A method for synthesizing (s)-rhododendrol and analogs thereof

Abstract

The application provides a synthesis method of (S)-Rhododendrol and analogs thereof, and belongs to the technical field of organic synthesis. The synthesis method of (S)-Rhododendrol and analogs thereof provided by the application uses commercially available raw materials, and only needs to realize the synthesis of (S)-Rhododendrol through three steps, and also provides an efficient way for the synthesis of analogs thereof. The core advantage of the application is that cheap metal nickel and a chiral ligand are used as catalysts to convert olefins into chiral alcohols under oxygen conditions, and the application is an effective, green and cheap method for synthesizing (S)-Rhododendrol and analogs thereof.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing (S)-Rhododendrol and its analogues. Background Technology

[0002] (S)-Rhododendrol is an optically active phenylpropanol compound, one of the two enantiomers of the natural product rhododendrol. Originally isolated from plants in the Ericaceae family, it is also found in some mushrooms and plants. In the early 2010s, several Japanese cosmetic companies (such as Shiseido) used it as an active ingredient in whitening skincare products. Rhododendrol has become an important model compound for studying chemical vitiligo and melanocyte cytotoxicity. It is used to explore tyrosinase substrate specificity, differences in chiral compound metabolism in the skin, and the association between oxidative stress and autoimmune skin diseases.

[0003] However, the current method for synthesizing the chiral isomer of Rhododendrol is as shown below (Reference Synth. Commun. 2007, 37, 1683-1688.), usually requires the synthesis of the chiral precursor of the product before deprotection, which is a lengthy process, and the use of the noble metal palladium increases the reaction cost.

[0004] . Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing (S)-Rhododendrol and its analogues. This invention uses olefins as raw materials and, under oxygen conditions, achieves the synthesis of (S)-Rhododendrol and its analogues through a nickel-catalyzed asymmetric hydration reaction of olefins in a low-cost and efficient manner.

[0006] To achieve the objectives of this invention, the following technical solutions are provided: A method for synthesizing (S)-Rhododendrol and its analogues includes the following steps: Benzyl halide and allyl magnesium halide were mixed and coupled under a nitrogen atmosphere to obtain an olefin intermediate. The structural formula of the benzyl halide is: , where R 1 X is an alkoxy group, hydrogen, halogen, phenyl, or hydroxyl group. 1 It can be Cl, Br, or I; The structural formula of the allyl magnesium halide is: , where X 2 It is Cl or Br; The structural formula of the olefin intermediate is: ; The olefin intermediate, nickel-based catalyst, reducing agent, alkali metal weak acid salt, and phase transfer agent are mixed and hydrated under oxygen conditions to obtain (S)-Rhododendrol and its analogues; the nickel-based catalyst comprises a nickel donor and a chiral bisoxazoline ligand. The structural formula of (S)-Rhododendrol and its analogues is: .

[0007] Preferably, the nickel donor is a nickel complex and / or an inorganic nickel salt, wherein the nickel complex includes one or more of nickel-phosphine complexes, nickel-ether complexes, and nickel-olefin complexes; The chiral bioxazoline ligand is a substituted benzyl chiral bioxazoline or a substituted halobenzyl chiral bioxazoline; the substituent is a C1-C5 alkyl and / or phenyl group.

[0008] Preferably, the nickel donor is one of nickel bromide bis(triphenylphosphine) complex, nickel chloride bis(triphenylphosphine) complex, nickel bromide ethylene glycol dimethyl ether complex, nickel bromide diethylene glycol dimethyl ether complex, nickel bromide, nickel acetate, and bis(1,5-cyclooctadiene) nickel; The chiral bisoxazoline ligand is one of phenyl-dimethyl-benzylbisoxazoline, phenyl-diethyl-benzylbisoxazoline, phenyl-dimethyl-4-tert-butylbenzylbisoxazoline, phenyl-dimethyl-4-fluorobenzylbisoxazoline, phenyl-dimethyl-2,4-difluorobenzylbisoxazoline, phenyl-dimethyl-2-methyl-benzylbisoxazoline, phenyl-dimethyl-2-bromobenzylbisoxazoline, and phenyl-dimethyl-methyl-benzylbisoxazoline.

