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. 2024 Sep 26;9(40):41355–41360. doi: 10.1021/acsomega.4c04016

Room Temperature Regioselective Debenzylative Cycloetherification Reaction

Samuel Kwain †, Colin D McMillen †, Daniel C Whitehead †,‡,*
PMCID: PMC11465265  PMID: 39398131

Abstract

graphic file with name ao4c04016_0009.jpg

A regio- and stereoselective debenzylative cycloetherification (DBCE) reaction of protected hexoses to form stereodefined hydroxylated tetrahydrofurans of synthetic utility has been investigated under very mild room temperature reaction conditions. This study revealed the potential application of the DBCE reaction of simple, abundant starting materials to access stereochemically rich tetrahydrofuran compounds under mild reaction conditions.

Introduction

Hydroxylated tetrahydrofurans (THFs) are an important and unique structural moiety found in many natural products and other biologically active molecules.1−7 For example, annonaceous acetogenins containing hydroxylated THFs such as mucoxin, obtusallene III, and the polyether X14766A have shown exceptional antitumor and antibacterial activity (Figure 1).8−11 Quite recently, hydroxylated THF moieties have been explored to target GLUT5-transporters as a nonradiolabeled positron emission tomography (PET) imaging probe for potential applications in cancer therapy (Figure 1).12

Figure 1.

Figure 1

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Pharmaceuticals containing hydroxylated tetrahydrofuran derivatives.

Despite their utility, the stereocontrolled synthesis of hydroxylated THF derivatives remains synthetically challenging due to their stereochemical complexity.13 Synthetic methods targeting their preparation still remain the subject of active research.14 The oxidation of alkenes, dienes, and polyenes remains an excellent approach to construct the motif in a stereoselective fashion. In 2003, Donohoe and co-workers reported the oxidative cyclization of 1,5-dienes for the construction of hydroxylated THF compounds (Scheme 1a).15 Springboarding from earlier efforts to access the motif,16−18 Borhan and co-workers developed a tactic that engaged chiral epoxy-alcohols (arising from Sharpless asymmetric epoxidation (SAE)) with dimethylsulfoxonium methylide to induce a nucleophilic ring-opening, Payne rearrangement, cyclization cascade that delivered 2,3-disubstituted hydroxylated THFs (Scheme 1b).19 The same group also exploited the ionization and cyclization of orthoesters arising from chiral 1,2,n-triols to generate the motif (Scheme 1c).20 These enabling technologies were subsequently leveraged to complete several enantioselective total syntheses of hydroxy-THF containing natural products.21,22 Castillón and co-workers also constructed stereoselective hydroxylated THF by alkene haloetherification. This approach involves the electrophilic cycloetherification of 4-penten-1,2,3-triol to access the hydroxylated THF derivative (Scheme 1d).23 Furthermore, other methods for accessing the motif include the intramolecular capture of reactive oxonium ion intermediates by tethered nucleophilic alkenes.24,25 Additionally, cycloaddition and annulation reactions involving two- and three-atom components such as carbonyl ylides, cyclopropanes, epoxides, and alkenes as well as O–H insertion into diazo-derived iron carbenes have also proven valuable in generating hydroxylated THFs.26−28

Scheme 1. Literature Reports and Our Approach.

Scheme 1

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Despite these advances, some challenges remain including the need to access cumbersome starting materials through several synthetic steps, the use of metal catalysts, and the frequent isolation of diastereomeric mixtures. In the recent past, the debenzylative cycloetherification (DBCE) of linear carbohydrates has been explored to access stereospecific substituted THF derivatives.29−36 The DBCE reaction normally involves a nucleophilic attack by the oxygen atom of a benzyl ether onto a carbon in the δ-position that bears an activated alcohol as a leaving group to give stereospecific tetrahydrofurans. It is noteworthy that this transformation traditionally requires rather high reaction temperatures (110–120 °C) and long reaction times.

Herein, we report the development of regio- and stereoselective DBCE of acyclic carbohydrates to give hydroxylatyed THF derivatives under very mild reaction, room temperature conditions (Scheme 1e).

