SYNTHESIS OF ADRIAMYCIN SUGARS AND THIENAMYCIN

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Adriamycin, a member of the anthracycline family of antibiotics, has been found to be highly effective against a wide variety of cancers. Thienamycin is a Beta-lactam antibiotic isolated from streptomyces cattleya that has shown unusually high potency against both gram-positive and gram-negative bacteria. The chirality in these molecules plays a crucial role in their biological activities. Hence the synthesis of the optically active forms of these compounds is important. We have recently developed two new methods for preparing optically-active molecules: asymmetric reductions via trialkylboranes, and control of stereochemistry at the migration terminus of organoborate rearrangements. The asymmetric reduction of propargyl ketones makes essentially optically-pure propargyl alcohols readily available, and the acetylene handle makes alcohols attractive intermediates for further elaboration. The study of organoborane rearrangements has made optically-active allylboranes readily accessible for the first time. Addition of these organoboranes to a ketone or aldehyde produces optically-active alcohols with several contiguous chiral centers. These processes will be used in a novel lactone ring expansion reaction that provides a series of closely related chiral lactones that can be applied to both thienamycin and the sugar portion of adriamycin.