A unified approach to (‒)-FR901483 and (+)-TAN1251B

Girault, Malory P.Y. (2010) A unified approach to (‒)-FR901483 and (+)-TAN1251B. PhD thesis, University of Nottingham.

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Abstract

This thesis describes studies, which have been realised towards the total syntheses of two natural products (–)-FR901483 (1) and (+)-TAN1251B (3), which are thought to be biosynthetically related.

The introduction summarises the isolation and biological activities of both natural products. It then focuses on previous methods used to overcome the key challenges in their syntheses: formation of their related tricyclic cores and the quaternary stereocentre next to nitrogen. Our initial retrosynthetic analysis is presented, which proposes the formation of both targets from a common intermediate. 1,5-CH insertion of an alkylidene carbene would allow formation of this common intermediate, containing the challenging quaternary stereocentre adjacent to nitrogen, in a stereoselective fashion. A brief review of work employing this methodology, which has been described within the Hayes group towards these natural products follows.

The results and discussion begins with the synthesis of the common intermediate. From here, work towards the formation of the tricyclic core of (–)-FR901483 (1) is presented. The initially proposed route of closing the final ring of the tricyclic core via a regioselective intramolecular aldol cyclisation was found to be unsuccessful. A revised route involving an intramolecular peptide coupling as the key ring closing step gives our first tricyclic derivative of (–)-FR901483 (1). Formation of a related tricycle is subsequently achieved via a palladium-catalysed alkenylation reaction. The unsuccessful attempts at elaboration of this structure are then discussed. Finally, the progress made in a revised route towards the formation of a key intermediate in Fukuyama’s synthesis of (–)-FR901483 (1) is depicted. The progress made towards the target, and possible work for the future is then reviewed.

In the final part of the results and discussion, efforts made towards the synthesis of (+)-TAN1251B (3) are presented. The successful installation of the key hydroxyl group alpha to the ketone in a stereoselective manner via treatment of a silyl enol ether derived from the common intermediate with DMDO is reported. From here, formation of the tricyclic core is achieved using an intramolecular peptide coupling. Further elaboration allows installation of the side-chain and results in the carbon skeleton required for the total synthesis of (+)-TAN1251B (3). A summary of this work and the future steps required to complete the synthesis are then presented.

The thesis concludes with an experimental section, which gives detailed procedures and full characterisation data for the novel compounds discussed in the results and discussion part.

Item Type:Thesis (PhD)
Supervisors:Hayes, C.J.
Lygo, B.
Faculties/Schools:UK Campuses > Faculty of Science > School of Chemistry
ID Code:1658
Deposited By:M. Malory P. Y. GIRAULT
Deposited On:12 Apr 2011 11:46
Last Modified:12 Apr 2011 11:46

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