CN105198722A - Method for asymmetrically catalyzing and synthesizing (R)-4, 7-dimethyl-1-tetralone - Google Patents

Method for asymmetrically catalyzing and synthesizing (R)-4, 7-dimethyl-1-tetralone Download PDF

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CN105198722A
CN105198722A CN201510616896.0A CN201510616896A CN105198722A CN 105198722 A CN105198722 A CN 105198722A CN 201510616896 A CN201510616896 A CN 201510616896A CN 105198722 A CN105198722 A CN 105198722A
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methylphenyl
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tetralone
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CN105198722B (en
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钟江春
边庆花
武林
周云
李硕宁
杨燕青
王敏
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China Agricultural University
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Abstract

The invention discloses a method for asymmetrically catalyzing and synthesizing (R)-4, 7-dimethyl-1-tetralone. According to the method, an asymmetrical Kumada cross coupling reaction is conducted on racemization 2-halogenated propionate ester catalyzed by bis oxazoline/ cobalt and a methyl phenyl grignard reagent, and (S)-P-toluene propionate ester 2 is firstly generated; then, (S)-P-toluene propionate ester 2 is reduced to (S)-P-toluene propyl alcohol 3 through diisobutylaluminium hydride (DIBAL-H), and then (R)-4-p-methylphenyl-1-amylene 5 is obtained through bromine generation and coupling with and vinyl grignard reagent; next, a hydroboration-oxidation reaction and a Dess-Martin oxidizing reaction are sequentially conducted, and (R)-4-p-methylphenyl valeraldehyde 6 is obtained; finally, oxidation is conducted through silver oxide, an intramolecular Fourier acyl reaction is conducted, and (R)-4,7-dimethyl-1-tetralone is obtained in a ring-closure synthesis mode. The synthesis route is simple and concise, 8 reactions are conducted in all, the total yield is 27%, and the optical purity of a product is 90%.

Description

A kind of method of asymmetry catalysis synthesis (R)-4,7-dimethyl-ALPHA-tetralone
Technical field
The present invention relates to natural product chemistry synthesis field, be specifically related to the method for a kind of new asymmetry catalysis synthesis (R)-4,7-dimethyl-ALPHA-tetralone.
Background technology
4,7-dimethyl-ALPHA-tetralone (4,7-dimethyl-1-tetralone) is the common natural terpenoids of a class, is mainly present in (Ali, A. in the volatile oil of the plants such as the red sage root, lavandula angustifolia, cistus creticus, the fragrant tree of sincere cotton-padded mattress; Tabanca, N.; Demirci, B.; Blythe, E.K.; Ali, Z.; Baser, K.H.C.; Khan, I.A., J.Agric.FoodChem.2015,63 (2), 447 – 456.Kaiser, R.; Lamparsky, D., Helv.Chim.Acta1983,66 (6), 1843 – 1849.Weyerstahl, P.; Marschall, H.; Weirauch, M.; Thefeld, K.; Surburg, H., FlavourFragranceJ.1998,13 (5), 295 – 318.Kivcak, B.; Akay, S.; Demirci, B.; Baser, K.H.C., Pharm.Biol.2004,42 (4 – 5), 360 – 366.).The research of Imelouane etc. shows, containing 4, the Herba Lysimachiae foenumgraeci quintessence oil of 7-dimethyl-ALPHA-tetralone has oxidation resistant activity, for cancer cells such as human lymphoma cancer cells (P388D1), human glioma cells (U-373MG), there is cytotoxicity simultaneously, there is potential anti-tumor activity (Imelouane, B.; Elbachiri, A.; Wathelet, J.-P.; Dubois, J.; Amhamdi, H., WorldJ.Chem.2010,5 (2), 103 – 110.).Calendar year 2001, Asakawa etc. utilize chirality GC-MS to determine (R)-4,7-dimethyl-ALPHA-tetralone and its enantiomer are present in jointly cuts (Nagashima, F. in Ye Yetai; Asakawa, Y., Phytochemistry2001,56 (4), 347 – 352.).(R)-4,7-dimethyl-ALPHA-tetralone is found to be present in nutgrass flatsedge (Cyperusrotundus), and has antimalarial active (Thebtaranonth, C.; Thebtaranonth, Y.; Wanauppathamkul, S.; Yuthavong, Y., Phytochemistry1995,40 (1), 125 – 128.).(R) structural formula of-4,7-dimethyl-ALPHA-tetralone as shown in Equation 1, has a chiral carbon atom in molecule.
