Mechanisms of Glycosylation Reactions Studied by Low

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Mechanisms of Glycosylation Reactions Studied by LowTemperature Nuclear Magnetic Resonance Tobias Gylling Frihed, Mikael Bols, and Christian Marcus Pedersen* Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark in synthesis and purification.1−4 One of the major problems to be solved now is to improve efficiency and control stereoselectivity in glycosylations. In order to improve this very central reaction in oligosaccharide synthesis, extensive efforts have been made to understand the mechanism behind glycosylation.5−10 Knowledge of reactive intermediates or the transition states are crucial for the development of better methods, which avoid side reactions and give close to quantitative yields and selectivity. To investigate transition states or reactive intermediates, three significant types of studies CONTENTS have led to some hypotheses for such species: namely, kinetic 1. Introduction A isotope effects,11−13 computational studies of hypothetical 2. Historical Aspects B transition states,10,14−16 and NMR studies of the donor under 3. O−S Species C activation conditions. Although many different reactive 3.1. Glycosyl Triflates (-OSO2CF3) C intermediates of many different carbohydrates have been 3.1.1. Mannosyl Triflates and Derivatives C described recently, it is still very difficult to predict whether 3.1.2. Glucosyl Triflates and Derivatives P these intermediates (most often anomeric triflates) are indeed 3.1.3. Galactosyl Triflates U involved in the product-forming step or merely serve as a 3.1.4. Rhamnosyl Triflates V reservoir for a more reactive species (an oxocarbenium ion-like 3.1.5. Furanosyl Triflates W species). This review covers variable-temperature nuclear 3.1.6. Uronic Acid Triflates and Derivatives W magnetic resonance (VT-NMR) used to study reaction 3.2. Other Glycosyl Sulfonates (-OSO2R) Y intermediates and mechanisms in glycosylations. NMR has 3.3. Glycosyl Oxosulfonium Ions (-OS+R2) Y revolutionized this field, and no other techniques have been 3.4. Glycosyl Sulfenates (-OSR) Z able to give the same insight into what goes on when a glycosyl 4. S/Se Species AC + donor is activated. As instrumentation is continuously 4.1. Glycosyl Sulfonium and Selenium Ions (-S R2 improving, new discoveries still can be made when studying and -Se+R2) AC classic glycosylation reactions. As glycosylation goes through an 5. O Species AJ activated intermediate, often believed to be an oxocarbenium 5.1. Glycosyl Perchlorates (−OClO3) AJ ion, NMR at low temperature is required. As the main focus is 5.2. Glycosyl Dioxolenium Ions AJ 5.3. Glycosyl Imidates and Imidinium Ions the detection of these reactive intermediates in order to unravel [−OC(N+R2)R′] AK the mechanism or explain side reactions, the focus is on NMR 6. Miscellaneous AN performed at low temperature. Therefore, we do not 6.1. Glycosyl Halides AN distinguish between VT-NMR and low-temperature NMR in 6.2. Glycosyl Phosphonium Salts (-P+R3) AP this review. A few reviews have touched upon glycosyl 6.3. Glycosyl Ammonium Ions (-N+R3) AS intermediates detected by NMR, but these have not been 7. Conclusion and Future Direction AT comprehensive.17−21 The observation of reactive glycosyl Author Information AU intermediates by low-temperature NMR has been performed Corresponding Author AU regularly since the first NMR detection of a glycosyl Notes AU dioxolenium ion in 1966−1967 but increased dramatically Biographies AU after Crich’s discovery, in the mid-1990s, that glycosyl triflate Acknowledgments AV intermediates could be observed in glycosylations (Figure Abbreviations AV 1).8,22 References AV Some groundbreaking discoveries have been made that contribute to understanding and interpretation of the glycosylation reaction from a mechanistic aspect and assist in 1. INTRODUCTION optimizing glycosylation conditions (Figure 2). Synthesis of oligosaccharides has, for the past couple of decades, been greatly improved by new methods and the Received: August 9, 2014 ongoing development of new technologies, such as automation © XXXX American Chemical Society

A

DOI: 10.1021/cr500434x Chem. Rev. XXXX, XXX, XXX−XXX

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between the oxygens on C1 and C2. Reeves25 termed this the Δ2 condition (Δ2 effect). It was also realized that conformational changes occur during substitution on the anomeric position, first by flattening the ring to a half-chair followed by a complete ring flip when the new bond had been formed. The anomeric substitution occurs with Walden inversion in a SN2like fashion forcing a ring flip, which finally equilibrates back to the thermodynamically most stable ring.24 Reeves25 formulated the following in a review article: “A direct check on the accuracy of the prediction of Hassel and Ottar is not possible, since no experimental methods have yet been developed capable of determining the shape of pyranose rings of a reducing sugar in solution”. This statement underlines the problems in the early work on pyranose conformations. The anomeric stereochemistry could in most cases be assigned by using Hudson’s rules of isorotation26,27 but with some uncertainty. On the basis of Hudson’s work, Isbell28,29 used optical rotation to compare the ring structure of different carbohydrates. A few years after the statement by Reeves,25 a breakthrough came; nuclear magnetic resonance revolutionized the study of carbohydrates in solution completely. A pioneer in the use of NMR for carbohydrates was Lemieux, who together with coworkers30 recorded the first spectra of carbohydrates in solution. The conformation could now be studied and the fundamental concepts could be established within a few years despite the low resolution of the spectra. Within a decade, all major carbohydrate chemistry groups had access to a NMR facility, and with the increasing resolution, more and more information about the carbohydrates could be obtained. With the development of NMR technology, studies became more sophisticated. Horton and co-workers31,32 were at the forefront in studying the conformation of pyranose sugar rings at low temperature and furthermore had the advantage of being among the first in the community with access to a 220 MHz NMR with a superconducting solenoid. This advantage let to a series of papers on the “application of 220 MHz NMR to the solution of stereochemical problems”, where some of them used low-temperature NMR. With access to a high field, the conformation of carbohydrates could be studied in greater detail, and by cooling the sample, it was possible to “freeze out”

Figure 1. Articles and accumulated articles per year that use VT-NMR.

In this review we collect all NMR data available on reactive intermediates obtained at low temperature (T ≤ 0 °C) during the last 5 decades. With a collected overview of the available NMR shifts and decomposition temperatures for all the different donor types, one can easily obtain the information relevant for optimizing glycosylation conditions or to study the reaction. The NMR data, and other relevant observations, known for each donor type have been collected in tables to allow easy access and comparability.

2. HISTORICAL ASPECTS The conformation of carbohydrates has been a central issue in carbohydrate chemistry for nearly a century. For many years, the predictions could not be evaluated since no spectroscopic methods existed for the determination of carbohydrate conformation. Some experimental procedures had been developed to determine the spatial relationship between vicinal hydroxyl groups; examples of this are metal complex formation using, for example, cupraammonium.23 Several “rules” appeared to predict the conformation of the sugar ring, and “instability factors” were introduced in order to rationalize which conformation was preferred. Hassel and Ottar24 introduced lying and erected (now termed equatorial and axial) for the substituents on the pyranose ring and the destabilizing effect of having 1,3-diaxial interaction. The early work on conformations was rather speculative and often unclear since the definitions of, for example, α and β were vague. It was also realized that having an axial oxygen on C2 represent a special case with increased instability of β-glycoside due to the unfavorable interaction

Figure 2. Chronological evolution of glycosyl intermediates observed by low-temperature NMR. B


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acetonitrile. This afforded the α-rhamnosyl tosylate as indicated by 1H NMR (δH1 6.07 ppm, 3JH1,H2 2.2 Hz). These indications of anomeric tosylates point to instability, and therefore studies of these highly labile intermediates require low-temperature NMR for characterization. The first study of glycosyl triflate by VT-NMR was performed by Pavia and Ung-Chhun,45 where trifluoromethanesulfonic anhydride (Tf2O) was used to synthesize symmetrical 1,1′-glycosyl glycosides. Using 19F NMR at low temperature, the authors provided evidence that, in situ, TfOH formed a stable, insoluble hydroxonium trifluoromethanesulfonate, CF3SO3−H3O+.

conformations when present in a fast equilibrium at room temperature. The first example of obtaining NMR spectra of two chairs was obtained on β-D-ribopyranose tetraacetate, where two distinct set of signals appear upon cooling the sample from 20 to −84 °C. The appearance of two conformations in a rapid equilibrium illustrates that the energy difference between the chairs is small. When the same experiment was performed on α-D-lyxopyranose tetraacetate, only one conformation could be observed at low temperature, thereby confirming the greater stability of the 4C1 conformation.31 With the NMR spectrometer becoming a standard instrument, the interest in studying reactive and nonisolable intermediates appeared as a natural consequence. For this purpose, cooling of the sample during the measurement became essential. Hall and Manville33 were also studying the conformation of sugars and used fluorine as a second nucleus since it is more sensitive to conformational changes. It was early realized that 2,3,4-tri-O-acetyl-β-D-xylopyranosyl fluoride preferred a 1C4 conformation despite the obviously unfavorable steric interaction between the all-axial substituents and in contrast to the α-anomer having the substituents equatorial. Low-temperature NMR experiments, by Hall and Manville in collaboration with Bhacca,34 at 170 K revealed that the signals changed more for the β-anomer, but only one conformation was observed. Other pioneers in NMR and especially lowtemperature NMR were Pedersen and Paulsen, but since these groups were studying reactions and mechanism, their work will be discussed later in this review. With the pioneering work by a few groups, the importance of NMR in studying carbohydrates had been settled and NMR quickly became an indispensable tool in every research group. In this review we will focus on NMR as a tool for studying reactive intermediates in carbohydrate chemistry. The topic has been limited to lowtemperature NMR (i.e., VT-NMR), which has arbitrarily been set to be 0 °C or below. The interest in studying reactive intermediates have never been higher than now, which is reflected in the growing number of publications per year (Figure 1). Here we summarize the research performed up to July 2014.

