Catalytic enantioselective divergent reaction of thioimidates with naphthols: construction of N,S-acetal-containing tetrasubstituted carbon centers

Abstract

Enantiopure N,S-acetals are distributed in numerous natural products and pharmaceuticals, exhibiting a broad spectrum of biological activities. Herein we open a new avenue for accessing N,S-acetal-containing tetrasubstituted carbon stereogenic centers through an enantioselective divergent reaction between cyclic α-carbonyl thioimidates and naphthols. Using 2-naphthols as nucleophilic partners, the reaction enabled the formation of structurally diverse furanonaphthobenzo[b]thiophene derivatives bearing two vicinal diheteroatom-containing tetrasubstituted carbon stereogenic centers with high optical purities through a domino aza-Friedel–Crafts/O-hemiacetalization of the exocyclic CO bond. In contrast, the enantioselective addition of 1-naphthols/electron-rich phenols to cyclic α-carbonyl thioimidates led to the formation of N,S-acetal-containing tetrasubstituted carbon stereogenic centers in high yields and excellent enantioselectivities. DFT studies provide valuable insights into the reaction mechanism and the origin of enantioselectivity, as well as the reaction divergence observed with 2-naphthols and 1-naphthols, respectively. The results suggest that the C–C bond formation during the addition of naphthols to thioimidates is the enantioselectivity-determining step, while the rate-determining step is the C–H bond cleavage. Additionally, both kinetically and thermodynamically, the reaction with 2-naphthols favors the subsequent O-hemiacetalization to yield cyclization products, whereas the addition of 1-naphthols to thiomidates is thermodynamically driven for the synthesis of chiral N,S-acetals through the subsequent protonation process.