CN104788462B - Chiral polysubstituted 4-hydroxychroman compound, and preparation method and application thereof - Google Patents

Chiral polysubstituted 4-hydroxychroman compound, and preparation method and application thereof Download PDF

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CN104788462B
CN104788462B CN201410030609.3A CN201410030609A CN104788462B CN 104788462 B CN104788462 B CN 104788462B CN 201410030609 A CN201410030609 A CN 201410030609A CN 104788462 B CN104788462 B CN 104788462B
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hydroxychroman
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CN104788462A (en
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王梅祥
王德先
何玲
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Institute of Chemistry CAS
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Abstract

The invention discloses a chiral polysubstituted 4-hydroxychroman compound, and a preparation method and application thereof. The compound has a general structural formula as shown in a formula I which is described in the specification. The preparation method comprises a step of subjecting a salicylaldehyde compound as shown in a general structural formula II and a tertiary alkenyl amide as shown in a general structural formula III to an intermolecular nucleophilic tandem reaction in the presence of a chiral Lewis acid catalyst so as to realize high-efficiency high-selectivity preparation of the chiral polysubstituted 4-hydroxychroman compound. According to the method, the raw material alkenyl amide which can be easily prepared on large scale and the cheap and easily available chiral catalyst are used, and the novel chiral polysubstituted 4-hydroxychroman bicyclo derivative product which cannot be synthesized by using other methods is prepared under mild reaction conditions; and the produce has a stable structure, high yield and enantioselectivity and good application prospects and can be easily separated and purified.

Description

Chiral polysubstituted 4- hydroxychroman class compound and preparation method and application
Technical field
The present invention relates to a kind of chiral polysubstituted 4- hydroxychroman class compound and preparation method and application.
Background technology
Chiral 4- hydroxychroman skeleton is widely present in the Structures of Natural Products with biological activity.For example Myrochromanol(Tamm,C.Helv.Chim.Acta.1972,55,510-518.),Erythrostominon(Cross, B.E.J.Chem.Soc.,Perkins Trans.I,1972,380.),Perinadine A(Kobayashi, J.Org.Chem.2005,7,4261-4264.).Additionally, it can also participate in a series of differences as organic reaction intermediate Chemical conversion (Showell, G.A.J.Med.Chem.1984,27,1127-1131.;Ellis,G.P.,Chromenes, Chromanones, and Chromones, John Wiley＆Sons Ltd, New York, 1977.), many by this composite structure The nitrogen-containing heterocycle compound of sample or natural product.
For the synthesis of 4- hydroxychroman class compound, existing synthetic method mainly include 4- chromanone reduction or with Grignard reagent is reacted, the hydrolysis of 4- halo chromane and the necleophilic reaction of salicylide etc. (Ellis, G.P., Chromenes, Chromanones,and Chromones,John Wiley&Sons Ltd,New York,1977.;Paquette, L.A.J.Org.Chem.,1966,31,1232-1235.;Dean,F.M.,J.Chem.Soc.,Perkins Trans.I, 1982,11,2771-2775.;Noyori,R.,J.Am.Chem.Soc.,2006,128,8724-8725.).But existing synthesis Method still has low yield, raw material preparation complexity, and is not effectively realized direct stereoselective syntheses 4- hydroxyl The method of chroman compound, the synthetic method therefore developing new chiral 4- hydroxychroman structure is necessary.
Content of the invention
It is an object of the invention to provide a kind of chiral polysubstituted 4- hydroxychroman class compound and preparation method and application.
The chirality polysubstituted 4- hydroxychroman class compound that the present invention provides, its general structure is as shown in formula I：
In described Formulas I general structure, * represents chirality, is R or S；
In described Formulas I general structure, * represents chirality, is R or S；
R1、R2、R3、R4And R5It is selected from any one in following radicals：Hydrogen atom, C1-C3Alkyl, methoxyl group, benzyloxy Base（Namely-OBn）, phenyl, the phenyl containing substituent group, cyano group, fluorine, chlorine, bromine, the alkoxy carbonyl of C1-C5 and (methylenedioxy) Base；
In the described phenyl containing substituent group, substituent group is selected from least one in chlorine and methoxyl group；
N represents the number of carbon atom, is 0,1 or 2.
Described C1-C3Alkyl is specially methyl, ethyl, n-pro-pyl or isopropyl；
The alkoxy carbonyl of described C1-C5 is specially in methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl at least A kind of；
The method preparing above-mentioned chiral polysubstituted 4- hydroxychroman class compound that the present invention provides, comprises the steps：
Under conditions of chiral lewis acid catalyst exists, by bigcatkin willow aldehyde compound and formula shown in formula II general structure There is intramolecular nucleophilic cascade reaction in three-level acrylamide shown in III general structure, reaction finish obtain shown in described formula I chiral many Replace 4- hydroxychroman class compound；
In described formula II and formula III general structure, R1、R2、R3、R4And R5Define identical with the definition in aforementioned Formulas I；
N is 0,1 or 2.
In said method, react the intramolecular nucleophilic cascade reaction for bigcatkin willow aldehyde compound and three-level acrylamide, reaction Equation is as follows：
In the method, compound shown in formula III general structure is acrylamide compound, can be according to following document reports Method is prepared in a large number：Nomura,Y.Chem.Lett.1977,693-696;Kraus,G.A.J.Org.Chem.1981,46, 4791-4792.;Marais,W.Synth.Commun.1998,28,3681-3691..
In the method, described chirality lewis acid catalyst is double oxazoline pyridine-tin complex catalyst shown in formula IV Or chiral binaphthol-titanium complex catalyst shown in formula V or formula VI or formula VII：
In described formula IV, R1'For isopropyl or phenyl, R2'For chlorine or trifluoromethanesulfonic acid root anion；
In described formula V, formula VI and formula VII, R is isopropyl.
The consumption of described chirality lewis acid catalyst is the mole dosage of compound shown in described formula III general structure 0.1%-200%, preferably 5-50%, more specifically 10%.
The product good in order to obtain optical purity, can add additive in reaction system, and described additive is chosen in particular from Water, phenol, ethanol, methanol,Molecular sieve,Molecular sieve,At least one in molecular sieve and sodium carbonate.
In described intramolecular nucleophilic cascade reaction step, temperature is -40 to 110 DEG C, specially -10 DEG C to 60 DEG C, more Body is 40 DEG C；
Time be 30 minutes -168 hours, specially 30 minutes -48 hours, more specifically 1 hour, 2 hours, 3 hours, 5 Hour, 6 hours, 17 hours, 24 hours, 120 hours, 168 hours, 1-168 hour, 1-120 hour, 2-168 hour, 2-120 Hour, 1-24 hour, 2-17 hour, 5-120 hour or 5-168 hour.
