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DOI: 10.1055/s-0042-1751553
Synthesis of C-Glucoside Analogues of Naturally Occurring Phenylethanoid O-Glucosides
Abstract
Structural modifications of natural products has been a highly effective approach in the search for new leads with improved biological activity, aqueous solubility, and stability. Phenylethanoid glycosides (PEGs), as natural compounds, have attracted great attention due to their promising biological activities. These activities include neuroprotection, antioxidant, immunoregulation, anti-inflammatory, and analgesic effects, as well as antitumor, antiviral, and hepatoprotective abilities. Three potent PEGs, acteoside, echinacoside, and salidroside, are gaining renewed interest in this class of compounds. However, being O-glycosides, PEGs have low bioavailability due to factors such as poor intestinal permeability and low hydrolytic stability. The promising pharmacological properties and the limitations have inspired us to synthesize C-analogues that are expected to be hydrolytically stable.
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Key words
phenylethanoid glycosides - C-glucosides - O-glucosides - C-glycosides - O-glycosides - Julia olefinationThe O-glycosides of phenylethyl alcohol 1, commonly referred to as phenylethanoid glycosides (PEGs), are a water-soluble family of natural products that are widely distributed in several plant species and they display significant bioactivities.[1] Most of the PEGs are isolated from garden plants and medicinal herbs and exhibit diverse pharmacological activities including, antibacterial, antiviral, anti-inflammatory, antioxidant, antitumor, immunomodulatory, hepatoprotective and neuroprotective activity, among others. Three PEGs, namely acteoside 2,[2] echinacoside 3,[3] and salidroside 4 [4] have attracted wide attention due to their potency, which has rekindled heightened keen interests in this class of compounds.[5] Salidroside 4, isolated from the perennial flowering herb of Rhodiola rosea with proven protective effects on myocardial injury and liver cancer, has now emerged as a highly promising neuroprotection agent.[4]
Although PEGs have evoked interest, precise mechanisms for their pharmacological activities remain obscure and merit structure-activity relationship studies for their successful therapeutic applications. Furthermore, being O-glycosides, they are hydrolytically unstable and have poor bioavailability. Gastric acid and digestive enzymes hydrolyze these glucosides and liberate the aglycone; the half-life of salidroside 4 ranges from 20 minutes to 2 hours. In this context, and given the fact that C-glycosides[6] are hydrolytically stable and have successfully contributed towards therapeutic applications, we were emboldened to envision hitherto unknown C-glucosides 5 as targets for the synthesis and biological evaluation (Figure [1]).
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The targeted C-glucosides 5 are stable analogues of O-glucosides because the glycosidic oxygen atom linking the glycone and the aglycone part is replaced with an isosteric methylene unit (-CH2). The oxygenation pattern on the aryl ring was inspired by natural products that demonstrate potent antioxidant and anti-inflammatory activities.[7]
A synthesis of targeted C-glucoside analogues 5 was envisaged using the Julia–Kocienski reaction between the pyranoside-based sulfone building block 6 and suitably protected aryl aldehydes 7 as a representative example for developing a synthetic route for this class of compounds (Figure [2]). A furanoside-based sulfone building block was reported previously.[8]
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The sulfone building block 6 was prepared from ester 8, which, in turn, was prepared in two steps by a known method using tetra-O-benzyl-d-gluconolactone as starting material.[9] Reduction of the ester functionality followed by Mitsunobu reaction of alcohol 9 and 2-mercapto benzothiazole provided sulfide 10. The oxidation of sulfide 10 using m-chloroperbenzoic acid furnished the requisite building block 6 in good yields (Scheme [1]). Multigram quantities of 6 can be made by using this scheme. The β-configuration of the substituted alkyl residue at the C-1 position of the d-glucose unit was confirmed through X-ray diffraction data at the sulfide 10 stage (Figure [3]).[10]
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The carbanion from the sulfone 6 was easily prepared using NaH as a base at –78 °C. The formed carbanion then reacted with aldehydes 7a–f, leading to the formation of olefinated products 11a–f in moderate to good yields. The products were predominantly E-configured, as indicated from the coupling constant (J) value of the benzylic C–H olefinic proton. The olefinated products 11a–f, after purification over silica-gel chromatography, were directly subjected to hydrogenation. The hydrogenation reaction failed to occur with Pd/C as a catalyst, despite variations in reaction solvent and pressure of hydrogen gas. However, to our satisfaction, facile hydrogenation of the double bond and concomitant debenzylation of the glucosyl residue occurred with the use of 10 mol% Pd(OH)2 in dry MeOH at normal atmospheric pressure. The desired targeted products 5a–f (71–96%) were obtained after purification over silica-gel-based chromatography using 5% MeOH in dichloromethane as eluent (Scheme [2]). The obtained products gave satisfactory spectroscopy and mass spectrometry data.
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In conclusion, the work presented in this paper constitutes the first report on the synthesis of C-glucoside analogues of naturally occurring O-glucoside phenylethanoid glycosides (PEGs). The developed synthetic scheme illustrates the usefulness of the Julia–Kocienski olefination procedure. A small library of such compounds is being generated for assessing their biological activity in a variety of pharmacological applications.
