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.

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.

We discuss our laboratory’s research in the activation of alcohol derivatives in cross-coupling and cross-electrophile coupling reactions. Our developed methods enable the use of secondary alcohols to afford tertiary stereogenic centers, which we applied to the synthesis of pharmaceutically relevant compounds and substructures. We first ­discuss the synthesis of bioactive compounds through stereospecific Kumada cross-coupling reactions and follow this with a discussion on the development of our stereoselective cross-electrophile coupling ­reaction to synthesize cyclopropanes.1 Introduction2 Cross-Coupling Reactions3 Cross-Electrophile Coupling Reactions4 Conclusion

A focused small library of carbamates and alcohols was prepared employing stereospecific Kumada-ring opening reactions of tetrahydropyrans. The core framework of the library members is acyclic and incorporates 1,3-substituents, to provide a conformational bias in avoiding syn-pentane interactions. A new compound with micromolar activity against MOLT-4, CCRF-CEM, and HL-60(TB) leukemia cell lines was identified from this series. Scheme 1. a) Stereospecific ring-opening Kumada reaction. b) Library synthesis. Scheme 2. Alcohols synthesized via Kumada ring-opening crosscoupling reaction. Syn-(�)-5 used rac-BINAP as the ligand. Scheme 3. Dimethyl and morpholine carbamate derivatives. CommunicationIsr. J. Chem. 2020, 60, 402 -405