3.1. Glycosyl Triflates (-OSO2CF3)

One of the most-studied species for mechanistic studies is glycosyl triflate.8 Triflates are generated from various sources and are sufficiently stable for detection in low-temperature NMR experiments.17 3.1.1. Mannosyl Triflates and Derivatives. The βmannosidic bond is considered as one of the most challenging to form, owing to the need to overcome the anomeric effect, unfavorable neighboring group effect, shielding of the β-face by C2−O2 protecting groups, and the Δ2 effect.25 Alternatively, βmannosides have most often been synthesized by indirect methods like formation of the facile β-glucoside followed by C2 epimerization or by intramolecular aglycon delivery (IAD).1,46−48 Excellent reviews regarding β-mannosylation have previously been published elsewhere.8,46,47,49−51 β-Directing 4,6-O-Benzylidene-Protected Mannopyranosides via Observed α-Triflates. Crich and Sun52 discovered that a 4,6-O-acetal protecting group could direct the formation of the β-mannosidic linkage (using the sulfoxide method of Kahne and co-workers53,54). In the procedure, the order of addition of alcohol and activation reagents was found to be critical to the stereoselective outcome (Scheme 1). Scheme 1. Stereoselective Outcome Dependence on Mixing Order

3. O−S SPECIES In the first reported synthesis of an anomeric tosylate described by Helferich and Gootz,35 the tosylate was not characterized and decomposed rapidly. Since then, several decades passed before anomeric sulfonates were investigated again. The first reported glycosyl triflate was described by Kronzer and Schuerch.36 It was found to be a highly unstable intermediate and therefore used directly in glycosylation. Later, glycosyl sulfonates (triflates, brosylates, nosylates, and tosylates) was prepared in situ as intermediates for glycosylations in the gluco, galacto, and manno series.37−42 The highly unstable anomeric tosylates have been characterized by 1H NMR at room temperature, where it was found that perbenzylated α-1-Otosyl-D-glucopyranose and the 6-O-(N-phenylcarbamoyl) equivalent both resonated at δH1 6.1 ppm (3JH1,H2 3.5 Hz).43 Furthermore, a small amount of the β-tosylate was found for the 6-O-(N-phenylcarbamoyl)-protected glucoside resonating at δH1 5.5 ppm (3JH1,H2 8.0 Hz). The synthesis of the anomeric tosylate relied on highly anhydrous conditions and Schlenk techniques. In an attempt to synthesize β-L-rhamnosides, Srivastava and Schuerch44 prepared the 3,4,6-tri-O-benzyl-2O-mesyl-protected α-rhamnosyl tosylate by reaction of the corresponding glycosyl chloride with p-toluenesulfonate in

Addition of Tf2O to a mixture of 4,6-O-benzylideneprotected sulfoxide donor 1, acceptor 2, and 2,6-di-tert-butyl4-methylpyridine (DTBMP) in diethyl ether at −78 °C preferably led to the formation of the α-mannoside (β/α 1:10) in 65% yield (protocol A). This stereoselectivity could be reversed by a preactivation procedure where the sulfoxide donor 1 was mixed with Tf2O and DTBMP in diethyl ether at −78 °C for 5 min before addition of the acceptor 2 (protocol B). This gave predominantly the β-mannoside 3 in a β/α 10.5:1 ratio and good yield (93%). Subsequently, it was found that when the reaction was performed in dichloromethane, better βselectivity was obtained.55 The formation of β-mannosides has been extensively reviewed.8,17,50,56 To explain the reversal of stereoselectivity, Crich and Sun55 proposed an initial mechanistic hypothesis (Scheme 2). According to this, reaction of Tf2O with the sulfoxide donor forms a highly active glycosyl sulfonium ion 4 that collapses to the oxocarbenium ion 5. In the presence of an acceptor, the oxocarbenium ion leads to formation of the α-mannoside 6. In C


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consumed in favor of the formation of methyl α- and βmannoside in a 1:7 ratio. During the glycosylation, the signal at δ −0.037 ppm in the 19F NMR spectrum disappeared in favor of the one at δ −3.21 ppm (di-tert-butylmethylpyridinium triflate). This further suggested that the mechanism goes through α-triflate 15. The same α-triflate 15 has been generated and studied by VT-NMR using different anomeric leaving groups and a variety of promoter systems. Mannosyl sulfoxide 9 can also be activated by PhSOTf in the presence of DTBMP (Scheme 3A).59 Alternatively, mannosyl bromide 10 was activated with AgOTf in the presence of DTBMP in CD2Cl2 at −78 °C (Scheme 3B).22,60 Direct activation of thiomannopyranoside 11 by PhSOTf in the presence of DTBMP is a more convenient method that avoids the oxidation step to the sulfoxide (Scheme 3C).61 In subsequent work with benzyl ethers in place of the methyl ethers, Crich and Smith62,63 managed to prepare the corresponding glycosyl triflate 16 by activation of the thiomannoside 13α with either S-phenyl benzenethiosulfinate or 1-benzenesulfinyl piperidine (BSP, Scheme 3E) and studied it by low-temperature NMR. For both activation methods, donor 13α was mixed with base (either DTBMP or 2,4,6-tri-tert-butylpyrimidine, TTBP) and promoter in CD2Cl2 at −78 °C, followed by addition of Tf2O. In both cases the glycosyl triflate 16 was formed and characterized by its anomeric proton resonating at δ 6.17 ppm (S-phenyl benzenethiosulfinate/Tf2O activation) and δ 6.05 ppm (BSP activation). The difference in chemical shift can be explained by experimental inaccuracy. Direct glycosylation with the reduced sugar 4,6-di-Obenzylidene-protected mannose 14 was employed by Kim and co-workers64,65 for synthesis of β-mannosides via the αtriflate 16. The manno-lactol was activated in a three-step protocol by mixing the 4,6-di-O-benzylidene-protected mannosyl donor, phthalic anhydride (or 3-fluorophthalic anhydride), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) at room temperature. Subsequently, the mixture was cooled to −78 °C

Scheme 2. Initial Mechanistic Hypothesis

the preactivation protocol, the oxocarbenium ion is trapped as it is covalently attached to α-triflate 7, leading to the βmannoside 8 through SN2-like displacement when the alcohol is added. To support the hypothesis of a covalently attached α-triflate, a simplified mannosyl sulfoxide 9 was prepared and dissolved in CD2Cl2 in the presence of DTBMP (Scheme 3A).22,57 A 1H NMR spectrum was recorded at −78 °C before the addition of 10% excess Tf2O. Within 4) upon activation, which turned into the drawn α-triflate upon warming to between −15 and −10 °C.

Table 8. Furanosyl Triflates Detected by VT-NMR

a

Several intermediates equilibrating into one over 80 min. Warming the sample accelerated this process. bSeveral species (>4) upon activation, which turned into drawn α-triflate upon warming to given temperature; see conditions. cSeveral anomeric signals, which turned into α-triflate upon warming in the given interval.

Galactosyl triflates have also been generated and studied by VT-NMR with N-iodosuccinimide (NIS)/TfOH as the activation system (entries 3 and 4, Table 6).127 3.1.4. Rhamnosyl Triflates. Synthesis of β-rhamnoside constitutes one of the most challenging problems in carbohydrate chemistry.128 Since the β-rhamnoside linkage is 1,2-cis, the neighboring group effect cannot be applied. Likewise, both the anomeric effect and the Δ2 effect favor formation of the α-rhamnoside.25 Due to the lack of a 6-OH, locking the conformation, as has been done in synthesis of βmannosides, is not possible. In an attempt to circumvent these problems, Crich et al.83 attempted to stabilize an α-triflate, thereby favoring a more covalent α-triflate as in the manno case. Two donors 171 and 173, having highly electron-withdrawing substituent at the O2 position (sulfonate and cyanate), were synthesized (entries 4 and 5, Table 7). To study α-triflate

intermediate from 162 but not from 158. Furthermore, the nature of the dioxolenium ion is also important. Benzoxonium ions stabilize the positive charge much better than acetoxonium ions. This can be seen for 121 (Scheme 19), which is the intermediate case. Here, the acetyl group is also less deactivating than the benzoyl group, giving rise to both αtriflate and dioxolenium ion. Electrochemical generation of an α-galactosyl triflate has been accomplished by Yoshida and co-workers.66 They studied the conversion of perbenzylated thiogalactoside 164 to its αtriflate 165 using VT-NMR (entry 2, Table 6). The conversion was performed under anodic oxidation in the presence of Bu4NOTf in CD2Cl2 at −78 °C, giving the α-triflate resonating at δH1 6.10 ppm (3JH1,H2 2.9 Hz) and δC1 106.9 ppm. Decomposition of the α-triflate was observed to take place above −60 °C, almost the same as the α-glucosyl triflate. αV


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stability, VT-NMR was conducted by activating the donors in CD2Cl2 at −60 °C with BSP/Tf2O. Both donors were activated in less than a minute, giving rise to an α-triflate with the sulfonate 172 resonating at δH1 6.26 ppm (3JH1,H2 1.8 Hz) and the cyanate 174 at δH1 6.24 ppm as a singlet (entries 4 and 5, Table 7). The α-triflate decomposed upon warming the NMR sample at −30 °C (cyanate-protected 174) and −10 °C (sulfonate 172), respectively. Glycosylation with the donors was greatly hampered by the highly disarming substituents. Therefore, Crich et al. concluded that a donor can be too disarmed. Conformationally constricted rhamnosyl donors have also been synthesized in an attempt to favor β-rhamnosylation. Thiorhamnosyl donors constricted by a 2,3- or 3,4-carbonate were synthesized (175 and 177) and studied with VT-NMR (entries 6 and 7, Table 7). 83 2,3-Carbonate-protected rhamnosyl donor 175 was activated with BSP/Tf2O in CD2Cl2 at −60 °C. Slow conversion into several species was observed, which subsequently converted exclusively into the αrhamnosyl triflate 176 (δH1 6.51 ppm). Upon warming to −15 °C, decomposition started without product being obtained, and therefore this donor was abandoned. Instead, 3,4-carbonateprotected rhamnosyl donor 177 was activated in the same manner, giving rise to a single α-triflate 178 (δH1 6.07 ppm, 3 JH1,H2 1.2 Hz). Warming the α-triflate in intervals revealed a relatively high degradation temperature of +30 °C. Glycosylation with this donor was possible, giving a 6:1 β/α-mixture with 3β-cholesterol as an acceptor but in moderate 62% yield. 3.1.5. Furanosyl Triflates. Lowary and co-workers129,130 used VT-NMR in a study of glycosylation with 2,3anhydrofuranosyl sulfoxides 188 and 190 (entries 1 and 2, Table 8). The 2,3-anhydrofuranosyl sulfoxide 188 was activated with Tf2O in the presence of DTBMP at −78 °C in CD2Cl2, giving rise to several peaks in the anomeric region. Upon warming to −40 °C over a 1 h period, the anomeric peaks were converted to a single signal, assigned as the α-triflate 189, δH1 6.4 ppm, δC1 109.2 ppm (1JH1,C1 197.2 Hz) (entry 1, Table 8). The same procedure was used on 2,3-anhydrofuranosyl sulfoxide 190, with the opposite epoxide giving the triflate 191, δH1 6.41 ppm, δC1 109.2 ppm (1JH1,C1 197.2) (entry 2, Table 8). The results were used to optimize the selectivity from moderate to giving only the desired anomer. Crich et al.131 have also observed, using VT-NMR, that the stereoselectivity in glycosylation with arabinofuranosyl donors was highly dependent on activation method. When 3,5-O-ditert-butylsilylene-protected thioglycoside donor 179 was activated with BSP/Tf2O in CD2Cl2 at −55 °C, a complicated anomeric mixture arose (Scheme 25a). Upon warming of the NMR sample to 0 °C, the mixture converted to essentially one anomer, assigned as the α-triflate 180 (δH1 6.1 ppm, 3JH1,H2 2.5 Hz). Further warming resulted in degradation of the triflate to the Friedel−Crafts product 181. In a different VT-NMR experiment, activation of 179 at −55 °C was followed by warming to −25 °C to ensure α-triflate formation. Then the sample was recooled to −70 °C before MeOH was added, giving 182 as an α/β-mixture of 1:3. These optimized conditions were used in glycosylation with sugar acceptors, giving higher β-selectivity than previously obtained. Likewise, similar results were essentially obtained with the enantiomer of this donor (183), although conversion to a single α-triflate 184 now occurred at −50 °C (Scheme 25b). The 3,5-Obenzylidene-protected thioglycoside donor 186 also underwent activation to give the α-triflate 187 (δH1 6.2 ppm, 3JH1,H2 2.3