Results and Discussion

To explore the DBCE transformation, the mesylate 1 was first subjected to reaction with sodium bromide in DMF at 90 °C over 6 h to afford cyclized product 2 in 88% yield (Scheme 2). Benzyl bromide was isolated as a stoichiometric byproduct. We then attempted to determine the feasibility of the DBCE reaction at ambient conditions. Intriguingly, treating 1 with sodium bromide and 15-crown-5 ether in CH3CN at room temperature for 24 h gave a satisfactory yield of 75% of the desired cyclized product 2 as well.

Scheme 2. Exploring the DBCE Reaction at Elevated and Room Temperatures to Access Hydroxylated THF.

Scheme 2

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Moving forward, we explored the DBCE transformation under ambient conditions on the mesylates of tetra-O-benzylated derivatives of d-glucose and D-galactose (Chart 1). The glucose derivatives 1 and 4 were investigated to show the stereospecific cyclization of the DBCE reaction through a nucleophilic attack on the primary and secondary sp3 reactive centers. A similar transformation was also investigated with galactose derivatives 3 and 7. The influence of the relative stereoconfiguration of the leaving group (activated alcohol) and the nucleophile on the DBCE transformation was also investigated with substrates 8 and 9 which are C5 epimers of substrates 1 and 3 respectively. Substrates 5 and 6 were also included to show the synthetic utility of this DBCE transformation. In addition, we investigated the regioselectivity of this DBCE transformation with dimesylate glucose derivative 10. The synthesis of substrates 1 and 3–10 is outlined in detail in the ESI.

Chart 1. Substrates Evaluated for DBCE Transformation.

Chart 1

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We next focused on the DBCE transformation of substrates 3–10 under ambient conditions. Recall that the reaction of mesylate-glucose derivative 1 with sodium bromide and 15-crown-5 ether in CH3CN at room temperature for 24 h afforded the desired cyclized product 2 in 75% yield. To confirm the absolute stereochemistry of 2, we envisioned that its di-O-iso-propylidene derivative 12 might yield a crystalline solid suitable for X-ray analysis. Thus, removal of the benzyl protecting groups of 2, followed by subsequent treatment of the corresponding unprotected THF derivative 11 with CuSO4 in acetone and a catalytic amount of H2SO4, afforded the di-O-iso-propylidene-THF derivative 12 in 95% yield. Gratifyingly, bis-ketal 12 formed a single crystal on slow evaporation of a 1:1 DCM/hexane solution of the compound (Scheme 3; SI Figures S1, S2, Table S1).

Scheme 3. DCBE of Mesylate 1 and Conversion to 12 for X-ray Analysis.

Scheme 3

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Following the DBCE reaction conditions above, the mesylate-galactose derivative 3 also conformed well to the DBCE reaction to give the desired cyclized product 13 in 66% yield (Scheme 4, eq 1). Primary mesylate substrates 4–7 were successfully converted to their respective THF derivatives 14–17 in satisfactory yields (4 to 14: 85%; 5 to 15: 73%; 6 to 16: 71%; 7 to 17: 65%). Also, the C5 glucose and galactose epimers 8 and 9 provided THF products 18 and 19 in 64% and 62% yields, respectively. This shows that the relative stereoconfiguration of the leaving group (activated alcohol) and the nucleophile do not affect the DBCE transformation as long as the leaving group is located on a carbon which is four bonds away from the nucleophilic oxygen of the benzyl ether group.

Scheme 4. Expanded Substrate Scope of DBCE Reaction of Sugar Mesylates.

Scheme 4

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Moving forward, we decided to investigate the regioselectivity of the DBCE reaction with dimesylate glucose derivative 10. Interestingly, the reaction of 10 afforded both cyclized THF derivatives 20 and 21 in a 2:1 regioisomeric ratio (rr) determined from crude 1H NMR (Scheme 5). To explore whether the reaction temperature could influence a regioselective DBCE cyclization favoring the formation of either 20 or 21, we subjected compound 10 to reaction with sodium bromide in DMF at temperatures of 25, 50, 110, and 120 °C. At 25 °C for 24 h, the starting material was unchanged, with no detection of 20 or 21. Increasing the temperature to 50 °C for 24 h resulted in more than 60% of the starting material remaining, with both 20 and 21 observed in the same 2:1 regioisomeric ratio. There was no significant difference observed at 110 °C for 6 h compared to the reaction at 90 °C. However, at 120 °C, neither the starting material nor products 20 or 21 were detected; 1H NMR analysis indicated that the starting material decomposed at this temperature. Interestingly, when the reaction was conducted in acetonitrile in the presence of 15-crown-5 at 90 °C, the reaction was completed in less than 1 h, with both 20 and 21 observed in the same 2:1 regioisomeric ratio. However, conducting the reaction at 0 °C in the presence of 15-crown-5 in either DMF or acetonitrile resulted in no conversion of the starting material. These results shed light on the mechanistic pathway of the reaction, indicating that ambient temperature is optimal for DBCE cyclization as long as sodium bromide is dissolved, which can be achieved by incorporating a phase transfer catalyst or increasing the reaction temperature. Furthermore, this suggests that the reaction progresses more favorably when the leaving group is positioned on a primary carbon atom rather than a secondary position, which is consistent with typical SN2 processes.

