Diarylborinic Acid-Catalyzed, Site-Selective Sulfation of Carbohydrate

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Article Cite This: J. Org. Chem. 2019, 84, 900−908

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Diarylborinic Acid-Catalyzed, Site-Selective Sulfation of Carbohydrate Derivatives Daniel Gorelik, Yu Chen Lin, Alvaro I. Briceno-Strocchia, and Mark S. Taylor* Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON M5S 3H6, Canada

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S Supporting Information *

ABSTRACT: Sulfated carbohydrates have been implicated in diverse biological processes, with the position and extent of sulfation of a glycoside often playing important roles in determining the affinity and specificity of its binding to a biomolecular partner. Methods for the site-selective introduction of sulfate groups to carbohydrates are thus of interest. Here, we describe the development of a diarylborinic acid-catalyzed protocol for selective sulfation of pyranoside derivatives at the equatorial position of a cis-1,2-diol group. This method, which employs the sulfur trioxide−trimethylamine complex as the electrophile, has been employed for installation of a sulfate group at the 3-position of a range of galacto- and mannopyranosides, including substrates having a free primary OH group. By using a full equivalent of the diarylborinic acid, selective syntheses of more complex monosulfated glycosides, namely, a 3′-sulfolactose derivative and 3′-sulfo-β-galactosylceramide, have been accomplished. Preliminary kinetics experiments suggested that the catalyst resting state is a tetracoordinate diarylborinic ester that reacts with the SO3 complex in the turnover-limiting step. Catalyst inhibition by the pyranoside sulfate product and trialkylamine byproduct of the reaction was demonstrated.

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INTRODUCTION Sulfation of hydroxyl (OH) groups is an important “postglycosylation modification” that is relevant to numerous biochemical processes involving recognition of carbohydratederived partners.1−4 Because the negatively charged sulfate group can confer affinity for positively charged residues, such as lysine or arginine moieties, the position and degree of sulfation often play decisive roles in carbohydrate−protein interactions. Methods for the site-selective installation of sulfate groups to carbohydrates are thus needed for the preparation of prospective therapeutic agents or as tools for studying interactions relevant to glycobiology.5,6 Reactions of partially protected carbohydrate derivatives with electrophiles, such as SO3−Lewis base complexes, sulfuric acid, sulfamic acid, pyridine-N-sulfonic acid, chlorosulfonic acid, and sulfuryl chloride, followed by removal of the protective groups, have been used to introduce sulfate groups at particular positions. The development of “masked” sulfating agents, chlorosulfate esters and related electrophiles, has been an important advance, since the direct installation of charged sulfate groups can create purification challenges or chemical incompatibilities.7 Ring-opening of diol-derived cyclic sulfates is another approach that has been pursued successfully.8 In addition to methods that rely on protective groups, siteselective sulfation of carbohydrate derivatives bearing two or more free OH groups has been investigated as a way to reduce the number of steps needed to access a target of interest. Reactions of SO3 complexes or masked sulfating reagents with partially protected carbohydrate substrates have been documented by several research groups,9−18 including examples that make use of boronic esters as transient protective groups.19 In © 2019 American Chemical Society

general, such reactions allow for installation of a sulfate group at the least sterically hindered position. Selective activation of a particular OH group toward sulfation has been achieved through the use of stannylene acetals, taking advantage of the enhanced nucleophilicity of these cyclic diorganotin adducts toward SO3−amine complexes.20−27 In some cases, conventional reactivity patterns of carbohydrate OH groups can be overcome using stannylene acetal methodology; for example, secondary OH groups have been sulfated in the presence of free primary OH groups. Sulfations of this type are two-step protocols involving an initial condensation with a stoichiometric quantity of the organotin compound (e.g., dibutyltin oxide). Site-selective sulfations of carbohydrates that operate under catalytic conditions could offer advantages in terms of efficiency and operational simplicity. Whereas chemoenzymatic sulfations using sulfotransferase enzymes28 have been employed in late-stage modifications of complex glycans,29−32 synthetic catalysts for selective sulfation have yet to be developed.33 Research carried out in our laboratory has led to the identification of diarylborinic acids (Ar2BOH) as catalysts for selective activation of 1,2- and 1,3-diol groups in carbohydrate substrates.34 Monofunctionalizations of diols and sugar derivatives with a range of electrophiles, including acyl,35 sulfonyl,36 and alkyl halides,37,38 as well as glycosyl donors39−42 and transition metal complexes,43−45 have been achieved using this mode of catalysis, which is proposed to involve the formation of tetracoordinate borinic esters as activated Received: October 31, 2018 Published: January 8, 2019 900

DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

Article

The Journal of Organic Chemistry

(iPr2NHEt)+. An expanded version of Table 1 that includes the yields of these side products is provided as Supporting Information (SI). Catalyst 2b was selected for further experiments due to its slightly higher activity relative to 2a as well as its straightforward synthesis from diphenyl ether.46 The efficiency of the borinic acid-catalyzed sulfation was dependent on the SO3 complex employed, with SO3·NEt3, SO3·pyridine, and SO3·DMF providing inferior results to that obtained using SO3·NMe3 (entries 5−8). In the case of SO3· NEt3, the major side product was the 3,6-bis-sulfate 4a· 2(iPr2NHEt)+ (56% NMR assay yield), while SO3·pyridine and SO3·DMF gave more complex reaction mixtures. The higher conversion obtained using SO3·NEt3 in place of SO3· NMe3 appears to be consistent with a documented trend of higher reactivity for SO3 complexes derived from less Lewis basic amine partners.5,47 Presumably the lower selectivity was the result of a higher background rate of sulfation in the presence of SO3·NEt3, without the involvement of the organoboron catalyst. The screen of sulfating reagents was carried out using three equivalents of base, which provided a higher conversion and yield of 3a·(iPr2NHEt)+ versus the lower loading used in entry 4. Increasing the base concentration further (20 equiv of iPr2NEt) led to an additional improvement, resulting in a 69% NMR assay yield of the 3-sulfated product (entry 9). The higher conversion obtained using 20 equiv of base may reflect an increased catalyst−substrate complex concentration, since borinic acid− diol binding is promoted by Brønsted bases.36,42 Another beneficial effect of the higher base loading was the formation of 4a·2(iPr2NHEt)+ rather than 3a′·(iPr2NHEt)+ as the major side product, since it was more straightforward to separate 3a· (iPr2NHEt)+ from a bis-sulfated byproduct than from an isomeric monosulfate. Substrate Scope. Using the optimized reaction conditions, preparative sulfations of pyranoside derivatives 1a−1l were conducted (Scheme 1). The diisopropylethylammonium salts generated as direct products of the reactions were purified by chromatography on silica gel, followed by treatment with an ion-exchange resin to generate the sodium salts. The yield of product 3a·Na+ obtained under these conditions (on 1.0 mmol scale) was in good agreement with the assay yield shown in Table 1, entry 9. Selective 3-sulfation in the presence of free 6OH groups was also achieved for β- and α-galactopyranosides (1b−1d) as well as α-mannopyranosides (1e−1g). Pyranosidederived triols lacking a free OH group (protected βgalactopyranoside 1h, and 6-deoxysugar derivatives 1i and 1j) underwent 3-sulfation in particularly high yields and required only 3 equiv (rather than 20) of iPr2NEt. Lactose-derived β-thioglycoside 1l and β-galactosylceramide 1m were employed to evaluate the utility of the organoboronpromoted sulfation protocol for more complex substrates. The latter was synthesized using a diphenylborinic acid-catalyzed site and stereoselective glycosylation of N-palmitoylceramide developed recently in our laboratory.48 For both 1l and 1k, the rate of sulfation was relatively low under the borinic acidcatalyzed conditions, presumably a result of the low solubility and propensity toward aggregation of these glycosides in acetonitrile. However, the use of a full equivalent of borinic acid 2b resulted in significantly higher conversions, leading to synthetically useful yields of 3′-sulfo-lactose 3l·Na+ and sulfatide 3k·Na+ (Scheme 2). Although the requirement for a stoichiometric quantity of the organoboron activator is not ideal, the ability to achieve monosulfation of a secondary OH

nucleophiles. Here, we describe the development and application of processes for selective sulfations of sugar derivatives using diarylborinic acid catalysis. These processes enable the formation of sulfates at the equatorial positions of cis-1,2-diol groups in pyranosides, including derivatives having free primary OH groups.

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RESULTS AND DISCUSSION Reaction Optimization. Conditions catalyzed, site-selective sulfation were galactose-derived β-thioglycoside 1a as (Table 1). Heterocyclic borinic acids 2a

for borinic acidevaluated using a test substrate and 2b displayed

Table 1. Evaluation of Catalysts and Reaction Conditions for Selective Sulfation of Galactopyranoside 1a

entry

catalyst

SO3·B

iPr2NEt (equiv)

conversion (%)a

yield (%)a

1 2 3 4 5 6 7 8 9

none Ph2BOH 2a 2b 2b 2b 2b 2b 2b

SO3·NMe3 SO3·NMe3 SO3·NMe3 SO3·NMe3 SO3·NMe3 SO3·NEt3 SO3·pyridine SO3·DMF SO3·NMe3

1.5 1.5 1.5 1.5 3 3 3 3 20

9 18 47 49 82 >95 81 80 92

5 11 35 37 58 44 22 45 69

a

Conversion of 1a and yield of 3a·(iPr2NHEt)+ were determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as a quantitative internal standard. 1

higher activity than the parent Ph2BOH for sulfation with SO3· trimethylamine (entries 2−4). Such fused-ring borinic acids have been shown to be highly active catalysts for sulfonylation, alkylation and glycosylation reactions,38,42,44−46 an effect that we have attributed to acceleration of the turnover-limiting functionalization of the tetracoordinate borinic ester due to the incorporation of the borinic acid group into a 6-π electron system.46 In the present case, it is noteworthy that catalysts 2a and 2b enabled selective functionalization of a secondary OH group in a pyranoside substrate having a free primary OH group. Protection of the 6-OH group has generally been required for efficient activation of secondary cis-1,2-diol groups in pyranosides by borinic acids, presumably due to a competing binding mode involving the 1,3-diol group. The use of the heterocyclic borinic acid catalyst in conjunction with a sterically unhindered electrophile appears to be important for achieving the selective activation of the secondary OH group in 1a. Under these conditions, the major byproducts were the 6-sulfate 3a′·(iPr 2 NHEt) + and the bis-sulfate 4a·2901

DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

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The Journal of Organic Chemistry

transformations, including sulfonylations and glycosylations of diol-containing substrates36,39,42,46 as well as chloroacylations of 2,3-epoxy alcohols.50 The general picture to emerge from this work involves the formation of a tetracoordinate borinic ester that reacts with the electrophilic species in the turnoverlimiting step of the catalytic cycle. Although diarylborinic acids, such as 2b, exist as dimeric anhydrides (Ar2B)2O in the solid state, they dissociate rapidly to generate active monomeric species under the conditions of catalysis. To obtain preliminary data on the kinetics of borinic acid-catalyzed sulfation, the reaction of protected α-mannopyranoside 1i with SO3·NMe3 in acetonitrile-d3 was monitored by 1H NMR spectroscopy (Scheme 3). The concentration of product was determined by

