Scalable Total Synthesis of Piceatannol-3′-O-β-d-glucopyranoside and the 4′-Methoxy Congener Thereof: An Early Stage Glycosylation Strategy

Abstract

Scalable syntheses of piceatannol-3′-O-β-d-glucopyranoside and the 4′-methoxy congener thereof were achieved. This route features an early implemented Fischer-like glycosylation reaction, a regioselective iodination of phenolic glycoside under strongly acidic conditions, a highly telescoped route to access the styrene derivative, and a key Mizoroki–Heck reaction to render the desired coupled products in high overall yield.

Piceatannol-3′-O-β-d-glucopyranoside (1) (Figure [1]) is a stilbene glucoside discovered in rhubarb in 1984.[1] It was found to possess numerous interesting bioactivities, such as anti-metastasis and anti-angiogenesis activity against cancer cells[2] and inhibition of ferroptosis.[3] It was also found to be able to inhibit the activity of arginase I and II prepared from mouse liver and kidney lysates, respectively, and therefore it could potentially be used in the therapy of endothelial dysfunction.[4] [5] [6] [7] Currently it is under clinical trial as a potential medication for the treatment of ischemic stroke. The current procurement of this compound solely depends on its extraction from rhubarb, and its yield is subject to many unpredictable factors, such as climate fluctuations and pest infestation. A short and scalable synthetic route is thus necessary to solve this supply problem. A synthetic route also offers an entry to structural modifications, if necessary. We previously reported a total synthesis that involved extensive protecting-group manipulations and hence not very practical to scale-up.[8] Herein we report a new route that has fewer steps and scalable for large-scale production.

The primary problem in the synthesis of 1 lies in the regiocontrol of the glycosylation of the phenolic hydroxyl groups. In the structure of the aglycone piceatannol (Figure [1]), the degrees of steric hindrance that the 1′-vinyl group exerts on the 3′- and 4′-hydroxyl groups are almost the same, hence a direct mono-glycosylation at the desired 3′-hydroxyl group in a conceived substrate where 3-, and 5-hydroxyl groups are protected would yield a mixture of glycosides with poor regioselectivity. This poses a challenge to the addition of a carbohydrate moiety at the desired position. Meanwhile, because glycosidic bonds are not stable under many reaction conditions, such as acidic conditions, conventional strategies for glycoside synthesis involve glycosylation at the late stage in the reaction.[9] [10] [11] To accomplish this, we would have to rely on putting orthogonal protecting groups to differentiate the 3′- and 4′- hydroxyl groups so that the glycosylation at the desired site could be ensured. Our previous efforts to synthesize piceatannol-3′-O-β-d-glucopyranoside, which have been reported under a Chinese patent, followed this strategy (see Scheme [1]).[8] As a result, there are extensive protecting group manipulations in this route to achieve the desired regiocontrol.

To develop an alternative route that is suitable for large-scale synthesis, to access 1, it is necessary to minimize the use of protecting groups during synthesis. We predicted that if we implemented the glycosylation step at the early stage of synthesis, it would reduce the number of steps in the synthetic scheme. Meanwhile, the Mizoroki–Heck reaction was considered when planning the construction of the stilbene moiety, because it requires minimal prefunctionalization of the coupling partners, and hence further reduces the number of steps.

In the glycosylation step, we expected that a Fischer-like glycosylation would work well, to further reduce the number of steps. Based on these assumptions, we designed our retrosynthetic plan as shown in Scheme [2].

First, the advanced intermediate peracetate 3 (precursor to 1, see Scheme [5], vide infra) could be synthesized by a Mizoroki–Heck reaction between iodide 4 and styrene 5. Iodide 4 could be prepared by regioselective iodination of glycoside 6 with NIS in the presence of trifluoroacetic acid, and glycoside 6 itself could be prepared by Fischer-like glycosylation between 7 and catechol (8).

The synthesis started with the commercially available starting material glucose pentaacetate (Scheme [3]). Glucose pentaacetate was selectively hydrolyzed at the anomeric position using a known method to give glucose tetraacetate 7.[12] This product was used without purification in the next step. Treating a mixture of catechol and tetraacetate glucose 7 with boron trifluoride etherate effectively yielded the desired glucoside 6 in a 44% yield over two steps. By following a procedure for the preparation of a bromide analogue,[13] compound 6 was then dissolved in a mixture of trifluoroacetic acid and dichloromethane and treated with N-iodosuccinimide at 0 °C for 12 hours to provide iodide 4 in a 71% yield. It is noteworthy that the β-glucosidic bond in intermediate 6 could tolerate the strongly acidic conditions used in the iodination step.

The synthesis of another fragment, styrene 5, began with the commercially available starting material 3,5-dihydroxybenzoic acid (Scheme [4]). The acid was initially converted to TBS protected methyl ester 10 in two steps. Thus, 3,5-dihydroxybenzoic acid was treated with thionyl chloride in a cold methanolic solution to give the methyl ester, which was subsequently protected with TBS groups. Reduction of methyl ester 10 with LiAlH₄ cleanly resulted in alcohol 11. The crude product was then oxidized under very mild conditions, namely (diacetoxyiodo)benzene with a catalytic amount of TEMPO, to provide aldehyde 12. Aldehyde 12 was then converted to styrene 13 under conventional conditions for Wittig olefination. In practice, there was no need to purify all crude intermediates until this step. The overall yield for the five steps was 78%.

