Enantiospecific Total Synthesis of Natural (+)-Taxusin. 1. Retrosynthesis, Advancement to Diastereomeric trans-Δ9,10-Tricyclic Olefinic Intermediates, and the Stereocontrol Attainable Because of Intrinsic Rotational Barriers Therein

In a study directed toward the expeditious construction of heavily functionalized taxane intermediates, 1-vinyl-2-cyclohexenyl-7,7-dimethyl- exo -norbornan-2-ols such as 9, which are derived from D -camphor are shown to undergo stereocontrolled oxyanionic Cope rearrangement to give tricyclic unsaturated ketones. In the specific example of 13, only three subsequent steps are required to effect 1,2-bridge migration with formation of triketone 6 . Once the relative reactivities of the carbonyl groups in 6 were elucidated, its direct conversion to the diastereomeric trans olefins 25 and 26 was accomplished. As expected, both intermediates exhibit restricted rotation due to transannular steric constraints, with 25 being the more thermodynamically stable. These compounds can be regioselectively dihydroxylated, but the more advanced substrates 30 and 32 were shown not to perform well under Wittig olefination conditions. This warranted prior exocyclic olefination in ring C, a strategy which allowed for the highly efficient conversion of 33 to 39 having the complete array of functionality demanded of the B and C rings in taxusin.