A “Traceless” Directing Group Enables Catalytic S_N2 Glycosylation toward 1,2-cis-Glycopyranosides

Abstract

Generally applicable and stereoselective formation of 1,2-cis-glycopyranosidic linkage remains a long sought after yet unmet goal in carbohydrate chemistry. This work advances a strategy to this challenge via stereoinversion at the anomeric position of 1,2-trans glycosyl ester donors. This S N 2 glycosylation is enabled under gold catalysis by an oxazole-based directing group optimally tethered to a leaving group and achieved under mild catalytic conditions, in mostly excellent yields, and with good to outstanding selectivities. The strategy is also applied to the synthesis of oligosaccharides.

Guidelines for O-Glycoside Formation from First Principles

“…Glycosylation reactions, however, have long been depicted mostly as S N 1 reactions proceeding through intermediate oxocarbenium ions with the obligatory counterions considered as mere spectators and so typically omitted from reaction schemes. As we have discussed elsewhere, this viewpoint is no longer sustainable in the light of the current physical organic record. − , In brief, glycosyl oxocarbenium ions are highly destabilized by the presence of multiple electron-withdrawing C–O bonds to the extent that they might be considered borderline “superelectrophiles” ,,, and have yet to be observed spectroscopically, with the exception of the 2-deoxy and 2-deoxy-2-bromo pyranose series lacking the C–O bond at the 2-position even in superacid media. − On the other hand, the NMR spectra of many activated covalent glycosyl donors in solvents typically employed for glycosyl reactions have been reported in the literature, ,− with the continual addition of new examples. , Modern kinetic analyses of glycosylation reactions, including computational studies when conducted in the presence of the counterion, come down on the side of associative mechanisms. , The preponderance of evidence therefore suggests that typical homogeneous glycosylation reactions conducted in organic solution with rare exceptions − will hew to the S N 2 end of the mechanistic spectrum . On the basis of this understanding, we offer here a series of guidelines derived from first principles that are intended to help practitioners and nonpractitioners alike derive and execute O -glycosylation reactions with increased reproducibility.…”

“…As we have discussed elsewhere, 16 this viewpoint is no longer sustainable in the light of the current physical organic record. [18][19][20][21]23 ions are highly destabilized by the presence of multiple electron-withdrawing C−O bonds to the extent that they might be considered borderline "superelectrophiles" 14,15,40,41 and have yet to be observed spectroscopically, with the exception of the 2-deoxy and 2-deoxy-2-bromo pyranose series lacking the C−O bond at the 2-position even in superacid media. 42−45 On the other hand, the NMR spectra of many activated covalent glycosyl donors in solvents typically employed for glycosyl reactions have been reported in the literature, 18,46−49 with the continual addition of new examples.…”

“…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.…”

“…The formation of glycosidic bonds is most frequently practiced by a nucleophilic substitution reaction in which a leaving group is displaced from an electrophilic glycosyl donor by a nucleophilic glycosyl acceptor typically with the aid of a promoter. − Unfortunately, while enormous progress has been made in glycosylation in recent decades, particularly since the advent of homogeneous glycosylation conditions and the thioglycoside and trichloroacetimidate classes of donors, − the field suffers from a long-standing reputation for unpredictability and irreproducibility that, according to the NRC report, hinders broader application by nonspecialists . 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 .…”