Described intramolecular nucleophilic cascade reaction is carried out in a solvent；Described solvent is chosen in particular from dichloromethane, trichlorine Methane, carbon tetrachloride, benzene, toluene, o-Dimethylbenzene, meta-xylene, xylol, sym-trimethylbenzene., ether, oxolane, Isosorbide-5-Nitrae- In dioxane, acetonitrile, propionitrile, dimethyl sulfoxide, DMF, N,N-dimethylacetamide and water at least one Kind.
The chiral polysubstituted 4- hydroxychroman class compound shown in Formulas I that the invention described above provides is in preparing antibacterial product Application, falls within protection scope of the present invention.Wherein, described bacterium is selected from staphylococcus aureuses, staphylococcus epidermidiss, hay bar At least one in bacterium and escherichia coli.
The present invention is from easily a large amount of raw material acrylamides prepared, bigcatkin willow aldehyde compound cheap and easy to get and chiral catalysis Agent, makes raw material acrylamide, with bigcatkin willow aldehyde compound, intermolecular reaction occur, a step is efficiently prepared chiral polysubstituted 4- hydroxyl Base chroman compound, reaction condition is gentle, and the yield of product is very high and enantioselectivity is very high, and products therefrom is in air In stable and easily separated purification, there is good application prospect.
The present invention from the raw material three-level acrylamide being easy to get, by the molecule with cheap and easily-available bigcatkin willow aldehyde compound Between necleophilic reaction, under chiral Louis acid catalysis, can be simple and effective obtain multi-substituted chiral 4- hydroxychroman compound.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Institute Method of stating is conventional method if no special instructions.Described raw material all can obtain from open commercial sources if no special instructions.
Chirality polysubstituted 4- chroman compound shown in embodiment 1, formula Ia general structure（R1To R4For hydrogen, R5For Phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, add magneton in drying, clean reaction tube, replace system hollow gas with argon, successively Injection adds the salicylide shown in formula II a structure（122mg, 1.0mmol）The o-Dimethylbenzene solvent that is dried of 0.6mL sodium and in situ Chiral binaphthol-titanium complex catalyst (2mL, 0.025mol/L) shown in the Formula V preparing, is placed in stirring under 40 DEG C of oil baths 0.5 hour, add the o-Dimethylbenzene solvent that the 0.4mL sodium of three-level acrylamide (87mg, 0.50mmol) shown in formula III a is dried, Temperature of reaction system is kept to be 40 DEG C, after reacting 17 hours, thin-layer chromatographic analysis display raw material III a consumes completely.To reaction system Middle addition 20mL saturated sodium bicarbonate solution is quenched reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturation is eaten Salt water washing（25ml × 1 time）, anhydrous sodium sulfate drying, after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column layer Analysis, acetone and petroleum ether mixed solvent（1：3）Drip washing.Separate to obtain the compound 145mg shown in formula I a structure, yield 98%, nuclear-magnetism Hydrogen spectrum shows that cis-selectivity is>20:1.Chirality can be carried out using high performance liquid chromatography ADH post to compound shown in I a structure Split, result shows that the enantioselectivity of the compound shown in I a structure is 96.5%.
This product is solid；
Fusing point mp：147-149℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.84(d,J=6.8Hz,2H),7.39-7.48(m,3H),7.24- 7.31(m,2H),6.94-6.98(m,2H),5.61(d,J=3.6Hz,1H),4.68(d,J=1.2Hz,1H),3.80-3.88(m, 1H),3.66-3.72(m,1H),2.59-2.63(m,1H),2.19(br,1H),2.06-2.13(m,1H), 1.59-1.71(m, 1H)；
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,151.6,135.6,130.7,130.6,129.9, 128.3,127.9,121.5,120.5,117.2,83.6,65.8,45.3,45.0,23.8；
IR(KBr,ν/cm-1)3382,1620,1434,1222cm-1;
MS(CI)m/z(%)295[M]+(8),77(31),105(100),173(41),277(17);
Anal.Calcd.for C18H17NO3:C,73.20;H,5.80;N,4.74.Found:C,73.45;H,5.85;N, 4.72.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I a.
Wherein, it is to make as follows as binaphthol-titanium complex catalyst chiral shown in the formula V of reactant Standby and obtain：Sequentially add magneton, R type binaphthol in drying, clean 10mL single port bottle（28.7mg, 0.1mmol）, add The o-Dimethylbenzene 2mL that sodium is dried, sequentially adds water after dissolving completely（1.8 μ L, 0.1mmol）And tetraisopropoxy titanium （14.3mg, 0.05mmol）, solution is changed into peony at once.Under room temperature, reaction prepares handss shown in Formula V after 2 hours in situ Property binaphthol-titanium complex catalyst, this catalyst need not isolate and purify, you can be directly catalyzed the reaction of next step.
Shown in formula III a, the preparation method of compound is as follows：
NaOH solid is sequentially added in 250mL round-bottomed flask（4.0g,100mmol）, H2O（50mL）, AgNO3 (42.2mg, 0.25mmol) and pyrrolidine（3.6g,50mmol）, reaction bulb is placed in 0 DEG C of ice bath, is slowly added dropwise 25%Na2S2O8 The aqueous solution of (11.9g, 50mmol)（35mL）.Completion of dropping, after continuing to react 30min at 0 DEG C, adds dichloromethane extraction （50mL × 3 time）, merge organic faciess, saturated common salt water washing（50mL × 1 time）, anhydrous sodium sulfate drying.Under room temperature after filtration It is spin-dried for solvent, obtain pyrrolin trimer（Yellow oil）, directly carry out next step reaction.
Under argon protection, in 250mL there-necked flask, sequentially add DIPEA (diisopropylethylamine, 6.5g, 50mmoL), be dried Toluene（25mL）With PhCOCl (7.1g, 50mmol), the toluene of the pyrrolin trimer of Deca previous step preparation under room temperature Solution（75mL）.After completion of dropping, reaction temperature is risen to 80 DEG C, and continue reaction 30min at this temperature.Reaction finishes, Add water（30mL）Reaction is quenched, organic faciess add water（50mL × 3 time）Washing, saturated aqueous common salt（30mL × 1 time）Washing, anhydrous Sodium sulfate is dried.After filtration, it is spin-dried for removing solvent, Et3100-200 mesh silica gel column chromatography, ethyl acetate and the petroleum ether of N deactivation Mixed solvent（1：3）Drip washing, separates to obtain compound 3.3g shown in formula III a, yield 38%.
Embodiment 2, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I b general structure（R1For hydrogen, R2For Fluorine, R3、R4For hydrogen, R5For phenyl）
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- fluorine salicylide shown in II b （140mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 2 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 143mg shown in formula I b structure, yield 91%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I b structure, result shows the chemical combination shown in I b structure The enantioselectivity of thing is 97.9%.
