CN107216241A - The pentanediol derivative of optical activity 1,5 and its synthetic method and application - Google Patents

The pentanediol derivative of optical activity 1,5 and its synthetic method and application Download PDF

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CN107216241A
CN107216241A CN201710079316.8A CN201710079316A CN107216241A CN 107216241 A CN107216241 A CN 107216241A CN 201710079316 A CN201710079316 A CN 201710079316A CN 107216241 A CN107216241 A CN 107216241A
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phenyl
formula
derivative
optical activity
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CN107216241B (en
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刘顺英
李明凤
贾凯莉
胡文浩
董素珍
储睿
郑庆
郭鑫
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East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1782—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention discloses a kind of pentanediol derivative of optical activity 1,5 and its synthetic method, shown in the pentanediol derivant structure of optical activity 1, the 5 such as formula (Ia) and formula (Ib)；The preparation method of the derivative includes：With diazonium compound, benzylalcohol derivative and α, β unsaturated aldehyde for raw material, withMolecular sieve is water absorbing agent, using metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether and substituted benzoic acid as catalyst system and catalyzing, bears hydrogen reagent as reducing agent using metal, reaction obtains the pentanediol derivative of optical activity 1,5.Synthetic method of the present invention has the advantage of atom economy, high selectivity, high yield, and reaction condition is gentle, safety simple to operate.The pentanediol derivative of a pair of optical activities 1,5 that the present invention is obtained has high enantioselectivity, and with bioactivity, it is adaptable to the application and preparation of antineoplastic.

Description

Optical activity 1,5- pentanediols derivative and its synthetic method and application
Technical field
The invention belongs to synthesize field of medicine and chemical technology, relate generally to optical activity 1,5-PD derivative and its chemistry is closed Into methods and applications.
Background technology
1,5-PD derivative is important chemical intermediate, is widely used in polyester, polyurethane, plasticizer, coating, perfume (or spice) The products such as material, adhesive, ink, fiber, pharmaceutical intermediate, sealant and lead stamp.Recently, Chinese patent CN101316508A The combination for reporting 1,5-PD can be used for reducing and/or eliminate the smell from mammal, the smell as from urine, Excrement, leg ulcer liquid, decubital ulcer, the smell of blood and sweat, can be used for making absorbent products or disposable Health product.Therefore synthesis 1,5- pentanediol derivatives are significant.
The synthetic method that lot of documents reports 1,5- pentanediol derivatives is had in recent years.Chinese patent CN1072168A The acrolein reaction with substituted vinyl ethyl ether and substitution is reported, 3, the 4- dihydropyran of substitution, substituted 3,4- is generated The glutaraldehyde of dihydropyran acid-catalyzed hydrolysis generation substitution, then Ni is made catalyst carry out hydrogenation reaction on alumina Generate the pentanediol of substitution.Chinese patent CN101225022A is reported the glutaraldehyde being catalyzed with nickel-A/X loaded catalysts and added Hydrogen reaction obtains pentanediol, and wherein component A is Co, Mn, Cu, Cr etc., and carrier X is molecular sieve, Al2O3、SiO2Deng.But it is above-mentioned In the method for producing 1,5-PD derivative, the problem of it exists jointly is that catalytic hydrogenation reaction pressure is universal all very high, this Sample certainly will be higher to the pressure requirements of consersion unit, correspondingly will increase the one-time investment of generating means, production cost Increase, while can also increase the operation difficulty in production.Meanwhile, asymmetric synthesizing optical is realized by above-mentioned catalytic hydrogenation method Active 1,5- pentanediols derivative is also be difficult.It is unfavorable for optical activity 1,5- pentanediols derivative in industry and organic synthesis In application and its industry be combined to.
The content of the invention
Instant invention overcomes the drawbacks described above of the active 1,5-PD derivative of prior art synthesizing optical, it is proposed that a kind of Optical activity 1,5- pentanediol derivatives and preparation method thereof.In preparation method of the present invention ratio is constructed using the method for three components The increasingly complex optical activity 1,5- pentanediol derivatives of existing two component methods；The raw material hand used in preparation method of the present invention Property diaryl dried meat ammonia alcohol silicon ether is naturally occurring chiral amino acid derivative, and chemical synthesis is cheap and easy to get；Preparation side of the invention Method has an efficient Atom economy, high enantioselectivity, high yield, wide application range of substrates, the beneficial effect such as safety simple to operate Really.Optical activity 1,5-PD derivative prepared by the present invention has high enantioselectivity, and to HCT116, (human colon carcinoma is thin Born of the same parents) there is obvious inhibiting effect, it is adaptable to the application and preparation of antineoplastic.
Shown in optical activity 1,5-PD derivative proposed by the present invention, its structure such as formula (Ia) and formula (Ib),
Wherein, Ar1For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 alkyl replaced selected from phenyl, halogen takes Phenyl, the phenyl of nitro substitution in generation；
Ar2For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl；
Ar3For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl.
Preferably, the Ar1For aryl, selected from phenyl, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 3- bromophenyls, 4- methoxyphenyls, 4- aminomethyl phenyls, 4- nitrobenzophenones, 3- aminomethyl phenyls, 2- aminomethyl phenyls or 3- methoxyphenyls；
Ar2For aryl, selected from phenyl, 2- aminomethyl phenyls, 2- bromophenyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 4- first Base phenyl, 4- bromophenyls, 4- fluorophenyls or 4- methoxyphenyls；
Ar3For aryl, selected from phenyl, 2- aminomethyl phenyls, 2- bromophenyls, 3- aminomethyl phenyls, 3- bromophenyls, 3- methoxyl groups Phenyl, 4- aminomethyl phenyls, 4- bromophenyls, 4- fluorophenyls or 4- methoxyphenyls.
It is further preferred that the optical activity 1,5-PD derivative is selected from：
Aminomethyl phenyl -1,5- pentanediols (1a) between (2S, 3S) -2- benzyloxy -2- phenyl -3-
Aminomethyl phenyl -1,5- pentanediols (1b) between (2R, 3S) -2- benzyloxy -2- phenyl -3-
(2S, 3S) -2- benzyloxy -2- phenyl -3- p-methylphenyl -1,5- pentanediols (2a)
(2R, 3S) -2- benzyloxy -2- phenyl -3- p-methylphenyl -1,5- pentanediols (2b)
(2S, 3S) -2- benzyloxy -2- phenyl -3- p-methoxyphenyl -1,5- pentanediols (3a)
(2R, 3S) -2- benzyloxy -2- phenyl -3- p-methoxyphenyl -1,5- pentanediols (3b)
(2S, 3S) -2- is to the double phenyl -1,5- pentanediols (4a) of bromo-benzyloxy -2,3-
(2R, 3S) -2- is to the double phenyl -1,5- pentanediols (4b) of bromo-benzyloxy -2,3-
Double phenyl -1,5- the pentanediols (5a) of bromo-benzyloxy -2,3- between (2S, 3S) -2-
Double phenyl -1,5- the pentanediols (5b) of bromo-benzyloxy -2,3- between (2R, 3S) -2-
(2S, 3S) -2- is to the double phenyl -1,5- pentanediols (6a) of methoxybenzyl epoxide -2,3-
(2R, 3S) -2- is to the double phenyl -1,5- pentanediols (6b) of methoxybenzyl epoxide -2,3-
(2S, 3S) -2- benzyloxy -2- m-methoxyphenyl -3- phenyl -1,5- pentanediols (7a)
(2R, 3S) -2- benzyloxy -2- m-methoxyphenyl -3- phenyl -1,5- pentanediols (7b)
(2S, 3S) -2- benzyloxy -2- o-bromophenyl -3- phenyl -1,5- pentanediols (8a)
(2R, 3S) -2- benzyloxy -2- o-bromophenyls -3- phenyl -1,5-PD (8b)
(2S, 3S) -2- benzyloxy -2- p-methylphenyl -3- phenyl -1,5- pentanediols (9a)
(2R, 3S) -2- benzyloxy -2- p-methylphenyl -3- phenyl -1,5- pentanediols (9b)
(2S, 3S) -2- benzyloxy -2- p-bromophenyl -3- phenyl -1,5- pentanediols (10a)
(2R, 3S) -2- benzyloxy -2- p-bromophenyl -3- phenyl -1,5- pentanediols (10b)
Optical activity 1,5-PD derivative proposed by the present invention has two chiral centres, including formula (Ia) and formula (Ib) a pair of optical activity 1,5- pentanediol derivatives shown in.
