Automated Quantification of Hydroxyl Reactivities: Prediction of Glycosylation Reactions

Abstract

The stereoselectivity and yield in glycosylation reactions are paramount but unpredictable. We have developed a database of acceptor nucleophilic constants (Aka) to quantify the nucleophilicity of hydroxyl groups in glycosylation influenced by the steric, electronic and structural effects, providing a connection between experiments and computer algorithms. The subtle reactivity differences among the hydroxyl groups on various carbohydrate molecules can be defined by Aka, which is easily accessible by a simple and convenient automation system to assure high reproducibility and accuracy. A diverse range of glycosylation donors and acceptors with well‐defined reactivity and promoters were organized and processed by the designed software program “GlycoComputer” for prediction of glycosylation reactions without involving sophisticated computational processing. The importance of Aka was further verified by random forest algorithm, and the applicability was tested by the synthesis of a Lewis A skeleton to show that the stereoselectivity and yield can be accurately estimated.

Guidelines for O-Glycoside Formation from First Principles

“…The influence of acceptor protecting groups and steric hindrance on glycosylation selectivity, while long recognized, have been most clearly illustrated by the systematic studies of van der Marel, Codeé, and their co-workers, 112 and by the more recent and more extensive predictive nucleophilicity scales of Wong and Wang and their co-workers. 29 As the area has recently been thoroughly reviewed, 35 we simply offer the following guideline.…”

“… 30 − 32 The guidelines we present are general considerations for reactions conducted at the S N 1/S N 2 interface 18 without the assistance of neighboring group participation, which fall under a different kinetic regime. 19 Finally, we note that while the choice of nonparticipating groups for both glycosyl donors and acceptors can significantly influence the overall rate of a glycosylation reaction under a given set of conditions by shifting the S N 1/S N 2 interface, 25 − 27 , 29 , 33 − 35 the guidelines that we offer are general, and their application should improve reproducibility whatever the protecting group regime.…”

“…Both Wang and co-workers and Seeberger and co-workers have made significant contributions, with additional input from Jensen and co-workers, 24 with similar goals in mind recently, but do not take into account the kinetic differences between reactions proceeding through associative as opposed to dissociative mechanisms in their, in some cases, necessarily empirical approaches. 25 − 29 We limit ourselves to the formation of O -glycosides, believing them to be more central to glycobiology, and do not anticipate that the guidelines we offer will extrapolate directly to C -glycoside formation, which operate more closely to the S N 1 end of the mechanistic spectrum and appear to depend heavily on the conformational dynamics of the putative oxocarbenium ion. 30 − 32 The guidelines we present are general considerations for reactions conducted at the S N 1/S N 2 interface 18 without the assistance of neighboring group participation, which fall under a different kinetic regime.…”

Towards a Systematic Understanding of the Influence of Temperature on Glycosylation Reactions

“…Structure and electronics of the glycosyl donor impart distinct reactivity (Figure 4), [20,21] and each hydroxyl nucleophile (acceptor) in the growing glycan differs from the previous acceptor depending on the desired linkage. [28] To date, a general coupling protocol that is applicable to a range of glycosyl donors is used that evolved during the development of AGA. [34] In a standard cycle, 6.5 equiv.…”

“…The coupling step also involves the nucleophile glycosyl acceptor, and interactions between the activated glycosyl donor and acceptor likely require a distinct temperature for optimal conversion to the product. [28] Further studies will help to elucidate the delicate balance between nucleophilicity of acceptor, donor reactivity, and temperature.…”