, isolated after reversephase chromatography (Merck LiChroprep RP18, water); 1H NMR (90 MHz, D-O) 6 1.30 (3H, d, J=6 Hz, CH>CH), 3.77 (IH, dd, J=1.8 and 6.5 Hz, H-6), 4.18 (1H, m, H-8), 4.55 (2H, br s, CH5S), 5.50 (1H, d, J=1.8 Hz, H-5), 6.50 (1H, s, Ar); IR (KBr) cm-1 3500-3150, 1760, 1660, 1625; UV i.HS„nm (s) 262 (11,170), 299 (10,180). The in vitro antimicrobial activity of the new penems against a selection of most representative Gram-positive and Gram-negative bacteria is reported in Table 1. Apart from the tetrazolecarboxylic acid derivatives 1c, d, all compounds were particularly active against Gram-positive bacteria, whereas activity against Gram-negative strains, being inferior by at least one order of magnitude, ranged from moderate to good. The tetrazole (1a, b, eg) and triazinone (lo, p) derivatives ranked among the most interesting compounds for broadness of antibacterial spectrum, specific activity and resistance to ;5-