All the reactions that required anhydrous conditions were carried out by standard procedures under a nitrogen atmosphere. Unless otherwise specified, all chemicals were purchased from commercial vendors and used as received. Solvents used for column chromatography were laboratory reagent grade. Solvents were distilled from CaH2 (CH2Cl2, acetonitrile, DMF), Na/benzophenone (THF), and Mg/I2 (MeOH). Reactions were monitored by thin-layer chromatography (TLC) with silica gel 60 plates under UV light or by dipping into a solution of cerium(IV) sulfate (2.5 g) and ammonium molybdate (6.25 g) in 10% sulfuric acid (250 mL) followed by charring on a hot plate. Melting points were determined for compounds 6, 9, and 10, which were purified by silica gel column chromatography using EtOAc/n-hexane. Compound 10 was recrystallized from CH2Cl2/hexanes. Infrared spectra were recorded with a JASCO-FT/IR-4100 spectrophotometer with KBr and reported in wavenumbers (cm–1). 1H (400 MHz and 500 MHz) and 13C (100 MHz, and 125 MHz) high-resolution NMR experiments were recorded with Brucker AV 400 and 500 FT NMR spectrometers using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported relative to chloroform (δ = 7.26 ppm), or MeOH (δ = 4.75 ppm) for 1H NMR and chloroform (δ= 77.2 ppm), or MeOH (δ = 47.65 ppm) for 13C NMR. Multiplicities are given as, s = singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiplet, and brs = broad singlet. High-resolution mass spectra were recorded with an LC-QTOF mass spectrometer by using the ESI technique. Optical rotations were recorded with a polarimeter equipped with a sodium lamp source (589 nm). Crystal structures were recorded with a Bruker D8 venture SC-XRD with Cu radiation.
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2-((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethan-1-ol (9)
To a solution of the ester 8 (0.75 g, 1.22 mmol) in anhydrous THF (10 mL) at 0 °C was added LiAlH4 (0.09 g, 2.45 mmol). The reaction mixture was stirred at r.t. for 4 h. The reaction was slowly quenched with saturated NH4Cl solution (10 mL) and the mixture was filtered. The filtrate was concentrated to remove THF and extracted with EtOAc (3 × 20 mL). The collected organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexanes, 2:8) to afford the alcohol 9.
Yield: 0.55 g (78%); white solid; mp 71–73 °C (Lit.[11]); [α]D 27 –25.44 (c = 0.1, CHCl3).
IR (KBr): 3477, 2922, 2857, 1657, 1454, 1373, 1012, 773 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.35–7.23 (m, 18 H), 7.2–7.15 (m, 2 H), 4.92–4.86 (m, 3 H), 4.81 (d, J = 10.8 Hz, 1 H), 4.63 (d, J = 4.9 Hz, 1 H), 4.57–4.48 (m, 3 H), 3.80–3.74 (m, 2 H), 3.71–3.64 (m, 2 H), 3.61–3.54 (m, 2 H), 3.51–3.44 (m, 2 H), 3.32 (t, J = 9.2 Hz, 1 H), 2.62 (brs, 1 H), 2.08–2.01 (m, 1 H), 1.77–1.69 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 138.5 (1-C), 137.9 (1-C), 137.9 (2-C), 128.5 (3-CH), 128.4 (3-CH), 128.4 (4-CH), 128.0 (2-CH), 128.0 (2-CH), 127.9 (1-CH), 127.8 (2-CH), 127.7 (1-CH), 127.7 (2-CH), 87.0 (1-CH), 81.8 (1-CH), 79.7 (1-CH), 78.6 (1-CH), 78.5 (1-CH), 75.6 (1-CH2), 75.3 (1-CH2), 75.0 (1-CH2), 73.5 (1-CH2), 69.1 (1-CH2), 61.4 (1-CH2-OH), 33.7 (1-CH2).
MS (ESI): m/z (%) = 569 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C36H41O6: 569.2903; found: 569.2921.
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2-((2-((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)thio)benzo[d]thiazole (10)
In an oven-dried, round-bottom flask, alcohol 9 (1.4 g, 2.46 mmol) was dissolved in anhydrous THF (10 mL). PPh3 (1.29 g, 4.92 mmol) and 2-mercaptobenzothiazole (0.49 g, 2.95 mmol) were added and the solution was stirred at r.t. The solution is then maintained at 0 °C and DEAD (0.77 mL, 4.92 mmol) was added slowly. The reaction mixture was allowed to come to r.t. and stirring was continued for 4 h (the reaction n was monitored by TLC). Upon completion, the reaction was quenched with saturated NH4Cl solution (10 mL), and the mixture was extracted with EtOAc (3 × 20 mL), and washed with water (2 × 20 mL) and brine solution (2 × 20 mL). The collected organic layers were dried using anhydrous NaSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexanes, 1:9) and recrystallized (CH2Cl2/n-hexane) to afford the sulfide 10.
Yield: 1.4 g (80%); colorless crystals; mp 101–103 °C; [α]D 27 –34.68 (c = 0.1, CHCl3).
