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