Scheme 5. DBCE of Bismesylate 10.

Scheme 5

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The proposed mechanism of the DBCE reaction involves, first, an attack of the nucleophilic oxygen of the benzyl ether group onto the reactive sp3-carbon bearing the activated alcohol in a classical SN2 fashion to give either oxonium intermediate Im-2 or Im-5. Subsequent attack by the bromide anion at the most electrophilic benzylic carbon gives the final cyclized products (Scheme 6).

Scheme 6. Proposed Mechanism for DCBE Reaction of Bismesylate 10.

Scheme 6

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Conclusions

In conclusion, we have investigated the debenzylative cycloetherification (DBCE) reaction of hexoses to form stereochemically defined hydroxylated THF derivatives of synthetic utility using a very mild, room temperature tansformation deploying sodium bromide and 15-crown-5 in acetonitrile. This work demonstrates the efficiency of the DBCE transformation under very mild reaction conditions, making it suitable for synthesizing a wide range of hydroxylated THF derivatives, including those with labile substituents that are of biological relevance.

Experimental Section

General Information

All reagents were purchased from commercial sources and used without purification, unless otherwise noted. Unless otherwise noted, all nonaqueous reactions were performed under an inert atmosphere of nitrogen in flame-dried glassware containing a stir bar. Acetonitrile (ACN), tetrahydrofuran (THF), dichloromethane (DCM), methanol (MeOH), dimethylformamide (DMF), and pyridine (py) were obtained from commercial sources and dried following standard distillation procedures. All other solvents were obtained from commercial sources and used without drying, unless otherwise noted. All water and aqueous solutions were made by using deionized (DI) water. Flash column chromatography was carried out using ZEOCHEM silica gel (40–63 μm). Analytical and preparative thin-layer chromatographies (TLC) were performed on Sorbtech silica G TLC plates. 1H and 13C NMR spectra were obtained using Bruker avance 500 MHz spectrometers. Chemical shifts are reported in parts per million (ppm). Spectra are referenced to residual solvent peaks. Infrared spectroscopy data were collected using an IR Affinity-1S instrument (with an MIRacle 10 single reflection ATR accessory). All known compounds were characterized by 1H and 13C NMR and are in complete agreement with samples reported elsewhere. All new compounds were characterized by 1H and 13CNMR, ATR-FTIR, HRMS, XRD, and melting points (where appropriate). HRMS data were collected using an instrument equipped with electrospray ionization in positive mode (ESI+) and a time-of-flight (TOF) detector.

Procedure for the Synthesis of Hydroxylated THFs

The following procedure was used for thermal cyclization. To a flame-dried round-bottom flask equipped with a water-cooled condenser and a stir bar were added NaBr (2 mmol, 2 equiv) and 5 mL of anhydrous DMF. To this stirring solution was added the mesylate hexose derivative (1 mmol, 1 equiv) in 2 mL of anhydrous DMF. The reaction mixture was then stirred at 90 °C for 6 h. Upon completion, water was added and the mixture was then extracted with ethyl acetate (3 × 25 mL), and the combined organic layer was dried over MgSO4, filtered, and concentrated in a vacuum. The residue was purified by flash chromatography on silica gel with DCM and MeOH (100% DCM to 97:3 DCM/MeOH) to afford the corresponding hydroxylated THF derivatives.