Scheme 1. Site-Selective Sulfations of Pyranosides Catalyzed by Borinic Acid 2bc

Scheme 3. Experiments Used To Determine Kinetic Orders for the Borinic Acid-Catalyzed Sulfation of 1i

integration of the signal at 4.44 ppm (methine hydrogen at C3) and/or 4.13 ppm (methine hydrogen at C-2), relative to the 1,3,5-trimethoxybenzene internal standard (δ = 6.09 ppm). A representative 1H NMR spectrum illustrating these signals is included in the SI (Figure S52). Initial reaction rates (from data points corresponding to roughly 10% conversion or less of the pyranoside substrate) were determined by linear fitting of graphs of product concentration versus time. The results of experiments aimed at assessing the kinetic orders in catalyst 2b, SO3·NMe3, and iPr2NEt are depicted in Figure 1. Under the standard conditions, an initial rate k0 of 0.035 ± 0.001 mM/s was determined. Decreasing the initial concentration of catalyst or sulfating agent by half resulted in a roughly 2-fold drop in the initial rate (k0 = 0.016 ± 0.002 mM/s and 0.015 ± 0.002 mM/s, respectively), thus indicating first order kinetics in these species. In contrast, the reaction rate showed only a minimal change upon halving the initial concentration of iPr2NEt (k0 = 0.032 ± 0.002 mM/s) or doubling the concentration of the pyranoside substrate 1i (k0 = 0.033 ± 0.006 mM/s), suggesting pseudo zero-order (saturation) kinetics in these two species within the concentration regimes examined. It should be noted that the improvement in yield upon addition of excess base (Table 1, entry 9) applied only to substrates having a free primary OH group, and so the observation of apparent zero-order kinetics in base for the sulfation of 1i is not at odds with the optimization experiments

a

20 equiv of iPr2NEt were used. b3.0 equiv of iPr2NEt were used. Yields after purification of the diisopropylethylammonium salt by column chromatography on silica gel, followed by ion exchange to the sodium salt, are listed. Reactions were conducted on 0.5 mmol scale of the pyranoside substrate, with the exception of the sulfation of 1a, which was conducted on 1 mmol scale. c

group in substrates having this level of complexity is a noteworthy result.49 Reaction Kinetics. Our group has carried out detailed studies of the kinetics of several diarylborinic acid-catalyzed

Scheme 2. Diarylborinic Acid-Mediated Monosulfation of Lactoside 1l and Ceramide 1k

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DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

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The Journal of Organic Chemistry

Figure 1. Plots of concentration versus time for the transformation shown in Scheme 3. [1i]0 = 0.2 M, [SO3·NMe3]0 = 0.4 M, [2b]0 = 0.02 M, [iPr2NEt]0 = 0.6 M, k0 = 0.035 ± 0.001 mM/s (circle, purple); [1i]0 = 0.2 M, [SO3·NMe3]0 = 0.4 M, [2b]0 = 0.02 M, [iPr2NEt]0 = 0.3 M, k0 = 0.032 ± 0.002 mM/s (diamond, blue); [1i]0 = 0.4 M, [SO3·NMe3]0 = 0.4 M, [2b]0 = 0.02 M, [iPr2NEt]0 = 0.6 M, k0 = 0.033 ± 0.006 mM/s (triangle, green); [1i]0 = 0.2 M, [SO3· NMe3]0 = 0.4 M, [2b]0 = 0.01 M, [iPr2NEt]0 = 0.6 M, k0 = 0.016 ± 0.002 mM/s (×, orange); [1i]0 = 0.2 M, [SO3·NMe3]0 = 0.2 M, [2b]0 = 0.02 M, [iPr2NEt]0 = 0.6 M, k0 = 0.015 ± 0.002 mM/s (square, red). Yields of product 3i·(iPr2NHEt)+ were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as a quantitative internal standard. Initial rate constants k0 were determined from the slopes of lines of best fit to data corresponding to a maximum of approximately 10% conversion of 1i. For experiments conducted in duplicate or triplicate, the standard deviations of the k0 values were used as estimates of the uncertainties.

Figure 2. Plots of product concentration versus time for the sulfation reactions depicted in Scheme 4. [Et3N]0 = 0 M, k0 = 0.078 ± 0.015 mM/s (circle, blue); [Et3N]0 = 0.48 M, k0 = 0.050 ± 0.002 mM/s (square, green); [Et3N]0 = 0.96 M, k0 = 0.042 mM/s (triangle, red). Yields of product 3i·(iPr2NHEt)+ were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as a quantitative internal standard. For experiments conducted in duplicate, the standard deviations of the k0 values were used as estimates of the uncertainties.

that the concentrations of amine employed in this experiment exceed the maximum that would be achieved under the synthetically relevant conditions. A previous study showed that addition of exogenous trimethylamine had no effect on the rate of hydrolysis of SO3·NMe3 in aqueous DMSO at 25 °C.51 We thus propose that the relatively minor inhibitory effect of Et3N is the result of a Lewis acid−base interaction with the organoboron catalyst. Considering that trimethylamine is more volatile than triethylamine but is also a stronger Lewis base, it is difficult to extrapolate this observation directly to sulfation with SO3·NMe3. The possibility of catalyst inhibition by the sulfated pyranoside product was also investigated. Instead of initial rate determinations of the type described in the preceding paragraphs, the effect of added pyranoside sulfate on the yield of the diarylborinic acid-catalyzed process was evaluated. In particular, sulfations of 1a and 1i were carried out in the presence of 1 equiv of rhamnopyranoside sulfate 3k· (iPr2NHEt)+ (Scheme 5). In both cases, an appreciable decrease in the yield of the corresponding sulfate product was evident for the reaction conducted with exogenous 3k· (iPr2NHEt)+. An inhibitory effect of tetrabutylammonium methanesulfonate was previously noted in diarylborinic acidcatalyzed couplings of glycosyl methanesulfonates, and was ascribed to an interaction of the anion with the organoboron catalyst.42 It is likely that such an interaction is also responsible for the effect of 3k·(iPr2NHEt)+ on sulfation yield. Scheme 6 depicts a proposed catalytic cycle that takes into account the kinetic orders inferred from the initial rate determinations as well as the effects of added triethylamine and 3k·(iPr2NHEt)+. It is noteworthy, that both the pyranoside sulfate product and the trialkylamine byproduct of the sulfation reaction act as inhibitors of the diarylborinic acid catalyst. Although the magnitudes of these effects were relatively modest in the case of substrate 1i, the problem is likely to be more significant for carbohydrate substrates that display low solubilities in acetonitrile. This issue may have contributed to the limited efficiency of the catalytic system for sulfation of lactoside 1l and ceramide 1m. The potential inhibitory