It is well known that the Mizoroki–Heck reaction gives the best regioselectivities when electronic-deficient olefins are used.[14] Therefore, we further converted olefin 13 to the more electron-deficient olefin 5. Accordingly, 13 was first treated with tetrabutylammonium fluoride to remove the silyl protecting groups. The crude product was then reacted with acetic anhydride to give 5 in an excellent yield over two steps (Scheme [4]).

With the two requisite coupling fragments now produced, we conducted the Mizoroki–Heck reaction (Scheme [5]). Compound 5 was mixed and heated overnight with iodide 4 and a catalytic amount of palladium acetate in the presence of triethylamine in DMF. The Mizoroki–Heck reaction was effectively conducted and produced the desired product in excellent yields. Unfortunately, however, the phenolic acetate moieties were not stable under the basic conditions used in the Mizoroki–Heck reaction. A considerable amount of deacetylated products were found in the resulting mixture, presumably because trace amounts of water in the system hydrolyzed the product. This problem was easily solved by adding in situ acetic anhydride upon completion of the desired Mizoroki–Heck reaction, to convert all the Mizoroki–Heck products to the peracetylated product 3, which simplified the purification of products and the calculation of yields.

Then, the endgame step of the synthesis was achieved by treating intermediate 3 with sodium methoxide in a methanol solution at room temperature (Scheme [5]). After purification by short-pad silica gel chromatography followed by recrystallization from hot water, the desired final product 1 was obtained in a 65% yield. The resulting final product matched the natural product in all aspects (¹H, ¹³C NMR, specific optical rotation, IR, and HRMS).

The synthetic route could also be used to prepare the methyl congener 2 found in the extracts of natural product 1. Such a methylated product could be used for the quality control of the natural product extracts or the corresponding clinical study of 1.

To synthesize 2, iodide 4 was treated with methyl iodide in the presence of K₂CO₃ in DMF to give 9 in a 96% yield (Scheme [3]). Under conditions similar to the synthesis of 1 (see Scheme [5]), the final compound, impurity 2, was effectively synthesized from iodide 9 in a high yield (Scheme [5]).

In conclusion, the syntheses of the natural products piceatannol-3′-O-β-d-glucopyranoside (1) and the 4′-methoxy congener 2 thereof were accomplished in nine steps for 1 and ten steps for 2, with the longest linear sequence being seven steps. The overall yield is 39% for 1 and 40% for 2. The syntheses feature the early implementation of glycosylation, a Fischer-like glycosylation, a highly regioselective iodination of phenolic glycoside in strongly acidic conditions, and a Mizoroki–Heck reaction. Other highlights in the design include the well-planned sequence of reactions around the catechol to achieve the desired pattern of substitutions and connections without the use of protective groups and the telescoped routes to minimize the use of chromatography for purifications. Combined with the high overall yield, this allows the scale-up of the synthesis of piceatannol glucoside 1. Furthermore, the synthetic route also allows the preparation of O-methylated piceatannol glucoside 2, which can be used as a reference in the quality control of 1 as well as the clinical study thereof.

¹H and ¹³C NMR spectra were recorded on Bruker Avance DRX-600 spectrometers. IR spectra were recorded on a PerkinElmer spectrophotometer. Optical rotations were recorded on a PerkinElmer 341 polarimeter. Mass spectra were obtained at Yunnan University Campus-wide Mass Spectrometry Center. Anhydrous solvents were obtained as follows. THF was purified by distillation from Na/K alloy and benzophenone; Et₃N and CH₂Cl₂ from CaH₂. DMF was purified by standing over 3 Å molecular sieves (20 wt%) for 24 h and then distilled under reduced pressure. All moisture sensitive reactions were carried out in a flame- dried flask under an argon atmosphere. Column chromatography was performed with Tsingtao Ocean 240–400 mesh silica gel under low pressure (3–5 psi). TLC was carried out with Tsingtao Ocean silica gel 60-F-254 plates. All reactions were conducted under an argon atmosphere unless otherwise mentioned. Room temperature (rt) refers to 20 ± 5 °C. The ion exchange resin used in the experiments is strongly acidic type of resin equivalent to Amberlite, called Fuchen 732 resin, made in China.

2,3,4,5-Tetra-O-acetyl-d-glucopyranose (7)

A solution of glucose pentaacetate (290 g, 743 mmol) and NH₄OAc (68.72 g, 892 mmol, 1.2 equiv) in DMF (740 mL, 1.0 M) was stirred at 40 °C for 16 h. Upon completion of the reaction, the solution was poured into H₂O (4 L) after ca. 2/3 of DMF was removed in vacuo. The mixture was extracted with EtOAc/PE (1:1 v/v, 3 × 300 mL). The combined organic layers were washed with H₂O, dried (Na₂SO₄), filtered, and concentrated in vacuo to give a dark colored syrup (ca. 250 g), which was used directly in the next step. An aliquot of crude product was purified by silica gel column chromatography for analytical purposes; [α]_D ^25.6 +49.6 (c = 0.5, CHCl₃).

