Synthesis of Chiral 3-Substituted Phthalides by a Sequential Organocatalytic Enantioselective Aldol-Lactonization Reaction. Three-Step Synthesis of (S)-(-)-3-Butylphthalide

The development of efficient methods for the facile construction of important molecular frameworks is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in it large collection of natural products with broad, potent, and potentially path-pointing biological activities. In this investigation, we have uncovered all unprecedented organocatalytic asymmetric aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient construction of the enantioenriched privileged scaffold. As a result of the sensitive nature Of Substrate structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interestingly, it is found that in this reaction, addition of an acid additive PhCO2H can significantly enhance reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the sensitivity of reaction conditions toward it sequential aldol-lactonization process without affecting enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile lactonization reaction in the presence of K2CO3. The aldol-lactonization processes serve as it powerful approach to the preparation of synthetically and biologically important 3-substitued phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the natural product of 3-butylphthalide is reported.