The following procedure was used for the cyclization under ambient conditions. To a solution of NaBr (2 mmol, 2 equiv) and 15-crown-5 (3 mmol, 1.5 equiv) in 6 mL of anhydrous acetonitrile under nitrogen was added dropwise a solution of the mesylate hexose derivative (1 mmol, 1 equiv) in 4 mL of anhydrous acetonitrile. The reaction mixture was allowed to stir at room temperature for 24 h. Upon completion, water was added; the mixture was then extracted with ethyl acetate (3 × 25 mL), and the combined organic layer was dried over MgSO4, filtered, and concentrated in a vacuum. The residue was purified by flash chromatography on silica gel with hexane and ethyl acetate (100% hexane to 90:10 hexane/ethyl acetate) to afford the corresponding hydroxylated THF derivative.

2 (((2S,3R,4R,5S)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)methyl pivalate)

Pale yellow oil; yield 75% (0.52 g), IR: 2941 (w), 2352 (w), 1731 (s), 1442 (m), 1283 (m), 1156 (m), 1078 (s), 1028 (m), 915 (m), 742 (w), 697 (w) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.43–7.28 (m, 15H), 4.67 (d, J = 12.1 Hz, 1H), 4.61–4.57 (m, 3H), 4.56 (d, J = 3.2 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.46–4.43 (m, 1H), 4.41–4.37 (m, 1H), 4.36–4.33 (m, 1H), 4.10 (dd, J = 3.9, 1.5 Hz, 1H), 4.05 (dd, J = 4.0, 1.7 Hz, 1H), 3.82–3.73 (m, 2H), 1.25 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 178.33, 138.27, 137.85, 137.64, 128.55, 128.54, 128.41, 128.41, 127.97, 127.87, 127.74, 127.66, 127.64, 81.63, 81.20, 79.21, 77.96, 73.50, 72.45, 72.27, 68.31, 62.95, 38.76, 27.27; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H39O6 519.2747; Found 519.2734.

13 (((2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)methyl pivalate)

Pale yellow oil; yield 66% (0.46 g), IR: 2970 (w), 1724 (m), 1454 (m), 1358 (m), 1281 (m), 1153 (m), 1092 (m), 1061 (m), 1026 (s), 914 (m), 733 (w), 698 (w) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.36–7.31 (m, 15H), 4.77 (d, J = 11.7 Hz, 2H), 4.73–4.69 (m, 1H), 4.65–4.62 (m, 2H), 4.61–4.56 (m, 3H), 4.52–4.49 (m, 1H), 4.40 (ddd, J = 10.3, 4.3, 2.0 Hz, 2H), 4.30–4.24 (m, 2H), 4.13 (q, J = 4.3 Hz, 1H), 4.10–4.06 (m, 1H), 3.64 (dd, J = 10.8, 3.4 Hz, 1H), 3.54 (dd, J = 10.7, 3.8 Hz, 1H), 1.23 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 178.36, 138.17, 138.08, 137.86, 128.42, 128.39, 128.36, 127.81, 127.79, 127.68, 127.66, 80.11, 79.22, 77.99, 77.59, 73.44, 73.35, 72.62, 69.92, 63.34, 38.77, 27.24; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H39O6 519.2747; Found 519.2741.

14 ((2S,3S,4R)-3,4-Bis(benzyloxy)-2-((R)-1,2-bis(benzyloxy)ethyl)tetrahydrofuran)

Pale yellow oil; yield 85% (0.60 g), IR: 2924 (w), 1454 (m), 1096 (s), 1057 (s), 1026 (m), 733 (m), 694 (m) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.44–7.28 (m, 20H), 4.88 (d, J = 11.5 Hz, 1H), 4.65 (d, J = 7.7 Hz, 2H), 4.59–4.55 (m, 3H), 4.53 (d, J = 12.4 Hz, 2H), 4.22–4.20 (m, 2H), 4.19–4.17 (m, 1H), 4.11 (d, J = 1.6 Hz, 1H), 4.11–4.08 (m, 1H), 3.97 (dd, J = 10.7, 2.0 Hz, 1H), 3.89 (dd, J = 9.9, 1.7 Hz, 1H), 3.77 (dd, J = 10.6, 5.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 139.02, 138.68, 137.97, 137.81, 128.50, 128.44, 128.32, 128.28, 127.83, 127.79, 127.67, 127.65, 127.61, 127.44, 127.39, 81.66, 81.60, 79.78, 76.21, 73.47, 72.54, 72.08, 71.49, 71.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C34H37O5 525.2641; Found 525.2637.

