Divergent Stereochemical Outcomes in the Insertion of Donor/Donor Carbenes into the C–H Bonds of Stereogenic Centers

Abstract

Intramolecular C-H insertions with donor/donor dirhodium carbenes provide a concise and highly stereoselective method to set two contiguous stereocenters in a single step. Herein, we report the insertion of donor/donor carbenes into stereogenic carbon centers allowing access to trisubstituted benzodihydrofurans in a single step. This study illuminates, for the first time, the stereochemical impact on the carbene center and delineates the structural factors that enable control over both stereogenic centers. Sterically bulky, highly activated C-H insertion centers exhibit high substrate control yielding a single diastereomer and a single enantiomer of product regardless of the catalyst used. Less bulky, less activated C-H insertion centers exhibit catalyst control over the diastereomeric ratio (dr), where a single enantiomer of each diastereomer is observed with high selectivity. A combination of experimental studies and DFT calculations elucidate the origin of these results. First, hydride transfer from the stereogenic insertion site proceeds with high stereoselectivity to the carbene center, thus determining the absolute configuration of the product. Second, the short lived zwitterionic intermediate can diastereoselectively ring-close by a hitherto unreported SE2 mechanism that is either controlled by the substrate or the catalyst. These results demonstrate that donor/donor carbenes undergo uniquely stereoselective reactions that originate from a stepwise reaction mechanism, in contrast to the analogous concerted reactions of carbenes with one or more electron-withdrawing groups attached.

Effects of Axial Solvent Coordination to Dirhodium Complexes on the Reactivity and Selectivity in C–H Insertion Reactions: A Computational Study

“…136,137 However, Shaw and coworkers have found that donor/donor carbenes can undergo two-step, stepwise C-H insertions, 138 or exist at the borderlands 139 of concerted and stepwise. 140 Finally, dissociation of product 4 from weakly bound complex 9 regenerates catalyst 3. It is unclear whether axial solvent ligation is relevant at any point in this catalytic cycle (Figure 1, outer green circle versus inner blue circle).…”

Modulating Escape Channels of Cycloheptatrienyl Rhodium Carbenes to Form Semibullvalene

“…Metal-carbene mediated chemistry has a long and winding history. 10 Our group has worked independently and collaborated closely with experimental groups to understand mechanisms of Rh-carbene mediated transformations, including C-H insertion 64,65 and ylide formation reactions, [66][67][68] with the aim of developing synthetically useful models of reactivity and selectivity. This chemistry has proven to be a playground of its own-a family of synthetically relevant organometallic reactions that display behaviors considered by some to be esoteric, but which play important roles in determining product distributions.…”

Effects of Axial Solvent Coordination to Dirhodium Complexes on Reactivity and Selectivity in C–H Insertion Reactions: A Computational Study

“…137,138 However, Shaw and coworkers have found that donor/donor carbenes can undergo two-step, stepwise C-H insertions, 139 or exist at the borderlands 140 of concerted and stepwise. 141 Finally, dissociation of product 4 from weakly bound complex 9 regenerates catalyst 3. It is unclear whether axial solvent ligation is relevant at any point in this catalytic cycle (Figure 1, outer green circle versus inner blue circle).…”