Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Herzon, Seth
Abstract
In this thesis, I describe our progress towards the synthesis of the cytotoxic tetraterpenoid (–)-gukulenin A (1). (–)-Gukulenin A (1) is a challenging target for synthesis due to its congested syn-syn-quaternary cyclopentanes, tri-substituted and tetra- substituted α-tropolone moieties, and central ethyl-keto bridging subunit. (–)-Gukulenin A (1) has produced a dose-dependent reduction in the size of grafted human ovarian cancer tumors (A2780) in a murine model. Although the mechanism of action is unknown, it has been established that (–)-gukulenin A (1) associated cell death is reliant upon the activation of procaspases-3, -8, and -9. Access to dimeric gukulenin A (1) derivatives was enabled by deriving the cyclopentane fragment of (–)-gukulenin A (1) from the C–H arylation of the picolinamide 88. Conversion of the arylated bicyclo[2.2.1]heptane derivative to the requisite cyclopentane was achieved through a single flask Grob fragmentation–alkylation strategy. Development and optimization of two ring expansion reactions related to the Tiffeneau– Demjanov rearrangement converted masked ortho-benzoquinones to α-tropolones, which garnered access to the monomeric unit of (–)-gukulenin A (1). Dimerization of the monomer to a dimeric derivative with the central ethyl-keto bridge was accomplished through the synthesis of the novel linchpin Stille reagent 205. Current and future work is focused on the completion of the route to (–)-gukulenin A (1) through a proposed biomimetic sequence.
Recommended Citation
Combs, Joshua Benjamin, "Synthetic Studies of (–)-gukulenin A" (2022). Yale Graduate School of Arts and Sciences Dissertations. 739.
https://elischolar.library.yale.edu/gsas_dissertations/739
