UC Irvine

Traditional methods to perform cyclopropane synthesis typically utilize nucleophiles orcarbenoid intermediates reacting with olefins to form two C–C bonds in a single reaction. In order to find new ways to synthesize these functional groups, it is necessary to find orthogonal techniques that offer new ways to access similar products and stereochemical outcomes as these methods. One way to accomplish this is by using alcohols, one of the most prevalent functional groups in chemistry, as a starting material. Alcohols will readily generate electrophiles, such as sulfonates and halides, that can be activated by transition metals. Methods utilizing this reactivity will be reported in this dissertation to perform cross-electrophile coupling reactions that generate cyclopropanes. In Chapter 1, a nickel-catalyzed cross-electrophile coupling to synthesize alkylcyclopropanes from 1,3-dimesylates is reported. This reaction is tolerant of a range of pendent aryl substituents to provide mono- and di-substituted cyclopropanes. The mechanism of the reaction was investigated to show a stereoablative oxidative addition at the secondary electrophilic center. Notably, the reaction proceeds through a 1,3-diiodide that is formed in-situ using the Grignard reagent. This reaction took advantage of the secondary radical intermediate to render the method diastereoselective towards trans-disubstituted cyclopropanes. Finally, an enantioenriched 1,3-dimesylate substrate provided an enantiopure disubstituted cyclopropane without requiring directing groups, a technique traditionally used in asymmetric cyclopropane synthesis. The mechanism of this reaction was further defined in Chapter 3, leading to new insights in the iodide source, stereochemistry, and radical intermediates in the reaction. After stereospecific 1,3-diiodide formation by the agency of the Grignard reagent, the nickel catalyst engages the secondary mesylate in a halogen atom transfer to form a long-lived alkyl radical. Radical rebound of the nickel catalyst allows for a stereospecific SN2-type reaction onto the primary alkyl iodide leading to double inversion at the primary center. A reaction to synthesize fluorinated cyclopropanes from benzylic ethers and gemdifluoromethyl groups is reported in Chapter 2. Utilizing recent methods in photocatalytic olefin difluoromethylation, the substrates were accessed in two synthetic steps. This reaction is proposed to undergo a stereospecific oxidative addition of the benzylic ether and subsequent SN2-type reaction onto the alkyl fluoride to synthesize the cyclopropane products. In order to expand the substrate scope of the cross-electrophile coupling of 1,3-dimesylates, new conditions were developed (Chapter 4). 1,3-Dimesylates are readily transformed into 1,3- dihalides using halide salts in organic solvents. Reacting these 1,3-dihalides, formed in-situ, with zinc dust provides a scalable synthesis of cyclopropane products in high yields low-cost reagents. End stage modification of statin medicinal agents was performed to show the wide functional group tolerance of these conditions. Finally, a method to synthesize vinyl fluoride-substituted cyclopropanes from secondary mesylates and allylic gem-difluorides is reported in Chapter 5. This reaction is tolerant of a range of functional groups by using zinc metal as a reductant for the nickel catalyst. Mechanistic investigations of this reaction support an oxidative addition by the nickel catalyst to the allylic gem-difluoride before an SN2-type reaction on the mesylate to form the products. Computational studies show two mechanistic pathways that are hypothesized to occur with similar rates, both starting with coordination of the nickel catalyst to the electron-deficient alkene.