How do Various Reaction Parameters Influence Anomeric Selectivity in Chemical Glycosylation with Thioglycosides and NIS/TfOH Activation?

Abstract

The reaction of glycosyl donor phenyl 2,3,4,6-tetra-O-benzyl-1thio-β-D-glucopyranoside with NIS/TfOH(cat.) was systematically studied under various reaction conditions. Neither the molecular sieve pore size nor amount of NIS activator was found to have an effect on the α/β-ratio in the reaction with L-menthol as glycosyl acceptor. Increasing concentration and the amount of triflic acid catalyst, however was found to increase the βselectivity in certain cases. Moreover, lowering temperature was found to have a strong effect on the glycosylation outcome.

Guidelines for O-Glycoside Formation from First Principles

“…Nevertheless, it is commonly considered that S N 1 reactions typically possess greater positive or smaller negative entropies of activation than closely analogous S N 2 reactions, 70,71 such that the rate of S N 1 reactions increases with temperature to a greater extent than that of corresponding S N 2 reactions. The gradual erosion of stereoselectivity with increasing temperature catalogued by Seeberger and others 23,24,27,28 can therefore be understood in terms of a shift in mechanism toward the S N 1like end of the continuum as reaction temperature is increased.…”

“…The dependence of glycosylation selectivity on temperature is evident in the empirical studies published by the Seeberger laboratory, 27,28 and is described in recent work by the Jensen and Zhang laboratories. 23,24 It follows that if a glycosylation reaction is to be reproducible, the temperature at which it is conducted must be recorded and adhered to. Reactions initiated by warming from low temperature to zero or room temperature are unlikely to give reproducible selectivities from laboratory to laboratory simply because the rate of warming is difficult to reproduce, especially as reaction scale and cooling bath sizes are varied.…”

“…We have long maintained − that improved, more reproducible, and more broadly applicable glycosylation reactions will logically follow an enhanced understanding of glycosylation reaction mechanisms, and with that in mind, have recently reviewed the evidence supporting our current understanding of glycosylation reaction mechanisms both without and with participation by neighboring groups. , Building on this growing body − of physical organic studies directed at the mechanism(s) of glycosylation reactions, we derive here a set of simple guidelines to help practitioners think about the manner in which they conduct glycosylation reactions with the overall goal of rendering them more predictable and reproducible and so helping to open up the field to nonspecialists. Both Wang and co-workers and Seeberger and co-workers have made significant contributions, with additional input from Jensen and co-workers, 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. − 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. − The guidelines we present are general considerations for reactions conducted at the S N 1/S N 2 interface without the assistance of neighboring group participation, which fall under a different kinetic regime . 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, − ,,− the guidelines that we offer are general, and their application should improve reproducibility whatever the protecting group regime.…”

“…18,19 Building on this growing body 20−23 of physical organic studies directed at the mechanism(s) of glycosylation reactions, we derive here a set of simple guidelines to help practitioners think about the manner in which they conduct glycosylation reactions with the overall goal of rendering them more predictable and reproducible and so helping to open up the field to nonspecialists. 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.…”

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

“…[3] Reported yields can be difficult to reproduce, and crucial reaction conditions often go unreported. Despite recent advances in the standardization of glycosidic bond formation, as well as an improved physical organic and mechanistic understanding of the factors governing the outcomes, [4][5][6][7][8][9] irreproducibility and poor transferability stymie progress. Here, we aim to decrypt the fundamental role of temperature, a key parameter influencing the yield and selectivity of glycosylations.…”