CN104418707A - Natural product fructus psoraleae phenol and asymmetric synthesis method of enantiomer thereof - Google Patents

Abstract

The invention discloses a natural product fructus psoraleae phenol and an asymmetric synthesis method of an enantiomer thereof, belongs to the field of chemical synthesis, relates to a chemical synthesis technology, and particularly relates to a natural product Bakuchoil with optical activity and a preparation method of the enantiomer ent-Bakuchoil of the natural product. According to the method disclosed by the invention, tiglic acid and tert-butyl acetate which are easily available industrially are taken as initial raw materials to synthesize a key midbody compound 11, subsequently based of the key midbody, the natural product Bakuchoil with optical activity and the enantiomer ent-Bakuchoil thereof can be respectively synthesized by two short synthesis strategies. The method disclosed by the invention is simple to operate, convenient in separation operation, high in yield and good in selectivity, and the used reagents are all common reagents.

Description

Asymmetric synthesis method of natural product bakuchiol and its enantiomers

technical field

The invention belongs to the field of chemical synthesis and relates to a preparation method of natural product Bakuchiol and its enantiomer ent-Bakuchiol.

Background technique

The prior art discloses that bakuchiol (bakuchiol) is one of the main components of the traditional Chinese medicine psoralen, which was first isolated from the seeds of psoralen by Dev et al. in 1966 (Tetrahedron lett, 1966, 7:4561-4567.) , and determined its structure in 1973 (Tetrahedron, 1973, 29:1127-1130.). Bakuchiol has a variety of biological activities, such as anti-inflammatory immune activity (Bioorg Med Chem,2008,16:2403-2411.), antibacterial activity (Planta Med,2005,71:508.), antioxidant effect (Chem ResToxicol ,2003,16:1062-1069.), Inhibition of DNA polymerase (JNat Prod,1998,61:362-366.), etc. The synthesis of bakuchiol has been reported (Lett Org Chem, 2008, 5: 467-469. Tetrahedron Lett, 2008, 49: 6846-6849. J Org Chem, Nat Prod Res, 1999, 14: 1-4. J Chem SocPerkin Trans1,1991,10:2395-2397.Tetrahedron Lett,1990,31:3325-3326.Tetrahedron,1973,29:1209-1213.J Chem Soc C,1968,21:2671-2673.ChemCommun,1967, 12:606-607.), the key to its synthesis is the construction of the quaternary carbon center.

The inventors of the present application intend to provide a simple method for asymmetrically synthesizing the natural product bakuchiol and its enantiomers.

Contents of the invention

The purpose of the present invention is to provide a new preparation method of optically active natural product Bakuchiol and its enantiomers. The invention completes the asymmetric synthesis of Bakuchiol and its enantiomers through converging synthesis with cheap and easy-to-obtain starting materials; each step of the method is simple in operation, convenient in separation and purification, and has high yield and selectivity .

In the present invention, a functionally diverse chiral quaternary carbon compound is used as a key intermediate, and the cross-coupling reaction between an Fe-catalyzed alkyl halide and an alkenyl magnesium Grignard reagent is used as a key step, and a short route is synthesized or Bakuchiol and its enantiomers (bakuchiol/ent-bakuchiol) were obtained.

Specifically, the present invention uses commercially available tiqueric acid and tert-butyl bromoacetate as starting materials to synthesize the key intermediate compound 11, and then proceeds from the key intermediate to synthesize optically active compound 11 through two short synthetic strategies. The natural product Bakuchiol and its enantiomer ent-Bakuchiol.

In the following statement examples, specific synthetic products are represented by Arabic numerals according to the numbering in the structural formula;

Among them, TBDPS- means tert-butyldiphenylsilyl, and TMEDA means N,N,N',N'-tetramethylethylenediamine.

More specifically, the asymmetric synthesis method of a natural product Bakuchiol and its enantiomer ent-Bakuchiol of the present invention is characterized in that, through the following synthetic route, through optically active intermediates 7 and 11, Preparation of optically active Bakuchiol and its enantiomer ent-Bakuchiol:

in,

1) R ₁ is a hydroxyl protecting group, which can be a silyl protecting group, such as Me ₃ Si, Et ₃ Si, i-Pr ₃ Si, t-BuPh ₂ Si, preferably t-BuPh ₂ Si;

2) _R2 is C1-C7 alkyl, which can be methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl, allyl, preferably tert-butyl;

3) The stereo configuration of intermediate 7 can be R or S configuration;

4) The stereo configuration of intermediate 11 derived from intermediate 7 is the corresponding stereo configuration, that is, intermediate 7 of S configuration can be derived from intermediate 11 of S configuration, and intermediate 7 of R configuration can be derived of R configuration Type intermediate 11; 5) Optically active Bakuchiol and its enantiomer ent-Bakuchiol can be derived from intermediate 11 in S configuration or R configuration;

In the synthetic method of the present invention, commercially available compounds 1 and 4 are used as starting materials, and the optically active intermediate 11 is synthesized according to the Scheme 1 synthesis strategy:

in:

Step a: react compound 1 with thionyl chloride under heating conditions, and obtain compound 2 through distillation. Said heating condition refers to reflux condition; Said distillation refers to atmospheric distillation;

Step b: compound 4 is reacted with an inorganic salt in an organic solvent, and compound 5 is obtained after distillation. Said organic solvent refers to acetone; said inorganic salt refers to sodium iodide; said distillation refers to vacuum distillation;

Step c: compound 2 is reacted with an optically active amide in an organic solvent, and compound 3 is obtained after neutralization, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran said a kind of amide refers to the optically active Evans prosthetic group, the intermediate 6 of the S configuration can be produced by the R-type Evans prosthetic group; the intermediate 6 of the R configuration can be produced by the S-type Evans prosthetic group;

Step d: Compound 3 is reacted with an alkylating agent in an organic solvent at low temperature, quenched with acid, extracted, dried, and concentrated to silica gel column chromatography to obtain compound 6, said one The organic solvent refers to tetrahydrofuran; said alkylating agent refers to tert-butyl iodoacetate; said low temperature condition refers to -78°C～-50°C;

Step e: compound 6 is reacted with a reducing agent in an organic solvent at low temperature, extracted, dried, concentrated, and purified by a silica gel column to obtain compound 7, wherein the organic solvent is tetrahydrofuran; the The low temperature condition refers to 0°C, and the reducing agent refers to lithium borohydride, the intermediate 7 of the S configuration can be prepared from the intermediate 6 of the S configuration; the intermediate 6 of the R configuration can be prepared Intermediate 7 in R configuration;