(R)-4,7-dimethyl-ALPHA-tetralone can be chiral raw material by (R)-Glycerose, obtain through polystep reaction synthesis such as Wittig reaction, Jones oxidation, Fu Shi acylations, natural terpenoids (+)-laevigatin (Chavan, the S.P. of composite structure complexity can also be further used for; Dhondge, V.D.; Patil, S.S.; Rao, Y.T.S.; Govande, C.A., Tetrahedron:Asymmetry1997,8 (15), 2517 – 2518.).Although (R)-4,7-dimethyl-ALPHA-tetralone has important physiologically active, and it is the important intermediate of other complicated natural products of synthesis.But content is little in corresponding plants, limits and bioactivity research and synthesis application research are carried out further to it.Therefore, the asymmetric synthesis studying (R)-4,7-dimethyl-ALPHA-tetralone has great importance.
Summary of the invention
The present invention aims to provide a kind of asymmetric Kumada cross-coupling reaction of bisoxazoline/cobalt catalysis that utilizes and builds chiral carbon atom, for the synthesis of the novel method of (R)-4,7-dimethyl-ALPHA-tetralone.The present invention utilizes the asymmetric Kumada cross-coupling reaction of the racemize 2-halogen propionic ester of bisoxazoline/cobalt catalysis and p-methylphenyl Grignard reagent, first generate (S)-to toluene propionic ester 2.Then use diisobutyl aluminium hydride (DIBAL-H) that ester group is reduced to alcoholic extract hydroxyl group, to obtain (S)-to mephenesin 3, then with CBr 4with PPh 3reaction generates (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4.Then react obtained (R)-4-p-methylphenyl-1-amylene 5 with vinyl Grignard reagent, terminal olefin 5 is carried out successively hydroboration-oxidation reaction and Dess-Martin oxidizing reaction, obtain (R)-4-p-methylphenyl valeral 6.Finally with silver suboxide oxidation, then in polyphosphoric acid catalyzed generation molecule Fu Shi acylation reaction, close cyclization become (R)-4,7-dimethyl-ALPHA-tetralone.Synthetic route of the present invention is simple and direct, and reaction conditions is gentle.Comprise 8 step reactions, overall yield is 27%, and product optical purity is 90%.The synthetic route of asymmetry catalysis synthesis (R)-4,7-dimethyl-ALPHA-tetralone of the present invention is see formula 2.
The method of asymmetry catalysis synthesis (R)-4,7-dimethyl-ALPHA-tetralone of the present invention comprises the steps.
(1) synthesis of (S)-to toluene propionic ester 2
Under argon shield, at cobalt salt Yu add racemic 2-halogeno-benzene propionic ester in the solution of bisoxazoline chiral ligand, stirred at ambient temperature.After being lowered the temperature by mixed solution, then add p-methylphenyl grignard reagent solution, stirring reaction.Reaction terminates rear cancellation reaction, and extraction is dry, through silica gel chromatography after concentrating under reduced pressure, obtained (S)-to toluene propionic ester 2.
(2) synthesis of (S)-to mephenesin 3
Under argon shield, at (S)-to the dichloromethane solution Zhong ， – 78 DEG C of toluene propionic ester 2, slowly add the toluene solution of diisobutyl aluminium hydride (DIBAL-H).Mixed solution is warming up to 0 DEG C and continues stirring reaction, and reaction terminates rear cancellation reaction.Extraction is dry, through silica gel chromatography after concentrating under reduced pressure, obtained (S)-to mephenesin 3.
(3) synthesis of (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4
Under room temperature, by (S)-be dissolved in methylene dichloride to mephenesin 3, triphenylphosphine and carbon tetrabromide, stirring reaction.Reaction terminates rear concentrating under reduced pressure, through silica gel chromatography, and obtained (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4.
