Structural, Mechanistic, and Computational Analysis of the Effects of Anomeric Fluorines on Anomeric Fluoride Departure in 5-Fluoroxylosyl Fluorides

The effects of fluorine substitution at the C-5 center of pyranosyl fluorides on the reactivity at the C-1 anomeric center was probed by studying a series of 5-fluoroxylosyl fluoride derivatives. X-ray structures of their per-O-acetates detailed the effects on the ground-state structures. First-order rate constants for spontaneous hydrolysis, in conjunction with computational studies, revealed that changes in the stereochemistry of the 5-fluorine had minimal effects on the solvolysis rate constants and that the observed rate reductions were broadly similar to those caused by additional fluorine substitution at C-1 but significantly less than those due to substitution at C-2. Differences in the trapping behavior of 5- versus 2-fluoro-substituted glycosyl fluorides with α- and β-glycosidases arise more from differences in steric effects and hydrogen-bonding interactions than from intrinsic reactivity differences.本研究通过对一系列5-氟木糖氟化物衍生物的实验探究，剖析了吡喃糖氟化物C-5位的氟取代对C-1异头碳中心反应活性的影响。其全O-乙酰化物的X射线晶体结构，详细阐明了该取代效应对分子基态结构的作用。自发水解的一级速率常数结合计算研究结果显示：5-氟原子的立体构型变化对溶剂解速率常数的影响极小，观测到的速率降低幅度与C-1位额外氟取代所引发的降幅大体相近，但显著小于C-2位氟取代导致的速率降幅。相较于5-氟取代的糖基氟化物，2-氟取代的糖基氟化物与α-、β-糖苷酶的捕获行为差异，更多源于空间位阻效应与氢键相互作用的不同，而非本征反应活性的差异。