Comparative Studies on the Reactivity of 4-Methylene-1-oxa-6,9-diazaspirodecane-7,10-dione, 1-Acetyl-3-hydroxy-3-vinyl-2,5-piperazinedione, and Bicyclomycin. Examination of a Key Structural Element Necessary for Bicyclomycin-Mediated Transformations

Article abstract of DOI:10.1021/jo00039a028

Two select mimics, 4-methylene-1-oxa-6,9-diazaspiro<4,5>decane-7,10-dione (8) and 1-acetyl-3-hydroxy-3-vinyl-2,5-piperazinedione (7) of the structurally novel antibiotic, bicyclomycin (1), have been prepared.Comparison of the chemical reactivity of 7 versus 1 both in the presence and absence of added nucleophiles at various "pH" values has been provided important new information concerning the role of key structural elements present in bicyclomycin.The product profiles determined for 7 indicated that modification of the terminal double bond proceeded through an α,β-unsaturated ring imine intermediate (i.e., 43).Correspondingly, activation of the exo-methylene group in bicyclomycin is believed to occur through initial hemiaminal bond scission to give a ring-opened α,β-unsaturated carbonyl species (i.e., 2).Functionalization of the terminal double bond in 7 has been shown to proceed under milder conditions than that required for 1.These results demonstrated that incorporation of the exo-methylene group within the O(2)-C(3)-C(4)-C(5) bridge in 1 required that the terminal double bond activation pathway procced by an alternative, energetically more-demanding pathway than that observed for 7.Ramifications of the decreased reactivity noted for 1 are to allow other functional groups (i.e., the C(1)-triol moiety) in the antibiotic to have important catalytic roles in the drug modification processes and to permit thiolate species (the proposed biological targets?) to effectively compete with other nucleophiles for 2.