Ring-closing metathesis cascade toward a formal synthesis of taxol

Letort, Aurelien (2015) Ring-closing metathesis cascade toward a formal synthesis of taxol. PhD thesis, University of Glasgow.

Abstract

TaxolTM and its derivatives are the largest selling anticancer drugs of all time. Numerous synthetic works and total syntheses have been published since its discovery, but to date no high yielding synthesis with less than 37 steps has been achieved. In this thesis is presented our synthetic efforts toward such a robust and efficient synthesis of Taxol.

The optimisation of the Shapiro coupling fragments syntheses were investigated to enhance the robustness of our strategy. Then the C7-deoxy model ABC tricycle ring-system of Taxol, which lacks the oxygenated substituent at C7, has been efficiently synthesised by a dienyne ring-closing metathesis cascade (RCDEYM). This cascade closed the AB 6/8 membered ring system in a single operation. Other dienyne ring-closing metathesis cascades with similar substrates were also performed, assessing the influence of ruthenium catalysts, C1-C2 diol protecting groups (R1, R2), and substitution of the alkene at C13.

Synthetic efforts were also devoted to apply such a powerful method toward a formal synthesis of Taxol from an intermediate Holton and co-workers synthesised. During our studies, the C7-oxy group was found to be critical to access the ABC tricyclic core of Taxol by metathesis cascade. Understanding of the importance of this C7-oxy group was undertaken and led to the conception of a metathesis cascade prediction model.

Once the metathesis cascade was optimised, differentiation of the three trisubstituted alkenes present on the ABC tricyclic ring system was studied and elaboration of a formal synthesis was endeavoured.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Taxol, Formal Synthesis, Metathesis Cascade, Organic Synthesis
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Prunet, Dr. Joëlle
• Date of Award: 2015
• Depositing User: Aurelien Letort
• Unique ID: glathesis:2015-6677
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 01 Oct 2015 12:03
• Last Modified: 07 Oct 2015 10:50
• URI: https://theses.gla.ac.uk/id/eprint/6677