Within this thesis are described synthetic approaches towards the phomactins which are novel platelet activating factor antagonists. The synthesis of known alcohol 162 is described, the two key intermediates being aldehyde 160 and vinyl iodide 161. The key step of the synthesis of aldehyde 160 is a [2,3]-Wittig-Still rearrangement of stannane 159 which introduces the hindered C1-C2 bond present in the phomactins. The vinyl iodide 161 is made in four steps from 4-pentyn-1-ol. Addition of the vinyl ytterbium species derived from the vinyl iodide to aldehyde 160 gave secondary alcohol 162. Subsequent transformations furnished the bisprotected macrocyclic sulfone 174 in four steps from alcohol 162 to give the C2 SEM protected macrocycle. Elaboration of the macrocycle to ketoaldehyde 206 was made possible by the TPAP oxidation/rearrangement reaction. Reduction with DIBAL-Hgave diol 175. Attempts at removing the sulfone appendage proved difficult so the diol was protected as the bis-acetate to attempt a selective epoxidation of the D3,4 olefin in the presence of the D1,15 olefin. Although this looked promising with the formation of the mono-epoxide 213, the inefficiency of removing the SEM group at C2 prior to the epoxidation meant the route was not viable. Removing both protecting groups from macrocycle 174 was possible with refluxing TBAF and after incorporating the epoxide of the D3,4 olefin, the macrocycle was elaborated to the benzyl ether 217. Applying the TPAP oxidation/DIBAL-H reduction sequence furnished advanced intermediate 179 which has the full carbon skeleton found in phomactin A and also had oxygen functionality at all the required positions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:538357 |
| Date | January 2011 |
| Creators | Irshad, Abdur Rehman |
| Contributors | Thomas, Jim |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/approaches-towards-a-total-synthesis-of-the-phomactins(49b617f3-dd49-4217-8828-be93af835554).html |
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