CN107488089A

CN107488089A - Have axial chirality and the high optical activity allenic compound and its construction method of central chirality and application concurrently

Info

Publication number: CN107488089A
Application number: CN201710669453.7A
Authority: CN
Inventors: 麻生明; 戴健鑫; 段鑫宇; 傅春玲
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2017-08-08
Filing date: 2017-08-08
Publication date: 2017-12-19

Abstract

Have the method for the high optical activity allenic compound of axial chirality and central chirality concurrently the invention discloses a kind of direct construction, that is formula (1) 2,3 alkenyl-functional groups compounds and formula (2) nucleopilic reagent, in the presence of palladium catalyst, chiral diphosphine ligand and alkali, reacted in organic solvent, a step direct construction has the high optical activity allenic compound of axial chirality and central chirality concurrently.The inventive method is simple to operate, and raw material and reagent are easy to get, and reaction condition is gentle, and substrate universality is wide, and functional group compatibility is good, the stereoselectivity of product it is extremely outstanding (>99:1d.r., 95%~>99%ee).The high optical activity allenic compound that the present invention obtains, the compounds such as single fluoromethylation connection alkene containing multiple chiral centers, γ connection olefin(e) acids ester, γ connection olefin(e) acid, γ connection enol, gamma butyrolactone can be constructed as important intermediate.

Description

Have axial chirality and the high optical activity allenic compound of central chirality and its structure side concurrently Method and application

Technical field

The invention belongs to chemosynthesis technical field, specifically, is related to a kind of direct construction and has axial chirality and center concurrently The method of chiral high optical activity allenic compound.

Background technology

It is well known that chiral phenomenon is widely existed in nature.Research for chirality, the mankind have been inspired to changing Learn, physics and life science are re-recognized.Chiral molecules can be divided into polytype, in being widely studied The heart is chiral outer, also axial chirality, planar chiral；The chiral molecules of various configuration may have different physics and chemical property with And physiologically active.Therefore, how efficiently to construct chiral molecules is extremely important part in spatial chemistry research.Shi Zhijin Day, although how people are being constructed only containing having made substantial progress on a kind of molecule of chiral centre, how efficiently structure Build the molecule containing a variety of chiral centres be still one challenge, and at this stage asymmetric chemistry research emphasis.Some are multiple Miscellaneous drug molecule and natural products would generally include multiple, even a variety of chiral centres.For example, many have potential application valency The connection alkene natural products and drug molecule of value just contain axial chirality and central chirality (Ref simultaneously:(a)Kennedy,D.J.； Selby,I. A.；Cowe,H.J.；Cox,P.J.；Thomson,R.H.J.Chem.Soc.,Chem.Commun.1984,153. (b)Umehara,K.；Hattori,I.；Miyase,T.；Ueno,A.；Hara,S.；Kageyama,C.Chem. Pharm.Bull.1988,36,5004.(c)Eglen,R.M.；Whiting,R.L.；Br.J.Pharmacol.1989, 98, 1335.(d)Liu,L.；Liu,S.；Chen,X.；Guo,L.；Che,Y.Bioorgan.Med.Chem.2009, 17,606.). Therefore, the novel strategy of practicality is developed, it is efficient, highly-solid selectively to construct the molecule containing a variety of chiral centres, draw The great interest of scientific worker is played.

At present, enol derivatives and nucleopilic reagent (such as malonate, mono-substituted malonic acid are joined using 2, the 3- to disappear outside Ester, primary amine, secondary amine etc.) reacted under the catalysis of different Phosphine ligands and palladium, it can be obtained in when outstanding enantioselectivity To a series of optically active allenic compounds.But in existing document report, only when reactant is the nucleophilic of big steric hindrance When reagent or connection alkene containing one big steric hindrance R group, chiral connection ene product could be obtained with higher enantioselectivity；And this Class method can only be used to synthesis and only have a kind of high optical activity allenic compound of chiral centre so far, otherwise only contain axle Chirality (Ref:(a)Imada,Y.；Ueno,K.； Kutsuwa,K.；Murahashi,S.-I.Chem.Lett.2002,140. (b)Imada,Y.；Nishida,M.； Kutsuwa,K.；Murahashi,S.-I.；Naota,T.；Org,Lett.2005,7, 5837.(c)Imada,Y.； Nishida,M.；Naota,T.Tetrahedron Lett.2008,49,4915.(d)Trost, B.M.；Fandrick,D. R.；Dinh,D.C.J.Am.Chem.Soc.2005,127,14186.(e)Nemoto,T.； Kanematsu,M.； Tamura,S.；Hamada,Y.Adv.Synth.Catal.2009,351,1773.(f)Wan,B.；Ma, S. Angew.Chem.Int.Ed.2013,52,441.), or only contain central chirality (Ref:(a)Li,Q.；Fu,C.； Ma, S.Angew.Chem.Int.Ed.2012,51,11783.(b)Li,Q.；Fu,C.；Ma,S.Angew. Chem.Int.Ed.2014,53,6511.).So contain a variety of hands simultaneously using constructing for this high enantioselectivity of strategy The allenic compound at property center still suffers from huge challenge.

The content of the invention

The high optical activity for having axial chirality and central chirality concurrently it is an object of the invention to provide a kind of direct construction joins alkylene The method of compound, i.e., alkenyl-functional groups compound and nucleopilic reagent are joined by 2,3-, in palladium catalyst, chiral diphosphine ligand and alkali In the presence of, react in organic solvent, a step direct construction has the high optical activity connection alkylene of axial chirality and central chirality concurrently Compound.

