Asymmetric Construction of All‐Carbon Quaternary Stereocenters via Organocatalytic α‐Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde

An organocatalyzed α‐hydroxymethylation of α‐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 α‐hydroxymethylation of a malonic diester. The enantioenriched α‐hydroxymethyl products could be recrystallized with high recovery, yielding optically pure materials. Moreover, to demonstrate the utility of this methodology, the all‐carbon substituted α‐quaternary stereogenic malonate was converted to both (S)‐ and (R)‐4,4‐disubstituted oxazolidin‐2‐ones without loss of optical purity. An organocatalyzed α‐hydroxymethylation of α‐monoalkyl malonic diesters using 37% aqueous formaldehyde (formalin) as a one‐carbon electrophilic unit has been developed. This is the first example of an enantioselective α‐hydroxymethylation of a malonic diester. The enantioenriched products could be easily transformed to both (S)‐ and (R)‐4,4‐disubstituted oxazolidin‐2‐ones without loss of optical purity.