The invention also provides the formula (Ia) and the synthetic method of formula (Ib) optical activity 1,5-PD derivative, In organic solvent, with formula (1) α, beta-unsaturated aldehyde, formula (2) diazonium compound, formula (3) benzylalcohol derivative are raw material, withPoint Son sieve is water absorbing agent, negative with metal using metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether and substituted benzoic acid as catalyst system and catalyzing Hydrogen reagent is reducing agent, is reacted, and obtains the optical activity 1,5- of the high enantioselectivity as shown in formula (Ia) and formula (Ib) Pentanediol derivative；
Specifically, it the described method comprises the following steps：In organic solvent, with formula (1) α, beta-unsaturated aldehyde, formula (2) weight Nitrogen compound, formula (3) benzylalcohol derivative are raw material, withMolecular sieve is water absorbing agent, with metallic catalyst, chiral diaryl dried meat Ammonia alcohol silicon ether and substituted benzoic acid are catalyst system and catalyzing, carry out three component reactions, then bear hydrogen reagent as reducing agent using metal, are gone back Original reaction, obtains the optical activity 1,5-PD derivative of the high enantioselectivity as shown in formula (Ia) and formula (Ib).It is described Shown in course of reaction such as formula (II)：
Wherein, Ar1For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 alkyl replaced selected from phenyl, halogen takes Phenyl, the phenyl of nitro substitution in generation；
Ar2For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl；
Ar3For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl.
Preferably, the Ar1For aryl, selected from phenyl, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 3- bromophenyls, 4- methoxyphenyls, 4- aminomethyl phenyls, 4- nitrobenzophenones, 3- aminomethyl phenyls, 2- aminomethyl phenyls or 3- methoxyphenyls；
Ar2For aryl, selected from phenyl, 2- aminomethyl phenyls, 2- bromophenyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 4- first Base phenyl, 4- bromophenyls, 4- fluorophenyls or 4- methoxyphenyls；
Ar3For aryl, selected from phenyl, 2- aminomethyl phenyls, 2- bromophenyls, 3- aminomethyl phenyls, 3- bromophenyls, 3- methoxyl groups Phenyl, 4- aminomethyl phenyls, 4- bromophenyls, 4- fluorophenyls or 4- methoxyphenyls.
It is further preferred that the optical activity 1,5-PD derivative is selected from：
Aminomethyl phenyl -1,5- pentanediols (1a) between (2S, 3S) -2- benzyloxy -2- phenyl -3-
Aminomethyl phenyl -1,5- pentanediols (1b) between (2R, 3S) -2- benzyloxy -2- phenyl -3-
(2S, 3S) -2- benzyloxy -2- phenyl -3- p-methylphenyl -1,5- pentanediols (2a)
(2R, 3S) -2- benzyloxy -2- phenyl -3- p-methylphenyl -1,5- pentanediols (2b)
(2S, 3S) -2- benzyloxy -2- phenyl -3- p-methoxyphenyl -1,5- pentanediols (3a)
(2R, 3S) -2- benzyloxy -2- phenyl -3- p-methoxyphenyl -1,5- pentanediols (3b)
(2S, 3S) -2- is to the double phenyl -1,5- pentanediols (4a) of bromo-benzyloxy -2,3-
(2R, 3S) -2- is to the double phenyl -1,5- pentanediols (4b) of bromo-benzyloxy -2,3-
Double phenyl -1,5- the pentanediols (5a) of bromo-benzyloxy -2,3- between (2S, 3S) -2-
Double phenyl -1,5- the pentanediols (5b) of bromo-benzyloxy -2,3- between (2R, 3S) -2-
(2S, 3S) -2- is to the double phenyl -1,5- pentanediols (6a) of methoxybenzyl epoxide -2,3-
(2R, 3S) -2- is to the double phenyl -1,5- pentanediols (6b) of methoxybenzyl epoxide -2,3-
(2S, 3S) -2- benzyloxy -2- m-methoxyphenyl -3- phenyl -1,5- pentanediols (7a)
(2R, 3S) -2- benzyloxy -2- m-methoxyphenyl -3- phenyl -1,5- pentanediols (7b)
(2S, 3S) -2- benzyloxy -2- o-bromophenyl -3- phenyl -1,5- pentanediols (8a)
(2R, 3S) -2- benzyloxy -2- o-bromophenyl -3- phenyl -1,5- pentanediols (8b)
(2S, 3S) -2- benzyloxy -2- p-methylphenyl -3- phenyl -1,5- pentanediols (9a)
(2R, 3S) -2- benzyloxy -2- p-methylphenyl -3- phenyl -1,5- pentanediols (9b)
(2S, 3S) -2- benzyloxy -2- p-bromophenyl -3- phenyl -1,5- pentanediols (10a)
(2R, 3S) -2- benzyloxy -2- p-bromophenyl -3- phenyl -1,5- pentanediols (10b)
Specifically, methods described includes：(1) in organic solvent, with formula (1) α, beta-unsaturated aldehyde, formula (2) diazo compounds Thing, formula (3) benzylalcohol derivative are raw material, withMolecular sieve is water absorbing agent, with metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon Ether and substituted benzoic acid are catalyst system and catalyzing, and three component reactions are carried out under the conditions of 0~40 DEG C and obtain intermediate 2- benzyloxy -5- oxygen The double arylpentanoic ester derivants of generation -2,3-；(2) in organic solvent, hydrogen reagent is born as reducing agent using metal, at 20~50 DEG C Under the conditions of carry out reduction reaction obtain target product optical activity 1,5- pentanediol derivatives.
More specifically, methods described includes：By alpha, beta-unsaturated aldehyde, metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether, Substituted benzoic acid andMolecular sieve is dissolved in organic solvent, is configured to mixed solution A；Diazonium compound, benzylalcohol derivative are dissolved in Organic solvent is configured to B；Mixed solution B is added in foregoing mixed solution A, reacted；Treat diazo decomposition completely, after purification Obtain intermediate；Second step is reacted, and intermediate is dissolved in into organic solvent, is added metal and is born hydrogen reagent, after reaction purifying obtain as The optical activity 1,5- pentanediol derivatives of high enantioselectivity shown in formula (Ia) and formula (Ib)；The pair of optical activity 1, Shown in the structure such as formula (Ia) and formula (Ib) of 5- pentanediol derivatives.
In the inventive method, the temperature of the reaction of the active 1,5-PD derivative of the synthesizing optical is 0~50 DEG C；It is excellent Selection of land, is 25 DEG C, 40 DEG C.It is further preferred that two-step reaction temperature is different in the reaction, the temperature of step (1) reaction is 0 ~40 DEG C, the temperature of step (2) reaction is 20~50 DEG C；Preferably, the temperature of step (1) reaction is 25 DEG C, step (2) reaction Temperature be 40 DEG C.
In the inventive method, formula (2) diazonium compound：Formula (3) benzylalcohol derivative：Formula (1) alpha, beta-unsaturated aldehyde：Metal is urged Agent：Chiral diaryl dried meat ammonia alcohol silicon ether：Substituted benzoic acid：The mol ratio that metal bears hydrogen reagent is 1.0-3.0:1.0-2.5: 1.0:0.05-0.2:0.15-0.2:0.15-0.5:10.Preferably, diazonium compound：Benzylalcohol derivative：Alpha, beta-unsaturated aldehyde： Metallic catalyst：Chiral diaryl dried meat ammonia alcohol silicon ether：Substituted benzoic acid：The mol ratio that metal bears hydrogen reagent is 3.0:2.5:1.0: 0.2:0.2:0.5:10、1.0:1.0:1.0:0.05:0.15:0.15:10、2.0:2.0:1.0:0.1:0.2:0.4:10。Point Son sieve inventory is 50~100mg/mmol on the basis of alpha, beta-unsaturated aldehyde.Preferably,Molecular sieve inventory is 90mg/ mmol.Consumption of organic solvent and the ratio of alpha, beta-unsaturated aldehyde consumption are 8-20mL：0.8-1.2mmol；Preferably, it is 10mL: 1mmol。
In the inventive method, the optical activity 1,5-PD derivative progress separation that can also include obtaining reaction is pure The step of change, isolating and purifying with volume ratio for first step reaction is ethyl acetate：Petroleum ether=1:500~1:80 eluant, eluents are carried out Column chromatography, isolating and purifying with volume ratio for second step reaction is ethyl acetate：Petroleum ether=1:50~1:8 eluant, eluents carry out post layer Analysis.Preferably, isolating and purifying with volume ratio for first step reaction is ethyl acetate：Petroleum ether=1:100 eluant, eluents carry out post layer Analysis, isolating and purifying with volume ratio for second step reaction is ethyl acetate：Petroleum ether=1:10 eluant, eluents carry out column chromatography.