The present invention is realized using technical scheme in detail below：

The method that direct construction provided by the invention has the high optical activity allenic compound of axial chirality and central chirality concurrently, Including：In the presence of palladium catalyst, chiral diphosphine ligand and alkali, 2,3- shown in formula (1) connection alkenyl-functional groups compound and Nucleopilic reagent shown in formula (2) carries out transition metal-catalyzed asymmetric connection olefination, step generation in organic solvent Have the high optical activity allenic compound of axial chirality and central chirality concurrently, course of reaction is reacted shown in formula (I) as follows：

Wherein, 2 described, 3- connection alkenyl-functional groups compound 1 is outer disappear substrate or optical activity substrate.

Wherein, R¹For alkyl, the alkyl with functional group, phenyl, aryl or heterocyclic radical；R²For hydrogen atom, alkyl, band There are the alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For alkyl, the alkyl with functional group, phenyl or aryl；LG For acetate, carbonic ester, phosphate, phosphite ester, sulphonic acid ester or halogen atom；R is hydrogen atom, halogen atom, alkyl, benzene Base or aryl；E is drawing electron group, is one kind in ester group, sulfonyl, cyano group, acyl group.The aryl is o-, m-, contraposition There is the phenyl of electrophilic or electron substituent；The heterocyclic radical is thiophene, furans or pyridine or has electrophilic or electron Thiophene, furans or the pyridine of substituent.

Preferably, R¹For C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical； R²For hydrogen atom, C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For C1- C20 alkyl, end carry the C1-C20 alkyl of functional group, phenyl or aryl；LG is acetate, carbonic ester, phosphate, or Halogen atom；R is hydrogen atom, halogen atom, C1-C20 alkyl, phenyl or aryl；E is drawing electron group, is ester group, sulphonyl One kind in base, cyano group, acyl group.Wherein, in C1-C20 alkyl of the end with functional group, it is double that the functional group is selected from carbon-to-carbon Key, the key of carbon-to-carbon three, hydroxyl, oxyl, silicon ether, acyloxy, ester group, acyl group, amide groups, sulfonic group, halogen, sulfonyl, carboxylic Base, cyano group, nitro, the amino of alkyl substitution, the amino of acyl group substitution；The aryl is o-, m-, contraposition has electrophilic or to electricity The phenyl of sub- substituent, the heterocyclic radical be thiophene, furans or pyridine or have the thiophene of electrophilic or electron substituent, Furans or pyridine, the electron-withdrawing substituent include halogen, nitro, ester group, carboxyl, acyl group, amide groups, sulfonyl, sulfonic group, Cyano group, the electron substituent include alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, amino, acyloxy, alkyl substitution Amino, acyl group substitution amino.

It is further preferred that R¹For C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl, aryl or Heterocyclic radical；R²For hydrogen atom, C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³ For C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl or aryl；LG is acetate, carbonic ester, phosphoric acid Ester；R is hydrogen atom, halogen atom, C1-C10 alkyl, phenyl or aryl；E is drawing electron group, is ester group, sulfonyl, cyanogen One kind in base.Wherein, in C1-C10 alkyl of the end with functional group, the functional group is selected from Wherein, R is C1~C20 alkyl, Phenyl, or aryl, n=0~20, Y are hydrogen, C1~C20 alkyl, acyl group, silicon ethers protection group (including tert-butyldimethyl silyl Base (TBS), triethyl group silicon substrate (TES), tert-butyl diphenyl silicon substrate (TBDPS))；The aryl is o-, m-, contraposition has electrophilic Or the phenyl of electron substituent, the heterocyclic radical are thiophene, furans or pyridine or have electrophilic or electron substituent Thiophene, furans or pyridine, the electron-withdrawing substituent include halogen, nitro, ester group, carboxyl, acyl group, sulfonyl, sulfonic group, cyanogen Base, the electron substituent include alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, amino, acetylamino, diformazan ammonia Base.

It is further preferred that R¹Selected from C1-C10 straight chained alkyls, C1-C10 cycloalkyl, end carries the C1-C10 of functional group Alkyl, phenyl, the phenyl of alkyl substitution, the phenyl of halogen substitution, the phenyl of oxyl substitution；R²Selected from hydrogen, C1-C10 straight chains Alkyl, C1-C10 cycloalkyl, C1-C10 alkyl of the end with functional group, phenyl, the phenyl of alkyl substitution, halogen substitution Phenyl, the phenyl of oxyl substitution；R³Selected from C1-C10 straight chained alkyls, end carries the C1-C10 alkyl of functional group, phenyl, The phenyl of alkyl substitution, the phenyl of halogen substitution, the phenyl of oxyl substitution；LG is selected from acetate；R is selected from hydrogen, fluorine, chlorine, bromine, Iodine, C1-C6 alkyl, phenyl；E is selected from ester group, sulfonyl；Wherein, it is described in C1-C10 alkyl of the end with functional group Functional group is selected fromWherein, R is C1~C10 alkyl, n=0~10, Y be hydrogen, C1~C10 alkyl, acyl group, silicon ethers protection group (including t-Butyldimethylsilyl (TBS), triethyl group silicon substrate (TES), tertiary fourth Base diphenyl silicon substrate (TBDPS)).

