The overall objectives for the 12-15 years of this research program are: (A) to complete a unified, stereocontrolled synthetic approach to the FK506 family of potent immunosuppressants; (B) to execute an enantioselective construction of the related immunosuppressant rapamycin; and (C) to synthesize representative members of the furaquinocin class of cytotoxic antibiotics. As a key strategic element of the FK506 and rapamycin ventures, we will exploit stereospecific sigma-bond olefin constructions to address two significant shortcomings of other approaches to these complex targets: (1) poor stereoselectivity in Wittig and Horner-Emmons olefinations, and (2) inefficient coupling of advanced intermediates. 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. In conjunction with the FK506-rapamycin program, we plan to design and synthesize analogs of FK506 and rapamycin embodying the recently defined bound-state conformation of the effector domain of these drugs. The design of new and possibly more effective immunosuppressive agents should then be feasible. 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 by this proposal.
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