IR (KBr): 2912, 2857, 1713, 1657, 1459, 1017, 768 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 7.73 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.34–7.29 (m, 2 H), 7.29–7.15 (m, 14 H), 7.14–7.01 (m, 6 H), 4.89–4.71 (m, 4 H), 4.65–4.44 (m, 4 H), 3.72–3.54 (m, 4 H), 3.51–3.28 (m, 4 H), 3.28–3.18 (m, 1 H), 2.45–2.28 (m, 1 H), 1.93–1.79 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 165.9 (1-C), 152.3 (1-C), 137.5 (1-C), 137.1 (2-C), 136.7 (1-C), 134.2 (1-C), 127.4 (2-CH), 127.3 (2-CH), 127.3 (3-CH), 127.3 (1-CH), 127.2 (1-CH), 127.0 (2-CH), 126.8 (2-CH), 126.7 (2-CH), 126.7 (1-CH), 126.6 (2-CH), 126.5 (2-CH), 124.9 (1-CH), 123.0 (1-CH), 120.5 (1-CH), 119.8 (1-CH), 86.1 (1-CH), 80.8 (1-CH), 77.8 (1-CH), 77.4 (1-CH), 76.5 (1-CH), 76.2 (1-CH2), 76.0 (1-CH2), 75.7 (1-CH2), 72.5 (1-CH2), 67.9 (1-CH2), 30.6 (1-CH2-S), 28.8 (1-CH2).
MS (ESI): m/z (%) = 740 (100.0), 741 (49.1) [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C43H44NO5S2: 718.2660; found: 718.2642.
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2-((2-((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)ethyl)sulfonyl)benzo[d]thiazole (6)
To a solution of sulfide 10 (1.4 g, 1.95 mmol) in anhydrous CH2Cl2 (20 mL), m-chloroperbenzoic acid (1.68 g, 9.75 mmol) was added at r.t. To the stirred solution was immediately added NaHCO3 (1.63 g, 19.5 mmol) portion-wise and stirring was continued until precipitation was complete (ca. 30 min). The reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc (2 × 20 mL). Combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexanes, 2:8) to afford the sulfone 6.
Yield: 1.2 g (85%); white solid; mp 110–112 °C; [α]D 27 –32.80 (c = 0.1, CHCl3).
IR (KBr): 2922, 2856, 1644, 1458, 1371, 1025 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 8.16 (d, J = 7.6 Hz, 1 H), 8.00 (d, J = 7.4 Hz, 1 H), 7.66–7.56 (m, 2 H), 7.36–7.23 (m, 14 H), 7.21–7.12 (m, 6 H), 4.92–4.76 (m, 4 H), 4.59–4.47 (m, 4 H), 3.75–3.52 (m, 6 H), 3.38–3.19 (m, 3 H), 2.47–2.34 (m, 1 H), 2.05–1.92 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 165.6 (1-C), 152.7 (1-C), 138.4 (1-C), 137.9 (1-C), 137.9 (1-C), 137.4 (1-C), 136.7 (1-C), 128.4 (4-CH), 128.4 (4-CH), 128.1 (2-CH), 128.0 (1-CH), 127.9 (1-CH), 127.9 (2-CH), 127.8 (3-CH), 127.7 (2-CH), 127.6 (3-CH), 125.5 (1-CH), 122.3 (1-CH), 86.9 (1-CH), 81.3 (1-CH), 78.9 (1-CH), 78.2 (1-CH), 76.8 (1-CH), 75.5 (1-CH2), 75.2 (1-CH2), 75.0 (1-CH2), 73.4 (1-CH2), 68.7 (1-CH2), 51.4 (1-CH2-SO2), 25.1 (1-CH2).
MS (ESI): m/z (%) = 750 (100.0), 751 (48.9) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C43H44NO7S2: 750.2559; found: 750.2522.
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Julia–Kocienski Olefination (A); General Procedure
To a solution of sulfone 6 (0.7 g, 0.93 mmol) in anhydrous THF (5 mL) at –78 °C was added NaH (0.07 g, 1.96 mmol). At the same temperature, after 10 minutes a solution of aldehyde 7a–f (1 equiv) in THF (2 mL) was added, and the reaction mixture was allowed to reach r.t. over 3 h (the reaction was monitored by TLC). The reaction was quenched with saturated NH4Cl solution (10 mL), the mixture was extracted with EtOAc (3 × 10 mL), and washed with water (2 × 10 mL) and brine solution (2 × 10 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/hexanes, 1:9) to afford olefin 11a–f.
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(2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((E)-3-(3,4,5-trimethoxyphenyl)allyl)tetrahydro-2H-pyran (11a)
General Procedure A using 3,4,5-trimethoxybenzaldehyde 7a (0.182 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave the olefin 11a.
Yield: 0.56 g (82%); pale-yellow gum; Rf = 0.4 (EtOAc/hexanes, 3:17); [α]D 27 –31.12 (c = 0.1, CHCl3).
IR (KBr): 2922, 2850, 1577, 1500, 1454, 1412, 1350, 1237, 1123, 1004, 736, 690 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 7.25–7.16 (m, 18 H), 7.12–7.09 (m, 2 H), 6.44 (s, 2 H), 6.26 (d, J = 15.7 Hz, 1 H), 6.19–6.10 (m, 1 H), 4.87–4.72 (m, 4 H), 4.62–4.47 (m, 4 H), 3.75 (s, 3 H), 3.72 (s, 6 H), 3.68–3.62 (m, 3 H), 3.58–3.53 (m, 1 H), 3.40–3.36 (m, 1 H), 3.35–3.28 (m, 2 H), 2.69–2.61 (m, 1 H), 2.44–2.35 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 153.2 (2-C), 138.5 (1-C), 138.2 (2-C), 138.1 (1-C), 137.4 (1-C), 133.4 (1-C), 132.1 (1-CH), 128.4 (3-CH), 128.4 (3-CH), 128.3 (2-CH), 127.9 (2-CH), 127.9 (1-CH), 127.8 (2-CH), 127.8 (1-CH), 127.7 (1-CH), 127.6 (4-CH), 127.5 (1-CH), 126.0 (1-CH), 103.2 (2-CH), 87.3 (1-CH), 81.6 (1-CH), 79.1 (1-CH), 78.8 (1-CH), 78.6 (1-CH), 75.5 (1-CH2), 75.1 (1-CH2), 75.0 (1-CH2), 73.4 (1-CH2), 69.0 (1-CH2), 60.9 (1-CH3), 56.0 (2-CH3), 35.3 (1-CH2).
