The chemical reactivity of the clinically important antibiotic bicyclomycin (1) with thiols has been investigated. Emphasis has been placed on discerning the product profiles obtained with cysteine derivatives in light of earlier projections on the likely in vivo biological nucleophile in bicyclomycin-mediated transformations. Three different types of products were observed as a function of "pH". At near neutral 'pH" values, the novel piperidinedione adducts 16 were generated stereospecifically and efficiently. Correspondingly, under moderately basic conditions ("pH" 10.2-10.5), the direct C(5a)-substituted compounds 14 were observed as the predominant products, while at higher pH values (pH 12.5) the ring-opened adducts 13 were isolated. New information concerning the importance of the C( I)-triol group in the C(5)-C(5a) functionalization process was also secured by comparing the reactivity of the two bicyclomycin derivatives: 3'-S-ethylbicyclomycin (2) and bicyclomycin-2',3'-acetonide (4) versus 1. Both 2 and 4 did not react with thiols at room temperature at near neutral "pH". Elevation of the "pH" to 10.2 led to the formation of the corresponding C(5a)-direct-substitution adducts. In no cases were piperidinedione products (Le., 16) observed. Correspondingly, dissolution of 1,2, and 4, respectively, in '*O-enriched water-tetrahydrofuran mixtures ("pH" 7.8 and 10.2) in the absence of thiols led to substantial amounts of l8O incorporation in recovered samples of 1, but not 2 and 4. Analysis of the composite data permitted an unifying mechanism to be proposed for thiolate-induced bicyclomycin processes. Furthermore, the role(s) of the C( 1)-triol substituent in these transformations is discussed.

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Atomic coordinates, temperature factors, bond lengths, and bond angles for lc-HN3 (4 pages); structure factors for dimethyldioxo [16]aneN5-HN3 (20 pages). Ordering information is given on any current masthead page.

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