UC Irvine

While palladium-catalyzed cross-coupling reactions have unquestionably transformed synthetic organic chemistry, nickel catalysis offers a unique set of advantages. From a reactivity perspective, two advantages of nickel catalysis are the ability to access additional oxidation states and engage a broader range of electrophiles compared to that of palladium catalysis. These properties ultimately allow for multiple mechanisms of oxidative addition to occur. In recent years, it has been established that nickel catalysts undergo stereospecific oxidative additions to C–N or C–O bonds. In contrast, oxidative addition at carbon-halogen bonds, such as C–I, are frequently stereoablative. Both of these modes of oxidative addition occur in the methods reported in this dissertation.In Chapter 1, the synthesis of an arylalkane library utilizing a stereospecific Kumada cross- coupling reaction is described. The results of biological testing for anti-cancer activity are also reported. Aryltetrahydropyran starting materials are synthesized in a one-step, diastereoselective Prins reaction. A nickel-catalyst engages the benzylic Csp3–O bond in a stereospecific manner and xiv undergoes a Kumada cross-coupling reaction with methylmagnesium iodide in solution. The resulting products are acyclic arylalkanes that were tested for anti-cancer activity through a collaboration with the NIH. One compound in the library exhibited micromolar anti-cancer activity. A limitation of the method above—and similar stereospecific methods—is that the electrophilic Csp3–O bond must be allylic or benzylic to allow for facile oxidative addition by a nickel catalyst. In an approach to engage alkyl Csp3–O bonds that are not benzylic or allylic, the cross-electrophile coupling reaction of 1,3-dimesylates for alkylcyclopropane synthesis was developed and discussed in Chapters 2 and 3 of this dissertation. While optimized reaction conditions are similar to the Kumada reaction described above, a key 1,3-diiodide intermediate alters the reaction mechanism leading the nickel catalyst to instead perform a stereoablative oxidative addition. Mono- and 1,2-disubstituted alkylcyclopropanes were synthesized, the latter with moderate diastereoselectivity. Lastly, the optimization of a cross-electrophile coupling reaction of secondary alkyl mesylates with allylic difluorides is described in Chapter 4. This work builds on the cross- electrophile coupling reaction of 1,3-dimesylates described in Chapters 2 and 3. The resulting β- fluorovinyl cyclopropanes are synthesized as a 1:1 diastereomeric ratio of cis and trans cyclopropanes and one alkene isomer. The currently available evidence is consistent with a stereoablative mechanism for oxidative addition, similar to that previously reported with 1,3- dimesylates. However, the specific details of the mechanism and expansion of scope are currently under investigation.