(4) synthesis of (R)-4-p-methylphenyl-1-amylene 5
Under argon shield, in the mixture of CuI and ether, add vinyl Grignard reagent.Then at 0 DEG C, add the diethyl ether solution of (R)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4, continue stirring reaction.Reaction terminates rear cancellation reaction, and extraction is dry, through silica gel chromatography after concentrating under reduced pressure, and obtained (R)-4-p-methylphenyl-1-amylene 5.
(5) synthesis of (R)-4-p-methylphenyl valeral 6
Under argon shield, in the tetrahydrofuran solution of (S)-4-p-methylphenyl-1-amylene 5, add the tetrahydrofuran solution of 9-BBN.Stirred at ambient temperature reacts, and reaction terminates rear sodium hydroxide solution and superoxol cancellation reaction.Extraction is dry, concentrating under reduced pressure obtains (S)-4-p-methylphenyl amylalcohol crude product.Primary alconol crude product is dissolved in methylene dichloride, then adds in the dichloromethane solution of Dess-Martin oxygenant at 20 DEG C, stirring reaction.Reaction terminates rear cancellation reaction.Extraction, washing, drying, through silica gel chromatography after concentrating under reduced pressure, obtain (R)-4-p-methylphenyl valeral 6.
(6) synthesis of (R)-4-p-methylphenyl valeric acid 7
In the tetrahydrofuran (THF) of (R)-4-p-methylphenyl valeral 6 and the mixing solutions of water, add AgNO 3the aqueous solution, drips aqueous sodium hydroxide solution under room temperature, stirring reaction.Reaction terminates rear filtration, filtrate extracted with diethyl ether, and after aqueous phase as acidified, extraction is dry, through obtained (the R)-4-p-methylphenyl valeric acid 7 of silica gel chromatography after concentrating under reduced pressure.
(7) synthesis of (R)-4,7-dimethyl-ALPHA-tetralone
At 70 DEG C, added in the polyphosphoric acid of vigorous stirring by (R)-4-p-methylphenyl valeric acid 7, reaction terminates rear cancellation reaction in batches.Extraction is dry, through obtained (R)-4, the 7-dimethyl-ALPHA-tetralone of silica gel chromatography after concentrating under reduced pressure.
Embodiment
Embodiment 1
(S)-synthesis to toluene benzyl propionate 2
Under argon shield, take anhydrous CoI fast 2(0.63g, 2mmol) in 200mLSchlenk reaction flask, vacuum-drying 30min.After being cooled to room temperature, add bisoxazoline chiral ligand L1 (0.87g, 2.4mmol), inject anhydrous tetrahydro furan (15mL) with syringe, stirred at ambient temperature 1h.Then racemic 2-bromo-hydrocinnamic acid benzyl ester (4.86g, 20mmol) is added, after dropwising, by mixeding liquid temperature Jiang Zhi – 78 DEG C.(30mL, 1.0MTHF solution continues stirring reaction 8h at 30mmol) ， – 78 DEG C slowly to add p-tolylmagnesium bromide.Add saturated aqueous ammonium chloride (20mL) cancellation reaction after reaction terminates, separate organic layer.Water layer ether (3 × 20mL) extraction, merges organic layer, washs with saturated sodium-chloride water solution (20mL).Through anhydrous Na 2sO 4concentrating under reduced pressure after dry, finally uses silica gel column chromatography (petrol ether/ethyl acetate 80:1) purifying, obtained oily liquids (S)-and to toluene benzyl propionate 2 (4.48g, productive rate 88%, optical purity 92%).[α] D 20＝20.0(c1.2,CHCl 3). 1HNMR(300MHz,CDCl 3)δ7.34–7.11(m,9H),5.14(d,J＝12.5Hz,1H),5.06(d,J＝12.5Hz,1H),3.74(q,J＝7.2Hz,1H),2.33(s,3H),1.50(d,J＝7.2Hz,3H)； 13CNMR(75MHz,CDCl 3)δ174.5,137.5,136.8,136.1,129.3,128.5,128.0,127.9,127.4,66.4,45.2,21.0,18.5.HRMS(APCI-TOF)calcdforC 17H 19O 2[M+H] +255.1385,found255.1391.
The structure of bisoxazoline chiral ligand L1 is see formula 3.
