Catalytic asymmetric C–H insertion reactions of vinyl carbocations

Abstract

From the preparation of pharmaceuticals to enzymatic construction of natural products, carbocations are central to molecular synthesis. Although these reactive intermediates are engaged in stereoselective processes in nature, exerting enantiocontrol over carbocations with synthetic catalysts remains challenging. Many resonance-stabilized tricoordinated carbocations, such as iminium and oxocarbenium ions, have been applied in catalytic enantioselective reactions. However, their dicoordinated counterparts (aryl and vinyl carbocations) have not, despite their emerging utility in chemical synthesis. We report the discovery of a highly enantioselective vinyl carbocation carbon–hydrogen (C–H) insertion reaction enabled by imidodiphosphorimidate organocatalysts. Active site confinement featured in this catalyst class not only enables effective enantiocontrol but also expands the scope of vinyl cation C–H insertion chemistry, which broadens the utility of this transition metal–free C(sp 3 )–H functionalization platform.

Computational Exploration of the Nature of Li+-Ureide Anion Catalysis on Formation of Highly Reactive Vinyl Carbocations and Subsequent C–C Bond Forming Reactions

“…Finally, during the revision of this manuscript, our groups have described an enantioselective vinyl cation C–H insertion reaction. Our studies of vinyl carbocations generated from the Li + -ureide catalyst provide further evidence for the nature of ion pairs generated in these reactions.…”

When Does Hammond's Postulate Predict Stabilities of Carbocations?

“…[35] The low electrophilicities of vinyl cations also enable their use in enantioselective CÀ H insertion reactions as recently demonstrated by Nelson and colleagues. [36]…”

Dual-Hydrogen-Bond Donor and Brønsted Acid Cocatalysis Enables Highly Enantioselective Protio-Semipinacol Rearrangement Reactions

“…Traditionally, enantioselective semipinacol rearrangement reactions have relied on the use of electrophilic atom-transfer reagents to generate bridged cationic intermediates as the first step in the 1,2-ring expansion process. , The few examples of enantioselective protio-semipinacol rearrangement methods that have been reported to date rely on substrates that undergo protonation to generate heteroatom-stabilized cationic intermediates. , This substrate limitation likely results from the challenges associated with generating and controlling the stereoselectivity of high-energy intermediates . Given that chiral HBD catalysts have been demonstrated to induce high levels of enantiocontrol through networks of attractive noncovalent interactions in reactions proceeding through ionic mechanisms, we considered whether the cooperative effect of an HBD with HCl may generate a chiral environment amenable to an enantioselective protio-semipinacol ring-expansion process that does not require heteroatom stabilization of the cationic intermediate.…”