Mechanistic and enantioselectivity insights into a chiral phosphoric acid-catalyzed asymmetric aza-pinacol rearrangement to synthesis doline

A comprehensive mechanistic study on the chiral phosphoric acid catalyzed an enantioselective asymmetric aza-pinacol rearrangement of 4-chloro-<italic>N</italic>-(2-(3'-hydroxy-1'-phenylspiro[cyclopentane-1,2'-indolin]-3'-yl)ethyl) (<bold>1a</bold>) is investigated at the M06-2X/6-311+G(d,p) level. Our computational results suggest that the whole catalytic cycle proceeds through dehydration of <bold>1a</bold>, enantioselective aza-pinacol rearrangement, intramolecular cyclization and catalyst regeneration to deliver the fused indoline product. The aza-pinacol rearrangement is the key stereocontrolling step of the title reaction. The chiral catalyst controls the orientation of the transition states of the enantioselective step through two potential binding sites between the bifunctional chiral phosphate and the aza-ortho-xylylene intermediate. Moreover, theoretical studies identified that the multiple C—H···<italic>π</italic>, C—H···O, and C—H···N hydrogen bonds and N—H···O^– electrostatic interactions between the substrates and the arms as well as functional oxygen anion of the chiral catalyst (<italic>R</italic>)-<bold>4c</bold> play a crucial role in determining the stereochemical outcomes. And the strong N—H···O^– interaction in the major transition state was found to contribute to the high levels of enantioselectivity. Additionally, the predicted enantiomeric excess (<italic>ee</italic>) of 89% based on the 6.3 kJ·mol^–1 energy difference between the enantioselective <bold>TS-2-major</bold> and <bold>TS-2-minor</bold> is in agreement with the experimental results of 90%.