Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor

Two syntheses of the class-selective histone deacetylase inhibitor <b>1</b> are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording <i>trans</i>-<i>rac</i>-<b>5</b> and its resolution. In the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the <i>cis</i>-(<i>S,S</i>)-3,4-disubstituted pyrrolidine <b>18</b> followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to generate the key intermediate <i>trans</i>-(<i>R,S</i>)-3,4-disubstituted pyrrolidine <b>19</b>. The overall yield increased from ∼6% for the resolution approach to ∼26% for the enantioselective approach