Scheme 25. VT-NMR of Furanosyl Donors for Glycosylation Optimization

Hz), with decomposition setting in at −30 °C (Scheme 25c). Unfortunately, this donor was essentially unselective in glycosylation and very labile. 3.1.6. Uronic Acid Triflates and Derivatives. The first VT-NMR on uronic acids was performed by Codée, van der Marel, and co-workers132 in the mannuronic acid series. BDAprotected thiomannuronate 193 was activated with Ph2SO/ Tf2O in which an α-triflate 194 appeared, on the basis of the heteronuclear coupling constant (1JH1,C1 176 Hz; entry 1, Table 9).133 Decomposition was observed to initiate at −10 °C, which is 15 °C lower than for the nonoxidized counterpart according to Crich et al.87 (Scheme 12). This means the C5 carboxylate slightly destabilizes the α-triflate. The donor was moderately to highly α-selective in glycosylations, thereby excluding the αtriflate as the only reactive intermediate. Further VT-NMR studies of mannoazide uronate intermediates have been reported (Scheme 26).134,135 Activation of the thioglycoside donor 188 by Ph2SO/Tf2O or the imidate donor 189 by TfOH, both in CD2Cl2 at −80 °C, led to the formation of two triflates, one resonating at δH1 6.00 ppm, as a singlet, and one at δH1 6.22 ppm, with a coupling constant of 3JH1,H2 8.8 Hz. Upon warming of the NMR sample to −40 °C, the two resonance sets merged to one averaged set of signals. Recooling to −80 °C restored the two signals, indicating an equilibrium between the two compounds. This observation together with the large coupling constant led the authors to propose an equilibrium between α-triflates found in the 4C1 (190a) and 1C4 (190b) conformations, respectively. The latter conformation was found to be the most predominant (3:1). The method developed has been used for synthesis of highly anionic polymers of alginates consisting of β-mannuronic acids or β-mannuronic acids linked to the rare L-sugar137−141 α-L-guluronic acid.136,142 The preactivation method to give the α-triflates was additionally used in automated solid-phase synthesis of oligomers of βmannuronic acid alginates, which gave only the desired βglycoside.143 In a study on stereoselective synthesis of 2,3-diamino-2,3dideoxy-β-mannopyranosyl uronates, Codée, van der Marel, and co-workers106 studied the possible intermediate by VTNMR in glycosylation of various 2,3-diazido-2,3-dideoxythiomannosyl donors 115β, 117, and 191 (Scheme 27). All three donors were activated with Ph2SO/Tf2O at −80 °C, giving the W


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Table 9. Uronic Acid Triflates and Derivatives Detected by VT-NMR

a Gradual warming of the mixture was unproductive. bα-SPh was first converted to triflate at −40 °C. cAddition of MeOH resulted in 60% (α/β 1:5) methyl mannoside and regenerated donor. dAddition of MeOH resulted in 50% (α/β 1:5) methyl mannoside and regenerated donor and reduced thioglycoside donor. eα-Anomer required higher temperature for complete activation (−40 °C). fα-Anomer required higher temperature for activation (−10 °C), which matched the decomposition temperature. gInterconversion of the two chairs was so fast that no separation of signals was observed in 1H NMR. Conformation was greatly affected by temperature. No other NMR data available.

α-triflate as determined by VT-NMR. Coupling with acceptors clearly indicated a preference for the β-anomer (α/β 1:5.5) in the case of mannuronate donor 191, whereas unrestricted

mannosyl donor 115β was unselective (α/β 1:1) and 4,6-di-Obenzylidene-protected mannosyl donor 117 was α-selective (α/ β 3:1). Interestingly, mannuronic acid triflates 192a and 192b X


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triflates (kF > kN3 > kOBn). The former trend is attributed to more oxocarbenium character at C1 and therefore the mannuronic acid triflates tend to flatten their chair structures to accommodate this charge, thereby accelerating the conformational flipping. The latter was explained by the presence of smaller and more electronegative substituents to accommodate the positive charge on C1. Competition glycosylation between the three mannuronic acid triflates with methanol at −80 °C indicated that 2-OBn was slightly faster than 2-N3, which again was much faster than 2-F glycosyl triflate. Glycosylation of the latter did not even take place at −80 °C but required warming and excess acceptor. From these competition experiments, the authors concluded that the enhanced reactivity of the mannuronic acid triflate was not improved by the rate of ring flipping but is a consequence of the actual flip to the more reactive 1C4 conformation.145−149 A constricted galacturonic acid lactone 204 has also been studied by VT-NMR, in which an β-triflate 205 was observed, δH1 6.06 ppm, δC1 104.2 ppm (1JH1,C1 189 Hz) (entry 12, Table 9).150 This result was used to explain the high glycosylation selectivity under preactivation conditions. The preactivation method has been used in the synthesis of a trisaccharide repeating unit of the zwitterionic polysaccharide Sp1.151

Scheme 26. Mannuronic Acid Triflates Observed by VTNMR

Scheme 27. VT-NMR Studies on 2,3-Diazido-2,3Dideoxythiomannosyl Uronates

3.2. Other Glycosyl Sulfonates (-OSO2R)

In a recent paper by Issa and Bennett,152 building on earlier work by Schuerch and co-workers,37−39,43,44 anomeric tosylates of 2-deoxy hemiacetals were synthesized and substituted with sugar alkoxides. Issa and Bennett provided evidence for a covalent α-tosylate 207 using VT-NMR (Scheme 28). The hemiacetal 206 and TTBP were dissolved in deuterated tetrahydrofuran, THF-d8, followed by addition at −78 °C of potassium hexamethyldisilazide (KHMDS) before p-toluenesulfonic anhydride (Ts2O) was added. VT-NMR indicated an α-tosylate 207, resonating at δH1 6.11 ppm and δC1 102.3 ppm, which was stable up to −5 °C, by which the glycal was formed. Addition of sugar alkoxides to various 2-deoxy hemiacetals provided the β-linked disaccharide in moderate to good yield. Permethylated mannosyl phenylsulfonate 211 has been prepared and studied in VT-NMR from the corresponding fluoride 28 by reaction with trimethylsilyl benzenesulfonate (PhSO3TMS) in CD2Cl2 at 0 °C, giving the α-anomer (entry 2, Table 10).153 This was performed to verify this reactive intermediate in the sulfoxide covalent catalysis in which the process of hemiacetal sulfonylation was explored.153,154

were found to exist as a mixture of 4C1 and 1C4 conformers on the basis of the coupling constant, 3JH1,H2 8.4 Hz. By comparison of the decomposition temperatures, it is clear that the C5 ester has a destabilizing effect on the α-triflate. On the other hand, when decomposition temperatures of the 2,3diazido-2,3-dideoxymannuronic acid triflate are compared with those of mannuronic acid triflates having one or no azido groups (Table 9, entries 4 and 5; decomp −40 °C for both), it is clear that two azido groups greatly stabilize the triflate. The fact that mannuronic acid triflates (entries 4, 5, and 11, Table 9) are found in an equilibrium between two chair conformations (4C1 and 1C4) was studied by VT-NMR by Rönnols et al.144 The goal was to investigate the effect of the substituent’s influence on the conformation of the pyranose ring. First, it was found that mannuronic triflates preferred the 1 C4 conformation whereas methyl mannosides preferred the 4 C1 conformation. Second, by use of dynamic NMR spectroscopy at low temperature, it was concluded that the conformational exchange rate increased with increasing electronegativity of the aglycon (kOTf > kOMe > kSTol) and that smaller substituents at C2 leads to faster ring inversion of the glycosyl

3.3. Glycosyl Oxosulfonium Ions (-OS+R2)

Dehydrative glycosylation of the hemiacetals with an activated diphenyl sulfonium reagent has been disclosed by Gin and coworkers.155 In their mechanistic studies, they proposed the formation of a reactive oxosulfonium ion intermediate formed from reaction of the lactol with activated diphenyl sulfoxide (Scheme 29).67 This mechanism was verified on the basis of isotopic labeling and VT-NMR detection of reactive

Scheme 28. VT-NMR of 2-Deoxy Tosylates

Y


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Table 10. Other Glycosyl Sulfonates Detected by VT-NMR

a

A second species, resonating at δ 5.48 (3JH1,H2 = 3.9 Hz), was assigned to transient α-mannosyl oxosulfonium ion.

activation with Ph2SO/Tf2O, combining VT-NMR with selectively labeled donors and reagent. The proposed mechanism was confirmed by the detection of reactive intermediates by VT-NMR. First of all, activation of glycal 216 with Ph2SO and Tf2O in CD2Cl2 at −78 °C, followed by warming to −40 °C, led to oxosulfonium ion 218 (VT-NMR data, entries 2 and 4, Table 11). The conformation was established to be a twisted boat on the basis of all detected coupling constants in the pyranose and C1−H1 coupling, 1 JC1,H1 189 Hz (NMR data, entry 8, Table 11). Recooling to −78 °C followed by addition of MeOH/Et3N led to the glycosyl oxosulfurane intermediate 219, which could be observed by NMR (entries 3 and 5, Table 11). This glycosyl oxosulfurane was observed to be in a regular 4C1 conformation with manno stereochemistry as determined in an independent experiment (NMR data, entry 9, Table 11). Upon warming of the glycosyl sulfurane 219 to −20 °C, 1,2-anhydropyranoside 220 was revealed (NMR data, entries 6 and 7, Table 11). Introduction of a nucleophile and warming the reaction to room temperature led to formation of the 1,2-trans-linked glucoside 221. A minor byproduct (∼20%), corresponding to the C2-sulfonium glucal (δC1 161.245 ppm and δC2 97.567 ppm), was observed in the VT-NMR experiment, presumably a result of elimination of H2 (Scheme 31). In an attempt to direct the formation of the epoxide at the βface, Gin and co-workers157,158 used dibenzothiophene-5-oxide (DBTO) instead of Ph2SO. Opening of these epoxides with nucleophiles led to the formation of 2-hydroxy-α-mannosides. In VT-NMR experiments only the oxosulfonium ion (VTNMR data, entries 10 and 12, Table 11) and the β-faced 1,2anhydropyranoside (VT-NMR data, entries 11 and 13, Table 11) were observed, whereas the glycosyl oxosulfurane was not detected. An α-oxosulfonium ion 94 has been detected by VT-NMR in the 2-deoxy-gluco series, when the 4,6-di-O-benzylidene-3-Obenzyl-protected 2-deoxythioglucoside was activated with Ph2SO (2 equiv) and Tf2O (1.1 equiv) in CD2Cl2 at −60 °C (entry 17, Table 11). The anomeric proton resonated at δH1 6.51 ppm (3JH1,H2 2.4 Hz). No triflate or sulfonium ion was detected when BSP/Tf2O was used. An equatorial oxosulfonium ion 230 was observed when the hemiacetal of a mannuronic acid was activated with Ph2SO/ Tf2O (entry 18, Table 11).135 The compound was found to be in its 1C4 conformation on the basis of its anomeric shift and coupling constant (δH1 5.78 ppm, 3JH1,H2 8.3 Hz).