It is further preferred that R¹Selected from normal-butyl, n-heptyl, cyclohexyl, cyclopropyl, phenylpropyl, phenyl, to methylbenzene Base, p-bromophenyl, rubigan；R²Selected from hydrogen, normal-butyl, n-heptyl, cyclohexyl, cyclopropyl, phenylpropyl, phenyl, to methyl Phenyl, p-bromophenyl, rubigan；R³Selected from normal-butyl, n-hexyl, n-heptyl, n-nonyl,LG is selected from acetate；R is selected from hydrogen, fluorine；E is selected from carbethoxyl group (CO₂Et), benzene sulfonyl Base (SO₂Ph)。

As a further improvement, the concrete operation step of the present invention is as follows：

1) in glove box, in oil bath, put into successively into dry reaction tube palladium catalyst, chiral diphosphine ligand and Alkali, reaction tube is taken out, add the organic solvent of certain volume in a nitrogen atmosphere；Reaction tube is placed in and is previously heated to necessarily In the oil bath of temperature, 5-60 minutes (preferably 30 minutes) are stirred；Wherein, the organic solvent of the certain volume refers to 1 material On the basis of the dosage of (2, the 3- connection alkenyl-functional groups compound shown in formula (1)), the dosage of the organic solvent is 0.5- 10.0mL/mmol, the certain temperature refer to 20-50 DEG C；

2) after the completion for the treatment of step 1), reaction tube is proposed from oil bath, 2,3- connection alkenyl-functional groups are added under nitrogen atmosphere The organic solvent of compound, nucleopilic reagent and certain volume, then reaction tube is put back in oil bath and heated, stirring reaction；Wherein, institute The organic solvent for stating certain volume refers to that on the basis of the dosage of 1 material the dosage of the organic solvent is 0.5-10.0mL/ mmol；

3) after step 2) reaction completely, the ethyl acetate of certain volume is added into reaction tube, gained mixed liquor is used full Washed 3 times with salt, separate organic phase, the ether of aqueous phase certain volume extracts 1 time, merges all organic phases, use is anhydrous Sodium sulphate is dried, and is filtered, and concentration, rapid column chromatography obtains final product；Wherein, the ethyl acetate of the certain volume refers to chemical combination Thing；Wherein, the ethyl acetate of the certain volume refers on the basis of the dosage of 1 material, and the dosage of the ethyl acetate is 1.0-100mL/mmol, the ether of the certain volume refer to that on the basis of the dosage of 1 material the dosage of the ether is 1.0- 100mL/mmol。

As a further improvement, palladium catalyst of the present invention is two (cinnamyl palladium bichlorides), two (pi-allyl chlorinations Palladium), tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium, two (dibenzalacetone) one palladium, palladium bichloride, palladium, two (triphenylphosphine) palladium bichloride, any one or more in two (acetonitrile) palladium bichlorides；Preferably, it is two (cinnamyl palladium bichlorides).

As a further improvement, (R)-L1~(R) of the chiral diphosphine ligand of the present invention selected from following structure- L5 and its enantiomter (S)-L1~(S)-L5 one or more；Wherein Ar is phenyl, aryl or heterocyclic radical, the aryl It is o-, m-, aligns the phenyl for having alkyl or oxyl substitution, the heterocyclic radical is thiophene, furans or pyridine；Preferably, it is described Ar is phenyl, 3,5- di-t-butyl -4- methoxyphenyls.

Preferably, described chiral diphosphine ligand is (R)-L5 and/or its enantiomter (S)-L5, wherein Ar are benzene Base, aryl or heterocyclic radical, the aryl is o-, m-, contraposition has alkyl or the phenyl of oxyl substitution, wherein, the alkyl bag Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group are included, the oxyl includes ethyoxyl, propoxyl group, isopropyl oxygen Base, butoxy, isobutoxy, tert-butoxy, oxyl；The heterocyclic radical is thiophene, furans or pyridine；Preferably, the Ar For phenyl, 3,5- di-t-butyl -4- methoxyphenyls.

As a further improvement, chiral diphosphine ligand of the present invention is selected from (R)-L5a or its enantiomter (S) one or more in-L5a, (R)-L5b or its enantiomter (S)-L5b, wherein, (the R)-L5a, (R)-L5b Structure it is as follows：

(R)-L5a, Ar=3,5- di-t-butyl -4- methoxyphenyls

(R)-L5b, Ar=phenyl

As a further improvement, alkali of the present invention is inorganic base, selected from potassium carbonate, cesium carbonate, sodium phosphate, phosphoric acid Potassium, sodium dihydrogen phosphate, potassium hydroxide, sodium hydroxide, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide, any one in sodium hydride It is or a variety of；Preferably, it is potassium carbonate.

As a further improvement, organic solvent of the present invention is 1-METHYLPYRROLIDONE, and N, N- dimethyl formyls Amine, DMA, dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, acetonitrile, ether, butyl ether, methyl tertbutyl Any one or more in ether；Preferably, it is the mixture of 1-METHYLPYRROLIDONE, DMF or both.

As a further improvement, the temperature of reaction of the present invention is 20-50 DEG C；Preferably, it is 30 DEG C.

As a further improvement, the time of reaction of the present invention is 2-48 hours；Preferably, it is 12 hours.

As a further improvement, formula (1) 2 of the present invention, 3- connection alkenyl-functional groups compound, the examination of formula (2) nucleophilic Agent, palladium catalyst, the mol ratio (or mass ratio) of chiral diphosphine ligand and alkali are 1.0：1.0–3.0： 0.005–0.1：0.012– 0.24：1.0–3.0；Preferably, it is 1.0：2.0：0.025：0.06：2.0.