Embodiment 2
(S)-synthesis to mephenesin 3
Under argon shield, with syringe by anhydrous CH 2cl 2(25mL) 100mLSchlenk reaction flask is injected, slowly add (S)-to toluene benzyl propionate 2 (3.81g, 15mmol).By mixeding liquid temperature Jiang Zhi – 78 DEG C, syringe pump is used slowly to drip diisobutyl aluminium hydride (DIBAL-H) (22mL, 1.5M toluene solution, 33mmol).At this temperature, stirring reaction 30min, is then warming up to 0 DEG C, then stirring reaction 30min.After reaction terminates, by reacting liquid temperature Jiang Zhi – 78 DEG C, react with methyl alcohol (1mL) cancellation.Then, add aqueous sodium potassium tartrate (66mL, 0.5M, 33mmol), mixeding liquid temperature is risen to room temperature, continue to stir 12h.Be separated by organic layer, water layer uses CH 2cl 2(3 × 50mL) extracts.Organic layer is merged, through anhydrous Na 2sO 4drying, with silica gel chromatography (petrol ether/ethyl acetate 5:1) after concentrating under reduced pressure, obtains colorless oil (S)-to mephenesin 3 (2.10g, productive rate 93%, optical purity 91%).[α] D 20＝–21.1(c1.3,CHCl 3). 1HNMR(300MHz,CDCl 3)δ7.14(d,J＝9.0Hz,2H),7.11(d,J＝9.0Hz,2H),3.70–3.66(m,2H),2.97–2.86(m,1H),2.33(s,3H),1.33(t,J＝6.2Hz,1H),1.26(d,J＝7.0Hz,3H)； 13CNMR(75MHz,CDCl 3)δ140.6,136.2,129.3,127.3,68.7,42.0,21.0,17.7.HRMS(APCI-TOF)calcdforC 10H 13[M-OH] +133.1017,found133.1019.
Embodiment 3
(S) synthesis of-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4
By (R)-add in 100mL reaction flask to mephenesin 3 (1.50g, 10mmol) and triphenylphosphine (3.15g, 12mmol), then add CH 2cl 2(33mL), stir.Slowly add CBr 4(3.42g, 10.3mmol), rises to room temperature by reacting liquid temperature, continues stirring reaction 4h.Concentrating under reduced pressure, except desolventizing, adds sherwood oil (40mL), suction filtration, filter residue petroleum ether, merging filtrate in resistates.Use anhydrous Na 2sO 4drying, through silica gel column chromatography (sherwood oil) purifying after concentrating under reduced pressure, obtains pale yellow oily liquid body (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4 (2.01g, productive rate 94%yield, optical purity 92%).[α] D 20＝–22.7(c1.3,CHCl 3). 1HNMR(300MHz,CDCl 3)δ7.15(d,J＝8.3Hz,2H),7.11(d,J＝8.3Hz,2H),3.58(dd,J＝9.8,6.1Hz,1H),3.46(dd,J＝9.8,8.0Hz,1H),3.17–3.04(m,1H),2.33(s,3H),1.40(d,J＝6.9Hz,3H)； 13CNMR(75MHz,CDCl 3)δ140.7,136.6,129.3,126.9,41.8,40.2,21.1,20.0.HRMS(APCI-TOF)calcdforC 10H 14Br[M+H] +213.0279,found213.0282.
Embodiment 4
(R) synthesis of-4-p-methylphenyl-1-amylene 5
Under argon shield, take anhydrous CuI (1.98g, 10.4mmol) in 200mLSchlenk reaction flask, add anhydrous diethyl ether (72mL), stir.Then mixeding liquid temperature is down to 0 DEG C, slowly drips vinyl magnesium bromide (30mL, 1.0MTHF solution, 30mmol).After dropwising, stir 10min.Then (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE 4 (2.13g, 10mmol) is carefully added with syringe, continue stirring reaction 12h.After reaction terminates, use saturated NH 4the Cl aqueous solution (20mL) cancellation is reacted, and is separated by organic layer.By ether (3 × 20mL) aqueous layer extracted, merge organic layer.With saturated NaCl solution washing organic layer, then use anhydrous Na 2sO 4dry.With silica gel column chromatography (sherwood oil) purifying after concentrating under reduced pressure, obtain colorless oil (R)-4-p-methylphenyl-1-amylene 5 (1.23g, productive rate 77%).[α] D 20＝–23.0(c0.9,CHCl 3). 1HNMR(300MHz,CDCl 3)δ7.11(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),5.78–5.64(m,1H),5.02–4.93(m,2H),2.81–2.69(m,1H),2.39–2.21(m,5H),1.23(d,J＝6.9Hz,3H)； 13CNMR(75MHz,CDCl 3)δ143.9,137.1,135.2,128.8,126.7,115.6,42.5,39.2,21.4,20.8.HRMS(APCI-TOF)calcdforC 12H 17[M+H] +161.1330,found161.1337.
