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The synthesis of the unsymmetrical biphenyls 40 and 25 has been carried out b y the palladium(o) catalysed coupling of the aryl boronic acid derivatives 5 and 20 with the aryl bromides 9 and 23 derived from (R) -4hydroxyphenylglycine and (S) -tyrosine. In the former case unsuccessful attempts were made to bring about cyclization to compound 4 which is an analogue of the biphenyl ring system found in vancomycin. In the latter case, a variety of cyclization methods were used to give the cyclic products 34 and 35 which are analogues of the biphenomycin antibiotics.

A series of 6-(substituted oxyethyl)penem esters having the (5S) stereochemistry which are potent inhibitors of Escherichia coli leader peptidase is described. Structure-activity relationships are discussed.Protein secretion in bacteria is becoming a pathway of widespread interest for the derivation of antibacterial agents1}. The final destination of considerable quantities of protein (up to 20%) synthesised by bacteria lies outside the cytoplasm. The cytoplasmic membranerepresents a hydrophobic barrier which must be crossed by all of these proteins. Signal peptidases ensure release of secreted proteins from the outer surface of the plasma membrane by removal of the hydrophobic signal sequence, or cleavable membrane anchor, from the pre-proteins2). These signal peptidases represent attractive targets for novel antibacterial agents.In E. coli there appears to be an essential enzyme, leader peptidase, which fulfils the signal peptidase function3'4). It is anchored to the membrane by two hydrophobic domains and the catalytic portion of the molecule is located in the periplasm5). Wehave reported briefly that C-3 esters and amides of penems having the 5S stereochemistry are inhibitors of E. coli leader peptidase, and that of particular interest were the 6-substituted penems (la and lb), with 5S, 65, YR stereochemistry6). We now wish to report the synthesis and structure-activity relationships of a series of derivatives of la. ChemistryIt appeared that an efficient approach to the synthesis of homochiral 5S penems could make use of well established methods for synthesis of 5R penems followed by a photoisomerisation at C-57). Thus the preparation of la was from the monocyclic /Mactam (2)8). The 5R penem system was built up by the commonlyused phosphorane route, and then subjected to UVirradiation from a mediumpressure lamp to provide an equilibrium Reagents: (i) allyl glyoxylate, (ii) SOC12, 2,6-lutidine, (iii) PPh3, 2,6-lutidine (70% for i~iii), (iv) AgNO3, pyridine, MeOH, (v) acetic formic anhydride, DMAP, Et3NHCl (85% for iv~v), (vi) hv (62%), (vii) Bu4NF, HOAc (95%).

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