Asymmetric Total Synthesis of Havellockate and Investigation into Chiral Palladium Enolate: Synthesis, Reactivity, and Applications

Citation

Chan, Tsam Mang Melinda (2024) Asymmetric Total Synthesis of Havellockate and Investigation into Chiral Palladium Enolate: Synthesis, Reactivity, and Applications. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/kb44-n573. https://resolver.caltech.edu/CaltechTHESIS:06032024-082931807

Abstract

Research in the Stoltz group focuses on the synergy of complex natural product synthesis and method development in that we strive to invent new and efficient methodologies that have great synthetic potential in the use for pharmaceuticals and natural products. Herein we describe an asymmetric total synthesis of Havellockate, a polycyclic furanobutenolide-derived cembranoid diterpenoid that exhibits biological activities such as anti-inflammatory, anti-microbial, and cytotoxic. The strategy for this synthesis is highlighted by a convergent Julia–Kocienski olefination, followed by an acylation/intramolecular [4+2] cycloaddition cascade, which furnishes the main core of the natural product in high efficiency.

Another synthetic route toward the total synthesis of Havellocate is presented, using a propargyl ether as a key intermediate. Though the route was unfruitful in compleing the synthesis, the Diels–Alder cascade had significant improvement of yield and stability with this route, and it constitutes tremendous value for the synthesis of other targets within the furanobutenolide-derived natural product family.

Next, the synthesis, isolation, and reactivity of a chiral Pd enolate is described. The Pd enolate is arose by an alpha bromo acetophenone oxidative addition complex with Pd2(dba)3 and PHOX ligand. A crystal structure is obtained to show that the enolate is C- bound and highly regioselective. The novelty of this isolation can shine light on the applications of such Pd enolate for future developments.

Then, we outlined a Pd-catalyzed asymmetric vinylation of γ-lactams to construct all-carbon quaternary stereocenters. The use of canonically inactive vinyl chloride electrophiles afforded the highest yields and levels of stereoselectivity, and a range of tri-substituted vinyl chlorides were found to be proficient in promoting this transformation. These stereogenically congested products could be further elaborated to functionally rich scaffolds, proving the synthetic utility of this transformation.

Lastly, we describe the work of organizing the inaugural Day of Inclusion event of CCE. The event was orchestrated by the Diversity in Chemistry Initiative (DICI), aimed to foster cohesion and to inspire concerted efforts towards Diversity, Equity, and Inclusivity (DEI) within the Chemistry and Chemical Engineering (CCE) division at Caltech.

Thesis Files