Recently, we determined the structural bases required for CH/π catalysis to happen under normal lab glycosylation conditions. Two families of glycosides were synthesized, one exhibiting a modified benzylidene group equipped with an aromatic appendage, and the other composed of a series of more rigid disaccharides skeletons. Interestingly, the monitorization by NMR of these species during glycosylations revealed a diverging reactivity trend: while the first family of compounds did experience a noticeable rate enhancement of in the presence of the aromatic ring, the second family of compounds underwent a significant rate deceleration accompanied by an improvement in the stereoselectivity of the process. These experimental results underline the opposing influence exerted by van der Waals and Coulombic forces, and how they can be affected by dynamic aromatic/glycosyl cation contacts; the conclusions of our study suggest there is an open window for aromatic assistance to glycosylation processes, especially for glycosyl donors participating in dissociative mechanisms, with far reaching implications for enzyme engineering and organocatalysis.
During the course of this study, the monitorization of activated reaction mixtures devoid of glycosyl acceptor allowed the identification of several intermediates, where the alpha-glycosyl triflate was the predominant species. Unfortunately, no signals could be directly ascribed to an oxocarbenium-like species, despite the sugar donor laid on a stabilizing aromatic platform, overall indicating that no such intermediates were accumulating and instead, if any, they were very minor or had a transition-state character. However, these findings sparked a more fundamental study on glycosylation mechanisms. With this aim in mind, we set out to gauge the scope of our methodology in isolating activated reaction species acting as oxocarbenium reservoirs. In particular, we focused on α-selective glycosylations involving poor acceptors, for which an SN1 has been traditionally invoked. A similar methodology was applied, relying on the synthesis of 13C-labeled sugar donors and their analysis by low temperature NMR. For glucose, these experiments revealed the presence of an apparently exclusive α-triflate species (>99%), in agreement with previous reports. In fact, despite the extra sensitivity provided by the isotopically labeled samples, significant accumulation times were required before an anomeric cross-peak could be confidently assigned to a β-triflate intermediate. Further experiments conducted on a more favorable allose model showed a much higher ratio of β-triflate, which allowed the first-ever structural and kinetic characterization of such intermediate. To our delight, additional 13C kinetic isotopic effects and in silico calculations pointed toward an oxocarbenium cationic species, in the form of a contact ion pair, as the key intermediate in the production of the major glycoside. Thus, the detected anomeric β-triflate acts as a high-energy reservoir of even more unstable species. Ultimately, the obtained results showed that the analyzed glycosylations do not satisfy the Curtin−Hammett boundary requirements for which triflate anomerization should be much faster than the alcohol substitution. This conclusion is illustrated by the preferential consumption of the β-allosyl triflate over its α-counterpart.
This work is described in: Andrés G. Santana, Laura Montalvillo-Jiménez, Laura Díaz-Casado, Francisco Corzana, Pedro Merino, Francisco J. Cañada, Gonzalo Jiménez-Osés, Jesús Jiménez-Barbero, Ana M. Gómez, Juan Luis Asensio: Dissecting the Essential Role of Anomeric β‑Triflates in Glycosylation Reactions. J. Am. Chem. Soc. 2020, 142, 12501-12514.
