Towards the total synthesis of Thapsigargin

Jeuken, Alan (2019) Towards the total synthesis of Thapsigargin. PhD thesis, University of Glasgow.

Abstract

Thapsigargin is a sesquiterpene lactone of the guaianolide class whose structure was first assigned in 1984. It is a highly cytotoxic agent, inhibiting the sarco/endoplasmic Ca2+- ATPase (SERCA) at sub-nanomolar concentrations (KD = 0.4 nM), and its prodrug formulations have been of intense interests for many oncological applications.

In collaboration with the group of J.-P. Férézou, a strategy towards the construction of the carbon skeleton of thapsigargin and related natural and unnatural analogues was developed based on a ring-closing ene-yne metathesis (RCEYM) step. In this work the scope of that strategy was expanded to fulfil the enantioselectivity requirement of the synthesis via the use of asymmetric transfer hydrogenation under dynamic kinetic resolution conditions on a cyclopentenone γ-ester. These enantioenriched cyclopentenone derivatives have then been used to construct [5,7]-bicyclic structures with varying substitutions.

These resulting bicyclic derivates were sensitive to many subsequent reaction conditions, however a robust synthetic strategy was found to chemoselectively oxidise the C-7/8 double bond and from there further derivation was possible, resulting in an advanced [5,7,5]-tricyclic derivative.

Finally, the flexibility of the RCEYM strategy was demonstrated through the concise synthesis of an unnatural [5,8]-bicyclic thapsigargin core analogue from a common ketone precursor.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Total synthesis, Thapsigargin, Ring Closing Ene-yne metathesis, RCEYM, SERCA.
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Prunet, Dr. Joëlle
• Date of Award: 2019
• Depositing User: Dr Alan Jeuken
• Unique ID: glathesis:2019-41000
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Mar 2019 13:42
• Last Modified: 05 Mar 2020 22:00
• Thesis DOI: 10.5525/gla.thesis.41000
• URI: https://theses.gla.ac.uk/id/eprint/41000