Synthetic Study of Antibiotic Aquayamycin, Biologically Active Sugar-Aromatic Hybrid

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Synthetic study of aquayamycin, an antibiotic which exhibits the hybid structure composed of sugar moiety and aromatic chromophore, was executed with the aim at exploring new direction of carbohydrate synthesis and aromatic synthesis.In the early stage of the program, we focused on pioneering the first generation route to aquayamycin. The O→C-glycoside rearrangement and the [2+2] cycloaddition of benzyne and ketene silyl acetal, both of which were originally developed by us, were successfully applied for synthesizing the AB ring fragment, i.e. a 3-(phenylsulfonyl)phthalide possessing the C-olivoside. The CD ring fragment, a highly oxygen-functionalized chiral cyclohexene, was synthesized in an enantiomerically pure form via the lipase-promoted asymmetric desymmetrization of cyclohexane-1,2,3-triol derivative as a key step. These two fragments were condensed by the Hauser's method to give the highly substituted 1-anthrone derivative possessing the C-olivoside moiety. Cyclization by pinacol coupling between the C(1) carbonyl of this anthrone and the aldehyde moiety on the side chain furnished the carved tetracyclic framework of the target molecule, and final functional group interconversions led to the accomplishment of the first total synthesis of aquayamycin.Further detailed studies ultimately shortened and revised the synthetic routes so as to render a multi-gram synthesis of each fragment.For the purpose of application to the synthesis of physiologically useful analogue, we also examined to develop new efficient promoter of C-glycosidation of amino sugar.Another significant finding was that scandium(III) triflate efficiently promotes aryl C-glycosidation of amino sugar derivatives, opening an opportunity of synthesizing physiologically useful analogues.