An Organocatalytic Mannich/Denitration Reaction for the Asymmetric Synthesis of 3-Ethylacetate-Substitued 3-Amino-2-Oxindoles: Formal Synthesis of AG-041R

The highly enantioselective organocatalytic addition of ethyl nitroacetate to isatin-derived N-Boc ketimines (Boc= tert-butoxycarbonyl), followed by the removal of the nitro group, is described. The scalable reaction sequence leads to the title compounds as important intermediates of pyrroloindoline alkaloids and related drugs in excellent yields and enantioselectivities. The synthesis of the hexahydrofurano[2,3-b] indole skeleton, the spirocarbamate oxindole unit, and the formal synthesis of AG-041R have been carried out to demonstrate the synthetic utility of this protocol.