15 ((2S,3S,4R)-3,4-Bis(benzyloxy)-2-((R)-2-(benzyloxy)-1-methoxyethyl)tetrahydrofuran)

Pale yellow oil; yield 73% (0.46 g), IR: 2924 (m), 1454 (m), 1096 (s), 1057 (s), 1026 (m), 733 (w), 694 (w) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.39–7.31 (m, 15H), 4.65–4.61 (m, 5H), 4.56–4.52 (m, 2H), 4.47 (d, J = 11.9 Hz, 1H), 4.19–4.16 (m, 1H), 4.16–4.14 (m, 1H), 4.11 (d, J = 3.5 Hz, 1H), 4.10–4.07 (m, 2H), 3.92 (dd, J = 10.7, 2.0 Hz, 1H), 3.85 (dd, J = 9.8, 1.8 Hz, 1H), 3.77 (ddd, J = 9.1, 5.1, 2.1 Hz, 1H), 3.69–3.62 (m, 2H), 3.47 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 138.64, 138.01, 137.78, 128.52, 128.48, 128.44, 128.29, 127.83, 127.81, 127.61, 127.41, 81.82, 81.45, 79.46, 77.42, 73.46, 72.19, 72.06, 71.31, 70.12, 57.91; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H33O5 449.2328; Found 449.2324.

16 ((2S,3S,4R)-3,4-Bis(benzyloxy)-2-((R)-2-(benzyloxy)-1-(prop-2-yn-1-yloxy)ethyl)tetrahydrofuran)

Pale yellow oil; yield 71% (0.43 g), IR: 2862 (m), 1454 (m), 1092 (s), 1057 (s), 1026 (m), 733 (m), 694 (m) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.40–7.30 (m, 15H), 4.69 (dd, J = 29.8, 18.1 Hz, 2H), 4.63–4.56 (m, 2H), 4.53 (d, J = 11.9 Hz, 1H), 4.49–4.45 (m, 1H), 4.45–4.42 (m, 1H), 4.26 (dd, J = 15.4, 2.5 Hz, 1H), 4.20–4.18 (m, 1H), 4.16 (dd, J = 9.9, 4.7 Hz, 1H), 4.11 (dd, J = 9.1, 3.4 Hz, 1H), 4.07 (dd, J = 2.7, 1.5 Hz, 1H), 4.06–4.03 (m, 1H), 3.94 (dd, J = 10.8, 1.9 Hz, 1H), 3.85 (dd, J = 9.9, 1.6 Hz, 1H), 3.71 (dd, J = 10.8, 5.8 Hz, 1H), 2.39 (t, J = 2.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 138.47, 137.99, 137.72, 128.48, 128.44, 128.33, 127.89, 127.84, 127.81, 127.61, 127.60, 127.48, 81.68, 81.27, 80.37, 79.46, 75.65, 74.11, 73.46, 72.40, 72.15, 71.28, 71.19, 57.83; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C30H33O5 473.2328; Found 473.2322.

18 (((2S,3R,4R,5R)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)methyl pivalate)

Pale yellow oil; yield 64% (0.44 g), IR: 2916 (w), 1728 (m), 1454 (m), 1281 (m), 1157 (m), 1088 (ms), 1072 (s), 1026 (m), 737 (m), 694 (m) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.41–7.23 (m, 15H), 4.59 (dd, J = 15.8, 12.1 Hz, 2H), 4.54–4.49 (m, 2H), 4.43–4.41 (m, 1H), 4.40–4.38 (m, 1H), 4.30 (d, J = 6.4 Hz, 1H), 4.27–4.23 (m, 1H), 4.19–4.12 (m, 2H), 3.99 (d, J = 3.2 Hz, 2H), 3.65 (dd, J = 9.9, 5.8 Hz, 1H), 3.55 (dd, J = 9.9, 6.8 Hz, 1H), 1.21 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 178.29, 138.16, 137.69, 137.60, 128.48, 128.46, 128.35, 127.87, 127.83, 127.79, 127.73, 127.63, 127.58, 83.26, 82.86, 82.78, 78.98, 73.33, 71.62, 71.53, 70.41, 62.74, 38.72, 27.21; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H39O6 519.2747; Found 519.2744.