Present invention also offers the high optical activity allenic compound for having axial chirality and central chirality concurrently, its structure is such as (R_a,S)-3,(S_a, R) and shown in -3：

Wherein, R¹For alkyl, the alkyl with functional group, phenyl, aryl or heterocyclic radical；R²For hydrogen atom, alkyl, band There are the alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For alkyl, the alkyl with functional group, phenyl or aryl；LG For acetate, carbonic ester, phosphate, phosphite ester, sulphonic acid ester or halogen atom；R is hydrogen atom, halogen atom, alkyl, benzene Base or aryl；E is drawing electron group, is one kind in ester group, sulfonyl, cyano group, acyl group.Wherein, the aryl be it is adjacent, Between, contraposition have the phenyl of electrophilic or electron substituent；The heterocyclic radical is thiophene, furans or pyridine or has electrophilic Or thiophene, furans or the pyridine of electron substituent.

Preferably, R¹For C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical； R²For hydrogen atom, C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For C1- C20 alkyl, end carry the C1-C20 alkyl of functional group, phenyl or aryl；LG is acetate, carbonic ester, phosphate, phosphorous Acid esters, sulphonic acid ester or halogen atom；R is hydrogen atom, halogen atom, C1-C20 alkyl, phenyl or aryl；E is drawing electronics Group, it is one kind in ester group, sulfonyl, cyano group, acyl group.Wherein, in C1-C20 alkyl of the end with functional group, the official It can roll into a ball selected from carbon-to-carbon double bond, the key of carbon-to-carbon three, hydroxyl, oxyl, silicon ether, acyloxy, ester group, acyl group, amide groups, sulfonic acid Base, halogen, sulfonyl, carboxyl, cyano group, nitro, the amino of alkyl substitution, the amino of acyl group substitution；The aryl be it is o-, m-, Contraposition has the phenyl of electrophilic or electron substituent, the heterocyclic radical be thiophene, furans or pyridine or have electrophilic or to Thiophene, furans or the pyridine of electron substituent group, the electron-withdrawing substituent include halogen, nitro, ester group, carboxyl, acyl group, acid amides Base, sulfonyl, sulfonic group, cyano group；The electron substituent includes alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, ammonia Base, acyloxy, the amino of alkyl substitution, the amino of acyl group substitution.

It is further preferred that R¹For C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl, aryl or Heterocyclic radical；R²For hydrogen atom, C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³ For C1-C10 alkyl, end carries the C1-C10 alkyl of functional group, phenyl or aryl；LG is acetate, carbonic ester, phosphoric acid Ester,；R is hydrogen atom, halogen atom, C1-C10 alkyl, phenyl or aryl；E is drawing electron group, be ester group, sulfonyl, One kind in cyano group, acyl group.Wherein, in alkyl of the end with functional group, wherein, end carries the C1-C10 alkyl of functional group In, the functional group is selected fromIts In, R is C1~C20 alkyl, phenyl, aryl, n=0~20, Y be hydrogen, C1~C20 alkyl, acyl group, silicon ethers protection group (including T-Butyldimethylsilyl (TBS), triethyl group silicon substrate (TES), tert-butyl diphenyl silicon substrate (TBDPS))；The aryl be it is adjacent, Between, contraposition have the phenyl of electrophilic or electron substituent, the heterocyclic radical is thiophene, furans or pyridine or has electrophilic Or thiophene, furans or the pyridine of electron substituent, the electron-withdrawing substituent include halogen, nitro, ester group, carboxyl, acyl group, Sulfonyl, sulfonic group, cyano group；The electron substituent include alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, amino, Acetylamino, dimethylamino.

It is further preferred that R¹Selected from C1-C10 straight chained alkyls, C1-C10 cycloalkyl, end carries the C1-C10 of functional group Alkyl, phenyl, the phenyl (such as methyl substituted phenyl) of alkyl substitution, the phenyl of halogen substitution, the phenyl of oxyl substitution；R² Selected from hydrogen, C1-C10 straight chained alkyls, C1-C10 cycloalkyl, end carries the C1-C10 alkyl of functional group, phenyl, alkyl substitution Phenyl (such as methyl substituted phenyl), the phenyl of halogen substitution, the phenyl of oxyl substitution；R³Selected from C1-C10 straight chained alkyls, End carries the C1-C10 alkyl of functional group, phenyl, the phenyl of alkyl substitution, the phenyl of halogen substitution, the benzene of oxyl substitution Base；LG is selected from acetate；R is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, phenyl；E is selected from ester group, sulfonyl；Wherein, In C1-C10 alkyl of the end with functional group, the functional group is selected from Its In, R is C1~C10 alkyl, and n=0~10, Y are hydrogen, C1~C10 alkyl, acyl group, silicon ethers protection group (including the tert-butyl group two Methylsilyl (TBS), triethyl group silicon substrate (TES), tert-butyl diphenyl silicon substrate (TBDPS)).

Present invention also offers formula (R_a,S)-3,(S_a, R) shown in -3 have axial chirality concurrently and the high optics of central chirality is lived Property allenic compound prepare containing multiple chiral centers single fluoromethylation connection alkene, γ-connection olefin(e) acid ester, γ-connection olefin(e) acid, γ- Join enol, the application in gamma-butyrolacton compound, wherein, the multiple chiral centre refer to two or more it is identical or The chiral centre differed.

