Mechanism and Origin of Remote Stereocontrol in the Organocatalytic Enantioselective Formal C(sp²)–H Alkylation Using Nitroalkanes as Alkylating Agents

Abstract

Experimental 13C kinetic isotope effects (KIEs) and density functional theory (DFT) calculations are used to evaluate the mechanism and origin of enantioselectivity in the formal 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 (∼1.033) 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 the 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 E1cB transition states leading to both enantiomers.

Molecular Understanding and Practical In Silico Catalyst Design in Computational Organocatalysis and Phase Transfer Catalysis—Challenges and Opportunities

“…Hirschi, Mukherjee, and co-workers used 13 C KIE as evidence to differentiate between various mechanistic scenarios. Experimental and calculated 13 C KIE synergistically provide support for an E1cB mechanism [ 181 ]. They observed a significant inverse 13 C KIE, usually associated with increased steric congestion at the carbon center on C2 ( Figure 21 ).…”

“… Urea-catalyzed desymmetrization [ 182 ]. All values are obtained from the work of Hirschi, Mukherjee, and co-workers [ 181 ]. “ Expt ” refers to the experimental 13 C KIE relative (please refer to the cited reference for details.…”

Unified and green oxidation of amides and aldehydes for the Hofmann and Curtius rearrangements

“…Chiral ureas are powerful organocatalysts that have been widely used in asymmetric catalysis. However, their preparation [65][66][67][68][69] is generally limited to the availability of Scheme 4 The oxone-halide mediated oxidative Hofmann and Curtius rearrangements with other nucleophiles (not methanol). For the Curtius reaction, the yields in blue color in parentheses were obtained in PhCF 3 , while the yields in gray color in square brackets were obtained in CCl 4 .…”

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes

“…We performed distortion-interaction analysis , on the oxidative addition transition states, TS OA‑Inv and TS OA‑F (Figure ). This analysis decomposes the transition state energy into a distortion term, i.e., the energy needed for the separated reactants in their ground-state geometries to distort into the geometries resembling the transition structure, and an interaction term, i.e., the interactions between these distorted geometries as they come together to form the transition state.…”