In the inventive method, the organic solvent includes dichloromethane, tetrahydrofuran, toluene or chloroform；Preferably, it is two Chloromethanes.
In the inventive method, the metallic catalyst is iridium compound, rhodium complex or palladium compound；Preferably, it is described Metallic catalyst is iridium compound；It is further preferred that being double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium.
In the inventive method, shown in the chiral diaryl dried meat ammonia alcohol silicon ether structure such as formula (III),
Wherein, R1For trimethyl silicon substrate, triethyl group silicon substrate or dimethyl tertiary butyl silicon substrate；Ar4For phenyl or the double trifluoros of 3,5- Aminomethyl phenyl.Preferably, R1For dimethyl tertiary butyl silicon substrate, Ar4For phenyl.
In the inventive method, shown in the substituted benzoic acid structure such as formula (IV),
Wherein, R includes hydrogen, 3,5- bis trifluoromethyls, nitro, methoxyl group, halogen.Preferably, R is 4- nitros.
In the inventive method, it is Lithium Aluminium Hydride or sodium borohydride that the metal, which bears hydrogen reagent,；Preferably, it is sodium borohydride.
In a specific embodiment, the synthetic method of optical activity 1,5-PD derivative is in the present invention：The Single step reaction, by diazonium compound, benzylalcohol derivative, α, beta-unsaturated aldehyde, iridium compound, chiral diaryl dried meat ammonia alcohol silicon ether, Substituted benzoic acid mol ratio is 2.0:2.0:1.0:0.1:0.2:0.4 weighs raw material, with α, is measured on the basis of beta-unsaturated aldehyde consumption TakeMolecular sieve, organic solvent, by α, beta-unsaturated aldehyde, iridic compound, chiral diaryl dried meat ammonia alcohol silicon ether, substituted benzoic acid andMolecular sieve is dissolved in organic solvent, is configured to mixed solution A；At 25 DEG C, by diazonium compound, benzylalcohol derivative is dissolved in has Machine solvent is configured to mixed solution B；Mixed solution B is added in foregoing mixed solution A with syringe pump, reacted；Treat diazonium Decompose complete, crude product is subjected to column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent) obtain intermediate；Second Step reaction, organic solvent is dissolved in by intermediate, with α, on the basis of beta-unsaturated aldehyde consumption, by α, beta-unsaturated aldehyde：Metal bears hydrogen Reagent=1.0:10.0, which add metal, bears hydrogen reagent, and crude product is carried out into column chromatography (with ethyl acetate after reaction：Petroleum ether=1: 10 be eluant, eluent) the optical activity 1,5- pentanediols that obtain high a pair enantioselectivity as shown in formula (Ia) and formula (Ib) derive Thing.
In the present invention, the optical activity 1,5-PD derivative as shown in formula (Ia) and formula (Ib) is high a pair right Reflect selective compound.
The invention also provides the light as shown in formula (Ia) and formula (Ib) prepared as synthetic method of the present invention Learn activity 1,5- pentanediol derivatives；Optical activity 1,5- pentanediols derivative shown in the formula (Ia) and formula (Ib) has two Individual chiral centre.
The invention also provides the optical activity 1,5- pentanediol derivatives as shown in formula (Ia) and formula (Ib)；The formula (Ia) the optical activity 1,5- pentanediols derivative and shown in formula (Ib) has two chiral centres.
The invention also provides the optical activity 1,5- pentanediols derivative as shown in formula (Ia) and formula (Ib) is preparing doctor Application in medicine intermediate.
The invention also provides the optical activity 1,5- pentanediols derivative as shown in formula (Ia) and formula (Ib) is anti-in preparation Application in tumour medicine.Wherein, the tumor disease is including colon cancer etc..
The invention also provides the optical activity 1,5- penta of high a pair enantioselectivity as shown in formula (Ia) and formula (Ib) Application of the diol, derivatives in drugs against colon cancer is prepared.
A pair of optical activity 1,5- as shown in formula (Ia) and formula (Ib) with two chiral centres proposed by the present invention Pentanediol derivative is important chemical industry and medicine intermediate, in field of medicine and chemical technology extensive use, with very big application prospect. The preparation method of the present invention using compound cheap and easy to get as raw material, with reaction condition is gentle, reactions steps are few, reaction is fast, The beneficial effects such as cost is low, few waste that is producing, safety simple to operate, Atom economy is high, selectivity is high, yield height.
Brief description of the drawings
Fig. 1 is the products therefrom of embodiment 1 (1a)1H NMR schematic diagrames.
Fig. 2 is the products therefrom of embodiment 1 (1a)13C NMR schematic diagrames.
Fig. 3 is the racemic product liquid phase figure of the products therefrom of embodiment 1 (1a).
Fig. 4 is the chiral product liquid phase figure of the products therefrom of embodiment 1 (1a).
Fig. 5 is the products therefrom of embodiment 1 (1b)1H NMR schematic diagrames.
Fig. 6 is the products therefrom of embodiment 1 (1b)13C NMR schematic diagrames.
Fig. 7 is the racemic product liquid phase figure of the products therefrom of embodiment 1 (1b).
Fig. 8 is the chiral product liquid phase figure of the products therefrom of embodiment 1 (1b).
Fig. 9 is the products therefrom of embodiment 2 (2a)1H NMR schematic diagrames.
Figure 10 is the products therefrom of embodiment 2 (2a)13C NMR schematic diagrames.
Figure 11 is the racemic product liquid phase figure of the products therefrom of embodiment 2 (2a).
Figure 12 is the chiral product liquid phase figure of the products therefrom of embodiment 2 (2a).
Figure 13 is the products therefrom of embodiment 2 (2b)1H NMR schematic diagrames.
Figure 14 is the products therefrom of embodiment 2 (2b)13C NMR schematic diagrames.
Figure 15 is the racemic product liquid phase figure of the products therefrom of embodiment 2 (2b).
Figure 16 is the chiral product liquid phase figure of the products therefrom of embodiment 1 (2b).
Figure 17 is the products therefrom of embodiment 3 (3a)1H NMR schematic diagrames.
Figure 18 is the products therefrom of embodiment 3 (3a)13C NMR schematic diagrames.
Figure 19 is the racemic product liquid phase figure of the products therefrom of embodiment 3 (3a).
Figure 20 is the chiral product liquid phase figure of the products therefrom of embodiment 3 (3a).
Figure 21 is the products therefrom of embodiment 3 (3b)1H NMR schematic diagrames.
Figure 22 is the products therefrom of embodiment 3 (3b)13C NMR schematic diagrames.
Figure 23 is the racemic product liquid phase figure of the products therefrom of embodiment 3 (3b).
Figure 24 is the chiral product liquid phase figure of the products therefrom of embodiment 3 (3b).
Figure 25 is the products therefrom of embodiment 4 (4a)1H NMR schematic diagrames.
Figure 26 is the products therefrom of embodiment 4 (4a)13C NMR schematic diagrames.
Figure 27 is the racemic product liquid phase figure of the products therefrom of embodiment 4 (4a).
Figure 28 is the chiral product liquid phase figure of the products therefrom of embodiment 4 (4a).
Figure 29 is the products therefrom of embodiment 4 (4b)1H NMR schematic diagrames.
Figure 30 is the products therefrom of embodiment 4 (4b)13C NMR schematic diagrames.
Figure 31 is the racemic product liquid phase figure of the products therefrom of embodiment 4 (4b).
Figure 32 is the chiral product liquid phase figure of the products therefrom of embodiment 4 (4b).
Figure 33 is the products therefrom of embodiment 5 (5a)1H NMR schematic diagrames.
Figure 34 is the products therefrom of embodiment 5 (5a)13C NMR schematic diagrames.
Figure 35 is the racemic product liquid phase figure of the products therefrom of embodiment 5 (5a).
Figure 36 is the chiral product liquid phase figure of the products therefrom of embodiment 5 (5a).
Figure 37 is the products therefrom of embodiment 5 (5b)1H NMR schematic diagrames.
Figure 38 is the products therefrom of embodiment 5 (5b)13C NMR schematic diagrames.
Figure 39 is the racemic product liquid phase figure of the products therefrom of embodiment 5 (5b).
Figure 40 is the chiral product liquid phase figure of the products therefrom of embodiment 5 (5b).
Figure 41 is the products therefrom of embodiment 6 (6a)1H NMR schematic diagrames.
Figure 42 is the products therefrom of embodiment 6 (6a)13C NMR schematic diagrames.
Figure 43 is the racemic product liquid phase figure of the products therefrom of embodiment 6 (6a).
Figure 44 is the chiral product liquid phase figure of the products therefrom of embodiment 6 (6a).
Figure 45 is the products therefrom of embodiment 6 (6b)1H NMR schematic diagrames.