discussed above. A similar kinetic profile, first-order kinetics in electrophile and catalyst and apparent zero-order kinetics in pyranoside substrate and amine base, was observed for site and stereoselective couplings of glycosyl methanesulfonates catalyzed by 2b.42 We sought to determine whether the amine released upon sulfation of the alcohol by the SO3·amine complex had an effect on the borinic acid-catalyzed process. Due to the volatility of Me3N, we carried out this study by examining the effect of added triethylamine on the borinic acid-catalyzed reaction of 1i with SO3·NEt3 (Scheme 4). Although the latter Scheme 4. Conditions Used To Evaluate the Effect of Added Triethylamine on the Rate of Borinic Acid-Catalyzed Sulfation with SO3•NEt3

was not the optimal sulfating agent for carbohydrate derivatives having a free primary OH group (see Table 1), it gave rise to similar site-selectivity as SO3·NMe3 for the borinic acidcatalyzed sulfation of triol 1i. The initial rate of sulfation with SO3·NEt3 (k0 = 0.078 ± 0.015 mM/s) was roughly twice that of sulfation with SO3·NMe3, consistent with the complex with the less Lewis basic amine being the more reactive sulfating agent, as discussed above.5,47 A modest level of inhibition by Et3N was observed (Figure 2), although it should be noted, 903

DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

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The Journal of Organic Chemistry Scheme 5. Effect of Added 3k·(iPr2NHEt)+ on the Yield of Borinic Acid-Catalyzed Sulfationa

further illustrate the versatility of diarylborinic acids as catalysts for activation of sugars toward reactions with a wide range of electrophiles and establish a catalytic method for installation of an important “postglycosylation modification” of carbohydrates.

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EXPERIMENTAL SECTION

General. All reactions were carried out under an argon atmosphere, unless specifically indicated. Stainless steel needles and gastight syringes were used to transfer air- and moisture-sensitive liquids. Flash chromatography was performed using neutral silica gel. Analytical thin layer chromatography (TLC) was carried out using aluminum-backed silica gel 60 F254 plates and visualized using shortwave UV light or ceric ammonium molybdate stain with appropriate heating. Materials. HPLC grade acetonitrile was initially purified and dried using a solvent purification system equipped with a column of activated alumina, under nitrogen, and further dried over activated 4 Å sieves. Distilled water was obtained from an in-house supply. All other commercially available reagents and chemicals were used without further purification. Instrumentation. 1H, 13C{1H}, COSY, and HSQC spectra were recorded in CD3OD or D2O, at ambient temperature, using either a 500 or a 600 MHz NMR spectrometer. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual protium in the solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, complex multiplet; and app, apparent), number of protons; coupling constants (J, Hz), and assignment. Assignments are based on analysis of coupling constants, COSY and HSQC spectra. High-resolution mass spectra (HRMS) were carried out using a time-of-flight mass spectrometer equipped with an electrospray ionization (ESI) ion source. Infrared (IR) spectra were obtained using an FTIR spectrometer equipped with a singlebounce diamond/ZnSe ATR attachment, either in the solid form or as a neat liquid, as indicated. Spectral features are tabulated as follows: wavenumber (cm−1), intensity (s, strong; m, medium; w, weak; and br, broad). Optical rotations were measured in a 50 mm cell on polarimeter equipped with a sodium lamp source (589 nm) and are reported as follows: [α]T °CD (c in g/100 mL, solvent). General Procedure. Sulfation of Carbohydrates Catalyzed by 2b. To a septum-capped, oven-dried 2 dram vial was added to the pyranoside substrate (0.5 mmol, 1.0 equiv), sulfur trioxide trimethylamine complex (1.5 mmol, 3.0 equiv), and 2b46 (0.05 mmol, 10 mol %). The vial was evacuated and purged with argon three times, then dry acetonitrile (2.5 mL) was added, followed by N,N-diisopropylethylamine (1.74 mL, 10.0 mmol, 20 equiv). The septum was quickly replaced with a plastic cap, and the vial was sealed with Teflon tape. The vial was placed in an aluminum heating block at a temperature of 60 °C and stirred for 3−5 h. The solvent was evaporated, and the crude product was purified by flash chromatography on silica gel. After evaporation of the eluent, the resulting sulfated product (obtained as the diisopropylethylammonium salt) was resuspended in methanol and stirred with 10 g of Amberlite IR120 (Na+ form) resin for 2 h. The resin was removed by filtration, 10 g of fresh resin was added to the solution, and the solution was stirred for an additional 2 h. This step was repeated once more. On occasion, additional portions of resin were required to observe complete conversion by NMR. The solution was then concentrated to afford the sodium salt of the sulfated carbohydrate. Isopropyl-β-D-thiogalactopyranoside 3-Sulfate, Sodium Salt (3a· Na+). The reaction was conducted on a 1.0 mmol scale (238.3 mg of 1a) according to the general procedure, using 10 mol % of catalyst 2b (19.6 mg), 3 equiv of SO3·NMe3 (417.5 mg, 3.0 mmol), 20 equiv of iPr2NEt (3.48 mL, 20.0 mmol), and 5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 67% yield (231.4 mg, 99% purity as judged by 1H NMR spectroscopy).

a

Conversions and yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as a quantitative internal standard.