Step f: compound 7 reacts with a protective agent in the presence of heterocyclic compounds in a halogenated hydrocarbon solvent, and obtains compound 8 after extraction, drying, concentration, and silica gel column chromatography. The said halogenated hydrocarbon is Refers to dichloromethane; said heterocyclic compound refers to imidazole; said protective agent refers to TBDPSCl, intermediate 8 of S configuration can be prepared from intermediate 7 of S configuration; intermediate 7 of R configuration , intermediate 8 in R configuration can be prepared;

Step g: compound 8 reacts with a reducing agent in a halogenated hydrocarbon solvent, and undergoes acid quenching, extraction, drying, and concentration to obtain compound 9. The halogenated hydrocarbon refers to dichloromethane; the reduction The agent refers to DIBAL-H; said acid refers to ammonium chloride, and the intermediate 9 of the S configuration can be prepared from the intermediate 8 of the S configuration; the intermediate 8 of the R configuration can be prepared from the intermediate 8 of the R configuration. Intermediate 9;

Step h: Compound 9 reacts with a halogenated hydrocarbon reagent in a halogenated hydrocarbon solvent under the action of PPh ₃ to obtain compound 10 after filtering, concentrating and purifying. The said halogenated hydrocarbon solvent refers to two Chloromethane; said halogenated hydrocarbon reagent refers to CBr ₄ ; intermediate 10 of S configuration can be prepared from intermediate 9 of S configuration; intermediate 9 of R configuration can be prepared intermediate of R configuration 10;

Step i: Compound 10 reacts with a Grignard reagent in a catalyst-containing solvent to obtain Compound 11, where the Grignard reagent refers to 2-methyl-1-propenylmagnesium bromide; the solvent refers to Tetrahydrofuran; said catalyst refers to anhydrous iron trichloride, intermediate 11 of S configuration can be prepared from intermediate 10 of S configuration; intermediate 10 of R configuration can be prepared intermediate of R configuration 11.

In the synthetic method of the present invention, starting from the key intermediate 11, according to the Scheme2 synthesis strategy, the natural product bakuchiol or its optical isomer ent-bakuchiol is synthesized with high yield and high selectivity:

in:

Step j: compound 11 is reacted with a fluoride in an organic solvent, and compound 12 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran; the fluoride refers to Tetrabutylammonium fluoride, intermediate 12 of S configuration can be prepared from intermediate 11 of S configuration; intermediate 12 of R configuration can be prepared from intermediate 11 of R configuration;

Step k: Compound 12 is reacted with an oxidizing agent in an organic solvent, and compound 13 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to dimethyl sulfoxide ; Said a kind of oxidizing agent refers to IBX; The intermediate 13 of S configuration can be prepared by the intermediate 12 of S configuration; The intermediate 13 of R configuration can be prepared by the intermediate 12 of R configuration;

Step 1: Compound 13 is reacted with Grignard reagent at low temperature in an organic solvent, and compound 14 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran; Said low temperature condition refers to 0°C; said Grignard reagent refers to 4-methoxybenzylmagnesium chloride, intermediate 14 of S configuration can be prepared from intermediate 13 of S configuration; intermediate of R configuration 13. Intermediate 14 in R configuration can be prepared;

Step m: Compound 14 is reacted with a sulfonating reagent in an organic solvent, and compound 15 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography, and the organic solvent refers to anhydrous pyridine; Said sulfonating reagent is methanesulfonyl chloride. The intermediate 15 of the S configuration can be prepared from the intermediate 14 of the S configuration; the intermediate 15 of the R configuration can be prepared from the intermediate 14 of the R configuration;

Step n: compound 15 is reacted with a strong base in an organic solvent, and compound 16 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to anhydrous dimethyl methacrylate Sulfone; said a strong base refers to potassium tert-butoxide, intermediate 16 of S configuration can be prepared from intermediate 15 of S configuration; intermediate 15 of R configuration can be prepared from intermediate 15 of R configuration body 16;

Step o: Compound 16 reacts with Grignard reagent at high temperature under the condition of an inorganic solvent, and obtains Compound 17 after quenching, extraction, drying, concentration, and silica gel column chromatography; the organic solvent refers to diethyl ether; Said a Grignard reagent methylmagnesium iodide; said high temperature condition refers to 180 ° C, from the S-configuration intermediate 16 can prepare S-configuration 17, namely bakuchiol; from the R-configuration intermediate 16, The R configuration of 17, ent-bakuchiol, can be prepared.

or,

In the synthesis method of the present invention, starting from the key intermediate intermediate 11, the natural product bakuchiol or its optical isomer ent-bakuchiol is synthesized with high yield and high selectivity according to the Scheme3 synthesis strategy:

in:

Step p: compound 11 is reacted in an organic solvent under a palladium-containing catalyst, and compound 18 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to anhydrous N,N-dimethylformamide; said a palladium-containing catalyst refers to tetrakis triphenylphosphine palladium, intermediate 18 of S configuration can be prepared from intermediate 11 of S configuration; by R configuration The intermediate 11 of the intermediate 18 of the R configuration can be prepared;

Step q: compound 18 is reacted with a fluoride in an organic solvent, and compound 19 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran; the fluoride refers to Tetrabutylammonium fluoride, intermediate 19 of S configuration can be prepared from intermediate 18 of S configuration; intermediate 19 of R configuration can be prepared from intermediate 18 of R configuration;

Step r: Compound 19 is reacted with an oxidizing agent in an organic solvent, and compound 20 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to dimethyl sulfoxide ; Said a kind of oxidizing agent refers to IBX; The intermediate 20 of S configuration can be prepared by the intermediate 19 of S configuration; The intermediate 20 of R configuration can be prepared by the intermediate 19 of R configuration;

Step s: Compound 20 is reacted with a phosphorus-containing reagent in an organic solvent under strong alkali conditions, and compound 21 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran , dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide dichloromethane or trichloromethane, especially tetrahydrofuran; said a phosphorus-containing reagent is Refers to methyl triphenyl phosphorus iodide, said a strong base refers to n-butyllithium, the intermediate 21 of R configuration can be prepared from the intermediate 20 of S configuration; by the intermediate 20 of R configuration, Intermediate 21 in S configuration can be prepared;

Step t: Compound 21 reacts with Grignard reagent at high temperature under the condition of an inorganic solvent, and obtains Compound 22 after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to diethyl ether; Said a Grignard reagent methylmagnesium iodide; said high-temperature condition refers to 180 ° C, from the S-configuration intermediate 21 can prepare S-configuration 22, namely bakuchiol; from the R-configuration intermediate 21, The R configuration of 22, ent-bakuchiol, can be prepared.