This product is solid；
Fusing point mp：148-149℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.76(d,J=7.2Hz,2H),7.36-7.45(m,3H),6.93- 6.98(m,2H),6.84-6.88(m,1H),5.52(d,J=4.4Hz,1H),4.52(s,1H),3.56-3.74(m,3H), 2.46-2.49(m,1H),1.97-2.04(m,1H),1.52-1.63(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.9,157.1(d,J=238.4Hz),147.3,135.3, 130.8,128.3,127.8,121.9(d,J=6.7Hz),118.2(d,J=7.6Hz),117.1(d,J=23.8Hz),115.8 (d,J=22.8Hz),83.8,65.2,45.4,44.9,23.8;
IR(KBr,ν/cm-1)3383,1626,1492,1419,1208cm-1;
MS(CI)m/z(%)313[M]+(5),105(100),173(32),295(30;
Anal.Calcd.for C18H16FNO3:C,69.00;H,5.15;N,4.47.Found:C,68.93;H,5.30;N, 4.65.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I b.
Embodiment 3, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I c general structure（R1For hydrogen, R2For Bromine, R3、R4For hydrogen, R5For phenyl）
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromosalicylaldehyde shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 3 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 176mg shown in formula I c structure, yield 94%, nucleus magnetic hydrogen spectrum display cis-selectivity is>99:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I c structure, result shows the chemical combination shown in I c structure The enantioselectivity of thing is 97.8%.
This product is solid；
Fusing point mp：171-173℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.81(d,J=7.2Hz,2H),7.36-7.49(m,5H),6.83- 6.86(m,1H),5.61(d,J=3.2Hz,1H),4.64(s,1H),3.80-3.88(m,1H),3.66-3.71(m,1H), 2.60-2.64(m,1H),2.29(br,1H),2.07-2.14(m,1H),1.56-1.67(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,150.8,135.5,133.4,132.5,130.8, 128.3,127.9,122.5,119.2,113.2,83.9,65.5,45.1,45.0,23.7;
IR(KBr,ν/cm-1)3297,1615,1475,1428,1221;
MS(CI)m/z(%)373[M]+(2),375[M+2]+(3),77(28),105(100),173(35);
Anal.Calcd.for C18H16BrNO3:C,57.77;H,4.31;N,3.74.Found:C,57.42;H,4.33; N,3.63.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I c.
Embodiment 4, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I d general structure（R1For hydrogen, R2For Chlorine, R3、R4For hydrogen, R5For phenyl）
This reaction equation is as follows:
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- chloro-salicylic aldehyde shown in II d （157mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 3 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 141mg shown in formula I d structure, yield 86%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I d structure, result shows the chemical combination shown in I d structure The enantioselectivity of thing is 96.5%.
This product is solid；
Fusing point mp：172-174℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.80(d,J=7.2Hz,2H),7.39-7.48(m,3H),7.21- 7.24(m,2H),6.87-6.90(m,1H),5.60(d,J=4.0Hz,1H),4.62(d,J=1.6Hz,1H),3.77-3.85(m, 1H),3.64-3.69(m,1H),2.58-2.61(m,1H),2.50(br,1H),2.05-2.12(m,1H),1.55-1.66(m, 1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,150.2,135.4,130.8,130.4,129.6, 128.3,127.8,126.0,122.0,118.7,83.9,65.4,45.2,45.0,23.7;
IR(KBr,ν/cm-1)3299,1617,1478,1415,1221;
MS(CI)m/z(%)329[M]+(5),105(100),173(39),311(19);
Anal.Calcd.for C18H16ClNO3:C,65.56;H,4.89;N,4.25.Found:C,65.24;H,5.03; N,4.08.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I d.
Embodiment 5, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I e general structure（R1For hydrogen, R2For Cyano group, R3、R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- cyano group salicylide shown in II e （147mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 3 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 146mg shown in formula I e structure, yield 91%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I d structure, result shows the chemical combination shown in I d structure The enantioselectivity of thing is 96.1%.
This product is solid；
Fusing point mp：206-208℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.76(d,J=7.6Hz,2H),7.40-7.59(m,5H),7.00 (d,J=8.8Hz,1H),5.69(d,J=4.0Hz,1H),4.67(s,1H),3.77-3.85(m,1H),3.64-3.69(m,1H), 3.41(br,1H),2.64-2.67(m,1H),2.07-2.14(m,1H),1.49-1.60(m,1H)；
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.9,155.4,135.1,135.0,134.1,131.0, 128.4,127.7,121.8,118.8,118.4,104.4,84.6,64.7,45.0,44.9,23.6;
IR(KBr,ν/cm-1)3299,2223,1609,1491,1418,1229;
MS(CI)m/z(%)320[M]+(10),77(33),105(100),173(43);
HRMS Calcd for C19H16N2O3[M+1]+321.1234,found321.1232.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I e.
Embodiment 6, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I f general structure（R1For hydrogen, R2For Methoxycarbonyl, R3、R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- methoxycarbonyl water shown in II f Poplar aldehyde（180mg,1.0mmol）, replace system hollow gas with argon, injection adds chiral di- shown in the Formula V preparing in situ Naphthols-titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of three-level acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, After reacting 5 hours, thin-layer chromatographic analysis display raw material III a consumes completely.Add 20mL saturated sodium bicarbonate molten in reaction system Liquid is quenched reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous Sodium sulfate is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1： 3）Drip washing.Separate to obtain the compound 165mg shown in formula I f structure, yield 93%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20: 1.Chiral separation can be carried out using high performance liquid chromatography ADH post to compound shown in I f structure, result shows shown in I f structure The enantioselectivity of compound is 97.0%.
This product is solid；
Fusing point mp：175-176℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.98(s,1H),7.94(d,J=8.4Hz,1H),7.80(d,J= 7.2Hz,2H),7.40-7.48(m,3H),6.96(d,J=8.8Hz,1H),5.69(d,J=3.6Hz,1H),4.72(s,1H), 3.79-3.90(m,4H),3.65-3.71(m,1H),2.92(br,1H),2.64-2.67(m,1H),2.06-2.13(m,1H), 1.51-1.62(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.8,166.5,155.7,135.4,132.4,132.0, 130.8,128.4,127.8,123.2,120.4,117.2,84.4,65.3,52.1,45.0,44.9,23.6;
IR(KBr,ν/cm-1)3341,1712,1614,1416cm-1;
MS(CI)m/z(%)353[M]+(10),77(42),105(100),173(70);
HRMS calcd for C20H19NO5[M+1]+354.1336,found354.1336.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in Formulas I f.
Embodiment 7, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I g structure formula（R1For hydrogen, R2For Bromine, R3For hydrogen, R4For bromine, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 3,5- Dibromosalicylaldehyde shown in II g （280mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 2 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 202mg shown in formula I g structure, yield 89%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I g structure, result shows the chemical combination shown in I g structure The enantioselectivity of thing is 95.1%.
