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    Asymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C

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    Thomas_ku_0099D_11249_DATA_1.pdf (9.940Mb)
    Issue Date
    2010-12-16
    Author
    Thomas, Christopher Daniel
    Publisher
    University of Kansas
    Format
    218 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    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.
    URI
    http://hdl.handle.net/1808/7750
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    • Dissertations [3958]
    • Chemistry Dissertations and Theses [171]

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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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