Moons Peter H, de Kleijne Frank F J, van Wieringen Teun, Ter Braak Floor, Almizori Hero R, Jakobs Luuk J H, de Kleijne Willem P M, Rutjes Floris P J T, Martens Jonathan, Oomens Jos, Korevaar Peter A, White Paul B, Boltje Thomas J
Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
FELIX Laboratory, Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 7, 6525 ED Nijmegen, The Netherlands.
J Am Chem Soc. 2025 Jul 2;147(26):22597-22608. doi: 10.1021/jacs.5c03519. Epub 2025 Jun 23.
The glycosylation reaction represents a crucial and challenging reaction used in oligosaccharide synthesis. Specifically, attaining complete stereocontrol during glycosylation reactions remains challenging. Its complex nature is defined by the highly reactive intermediates that form upon the activation of a glycosyl donor. Low-abundant species may afford the major product via Curtin-Hammett kinetics and have long been proposed to play a major role. Therefore, characterizing these elusive stereodirecting intermediates is key to understanding glycosylation reaction mechanisms. Herein, we applied a combination of (exchange) NMR techniques to establish the equilibration rates of glycosyl triflate reaction intermediates and their ensuing glycosylation reaction kinetics. To this end, we studied the glycosylation reactions of 6,3-mannuronic acid and 6,3-glucuronic acid lactone donors. Using the complete set of reaction kinetics data, we constructed a computational kinetic model that shows that these compounds indeed react according to a Curtin-Hammett scenario. Furthermore, we were able to rationalize the observed stereochemical reaction outcomes using quantum-chemically computed potential energy surfaces for these glycosylation reactions. Hence, this workflow can now be used to obtain a complete reaction kinetics overview to retrieve the reaction pathway(s) that drive product formation.
糖基化反应是寡糖合成中一种关键且具有挑战性的反应。具体而言，在糖基化反应过程中实现完全的立体控制仍然具有挑战性。其复杂的性质是由糖基供体活化后形成的高活性中间体所决定的。低丰度物种可能通过柯廷-哈米特动力学产生主要产物，长期以来人们一直认为它们起着主要作用。因此，表征这些难以捉摸的立体定向中间体是理解糖基化反应机制的关键。在此，我们应用了（交换）核磁共振技术的组合来确定糖基三氟甲磺酸酯反应中间体的平衡速率及其随后的糖基化反应动力学。为此，我们研究了6,3-甘露糖醛酸和6,3-葡萄糖醛酸内酯供体的糖基化反应。利用完整的反应动力学数据集，我们构建了一个计算动力学模型，该模型表明这些化合物确实按照柯廷-哈米特情况进行反应。此外，我们能够使用这些糖基化反应的量子化学计算势能面来合理解释观察到的立体化学反应结果。因此，现在可以使用这个工作流程来获得完整的反应动力学概述，以检索驱动产物形成的反应途径。
