Catalytic enantioselective alpha-amination of 2-oxindoles and a new route to the bio-active compound AG-041R

AG-041R is a chiral, enantiopure 2-oxindole urea derivative provided with a remarkable bio-activity that ranges from anti-ulcer, to condrogenic and anti-proliferative. Following the introduction by our group of a convenient protocol for the organocatalytic, asymmetric alpha-amination (AaA) of N-unprotected 3-alkyl-2-oxindoles with bis(trichloroethyl)¬azodicarboxylate (BTCEAD), we report herein a novel route to AG-041R, which takes advantage of the prompt elaboration of chiral hydrazine derivatives masked as trichloroethyl carbamates. In addition to the optimization of the AA step and the subsequent elaboration of the resulting aminated product, the possibility to enhance the enantiomeric purity of suitable intermediates, by selective crystallization of the racemate, will be briefly discussed.