Scheme 29. Proposed Mechanism for Dehydrative Glycosylation via Oxosulfonium Ion Observed by VT-NMR

intermediates. The α-oxosulfonium ion 213 was detected in the reaction when permethylated mannose 212 was activated with Tf2O/Ph2SO and compared with a reference compound synthesized from its α-triflate 29 (see entry 1 in Table 11). The permethylated mannosyl α-oxosulfonium ion 213 was found to resonate at δH1 6.32 ppm. Furthermore, when an acid scavenger (2-chloropyridine) was added, a new intermediate appeared in the 1H NMR spectrum, corresponding to the glycosylpyridinium salt 214 as an α/β-mixture (α, δH1 6.63 ppm; β, δH1 6.49 ppm). This was confirmed by comparing with a synthesized reference compound. A similar α-oxosulfonium ion was observed by Boebel and Gin153 when the permethylated mannosyl α-triflate 29 was reacted with Bu2SO. The α-oxosulfonium ion 227 resonated at δH1 5.50 ppm (3JH1,H2 4.2 Hz) and δC1 108.27 ppm (1JC1,H1 178.5 Hz). Compared to their previous result with Ph2SO, a difference of Δδ 0.8 ppm is observed (compare entries 1 and 14, Table 11). Given the coupling constant between H1 and H2 (3JH1,H2 4.2 Hz) and the coupling between H1 and C1 (1JC1,H1 178.5 Hz), the conformation of pyranosides must be distorted or the anomer incorrectly assigned. Later, Frihed et al.69 observed the same tendency of glycosyl triflates to generate an oxosulfonium ion. In contrast to Gin and co-workers’ detection of an α-oxosulfonium ion, Frihed et al. characterized the first β-oxosulfonium ion 114β (δH1 5.78 ppm), which upon warming anomerized to the more stable αanomer 114α (δH1 6.47 ppm) (Scheme 30 and entry 19, Table 11). When MeOD-d3 was added to the mixture of α- and βoxosulfonium ion, the β-anomer reacted significantly faster. Gin and co-workers156,157 have also explored the mechanism regarding their oxidative glycosylation with glycal donors by

3.4. Glycosyl Sulfenates (-OSR)

Rearrangement of anomeric sulfoxides to their glycosyl sulfenates has been reported by Kahne and co-workers160 Z


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Table 11. Glycosyl Oxosulfonium Ions Detected by VT-NMR

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Table 11. continued

No other NMR data available. bAddition of extra Ph2SO led to conversion of α-triflate to β-oxosulfonium ion. Upon warming, β-oxosulfonium ion anomerized to α-oxosulfonium ion. DBTP = dibenzothiophene 5-oxide, Tf2O = trifluoromethanesulfonic anhydride (triflic anhydride), TTBP = tri(tert-butyl)pyrimidine. a

Scheme 30. Relative Ratios of Reactive Intermediates Observed in VT-NMR Experiments When 36 Is Activated at −80 °C

Scheme 31. Mechanism of Oxidative Glycosylation with Glycal Donors Explained by Intermediates Observed by VT-NMR

during Tf2O activation of glycosyl sulfoxides. Sulfenate 234 was observed by VT-NMR when perbenzylated fucosyl sulfoxide 232 was treated with Tf2O (0.34 equiv) at −78 °C giving the sulfenate, (δH1 5.01 ppm, 3JH1,H2 3.6 Hz, δC1 106.9 ppm; entry 1, Table 12). The experiment demonstrated that the catalytic cycle for conversion of sulfoxide to sulfenate is at play. This led Kahne and co-workers to propose a mechanism taking the sulfenate into account (Scheme 32). The sulfoxide can either be triflated to produce the activated species (path A) or

glycosylated to form the sulfenate (path B). The reactive intermediate can react either with an acceptor (path C) or with the sulfoxide (path B). Kahne and co-workers noticed that the sulfenate could be activated at higher temperatures, complicating the mechanistic understanding of Tf2O-mediated activation of sulfoxides. Glycosyl sulfenate 236 has also been synthesized by Lowary and co-workers129 from the corresponding lactol 235 (entry 2, Table 12), in order to exclude the intermediate in activation of furanosyl sulfoxide. AB


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Table 12. Glycosyl Sulfenates Detected by VT-NMR

a

Several anomers equilibrating into one over 80 min.

di-O-benzyl-5-deoxy-5-thio-α-D-xylopyranose. This thioglycoside was activated by methylation, which could be monitored by NMR. As Lundt showed (in the early 1980s), these type of compounds are stable even at room temperature. Formation of a similar bicyclic sulfonium intermediate has also been found upon glycosylation of 6-thiomannosides. Codée and co-workers163 studied the reaction by VT-NMR, where the 6-thiophenyl-6-deoxymannosyl donor 238 was activated at −80 °C using an equimolar amount of TfOH in CD2Cl2 (Scheme 33). Bicyclic sulfonium ion 239 was formed instantaneously and proved to be stable even at room temperature (entry 32, Table 13). Quenching the reaction with MeOH-d4 at room temperature gave the methyl mannoside 240 as an anomeric mixture, whereas β-selectivity was restored upon cooling to −60 °C. This selectivity was suggested to be dependent on a Curtin−Hammett scenario, where the reaction on the 3H4 oxocarbenium ion provides the selectivity and the bicyclic sulfonium ion functions as a reservoir of this conformation. Direct attack, at higher temperatures, on the sulfonium ion results in α-selectivity. Similar selectivity was obtained with other heteroatoms on C6. The first low-temperature NMR studies of sulfonium ion intermediates appeared from Liu and Gin,164 who were studying the mechanism of a novel glycosylation method with Tf2O and thianthrene-5-oxide as the promoter system for a one-pot C2-amidoglycosylation for synthesis of 2-N-acetyl-2deoxy-β-pyranosides from glycals (Scheme 34). The mechanism was studied by use of labeled glucals, i.e. 13 C-1 or 13C-2. 15N-Labeled N-(TMS)-benzamide, the Nnucleophile, was also included in the study, to verify the attack on the anomeric position by 15N−13C three-bond coupling. When the labeled glucal derivatives were activated by the promoter system at −60 °C, a complex mixture of reactive intermediates appeared. However, this simplified upon addition of the N-nucleophile at −20 °C (entries 1−3, 5, and 7, Table 13). Raising the temperature to 20 °C resulted in formation of

Scheme 32. Potential Pathways in Activation of Sulfoxide

4. S/SE SPECIES 4.1. Glycosyl Sulfonium and Selenium Ions (-S+R2 and -Se+R2)

Migration of alkyl- and arylthiols is a common byproduct of nucleophilic displacement reactions on, for example, thioglycosides, and a sulfonium ion was therefore early suggested as a transient intermediate. The existence of this normally highly reactive salt was proven by the isolation of 2,3,4-tri-O-acetyl1,6-anhydro-6-thio-β-D-glucopyranose-(S)-ethylsulfonium tetrafluoroborate 237 by Lundt and Skelbæk-Pedersen161 (Figure 6). Interestingly, it was observed that hard nucleophiles preferred reaction at the anomeric carbon, whereas softer sulfur nucleophiles preferred C6.

Figure 6. First isolated sulfonium ion.

A similar cyclic sulfonium ion has recently been studied by NMR by Turnbull et al.,162 who synthesized 1,4-anhydro-2,3-

Scheme 33. Formation of Bicyclic Sulfonium Ion Observed by VT-NMR

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Scheme 34. Mechanistic Study of Formation of Aminoglycoside from Glycals by Use of VT-NMR

in solid-supported synthesis using the chiral auxiliary to provide the 1,2-cis selectivity.167 In a later study by Boons and coworkers,168 substituent effects were studied and the benzylated donor with the C2 chiral moiety was monitored by VT-NMR. The trans-decaline sulfonium ion was again observed (entry 9, Table 13) when the donor was activated at −50 °C, followed by an increase in temperature to −20 °C. No signal attributed to glycosyl triflates, oxocarbenium ion, or α-sulfonium ion were observed. The anomeric selectivity was, however, not preserved, which was explained with a Curtin−Hammett scenario, where a more reactive (unstable) intermediate competed with the trans-decaline system. Recent studies by Boons and co-workers169 have revealed that the intermediate cyclic sulfonium ions are stable even above room temperature and that the corresponding sulfoxides can be activated selectively over the cyclic sulfides, that is, an active-latent glycosylation strategy (entries 10−16, Table 13). Inspired by the work of Boons, Turnbull and co-workers170 developed a similar participating sulfide, which could be installed more easily than the initial moiety developed by Boons. Introduction of the directing moiety was mediated by synthesis of a thioglycoside that contained a ketone in the aglycon (Scheme 37). This cyclized, upon treatment with acidic methanol, to regio- and stereoselectively give a methyl ketal with the unprotected 2-OH. Oxidation of the cyclic sulfides gave the corresponding sulfoxides 250, which could be activated by Tf2O in CDCl3 followed by the addition of 1,3,5-trimethoxybenzene. The activation was monitored by VTNMR at −30 °C and the trans-decaline system could be observed, confirming the formation of a six-membered cyclic sulfonium ion 252 (entry 17, Table 13). The splitting of the aromatic signals at low temperature followed by coalescence by gradually warming the sample and finally sharpening indicated hindered rotation of the aromatic group. The mechanism of the oxathiane induced stereoselectivity on glycosylation has been further studied to elaborate whether the sulfonium ion engages in neighboring group participation (SN2 type reaction) or if they are simply just a stable intermediate (SN1 type reaction).171 To increase the stability of the glycosylation product, oxathiane spiroketal donor 253 was developed and activated by the sulfoxide method described above (Scheme 38). Formation of sulfonium ion 254 was followed by NMR

the oxazoline (entries 4 and 6, Table 13). The attack by oxygen at the anomeric position, by the neighboring amido group, could be confirmed by use of a 47% 18O-labeled amide, which resulted in two 13C-1 signals. Performing the same experiment on the 13C-2-labeled glucal did not induce a shift. The conformation of the intermediates was determined by VTNMR with deuterated benzyl groups to avoid overlap with the carbohydrate signals in the 1 H NMR spectra. A 4 C 1 conformation with manno stereochemistry was suggested on the basis of this experiment. Related to the mechanism studied by Gin, where an amide migrated from C1 to C2 during the glycosylation, Lowary and co-workers165 have studied a 2,3-anhydrosugar migration− glycosylation reaction of thioglycosides (Scheme 35). VT-NMR studies at −78 °C with TMSOTf as the activator revealed that a complex mixture of activated species appeared. Increasing the temperature in 10 °C intervals did not simplify the spectra. Attempts to generate the proposed episulfonium ion by other means gave the same complex mixture. Allowing the reaction to reach room temperature resulted in hydrolyzed donor. Furthermore, the reaction was studied by the aid of density functional theory (DFT) calculations, substituent effects, and kinetic isotope effects. On the basis of these studies and VTNMR, a mechanism, without an episulfonium ion intermediate, was suggested. The ring size of the sulfonium ion intermediate is clearly crucial for its stability and hence detection by VT-NMR. The three-membered episulfonium ion could not be observed directly, but the high stereoselectivity suggests its existence. The increased stability of larger rings has been used to form stable but reactive intermediates in glycosylation reactions. Boons and co-workers166 were pioneers in this area, and with the use of VT-NMR they could establish that 1,2-trans-vicinal six-membered sulfonium ions 248 are formed, when (1S)phenyl-2-(phenylsulfenyl)ethyl is present as a moiety at C2 of a glycosyl donor 247 (Scheme 36). The (S)-stereochemistry of the C2 moiety is decisive for the selectivity, as it forms a stable trans-decaline ring system (entry 8, Table 13). As the transdecaline system shields the β-site 1,2-cis selectivity is obtained; that is opposite to the 1,2-trans selectivity with classical fivemembered ring neighboring group participation. Changing the C2 moiety to the opposite (1R)-stereochemistry resulted in an anomeric mixture (α/β ∼ 1:1). The new concept for neighboring group participation has been used AD


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Table 13. Glycosyl Sulfonium and Selenium Ions Observed by VT-NMR

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Table 13. continued

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Table 13. continued

a

Changes in chemical shift were observed for H1 and H8a/b upon activation, and cross-correlations were seen between C1 and H8eq in HMBC spectra. bReversible temperature dependence upon addition of SnBr4 at −50 °C. Complete conversion to sulfonium ion was seen at −80 °C, while only traces of this ion were seen at −20 °C.

