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Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR
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Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR
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  • Frank F. J. de Kleijne
    Frank F. J. de Kleijne
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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  • Floor ter Braak
    Floor ter Braak
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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  • Dimitrios Piperoudis
    Dimitrios Piperoudis
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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  • Peter H. Moons
    Peter H. Moons
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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    Orcidhttps://orcid.org/0009-0002-6425-8273
  • Sam J. Moons
    Sam J. Moons
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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    Hidde Elferink
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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    Paul B. White
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
    *Email: [email protected]
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  • Thomas J. Boltje*
    Thomas J. Boltje
    Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
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Cite this: J. Am. Chem. Soc. 2023, 145, 48, 26190–26201
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https://doi.org/10.1021/jacs.3c08709
Published November 26, 2023

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Abstract

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The stereoselective introduction of glycosidic bonds (glycosylation) is one of the main challenges in the chemical synthesis of carbohydrates. Glycosylation reaction mechanisms are difficult to control because, in many cases, the exact reactive species driving product formation cannot be detected and the product outcome cannot be explained by the primary reaction intermediate observed. In these cases, reactions are expected to take place via other low-abundance reaction intermediates that are in rapid equilibrium with the primary reaction intermediate via a Curtin–Hammett scenario. Despite this principle being well-known in organic synthesis, mechanistic studies investigating this model in glycosylation reactions are complicated by the challenge of detecting the extremely short-lived reactive species responsible for product formation. Herein, we report the utilization of the chemical equilibrium between low-abundance reaction intermediates and the stable, readily observed α-glycosyl triflate intermediate in order to infer the structure of the former species by employing exchange NMR. Using this technique, we enabled the detection of reaction intermediates such as β-glycosyl triflates and glycosyl dioxanium ions. This demonstrates the power of exchange NMR to unravel reaction mechanisms as we aim to build a catalog of kinetic parameters, allowing for the understanding and eventual prediction of glycosylation reactions.

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Introduction

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The stereoselective introduction of glycosidic bonds (glycosylation) is one of the main challenges in the chemical synthesis of carbohydrates. In a chemical glycosylation reaction, an electrophile (the glycosyl donor) is activated by a chemical promoter and reacts with a nucleophile (the glycosyl acceptor). The nucleophile can add to the α- or β-face of reactive intermediates, thereby leading to the formation of α- or β-diastereoisomers, respectively. Controlling the diastereoselectivity of glycosylation reactions can be achieved by the application of two main strategies.
First, a stereo-directing group present on the donor molecule can be employed to stabilize the glycosyl cation formed upon activation. An example of this principle is neighboring group participation (NGP) of an acyl group at the C-2 position affording a bicyclic dioxolanium ion intermediate 3 that reacts in a stereospecific manner with a glycosyl acceptor to afford a 1,2-trans product (Figure 1A). (1−4) Extension of this principle to acyl functionalities positioned on the C-3, C-4, or C-6 hydroxyl groups via NGP has also been suggested to direct the stereoselectivity of glycosylation reactions. However, whether selectivity can be attributed to NGP of the acyl group or other stereoelectronic effects is a subject of much debate. (4−19) The second main strategy utilizes glycosyl donors that contain protecting groups that are less capable of neighboring group participation, e.g., benzyl ethers. In this case, the glycosyl cation is trapped by the promotor system counterion or a solvent additive to afford quasi-stable intermediates that can be displaced in an SN2-like reaction pathway to afford a glycosylation product. (20−22) Most modern promotor systems give rise to the formation of glycosyl triflates and since these covalent adducts can exist in the α- (1) or β-form (6), reactions proceeding via these intermediates can in principle form the β- or α-product via an SN2-like reaction pathway, respectively. (22,23) The nucleophilic displacement of α-glycosyl triflates 1 is likely to take place via an intermediate α-contact ion pair (CIP) 2 which maintains its stereochemical memory to form the β-product. (24) Full dissociation of the triflate would lead to the solvent-separated ion pair (SSIP) 4, which can afford glycosylation products via an SN1-like pathway. (25−27) The conformation of monosaccharide-derived SSIPs is dictated by the relative stereochemistry of its substituents (10) and is a crucial determinant of their stereoselectivity in glycosylation reactions. (25) Finally, β-glycosyl triflate CIP 5 and its corresponding covalent adduct 6 can form during glycosylation reactions from the SSIP or SN2-like displacement of the α-glycosyl triflate 1 by another triflate anion. (20) The equatorial β-glycosyl triflates (on d-sugars) are not stabilized by the anomeric effect and hence are less stable and more reactive. Since glycosylation reactions take place in a mechanistic continuum between these SN1- and SN2-like reaction pathways, they are difficult to predict and control and very sensitive to parameters such as solvent, (28,29) type of monosaccharide, (17,30) strength of the nucleophile, (31) reaction solvent, (32) and temperature. (33,34)

Figure 1

Figure 1. (A) Glycosylation reaction intermediates and their characteristic resonances monitored by exchange NMR. (B) Glycosyl donors used in this study.

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To address this challenge, the characterization of reaction intermediates that drive product formation in glycosylation reactions is required. Glycosylation reaction intermediates can be characterized by employing nuclear magnetic resonance (NMR) spectroscopy and infrared-ion spectroscopy (IRIS), for example. (26,35,36) These techniques have allowed for the characterization of intermediates such as glycosyl triflates, (22,23,35) dioxolanium ions, (18,37,38) dioxanium ions, (17) and even oxocarbenium ions. (25,26,37,39) However, IRIS is performed in the gas phase, and the structure of reaction intermediates under these conditions may not always be relevant to those formed in solution. NMR can be used to detect reaction intermediates in solution under relevant reaction conditions and is a powerful tool for studying reaction mechanisms. (40) However, a challenge in studying glycosylation reactions is that observing a reaction intermediate does not automatically mean it is a reactive intermediate and, hence, relevant to product formation. In many cases, the exact reactive species driving glycoside product formation remains unknown as the product outcome cannot be explained by the primary reaction intermediate observed. In these cases, glycosylation reactions are expected to take place via other low-abundance reaction intermediates that are in rapid equilibrium with the primary reaction intermediate via a Curtin–Hammett scenario (Figure 1). (20,41) Therefore, the stereochemical outcome of the reaction does not necessarily depend on the population of the intermediate leading to a given product but rather the overall barrier height when the barrier to intermediate interconversion is lower than the irreversible product-forming step. (20) Despite this principle being well-known in organic synthesis, mechanistic studies investigating this model in glycosylation reactions are complicated by the challenge of detecting the extremely short-lived reactive species responsible for product formation and measuring their exchange kinetics. The low abundance and short lifetime of these intermediates, such as 2–6, complicate their characterization as they readily equilibrate back to form the more stable, readily observable but less reactive α-glycosyl triflate intermediate 1. Elegant studies by Taylor and co-workers, and Asensio and co-workers, have employed exchange NMR spectroscopy (EXSY) to characterize the dynamic equilibrium of α- and β-glycosyl sulfonate intermediates. (23,42) The use of EXSY is unfortunately limited to readily observed species and hence applies only to rather stable β-glycosyl sulfonates. We have recently overcome this challenge by utilizing the chemical equilibrium between low-abundance reaction intermediates and the stable, readily observed α-glycosyl triflate intermediate in order to infer the structure of the former species. (17) Using chemical exchange saturation transfer (CEST) NMR, we demonstrated that high-energy or “invisible” mannosyl dioxanium ions, which are formed by intramolecular stabilization of a C-3 ester, are in chemical exchange with the highly populated α-glycosyl triflate intermediate. (17)
Herein, we report the application of this principle to detect the presence of other virtually undetectable high-energy reaction intermediates relevant to product formation such as β-triflates and dioxanium ions formed by internal stabilization. We characterized the reactive intermediates for a systematic set of eight frequently used glycosyl donors 7–14 (Figure 1B). Not only the presence of reactive intermediates but also their exchange kinetics were measured, thereby providing valuable quantitative data to elucidate the formation mechanism of the reactive intermediates. We report an integrated exchange NMR workflow to measure the reactivity of α-glycosyl triflates by monitoring the dissociation of the triflate ion using 19F exchange NMR spectroscopy (EXSY NMR). In addition, we established the mechanism of triflate dissociation with the same technique. A clear difference between mannose and glucose monosaccharides was observed in their triflate dissociation kinetics and mechanism. Mannosides were able to form dioxanium ions 7d and 8d via the participation of a C-3 acyl group, whereas their glucoside counterparts were not and formed β-glycosyl triflates 11βOTf and 12βOTf instead. We were able to indirectly detect the presence of these low-population intermediates via their chemical equilibrium with the observable α-glycosyl triflate using 13C CEST, 1H CEST, and 19F CEST NMR. Finally, we were also able to characterize selected examples of the dioxanium ion and β-glycosyl triflate using more classical NMR techniques to unequivocally establish their structure. These results demonstrate the power of chemical exchange NMR to detect fleeting reaction intermediates to build a catalog of kinetic parameters that allow for the understanding and ultimately prediction of glycosylation reactions. We expect this technique to be applicable to various other types of glycosylation reaction intermediates such as additives and solvents commonly used in glycosylation reactions, both of which tend to be rich in NMR-active nuclei that are sensitive to changes in the chemical environment. Finally, the application of the workflow laid out herein should be applicable to other types of reactions that are under Curtin–Hammett control.

Results and Discussion

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We started by investigating the stability and reactivity of glycosyl triflates derived from 7 to 14 to assess their likelihood of acting as reactive intermediates in glycosylation reactions. Previous experiments have investigated the decomposition temperature of glycosyl triflates as a measure of their stability/reactivity. While indicative of their thermal stability, such metrics do not necessarily speak to their relevance in product formation during a glycosylation event. (43) In addition, 1H EXSY NMR has been used to monitor the interconversion of α- and β-glycosyl triflates (23) and mesylates (42) providing kinetics of their interconversion. However, a major limitation of 1H EXSY is that it requires both interconverting species to be visible in 1D NMR. This means that for the vast majority of glycosyl donors, intermediate exchange kinetics cannot be recorded due to the low-populated state of the highly reactive β-triflate intermediates. Another means of measuring α-glycosyl triflate stability and reactivity is by observing the kinetics of triflate dissociation in the absence of an acceptor using 19F EXSY NMR. Since both the α-glycosyl triflate and unbound triflate anion, which results from the activation step (vide infra), are always observed and exist as strong signals, we reasoned that if we could observe the interconversion between bound and free triflate, then that would indicate the presence of an unobserved intermediate. Hence, we started by investigating the stability and reactivity of eight glycosyl triflates derived from 7–14 using 19F EXSY NMR, which revealed that all eight species underwent triflate exchange. The preparation of the thioglycoside precursors used to generate glycosyl triflates 7αOTf–14αOTf is described in the Supporting Information (SI pages S12–S31). The glycosyl triflates were generated by activating the corresponding glycosyl sulfoxide donor with triflic anhydride (Tf2O) in the presence of the non-nucleophilic base 2,4,6-tritert-butyl-pyrimidine (TTBP) in CD2Cl2 at −80 °C inside an NMR tube (please see pages S7–S10). (44) Clean formation of glycosyl triflates (7αOTf–14αOTf) was observed in all cases (Figures S4–S11). Dissociation of the anomeric triflate to unbound triflate could be monitored using selective 19F EXSY NMR (SI pages S2–S4, S7). Magnetization of the selectively excited CF3 resonance of the α-glycosyl triflate is transferred to the unbound triflate ion upon triflate dissociation during the ZZ-exchange mix time (Figure 2A). By plotting the mix time vs the extent of magnetization transfer, the rate of triflate dissociation was measured, which we propose is an indicator of α-glycosyl triflate stability (Figure 2B). In order to compare measurements across different sugars and samples while also taking into account multiple mechanisms, the reported rates in Figure 2 are normalized by dividing the measured rate by the initial α-triflate concentration (see SI pages S2–S4). By subsequently repeating this process at different temperatures, the normalized rate of triflate dissociation as a function of temperature was established (Figures 2C and S50–S86). A few important considerations are needed to ensure that reliable kinetic data emerge from the 19F EXSY experiments. First, the exchanging system needs to be in the slow-exchange regime which is defined by the rate of exchange being much lower than the frequency difference between the interconverting species (k1 + k–1 ≪ ΔωA-B). Second, to reduce the complexity of modeling the kinetics, we chose to measure initial rates for the exchange processes, which puts a rough limit on the maximum normalized rate of ∼100 s–1 (10% conversion at 1 ms mix time). Furthermore, the slowest measurable rate is related to the T1 of the observed nucleus. Hence, the T1 of the nuclei, and more importantly, the difference in T1 between the resonances of interest, should be taken into consideration when setting the maximum mix time. For 19F, the T1s of the α-triflate 10αOTf and soluble triflate salt were measured at −80 °C where the exchange was frozen and found to be roughly identical (0.31 and 0.42 s, respectively, Figure S49). This allowed us to make the approximation that T1 losses for each were roughly equivalent and hence could be ignored thereby allowing us to extend our mix range past T1. Therefore, we were able to measure normalized rates accurately down to ∼0.1 s–1. Third, the population of the α-glycosyl triflate and free triflate should not significantly change from the beginning to the end of the experiment. Therefore, once thermal decomposition begins to take hold, these experiments become unreliable and thus limit the upper limit of the temperature window.

Figure 2

Figure 2. (A) Working principle behind 19F EXSY NMR to monitor triflate dissociation. The α-glycosyl triflate is selectively excited and then observed over time to transform into free triflate. (B) Determination of the initial rate of triflate dissociation. (C) Summary of normalized triflate dissociation rates (s–1) across the studied glycoside series as a function of temperature.

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Keeping in mind these considerations, the rates of dissociation of triflate from the parent α-glycosyl triflates 7αOTf–14αOTf at various temperatures were obtained (Figure 2C). Interestingly, clear differences in triflate dissociation were observed related to the relative stereochemistry of the monosaccharide (mannose vs glucose) and the protecting group pattern. Mannosyl triflates 7αOTf and 8αOTf carrying a single benzoate ester at C-3 showed the fastest triflate dissociation. Interestingly, the benzylidene-protected mannosyl analogue 8αOTf carrying a C-3 benzoate ester was the second fastest in the mannose series. Benzylidene-protected monosaccharides are typically classified as disarmed due to the torsional (45,46) and electronic effects (47) induced by the fused benzylidene ring system. (43) Indeed triflate dissociation for 8αOTf was slower than that of the corresponding benzylated analogue 7αOTf but still faster than that of the fully benzylated compound 9αOTf. This suggests a role of the C-3 ester in driving triflate release, overpowering the disarming effect induced by the benzylidene. This is confirmed by the fact that the benzylidene-protected mannosyl triflate containing benzyl ethers at C-2 and C-3 was the slowest in the mannose series in triflate dissociation. Interestingly, the opposite trend was observed in the glucose series. The difference in rate for the C-3 benzoyl 11αOTf and 12αOTf vs C-3 benzyl 13αOTf and 14αOTf analogues was much smaller with the former being slower, particularly at higher temperatures. As expected, the benzylidene-protected analogues 12αOTf and 14αOTf showed slower triflate dissociation compared to that of their benzylated counterparts 11αOTf and 13αOTf. Overall, these results indicate that the presence of a benzylidene acetal compared to the benzylated analogue slows down triflate dissociation for both the mannose and glucose series. However, the introduction of a C-3 benzoyl group speeds up triflate dissociation in the mannose series and slows down triflate release in the glucose series.
The striking differences in triflate dissociation rates are likely the result of a different mechanism of triflate dissociation, but these cannot be established from the rates alone. Hence, we set out to investigate the mechanism of triflate dissociation of 7αOTf–14αOTf to explain their dissociation rate differences. We foresee three main equilibria that would lead to the dissociation of the triflate anion (Figure 3A). First, dissociation of the triflate anion could lead to an SSIP. Second, NGP of the C-3 acyl substituent present in molecules 7αOTf–8αOTf could take place to form a dioxanium ion with or without an intermediary SSIP. Third, a triflate anion could displace the α-glycosyl triflate in an SN2-like manner to form the corresponding β-triflate. To dissect the mechanism(s) responsible for triflate dissociation, we investigated the rate of this process as a function of the triflate anion concentration. The rate of triflate dissociation from the α-glycosyl triflate via SSIP or dioxanium ion formation should be insensitive to the triflate concentration. The rate of triflate dissociation from the α-glycosyl triflate via SN2-like displacement to form the corresponding β-glycosyl triflate should be first order with respect to the triflate concentration. In case both processes operate simultaneously, the sum of the rates would constitute the overall rate of triflate dissociation (Figure 3A). The temperature for the study was chosen so that if a first-order dependence was found, it would not move the kinetics outside the window for EXSY and at the same time would be suitably fast enough to study if no dependence was discovered. Next, using the aforementioned 19F EXSY scheme, we measured the triflate dissociation as a function of triflate concentration at a single temperature by the addition of tetrabutylammonium triflate (TBAT).

Figure 3

Figure 3. (A) SN1 and SN2-like triflate dissociation mechanisms. (B) Reaction order determination for triflate dissociation in the mannose series and (C) glucose series.

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To this end, the triflate concentration was increased in steps by taking the sample out of the probe and adding 1 M TBAT solution to dry CD2Cl2 at −80 °C to approximately double the triflate concentration in each step. The exact triflate concentration was determined by comparison to the trimethyl(4-(trifluoromethyl)-phenyl)silane internal standard. The results are plotted in Figure 3B,C and show a clear dichotomy in the mechanism of triflate dissociation, consistent with the observed temperature-dependent rate differences listed in Figure 2C and Tables S1–S4. C-3 Benzoyl-containing mannosides 7αOTf–8αOTf showed a zeroth-order rate dependence with respect to the triflate concentration. These results indicate that internal stabilization of the C-3 benzoyl, which forms the dioxanium ion, drives triflate dissociation. In contrast, all glucosides (11αOTf–14αOTf) and both mannosides lacking the C-3 benzoyl group (9αOTf–10αOTf) show a first-order triflate concentration dependence for the rate of triflate dissociation (Figure 3B, C). These data suggest that these molecules likely undergo an SN2-like triflate displacement to form the β-glycosyl triflate. Furthermore, this demonstrates that internal stabilization by the C-3 acyl group is reserved for the mannose donors, while the glucose counterparts likely form β-glycosyl triflates.
The above 19F EXSY studies established the rates of triflate dissociation as well as provided evidence for its mechanism but did not confirm the presence of the intermediates proposed in such mechanisms. Since EXSY can only be applied if both intermediates are readily visible in 1D NMR, it cannot be used to study the expected dioxanium ions and/or β-glycosyl triflate intermediates due to their low population at equilibrium. Hence, to solve this challenge, a different technique is needed. As mentioned above, CEST NMR is well suited to detect a very low population of “invisible” reaction intermediates that are in a chemical equilibrium with a visible reaction intermediate. This technique, originally developed as a contrasting approach in MRI, (48) has been applied by Gschwind and co-workers to detect iminium ions and by us to detect mannosyl dioxanium ions, for example. (17,49) The main advantage of CEST NMR is that no prior information about the chemical shift of the low-populated intermediate resonance is required since the experiment scans a given frequency domain by incrementing the saturation offset frequency while monitoring the transfer of saturation to the main observable species via chemical exchange (Figure 4A). To detect the formation of dioxanium ions, we used the 13C-labeled C-3 benzoyl signal belonging to the α-triflate species as the reporter peak. By plotting the degree of saturation transfer toward this reporter peak at a given frequency offset, a CEST profile is obtained (Figure 4A). In the case where saturation transfer is observed at a frequency offset different to that of the reporter peak, it shows up as a dip in the CEST profile and indicates the presence of a species that is in chemical exchange with the reporter species. Notably, the degree of saturation transfer is dependent on the observed nucleus, resonance frequency, frequency difference between the two species, the exchange rates between exchanging species, the field strength, saturation width, and saturation time. Hence, by plotting the saturation time versus the degree of saturation transfer, the interconversion kinetics of the equilibrating intermediates can be quantified. (50) The limitations of CEST are similar to EXSY: the chemical exchange is slow on the NMR time scale (k1 + k–1 ≪ ΔωA-B), and the detection window is defined by a combination of relative population exchanging species and longitudinal relaxation rate (R1). (48,51) Since the dioxanium ions can only form from the C-3 benzoyl-containing compounds 7–8, we investigated this set using 13C CEST NMR. To this end, 13C-labeled substrates 713C and 813C were prepared to enable the sensitive detection of the carbonyl quaternary carbon (SI pages S12–S31). By incrementing the saturation offset frequency while monitoring the transfer of saturation to a reporter peak (13C═O) on the main observable species (α-glycosyl triflate) via a chemical exchange, we investigated the detection of mannosyl and glucosyl dioxanium ion formation (Figures 4A and S13–S17). Apart from the use of a 13C-labeled starting material, the CEST NMR experiments were performed under identical conditions as the EXSY experiments. As expected, the mannosyl triflate 713CαOTf showed saturation transfer at the chemical shift expected for the dioxanium ion (δC = 177 ppm, Figure 4B). In contrast, the mannosyl benzylidene derivative 813CαOTf did not (Figure 4C), even though the formation of a dioxanium ion was expected based on an observed zeroth-order triflate dependence.

Figure 4

Figure 4. (A) Mechanism of 13C CEST NMR to detect neighboring group participation. (B–E) CEST profiles for 13C-labeled C-3 acyl-protected mannosyl and glucosyl donors. (F) Characterization of the mannosyl dioxanium ion using HMBC and COSY.