The method of the invention is simple in operation, convenient in separation, high in yield and good in selectivity, and the reagents used are all common reagents.

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example 1

1. Synthesis of compound 2 in step 1

Add tiqueric acid (40g, 0.4mol) into a 100ml dry reaction flask, add thionyl chloride (44ml, 0.6mol) dropwise in an ice-water bath, connect to the tail gas treatment device, react under reflux for 5h, cool to room temperature and then distill Device, atmospheric distillation (142°C) to obtain the product, 9.7g of colorless liquid, yield 82%;

2. Synthesis of compound 5 in step 2

Add sodium iodide (30g, 0.2mol) and 200ml acetone to a dry 500ml reaction flask, add tert-butyl bromoacetate (14.6ml, 0.1mol) under stirring, reflux for 4h under the protection of argon, cool to room temperature, Filtrate, concentrate the filtrate under reduced pressure, dissolve the residue in 200ml of water, extract with ethyl acetate (200ml×3), combine the organic phases, and wash with 10% sodium thiosulfate (200ml) and saturated brine (200ml) successively, Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then distill under reduced pressure to obtain the product, 18.6 g of light yellow liquid, yield 77%;

3. Synthesis of compound 5 in step 3

Add the R-type Evans prosthetic group into a 250ml dry reaction flask, dissolve in 70ml anhydrous THF, cool to -78°C, then slowly add n-BuLi (18.5ml, 46.3mmol), react for 30min, add (E) -2-Methyl-2-butenoyl chloride (5.0g, 42.5mmol), reacted for 30min, raised the temperature to 0°C, and continued to react for 15min. Quench the reaction with 20ml of saturated ammonium chloride, separate the organic phase, extract the aqueous phase with ethyl acetate (20ml×3), combine the organic phases, wash with saturated brine (40ml), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrated under reduced pressure, column chromatography of the residue (elution condition, petroleum ether: ethyl acetate = 10:1) to obtain the product, 7.7g of white solid, yield 94%;

R _f =0.40 (petroleum ether: ethyl acetate = 5:1)

¹ H NMR (400MHz, CDCl ₃ )δ6.21(q,J=6.8Hz,1H,C(2)H),4.58–4.46(m,1H),4.32(t,J=8.9Hz,1H), 4.17(dd,J=8.9,5.6Hz,1H),2.42–2.28(m,1H,C(13)H),1.91(s,3H,C(5)H ₃ ),1.81(d,J=6.8 Hz,3H,C(1)H ₃ ),0.96–0.86(m,6H).

ESI-MS: 212.1[M+H]

HRMS(ESI): Calcd.for C ₁₁ H ₁₇ NO ₃ Na ⁺ [M+Na]: 234.1106, found: 234.1101.

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 20</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 78.5</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.13</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span>$

4. Synthesis of compound 6 in step 4

Add compound 2 (211mg, 1.0mmol) to a dry 250ml reaction flask, dissolve in 40ml of anhydrous THF, cool to -78°C, slowly add NaHMDS (1.0ml, 2.0mmol) dropwise, and react for 30min after dropping Slowly add tert-butyl iodoacetate (484mg, 2.0mmol), raise the temperature to -50°C, react overnight, quench the reaction with 5ml of saturated ammonium chloride, dilute with 5ml of water, extract with ethyl acetate (10ml×3), and add saturated salt Wash with water (10ml), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and obtain the product by column chromatography (elution conditions, petroleum ether:ethyl acetate=50:1) as a colorless oily liquid, 222mg. The rate is 68%.

R _f =0.59 (petroleum ether: ethyl acetate = 5:1)

¹ H NMR (400MHz, CDCl ₃ ) δ6.21 (dd, J=17.6, 10.7Hz, 1H, C(11)H), 5.08(d, J=10.7Hz, 1H, C(12)H), 5.01 (d,J=17.6Hz,1H,C(12)H),4.57(dt,J=8.1,3.0Hz,1H,C(19)H),4.23(m,2H,C(18)H ₂ ) ,3.59(d,J=16.8Hz,1H,C(3)H),2.74(d,J=16.8Hz,1H,C(3)H),2.50–2.36(m,1H,C(21)H ),1.47(s,3H,C(13)H ₃ ),1.42(s,9H,OC(CH ₃ ) ₃ ),0.92(d,J=7.1Hz,3H,),0.87(d,J=6.8 Hz,3H)(CH(CH ₃ ) ₂ ).

¹³ C NMR (100MHz, CDCl ₃ ) δ174.0(C5), 170.7(C2), 152.9(C16), 141.0(C11), 113.5(C12), 80.8(C7), 63.1(C19), 60.1(C18) , 48.8(C4), 43.7(C3), 28.1(OC Me ₃ ), 27.9(C21), 24.6(C13), 18.2, 14.5(C22,C23).

ESI-MS: 348.0 [M+Na]

HRMS (ESI): Calcd. for C ₁₇ H ₂₇ NO ₅ Na ⁺ [M+Na]: 348.1781, found: 348.1782.

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 20</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 49.1</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.11</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span>$

5. Synthesis of compound 7 in step 5

A 100ml reaction flask containing compound 3 (1.47g, 4.5mmol) was protected with argon, dissolved in 10ml of anhydrous THF, cooled to 0°C, and then a THF solution (10ml) of lithium borohydride (196mg, 9mmol) was slowly added dropwise, After dropping, methanol (0.55ml, 13.5mmol) was added to trigger the reaction. React for 3 hours, TLC monitors that the reaction is complete, 10ml of saturated sodium bicarbonate is quenched, diluted with 10ml of water, the organic phase is separated, the aqueous phase is extracted with ethyl acetate (20ml×3), the organic phases are combined, washed with saturated brine (30ml), Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is subjected to column chromatography (elution condition, petroleum ether: ethyl acetate = 15:1) to obtain the product, 638 mg of a colorless oily liquid, with a yield of 71%;

R _f =0.43 (petroleum ether: ethyl acetate = 5:1)

¹ H NMR (400MHz, CDCl ₃ ) δ5.83 (dd, J=17.7, 11.0Hz, 1H, C(11)H), 5.11(d, J=11.0Hz, 1H(C(12)H)), 5.06(d,J=17.7Hz,1H,C(12)H),3.46(s,2H,C(5)H ₂ ),2.50(brs,1H,OH),2.37–2.24(m,2H,C (3)H ₂ ), 1.43(s,9H,OC(CH ₃ ) ₃ ), 1.09(s,3H,C(13)H ₃ ).

