An approach to taxodione involving biomimetic polyene cyclization methodology

Abstract

A novel synthesis of 11,12-dimethoxyabieta-8,11,13-triene ( 4), involving the biomimetic cyclization of allylic alcohol 5 is described. This represents a formal total synthesis of taxodione ( 1), a tumor-inhibitory diterpenoid quinone methide. Treatment of the sodium salt of 8 with allyl bromide gave a 91% yield of allyl ether 19 which readily underwent a Claisen rearrangement to give (after methylation with dimethyl sulfate) the dimethoxy olefin 21 in 90% yield. Hydroboration with disiamylborane, followed by oxidative work-up gave alcohol 17 in 98% yield. Oxidation with Collins' reagent afforded 22 in 83% yield. which, upon treatment with isopropenylmagnesium bromide, gave allylic alcohol 23 in 91% yield. Conversion of 23 into chloro ketone 25 was readily effected in 80% yield via a chloro ketal Claisen rearrangement. This substance afforded epoxide 26 in 94% yield when treated with isopropenyllithium. Reduction of 26 with lithium in liquid ammonia gave the desired substrate 5 in 93% yield. When 5 was treated with trifluoroacetic acid in methylene chloride at ca −45° for 45 min, a 90% yield of the desired tricyclic material 6 was obtained. Conversion of 6 to dl-11,12-dimethoxy-abieta-8,11,13-triene ( 4) was effected in 59% yield by ruthenium tetroxide oxidation (to give 30) followed by sodium cyanoborohydride reduction of the corresponding tosylhydrazone of 30. Resolution of 30 involved the separation of the diastereomeric ketals 31. Conversion of d- 30 into d-11,12-dimethoxyabieta-8,11,13-triene ( 4) was effected in the aforementioned manner used in the dl-series.