The innovative point of the present invention is that the present invention passes through in formula (1) 2, the α of the connection alkenyl of 3- connection alkenyl-functional groups compounds Position introduces a R³Group, utilize R³Group caused space steric effect in the reaction, is controlled with higher enantioselectivity The axial chirality of product；Further, since a new asymmetric carbon atom (central chirality), both different types are introduced simultaneously Chiral centre between there is cooperative effect；Therefore, under single chiral part and palladium chtalyst, the present invention realizes asymmetry Axial chirality and controlled in connection olefination while central chirality, developed first based on this it is a kind of efficiently, practical, high selection The method that one step direct construction of property has the high optical activity allenic compound of axial chirality and central chirality concurrently.What the present invention obtained Chirality connection ene product, single fluoromethylation connection alkene, the γ-connection containing multiple chiral centers can be constructed as important intermediate The compounds such as olefin(e) acid ester, γ-connection olefin(e) acid, γ-connection enol, gamma-butyrolacton.

Beneficial effects of the present invention also include：Raw material and reagent are simple and easy to get, and it is convenient to prepare；Reaction condition is gentle, operation Simply；Substrate universality is wide；Functional group compatibility is good, can the very small group of compatible steric hindrance；Nucleopilic reagent can be not only Malonic acid ester type compound or the double benzene sulfonic acid methane of double benzene sulfonic acid methane and fluoro；Can a step structure contain an axle Chiral and a central chirality optical voidness connection alkene；The stereoselectivity of product it is extremely outstanding (>99:1d.r., 95%~>99% ee)；Easily separated purifying of product etc..

Embodiment

With reference to specific examples below, the present invention is described in further detail.Implement the present invention process, condition, Experimental method etc., it is the universal knowledege and common knowledge of this area in addition to the following content specially referred to, the present invention does not have Especially limitation content.The concrete structure formula of involved chiral diphosphine ligand and reference numeral are as follows in all embodiments：

Embodiment 1

Wherein, equiv represents equivalent, mol expressions mole, and d.r. represents diastereoisomer ratio, and NMP represents N- methyl Pyrrolidones, ee represent enantiomter excess.

In glove box, sequentially added in the Schlenk reaction tubes dry toward one [Pd (π-cinnamyl) Cl]₂ (0.0134g, 0.025mmol), chiral diphosphine ligand (R)-L5a (0.0709g, 0.06mmol), and K₂CO₃ (0.2763g, 2mmol).NMP (5mL) is then added under nitrogen protection, and reaction tube is placed in one and is previously heated in 30 DEG C of oil bath, is stirred After mixing 30 minutes, it will be proposed in reaction tube from oil bath, nitrogen protection is lower to add 2,3- connection enol acetates (R_a*,S*)-1a (0.2781g, 1mmol) and NMP (5mL), dibenzenesulfonyl methane 2a (0.6105g, 2mmol).Reaction tube is put into 30 again In DEG C oil bath, stirring, after 12 hours thin-layer chromatography (TLC) monitoring reaction complete.Add ethyl acetate (30mL) diluting reaction, institute Mixed liquor is obtained to be washed (20mL × 3) with salt.Organic phase is separated, merges aqueous phase and is extracted with ether (20mL), merging is all to be had Machine phase, anhydrous sodium sulfate drying.Filtering, concentration, rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ethyl acetate= 8/1) the chiral connection ene product (R of oily is obtained_a, S) and -3aa (0.3965g, 77%):96%ee (HPLC conditions: Chiralcel OZ-H column, n-hexane/i-PrOH=90/10,0.5mL/min, λ=214nm, t_R(major)= 23.7min,t_R(minor)=50.9min)；[α]_D ²⁰=-87.5 (c=1.03, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 7.92 (d, J=7.2Hz, 2H, ArH), 7.85 (d, J=7.2 Hz, 2H, ArH), 7.64 (t, J=7.5Hz, 2H, ArH), 7.57-7.42 (m, 4H, ArH), 5.51-5.40 (m, 1H ,=CH), 5.12 (td, J₁=6.2Hz, J₂=1.7Hz, 1H ,= ), CH 4.67 (d, J=1.2Hz, 1H, CH), 3.09-2.96 (m, 1H, CH), 2.01-1.73 (m, 3H, CH₂and CH), 1.72-1.52(m,5H,5H from Cy),1.46-0.90(m,13H,5H from Cy and CH₂× 4), 0.86 (t, J= 6.9Hz,3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ202.7,140.1,138.4,134.2,134.0,129.1,128.9, 128.74, 128.70,98.7,92.7,87.4,40.4,36.8,32.8,31.4,29.8,28.4,28.1,25.72,25.66, 22.3, 13.8；IR(neat)ν(cm^-1)3066,2924,2852,1960,1584,1478,1463,1448,1334,1312, 1291,1158,1079；MS (70ev, EI) m/z (%) 514 (M⁺,1.46),77(100)；HRMS calcd.for C₂₉H₃₈O₄S₂ [M⁺]:514.2212,found:514.2216.

