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

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dc.contributor.advisorColtart, Don M.
dc.contributor.committeeMemberGilbertson, Scott R.
dc.contributor.committeeMemberCai, Chengzhi
dc.contributor.committeeMemberXu, Shoujun
dc.contributor.committeeMemberBall, Zachary T.
dc.creatorRastelli, Ettore Joseph 1990-
dc.date.accessioned2018-03-12T18:06:01Z
dc.date.available2018-03-12T18:06:01Z
dc.date.createdDecember 2017
dc.date.issued2017-12
dc.date.submittedDecember 2017
dc.date.updated2018-03-12T18:06:01Z
dc.description.abstractThe 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.
dc.description.departmentChemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10657/2859
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectMefloquine
dc.subjectHydoacylation
dc.subjectAsymmetric
dc.subjectUmpolung
dc.subjectAzoalkene
dc.subjectTotal synthesis
dc.subjectCatalysis
dc.titleAsymmetric 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
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2019-12-01
local.embargo.terms2019-12-01
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentChemistry, Department of
thesis.degree.disciplineChemistry
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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