Limitations in the application of anionic oxy-cope sigmatropy to elaboration of the forskolin nucleus

Abstract

The functionallzed blcyclo[2.2.2]octenone 6 has been synthesized in four steps fron 2,4,4-trimethyl-2-cyclohexenone. This ketone undergoes 1,2-addition with 6-lithlodlhydropyran to deliver alcohols 16 and 17 In a 1:1.8 ratio. The potassium salt of 17 experiences oxy-Cope rearrangement In refluxing tetrahydrofuran solution containing 18-crown-6 and gives rise under these conditions to the thermodynanlic enolate 19. This intermediate has been Crapped with several electrophiles, the most relevant to elaboration of the forskolln nucleus being phenylselenenyl chloride. A route Co tricyclic ketones 25 and 26 Is thereby opened. In an attempt to expand upon this chemistry, several more highly functionallzed 3,4-dlhydro-2H-pyrans were prepared; some were obtained in enantiomerlcally pure condition since they originated from carbohydrate precursors. The complications associated with metalation of these heterocycles at C-6 are delineated. Since no indication of oxyanionic Cope rearrangement was observed in those adducts ( 41 42 , 46, and 51) which were synthesized, we conclude that steric (and perhaps electronic) influences exert a particularly strong rate-retarding effect on the key [3,3] sigmatropic step.