MS (ESI): m/z (%) = 731 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C46H51O8: 731.3583; found: 731.3585.
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(2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((E)-3-(3,5-dimethoxyphenyl)allyl)tetrahydro-2H-pyran (11b)
General Procedure A using 3,5-dimethoxybenzaldehyde 7b (0.127 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave olefin 11b.
Yield: 0.51 g (78%); pale-yellow gum; Rf = 0.4 (EtOAc/hexanes, 3:17); [α]D 27 –4.52 (c = 0.1, CHCl3).
IR (KBr): 3034, 2873, 1684, 1594, 1480, 1263, 1211, 1079, 980, 806, 730, 696, 634 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.26–7.12 (m, 19 H), 7.11–7.07 (m, 2 H), 6.40–6.37 (m, 2 H), 6.27–6.22 (m, 2 H), 4.85–4.78 (m, 3 H), 4.73 (d, J = 10.8 Hz, 1 H), 4.58 (d, J = 11.0 Hz, 1 H), 4.56–4.45 (m, 3 H), 3.65 (s, 6 H), 3.64–3.59 (m, 3 H), 3.56–3.51 (m, 1 H), 3.38–3.24 (m, 3 H), 2.70–2.57 (m, 1 H), 2.43–2.31 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 160.9 (2-C), 139.7 (1-C), 138.6 (1-C), 138.3 (1-C), 138.3 (1-C), 138.2 (1-C), 132.3 (1-CH), 128.4 (2-CH), 128.4 (2-CH), 128.4 (2-CH), 128.3 (2-CH), 127.9 (2-CH), 127.9 (2-CH), 127.8 (1-CH), 127.7 (3-CH), 127.6 (2-CH), 127.6 (1-CH), 127.5 (1-CH), 127.1 (1-CH), 104.3 (2-CH), 99.5 (1-CH), 87.4 (1-CH), 81.6 (1-CH), 79.2 (1-CH), 78.8 (1-CH), 78.7 (1-CH), 75.5 (1-CH2), 75.1 (1-CH2), 75.0 (1-CH2), 73.5 (1-CH2), 69.1 (1-CH2), 55.3 (2-OCH3), 35.2 (1-CH2).
MS (ESI): m/z (%) = 701.35 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C45H48O7: 701.3478; found: 701.3472.
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(2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((E)-3-(4-methoxyphenyl)allyl)tetrahydro-2H-pyran (11c)
General Procedure A using 4-methoxybenzaldehyde 7c (0.127 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave olefin 11c.
Yield: 0.42 g (67%); pale-yellow gum; Rf = 0.35 (EtOAc/hexanes, 3:17); [α]D 27 –74.40 (c = 0.1, CHCl3).
IR (KBr): 2922, 2856, 1659, 1458, 1237, 1067, 747, 696 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.25–7.18 (m, 16 H), 7.18–7.15 (m, 4 H), 7.12–7.09 (m, 2 H), 6.76–6.71 (m, 2 H), 6.29 (d, J = 12.72 Hz, 1 H), 6.14–6.06 (m, 1 H), 4.87–4.79 (m, 3 H), 4.74 (d, J = 8.64 Hz, 1 H), 4.60 (d, J = 8.96 Hz, 1 H), 4.58–4.48 (m, 3 H), 3.72 (s, 3 H), 3.71–3.65 (m, 2 H), 3.64–3.60 (m, 2 H), 3.54 (t, J = 7.4 Hz, 1 H), 3.39–3.34 (m, 1 H), 3.34–3.27 (m, 2 H), 2.69–2.59 (m, 1 H), 2.42–2.33 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 157.7 (1-C), 137.5 (1-C), 137.3 (1-C), 137.2 (1-C), 137.1 (1-C), 130.5 (2-CH), 129.4 (1-C), 127.4 (2-CH), 127.4 (2-CH), 127.3 (2-CH), 127.2 (2-CH), 126.9 (3-CH), 126.7 (1-CH), 126.7 (1-CH), 126.6 (2-CH), 126.6 (2-CH), 126.5 (1-CH), 126.4 (1-CH), 126.1 (2-CH), 123.2 (1-CH), 112.8 (2-CH), 86.3 (1-CH), 80.5 (1-CH), 78.0 (1-CH), 77.9 (1-CH), 77.6 (1-CH), 74.5 (1-CH2), 74.1 (1-CH2), 73.9 (1-CH2), 72.4 (1-CH2), 68.0 (1-CH2), 54.2 (1-CH3), 34.1 (1-CH2).
MS (ESI): m/z (%) = 671.34 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C44H47O6: 671.3372; found: 671.3396.
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5-((E)-3-((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)prop-1-en-1-yl)benzo[d][1,3]dioxole (11d)
General Procedure A using piperonal 7d (0.14 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave olefin 11d.
