APPROACHES TO THE D-E RING OF THE POLYETHER ANTIBIOTIC SALINOMYCIN USING SHARPLESS ASYMMETRIC DIHYDROXYLATION

The work described herein provides a model system for appendage of the E ring of epi-17-deoxy-(O-8)-salinomycin 3 onto bis-spiroacetal aldeh yde 6. The conversion of aldehyde 7 to bicyclic ether 8 via silver ass isted ring expansion of the mesylate derived from tetrahydrofuran alco hol 33 is described. Attempts to provide a stereoselective synthesis o f epoxide 27 required for the preparation of 33 and hence 8 are report ed. Alcohol 9 was prepared by chelation controlled addition of the Gri gnard reagent derived from bromide 15 to aldehyde 7. Bromide 15 in tur n was prepared as a 9:1 E:Z mixture of isomers with the required E-ste reochemistry being introduced via a stereoselective Julia ring opening of cyclopropane 20. Sharpless asymmetric dihydroxylation of alkenes 1 0 and 11 readily provided diols 22 and 25 [or 23 and 26 respectively], however, their subsequent conversion to epoxides 27 and 30 with reten tion of stereochemistry proved unsuccessful. Cyclic sulfites 37, 39 an d sulfates 42, 45 were investigated as epoxide equivalents. Base induc ed cyclization of sulfites 37, 39 only afforded triols 21, 24. Analogo us reaction using sulfates 42, 45 favoured endo cyclization to a tetra hydropyran ring, however, the acidic conditions required for hydrolysi s of the initial alkyl sulfate effected undesired elimination of the r esultant tertiary alcohol. Whilst a stereoselective synthesis of the c orrect epoxide 27 required for preparation of tetrahydropyran 8 via ri ng 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 whic h were separable by flash chromatography. Subsequent ring expansion of these tetrahydrofurans 33 and 34 to tetrahydropyrans 8 and 14 was eff ected upon treatment with methanesulfonyl chloride followed by silver carbonate. (C) 1998 Elsevier Science Ltd. All rights reserved.