This product is solid；
Fusing point mp：217-219℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.94(d,J=6.8Hz,2H),7.67(d,J=2.4Hz,1H), 7.41-7.50(m,3H),7.35(d,J=2.4Hz,1H),5.61(d,J=4.4Hz,1H),4.66(s,1H),3.79-3.86(m, 1H),3.69-3.74(m,1H),2.63-2.66(m,1H),2.43(br,1H),2.09-2.16(m,1H),1.56-1.68(m, 1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)171.2,147.8,136.1,135.3,131.7,130.9, 128.3,128.1,123.7,113.1,112.2,84.8,65.5,45.2,45.1,23.7;
IR(KBr,ν/cm-1)3399,1626,1449,1416,1227cm-1;
MS(CI)m/z(%)453[M]+(4),77(44),105(100),173(57);
Anal.Calcd.for C18H15Br2NO3:C,47.74;H,3.34;N,3.09.Found:C,47.68;H,3.39; N,3.06.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I g.
Embodiment 8, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I h general structure（R1For chlorine, R2For Hydrogen, R3For chlorine, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 4,6- dichloro-salicylaldehyde shown in II h （191mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 2 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 165mg shown in formula I h structure, yield 90%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I h structure, result shows the chemical combination shown in I h structure The enantioselectivity of thing is 96.0%.
This product is solid；
Fusing point mp：161-163℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.78(d,J=7.2Hz,2H),7.41-7.50(m,3H),7.03 (d,J=2.0Hz,1H),6.92(d,J=2.0Hz,1H),5.62(d,J=4.0Hz,1H),4.96(s,1H),3.81-3.89(m, 1H),3.67-3.72(m,1H),2.65-2.68(m,2H),2.10-2.16(m,1H),1.53-1.64(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.6,153.2,135.7,135.5,135.3,130.9, 128.4,127.8,122.2,117.4,116.5,84.0,62.6,44.8,44.3,23.5;
IR(KBr,ν/cm-1)3405,1630,1595,1567,1404,1224cm-1;
MS(CI)m/z(%)364[M]+(0.5),365[M+1]+(1),77(29),105(100),173(70);
Anal.Calcd.for C18H15Cl2NO3:C,59.36;H,4.15;N,3.85.Found:C,59.37;H,4.21; N,3.76.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I h.
Embodiment 9, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I i general structure（R1For hydrogen, R2For Phenyl, R3For hydrogen, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- phenyl salicylic aldehyde shown in II i （198mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 6 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 184mg shown in formula I i structure, yield 99%, nucleus magnetic hydrogen spectrum display cis-selectivity is>99:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I i structure, result shows the chemical combination shown in I i structure The enantioselectivity of thing is 98.2%.
This product is solid；
Fusing point mp：197-198℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.86(d,J=7.2Hz,2H),7.52-7.54(m,3H),7.40- 7.49(m,6H),7.30-7.34(m,1H),7.03(d,J=8.4Hz,1H),5.65(d,J=3.6Hz,1H),4.75(d,J= 2.0Hz,1H),3.83-3.90(m,1H),3.69-3.74(m,1H),2.63-2.66(m,1H),2.09-2.16(m,2H), 1.64-1.76(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,151.2,140.2,135.6,134.8,130.7, 129.3,128.8,128.5,128.3,127.9,127.0,126.7,120.8,117.7,83.9,66.0,45.4,45.0, 23.8;
IR(KBr,ν/cm-1)3383,1615,1482,1407,1223cm-1;
MS(CI)m/z(%)371[M]+(2),105(100),173(39),353(32);
Anal.Calcd.for C24H21NO3:C,77.61;H,5.70;N,3.77.Found:C,77.57;H,5.75;N, 3.65.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I i.
The preparation of compound shown in formula II i is as follows：
Under argon protection, in 250mL there-necked flask, sequentially add 5- bromosalicylaldehyde（4.0g,20mmol）, PhB (OH)2 (2.4g,20mmol),K2CO3(6.9g, 50mmol), the toluene being dried（100mL）With EtOH (20mL), under room temperature, add Pd (PPh3)4(2.3g, 2mmol), after continuing reaction 30min at this temperature, reaction temperature is risen to 75-80 DEG C, and in this temperature After lower reaction 2h, thin layer chromatography display 5- bromosalicylaldehyde converts completely.Rotary evaporation removes solvent, adds ethyl acetate （100mL）, add water（30mL × 3 time）Washing, organic faciess saturated aqueous common salt（30mL × 1 time）Washing, anhydrous sodium sulfate drying, mistake Filter vacuum distillation removes solvent, 100-200 mesh silica gel column chromatography, ethyl acetate and petroleum ether mixed solvent（1：20）Drip washing, point From obtaining compound 3.1g shown in formula II i, yield 78%.
Embodiment 10, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I j general structure（R1For hydrogen, R2 For methyl, R3For hydrogen, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- cresotinic acid aldehyde shown in II j （136mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 17 hours, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added in reaction system Reaction is quenched.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous sulfur Sour sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3） Drip washing.Separate to obtain the compound 142mg shown in formula I j structure, yield 92%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1. Using high performance liquid chromatography ADH post, compound shown in I j structure can be carried out with chiral separation, result shows the change shown in 1j structure The enantioselectivity of compound is 97.1%.
This product is solid；
Fusing point mp：153-155℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.84(d,J=7.2Hz,2H),7.39-7.48(m,3H),7.09 (d,J=8.4Hz,1H),7.05(s,1H),6.85(d,J=8.4Hz,1H),5.58(d,J=3.2Hz,1H),4.64(s,1H), 3.81-3.88(m,1H),3.67-3.72(m,1H),2.57-2.61(m,1H),2.29(s,3H),2.06-2.13(m,2H), 1.60-1.71(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,149.3,135.6,131.3,130.9,130.7, 130.0,128.3,127.9,120.2,117.0,83.6,65.9,45.5,45.0,23.8,20.5;
IR(KBr,ν/cm-1)3348,1624,1496,1415,1215cm-1;
MS(CI)m/z(%)309[M]+(2),77(46),105(100),173(29),291(17);
Anal.Calcd.for C19H19NO3:C,73.77;H,6.19;N,4.53.Found:C,73.66;H,6.21;N, 4.55.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I j.
Embodiment 11, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I k general structure（R1For hydrogen, R2 For hydrogen, R3For bromine, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 4- bromosalicylaldehyde shown in II l （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 6 After hour, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3） Drip washing.Separate to obtain the compound 186mg shown in formula I k structure, yield 99%, nucleus magnetic hydrogen spectrum display cis-selectivity is 15:1. Using high performance liquid chromatography ADH post, compound shown in I k structure can be carried out with chiral separation, result shows the change shown in 1k structure The enantioselectivity of compound is 95.3%.