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Due to the presence of the benzylidene, the molecule is less flexible and requires the formation of a tricyclic dioxanium ion which is likely much slower and less stable than the nonbenzylidene derivative 7d. This may explain why CEST NMR was unable to pick up the dioxanium ion as the CEST NMR technique is limited by the population of the minor exchanging species and the rates of dioxanium ion formation and consumption (kα→d and kd→α, respectively). If the population of the intermediate is well below 1% or the exchange has moved into the intermediate or fast regime (kα→d + kd→α > Δϖdα), then the minor exchanging species cannot be detected. Due to the intrinsically high reactivity of a tricyclic dioxanium ion, it is likely that dioxanium ion consumption (kd→α) is exceedingly fast, hence limiting detection of the ion by 13C CEST NMR. The corresponding glucose series (1113C and 1213C) did not show dioxanium ion formation via CEST (Figures S14 and S16), fully consistent with the first-order triflate dependence (Figure 3C). In light of the conflicting CEST results with the triflate order in the case of mannosyl triflate 8αOTf, we reasoned that we could approach the limitation of the CEST NMR viewing window outlined above. Therefore, we wanted to boost the observable population of the dioxanium ion by preparing the corresponding p-anisoyl derivatives 1513C and 1613C of the mannose series, as the electron-donating methoxy group should increase the stability of the dioxanium ion and slow down the α-glycosyl triflate formation. Additionally, we performed the activation of 1513C and 1613C in the absence of TTBP to minimize the free triflate anion concentration in an effort to further boost the population of dioxanium ions. (17) Under these conditions, saturation transfer of the dioxanium ion was observed in both cases (Figure 4D, E) at ∼175 ppm. For benzylidene derivative 1613C, it was now possible to detect the dioxanium ion with 13C CEST NMR, which aligned with its zeroth-order triflate dependence. Furthermore, mannosyl donor 1513C showed a much higher population (∼45%) of dioxanium ion compared to benzoyl derivative 7. Due to the very high population of dioxanium upon activating donor 1513C, we were able to use the dioxanium ion signal as the reporter peak of the CEST NMR experiment in order to detect if there were additional intermediates in chemical exchange with it. Identical to the benzoyl derivative, the α-glycosyl triflate was the only detectable species in chemical exchange with the dioxanium ion. Fortunately, due to the high population of ion 1513Cd, we could fully characterize it using 1H–13C HMBC and 1H–1H COSY experiments (Figure 4F). We had previously reported the characterization of a similar 3-benzoyl-2,4,6-trimethylated mannosyl dioxanium ion, but these results now demonstrate its formation with relevant protecting groups, which are routinely used in oligosaccharide synthesis. Hence, although not directly characterized, we expect the characteristic saturation transfer at δC of 175 ppm for benzylidene derivative 1613C to correspond to the tricyclic mannosyl dioxanium ion 1613Cd. Calculations were performed to compute the chemical shift of the 13C-labeled dioxanium bridge which was in very good agreement with the observed chemical shift (computational chemical shift: δC 173.7 ppm, experimental chemical shift: δC 174.5 ppm, Figure S35). To further solidify this hypothesis, we measured the triflate dissociation of 1613CαOTf with 19F EXSY and dioxanium ion formation using 1H and 13C CEST NMR (pages S4 and S5). The measured rate from these techniques was 0.28 ± 0.02, 0.28 ± 0.01, and 0.26 ± 0.004 s–1, respectively, indicating that the processes for forming the dioxanium and dissociating the triflate group are clearly coupled (Figure 4E). From these results, it is clear that mannoside 1513C and 1613C showed the formation of the C-3 dioxanium ion, which is consistent with the α-selective glycosylation behavior of 7 and 8 and the observation that their triflate dissociation rates are irrespective of the triflate anion concentration. The C-3 acylated mannosides are a privileged class of glycosides, as all of the other cases (9αOTf–14αOT) displayed a first-order triflate anion concentration dependence for triflate dissociation. These observations are consistent with an equilibrium between an α- and β-glycosyl triflate. β-glycosyl triflates are exceedingly difficult to detect and have only been observed in the case of benzylidene-protected methylated glucose and allose donors using 13C-labeled monosaccharides. (23) Only in the case of the allose, a large enough population of β-glycosyl triflate was formed that allowed for the investigation of its exchange kinetics using 1H EXSY. (23) Furthermore, an equatorial triflate not stabilized by the anomeric effect formed via a conformational ring flip was observed by Van der Marel and co-workers. (52) To the best of our knowledge, these two reports form the summative collection of observed glycosyl triflates not stabilized by the anomeric effect. To enable the detection of unstable and very-low-populated β-glycosyl triflates, we again applied CEST NMR but focused on the 1H and 19F nuclei. For 1H CEST NMR, the H-1 signal belonging to the α-glycosyl triflate was used as a reporter peak, and the saturation offset frequency was scanned while monitoring saturation transfer to this peak (Figure 5A). Upon detection of a possible β-glycosyl triflate, saturation transfer from an upfield peak position (δH ∼ 5.5–5.7 ppm) would be expected to be observed. None of the mannoside donors displayed a chemical equilibrium with an upfield resonance with the exception of benzylidene derivative 10, which we tentatively assigned as β-glycosyl triflate 10βOTf (Figures 5B–I and S27–S34). These results are consistent with the triflate orders obtained for three of these compounds, 7 and 8 (zeroth order, no β-glycosyl triflate detected) and 10 (first order, β-glycosyl triflate detected). Only for perbenzyl mannosyl donor 9, we did not detect a β-glycosyl triflate even though its triflate dissociation rate is on the order of first in triflate concentration. This could be due to a very low population of β-glycosyl triflate at equilibrium or the system has moved out of the slow-exchange regime, in which case it would be difficult or impossible to detect with 1H CEST NMR. In contrast, all of the glucose series donors (11–14) showed clear saturation transfer via an upfield peak that we presume is a β-glycosyl triflate. These results are fully consistent with their first-order triflate dependence (Figure 3B, C). We validated these results by repeating β-glycosyl triflate detection using the 19F channel. For 19F CEST NMR, the CF3 signal belonging to the triflate ion was used as a reporter peak, and the saturation offset frequency was scanned while monitoring saturation transfer to this peak (Figures S19–S26).

Figure 5

Figure 5. (A) Mechanism of 1H CEST NMR to detect β-glycosyl triflates. (B–I) 1H CEST profiles for 7αOTf–14αOTf..

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As a consequence, all 19F CEST NMR spectra identify chemical exchange with the “free” triflate anion pool, which can arise from either the α- or β-glycosyl triflate. The 19F CEST NMR results are fully consistent with those obtained from the 1H CEST NMR experiments. For the mannose series, the chemical exchange of the α-glycosyl triflate with the unbound triflate anion could be clearly observed via saturation transfer monitored from the α-glycosyl triflate at −75.9 ppm. Only for the benzylidene derivative 10, an additional saturation transfer from a presumed β-glycosyl triflate was observed at δF −75.0 ppm, similar to the 1H CEST NMR. Moreover, in the case of the glucose series, saturation transfer from β-glycosyl triflates could be detected in all cases using 19F CEST NMR as was the case for the corresponding 1H experiments.
To obtain additional proof that the saturation transfer originates from exchange with the β-glycosyl triflate, we set out to further characterize this low-population species. From the glucose set, benzylidene derivative 14 displayed the clearest formation of this species, and we thus investigated this molecule further. The only reported direct spectroscopic evidence of a β-glycosyl triflate was obtained for a very similar compound, 4,6-benzylidene-2,3-di-O-methyl glucosyl-β-triflate, by Asensio and co-workers. (23) We prepared the corresponding benzyl protected compound with a C-1 13C isotope label (1413C-1) in order to measure the 1JC1–H1 and 3JH1–H2 coupling constants, which are indicative of the stereochemistry at C-1. Upon activation, this derivative formed a small (≈1%, SI, Figures S46 and S47) population of β-glucosyl triflate that could be characterized using a 1H–13C HSQC NMR experiment, when the 13C decoupler was not applied during the acquisition period (Figure 6). This experiment serves as a simple method for measuring the 1JCH as well as allowing for long F2 acquisition times to obtain high-resolution peaks in the 1H dimension suitable for measuring 1H–1H couplings. The 1JC1–H1 coupling constant for the minor species was determined to be 175 Hz compared to 183 Hz for the corresponding α-derivative (Figure 6). This 8 Hz decrease in coupling constant is indicative of an axial H-1 found in β-configured molecules. (53) Most importantly, the 3JH1–H2 coupling constant was measured to be 7.1 Hz, which is consistent with the axial–axial coupling expected for a β-glycosyl triflate intermediate. Lastly, the chemical shifts of C-1 and H-1 are also consistent with a glycosyl triflate species, and the two 13C resonances at δC 106.4 ppm (α-triflate) and δC 104.3 ppm (β-triflate) as determined from the HSQC were shown to undergo chemical exchange via 13C CEST NMR (Figure S48).

Figure 6

Figure 6. Characterization of β-glycosyl triflate 14 using HSQC without 13C decoupling in order to measure 1JC1–H1 and 3JH1–H2.

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The systematic set of exchange NMR experiments described above allows for the development of a rationale for the reaction pathways leading to the stereoselective formation of glycosylation product(s) for each of the eight glycosyl donors 7–14 studied. For all eight examples, the main reaction intermediate formed after activation is α-glycosyl triflate. A baseline of SN2-like displacement pathway leading to the β-product can therefore be expected in all cases. The SSIPs involved in the reactions could not be detected due to their instability, but both the mannose (10,25) and glucose (25) series are expected to react via their α-selective 4H3 half-chair conformers. Additional pathways proceeding via C-3 participation and the β-glycosyl triflate intermediate can also lead to α-selective product formation. The applied exchange NMR techniques have enabled the (indirect) detection of the unstable, reactive, and low-population mannosyl dioxanium ion and β-glucosyl triflate reaction intermediates. Even though these are low-population reaction intermediates and their exact abundance at equilibrium remains unknown, they can be the main product-forming species if the barrier to reaction intermediate interconversion is smaller than the barrier to product formation according to the Curtin–Hammett principle. Therefore, the rate differences of reaction intermediate interconversion and the ensuing product-forming step dictate the stereospecific outcome as outlined by Lemieux and co-workers. (20) The stereoselectivity for all eight glycosyl donors 7–14 as a function of acceptor reactivity was investigated separately. (18,54)
Starting with the mannose series, C-3 benzoyl mannosyl donor 7 provides α-mannosides upon glycosylation. (17,18) The corresponding α-glycosyl triflate 7αOTf is the main observable reaction intermediate but does not give direct access to the α-product via an SN2-like pathway. Hence, glycosylation likely takes place via rapidly equilibrating dioxanium ion 7d and/or β-glycosyl triflate 7βOTf which would afford the α-product. Dioxanium ion 7d was observed via CEST NMR, while the β-glycosyl triflate was not nor was it expected to be based on its zeroth-order triflate dependence. Therefore, we confidently propose that the reactive intermediate in this case is the dioxanium ion and that the system is under Curtin–Hammett control (Figure 7).

Figure 7

Figure 7. Spectroscopic summary of mannosyl intermediates.

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The corresponding C-3 benzoyl-4,6-benzylidene mannoside 8 shows a similar profile. The α-mannoside is formed upon glycosylation which cannot be explained via the observable α-glycosyl triflate intermediate. (55) CEST NMR was unable to confirm the presence of dioxanium ion 8d or β-triflate 8βOTf. However, the rate of triflate dissociation from 8αOTf was independent of the triflate concentration pointing toward triflate dissociation via C-3 participation. By substituting the C-3 benzoyl for anisoyl in order to further stabilize the cation, the resulting dioxanium ion was detected for the first time. The existence of this intermediate has long been debated but was never characterized. (5,6) (5,14,55) However, the experiments reported herein now support the formation of 8d as the chemical shift, triflate order, and glycosylation stereoselectivity all support its existence and role as a product-forming intermediate (Figure 7).
Perbenzyl mannoside 9 is a much less selective glycosylation donor. The first order of the triflate concentration on triflate dissociation supports the formation of a β-glycosyl triflate although this species could not be detected via the exchange NMR experiments. We hypothesize that a dynamic equilibrium of α- and β-glycosyl triflates and possibly the SSIP is present leading to various product-forming pathways and hence mixed stereoselectivity.
4,6-Benzylidene mannoside 10 is known to provide β-products upon glycosylation. (41) This can be explained by an SN2-like displacement of the corresponding α-contact ion pair. (24) Hence, in this case, the main observed reaction intermediate is assigned to the reactive intermediate. Interestingly, CEST NMR did show the presence of an equilibrium with the β-triflate intermediate, which is consistent with its first-order triflate dependence. This equilibrium is not relevant for product formation with most nucleophiles and therefore represents a situation in which the β-triflate is the less reactive species (Figure 7).
The glucose series showed very different stereoselectivity in glycosylations compared to the corresponding mannose series as noted earlier by Crich and co-workers. (30) In sharp contrast to the mannose series, no evidence for dioxanium ion formation by a C-3 acyl neighboring group in 11 and 12 was found (Figure 8). The origin of this striking difference was investigated further in a separate study. (54) Both molecules form β-glycosyl triflates, whereas the mannosides do not, but these lead to a lower α-selectivity than the dioxanium ions in the case of their mannose counterparts. (18) Also the origin of this clear divergence was investigated further in a separate study. (54)

Figure 8

Figure 8. Spectroscopic summary of glucosyl intermediates.

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A role for the SSIP, which is expected to adopt an 4H3 half-chair conformer and drives the formation of α-product as reported by Codée and co-workers, cannot be excluded. (25) The simultaneous operation of multiple product-forming pathways likely leads to lower stereoselectivity in these cases. The two glucosides 13 and 14 lacking the C-3 benzoyl group show a similar, moderate stereoselectivity compared to their C-3 benzoyl counterparts (Figure 8). (18) This underscores the lack of stereo-directing capability of the C-3 substituent in glucose. (18) The benzylidene derivative 14 has been demonstrated to be α-selective in contrast to its mannose derivative. (30) Since 14 also clearly showed to be in equilibrium with the β-glycosyl triflate, we assign this as a major reactive intermediate driving α-product formation (Figure 8).

Conclusions

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We were able to directly and indirectly detect the presence of low-population reaction intermediates via their chemical equilibrium with the readily observable α-glycosyl triflate for a collection of eight gluco- and mannosides bearing either C-3 acyl or benzyl substituent. The stability of α-glycosyl triflates and their mechanism for dissociation could be readily measured by using 19F EXSY NMR. This allowed for their role in glycosylation reactions to be ascertained. Furthermore, equilibria with low-population intermediates such as dioxanium ions and β-glycosyl triflates could be detected using 13C CEST, 1H CEST, and 19F CEST NMR. Finally, selected examples of the dioxanium ion and β-glycosyl triflate were characterized using classical NMR techniques to unequivocally establish their identity. The results provide the first mechanistic proof for the existence of mannosyl dioxanium ions and β-glucosyl triflates utilizing relevant protecting groups under actual reaction conditions. These observations allow for the rationalization of their observed α-selectivity and demonstrate the power of chemical exchange NMR to detect transient intermediates. Ultimately, we aim to build a catalog of kinetic parameters, allowing for the understanding and eventual prediction of glycosylation reactions. We expect this technique to be applicable to various other types of glycosylation reaction intermediates such as additives (e.g., DMF, PPh3O) and coordinating solvents (e.g., Et2O, MeCN). Finally, the application of the workflow laid out herein should be applicable to other types of reactions that are under Curtin–Hammett control.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c08709.

  • Synthetic procedures for the synthesis of donors 7-14, 1513C, 1613C, and the precursor for 14αOTf(13C-1). Theoretical and practical description of the EXSY and CEST experiments, VT-NMR procedures, and additional variable temperature NMR spectra and raw 19F EXSY, 13C CEST, and 1H CEST NMR data (PDF)

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Author Information

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  • Corresponding Authors
    • Paul B. White - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands;  Email: [email protected]
    • Thomas J. Boltje - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands;  Orcidhttps://orcid.org/0000-0001-9141-8784;  Email: [email protected]
  • Authors
    • Frank F. J. de Kleijne - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
    • Floor ter Braak - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
    • Dimitrios Piperoudis - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
    • Peter H. Moons - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands;  Orcidhttps://orcid.org/0009-0002-6425-8273
    • Sam J. Moons - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
    • Hidde Elferink - Institute for Molecules and Materials (IMM), Synthetic Organic Chemistry, Radboud University, 6525 AJ Nijmegen, The Netherlands
  • Author Contributions

    F.F.J.d.K. and F.t.B. contributed equally.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank Pepijn Geutjes, dr. Tom Bloemberg, and Luuk van Summeren from the Radboud University Faculty of Science teaching laboratories for allowing us to use their Bruker 300 MHz Avance III HD nanobay NMR spectrometer for conducting this research. Additionally, we would like to thank Luuk van Summeren for helping with the synthesis of 4-methoxy-[α-13C]-benzoic acid. We would also like to thank Dr. Adolfo Botana from the JEOL UK applications group for providing the CEST and modified EXSY pulse sequences and assisting in their implementation. This work was supported by a Dutch Research Council NWO-VIDI grant (VI.Vidi.192.070) awarded to T.J.B.