Scheme 35. Proposed Mechanism for Formation of 2-Deoxy-2-thioaryl Glycosides

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Scheme 36. Chiral Auxiliary-Mediated 1,2-cis-Glycosylation

Scheme 37. Generation of Chiral Auxiliary from Sulfoxide As Detected by VT-NMR

Scheme 38. Spiroketal-Generated Sulfonium Ion Detected by VT-NMR

α-selectivity was notably found to be higher for the armed analogue (R = Bn). The use of five-membered cyclic sulfonium ions to control the stereoselectivity has obviously also been used and resembles the more classical neighboring-group participation of C2 ester groups. Wei and co-workers174 have used glycosyl dithiocarbamates, for example, donor 258, and studied the activation by CuOTf(C6H6)0.5, monitoring the reaction with VT-NMR (Scheme 40). The donors were synthesized from the corresponding glycal by use of dimethyldioxirane (DMDO) for epoxide formation, followed by opening with R2NH and CS2 to give the dithiocarbamate with a free 2-OH. Activation at −50 °C resulted in disappearance of the dithiocarbamate signal (C7) as well as the characteristic carbohydrate signals (e.g., C1). At −10 °C two major products, in a 1:1 ratio, were observed and attributed to the five-membered o-dithiocarbamate copper complex 259 (entry 33, Table 13). The appearance of the minor signal at 197.0 ppm was suggested to appear from a stabilized oxocarbenium ion species 260, but it is probably more likely to be the ion 261. Performing the study on tetra-O glucosyl dithiocarbamate 295 showed mainly one activated species and again a signal at 197.2 ppm (entry 34, Table 13). No further studies were performed to clarify the structure of these activated species. The use of sulfonium ions in glycosylation chemistry has very recently received more attention, as stable glycosyl donors but also as intermediates in glycosylations where sulfides have been

(entry 18, Table 13). The increased stability resulted in slow glycosylations even at ambient temperatures.172 The generality of neighboring-group participation via sixmembered ring systems has been further studied by Fairbanks and co-workers,173 using 2-iodo- and 2-(phenylseleno)ethyl ethers 255 and 256 as the C2 moiety (Scheme 39). Scheme 39. Glycosyl Selenium Ion Detected by VT-NMR

Surprisingly, it was observed that the more reactive (armed) donors were more α-selective, which is in contrast to the observations by Boons and Turnbull. Low-temperature NMR at −78 °C revealed that the 2-iodoethyl ether did not form cyclic intermediates, and hence no evidence for participation could be demonstrated. However, the corresponding disarmed phenylseleno donors 256 formed cyclic selenium ion 257, which was seen from the chemical shifts of H1 and H8eq changing upon activation (entries 19−21, Table 13). The formed ring was found to be β-configured from 3JH1,H2 (9−10 Hz). Correlations, observed by heteronuclear multiple-bond correlation (HMBC) spectra, between C1 and H8eq confirmed the connectivity. The

Scheme 40. Intermediates Detected by VT-NMR from Activation of Glycosyl Dithiocarbamates

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Scheme 41. Glycosylation with Intermediate Sulfonium Ions As Detected by VT-NMR

used as additives, somewhat similar to the so-called “ether effect”.19,175 Boons and co-workers125 used ethyl phenyl sulfide and thiophene as additives to promote α-selectivity in the glycosylation with 2-azido-2-deoxyglucosides (Scheme 41 and entry 22, Table 13). Activation of the trichloroacetimidate donor 154 was monitored by VT-NMR, which confirmed the formation of two diastereomeric β-sulfonium ions 156 (δH1 5.95 ppm, d, 3JH1,H2 10.0 Hz; δH1 5.48 ppm, d, 3JH1,H2 10.0 Hz) as well as an intermediate α-triflate 155 (δH1 6.50 ppm, d, 3 JH1,H2 3.5 Hz), which upon heating to 0 °C was transformed into β-sulfonium ions 156. The connectivity was confirmed by a HMBC spectrum and the stereochemistry by NOESY. Nokami et al.122 generated the same intermediate α-triflate 155 by electrochemical oxidation of the corresponding thioglycoside 157. This α-triflate was reacted with dimethyl sulfide at −78 °C and two new compounds appeared (Scheme 42). VT-NMR studies revealed that both 264β, as observed

of the reaction showed the formation of one major sulfonium ion with β-stereochemistry. Monitoring of the reaction at higher temperature revealed that the dimethyl sulfonium ion 265 was stable at 0 °C, whereas the methyl phenyl sulfonium ion 266 decomposed. This difference in stability was also observed in their respective reactivity in glycosylation reactions, where the dimethyl sulfonium ion was activated at 23 °C and the methyl phenyl sulfonium ion at −30 or −10 °C. The difference in reactivity between the two diastereomeric methyl phenyl sulfonium ions was also studied by NMR between −80 and −10 °C. Stereoselectivity was ensured by the participating N-phthalimide group. The addition of thiophene and dimethyl sulfide to glycosylations of oxazolidinone-protected glucosamine and galactosamine was studied by Geng and Ye.115 Preactivation of the thioglycoside was used as the glycosylation method to give an α-glycosyl triflate. Addition of thiophene gave high αselectivity, and from low-temperature NMR it was proposed that the α-triflate was the glycosylating species, since no other intermediates could be observed. The β-product was found to be the kinetic product, which then anomerized to the thermodynamic α-anomer. Dimethyl sulfide as an additive gave rise to formation of a β-sulfonium ion, depending on the equivalents used; that is, more dimethyl sulfide gave more βproduct, while catalytic amounts resulted in α-selectivity (entry 26, Table 13). These effects of the additives were explained by different effects on the anomerization taking place after glycosylation, which could then be slowed down by the dimethyl sulfide. Access to glycosyl sulfonium ions can also be obtained directly from the thioglycoside by S-alkylation, as already describe for the cyclic sulfonium ions. Demchenko and coworkers176 have studied the methylation of ethyl thioglycosides and found that the β-anomer was significantly more stable than the α-anomer and that a participating benzoyl ester on C2 increased the reactivity. β-Sulfonium donors having a nonparticipating group on C2 and electron-withdrawing groups on the remaining positions could be isolated and NMR spectra recorded at room temperature. NMR spectral data of the C2 benzoyl derivative could not even be obtained by lowtemperature NMR due to neighboring-group participation. The existence of sulfonium bistriflate species has also been suggested on the basis of VT-NMR studies (Scheme 44). Van der Marel and co-workers135 observed the formation upon activating an sulfoxide donor 199a with Tf2O at −50 °C: when MeOH-d4 was added to the reaction, the methyl glycoside as

Scheme 42. Glycosyl Sulfonium Ions from Dimethyl Sulfide Observed by VT-NMR

earlier, but also α-sulfonium ions 263α were generated (entry 23, Table 13). Whereas the β-sulfonium ion was found to reside in a 4C1 conformation, NMR of the α-anomer indicated a distorted conformation, which was further supported by molecular orbital calculations. The anomeric ratio remained constant even at room temperature and is probably the kinetic products from reaction of various conformations of the oxocarbenium ion intermediate. Reaction of sulfonium ion 264β with MeOH revealed that the α-anomer was consumed first, giving a 1:3 (α:β) product ratio, again suggesting an oxocarbenium ion as the reactive intermediate. The β-anomer reacted only slowly and did not alter the product ratio. The generation and stability of glycosyl sulfonium ions were further studied with the N-phthalimide-protected thioglycoside 146, which was transformed into the reactive α-glycosyl triflate 147 (Scheme 43).123 Reacting this with dimethyl sulfide or methyl phenyl sulfide gave the corresponding sulfonium ions 265 and 266 (entries 24 and 25, Table 13). VT-NMR studies

Scheme 43. Various Glycosyl Sulfonium Ions Detected by VT-NMR from Corresponding α-Triflates

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understanding what is now regarded as fundamental organic chemistry, such as neighboring-group participation. Two research groups were at the forefront in these studies on carbohydrates by low-temperature NMR: Paulsen and Pedersen with their respective collaborators. Paulsen et al.179 studied the preparation of 1,2-acetoxonium ions in hexoses and pentoses and were able to record the first NMR spectra of these very reactive intermediates in the mid1960s. Dioxolenium ions were prepared from, for example, peracetylated β-D-glucosyl chloride 302 by treating it with antimony pentachloride (SbCl5) (Scheme 46). The NMR

Scheme 44. Generation of Mannuronic Acid Sulfonium Ions from Their Corresponding Sulfoxides

Scheme 46. Acetoxonium Ions Detected in Inversion of DGlucose to D-Idose

well as the regenerated donor were observed, which supports a sulfonium bistriflate as the reactive intermediate. Furthermore, low-temperature NMR showed that α- and β-sulfoxide donors 199a and 199b gave different intermediates and that the 13C NMR shifts indicated an anomeric thio group (entries 27−29, Table 13). The two different sulfur diastereomers of the αdonor did also activate to give different intermediates, and the addition of MeOH-d4 gave, besides the methyl glycosides, also the corresponding parent sulfoxide donor and the thioglycoside. As illustrated above, only little is known about the mechanism of some of the most-used glycosylation reactions, and not until the past decade have some of the effects influencing stereochemical selectivity and reactivity been discovered.

