I. Completion of a Total Synthesis of Peloruside A. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine

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I. Completion of a Total Synthesis of Peloruside A. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine

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Title: I. Completion of a Total Synthesis of Peloruside A. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine
Author: Speed, Alexander William Harrison
Citation: Speed, Alexander William Harrison. 2012. I. Completion of a Total Synthesis of Peloruside A. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine. Doctoral dissertation, Harvard University.
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Abstract: I. Completion of a Total Synthesis of Peloruside A: The completion of a 22 step synthesis of the marine natural product peloruside A is presented. The second generation strategy cuts 10 steps from longest linear sequence of the Evans group’s first generation synthesis of peloruside A by changing the order of fragment coupling operations and maintaining \(C_1\) and \(C_9\) at their final oxidation states over the course of most of the synthesis. Key steps include two highly diastereoselective aldol fragment couplings, a tin tetrachloride mediated hydrosilylation and a macrolactonization on a seco acid containing no cyclic templating elements. II. Studies toward the Total Synthesis of Spiro-Prorocentrimine: The development of an intermolecular Diels–Alder approach toward the marine natural product spiro–prorocentrimine is described. This work began with the adaptation of the Evans group’s previous intramolecular Diels–Alder approach. It was found that protonated imines bearing non-coordinating counterions were of sufficient reactivity to allow cycloaddition to occur even on dienes that were unreactive under the previous best conditions. In the course of these studies, isomerization of a macrocyclic diene during the course of a Diels–Alder reaction complicated the stereochemical outcome of the reaction. Reaction conditions to suppress the isomerization and obtain Diels–Alder adducts bearing the correct configuration at both \(C_9\) and \(C_{33}\) were developed based on a qualitative consideration of the pKas of species present in the reaction. The of several macrocyclic dienes was examined to help explain the course of the Diels–Alder reaction. Other key steps include an iron catalyzed olefin formation, the highly diastereoselective hydrogenation of a trisubstituted olefin in the presence of an enol ether, protecting group studies to suppress the contraction of a 15 membered lactone to a 6 membered lactone and studies of a protecting group strategy to allow installation of a sulfate. Lessons learned from this work and previous efforts are combined in a proposal for a bioinspired synthesis of spiro-prorocentrimine with a longest linear sequence of less than 30 steps.
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10364581
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