Embodiment 5
(R) synthesis of-4-p-methylphenyl valeral 6
Under argon shield, 9-BBN (26mL, 0.5MTHF solution, 13mmol) solution is added in 100mLSchlenk reaction flask, mixeding liquid temperature is down to 0 DEG C.Then (R)-4-p-methylphenyl-1-amylene 5 (1.60g, 10mmol) is slowly added, then reacting liquid temperature is risen to room temperature, continue stirring reaction 3h.Then after reacting liquid temperature being down to 0 DEG C, after using syringe slowly to add the NaOH aqueous solution (5.6mL, 3M, 16.8mmol), then by 35%H 2o 2the aqueous solution (5.6mL) slowly adds, and stirs.Mixeding liquid temperature is risen to 50 DEG C, continue stirring reaction 1h.After mixed solution is cooled to room temperature, with deionized water (30mL) dilute reaction solution, organic layer is separated.With extracted with diethyl ether (3 × 40mL) water layer, organic layer is merged.Organic over anhydrous Na 2sO 4drying, concentrating under reduced pressure obtains (R)-4-p-methylphenyl amylalcohol crude product.
Take Dess-Martin oxygenant (5.09g, 12mmol) in 200mL reaction flask, add CH 2cl 2(60mL).Then, at 20 DEG C, syringe is used to add the CH being dissolved with alcohol crude product 2cl 2(24mL) solution, continues stirring reaction 30min, and reaction solution becomes muddy.Use anhydrous Et 2o (84mL) dilute reaction solution, then pours Na into 2s 2o 3.5H 2the saturated NaHCO of O (17.37g, 70mmol) 3the aqueous solution (240mL), then stir 10min.Organic layer is separated, uses saturated NaHCO successively 3the aqueous solution and deionized water wash organic layer.Use anhydrous Na 2sO 4drying, through silica gel column chromatography (petrol ether/ethyl acetate 20:1) purifying after concentrating under reduced pressure, obtains colorless oil (R)-4-p-methylphenyl valeral 6 (1.46g, 2 step reaction overall yields 83%).[α] D 20＝–25.4(c1.8,CHCl 3). 1HNMR(300MHz,CDCl 3)δ9.67(s,1H),7.11(d,J＝8.1Hz,2H),7.05(d,J＝8.1Hz,2H),2.74–2.61(m,1H),2.43–2.22(m,5H),1.99–1.78(m,2H),1.26(d,J＝6.9Hz,3H)； 13CNMR(75MHz,CDCl 3)δ202.2,142.8,135.6,129.0,126.7,42.0,38.7,30.2,22.1,20.8.HRMS(APCI-TOF)calcdforC 12H 15O[M-H] +175.1123,found175.1126.
Embodiment 6
(R) synthesis of-4-p-methylphenyl valeric acid 7
(R)-4-p-methylphenyl valeral 6 (1.76g, 10mmol) is dissolved in THF and H 2mixed solvent (30mL, the THF/H of O 2o3:1), stir.Then at room temperature AgNO is added 3(2.6g, 15.3mmol) aqueous solution (100mL), then add the 10%NaOH aqueous solution (50mL), continue stirring reaction 2h.Reaction terminates rear suction filtration, and organic layer, with ether (150mL) extraction, is separated by filtrate.At 0 DEG C, water layer concentrated hydrochloric acid is acidified to pH=3, uses CH 2cl 2(4 × 150mL) extracts, combining extraction liquid, anhydrous Na 2sO 4drying, concentrating under reduced pressure, through silica gel column chromatography (petrol ether/ethyl acetate 2:1) separation and purification, obtained faint yellow viscous liquid (R)-4-p-methylphenyl valeric acid 7 (1.21g, productive rate 63%).[α] D 20＝–28.3(c2.1,CHCl 3). 1HNMR(300MHz,CDCl 3)δ11.40(brs,1H),7.10(d,J＝8.2Hz,2H),7.06(d,J＝8.2Hz,2H),2.75–2.60(m,1H),2.31(s,3H),2.25–2.16(m,2H),1.98–1.79(m,2H),1.25(d,J＝6.9Hz,3H)； 13CNMR(75MHz,CDCl 3)δ180.1,142.8,135.6,129.0,126.7,38.7,32.8,32.1,22.1,20.8.HRMS(APCI-TOF)calcdforC 12H 17O 2[M+H] +193.1229,found193.1233.
