A model study for the synthesis of the fungal metabolites phomoidride A and B is presented. Building on previous studies from our group, the carbocyclic core of these molecules was constructed using a [6+4] cycloaddition between tropone 41 and the silyl enol ether of 2-cyclopenten-1-one. Efforts to install the C-17 phomoidride sidechain on substrates derived from this carbocycle met with limited success. This led us to revise our strategy by employing the novel 5-substituted cyclopentadiene 118. In contrast to the known instability of 5 substituted cyclopentadienes towards [1,5] hydrogen shifts, the 2-silyloxy moiety of 118 imparted remarkable thermal stability on the diene. A practical method was developed for the multigram-scale synthesis of cyclopentenone 132, a useful synthon and precursor to 118. Diene 118 underwent smooth [6+4] cycloaddition with tropone 41 at 23°C to give 133 in 51-54% yield.* / Attempts to install the C-17 stereocenter of the phomoidrides through hydroboration of alkene 120 were thwarted by low yields. Remarkably, significant amounts of Markovnikoff products (9-23%) were isolated after the hydroboration of 120 and related alkenes with BH3·DMS. We undertook a series of DFT studies (B3LYP16-31G*) to understand the origins of reduced anti-Markovnikoff selectivity. These studies suggested that the bridging ketones and remote diene both contributed to this phenomenon. These studies led us to synthesize carbocycle 158. In line with predictions, hydroboration of saturated diketone 158 was completely selective for the anti-Markovnikoff product.* / The C-17 sidechain of the phomoidrides was successfully extended through a conjugate addition reaction. Compound 189, which contains the correct stereochemistry of the C-9 and C-17 sidechains, represents our furthest progress to date on the molecules.* / *Please refer to dissertation for diagrams.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.102953 |
| Date | January 2006 |
| Creators | Ashenhurst, James Alexander. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Chemistry.) |
| Rights | © James Alexander Ashenhurst, 2006 |
| Relation | alephsysno: 002608394, proquestno: AAINR32141, Theses scanned by UMI/ProQuest. |
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