Nickel Catalyzed Homoallylation Reactions and Synthesis of Potent Inhibitors of YopH
Doctor of Philosophy
Date of Defense
Christopher D. Spilling, Ph.D.
Prof. Chung F. Wong
Prof. Eike Bauer
Prof. Janet B. Wilking
Amphidinolides are cytotoxic natural products isolated from marine dinoflagellate Amphidinium species. Amphidinolides C, C2 and F are active against cancer cell lines. Homoallylation of aldehydes with isoprene and triethylborane catalyzed by Ni(acac)2 gave hydroxyalkenes in good yield with excellent regio- and stereoselectivity. Cross metathesis of the hydroxyalkenes with methyl acrylate using second-generation Grubbs catalyst and copper(I) iodide afforded α,β-unsaturated esters, which underwent cyclization in the presence of DBU to produce tetrahydrofurans with the correct relative configuration for the C1-C9 fragment of amphidinolides C, C2, and F. Homoallylation of chiral and achiral diene carboxylate esters and dienecarboxamides with various aldehydes were investigated. The homoallylation of diene carboxylate esters with aldehydes afforded ε-hydroxy-α,β-unsaturated ester in excellent regioselectivity (>99:1) and modest diastereoselectivity (upto 5:1). The homoallylation of chiral diene carboxylate esters and chiral aldehydes were also investigated. YopH is a virulence protein excreted by pathogenic bacteria Yersinia pestis (the causative agent of the Black Death). A series of bidentate ligands were designed to investigate the structure activity relationship of these ligands towards the inhibition of YopH protein. Several of these ligands were synthesized and tested against different protein tyrosine phosphatases (PTPs). Many inhibitors prepared showed very good activity against YopH and some other human phosphatases (low to mid micro-molar range).
Paudyal, Mahesh Prasad, "Nickel Catalyzed Homoallylation Reactions and Synthesis of Potent Inhibitors of YopH" (2017). Dissertations. 17.
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