Enhancing the Synthetic Utility of Enantioconvergent Addition Reactions and Progress Towards a Convergent, De Novo Synthesis of Jervine

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  • March 19, 2019
Creator
  • Zavesky, Blane
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • I. Direct Zn(II)-Catalyzed Enantioconvergent Additions of Terminal Alkynes to α-Keto Esters The addition of terminal alkynes to β-stereogenic α-keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by an abundant and non-toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition. II. Palladium-Catalyzed β-Arylation of α-Keto Esters A catalyst system derived from commercially available Pd2(dba)3 and PtBu3 has been applied to the coupling of α-keto ester enolates and aryl bromides. The reaction provides access to a versatile array of β-stereogenic α-keto esters. When the air stable ligand precursor PtBu3·HBF4 is employed, the reaction can be carried out without use of a glovebox. The derived products are of broad interest given the prevalence of the β-keto acid substructure in biologically important molecules. III. Progress Towards a Convergent, De Novo Synthesis of Jervine A convergent approach towards the synthesis of the Veratrum alkaloid jervine is presented. The two requisite complex fragments were stereoselectively and efficiently fashioned from cheap and readily available reagents. Key to this route were the uses of a highly diastereoselective Ireland-Claisen rearrangement to set the relative configuration of the amine and exocyclic methyl group present on the tetrahydrofuran ring, and a selenoetherification reaction, which enabled the assembly of the quaternary stereocenter present at the D and E ring junction. IV. Progress Towards the First Asymmetric Synthesis of Matrine The captivating biological activity of matrine has been of interest since its isolation in 1889 from the traditional medical herb Sophora flavescens, however no asymmetric synthesis of the molecule exists. Herein, we disclose the synthesis of an advanced enantiopure piperidone building block beginning from commercial L-aspartic acid β-methyl ester hydrochloride, and show our efforts in addressing the remaining synthetic challenges.
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  • In Copyright
Advisor
  • Gagné, Michel
  • Crimmins, Michael
  • Leibfarth, Frank
  • Johnson, Jeffrey
  • Alexanian, Erik
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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