Embodiment 7
(R) synthesis of-4,7-dimethyl-ALPHA-tetralone
In 100mL reaction flask, add polyphosphoric acid (15mL), be heated to 70 DEG C, then with vigorous stirring, (R)-4-p-methylphenyl valeric acid 7 (0.96g, 5mmol) is slowly added, reaction solution becomes orange-yellow, continues stirring reaction 2h.Reaction solution is cooled to 0 DEG C, adds deionized water (20mL), stir 30min.With extracted with diethyl ether (3 × 20mL), merge organic layer, anhydrous Na 2sO 4drying, concentrating under reduced pressure, finally by silica gel column chromatography (petrol ether/ethyl acetate 20:1) purifying, obtained yellow oily liquid (R)-4,7-dimethyl-ALPHA-tetralone (0.62g, productive rate 71%, optical purity 90%).[α] D 20＝12.8(c1.3,CHCl 3). 1HNMR(300MHz,CDCl 3)δ7.84(d,J＝1.3Hz,1H),7.34–7.21(m,2H),3.11–2.99(m,1H),2.83–2.73(m,1H),2.63–2.53(m,1H),2.36(s,3H),2.28–2.18(m,1H),1.93–1.82(m,1H),1.38(d,J＝7.0Hz,3H)； 13CNMR(75MHz,CDCl 3)δ198.4,145.9,135.9,134.3,131.5,127.1,36.3,32.3,30.6,20.7,20.5.HRMS(APCI-TOF)calcdforC 12H 15O[M+H] +175.1123,found175.1124。

Claims (8)

1. asymmetry catalysis synthesis (R)-4, the method of 7-dimethyl-ALPHA-tetralone, under it is characterized in that the coordination compound catalysis comprising the steps: that bisoxazoline chiral ligand and cobalt are formed, first there is Kumada cross-coupling reaction with p-methylphenyl Grignard reagent in racemic 2-halopropanoic acid ester, and obtained (S)-to toluene propionic ester.Then and CBr diisobutyl aluminium hydride (DIBAL-H) is used to be reduced to (S)-2-to mephenesin again, 4with PPh 3reaction generates (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE; then with the coupling of vinyl Grignard reagent; generate (R)-4-p-methylphenyl-1-amylene; carry out hydroboration-oxidation and Dess-Martin more successively and be oxidized obtained (R)-4-p-methylphenyl valeral; finally be oxidized to (R)-4-p-methylphenyl valeric acid with silver suboxide; again through Fu Shi acylation reaction, synthesis (R)-4,7-dimethyl-ALPHA-tetralone.
2. the method for asymmetric synthesis according to claim 1 (R)-4,7-dimethyl-ALPHA-tetralone, is characterized in that the method adopting asymmetry catalysis Kumada cross-coupling, as shown in the formula 1, and synthesis (S)-to toluene propionic ester:
The substituent R of above formula 1 Zhong bisoxazoline chiral ligand ' be methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, phenyl, benzyl and styroyl; Cobalt salt is CoI 2, CoBr 2, CoCl 2, Co (OAc) 2, Co (acac) 2, Co (acac) 3, Co (dppe) Cl 2with Co (PPh 3) Cl 2; The halogen atom X' of 2-halopropanoic acid ester is chlorine, bromine and iodine, and substituent R is methyl, ethyl, sec.-propyl, the tertiary butyl, bromotrifluoromethane, cyclopentyl, cyclohexyl, cyclohexyl methyl, isopentene group, phenyl and benzyl; In p-methylphenyl Grignard reagent, halogen atom X is bromine and chlorine; Product (S)-to the substituent R of toluene propionic ester is methyl, ethyl, sec.-propyl, the tertiary butyl, bromotrifluoromethane, cyclopentyl, cyclohexyl, cyclohexyl methyl, isopentene group, phenyl and benzyl.