IR (film): 3472, 2975, 1755, 1436, 1379, 1248, 1158, 1103, 1045 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 5.52 (t, J = 9.8 Hz, 1 H), 5.44 (d, J = 3.6 Hz, 1 H), 5.09–5.01 (m, 1 H), 4.92–4.83 (m, 1 H), 4.31–4.17 (m, 2 H), 4.16–4.08 (m, 1 H), 3.80–3.69 (m, 1 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 171.0, 170.3, 169.8, 95.6, 90.2, 73.3, 72.4, 72.2, 71.2, 70.0, 68.6, 68.5, 67.3, 62.1, 20.9, 20.8, 20.7.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₄H₂₀O₁₀Na: 317.0954; found: 371.0949.

2-Hydroxyphenyl-2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (6)

To a 2-L round-bottomed flask containing DCM (1.3 L) was added 7 (249 g, 715 mmol) and catechol (90.00 g, 739 mmol, 1.1 equiv) under argon atmosphere. The mixture was stirred until the solids were dissolved. Then this solution was chilled to 0 °C and BF₃·OEt₂ (458 mL, 3.71 mol, 5 equiv) was added in 1 h. Afterwards, the solution was warmed up to 25 °C and stirred for another 1.5 h until 7 was completely consumed. The reaction mixture was poured into iced water (1.5 L). The organic layer was washed with sat. aq NaHCO₃ (2 L). The aqueous layer was extracted with DCM (3 × 500 mL). All organic layers were combined and dried (Na₂SO₄) and then filtered. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent 10% EtOAc/PE) to furnish the desired product; yield: 144 g (44% over two steps); a white foam; [α]_D ^25.6 –9.14 (c = 3.5, CHCl₃) {Lit.[8] [α]_D ²⁰ –14.6 (c = 3.5, CHCl₃)}.

IR (film): 3454, 1743, 1725, 1495, 1365, 1212 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.02 (td, J = 7.7, 1.5 Hz, 1 H), 6.98–6.94 (m, 2 H), 6.82 (td, J = 7.8, 1.6 Hz, 1 H), 6.00 (s, 1 H), 5.39–5.23 (m, 2 H), 5.20–5.11 (m, 1 H), 4.95 (d, J = 7.6 Hz, 1 H), 4.30 (dd, J = 12.3, 5.4 Hz, 1 H), 4.18 (dd, J = 12.4, 2.5 Hz, 1 H), 3.87–3.82 (m, 1 H), 2.11 (s, 3 H), 2.10 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 170.5, 170.1, 169.9, 169.3, 147.5, 144.2, 125.4, 120.3, 117.8, 116.4, 101.7, 72.3, 71.4, 68.2, 61.7, 20.7, 20.6, 20.6, 20.5.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₀H₂₄O₁₁Na: 463.1216; found: 463.1206.

4-Iodo-2-hydroxyphenyl-2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (4)

Glucoside 6 (130 g, 295 mmol) was dissolved in a 1:1 TFA/DCM mixture (1.2 L, v/v) and cooled to 0 °C. To this solution was added batchwise the reagent NIS (69.73 g, 1.05 equiv). The mixture was stirred at rt for 14 h until 6 was consumed (monitored by HPLC). The resulting solution was concentrated in vacuo and poured onto crushed ice. Then the crude product was extracted with DCM (4 × 200 mL). The combined organic layers were washed with sat. aq NaHCO₃, dried (Na₂SO₄), and concentrated. The crude product was purified by silica gel column chromatography to give 4 as a white powder; yield: 120 g (71%); [α]_D ^25.6 –3.90 (c = 1.0, CHCl₃).

IR (film): 3383, 1741, 1718, 1498, 1373, 1290, 1231, 1082, 1053, 1036 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.29 (dd, J = 8.5, 2.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 6.70 (d, J = 8.5 Hz, 1 H), 5.97 (s, 1 H), 5.31 (t, J = 9.5 Hz, 1 H), 5.23 (dd, J = 9.8, 7.9 Hz, 1 H), 5.11 (t, J = 9.7 Hz, 1 H), 4.93 (d, J = 7.9 Hz, 1 H), 4.24 (dd, J = 12.3, 6.2 Hz, 1 H), 4.19 (dd, J = 12.3, 2.4 Hz, 1 H), 3.89 (ddd, J = 10.1, 6.1, 2.4 Hz, 1 H), 2.14 (s, 3 H), 2.10 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 170.7, 170.3, 170.1, 169.5, 147.4, 145.0, 134.1, 126.1, 118.3, 101.3, 80.6, 72.5, 72.2, 71.5, 68.3, 62.0, 21.0, 20.9, 20.7.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₀H₂₃IO₁₁Na: 589.0183; found: 589.0177.

