Addition of a Grignard reagent to bis-spiroacetal aldehydes: appendage of a tetrahydrofuran ring

Abstract

The synthesis of tetracyclic polyethers 16 and 17, which are closely related to the polyether antibiotics epi-17-deoxy-(O-8)-salinomycin 3 and CP44,161 4, is described. The key step involved Barbier–Grignard addition of bromide 8 to bis-spiroacetal aldehyde 7a which proceeded via chelation control to provide erythro alcohol 9a as the major product. Addition of the Grignard reagent derived from bromide 8 to the isomeric bis-spiroacetal aldehydes 7b,7c,7d also afforded erythro alcohols 9b,9c,9d, respectively as the major products. A rationale for this observed stereoselectivity is provided. Attempts to effect iodoetherification of alkene 9a resulted in decomposition of the sensitive bis-spiroacetal ring system, however, epoxidation followed by acid catalyzed cyclization of the resultant epoxides 14,15 afforded bis-spiroacetal tetrahydrofurans 16,17. Attempts to effect ring expansion of tetrahydrofuran alcohols 16,17 to tetrahydropyrans 18,19 were unsuccessful.