Figure 46 is the products therefrom of embodiment 6 (6b)13C NMR schematic diagrames.
Figure 47 is the racemic product liquid phase figure of the products therefrom of embodiment 6 (6b).
Figure 48 is the chiral product liquid phase figure of the products therefrom of embodiment 6 (6b).
Figure 49 is the products therefrom of embodiment 7 (7a)1H NMR schematic diagrames.
Figure 50 is the products therefrom of embodiment 7 (7a)13C NMR schematic diagrames.
Figure 51 is the racemic product liquid phase figure of the products therefrom of embodiment 7 (7a).
Figure 52 is the chiral product liquid phase figure of the products therefrom of embodiment 7 (7a).
Figure 53 is the products therefrom of embodiment 7 (7b)1H NMR schematic diagrames.
Figure 54 is the products therefrom of embodiment 7 (7b)13C NMR schematic diagrames.
Figure 55 is the racemic product liquid phase figure of the products therefrom of embodiment 7 (7b).
Figure 56 is the chiral product liquid phase figure of the products therefrom of embodiment 7 (7b).
Figure 57 is the products therefrom of embodiment 8 (8a)1H NMR schematic diagrames.
Figure 58 is the products therefrom of embodiment 8 (8a)13C NMR schematic diagrames.
Figure 59 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (8a).
Figure 60 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (8a).
Figure 61 is the products therefrom of embodiment 8 (8b)1H NMR schematic diagrames.
Figure 62 is the products therefrom of embodiment 8 (8b)13C NMR schematic diagrames.
Figure 63 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (8b).
Figure 64 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (8b).
Figure 65 is the products therefrom of embodiment 8 (9a)1H NMR schematic diagrames.
Figure 66 is the products therefrom of embodiment 8 (9a)13C NMR schematic diagrames.
Figure 67 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (9a).
Figure 68 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (9a).
Figure 69 is the products therefrom of embodiment 8 (9b)1H NMR schematic diagrames.
Figure 70 is the products therefrom of embodiment 8 (9b)13C NMR schematic diagrames.
Figure 71 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (9b).
Figure 72 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (9b).
Figure 73 is the products therefrom of embodiment 8 (10a)1H NMR schematic diagrames.
Figure 74 is the products therefrom of embodiment 8 (10a)13C NMR schematic diagrames.
Figure 75 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (10a).
Figure 76 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (10a).
Figure 77 is the products therefrom of embodiment 8 (10b)1H NMR schematic diagrames.
Figure 78 is the products therefrom of embodiment 8 (10b)13C NMR schematic diagrames.
Figure 79 is the racemic product liquid phase figure of the products therefrom of embodiment 8 (10b).
Figure 80 is the chiral product liquid phase figure of the products therefrom of embodiment 8 (10b).
Figure 81 is that (human colon carcinoma is thin to HCT116 for two kinds of the compounds of this invention (FB1-3-S, FB1-3-X) of various concentrations Born of the same parents) concentration-Survival curves figure.
Embodiment
With reference to specific examples below and accompanying drawing, the present invention is described in further detail, protection content of the invention It is not limited to following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change Change and advantage is all included in the present invention, and using appended claims as protection domain.The process of the implementation present invention, Condition, reagent, experimental method etc., are the universal knowledege and common knowledge of this area in addition to the following content specially referred to, Content is not particularly limited in the present invention.
The preparation method of the optical activity 1,5-PD derivative of the present invention, first step reaction, by α, beta-unsaturated aldehyde, Metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether, substituted benzoic acid andMolecular sieve is dissolved in organic solvent, is configured to mixing Solution A；Diazonium compound, benzylalcohol derivative are dissolved in organic solvent and are configured to B；Mixed solution B is added into foregoing mixed solution A In, reacted；Treat that diazo decomposition completely, obtains intermediate after purification；Second step is reacted, and intermediate is dissolved in into organic solvent, Add metal and bear hydrogen reagent, purifying obtains the optical activity 1 of the high enantioselectivity as shown in formula (Ia) and formula (Ib) after reaction, 5- pentanediol derivatives；Shown in the synthetic reaction such as formula (II)：
Wherein, Ar1For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 alkyl replaced selected from phenyl, halogen takes Phenyl, the phenyl of nitro substitution in generation；
Ar2For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl；
Ar3For aryl, phenyl, the phenyl of methoxy substitution, the C1-C3 replaced selected from phenyl, halogen is alkyl-substituted Phenyl.
Embodiment 1
The first step is reacted, by 3- methyl cinnamic aldehydes (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chiral benzhydryl base dried meat ammonia alcohol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium Methyl acetate (2.0mmol), benzylalcohol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；, will be mixed at 25 DEG C Close solution B to be added in foregoing mixed solution A with syringe pump, stirring is reacted.Treat diazo decomposition completely, will after reaction terminates Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this Intermediate is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, will Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain net product, its structure such as formula (1a) and Shown in (1b), (1a) is aminomethyl phenyl -1,5-PD between (2S, 3S) -2- benzyloxy -2- phenyl -3-, (1b) be (2R, 3S) - Aminomethyl phenyl -1,5-PD between 2- benzyloxy -2- phenyl -3-, the gross production rate of (1a) and (1b) is 75%, dr values (1a)： (1b) is equal to 50：50.The ee values of (1a) are equal to 99%, and the ee values of (1b) are equal to 95%.
Optical activity product (1a)1H NMR schematic diagrames as shown in figure 1, its13C NMR schematic diagrames are as shown in Fig. 2 it disappears Product liquid phase figure is revolved as shown in figure 3, its chiral product liquid phase figure is as shown in Figure 4.
1H NMR(400MHz,CDCl3) δ 7.34 (dt, J=14.8,7.2Hz, 4H), 7.23 (td, J=5.6,3.8Hz, 3H), 7.19 (s, 1H), 6.96 (d, J=3.7Hz, 2H), 6.87 (d, J=8.0Hz, 2H), 6.57 (d, J=6.8Hz, 2H), 4.37 (s, 2H), 3.86 (s, 2H), 3.46 (dd, J=11.6,3.2Hz, 1H), 3.34 (ddd, J=20.6,12.5,6.5Hz, 2H), (m, the 1H) of 2.45 (ddd, J=10.1,6.7,3.9Hz, 1H), 2.21 (s, 3H), 1.93 (s, 1H), 1.70-1.57
13C NMR(100MHz,CDCl3)δ138.59,137.29,136.48,136.07,129.92,128.58, 128.40,127.96,127.66,127.58,127.14,84.08,77.32,77.01,76.69,64.85,62.00,61.83, 47.60,31.69,21.03.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=33.13 minutes, tminor=8.15 minutes
Optical activity product (1b)1H NMR schematic diagrames as shown in figure 5, its13C NMR schematic diagrames are as shown in fig. 6, it disappears Product liquid phase figure is revolved as shown in fig. 7, its chiral product liquid phase figure is as shown in Figure 8.
1H NMR(400MHz,CDCl3) δ 7.39-7.25 (m, 6H), 7.20 (dd, J=12.4,4.5Hz, 4H), 7.06 (d, J=7.7Hz, 2H), 6.99 (d, J=7.6Hz, 2H), 4.51 (q, J=12.1Hz, 2H), 4.08-3.91 (m, 2H), 3.33- 3.22 (m, 1H), 3.11 (dd, J=15.6,9.2Hz, 1H), 2.99 (dd, J=11.4,2.7Hz, 1H), 2.23 (d, J= 14.4Hz,3H),2.05–1.93(m,1H),1.86(s,1H),1.55–1.48(m,2H).
13C NMR(100MHz,CDCl3)δ140.51,139.39,136.62,136.55,129.91,128.80, 128.44,128.41,127.34,127.17,126.88,126.75,84.15,77.34,77.02,76.71,65.71, 65.66,61.18,52.10,32.81,21.06.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=7.39 minutes, tminor=12.91 minutes
Embodiment 2
The first step is reacted, by 4- methyl cinnamic aldehydes (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chiral benzhydryl base dried meat ammonia alcohol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium Methyl acetate (2.0mmol), benzylalcohol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；, will be mixed at 25 DEG C Close solution B to be added in foregoing mixed solution A with syringe pump, stirring is reacted.Treat diazo decomposition completely, will after reaction terminates Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this Intermediate is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, will Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain net product, its structure such as formula (2a) and Shown in (2b), (2a) is (2S, 3S) -2- benzyloxy -2- phenyl -3- p-methylphenyls -1,5-PD, (2b) be (2R, 3S) - 2- benzyloxy -2- phenyl -3- p-methylphenyls -1,5-PD, the gross production rate of (2a) and (2b) is 80%, dr values (2a)： (2b) is equal to 50：50.The ee values of (2a) are equal to 53%, and the ee values of (2b) are equal to 98%.