4-Iodo-2-methoxyphenyl-2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (9)

To a 2 L round-bottomed flask containing anhyd DMF (700 mL) was added 4 (100 g, 177 mmol) and K₂CO₃ (48.81 g, 2.0 equiv) under an argon atmosphere. MeI (38 mL, 3.5 equiv) was added dropwise to the mixture. After completion of the addition, the mixture was heated at 30 °C and allowed to stir overnight. The reaction should be monitored with HPLC due to the failure to separate the product from 4 on TLC plates. When 4 was consumed, the reaction mixture was poured into H₂O (3.5 L). The product was extracted with a 1.1 mixture of EtOAc/PE (2 × 2 L). All organic layers were combined and dried (Na₂SO₄) and then filtered. The filtrate was concentrated and the resulting crude product was purified by trituration with 20% EtOAc/PE to furnish the desired product 9; yield: 98 g (96%); a white powder; [α]_D ^25.6 –8.50 (c = 1.0, CHCl₃).

IR (film): 2990, 2952, 2912, 2847, 1733, 1582, 1498, 1469, 1420, 1371, 1235, 1139, 1052 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.40 (d, J = 2.0 Hz, 1 H), 7.34 (dd, J = 8.6, 2.0 Hz, 1 H), 6.63 (d, J = 8.6 Hz, 1 H), 5.29–5.21 (m, 2 H), 5.10 (t, J = 9.4 Hz, 1 H), 4.92 (d, J = 7.3 Hz, 1 H), 4.19 (ddd, J = 14.4, 12.2, 4.2 Hz, 2 H), 3.83–3.79 (m, 1 H), 3.77 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H), 2.01 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 170.7, 170.3, 169.5, 169.3, 150.9, 147.1, 133.5, 128.6, 114.8, 100.7, 81.9, 77.4, 77.2, 77.0, 72.6, 72.3, 71.2, 68.6, 62.3, 56.2, 21.0, 20.7.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₁H₂₅IO₁₁Na: 603.0339; found: 603.0333.

Methyl 3,5-Dihydroxybenzoate

3,5-Dihydroxybenzoic acid (60.00 g, 389 mmol) was suspended in MeOH (780 mL, 0.5 M) and cooled to 0 °C. To this mixture was added dropwise SOCl₂ (113 mL, 4.0 equiv). The mixture was allowed to warm to rt and reflux for 1 h. The solvent was then removed in vacuo. The crude product was used without further purification in the next step (an aliquot was purified for analytical purposes).

IR (film): 3365, 3228, 1686, 1600, 1509, 1485, 1439, 1297, 1176, 1009, 764, 686 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 9.61 (s, 2 H), 6.81 (d, J = 2.2 Hz, 2 H), 6.44 (t, J = 2.2 Hz, 1 H), 3.79 (s, 3 H).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 166.2, 158.5, 131.3, 107.2, 107.1, 51.9.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₈H₈O₄Na: 191.0320; found: 191.0314.

Methyl 3,5-Bis(tert-butyldimethylsilyloxy)benzoate (10)

The crude methyl 3,5-dihydroxybenzoate was dissolved in DMF (400 mL, 1 M) together with imidazole (133 g, 5.0 equiv) and cooled to 0 °C. To the mixture was added TBSCl (141 g, 2.4 equiv) batchwise. The mixture was stirred at 0 °C for 20 min and then warmed to rt and quenched with sat. aq NH₄Cl (3 L) and the crude product was extracted with EtOAc (3 × 1 L). The combined organic layers were washed with brine, dried (Na₂SO₄) and then filtered. The filtrate was concentrated in vacuo, which was used directly in the next step (an aliquot of crude product was purified by silica gel column chromatography for analytical purposes).

IR (film): 2954, 2930, 2896, 2886, 2858, 1727, 1588, 1468, 1338, 1252, 1164, 1028, 1011 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.12 (d, J = 2.3 Hz, 2 H), 6.52 (t, J = 2.3 Hz, 1 H), 3.88 (s, 3 H), 0.98 (s, 18 H), 0.21 (s, 12 H).

¹³C NMR (151 MHz, CDCl₃): δ = 167.0, 156.7, 132.0, 117.0, 114.7, 52.3, 25.8, 18.4, –4.3.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₀H₃₆O₄Si₂Na: 419.2055; found: 419.2046.

3,5-Bis(tert-butyldimethylsilyloxy)benzyl Alcohol (11)

LiAlH₄ (16.25 g, 1.1 equiv) was suspended in THF (1 L) and cooled to 0 °C. To this mixture was added a solution of ester 10 (158 g, crude) in THF (100 mL). After the addition, the mixture was stirred at 0 °C for 1 h at rt for 30 min. The reaction was quenched by first adding EtOAc (200 mL) and stirring for 30 min and then adding H₂O (1.5 L) and stirring for another 5 min. The resulting paste was mixed with Celite (ca.100 g) and then filtered. The filter cake was extensively washed with THF and monitored by TLC until no product was found in the wash. The filtrates were combined and concentrated in vacuo. The crude product was mixed with H₂O (1.2 L) and the mixture was extracted with EtOAc (2 × 1 L). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to provide the crude product as a yellow-orange oil (146 g), which was directly used in the next step. An aliquot of the crude product was purified by silica gel column chromatography for analytical purpose.