19 (((2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)methyl pivalate)

Pale yellow oil; yield 62% (0.43 g), IR: 2928 (w), 1724 (m), 1281 (m), 1153 (m), 1084 (s), 1026 (s), 733 (m), 698 (m) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.39–7.31 (m, 15H), 4.76 (dd, J = 19.0, 11.8 Hz, 2H), 4.68–4.61 (m, 3H), 4.57 (d, J = 11.9 Hz, 1H), 4.51 (dd, J = 11.5, 4.1 Hz, 1H), 4.35 (dd, J = 11.5, 7.4 Hz, 1H), 4.31–4.24 (m, 2H), 4.21–4.16 (m, 2H), 3.88 (dd, J = 10.1, 5.4 Hz, 1H), 3.76 (dd, J = 10.1, 6.6 Hz, 1H), 1.25 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 178.46, 138.35, 138.22, 137.95, 128.46, 128.40, 128.37, 127.83, 127.75, 127.69, 127.59, 127.57, 127.42, 79.35, 78.59, 78.33, 76.75, 73.48, 73.43, 73.17, 69.86, 64.99, 38.77, 27.27; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H39O6 519.2747; Found 519.2743.

20 ((R)-2-(Benzyloxy)-1-((2R,3S,4R)-3,4-bis(benzyloxy)tetrahydrofuran-2-yl)ethylmethanesulfonate)

Pale yellow oil; yield 65% (0.45 g), IR: 2866(w), 1454(m), 1173 (m), 1092 (m), 1076 (m), 737 (m), 694 (w), 602 (w) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.42–7.32 (m, 15H), 5.34–5.26 (m, 1H), 4.76 (d, J = 11.2 Hz, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.59–4.52 (m, 3H), 4.48 (d, J = 11.9 Hz, 1H), 4.24 (dd, J = 7.8, 3.5 Hz, 1H), 4.18 (dd, J = 3.5, 1.0 Hz, 1H), 4.13 (dd, J = 9.8, 4.4 Hz, 1H), 4.04 (dt, J = 4.4, 1.2 Hz, 1H), 3.97 (dd, J = 11.6, 2.1 Hz, 1H), 3.90–3.79 (m, 2H), 3.05 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.69, 137.66, 137.52, 128.55, 128.46, 128.27, 127.98, 127.96, 127.86, 127.84, 127.65, 81.19, 81.15, 79.20, 78.53, 73.33, 72.72, 72.39, 71.44, 70.35, 39.03; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H33O7S 513.1947; Found 513.1944.

21 (((2S,3R,4R,5S)-3,4-Bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)methylmethanesulfonate)

Pale yellow oil; yield 30% (0.21 g), IR: 2913 (m), 1458 (m), 1288 (m), 1152 (m), 1085 (ms), 1078 (s), 1028 (m), 736 (m) cm–1; 1H NMR (500 MHz, CDCl3) δ 7.38–7.30 (m, 15H), 5.06–4.95 (m, 1H), 4.60–4.55 (m, 2H), 4.54–4.52 (m, 1H), 4.52–4.49 (m, 4H), 4.18–4.10 (m, 2H), 4.09–4.04 (m, 3H), 3.99–3.91 (m, 2H), 3.79–3.69 (m, 2H), 3.07 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.54, 137.46, 137.38, 128.54, 128.52, 128.50, 128.43, 127.94, 127.92, 127.89, 127.85, 127.83, 83.49, 82.93, 82.54, 80.72, 73.49, 72.06, 71.80, 71.29, 69.71, 38.62; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H33O7S 513.1947; Found 513.1944.

Acknowledgments

The authors gratefully acknowledge Prof. R. Adam Mosey (Lake Superior State University, Sault Ste. Marie, MI, USA) for HRMS analysis. Work in the Whitehead lab is partially supported by a RPL grant to D. C. W. from an NIH COBRE grant 1P20GM146584-01.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c04016.

  • Synthetic procedures for substrates 1–10, X-ray data for 12, and copies of 1H and 13C NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao4c04016_si_001.pdf (7.8MB, pdf)

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