¹³ C NMR (101MHz, CDCl ₃ ) δ172.0(C2), 143.1(C11), 113.9(C12), 81.1(C7), 69.7(C5), 43.3(C3), 41.8(C4), 28.2(OC Me ₃ ), 21.5(C13).

ESI-MS: 223.1[M+Na]

HRMS(ESI): Calcd.for C ₁₁ H ₂₀ O ₃ Na ⁺ [M+Na]: 223.1305, found: 223.1310

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 20</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 2.7</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.30</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span>$

6. Synthesis of compound 8 in step 6

Add compound 7 (5.00g, 25mmol) and imidazole (4.26g, 62.5mmol) to a dry 250ml reaction flask, dissolve in 80ml anhydrous DCM, add TBDPSCl (7.69g, 28mmol) in anhydrous DCM solution (50ml ), react at room temperature for 5h. Stop the reaction, concentrate the reaction solution under reduced pressure, remove the solvent as much as possible, dissolve the residue with 50ml of water, then extract with ethyl acetate (50ml×3), combine the organic phases, wash with saturated brine (50ml), anhydrous sulfuric acid Dried over magnesium, filtered, concentrated the filtrate under reduced pressure, and subjected the residue to column chromatography (elution condition, petroleum ether: dichloromethane = 5:1) to obtain the product, 9.83 g of light yellow liquid, with a yield of 83%;

R _f =0.46 (petroleum ether: dichloromethane = 5:1)

¹ H NMR (400MHz, CDCl ₃ )δ7.65(m,4H),7.40(m,6H),5.92(dd,J=17.6,10.9Hz,1H),5.04(m,2H),3.52(d, J=9.5Hz,1H),3.46(d,J=9.5Hz,1H),2.43(d,J=13.8Hz,1H),2.37(d,J=13.8Hz,1H),1.40(s,9H) ,1.16(s,3H),1.06(s,9H).

¹³ C NMR (100MHz, CDCl ₃ ) δ171.60, 143.49, 135.98, 133.85, 129.87, 127.88, 113.45, 80.41, 71.25, 43.27, 41.97, 28.43, 27.16, 20.98, 19.72.

ESI-MS: 461.2[M+Na].

HRMS(ESI): Calcd.for C ₂₇ H ₃₈ O ₃ SiNa ⁺ [M+Na]: 461.2488, found: 461.2480

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 15.9</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.22</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span>$

7. Synthesis of compound 9 in step 7

Add compound 8 (7.80g, 17.8mmol) to a dry 100ml reaction flask, protect with argon, dissolve in 60ml of anhydrous DCM, cool to -40°C, then slowly add DIBALH (26ml, 39.2mmol) dropwise, and react 2h. Quench with 30ml of saturated ammonium chloride, dilute with 30ml of water, filter with diatomaceous earth, separate several layers, extract the aqueous phase with ethyl acetate (50ml×2), combine the organic phases, wash with saturated brine (50ml), anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was subjected to column chromatography (elution condition, petroleum ether: ethyl acetate = 10:1) to obtain 6.17 g of a colorless liquid, with a yield of 94%;

R _f =0.17 (petroleum ether: dichloromethane = 5:1)

¹ H NMR (400MHz, CDCl ₃ )δ7.64(m,4H),7.41(m,6H),5.85(dd,J=17.7,10.9Hz,1H),5.11(dd,J=10.9,1.1Hz, 1H),5.02(dd,J=17.6,1.1Hz,1H),3.67(m,2H),3.46(d,J=9.7Hz,1H),3.39(d,J=9.7Hz,1H),1.87( brs,1H),1.76(m,2H),1.07(s,9H),1.03(s,3H).

¹³ C NMR (100MHz, CDCl3) δ144.26, 135.70, 133.27, 129.67, 127.63, 113.19, 71.44, 59.64, 41.29, 40.29, 26.87, 20.58, 19.36.

ESI-MS: 391.2[M+Na].

HRMS (ESI): Calcd. for C ₂₃ H ₃₂ O ₂ SiNa+[M+Na]: 391.2069, found: 391.2066.

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 7.3</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.00</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span>$

Step 8: Synthesis of Compound 10

9 (6.4g, 17mmol) and CBr ₄ (8.4g, 25.5mmol) were dissolved in anhydrous DCM (40ml) into a 250mL dry single-necked bottle, and PPh ₃ (6.83g, 26mmol) was added, protected by Ar, and reacted at room temperature for 0.5 hours . The reaction solution was concentrated, and the residue was subjected to column chromatography (elution condition: petroleum ether) to obtain 15.8 g of a light yellow liquid with a yield of 86%;

R _f (petroleum ether) 0.76,

¹ H NMR (400MHz, CDCl ₃ )δ7.67(m,4H),7.42(m,6H),5.79(dd,J=17.6,10.9Hz,1H),5.11(dd,J=10.9,1.1Hz, 1H), 5.02(dd, J=17.6, 1.1Hz, 1H), 3.44(d, J=9.6Hz, 1H), 3.38d, J=9.6Hz, 1H), 3.31(m, 2H), 2.10(m ,2H),1.09(s,9H),1.06(s,3H).

¹³ C NMR (100MHz, CDCl3) δ142.66, 135.64, 133.32, 129.66, 127.64, 113.98, 70.81, 43.30, 40.85, 29.31, 26.85, 20.12, 19.36.