spetrum was recorded in CD3NO2 and compared with the shifts found by Winstein and co-workers.180 The exact conditions for NMR measurements are unfortunately not clear from this paper, but later studies suggest that the temperature was around −25 °C. With formation of the 1,2-Oacetoxonium ion 303 upon treatment of glucosyl chloride 302 with SbCl5 established, the reaction was studied in detail. This resulted in the very elegant synthesis of D-idose from D-glucose via acetoxonium ion rearrangements along the sugar ring, driven by the crystallinity of the acetoxonium salt of the tetraacetylidose 304, which could be studied by VTNMR.181,182 Interestingly, it was observed that the rearrangements were strongly dependent on the anion to the acetoxonium ion, where the BF4 salt was stable in the gluco form but the SbCl6 salt spontaneously rearranged to the D-ido form. In a seminal paper by Pedersen183 on the reaction of cis- and trans-1,2-diacetoxycyclohexane with anhydrous HF, it was stated that 2-methyl- and 2-phenyl-1,3-dioxolenium cations are formed in carbohydrates. The details of this work are described together with Lundt,184 where tetra-O-benzoyl-2deoxy-D-arabino-hexopyranose 306 is converted into the 3,4,6tri-O-benzoyl-2-deoxy-α-D-ribo-hexopyranosyl fluoride 308 via inversion (Scheme 47). The intermediate 2-methyl- or 2-

5. O SPECIES 5.1. Glycosyl Perchlorates (−OClO3)

One of the first reactive intermediates to be synthesized and studied by VT-NMR was glycosyl perchlorate. Igarashi et al.178 treated both α- and β-3,4,6-tri-O-acetyl-2-chloro-2-deoxyglycosyl chloride in the gluco 298 and manno 300 series with silver perchlorate (Scheme 45). In the gluco series, both α- and βScheme 45. Glycosyl Perchlorates Observed by VT-NMR

Scheme 47. Dioxolenium Ion Detected by VT-NMR

chloride formed an unstable α-perchlorate 299 as observed by VT-NMR at −5 °C, resonating at δH1 5.52 ppm and 3JH1,H2 4.0 Hz. In regard to the manno series, a similar α-perchlorate 301 was recorded (δH1 5.89 ppm and 3JH1,H2 1.5 Hz). Methanolyses of the α-perchlorates gave rise to the expected methyl glycosides, respectively. These results indicate that the perchlorate ion can form a covalently attached intermediate and does not necessarily give rise to the oxocarbenium ion.

phenyl-1,3-dioxolenium ion 310 was observed at −70 °C, where the respective signals appeared after approximately 10 days reaction time. Raising the reaction temperature to −10 °C decreases the reaction time to 40 min. Reactions of sugar esters in anhydrous HF were expanded to hexoses, where the pentaacetates of D-glucose, D-mannose, and 185 D-altrose were found to give complicated product mixtures. Treatment of the tetraacetates or tetrabenzoates of the corresponding methyl glycosides 311 with HF gave higher

5.2. Glycosyl Dioxolenium Ions

Dioxolenium ions represent the first ionic glycosylation intermediates studied by VT-NMR and an area where the (at the time) new NMR technique had a huge impact on AJ


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Scheme 48. Dioxolenium Ion Observed by VT-NMR

neighboring-group participation but unlikely to give the orthoester byproduct.127 The mechanism was studied by VTNMR, and it was found that the per-Mez-protected donor initially transformed into the galactosyl triflate when activated at −60 °C. In time and at higher temperatures (around −10 °C), the triflate was transformed into the dioxolenium ion, which was the major product at 0 °C (entries 17 and 18, Table 14). The ratio between galactosyl triflate and dioxolenium ion was found to be dependent on the protective group pattern; when only one Mez group was introduced, a 1:1 mixture was obtained and remained unchanged despite temperature variation. The 1H and 13C shifts observed by Williams et al.107 (entry 20, Table 14) are comparable to those obtained by Huang with acetyl and benzoyl as the participating neighboring group. Similar dioxolenium ions have been observed in the carbohydrate-related inositols, where acid hydrolysis of myoinositol 1,3,5-orthobenzoate 317 was found to give a 1,2dioxolenium ion 319, which suggested migration of an 1,3dioxolenium intermediate 318 (Scheme 50). The VT-NMR study provided mechanistic details explaining the high selectivity for formation of 2-O-benzoyl-myo-inositol.190192

yields of the 1,6-anhydride (such as 314). The reactions were monitored by VT-NMR at 0 °C, and signals from several acyloxonium ions were observed (Scheme 48). Monitoring of the reactions furthermore revealed that the anomeric fluorides were the initial products and the formation temperature of the acyloxonium ions depended on the exact configuration of the sugar. With the aid of monitoring the reactions by VT-NMR, methyl tetra-O-benzoyl-α-D-glucopyranoside 312 was transformed into 1,6-anhydro-β-D-altropyranose 314 in 45% yield (after debenzoylation). The selective formation of altrose in HF contradicted the observation by Paulsen, described above, where idose was the major product; this can be explained by the 1,6-anhydro formation, which only takes place in HF. Similar studies were performed on the reaction of D-xylose and D-lyxose derivatives in anhydrous HF, where tetra-Obenzoyl-α-D-xylofuranose rearranges via the acyloxonium ion to tri-O-benzoyl-α-D-lyxofuranosyl fluoride. The other tetraacetate derivatives, lyxo-furanoses and pyranoses as well as xylopyranose, gave complex mixtures. NMR spectra of the dioxolenium ions were recorded at 0 °C, and the 13C NMR spectra of eight species were obtained.186 Defaye, Pedersen, and co-workers187 studied the synthesis of oxolanes from alditols, hexoses, and hexonolactones mediated by carboxylic acids in anhydrous HF. The intermediate acyloxonium ions were observed in 13C NMR at −10 °C, and 17 different dioxolenium ions were assigned. As described above, the first 25 years of studies of dioxolenium ions focused on monosaccharide conversion by inversion of stereocenters and dehydrations. At the edge of the new millennium, the focus changed toward glycosylation mechanism, where neighboring-group participation via a dioxolenium ion has been a tenet in stereoselective glycosylation since the very beginning. With the interest in glycosylation intermediates from the work on glycosyl triflates, Crich et al.188 studied bridging dioxolenium ions by VT-NMR at −78 °C and were able to obtain spectra of the intermediate 316 in a β-xylosylation (Scheme 49). The observed shifts were

5.3. Glycosyl Imidates and Imidinium Ions [−OC(N+R2)R′]

Despite the fact that imidates are among the most widely used glycosyl donors, only a few studies have appeared investigating these reactions at low temperature by NMR. An early study was performed by Gross and co-workers, who treated the sugar hemiacetal 346 with the Vilsmeier−Haack reagent N,Ndimethylformamide (DMF)−COCl2 to achieve an anomeric mixture of glycosyl imidinium ions 347, which could be observed at −50 °C by NMR (Scheme 51).201 Upon heating the sample to room temperature, all the signals from the activated species disappeared, and the signal from glycosyl chloride 348 appeared. This less-reactive donor could then eventually be transformed into the more reactive α-tosylate by reaction with AgOTs. The high α-selectivity obtained with mannofuranoside as the donor was explained by interaction of DMF, where the β-imidinium salt presumably was more reactive and α-selective. Without the presence of DMF, anomeric mixtures were obtained. This suggests a Curtin− Hammett scenario, which drives the reaction toward the αproduct. Since the pioneering work by Gross, several similar methods using DMF as an additive to enhance the α-selectivity have appeared, and the mechanism has been studied.193,194 Investigations of the effects of DMF in modulating the outcome of glycosylation reactions have recently been carried out by Mong and co-workers195,196 using NMR. Initially the reactions were initiated at low temperature and analyzed by NMR (presumably at room temperature). In later studies with 2-azido-2-deoxyglycosyl donor 349, low-temperature NMR was applied to probe the glycosyl imidinium adducts.197 From these

Scheme 49. Dioxolenium Ion Detected by VT-NMR

similar to the ones observed by Pedersen described above. The mechanism for neighboring-group participation suggested by Crich was in line with computational work by Whitfield and coworkers.189 Williams et al.107 performed a similar study in the galacto series, using NIS and equivalent amounts of TfOH to activate the thiogalactoside. 2,4,6-Trimethylbenzoyl (Mez) was used as a sterically hindered ester protective group capable of AK


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Table 14. Glycosyl Dioxolenium Ions Observed by VT-NMR

AL


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Table 14. continued

a

Upon further reaction with HF, ions rearranged to 2,3-acyloxonium ions; see entry below. bUpon further reaction with HF, 1,2:3,4dibenzyloxonium ion was formed; see entry below. cSignificant anomeric downfield shift from 4.98 to 7.34 ppm (H1) upon activation, while H2 shifted slightly from 5.66 to 5.77 ppm. Likewise, in 13C NMR the benzoyl C7 peak at δC7 165.6 ppm decreased and a new appeared at 180.8 ppm. Mez =2,4,6-trimethylbenzoyl.

Scheme 50. Dioxolenium Ion from Inositols Detected by VT-NMR

Scheme 51. Imidinium Ions Observed by VT-NMR upon Treating the Lactol with Vilsmeier−Haack Reagent

VT-NMR studies using different amide additivesDMF, diisopropylformamide (DIPF), and N-formylmorpholine (NFM)both imidinium anomers were observed and the respective equilibrium constants could be determined (Scheme 52 and entries 4−6, Table 15). Interestingly, it was observed that the β-imidinium ions, which were less favored, also gave

the fastest reaction. This is similar to the in situ anomerization method, catalyzed by halide ions, developed by Lemieux et al.198 The α-imidinium adducts were in all cases more stable as judged from the equilibrium constants, but the reaction was αselective as observed by Gross. AM


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Scheme 52. Imidinium Ions Observed by VT-NMR Used as Modulating Reagents in Glycosylation

and converted into the triflate when the acceptor was added. This suggests that p-TolCl is the actual promoter, whereas silver salts are driving the reaction by precipitation of AgCl. TMSOTf did not promote the reaction of the intermediate glycosyl chloride. Whether this new proposed reaction path is general for Koenigs−Knorr-type glycosylations has yet to be studied. Demchenko and co-workers205 studied the activation of thioglycosides 370 in the presence of bromine and found, by VT-NMR, that the more reactive β-glycosyl bromide 371β was the kinetic product and the actual glycosyl donor (Scheme 57). This VT-NMR study was conducted by freezing a NMR tube containing the thioglycoside to −196 °C, followed by addition of bromine and insertion into the NMR instrument. This method allows measurement of the initial product formation but at the expense of any precise knowledge of the actual temperature in the sample. Reaction of the formed β-glycosyl bromide 371β with a sugar hydroxyl group gave the α-linked 372 with high selectivity. Furthermore, it was found that the βbromide 371β slowly anomerized to the unreactive α-anomer 371α. A similar approach was conducted by Daly and Scanlan206 for formation of a fucosyl bromide from 2,4-di-O-silyl-protected thiofucoside having an unprotected 3-OH (entry 9, Table 16). In contrast to the work by Demchenko and co-workers on glucosides, it was found that only the α-bromide was formed and this was stable even at 0 °C. Additionally, it was realized that silver triflate promotion was required for glycosylation. Use of glycosyl iodides as glycosylating agents has traditionally been limited due to their low stability and shelf life. Recently, however, there has been increasing interest in using glycosyl iodides, and several approaches for their in situ syntheses have appeared. Gervay-Hague and co-workers207,208 have developed a method based on regioselective silyl exchange, where a fully silylated saccharide is converted to the glycosyl iodide by use of TMSI (entries 10−13, Table 16). Glycosylation with an additional iodide source, such as TBAI, results in a Curtin−Hammett scenario, where the more reactive β-anomer reacts and preferentially gives the α-glycoside. The formation of α-lactosyl iodide 374 has been monitored by VTNMR at 0 °C (Scheme 58 a). Similarly, conversion of peracetylated lactose 384 to β-iodide 385β has been monitored, as well as the following anomerization to the less reactive αlactosyl iodide 385α (compare entries 12 and 13, Table 16).209 This glycosylation method has been used for the synthesis of tumor-associated carbohydrate antigens, such as globotriosyl and isoglobotriosyl ceramide (GB3 and iGb3). Formation of the peracetylated globotriosyl iodide 376 was also monitored by VT-NMR (0 °C to rt, Scheme 58 b).208

