Competitive Cationic Pathways and the Asymmetric Synthesis of 1,2-Disubstituted Cyclopropanes: Insight into the Cyclopropylcarbinyl Cation

Cyclopropanes have played an important role in organic chemistry due to their strained structure, interesting bonding characteristics, and value as internal mechanistic probes. The frequencies with which biologically active, cyclopropane containing natural products appear have compelled chemists to find novel and diverse approaches to their synthesis. This dissertation will discuss the development several related methods for the stereoselective preparation of diastereo- and enantiomerically enriched 1,2-disubstituted cyclopropanes. Biological examples of oligocyclopropanes were first isolated in the microbe metabolites, FR-900848 and U-106305. Oligocyclopropanes were the target of synthetic methodology for the formation of contiguous cyclopropane units. Discouragingly, our novel cationic method was unsuccessful in formation of these structures due to reduced electron demand of the system, allowing for the formation of various fragmentation and elimination products.Yet, there was much success in formation of single instances of 1,2-disubstituted cyclopropanes. They were synthesized in a non-racemic fashion via activation of the corresponding homoallylic alcohols. Rooted in the classic homoallylic cation rearrangement, in situ generated aryl sulfonates readily provided vinyl cyclopropanes in excellent yields. Initial studies included activation using triflic anhydride and 2,6-lutidine at low temperature. Mesyl anhydride and HÌÄå_nig's base proved to be a more efficient alternative to the original conditions for homoallylic activation. An array of substituted phenyl rings showed higher enantioselectivity for the cyclization as the group increased in electron withdrawing ability. Lowered enantioselectivity was observed for the electron donating cases. Electron rich aryl cyclopropanes were ultimately synthesized through transition metal couplings of aryl bromides that cyclized with high enantioselectivity. Applications of this method to imidazole substituted species and the formal synthesis of the histamine H3 antagonist GT-2331 were endeavored. The final evolution of the project included the formation of aryl cyclopropylaldehydes through a biomimetic process. Enantioselective organocatalysis for the reduction of Ì_å±, Ì_å_-unsaturated aldehydes developed by MacMillan and List provided an excellent resource for the formation of γ-halo-Ì_å_-aryl aldehydes. These aldehydes, when exposed to the organocatalytic conditions and base, readily provided aryl cyclopropylaldehydes in high yields. Mechanistic discussions of the aforementioned process were also presented.