Asymmetric Total Synthesis of (-)-Azaspirene by Utilizing Ti-Claisen Condensation and Ti-Direct Aldol Reaction

A successful asymmetric total synthesis of (-)-azaspirene has been accomplished by utilizing (3R)-6-cinnamyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione, a readily accessible chiral template. The present method involves two distinctive TiCl4/amine-mediated reactions: (i) an asymmetric Ti-crossed-Claisen condensation of the chiral template with propanoyl chloride followed by methanolysis to afford methyl (2R)-(4E)-2-hydroxy-5-phenyl-2-propanoylpent-4-enoate, the key chiral syn-thon and (ii) a robust Ti-direct aldol addition reaction, instead of the reported lithium diisopropylamide/hexamethylphosphorictriamide (LDA/HMPA) or potassium hexamethyldisilazide (KHMDS)-mediated reaction, by using the trimethylsilyl (TMS) ether of alpha-acyl-gamma-lactam to successfully furnish the new aldol adduct. Final oxidation, cyclization, and tert-butyldimethylsilyl (TBS) removal produced (-)-azaspirene from the key template in 23 steps (total yield 1.7 %).