References

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    Tetrahedron Letters (1999), 40 (36), 6523-6526CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    Iodonium-ion promoted glycosylations in 1,4-dioxane/toluene with galactosyl donors having an electron-donating neighboring group participating functionality at C-4 give exceptional high α-anomeric selectivities.
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  9. 9
    Baek, J. Y.; Kwon, H.-W.; Myung, S. J.; Park, J. J.; Kim, M. Y.; Rathwell, D. C. K.; Jeon, H. B.; Seeberger, P. H.; Kim, K. S. Directing effect by remote electron-withdrawing protecting groups at O-3 or O-4 position of donors in glucosylations and galactosylations. Tetrahedron 2015, 71 (33), 5315– 5320,  DOI: 10.1016/j.tet.2015.06.014
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    9
    Directing effect by remote electron-withdrawing protecting groups at O-3 or O-4 position of donors in glucosylations and galactosylations
    Baek, Ju Yuel; Kwon, Hea-Won; Myung, Se Jin; Park, Jung Jun; Kim, Mi Young; Rathwell, Dominea C. K.; Jeon, Heung Bae; Seeberger, Peter H.; Kim, Kwan Soo
    Tetrahedron (2015), 71 (33), 5315-5320CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    Glucosylations and galactosylations of various acceptors with donors possessing an electron-withdrawing benzylsulfonyl, benzoyl, or acetyl group at the O-3 or O-4 position were performed. A β-directing effect by the benzylsulfonyl group at O-3 of the glucosyl donors and by the benzylsulfonyl and acyl groups at O-4 of the glucosyl donors was obsd. In contrast, acyl groups at O-3 of the glucosyl donors and acyl groups at O-3 and O-4 of the galactosyl donors exhibited an α-directing effect. The α-directing effect is partly considered to remote participation of the acyl groups, whereas the β-directing effect is somewhat attributed to the SN2-like reaction of the acceptor with the glycosyl triflate or the contact ion pair, which is stabilized by remote electron-withdrawing groups. Further evidence for the stability of the α-glycosyl triflates was detd. by a low-temp. NMR study.
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  10. 10
    Ayala, L.; Lucero, C. G.; Romero, J. A.; Tabacco, S. A.; Woerpel, K. A. Stereochemistry of nucleophilic substitution reactions depending upon substituent: evidence for electrostatic stabilization of pseudoaxial conformers of oxocarbenium ions by heteroatom substituents. J. Am. Chem. Soc. 2003, 125 (50), 15521– 8,  DOI: 10.1021/ja037935a
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    10
    Stereochemistry of Nucleophilic Substitution Reactions Depending upon Substituent: Evidence for Electrostatic Stabilization of Pseudoaxial Conformers of Oxocarbenium Ions by Heteroatom Substituents
    Ayala, Leticia; Lucero, Claudia G.; Romero, Jan Antoinette C.; Tabacco, Sarah A.; Woerpel, K. A.
    Journal of the American Chemical Society (2003), 125 (50), 15521-15528CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This anal. is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-Bu group at C-2 was high 1,2-trans selectivity obsd. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.
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  11. 11
    Ma, Y.; Lian, G.; Li, Y.; Yu, B. Identification of 3,6-di-O-acetyl-1,2,4-O-orthoacetyl-α-d-glucopyranose as a direct evidence for the 4-O-acyl group participation in glycosylation. Chem. Commun. 2011, 47 (26), 7515– 7517,  DOI: 10.1039/c1cc11680k
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    11
    Identification of 3,6-di-O-acetyl-1,2,4-O-ortho-acetyl-α-D-glucopyranose as a direct evidence for the 4-O-acyl group participation in glycosylation
    Ma, Yuyong; Lian, Gaoyan; Li, Yao; Yu, Biao
    Chemical Communications (Cambridge, United Kingdom) (2011), 47 (26), 7515-7517CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The formation of 3,6-di-O-acetyl-1,2,4-O-ortho-acetyl-α-D-glucopyranose was obsd. in the gold(I)-catalyzed glycosylation of peracetyl glucopyranosyl ortho-hexynyl-benzoate; expts. with substrates bearing deuterium labeled 2-O-acetyl or 4-O-acetyl groups indicated that the orthoacetate was derived from the 4-O-acetyl group, which provided a direct evidence for the remote participation of the 4-O-acyl group in glycosylation.
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  12. 12
    Komarova, B. S.; Orekhova, M. V.; Tsvetkov, Y. E.; Nifantiev, N. E. Is an acyl group at O-3 in glucosyl donors able to control α-stereoselectivity of glycosylation? The role of conformational mobility and the protecting group at O-6. Carbohydr. Res. 2014, 384, 70– 86,  DOI: 10.1016/j.carres.2013.11.016
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    12
    Is an acyl group at O-3 in glucosyl donors able to control α-stereoselectivity of glycosylation? The role of conformational mobility and the protecting group at O-6
    Komarova, Bozhena S.; Orekhova, Maria V.; Tsvetkov, Yury E.; Nifantiev, Nikolay E.
    Carbohydrate Research (2014), 384 (), 70-86CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
    The stereodirecting effect of a 3-O-acetyl protecting group, which is potentially capable of the remote anchimeric participation, and other protecting groups in 2-O-benzyl glucosyl donors with flexible and rigid conformations has been investigated. To this aim, an array of N-phenyltrifluoroacetimidoyl and sulfoxide donors bearing either 3-O-acetyl or 3-O-benzyl groups in combination with 4,6-di-O-benzyl, 6-O-acyl-4-O-benzyl, or 4,6-O-benzylidene protecting groups was prepd. The conformationally flexible 3-O-acetylated glucosyl donor protected at other positions with O-benzyl groups demonstrated very low or no α-stereoselectivity upon glycosylation of primary or secondary acceptors. On the contrary, 3,6-di-O-acylated glucosyl donors proved to be highly α-stereoselective as well as the donor having a single potentially participating acetyl group at O-6. The 3,6-di-O-acylated donor was shown to be the best α-glucosylating block for the primary acceptor, whereas the best α-selectivity of glycosylation of the secondary acceptor was achieved with the 6-O-acylated donor. Glycosylation of the secondary acceptor with the conformationally constrained 3-O-acetyl-4,6-O-benzylidene-protected donor displayed under std. conditions (-35 °) even lower α-selectivity as compared to the 3-O-benzyl analog. However, increasing the reaction temp. essentially raised the α-stereoselectivities of glycosylation with both 3-O-acetyl and 3-O-benzyl donors and made them almost equal. The stereodirecting effects of protecting groups obsd. for N-phenyltrifluoroacetimidoyl donors were also generally proven for sulfoxide donors.
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  13. 13
    Dejter-juszynski, M.; Flowers, H. M. Studies on the koenigs-knorr reaction: Part IV: The effect of participating groups on the stereochemistry of disaccharide formation. Carbohydr. Res. 1973, 28 (1), 61– 74,  DOI: 10.1016/S0008-6215(00)82857-8
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    13
    Koenigs-Knorr reaction. IV. Effect of participating groups on the stereochemistry of disaccharide formation
    Dejter-Juszynski, Marta; Flowers, Harold M.
    Carbohydrate Research (1973), 28 (1), 61-74CODEN: CRBRAT; ISSN:0008-6215.
    Partial benzylation of Me 2-O-benzyl-α-L-fucopyranoside gave a mixt. of Me 2,3-, and 2,4-di-O-benzyl-α-L-fucopyranoside which were sepd. by means of their monoacetates. Partial benzylation of Me α-L-fucopyranoside gave the 2,4-, and 3,4-di-O-benzyl ethers in the ratio of 3:2. The structures of the ethers were detd. by NMR anal. of their acetates, and by methylation, debenzylidenation, and characterization of the Me ethers of the Me glycosides. Acid hydrolysis of these compds. gave two known monomethyl ethers ofL-fucose and 4-O-methyl-L-fucose, a new compd. Selective p-nitrobenzoylation of 2,3-, 2,4-, and 3,4-di-O-benzyl-L-fucose, followed by acetylation and treatment with HBr in CH2Cl2, gave the three possible mono-O-acetyl-di-O-benzyl-α-L-fucopyranosyl bromides, which were condensed with benzyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-α-D-glucopyranoside. The disaccharide derived from the 2-O-acetyl substituted bromide was enriched in β-L-fucopyranoside, whereas the other two bromides gave the α-L-linked anomer. Participation of acyl groups and electronic-steric influences were discussed as possible explanations for the steric course of the reaction.
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  14. 14
    Mcmillan, T. F.; Crich, D. Influence of 3-Thio Substituents on Benzylidene-Directed Mannosylation. Isolation of a Bridged Pyridinium Ion and Effects of 3-O-Picolyl and 3-S-Picolyl Esters. Eur. J. Org. Chem. 2022, 2022 (20), e202200320  DOI: 10.1002/ejoc.202200320
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    14
    Influence of 3-Thio Substituents on Benzylidene-Directed Mannosylation. Isolation of a Bridged Pyridinium Ion and Effects of 3-O-Picolyl and 3-S-Picolyl Esters
    McMillan, Timothy F.; Crich, David
    European Journal of Organic Chemistry (2022), 2022 (20), e202200320CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The influence on glycosyl selectivity of substituting oxygen for sulfur at the 3-position of 4,6-O-benzylidene-protected mannopyranosyl thioglycosides is reported and varies considerably according to the protecting group employed at the 3-position. The substitution of a thioether at the 3-position for the more usual 3-O-benzyl ether results in a significant loss of selectivity. The installation of a 3-S-picolinyl thioether results in a complex reaction mixt., from which a stable seven-membered bridged bicyclic pyridinium ion is isolated, while the corresponding 3-O-picolinyl ether affords a highly α-selective coupling reaction. A 3-O-picolyl ester provides excellent β-selectivity, while the analogous 3-S-picolyl thioester gives a highly α-selective reaction. The best β-selectivity is seen with a 3-deoxy-3-(2-pyridinyldisulfanyl) system. These observations are discussed in terms of the influence of the various substituents on the central glycosyl triflate - ion pair equil.
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  15. 15
    Elferink, H.; Remmerswaal, W. A.; Houthuijs, K. J.; Jansen, O.; Hansen, T.; Rijs, A. M.; Berden, G.; Martens, J.; Oomens, J.; Codée, J. D. C.; Boltje, T. J. Competing C-4 and C-5-Acyl Stabilization of Uronic Acid Glycosyl Cations. Chem. – Eur. J. 2022, 28 (63), e202201724  DOI: 10.1002/chem.202201724
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    15
    Competing C-4 and C-5-Acyl Stabilization of Uronic Acid Glycosyl Cations
    Elferink, Hidde; Remmerswaal, Wouter A.; Houthuijs, Kas J.; Jansen, Oscar; Hansen, Thomas; Rijs, Anouk M.; Berden, Giel; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.; Boltje, Thomas J.
    Chemistry - A European Journal (2022), 28 (63), e202201724CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramol. stabilization of uronic acid cations by the C-5 carboxylic acid or the C-4 acetyl group was studied with IR ion spectroscopy (IRIS). IRIS reveals that a mixt. of bridged ions is formed, in which the mixt. is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population anal. and interconversion barrier computations show that the two bridged structures are not in dynamic equil. and that their ratio parallels the d. functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products.
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  16. 16
    Remmerswaal, W. A.; Houthuijs, K. J.; Van de ven, R.; Elferink, H.; Hansen, T.; Berden, G.; Overkleeft, H. S.; Van der marel, G. A.; Rutjes, F. P. J. T.; Filippov, D. V.; Boltje, T. J.; Martens, J.; Oomens, J.; Codée, J. D. C. Stabilization of Glucosyl Dioxolenium Ions by “Dual Participation” of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation. Journal of Organic Chemistry 2022, 87 (14), 9139– 9147,  DOI: 10.1021/acs.joc.2c00808
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    16
    Stabilization of Glucosyl Dioxolenium Ions by "Dual Participation" of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation
    Remmerswaal, Wouter A.; Houthuijs, Kas J.; van de Ven, Roel; Elferink, Hidde; Hansen, Thomas; Berden, Giel; Overkleeft, Herman S.; van der Marel, Gijsbert A.; Rutjes, Floris P. J. T.; Filippov, Dmitri V.; Boltje, Thomas J.; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.
    Journal of Organic Chemistry (2022), 87 (14), 9139-9147CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The stereoselective introduction of glycosidic bonds is of paramount importance to oligosaccharide synthesis. Among the various chem. strategies to steer stereoselectivity, participation by either neighboring or distal acyl groups is used particularly often. Recently, the use of the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection group was shown to offer enhanced stereoselective steering compared to other acyl groups. Here, we investigate the origin of the stereoselectivity induced by the DMNPA group through systematic glycosylation reactions and IR ion spectroscopy (IRIS) combined with techniques such as isotopic labeling of the anomeric center and isomer population anal. Our study indicates that the origin of the DMNPA stereoselectivity does not lie in the direct participation of the nitro moiety but in the formation of a dioxolenium ion that is strongly stabilized by the nitro group.
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  17. 17
    De kleijne, F. F. J.; Elferink, H.; Moons, S. J.; White, P. B.; Boltje, T. J. Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy. Angew. Chem., Int. Ed. 2022, 61 (6), e202109874  DOI: 10.1002/anie.202109874
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    17
    Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy
    de Kleijne, Frank F. J.; Elferink, Hidde; Moons, Sam J.; White, Paul B.; Boltje, Thomas J.
    Angewandte Chemie, International Edition (2022), 61 (6), e202109874CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low-populated, rapidly equilibrating mannosyl dioxanium ions that arise from participation of a C-3 acyl group using chem. exchange satn. transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α-selective couplings were obsd. suggesting glycosylation took place via this elusive intermediate.
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  18. 18
    Hansen, T.; Elferink, H.; Van hengst, J. M. A.; Houthuijs, K. J.; Remmerswaal, W. A.; Kromm, A.; Berden, G.; Van der vorm, S.; Rijs, A. M.; Overkleeft, H. S.; Filippov, D. V.; Rutjes, F. P. J. T.; Van der marel, G. A.; Martens, J.; Oomens, J.; Codée, J. D. C.; Boltje, T. J. Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions. Nat. Commun. 2020, 11 (1), 2664,  DOI: 10.1038/s41467-020-16362-x
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    18
    Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions
    Hansen, Thomas; Elferink, Hidde; van Hengst, Jacob M. A.; Houthuijs, Kas J.; Remmerswaal, Wouter A.; Kromm, Alexandra; Berden, Giel; van der Vorm, Stefan; Rijs, Anouk M.; Overkleeft, Hermen S.; Filippov, Dmitri V.; Rutjes, Floris P. J. T.; van der Marel, Gijsbert A.; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.; Boltje, Thomas J.
    Nature Communications (2020), 11 (1), 2664CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Controlling the chem. glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general soln. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using IR ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochem. outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biol. research.
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  19. 19
    Elferink, H.; Mensink, R. A.; Castelijns, W. W. A.; Jansen, O.; Bruekers, J. P. J.; Martens, J.; Oomens, J.; Rijs, A. M.; Boltje, T. J. The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones. Angew. Chem., Int. Ed. 2019, 58 (26), 8746– 8751,  DOI: 10.1002/anie.201902507
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    19
    The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones
    Elferink, Hidde; Mensink, Rens A.; Castelijns, Wilke W. A.; Jansen, Oscar; Bruekers, Jeroen P. J.; Martens, Jonathan; Oomens, Jos; Rijs, Anouk M.; Boltje, Thomas J.
    Angewandte Chemie, International Edition (2019), 58 (26), 8746-8751CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Uronic acids are important constituents of polysaccharides found on the cell membranes of different organisms. To prep. uronic-acid-contg. oligosaccharides, uronic acid 6,3-lactones can be employed as they display a fixed conformation and a unique reactivity and stereoselectivity. Herein, we report a highly β-selective and efficient mannosyl donor based on C-4 acetyl mannuronic acid 6,3-lactone donors. The mechanism of glycosylation is established using a combination of techniques, including IR ion spectroscopy combined with quantum-chem. calcns. and variable-temp. NMR (VT NMR) spectroscopy. The role of these intermediates in glycosylation is assayed by varying the activation protocol and acceptor nucleophilicity. The obsd. trends are analogous to the well-studied 4,6-benzylidene glycosides and may be used to guide the development of next-generation stereoselective glycosyl donors.
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    Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. Halide ion catalyzed glycosidation reactions. Syntheses of.alpha.-linked disaccharides. J. Am. Chem. Soc. 1975, 97 (14), 4056– 4062,  DOI: 10.1021/ja00847a032
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    20
    Halide ion catalyzed glycosidation reactions. Syntheses of α-linked disaccharides
    Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K.
    Journal of the American Chemical Society (1975), 97 (14), 4056-62CODEN: JACSAT; ISSN:0002-7863.
    Eight α-linked disaccharides were synthesized in 90% yield and in a highly stereoselective manner by reaction of per-O-benzyl-α-glycopyraaosyl bromides of the D-gluco, D-galacto, and L-galacto(L-fuco) configurations with suitably protected derivs. of D-glucose and D-galactose in the presence of Et4NBr. The main characteristics of the halide ion catalyzed reaction were established by studies of the reactions of tetra-O-benzyl-α-D-glucopyranosyl chloride and bromide with simple alcs. The more rapid route provided by the β-glycosyl halide is attributed to the stereoelectronic requirement of an antiparallel orientation of a ring-oxygen lone pair of electrons in both bond breaking and bond making at the anomeric center.
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  21. 21
    Lu, S.-R.; Lai, Y.-H.; Chen, J.-H.; Liu, C.-Y.; Mong, K.-K. T. Dimethylformamide: An Unusual Glycosylation Modulator. Angew. Chem., Int. Ed. 2011, 50 (32), 7315– 7320,  DOI: 10.1002/anie.201100076
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    21
    Dimethylformamide: An Unusual Glycosylation Modulator
    Lu, Shao-Ru; Lai, Yen-Hsun; Chen, Jiun-Han; Liu, Chih-Yueh; Mong, Kwok-Kong Tony
    Angewandte Chemie, International Edition (2011), 50 (32), 7315-7320, S7315/1-S7315/125CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    When N,N-dimethylformamide was used to direct the stereochem. course of glycosylation reactions, 1,2-cis glycosylation products were formed with excellent selectivity. A straightforward highly α-stereoselective glycosylation involving preactivation should find broad application and be esp. useful for sequential glycosylation reactions to form oligosaccharides.
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    Crich, D.; Sun, S. Are Glycosyl Triflates Intermediates in the Sulfoxide Glycosylation Method? A Chemical and 1H, 13C, and 19F NMR Spectroscopic Investigation. J. Am. Chem. Soc. 1997, 119 (46), 11217– 11223,  DOI: 10.1021/ja971239r
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    22
    Are Glycosyl Triflates Intermediates in the Sulfoxide Glycosylation Method? A Chemical and 1H, 13C, and 19F NMR Spectroscopic Investigation
    Crich, David; Sun, Sanxing
    Journal of the American Chemical Society (1997), 119 (46), 11217-11223CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The title question is addressed by low-temp. 1H, 13C, and 19F NMR spectroscopies in CD2Cl2 as well as by the prepn. of authentic samples from glycopyranosyl bromides and AgOTf. At -78 °C glycosyl triflates are cleanly generated with either non-participating or participating protecting groups at O-2. The glycosyl triflates identified in this manner were allowed to react with methanol, resulting in the formation of Me glycosides. Glycosyl triflates were generated at -78 °C in CD2Cl2 and allowed to warm gradually until decompn. was detected by 1H and 19F NMR spectroscopy. The decompn. temp. and products are functions of the protecting groups employed.
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  23. 23
    Santana, A. G.; Montalvillo-jiménez, L.; Díaz-casado, L.; Corzana, F.; Merino, P.; Cañada, F. J.; Jiménez-osés, G.; Jiménez-barbero, J.; Gómez, A. M.; Asensio, J. L. Dissecting the Essential Role of Anomeric β-Triflates in Glycosylation Reactions. J. Am. Chem. Soc. 2020, 142 (28), 12501– 12514,  DOI: 10.1021/jacs.0c05525
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    Dissecting the Essential Role of Anomeric β-Triflates in Glycosylation Reactions
    Santana, Andres G.; Montalvillo-Jimenez, Laura; Diaz-Casado, Laura; Corzana, Francisco; Merino, Pedro; Canada, Francisco J.; Jimenez-Oses, Gonzalo; Jimenez-Barbero, Jesus; Gomez, Ana M.; Asensio, Juan Luis
    Journal of the American Chemical Society (2020), 142 (28), 12501-12514CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biol. and chem. interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and β-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be exptl. described, seem to be particularly relevant in α-selective processes, involving weak acceptors. Herein, we report a detailed anal. of several paradigmatic and illustrative examples of such reactions, employing a combination of chem., NMR, kinetic and theor. approaches, culminating in the unprecedented detection and quantification of the true β-glycosyl triflate intermediates within activated donor mixts. This achievement was further employed as a stepping-stone for the characterization of the triflate anomerization dynamics, which along with the acceptor substitutions, govern the stereochem. outcome of the reaction. The obtained data conclusively show that, even for highly dissociative reactions involving β-close ion pair (β-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimol. α → β triflate interconversion, which under certain circumstances becomes the rate-limiting step. Overall, our results rule out the prevalence of the Curtin-Hammett fast-exchange assumption for most glycosylations and highlight the distinct reactivity properties of α- and β-glycosyl triflates against neutral and anionic acceptors.
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    Crich, D.; Chandrasekera, N. S. Mechanism of 4,6-O-Benzylidene-Directed β-Mannosylation as Determined by α-Deuterium Kinetic Isotope Effects. Angew. Chem., Int. Ed. 2004, 43 (40), 5386– 5389,  DOI: 10.1002/anie.200453688
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    24
    Mechanism of 4,6-O-benzylidene-directed β-mannosylation as determined by α-deuterium kinetic isotope effects
    Crich, David; Chandrasekera, N. Susantha
    Angewandte Chemie, International Edition (2004), 43 (40), 5386-5389CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Considerable oxacarbenium ion character may be in the transition state of a highly β-selective mannosylation reaction that proceeds via an α-mannosyl triflate. An α-deuterium kinetic isotope effect of 1.2 was measured at -78°C (=1.1 at 25°C). This information may be interpreted in terms of a stereoselective trapping of a transient contact ion pair or, alternatively, as representative of an "exploded" transition state.
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  25. 25
    Hansen, T.; Lebedel, L.; Remmerswaal, W. A.; Van der vorm, S.; Wander, D. P. A.; Somers, M.; Overkleeft, H. S.; Filippov, D. V.; Désiré, J.; Mingot, A.; Bleriot, Y.; Van der marel, G. A.; Thibaudeau, S.; Codée, J. D. C. Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations. ACS Central Science 2019, 5 (5), 781– 788,  DOI: 10.1021/acscentsci.9b00042
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    Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations
    Hansen, Thomas; Lebedel, Ludivine; Remmerswaal, Wouter A.; van der Vorm, Stefan; Wander, Dennis P. A.; Somers, Mark; Overkleeft, Herman S.; Filippov, Dmitri V.; Desire, Jerome; Mingot, Agnes; Bleriot, Yves; van der Marel, Gijsbert A.; Thibaudeau, Sebastien; Codee, Jeroen D. C.
    ACS Central Science (2019), 5 (5), 781-788CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    The broad application of well-defined synthetic oligosaccharides in glycobiol. and glycobiotechnol. is largely hampered by the lack of sufficient amts. of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the detn. of clear structure-reactivity-stereoselectivity principles for these species. We report a combined exptl. and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quant. manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodol.
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    Franconetti, A.; Ardá, A.; Asensio, J. L.; Blériot, Y.; Thibaudeau, S.; Jiménez-barbero, J. Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions. Acc. Chem. Res. 2021, 54 (11), 2552– 2564,  DOI: 10.1021/acs.accounts.1c00021
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    26
    Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions
    Franconetti, Antonio; Arda, Ana; Asensio, Juan luis; Bleriot, Yves; Thibaudeau, Sebastien; Jimenez-barbero, Jesus
    Accounts of Chemical Research (2021), 54 (11), 2552-2564CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Carbohydrates (glycans, saccharides, sugars) are essential mols. in all domains of life. Research on glycoscience spans from chem. to biomedicine, including material science and biotechnol. The access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is supposed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of these glycosyl cations is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theor. and exptl. approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity. We also highlight that, from a chem. perspective, the glycosylation reaction can be described as a continuum, from unimol. SN1 with naked oxocarbenium cations as intermediates to bimol. SN2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-sepd. ion pairs, solvent-equilibrated ion pairs) with bimol. features in most reactions is also highlighted. The role of theor. calcns. to predict the conformation, dynamics and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow the access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under SN1-like conditions. Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterizing the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid soln. by NMR spectroscopy. We also pay special attention to the reactivity of these glycosyl ions that depends on the conditions, including the counterions, the possible intra- or intermol. participation of functional groups that may stabilize the cation and the chem. nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different exptl. perspectives, which identified the involved ionic intermediates, estg. their lifetimes and reactivities and studying their interactions with other mols. In this context, we also emphasize the relationship between the chem. methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of mols. that regulate the stability and reactivity of glycosyl cations.
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    Huang, M.; Retailleau, P.; Bohé, L.; Crich, D. Cation Clock Permits Distinction Between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series: Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion. J. Am. Chem. Soc. 2012, 134 (36), 14746– 14749,  DOI: 10.1021/ja307266n
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    Cation Clock Permits Distinction Between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series: Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion
    Huang, Min; Retailleau, Pascal; Bohe, Luis; Crich, David
    Journal of the American Chemical Society (2012), 134 (36), 14746-14749CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The use of a cationic cyclization reaction as a probe of the glycosylation mechanism has been developed and applied to the 4,6-O-benzylidene-protected mannopyranoside system. Cyclization results in the formation of both cis- and trans-fused tricyclic systems, invoking an intermediate glycosyl oxocarbenium ion reacting through a boat conformation. Competition reactions with isopropanol and trimethyl(methallyl)silane are interpreted as indicating that β-O-mannosylation proceeds via an associative SN2-like mechanism, whereas α-O-mannosylation and β-C-mannosylation are dissociative and SN1-like. Relative rate consts. for reactions going via a common intermediate can be estd.
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    Chatterjee, S.; Moon, S.; Hentschel, F.; Gilmore, K.; Seeberger, P. H. An Empirical Understanding of the Glycosylation Reaction. J. Am. Chem. Soc. 2018, 140 (38), 11942– 11953,  DOI: 10.1021/jacs.8b04525
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    An Empirical Understanding of the Glycosylation Reaction
    Chatterjee, Sourav; Moon, Sooyeon; Hentschel, Felix; Gilmore, Kerry; Seeberger, Peter H.
    Journal of the American Chemical Society (2018), 140 (38), 11942-11953CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Reliable glycosylation reactions that allow for the stereo- and regioselective installation of glycosidic linkages are paramount to the chem. synthesis of glycan chains. The stereoselectivity of glycosylations is exceedingly difficult to control due to the reaction's high degree of sensitivity and its shifting, simultaneous mechanistic pathways that are controlled by variables of unknown degree of influence, dominance, or interdependency. An automated platform was devised to quickly, reproducibly, and systematically screen glycosylations and thereby address this fundamental problem. Thirteen variables were investigated in as isolated a manner as possible, to identify and quantify inherent preferences of electrophilic glycosylating agents (donors) and nucleophiles (glycosyl acceptors). Ways to enhance, suppress, or even override these preferences using judicious environmental conditions were discovered. Glycosylation involving two specific partners can be tuned to produce either 11:1 selectivity of one stereoisomer or 9:1 of the other by merely changing the reaction conditions.
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    Satoh, H.; Hansen, H. S.; Manabe, S.; Van gunsteren, W. F.; Hünenberger, P. H. Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex. J. Chem. Theory Comput. 2010, 6 (6), 1783– 1797,  DOI: 10.1021/ct1001347
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    Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex
    Satoh, Hiroko; Hansen, Halvor S.; Manabe, Shino; van Gunsteren, Wilfred F.; Hunenberger, Philippe H.
    Journal of Chemical Theory and Computation (2010), 6 (6), 1783-1797CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    The mechanism of solvent effects on the stereoselectivity of glycosylation reactions is investigated using quantum-mech. (QM) calcns. and mol. dynamics (MD) simulations, considering a methyl-protected glucopyranoside triflate as a glycosyl donor equiv. and the solvents acetonitrile, ether, dioxane, or toluene, as well as gas-phase conditions (vacuum). The QM calcns. on oxacarbenium-solvent complexes do not provide support to the usual solvent-coordination hypothesis, suggesting that an exptl. obsd. β-selectivity (α-selectivity) is caused by the preferential coordination of a solvent mol. to the reactive cation on the α-side (β-side) of the anomeric carbon. Instead, explicit-solvent MD simulations of the oxacarbenium-counterion (triflate ion) complex (along with corresponding QM calcns.) are compatible with an alternative mechanism, termed here the conformer and counterion distribution hypothesis. This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, (1) the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the α or β face, and (2) the preferential coordination of the counterion to the oxacarbenium cation on one side of the anomeric carbon, hindering a nucleophilic attack from this side. For example, in acetonitrile, the calcns. suggest a dominant B2,5 ring conformation of the cation with preferential coordination of the counterion on the α side, both factors leading to the exptl. obsd. β selectivity. Conversely, in dioxane, they suggest a dominant 4H3 ring conformation with preferential counterion coordination on the β side, both factors leading to the exptl. obsd. α selectivity.
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    Crich, D.; Cai, W. Chemistry of 4,6-O-Benzylidene-d-glycopyranosyl Triflates: Contrasting Behavior between the Gluco and Manno Series. Journal of Organic Chemistry 1999, 64 (13), 4926– 4930,  DOI: 10.1021/jo990243d
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    Chemistry of 4,6-O-Benzylidene-D-glycopyranosyl Triflates: Contrasting Behavior between the Gluco and Manno Series
    Crich, David; Cai, Weiling
    Journal of Organic Chemistry (1999), 64 (13), 4926-4930CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Activation of either anomer of S-Ph 2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia-D-glucopyranoside with triflic anhydride in dichloromethane at -78 °C in the presence of 2,6-di-tert-butyl-4-methylpyridine affords a highly active glycosylating species which, on addn. of alcs., provides α-glucosides with high selectivity. This selectivity stands in stark contrast to the analogous mannopyranoside series, which affords the β-mannosides with excellent selectivity under the same conditions. Low-temp. NMR expts. support the notion that a glucosyl triflate is formed in the initial activation step. Possible reasons for the diverging stereoselectivity in the gluco and manno series are discussed.
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    Van der vorm, S.; Hansen, T.; Van hengst, J. M. A.; Overkleeft, H. S.; Van der marel, G. A.; Codée, J. D. C. Acceptor reactivity in glycosylation reactions. Chem. Soc. Rev. 2019, 48 (17), 4688– 4706,  DOI: 10.1039/C8CS00369F
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    Acceptor reactivity in glycosylation reactions
    van der Vorm, Stefan; Hansen, Thomas; van Hengst, Jacob M. A.; Overkleeft, Herman S.; van der Marel, Gijsbert A.; Codee, Jeroen D. C.
