Organocatalytic Asymmetric Sulfa-Michael Addition of 2-Aminothiophenols to Chalcones: First Enantioselective Access to 2,3,4,5-Tetrahydro-1,5-benzothiazepines

1,5-Benzothiazepine frameworks are highly relevant in medicinal chemistry. Reported catalytic asymmetric approaches to these scaffolds have targeted 2,3-dihydro-1,5-benzothiazepin-4-ones but leave the corresponding amines (i.e., 2,3,4,5-tetrahydro-1,5-benzothiazepines) out of reach. Herein, we present the first entry to these important compounds in enantioenriched form. Our approach is based on the catalytic asymmetric sulfa-Michael addition of 2-aminothiophenols to trans-chalcones, followed by intramolecular reductive amination. Both reactions required careful study to solve several challenging issues. The resulting optimized two-step protocol afforded a range of 2,3,4,5-tetrahydro-1,5-benzothiazepines as single trans diastereomers in moderate to good yields and enantioselectivities.