Asymmetric Synthesis and Method Development: Asymmetric Total Synthesis of (+)-anti- and (–)-syn-Mefloquine Hydrochloride, Asymmetric Induction in Hydroacylation by Cooperative Iminium-Ion–Transition-Metal Catalysis, and Dipolar Reactions with 3-alkoxy-1-N-aryl Azopropenes

The research discussed in this dissertation pertains to three separate synthetic endeavors. The first of which is the concise asymmetric (er > 99:1) total synthesis of (+)-anti- and (–)-syn-mefloquine hydrochloride from a common intermediate. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol serves as the common intermediate and is converted into either a trans- or cis-epoxide, and these are subsequently converted to (+)-anti- and (–)-syn-mefloquine hydrochloride, respectively. X-ray crystallographic analysis of derivatives of (+)-anti- and (–)-syn-mefloquine is used to annul a 40 year argument regarding the absolute stereochemistry of the mefloquines. A formal asymmetric (er > 99:1) synthesis (+)-anti-mefloquine hydrochloride is also presented that uses a Sharpless asymmetric epoxidation as a key step. The second research project discusses a new strategy for the rhodium-catalyzed enantioselective hydroacylation. This was achieved through the merger of iminium-ion and transition-metal catalysis such that asymmetric induction derives from a readily accessible, inexpensive chiral nonracemic secondary amine catalyst rather than a chiral nonracemic phosphines as is typical of conventional asymmetric hydroacylation reactions. Finally, the third research project discusses the use of the 3-alkoxy-1-N-aryl azopropene structural motif in non Eschenmoser-Tanabe Fragmentation pathways. This structure has been known for almost 50 years, yet one untapped and very interesting feature of these intermediates is their putative 1,3-dipolar nature. We describe a transformation that leverages this reactivity to synthesize b,g-fused bicyclic g-lactones – an important class of oxygen heterocycles – by the simple combination of an ester or acyl pyrrole, an a-epoxy-2-nitrophenyl hydrazone, and KHMDS or LiHMDS. The products of this reaction, including those containing quaternary centers, are generated in a highly (up to >25:1) diastereoselective manner. Conveniently, both syn- and anti-fused bicyclic systems can be generated stereoselectively by simply changing the counter-ion of the base. We also discovered that the 3-alkoxy-N-aryl azopropene was found to be highly stable in its protonated hydroxy azoalkene form. Several of these compounds were found to be competent dienes in a highly (up to >25:1) diastereoselective cascading Tsuji-Trost [4+2] cycloaddition, producing an array of fused furan-tetrahydropyridazine derivatives.