Studies towards the synthesis of LL-Z1640-2 and spirocyclic systems

Harnor, Suzannah Jane (2010) Studies towards the synthesis of LL-Z1640-2 and spirocyclic systems. PhD thesis, University of Glasgow.

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Resorcyclic acid lactones (RALs) are natural products, with some having been shown to be potent inhibitors of several protein kinases and mammalian cell proliferation and tumour growth in animals. LL-Z1640-2 (also known as 5Z-7-oxo-zeanol or C292) is a cis-enone RAL, isolated in 1978 from fungal broth and classified as an anti-protozoal agent. Later, in 1999, its cytokine releasing inhibiting activity was discovered, with subsequent data showing it could selectively and irreversibly inhibit transforming growth factor activating kinase-1 (TAK1) activity at low concentrations. It is also reported as having significant activity versus tumour necrosis factor-alpha (TNF-α) production in cells.
This thesis documents and describes the work undertaken towards a total synthesis of the 14-membered macrocycle, LL-Z1640-2. The presence of two internal bonds and three stereogenic centres poses a challenge synthetically, but this has been effectively overcome with the development of a flexible, economic and efficient synthesis, beginning from the commercially available starting materials, methyl 2,4,6-trihydroxybenzoate and 2-deoxy-D-ribose.
The original route relied on a Wittig olefination to introduce the E-double bond, with moderate selectivity and success. Later, an improved method was built upon, which utilised Grubbs mediated cross-metathesis to form the desired E-olefin in good yield and selectivity. Once the entire carbon framework had been established via a one-pot oxidation-Grignard adition of the appropriate alkyne unit, subsequent transformations enabled the formation of the seco-acid. This very successfully underwent Mitsunobu macrolactonisation, with complete inversion of the stereocentre, to afford the macrocyclic lactone. From this intermediate, the desired natural product LL-Z1640-2 could be generated in three steps.

A number of natural products and biologically important compounds contain spirocyclic pyran and piperidines ring systems as part of their overall structures. In 1996, pinnaic acid and halichlorine were isolated from their respective marine natural sources. It was subsequently shown that they exhibited inhibitory activity towards certain biological substances and for this reason they became targets for total synthesis. Characterised by an azaspiro[4.5]decane ring system, the difficulty in achieving total syntheses of such compounds is immense. The aim of the project was to develop a concise method towards the generation of highly functionalised spirocyclic piperidine units. The regioselective aza-Achmatowicz oxidative rearrangement was used as the key step to rearrange α-amino furan building blocks into their respective enones. Importantly, this rearrangement was proven to be viable and to proceed with compounds possessing a terminal olefin, with no over-oxidation observed. This thesis also describes the investigation and efforts made into the production of more functionalised units, as well as studies into the synthesis of the cores of halichlorine and polymaxenolide, again using the aza-Achmatowicz and Achmatowicz rearrangement respectively.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Marquez, Dr. Rodolfo
Date of Award: 2010
Depositing User: Miss Suzannah J Harnor
Unique ID: glathesis:2010-2016
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Jul 2010
Last Modified: 10 Dec 2012 13:49

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