    Chemical Society Reviews (2019), 48 (17), 4688-4706CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    The outcome of a glycosylation reaction critically depends on the reactivity of all reaction partners involved: the donor glycoside (the electrophile), the activator (that generally provides the leaving group on the activated donor species) and the glycosyl acceptor (the nucleophile). The influence of the donor on the outcome of a glycosylation reaction is well appreciated and documented. Differences in donor reactivity have led to the development of chemoselective glycosylation reactions and the reactivity of donor glycosides has been tuned to affect stereoselective glycosylation reactions. The quantification of donor reactivity has enabled the conception of streamlined one-pot glycosylation sequences. In contrast, although it has long been known that the nature and the reactivity of the nucleophile influence the outcome of a glycosylation, the knowledge of acceptor reactivity and insight into the consequences thereof are often circumstantial or anecdotal. This review documents how the reactivity impacts the glycosylation reaction outcome both in terms of chem. yield and stereoselectivity. The effect of acceptor nucleophilicity on the reaction mechanism is described and steric, conformational and electronic influences are outlined. Quant. and computational approaches to comprehend acceptor nucleophilicity are assessed. The increasing insight into the stereoelectronic effects governing glycoside reactivity will eventually enable the conception of effective stereoselective glycosylation methodol. that can be tuned to the reaction partners at hand.
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    Andreana, P. R.; Crich, D. Guidelines for O-Glycoside Formation from First Principles. ACS Central Science 2021, 7 (9), 1454– 1462,  DOI: 10.1021/acscentsci.1c00594
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    Guidelines for O-Glycoside Formation from First Principles
    Andreana, Peter R.; Crich, David
    ACS Central Science (2021), 7 (9), 1454-1462CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    The complexity and irreproducibility of glycosylation reactions retard progress in the glyco-sciences. Application of the steady-state hypothesis to transient oxocarbenium ion-counterion pair intermediates reveals the importance of concn., temp., and other factors in glycosylation stereoselectivity. Guidelines are then adduced for the practice of O-glycosylation reactions on the basis of which more reproducible, practical protocols can be established.
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    Crich, D. En route to the transformation of glycoscience: A chemist’s perspective on internal and external crossroads in glycochemistry. J. Am. Chem. Soc. 2021, 143 (1), 17– 34,  DOI: 10.1021/jacs.0c11106
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    En Route to the Transformation of Glycoscience: A Chemist's Perspective on Internal and External Crossroads in Glycochemistry
    Crich, David
    Journal of the American Chemical Society (2021), 143 (1), 17-34CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A review with refs. Carbohydrate chem. is an essential component of the glycosciences and is fundamental to their progress. This perspective takes the position that carbohydrate chem., or glycochem., has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other labs. The first of these potential inflection points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the exptl. evidence supports bimol. SN2-like mechanisms for typical glycosylation reactions over unimol. ones involving stereoselective attack on naked glycosyl oxocarbenium ions. A second crossroads is that between mainstream org. chem. and glycan synthesis. A third crossroads is that between carbohydrate chem. and medicinal chem., where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but the creativity, input and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.
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    Adero, P. O.; Amarasekara, H.; Wen, P.; Bohé, L.; Crich, D. The Experimental Evidence in Support of Glycosylation Mechanisms at the S(N)1-S(N)2 Interface. Chem. Rev. 2018, 118 (17), 8242– 8284,  DOI: 10.1021/acs.chemrev.8b00083
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    The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface
    Adero, Philip Ouma; Amarasekara, Harsha; Wen, Peng; Bohe, Luis; Crich, David
    Chemical Reviews (Washington, DC, United States) (2018), 118 (17), 8242-8284CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. A crit. review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the SN1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temp., and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the detn. of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a crit. appraisal of the state of the art.
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    Frihed, T. G.; Bols, M.; Pedersen, C. M. Mechanisms of glycosylation reactions studied by low-temperature nuclear magnetic resonance. Chem. Rev. 2015, 115 (11), 4963– 5013,  DOI: 10.1021/cr500434x
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    Mechanisms of Glycosylation Reactions Studied by Low-Temperature Nuclear Magnetic Resonance
    Frihed, Tobias Gylling; Bols, Mikael; Pedersen, Christian Marcus
    Chemical Reviews (Washington, DC, United States) (2015), 115 (11), 4963-5013CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review.
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    Braak, F. t.; Elferink, H.; Houthuijs, K. J.; Oomens, J.; Martens, J.; Boltje, T. J. Characterization of Elusive Reaction Intermediates Using Infrared Ion Spectroscopy: Application to the Experimental Characterization of Glycosyl Cations. Acc. Chem. Res. 2022, 55, 1669– 1679,  DOI: 10.1021/acs.accounts.2c00040
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    Characterization of Elusive Reaction Intermediates Using Infrared Ion Spectroscopy: Application to the Experimental Characterization of Glycosyl Cations
    Braak, Floor ter; Elferink, Hidde; Houthuijs, Kas J.; Oomens, Jos; Martens, Jonathan; Boltje, Thomas J.
    Accounts of Chemical Research (2022), 55 (12), 1669-1679CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. A detailed understanding of the reaction mechanism(s) leading to stereoselective product formation is crucial to understanding and predicting product formation and driving the development of new synthetic methodol. One way to improve our understanding of reaction mechanisms is to characterize the reaction intermediates involved in product formation. Because these intermediates are reactive, they are often unstable and therefore difficult to characterize using exptl. techniques. For example, glycosylation reactions are crit. steps in the chem. synthesis of oligosaccharides and need to be stereoselective to provide the desired α- or β-diastereomer. It remains challenging to predict and control the stereochem. outcome of glycosylation reactions, and their reaction mechanisms remain a hotly debated topic. In most cases, glycosylation reactions take place via reaction mechanisms in the continuum between SN1- and SN2-like pathways. SN2-like pathways proceeding via the displacement of a contact ion pair are relatively well understood because the reaction intermediates involved can be characterized by low-temp. NMR spectroscopy. In contrast, the SN1-like pathways proceeding via the solvent-sepd. ion pair, also known as the glycosyl cation, are poorly understood. SN1-like pathways are more challenging to investigate because the glycosyl cation intermediates involved are highly reactive. The highly reactive nature of glycosyl cations complicates their characterization because they have a short lifetime and rapidly equilibrate with the corresponding contact ion pair. To overcome this hurdle and enable the study of glycosyl cation stability and structure, they can be generated in a mass spectrometer in the absence of a solvent and counterion in the gas phase. The ease of formation, stability, and fragmentation of glycosyl cations have been studied using mass spectrometry (MS). However, MS alone provides little information about the structure of glycosyl cations. By combining mass spectrometry (MS) with IR ion spectroscopy (IRIS), the detn. of the gas-phase structures of glycosyl cations has been achieved. IRIS enables the recording of gas-phase IR spectra of glycosyl cations, which can be assigned by matching to ref. spectra predicted from quantum chem. calcd. vibrational spectra. Here, we review the exptl. setups that enable IRIS of glycosyl cations and discuss the various glycosyl cations that have been characterized to date. The structure of glycosyl cations depends on the relative configuration and structure of the monosaccharide substituents, which can influence the structure through both steric and electronic effects. The scope and relevance of gas-phase glycosyl cation structures in relation to their corresponding condensed-phase structures are also discussed. We expect that the workflow reviewed here to study glycosyl cation structure and reactivity can be extended to many other reaction types involving difficult-to-characterize ionic intermediates.
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  37. 37
    Elferink, H.; Severijnen, M. E.; Martens, J.; Mensink, R. A.; Berden, G.; Oomens, J.; Rutjes, F. P. J. T.; Rijs, A. M.; Boltje, T. J. Direct Experimental Characterization of Glycosyl Cations by Infrared Ion Spectroscopy. J. Am. Chem. Soc. 2018, 140 (19), 6034– 6038,  DOI: 10.1021/jacs.8b01236
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    Direct Experimental Characterization of Glycosyl Cations by Infrared Ion Spectroscopy
    Elferink, Hidde; Severijnen, Marion E.; Martens, Jonathan; Mensink, Rens A.; Berden, Giel; Oomens, Jos; Rutjes, Floris P. J. T.; Rijs, Anouk M.; Boltje, Thomas J.
    Journal of the American Chemical Society (2018), 140 (19), 6034-6038CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Glycosyl cations are crucial intermediates formed during enzymic and chem. glycosylation. The intrinsic high reactivity and short lifetime of these reaction intermediates make them very challenging to characterize using spectroscopic techniques. Herein, we report the use of collision induced dissocn. tandem mass spectrometry to generate glycosyl cations in the gas phase followed by IR ion spectroscopy using the FELIX IR free electron laser. The exptl. obsd. IR spectra were compared to DFT calcd. spectra enabling the detailed structural elucidation of elusive glycosyl oxocarbenium and dioxolenium ions.
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  38. 38
    Mucha, E.; Marianski, M.; Xu, F.-F.; Thomas, D. A.; Meijer, G.; Von helden, G.; Seeberger, P. H.; Pagel, K. Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy. Nat. Commun. 2018, 9 (1), 4174,  DOI: 10.1038/s41467-018-07184-z
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    Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy
    Mucha Eike; Marianski Mateusz; Thomas Daniel A; Meijer Gerard; von Helden Gert; Pagel Kevin; Mucha Eike; Seeberger Peter H; Pagel Kevin; Marianski Mateusz; Xu Fei-Fei; Seeberger Peter H
    Nature communications (2018), 9 (1), 4174 ISSN:.
    Glycosyl cations are the key intermediates during the glycosylation reaction that covalently links building blocks during the synthetic assembly of carbohydrates. The exact structure of these ions remained elusive due to their transient and short-lived nature. Structural insights into the intermediate would improve our understanding of the reaction mechanism of glycosidic bond formation. Here, we report an in-depth structural analysis of glycosyl cations using a combination of cold-ion infrared spectroscopy and first-principles theory. Participating C2 protective groups form indeed a covalent bond with the anomeric carbon that leads to C1-bridged acetoxonium-type structures. The resulting bicyclic structure strongly distorts the ring, which leads to a unique conformation for each individual monosaccharide. This gain in mechanistic understanding fundamentally impacts glycosynthesis and will allow to tailor building blocks and reaction conditions in the future.
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  39. 39
    Martin, A.; Arda, A.; Désiré, J.; Martin-mingot, A.; Probst, N.; Sinaÿ, P.; Jiménez-barbero, J.; Thibaudeau, S.; Blériot, Y. Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid. Nat. Chem. 2016, 8 (2), 186– 91,  DOI: 10.1038/nchem.2399
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    Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid
    Martin, A.; Arda, A.; Desire, J.; Martin-Mingot, A.; Probst, N.; Sinay, P.; Jimenez-Barbero, J.; Thibaudeau, S.; Bleriot, Y.
    Nature Chemistry (2016), 8 (2), 186-191CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    Glycosyl cations are universally accepted key ionic intermediates in the mechanism of glycosylation, the reaction that covalently links carbohydrates to other mols. These ions have remained hypothetical species so far because of their extremely short life in org. media as a consequence of their very high reactivity. Here, we report the use of liq. hydrofluoric acid-antimony pentafluoride (HF/SbF5) superacid to generate and stabilize the glycosyl cations derived from peracetylated 2-deoxy and 2-bromoglucopyranose in a condensed phase. Their persistence in this superacid medium allows their three-dimensional structure to be studied by NMR, aided by complementary computations. Their deuteration further confirms the impact of the structure of the glycosyl cation on the stereochem. outcome of its trapping.
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  40. 40
    Ben-tal, Y.; Boaler, P. J.; Dale, H. J. A.; Dooley, R. E.; Fohn, N. A.; Gao, Y.; García-domínguez, A.; Grant, K. M.; Hall, A. M. R.; Hayes, H. L. D.; Kucharski, M. M.; Wei, R.; Lloyd-jones, G. C. Mechanistic analysis by NMR spectroscopy: A users guide. Prog. Nucl. Magn. Reson. Spectrosc. 2022, 129, 28– 106,  DOI: 10.1016/j.pnmrs.2022.01.001
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    Mechanistic analysis by NMR spectroscopy: A users guide
    Ben-Tal, Yael; Boaler, Patrick J.; Dale, Harvey J. A.; Dooley, Ruth E.; Fohn, Nicole A.; Gao, Yuan; Garcia-Dominguez, Andres; Grant, Katie M.; Hall, Andrew M. R.; Hayes, Hannah L. D.; Kucharski, Maciej M.; Wei, Ran; Lloyd-Jones, Guy C.
    Progress in Nuclear Magnetic Resonance Spectroscopy (2022), 129 (), 28-106CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
    A review principles and practice tutorial-style review of the application of soln.-phase NMR in the anal. of the mechanisms of homogeneous org. and organometallic reactions and processes. This review of 345 refs. summarises why soln.-phase NMR spectroscopy is uniquely effective in such studies, allowing non-destructive, quant. anal. of a wide range of nuclei common to org. and organometallic reactions, providing exquisite structural detail, and using instrumentation that is routinely available in most chem. research facilities. The review is in two parts. The first comprises an introduction to general techniques and equipment, and guidelines for their selection and application. Topics include practical aspects of the reaction itself, reaction monitoring techniques, NMR data acquisition and processing, anal. of temporal concn. data, NMR titrns., DOSY, and the use of isotopes. The second part comprises a series of 15 Case Studies, each selected to illustrate specific techniques and approaches discussed in the first part, including in situ NMR (1/2H, 10/11B, 13C, 15N, 19F, 29Si, 31P), kinetic and equil. isotope effects, isotope entrainment, isotope shifts, isotopes at natural abundance, scalar coupling, kinetic anal. (VTNA, RPKA, simulation, steady-state), stopped-flow NMR, flow NMR, rapid injection NMR, pure shift NMR, dynamic nuclear polarisation, 1H/19F DOSY NMR, and in situ illumination NMR.
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    Crich, D. Mechanism of a chemical glycosylation reaction. Accounts of chemical research 2010, 43 (8), 1144– 1153,  DOI: 10.1021/ar100035r
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    Mechanism of a Chemical Glycosylation Reaction
    Crich, David
    Accounts of Chemical Research (2010), 43 (8), 1144-1153CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Glycosylation is arguably the most important reaction in the field of glycochem., yet it involves one of the most empirically interpreted mechanisms in the science of org. chem. The β-mannopyranosides, long considered one of the more difficult classes of glycosidic bond to prep., were no exception to this rule. Several logical but circuitous routes for their prepn. were described in the literature, but they were accompanied by a greater no. of mostly ineffective recipes for their direct access. This situation changed in 1996 with the discovery of the 4,6-O-benzylidene acetal as a control element permitting direct entry into the β-mannopyranosides, typically with high yield and selectivity. The unexpected nature of this phenomenon demanded study of the mechanism, leading first to the demonstration of the α-mannopyranosyl triflates as reaction intermediates and then to the development of α-deuterium kinetic isotope effect methods to probe their transformation into the product glycosides. In this account, the authors assemble their observations into a comprehensive assessment consistent with a single mechanistic scheme. The realization that in the glucopyranose series the 4,6-O-benzylidene acetal is α- rather than β-directing led to further investigations of substituent effects on the stereoselectivity of these glycosylation reactions, culminating in their explanation in terms of the covalent α-glycosyl triflates acting as a reservoir for a series of transient contact and solvent-sepd. ion pairs. The function of the benzylidene acetal, as explained by Bols and co-workers, is to lock the C6-O6 bond antiperiplanar to the C5-O5 bond, thereby maximizing its electron-withdrawing effect, destabilizing the glycosyl oxocarbenium ion, and shifting the equil. as far as possible toward the covalent triflate. β-Selective reactions result from attack of the nucleophile on the transient contact ion pair in which the α-face of the oxocarbenium ion is shielded by the triflate counterion. The α-products arise from attack either on the solvent-sepd. ion pair or on a free oxocarbenium ion, according to the dictates of the anomeric effect. Changes in selectivity from varying stereochem. (glucose vs. mannose) or from using different protecting groups can be explained by the shifting position of the key equil. and, in particular, by the energy differences between the covalent triflate and the ion pairs. Of particular note is the importance of substituents at the 3-position of the donor; an explanation is proposed that invokes their evolving torsional interaction with the substituent at C2 as the chair form of the covalent triflate moves toward the half-chair of the oxocarbenium ion.
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    D’angelo, K. A.; Taylor, M. S. Borinic Acid Catalyzed Stereo- and Regioselective Couplings of Glycosyl Methanesulfonates. J. Am. Chem. Soc. 2016, 138 (34), 11058– 11066,  DOI: 10.1021/jacs.6b06943
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    Borinic Acid Catalyzed Stereo- and Regioselective Couplings of Glycosyl Methanesulfonates
    D'Angelo, Kyan A.; Taylor, Mark S.
    Journal of the American Chemical Society (2016), 138 (34), 11058-11066CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    In the presence of a diarylborinic acid catalyst, glycosyl methanesulfonates engage in regio- and stereoselective couplings with partially protected pyranoside and furanoside acceptors. The methanesulfonate donors are prepd. in situ from glycosyl hemiacetals, and are coupled under mild, operationally simple conditions (amine base, organoboron catalyst, room temp.). The borinic acid catalyst not only influences site-selectivity via activation of 1,2- or 1,3-diol motifs, but also has a pronounced effect on the stereochem. outcome: 1,2-trans-linked disaccharides are obtained selectively in the absence of neighboring group participation. Reaction progress kinetic anal. was used to obtain insight into the mechanism of glycosylation, both in the presence of catalyst and in its absence, while rates of interconversion of methanesulfonate anomers were detd. by NMR exchange spectroscopy (EXSY). Together, the results suggest that although the uncatalyzed and catalyzed reactions give rise to opposite stereochem. outcomes, both proceed by associative mechanisms.
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    Aubry, S.; Sasaki, K.; Sharma, I.; Crich, D. Influence of protecting groups on the reactivity and selectivity of glycosylation: chemistry of the 4,6-o-benzylidene protected mannopyranosyl donors and related species. Top Curr. Chem. 2010, 301, 141– 88,  DOI: 10.1007/128_2010_102
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    Kahne, D.; Walker, S.; Cheng, Y.; Van engen, D. Glycosylation of unreactive substrates. J. Am. Chem. Soc. 1989, 111 (17), 6881– 6882,  DOI: 10.1021/ja00199a081
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    Glycosylation of unreactive substrates
    Kahne, Daniel; Walker, Suzanne; Cheng, Yuan; Van Engen, Donna
    Journal of the American Chemical Society (1989), 111 (17), 6881-2CODEN: JACSAT; ISSN:0002-7863.
    A rapid method to glycosylate unreactive substrates in good yield involves activation of an anomeric Ph sulfoxide with triflic anhydride followed by trapping of a nucleophile. The efficacy of the reaction is demonstrated by glycosylation of an amide on nitrogen. This is the first report of direct glycosylation of an amide nitrogen by non-enzymic means. Other nucleophiles trapped include hindered alcs. and derivs. of phenol. In many cases, either the α or the β isomer of the glycosylated product can be obtained stereoselectively. Crystal structure of chenodeoxycholic acid glycopyranoside was detd.
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    Fraser-reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen, J. P. Torsional effects in glycoside reactivity: saccharide couplings mediated by acetal protecting groups. J. Am. Chem. Soc. 1991, 113 (4), 1434– 1435,  DOI: 10.1021/ja00004a066
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    Torsional effects in glycoside reactivity: saccharide couplings mediated by acetal protecting groups
    Fraser-Reid, Bert; Wu, Zufan; Andrews, C. Webster; Skowronski, Evan; Bowen, J. Phillip
    Journal of the American Chemical Society (1991), 113 (4), 1434-5CODEN: JACSAT; ISSN:0002-7863.
    Cyclic acetal protecting groups cause reactions at the anomeric center of pyranosides to be much slower in the non-acetalated analogs. The differences are sometimes great enough so that an armed/disarmed protocol for saccharide coupling can be based on the presence or absence of the cyclic acetal. The torsional effects responsible for these reactivity differences are predicted by PM3 computational methods, which suggests that a qual. assessment of exptl. feasibility can be readily made.
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    Andrews, C. W.; Rodebaugh, R.; Fraser-reid, B. A Solvation-Assisted Model for Estimating Anomeric Reactivity. Predicted versus Observed Trends in Hydrolysis of n-Pentenyl Glycosides1. Journal of Organic Chemistry 1996, 61 (16), 5280– 5289,  DOI: 10.1021/jo9601223
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    A Solvation-Assisted Model for Estimating Anomeric Reactivity. Predicted versus Observed Trends in Hydrolysis of n-Pentenyl Glycosides
    Andrews, C. Webster; Rodebaugh, Robert; Fraser-Reid, Bert
    Journal of Organic Chemistry (1996), 61 (16), 5280-5289CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    An attempt has been made to predict qual. trends in reactivity at the anomeric center, using N-bromosuccinimide-induced hydrolysis of n-pentenyl glycosides (NPGs) as the exptl. model. Calcd. relative activation energies based on internal energy differences of a reactant and the assocd. intermediate are not always in agreement with exptl. observations. However, solvation energies obtained by the generalized Born surface area model in MacroModel developed by Still et al. give modified activation energies that are in excellent agreement with the exptl. obsd. trends. It is shown that the solvation model does not disturb the normally obsd. reactivity trends that can be rationalized on the basis of internal energies alone. The value of the methodol. has been demonstrated for several substrates by first calcg. their relative activation energies, then testing them exptl., and finding excellent agreement with predictions.
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    Jensen, H. H.; Nordstro̷m, L. U.; Bols, M. The Disarming Effect of the 4,6-Acetal Group on Glycoside Reactivity: Torsional or Electronic?. J. Am. Chem. Soc. 2004, 126 (30), 9205– 9213,  DOI: 10.1021/ja047578j
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    The Disarming Effect of the 4,6-Acetal Group on Glycoside Reactivity: Torsional or Electronic?
    Jensen, Henrik Helligso; Nordstrom, Lars Ulrik; Bols, Mikael
    Journal of the American Chemical Society (2004), 126 (30), 9205-9213CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An evaluation of whether the well-known deactivating effect of a 4,6-acetal protection group on glycosyl transfer is caused by torsional or an electronic effect from fixation of the 6-OH in the tg conformation was made. Two conformationally locked probe mols., 2,4-dinitrophenyl 4,8-anhydro-7-deoxy-2,3,6-tri-O-methyl-β-D-glycero-D-gluco-octopyranoside (I) and the L-glycero-D-gluco isomer (II), were prepd., and their rate of hydrolysis was compared to that of the flexible 2,4-dinitrophenyl 2,3,4,6-tetra-O-methyl-β-D-glucopyranoside (III) and the locked 2,4-dinitrophenyl 4,6-O-methylidene-2,3-di-O-methyl-β-D-glucopyranoside (IV). The rate of hydrolysis at pH 6.5 was III > I > II > IV, which showed that the deactivating effect of the 4,6-methylene group is partially torsional and partially electronic. A comparison of the rate of acidic hydrolysis showed that the of the corresponding Me α-glycoside probe mols. of I and II hydrolyzed significantly slower than Me tetra-O-methyl-glucoside, confirming a deactivating effect of locking the saccharide in the 4C1 conformation. The expts. showed that the hydroxymethyl rotamers deactivate the rate of glycoside hydrolysis in the order tg » gt > gg.
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    Van zijl, P. C.; Yadav, N. N. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t?. Magn Reson Med. 2011, 65 (4), 927– 48,  DOI: 10.1002/mrm.22761
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    Chemical exchange saturation transfer (CEST): what is in a name and what isn't?
    van Zijl, Peter C. M.; Yadav, Nirbhay N.
    Magnetic Resonance in Medicine (2011), 65 (4), 927-948CODEN: MRMEEN; ISSN:0740-3194. (Wiley-Liss, Inc.)
    A review. Chem. exchange satn. transfer (CEST) imaging is a relatively new magnetic resonance imaging contrast approach in which exogenous or endogenous compds. contg. either exchangeable protons or exchangeable mols. are selectively satd. and after transfer of this satn., detected indirectly through the water signal with enhanced sensitivity. The focus of this review is on basic magnetic resonance principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast. In CEST magnetic resonance imaging, transfer of magnetization is studied in mobile compds. instead of semisolids. Similar to magnetization transfer contrast, CEST has contributions of both chem. exchange and dipolar cross-relaxation, but the latter can often be neglected if exchange is fast. Contrary to magnetization transfer contrast, CEST imaging requires sufficiently slow exchange on the magnetic resonance time scale to allow selective irradn. of the protons of interest. As a consequence, magnetic labeling is not limited to radio-frequency satn. but can be expanded with slower frequency-selective approaches such as inversion, gradient dephasing and frequency labeling. The basic theory, design criteria, and exptl. issues for exchange transfer imaging are discussed. A new classification for CEST agents based on exchange type is proposed. The potential of this young field is discussed, esp. with respect to in vivo application and translation to humans.
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    Lokesh, N.; Seegerer, A.; Hioe, J.; Gschwind, R. M. Chemical Exchange Saturation Transfer in Chemical Reactions: A Mechanistic Tool for NMR Detection and Characterization of Transient Intermediates. J. Am. Chem. Soc. 2018, 140 (5), 1855– 1862,  DOI: 10.1021/jacs.7b12343
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    Chemical Exchange Saturation Transfer in Chemical Reactions: A Mechanistic Tool for NMR Detection and Characterization of Transient Intermediates
    Lokesh, N.; Seegerer, Andreas; Hioe, Johnny; Gschwind, Ruth M.
    Journal of the American Chemical Society (2018), 140 (5), 1855-1862CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The low sensitivity of NMR and transient key intermediates below detection limit are the central problems studying reaction mechanisms by NMR. Sensitivity can be enhanced by hyperpolarization techniques such as dynamic nuclear polarization or the incorporation/interaction of special hyperpolarized mols. However, all of these techniques require special equipment, are restricted to selective reactions, or undesirably influence the reaction pathways. Here, we apply the chem. exchange satn. transfer (CEST) technique for the first time to NMR detect and characterize previously unobserved transient reaction intermediates in organocatalysis. The higher sensitivity of CEST and chem. equil. present in the reaction pathway are exploited to access population and kinetics information on low populated intermediates. The potential of the method is demonstrated on the proline-catalyzed enamine formation for unprecedented in situ detection of a DPU stabilized zwitterionic iminium species, the elusive key intermediate between enamine and oxazolidinones. The quant. anal. of CEST data at 250 K revealed the population ratio of [Z-iminium]/[exo-oxazolidinone] 0.02, relative free energy +8.1 kJ/mol (calcd. +7.3 kJ/mol), and free energy barrier of +45.9 kJ/mol (ΔG⧺calc.(268 K) = +42.2 kJ/mol) for Z-iminium → exo-oxazolidinone. The findings underpin the iminium ion participation in enamine formation pathway corroborating our earlier theor. prediction and help in better understanding. The reliability of CEST is validated using 1D EXSY-build-up techniques at low temp. (213 K). The CEST method thus serves as a new tool for mechanistic investigations in organocatalysis to access key information, such as chem. shifts, populations, and reaction kinetics of intermediates below the std. NMR detection limit.
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    Serianni, A. S.; Pierce, J.; Huang, S. G.; Barker, R. Anomerization of furanose sugars: kinetics of ring-opening reactions by proton and carbon-13 saturation-transfer NMR spectroscopy. J. Am. Chem. Soc. 1982, 104 (15), 4037– 4044,  DOI: 10.1021/ja00379a001
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    Anomerization of furanose sugars: kinetics of ring-opening reactions by proton and carbon-13 saturation-transfer NMR spectroscopy
    Serianni, Anthony S.; Pierce, John; Huang, Shaw Guang; Barker, Robert
    Journal of the American Chemical Society (1982), 104 (15), 4037-44CODEN: JACSAT; ISSN:0002-7863.
    With the tetroses D-threose and D-erythrose, kinetic and thermodn. parameters for the interconversion of α- and β-furanoses and the acyclic hydrate with the intermediate aldehyde form have been obtained from 1H and 13C NMR measurements. Unidirectional rate consts. for the various equil. involving the aldehyde have been detd., and from them the overall rate consts. for interconversion of the abundant species.
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    Woods, M.; Woessner, D. E.; Sherry, A. D. Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. Chem. Soc. Rev. 2006, 35 (6), 500– 511,  DOI: 10.1039/b509907m
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    Paramagnetic lanthanide complexes as PARACEST agents for medical imaging
    Woods, Mark; Woessner, Donald E.; Sherry, A. Dean
    Chemical Society Reviews (2006), 35 (6), 500-511CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chem. shift satn. transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiol. or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chem. shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.
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    Walvoort, M. T. C.; Lodder, G.; Mazurek, J.; Overkleeft, H. S.; Codée, J. D. C.; Van der marel, G. A. Equatorial Anomeric Triflates from Mannuronic Acid Esters. J. Am. Chem. Soc. 2009, 131 (34), 12080– 12081,  DOI: 10.1021/ja905008p
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    Equatorial Anomeric Triflates from Mannuronic Acid Esters
    Walvoort, Marthe T. C.; Lodder, Gerrit; Mazurek, Jaroslaw; Overkleeft, Herman S.; Codee, Jeroen D. C.; van der Marel, Gijsbert A.
    Journal of the American Chemical Society (2009), 131 (34), 12080-12081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Activation of mannuronic acid esters leads to a conformational mixt. of α-anomeric triflates, in which the equatorial triflate (1C4 chair) is formed preferentially. This unexpected intermediate clearly opposes the anomeric effect and is mainly stabilized by the electron-withdrawing carboxylate function at C-5. Because the anomeric center carries a significant pos. charge, the 1C4 mannopyranosyl chair approximates the favored 3H4 half-chair oxacarbenium ion conformation. The excellent β-selectivity in glycosylations of mannuronates is postulated to originate from the cooperative action of the triflate counterion and the (stereo)electronic effects governing oxacarbenium ion stabilization in the transition state leading to the 1,2-cis product.
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    Highly Diastereoselective α-Mannopyranosylation in the Absence of Participating Protecting Groups
    Crich, David; Cai, Weiling; Dai, Zongmin
    Journal of Organic Chemistry (2000), 65 (5), 1291-1297CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    S-Ph 2,6-di-O-benzyl-3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-1-thia-α-D-mannopyranoside and its sulfoxide, following activation at -78 °C with benzenesulfenyl triflate or triflic anhydride, resp., provide the corresponding α-mannosyl triflate as demonstrated by NMR spectroscopy. On addn. of an acceptor alc. α-mannosides are then formed. Similarly, S-Ph 2,3-O-carbonyl-4,6-O-benzylidene-1-thia-α-D-mannopyranoside and Et 3-O-benzoyl-4,6-O-benzylidene-2-O-(tert-butyldimethylsilyl)-1-thia-α-D-mannopyranoside both provide α-mannosides on activation with benzenesulfenyl triflate followed by addn. of an alc. These results stand in direct contrast to the highly β-selective couplings of comparable glycosylations with 2,3-di-O-benzyl-4,6-O-benzylidene protected mannosyl donors and draw attention to the subtle interplay of reactivity and structure in carbohydrate chem.
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  1. Vanessa A. Jones, Gideon Q. Bennett, Jennifer R. Pierre-Louis, Clay S. Bennett. Development of a Cryogenic Flow Reactor to Optimize Glycosylation Reactions Based on the Active Donor Intermediate. Organic Process Research & Development 2024, 28 (7) , 2819-2826. https://doi.org/10.1021/acs.oprd.4c00140
  2. Wouter A. Remmerswaal, Hidde Elferink, Kas J. Houthuijs, Thomas Hansen, Floor ter Braak, Giel Berden, Stefan van der Vorm, Jonathan Martens, Jos Oomens, Gijsbert A. van der Marel, Thomas J. Boltje, Jeroen D. C. Codée. Anomeric Triflates versus Dioxanium Ions: Different Product-Forming Intermediates from 3-Acyl Benzylidene Mannosyl and Glucosyl Donors. The Journal of Organic Chemistry 2024, 89 (3) , 1618-1625. https://doi.org/10.1021/acs.joc.3c02262
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  • Abstract