Optical activity product (2a)1H NMR schematic diagrames as shown in figure 9, its13As shown in Figure 10, it disappears C NMR schematic diagrames Revolve product liquid phase figure as shown in figure 11, its chiral product liquid phase figure is as shown in figure 12.
1H NMR(400MHz,CDCl3).δ7.39–7.27(m,4H),7.27–7.16(m,4H),6.99–6.84(m,4H), 6.44 (s, 2H), 4.37 (s, 2H), 3.86 (s, 2H), 3.44 (dd, J=11.6,3.2Hz, 1H), 3.36 (ddd, J=11.8, 7.5,4.7Hz, 1H), 3.28 (dd, J=16.3,8.7Hz, 1H), 2.52-2.38 (m, 1H), 2.11 (s, 3H), 1.98 (d, J= 24.6Hz,1H),1.71–1.61(m,1H),1.38–1.36(m,1H).
13C NMR(100MHz,CDCl3)δ139.15,138.62,137.38,137.05,130.88,128.58, 127.99,127.67,127.61,127.59,127.49,127.16,84.04,77.35,77.04,76.72,64.86, 62.03,61.79,47.95,31.66,21.34.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=17.58 minutes, tminor=6.54 minutes.
Optical activity product (2b)1H NMR schematic diagrames are as shown in figure 13, its13C NMR schematic diagrames are as shown in figure 14, its As shown in figure 15, its chiral product liquid phase figure is as shown in figure 16 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.44-7.26 (m, 9H), 7.25-7.23 (m, 1H), 7.14 (t, J=7.7Hz, 1H), 7.04 (t, J=8.1Hz, 3H), 4.59 (dd, J=27.1,12.0Hz, 2H), 4.08 (s, 2H), 3.36 (ddd, J= 11.1,6.9,4.5Hz, 1H), 3.20 (dd, J=15.8,9.4Hz, 1H), 3.08 (dd, J=11.6,3.3Hz, 1H), 2.29 (s, 3H), 2.13-2.01 (m, 1H), 1.93 (ddd, J=8.9,6.9,3.4Hz, 1H), 1.36-1.34 (m, 1H), 1.09- 1.07(m,1H).
13C NMR(100MHz,CDCl3)δ140.37,139.62,139.34,137.43,131.02,128.39, 127.87,127.73,127.37,127.19,126.99,126.91,126.83,84.16,77.33,77.21,77.01, 76.69,65.67,65.59,61.23,52.29,32.75,21.43.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=7.46 minutes, tminor=9.88 minutes
Embodiment 3
The first step is reacted, by 4- methoxycinnamic aldehydes (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chiral benzhydryl base dried meat ammonia alcohol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium Methyl acetate (2.0mmol), benzylalcohol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；, will be mixed at 25 DEG C Close solution B to be added in foregoing mixed solution A with syringe pump, stirring is reacted.Treat diazo decomposition completely, will after reaction terminates Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this Intermediate is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, will Crude product carries out column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain net product, its structure such as formula (3a) and Shown in (3b), (3a) is (2S, 3S) -2- benzyloxy -2- phenyl -3- p-methoxyphenyls -1,5-PD, (3b) for (2R, 3S) -2- benzyloxies -2- phenyl -3- p-methoxyphenyls -1,5-PD, the gross production rate of (3a) and (3b) is 84%, dr values (3a)：(3b) is equal to 50：50.The ee values of (3a) are equal to 97%, and the ee values of (3b) are equal to 98%.
Optical activity product (3a)1H NMR schematic diagrames are as shown in figure 17, its13C NMR schematic diagrames are as shown in figure 18, its As shown in figure 19, its chiral product liquid phase figure is as shown in figure 20 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.47-7.35 (m, 4H), 7.29 (t, J=14.9Hz, 4H), 7.02 (s, 2H), 6.67 (s, 4H), 4.43 (s, 2H), 3.93 (s, 2H), 3.76 (s, 3H), 3.52 (dd, J=11.5,2.6Hz, 1H), 3.44 (dd, J=13.0,8.8Hz, 1H), 3.40-3.29 (m, 1H), 2.63-2.45 (m, 1H), 2.07 (s, 1H), 1.67 (dd, J= 15.0,9.0Hz,2H).
13C NMR(100MHz,CDCl3)δ158.47,138.59,137.27,131.15,131.01,128.59, 127.92,127.69,127.67,127.59,127.15,113.04,84.16,77.35,77.03,76.71,64.88, 61.94,61.76,55.14,47.06,31.69.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=22.97 minutes, tminor=8.82 minutes
Optical activity product (3b)1H NMR schematic diagrames are as shown in figure 21, its13C NMR schematic diagrames are as shown in figure 22, its As shown in figure 23, its chiral product liquid phase figure is as shown in figure 24 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.33 (ddd, J=19.0,13.4,7.1Hz, 8H), 7.24 (d, J=7.6Hz, 2H), 7.13 (d, J=8.3Hz, 2H), 6.79 (d, J=8.4Hz, 2H), 4.57 (q, J=12.1Hz, 2H), 4.07 (s, 2H), 3.79 (s, 3H), 3.46-3.29 (m, 1H), 3.27-3.13 (m, 1H), 3.08 (dd, J=11.4,2.9Hz, 1H), 1.99 (dd, J=20.5,14.8Hz, 2H), 1.66 (s, 2H)
13C NMR(100MHz,CDCl3)δ158.59,140.34,139.36,131.57,131.00,128.42, 127.36,127.19,126.90,126.72,113.41,84.22,77.36,77.04,76.72,65.58,65.47,61.13, 55.20,51.38,32.83.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=7.97 minutes, tminor=12.59 minutes
Embodiment 4
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium methyl acetate (2.0mmol), 4- bromobenzenes methanol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, it will mix Solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Treat diazo decomposition completely, will be thick after reaction terminates Product carries out column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this Mesosome is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, will be thick Product carries out column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain net product, its structure such as formula (4a) and Shown in (4b), (4a) be (2S, 3S) -2- to the double phenyl -1,5-PDs of bromo-benzyloxy -2,3-, (4b) is -2- pairs of (2R, 3S) Double phenyl-the 1,5-PDs of bromo-benzyloxy -2,3-, the gross production rate of (4a) and (4b) is 75%, dr values (4a)：(4b) is equal to 50： 50.The ee values of (4a) are equal to 98%, and the ee values of (4b) are equal to 99%.
Optical activity product (4a)1H NMR schematic diagrames are as shown in figure 25, its13C NMR schematic diagrames are as shown in figure 26, its As shown in figure 27, its chiral product liquid phase figure is as shown in figure 28 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.50 (d, J=7.7Hz, 2H), 7.32 (d, J=22.0Hz, 5H), 7.21- 7.07 (m, 3H), 6.99 (s, 2H), 6.76 (s, 2H), 4.39 (dd, J=25.7,11.8Hz, 2H), 3.95 (s, 2H), 3.55 (d, J=10.6Hz, 1H), 3.43 (s, 1H), 3.33 (d, J=6.6Hz, 1H), 2.56-2.40 (m, 1H), 2.12 (s, 1H), 1.73 (dd, J=18.4,13.0Hz, 2H)
13C NMR(100MHz,CDCl3)δ139.10,137.62,137.23,131.65,130.07,128.77, 128.54,127.99,127.79,127.71,126.99,126.07,121.36,84.09,77.35,77.04,76.72, 64.22,62.22,61.53,48.03,31.59.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=10：1, the ml/min of flow velocity=1.0 Clock), tmajor=26.81 minutes, tminor=13.34 minutes
Optical activity product (4b)1H NMR schematic diagrames are as shown in figure 29, its13C NMR schematic diagrames are as shown in figure 30, its As shown in figure 31, its chiral product liquid phase figure is as shown in figure 32 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.50 (d, J=7.9Hz, 2H), 7.43-7.14 (m, 12H), 4.53 (dd, J= 33.1,12.3Hz, 2H), 4.06 (q, J=12.5Hz, 2H), 3.35 (d, J=3.7Hz, 1H), 3.25-3.07 (m, 2H), 2.00 (dd, J=23.2,17.4Hz, 2H), 1.64 (s, 2H)
13C NMR(100MHz,CDCl3)δ139.94,139.59,138.33,131.49,130.08,128.52, 128.36,128.02,127.51,127.07,126.82,120.94,84.33,77.35,77.03,76.71,65.58, 65.03,60.97,51.97,32.71.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=8.0：1, the ml/min of flow velocity=1.0 Clock), tmajor=19.29 minutes, tminor=14.99 minutes
Embodiment 5
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium methyl acetate (2.0mmol), 3- bromobenzenes methanol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, it will mix Solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Treat diazo decomposition completely, will be thick after reaction terminates Product carries out column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this Mesosome is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, will be thick Product carries out column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), obtain net product, its structure such as formula (5a) and Shown in (5b), (5a) is the double phenyl -1,5-PDs of bromo-benzyloxy -2,3- between (2S, 3S) -2-, and (5b) is between (2R, 3S) -2- Double phenyl-the 1,5-PDs of bromo-benzyloxy -2,3-, the gross production rate of (5a) and (5b) is 75%, dr values (5a)：(5b) is equal to 50： 50.The ee values of (5a) are equal to 87%, and the ee values of (5b) are equal to 99%.
