Total synthesis of C17-benzene ansamycins via carbon-carbon bond forming hydrogenations

dc.contributor.advisorMartin, Stephen F.
dc.creatorDel Valle, David Johnen
dc.date.accessioned2014-03-11T14:42:51Zen
dc.date.issued2013-12en
dc.date.submittedDecember 2013en
dc.date.updated2014-03-11T14:42:51Zen
dc.descriptiontexten
dc.description.abstractAnsamycin natural products have historically been a rich source of new drugs for the treatment of bacterial infections and cancer. The C17-benzene ansamycins in particular have shown excellent preclinical results as potential anti-fungal and anti-cancer medicines. However, their thorough clinical evaluation has been hampered by the absence of a concise synthetic strategy. In order to address this issue, recently developed hydrogenative carbon-carbon bond forming methods were applied toward a short total synthesis of C17-benzene ansamycins. This class of natural products provides a challenging testing ground for these methods while facilitating the further development of compounds which may be used as treatments for life threatening diseases. In the first synthetic approach to the C17-benzene ansamycins key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core. The second approach toward triene-containing C17-benzene ansamycins resulted in the syntheses of trienomycins A and F, which were prepared in 16 steps (longest linear sequence) and 28 total steps. The C11-C13 stereotriad was generated via enantioselective ruthenium-catalyzed alcohol CH syn crotylation followed by chelation-controlled carbonyl dienylation. Finally, diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and eight steps shorter than any prior synthesis of a triene-containing C17-benzene ansamycin.en
dc.description.departmentChemistryen
dc.format.mimetypeapplication/pdfen
dc.identifier.urihttp://hdl.handle.net/2152/23479en
dc.subjectC-C bond forming hydrogenationen
dc.subjectAnsamycinen
dc.subjectNatural product synthesisen
dc.subjectMetathesisen
dc.titleTotal synthesis of C17-benzene ansamycins via carbon-carbon bond forming hydrogenationsen
dc.typeThesisen
thesis.degree.departmentChemistryen
thesis.degree.disciplineChemistryen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen
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