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表征与分析，探究了吡喃糖氟化物C-5位氟取代对其C-1异头碳位反应活性的调控效应。其全O-乙酰化产物的X射线晶体结构，详细阐明了该氟取代对基态分子结构的影响。自发水解一级速率常数结合计算模拟研究结果显示：5-位氟原子的立体化学差异对溶剂解速率常数的影响微乎其微；观测到的反应速率降低幅度，与C-1位额外氟取代所引发的速率降低整体相近，但显著低于C-2位氟取代带来的速率降低。5-位与2-位氟取代的糖基氟化物，在被α-糖苷酶和β-糖苷酶捕获的行为差异，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。