Tetrodecamycin (1) is a novel α-(γ-hydroxyacyl) tetronic acid based polyketide antibiotic isolated from the culture broth of Streptomyces nashvillensis MJ885-mF8 by Takeuchi et al. in 1994. Compound 1 shows potent inhibitory activity against Gram-positive bacteria including Bacillus anthracis and methicillin resistant Staphylococcus aureus (MRSA). It was proposed that an Aldol reaction of trans-decalin core 2 and tetronic acid derivative 3 followed by a face selective epoxidation and a subsequent epoxide-opening reaction would deliver the 6,6,7,5-skeleton of tetrodecamycm (1). To investigate this proposal, the silyl enol ether 5 was prepared from cycloheptene 4 in 7 steps. An unusual domino silyl enol ether reaction sequence was observed when the silyl enol ether 5 was submitted to a Diels-Alder reaction. It afforded cycloadduct 6, which was converted to the key intermediate 2 after another 3 steps (Scheme 1). Concurrently, double functionalisation of simple cyclic silyl enol ethers was investigated. Because of some difficulties in reproducing good overall yields to the cycloadduct 6, a second synthetic route was proposed. It was envisaged that a palladium-catalysed oxidative cyclisation or an organoselenium-mediated cyclisation reaction of compound 8 would construct the 6,6,7,5- skeleton 7, which would be converted to tetrodecamycin (1) via dihydroxylation followed by an introduction of the exo-methylene group. The intramolecular Diels-Alder reaction of trienal 11 afforded trans-decalin 10, which was converted to β-keto ester 9 in 2 steps. A Dieckmann-type cyclisation of 9 afforded compound 8 in good yield. However, so far transformation to compound 7 has not been achieved (Scheme 2).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:491527 |
| Date | January 2007 |
| Creators | He, Jing |
| Contributors | Baldwin, Jack E. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:3a2ab5cb-2757-4e53-b8cf-c635aef99455 |
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