Abstract:
A method has been established for the synthesis of the 5,5-spiroacetal moiety of the anti-Helicobacter pylori agents CJ-12,954 1 and CJ-13,014 2 in racemic form and as a mixture of stereoisomers. Retrosynthetically the key spiroacetal 9 is derived from the acyclic protected dihydroxyketone precursor 10 or 11 which in turn are available from enynone 25 or 26. Enynones 25 and 26 were prepared via addition of the acetylide derived from acetylenes 13 or 14 to aldehyde 12 followed by oxidation of the resultant alcohols 23 and 24 respectively. Acetylenes 13 and 14 in turn were available via [2,3]-sigmatropic rearrangement of allyl propargyl ether 16. Extension of this reaction in an asymmetric sense by use of a chiral base would have provided acetylene 14 in enantioenriched form, however, efforts towards this end were disappointing. Enynones 25 and 26 were converted to keto epoxides 10 and 11 respectively by treatment with meta-chloroperbenzoic acid followed by hydrogenation of the acetylene. Attempts to effect deprotection and cyclization of bis-silyl ethers 10 and 11 to spiroacetal 9 were complicated by the presence of the epoxide. In an alternative approach enynone 26 was converted to methyl acetal 29 upon treatment with camphorsulfonic acid in methanol. Subsequent epoxidation of the terminal alkene 29 afforded epoxide 30 which then underwent smooth hydrogenation and cyclization in situ to the desired spiroacetal 9.
