Danishefsky Taxol Total Synthesis - D Ring Synthesis

D Ring Synthesis

Scheme 1 shows the synthesis of the oxetane D ring from the C ring starting from the (+) enantiomer of the Wieland-Miescher ketone (1). Reduction of this diketone with sodium borohydride provided unsaturated ketoalcohol 2, which was protected as an acetate. Formation of the ketal was accomponied by alkene rearrangement. The acetyl group was replaced by a tert-butyldimethylsilyl protecting group. Hydroboration followed by oxidation with hydrogen peroxide gave alcohol 5. The hydroxyl group was then oxidized to a carbonyl group giving ketone 6 by action of pyridinium dichromate. With all the sensitive functional groups protected, the methylene group required for the oxetane ring D was then provided by the Corey-Chaykovsky reagent, which converted the carbonyl group to an epoxide (7). Treatment of this epoxide with aluminium isopropoxide gave allylic alcohol 8. Two more hydroxyl groups were added by oxidation of the newly formed double bond with a catalytic amount of osmium tetroxide in the presence of N-methylmorpholine N-oxide. This reaction lacked stereospecificity and the yield of triol 9 with the correct stereochemistry was therefore reduced. The primary alcohol was protected as a silyl ether and the secondary alcohol was activated as a triflate (11). Heating this trimethylsilyl protected triflate in refluxing ethlyene glycol closed the ring to give oxetane 12.