Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist

Abstract

The development and execution of a practical asymmetric synthesis of the estrogen receptor beta selective agonist (8R,10aS)-6-(trifluoromethyl)-8,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(3H)-one is described. The optimized route features a key chiral auxiliary-mediated dialkylation approach to set the all-carbon quaternary center with exceptional stereocontrol. Overall, the chemistry has been used to prepare >30 kg of drug candidate in 21% overall yield through 13 longest linear steps and with >99% ee.