Enantioselective C–P Bond Formation through C(sp3)–H Functionalization

Abstract

An unprecedented enantioselective C–P bond formation has been developed through a C(sp3)–H activation in an oxidation step followed by an organocatalyzed hydrophosphonylation protocol. The asymmetric organocatalytic Pudovik reaction has been successfully achieved following a one-pot strategy, starting from different benzylic alcohols and dibenzylphosphite, using MnO2 as the oxidant and a chiral squaramide as organocatalyst. The scope of the reaction provides enantiomerically enriched α-hydroxy phosphonates in good to excellent yields (up to >95%) and high enantioselectivities (up to >99%). Furthermore, the use of this methodology has been successfully demonstrated to form a quaternary centre, generating an acetophenone derivative in situ, using diphenyl phosphite. Therefore, this approach represents a highly effective strategy for constructing chiral C–P bonds, which are of significant interest to the pharmaceutical industry. This proof of concept represents a significant breakthrough in the field of chemistry.

Enantioselective C−P Bond Formation through C(sp3)−H Functionalization

“…Interestingly, this CÀ P bond formation occurs through a C(sp 3 )À H activation in a cascade procedure, starting from stable and commercially available benzylic and allylic alcohols 1, in an organocatalytic asymmetric reaction for the first time. [23] The protocol involves an asymmetric organocatalytic Pudovik reaction, in which a first oxidation step is carried out using MnO 2 as oxidant and a second organocatalyzed step using a chiral squaramide catalyst. The scope of the reaction has conducted to a series of enantiomerically enriched α-hydroxy phosphonates 5 with yields from 40% to > 95% and enantioselectivities from 64% to > 99%, some of them, intermediates of biologically active products.…”