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    Figure 1

    Figure 1. (A) Glycosylation reaction intermediates and their characteristic resonances monitored by exchange NMR. (B) Glycosyl donors used in this study.

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    Figure 2

    Figure 2. (A) Working principle behind 19F EXSY NMR to monitor triflate dissociation. The α-glycosyl triflate is selectively excited and then observed over time to transform into free triflate. (B) Determination of the initial rate of triflate dissociation. (C) Summary of normalized triflate dissociation rates (s–1) across the studied glycoside series as a function of temperature.

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    Figure 3

    Figure 3. (A) SN1 and SN2-like triflate dissociation mechanisms. (B) Reaction order determination for triflate dissociation in the mannose series and (C) glucose series.

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    Figure 4

    Figure 4. (A) Mechanism of 13C CEST NMR to detect neighboring group participation. (B–E) CEST profiles for 13C-labeled C-3 acyl-protected mannosyl and glucosyl donors. (F) Characterization of the mannosyl dioxanium ion using HMBC and COSY.

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    Figure 5

    Figure 5. (A) Mechanism of 1H CEST NMR to detect β-glycosyl triflates. (B–I) 1H CEST profiles for 7αOTf–14αOTf..

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    Figure 6

    Figure 6. Characterization of β-glycosyl triflate 14 using HSQC without 13C decoupling in order to measure 1JC1–H1 and 3JH1–H2.

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    Figure 7

    Figure 7. Spectroscopic summary of mannosyl intermediates.

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    Figure 8

    Figure 8. Spectroscopic summary of glucosyl intermediates.