Embodiment 2

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1b(0.3330g,1 mmol)/NMP(5mL) Reacted 12 hours with bis (phenylsulfonyl) methane (2a) (0.6105g, 2mmol).Rapid column chromatography (eluent: Petroleum ether (30~60 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (R of oily_a, S) and -3ba (0.3990g, 70%): 98%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=90/10,1.0mL/ Min, λ=214nm, t_R(major)=21.5min, t_R(minor)=48.7min)；[α]_D ²⁰=-78.5 (c=0.995, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.94 (d, J=7.5Hz, 2H, ArH), 7.88 (d, J=7.2Hz, 2H, ArH), 7.66 (t, J=7.4Hz, 2H, ArH), 7.59-7.42 (m, 4H, ArH), 5.91-5.72 (m, 1H ,=CH), 5.49-5.36 (m, 1H ,=CH), 5.12 (td, J₁=6.2Hz, J₂=2.0Hz, 1H ,=CH), 5.06-4.87 (m, 2H ,=CH₂),4.66 (d, J=1.8Hz, 1H, CH), 3.09-2.94 (m, 1H, CH), 2.04 (q, J=7.0Hz, 2H, CH₂),1.97-1.52(m, 8H,5H from Cy,CH₂,and CH),1.48-0.79(m,17H,5H from Cy and CH₂×6)；¹³C NMR(75 MHz,CDCl₃)δ202.8,140.3,139.0,138.5,134.3,134.1,129.3,129.0,128.9,128.8, 114.0,98.9,92.8,87.6,40.5,37.0,33.7,32.9,32.8,29.9,29.3,29.2,28.9,28.7,28.3, 25.9,25.8；IR(neat)ν(cm^-1)3069,2924,2852,1962,1640,1584,1478,1463,1448, 1334, 1312,1292,1159,1080；MS (70ev, EI) m/z (%) 568 (M⁺,2.36),55(100)； HRMS calcd.for C₃₃H₄₄O₄S₂[M⁺]:568.2681,found:568.2687.

Embodiment 3

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0710 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1c(0.2521g,1 mmol)/NMP(5mL) Reacted 17 hours with bis (phenylsulfonyl) methane (2a) (0.6105g, 2mmol).Rapid column chromatography (eluent: Petroleum ether (30~60 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (R of oily_a, S) and -3ca (0.3428g, 70%): 97%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=80/20,1.0mL/ Min, λ=214nm, t_R(major)=17.8min, t_R(minor)=31.2min)；[α]_D ²⁰=-65.9 (c=1.05, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 8.01-7.83(m,4H,ArH),7.73-7.59(m,2H,ArH),7.59-7.45 (m, 4H, ArH), 5.44-5.32 (m, 1H ,=CH), 5.15 (qd, J₁=6.6Hz, J₂=2.1Hz, 1H ,=CH), 4.67 (d, J =1.5Hz, 1H, CH), 3.13-3.00 (m, 1H, CH), 2.04-1.78 (m, 3H, 1H from CH₂and CH₂),1.77- 1.61(m, 1H,1H from CH₂),1.50-1.00(m,12H,CH₂×6),0.97-0.79(m,6H,CH₃×2)；¹³C NMR (75MHz,CDCl₃)δ204.0,140.1,138.6,134.3,134.1,129.4,128.93,128.92, 128.89,93.1, 91.4,87.3,40.1,31.5,31.2,30.3,28.6,28.2,28.1,22.4,22.1,13.9,13.8； IR(neat)ν (cm^-1)3066,2956,2927,2871,2857,1964,1584,1479,1466,1448,1335, 1312,1158,1080； MS (70ev, EI) m/z (%) 488 (M⁺,3.62),77(100)；HRMS calcd.for C₂₇H₃₆O₄S₂[M⁺]:488.2055, found:488.2061.

Embodiment 4

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a (0.0709g,0.06mmol),K₂CO₃(0.2761g,2mmol),NMP(5mL),(R_a*,S*)-1d(0.2441 g,1mmol)/ NMP (5mL) and bis (phenylsulfonyl) methane (2a) (0.6105g, 2mmol) reacts 15 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ethyl acetate=6/1) obtain Solid Chiral connection ene product (R_a,S)-3da(0.2639g, 55%):98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=92/8,1.0mL/ Min, λ=214nm, t_R(major)=51.2min, t_R(minor)=68.9min)；[α]_D ²⁰=-233.3 (c=1.06, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 7.99-7.78(m,4H,ArH),7.66-7.53(m,2H,ArH),7.53-7.37 (m,4H,ArH),7.34-7.13 (m,5H,ArH),6.22(dd,J₁=6.5Hz, J₂=2.9Hz, 1H ,=CH), 5.88 (t, J =6.6Hz, 1H ,=CH), 4.76 (d, J=1.2Hz, 1H, CH), 3.28-3.11 (m, 1H, CH), 2.06-1.86 (m, 1H, 1H from CH₂),1.85-1.66(m,1H,1H from CH₂),1.45-1.00(m,4H,CH₂× 2), 0.78 (t, J=7.1Hz, 3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ205.2,139.9,138.7,134.4,134.2, 133.6,129.4,129.1, 129.0,128.9,128.6,127.2,127.0,97.0,95.3,86.4,39.7,30.4, 30.3,22.1,13.8；IR (neat)ν(cm^-1)3063,3030,2957,2928,2871,1951,1597,1584, 1495,1478,1458,1447, 1332,1312,1157,1079,1025；MS (ESI) m/z (%) 498 (M+ NH₄ ⁺)；HRMS calcd.for C₂₇H₃₂NO₄S₂[M +NH₄ ⁺]:498.1767,found:498.1768.

