dc.contributor.advisor | Hanson, Paul R. | |
dc.contributor.author | Thomas, Christopher Daniel | |
dc.date.accessioned | 2011-07-04T20:13:01Z | |
dc.date.available | 2011-07-04T20:13:01Z | |
dc.date.issued | 2010-12-16 | |
dc.date.submitted | 2010 | |
dc.identifier.other | http://dissertations.umi.com/ku:11249 | |
dc.identifier.uri | http://hdl.handle.net/1808/7750 | |
dc.description.abstract | The 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.extent | 218 pages | |
dc.language.iso | en | |
dc.publisher | University of Kansas | |
dc.rights | This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author. | |
dc.subject | Organic chemistry | |
dc.subject | Chain elongation | |
dc.subject | Diastereotopic differentiation | |
dc.subject | Dolabelide c | |
dc.subject | Phosphorus | |
dc.subject | Terminus differentiation | |
dc.title | Asymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C | |
dc.type | Dissertation | |
dc.contributor.cmtemember | Prisinzano, Thomas E. | |
dc.contributor.cmtemember | Carlson, Robert G. | |
dc.contributor.cmtemember | Givens, Richard S | |
dc.contributor.cmtemember | Barybin, Mikhail V. | |
dc.thesis.degreeDiscipline | Chemistry | |
dc.thesis.degreeLevel | Ph.D. | |
kusw.oastatus | na | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
kusw.bibid | 7642758 | |
dc.rights.accessrights | openAccess | |