Scheme 6. Proposed Catalytic Cycle for Diaryborinic AcidCatalyzed Sulfation of 1i

activities of the reaction products may be an issue to keep in mind when exploring other Lewis acid catalysts for sulfation of OH groups.

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CONCLUSION In summary, benzo-fused heterocyclic borinic acid 2b catalyzes site-selective sulfations at the equatorial position of cis-1,2-diol motifs in carbohydrate-derived substrates, using SO3·NMe3 as the electrophile. Galacto- and mannopyranoside derivatives having three secondary OH groups undergo high-yielding monosulfation under these conditions, but the process can also be employed to achieve sulfations of pyranoside-derived secondary OH groups in the presence of a free primary OH group. Although the sulfations of the lactose derivative 1l and galactosylceramide 1m required a full equivalent of the diarylborinic acid, it is noteworthy that monosulfated glycosides of this level of complexity could be generated in a selective fashion. Preliminary kinetics experiments were consistent with a mechanism involving turnover-limiting attack of SO3·NMe3 on a catalyst−substrate complex, presumably a tetracoordinate diarylborinic ester. Inhibition of the catalyst by both the sulfated carbohydrate product and triethylamine (a model for the trimethylamine released as a byproduct from SO3·NMe3) was demonstrated. The results of this study 904

DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

Article

The Journal of Organic Chemistry [α]20D = −5.5° (c 0.65, H2O). mp 216−217 °C (decomp). IR (powder, cm−1): 3401 (br, m), 2965 (m), 2536 (br, m), 1644 (br, w), 1219 (s), 1056 (s), 879 (s), 796 (s). 1H NMR (500 MHz, methanold4, δ): 4.49 (d, J = 9.7 Hz, 1H, H-1), 4.28 (dd, J = 3.2, 0.9 Hz, 1H, H4), 4.24 (dd, J = 9.3, 3.2 Hz, 1H, H-3), 3.76−3.67 (m, 3H, H-2, H-6a, H-6b), 3.61−3.53 (m, 1H, H-5), 3.26 (app hept, J = 6.7 Hz, 1H, SCH), 1.31 (dd, J = 9.3, 6.8 Hz, 6H, CH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 86.8, 83.1, 80.1, 69.7, 68.8, 62.4, 35.7, 24.4, 24.3. HMRS (ESI−) (m/z): [M − Na]− calculated for C9H17O8S2, 317.0370; found, 317.0370. Methyl-β-D-galactopyranoside 3-Sulfate, Sodium Salt (3b·Na+). The reaction was conducted on 0.5 mmol scale (97.1 mg of 1b) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−30% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 64% yield (96.3 mg, 99% purity as judged by 1H NMR spectroscopy). [α]20D = +8.7° (c 1.2, H2O). Lit20 [α]25D = +8.5 (c 1.2, H2O). mp 228−230 °C (decomp). IR (powder, cm−1): 3387 (br, m), 2939 (w), 2849 (w), 1643 (br, m), 1383 (br, m), 1216 (s), 996 (s), 811 (m). 1H NMR (600 MHz, methanol-d4, δ): 4.30−4.18 (m, 3H, H-1, H-3, H-4), 3.80−3.71 (m, 2H, H-6a, H-6b), 3.71−3.64 (m, 1H, H-2), 3.58−3.52 (m, 4H, H-5, 1-OCH3). 13C{1H} NMR (151 MHz, methanol-d4, δ): 105.6, 81.8, 76.2, 707, 68.6, 62.3, 57.2. HMRS (ESI−) (m/z): [M − Na]− calculated for C7H13O9S, 273.0286; found, 273.0291. Octyl-β-D-galactopyranoside 3-Sulfate, Sodium Salt (3c·Na+). The reaction was conducted on 0.5 mmol scale (146.2 mg of 1c) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−20% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 66% yield (130.2 mg, > 99% purity as judged by 1H NMR spectroscopy). [α]20D = +7.9° (c 0.63, H2O). mp 215−216 °C (decomp). IR (powder, cm−1): 3422 (br, m), 2926 (m), 2856 (m), 2544 (br, w), 1647 (w), 1376 (w), 1220 (s), 1058 (s), 987 (s), 811 (s). 1H NMR (500 MHz, methanol-d4, δ): 4.31 (d, J = 7.8 Hz, 1H, H-1), 4.25 (dd, J = 3.3, 0.8 Hz, 1H, H-4), 4.22 (dd, J = 9.6, 3.3 Hz, 1H, H-3), 3.89 (dt, J = 9.5, 6.9 Hz, 1H, O−CH2), 3.77−3.72 (m, 2H, H-6a, H-6b), 3.72−3.66 (m, 2H, H-2), 3.60−3.50 (m, 2H, H-5, O−CH2), 1.62 (app p, J = 6.8 Hz, 2H, CH2), 1.44−1.23 (m, 10H, CH2), 0.95−0.84 (m, 3H, CH3). 13 C{1H} NMR (126 MHz, methanol-d4, δ): 104.7, 82.0, 76.2, 70.9, 70.7, 68.6, 62.3, 33.0, 30.8, 30.6, 30.4, 27.1, 23.7, 14.4. HRMS (ESI−) (m/z): [M − Na]− calculated for C14H27O9S, 371.1381; found 371.1380. Methyl-α-D-galactopyranoside 3-Sulfate, Sodium Salt (3d·Na+). The reaction was conducted on 0.5 mmol scale (97.1 mg of 1d) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol) and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (20−30% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 68% yield (103.7 mg, 98% purity as judged by 1H NMR spectroscopy). [α]20D = +147.0° (c 1.1, H2O). Lit52 [α]20D = +146.0 (c 1.1, H2O). mp 195− 197 °C (decomp). IR (powder, cm−1): 3413 (br, m), 2938 (m), 2538 (br, m), 1644 (m), 1211 (s), 1001 (s), 972 (s), 859 (s). 1H NMR (500 MHz, methanol-d4, δ): 4.68 (d, J = 1.7 Hz, 1H, H-1), 4.48 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 4.17 (dd, J = 3.2, 1.9 Hz, 1H, H-2), 3.88− 3.80 (m, 2H, H-4, H-6a), 3.76 (dd, J = 11.8, 5.1 Hz, 1H, H-6b), 3.57 (ddd, J = 9.7, 5.0, 2.4 Hz, 1H, H-5), 3.39 (s, 3H, 1-OCH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 102.5, 80.3, 74.4, 70.3, 66.5, 62.4, 55.2. HMRS (ESI−) (m/z): [M − Na]− calculated for C7H13O9S, 273.0286; found, 273.0288. Methyl-α-D-mannopyranoside 3-Sulfate, Sodium Salt (3e·Na+). The reaction was conducted on 0.5 mmol scale (97.1 mg of 1e) according to the general procedure, using 10 mol % of catalyst 2b (9.8

mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (20−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 71% yield (106.7 mg, 99% purity as judged by 1H NMR spectroscopy). [α]20D = +53.0° (c 0.9, MeOH). Lit53 [α]20D = +55.0° (c 0.9, MeOH). mp 232−234 °C (decomp). IR (powder, cm−1): 3461 (br, m), 2690 (br, m), 1201 (s), 1045 (s), 964 (s), 839 (s), 788 (m). 1H NMR (500 MHz, methanol-d4, δ): 4.67 (d, J = 1.8 Hz, 1H, H-1), 4.47 (dd, J = 9.6, 3.3 Hz, 1H, H-3), 4.17 (dd, J = 3.2, 1.9 Hz, 1H, H-2), 3.87−3.80 (m, 2H, H-6a, H-4), 3.74 (dd, J = 11.8, 5.5 Hz, 1H, H-6b), 3.57 (ddd, J = 9.7, 5.4, 2.3 Hz, 1H, H-5), 3.39 (s, 3H, 1-OCH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 102.5, 80.4, 74.5, 70.4, 66.7, 62.6, 55.2. HMRS (ESI−) (m/z): [M − Na]− calculated for C7H13O9S, 273.0286; found, 273.0285. Propynyl-α-D-mannopyranoside 3-Sulfate, Sodium Salt (3f·Na+). The reaction was conducted on 0.5 mmol scale (109.1 mg of 1f54) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (20−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 75% yield (121.7 mg, 99% purity as judged by 1H NMR spectroscopy). [α]20D = 53.3° (c 0.39, H2O). mp 120−125 °C (decomp). IR (powder, cm−1): 3411 (br, m), 3282 (m), 2929 (w), 1230 (s), 1055 (s), 981 (s), 921 (s), 840 (s), 795 (s). 1H NMR (500 MHz, methanol-d4, δ): 4.99 (d, J = 1.7 Hz, 1H, H-1), 4.48 (dd, J = 9.6, 3.3 Hz, 1H, H-3), 4.29 (d, J = 2.4 Hz, 2H, 1-OCH2), 4.19 (dd, J = 3.2, 1.9 Hz, 1H, H-2), 3.88−3.80 (m, 2H, H-4, H-6a), 3.73 (dd, J = 11.8, 5.5 Hz, 1H, H6-b), 3.60 (ddd, J = 9.7, 5.5, 2.3 Hz, 1H, H-5), 2.86 (t, J = 2.4 Hz, 1H, CH). 13C{1H} NMR (126 MHz, methanol-d4, δ): 99.7, 80.2, 79.8, 76.1, 75.1, 70.3, 66.6, 62.6, 54.9. HMRS (ESI−) (m/z): [M − Na]− calculated for C9H13O9S, 297.0280; found 297.0284. Phenyl-α-D-thiomannopyranoside 3-Sulfate, Sodium Salt (3g· Na+). The reaction was conducted on 0.5 mmol scale (136.2 mg of 1g) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 75% yield (140.4 mg, > 99% purity as judged by 1H NMR spectroscopy). [α]20D = +165.5° (c 0.66, H2O). mp 181−184 °C (decomp). IR (powder, cm−1): 3391 (br, m), 2935 (w), 2499 (br, m), 1638 (br, w), 1220 (s), 1056 (s), 995 (s), 738 (s). 1H NMR (500 MHz, methanol-d4, δ): 7.56−7.50 (m, 2H, 1-SPh), 7.35−7.24 (m, 3H, 1-SPh), 5.46 (d, J = 1.2 Hz, 1H, H-1), 4.53−4.45 (m, 2H, H-2, H-3), 4.12 (dt, J = 9.7, 3.6 Hz, 1H, H-5), 3.95 (app t, J = 9.5 Hz, 1H, H-4), 3.80 (d, J = 3.7 Hz, 2H, H-6a, H-6b). 13C{1H} NMR (126 MHz, methanol-d4, δ): 135.4, 133.1, 130.1, 128.6, 89.0, 80.4, 75.7, 71.9, 66.7, 62.3. HMRS (ESI−) (m/z): [M − Na]− calculated for C12H15O8S2, 351.0214; found 351.0207. Isopropyl-6-(tert-butyldimethylsilyloxy)-β-D-thiogalactopyranoside 3-Sulfate, Sodium Salt (3h·Na+). The reaction was conducted on 0.5 mmol scale (176.3 mg of 1h35) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3· NMe3 (208.8 mg, 1.5 mmol), 3 equiv of iPr2NEt (0.26 mL, 1.5 mmol), and 2.5 mL of acetonitrile, at 60 °C for 5 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 94% yield (213.7 mg, > 99% purity as judged by 1H NMR spectroscopy). [α]20D = −5.5° (c 0.65, H2O). mp 190−195 °C (decomp). IR (powder, cm−1): 3616 (m), 3502 (br, m), 2955 (m), 2930 (m), 2859 (m), 1632 (m), 1233 (s), 1072 (s), 989 (s), 837 (s). 1H NMR (500 MHz, methanol-d4, δ): 4.50 (d, J = 9.7 Hz, 1H, H-1), 4.28 (dd, J = 3.2, 0.9 Hz, 1H, H-4), 4.25 (dd, J = 9.2, 3.2 Hz, 1H, H-3), 3.84−3.76 (m, 2H, H-6a, H-6b), 3.74−3.67 (m, 1H, H-2), 3.58 (td, J = 6.0, 0.9 Hz, 1H, H-5), 3.23 (hept, J = 6.8 Hz, 905

DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

Article

The Journal of Organic Chemistry

[α]20D = −27.1° (c 0.84, H2O). mp 235−243 °C (decomp). Spectral data were in agreement with those reported in the literature.55 (2S,3R,4E)-2-(Hexadecanoylamino)-3-hydroxy-1-[[3-O- (sodium oxysulfonyl)-β-D-galactopyranosyl]oxy]-4-octadecene (3m·Na+). The reaction was conducted on 0.0154 mmol scale (10.8 mg of 1m48) according to the general procedure, using 1 equiv of catalyst 2b (3.0 mg, 0.015 mmol), 3 equiv of SO3·NMe3 (6.4 mg, 0.046 mmol), 45 equiv of iPr2NEt (120 μL, 0.70 mmol), and 600 μL of acetonitrile, at 60 °C for 6 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (10−20% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 63% yield (7.8 mg, > 99% purity as judged by 1H NMR spectroscopy). 1H NMR (500 MHz, CDCl3/CD3OD (5:1), δ): 5.66 (dt, J = 13.6, 6.7 Hz, 1H, H-5), 5.40 (dd, J = 15.3, 7.5 Hz, 1H, H-4), 4.28 (d, J = 7.7 Hz, 1H, H-1′), 4.25−4.18 (m, 2H, H-2′, H-3′), 4.11 (dd, J = 10.3, 4.7 Hz, 1H, CH2, H-1a), 4.05 (app t, J = 7.6 Hz, 1H, H3), 3.94 (m, 1H, H-2), 3.78 (dd, J = 11.8, 6.2 Hz, 1H, H-6′b), 3.74− 3.68 (m, 2H, H-4′, H-6′a), 3.58 (dd, J = 10.3, 3.1 Hz, 1H, CH2, H1b), 3.52 (app t, J = 5.4 Hz, 1H, H-5′), 2.17−2.09 (m, 2H), 1.97 (m, 2H, H-6), 1.60−1.45 (m, 2H), 1.35−1.15 (m, 46H, CH2), 0.84 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3/CD3OD (5:1), δ): 175.1, 134.7, 129.4, 103.6, 80.3, 77.6, 74.8, 72.2, 69.7, 69.3, 67.9, 61.8, 53.6, 49.9, 36.7, 32.6, 32.2, 30.0, 29.93, 29.90, 29.84, 29.75, 29.66, 29.64, 29.60, 29.53, 26.2, 22.9, 14.2. HRMS (ESI−) (m/z): [M − Na]− calculated for C40H76NO11S, 778.5145; found 778.5139. Kinetics Experiments. An oven-dried 10 mL round-bottomed flask and stir bar were cooled in a desiccator. The flask was then charged with methyl 6-O-tert-butyldimethylsilyl-α-D-mannopyranoside (1i, 61.7 mg, 0.2 mmol), SO3·NMe3 (55.7 mg, 0.4 mmol, 2.0 equiv), catalyst 2b (4.0 mg, 0.02 mmol, 10 mol %), and 1,3,5trimethoxybenzene (8.4 mg, 0.05 mmol). The flask was capped with a rubber septum and purged under a flow of argon gas for 15 min. Under a balloon of argon gas, dry acetonitrile-d3 (1.0 mL) was dispensed by syringe, and the flask was immersed into an oil bath at a temperature of 60 °C. The mixture was stirred, and iPr2NEt (105 μL, 0.6 mmol, 3.0 equiv) was added by syringe to initiate the reaction. Aliquots (approximately 25 μL) were withdrawn by syringe at 1 min intervals for the first 10 min and then after 12, 15, and 20 min. The aliquots were quenched by addition to methanol-d4 (approximately 200 μL) and analyzed by 1H NMR spectroscopy (700 MHz). The concentration of product 3i·(iPr2NHEt)+ was determined by integration of the signal(s) at 4.44 ppm (methine hydrogen at C-3) and/or 4.13 ppm (methine hydrogen at C-2), relative to the 1,3,5trimethoxybenzene internal standard (δ = 6.09 ppm). An example spectrum illustrating these signals is included in the Supporting Information (Figure S52). The experiment was repeated using the concentrations of the reagents shown in Scheme 3, in each case using a 1.0 mL volume of acetonitrile-d3. Each experiment was conducted in duplicate. For the experiments shown in Scheme 4, the following modifications to the procedure were made, (i) SO3·NEt3 was employed as the sulfating agent; and (ii) Et3N was added to the reaction mixture concurrently with iPr2NEt.