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 3.9</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.95</span>}<span\; class="notranslate">\; ,</span>\mathrm{<span\; class="notranslate">\; CHCl</span>}\mathrm{<span\; class="notranslate">\; 3</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Step 9: Synthesis of compound 11

Add compound 10 (4.00g, 9.27mmol) and FeCl ₃ (0.15g, 0.93mmol) into a 250mL single-necked bottle, dissolve it in anhydrous THF (30ml), stir at 0°C, and then add 2-methyl-1- Propylmagnesium bromide (37ml, 18.5mmol, 0.5MinTHF) and TMEDA (137mg, 1.75mmol) were stirred at 0°C for 0.5h, and reacted at room temperature for 4h. Quenched with 10ml of saturated ammonium chloride, extracted with ethyl acetate (150mL×3), dried the organic phase with anhydrous MgSO ₄ , filtered, concentrated, and the residue was column chromatographed (elution condition: petroleum ether) to obtain 2.94g of light yellow liquid , yield 78%;

R _f (petroleum ether) 0.85,

¹ H NMR (400MHz, CDCl3) δ7.71–7.61 (m, 4H), 7.38 (m, 6H), 5.80 (dd, J=17.6, 10.8Hz, 1H), 5.08 (m, 1H), 5.02 (d ,J=10.8Hz,1H),4.99(d,J=17.6Hz,1H),3.40(m,2H),1.87(m,2H),1.67(s,3H),1.57(s,3H),1.42 (m,2H),1.06(s,9H),1.02(s,3H).

¹³ C NMR (100MHz, CDCl3) δ144.56, 135.69, 133.75, 131.01, 129.48, 127.52, 125.05, 112.77, 71.04, 42.14, 37.08, 26.86, 25.71, 22.70, 20.29, 19.41, 17.61.

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1.2</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.00</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Example 2

Step 1: Synthesis of compound 12

Add compound 11 (406mg, 1.8mmol) to a 50ml reaction bottle, dissolve in 2ml of anhydrous THF, protect with argon, dissolve in 2ml of anhydrous THF, then add TBAF (1M in THF, 2ml, 2mmol), stir at room temperature for 3h, the reaction solution From colorless and transparent to light yellow, the reaction has been completed by TLC monitoring, the reaction is quenched with 5ml of water, the color of the reaction solution becomes colorless, extracted with ethyl acetate (20ml×3), washed with saturated brine (20ml×1), no Dry over sodium sulfate, filter, concentrate under reduced pressure, and perform column chromatography (elution condition, petroleum ether/ethyl acetate = 10:1) to obtain 153 mg of a colorless oily liquid with a yield of 91%;

R _f (petroleum ether/ethyl acetate=5:1)0.49

¹ H NMR (400MHz, CDCl ₃ )δ5.71(dd, J=17.2,10.8Hz,1H),5.18(dd,J=10.9,1.3Hz,1H),5.07(m,2H),3.39(d, J=10.6Hz,1H),3.33(d,J=10.6Hz,1H),1.90(m,2H),1.67(s,3H),1.58(s,3H),1.34(m,2H),1.03( s,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ143.89, 131.44, 124.56, 114.71, 70.08, 42.30, 37.16, 25.65, 22.44, 19.46, 17.56.

ESI-MS: 169.2[M+H].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 12.4</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.23</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Step 2: Synthesis of compound 13

Substrate 12 (168mg, 1mmol) and IBX (420mg, 1.5mmol) were added to a 50ml reaction vial, dissolved in 5ml DMSO, and reacted overnight at room temperature under the protection of argon. Quench the reaction with 5ml NaHCO ₃ , extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20ml), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography on the residue (elution conditions : Petroleum ether) to obtain 156mg of colorless oily liquid, yield 94%;

R _f (Petroleum ether)0.28, ${\left[\mathrm{\&alpha;}\right]}_{\mathrm{D.}}^{27.5}=+9.5(c=1.00,{\mathrm{CHCl}}_3).$

Step 3: Synthesis of compound 14

Add the substrate aldehyde 13 (210mg, 1.26mmol) into a 100ml reaction flask, dissolve it with 5ml of anhydrous THF, slowly add 4-methoxybenzylmagnesium chloride (0.25MinTHF, 10mL, 2.5mmol) dropwise under stirring at 0°C, and add 15min Complete, react at room temperature for 2 h, quench with 2 ml of saturated ammonium chloride, extract with ethyl acetate (15 mL×3), wash with saturated brine (15 ml), dry the organic phase over anhydrous MgSO ₄ , filter, concentrate, and column the residue Analysis (elution condition, petroleum ether/ethyl acetate=20:1), obtained 316mg of colorless oily liquid, yield 87%;

R _f (petroleum ether/ethyl acetate=10:1)0.61,

¹ HNMR(400MHz,CDCl ₃ )δ7.12(d,J=8.5Hz,2H),6.83(d,J=8.5Hz,2H),5.83(m,1H),5.19(t,J=9.9Hz, 1H),5.10(m,2H),3.77(s,3H),3.48(m,1H),2.81(d,J=13.9Hz,1H),2.10(m,1H),1.92(m,2H), 1.68(s,3H),1.59(s,3H),1.48(m,2H),1.07(s,3H).

Step 4: Synthesis of compound 15

Add substrate alcohol 14 (300mg, 1.04mmol) into a 100ml reaction bottle, dissolve it with 15ml of anhydrous pyridine, slowly add MeSO ₂ Cl (93μl, 1.14mmol, d=1.48mg/mL) dropwise under stirring, and react overnight at room temperature. Add 5ml of water to quench the reaction, extract with ethyl acetate (30mL×3), wash with saturated brine (30ml), dry the organic phase over anhydrous MgSO ₄ , filter, concentrate, and the residue is subjected to column chromatography (elution condition, petroleum ether /ethyl acetate=20:1), to obtain 180mg of colorless oily liquid, yield 89%;

R _f (petroleum ether/ethyl acetate=20:1)0.15,

¹ H NMR (400MHz, CDCl ₃ )δ7.14(d, J=8.4Hz, 2H), 6.85(d, J=8.4Hz, 2H), 5.84(m, 1H), 5.26(m, 1H), 5.18 –5.07(m,2H),4.82(m,1H),3.78(s,3H),3.00(m,1H),2.77–2.68(m,1H),2.10(s,3H),1.95(m,2H ),1.67(s,3H),1.59(s,3H),1.51(m,2H),1.17(s,3H).

