Desymmetrization of meso-Anhydride Enabled Enantioselective Synthesis of (-)-7-(Bromomethylene)-3-amidobicyclo[2.2.1]heptane-2-carboxamide, a Scaffold for Divergent Drug Discovery Synthesis.

An enantioselective synthesis (>99% ee) of (-)-(1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((-)-1), a scaffold for divergent drug discovery synthesis, has been developed. The synthesis employed dimethyl(phenyl)silyl moiety as a "masked" hydroxy group and started with an exclusively endo selective Diels-Alder reaction of readily available cyclopenta-2,4-dien-1-yldimethyl(phenyl)silane (8) with maleic anhydride (3) to afford the tricyclic anhydride 17. Desymmetrization of this meso-anhydride 17 was enabled by a high yielding quinidine-mediated opening with benzyl alcohol to generate the benzyl hemiester 4 with >93% ee which was upgraded to greater than 99% ee by chiral resolution with (1R,2R)-(-)-1,2-diaminocyclohexane 19. Other key features of this synthetic route involved a Curtius rearrangement for the formation Teoc-protected amino bicyclo[2.2.1]heptane intermediate 23, a Fleming-Tamao oxidation for the conversion of dimethyl(phenyl)silyl to the hydroxy group and a Swern oxidation of the alcohol 30 to the strained-ring ketone 31. Finally, the bromo olefin of (-)-1 was installed by a stereoselective Wittig reaction of 31 using (bromomethyl)triphenylphosphonium bromide.