Optical activity product (5a)1H NMR schematic diagrames are as shown in figure 33, its13C NMR schematic diagrames are as shown in figure 34, its As shown in figure 35, its chiral product liquid phase figure is as shown in figure 36 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.56 (s, 1H), 7.43 (d, J=7.7Hz, 1H), 7.34 (d, J=5.0Hz, 2H), 7.29 (s, 3H), 7.14 (dd, J=15.2,7.5Hz, 3H), 6.99 (d, J=4.6Hz, 2H), 6.76 (d, J=5.7Hz, 2H), 4.41 (dd, J=24.6,11.9Hz, 2H), 3.96 (s, 2H), 3.55 (d, J=10.3Hz, 1H), 3.43 (d, J= 3.6Hz,1H),3.38–3.22(m,1H),2.56–2.40(m,1H),2.19(s,1H),1.76(s,2H).
13C NMR(100MHz,CDCl3)δ140.99,139.08,137.29,130.59,130.12,130.10, 128.53,127.82,127.77,127.71,126.99,126.08,125.61,122.61,84.10,77.37,77.05, 76.73,64.15,62.29,61.47,48.09,31.57.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1), tmajor=6.15 minutes, tminor=9.43 minutes
Optical activity product (5b)1H NMR schematic diagrames are as shown in figure 37, its13C NMR schematic diagrames are as shown in figure 38, its As shown in figure 39, its chiral product liquid phase figure is as shown in figure 40 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.54 (s, 1H), 7.42 (d, J=7.7Hz, 1H), 7.36 (t, J=7.3Hz, 2H), 7.29 (dd, J=14.8,7.2Hz, 5H), 7.22 (t, J=5.5Hz, 5H), 4.55 (dd, J=33.2,12.5Hz, 2H), 4.15-3.99 (m, 2H), 3.37 (dd, J=9.5,5.2Hz, 1H), 3.25-3.11 (m, 2H), 2.03 (dt, J=10.9, 7.0Hz, 1H), 1.95 (dd, J=13.4,5.3Hz, 1H), 1.62 (s, 1H), 1.14 (d, J=8.2Hz, 1H)
13C NMR(100MHz,CDCl3)δ141.67,139.76,139.46,130.22,130.12,129.93, 129.68,128.53,128.06,127.53,127.12,126.83,125.12,122.58,84.37,77.34,77.02, 76.70,65.50,64.89,60.99,51.80,32.67.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=20：1, the ml/min of flow velocity=1.0 Clock), tmajor=5.76 minutes, tminor=9.71 minutes
Embodiment 6
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By phenyldiazonium methyl acetate (2.0mmol), 4- methoxy benzyl alcohols (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；, will at 25 DEG C Mixed solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Treat diazo decomposition completely, after reaction terminates, Crude product is subjected to column chromatography (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, will This intermediate is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, and sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, Crude product is subjected to column chromatography (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), net product is obtained, its structure such as formula (6a) Shown in (6b), (6a) is (2S, 3S) -2- to the double phenyl -1,5-PDs of methoxybenzyl epoxide -2,3-, (6b) for (2R, 3S) -2- is to the double phenyl -1,5-PDs of methoxybenzyl epoxide -2,3-, and the gross production rate of (6a) and (6b) is 74%, dr values (6a)： (6b) is equal to 50：50.The ee values of (6a) are equal to 98%, and the ee values of (6b) are equal to 99%.
Optical activity product (6a)1H NMR schematic diagrames are as shown in figure 41, its13C NMR schematic diagrames are as shown in figure 42, its As shown in figure 43, its chiral product liquid phase figure is as shown in figure 44 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.36-7.28 (m, 5H), 7.20-7.08 (m, 3H), 7.02 (d, J=4.2Hz, 2H), 6.93 (d, J=8.6Hz, 2H), 6.74 (d, J=5.7Hz, 2H), 4.44-4.28 (m, 2H), 3.92 (s, 2H), 3.83 (s, 3H), 3.55 (dd, J=11.3,3.4Hz, 1H), 3.43 (ddd, J=11.7,7.4,4.7Hz, 1H), 3.36 (dd, J= 15.9,9.1Hz,1H),2.59–2.46(m,1H),2.07(s,1H),1.78–1.67(m,1H).
13C NMR(100MHz,CDCl3)δ159.20,139.38,137.29,130.56,130.07,128.81, 127.98,127.67,127.31,126.90,114.04,84.00,77.34,77.02,76.70,64.64,61.94,61.80, 55.32,48.02,31.71.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=38.04 minutes, tminor=20.48 minutes
Optical activity product (6b)1H NMR schematic diagrames are as shown in figure 45, its13C NMR schematic diagrames are as shown in figure 46, its As shown in figure 47, its chiral product liquid phase figure is as shown in figure 48 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3) δ 7.47-7.28 (m, 6H), 7.27-7.13 (m, 6H), 6.93 (d, J=8.5Hz, 2H), 4.50 (q, J=11.5Hz, 2H), 4.19-3.98 (m, 2H), 3.83 (s, 3H), 3.45-3.28 (m, 1H), 3.24-3.14 (m, 1H), 3.11 (dd, J=11.4,3.3Hz, 1H), 2.13-1.86 (m, 2H)
13C NMR(100MHz,CDCl3)δ158.91,140.35,139.82,131.36,130.10,128.40, 128.30,127.96,127.38,126.94,113.88,84.13,77.34,77.02,76.71,65.42,61.15,55.32, 52.31,32.81.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=22.18 minutes, tminor=38.56 minutes
Embodiment 7
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) is molten In 5mL dichloromethane, mixed solution A is configured to, is stirred 1 hour at 25 DEG C；By 3- methoxyphenyl diazoacetic acid methyl esters (2.0mmol), phenmethylol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, by mixed solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Diazo decomposition is treated completely, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this intermediate It is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), net product is obtained, its structure such as formula (7a) and (7b) institute Show, (7a) is (2S, 3S) -2- benzyloxy -2- m-methoxyphenyls -3- phenyl -1,5-PD, (7b) is (2R, 3S) -2- benzyls Epoxide -2- m-methoxyphenyls -3- phenyl -1,5-PD, the gross production rate of (7a) and (7b) is 81%, dr values (7a)：(7b) Equal to 50：50.The ee values of (7a) are equal to 96%, and the ee values of (7b) are equal to 97%.
Optical activity product (7a)1H NMR schematic diagrames are as shown in figure 49, its13C NMR schematic diagrames are as shown in figure 50, its As shown in figure 51, its chiral product liquid phase figure is as shown in figure 50 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.46–7.27(m,4H),7.26–7.19(m,1H),7.16–6.96(m,4H), 6.81–6.62(m,3H),6.58–6.39(m,2H),4.38(s,2H),3.93–3.76(m,2H),3.59(s,3H),3.48 (dd, J=11.6,3.1Hz, 1H), 3.41-3.30 (m, 1H), 3.30-3.17 (m, 1H), 2.52-2.35 (m, 1H), 2.11 (brs,1H),1.79–1.65(m,1H),1.53(brs,1H).
13C NMR(100MHz,CDCl3)δ158.05,138.23,138.07,137.60,129.12,127.63, 127.54,126.60,126.53,126.07,125.89,119.23,112.67,112.16,83.02,63.94,61.17, 60.62,54.10,47.01,30.56.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=9.22 minutes, tminor=8.06 minutes
Optical activity product (7b)1H NMR schematic diagrames are as shown in figure 50, its13C NMR schematic diagrames are as shown in figure 50, its As shown in figure 55, its chiral product liquid phase figure is as shown in figure 50 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.40–7.34(m,4H),7.31–7.19(m,7H),6.86–6.79(m,2H), 6.77 (s, 1H), 4.58 (q, J=12.2Hz, 2H), 4.04 (q, J=12.7Hz, 2H), 3.64 (s, 3H), 3.40-3.27 (m, 1H),3.24–3.08(m,2H),2.13–1.98(m,1H),1.99–1.86(m,1H),1.79(brs,1H),1.42(brs, 1H).
