This proposal is specifically aimed at the synthesis of the two marine natural products calyculin A (1), C50H81N4015P, isolated from the sponge Discodermia calyx, 1 and scytophycin C(2), C45H74NO10, from the blue-green alga Scytonema pseudohofmanni Bharadwaja. Both target molecules exhibit remarkable antitumor activity. For instance, calyculin in highly cytotoxic to tumor cells (IC50:1.75 x 10-3 mug/ml;L1210), while the minimum toxic doses of scytophycins against KB human epidermoid carcinoma and NIH/3T3 mouse fibroblast cell lines are 1 ng/mL and 0.65 ng/mL, respectively. This project, like its predecessor, concerns the synthesis of potential antitumor agents which meet two criteria: (1) their availability from natural sources is severely limited and more importantly, (2) they comprise synthetically attractive structural units, the construction of which appears feasible by the application of newly developed synthetic methods and/or reagents. Calyculin A and Scytophycin C do indeed display such characteristics and hence represent exciting synthetic targets. Both 1 and 2 consist largely of polyketides and numerous 1,3-diol units varying in structure and stereochemistry. The efficient construction of these repeating units now appears practical (even for complex molecules such as 1 and 2), using a full set of homochiral reagents, most of which have been developed over the past year for the stereoselective aldol reaction and allylboration. In addition to this polyketide problem, calyculin A comprises a novel spiro ketal of a rather unusual skeleton bearing phosphate, oxazole, nitrile, and amide functionalities, while scytophycin C is uniquely characterized by the presence of a N-methylformamide group. Functional group assembly in the final stages of both syntheses present a challenging task for which workable methods are proposed. Natural products continue to provide the testing grounds for concepts, synthetic strategies and methods. During the synthetic pursuit they further help identify fundamental problems yet to be investigated.
