Highly enantioselective synthesis of 1,3-bis(hydroxymethyl)-2-oxindoles from unprotected oxindoles and formalin using a chiral NdIII complex

Abstract

Highly enantioselective synthesis of 1,3-bis(hydroxymethyl)-2-oxindoles was established through chiral Nd^III-N,N′-dioxide in up to 93% yield and >99% ee under mild conditions. The key features of this approach include using cheap and readily available formalin as a hydroxymethylation C1 unit and unprotected 3-substituted-2-oxindoles as nucleophiles directly. The initial C-aldol product from 3-substituted-2-oxindole was converted to the corresponding 1,3-bis(hydroxymethyl)-2-oxindole derivative immediately under the reaction conditions. Moreover, the catalyst was water-tolerant, and ligand and Nd(OTf)₃ could be easily recovered and reused with no loss in catalytic activity and enantioselectivity. The synthetic utility of this methodology was accomplished with the synthesis of key intermediates of physostigmine and coerulescine.