Mechanism and Origin of Remote Stereocontrol in the Organocatalytic C(sp2)-H Alkylation using Nitroalkanes as Alkylating Agents

Abstract

Experimental 13C kinetic isotope effects (KIEs) and DFT calculations are used to evaluate the mecha-nism and the origin of enantioselectivity in the C(sp2)‒H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (~0.980) and a normal (~1.030) KIE is observed on the bond-forming carbon atoms of the cyclopentene-1,3-dione and nitroalkane, respectively. These data provide strong support for a mechanism involving reversible carbon-carbon bond-formation followed by rate- and enantioselectivity-determining nitro-group elimination. The theoretical free energy profile and predicted KIEs indicate that this elimination event occurs via an E1cB pathway. The origin of remote stereocontrol is evaluated by distortion-interaction and SAPT0 analyses of the enantiomeric E1cB transition states.