[0009] Preferably, the molar ratio of the nickel donor to the chiral bisoxazoline ligand is 1:0.5~2.

[0010] Preferably, the molar ratio of the benzyl halide to the allyl magnesium halide is 1:1 to 3.

[0011] Preferably, the molar ratio of the olefin intermediate to the nickel-based catalyst is 0.1~1:0.02~2.

[0012] Preferably, the phase transfer agent is a quaternary ammonium salt and / or an inorganic iodide; The molar ratio of the phase transfer agent to the olefin intermediate is 0.5~2:0.1~1.

[0013] Preferably, the reducing agent is one or more selected from organosilane reducing agents, sodium borohydride, and pinacolborane; The molar ratio of the reducing agent to the olefin intermediate is 0.5~5:0.1~1.

[0014] Preferably, the coupling reaction is carried out at a temperature of -30 to 30°C for 1 to 12 hours.

[0015] Preferably, the hydration reaction is carried out at a temperature of -30 to 30°C for 1 to 12 hours.

[0016] This invention provides a method for synthesizing (S)-Rhododendrol and its analogues, comprising the following steps: mixing a benzyl halide and allyl magnesium halide, and carrying out a coupling reaction under a nitrogen atmosphere to obtain an olefin intermediate; mixing the olefin intermediate, a nickel-based catalyst, a reducing agent, an alkali metal weak acid salt, and a phase transfer agent, and carrying out a hydration reaction under oxygen conditions to obtain the (S)-Rhododendrol and its analogues; wherein the nickel-based catalyst comprises a nickel donor and a chiral bisoxazoline ligand. Compared with conventional synthetic methods, this invention uses commercially available raw materials, performs a nucleophilic substitution reaction between the benzyl halide and allyl magnesium halide, reduces the methoxy group to a phenolic hydroxyl group, and finally achieves the conversion of the olefin to a chiral alcohol under oxygen conditions via asymmetric nickel catalysis. This method achieves the synthesis of (S)-Rhododendrol in only three steps and also provides an efficient route for the synthesis of its analogues. The core advantage of this invention is that it uses inexpensive nickel as a catalyst to convert olefins into chiral alcohols under oxygen conditions. This is an effective, green, and inexpensive method for synthesizing (S)-Rhododendrol and its analogues. Detailed Implementation

[0017] This invention provides a method for synthesizing (S)-Rhododendrol and its analogues, comprising the following steps: Benzyl halide and allyl magnesium halide were mixed and coupled under a nitrogen atmosphere to obtain an olefin intermediate. The structural formula of the benzyl halide is: , where R 1 X is an alkoxy group, hydrogen, halogen, phenyl, or hydroxyl group. 1 It can be Cl, Br, or I; The structural formula of the allyl magnesium halide is: , where X 2 It is Cl or Br; The structural formula of the olefin intermediate is: ; The olefin intermediate, nickel-based catalyst, reducing agent, alkali metal weak acid salt, and phase transfer agent are mixed and hydrated under oxygen conditions to obtain (S)-Rhododendrol and its analogues; the nickel-based catalyst comprises a nickel donor and a chiral bisoxazoline ligand. The structural formula of (S)-Rhododendrol and its analogues is: .

[0018] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0019] This invention involves mixing benzyl halides and allyl magnesium halides and carrying out a coupling reaction under a nitrogen atmosphere to obtain an olefin intermediate.

[0020] In this invention, R in the benzyl halide 1 The alkoxy group is an alkoxy group, hydrogen, halogen, phenyl, or hydroxyl group, wherein the alkoxy group is a C1-5 alkoxy group, and the halogen is F, Cl, Br, or I; the X group is... 1 The halogen can be Cl, Br, or I; in specific embodiments of the present invention, the benzyl halide can be benzyl bromide, p-methoxybenzyl bromide, p-hydroxybenzyl bromide, p-fluorobenzyl bromide, or p-phenylbenzyl bromide.

[0021] In this invention, the allyl magnesium halide can specifically be allyl magnesium bromide or allyl magnesium iodide.

[0022] In this invention, the molar ratio of the benzyl halide to the allyl magnesium halide is 1:1 to 3, and in specific embodiments it can be 1:1.2, 1:1.5, 1:2 or 1:2.6.

