Enantioselective synthesis of chiral 1,2-oxazinane spiro-oxindoles via carbene-catalyzed [3 + 3] annulation of isatin-derived nitrones with enals

Abstract

An N-heterocyclic carbene (NHC)-catalyzed enantioselective [3 + 3] annulation of isatin-derived nitrones with α,β-unsaturated aldehydes has been developed. This protocol provides straightforward and efficient access to a variety of chiral 1,2-oxazinane spiro-oxindole derivatives bearing two contiguous stereocenters, in moderate to good yields with good to excellent diastereo- and enantioselectivities. The reaction features mild conditions, broad substrate scope, and gram-scale practicality. The products can be conveniently converted into chiral γ-hydroxy amino methyl esters via a one-pot alcoholysis ring-opening process, thereby highlighting the synthetic utility of this method. This work represents the first example of constructing stable chiral 1,2-oxazinane spiro-oxindole frameworks via NHC organocatalysis.