Embodiment 5

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0710 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1e(0.2860g,1 mmol)/NMP(5mL) Reacted 12 hours with bis (phenylsulfonyl) methane (2a) (0.6105g, 2mmol).Rapid column chromatography (eluent: Petroleum ether (30~60 DEG C)/ethyl acetate=7/1) obtain the chiral connection ene product (R of oily_a, S) and -3ea (0.3402g, 65%): 97%ee (HPLC conditions:Chiralcel AD-H column, n-hexane/i-PrOH=95/5,0.7mL/ Min, λ=214nm, t_R(major)=36.6min, t_R(minor)=38.9min)；[α]_D ²⁰=-219.2 (c=0.965, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.91 (d, J=7.5Hz, 2H, ArH), 7.85 (d, J=7.2Hz, 2H, ArH), 7.62 (q, J=7.3Hz, 2H, ArH), 7.55-7.38 (m, 4H, ArH), 7.17 (d, J=8.1Hz, 2H, ArH), 7.11 (d, J =8.1Hz, 2H, ArH), 6.20 (dd, J₁=6.3Hz, J₂=2.7Hz, 1H ,=CH), 5.85 (t, J=6.5Hz, 1H ,= ), CH 4.77 (d, J=1.2Hz, 1H, CH), 3.25-3.12 (m, 1H, CH), 2.33 (s, 3H, CH₃),2.04-1.84(m,1H, 1H from CH₂),1.79-1.64(m,1H,1H from CH₂),1.47-0.98(m,8H,CH₂× 4), 0.84 (t, J= 6.9Hz,3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ204.8,139.9,138.5,137.0,134.4, 134.2,130.6, 129.5,129.3,129.2,129.0,128.9,126.9,97.0,95.2,86.4,39.7,31.5, 30.5,28.6,28.2, 22.4,21.1,13.9；IR(neat)ν(cm^-1)3063,2955,2925,2856,1951, 1584,1512,1447,1332, 1312,1157,1079；MS (ESI) m/z (%) 540 (M+NH₄ ⁺)； HRMS calcd.for C₃₀H₃₈NO₄S₂[M+NH₄ ⁺]: 540.2237,found:540.2236.

Embodiment 6

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0135g,0.025mmol),(R)-L5a (0.0709g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1f(0.3509 g,1mmol)/ NMP (5mL) and bis (phenylsulfonyl) methane (2a) (0.6104g, 2mmol) reacts 18 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ethyl acetate=7/1) obtain the chiral connection ene product (R of oily_a,S)-3fa(0.3510g, 60%):97%ee (HPLC conditions:Chiralcel AD-H column, n-hexane/i-PrOH=80/20, 1.0mL/min, λ=214nm, t_R(major)=20.4min, t_R(minor)=25.0min)；[α]_D ²⁰=-229.2 (c= 1.06,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.92 (d, J=7.5Hz, 2H, ArH), 7.84 (d, J=7.2Hz, 2H, ), ArH 7.70-7.58 (m, 2H, ArH), 7.57-7.37 (m, 6H, ArH), 7.15 (d, J=8.7Hz, 2H, ArH), 6.18 (dd,J₁=6.5Hz, J₂=2.6 Hz, 1H ,=CH), 5.89 (t, J=6.6Hz, 1H ,=CH), 4.72 (d, J=1.5Hz, 1H, CH),3.25-3.14 (m,1H,CH),2.02-1.82(m,1H,1H from CH₂),1.77-1.57(m,1H,1H from CH₂), 1.41-0.98(m,8H,CH₂× 4), 0.84 (t, J=7.1Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃) δ 205.5,139.6,138.7,134.5,134.3,132.7,131.7,129.5,129.2,129.03,129.00,128.6, 120.9,96.2,95.4,86.2,39.5,31.5,31.1,28.6,28.1,22.4,14.0；IR(neat)ν(cm^-1) 3064, 2955,2926,2856,1953,1584,1488,1466,1447,1332,1312,1157,1147,1079, 1024,1010； MS (ESI) m/z (%) 611 (M (⁸¹Br)+Na⁺),609(M(⁷⁹Br)+Na⁺)；HRMS calcd.for C₂₉H₃₅BrNO₄S₂[M (⁷⁹Br)+NH₄ ⁺]:604.1185,found:604.1183.

Embodiment 7

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1g(0.3213g,1 mmol)/NMP(5mL) Reacted 18 hours with bis (phenylsulfonyl) methane (2a) (0.6100g, 2mmol).Rapid column chromatography (eluent: Petroleum ether (30~60 DEG C)/ethyl acetate=7/1) obtain the chiral connection ene product (R of oily_a, S) and -3ga (0.3060g, 55%): 98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=90/10,1.0mL/min, λ=214nm, t_R(major)=26.5min, t_R(minor)=34.4min)；[α]_D ²⁰=-214.5 (c=1.035, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.91 (d, J=7.5Hz, 2H, ArH), 7.84 (d, J=7.2Hz, 2H, ArH), 7.69-7.56 (m, 2H, ArH), 7.56-7.38 (m, 4H, ArH), 7.27 (d, J=9.1Hz, 2H, ArH), 7.21 (d, J= 8.7Hz,2H,ArH), 6.19(dd,J₁=6.6Hz, J₂=2.7Hz, 1H ,=CH), 5.91 (t, J=6.8Hz, 1H ,=CH), 4.73 (d, J=1.5Hz, 1H, CH), 3.29-3.15 (m, 1H, CH), 2.03-1.82 (m, 1H, 1H from CH₂), 1.79- 1.60(m,1H,1H from CH₂),1.41-1.00(m,10H,CH₂× 5), 0.86 (t, J=6.9Hz, 3H, CH₃)；¹³C NMR (75MHz,CDCl₃)δ205.4,139.5,138.7,134.5,134.3,132.7, 132.2,129.4,129.1,128.99, 128.96,128.7,128.2,96.0,95.3,86.1,39.5,31.6,31.1, 28.94,28.86,28.1,22.5,14.0； IR(neat)ν(cm^-1)3065,2955,2926,2855,1954,1584, 1491,1466,1448,1332,1312,1157, 1079,1013；MS (ESI) m/z (%) 576 (M (³⁷Cl)+ NH₄ ⁺),574(M(³⁵Cl)+NH₄ ⁺)；HRMS calcd.for C₃₀H₃₇ClNO₄S₂[M(³⁵Cl)+NH₄ ⁺]: 574.1847,found:574.1847.