[0023] In this invention, the temperature of the coupling reaction is -30~30℃, and in specific embodiments it can be -5℃, 0℃ or 10℃; the time is 1~12h, and in specific embodiments it can be 3, 5 or 8h.

[0024] In this invention, the organic solvent used in the hydration reaction can be one or more of tetrahydrofuran, diethyl ether, isopropyl ether, and 2-methyltetrahydrofuran, and in specific embodiments, it can be a mixture of tetrahydrofurans.

[0025] In this invention, the coupling reaction is quenched with saturated NaCl solution after completion; the resulting hydrated reaction system is extracted, and the organic phase is successively dried, separated into solid and liquid phases, concentrated, and purified; the extractant used for extraction is EtOAc; the reagent used for drying is MgSO4; the solid-liquid separation method is filtration; the purification is column chromatography purification, with petroleum ether and ethyl acetate as eluents, the volume ratio of petroleum ether to ethyl acetate being 5~10:1, and the elution program being: petroleum ether ratio / ethyl acetate (v / v) = 10:1, 200mL; petroleum ether ratio / ethyl acetate (v / v) = 5:1, 200mL.

[0026] In this invention, the nickel donor can be one of nickel bis(triphenylphosphine) bromide (NiBr2·(PPh3)2), nickel bromide (NiBr2), nickel chloride bis(triphenylphosphine) chloride (NiCl2·(PPh3)2), nickel bromide ethylene glycol dimethyl ether (NiBr2·DME), nickel bromide diethylene glycol dimethyl ether (NiBr2·diglyme), nickel bromide trihydrate (NiBr2·3H2O), nickel acetate (Ni(OAc)2), and bis(1,5-cyclooctadiene)nickel (Ni(COD)2), and in a specific embodiment, it can be NiBr2·(PPh3)2.

[0027] In this invention, the chiral bisoxazoline ligand is one of phenyl-dimethyl-benzylbisoxazoline, phenyl-diethyl-benzylbisoxazoline, phenyl-dimethyl-4-tert-butylbenzylbisoxazoline, phenyl-dimethyl-4-fluorobenzylbisoxazoline, phenyl-dimethyl-2,4-difluorobenzylbisoxazoline, phenyl-dimethyl-2-methyl-benzylbisoxazoline, phenyl-dimethyl-2-bromobenzylbisoxazoline, and phenyl-dimethyl-methyl-benzylbisoxazoline. In a specific embodiment, it can be phenyl-dimethyl-4-fluorobenzylbisoxazoline.

[0028] In this invention, the molar ratio of the nickel donor to the chiral bisoxazoline ligand is 1:0.5~2.

[0029] In this invention, the molar ratio of the olefin intermediate to the nickel-based catalyst is 0.1~1:0.02~2.

[0030] In this invention, the phase transfer agent is a quaternary ammonium salt and an inorganic iodide. The quaternary ammonium salt can be an aryl quaternary ammonium salt or an alkyl quaternary ammonium salt. In specific embodiments, it can be one or more of phenyltriethylammonium iodide, phenyltrimethylammonium iodide, benzyltriethylammonium iodide, methyltriethylammonium iodide, tetrabutylammonium iodide, tetrabutylammonium chloride, and tetrabutylammonium bromide. In specific embodiments, it can be phenyltriethylammonium iodide. The inorganic iodide is sodium iodide. The molar ratio of the phase transfer agent to the olefin intermediate is 0.5~2:0.1~1.

[0031] In this invention, the reducing agent is one or more of organosilane reducing agents, sodium borohydride, and pinacolborane. The organosilane reducing agent can be one of benzylsilane, diphenylsilane, phenyldimethylsilane, trimethoxysilane, triethoxysilane, diethoxymethylsilane, triethylsilane, and triisopropoxysilane. In a specific embodiment, it can be benzylsilane. The molar ratio of the reducing agent to the olefin intermediate is 0.5~5:0.1~1.

