A mechanochemical addition/reduction cascade process for the synthesis of dual stereocentered chiral δ-hydroxysulfones

Abstract

The development of mechanochemical dual asymmetric catalysis presents a promising avenue for producing high-value compounds containing multiple stereocenters. However, a notable methodological hurdle emerges in harmonizing two incompatible chiral catalysts within a mechanochemical process. To address this concern, we have devised an innovative approach wherein β-cyclodextrin serves as an isolated protective shield, creating two independent compartments to confine chiral squaramide and ruthenium species within their respective compartments. This method addresses issues of dual asymmetric catalysis related to the intrinsic mutual deactivation of dual chiral species and extrinsic unmatched reaction conditions, enabling an efficient addition/reduction cascade process. Mechanistic and dynamic investigations reveal a sequential reaction route, which involves the Michael addition of enones and α-nitrosulfones, followed by the asymmetric transfer hydrogenation of in situ-generated intermediate ketones. As we envisioned, this mechanochemical dual asymmetric catalysis substantially boosts catalytic efficiency for the synthesis of various chiral δ-hydroxysulfones with two stereocenters.