Asymmetric Construction of All-Carbon Quaternary Stereocenters via Organocatalytic alpha-Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde

An organocatalyzed alpha-hydroxymethylation of alpha-monoalkyl malonic diesters using 37% aqueous formaldehyde (formalin) as a one-carbon electrophilic unit to generate all-carbon substituted quaternary stereocenters has been developed. In the course of our exploration of catalytic methodologies, a metal-free cooperative catalytic approach with cinchonidine and squaramide co-catalysts was found to improve both reactivity and enantioselectivity in this transformation. Our organocatalytic method represents the first example of an enantioselective alpha-hydroxymethylation of a malonic diester. The enantioenriched alpha-hydroxymethyl products could be recrystallized with high recovery, yielding optically pure materials. Moreover, to demonstrate the utility of this methodology, the all-carbon substituted alpha-quaternary stereogenic malonate was converted to both (S)- and (R)-4,4-disubstituted oxazolidin-2-ones without loss of optical purity.