This product is solid；
Fusing point mp：190-191℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.77(d,J=6.8Hz,2H),7.39-7.48(m,3H),7.05- 7.12(m,3H),5.59(d,J=4.0Hz,1H),4.60(s,1H),3.74-3.81(m,1H),3.61-3.67(m,1H),2.69 (br,1H),2.56-2.59(m,1H),2.03-2.09(m,1H),1.52-1.63(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.8,152.3,135.3,131.3,130.8,128.3, 127.8,124.6,123.5,120.3,119.5,83.9,65.1,45.2,45.0,23.7;
IR(KBr,ν/cm-1)3401,1626,1599,1576,1403,1214,956cm-1;
MS(CI)m/z(%)373[M]+(3),375[M+2]+(4),77(34),105(100),173(45);
Anal.Calcd.for C18H16BrNO3:C,57.77;H,4.31;N,3.74.Found:C,57.42;H,4.33; N,3.63.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I k.
Embodiment 12, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I l general structure（R1For hydrogen, R2 For hydrogen, R3For methoxyl group, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 4-methoxysalicylaldehyde shown in II m （152mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III a The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (87mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 168 hours, thin-layer chromatographic analysis display raw material III a consumes completely.20mL saturated sodium bicarbonate solution is added in reaction system Reaction is quenched.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous sulfur Sour sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1： 3）Drip washing.Separate to obtain the compound 63mg shown in formula I l structure, yield 39%, nucleus magnetic hydrogen spectrum display cis-selectivity is 9:1. Using high performance liquid chromatography ADH post, compound shown in I l structure can be carried out with chiral separation, result shows the change shown in 1l structure The enantioselectivity of compound is 51.2%.
This product is solid；
Fusing point mp：154-156℃；
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.83(d,J=7.6Hz,2H),7.40-7.48(m,3H),7.13 (d,J=8.4Hz,1H),6.53(d,J=8.8Hz,1H),6.46(s,1H),5.60(d,J=3.2Hz,1H),4.62(s,1H), 3.81-3.86(m,4H),3.65-3.70(m,1H),2.55-2.58(m,1H),2.36(br,1H),2.03-2.10(m,1H), 1.57-1.68(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,161.4,152.7,135.6,130.8,130.7, 128.3,127.9,112.9,108.7,101.5,83.8,65.3,55.4,45.4,45.0,23.7;
IR(KBr,ν/cm-1) 3335,1624,1417,1102cm-1;
MS(CI)m/z(%)325[M]+(10),105(86),173(100),307(38);
HRMS calcd for C19H19NO4[M+1]+326.1387,found326.1387.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I l.
Embodiment 13, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I m general structure（R1For hydrogen, R2 And R3For methylene-dioxy, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 4,5- methylene-dioxy shown in II n Salicylide（166mg,1.0mmol）, replace system hollow gas with argon, injection adds chiral connection shown in the Formula V preparing in situ Bisnaphthol-titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add formula III a institute Show the o-Dimethylbenzene solvent that the 1.0mL sodium of three-level acrylamide (87mg, 0.50mmol) is dried, keep temperature of reaction system to be 40 DEG C, after reacting 24 hours, thin-layer chromatographic analysis display raw material III a consumes completely.20mL unsaturated carbonate hydrogen is added in reaction system Sodium solution is quenched reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, Anhydrous sodium sulfate drying, rotary evaporation removing solvent after filtration, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixing are molten Agent（1：3）Drip washing.Separate to obtain the compound 46mg shown in formula I m structure, yield 27%, nucleus magnetic hydrogen spectrum display cis-selectivity is 9:1.Using high performance liquid chromatography ADH post, compound shown in I m structure can be carried out with chiral separation, shown in result display 1m structure Compound enantioselectivity be 81.9%.
This product is solid；
Fusing point mp:99-100℃;
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.80(d,J=7.2Hz,2H),7.39-7.47(m,3H),6.67 (s,1H),6.46(s,1H),5.92(s,1H),5.91(s,1H),5.51(d,J=3.6Hz,1H)),4.55(s,1H),3.77- 3.84(m,1H),3.65-3.70(m,1H),2.51-2.54(m,2H),2.04-2.11(m,1H),1.60-1.72(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.7,149.2,146.8,142.5,135.9,130.6, 128.3,127.9,112.8,108.0,101.4,98.9,83.8,66.1,45.8,45.1,24.1;
IR(KBr,ν/cm-1)3397,1626,1481,1415,1145cm-1;
MS(CI)m/z(%)339[M]+(10),41(100),105(99),173(65),321(58);
HRMS calcd for C19H19NO4[M+1]+340.1179,found340.1177.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I m.
The preparation of compound shown in formula II m is as follows：
Sesamol is added in 100mL round-bottomed flask（4.1g,30mmol）With DMF (24mL), after being completely dissolved, it is placed in 0 DEG C of ice After the lower cooling of bath, it is slowly added dropwise POCl3(16mL).Completion of dropping, reaction temperature rises to 100 DEG C, and continues anti-at this temperature Answer 1 hour.After cooling, reactant mixture is poured in 250mL saturation sodium acetate solution, be heated to 100 DEG C and react 45 minutes, cold But, after, add dichloromethane extraction（100mL × 3 time）, organic faciess saturated aqueous common salt（100mL × 3 time）Washing, anhydrous sodium sulfate It is dried, filter vacuum distillation and remove solvent, 100-200 mesh silica gel column chromatography, ethyl acetate and petroleum ether mixed solvent（1：20） Drip washing, separates and obtains compound 3.0g shown in formula II m, yield 61%.
Embodiment 14, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I n general structure（R1For hydrogen, R2 For bromine, R3For hydrogen, R4For hydrogen, R5For 4- chlorophenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromomethyl salicylide shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III b The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (104mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 4 hours, thin-layer chromatographic analysis display raw material III b consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 194mg shown in formula I n structure, yield 95%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Compound shown in I n structure can be carried out with high performance liquid chromatography ADH post with chiral separation, result shows the chemical combination shown in 1n structure The enantioselectivity of thing is 99.2%.
This product is solid；
Fusing point mp:212-214℃;
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.77(d,J=8.4Hz,2H),7.37-7.42(m,4H),6.82- 6.84(m,1H),5.58(d,J=3.2Hz,1H),4.65(s,1H),3.77-3.85(m,1H),3.64-3.69(m,1H), 2.61-1.65(m,1H),2.40(br,1H),2.07-2.14(m,1H),1.55-1.67(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)169.6,150.6,137.0,133.7,133.4,132.5, 129.4,128.6,122.5,119.1,113.3,83.9,65.3,45.1,45.0,23.7;
IR(KBr,ν/cm-1)3368,1618,1476,1420,1220cm-1;
MS(CI)m/z(%)407[M]+(2),409[M+2]+(2),111(25),139(100),141(34),207(33), 209(14);
Anal.Calcd.for C18H15BrClNO3:C,52.90;H,3.70;N,3.43.Found:C,53.15;H, 3.70;N,3.42.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I n.
