The overall objective of the proposed research is total synthesis of spatol. More importantly, the synthesis would provide: (1) means for preparing modified derivatives, not available from biological sources, which would exhibit higher therapeutic ratios and selectivities than the natural product, and (2) ready access to radiolabeled derivatives which are valuable for studying the binding of such molecules and analogues with biological macromolecules as well as the transport and metabolism of these new drugs. Our synthetic strategies for spatol involve rapid and efficient stereoselective construction of the cis-anti-cis-tricyclo[5.3.0.02,6]decane nucleus by photocycloaddition. In one approach the correct relative stereochemistry at carbons 4, 5, 8, 9, and 10 is assured by the temporary bridge of a bicyclo[2.2.1]hept-5-en-2-one intermediate. Preliminary results show that the required isomers generated in the key photoreaction are readily obtained pure and in good yield. In a second, more convergent strategy, a temporary bridge between C-11 and C-15 of enantiomerically pure cyclopentene intermediates assures the correct absolute stereochemistry at carbons 1, 4, 7, 8, 9, and 10. Remote hydroxyl group directed hydride reductions provide novel solutions for the remaining stereocontrol required by these strategies for the tricyclic spatol nucleus. Stereocontrol during construction of the allylic diepoxide side chain will be achieved by a combination of stereoselective partial hydrogenation of a 15,16-alkyne and highly stereoselective reactions of modern chiral reagents. Control of absolute configurations in the side chain would not rely upon the remote asymmetry located in the tricyclic nucleus. Spatol inhibits cell division in human T242 Melanoma and 224C Astrocytoma neoplastic cell lines. Therefore, we consider this novel diterpenoid natural diepoxide to be a template for the design of chemotherapeutic agents for, inter alia, human skin and brain tumor inhibitors. The management and cure of brain and other central nervous system cancer by chemotherapy are very urgently needed. Hopefully, with the use of spatol or analogues crossing the blood-brain barrier, this most worthwhile goal will be realized. The antitumor activity of spatol probably involves inhibition of mitotic spindle formation via inhibition of tubulin polymerization since this cytotoxin also is a potent inhibitor of the synchronous cell division of the fertilized sea urchin egg. This biological action is also a characteristic of several potent antitumor agents, including colchicine, maytansine, vincristine and vinblastine, which have proven clinically useful.
