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


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.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Total synthesis, asymmetric catalysis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:Idea (Inclusion, Diversity, Equity, and Accessibility) Allyship & Advocacy Award, 2024.
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Reisman, Sarah E. (chair)
  • Gray, Harry B.
  • Nelson, Hosea M.
  • Stoltz, Brian M.
Defense Date:23 May 2024
Funding AgencyGrant Number
Record Number:CaltechTHESIS:06032024-082931807
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Ch. 1
Chan, Tsam Mang Melinda0000-0002-2495-0110
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16480
Deposited By: Tsam Mang Melinda Chan
Deposited On:04 Jun 2024 20:32
Last Modified:17 Jun 2024 19:30

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