[0032] In this invention, the alkali metal weak acid salt is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate, potassium bicarbonate, potassium phosphate, potassium phosphate trihydrate, potassium phosphate monohydrate, and cesium carbonate, and in a specific embodiment it can be sodium carbonate; the molar ratio of the alkali metal weak acid salt to the olefin intermediate is 0.5~5:0.1~1.

[0033] In this invention, the pressure of the oxygen is 1~100 atm, and in specific embodiments it can be 10, 20 or 30 atm.

[0034] In this invention, the mixing sequence of the hydration reaction can be: Chiral bisoxazoline ligand, nickel donor, alkali metal weak acid salt and phase transfer agent are mixed; organic solvent is added under oxygen conditions, and after cooling to -30~30℃, reducing agent and olefin are added to carry out hydration reaction.

[0035] In this invention, the temperature of the hydration reaction is -30~30℃, and in specific embodiments it can be -5℃, 0℃ or 10℃; the time is 1~12h, and in specific embodiments it can be 3h, 5h or 8h.

[0036] In this invention, the organic solvent used in the hydration reaction can be one or more of hydrocarbon solvents, halogenated hydrocarbon solvents, alcohol solvents, nitrile solvents, and multifunctional solvents; specifically, it can be one or more of ethanol, isopropanol, tert-butanol, 2-methyl-tetrahydrofuran, and tetrahydrofuran. In a specific embodiment, it can be a mixed solvent of isopropanol and 2-methyl-tetrahydrofuran, with a volume ratio of 1:0.1~1.

[0037] In this invention, the hydration reaction is quenched with a saturated NaCl solution after completion; the resulting hydration reaction system is extracted, and the organic phase is successively dried, separated into solid and liquid phases, concentrated, and purified; the extractant used for extraction is EtOAc; the reagent used for drying is MgSO4; the solid-liquid separation is performed by filtration; the purification is performed by column chromatography, and the eluents are petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 10~5:1.

[0038] To further illustrate the present invention, the synthesis methods of (S)-Rhododendrol and its analogues provided by the present invention are described in detail below with reference to embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0039] Example 1 (S)-Rhododendrol was synthesized according to the synthetic pathway shown in Equation 1: Formula 1; The specific steps are as follows: Under an inert atmosphere, 10 mmol of p-methoxybenzyl bromide and 30 mL of tetrahydrofuran were added to a reaction flask, followed by slow dropwise addition of 15 mL of a 1 mol / L allyl magnesium chloride solution in tetrahydrofuran. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to give a yellow oily liquid. This colorless oily liquid was dissolved in 20 mL of dichloromethane, and 12 mL of a 1 mol / L boron tribromide solution in dichloromethane was slowly added dropwise at 0 °C. The reaction was maintained at 0 °C for 1 h. The mixture was concentrated, and rapid column chromatography (PE:EtOAc = 5:1) was performed to give a colorless oily liquid, p-hydroxyphenylbutene, in 46% yield.

[0040] Add L to a 16 mL screw-cap reaction flask equipped with a magnetic stirrer The following were added: NiBr2(PPh3)2 (9.3 mg, 0.016 mmol, 16 mol%), NiBr2(PPh3)2 (7.4 mg, 0.01 mmol, 10 mol%), Na2CO3 (37.1 mg, 0.35 mmol, 3.5 equiv.), and PhEt3NI (45.7 mg, 0.15 mmol, 1.5 equiv.). The reaction flask was sealed, and oxygen was purged five times using an oxygen bulb. iPrOH (1.2 mL) and 2-Me-THF (0.1 mL) were added sequentially under oxygen flow. After cooling to 0 °C, PhSiH3 (44 μL, 0.35 mmol, 3.5 equiv.) was added, and after stirring for 1 min, the above-mentioned p-hydroxyphenylbutene (0.1 mmol, 1.0 equiv.) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with saturated NaCl solution and extracted with EtOAc. The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated. The hydrated product, (S)-4-hydroxyphenylbutyl-2-ol, was obtained by column chromatography (PE:EtOAc = 5:1) in 55% yield with an enantiomeric excess of 96% ee.