With the influence of imidinium intermediates on the stereochemical outcome from armed perbenzylated glycosyl donors as well as disarmed 2-azido-2-deoxyglycosyl donors (described above), attention was shifted to the much more reactive 2-deoxy and 2,6-dideoxy sugars (e.g., 351), where the lack of a C2 substituent complicates stereocontrol for both αand β-anomers (Scheme 53). 199 Activation of the 2deoxythioglycoside in the presence of DMF was monitored by NMR at −40 °C. Again the α-imidinium ion 352 was found to be the major product. The β-anomer, however, could not be observed, which might be due to its high reactivity (entry 7, Table 15). In this case, low temperature was crucial due to the high reactivity of the intermediates, as they readily eliminate to the glucal 353 at −20 °C and above. Recently, Demchenko and co-workers200 have shown that 3,3-difluoroindole (HOFox) can catalyze glycosylation reactions by working as a nucleophilic catalyst (Scheme 54). Glucosyl bromide 356 was generated from the corresponding thioglycoside 354 and subsequently activated with Ag2O. In the presence of HOFox the reaction was accelerated, but the yield and anomeric selectivity remained essentially unaffected by the amount of catalyst used. In situ formation of an OFox donor 355 was observed by NMR at 0 °C (entry 8, Table 15), and in this case the β-anomer was found to be the major product (α/β ∼ 1:6).

6. MISCELLANEOUS 6.1. Glycosyl Halides

Glycosyl halides were traditionally the most widely used family of glycosyl donors, but their reactions have not been studied much by low-temperature spectroscopy. There are, however, several studies where glycosyl halides have been prepared in situ and transformed to other more reactive and hence unstable intermediates, such as dioxolenium ions and ammonium derivatives. Reactions involving a transient halide have been monitored by VT-NMR. D-Fructofuranosyl fluoride 366 was found to be an intermediate in the conversion of inulin and Dfructose to D-fructose dianhydrides with HF as an anhydrous solvent (Scheme 55 and entry 4, Table 16).202 Similar NMR studies (performed at 0 °C) of the behavior of L-sorbose dissolved in HF revealed that L-sorbofuranosyl fluoride was formed as an intermediate to the L-sorbose dianhydrides (entry 5, Table 16).203 2-Deoxyglycosyl chloride 368 has been observed as intermediate when a preactivation procedure of thioacetal 367 with AgOTf and p-TolSCl was performed (Scheme 56). This method has been developed for in situ formation of glycosyl triflates, and formation of the chloride 368 was therefore surprising. Verma and Wang204 studied the reaction by VT-NMR and found that the chloride 368 is initially formed AN


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Table 15. Glycosyl Imidates and Imidinium Ions Observed by VT-NMR

Higher temperature than −40 °C led to various amount of glycal approaching 100% at −10 °C, even with 8 equiv of DMF. DIPF = N,Ndiisopropylformamide, DMF = N,N-dimethylformamide, Fox = 3,3-difluoro-3H-indol-2-yl, NFP = N-formylmorpholine. a

Scheme 53. Imidinium Ions Observed by VT-NMR in the 2-Deoxy Series

AO


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Scheme 54. Glycosyl Imidates Detected in Regenerative Glycosylations

or intermediates has been well documented. The mechanistic studies are, however, more sporadic. As with the imidinium salts, Gross was a pioneer in this field, using VT-NMR to monitor the activation of anomeric hydroxyl groups with tris(dimethylamino)phosphine (TDAP) in combination with CCl4 to generate alkyloxy tris(dimethylamino)phosphonium (ATDP) salt 386 from 2,3,5,6-diisopropylidene-α-D-mannofuranose 346 (Scheme 59).210 The stability of the generated phosphonium salt was analyzed by gradually raising the temperature: at −10 °C, decomposition began, and at room temperature, only the mannosyl chloride 387 and hexamethyl-

Scheme 55. Glycosyl Fluoride Observed by VT-NMR

6.2. Glycosyl Phosphonium Salts (-P+R3)

Related to the use of imidinium ions as anomeric dehydrating agents, the use of phosphonium ions as glycosylation reagents Table 16. Glycosyl Halides Observed by VT-NMR

AP


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Scheme 56. Glycosyl Chloride Detected by VT-NMR

Scheme 57. Glycosyl Bromide Detected by VT-NMR

Scheme 58. Glycosyl Iodides Generated in Situ and Detected by VT-NMR

Scheme 59. Furanosyl Phosphonium Ions Detected by VT-NMR

Scheme 60. Mannosyl Phosphonium Ions Detected by VT-NMR

389 was reacted, only the α-anomeric oxyphosphonium chloride 390 was observed, but it could not be isolated.211 When this reactive intermediate was reacted with an alcohol acceptor, formation of the orthoester 391 was dominant, whereas the thiophenol, being a stronger nucleophile, gave the β-mannoside 392 with high selectivity (Scheme 60). In the

phosphoramide (HMPA) were observed. The chloride salt could also be exchanged to a tosylate or hexafluoroantimonate 388 by addition of their respective silver salts. The procedure for activation of the hemiacetal was extended to manno- and glucopyranosides, and the reactions were again monitored by VT-NMR at −40 °C. When the manno derivative AQ


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Table 17. Glycosyl Phosphonium Salts Observed by VT-NMR

D3PO4 was used as external reference. bUpon warming, α- and β-chloride were observed. cDownfield from phosphoric acid in hexadeuterioacetone as external standard. dThe minor anomer could not be analyzed due to peak overlap with CDHCl2. a

Scheme 61. Galactosyl Phosphonium Ion from Treatment of Lactol with Hendrickson Reagent

gluco case, two anomeric oxyphosphonium chlorides were observed by NMR at low temperature, and the α-anomer could be isolated as the corresponding hexafluorophosphate (entries 4 and 5, Table 17).212 As with mannosylation, orthoester formation was dominant with alcohol nucleophiles, whereas thiophenol gave an anomeric mixture of thioglycosides. The study was extended to both manno and gluco species.211−213 In the case of activation of 2,3,4,6-di-Oisopropylidene-α-D-mannopyranose, the undesired orthoester formation was not an issue.213 Formation of the alkoxy tris(dimethylamino)phosphonium chloride was monitored by NMR at −40 °C (entry 6, Table 17). The salt decomposed into a mixture of anomeric chlorides at room temperature. Reaction of the salt at low temperature with sulfur nucleophiles gave high β-selectivity, suggesting a SN2-type mechanism, whereas alcohol nucleophiles gave mixtures, with the α-anomer being the major product.

The use of diphosphonium salts (e.g., Hendrickson reagent) for dehydration of 2,3,5-tri-O-benzylribofuranose has also been studied by NMR (presumably at low temperature) by Mukaiyama and Suda,214 and the formation of two reactive species was observed. The approximate 1:1 ratio of reactive phosphonium intermediates gave reasonable α-selectivity with alcohol acceptors, suggesting a fast equilibrium between the two species or an oxocarbenium ion as the actual glycosylating species (entry 7, Table 17). The reaction was found to be nearly unaffected by solvent polarity, substituents on phosphorus, the amine base used, or the nucleophile. The use of Hendrickson reagent for activation of reducing sugars has recently been reinvestigated by Mossotti and Panza, 215 who used VT-NMR to detect the reactive intermediates formed (Scheme 61). The measurements were performed at −10 °C in CD2Cl2 or CDCl3 and revealed that at least two reactive intermediates are formed, with the αAR


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rotamers in the sugar, but instead pendant group orientations might cause the existence of multiple conformers. The galacto compound 406 gave, upon activation at −30 °C, one major compound 408 and after 24 h an additional compound, both having similar spectra and coupling constants. Upon heating to 0 °C, one additional compound appeared, similar to the gluco case described above. The lack of long-range couplings, vicinal coupling constants, and computational modeling led to the conclusion that 1S3 and 4C1 were the most likely conformations of these α-nitrilium ions. As the nitrile effect has become well-accepted, interest in studying the reactive nitrilium ions has diminished. An attempt to detect nitrilium ion formation with a rhamnosyl donor has failed.226 Recently, Mong and co-workers227 studied the effect of concentration on the nitrilium effect and found that equatorial selectivity was improved when the concentration was lowered. Attempts to prove the existence of nitrilium ions in their donor system also failed, demonstrating that this effect might be more complicated and altered for different glycosylations. Another phenomenon, which has led to even more debate than the nitrile effect, is the “reverse anomeric effect”, that is, the equatorial preference of glycosyl ammonium salts.228−230 As the effect has mainly been studied on stable protonated Nglycosides, such as pyridinium and imidazolium glycosides, only a few studies have made use of VT-NMR. Since the reverse anomeric effect change the conformational equilibrium between a neutral axial anomer and the equatorial anomer upon protonation, this can be studied by determining their ratio and the effect thereby quantified. NMR spectra obtained at room temperature often show an average between the two extreme conformations. Knowing the coupling constants in these, one can determine the ratio.231 Attempts to observe the two extremes by VT-NMR have proven difficult. Finch and Nagpurkar232 tried to “freeze out” the N-tetra-O-acetyl-α-Dglucopyranosyl imidazole and N-tetra-O-acetyl-α-D-mannopyranosyl imidazole in CDCl3 containing trifluoroacetic acid (TFA), but only line broadening appeared until the solution solidified. However, this confirmed that a dynamic conformational equilibrium existed. Studying high-pressure glycosylations, Dauben and Köhler233 isolated N-tetra-O-benzyl-α-Dglucopyranosyl collidinium salts, which showed line broadening in the signal from the o-methyl groups in the collidine residue. Lowering the temperature to −15 °C gave two distinct signals, due to hindered aryl rotation. The influence of lowering the temperature on the sugar ring conformation was unfortunately not described. The structure of N-glycosyl amides has also been studied and they were found to exist preferentially as the anti isomers without any changes (one conformer) when NMR spectra were recorded at lower temperatures (240 K).234 The “reverse anomeric effect” has recently been revisited by Davis and co-workers,235 who studied D-xylopyranosyl imidazolinium ions 410 and 411b in solution and gas phase. The 3JH,H2 coupling constants in the α-anomer indicated average values between two extremes, 4C1 (3JH2,H3 9.3 Hz, 3JH3,H4 9.5 Hz) and 1 C4 (3JH2,H3 3.0 Hz, 3JH,H4 2.8 Hz). This dynamic conformational equilibrium was confirmed by performing VT-NMR, which showed significant line broadening at −50 °C (Scheme 63). Lowering the temperature further to −80 °C resulted in even broader peaks and not a separation of two conformers. Smoot and Demchenko236 have studied the effects of having a 2-O-picolyl group in glycosyl donor 413 with respect to reactivity and selectivity (Scheme 64). It was found by NMR

phosphonium salt 394α being the major one and the minor one presumably the β-anomer 394β. Upon addition of acceptor, the 31P signals from the intermediates (δ 66.1 and 64.0 ppm) disappeared and a new signal appeared (δ 59.6 ppm). This new signal was assigned to be the phosphonium salt of the acceptor, supporting a competing mechanism where the reducing sugar 393 acts as the nucleophile and the acceptor as the electrophile. 6.3. Glycosyl Ammonium Ions (-N+R3)