Yield: 0.57 g (89%); pale-yellow gum; Rf = 0.25 (EtOAc/hexanes, 3:17); [α]D 27 +41.84 (c = 0.1, CHCl3).
IR (KBr): 2964, 2922, 2856, 1618, 1448, 1360, 1257, 1092, 1041, 793, 696 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.27–7.18 (m, 18 H), 7.13–7.08 (m, 2 H), 6.79 (s, 1 H), 6.68–6.61 (m, 2 H), 6.25 (d, J = 15.8 Hz, 1 H), 6.11–6.02 (m, 1 H), 5.85 (s, 2 H), 4.87–4.72 (m, 4 H), 4.62–4.47 (m, 4 H), 3.70–3.60 (m, 3 H), 3.57–3.51 (m, 1 H), 3.39–3.26 (m, 3 H), 2.67–2.58 (m, 1 H), 2.40–2.32 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 146.8 (1-C), 145.7 (1-C), 137.5 (1-C), 137.3 (1-C), 137.2 (1-C), 137.1 (1-C), 131.1 (1-C), 130.7 (1-CH), 127.4 (2-CH), 127.4 (3-CH), 127.3 (2-CH), 127.3 (2-CH), 126.9 (3-CH), 126.7 (1-CH), 126.7 (1-CH), 126.6 (2-CH), 126.6 (2-CH), 126.5 (1-CH), 126.4 (1-CH), 123.7 (1-CH), 119.4 (1-CH), 107.1 (1-CH), 104.5 (1-CH), 99.9 (1-CH2), 86.3 (1-CH), 80.5 (1-CH), 78.0 (1-CH), 77.9 (1-CH), 77.6 (1-CH), 74.5 (1-CH2), 74.0 (1-CH2), 73.9 (1-CH2), 72.4 (1-CH2), 68.0 (1-CH2), 34.1 (1-CH2).
MS (ESI): m/z (%) = 685.32 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C44H45O7: 685.3165; found: 685.3114.
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(2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((E)-3-(2,4-bis(benzyloxy)phenyl)allyl)tetrahydro-2H-pyran (11e)
General Procedure A using 2,4-bis(benzyloxy)benzaldehyde 7e (0.3 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave olefin 11e.
Yield: 0.5 g (62%); pale-yellow gum; Rf = 0.2 (EtOAc/hexanes, 3:17); [α]D 27 –10.12 (c = 0.1, CHCl3).
IR (KBr): 3067, 3036, 2911, 2871, 1608, 1500, 1454, 1366, 1263, 1170, 1103, 830, 731, 696 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 7.42–7.38 (m, 3 H), 7.38–7.32 (m, 5 H), 7.32–7.28 (m, 9 H), 7.27–7.24 (m, 11 H), 7.23–7.21 (m, 1 H), 7.19–7.16 (m, 2 H), 6.78 (d, J = 15.9 Hz, 1 H), 6.55–6.53 (m, 1 H), 6.52–6.48 (m, 1 H), 6.26–6.18 (m, 1 H), 5.02 (s, 2 H), 4.97 (s, 2 H), 4.92–4.87 (m, 2 H), 4.86–4.79 (m, 2 H), 4.67–4.59 (m, 2 H), 4.59–4.52 (m, 2 H), 3.74–3.65 (m, 3 H), 3.62–3.56 (m, 1 H), 3.45–3.35 (m, 3 H), 2.78–2.67 (m, 1 H), 2.55–2.41 (m, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 159.0 (1-C), 156.5 (1-C), 138.7 (1-C), 138.5 (1-C), 138.3 (2-C), 137.0 (2-C), 128.6 (2-CH), 128.5 (2-CH), 128.4 (6-CH), 128.3 (2-CH), 127.9 (3-CH), 127.9 (2-CH), 127.8 (1-CH), 127.7 (4-CH), 127.6 (2-CH), 127.5 (1-CH), 127.4 (2-CH), 127.4 (1-CH), 127.3 (2-CH), 127.1 (1-CH), 126.4 (1-CH), 125.0 (1-CH), 120.5 (1-C), 106.5 (1-CH), 100.8 (1-CH), 87.4 (1-CH), 81.5 (1-CH), 79.2 (1-CH), 79.0 (1-CH), 78.7 (1-CH), 75.4 (1-CH2), 75.1 (1-CH2), 74.9 (1-CH2), 73.5 (1-CH2), 70.3 (1-CH2), 70.2 (1-CH2), 69.1 (1-CH2), 35.6 (1-CH2).
MS (ESI): m/z (%) = 875 (100.0), 876 (62.6) [M + Na]+.
HRMS (ESI): m/z calcd for C57H56O7Na: 875.3923; found: 875.3961.
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(2R,3R,4R,5S,6S)-3,4,5-Tris(benzyloxy)-2-((benzyloxy)methyl)-6-((E)-3-(4-(benzyloxy)phenyl)allyl)tetrahydro-2H-pyran (11f)
General Procedure A using 4-(benzyloxy)benzaldehyde 7f (0.15 g, 0.93 mmol), with purification by column chromatography (silica gel, EtOAc/hexanes) gave olefin 11f.
Yield: 0.44 g (64%); white solid, mp 88–90 °C; Rf = 0.4 (EtOAc/hexanes, 3:17); [α]D 27 –9.53 (c = 1.00, CHCl3).