Shown in formula III b, the preparation method of compound is as follows：
NaOH solid is sequentially added in 250mL round-bottomed flask（4.0g,100mmol）, H2O（50mL）, AgNO3(42.2mg, 0.25mmol) and pyrrolidine（3.6g,50mmol）, reaction bulb is placed in 0 DEG C of ice bath, is slowly added dropwise 25%Na2S2O8(11.9g, Aqueous solution 50mmol)（35mL）.Completion of dropping, after continuing to react 30min at 0 DEG C, adds dichloromethane extraction（50mL× 3 times）, merge organic faciess, saturated common salt water washing（50mL × 1 time）, anhydrous sodium sulfate drying.After filtration room temperature backspin do molten Agent, obtains pyrrolin trimer（Yellow oil）, directly carry out next step reaction.
Under argon protection, in 250mL there-necked flask, sequentially add DIPEA (diisopropylethylamine, 6.5g, 50mmoL), be dried Toluene（25mL）With 4-ClPhCOCl (8.8g, 50mmol), the pyrrolin trimer of Deca previous step preparation under room temperature Toluene solution（75mL）.After completion of dropping, reaction temperature is risen to 80 DEG C, and continue reaction 30min at this temperature.React Finish, add water（30mL）Reaction is quenched, organic faciess add water（50mL × 3 time）Washing, saturated aqueous common salt（30mL × 1 time）Washing, Anhydrous sodium sulfate drying.After filtration, it is spin-dried for removing solvent, Et3100-200 mesh silica gel column chromatography, ethyl acetate and the stone of N deactivation Oily ether mixed solvent（1：3）Drip washing, separates to obtain compound 3.6g shown in formula III b, yield 35%.
This product is grease；
1H NMR(400MHz,DMSO-d6,120℃,TMS)δ(ppm)7.48-7.54(m,4H),6.60(s,1H),5.29- 5.32(m,1H),3.85-3.89(m,2H),2.64-2.69(m,2H).
13C NMR(100MHz,DMSO-d6,80℃,TMS)δ(ppm)165.2,135.5,135.2,130.6,129.8, 129.0,112.5,46.5,28.9.
IR(KBr,ν/cm-1)3059,2949,1610,1432,847,832.
MS(CI)207[M]+(10),111(35),139(100).
Anal.Cacld.for C11H10ClNO:C,63.62;H,4.85;N,6.75.Found:C,63.70;H,4.84; N,6.39.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula III b.
Embodiment 15, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I o general structure（R1For hydrogen, R2 For bromine, R3For hydrogen, R4For hydrogen, R5For 4- methoxyphenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromomethyl salicylide shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III c The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (102mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 2 hours, thin-layer chromatographic analysis display raw material III c consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 192mg shown in formula I o structure, yield 95%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Compound shown in I o structure can be carried out with high performance liquid chromatography ADH post with chiral separation, result shows the chemical combination shown in 1o structure The enantioselectivity of thing is 97.1%.
This product is solid；
Fusing point mp:197-198℃;
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.83(d,J=6.8Hz,2H),7.37-7.39(m,2H),6.92 (d,J=8.8Hz,2H),6.86(d,J=9.2Hz,1H),5.68(s,1H),4.65(s,1H),3.78-3.84(m,4H),3.62- 3.68(m,1H),2.59-2.63(m,1H),2.35(br,1H),2.06-2.13(m,1H),1.56-1.67(m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)170.2,161.6,150.8,133.4,132.5,129.9, 127.6,122.6,119.2,113.6,113.1,84.1,65.5,55.4,45.1,23.7;
IR(KBr,ν/cm-1)3382,1608,1401,1221cm-1;
MS(CI)m/z(%)404[M]+(0.5),135(100),203(21);
Anal.Calcd.for C19H18BrNO4:C,56.45;H,4.49;N,3.46.Found:C,56.39;H,4.56; N,3.44.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I o.
Shown in formula III c, the preparation method of compound is as follows：
NaOH solid is sequentially added in 250mL round-bottomed flask（4.0g,100mmol）, H2O（50mL）, AgNO3(42.2mg, 0.25mmol) and pyrrolidine（3.6g,50mmol）, reaction bulb is placed in 0 DEG C of ice bath, is slowly added dropwise 25%Na2S2O8(11.9g, Aqueous solution 50mmol)（35mL）.Completion of dropping, after continuing to react 30min at 0 DEG C, adds dichloromethane extraction（50mL× 3 times）, merge organic faciess, saturated common salt water washing（50mL × 1 time）, anhydrous sodium sulfate drying.After filtration room temperature backspin do molten Agent, obtains pyrrolin trimer（Yellow oil）, directly carry out next step reaction.
Under argon protection, in 250mL there-necked flask, sequentially add DIPEA (diisopropylethylamine, 6.5g, 50mmoL), be dried Toluene（25mL）With 4-OMePhCOCl (8.5g, 50mmol), the pyrrolin trimer of Deca previous step preparation under room temperature Toluene solution（75mL）.After completion of dropping, reaction temperature is risen to 80 DEG C, and continue reaction 30min at this temperature.React Finish, add water（30mL）Reaction is quenched, organic faciess add water（50mL × 3 time）Washing, saturated aqueous common salt（30mL × 1 time）Washing, Anhydrous sodium sulfate drying.After filtration, it is spin-dried for removing solvent, Et3100-200 mesh silica gel column chromatography, ethyl acetate and the stone of N deactivation Oily ether mixed solvent（1：3）Drip washing, separates to obtain compound 4.4g shown in formula III c, yield 43%.
Embodiment 16, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I p general structure（R1For hydrogen, R2 For bromine, R3For hydrogen, R4For hydrogen, R5For methyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromomethyl salicylide shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III d The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (56mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reacts 2 After hour, thin-layer chromatographic analysis display raw material III d consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 108mg shown in formula I p structure, yield 69%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I p structure, result shows the chemical combination shown in I p structure The enantioselectivity of thing is -43.2%.
This product is solid；
Fusing point mp:161-163℃;
1H NMR(400MHz,d-DMSO,120℃)δ(ppm)7.45(s,1H),7.33(d,J=8.4Hz,1H),6.76 (d,J=8.0Hz,1H),5.84(br,1H),5.33(s,1H),4.51(s,1H),3.47(br,2H),2.67(br,1H), 2.08-2.17(m,4H),1.39-1.45(m,1H);
13C NMR(100MHz,d-DMSO,120℃)δ(ppm)169.9,151.5,132.8,132.3,126.9, 119.2,112.4,84.7,64.8,46.2,44.7,25.1,22.3;
IR(KBr,ν/cm-1)3294,1629,1454,1426,1223cm-1;
HRMS calcd C13H14BrNO3 79Br[M+23]+334.0055,C13H14BrNO3 81Br[M+23]+336.0034; Found:334.0047,336.0026.
