Large-Scale Synthesis of Chiral Tetrahydropyran via Asymmetric Allylation Catalyzed by (S)-3,3′-Cl2-BINOL

Asymmetric synthesis of chiral tetrahydropyran 3, a key intermediate of PDE2 inhibitor 1, has been achieved in five linear steps with a 49% overall yield and >99:1 er on a large scale. The whole chemical process was realized without silica gel chromatography purification, starting from tert-butyl 2-chloro-5-(2-chloroacetyl)benzoate 7. The key features of current synthesis include asymmetric allylation catalyzed by an organocatalyst (S)-3,3′-Cl2-BINOL under solvent-free conditions.