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz,2H), 4.71 (br, 1H), 3.85-3.81 (m, 1H), 2.71-2.56 (m, 2H), 1.79-1.70 (m, 2H),1.25 (br, 1H), 1.23 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.8, 133.9,129.4, 115.3, 67.7, 41.0, 31.2, 23.5. [α] D 25 =+17.2 (c = 1.50, CHCl3). HPLC: CHIRALPAK AD-H, 210 nm, 25 o C, n hexane: i PrOH = 85:15, 1.0 mL / min, t R (major) = 8.0 min, t R (minor) = 8.6 min.

[0042] Example 2 (S)-Rhododendrol analogs were synthesized according to the synthetic pathway shown in Equation 2: Formula 2; The specific steps are as follows: Under an inert atmosphere, 10 mmol of p-methoxybenzyl bromide and 30 mL of tetrahydrofuran were added to a reaction flask, followed by slow dropwise addition of 15 mL of a 1 mol / L allyl magnesium chloride solution in tetrahydrofuran. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and purified by rapid column chromatography (PE:EtOAc = 30:1) to give a colorless oily liquid, p-methoxyphenylbutene, in 80% yield.

[0043] Add L to a 16 mL screw-cap reaction flask equipped with a magnetic stirrer The following were added: NiBr2(PPh3)2 (9.3 mg, 0.016 mmol, 16 mol%), NiBr2(PPh3)2 (7.4 mg, 0.01 mmol, 10 mol%), Na2CO3 (37.1 mg, 0.35 mmol, 3.5 equiv.), and PhEt3NI (45.7 mg, 0.15 mmol, 1.5 equiv.). The reaction flask was sealed, and oxygen was purged five times using an oxygen bulb. iPrOH (1.2 mL) and 2-Me-THF (0.1 mL) were added sequentially under oxygen flow. After cooling to 0 °C, PhSiH3 (44 μL, 0.35 mmol, 3.5 equiv.) was added, and after stirring for 1 min, the above-mentioned p-methoxyphenylbutene (0.1 mmol, 1.0 equiv.) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with saturated NaCl solution and extracted with EtOAc. The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated. Finally, the product was purified by column chromatography (PE:EtOAc=10:1) to obtain a colorless oily liquid, namely the hydrated product (S)-4-methoxyphenylbutyl-2-ol, with a yield of 71% and an enantiomeric excess of 94% ee.

[0044] 1 H NMR (400 MHz, Chloroform- d ) δ 7.12 (d, J = 8.6 Hz, 2H), 6.84 (d, J =8.6 Hz, 2H), 3.90 – 3.72 (m, 4H), 2.78 – 2.54 (m, 2H), 1.88 (s, 1H), 1.82 –1.65 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 157.75,134.18, 129.34, 113.84, 67.48, 55.30, 41.13, 31.27, 23.66. [α] D 25 = +14.1 (c =1.50, CHCl3). HPLC: CHIRALPAK IB, 210 nm, 25 o C, n hexane: i PrOH = 90:10, 1.0 mL / min, t R (major) = 10.4 min, tR (minor) = 9.1 min.

[0045] Example 3 Synthesize (S)-Rhododendrol analogs according to the synthetic pathway shown in Equation 3: Formula 3; The specific steps are as follows: Under an inert atmosphere, 10 mmol of p-fluorobenzyl bromide and 30 mL of tetrahydrofuran were added to a reaction flask, followed by slow dropwise addition of 15 mL of a 1 mol / L allyl magnesium chloride solution in tetrahydrofuran. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and purified by rapid column chromatography (PE:EtOAc = 50:1) to give a colorless oily liquid p-fluorophenylbutene in 75% yield.

[0046] Add L to a 16 mL screw-cap reaction flask equipped with a magnetic stirrer The following ingredients were added: NiBr2(PPh3)2 (9.3 mg, 0.016 mmol, 16 mol%), NiBr2(PPh3)2 (7.4 mg, 0.01 mmol, 10 mol%), Na2CO3 (37.1 mg, 0.35 mmol, 3.5 equiv.), and PhEt3NI (45.7 mg, 0.15 mmol, 1.5 equiv.). The reaction flask was sealed, and oxygen was purged five times using an oxygen bulb. iPrOH (1.2 mL) and 2-Me-THF (0.1 mL) were added sequentially under oxygen flow. After cooling to 0 °C, PhSiH3 (44 μL, 0.35 mmol, 3.5 equiv.) was added, and the mixture was stirred for 1 min before adding the above ingredients (0.1 mmol, 1.0 equiv.). The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with saturated NaCl solution and extracted with EtOAc. The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated. Finally, the product was purified by column chromatography (PE:EtOAc=10:1) to obtain a colorless oily liquid, namely the hydrated product (S)-4-fluorophenylbutyl-2-ol, with a yield of 56% and an enantiomeric excess of 92% ee.

