From C-glycosides to pyranopyrans: an approach to thyrsiferol using titanium(III)-promoted redox couplings

An approach to the pyranopyran ring system that is found in many natural products, including thyrsiferol, is described. The route entails the assembly of an alpha,beta-unsaturated ketone (11) from geraniol and dihydropyran (23) from acetyl acetaldehyde dimethyl acetal (19) and their titanium(III)-promoted coupling to afford a respectable 60% yield of keto alcohol 26. The sigma-bond formed in this process corresponds to the pro-C(9)-C(10) bond of thyrsiferol (4). Attempts to invert the stereochemistry at the pro-C(11) center were thwarted by the congestion imparted by the presence of the vicinal TBS-ether. Consequently, cyclization of the coupling adduct under conditions developed by Olah and Prakash and co-workers led to the cis-fused pyranopyran 27. X-ray analysis of this crystalline material confirmed each of the stereochemical assignments. After much effort, it was determined that the hydroxyl group at C(12) could be removed by treating the derived methyl xanthate with a tri-n-butylphosphine-borane complex under radical-forming conditions. The reaction sequence worked well, despite the hindered working environment and the presence of a potentially labile C-Br bond.