13C NMR(100MHz,CDCl3)δ159.67,141.84,139.67,139.36,130.21,129.49, 128.41,127.93,127.16,126.97,126.65,118.98,112.99,112.86,84.34,65.70,65.43, 61.06,55.09,51.81,32.74.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=6.61 minutes, tminor=10.59 minutes
Embodiment 8
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By 2- bromophenyl diazoacetic acid methyl esters (2.0mmol), phenmethylol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, by mixed solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Diazo decomposition is treated completely, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this intermediate It is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), net product is obtained, its structure such as formula (8a) and (8b) institute Show, (8a) is (2S, 3S) -2- benzyloxy -2- o-bromophenyls -3- phenyl -1,5-PD, (8b) is (2R, 3S) -2- benzyloxies Base -2- o-bromophenyls -3- phenyl -1,5-PD, the gross production rate of (8a) and (8b) is 68%, dr values (8a)：(8b) is equal to 37： 63.The ee values of (8a) are equal to 92%, and the ee values of (8b) are equal to 98%.
Optical activity product (8a)1H NMR schematic diagrames are as shown in figure 50, its13C NMR schematic diagrames are as shown in figure 50, its As shown in figure 59, its chiral product liquid phase figure is as shown in figure 50 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.54–7.36(m,4H),7.34–7.27(m,3H),7.22–7.08(m,3H), 7.06-6.97 (m, 2H), 6.88-6.60 (m, 2H), 4.56-4.29 (m, 2H), 3.94 (d, J=4.8Hz, 2H), 3.57 (dd, J =11.6,3.2Hz, 1H), 3.49-3.26 (m, 2H), 2.63-2.46 (m, 1H), 2.15-2.00 (m, 1H), 1.82-1.67 (m, 1H),1.36(s,1H).
13C NMR(100MHz,CDCl3)δ139.27,138.57,137.27,130.10,128.59,127.92, 127.71,127.67,127.60,127.15,126.93,84.04,64.88,62.05,61.73,48.02,31.66.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=15.82 minutes, tminor=5.99 minutes
Optical activity product (8b)1H NMR schematic diagrames are as shown in Figure 61, its13C NMR schematic diagrames are as shown in Figure 62, its As shown in Figure 63, its chiral product liquid phase figure is as shown in Figure 64 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.45–7.35(m,5H),7.34–7.26(m,4H),7.25–7.18(m,5H), 4.59 (q, J=12.2Hz, 2H), 4.17-3.98 (m, 2H), 3.44-3.31 (m, 1H), 3.25-3.16 (m, 1H), 3.13 (dd, J=11.6,3.3Hz, 1H), 2.14-2.03 (m, 1H), 2.01-1.90 (m, 1H), 1.09 (brs, 1H)
13C NMR(100MHz,CDCl3)δ140.23,139.77,139.32,130.10,128.46,128.43, 128.01,127.42,127.20,126.99,126.90,126.72,84.21,65.68,65.55,61.13,52.30, 32.81.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=5.77 minutes, tminor=8.11 minutes
Embodiment 9
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By 4- aminomethyl phenyl diazoacetic acid methyl esters (2.0mmol), phenmethylol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, by mixed solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Diazo decomposition is treated completely, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this intermediate It is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), net product is obtained, its structure such as formula (9a) and (9b) institute Show, (9a) is (2S, 3S) -2- benzyloxy -2- p-methylphenyls -3- phenyl -1,5-PD, (9b) is (2R, 3S) -2- benzyloxies Base -2- p-methylphenyls -3- phenyl -1,5-PD, the gross production rate of (9a) and (9b) is 66%, dr values (9a)：(9b) is equal to 50：50.The ee values of (9a) are equal to 96%, and the ee values of (9b) are equal to 98%.
Optical activity product (9a)1H NMR schematic diagrames are as shown in Figure 65, its13C NMR schematic diagrames are as shown in Figure 66, its As shown in Figure 67, its chiral product liquid phase figure is as shown in Figure 66 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.53–7.32(m,4H),7.32–7.25(m,1H),7.21–7.01(m,5H), 6.88 (d, J=7.4Hz, 2H), 6.83-6.52 (m, 2H), 4.40 (s, 2H), 3.88 (s, 2H), 3.54 (dd, J=11.3, 2.5Hz,1H),3.48–3.35(m,1H),3.35–3.21(m,1H),2.64–2.44(m,1H),2.34(s,3H),2.31– 2.10(m,1H),1.91–1.49(m,2H).
13C NMR(100MHz,CDCl3)δ139.48,138.70,137.35,134.18,130.16,128.58, 128.43,127.88,127.66,127.55,127.18,126.86,83.94,64.74,62.07,61.66,47.95, 31.75,21.12.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=18.20 minutes, tminor=6.11 minutes
Optical activity product (9b)1H NMR schematic diagrames are as shown in Figure 66, its13C NMR schematic diagrames are as shown in Figure 74, its As shown in Figure 71, its chiral product liquid phase figure is as shown in Figure 74 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.47–7.32(m,4H),7.30–7.26(m,1H),7.25–7.17(m,5H), 7.15-7.01 (m, 4H), 4.56 (d, J=12.2Hz, 1H), 4.50 (d, J=12.2Hz, 1H), 4.02 (s, 2H), 3.46- (brs, the 1H) of 3.26 (m, 1H), 3.12 (d, J=7.8Hz, 2H), 2.32 (s, 3H), 2.10-1.84 (m, 3H), 1.69
13C NMR(100MHz,CDCl3)δ139.81,139.48,137.03,136.88,130.28,129.10, 128.41,127.88,127.14,126.96,126.88,126.69,84.13,65.46,65.26,60.96,51.71, 32.77,21.08.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=5.91 minutes, tminor=8.33 minutes
Embodiment 10
The first step is reacted, by cinnamic acid (1.0mmol), double (1,5- cyclo-octadiene) tetrafluoro boric acid iridium (0.1mmol), chirality Diphenylprolinol dimethyl tertiary butyl silicon ether (0.2mmol), 4- nitrobenzoic acids (0.4mmol) andMolecular sieve (90mg) It is dissolved in 5mL dichloromethane, is configured to mixed solution A, is stirred 1 hour at 25 DEG C；By 4- bromophenyl diazoacetic acid methyl esters (2.0mmol), phenmethylol (2.0mmol) are dissolved in 5mL dichloromethane and are configured to mixed solution B；At 25 DEG C, by mixed solution B is added in foregoing mixed solution A with syringe pump, stirring, is reacted.Diazo decomposition is treated completely, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:100 be eluant, eluent), obtain intermediate.Second step reacts, by this intermediate It is dissolved in 5mL dichloromethane, is stirred at 40 DEG C, sodium borohydride (10.0mmol) is added portionwise, after reaction terminates, by crude product Column chromatography is carried out (with ethyl acetate：Petroleum ether=1:10 be eluant, eluent), net product is obtained, its structure such as formula (10a) and (10b) Shown, (10a) is (2S, 3S) -2- benzyloxy -2- p-bromophenyls -3- phenyl -1,5-PD, and (10b) is (2R, 3S) -2- benzyls Epoxide -2- p-bromophenyls -3- phenyl -1,5-PD, the gross production rate of (10a) and (10b) is 62%, dr values (10a)：(10b) Equal to 50：50.The ee values of (10a) are equal to 97%, and the ee values of (10b) are equal to 97%.
Optical activity product (10a)1H NMR schematic diagrames are as shown in Figure 74, its13C NMR schematic diagrames are as shown in Figure 74, its As shown in Figure 75, its chiral product liquid phase figure is as shown in Figure 75 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.55–7.36(m,6H),7.35–7.30(m,1H),7.22–7.07(m,3H), 6.89 (d, J=8.2Hz, 2H), 6.83-6.62 (m, 2H), 4.42 (dd, J=27.1,11.7Hz, 2H), 3.90 (s, 2H), 3.56 (dd, J=11.7,3.0Hz, 1H), 3.51-3.39 (m, 1H), 3.39-3.25 (m, 1H), 2.58-2.40 (m, 1H), 2.11(brs,1H),1.78–1.65(m,1H),1.42(brs,1H).
13C NMR(100MHz,CDCl3)δ138.88,138.29,136.69,130.84,130.05,129.67, 128.65,127.85,127.71,127.10,121.89,83.83,64.90,62.07,61.46,47.69,31.48.