IR (film): 3321, 2955, 2929, 2895, 2885, 1588, 1466, 1449, 1332, 1301, 1160, 1027, 1003 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 6.47 (d, J = 2.2 Hz, 2 H), 6.26 (t, J = 2.3 Hz, 1 H), 4.77–4.30 (m, 2 H), 1.71 (s, 1 H), 0.98 (s, 18 H), 0.19 (s, 12 H).

¹³C NMR (151 MHz, CDCl₃): δ = 156.9, 143.3, 111.9, 111.3, 65.3, 25.8, 18.3, –4.2.

HRMS (ESI⁺) m/z [M + Na]⁺ calcd for C₁₉H₃₆O₃Si₂Na: 391.2101; found: 391.2097.

3,5-Bis(tert-butyldimethylsilyloxy)benzaldehyde (12)

Crude alcohol 11 (146 g) was dissolved in DCM (1.3 L) and cooled to 0 °C. To this mixture was added TEMPO (6.20 g, 0.10 equiv) and the mixture was stirred. The oxidant PhI(OAc)₂ (138 g, 1.1 equiv) was added in four batches to the mixture at rt. After the disappearance of 11 (ca. 2.5 h), the reaction was quenched with sat. aq NaHCO₃ (1 L). The mixture was then extracted with DCM (3 × 500 mL), the combined organic layers were dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo. The crude product was used directly in the next step. An aliquot of crude product was purified by silica gel column chromatography for analytical purposes.

IR (film): 2955, 2930, 2858, 1702, 1587, 1457, 1332, 1253, 1165, 1030, 1005 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.86 (s, 1 H), 6.96 (d, J = 2.3 Hz, 2 H), 6.59 (t, J = 2.3 Hz, 1 H), 0.99 (s, 18 H), 0.22 (s, 12 H).

¹³C NMR (151 MHz, CDCl₃): δ = 191.9, 157.5, 138.6, 118.5, 114.5, 25.7, 18.4, –4.3.

HRMS (ESI⁺) m/z [M + H]⁺ calcd for C₁₉H₃₅O₃Si₂: 367.2125; found: 367.2119.

3,5-Bis(tert-butyldimethylsilyloxy)styrene (13)

A suspension of Ph₃PCH₃Br (181 g, 1.3 equiv) in THF (1.3 L, 0.4 M) was cooled to –78 °C. To this suspension was added n-BuLi (173 mL, 2.5 M in hexanes, 1.1 equiv). After the addition, the mixture was allowed to warm up to 0 °C with stirring for 30 min. The mixture was cooled back to –78 °C again. To this mixture was added a solution of aldehyde 12 (150 g, crude) in THF (100 mL). After addition, the resulting mixture was stirred for 1 h. Then the mixture was allowed to warm up to rt and the stirring was continued for 3 h. Upon completion of the reaction, Celite was added to the mixture and filtered. The filter cake was washed with THF a few times with TLC monitoring until no product was found in the wash. The organic filtrates were combined and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 1% EtOAc/PE) to give a colorless oil; yield: 110 g (78% yield over 5 steps).

IR (film): 2956, 2929, 2885, 2858, 1584, 1471, 1441, 1419, 1329, 1253, 1166, 1022 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 6.59 (dd, J = 17.6, 10.8 Hz, 1 H), 6.52 (d, J = 2.2 Hz, 2 H), 6.26 (t, J = 2.2 Hz, 1 H), 5.66 (dd, J = 17.4, 1.0 Hz, 1 H), 5.20 (dd, J = 10.8, 0.9 Hz, 1 H), 0.99 (s, 18 H), 0.20 (s, 12 H).

¹³C NMR (151 MHz, CDCl₃): δ = 156.8, 139.6, 136.9, 114.0, 111.9, 111.6, 26.0, 25.9, 25.8, 25.7, 18.4, –4.2.

HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₀H₃₇O₂Si₂: 365.2332; found: 365.2322.

3,5-Diacetoxystyrene (5)

Styrene 13 (110 g, 269 mmol) was dissolved in THF (500 mL) and cooled to 0 °C. To this solution was added TBAF solution (2.2 equiv, 1 M) dropwise. The resulting mixture was stirred for 1 h and then the solvent was removed in vacuo. The crude product was dissolved in DCM (700 mL) and cooled to 0 °C. To this solution was added Et₃N (126 mL, 3.0 equiv) and Ac₂O (71 mL, 2.5 equiv), respectively. The solution was allowed to warm up to rt and quenched with sat. aq NaHCO₃ (1 L). The aqueous layer was extracted with DCM (3 × 500 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10% EtOAc/PE) to afford a colorless oil; yield: 56 g (84% over two steps).