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      Hettikankanamalage, A. A.; Lassfolk, R.; Ekholm, F. S.; Leino, R.; Crich, D. Mechanisms of Stereodirecting Participation and Ester Migration from Near and Far in Glycosylation and Related Reactions. Chem. Rev. 2020, 120 (15), 7104– 7151,  DOI: 10.1021/acs.chemrev.0c00243
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      Mechanisms of stereodirecting participation and ester migration from Near and Far in glycosylation and related reactions
      Hettikankanamalage, Asiri A.; Lassfolk, Robert; Ekholm, Filip S.; Leino, Reko; Crich, David
      Chemical Reviews (Washington, DC, United States) (2020), 120 (15), 7104-7151CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review is the counterpart of a 2018 Chem. Reviews article that examd. the mechanisms of chem. glycosylation in the absence of stereodirecting participation. Attention is now turned to a crit. review of the evidence in support of stereodirecting participation in glycosylation reactions by esters from either the vicinal or more remote positions. As participation by esters is often accompanied by ester migration, the mechanism(s) of migration are also reviewed. Esters are central to the entire review, which accordingly opens with an overview of their structure and their influence on the conformations of six-membered rings. Next the structure and relative energetics of dioxacarbeniun ions are covered with emphasis on the influence of ring size. The existing kinetic evidence for participation is then presented followed by an overview of the various intermediates either isolated or characterized spectroscopically. The evidence supporting participation from remote or distal positions is critically examd., and alternative hypotheses for the stereodirecting effect of such esters are presented. The mechanisms of ester migration are first examd. from the perspective of glycosylation reactions and then more broadly in the context of partially acylated polyols.
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      Crich, D.; Hu, T.; Cai, F. Does neighboring group participation by non-vicinal esters play a role in glycosylation reactions? Effective probes for the detection of bridging intermediates. Journal of organic chemistry 2008, 73 (22), 8942– 8953,  DOI: 10.1021/jo801630m
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      Does Neighboring Group Participation by Non-Vicinal Esters Play a Role in Glycosylation Reactions? Effective Probes for the Detection of Bridging Intermediates
      Crich, David; Hu, Tianshun; Cai, Feng
      Journal of Organic Chemistry (2008), 73 (22), 8942-8953CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Neighboring group participation in glycopyranosylation reactions is probed for esters at the 3-O-axial and -equatorial, 4-O-axial and -equatorial, and 6-O-sites of a range of donors through the use tert-butoxycarbonyl esters. The anticipated intermediate cyclic dioxanyl cation is interrupted for the axial 3-O-deriv., leading to the formation of a 1,3-O-cyclic carbonate ester, with loss of a tert-Bu cation, providing convincing evidence of participation by esters at that position. However, no evidence was found for such a fragmentation of carbonate esters at the 3-O-equatorial, 4-O-axial and -equatorial, and 6-O positions, indicating that neighboring group participation from those sites does not occur under typical glycosylation conditions. Further probes employing a 4-O-(2-carboxy)benzoate ester and a 4-O-(4-methoxybenzoate) ester, the latter in conjunction with an 18O quench designed to detect bridging intermediates, also failed to provide evidence for participation by 4-O-esters in galactopyranosylation.
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      Baek, J. Y.; Lee, B.-Y.; Jo, M. G.; Kim, K. S. β-Directing Effect of Electron-Withdrawing Groups at O-3, O-4, and O-6 Positions and α-Directing Effect by Remote Participation of 3-O-Acyl and 6-O-Acetyl Groups of Donors in Mannopyranosylations. J. Am. Chem. Soc. 2009, 131 (48), 17705– 17713,  DOI: 10.1021/ja907252u
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      β-Directing Effect of Electron-Withdrawing Groups at O-3, O-4, and O-6 Positions and α-Directing Effect by Remote Participation of 3-O-Acyl and 6-O-Acetyl Groups of Donors in Mannopyranosylations
      Baek, Ju Yuel; Lee, Bo-Young; Jo, Myung Gi; Kim, Kwan Soo
      Journal of the American Chemical Society (2009), 131 (48), 17705-17713CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Mannosylations of various acceptors with donors possessing an electron-withdrawing o-trifluoromethylbenzenesulfonyl, benzylsulfonyl, p-nitrobenzoyl, benzoyl, or acetyl group at O-3, O-4, or O-6 positions were found to be β-selective except when donors had 3-O-acyl and 6-O-acetyl groups, which afforded α-mannosides as major products. The α-directing effect of 3-O-acyl and 6-O-acetyl groups was attributed to their remote participation, and the isolation of a stable bicyclic trichlorooxazine ring resulting from the intramol. trapping of the anomeric oxocarbenium ion by 3-O-trichloroacetimidoyl group provided evidence for this remote participation. The triflate anion, counteranion of the mannosyl oxocarbenium ion, was essential for the β-selectivity, and covalent α-mannosyl triflates with an electron-withdrawing group at O-3, O-4, or O-6 were detected by low-temp. NMR. The strongly electron-withdrawing sulfonyl groups, which exhibited a higher β-directing effect in the mannosylation, made the α-mannosyl triflates more stable than the weakly electron-withdrawing acyl groups. We therefore proposed the mechanism for the β-mannosylation and the origin of the β-directing effect: the electron-withdrawing groups would stabilize the α-mannosyl triflate intermediate, and the subsequent reaction of the α-triflate (or its contact ion pair) with the acceptor would afford the β-mannoside. The β-selective mannosylation of a sterically demanding acceptor was achieved by employing a donor possessing two strongly electron-withdrawing benzylsulfonyl groups at O-4 and O-6 positions.
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      Lei, J.-C.; Ruan, Y.-X.; Luo, S.; Yang, J.-S. Stereodirecting Effect of C3-Ester Groups on the Glycosylation Stereochemistry of L-Rhamnopyranose Thioglycoside Donors: Stereoselective Synthesis of α- and β-L-Rhamnopyranosides. Eur. J. Org. Chem. 2019, 2019 (37), 6377– 6382,  DOI: 10.1002/ejoc.201901186
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      Stereodirecting Effect of C3-Ester Groups on the Glycosylation Stereochemistry of L-Rhamnopyranose Thioglycoside Donors: Stereoselective Synthesis of α- and β-L-Rhamnopyranosides
      Lei, Jin-Cai; Ruan, Yu-Xiong; Luo, Sheng; Yang, Jin-Song
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      The tuning effect of C3-ester groups on the glycosylation stereochem. of L-rhamnopyranose (L-Rha) Et thioglycoside donors is described. On one hand, the L-Rha thioglycoside donors carrying 3-O-arylcarbonyl or levulinoyl group undergo highly α-selective glycosylation to afford a wide variety of α-L-rhamnoside products in high chem. yields. On the other hand, the glycosylation of the 3-O-4-nitropicoloyl and 2-pyrazinecarbonyl group substituted L-Rha thioglycosides displays β-stereoselectivity. Only or predominant β anomeric products are obtained when these L-Rha donors couple with the primary or reactive secondary acceptors, while the β-selectivity may decrease significantly when these donors react with less reactive secondary alcs. The synthetic utility of the newly developed α- and β-directing L-Rha donors I and II has been demonstrated by the efficient synthesis of a structurally unique trisaccharide III, which is derived from the cell wall polysaccharide of Sphaerotilus natans.
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      Demchenko, A. V.; Rousson, E.; Boons, G.-J. Stereoselective 1,2-cis-galactosylation assisted by remote neighboring group participation and solvent effects. Tetrahedron Lett. 1999, 40 (36), 6523– 6526,  DOI: 10.1016/S0040-4039(99)01203-4
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      Stereoselective 1,2-cis-galactosylation assisted by remote neighboring group participation and solvent effects
      Demchenko, Alexei V.; Rousson, Emmanuel; Boons, Geert-Jan
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      Iodonium-ion promoted glycosylations in 1,4-dioxane/toluene with galactosyl donors having an electron-donating neighboring group participating functionality at C-4 give exceptional high α-anomeric selectivities.
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      Baek, J. Y.; Kwon, H.-W.; Myung, S. J.; Park, J. J.; Kim, M. Y.; Rathwell, D. C. K.; Jeon, H. B.; Seeberger, P. H.; Kim, K. S. Directing effect by remote electron-withdrawing protecting groups at O-3 or O-4 position of donors in glucosylations and galactosylations. Tetrahedron 2015, 71 (33), 5315– 5320,  DOI: 10.1016/j.tet.2015.06.014
      9
      Directing effect by remote electron-withdrawing protecting groups at O-3 or O-4 position of donors in glucosylations and galactosylations
      Baek, Ju Yuel; Kwon, Hea-Won; Myung, Se Jin; Park, Jung Jun; Kim, Mi Young; Rathwell, Dominea C. K.; Jeon, Heung Bae; Seeberger, Peter H.; Kim, Kwan Soo
      Tetrahedron (2015), 71 (33), 5315-5320CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      Glucosylations and galactosylations of various acceptors with donors possessing an electron-withdrawing benzylsulfonyl, benzoyl, or acetyl group at the O-3 or O-4 position were performed. A β-directing effect by the benzylsulfonyl group at O-3 of the glucosyl donors and by the benzylsulfonyl and acyl groups at O-4 of the glucosyl donors was obsd. In contrast, acyl groups at O-3 of the glucosyl donors and acyl groups at O-3 and O-4 of the galactosyl donors exhibited an α-directing effect. The α-directing effect is partly considered to remote participation of the acyl groups, whereas the β-directing effect is somewhat attributed to the SN2-like reaction of the acceptor with the glycosyl triflate or the contact ion pair, which is stabilized by remote electron-withdrawing groups. Further evidence for the stability of the α-glycosyl triflates was detd. by a low-temp. NMR study.
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      Ayala, L.; Lucero, C. G.; Romero, J. A.; Tabacco, S. A.; Woerpel, K. A. Stereochemistry of nucleophilic substitution reactions depending upon substituent: evidence for electrostatic stabilization of pseudoaxial conformers of oxocarbenium ions by heteroatom substituents. J. Am. Chem. Soc. 2003, 125 (50), 15521– 8,  DOI: 10.1021/ja037935a
      10
      Stereochemistry of Nucleophilic Substitution Reactions Depending upon Substituent: Evidence for Electrostatic Stabilization of Pseudoaxial Conformers of Oxocarbenium Ions by Heteroatom Substituents
      Ayala, Leticia; Lucero, Claudia G.; Romero, Jan Antoinette C.; Tabacco, Sarah A.; Woerpel, K. A.
      Journal of the American Chemical Society (2003), 125 (50), 15521-15528CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This anal. is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-Bu group at C-2 was high 1,2-trans selectivity obsd. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.
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      Ma, Y.; Lian, G.; Li, Y.; Yu, B. Identification of 3,6-di-O-acetyl-1,2,4-O-orthoacetyl-α-d-glucopyranose as a direct evidence for the 4-O-acyl group participation in glycosylation. Chem. Commun. 2011, 47 (26), 7515– 7517,  DOI: 10.1039/c1cc11680k
      11
      Identification of 3,6-di-O-acetyl-1,2,4-O-ortho-acetyl-α-D-glucopyranose as a direct evidence for the 4-O-acyl group participation in glycosylation
      Ma, Yuyong; Lian, Gaoyan; Li, Yao; Yu, Biao
      Chemical Communications (Cambridge, United Kingdom) (2011), 47 (26), 7515-7517CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The formation of 3,6-di-O-acetyl-1,2,4-O-ortho-acetyl-α-D-glucopyranose was obsd. in the gold(I)-catalyzed glycosylation of peracetyl glucopyranosyl ortho-hexynyl-benzoate; expts. with substrates bearing deuterium labeled 2-O-acetyl or 4-O-acetyl groups indicated that the orthoacetate was derived from the 4-O-acetyl group, which provided a direct evidence for the remote participation of the 4-O-acyl group in glycosylation.
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      Komarova, B. S.; Orekhova, M. V.; Tsvetkov, Y. E.; Nifantiev, N. E. Is an acyl group at O-3 in glucosyl donors able to control α-stereoselectivity of glycosylation? The role of conformational mobility and the protecting group at O-6. Carbohydr. Res. 2014, 384, 70– 86,  DOI: 10.1016/j.carres.2013.11.016
      12
      Is an acyl group at O-3 in glucosyl donors able to control α-stereoselectivity of glycosylation? The role of conformational mobility and the protecting group at O-6
      Komarova, Bozhena S.; Orekhova, Maria V.; Tsvetkov, Yury E.; Nifantiev, Nikolay E.
      Carbohydrate Research (2014), 384 (), 70-86CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
      The stereodirecting effect of a 3-O-acetyl protecting group, which is potentially capable of the remote anchimeric participation, and other protecting groups in 2-O-benzyl glucosyl donors with flexible and rigid conformations has been investigated. To this aim, an array of N-phenyltrifluoroacetimidoyl and sulfoxide donors bearing either 3-O-acetyl or 3-O-benzyl groups in combination with 4,6-di-O-benzyl, 6-O-acyl-4-O-benzyl, or 4,6-O-benzylidene protecting groups was prepd. The conformationally flexible 3-O-acetylated glucosyl donor protected at other positions with O-benzyl groups demonstrated very low or no α-stereoselectivity upon glycosylation of primary or secondary acceptors. On the contrary, 3,6-di-O-acylated glucosyl donors proved to be highly α-stereoselective as well as the donor having a single potentially participating acetyl group at O-6. The 3,6-di-O-acylated donor was shown to be the best α-glucosylating block for the primary acceptor, whereas the best α-selectivity of glycosylation of the secondary acceptor was achieved with the 6-O-acylated donor. Glycosylation of the secondary acceptor with the conformationally constrained 3-O-acetyl-4,6-O-benzylidene-protected donor displayed under std. conditions (-35 °) even lower α-selectivity as compared to the 3-O-benzyl analog. However, increasing the reaction temp. essentially raised the α-stereoselectivities of glycosylation with both 3-O-acetyl and 3-O-benzyl donors and made them almost equal. The stereodirecting effects of protecting groups obsd. for N-phenyltrifluoroacetimidoyl donors were also generally proven for sulfoxide donors.
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    13. 13
      Dejter-juszynski, M.; Flowers, H. M. Studies on the koenigs-knorr reaction: Part IV: The effect of participating groups on the stereochemistry of disaccharide formation. Carbohydr. Res. 1973, 28 (1), 61– 74,  DOI: 10.1016/S0008-6215(00)82857-8
      13
      Koenigs-Knorr reaction. IV. Effect of participating groups on the stereochemistry of disaccharide formation
      Dejter-Juszynski, Marta; Flowers, Harold M.
      Carbohydrate Research (1973), 28 (1), 61-74CODEN: CRBRAT; ISSN:0008-6215.
      Partial benzylation of Me 2-O-benzyl-α-L-fucopyranoside gave a mixt. of Me 2,3-, and 2,4-di-O-benzyl-α-L-fucopyranoside which were sepd. by means of their monoacetates. Partial benzylation of Me α-L-fucopyranoside gave the 2,4-, and 3,4-di-O-benzyl ethers in the ratio of 3:2. The structures of the ethers were detd. by NMR anal. of their acetates, and by methylation, debenzylidenation, and characterization of the Me ethers of the Me glycosides. Acid hydrolysis of these compds. gave two known monomethyl ethers ofL-fucose and 4-O-methyl-L-fucose, a new compd. Selective p-nitrobenzoylation of 2,3-, 2,4-, and 3,4-di-O-benzyl-L-fucose, followed by acetylation and treatment with HBr in CH2Cl2, gave the three possible mono-O-acetyl-di-O-benzyl-α-L-fucopyranosyl bromides, which were condensed with benzyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-α-D-glucopyranoside. The disaccharide derived from the 2-O-acetyl substituted bromide was enriched in β-L-fucopyranoside, whereas the other two bromides gave the α-L-linked anomer. Participation of acyl groups and electronic-steric influences were discussed as possible explanations for the steric course of the reaction.
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    14. 14
      Mcmillan, T. F.; Crich, D. Influence of 3-Thio Substituents on Benzylidene-Directed Mannosylation. Isolation of a Bridged Pyridinium Ion and Effects of 3-O-Picolyl and 3-S-Picolyl Esters. Eur. J. Org. Chem. 2022, 2022 (20), e202200320  DOI: 10.1002/ejoc.202200320
      14
      Influence of 3-Thio Substituents on Benzylidene-Directed Mannosylation. Isolation of a Bridged Pyridinium Ion and Effects of 3-O-Picolyl and 3-S-Picolyl Esters
      McMillan, Timothy F.; Crich, David
      European Journal of Organic Chemistry (2022), 2022 (20), e202200320CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The influence on glycosyl selectivity of substituting oxygen for sulfur at the 3-position of 4,6-O-benzylidene-protected mannopyranosyl thioglycosides is reported and varies considerably according to the protecting group employed at the 3-position. The substitution of a thioether at the 3-position for the more usual 3-O-benzyl ether results in a significant loss of selectivity. The installation of a 3-S-picolinyl thioether results in a complex reaction mixt., from which a stable seven-membered bridged bicyclic pyridinium ion is isolated, while the corresponding 3-O-picolinyl ether affords a highly α-selective coupling reaction. A 3-O-picolyl ester provides excellent β-selectivity, while the analogous 3-S-picolyl thioester gives a highly α-selective reaction. The best β-selectivity is seen with a 3-deoxy-3-(2-pyridinyldisulfanyl) system. These observations are discussed in terms of the influence of the various substituents on the central glycosyl triflate - ion pair equil.
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    15. 15
      Elferink, H.; Remmerswaal, W. A.; Houthuijs, K. J.; Jansen, O.; Hansen, T.; Rijs, A. M.; Berden, G.; Martens, J.; Oomens, J.; Codée, J. D. C.; Boltje, T. J. Competing C-4 and C-5-Acyl Stabilization of Uronic Acid Glycosyl Cations. Chem. – Eur. J. 2022, 28 (63), e202201724  DOI: 10.1002/chem.202201724
      15
      Competing C-4 and C-5-Acyl Stabilization of Uronic Acid Glycosyl Cations
      Elferink, Hidde; Remmerswaal, Wouter A.; Houthuijs, Kas J.; Jansen, Oscar; Hansen, Thomas; Rijs, Anouk M.; Berden, Giel; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.; Boltje, Thomas J.
      Chemistry - A European Journal (2022), 28 (63), e202201724CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramol. stabilization of uronic acid cations by the C-5 carboxylic acid or the C-4 acetyl group was studied with IR ion spectroscopy (IRIS). IRIS reveals that a mixt. of bridged ions is formed, in which the mixt. is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population anal. and interconversion barrier computations show that the two bridged structures are not in dynamic equil. and that their ratio parallels the d. functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products.
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    16. 16
      Remmerswaal, W. A.; Houthuijs, K. J.; Van de ven, R.; Elferink, H.; Hansen, T.; Berden, G.; Overkleeft, H. S.; Van der marel, G. A.; Rutjes, F. P. J. T.; Filippov, D. V.; Boltje, T. J.; Martens, J.; Oomens, J.; Codée, J. D. C. Stabilization of Glucosyl Dioxolenium Ions by “Dual Participation” of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation. Journal of Organic Chemistry 2022, 87 (14), 9139– 9147,  DOI: 10.1021/acs.joc.2c00808
      16
      Stabilization of Glucosyl Dioxolenium Ions by "Dual Participation" of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation
      Remmerswaal, Wouter A.; Houthuijs, Kas J.; van de Ven, Roel; Elferink, Hidde; Hansen, Thomas; Berden, Giel; Overkleeft, Herman S.; van der Marel, Gijsbert A.; Rutjes, Floris P. J. T.; Filippov, Dmitri V.; Boltje, Thomas J.; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.
      Journal of Organic Chemistry (2022), 87 (14), 9139-9147CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The stereoselective introduction of glycosidic bonds is of paramount importance to oligosaccharide synthesis. Among the various chem. strategies to steer stereoselectivity, participation by either neighboring or distal acyl groups is used particularly often. Recently, the use of the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection group was shown to offer enhanced stereoselective steering compared to other acyl groups. Here, we investigate the origin of the stereoselectivity induced by the DMNPA group through systematic glycosylation reactions and IR ion spectroscopy (IRIS) combined with techniques such as isotopic labeling of the anomeric center and isomer population anal. Our study indicates that the origin of the DMNPA stereoselectivity does not lie in the direct participation of the nitro moiety but in the formation of a dioxolenium ion that is strongly stabilized by the nitro group.
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    17. 17
      De kleijne, F. F. J.; Elferink, H.; Moons, S. J.; White, P. B.; Boltje, T. J. Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy. Angew. Chem., Int. Ed. 2022, 61 (6), e202109874  DOI: 10.1002/anie.202109874
      17
      Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy
      de Kleijne, Frank F. J.; Elferink, Hidde; Moons, Sam J.; White, Paul B.; Boltje, Thomas J.
      Angewandte Chemie, International Edition (2022), 61 (6), e202109874CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low-populated, rapidly equilibrating mannosyl dioxanium ions that arise from participation of a C-3 acyl group using chem. exchange satn. transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α-selective couplings were obsd. suggesting glycosylation took place via this elusive intermediate.
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    18. 18
      Hansen, T.; Elferink, H.; Van hengst, J. M. A.; Houthuijs, K. J.; Remmerswaal, W. A.; Kromm, A.; Berden, G.; Van der vorm, S.; Rijs, A. M.; Overkleeft, H. S.; Filippov, D. V.; Rutjes, F. P. J. T.; Van der marel, G. A.; Martens, J.; Oomens, J.; Codée, J. D. C.; Boltje, T. J. Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions. Nat. Commun. 2020, 11 (1), 2664,  DOI: 10.1038/s41467-020-16362-x
      18
      Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions
      Hansen, Thomas; Elferink, Hidde; van Hengst, Jacob M. A.; Houthuijs, Kas J.; Remmerswaal, Wouter A.; Kromm, Alexandra; Berden, Giel; van der Vorm, Stefan; Rijs, Anouk M.; Overkleeft, Hermen S.; Filippov, Dmitri V.; Rutjes, Floris P. J. T.; van der Marel, Gijsbert A.; Martens, Jonathan; Oomens, Jos; Codee, Jeroen D. C.; Boltje, Thomas J.
      Nature Communications (2020), 11 (1), 2664CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: Controlling the chem. glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general soln. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using IR ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochem. outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biol. research.
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    19. 19
      Elferink, H.; Mensink, R. A.; Castelijns, W. W. A.; Jansen, O.; Bruekers, J. P. J.; Martens, J.; Oomens, J.; Rijs, A. M.; Boltje, T. J. The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones. Angew. Chem., Int. Ed. 2019, 58 (26), 8746– 8751,  DOI: 10.1002/anie.201902507
      19
      The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones
      Elferink, Hidde; Mensink, Rens A.; Castelijns, Wilke W. A.; Jansen, Oscar; Bruekers, Jeroen P. J.; Martens, Jonathan; Oomens, Jos; Rijs, Anouk M.; Boltje, Thomas J.
      Angewandte Chemie, International Edition (2019), 58 (26), 8746-8751CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Uronic acids are important constituents of polysaccharides found on the cell membranes of different organisms. To prep. uronic-acid-contg. oligosaccharides, uronic acid 6,3-lactones can be employed as they display a fixed conformation and a unique reactivity and stereoselectivity. Herein, we report a highly β-selective and efficient mannosyl donor based on C-4 acetyl mannuronic acid 6,3-lactone donors. The mechanism of glycosylation is established using a combination of techniques, including IR ion spectroscopy combined with quantum-chem. calcns. and variable-temp. NMR (VT NMR) spectroscopy. The role of these intermediates in glycosylation is assayed by varying the activation protocol and acceptor nucleophilicity. The obsd. trends are analogous to the well-studied 4,6-benzylidene glycosides and may be used to guide the development of next-generation stereoselective glycosyl donors.
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    20. 20
      Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. Halide ion catalyzed glycosidation reactions. Syntheses of.alpha.-linked disaccharides. J. Am. Chem. Soc. 1975, 97 (14), 4056– 4062,  DOI: 10.1021/ja00847a032
      20
      Halide ion catalyzed glycosidation reactions. Syntheses of α-linked disaccharides
      Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K.
      Journal of the American Chemical Society (1975), 97 (14), 4056-62CODEN: JACSAT; ISSN:0002-7863.
      Eight α-linked disaccharides were synthesized in 90% yield and in a highly stereoselective manner by reaction of per-O-benzyl-α-glycopyraaosyl bromides of the D-gluco, D-galacto, and L-galacto(L-fuco) configurations with suitably protected derivs. of D-glucose and D-galactose in the presence of Et4NBr. The main characteristics of the halide ion catalyzed reaction were established by studies of the reactions of tetra-O-benzyl-α-D-glucopyranosyl chloride and bromide with simple alcs. The more rapid route provided by the β-glycosyl halide is attributed to the stereoelectronic requirement of an antiparallel orientation of a ring-oxygen lone pair of electrons in both bond breaking and bond making at the anomeric center.
