Enantioselective domino carbopalladation/Csp3-Pd capture using carbenes generated from N-tosylhydrazones: Access to chiral 3,3-disubstituted oxindoles bearing chiral quaternary carbon center

N-tosylhydrazones have become convenient synthons in organic synthesis ever since their inception as diazo precursors. Yet, enantioselective processes involving N-tosylhydrazones are quite rare and challenging. In our continuing efforts in maneuvering Pd carbenes to synthesize complex heterocycles, we have developed a domino process for intercepting the enantioenriched alkyl-Pd species in a Mizoroki-Heck cascade. In this enantioselective domino process, N-alkyl acrylamides undergo a regiospecific 5-exo-trig cyclization to form an alkyl palladium species at a chiral quaternary carbon center that lacks a facile β-hydrogen. The alkyl palladium species formed is then trapped via carbene generated from bench-stable N-tosylhydrazones. The method constructs a chiral quaternary carbon center and provides direct access to chiral 3,3-disubstituted oxindoles with yields up to 91% and enantioselectivity >99% with tolerance for diverse functional groups. Mechanistic investigations revealed that a cationic Heck cascade is involved. The structure of the active catalytic species has been studied by HRMS analysis and linear relationship plot between the % ee of the catalyst and % ee of the product. Based on these experimental insights, computational studies of the catalytic cycle have been done to study the energetics of the steps involved. Further, the stereochemical outcome of the reaction has been justified by comparing the free energies of the diastereomeric transition states involved in the enantio-determining step. The constructed alkene handle next to the chiral center enhances the utility of this methodology. Apart from ease of functionalization, the proximity of the chiral center to the alkene, facilitates efficient transfer of chirality during transformations. This highlights the utility of the synthesized 3,3-disubstituted oxindoles as valuable chiral synthons. This has been demonstrated via a handful of synthetic transformations of the model oxindole and formal synthesis of five natural products, namely (+)-esermethole, (+)-physostigmine, (+)-deoxyseroline, (+)-phenserine and (+)-physovenine, which are a couple of steps apart in synthesis according to reported procedures.