Anal.Calcd.for C13H14BrNO3:C,50.02;H,4.52;N,4.49.Found:C,49.66;H,4.55; N,4.28.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I p.
Shown in formula III d, the preparation method of compound is as follows：
NaOH solid is sequentially added in 250mL round-bottomed flask（4.0g,100mmol）, H2O（50mL）, AgNO3(42.2mg, 0.25mmol) and pyrrolidine（3.6g,50mmol）, reaction bulb is placed in 0 DEG C of ice bath, is slowly added dropwise 25%Na2S2O8(11.9g, Aqueous solution 50mmol)（35mL）.Completion of dropping, after continuing to react 30min at 0 DEG C, adds dichloromethane extraction（50mL× 3 times）, merge organic faciess, saturated common salt water washing（50mL × 1 time）, anhydrous sodium sulfate drying.After filtration room temperature backspin do molten Agent, obtains pyrrolin trimer（Yellow oil）, directly carry out next step reaction.
Under argon protection, in 250mL there-necked flask, sequentially add DIPEA (diisopropylethylamine, 6.5g, 50mmoL), be dried Toluene（25mL）And CH3COCl (3.9g, 50mmol), the first of the pyrrolin trimer of Deca previous step preparation under room temperature Benzole soln（75mL）.After completion of dropping, reaction temperature is risen to 80 DEG C, and continue reaction 30min at this temperature.React Finish, add water（30mL）Reaction is quenched, organic faciess add water（50mL × 3 time）Washing, saturated aqueous common salt（30mL × 1 time）Washing, Anhydrous sodium sulfate drying.After filtration, it is spin-dried for removing solvent, Et3100-200 mesh silica gel column chromatography, ethyl acetate and the stone of N deactivation Oily ether mixed solvent（1：3）Drip washing, separates to obtain compound 2.7g shown in formula III d, yield 28%.
Embodiment 17, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I q general structure（R1For hydrogen, R2 For bromine, R3For hydrogen, R4For hydrogen, R5For benzyloxy）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromomethyl salicylide shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III e The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (102mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 1 hour, thin-layer chromatographic analysis display raw material III e consumes completely.20mL saturated sodium bicarbonate solution is added to quench in reaction system Go out reaction.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous slufuric acid Sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3）Drench Wash.Separate to obtain the compound 136mg shown in formula I q structure, yield 67%, nucleus magnetic hydrogen spectrum display cis-selectivity is>20:1.Profit Chiral separation can be carried out with high performance liquid chromatography ADH post to compound shown in I q structure, result shows the chemical combination shown in I q structure The enantioselectivity of thing is -80.2%.
This product is solid；
Fusing point mp:129-130℃;
1H NMR(400MHz,DMSO)δ(ppm)7.33-7.43(m,7H),6.74(dd,J1=8.4Hz,J2=3.2Hz, 1H),5.80-5.83(m,1H),5.65(d,J=5.2Hz,1H),5.17(d,J=14.8Hz,2H),4.48-4.49(m,1H), 3.39-3.45(m,2H),2.59-2.64(m,1H),2.02-2.03(m,1H),1.27-1.37（m,1H）;
13C NMR(100MHz,DMSO)δ(ppm)154.4,151.5,137.3,133.0,132.4,128.9,128.3, 128.0,126.4,119.1,112.2,83.9,66.9,64.6,45.4,45.2,25.5
IR(KBr,ν/cm-1)3465,1690,1411,1226,1131cm-1;
MS(ESI)m/z(%)426[79Br M+Na]+(61),428[81Br M+Na]+(56);
Anal.Calcd.for C19H18NO4:C,56.45;H,4.49;N,3.46.Found:C,56.20;H,4.53;N, 3.56.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I q.
Shown in formula III e, the preparation method of compound is as follows：
NaOH solid is sequentially added in 250mL round-bottomed flask（4.0g,100mmol）, H2O（50mL）, AgNO3(42.2mg, 0.25mmol) and pyrrolidine（3.6g,50mmol）, reaction bulb is placed in 0 DEG C of ice bath, is slowly added dropwise 25%Na2S2O8(11.9g, Aqueous solution 50mmol)（35mL）.Completion of dropping, after continuing to react 30min at 0 DEG C, adds dichloromethane extraction（50mL× 3 times）, merge organic faciess, saturated common salt water washing（50mL × 1 time）, anhydrous sodium sulfate drying.After filtration room temperature backspin do molten Agent, obtains pyrrolin trimer（Yellow oil）, directly carry out next step reaction.
Under argon protection, in 250mL there-necked flask, sequentially add DIPEA (diisopropylethylamine, 6.5g, 50mmoL), be dried Toluene（25mL）With CbzCl (8.5g, 50mmol), under room temperature, the toluene of the pyrrolin trimer of Deca previous step preparation is molten Liquid（75mL）.After completion of dropping, reaction temperature is risen to 80 DEG C, and continue reaction 30min at this temperature.Reaction finishes, plus Enter water（30mL）Reaction is quenched, organic faciess add water（50mL × 3 time）Washing, saturated aqueous common salt（30mL × 1 time）Washing, anhydrous sulfur Sour sodium is dried.After filtration, it is spin-dried for removing solvent, Et3The 100-200 mesh silica gel column chromatography of N deactivation, ethyl acetate and petroleum ether mix Bonding solvent（1：3）Drip washing, separates to obtain compound 3.5g shown in formula III e, yield 34%.
Embodiment 18, prepare the chirality polysubstituted 4- hydroxychroman class compound shown in formula I r general structure（R1For hydrogen, R2 For bromine, R3For hydrogen, R4For hydrogen, R5For phenyl）
This reaction equation is as follows：
Specifically preparation method is：
Under argon protection, in drying, clean reaction tube, sequentially add magneton and 5- bromomethyl salicylide shown in II c （201mg,1.0mmol）, replace system hollow gas with argon, chiral binaphthol shown in the Formula V that injection addition prepares in situ- Titanium complex catalyst (2mL, 0.025mol/L), is placed in and stirs 0.5 hour under 40 DEG C of oil baths, add three-level shown in formula III f The o-Dimethylbenzene solvent that the 1.0mL sodium of acrylamide (94mg, 0.50mmol) is dried, keeps temperature of reaction system to be 40 DEG C, reaction After 120 hours, thin-layer chromatographic analysis display raw material III f consumes completely.20mL saturated sodium bicarbonate solution is added in reaction system Reaction is quenched.Ethyl acetate extracts（25mL × 3 time）, merge organic faciess, saturated common salt water washing（25ml × 1 time）, anhydrous sulfur Sour sodium is dried, and after filtration, rotary evaporation removes solvent, 100-200 mesh silica gel column chromatography, acetone and petroleum ether mixed solvent（1：3） Drip washing.Separate to obtain the compound 126mg shown in formula I r structure, yield 65%, nucleus magnetic hydrogen spectrum display cis-selectivity is 11:1. Chiral separation can be carried out using high performance liquid chromatography ADH post to compound shown in I r structure, result shows the change shown in I r structure The enantioselectivity of compound is 96.6%.