IR (film): 2936, 1761, 1212, 1589, 1450, 1366, 1184, 1120, 1059, 1017 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.02 (d, J = 2.1 Hz, 2 H), 6.83 (t, J = 2.1 Hz, 1 H), 6.64 (dd, J = 17.5, 10.8 Hz, 1 H), 5.73 (d, J = 17.6 Hz, 1 H), 5.31 (d, J = 10.8 Hz, 1 H), 2.28 (s, 6 H).

¹³C NMR (151 MHz, CDCl₃): δ = 169.0, 151.4, 140.0, 135.5, 116.8, 116.8, 116.0, 116.0, 114.7, 114.7, 21.2.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₂O₄Na: 243.0633; found: 243.0625.

3,5,4′-Triacetoxy-3′-hydroxystilbene-3′-O-β-d-(2,3,4,6-tetra-O-acetyl)glucopyranoside (3)

Iodide 4 (15.00 g, 26.49 mmol), styrene 5 (7.00 g, 31.79 mmol, 1.2 equiv), tri(o-tolyl)phosphine (1.21 g, 31.79 mmol, 0.15 equiv) were dissolved in anhyd DMF (88 mL). The mixture was purged with an argon current in an ultrasonic bath for 30 min. Then Pd(OAc)₂ (297.3 mg, 1.32 mmol, 0.05 equiv) and Et₃N (37 mL, 265 mmol, 10 equiv) were added. Additional 15 min of purge with an argon current was conducted. Afterwards, the mixture was stirred at 60 °C for 18 h and cooled to 0 °C. To this mixture was added Ac₂O (7.5 mL, 3.0 equiv) and stirred for another 2 h. The reaction was quenched with H₂O (100 mL) and the crude product was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and filtered. The filtrate was concentrated in vacuo. The crude product was purified with silica gel column chromatography (2% EtOAc/DCM) to afford 3 as a foam; yield: 17.01 g (92%); [α]_D ^25.6 +0.30 (c = 1.0, CHCl­₃).

IR (film): 1742, 1591, 1366, 1257, 1193, 1126, 1039 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.16 (d, J = 8.3 Hz, 1 H), 7.14–7.10 (m, 3 H), 7.04–6.90 (m, 3 H), 6.82 (t, J = 2.1 Hz, 1 H), 5.36–5.28 (m, 2 H), 5.19–5.08 (m, 2 H), 4.29 (dd, J = 12.3, 5.7 Hz, 1 H), 4.19 (dd, J = 12.3, 2.4 Hz, 1 H), 4.01–3.95 (m, 1 H), 2.30 (s, 6 H), 2.27 (s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 170.7, 170.2, 169.7, 169.5, 169.1, 151.5, 148.5, 139.9, 139.2, 136.0, 129.7, 127.9, 123.7, 121.8, 117.1, 114.7, 113.4, 98.6, 72.7, 72.1, 70.6, 68.5, 62.3, 21.2, 20.8, 20.8, 20.7, 20.5.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₃₄H₃₆O₁₆Na: 723.1901; found: 723.1891.

Piceatannol-3′-O-β-d-glucopyranoside (1)

Peracetate 3 (17.00 g, 24.26 mmol) was dissolved in degassed MeOH (40 mL) and cooled to 0 °C. To this mixture was added a solution of NaOMe (5.5 equiv) in MeOH (80 mL). The mixture was allowed to warm to rt. Upon completion of the reaction, granules of the cationic ion exchange resin were added to the solution until pH <7. The mixture was filtered and concentrated in vacuo. The crude product was purified with short-pad of silica gel column chromatography (eluent: 5% MeOH/DCM) and recrystallized from hot H₂O to afford 1 as a white powder; yield: 6.4 g (65%); [α]_D ^25.6 –43.93 (c = 0.56, MeOH); {natural product sample[1] [α]_D ^25.6 –42.68 (c = 0.56, MeOH)}.

IR (film): 3402, 2917, 1594, 1515, 1473, 1429, 1335, 1259, 1216, 1178, 1153, 1086 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 9.22 (br s, 2 H), 8.74 (br s, 1 H), 7.46 (d, J = 2.1 Hz, 1 H), 7.06 (dd, J = 8.2, 2.0 Hz, 1 H), 6.88 (q, J = 16.3 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.40 (d, J = 2.1 Hz, 2 H), 6.13 (t, J = 2.1 Hz, 1 H), 5.52 (s, 1 H), 5.15 (d, J = 4.4 Hz, 1 H), 5.10 (d, J = 5.4 Hz, 1 H), 4.79 (t, J = 5.7 Hz, 1 H), 4.75 (d, J = 7.1 Hz, 1 H), 3.83–3.76 (m, 1 H), 3.53–3.47 (m, 1 H), 3.45–3.40 (m, 1 H), 3.37–3.29 (m, 2 H), 3.21–3.14 (m, 1 H).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 158.5, 146.7, 145.7, 139.3, 128.9, 127.9, 126.4, 122.2, 116.0, 114.3, 104.5, 102.5, 101.9, 77.5, 76.0, 73.5, 70.2, 61.0.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₀H₂₂O₉Na: 429.1162; found: 429.1156.

