Abstract:
The work described herein provides a model system for appendage of the E ring of epi-17-deoxy-(O-8)-salinomycin3 onto bis-spiroacetal aldehyde 6. The conversion of aldehyde 7 to bicyclic ether 8via silver assisted ring expansion of the mesylate derived from tetrahydrofuran alcohol 33 is described. Attempts to provide a stereoselective synthesis of epoxide 27 required for the preparation of 33 and hence 8 are reported. Alcohol 9 was prepared by chelation controlled addition of the Grignard reagent derived from bromide 15 to aldehyde 7. Bromide 15 in turn was prepared as a 9:1 E:Z mixture of isomers with the required E-stereochemistry being introduced via a stereoselective Julia ring opening of cyclopropane 20. Sharpless asymmetric dihydroxylation of alkenes 10 and 11 readily provided diols 22 and 25 [or 23 and 26 respectively], however, their subsequent conversion to epoxides 27 and 30 with retention of stereochemistry proved unsuccessful. Cyclic sulfites 37, 39 and sulfates 42, 45 were investigated as epoxide equivalents. Base induced cyclization of sulfites 37, 39 only afforded triols 21, 24. Analogous reaction using sulfates 42, 45 favoured endo cyclization to a tetrahydropyran ring, however, the acidic conditions required for hydrolysis of the initial alkyl sulfate effected undesired elimination of the resultant tertiary alcohol. Whilst a stereoselective synthesis of the correct epoxide 27 required for preparation of tetrahydropyran 8via ring expansion of tetrahydrofuran 33 has not been achieved, these latter conversions have been successfully demonstrated by the conversion of epoxides 28 and 31 to a 1:1 mixture of tetrahydrofurans 33 and 34 which were separable by flash chromatography. Subsequent ring expansion of these tetrahydrofurans 33 and 34 to tetrahydropyrans 8 and 14 was effected upon treatment with methanesulfonyl chloride followed by silver carbonate.