IR (KBr): 3062, 3031, 2956, 2919, 2856, 1696, 1601, 1509, 1449, 1357, 1246, 1091, 1052, 773, 733, 695 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 7.45–7.40 (m, 2 H), 7.40–7.35 (m, 3 H), 7.33–7.30 (m, 10 H), 7.28–7.25 (m, 6 H), 7.24–7.20 (m, 3 H), 7.19–7.04 (m, 3 H), 6.87 (d, J = 8.6 Hz, 2 H), 6.36 (d, J = 15.8 Hz, 1 H), 6.23–6.10 (m, 1 H), 5.05 (s, 2 H), 4.95–4.85 (m, 3 H), 4.81 (d, J = 10.7 Hz, 1 H), 4.70–4.65 (m, 1 H), 4.65–4.54 (m, 3 H), 3.79–3.66 (m, 3 H), 3.66–3.56 (m, 1 H), 3.49–3.32 (m, 3 H), 2.78–2.65 (m, 1 H), 2.51–2.39 (m, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 157.9 (1-C), 138.6 (1-C), 138.3 (1-C), 138.2 (1-C), 138.1 (1-C), 137.0 (1-C), 131.5 (2-CH), 128.6 (2-CH), 128.5 (3-CH), 128.4 (3-CH), 128.3 (2-CH), 127.9 (4-CH), 127.8 (1-CH), 127.7 (3-CH), 127.7 (2-CH), 127.5 (1-CH), 127.4 (2-CH), 127.2 (2-CH), 124.4 (1-CH), 114.8 (2-CH), 87.3 (1-CH), 81.6 (1-CH), 79.1 (1-CH), 79.0 (1-CH), 78.7 (1-CH), 75.5 (1-CH2), 75.1 (1-CH2), 75.0 (1-CH2), 73.4 (1-CH2), 70.0 (1-CH2), 69.0 (1-CH2), 35.2 (1-CH2).
MS (ESI): m/z (%) = 747.37 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C50H51O6: 747.3685; found: 747.3649.
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Debenzylation and Reduction; General Procedure B
To an oven-dried, round-bottom flask, olefin 11a–f (1 equiv) and anhydrous MeOH (5 mL) were added under a nitrogen atmosphere. To the stirred solution, Pd(OH)2 (10 mol%, 0.2 equiv) was added and the nitrogen was replaced with hydrogen using a bladder. Hydrogen was purged carefully and the mixture was stirred for 20–36 h. The reaction mixture was filtered using MeOH and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (MeOH/CH2Cl2, 1:19) to afford 5a–f.
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(2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-(3-(3,4,5-trimethoxyphenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol (5a)
General Procedure B using olefin 11a (170 mg, 0.23 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5a.
Yield: 62 mg (71%); colorless gum; Rf = 0.5 (MeOH/CH2Cl2, 1:9); [α]D 27 +5.48 (c = 0.1, MeOH).
IR (KBr): 3392, 2922, 2856, 1613, 1515, 1458, 1232, 1164, 1087 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.39 (s, 2 H), 3.75 (br s, 1 H), 3.71 (s, 6 H), 3.61 (s, 3 H), 3.60–3.46 (m, 2 H), 3.27–3.01 (m, 7 H), 2.98–2.91 (m, 1 H), 2.53–2.44 (m, 2 H), 1.84–1.75 (m, 2 H), 1.66–1.54 (m, 1 H), 1.41–1.28 (m, 1 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 152.8 (2-C), 138.8 (1-C), 135.6 (1-C), 105.3 (2-CH), 80.2 (1-CH), 79.3 (1-CH), 78.5 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 59.7 (1-CH3), 55.1 (2-CH3), 35.8 (1-CH2), 31.0 (1-CH2), 27.0 (1-CH2).
MS (ESI): m/z (%) = 373.19 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H29O8: 373.1862; found: 373.1934.
#
(2S,3R,4R,5S,6R)-2-(3-(3,5-Dimethoxyphenyl)propyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (5b)
General Procedure B using olefine 11b (100 mg, 0.25 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5b.
Yield: 47 mg (96%); colorless gum; Rf = 0.4 (MeOH/CH2Cl2, 1:9); [α]D 27 +5.88 (c = 0.1, MeOH).
IR (KBr): 3355, 2917, 2237, 2216, 2144, 2067, 1938, 1454, 1397, 1118, 969, 824 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.25 (s, 2 H), 6.17 (s, 1 H), 3.75 (s, 1 H), 3.72 (s, 1 H), 3.63 (s, 6 H), 3.56–3.50 (m, 1 H), 3.22–3.19 (m, 1 H), 3.19–3.11 (m, 2 H), 3.10–3.06 (m, 1 H), 3.05–3.01 (m, 1 H), 2.98–2.90 (m, 1 H), 2.45 (t, J = 8 Hz, 2 H), 1.82–1.74 (m, 2 H), 1.67–1.50 (m, 2 H), 1.46–1.24 (m, 2 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 160.7 (2-C), 144.8 (1-C), 106.1 (2-CH), 97.2 (1-CH), 80.2 (1-CH), 79.3 (1-CH), 78.4 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 54.2 (2-OCH3), 35.8 (1-CH2), 31.1 (1-CH2), 26.8 (1-CH2).
MS (ESI): m/z (%) = 343.18 (100.0), [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H27O7: 343.1756; found: 343.1755.
#
(2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-(3-(4-methoxyphenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol (5c)
General Procedure B using olefin 11c (100 mg, 0.23 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5c.
