The overall objectives for the 17-20 years of this research program are: (A) to achieve the total synthesis of breynin A, a glycoside closely related to the phyllanthostatin antitumor agents; (B) to complete syntheses of the antitumor antibiotics trienomycin A, B, and C; (C) to construct the cytotoxic sponge metabolite calyculin A; and (D) to develop an efficient route to the macrolactins, potent inhibitors of several pathogenic viruses including the human immunosuppressive virus (HIV). In addition to the proposed target work, we plan: (E) to embark upon a synthetic methods program employing substrate-derived dioxiranes for diastereoselective intramolecular epoxidation of keto olefins, as well as highly chemoselective remote oxidation of steroids and other substrates; and (F) to explore the utility of iodine monobromide for the Bartlett iodocarbonate cyclizations and related transformations. A central theme of these efforts is the development of novel synthetic strategies which are not single-target oriented, but instead will permit construction of entire classes of natural products. We believe that this philosophy of """"""""unified synthetic strategies will be further developed in this proposal. Beyond the specific synthetic objectives, a general, long-range aim of this program is the identification of molecular architecture responsible for the biological properties of these and related systems. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. The design of new and possibly more effective agents should then be feasible.
Showing the most recent 10 out of 61 publications
