In this article, we expand upon the catalytic hydrothiolation of 1,3-dienes to afford either allylic or homoallylic sulfides with high regiocontrol. Mechanistic studies support a pathway where regioselectivity is dictated by the choice of counter-ion associated with the Rh-center. Noncoordinating counter-ions, such as SbF 6 − , allow for η 4-diene coordination to Rh-complexes and result in allylic sulfides. In contrast, coordinating counter-ions, such as Cl − , favor neutral Rhcomplexes where the diene binds η 2 to afford homoallylic sulfides. We propose mechanisms that rationalize a fractional dependence on thiol for the 1,2-Markovnikov hydrothiolation while accounting for an inverse dependence on thiol in the 3,4-anti-Markovnikov pathway. Through the hydrothiolation of an essential oil (β-farnesene), we achieve the first enantioselective synthesis of (−)-agelasidine A.

Cross-electrophile coupling reactions of two Csp3–X bonds remain challenging. Herein we report an intramolecular nickel-catalyzed cross-electrophile coupling reaction of 1,3-diol derivatives. Notably, this transformation is utilized to synthesize a range of mono- and 1,2-disubstituted alkylcyclopropanes, including those derived from terpenes, steroids, and aldol products. Additionally, enantioenriched cyclopropanes are synthesized from the products of proline-catalyzed and Evans aldol reactions. A procedure for direct transformation of 1,3-diols to cyclopropanes is also described. Calculations and experimental data are consistent with a nickel-catalyzed mechanism that begins with stereoablative oxidative addition at the secondary center.

A method for incorporating cyclopropane motifs into complex molecules has been developed. Herein we report a zinc dust-mediated cross-electrophile coupling reaction of 1,3-dimesylates to synthesize cyclopropanes. 1,3-Dimesylates can be readily accessed from 1,3-diols, a functionality prevalent in many natural products and medicinal agents. The reaction conditions are mild, such that functional groups, including amides, esters, heterocycles, and alkenes, are tolerated. Notably, we have demonstrated late-stage cyclopropanation of statin medicinal agents.

Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

Cross-electrophile coupling reactions involving direct C−O bond activation of unactivated alkyl sulfonates or C−F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickelcatalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoridesubstituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C−F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C−O bond.