Efforts toward a stereocontrolled synthesis of CYP3A4 inhibitor GF-I-1 and stereoisomers

Abstract

Several furocoumarin compounds that show significant inhibition of the main human metabolic enzyme CYP3A4 have been isolated from grapefruit juice. The most potent of these is GF-I-1, an asymmetrical homodimer whose stereochemistry remains unknown. We sought to synthesize GF-I-1 and its three stereoisomers in a stereocontrolled fashion to unambiguously determine the absolute stereochemistry of natural GF-I-1. We were also interested in comparing the biological activities of the four synthetic isomers, following work that showed that CYP3A4 is not sensitive to the absolute configuration of a simpler grapefruit furocoumarin. * We have achieved the synthesis of a key dimeric intermediate in racemic form on the route towards GF-I-1. In doing so, we assessed the efficiencies of BiCl3 and CuII(BF4)2, two newly-discovered Lewis acid catalysts, for promoting the condensation of precious alcohols and epoxides. CuII(BF4)2 appears to be a promising catalyst for these transformations, for which well-established synthetic protocols have been notably absent. * We also progressed along the stereocontrolled route towards GF-I-1 and its stereoisomers, with the stereospecific synthesis of all required chiral precursors in greater than 96% enantiomeric excess. While the total synthesis was not completed due to a transformation that could not be efficiently accomplished during the allotted time for the project, we have laid the groundwork for the rapid stereocontrolled synthesis of GF-I-1 in the future.