[0047] 1 H NMR (400 MHz, Chloroform- d) δ 7.19 – 7.08 (m, 2H), 6.99 – 6.88 (m,2H), 3.88 – 3.75 (m, 1H), 2.80 – 2.57 (m, 2H), 1.82 – 1.70 (m, 2H), 1.67 (s,1H), 1.23 (d, J = 6.2 Hz, 3H). 19 F NMR (376 MHz, Chloroform- d δ -117.65 – -117.90 (m). 13 C NMR (101 MHz, Chloroform- d ) δ 161.31 (d, J = 243.3 Hz), 137.75(d, J = 3.2 Hz), 129.80 (d, J = 7.7 Hz), 115.19 (d, J = 21.1 Hz), 67.43, 41.01,31.39, 23.77. [α] D 25 = +26.9 (c = 0.9, CHCl3). HPLC: CHIRALPAK AD-H, 210 nm,25 o C, n hexane: i PrOH = 97:3, 1.0 mL / min, t R (major) = 11.4 min, t R (minor) = 12.0min.

[0048] Example 4 (S)-Rhododendrol analogs were synthesized according to the synthetic pathway shown in Equation 4: Equation 4; The specific steps are as follows: Under an inert atmosphere, 10 mmol of p-phenylbenzyl bromide and 30 mL of tetrahydrofuran were added to a reaction flask, followed by slow dropwise addition of 15 mL of a 1 mol / L allyl magnesium chloride solution in tetrahydrofuran. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and purified by rapid column chromatography (PE:EtOAc = 50:1) to give a colorless oily liquid p-phenylstyrene in 81% yield.

[0049] Add L to a 16 mL screw-cap reaction flask equipped with a magnetic stirrer The following were added: NiBr2(PPh3)2 (9.4 mg, 0.016 mmol, 16 mol%), NiBr2(PPh3)2 (7.4 mg, 0.01 mmol, 10 mol%), Na2CO3 (37.1 mg, 0.35 mmol, 3.5 equiv.), and PhEt3NI (45.7 mg, 0.15 mmol, 1.5 equiv.). The reaction flask was sealed, and oxygen was purged five times using an oxygen bulb. iPrOH (1.2 mL) and 2-Me-THF (0.1 mL) were added sequentially under oxygen flow. After cooling to 0 °C, PhSiH3 (44 μL, 0.35 mmol, 3.5 equiv.) was added, and after stirring for 1 min, the above-mentioned p-phenylbutene (0.1 mmol, 1.0 equiv.) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with saturated NaCl solution and extracted with EtOAc. The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated. Finally, the product was purified by column chromatography (PE:EtOAc=10:1) to obtain a white solid, namely the hydrated product (S)-4-phenylphenylbutyl-2-ol, in 74% yield with an enantiomeric excess of 95% ee.

[0050] 1 H NMR (400 MHz, Chloroform- d ) δ 7.63 (d, J = 7.6 Hz, 2H), 7.57 (d, J =7.9 Hz, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.40 – 7.35 (m, 1H), 7.32 (d, J = 7.9 Hz,2H), 3.96 – 3.82 (m, 1H), 2.93 – 2.63 (m, 2H), 1.92 – 1.69 (m, 3H), 1.28 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 141.28, 141.09, 138.83,128.92, 128.81, 127.21, 127.12, 127.06, 67.55, 40.85, 31.83, 23.71. [α] D 25= -6.8 (c = 1.90, CHCl3). HPLC: CHIRALPAK IB, 254 nm, 25 o C, n hexane: i PrOH = 92:8, 1.0 mL / min, t R (major) = 14.5 min, t R (minor) = 15.5 min.

