ABSTRACT: (-)-(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 (title compound (-)-1) was identified as a divergent scaffold for comprehensive SAR studies in a drug discovery programs. This presentation will describe two racemic syntheses (1^st and 2^nd generations) and focus on an enantioselective synthesis (3^rd generation, >99% ee) of the title compound (-)-1 as illustrated in the scheme. This scalable, enantioselective synthesis employed dimethyl(phenyl)silyl 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. Subsequent desymmetrization of this meso-anhydride was enabled by a high yielding quinidine-mediated opening with benzyl alcohol to generate the benzyl hemi ester (9) with > 93% ee which was upgraded to greater than 99% ee by chiral resolution with (1R,2R)-(-)-1,2-diaminocyclohexane. The other key features of this synthetic route involved Curtius rearrangement for the formation of the Teoc protected amino bicyclo[2.2.1]heptane intermediate, Fleming-Tamao oxidation for the conversion of dimethyl(phenyl)silyl to hydroxy group, and Swern oxidation of the bridgehead alcohol to the ketone. Finally, the bridgehead bromo olefin was installed by stereoselective Wittig reaction using (bromomethyl)triphenylphosphonium bromide. Over three hundred grams of the title compound (-)-1 was produced through this asymmetric synthesis.

Yoganand Shanmugam

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