3,5-Triacetoxy-4′-methoxy-3′-hydroxystilbene-3′-O-β-d-(2,3,4,6-tetra-O-acetyl)glucopyranoside (14)

Iodide 9 (120 g, 207 mmol), styrene 5 (52.37 g, 238 mmol, 1.15 equiv), tri(o-tolyl)phosphine (9.44 g, 31.02 mmol, 0.15 equiv) were dissolved in anhyd DMF (830 mL). The mixture was purged with an argon current in an ultrasonic bath for 30 min. Then Pd(OAc)₂ (2.32 g, 10.34 mmol, 0.05 equiv) and Et₃N (288 mL, 2.07 mol, 10 equiv) were added. Additional 15 min of purge with an argon current was conducted. Afterwards, the mixture was stirred at 60 °C for 18 h and cooled to 0 °C. To this mixture was added Ac₂O (59 mL, 3.0 equiv) and stirred for another 2 h. The reaction was quenched with H₂O and the crude product was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography to afford 14 as a foam; yield: 110 g (79%); [α]_D ^25.6 +16.7 (c = 1.0, CHCl₃).

IR (film): 2957, 1757, 1634, 1601, 1584, 1558, 1516, 1464, 1444, 1371, 1303, 1225, 1124, 1066, 1046 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.29 (d, J = 2.0 Hz, 1 H), 7.18 (dd, J = 8.4, 2.0 Hz, 1 H), 7.10 (d, J = 2.0 Hz, 2 H), 6.97 (t, J = 11.5 Hz, 1 H), 6.92–6.86 (m, 2 H), 6.80 (t, J = 2.0 Hz, 1 H), 5.34–5.26 (m, 2 H), 5.20–5.14 (m, 1 H), 5.03–4.97 (m, 1 H), 4.31 (dd, J = 12.2, 5.4 Hz, 1 H), 4.19 (dd, J = 12.2, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.83–3.79 (m, 1 H), 2.30 (s, 6 H), 2.09 (s, 3 H), 2.05–2.02 (m, 9 H).

¹³C NMR (151 MHz, CDCl₃): δ = 170.8, 170.4, 169.6, 169.5, 169.1, 151.5, 151.0, 146.3, 139.8, 130.1, 129.9, 125.9, 123.8, 118.5, 116.8, 114.3, 112.9, 100.9, 72.8, 72.3, 71.4, 68.7, 62.2, 56.3, 21.3, 20.8, 20.8, 20.8, 20.7.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₃₃H₃₆O₁₅: 695.1952; found: 695.1947.

Piceatannol-4′-methoxy-3′-O-β-d-glucopyranoside (2)

Peracetate 14 (100 g, 149 mmol) was dissolved in degassed MeOH (1 L) and cooled to 0 °C. To this mixture was added K₂CO₃ (10.27 g, 0.5 equiv) and stirred at 40 °C for 3 h. Upon completion of the reaction, cationic exchange resin beads were added to the solution until pH <7. The mixture was filtered and concentrated in vacuo. The crude product was purified with short silica gel column chromatography (eluent: 5% MeOH/DCM) and recrystallized from hot H₂O to afford an off-white powder; yield: 48.02 g (77%); [α]_D ^25.6 –70.75 (c = 0.40, H₂O/ acetone­ 1:1 v/v); {Lit.[1] [α]_D ¹⁶ –70 (c = 0.4, H₂O/acetone 1:1 v/v)}.

IR (film): 3392, 3276, 2945, 1620, 1596, 1517, 1332, 1072, 1020 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 9.21 (s, 2 H), 7.39 (s, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 5.4 Hz, 2 H), 6.40 (d, J = 2.1 Hz, 2 H), 6.13 (s, 1 H), 5.23 (d, J = 4.8 Hz, 1 H), 5.09 (d, J = 4.3 Hz, 1 H), 5.03 (d, J = 5.2 Hz, 1 H), 4.97 (d, J = 7.1 Hz, 1 H), 4.64 (t, J = 5.7 Hz, 1 H), 3.77 (s, 3 H), 3.76–3.69 (m, 1 H), 3.47 (dt, J = 11.9, 6.2 Hz, 1 H), 3.43–3.38 (m, 1 H), 3.33–3.25 (m, 2 H), 3.20–3.12 (m, 1 H).

¹³C NMR (151 MHz, DMSO-d ₆): δ = 158.4, 148.8, 146.8, 139.1, 130.0, 127.7, 127.1, 121.0, 113.0, 112.5, 104.5, 102.0, 100.3, 77.1, 77.0, 73.3, 69.9, 60.8, 55.7.

