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The synthesis and antimicrobial evaluation of novel bicyclomycin analogues are described. The series of analogues were prepared from the basic 8,10-diaza-2-oxabicyclo[4.2.2]decane-7,9-dione, 7,9-diaza-2-oxabicyclo[3.2.2]nonane-6,8-dione 8,10-diaza-5-methylene-2-oxabicyclo[4.2.2]decane-7,9-dione and 7,9-diaza-4-methylene-2-oxabicyclo[3.2.2]nonane-6,8-dione nuclei. For compounds where R1 = p-methoxybenzyl, deprotection of the lipophilic amides with ceric ammonium nitrate affords the corresponding lipophobic free amides. The basic bicyclic nucleus of bicyclomycin (8h, R1 = R2 = R3 = R4 = H) has been synthesized for the first time as well as increasingly more complex congeners bearing the C-6 OH, 5-methylene; C-1'-C-3' trihydroxyisobutyl group. In general, it has been found that the bicyclic nucleus of bicyclomycin is devoid of antimicrobial activity, the entire structure of bicyclomycin being generally obligate for activity. In one instance, the racemic analogue 10c (R1 = CH2Ph, R2 = OH, R3 = H) showed interesting antimicrobial activity against several Gram-positive organisms; the minimum inhibitory concentrations were of the same order of magnitude as bicyclomycin displays toward Gram-negative organisms. Totally synthetic (+/-)-bicyclomycin was half as active as the natural antibiotic. The design, synthesis, and antimicrobial activity (and/or lack thereof) of bicyclomycin and the analogues are discussed in the context of a proposed chemical mechanism of action.

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Disubstituted 2,5-piperazinediones (12) can be 3,6-dibrominated followed by displacement with sodium 2-mercaptopyridine to furnish sy -1,4-disubstituted 3,6-bis(2/-thiopyridyl)-2,5-piperazinediones (8) in high yield. Precomplexation of these sulfides with silver(I) triflate followed by addition of trimethylsilyl enol ethers leads to chemoselective C-C bond formation, furnishing the homologated piperazinediones 10. The remaining sulfide functionality of 10 is relatively inert to a second substitution. These electrophilic 2,5-piperazinediones provide access to relatively inaccessible, unsymmetrical 2,5-piperazinediones and provide advantages over the corresponding well-known enolate anion approach. Substrates that contain

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