Radical N-Glycosylation of Heterocycles with 1-Hydroxycarbohydrates Enabled by Copper Metallaphotoredox Catalysis

Abstract

Abstract N-Glycosylated heterocycles play important roles in biological systems and drug development. The synthesis of these compounds heavily relies on ionic N-glycosylation, which is usually constrained by factors like labile glycosyl donors, precious metal catalysts, and stringent conditions. Herein, we report an unprecedented glycosyl radical-based method for synthesizing N-glycosides by leveraging copper metallaphotoredox catalysis. Complementing with the well-established ionic approaches, our method employs inexpensive photo- and copper- catalysts and can tolerate some extent of water. Furthermore, readily available and stable 1-hydroxycarbohydrates are successfully utilized for the first time for N-glycosylation. The reaction exhibits a broad substrate scope, encompassing 76 examples, and demonstrates high stereoselectivity, favoring 1,2-trans selectivity for furanoses and α-selectivity for pyranoses. It also exhibits high site-selectivity for substrates containing multiple N-atoms. The synthetic utility was showcased through the late-stage functionalization of bioactive compounds and pharmaceuticals like Olaparib, Axitinib, and Metaxalone. Mechanistic studies proved the presence of glycosyl intermediates and the importance of copper metallaphotoredox catalysis.