93(P-34) Phomoidride Bの合成研究(ポスター発表の部)
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概要
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Phomoidride B was originally isolated from an unidentified fungus and was found to exhibit inhibitory activity towards ras-farnesyl transferase and squalene synthase. Structurally this compound possesses several characteristic features such as a chiral quaternary carbon center, a maleic anhydride moiety, an anti-Bredt double bond, and two hydrophobic side chains attached to the hydrophilic core. Arising from our interest in the biological evaluation of the hydrophobic side chains of ambiphilic natural products, we have designed a synthetic approach that would allow us to introduce the hydrophobic side chains (and possibly some variants) at a late stage of the synthesis. As key reactions for the construction of the bicyclic hydrophilic core, we decided to adopt [5+2] cycloaddition between an oxidopyrylium ylide and a fumaric ester or its variant for the Formation of the seven-membered ring, followed by the utilization of an intramolecular aldol reaction to complete the construction of the bicyclic core. To this end, three routes based upon our retrosynthetic plan were undertaken. The [5+2] reaction of oxidopyrylium-ylide precursor 12 with dimethyl fumarate in the presence of base furnished the corresponding cycloadduct with 13:1 stereoselectivity in favor of 4a. A systematic investigation of the reaction revealed that the stereoselectivity was governed by steric demands of both the side chain of the oxopyran (12-14) and the fumaric ester. Adduct 4a was converted to iodide 17, which was treated with Zn to give the ether ring cleaved 18. Allylation of TBS protected 19 resulted in the exclusive formation of 21. This could be converted to bicyclic 24a via several steps, which includes an intramolecular aldol reaction. A three component synthesis for the introduction of the two hydrophobic chains of enone 25 derived from 24a failed, and thus a four step procedure was required to obtain highly functionalized 6, which lacks only the quaternary carbon adjacent to a bridgehead. As an alternative pathway, intermediate 23 of the first route was converted to an enone (30), which was then treated with dimethyl malonate to furnish the Michael adduct. Intramolecular aldol reaction followed by oxidized gave 7, which is an analog of 24a and carries a tertiary carbon at the site required to be quaternized. Similar transformation should give rise to an advanced analog of 6. The third route involved cyanation of 4a followed by the Corey-Chaykovsky reaction to yield cyclopropane product 38. Reductive cleavage of the three-membered ring with SmI_2 proceeded regioselectively to produce 39 as the sole product. Transformation to iodide 41 gave way to ether ring opened acetal 8. Efforts towards the total synthesis of the target compound are currently ongoing using all three routes.
- 天然有機化合物討論会の論文
- 2002-09-01
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