Synthetic approach to potential precursors of sclerophytin A

Abstract

A direct approach to simple bicyclic analogues of the antitumor natural diterpene, sclerophytin A, is described. The readily available bicyclic ketone 8 (prepared from furan and trichloroacetone) was enantioselectively methylated to give the optically active ketone 11 . Regioselective allylation using Negishi's method afforded the α,α-dialkyl ketone 12 , which was converted to the chloroacetate 15 by hydroboration–oxidation and protection. Regioselective Baeyer–Villiger oxidation afforded the lactone 7a which could be transformed into the silyl ether 7b . Tebbe olefination furnished a mixture of two enol ethers in which the desired product 17 was the minor isomer. Several attempts to use the major endocyclic enol ether 18 to give the tricyclic analogues of sclerophytin proved unsuccessful. Opening of the lactone of 18 and selective protection of the diol afforded the primary alcohol 24 which was oxidized to the keto aldehyde 25 . Unfortunately pinacol coupling of 25 did not give any cyclic product. The diene 27 was also prepared from 25 but all attempts at ring-closing metathesis of 27 met with the same fate. The failure of these various cyclization methods underscores the difficulty in forming medium-sized ring systems, especially those cis-fused at the 2- and 5-positions of a tetrahydrofuran ring.