Towards the total synthesis of dolabelide C using metathesis reactions

Tiniakos, Alexander Felix (2019) Towards the total synthesis of dolabelide C using metathesis reactions. PhD thesis, University of Glasgow.

Abstract

Dolabelide C is a 24-membered macrolide isolated from the Japanese sea hare Dolabella auricularia that exhibits cytotoxicity against cervical cancer HeLa-S3 cells with an IC50 values of 1.9 μg/mL. Its complex molecular structure, which encompasses eight hydroxylated and three methylated stereogenic centers as well as two E-trisubstituted alkenes, makes it a synthetically challenging target. The synthesis of dolabelide C as well as the rest of the molecules of the dolabelide family have therefore been studied by several groups.
Herein, published synthetic efforts towards the construction of dolabelides found in the literature, as well as the use of silicon-tether ring closing metathesis in natural product synthesis, are described in the first chapter. A summary of the previous work carried out in the Prunet group is also discussed.
Our envisioned retrosynthesis involves disconnecting dolabelide C at the C1 lactone and at the C15-C16 bond. The second chapter of this thesis gives a detailed account of the investigation that took place while finding a reliable and high yielding route to prepare the protected C16-C30 fragment enantioselectivity using a silicon-tether ring closing metathesis strategy.
Synthetic endeavours to construct the C1-C15 fragment using cross metathesis as the key step between an enone and a few different homoallylic alcohol partners took place. Although we found a successful route to prepare a key advanced alkyne intermediate, the final step of the synthesis that involved transforming the alkyne into a vinyl iodide employing a Negishi carboalumination was unsuccessful. Installation of the required vinyl iodide moiety earlier during the synthesis was also attempted with no luck.
Finally, the silicon-tether ring closing metathesis sequence originally developed in the group to prepare E-trisubstituted alkenes selectively was successfully extended to the construction of Z-trisubstituted olefins starting from vinyldimetheylchlorosilane and an allylic
alcohol.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Dolabelide, natural product, total synthesis, organic chemistry, asymmetric synthesis, metathesis, cross metathesis silicon-tether ring closing metathesis, trisubstituted alkenes.
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Prunet, Dr. Joelle
• Date of Award: 2019
• Depositing User: Mr Alexander Felix Tiniakos
• Unique ID: glathesis:2019-79050
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 09 Mar 2020 14:36
• Last Modified: 18 Aug 2022 16:02
• Thesis DOI: 10.5525/gla.thesis.79050
• URI: https://theses.gla.ac.uk/id/eprint/79050

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