3. asymmetric synthesis according to claim 1 (R)-4; the method of 7-dimethyl-ALPHA-tetralone; it is characterized in that synthesis (S)-be to the method for mephenesin: under argon shield; the toluene solution of diisobutyl aluminium hydride (DIBAL-H) is slowly added at – 78 DEG C in (S)-to the dichloromethane solution of toluene propionic ester; mixed solution continues stirring reaction after being warming up to 0 DEG C; reaction terminates rear cancellation reaction; extraction is dry; through silica gel chromatography after concentrating under reduced pressure, obtained (S)-2-is to mephenesin.
4. asymmetric synthesis according to claim 1 (R)-4, the method of 7-dimethyl-ALPHA-tetralone, it is characterized in that the method for synthesizing (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE is: under room temperature, (S)-2-is dissolved in methylene dichloride to mephenesin, triphenylphosphine and carbon tetrabromide, stirring reaction, reaction terminates rear concentrating under reduced pressure, through silica gel chromatography, and obtained (S)-2-p-methylphenyl-1-N-PROPYLE BROMIDE.
5. asymmetric synthesis according to claim 1 (R)-4; the method of 7-dimethyl-ALPHA-tetralone; it is characterized in that the method for synthesizing (R)-4-p-methylphenyl-1-amylene is: under argon shield; in the mixture of CuI and ether; add vinyl magnesium bromide; then at 0 DEG C; add the diethyl ether solution of (R)-2-p-methylphenyl-1-N-PROPYLE BROMIDE; continue stirring reaction; reaction terminates rear cancellation reaction; extraction is dry, through silica gel chromatography after concentrating under reduced pressure, and obtained (R)-4-p-methylphenyl-1-amylene.
6. asymmetric synthesis according to claim 1 (R)-4, the method of 7-dimethyl-ALPHA-tetralone, it is characterized in that the method for synthesizing (R)-4-p-methylphenyl valeral is: under argon shield, by the tetrahydrofuran solution of (R)-4-p-methylphenyl-1-amylene, slowly add the tetrahydrofuran solution of 9-BBN, stirred at ambient temperature reacts, reaction terminates rear sodium hydroxide solution and superoxol cancellation reaction, extraction is dry, concentrating under reduced pressure obtains (R)-4-p-methylphenyl amylalcohol crude product, primary alconol crude product is dissolved in methylene dichloride, then add at 20 DEG C in the dichloromethane solution of Dess-Martin oxygenant, stirring reaction, reaction terminates rear cancellation reaction, extraction, washing, dry, through silica gel chromatography after concentrating under reduced pressure, obtain (R)-4-p-methylphenyl valeral.
7. asymmetric synthesis according to claim 1 (R)-4, the method of 7-dimethyl-ALPHA-tetralone, it is characterized in that the method for synthesizing (R)-4-p-methylphenyl valeric acid is: in the tetrahydrofuran (THF) of (R)-4-p-methylphenyl valeral and the mixing solutions of water, add AgNO 3the aqueous solution, drips aqueous sodium hydroxide solution under room temperature, stirring reaction, and reaction terminates rear filtration, filtrate extracted with diethyl ether, and after aqueous phase as acidified, extraction is dry, through obtained (the R)-4-p-methylphenyl valeric acid of silica gel chromatography after concentrating under reduced pressure.
8. asymmetric synthesis according to claim 1 (R)-4; the method of 7-dimethyl-ALPHA-tetralone; it is characterized in that through Fu Shi acylation reaction synthesis (R)-4; the method of 7-dimethyl-ALPHA-tetralone is: at 70 DEG C; (R)-4-p-methylphenyl valeric acid is added in the polyphosphoric acid of vigorous stirring in batches; reaction terminates rear cancellation reaction; extraction is dry; through obtained (R)-4, the 7-dimethyl-ALPHA-tetralone of silica gel chromatography after concentrating under reduced pressure.
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