[0051] Example 5 (S)-Rhododendrol analogs were synthesized according to the synthetic pathway shown in Equation 5: Formula 5; The specific steps are as follows: Under an inert atmosphere, benzyl bromide (10 mmol) and tetrahydrofuran (30 mL) were added to a reaction flask, followed by slow dropwise addition of a 1 mol / L tetrahydrofuran solution of allyl magnesium chloride (15 mL). The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and purified by rapid column chromatography (PE:EtOAc = 50:1) to give a colorless oily liquid styrene in 85% yield.

[0052] Add L to a 16 mL screw-cap reaction flask equipped with a magnetic stirrer The following were added: NiBr2(PPh3)2 (9.4 mg, 0.016 mmol, 16 mol%), NiBr2(PPh3)2 (7.4 mg, 0.01 mmol, 10 mol%), Na2CO3 (37.1 mg, 0.35 mmol, 3.5 equiv.), and PhEt3NI (45.7 mg, 0.15 mmol, 1.5 equiv.). The reaction flask was sealed, and oxygen was purged five times using an oxygen bulb. iPrOH (1.2 mL) and 2-Me-THF (0.1 mL) were added sequentially under oxygen flow. After cooling to 0 °C, PhSiH3 (44 μL, 0.35 mmol, 3.5 equiv.) was added, and after stirring for 1 min, the above-mentioned phenylbutene (0.1 mmol, 1.0 equiv.) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with saturated NaCl solution and extracted with EtOAc. The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated. Finally, the product was purified by column chromatography (PE:EtOAc=10:1) to obtain a colorless oily liquid, namely the hydrated product (S)-phenylbutyl-2-ol, in 70% yield with an enantiomeric excess of 95% ee.

[0053] 1H NMR (400 MHz, Chloroform- d ) δ 7.37 – 7.27 (m, 2H), 7.25 – 7.17 (m,3H), 3.90 – 3.78 (m, 1H), 2.83 – 2.59 (m, 2H), 1.90 (s, 1H), 1.84 – 1.72 (m,2H), 1.25 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 142.15, 128.47,125.88, 67.52, 40.91, 32.21, 23.66. [α] D 25 = +15.2 (c = 1.50, CHCl3). HPLC:CHIRALPAK IB, 210 nm, 25 o C, n hexane: i PrOH = 92:8, 1.0 mL / min, t R (major) = 11.0 min, t R (minor) = 8.4 min.

[0054] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing (S)-Rhododendrol and its analogues, characterized in that, Includes the following steps: Benzyl halide and allyl magnesium halide were mixed and coupled under a nitrogen atmosphere to obtain an olefin intermediate. The structural formula of the benzyl halide is: , where R 1 X is an alkoxy group, hydrogen, halogen, phenyl, or hydroxyl group. 1 It can be Cl, Br, or I; The structural formula of the allyl magnesium halide is: , where X 2 It is Cl or Br; The structural formula of the olefin intermediate is: ; The olefin intermediate, nickel-based catalyst, reducing agent, alkali metal weak acid salt, and phase transfer agent are mixed and hydrated under oxygen conditions to obtain (S)-Rhododendrol and its analogues; the nickel-based catalyst comprises a nickel donor and a chiral bisoxazoline ligand. The nickel donor is NiBr2·(PPh3)2, and the chiral bisoxazoline ligand is... The alkali metal weak acid salt is sodium carbonate, the reducing agent is benzylsilane, and the phase transfer agent is phenyltriethylammonium iodide; The structural formula of (S)-Rhododendrol and its analogues is: .

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the nickel donor to the chiral bisoxazoline ligand is 1:0.5~2.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the benzyl halide to the allyl magnesium halide is 1:1 to 3.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of the olefin intermediate to the nickel-based catalyst is 0.1~1:0.02~2.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the phase transfer agent to the olefin intermediate is 0.5~2:0.1~1.

6. The synthesis method according to claim 1, characterized in that, The molar ratio of the reducing agent to the olefin intermediate is 0.5~5:0.1~1.

7. The synthesis method according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of -30 to 30°C for 1 to 12 hours.

8. The synthesis method according to claim 1, characterized in that, The hydration reaction is carried out at a temperature of -30 to 30°C for 1 to 12 hours.

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