Step 5: Synthesis of compound 16

Add substrate 15 (320mg, 0.09mmol) into a 100ml reaction bottle, dissolve it with 5ml of anhydrous DMSO, add t-BuOK (196mg, 1.75mmol) at one time, react at room temperature for 5h, add 20ml of water to quench the reaction, ethyl acetate (20mL×3) extraction, washed with saturated brine (20ml), the organic phase was dried over anhydrous MgSO ₄ , filtered, concentrated, and the residue was chromatographed (elution condition: petroleum ether) to obtain 203mg of a colorless oily liquid, which was collected rate 86%;

R _f (Petroleumethe)0.64,

¹ H NMR (400MHz, CDCl ₃ )δ7.31(d, J=8.7Hz, 2H), 6.85(d, J=8.7Hz, 2H), 6.28(d, J=16.3Hz, 1H), 6.08(d ,J=16.3Hz,1H),5.90(dd,J=17.2,10.8Hz,1H),5.11(t,J=7.1Hz,1H),5.03(m,2H),3.81(s,3H),1.97 (m,2H),1.69(s,3H),1.59(s,3H),1.50(m,2H),1.21(s,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ158.67, 145.94, 135.74, 131.26, 130.63, 127.11, 126.47, 124.77, 113.85, 111.83, 55.25, 42.50, 41.26, 25.69, 23.31, 1-MS220.I7 +H].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 26.5</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.02</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Step 6: Synthesis of compound 17

Add substrate 16 (151mg, 0.56mmol) into a 100ml reaction flask, dissolve it with 5ml Et ₂ O, add MeMgI (0.28ml, 0.84mmol, 3.0MinEt ₂ O) slowly, vacuum the solvent, and react the residue at 180°C under the protection of Ar 10min, 20ml saturated NH ₄ Cl quenched the reaction, extracted with ethyl acetate (10ml×3), washed with saturated brine (10ml), dried the organic phase with anhydrous MgSO ₄ , filtered, concentrated, and the residue was column chromatographed (elution Conditions, petroleum ether/ethyl acetate=15:1), 129mg of colorless oily liquid was obtained, yield 90%;

R _f (petroleum ether/ethyl acetate=10:1)0.53,

¹ H NMR (400MHz, CDCl ₃ )δ7.24(d, J=8.5Hz, 2H), 6.76(d, J=8.5Hz, 2H), 6.25(d, J=16.2Hz, 1H), 6.05(d ,J=16.2Hz,1H),5.88(dd,J=17.2,10.8Hz,1H),5.11(t,J=7.1Hz,1H),5.02(m,2H)),1.95(m,2H), 1.67(s,3H),1.58(s,3H),1.49(m,2H),1.19(s,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ154.56, 145.90, 135.78, 131.30, 130.79, 127.32, 126.41, 124.75, 115.34, 111.86, 42.49, 41.23, 25.69, 23.28, 23.19, 2-MS.62.ESI ].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 24.9</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.98</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Example 3

Step 1: Synthesis of Compound 18

Add substrate 11 (240mg, 0.59mmol), 4-iodoanisole (168mg, 0.71mmol), Pd(PPh ₃ ) ₄ (8mg, 7μmol) and K ₂ CO ₃ (164mg, 1.18mmol) into a 100ml reaction vial , dissolved in 10ml of anhydrous DMF, reacted at 140°C for 7h under the protection of Ar, cooled to room temperature, quenched with 5ml of HCl (1N), extracted with ethyl acetate (20ml×3), washed with saturated brine (20ml), and the organic phase was anhydrous _MgSO4 was dried, filtered, concentrated, and the residue was column chromatographed (elution condition: petroleum ether) to obtain 126 mg of a colorless oily liquid, with a yield of 60% (based on the yield after recovering the raw material);

R _f (petroleum ether) 0.32.

¹ H NMR (400MHz, CDCl ₃ )δ7.65(dd, J=13.5,6.4Hz,4H),7.47–7.30(m,7H),7.26(d,J=2.5Hz,1H),6.85(d, J=8.7Hz,2H),6.28(d,J=16.4Hz,1H),6.07(d,J=16.4Hz,1H),5.11(s,1H),3.80(s,3H),3.49(d, J=3.6Hz,2H),2.01–1.87(m,2H),1.67(s,3H),1.57(s,3H),1.26(s,3H),1.14(s,2H),1.06(s,9H ).

Step 2: Synthesis of compound 19

Add substrate 18 (180mg, 0.35mmol) to a 25ml reaction bottle, add TBAF (1.0M in THF, 2mL, 2mmol) dropwise, react at room temperature for 3h, quench the reaction with 2ml saturated NH ₄ Cl, ethyl acetate (20ml×3) Extracted, washed with saturated brine (20ml), dried the organic phase over anhydrous MgSO ₄ , filtered, concentrated, and the residue was subjected to column chromatography (elution conditions, petroleum ether/ethyl acetate=10:1) to obtain a colorless oily liquid 83mg, yield 86%;

R _f (petroleum ether/ethyl acetate=10:1)0.18,

¹ H NMR (400MHz, CDCl ₃ )δ7.31(d, J=8.7Hz, 2H), 6.84(d, J=8.7Hz, 2H), 6.35(d, J=16.4Hz, 1H), 5.97(d ,J=16.4Hz,1H),5.15–5.07(m,1H),3.81(s,3H),3.47(d,J=10.7Hz,1H),3.41(d,J=10.7Hz,1H),2.03 –1.89(m,2H),1.67(s,3H),1.58(s,3H),1.5(brs,1H),1.47–1.40(m,2H),1.14(s,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ159.24, 133.77, 131.78, 130.43, 129.37, 127.52, 124.98, 114.24, 70.93, 55.61, 42.27, 38.13, 26.01, 22.96, 20.56, 17.96.

ESI-MS: 275.2[M+H].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 28.8</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 0.96</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Step 3: Synthesis of compound 20

Substrate 19 (103mg, 1.0mmol) and IBX (137mg, 0.49mmol) were added to a 50ml reaction vial, dissolved in 5ml DMSO, and reacted overnight at room temperature under argon protection. Quench the reaction with 5ml NaHCO ₃ , extract with ethyl acetate (10mL×3), combine the organic phases, wash with saturated brine (10ml), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Conditions, petroleum ether/ethyl acetate=20:1) to obtain 90mg of colorless oily liquid, yield 88%;

R _f (petroleum ether/ethyl acetate=20:1)0.30.