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    21. 21
      Lu, S.-R.; Lai, Y.-H.; Chen, J.-H.; Liu, C.-Y.; Mong, K.-K. T. Dimethylformamide: An Unusual Glycosylation Modulator. Angew. Chem., Int. Ed. 2011, 50 (32), 7315– 7320,  DOI: 10.1002/anie.201100076
      21
      Dimethylformamide: An Unusual Glycosylation Modulator
      Lu, Shao-Ru; Lai, Yen-Hsun; Chen, Jiun-Han; Liu, Chih-Yueh; Mong, Kwok-Kong Tony
      Angewandte Chemie, International Edition (2011), 50 (32), 7315-7320, S7315/1-S7315/125CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      When N,N-dimethylformamide was used to direct the stereochem. course of glycosylation reactions, 1,2-cis glycosylation products were formed with excellent selectivity. A straightforward highly α-stereoselective glycosylation involving preactivation should find broad application and be esp. useful for sequential glycosylation reactions to form oligosaccharides.
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    22. 22
      Crich, D.; Sun, S. Are Glycosyl Triflates Intermediates in the Sulfoxide Glycosylation Method? A Chemical and 1H, 13C, and 19F NMR Spectroscopic Investigation. J. Am. Chem. Soc. 1997, 119 (46), 11217– 11223,  DOI: 10.1021/ja971239r
      22
      Are Glycosyl Triflates Intermediates in the Sulfoxide Glycosylation Method? A Chemical and 1H, 13C, and 19F NMR Spectroscopic Investigation
      Crich, David; Sun, Sanxing
      Journal of the American Chemical Society (1997), 119 (46), 11217-11223CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The title question is addressed by low-temp. 1H, 13C, and 19F NMR spectroscopies in CD2Cl2 as well as by the prepn. of authentic samples from glycopyranosyl bromides and AgOTf. At -78 °C glycosyl triflates are cleanly generated with either non-participating or participating protecting groups at O-2. The glycosyl triflates identified in this manner were allowed to react with methanol, resulting in the formation of Me glycosides. Glycosyl triflates were generated at -78 °C in CD2Cl2 and allowed to warm gradually until decompn. was detected by 1H and 19F NMR spectroscopy. The decompn. temp. and products are functions of the protecting groups employed.
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    23. 23
      Santana, A. G.; Montalvillo-jiménez, L.; Díaz-casado, L.; Corzana, F.; Merino, P.; Cañada, F. J.; Jiménez-osés, G.; Jiménez-barbero, J.; Gómez, A. M.; Asensio, J. L. Dissecting the Essential Role of Anomeric β-Triflates in Glycosylation Reactions. J. Am. Chem. Soc. 2020, 142 (28), 12501– 12514,  DOI: 10.1021/jacs.0c05525
      23
      Dissecting the Essential Role of Anomeric β-Triflates in Glycosylation Reactions
      Santana, Andres G.; Montalvillo-Jimenez, Laura; Diaz-Casado, Laura; Corzana, Francisco; Merino, Pedro; Canada, Francisco J.; Jimenez-Oses, Gonzalo; Jimenez-Barbero, Jesus; Gomez, Ana M.; Asensio, Juan Luis
      Journal of the American Chemical Society (2020), 142 (28), 12501-12514CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biol. and chem. interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and β-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be exptl. described, seem to be particularly relevant in α-selective processes, involving weak acceptors. Herein, we report a detailed anal. of several paradigmatic and illustrative examples of such reactions, employing a combination of chem., NMR, kinetic and theor. approaches, culminating in the unprecedented detection and quantification of the true β-glycosyl triflate intermediates within activated donor mixts. This achievement was further employed as a stepping-stone for the characterization of the triflate anomerization dynamics, which along with the acceptor substitutions, govern the stereochem. outcome of the reaction. The obtained data conclusively show that, even for highly dissociative reactions involving β-close ion pair (β-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimol. α → β triflate interconversion, which under certain circumstances becomes the rate-limiting step. Overall, our results rule out the prevalence of the Curtin-Hammett fast-exchange assumption for most glycosylations and highlight the distinct reactivity properties of α- and β-glycosyl triflates against neutral and anionic acceptors.
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    24. 24
      Crich, D.; Chandrasekera, N. S. Mechanism of 4,6-O-Benzylidene-Directed β-Mannosylation as Determined by α-Deuterium Kinetic Isotope Effects. Angew. Chem., Int. Ed. 2004, 43 (40), 5386– 5389,  DOI: 10.1002/anie.200453688
      24
      Mechanism of 4,6-O-benzylidene-directed β-mannosylation as determined by α-deuterium kinetic isotope effects
      Crich, David; Chandrasekera, N. Susantha
      Angewandte Chemie, International Edition (2004), 43 (40), 5386-5389CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Considerable oxacarbenium ion character may be in the transition state of a highly β-selective mannosylation reaction that proceeds via an α-mannosyl triflate. An α-deuterium kinetic isotope effect of 1.2 was measured at -78°C (=1.1 at 25°C). This information may be interpreted in terms of a stereoselective trapping of a transient contact ion pair or, alternatively, as representative of an "exploded" transition state.
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    25. 25
      Hansen, T.; Lebedel, L.; Remmerswaal, W. A.; Van der vorm, S.; Wander, D. P. A.; Somers, M.; Overkleeft, H. S.; Filippov, D. V.; Désiré, J.; Mingot, A.; Bleriot, Y.; Van der marel, G. A.; Thibaudeau, S.; Codée, J. D. C. Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations. ACS Central Science 2019, 5 (5), 781– 788,  DOI: 10.1021/acscentsci.9b00042
      25
      Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations
      Hansen, Thomas; Lebedel, Ludivine; Remmerswaal, Wouter A.; van der Vorm, Stefan; Wander, Dennis P. A.; Somers, Mark; Overkleeft, Herman S.; Filippov, Dmitri V.; Desire, Jerome; Mingot, Agnes; Bleriot, Yves; van der Marel, Gijsbert A.; Thibaudeau, Sebastien; Codee, Jeroen D. C.
      ACS Central Science (2019), 5 (5), 781-788CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      The broad application of well-defined synthetic oligosaccharides in glycobiol. and glycobiotechnol. is largely hampered by the lack of sufficient amts. of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the detn. of clear structure-reactivity-stereoselectivity principles for these species. We report a combined exptl. and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quant. manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodol.
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    26. 26
      Franconetti, A.; Ardá, A.; Asensio, J. L.; Blériot, Y.; Thibaudeau, S.; Jiménez-barbero, J. Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions. Acc. Chem. Res. 2021, 54 (11), 2552– 2564,  DOI: 10.1021/acs.accounts.1c00021
      26
      Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions
      Franconetti, Antonio; Arda, Ana; Asensio, Juan luis; Bleriot, Yves; Thibaudeau, Sebastien; Jimenez-barbero, Jesus
      Accounts of Chemical Research (2021), 54 (11), 2552-2564CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Carbohydrates (glycans, saccharides, sugars) are essential mols. in all domains of life. Research on glycoscience spans from chem. to biomedicine, including material science and biotechnol. The access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is supposed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of these glycosyl cations is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theor. and exptl. approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity. We also highlight that, from a chem. perspective, the glycosylation reaction can be described as a continuum, from unimol. SN1 with naked oxocarbenium cations as intermediates to bimol. SN2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-sepd. ion pairs, solvent-equilibrated ion pairs) with bimol. features in most reactions is also highlighted. The role of theor. calcns. to predict the conformation, dynamics and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow the access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under SN1-like conditions. Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterizing the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid soln. by NMR spectroscopy. We also pay special attention to the reactivity of these glycosyl ions that depends on the conditions, including the counterions, the possible intra- or intermol. participation of functional groups that may stabilize the cation and the chem. nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different exptl. perspectives, which identified the involved ionic intermediates, estg. their lifetimes and reactivities and studying their interactions with other mols. In this context, we also emphasize the relationship between the chem. methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of mols. that regulate the stability and reactivity of glycosyl cations.
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    27. 27
      Huang, M.; Retailleau, P.; Bohé, L.; Crich, D. Cation Clock Permits Distinction Between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series: Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion. J. Am. Chem. Soc. 2012, 134 (36), 14746– 14749,  DOI: 10.1021/ja307266n
      27
      Cation Clock Permits Distinction Between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series: Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion
      Huang, Min; Retailleau, Pascal; Bohe, Luis; Crich, David
      Journal of the American Chemical Society (2012), 134 (36), 14746-14749CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The use of a cationic cyclization reaction as a probe of the glycosylation mechanism has been developed and applied to the 4,6-O-benzylidene-protected mannopyranoside system. Cyclization results in the formation of both cis- and trans-fused tricyclic systems, invoking an intermediate glycosyl oxocarbenium ion reacting through a boat conformation. Competition reactions with isopropanol and trimethyl(methallyl)silane are interpreted as indicating that β-O-mannosylation proceeds via an associative SN2-like mechanism, whereas α-O-mannosylation and β-C-mannosylation are dissociative and SN1-like. Relative rate consts. for reactions going via a common intermediate can be estd.
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    28. 28
      Chatterjee, S.; Moon, S.; Hentschel, F.; Gilmore, K.; Seeberger, P. H. An Empirical Understanding of the Glycosylation Reaction. J. Am. Chem. Soc. 2018, 140 (38), 11942– 11953,  DOI: 10.1021/jacs.8b04525
      28
      An Empirical Understanding of the Glycosylation Reaction
      Chatterjee, Sourav; Moon, Sooyeon; Hentschel, Felix; Gilmore, Kerry; Seeberger, Peter H.
      Journal of the American Chemical Society (2018), 140 (38), 11942-11953CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Reliable glycosylation reactions that allow for the stereo- and regioselective installation of glycosidic linkages are paramount to the chem. synthesis of glycan chains. The stereoselectivity of glycosylations is exceedingly difficult to control due to the reaction's high degree of sensitivity and its shifting, simultaneous mechanistic pathways that are controlled by variables of unknown degree of influence, dominance, or interdependency. An automated platform was devised to quickly, reproducibly, and systematically screen glycosylations and thereby address this fundamental problem. Thirteen variables were investigated in as isolated a manner as possible, to identify and quantify inherent preferences of electrophilic glycosylating agents (donors) and nucleophiles (glycosyl acceptors). Ways to enhance, suppress, or even override these preferences using judicious environmental conditions were discovered. Glycosylation involving two specific partners can be tuned to produce either 11:1 selectivity of one stereoisomer or 9:1 of the other by merely changing the reaction conditions.
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    29. 29
      Satoh, H.; Hansen, H. S.; Manabe, S.; Van gunsteren, W. F.; Hünenberger, P. H. Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex. J. Chem. Theory Comput. 2010, 6 (6), 1783– 1797,  DOI: 10.1021/ct1001347
      29
      Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex
      Satoh, Hiroko; Hansen, Halvor S.; Manabe, Shino; van Gunsteren, Wilfred F.; Hunenberger, Philippe H.
      Journal of Chemical Theory and Computation (2010), 6 (6), 1783-1797CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      The mechanism of solvent effects on the stereoselectivity of glycosylation reactions is investigated using quantum-mech. (QM) calcns. and mol. dynamics (MD) simulations, considering a methyl-protected glucopyranoside triflate as a glycosyl donor equiv. and the solvents acetonitrile, ether, dioxane, or toluene, as well as gas-phase conditions (vacuum). The QM calcns. on oxacarbenium-solvent complexes do not provide support to the usual solvent-coordination hypothesis, suggesting that an exptl. obsd. β-selectivity (α-selectivity) is caused by the preferential coordination of a solvent mol. to the reactive cation on the α-side (β-side) of the anomeric carbon. Instead, explicit-solvent MD simulations of the oxacarbenium-counterion (triflate ion) complex (along with corresponding QM calcns.) are compatible with an alternative mechanism, termed here the conformer and counterion distribution hypothesis. This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, (1) the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the α or β face, and (2) the preferential coordination of the counterion to the oxacarbenium cation on one side of the anomeric carbon, hindering a nucleophilic attack from this side. For example, in acetonitrile, the calcns. suggest a dominant B2,5 ring conformation of the cation with preferential coordination of the counterion on the α side, both factors leading to the exptl. obsd. β selectivity. Conversely, in dioxane, they suggest a dominant 4H3 ring conformation with preferential counterion coordination on the β side, both factors leading to the exptl. obsd. α selectivity.
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    30. 30
      Crich, D.; Cai, W. Chemistry of 4,6-O-Benzylidene-d-glycopyranosyl Triflates: Contrasting Behavior between the Gluco and Manno Series. Journal of Organic Chemistry 1999, 64 (13), 4926– 4930,  DOI: 10.1021/jo990243d
      30
      Chemistry of 4,6-O-Benzylidene-D-glycopyranosyl Triflates: Contrasting Behavior between the Gluco and Manno Series
      Crich, David; Cai, Weiling
      Journal of Organic Chemistry (1999), 64 (13), 4926-4930CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Activation of either anomer of S-Ph 2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia-D-glucopyranoside with triflic anhydride in dichloromethane at -78 °C in the presence of 2,6-di-tert-butyl-4-methylpyridine affords a highly active glycosylating species which, on addn. of alcs., provides α-glucosides with high selectivity. This selectivity stands in stark contrast to the analogous mannopyranoside series, which affords the β-mannosides with excellent selectivity under the same conditions. Low-temp. NMR expts. support the notion that a glucosyl triflate is formed in the initial activation step. Possible reasons for the diverging stereoselectivity in the gluco and manno series are discussed.
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    31. 31
      Van der vorm, S.; Hansen, T.; Van hengst, J. M. A.; Overkleeft, H. S.; Van der marel, G. A.; Codée, J. D. C. Acceptor reactivity in glycosylation reactions. Chem. Soc. Rev. 2019, 48 (17), 4688– 4706,  DOI: 10.1039/C8CS00369F
      31
      Acceptor reactivity in glycosylation reactions
      van der Vorm, Stefan; Hansen, Thomas; van Hengst, Jacob M. A.; Overkleeft, Herman S.; van der Marel, Gijsbert A.; Codee, Jeroen D. C.
      Chemical Society Reviews (2019), 48 (17), 4688-4706CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      The outcome of a glycosylation reaction critically depends on the reactivity of all reaction partners involved: the donor glycoside (the electrophile), the activator (that generally provides the leaving group on the activated donor species) and the glycosyl acceptor (the nucleophile). The influence of the donor on the outcome of a glycosylation reaction is well appreciated and documented. Differences in donor reactivity have led to the development of chemoselective glycosylation reactions and the reactivity of donor glycosides has been tuned to affect stereoselective glycosylation reactions. The quantification of donor reactivity has enabled the conception of streamlined one-pot glycosylation sequences. In contrast, although it has long been known that the nature and the reactivity of the nucleophile influence the outcome of a glycosylation, the knowledge of acceptor reactivity and insight into the consequences thereof are often circumstantial or anecdotal. This review documents how the reactivity impacts the glycosylation reaction outcome both in terms of chem. yield and stereoselectivity. The effect of acceptor nucleophilicity on the reaction mechanism is described and steric, conformational and electronic influences are outlined. Quant. and computational approaches to comprehend acceptor nucleophilicity are assessed. The increasing insight into the stereoelectronic effects governing glycoside reactivity will eventually enable the conception of effective stereoselective glycosylation methodol. that can be tuned to the reaction partners at hand.
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    32. 32
      Andreana, P. R.; Crich, D. Guidelines for O-Glycoside Formation from First Principles. ACS Central Science 2021, 7 (9), 1454– 1462,  DOI: 10.1021/acscentsci.1c00594
      32
      Guidelines for O-Glycoside Formation from First Principles
      Andreana, Peter R.; Crich, David
      ACS Central Science (2021), 7 (9), 1454-1462CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      The complexity and irreproducibility of glycosylation reactions retard progress in the glyco-sciences. Application of the steady-state hypothesis to transient oxocarbenium ion-counterion pair intermediates reveals the importance of concn., temp., and other factors in glycosylation stereoselectivity. Guidelines are then adduced for the practice of O-glycosylation reactions on the basis of which more reproducible, practical protocols can be established.
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    33. 33
      Crich, D. En route to the transformation of glycoscience: A chemist’s perspective on internal and external crossroads in glycochemistry. J. Am. Chem. Soc. 2021, 143 (1), 17– 34,  DOI: 10.1021/jacs.0c11106
      33
      En Route to the Transformation of Glycoscience: A Chemist's Perspective on Internal and External Crossroads in Glycochemistry
      Crich, David
      Journal of the American Chemical Society (2021), 143 (1), 17-34CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A review with refs. Carbohydrate chem. is an essential component of the glycosciences and is fundamental to their progress. This perspective takes the position that carbohydrate chem., or glycochem., has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other labs. The first of these potential inflection points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the exptl. evidence supports bimol. SN2-like mechanisms for typical glycosylation reactions over unimol. ones involving stereoselective attack on naked glycosyl oxocarbenium ions. A second crossroads is that between mainstream org. chem. and glycan synthesis. A third crossroads is that between carbohydrate chem. and medicinal chem., where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but the creativity, input and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.
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    34. 34
      Adero, P. O.; Amarasekara, H.; Wen, P.; Bohé, L.; Crich, D. The Experimental Evidence in Support of Glycosylation Mechanisms at the S(N)1-S(N)2 Interface. Chem. Rev. 2018, 118 (17), 8242– 8284,  DOI: 10.1021/acs.chemrev.8b00083
      34
      The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface
      Adero, Philip Ouma; Amarasekara, Harsha; Wen, Peng; Bohe, Luis; Crich, David
      Chemical Reviews (Washington, DC, United States) (2018), 118 (17), 8242-8284CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. A crit. review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the SN1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temp., and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the detn. of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a crit. appraisal of the state of the art.
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    35. 35
      Frihed, T. G.; Bols, M.; Pedersen, C. M. Mechanisms of glycosylation reactions studied by low-temperature nuclear magnetic resonance. Chem. Rev. 2015, 115 (11), 4963– 5013,  DOI: 10.1021/cr500434x
      35
      Mechanisms of Glycosylation Reactions Studied by Low-Temperature Nuclear Magnetic Resonance
      Frihed, Tobias Gylling; Bols, Mikael; Pedersen, Christian Marcus
      Chemical Reviews (Washington, DC, United States) (2015), 115 (11), 4963-5013CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review.
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    36. 36
      Braak, F. t.; Elferink, H.; Houthuijs, K. J.; Oomens, J.; Martens, J.; Boltje, T. J. Characterization of Elusive Reaction Intermediates Using Infrared Ion Spectroscopy: Application to the Experimental Characterization of Glycosyl Cations. Acc. Chem. Res. 2022, 55, 1669– 1679,  DOI: 10.1021/acs.accounts.2c00040
      36
      Characterization of Elusive Reaction Intermediates Using Infrared Ion Spectroscopy: Application to the Experimental Characterization of Glycosyl Cations
      Braak, Floor ter; Elferink, Hidde; Houthuijs, Kas J.; Oomens, Jos; Martens, Jonathan; Boltje, Thomas J.
      Accounts of Chemical Research (2022), 55 (12), 1669-1679CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. A detailed understanding of the reaction mechanism(s) leading to stereoselective product formation is crucial to understanding and predicting product formation and driving the development of new synthetic methodol. One way to improve our understanding of reaction mechanisms is to characterize the reaction intermediates involved in product formation. Because these intermediates are reactive, they are often unstable and therefore difficult to characterize using exptl. techniques. For example, glycosylation reactions are crit. steps in the chem. synthesis of oligosaccharides and need to be stereoselective to provide the desired α- or β-diastereomer. It remains challenging to predict and control the stereochem. outcome of glycosylation reactions, and their reaction mechanisms remain a hotly debated topic. In most cases, glycosylation reactions take place via reaction mechanisms in the continuum between SN1- and SN2-like pathways. SN2-like pathways proceeding via the displacement of a contact ion pair are relatively well understood because the reaction intermediates involved can be characterized by low-temp. NMR spectroscopy. In contrast, the SN1-like pathways proceeding via the solvent-sepd. ion pair, also known as the glycosyl cation, are poorly understood. SN1-like pathways are more challenging to investigate because the glycosyl cation intermediates involved are highly reactive. The highly reactive nature of glycosyl cations complicates their characterization because they have a short lifetime and rapidly equilibrate with the corresponding contact ion pair. To overcome this hurdle and enable the study of glycosyl cation stability and structure, they can be generated in a mass spectrometer in the absence of a solvent and counterion in the gas phase. The ease of formation, stability, and fragmentation of glycosyl cations have been studied using mass spectrometry (MS). However, MS alone provides little information about the structure of glycosyl cations. By combining mass spectrometry (MS) with IR ion spectroscopy (IRIS), the detn. of the gas-phase structures of glycosyl cations has been achieved. IRIS enables the recording of gas-phase IR spectra of glycosyl cations, which can be assigned by matching to ref. spectra predicted from quantum chem. calcd. vibrational spectra. Here, we review the exptl. setups that enable IRIS of glycosyl cations and discuss the various glycosyl cations that have been characterized to date. The structure of glycosyl cations depends on the relative configuration and structure of the monosaccharide substituents, which can influence the structure through both steric and electronic effects. The scope and relevance of gas-phase glycosyl cation structures in relation to their corresponding condensed-phase structures are also discussed. We expect that the workflow reviewed here to study glycosyl cation structure and reactivity can be extended to many other reaction types involving difficult-to-characterize ionic intermediates.
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    37. 37
      Elferink, H.; Severijnen, M. E.; Martens, J.; Mensink, R. A.; Berden, G.; Oomens, J.; Rutjes, F. P. J. T.; Rijs, A. M.; Boltje, T. J. Direct Experimental Characterization of Glycosyl Cations by Infrared Ion Spectroscopy. J. Am. Chem. Soc. 2018, 140 (19), 6034– 6038,  DOI: 10.1021/jacs.8b01236
      37
      Direct Experimental Characterization of Glycosyl Cations by Infrared Ion Spectroscopy
      Elferink, Hidde; Severijnen, Marion E.; Martens, Jonathan; Mensink, Rens A.; Berden, Giel; Oomens, Jos; Rutjes, Floris P. J. T.; Rijs, Anouk M.; Boltje, Thomas J.
      Journal of the American Chemical Society (2018), 140 (19), 6034-6038CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Glycosyl cations are crucial intermediates formed during enzymic and chem. glycosylation. The intrinsic high reactivity and short lifetime of these reaction intermediates make them very challenging to characterize using spectroscopic techniques. Herein, we report the use of collision induced dissocn. tandem mass spectrometry to generate glycosyl cations in the gas phase followed by IR ion spectroscopy using the FELIX IR free electron laser. The exptl. obsd. IR spectra were compared to DFT calcd. spectra enabling the detailed structural elucidation of elusive glycosyl oxocarbenium and dioxolenium ions.
