An Unexpected Inversion at the C-2 Stereocenter During Direct N-Glycosylation of Sugar Hemiacetals

<jats:p>The Conventional methods for N-glycosides synthesis require glycosyl donors bearing activated leaving groups at C-1, such as glycosyl trichloroacetimidates, glycosyl chlorides or bromides, glycosyl (Z)-ynenoates, glycosyl ortho-alkynyl benzoates, and glycosyl carbonates. The preparation of these donors often involves multiple synthetic steps and, in many cases, the use of metal catalysts. Herein, we delineate a direct and stereoselective strategy for the synthesis of a broad range of 2-deoxy-β-N-glycosides and β-N-glycosides directly from unactivated 2-deoxy sugar hemiacetals and sugar hemiacetals. The transformation proceeds through direct amination with various primary aromatic amines in the presence of a catalytic amount of indium trichloride, eliminating the need for preinstalled leaving group. Notably, the reaction is accompanied by an unexpected stereo-inversion at the C-2 stereocenter of the sugar hemiacetal, a structural feature unambiguously established by single-crystal X-ray diffraction and detailed NMR analyses. This method highlights a new approach to stereo-controlled carbohydrate functionalization with excellent stereoselectivity, ease of use, and adaptability, providing a leaving-group-free glycosyl donor and transition-metal-free synthesis of N-glycosides with high atom economy.</jats:p>