Step 4: Synthesis of compound 21

Add methyltriphenylphosphine iodide (1.53g, 3.8mmol) into a 100ml reaction flask, dissolve in 20ml of anhydrous THF, and slowly add n-BuLi (1.6ml, 3.7mmol; 2.3M in hexane) dropwise under stirring at 0°C , after the dropwise addition, continue to react at 0°C for 20min, dissolve the substrate 20 in 5ml of anhydrous THF, and then slowly add dropwise to the above system, after the dropwise addition, react at room temperature for 2h, add 1ml of acetone to quench the reaction, and use Dilute with 5ml of saturated brine, extract with ethyl acetate (50ml×3), combine the organic phases, wash with saturated brine (50ml), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography on the residue (elution conditions , petroleum ether/ethyl acetate=10:1) to obtain 540 mg of colorless oily liquid, yield 77%;

R _f (petroleum ether/ethyl acetate=10:1)0.91,

¹ H NMR (400MHz, CDCl ₃ )δ7.30(d, J=8.7Hz, 2H), 6.84(d, J=8.7Hz, 2H), 6.26(d, J=16.2Hz, 1H), 6.06(d ,J=16.2Hz,1H),5.88(dd,J=17.2,10.8Hz,1H),5.11(t,J=7.1Hz,1H),5.01(J=10.8Hz,1H),5.01(J=17.2 Hz,1H),3.80(s,3H),1.95(d,J=8.4Hz,2H),1.67(s,3H),1.58(s,3H),1.49(m,2H),1.20(s,3H ).

¹³ C NMR (100MHz, CDCl ₃ ) δ158.67, 145.95, 135.76, 131.28, 130.64, 127.12, 126.48, 124.77, 113.86, 111.83, 55.27, 42.51, 41.27, 29.69, 25.69, 0.MS:23.20.9,17 +Na].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 26.2</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.01</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Step 5: Synthesis of compound 22

Substrate 16 (151mg, 0.56mmol) was added to a 100ml reaction flask, dissolved with 5ml Et ₂ O, MeMgI (0.28ml, 0.84mmol, 3.0M in Et ₂ O) was added slowly, the solvent was dried in vacuo, and the residue was protected by Ar at 180 ℃ for 10 min, quenched with 20 ml of saturated NH ₄ Cl, extracted with ethyl acetate (10 ml×3), washed with saturated brine (10 ml), dried the organic phase with anhydrous MgSO ₄ , filtered, concentrated, and the residue was subjected to column chromatography ( Elution conditions, petroleum ether/ethyl acetate=15:1), to obtain 129mg of colorless oily liquid, yield 90%;

R _f (Petroleum ether/ethyl acetate=10:1)0.52,

¹ H NMR (400MHz, CDCl ₃ )δ7.25(d, J=8.4Hz, 2H), 6.77(d, J=8.4Hz, 2H), 6.25(d, J=16.2Hz, 1H), 6.05(d ,J=16.2Hz,1H),5.88(dd,J=17.2,10.8Hz,1H),5.11(t,J=7.0Hz,1H),5.03(d,J=10.8Hz,1H),5.02(d ,J=17.2Hz,1H),1.95(m,2H),1.67(s,3H),1.58(s,3H),1.49(m,2H),1.19(s,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ154.64, 146.04, 135.96, 131.29, 131.07, 127.31, 126.42, 124.75, 115.32, 111.85, 42.49, 41.31, 29.68, 25.67, 23.25, 17.86.

ESI-MS: 279.0[M+Na].

${<span\; class="notranslate">\; [</span>\mathrm{<span\; class="notranslate">\; \&alpha;</span>}<span\; class="notranslate">\; ]</span>}_{\mathrm{<span\; class="notranslate">\; D.</span>}}^{\mathrm{<span\; class="notranslate">\; 27.5</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 25.7</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; c</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1.00</span>}<span\; class="notranslate">\; ,</span>{\mathrm{<span\; class="notranslate">\; CHCl</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; .</span>$

Claims (6)

