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.