1H, S-CH), 1.31 (dd, J = 6.8, 5.3 Hz, 6H, CH3), 0.90 (s, 9H, CH3), 0.09 (s, 3H, CH3), 0.09 (s, 3H, CH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 86.7, 83.1, 80.2, 69.8, 68.6, 63.7, 35.8, 26.3, 24.5, 24.3, 19.1, −5.2, −5.3. HMRS (ESI−) (m/z): [M − Na]− calculated for C15H31O8S2Si, 431.1235; found, 431.1228. Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 3Sulfate, Sodium Salt (3i·Na+). The reaction was conducted on 0.5 mmol scale (154.2 mg of 1i35) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 3 equiv of iPr2NEt (0.26 mL, 1.5 mmol), and 2.5 mL of acetonitrile, at 60 °C for 5 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/ DCM). Following ion exchange, the sodium salt was isolated as a white solid in 97% yield (199.1 mg, > 99% purity as judged by 1H NMR spectroscopy). [α]20D = +35.5° (c 0.58, H2O). mp 195−201 °C (decomp). IR (powder, cm−1): 3536 (m), 3420 (br, m), 2957 (m), 2928 (m), 2855 (m), 1649 (m), 1231 (s), 1089 (s), 997 (s), 805 (s). 1H NMR (500 MHz, methanol-d4, δ): 4.64 (d, J = 1.7 Hz, 1H, H-1), 4.46 (dd, J = 9.5, 3.4 Hz, 1H, H-3), 4.16 (dd, J = 3.3, 1.8 Hz, 1H, H2), 3.98 (dd, J = 11.1, 1.9 Hz, 1H, H-6a), 3.82−3.70 (m, 2H, H-4, H6b), 3.57 (ddd, J = 9.7, 6.5, 1.7 Hz, 1H, H-5), 3.37 (s, 3H, 1-OCH3), 0.92 (s, 9H, CH3), 0.10 (s, 3H, CH3), 0.10 (s, 3H, CH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 102.4, 80.5, 75.0, 70.3, 66.8, 64.4, 55.0, 26.4, 19.2, 5.1. HMRS (ESI−) (m/z): [M − Na]− calculated for C13H27O9SSi, 387.1151; found, 387.1147. Methyl-α-L-fucopyranoside 3-Sulfate, Sodium Salt (3j·Na+). The reaction was conducted on 0.5 mmol scale (89.1 mg of 1j) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 3 equiv of iPr2NEt (0.26 mL, 1.5 mmol), and 2.5 mL of acetonitrile, at 60 °C for 5 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 90% yield (128.9 mg, 97% purity as judged by 1H NMR spectroscopy). [α]20D = −123.8° (c 1.3, H2O). mp 212−214 °C (decomp). IR (powder, cm−1): 3438 (br, m), 2946 (w), 1650 (br, m), 1216 (s), 1046 (s), 987 (s), 839 (s), 748 (m). 1H NMR (500 MHz, methanol-d4, δ): 4.69 (d, J = 3.9 Hz, 1H, H1), 4.47 (dd, J = 10.3, 3.1 Hz, 1H, H-3), 4.07 (dd, J = 3.1, 1.1 Hz, 1H, H-4), 3.97−3.91 (m, 2H, H-2, H-5), 3.39 (s, 3H, 1-OCH3), 1.23 (d, J = 6.6 Hz, 3H, 5-CH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 101.3, 79.3, 71.7, 67.9, 67.2, 55.5, 16.5. HMRS (ESI−) (m/z): [M − Na]− calculated for C7H13O8S, 257.0337; found 257.0341. Methyl-α-L-rhamnopyranoside 3-Sulfate, Sodium Salt (3k·Na+). The reaction was conducted on 0.5 mmol scale (89.1 mg of 1k) according to the general procedure, using 10 mol % of catalyst 2b (9.8 mg), 3 equiv of SO3·NMe3 (208.8 mg, 1.5 mmol), 3 equiv of iPr2NEt (0.26 mL, 1.5 mmol), and 2.5 mL of acetonitrile, at 60 °C for 3 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (15−25% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 92% yield (130.3 mg, 99% purity as judged by 1H NMR spectroscopy). [α]20D = −30.4° (c 0.67, H2O). mp 201−202 °C (decomp). IR (powder, cm−1): 3407 (br, m), 2943 (w), 2532 (br, m), 1653 (br, m), 1217 (s), 1049 (s), 970 (s), 840 (s), 782 (m). 1H NMR (500 MHz, methanol-d4, δ): 4.59 (d, J = 1.7 Hz, 1H, H-1), 4.42 (dd, J = 9.5, 3.3 Hz, 1H, H-3), 4.17 (dd, J = 3.3, 1.8 Hz, 1H, H-2), 3.63 (dq, J = 9.5, 6.1 Hz, 1H, H-5), 3.55 (app t, J = 9.5 Hz, 1H, H-4), 3.36 (s, 3H, 1-OCH3), 1.29 (d, J = 6.1 Hz, 3H, 5-CH3). 13C{1H} NMR (126 MHz, methanol-d4, δ): 102.5, 80.1, 71.93, 70.5, 69.7, 55.1, 18.0. HMRS (ESI−) (m/z): [M − Na]− calculated for C7H13O8S, 257.0337; found 257.0340. 2-Naphthyl-β-D-thiolactopyranoside 3′-Sulfate, Sodium Salt (3l· Na+). The reaction was conducted on 0.5 mmol scale (242.3 mg of 55 1l ) according to the general procedure, using 1 equiv of catalyst 2b (98 mg), 3 equiv of SO3·NMe3 (208.8 mg, 3.0 mmol), 20 equiv of iPr2NEt (1.74 mL, 10.0 mmol), and 2.5 mL of acetonitrile, at 60 °C for 2 h. The intermediate ammonium salt was purified by flash chromatography on silica gel (17.5−22.5% MeOH/DCM). Following ion exchange, the sodium salt was isolated as a white solid in 66% yield (193.6 mg, > 99% purity as judged by 1H NMR spectroscopy).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02792.

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Details of side product distributions from catalyst optimization experiments; copies of 1H, 13C{1H}, 1 H−1H COSY, and 1H−13C HSQC NMR spectra of products 3a·Na+−3m·Na+; and representative 1H NMR spectrum illustrating the signals used in the reaction monitoring experiments (PDF)

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DOI: 10.1021/acs.joc.8b02792 J. Org. Chem. 2019, 84, 900−908

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Mark S. Taylor: 0000-0003-3424-4380 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by NSERC, the McLean Foundation, the Canada Foundation for Innovation (project 17545 and 19119), and the Province of Ontario.

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