The goal of this proposal is the development of artificial P-450 enzymes as a practical alternative to microbiological methods in the selective functionalization of steroids. Steroid pharmaceuticals play a prominent rote in the treatment of diseases ranging from arthritis to neuronal disorders. The continued identification of exciting biological activities from novel steroid natural products suggests that the potential for steroid scaffold-based drugs is far from being exhausted. The current manufacture of steroid medicinals relies heavily upon the ability of microorganisms to selectively oxidize steroid scaffolds. This proposal outlines strategies to efficiently synthesize novel sets of geometrically diverse hetero- and homogeneous catalysts that will mimic, and potentially surpass, the site-selective microbiological functionalization of steroids. In specific, groups of unique cyclophane thiols will be constructed in a modular fashion on polymer-support and then condensed with tetra(pentafluorophenyl)porphyrin (TFPP). These proposed cyclophane-fluoroporphyrin conjugates were designed to address the limitations of current P-450 mimics, namely (1) the proclivity toward oxidative degradation and (2) the limited range of positions on the steroid scaffold that can be functionalized.
