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dc.contributor.advisorHanson, Paul R.
dc.contributor.authorThomas, Christopher Daniel
dc.date.accessioned2011-07-04T20:13:01Z
dc.date.available2011-07-04T20:13:01Z
dc.date.issued2010-12-16
dc.date.submitted2010
dc.identifier.otherhttp://dissertations.umi.com/ku:11249
dc.identifier.urihttp://hdl.handle.net/1808/7750
dc.description.abstractThe focus of this dissertation is the desymmetrization of C2-symmetric 1,3-anti-diols through the construction of pseudo-C2-symmetric phosphorus heterocycles, bearing a chirotopic, non-stereogenic center at phosphorus. Diastereotopic differentiation is achieved through cyclization via ring-closing metathesis (RCM), affording a chiral, non-racemic bicyclic P-heterocycle, which is stereogenic at phosphorus. This strategy is central to building skeletally diverse polyol subunits, which are commonly seen in polyketide-based natural products. Terminus differentiation and chain elongation through selective transformations on the previously reported bicyclo[4.3.1]phosphate (both antipodes), e.g. cross-metathesis, regioselective olefin reduction and regio- and diastereoselective allylic phosphate displacements, provide a rapid protocol to accessing the aforementioned motifs. The development of this methodology advanced into an application toward the total synthesis of dolabelide C (bearing two separate 1,3-anti-diol containing fragments), which exhibits cytotoxicity against cervical cancer HeLa-S3 cells with an IC50 value of 1.9 μg/mL. A route to this target was devised, where the final step was amending the 24-membered marcocycle through RCM. The result provided a diastereomeric mixture of E and Z isomers, which proved to be difficult to separate during initial efforts. However, LC-MS analysis of the mixture showed the contaminants were by-products arising from isomerization events occurring prior to RCM. Other reports coincide with this observation, mainly in the synthesis of medium to larger sized rings. Scale-up was required after this initial study to provide ample material for final characterization and the re-synthesis provided a copious amount of the RCM precursor. The large amount of material allowed for optimization studies and finally resulted in 14 mgs of analytically pure dolabelide C and 10 mgs of the non-natural Z-isomer, which to the best of our knowledge is the first synthesis of both compounds and the most synthetic material available of each to date.
dc.format.extent218 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsThis item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
dc.subjectOrganic chemistry
dc.subjectChain elongation
dc.subjectDiastereotopic differentiation
dc.subjectDolabelide c
dc.subjectPhosphorus
dc.subjectTerminus differentiation
dc.titleAsymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C
dc.typeDissertation
dc.contributor.cmtememberPrisinzano, Thomas E.
dc.contributor.cmtememberCarlson, Robert G.
dc.contributor.cmtememberGivens, Richard S
dc.contributor.cmtememberBarybin, Mikhail V.
dc.thesis.degreeDisciplineChemistry
dc.thesis.degreeLevelPh.D.
kusw.oastatusna
kusw.oapolicyThis item does not meet KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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