Date of Award

12-20-2024

Date Published

January 2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Nancy Totah

Keywords

Diastereoselective synthesis;Diels-Alder reaction;Dihydropyrone;Natural products;Regioselectivity

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

Oxadecalins are privileged scaffolds found in various natural products that show biological activity, such as platelet aggregating factor antagonism and activation of adenyl cyclase. As such, various synthetic methods such as intramolecular substitution reactions and [4+2] cycloadditions have been developed for the construction of these important intermediates. Studies towards the synthesis of a simplified core of the labdane diterpene, forskolin, are described. Forskolin is the only known supplement to naturally raise cAMP levels, thereby displaying important pharmacological properties. The synthetic route described features a Lewis acid catalyzed dihydropyrone Diels-Alder reaction for rapidly assembly of the ABC tricycle. Modified Saegusa-Ito oxidation conditions provided access to an C7,C8 alpha-beta unsaturated enone which was later found to be prone to beta-elimination following nucleophilic attack. Introduction of the cis C6,C7 diol was achieved via a regioselective Rubottom oxidation/reduction sequence. It was later discovered that regioselective functionalization might be complicated by the stereochemistry at the ABC ring junction. Chemical elaboration the tricyclic framework led to several advanced intermediates that provided further insights into the chemistry of these oxadecalin intermediates. The platelet aggregating factor inhibitor, phomactin A, was a second synthetic target for us. Several oxadecalin intermediates were prepared using the dihydropyrone Diels-Alder reaction. Successful introduction of an allyl sidechain to a simplified oxadecalin model prompted further investigation into C6 alkylation as part of our efforts towards the synthesis of a suitable macrocyclization precursor. Several palladium catalyzed coupling conditions were also explored. Post coupling modification of an alkyne substituted oxadecalin via a zirconium assisted carboalumination/iodination sequence resulted in the formation of an unexpected enol ether.

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