Controllable 1,3-Bis-Functionalization of 2‑Nitroglycals with High Regioselectivity and Stereoselectivity Enabled by a H‑Bond Catalyst

• Published in: JACS Au 2024-03, Vol.4 (3), p.974-984
• Main Authors: Li, Jiangtao, Fu, Zhengyan, Qiao, Zeen, Xie, Demeng, Zhang, Li, Liu, Ya-Zhou, Yang, Jian, Yan, Jia-Xin, Ma, Xiaofeng
• Format: Article
• Language: English
• ISSN: 2691-3704; 2691-3704
• DOI: 10.1021/jacsau.3c00727

The selective modification of carbohydrates is significant for producing their unnatural analogues for drug discovery. C1-functionalization (glycosylation) and C1,C2-difunctionalization of carbohydrates have been well developed. In contrast, C3-functionalization or C1,C3-difunctionalization of carbohydrates remains rare. Herein, we report such processes that efficiently and stereoselectively modify carbohydrates. Specifically, we found that trifluoroethanol (TFE) could promote 1,3-bis-indolylation/pyrrolylation of 2-nitroglycals generated carbohydrate derivatives in up to 93% yield at room temperature; slightly reducing the temperature could install two different indoles at the C1- and C3-positions. Switching TFE to a bifunctional amino thiourea catalyst leads to the generation of C3 monosubstituted carbohydrates, which could also be used to construct 1,3-di-C-functionalized carbohydrates. This approach produced a range of challenging sugar derivatives (over 80 examples) with controllable and high stereoselectivity (single isomer for over 90% of the examples). The potential applications of the reaction were demonstrated by a set of transformations including the synthesis of bridged large-ring molecules and gram scale reactions. Biological activities evaluation demonstrated that three compounds exhibit a potent inhibitory effect on human cancer cells T24, HCT116, AGS, and MKN-45 with IC50 ranged from 0.695 to 3.548 μM.