Yield: 42 mg (91%); white solid, mp 140–142 °C; Rf = 0.3 (MeOH/CH2Cl2, 1:9); [α] d 27 +7.86 (c = 0.1, MeOH).
IR (KBr): 3355, 2922, 2845, 2226, 2067, 1912, 1454, 1381, 1118, 969, 819 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.98 (d, J = 8.44 Hz, 2 H), 6.69 (d, J = 8.52 Hz, 2 H), 3.76–3.70 (m, 1 H), 3.64 (s, 3 H), 3.56–3.49 (m, 1 H), 3.23–3.11 (m, 4 H), 3.09–3.00 (m, 2 H), 2.97–2.88 (m, 1 H), 2.51–2.41 (m, 2 H), 1.81–1.73 (m, 2 H), 1.66–1.44 (m, 2 H),1.42–1.24 (m, 2 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 157.8 (1-C), 134.5 (1-C), 128.9 (2-CH), 113.2 (2-CH), 80.2 (1-CH), 79.3 (1-CH), 78.4 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 54.2 (1-OCH3), 34.7 (1-CH2), 31.1 (1-CH2), 27.3 (1-CH2).
MS (ESI): m/z (%) = 313.17 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H25O6: 313.1651; found: 313.1676.
#
(2S,3R,4R,5S,6R)-2-(3-(Benzo[d][1,3]dioxol-5-yl)propyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (5d)
General Procedure B using olefin 11d (130 mg, 0.18 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5d.
Yield: 45 mg (73%); colorless gum; Rf = 0.2 (MeOH/CH2Cl2, 1:9); [α]D 27 –9.84 (c = 0.1, MeOH).
IR (KBr): 3370, 2964, 2922, 1649, 1489, 1437, 1241, 1092, 1036, 995, 922, 804 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.62–6.65 (m, 2 H), 6.56–6.48 (m, 1 H), 5.75 (s, 2 H), 3.76–3.70 (m, 1 H), 3.57–3.50 (m, 1 H), 3.26–3.0 (m, 6 H), 2.99–2.90 (m, 1 H), 2.48–2.40 (m, 2 H), 1.82–1.71 (m, 2 H), 1.60–1.50 (m, 1 H), 1.37–1.27 (m, 1 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 147.5 (1-C), 145.5 (1-C), 136.4 (1-C), 120.8 (1-CH), 108.4 (1-CH), 107.5 (1-CH), 100.5 (1-CH2), 80.1 (1-CH), 79.3 (1-CH), 78.4 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 35.3 (1-CH2), 31.0 (1-CH2), 27.3 (1-CH2).
MS (ESI): m/z (%) = 327.14 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C16H23O7: 327.1443; found: 327.1426.
#
(2S,3R,4R,5S,6R)-2-(3-(2,4-Dihydroxyphenyl)propyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (5e)
General Procedure B using olefin 11e (200 mg, 0.23 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5e.
Yield: 55 mg (74%); colorless gum; Rf = 0.1 (MeOH/CH2Cl2, 1:9); [α]D 27 –22.13 (c = 0.1, MeOH).
IR (KBr): 2927, 2860, 1613, 1520, 1458, 1170, 1092, 995, 839 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.74 (d, J = 8.1 Hz, 1 H), 6.15 (d, J = 2 Hz, 1 H), 6.10 (dd, 1 J = 8 Hz, 2 J = 2 Hz, 1 H), 3.72 (dd, 1 J = 11.8 Hz, 2 J = 1.6 Hz, 1 H), 3.58–3.49 (m, 1 H), 3.28–2.99 (m, 6 H), 2.98–2.91 (m, 1 H), 2.45–2.35 (m, 2 H), 1.82–1.67 (m, 2 H), 1.57–1.44 (m, 1 H), 1.39–1.29 (m, 1 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 155.7 (1-C), 155.4 (1-C), 130.0 (1-CH), 120.0 (1-C), 105.9 (1-CH), 102.0 (1-CH), 80.1 (1-CH), 79.5 (1-CH), 78.5 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 31.3 (1-CH2), 29.1 (1-CH2), 25.8 (1-CH2).
MS (ESI): m/z (%) = 315.14 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H23O7: 315.1443; found: 315.1452.
#
(2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-(3-(4-hydroxyphenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol (5f)
General Procedure B using olefin 11f (120 mg, 0.16 mmol), with purification by column chromatography (silica gel, MeOH/CH2Cl2) gave 5f.
Yield: 40 mg (83%); white solid; mp 182–184 °C; Rf = 0.2 (MeOH/CH2Cl2, 1:9); [α]D 27 –4.44 (c = 1.0, MeOH).
IR (KBr): 3375, 2919, 2853, 1635, 1515, 1455, 1220, 1006, 827, 779, 756 cm–1.
1H NMR (MeOH-d 4, 400 MHz): δ = 6.89 (d, J = 7.5 Hz, 2 H), 6.57 (d, J = 7.5 Hz, 2 H), 3.72 (d, J = 11.7 Hz, 1 H), 3.57–3.48 (m, 1 H), 3.20 (brs, 3 H), 3.18–2.99 (m, 4 H), 2.97–2.87 (m, 1 H), 2.48–2.37 (m, 2 H), 1.82–1.71 (m, 2 H), 1.59–1.48 (m, 1 H), 1.36–1.27 (m, 1 H).
