Studies towards the synthesis of hexacyclinic acid

Mathieson, Michael (2014) Studies towards the synthesis of hexacyclinic acid. PhD thesis, University of Glasgow.

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Abstract

Hexacyclinic acid is a polyketide isolated from Streptomyces cellulosae bacteria in 2001. It possesses a complex and challenging hexacyclic ring system with various oxygen functionalities throughout. Hexacyclinic acid has also demonstrated some cytotoxic activity, making it an attractive target for total synthesis. However to date no full synthesis has been reported. Previously within the group significant progress had been made towards the synthesis of hexacyclinic acid, with construction of the ABC 5/6/5 tricyclic core being achieved via a diastereoselective Michael addition and Snider radical cyclisation. The synthesis ran into difficulties however when hydrolysis of the ethyl ester could not be accomplished and removal of the superfluous carboxylic acid moiety could not be realised. The approach within the group for the formation of the ABC tricycle was to continue the current strategy, joining the A and C-rings via the diastereoselective Michael reaction, and the closure of the 6-membered B-ring by Snider radical cyclisation. Progress was made using the tert-butyl and 2,2,2-trimethylsilylethyl ester analogues in an attempt to improve diastereoselectivities Progress was also made on the synthesis of the CDEF tricyclic system, utilising (R)-isopropylcyclopentenone as a C-ring model system. The DEF framework was attached to the model by a Michael addition, with further functionalisation setting up the necessary functionalities for cyclisation. Conditions were attempted to effect a challenging aldol condensation to form the 9-membered ring, however all attempts effect this transformation were fruitless. It was discovered that 2,2,2-trifluoromethylacetophenone can act as a replacement for benzaldehyde in the synthesis of protected syn-1,3-diols from homoallylic alcohols, with comparable yields and easier purification. Finally, an investigation was also made into the use of a bispidine ligand as a replacement for (−)-sparteine in Crimmins asymmetric aldol reactions, with the bispidine shown to give superior yields and diastereoselectivity when compared to TMEDA.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Funder's Name: UNSPECIFIED
Supervisor's Name: Prunet, Dr. Joëlle
Date of Award: 2014
Depositing User: Mr Michael Mathieson
Unique ID: glathesis:2014-5750
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Nov 2014 11:16
Last Modified: 12 Nov 2014 11:18
URI: http://theses.gla.ac.uk/id/eprint/5750

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