Synthetic studies towards the total synthesis of hexacyclinic acid

Audic, Alexandre (2016) Synthetic studies towards the total synthesis of hexacyclinic acid. PhD thesis, University of Glasgow.

Abstract

In the first chapter of this thesis, published works found in the literature about hexacyclinic acid and FR182877 are reported and commented. A quick summary of the previous work done in the Prunet group is also described.
In the second and third chapter, a more detailed account of the work undertaken during this PhD was given. Firstly, syntheses of two ABC tricycles incorporating tert-butyl and (trimethylsilyl)ethyl esters were undertaken. These syntheses include two key steps previously developed in the group, a diastereoselective Michael addition and a Snider cyclisation. Multiple conditions for the hydrolysis of the esters were attempted but none of them gave the desired product. The main part of this work is focused on the synthesis of a CDEF model and in particular about the development of the key step, the formation of a nine-membered ring. Several DEF fragments were synthesised in short synthetic sequences and as single isomers. Six different synthetic pathways were developed in total and a novel method, a Michael/elimination reaction, was found to be a very efficient way to close the desired medium-size ring. From the nine-membered ring, regioselective reduction and palladium catalysed allylic substitution led to the formation of the CDF tricycle. Final steps of the synthesis were fruitless and led only to decomposition. A synthesis of a chiral C-ring was also developed during this PhD.

Finally, another project was undertaken, not related to hexacyclinic acid. Methodology developed in the group for the diastereoselective formation of trisubstituted alkenes employing a temporary silicon-tethered ring-closing metathesis was extended to homoallylic alcohols. The first steps of the method were similar to the previous methodology but the end-game had to be modified in favour of an oxidation/reduction sequence to successfully obtain the desired products with the correct geometry. In the fourth chapter, procedures and analytical data for the synthesised compounds previously described are reported.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Total synthesis, hexacyclinic acid, medium size rings, silicon tether.
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Funder's Name: Engineering & Physical Sciences Research Council (EPSRC)
• Supervisor's Name: Prunet, Dr. Joelle
• Date of Award: 2016
• Depositing User: Dr. Alexandre Audic
• Unique ID: glathesis:2016-7790
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Nov 2016 13:45
• Last Modified: 27 Mar 2019 09:23
• URI: https://theses.gla.ac.uk/id/eprint/7790