Synthesis of C -Glucoside Analogues of Naturally Occurring Phenylethanoid O -Glucosides

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.

The 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. 5Salidroside 4, isolated from the peren-nial flowering herb of Rhodiola rosea with proven protective effects on myocardial injury and liver cancer, has now emerged as a highly promising neuroprotection agent. 4lthough 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 Oglycosides, 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).
The targeted C-glucosides 5 are stable analogues of Oglucosides because the glycosidic oxygen atom linking the glycone and the aglycone part is replaced with an isosteric methylene unit (-CH 2 ).The oxygenation pattern on the aryl ring was inspired by natural products that demonstrate potent antioxidant and anti-inflammatory activities. 7 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. 8he 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. 9Reduction 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 A. Subramanyam et al.

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block 6 in good yields (Scheme 1).Multigram quantities of 6 can be made by using this scheme.The -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 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

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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-gelbased chromatography using 5% MeOH in dichloromethane as eluent (Scheme 2).The obtained products gave satisfactory spectroscopy and mass spectrometry data.
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 CaH 2 (CH 2 Cl 2 , acetonitrile, DMF), Na/benzophenone (THF), and Mg/I 2 (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/nhexane.Compound 10 was recrystallized from CH 2 Cl 2 /hexanes.Infrared spectra were recorded with a JASCO-FT/IR-4100 spectrophotometer with KBr and reported in wavenumbers (cm -1 ). 1 H (400 MHz and 500 MHz) and 13 C (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 ( = 7.26 ppm), or ( = 4.75 ppm) for 1 H NMR and chloroform (= 77.2 ppm), or MeOH ( = 47.65 ppm) for 13 C 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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(the reaction n was monitored by TLC).Upon completion, the reaction was quenched with saturated NH 4 Cl 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 NaSO 4 and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (EtOAc/hexanes, 1:9) and recrystallized (CH 2 Cl 2 /n-hexane) to afford the sulfide 10.
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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/CH 2 Cl 2 , 1:19) to afford 5a-f.