(chiral IA posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=9.38 minutes, tminor=6.88 minutes
Optical activity product (10b)1H NMR schematic diagrames are as shown in Figure 75, its13C NMR schematic diagrames are as shown in Figure 75, its As shown in Figure 79, its chiral product liquid phase figure is as shown in Figure 75 for racemic product liquid phase figure.
1H NMR(400MHz,CDCl3)δ7.52–7.43(m,2H),7.42–7.34(m,4H),7.34–7.28(m,1H), 7.27-7.19 (m, 5H), 7.13 (d, J=8.5Hz, 2H), 4.54 (dd, J=43.5,12.1Hz, 2H), 4.05 (s, 2H), 3.38 (ddd, J=10.9,6.9,4.3Hz, 1H), 3.27-3.16 (m, 1H), 3.13 (dd, J=11.7,3.3Hz, 1H), 2.13–2.00(m,1H),1.98–1.86(m,1H),1.61(s,2H).
13C NMR(100MHz,CDCl3)δ139.50,139.39,138.97,131.50,130.09,128.79, 128.49,128.10,127.34,127.13,126.67,121.50,83.96,65.65,65.20,60.94,51.84, 32.62.
(chiral IC posts, wavelength is equal to 220 nanometers, n-hexane to HPLC：Isopropanol=4.5：1, the ml/min of flow velocity=1.0 Clock), tmajor=5.37 minutes, tminor=4.66 minutes.
Embodiment 11
The compounds of this invention bioactivity is tested with CCK8 methods in the present embodiment, prepared using embodiment 10 The compounds of this invention (10a), (2S, 3S) -2- benzyloxy -2- p-bromophenyls -3- phenyl-(numbering is FB1- to 1,5-PD 3-S) and embodiment 10 prepares the compounds of this invention (10b), (2R, 3S) -2- benzyloxy -2- p-bromophenyl -3- phenyl -1, 5- pentanediols (numbering is FB1-3-X) carry out its inhibitory action research to tumour cell.The specifically used cell of the present embodiment It is to be：HCT116 (human colon cancer cell).
1st, inoculating cell：It is made into the McCoy'5A nutrient solutions containing 10% hyclone, 1% penicillin and streptomysin single Cell suspension, 96 porocyte culture plates are inoculated into every 3000 cells in hole, per the μ l of pore volume 100.
2nd, the compounds of this invention is prepared as powdered drug by process step of milling, powdered drug is configured to final concentration For 10mM mother liquor, then gradient is diluted to 0.01mM, 0.03mM, 0.1mM, 0.3mM, 1mM, 3mM, 10mM, 30mM successively.Make For cell, every group of concentration sets three multiple holes.
3rd, it is administered：Gradient mother liquor is diluted to 0.01 μM of final concentration, 0.03 μM, 0.1 μM, 0.3 μM, 1 μ with complete medium M, 3 μM, 10 μM, 30 μM, DMSO contents in cell, every group of concentration three multiple holes of setting, nutrient solution are acted on per the μ l of hole 200 is 1‰。
4th, cultivate：5%CO2, 37 DEG C of saturated humidities educate incubator culture 72 hours.
5th, colour generation：Culture suctions out culture medium in 72 hours, and complete 1640 culture mediums of 100 μ l and 10 μ l CCK8,37 are added per hole DEG C be incubated 4 hours.
6th, colorimetric：Selection 620,450nm wavelength, determine each hole optical density (OD) value on ELIASA, record result.
7th, same hole 450nm absorption photometric value -620nm absorption photometric values (background absorption photometric value) are used as final extinction Degree, substitutes into below equation.
8th, cell proliferation activity (%)=[A (dosing)-A (blank)]/[A (0 dosing)-A (blank)] × 100
A (dosing)：The absorbance in the hole with cell, CCK solution and drug solution
A (blank)：With culture medium and CCK solution without the absorbance in the hole of cell
A (0 dosing)：With cell, CCK solution without the absorbance in the hole of drug solution
9th, test result indicates that：In the presence of concentration is 10,30 μM of the compounds of this invention, HCT116 cell-proliferation activities Substantially suppressed.
As shown in Figure 81 for HCT116 (human colon cancer cell) in the compounds of this invention (numbering FB1-3-S, FB1-3-X) no With the survival rate under concentration, using concentration as abscissa, survival rate is concentration-Survival curves that ordinate is drawn.From curve It can know, half lethal concentration IC of the compounds of this invention (FB1-3-S, FB1-3-X) to HCT116 (human colon cancer cell)50Point Wei not be 11.87 μM, 21.99 μM.
As can be seen here, FB1-3-S, FB1-3-X of the present invention are inhibited to HCT116 (human colon cancer cell) activity, Suitable for the application and preparation of antineoplastic.

Claims (11)

1. optical activity 1,5-PD derivative, it is characterised in that shown in structure such as formula (Ia) and formula (Ib),
Wherein,
Ar1For aryl, the phenyl that replaces selected from phenyl, halogen, the phenyl of methoxy substitution, the alkyl-substituted phenyl of C1-C3, The phenyl of nitro substitution；
Ar2For aryl, phenyl, the phenyl of methoxy substitution, the alkyl-substituted phenyl of C1-C3 replaced selected from phenyl, halogen；
Ar3For aryl, phenyl, the phenyl of methoxy substitution, the alkyl-substituted phenyl of C1-C3 replaced selected from phenyl, halogen.
2. the synthetic method of optical activity 1,5-PD derivative as claimed in claim 1, it is characterised in that organic molten In agent, with formula (1) α, beta-unsaturated aldehyde, formula (2) diazonium compound, formula (3) benzylalcohol derivative are raw material, withMolecular sieve is Water absorbing agent, using metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether and substituted benzoic acid as catalyst system and catalyzing, hydrogen reagent is born with metal For reducing agent, reacted, obtain the optical activity 1,5-PD of the high enantioselectivity as shown in formula (Ia) and formula (Ib) Derivative；Shown in the course of reaction such as formula (II)：
3. synthetic method as claimed in claim 2, it is characterised in that methods described specifically includes following steps：(1) with formula (1) α, beta-unsaturated aldehyde, formula (2) diazonium compound, formula (3) benzylalcohol derivative are raw material, withMolecular sieve is water absorbing agent, with Metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether and substituted benzoic acid are catalyst system and catalyzing, in organic solvent, at 0~40 DEG C Under the conditions of carry out three component reactions and obtain the double arylpentanoic ester derivants of intermediate 2- benzyloxy -5- oxos -2,3-；(2) with gold The negative hydrogen reagent of category in organic solvent, carries out reduction reaction as reducing agent under the conditions of 20~50 DEG C, obtains the optics and lives Property 1,5- pentanediol derivatives.
4. synthetic method as claimed in claim 2 or claim 3, it is characterised in that formula (2) diazonium compound, formula (3) benzylalcohol spread out Biology, formula (1) alpha, beta-unsaturated aldehyde, metallic catalyst, chiral diaryl dried meat ammonia alcohol silicon ether, substituted benzoic acid, metal bear hydrogen examination The mol ratio of agent is 1.0-3.0:1.0-2.5:1.0:0.05-0.2:0.15-0.2:0.15-0.5:10；Molecular sieve feeds intake Measure as 50~100mg/mmol alpha, beta-unsaturated aldehydes.
5. synthetic method as claimed in claim 2 or claim 3, it is characterised in that the structure of the chiral diaryl dried meat ammonia alcohol silicon ether As shown in formula (III),
Wherein, R1For trimethyl silicon substrate, triethyl group silicon substrate, dimethyl tertiary butyl silicon substrate；Ar4For phenyl or 3,5- bis trifluoromethyls Phenyl.
6. synthetic method as claimed in claim 2 or claim 3, it is characterised in that shown in the substituted benzoic acid structure such as formula (IV),
Wherein, R includes hydrogen, 3,5- bis trifluoromethyls, nitro, methoxyl group, halogen.
7. synthetic method as claimed in claim 2 or claim 3, it is characterised in that the metallic catalyst is iridium compound, palladium is combined Thing or rhodium complex；It is Lithium Aluminium Hydride or sodium borohydride that the metal, which bears hydrogen reagent,.
8. synthetic method as claimed in claim 2 or claim 3, it is characterised in that the organic solvent includes dichloromethane, tetrahydrochysene furan Mutter, toluene, chloroform.
9. the optical activity 1,5- pentanediols derivative as shown in formula (Ia) and formula (Ib) is preparing doctor as claimed in claim 1 Application in medicine intermediate.
10. the optical activity 1,5- pentanediols derivative shown in formula (Ia) as claimed in claim 1 and formula (Ib) is anti-in preparation Application in tumour medicine.
11. application as claimed in claim 10, it is characterised in that the tumour includes colon cancer.
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