This product is solid；
Fusing point mp:101-103℃;
1H NMR(400MHz,CDCl3,TMS)δ(ppm)7.41-7.46(m,5H),7.36(d,J=2.8Hz,1H),7.30 (dd,J1=8.8Hz,J2=2.8Hz,1H),6.80(d,J=8.4Hz,1H),5.89(s,1H),5.23(s,1H),4.31(s,1H), 4.02(d,J=11.6Hz,1H),3.03-3.10(m,1H),2.09-2.12(m,1H),1.57-1.74(m,3H),0.97-1.07 (m,1H);
13C NMR(100MHz,CDCl3,TMS)δ(ppm)172.1,152.3,135.1,133.1,132.8,130.3, 128.5,127.2,123.1,119.0,113.0,80.5,69.0,40.1,37.7,24.0,22.0;
IR(KBr,ν/cm-1)3398,1629,1477,1419,1228cm-1;
MS(CI)m/z(%)389[M+1]+(1),77(38),105(100),187(21);
Anal.Calcd.for C19H18BrNO3:C,58.78;H,4.67;N,3.61.Found:C,58.72;H,4.81; N,3.60.
From the foregoing, it will be observed that above-claimed cpd structure is correct, it is compound shown in formula I r.
Embodiment 19, antibacterial activity test
The antibacterial activity that above-described embodiment Ia-Ir prepares gained compound is measured using MIC method.Strain used is respectively removes from office Lan Shi positive bacterium S. aureus（Staphylococcus aureus）（The entitled ATCC6538 of bacterial strain uses therefor）, epidermis Staphylococcuses（Staphylococcus epidermidis）（The entitled ATCC12228 of bacterial strain uses therefor）, bacillus subtilis （Bacillius subtilis）（The entitled ATCC6051 of bacterial strain uses therefor）With gram negative bacteria escherichia coli （Escherichia coli）（The entitled ATCC8739 of bacterial strain uses therefor）, above bacterial strain is purchased from Beijing hundred star high-tech technological development Company limited.
Above-described embodiment 1-18 is prepared compound dissolution shown in gained Formulas I in dimethyl sulfoxide (DMSO), is made into The stock solution of 10mg/mL, 0.2 μm of membrane filtration, obtain antimicrobial fluid stock solution, standby.Using MH broth bouillon, use deionization Water configuration 5g/L TTC (TTC) is as developer.
Add blank meat soup in 96 orifice plates, be separately added into AMP comparison liquid and the stock solution through 10mg/mL is diluted to Variable concentrations drug solution, fully mixes, and cultivates 16～20 hours under the conditions of putting into 37 DEG C, observes antibacterial action result, gained Minimal inhibitory concentration (MIC) the results are shown in Table 1.
Table 1, embodiment 1-18 prepare the minimum inhibitory concentration of gained compound
As can be seen from Table 1, embodiment 1-18 prepares gained compound Ia-Ir all has different degrees of bacteriostatic activity, Little Mlc is between 64～256 μ g/mL, and shows certain substituent effect.

Claims (10)

1. chiral polysubstituted 4- hydroxychroman class compound shown in Formulas I,
In described Formulas I general structure, R1、R2、R3、R4And R5It is selected from any one in following radicals：Hydrogen atom, C1-C3Alkane Base, methoxyl group, benzyloxy, phenyl and the phenyl containing substituent group；
In the described phenyl containing substituent group, substituent group is selected from least one in chlorine and methoxyl group；
N represents the number of carbon atom, is 1 or 2.
2. a kind of method preparing chiral polysubstituted 4- hydroxychroman class compound shown in Formulas I described in claim 1, including as follows Step：
Under conditions of chiral lewis acid catalyst exists, bigcatkin willow aldehyde compound shown in formula II general structure is tied with formula III There is intramolecular nucleophilic cascade reaction in three-level acrylamide shown in structure formula, reaction finish obtain shown in described formula I chiral polysubstituted 4- hydroxychroman class compound；
In described formula II and formula III general structure, R1、R2、R3、R4And R5Definition identical with the definition in claim 1；
N is 1 or 2；
Described chirality lewis acid catalyst be double oxazoline pyridine-tin complex catalyst shown in formula IV or formula V or formula VI or Chiral binaphthol-titanium complex catalyst shown in formula VII：
In described formula IV, R1'For isopropyl or phenyl, R2'For chlorine or trifluoromethanesulfonic acid root anion；
In described formula V, formula VI and formula VII, R is isopropyl.
3. method according to claim 2 it is characterised in that：Described chirality lewis acid catalyst consumption is described formula III The 0.1%-200% of the mole dosage of compound shown in general structure.
4. method according to claim 3 it is characterised in that：The consumption of described chirality lewis acid catalyst is described formula The 5-50% of the mole dosage of compound shown in III general structure.
5. method according to claim 2 it is characterised in that：In described intramolecular nucleophilic cascade reaction step, temperature be- 40 to 110 DEG C；
Time is 30 minutes -168 hours.
6. method according to claim 5 it is characterised in that：In described intramolecular nucleophilic cascade reaction step, temperature be- 10 DEG C to 60 DEG C；
Time is 30 minutes -48 hours.
7. according to the arbitrary described method of claim 2-6 it is characterised in that：Described intramolecular nucleophilic cascade reaction is in solvent In carry out.
8. method according to claim 7 it is characterised in that：Described solvent is selected from dichloromethane, chloroform, four chlorinations Carbon, benzene, toluene, o-Dimethylbenzene, meta-xylene, xylol, sym-trimethylbenzene., ether, oxolane, Isosorbide-5-Nitrae-dioxane, second At least one in nitrile, propionitrile, dimethyl sulfoxide, DMF, N,N-dimethylacetamide and water.
9. application in preparing antibacterial product for the chiral polysubstituted 4- hydroxychroman class compound shown in formula I described in claim 1.
10. according to claim 9 application it is characterised in that：Described bacterium is selected from staphylococcus aureuses, epidermis Fructus Vitis viniferae ball At least one in bacterium, bacillus subtilis and escherichia coli.
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