Theses Doctoral

I. Radical Cyclizations Mediated by Transition Metal Hydrides II. Study toward the Total Synthesis of Pluraflavin A III. Cytoprotective Polyacetylenes Inspired by Panaxytriol

Hartung, John

The first part of the thesis describes radical cyclizations mediated by transition metal hydrides. CpCr(CO)₃H and (H₂O)₂Co(dmgBF₂)₂ under H₂ gas catalyzed the radical cyclization of 1,6-dienes to form 5- and 6-membered rings and the cyclization of a 1,6,11 triene to form a substituted decalin. Vanadium hydrides of the general formula HV(CO)₄(P-P), where P-P is a chelating bisphosphine, were used to initiate radical cyclizations, but could only be used stoichiometrically. The method was expanded to include the synthesis of tetrahydrofurans by employing vinyl ethers as substrates.

The second part of the thesis describes study toward the total synthesis of the highly potent anti-proliferative natural product pluraflavin A. Synthesis of the optically active des-carbohydrate core was accomplished by a key [3+2] cycloaddition and a Diels-Alder-aromatization sequence. A derivative of the des-carbohydrate bearing a bromine atom enabled the attachment of the C-glycosidic residue by Stille coupling. Subsequent stereoselective glycosylation reactions appended the O-glycosidic residues. The current approach furnished an advanced intermediate with all of the functionality of the target, albeit in protected form.

The third part of the thesis describes the synthesis and in vitro evaluation of a series of polyacetylenes inspired by the Ginseng-derived natural product, panaxytriol. Three series of analogs were synthesized by a convergent route featuring the Cadiot-Chodkiewicz reaction. The analogs were tested for their ability to induce cytoprotective enzymes by the Nrf2 cell-signaling pathway. The resulting structure-activity relationship suggested that the diyne and propargylic hydroxyl functionalities are necessary for phase II enzyme induction. While we have not yet necessarily attained the optimal structure for Nrf2 induction without accompanying cytotoxicity, several novel and potent analogs have been discovered.


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More About This Work

Academic Units
Thesis Advisors
Danishefsky, Samuel J.
Norton, Jack R.
Ph.D., Columbia University
Published Here
September 12, 2012