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(sp³)-H functionalization platform.

Fig. 1.. Selective reactions of carbocations.

(A) Challenges associated with high-energy intermediates in selective catalysis. (B) Properties associated with carbocation coordination number. (C) Discovery of enantioselective C–H insertion reactions of vinyl cations. high E int, high-energy intermediate; low E int, low-energy intermediate; OTs, p-toluenesulfonate; X, NSO₂CF₃ or CH₂.

Fig. 2.. Substrate scope.

All reported yields are isolated yields of purified product. *After single recrystallization. †96 hours at 75°C. ‡0.1M. §70°C. ¶60°C. #2.3 equivalents of silane used because of alcohol silylation; the crude reaction was then stirred with tetrabutylammonium fluoride. **0.025M using 3A. BPin, pinacol boronic ester; es, enantiospecificity; Me, methyl; Ph, phenyl; PhMe, toluene; PMP, p-methoxyphenyl; rt, room temperature; Tol, p-tolyl; TsOH, p-toluenesulfonic acid.

Fig. 3.. Mechanistic studies.

(A) Evidence for vinyl carbocation intermediacy. (B) Effect of isotopic labeling on enantioselectivity. Listed values are the average of triplicate runs. (C) Rearrangement products from a rebound mechanism that were not observed. (D) Proposed mechanism. (E) DFT-calculated diastereomeric TS structures with corresponding bond lengths (Å), electrostatic potential surfaces, and free-energy differences between major and minor TSs. Substrate atoms are rendered as a stick model, and the catalyst is rendered as a space-filling model. Electrostatic potential areas are colored red to indicate a more-negative potential and blue to indicate a more-positive potential. (F) Benzylic stereocenter epimerization is not likely. Et, ethyl.

Fig. 4.. Statistical modeling.

(A) Multivariate linear regression model with a pseudorandom 50:50 partitioning of the 91 data points into training set:validation set. (B) Visual representation of the molecular descriptors used in the model. (C) Substrate classification of X identity on the basis of PEOE₁₂.

Fig. 5.. Catalytic asymmetric synthesis of strained bicycles.

All reported yields are isolated yields. *After single recrystallization. Ar, aryl; DCM, dichloromethane; PCC, pyridinium chlorochromate; tBu, tert-butyl.