Mainly two categories of nitrogen-containing ions in carbohydrates have caught the interest of organic chemists: nitrilium ions in glycosylation and ammonium ions in connection with the so-called reverse anomeric effect. The effect of nitrilium ions in glycosylation is normally referred to as the “nitrile effect”, which gives equatorial selectivity in glycosylation due to substitution of axial nitrilium intermediates. The solvent effect was observed in carbohydrates in the late 1970s by several groups but with some debate about the stereochemistry of the ions.216−219 The generality of the nitrile effect was later demonstrated for different glycosyl donors and acceptors.220−224 With the unclear mechanism for the nitrile effect, interest in observing the reactive intermediate giving rise to the equatorial selectivity has led to several studies. Due to the low stability of the nitrilium ions, indirect methods such as trapping reactions have been most successful in clarifying the existence and stereochemistry.216,219 Detection by spectroscopic methods is rather rare. The first data were obtained by Schmidt and Rücker,218 who observed the same reactive intermediate when activating different glucosyl halides in MeCN. The experimental data are, however, limited to NMR shift of H1 (δH1 6.30 ppm) and a 3JH1,H2 8.0 Hz suggesting a β-configuration, opposing the general view that the nitrilium ion is axial (giving equatorial selectivity) but supporting the α-selectivity observed in the glycosylation. Furthermore, IR data showed absorption at 1640 cm−1, which is in accordance with a nitrilium ion. A more thorough study was later conducted by Sinaÿ and coworkers,225 combining low-temperature NMR and computational conformational analysis (Scheme 62). The nitrilium Scheme 62. Nitrile Effect Detected by VT-NMR

intermediate of a benzylated glucosyl donor 405 as well as a benzylated galactosyl donor 400 were generated in acetonitriled3 and analyzed by 1H, 13C, and 15N NMR. By activation of the gluco donor 405 with 1 equiv of TMSOTf at −30 °C, two new compounds appeared. When activation was conducted at 5 °C, a third product was observed, which transformed into two other intermediates at lower temperature. The compounds gave similar signals, for example, H1 shifts at δH1 6.21, 6.64, and 6.25 ppm, respectively (see entries 1 and 2, Table 18, for data). The coupling constants revealed that the conformation of the sugar ring was similar for the three intermediates and was not the 4C1 conformation. 15N shifts in the range δN 195.2−233.2 ppm were assigned to the nitrilium ions. With the aid of modeling, the conformation was proposed to be °S2. The observation of two major compounds at −30 °C cannot be explained by AS


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Table 18. Glycosyl Ammonium Ions Observed by VT-NMR

a Two species were detected, which equilibrated with a third compound upon warming to 5 °C (δH1 6.25 ppm, 3JH1,H2 7.8 Hz, δC1 88.30 ppm). Recooling restored the two compounds. bTwo species were detected, which equilibrated with a third compound upon warming to 0 °C (δH1 6.05 ppm, 3JH1,H2 6.8 Hz, δC1 83.31 ppm). Recooling restored the two compounds. cFurther assignment by TOCSY, NOESY, and HMBC. The β-anomer was completely unreactive in glycosylation.

Scheme 63. Reverse Anomeric Effect Detected by VT-NMR

Scheme 65. Detection of Glycosyl Pyridinium Ion by VTNMR

scavenger in the glycosylation method, and in this study it was realized that it can also react with the formed glycosyl triflate. It was furthermore shown that the pyridinium species 214 acts as a “glycosylation pool” for the reactive intermediate, probably an oxocarbenium ion or an oxosulfonium ion (entry 4, Table 18).

that both the α- and β-picolinium ions 414α and 414β were obtained upon activation at 0 °C and that both intermediates were stable (entry 3, Table 18). The formation of an anomeric mixture suggests initial formation of an oxocarbenium ion, which is intramolecularly trapped by the picoline moiety, and therefore no anchimeric assistance. In order to study the mechanism of their dehydrative glycosylation method, Garcia and Gin67 synthesized the 2chloropyridinium species 214 from the glycosyl triflate 29 (Scheme 65). The 2-pyridinium chloride is used as a triflic acid

7. CONCLUSION AND FUTURE DIRECTION VT-NMR, and in particular low-temperature NMR, has been central in studying carbohydrates and their chemistry for half a century. The first studies were focused on monosaccharide conversion, for example, to other rare monosaccharides, “freezing out” of conformations in fast equilibrium at low temperature, and the mechanism of neighboring-group participation. Focus changed at the beginning of the new

Scheme 64. Intramolecular Trapped Picolinium Ions Used To Control Stereoselectivity in Glycosylations

AT


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Biographies

millennium to the mechanism of glycosylation reactions. The monitoring of reactive intermediates at low temperature has given new insight into this highly complex reaction and paved the way for new methodologies taking advantage of controlled formation of species to give rise to the desired reactivity and selectivity. With all the data from VT-NMR collected, some general trends in terms of reactivity can be observed. The reactive intermediates formed generally follow the armed−disarmed concept: that is, more electron-withdrawing protecting groups reduce the reactivity, whereas more electron-donating protective groups increase it. This results in different

Tobias Gylling Frihed received his masters degree in chemistry from the University of Copenhagen (Denmark) in 2011 from the group of Professor Mikael Bols, working with glycosylation and in particular βmannosylation. He continued his Ph.D. studies in the same group, in which he investigated various aspects of carbohydrate chemistry with a special focus on understanding the mechanism and effects of glycosylation. This led to an interest in observable reactive intermediates in glycosylations. Furthermore, he has combined the hot topic of C−H activation with carbohydrate chemistry, which has resulted in synthesis of the rare but biologically important L-sugars. During his Ph.D. studies he was a visiting scientist in the group of Keith A. Woerpel, New York University, for 6 months, working with the synthesis of new silylene transfer reagents. His current research interest is carbohydrate chemistry in general, total synthesis, and organosilicon chemistry.

decomposition temperatures, which can be measured by VTNMR and used to rank the different glycosyl donors. Another aspect is the difference in reactivity between anomeric pairs of glycosyl donors, where some general rules also apply. When the anomeric leaving group is neutral at the atom connected to C1 (e.g., halides, triflates, oxosulfonium ions etc.), the equatorial anomer is found, by VT-NMR, to be less stable and hence more reactive. This is, however, opposite when the atom to C1 is positively charged (sulfonium, sulfoxide, ammonium, etc.), where the axial anomer is found to be more reactive, presumably due to participation by the lone pair on the ring oxygen or/and the reverse anomeric effect. However, there is still much to learn about the mechanism(s) in glycosylation reactions as each reaction appears to be a new case, where the interplay between multiple effects decides the outcome. This review has collected the knowledge obtained by studying reactions with low-temperature NMR for the first time. It will now be easier to compare glycosylation methods and find the optimal conditions. However, there is still more to be done before we understand glycosylation. One central piece of the puzzle, the oxocarbenium ion,6,7 has so far not been observed,237,238 despite the fact that this intermediate is the one most commonly used to explain the glycosylation mechanism. As mentioned, the oxocarbenium ion

Mikael Bols was born in 1961 in Copenhagen, Denmark. He received his M.Sc. (1985) and Ph.D. (1988) from the Technical University of Denmark under the supervision of Professor Inge Lundt. After a postdoctoral stay in 1988−1989 at Queen’s University, Canada, with Professor Walter Szarek, he joined Leo Pharmaceutical Products, where he was a research chemist from 1989 to 1991. He then returned to an assistant professorship at the Technical University of Denmark. In 1994 he did a sabbatical stay at Columbia University in Professor Gilbert Stork’s group. In 1995 he went to Aarhus University, where in 2000 he became a full professor. Finally, in 2007 he assumed his present position as head of the chemistry department at the University of Copenhagen. His research interests are medicinal chemistry, carbohydrates, and artificial enzymes.

has been suggested as one of the intermediates observed by NMR but without solid proof. The importance of VT-NMR is likely to increase and it is quickly becoming a standard tool when studying glycosylations, conformational equilibria, and reactions of carbohydrates in general.

AUTHOR INFORMATION Corresponding Author

*E-mail [email protected]. Notes

The authors declare no competing financial interest. AU


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TOCSY TTBP VT-NMR

total correlation spectroscopy 2,4,6-tritert-butylpyrimidine variable-temperature nuclear magnetic resonance

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Christian Marcus Pedersen studied chemistry at the University of Aarhus, where he received his Ph.D. in 2007 under the supervision of Professor Mikael Bols. During his Ph.D. studies he was a visiting scientist at the University of Illinois at Chicago, performing research with Professor David Crich. Postdoctoral studies were carried out at the University of Konstanz in the laboratories of Professor Richard R. Schmidt, working on the total synthesis of lipoteichoic acid from Streptococcus pneumoniae. He is currently an associate professor at the University of Copenhagen, where he is working on the total syntheses of lipoteichoic acids and in various fields of organic chemistry.

ACKNOWLEDGMENTS The Lundbeck Foundation is acknowledged for financial support. ABBREVIATIONS ATDP tris(dimethylamino)phosphonium BSM 1-benzenesulfinylmorpholine BSP 1-benzenesulfinylpiperidine CIP contact ion pair DBTO dibenzothiophene-5-oxide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-diisopropylethylamine DIPF diisopropylformamide DTBMP 2,6-di-tert-butyl-4-methylpyridine [emim][OTf] 1-ethyl-3-methylimidazolium trifluoromethanesulfonate EWG electron-withdrawing group Gb3 globotriosyl ceramide HMBC heteronuclear multiple-bond correlation spectroscopy HMPA hexamethylphosphoramide HOFox 3,3-difluoroindole IAD intramolecular aglycon delivery iGb3 isoglobotriosyl ceramide KHMDS potassium bis(trimethylsilyl)amide NFM N-formylmorpholine NIS N-iodosuccinimide NOESY nuclear Overhauser effect SSIP solvent-separated ion pair TBAB tetrabutylammonium bromide TBAI tetrabutylammonium iodide TBDMS tert-butyldimethylsilyl TDAP tris(dimethylamino)phosphine Tf2O trifluoromethanesulfonic anhydride TfOH trifluoromethanesulfonic acid TMSI trimethylsilyl iodide TMSOTf trimethylsilyl trifluoromethanesulfonate AV


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