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    38. 38
      Mucha, E.; Marianski, M.; Xu, F.-F.; Thomas, D. A.; Meijer, G.; Von helden, G.; Seeberger, P. H.; Pagel, K. Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy. Nat. Commun. 2018, 9 (1), 4174,  DOI: 10.1038/s41467-018-07184-z
      38
      Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy
      Mucha Eike; Marianski Mateusz; Thomas Daniel A; Meijer Gerard; von Helden Gert; Pagel Kevin; Mucha Eike; Seeberger Peter H; Pagel Kevin; Marianski Mateusz; Xu Fei-Fei; Seeberger Peter H
      Nature communications (2018), 9 (1), 4174 ISSN:.
      Glycosyl cations are the key intermediates during the glycosylation reaction that covalently links building blocks during the synthetic assembly of carbohydrates. The exact structure of these ions remained elusive due to their transient and short-lived nature. Structural insights into the intermediate would improve our understanding of the reaction mechanism of glycosidic bond formation. Here, we report an in-depth structural analysis of glycosyl cations using a combination of cold-ion infrared spectroscopy and first-principles theory. Participating C2 protective groups form indeed a covalent bond with the anomeric carbon that leads to C1-bridged acetoxonium-type structures. The resulting bicyclic structure strongly distorts the ring, which leads to a unique conformation for each individual monosaccharide. This gain in mechanistic understanding fundamentally impacts glycosynthesis and will allow to tailor building blocks and reaction conditions in the future.
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    39. 39
      Martin, A.; Arda, A.; Désiré, J.; Martin-mingot, A.; Probst, N.; Sinaÿ, P.; Jiménez-barbero, J.; Thibaudeau, S.; Blériot, Y. Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid. Nat. Chem. 2016, 8 (2), 186– 91,  DOI: 10.1038/nchem.2399
      39
      Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid
      Martin, A.; Arda, A.; Desire, J.; Martin-Mingot, A.; Probst, N.; Sinay, P.; Jimenez-Barbero, J.; Thibaudeau, S.; Bleriot, Y.
      Nature Chemistry (2016), 8 (2), 186-191CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Glycosyl cations are universally accepted key ionic intermediates in the mechanism of glycosylation, the reaction that covalently links carbohydrates to other mols. These ions have remained hypothetical species so far because of their extremely short life in org. media as a consequence of their very high reactivity. Here, we report the use of liq. hydrofluoric acid-antimony pentafluoride (HF/SbF5) superacid to generate and stabilize the glycosyl cations derived from peracetylated 2-deoxy and 2-bromoglucopyranose in a condensed phase. Their persistence in this superacid medium allows their three-dimensional structure to be studied by NMR, aided by complementary computations. Their deuteration further confirms the impact of the structure of the glycosyl cation on the stereochem. outcome of its trapping.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOmtrbM&md5=2aa975ffa9b03fbfa85ef717b8bd09b6
    40. 40
      Ben-tal, Y.; Boaler, P. J.; Dale, H. J. A.; Dooley, R. E.; Fohn, N. A.; Gao, Y.; García-domínguez, A.; Grant, K. M.; Hall, A. M. R.; Hayes, H. L. D.; Kucharski, M. M.; Wei, R.; Lloyd-jones, G. C. Mechanistic analysis by NMR spectroscopy: A users guide. Prog. Nucl. Magn. Reson. Spectrosc. 2022, 129, 28– 106,  DOI: 10.1016/j.pnmrs.2022.01.001
      40
      Mechanistic analysis by NMR spectroscopy: A users guide
      Ben-Tal, Yael; Boaler, Patrick J.; Dale, Harvey J. A.; Dooley, Ruth E.; Fohn, Nicole A.; Gao, Yuan; Garcia-Dominguez, Andres; Grant, Katie M.; Hall, Andrew M. R.; Hayes, Hannah L. D.; Kucharski, Maciej M.; Wei, Ran; Lloyd-Jones, Guy C.
      Progress in Nuclear Magnetic Resonance Spectroscopy (2022), 129 (), 28-106CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
      A review principles and practice tutorial-style review of the application of soln.-phase NMR in the anal. of the mechanisms of homogeneous org. and organometallic reactions and processes. This review of 345 refs. summarises why soln.-phase NMR spectroscopy is uniquely effective in such studies, allowing non-destructive, quant. anal. of a wide range of nuclei common to org. and organometallic reactions, providing exquisite structural detail, and using instrumentation that is routinely available in most chem. research facilities. The review is in two parts. The first comprises an introduction to general techniques and equipment, and guidelines for their selection and application. Topics include practical aspects of the reaction itself, reaction monitoring techniques, NMR data acquisition and processing, anal. of temporal concn. data, NMR titrns., DOSY, and the use of isotopes. The second part comprises a series of 15 Case Studies, each selected to illustrate specific techniques and approaches discussed in the first part, including in situ NMR (1/2H, 10/11B, 13C, 15N, 19F, 29Si, 31P), kinetic and equil. isotope effects, isotope entrainment, isotope shifts, isotopes at natural abundance, scalar coupling, kinetic anal. (VTNA, RPKA, simulation, steady-state), stopped-flow NMR, flow NMR, rapid injection NMR, pure shift NMR, dynamic nuclear polarisation, 1H/19F DOSY NMR, and in situ illumination NMR.
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    41. 41
      Crich, D. Mechanism of a chemical glycosylation reaction. Accounts of chemical research 2010, 43 (8), 1144– 1153,  DOI: 10.1021/ar100035r
      41
      Mechanism of a Chemical Glycosylation Reaction
      Crich, David
      Accounts of Chemical Research (2010), 43 (8), 1144-1153CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Glycosylation is arguably the most important reaction in the field of glycochem., yet it involves one of the most empirically interpreted mechanisms in the science of org. chem. The β-mannopyranosides, long considered one of the more difficult classes of glycosidic bond to prep., were no exception to this rule. Several logical but circuitous routes for their prepn. were described in the literature, but they were accompanied by a greater no. of mostly ineffective recipes for their direct access. This situation changed in 1996 with the discovery of the 4,6-O-benzylidene acetal as a control element permitting direct entry into the β-mannopyranosides, typically with high yield and selectivity. The unexpected nature of this phenomenon demanded study of the mechanism, leading first to the demonstration of the α-mannopyranosyl triflates as reaction intermediates and then to the development of α-deuterium kinetic isotope effect methods to probe their transformation into the product glycosides. In this account, the authors assemble their observations into a comprehensive assessment consistent with a single mechanistic scheme. The realization that in the glucopyranose series the 4,6-O-benzylidene acetal is α- rather than β-directing led to further investigations of substituent effects on the stereoselectivity of these glycosylation reactions, culminating in their explanation in terms of the covalent α-glycosyl triflates acting as a reservoir for a series of transient contact and solvent-sepd. ion pairs. The function of the benzylidene acetal, as explained by Bols and co-workers, is to lock the C6-O6 bond antiperiplanar to the C5-O5 bond, thereby maximizing its electron-withdrawing effect, destabilizing the glycosyl oxocarbenium ion, and shifting the equil. as far as possible toward the covalent triflate. β-Selective reactions result from attack of the nucleophile on the transient contact ion pair in which the α-face of the oxocarbenium ion is shielded by the triflate counterion. The α-products arise from attack either on the solvent-sepd. ion pair or on a free oxocarbenium ion, according to the dictates of the anomeric effect. Changes in selectivity from varying stereochem. (glucose vs. mannose) or from using different protecting groups can be explained by the shifting position of the key equil. and, in particular, by the energy differences between the covalent triflate and the ion pairs. Of particular note is the importance of substituents at the 3-position of the donor; an explanation is proposed that invokes their evolving torsional interaction with the substituent at C2 as the chair form of the covalent triflate moves toward the half-chair of the oxocarbenium ion.
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    42. 42
      D’angelo, K. A.; Taylor, M. S. Borinic Acid Catalyzed Stereo- and Regioselective Couplings of Glycosyl Methanesulfonates. J. Am. Chem. Soc. 2016, 138 (34), 11058– 11066,  DOI: 10.1021/jacs.6b06943
      42
      Borinic Acid Catalyzed Stereo- and Regioselective Couplings of Glycosyl Methanesulfonates
      D'Angelo, Kyan A.; Taylor, Mark S.
      Journal of the American Chemical Society (2016), 138 (34), 11058-11066CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      In the presence of a diarylborinic acid catalyst, glycosyl methanesulfonates engage in regio- and stereoselective couplings with partially protected pyranoside and furanoside acceptors. The methanesulfonate donors are prepd. in situ from glycosyl hemiacetals, and are coupled under mild, operationally simple conditions (amine base, organoboron catalyst, room temp.). The borinic acid catalyst not only influences site-selectivity via activation of 1,2- or 1,3-diol motifs, but also has a pronounced effect on the stereochem. outcome: 1,2-trans-linked disaccharides are obtained selectively in the absence of neighboring group participation. Reaction progress kinetic anal. was used to obtain insight into the mechanism of glycosylation, both in the presence of catalyst and in its absence, while rates of interconversion of methanesulfonate anomers were detd. by NMR exchange spectroscopy (EXSY). Together, the results suggest that although the uncatalyzed and catalyzed reactions give rise to opposite stereochem. outcomes, both proceed by associative mechanisms.
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    43. 43
      Aubry, S.; Sasaki, K.; Sharma, I.; Crich, D. Influence of protecting groups on the reactivity and selectivity of glycosylation: chemistry of the 4,6-o-benzylidene protected mannopyranosyl donors and related species. Top Curr. Chem. 2010, 301, 141– 88,  DOI: 10.1007/128_2010_102
      There is no corresponding record for this reference.
    44. 44
      Kahne, D.; Walker, S.; Cheng, Y.; Van engen, D. Glycosylation of unreactive substrates. J. Am. Chem. Soc. 1989, 111 (17), 6881– 6882,  DOI: 10.1021/ja00199a081
      44
      Glycosylation of unreactive substrates
      Kahne, Daniel; Walker, Suzanne; Cheng, Yuan; Van Engen, Donna
      Journal of the American Chemical Society (1989), 111 (17), 6881-2CODEN: JACSAT; ISSN:0002-7863.
      A rapid method to glycosylate unreactive substrates in good yield involves activation of an anomeric Ph sulfoxide with triflic anhydride followed by trapping of a nucleophile. The efficacy of the reaction is demonstrated by glycosylation of an amide on nitrogen. This is the first report of direct glycosylation of an amide nitrogen by non-enzymic means. Other nucleophiles trapped include hindered alcs. and derivs. of phenol. In many cases, either the α or the β isomer of the glycosylated product can be obtained stereoselectively. Crystal structure of chenodeoxycholic acid glycopyranoside was detd.
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    45. 45
      Fraser-reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen, J. P. Torsional effects in glycoside reactivity: saccharide couplings mediated by acetal protecting groups. J. Am. Chem. Soc. 1991, 113 (4), 1434– 1435,  DOI: 10.1021/ja00004a066
      45
      Torsional effects in glycoside reactivity: saccharide couplings mediated by acetal protecting groups
      Fraser-Reid, Bert; Wu, Zufan; Andrews, C. Webster; Skowronski, Evan; Bowen, J. Phillip
      Journal of the American Chemical Society (1991), 113 (4), 1434-5CODEN: JACSAT; ISSN:0002-7863.
      Cyclic acetal protecting groups cause reactions at the anomeric center of pyranosides to be much slower in the non-acetalated analogs. The differences are sometimes great enough so that an armed/disarmed protocol for saccharide coupling can be based on the presence or absence of the cyclic acetal. The torsional effects responsible for these reactivity differences are predicted by PM3 computational methods, which suggests that a qual. assessment of exptl. feasibility can be readily made.
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    46. 46
      Andrews, C. W.; Rodebaugh, R.; Fraser-reid, B. A Solvation-Assisted Model for Estimating Anomeric Reactivity. Predicted versus Observed Trends in Hydrolysis of n-Pentenyl Glycosides1. Journal of Organic Chemistry 1996, 61 (16), 5280– 5289,  DOI: 10.1021/jo9601223
      46
      A Solvation-Assisted Model for Estimating Anomeric Reactivity. Predicted versus Observed Trends in Hydrolysis of n-Pentenyl Glycosides
      Andrews, C. Webster; Rodebaugh, Robert; Fraser-Reid, Bert
      Journal of Organic Chemistry (1996), 61 (16), 5280-5289CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      An attempt has been made to predict qual. trends in reactivity at the anomeric center, using N-bromosuccinimide-induced hydrolysis of n-pentenyl glycosides (NPGs) as the exptl. model. Calcd. relative activation energies based on internal energy differences of a reactant and the assocd. intermediate are not always in agreement with exptl. observations. However, solvation energies obtained by the generalized Born surface area model in MacroModel developed by Still et al. give modified activation energies that are in excellent agreement with the exptl. obsd. trends. It is shown that the solvation model does not disturb the normally obsd. reactivity trends that can be rationalized on the basis of internal energies alone. The value of the methodol. has been demonstrated for several substrates by first calcg. their relative activation energies, then testing them exptl., and finding excellent agreement with predictions.
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    47. 47
      Jensen, H. H.; Nordstro̷m, L. U.; Bols, M. The Disarming Effect of the 4,6-Acetal Group on Glycoside Reactivity: Torsional or Electronic?. J. Am. Chem. Soc. 2004, 126 (30), 9205– 9213,  DOI: 10.1021/ja047578j
      47
      The Disarming Effect of the 4,6-Acetal Group on Glycoside Reactivity: Torsional or Electronic?
      Jensen, Henrik Helligso; Nordstrom, Lars Ulrik; Bols, Mikael
      Journal of the American Chemical Society (2004), 126 (30), 9205-9213CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An evaluation of whether the well-known deactivating effect of a 4,6-acetal protection group on glycosyl transfer is caused by torsional or an electronic effect from fixation of the 6-OH in the tg conformation was made. Two conformationally locked probe mols., 2,4-dinitrophenyl 4,8-anhydro-7-deoxy-2,3,6-tri-O-methyl-β-D-glycero-D-gluco-octopyranoside (I) and the L-glycero-D-gluco isomer (II), were prepd., and their rate of hydrolysis was compared to that of the flexible 2,4-dinitrophenyl 2,3,4,6-tetra-O-methyl-β-D-glucopyranoside (III) and the locked 2,4-dinitrophenyl 4,6-O-methylidene-2,3-di-O-methyl-β-D-glucopyranoside (IV). The rate of hydrolysis at pH 6.5 was III > I > II > IV, which showed that the deactivating effect of the 4,6-methylene group is partially torsional and partially electronic. A comparison of the rate of acidic hydrolysis showed that the of the corresponding Me α-glycoside probe mols. of I and II hydrolyzed significantly slower than Me tetra-O-methyl-glucoside, confirming a deactivating effect of locking the saccharide in the 4C1 conformation. The expts. showed that the hydroxymethyl rotamers deactivate the rate of glycoside hydrolysis in the order tg » gt > gg.
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    48. 48
      Van zijl, P. C.; Yadav, N. N. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t?. Magn Reson Med. 2011, 65 (4), 927– 48,  DOI: 10.1002/mrm.22761
      48
      Chemical exchange saturation transfer (CEST): what is in a name and what isn't?
      van Zijl, Peter C. M.; Yadav, Nirbhay N.
      Magnetic Resonance in Medicine (2011), 65 (4), 927-948CODEN: MRMEEN; ISSN:0740-3194. (Wiley-Liss, Inc.)
      A review. Chem. exchange satn. transfer (CEST) imaging is a relatively new magnetic resonance imaging contrast approach in which exogenous or endogenous compds. contg. either exchangeable protons or exchangeable mols. are selectively satd. and after transfer of this satn., detected indirectly through the water signal with enhanced sensitivity. The focus of this review is on basic magnetic resonance principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast. In CEST magnetic resonance imaging, transfer of magnetization is studied in mobile compds. instead of semisolids. Similar to magnetization transfer contrast, CEST has contributions of both chem. exchange and dipolar cross-relaxation, but the latter can often be neglected if exchange is fast. Contrary to magnetization transfer contrast, CEST imaging requires sufficiently slow exchange on the magnetic resonance time scale to allow selective irradn. of the protons of interest. As a consequence, magnetic labeling is not limited to radio-frequency satn. but can be expanded with slower frequency-selective approaches such as inversion, gradient dephasing and frequency labeling. The basic theory, design criteria, and exptl. issues for exchange transfer imaging are discussed. A new classification for CEST agents based on exchange type is proposed. The potential of this young field is discussed, esp. with respect to in vivo application and translation to humans.
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    49. 49
      Lokesh, N.; Seegerer, A.; Hioe, J.; Gschwind, R. M. Chemical Exchange Saturation Transfer in Chemical Reactions: A Mechanistic Tool for NMR Detection and Characterization of Transient Intermediates. J. Am. Chem. Soc. 2018, 140 (5), 1855– 1862,  DOI: 10.1021/jacs.7b12343
      49
      Chemical Exchange Saturation Transfer in Chemical Reactions: A Mechanistic Tool for NMR Detection and Characterization of Transient Intermediates
      Lokesh, N.; Seegerer, Andreas; Hioe, Johnny; Gschwind, Ruth M.
      Journal of the American Chemical Society (2018), 140 (5), 1855-1862CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The low sensitivity of NMR and transient key intermediates below detection limit are the central problems studying reaction mechanisms by NMR. Sensitivity can be enhanced by hyperpolarization techniques such as dynamic nuclear polarization or the incorporation/interaction of special hyperpolarized mols. However, all of these techniques require special equipment, are restricted to selective reactions, or undesirably influence the reaction pathways. Here, we apply the chem. exchange satn. transfer (CEST) technique for the first time to NMR detect and characterize previously unobserved transient reaction intermediates in organocatalysis. The higher sensitivity of CEST and chem. equil. present in the reaction pathway are exploited to access population and kinetics information on low populated intermediates. The potential of the method is demonstrated on the proline-catalyzed enamine formation for unprecedented in situ detection of a DPU stabilized zwitterionic iminium species, the elusive key intermediate between enamine and oxazolidinones. The quant. anal. of CEST data at 250 K revealed the population ratio of [Z-iminium]/[exo-oxazolidinone] 0.02, relative free energy +8.1 kJ/mol (calcd. +7.3 kJ/mol), and free energy barrier of +45.9 kJ/mol (ΔG⧺calc.(268 K) = +42.2 kJ/mol) for Z-iminium → exo-oxazolidinone. The findings underpin the iminium ion participation in enamine formation pathway corroborating our earlier theor. prediction and help in better understanding. The reliability of CEST is validated using 1D EXSY-build-up techniques at low temp. (213 K). The CEST method thus serves as a new tool for mechanistic investigations in organocatalysis to access key information, such as chem. shifts, populations, and reaction kinetics of intermediates below the std. NMR detection limit.
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    50. 50
      Serianni, A. S.; Pierce, J.; Huang, S. G.; Barker, R. Anomerization of furanose sugars: kinetics of ring-opening reactions by proton and carbon-13 saturation-transfer NMR spectroscopy. J. Am. Chem. Soc. 1982, 104 (15), 4037– 4044,  DOI: 10.1021/ja00379a001
      50
      Anomerization of furanose sugars: kinetics of ring-opening reactions by proton and carbon-13 saturation-transfer NMR spectroscopy
      Serianni, Anthony S.; Pierce, John; Huang, Shaw Guang; Barker, Robert
      Journal of the American Chemical Society (1982), 104 (15), 4037-44CODEN: JACSAT; ISSN:0002-7863.
      With the tetroses D-threose and D-erythrose, kinetic and thermodn. parameters for the interconversion of α- and β-furanoses and the acyclic hydrate with the intermediate aldehyde form have been obtained from 1H and 13C NMR measurements. Unidirectional rate consts. for the various equil. involving the aldehyde have been detd., and from them the overall rate consts. for interconversion of the abundant species.
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    51. 51
      Woods, M.; Woessner, D. E.; Sherry, A. D. Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. Chem. Soc. Rev. 2006, 35 (6), 500– 511,  DOI: 10.1039/b509907m
      51
      Paramagnetic lanthanide complexes as PARACEST agents for medical imaging
      Woods, Mark; Woessner, Donald E.; Sherry, A. Dean
      Chemical Society Reviews (2006), 35 (6), 500-511CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chem. shift satn. transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiol. or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chem. shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.
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    52. 52
      Walvoort, M. T. C.; Lodder, G.; Mazurek, J.; Overkleeft, H. S.; Codée, J. D. C.; Van der marel, G. A. Equatorial Anomeric Triflates from Mannuronic Acid Esters. J. Am. Chem. Soc. 2009, 131 (34), 12080– 12081,  DOI: 10.1021/ja905008p
      52
      Equatorial Anomeric Triflates from Mannuronic Acid Esters
      Walvoort, Marthe T. C.; Lodder, Gerrit; Mazurek, Jaroslaw; Overkleeft, Herman S.; Codee, Jeroen D. C.; van der Marel, Gijsbert A.
      Journal of the American Chemical Society (2009), 131 (34), 12080-12081CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Activation of mannuronic acid esters leads to a conformational mixt. of α-anomeric triflates, in which the equatorial triflate (1C4 chair) is formed preferentially. This unexpected intermediate clearly opposes the anomeric effect and is mainly stabilized by the electron-withdrawing carboxylate function at C-5. Because the anomeric center carries a significant pos. charge, the 1C4 mannopyranosyl chair approximates the favored 3H4 half-chair oxacarbenium ion conformation. The excellent β-selectivity in glycosylations of mannuronates is postulated to originate from the cooperative action of the triflate counterion and the (stereo)electronic effects governing oxacarbenium ion stabilization in the transition state leading to the 1,2-cis product.
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    53. 53
      Bock, K.; Pedersen, C. A study of 13CH coupling constants in hexopyranoses. J. Chem. Soc., Perkin Trans. 1974, 3, 293– 297,  DOI: 10.1039/p29740000293
      There is no corresponding record for this reference.
    54. 54
      Remmerswaal, W.; Elferink, H.; Houthuijs, K.; Hansen, T.; Ter braak, F.; Berden, G.; Van der vorm, S.; Martens, J.; Oomens, J.; Van der marel, G.; Boltje, T.; Codée, J. Anomeric Triflates vs Dioxanium ions: Different Product-Forming Intermediates from 1-Thiophenyl-2-O-Benzyl-3-O-Benzoyl-4, 6-O-Benzylidene-Mannose and Glucose. ChemRxiv 2023,  DOI: 10.26434/chemrxiv-2023-t45q6
      There is no corresponding record for this reference.
    55. 55
      Crich, D.; Cai, W.; Dai, Z. Highly Diastereoselective α-Mannopyranosylation in the Absence of Participating Protecting Groups. Journal of Organic Chemistry 2000, 65 (5), 1291– 1297,  DOI: 10.1021/jo9910482
      55
      Highly Diastereoselective α-Mannopyranosylation in the Absence of Participating Protecting Groups
      Crich, David; Cai, Weiling; Dai, Zongmin
      Journal of Organic Chemistry (2000), 65 (5), 1291-1297CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      S-Ph 2,6-di-O-benzyl-3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-1-thia-α-D-mannopyranoside and its sulfoxide, following activation at -78 °C with benzenesulfenyl triflate or triflic anhydride, resp., provide the corresponding α-mannosyl triflate as demonstrated by NMR spectroscopy. On addn. of an acceptor alc. α-mannosides are then formed. Similarly, S-Ph 2,3-O-carbonyl-4,6-O-benzylidene-1-thia-α-D-mannopyranoside and Et 3-O-benzoyl-4,6-O-benzylidene-2-O-(tert-butyldimethylsilyl)-1-thia-α-D-mannopyranoside both provide α-mannosides on activation with benzenesulfenyl triflate followed by addn. of an alc. These results stand in direct contrast to the highly β-selective couplings of comparable glycosylations with 2,3-di-O-benzyl-4,6-O-benzylidene protected mannosyl donors and draw attention to the subtle interplay of reactivity and structure in carbohydrate chem.
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  • Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c08709.

    • Synthetic procedures for the synthesis of donors 7-14, 1513C, 1613C, and the precursor for 14αOTf(13C-1). Theoretical and practical description of the EXSY and CEST experiments, VT-NMR procedures, and additional variable temperature NMR spectra and raw 19F EXSY, 13C CEST, and 1H CEST NMR data (PDF)


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