13C NMR (MeOH-d 4, 100 MHz): δ = 154.8 (1-C), 133.3 (1-C), 128.9 (2-CH), 114.5 (2-CH), 80.2 (1-CH), 79.4 (1-CH), 78.4 (1-CH), 74.1 (1-CH), 70.6 (1-CH), 61.7 (1-CH2), 34.7 (1-CH2), 31.1 (1-CH2), 27.3 (1-CH2).
MS (ESI): m/z (%) = 299.15 (100.0) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H23O6: 299.1494; found: 299.1504.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank the Department of Chemistry, IIT Madras for its major infrastructural facility. We also thank, Mr. Ramkumar for X-ray diffraction data interpretation.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751553.
- Supporting Information
-
References
- 1a Jimenez C, Riguera R. Nat. Prod. Rep. 1994; 11: 591
- 1b Fu G, Pang H, Wong YH. Curr. Med. Chem. 2008; 15: 2592
- 2 Alipieva K, Korkina L, Orhan IE, Georgiev MI. Biotechnol. Adv. 2014; 32: 1065
- 3 Liu J, Yang L, Dong Y, Zhang B, Ma X. Molecules 2018; 23: 1213
- 4 Jin M, Wang C, Xu Y, Zhang Z, Wu X, Ye R, Zhang Q, Han D. Biomed. Pharmacother. 2022; 156: 113746
- 5 Tian X.-Y, Li M.-X, Lin T, Qiu Y, Zhu Y.-T, Li X.-L, Tao W.-D, Wang P, Ren X.-X, Chen L.-P. Eur. J. Med. Chem. 2021; 209: 112563
- 6a Reddy MR, Thoti N, Aidhen IS. Bioactive C-Glycosides Inspired from Natural Products Towards Therapeutics. In Carbohydrates in Drug Discovery and Development. Tiwari VK. Elsevier; Amsterdam: 2020: 97-153
- 6b Thoti N, Aidhen IS. Chem. Rec. 2021; 21: 3131
- 6c Aidhen IS, Srikanth S, Lal H. Eur. J. Org. Chem. 2022; e202200758
- 6d Yang Y, Yu B. Chem. Rev. 2017; 117: 12281
- 7a Fernandez-Mar MI, Mateos R, Garcia-Parilla MC, Puertas B, Cantos-Villar E. Food Chem. 2012; 130: 797
- 7b Bartelli M, Kiani AK, Paolacci S, Manara E, Kurti D, Dhuli K, Bushati V, Miertus J, Pangallo D, Baglivo M, Beccari T, Michelini S. J. Biotechnol. 2020; 309: 29
- 8 Bull JA, Kunz H. Synthesis 2014; 1185
- 9a Chaytor JL, Ben RN. Bioorg. Med. Chem. Lett. 2010; 20: 5251
- 9b Reddy MR, Aidhen IS, Sruthi K, Reddy GB. Eur. J. Org. Chem. 2017; 7283
- 10 CCDC 2292110 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
- 11 Ling J, Bennet CS. Angew. Chem. Int. Ed. 2020; 59: 4304
Corresponding Author
Publication History
Received: 18 November 2023
Accepted after revision: 03 January 2024
Article published online:
25 January 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1a Jimenez C, Riguera R. Nat. Prod. Rep. 1994; 11: 591
- 1b Fu G, Pang H, Wong YH. Curr. Med. Chem. 2008; 15: 2592
- 2 Alipieva K, Korkina L, Orhan IE, Georgiev MI. Biotechnol. Adv. 2014; 32: 1065
- 3 Liu J, Yang L, Dong Y, Zhang B, Ma X. Molecules 2018; 23: 1213
- 4 Jin M, Wang C, Xu Y, Zhang Z, Wu X, Ye R, Zhang Q, Han D. Biomed. Pharmacother. 2022; 156: 113746
- 5 Tian X.-Y, Li M.-X, Lin T, Qiu Y, Zhu Y.-T, Li X.-L, Tao W.-D, Wang P, Ren X.-X, Chen L.-P. Eur. J. Med. Chem. 2021; 209: 112563
- 6a Reddy MR, Thoti N, Aidhen IS. Bioactive C-Glycosides Inspired from Natural Products Towards Therapeutics. In Carbohydrates in Drug Discovery and Development. Tiwari VK. Elsevier; Amsterdam: 2020: 97-153
- 6b Thoti N, Aidhen IS. Chem. Rec. 2021; 21: 3131
- 6c Aidhen IS, Srikanth S, Lal H. Eur. J. Org. Chem. 2022; e202200758
- 6d Yang Y, Yu B. Chem. Rev. 2017; 117: 12281
- 7a Fernandez-Mar MI, Mateos R, Garcia-Parilla MC, Puertas B, Cantos-Villar E. Food Chem. 2012; 130: 797
- 7b Bartelli M, Kiani AK, Paolacci S, Manara E, Kurti D, Dhuli K, Bushati V, Miertus J, Pangallo D, Baglivo M, Beccari T, Michelini S. J. Biotechnol. 2020; 309: 29
- 8 Bull JA, Kunz H. Synthesis 2014; 1185
- 9a Chaytor JL, Ben RN. Bioorg. Med. Chem. Lett. 2010; 20: 5251
- 9b Reddy MR, Aidhen IS, Sruthi K, Reddy GB. Eur. J. Org. Chem. 2017; 7283
- 10 CCDC 2292110 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
- 11 Ling J, Bennet CS. Angew. Chem. Int. Ed. 2020; 59: 4304
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