1. A kind of asymmetric synthesis method of natural product bakuchiol and its enantiomer, it is characterized in that, by following synthetic approach, by optically active intermediate 7 and 11, prepare optically active Bakuchiol and its enantiomer Body-Bakuchiol: in, 1) R ₁ is a hydroxyl protecting group, selected from silyl protecting groups, including: Me ₃ Si, Et ₃ Si, i-Pr ₃ Si, t-BuPh ₂ Si; 2) _R2 is C1-C7 alkyl, selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl, benzyl or allyl; 3) The stereo configuration of intermediate 7 is R or S configuration; 4) The stereo configuration of intermediate 11 derived from intermediate 7 is the corresponding stereo configuration, that is, intermediate 7 of S configuration derives intermediate 11 of S configuration, and intermediate 7 of R configuration derives of R configuration Intermediate 11; 5) Optically active Bakuchiol and its enantiomer ent-Bakuchiol are derived from intermediate 11 in S or R configuration. 2. The method of claim 1, wherein the silyl protecting group is t-BuPh ₂ Si. 3. The method of claim 1, wherein said alkyl group is t-butyl. 4. by the described method of claim 1, it is characterized in that, with compound 1 and 4 as starting material, synthesize optically active intermediate 11 by Scheme1 synthesis strategy: in: Step a: compound 1 reacts with thionyl chloride under heating conditions, and obtains compound 2 through distillation, and the heating conditions refer to reflux conditions; the distillation refers to atmospheric distillation; Step b: Compound 4 is reacted with an inorganic salt in an organic solvent, and compound 5 is obtained after distillation, wherein said organic solvent refers to acetone; said inorganic salt refers to sodium iodide; said distillation refers to Vacuum distillation; Step c: compound 2 is reacted with an optically active amide in an organic solvent, and compound 3 is obtained after neutralization, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran said a kind of amide refers to the optically active Evans prosthetic group, the intermediate 6 of the S configuration can be produced by the R-type Evans prosthetic group; the intermediate 6 of the R configuration can be produced by the S-type Evans prosthetic group; Step d: Compound 3 is reacted with an alkylating agent in an organic solvent at low temperature, quenched with acid, extracted, dried, and concentrated to silica gel column chromatography to obtain compound 6, said one The organic solvent refers to tetrahydrofuran; said alkylating agent refers to tert-butyl iodoacetate; said low temperature condition refers to -78°C～-50°C; Step e: compound 6 is reacted with a reducing agent in an organic solvent at low temperature, extracted, dried, concentrated, and purified by a silica gel column to obtain compound 7, wherein the organic solvent is tetrahydrofuran; the The low temperature condition refers to 0°C, and the reducing agent refers to lithium borohydride, the intermediate 7 of S configuration is prepared from the intermediate 6 of S configuration; the intermediate 6 of R configuration is prepared from the intermediate 6 of R configuration Type intermediate 7; Step f: compound 7 reacts with a protective agent in the presence of heterocyclic compounds in a halogenated hydrocarbon solvent, and obtains compound 8 after extraction, drying, concentration, and silica gel column chromatography. The said halogenated hydrocarbon is Refer to dichloromethane; said heterocyclic compound refers to imidazole; said protecting agent refers to TBDPSCl, prepares intermediate 8 of S configuration from intermediate 7 of S configuration; intermediate 7 of R configuration, Preparation of intermediate 8 in R configuration; Step g: compound 8 reacts with a reducing agent in a halogenated hydrocarbon solvent, and undergoes acid quenching, extraction, drying, and concentration to obtain compound 9. The halogenated hydrocarbon refers to dichloromethane; the reduction The agent refers to DIBAL-H; the acid refers to ammonium chloride, the intermediate 9 of the S configuration is prepared from the intermediate 8 of the S configuration; the intermediate 8 of the R configuration is prepared from the intermediate 8 of the R configuration 9; Step h: Compound 9 reacts with a halogenated hydrocarbon reagent in a halogenated hydrocarbon solvent under the action of PPh ₃ to obtain compound 10 after filtering, concentrating and purifying. The said halogenated hydrocarbon solvent refers to two Chloromethane; said halogenated hydrocarbon reagent refers to CBr ₄ ; intermediate 10 of S configuration is prepared from intermediate 9 of S configuration; intermediate 10 of R configuration is prepared from intermediate 9 of R configuration; Step i: Compound 10 is reacted with a Grignard reagent in a catalyst-containing solvent to obtain Compound 11. The Grignard reagent is 2-methyl-1-propenylmagnesium bromide; the solvent is tetrahydrofuran; the Said catalyst is anhydrous ferric chloride, the S-configuration intermediate 11 is prepared from the S-configuration intermediate 10; the R-configuration intermediate 11 is prepared from the R-configuration intermediate 10. 5. by the described method of claim 1, it is characterized in that, set out from key intermediate 11 with compound, by Scheme2 synthetic natural product bakuchiol or its optical isomer ent-bakuchiol: in: Step j: Compound 11 is reacted with a fluoride in an organic solvent, and compound 12 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent is tetrahydrofuran; the fluoride is tetrabutyl Based ammonium fluoride, the intermediate 12 of S configuration is prepared from the intermediate 11 of S configuration; the intermediate 12 of R configuration is prepared from the intermediate 11 of R configuration; Step k: Compound 12 is reacted with an oxidizing agent in an organic solvent, and compound 13 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to dimethyl sulfoxide ; Said a kind of oxidizing agent refers to IBX; The intermediate 13 of S configuration is prepared by the intermediate 12 of S configuration; The intermediate 13 of R configuration is prepared by the intermediate 12 of R configuration; Step 1: Compound 13 is reacted with Grignard reagent at low temperature in an organic solvent, and compound 14 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran; The said low temperature condition refers to 0°C; the said Grignard reagent refers to 4-methoxybenzyl magnesium chloride, and the intermediate 14 of the S configuration is prepared from the intermediate 13 of the S configuration; the intermediate 13 of the R configuration is , prepare intermediate 14 of R configuration; Step m: Compound 14 is reacted with a sulfonating reagent in an organic solvent, and compound 15 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography, and the organic solvent refers to anhydrous pyridine; Said sulfonating reagent is methanesulfonyl chloride, intermediate 15 of S configuration is prepared from intermediate 14 of S configuration; intermediate 15 of R configuration is prepared from intermediate 14 of R configuration; Step n: compound 15 is reacted with a strong base in an organic solvent, and compound 16 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to anhydrous dimethyl methacrylate Sulfone; said a strong base refers to potassium tert-butoxide, the intermediate 16 of the S configuration is prepared from the intermediate 15 of the S configuration; the intermediate 16 of the R configuration is prepared from the intermediate 15 of the R configuration ; Step o: Compound 16 reacts with Grignard reagent at high temperature under the condition of an inorganic solvent, and obtains Compound 17 after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to diethyl ether; Said a kind of Grignard reagent methylmagnesium iodide; said high temperature condition refers to 180 ℃, from S configuration intermediate 16 to prepare S configuration 17, namely bakuchiol; from R configuration intermediate 16, prepared 17 in R configuration, namely ent-bakuchiol. 6. by the described synthetic method of claim 1, it is characterized in that. Starting from the key intermediate Intermediate 11, the natural product bakuchiol or its optical isomer ent-bakuchiol was synthesized according to Scheme3: in: Step p: compound 11 is reacted in an organic solvent under a palladium-containing catalyst, and compound 18 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to anhydrous N,N-dimethylformamide; said palladium-containing catalyst refers to tetrakistriphenylphosphine palladium, intermediate 18 of S configuration is prepared from intermediate 11 of S configuration; intermediate 18 of S configuration is prepared from intermediate of R configuration intermediate 11, intermediate 18 of R configuration was prepared; Step q: compound 18 is reacted with a fluoride in an organic solvent, and compound 19 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to tetrahydrofuran; the fluoride refers to Tetrabutylammonium fluoride, intermediate 19 of S configuration is prepared from intermediate 18 of S configuration; Intermediate 19 of R configuration is prepared from intermediate 18 of R configuration; Step r: Compound 19 is reacted with an oxidizing agent in an organic solvent, and compound 20 is obtained after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to dimethyl sulfoxide ; Said a kind of oxidizing agent refers to IBX; The intermediate 20 of S configuration can be prepared by the intermediate 19 of S configuration; The intermediate 20 of R configuration is prepared by the intermediate 19 of R configuration; Step s: Compound 20 is reacted with a phosphorus-containing reagent in an organic solvent under strong alkali conditions, and compound 21 is obtained after extraction, drying, concentration, and silica gel column chromatography. The organic solvent is selected from tetrahydrofuran , dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide dichloromethane or chloroform, said a phosphorus-containing reagent refers to methyl triphenyl Phosphorus iodide, said a strong base refers to n-butyllithium, intermediate 21 of R configuration is prepared from intermediate 20 of S configuration; intermediate 20 of S configuration is prepared from intermediate 20 of R configuration Body 21; Step t: Compound 21 reacts with Grignard reagent at high temperature under the condition of an inorganic solvent, and obtains Compound 22 after quenching, extraction, drying, concentration, and silica gel column chromatography. The organic solvent refers to diethyl ether; Said a kind of Grignard reagent methylmagnesium iodide; said high temperature condition refers to 180 ℃, from S configuration intermediate 21 to prepare S configuration 22, namely bakuchiol; from R configuration intermediate 21, prepare 22 in R configuration, namely ent-bakuchiol.