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

Abstract

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