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₁H₂₄O₉Na: 443.1318; found: 443.1313.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 Kashiwada Y, Nonaka G, Nishioka I. Chem. Pharm. Bull. 1984; 32: 3501
  CrossrefSearch in Google Scholar
• 2 Kim A, Ma JY. Phytomedicine 2019; 57: 95
  CrossrefPubMedSearch in Google Scholar
• 3 Ouyang X, Li X, Liu J, Liu Y, Xie Y, Du Z, Xie H, Chen B, Lu W, Chen D. RSC Adv. 2020; 10: 31171
  CrossrefPubMedSearch in Google Scholar
• 4 Woo A, Shin W, Cuong TD, Min B, Lee JH, Jeon BH, Ryoo S. Int. J. Mol. Med. 2013; 31: 803
  CrossrefPubMedSearch in Google Scholar
• 5 Muller J, Cardey B, Zedet A, Desingle C, Grzybowski M, Pomper P, Foley S, Harakat D, Ramseyer C, Girard C, Pudlo M. RSC Med. Chem. 2020; 11: 559
  CrossrefPubMedSearch in Google Scholar
• 6 Abdelkawy KS, Lack K, Elbarbry F. Eur. J. Drug Metabol. Pharmacokinet. 2017; 42: 355
  CrossrefPubMedSearch in Google Scholar
• 7 Steppan J, Nyhan D, Berkowitz DE. Front. Immunol. 2013; 4: 1
  CrossrefPubMedSearch in Google Scholar
• 8 Li D, Li R, Li J, Yang Z. CN107200759A, 2017
• 9 Nicolaou KC, Mitchell HJ, Jain NF, Bando T, Hughes R, Winssinger N, Natarajan S, Koumbis AE. Chem. Eur. J. 1999; 5: 2648
  CrossrefSearch in Google Scholar
• 10 Shen R, Laval S, Cao X, Yu B. J. Org. Chem. 2018; 83: 2601
  CrossrefPubMedSearch in Google Scholar
• 11 Shao X, Wang X, Zhu K, Dang Y, Yu B. J. Org. Chem. 2020; 85: 12080
  CrossrefPubMedSearch in Google Scholar
• 12 Srinivas C, Blake H, Qian W. Lett. Org. Chem. 2006; 3: 35
  CrossrefSearch in Google Scholar
• 13 Mabic S, Lepoittevin J.-P. Tetrahedron Lett. 1995; 36: 1705
  CrossrefSearch in Google Scholar
• 14 Heck RF. Org. React. 1982; 27: 345
  Search in Google Scholar

Corresponding Authors

Publication History

Received: 12 July 2021

Accepted after revision: 07 September 2021

Accepted Manuscript online:
07 September 2021

Article published online:
21 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Kashiwada Y, Nonaka G, Nishioka I. Chem. Pharm. Bull. 1984; 32: 3501
  CrossrefSearch in Google Scholar
• 2 Kim A, Ma JY. Phytomedicine 2019; 57: 95
  CrossrefPubMedSearch in Google Scholar
• 3 Ouyang X, Li X, Liu J, Liu Y, Xie Y, Du Z, Xie H, Chen B, Lu W, Chen D. RSC Adv. 2020; 10: 31171
  CrossrefPubMedSearch in Google Scholar
• 4 Woo A, Shin W, Cuong TD, Min B, Lee JH, Jeon BH, Ryoo S. Int. J. Mol. Med. 2013; 31: 803
  CrossrefPubMedSearch in Google Scholar
• 5 Muller J, Cardey B, Zedet A, Desingle C, Grzybowski M, Pomper P, Foley S, Harakat D, Ramseyer C, Girard C, Pudlo M. RSC Med. Chem. 2020; 11: 559
  CrossrefPubMedSearch in Google Scholar
• 6 Abdelkawy KS, Lack K, Elbarbry F. Eur. J. Drug Metabol. Pharmacokinet. 2017; 42: 355
  CrossrefPubMedSearch in Google Scholar
• 7 Steppan J, Nyhan D, Berkowitz DE. Front. Immunol. 2013; 4: 1
  CrossrefPubMedSearch in Google Scholar
• 8 Li D, Li R, Li J, Yang Z. CN107200759A, 2017
• 9 Nicolaou KC, Mitchell HJ, Jain NF, Bando T, Hughes R, Winssinger N, Natarajan S, Koumbis AE. Chem. Eur. J. 1999; 5: 2648
  CrossrefSearch in Google Scholar
• 10 Shen R, Laval S, Cao X, Yu B. J. Org. Chem. 2018; 83: 2601
  CrossrefPubMedSearch in Google Scholar
• 11 Shao X, Wang X, Zhu K, Dang Y, Yu B. J. Org. Chem. 2020; 85: 12080
  CrossrefPubMedSearch in Google Scholar
• 12 Srinivas C, Blake H, Qian W. Lett. Org. Chem. 2006; 3: 35
  CrossrefSearch in Google Scholar
• 13 Mabic S, Lepoittevin J.-P. Tetrahedron Lett. 1995; 36: 1705
  CrossrefSearch in Google Scholar
• 14 Heck RF. Org. React. 1982; 27: 345
  Search in Google Scholar

• Supplementary Material