Embodiment 8

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1h(0.2920g,1 mmol)/NMP(5mL) Reacted 12 hours with fluorobis (phenylsulfonyl) methane (2b) (0.6301g, 2mmol).Rapid column chromatography (leaching Lotion:Petroleum ether (30~60 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (R of oily_a,S)-3hb(0.4420g, 81%):97%ee (HPLC conditions:Chiralcel PC-4 column, n-hexane/i-PrOH=95/5, 1.0mL/min, λ=214nm, t_R(major)=22.4min, t_R(minor)=27.4min)；[α]_D ²⁰=-82.8 (c= 0.97,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.91 (d, J=8.4Hz, 2H, ArH), 7.84 (d, J=8.4Hz, 2H, ), ArH 7.68 (t, J=7.5Hz, 2H, ArH), 7.57-7.46 (m, 4H, ArH), 5.27-5.17 (m, 1H ,=CH), 5.05 (t, J=6.2Hz, 1H ,=CH), 3.05-2.91 (m, 1H, CH), 2.41-2.24 (m, 1H, CH), 1.99-1.72 (m, 2H, CH₂), 1.72-1.40(m,6H,1H from CH₂and 5H from Cy),1.39-0.96(m,12H,1H from CH₂, 5H from Cy and CH₂×3),0.95-0.72(m,5H,CH₂and CH₃)；¹³C NMR(75MHz, CDCl₃)δ205.1, 136.6,135.2,134.9,134.8,130.94,130.92,130.8,128.8,128.5,115.4 (d, J=264.0Hz), 98.0,87.7 (d, J=6.9Hz), 45.8 (d, J=16.5Hz), 36.8,32.7,32.5,31.7,29.1,28.9,28.2, 28.0 (d, J=2.7Hz), 25.9,25.8,22.5,14.0；¹⁹F NMR(282 MHz,CDCl₃)(CFCl₃as internal standard at 0ppm)δ-128.6；IR(neat)ν(cm^-1)3066, 2925,2853,1963,1584,1448,1348, 1313,1167,1152,1079；MS (70ev, EI) m/z (%) 547 (M⁺+1,2.87),546(M⁺,1.11),125(100)； HRMS calcd.for C₃₀H₃₉O₄S₂F[M⁺]: 546.2274,found:546.2278.

Embodiment 9

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1h(0.2920g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3201g, 2mmol)/NMP (2.5mL) react 12 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3hc(0.2910g, 74%):98%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=200/1, 1.2mL/min, λ=214nm, t_R(major)=9.2min, t_R(minor)=12.2min)；[α]_D ²⁰=-41.0 (c= 1.09,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.20-5.05 (m, 2H ,=CH × 2), 4.28-4.07 (m, 4H, CH₂× 2), 3.36 (d, J=9.0Hz, 1H, CH), 2.86-2.70 (m, 1H, CH), 2.02-1.85 (m, 1H, CH), 1.82-1.56 (m, 5H,5H from Cy), 1.54-0.96(m,23H,5H from Cy,CH₂×6,and CH₃× 2), 0.88 (t, J=6.6Hz, 3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ202.4,168.4,168.1,98.4,92.3,61.0,60.9,56.9,38.9, 37.2,32.9,32.8,32.7,31.6,29.2,29.0,26.7,25.93,25.88,25.86,22.5,13.9；IR(neat) ν(cm^-1)2926,2853,1961,1755,1736,1732,1464,1448,1368,1303,1247,1174, 1155,1035； MS (70ev, EI) m/z (%) 392 (M⁺,17.60),134(100)；HRMS calcd.for C₂₄H₄₀O₄[M⁺]:392.2927, found:392.2924.

Embodiment 10 (gram level scale reaction)

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0533g,0.1mmol),(R)-L5a(0.2830g, 0.24mmol),K₂CO₃(1.1039g,8mmol),NMP(20mL),(R_a*,S*)-1h(1.1678g,4 mmol)/NMP(10mL) Reacted 15 hours with diethyl malonate (2c) (1.2802g, 8mmol)/NMP (10mL).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a, S) and -3hc (1.0847g, 69%):98%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=200/1,1.2mL/min, λ= 214nm,t_R(major)=12.9min, t_R(minor)=18.9min)；[α]_D ²⁰=-42.0 (c=0.99, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.19-5.06 (m, 2H ,=CH × 2), 4.27-4.07 (m, 4H, CH₂× 2), 3.36 (d, J= 9.3Hz,1H, CH),2.86-2.71(m,1H,CH),2.01-1.86(m,1H,CH),1.80-1.56(m,5H,5H from Cy), 1.54-0.97(m,23H,5H from Cy,CH₂×6,and CH₃× 2), 0.88 (t, J=6.6Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ202.4,168.4,168.2,98.5,92.4,61.1,61.0,56.9,38.9, 37.3,33.0, 32.9,32.7,31.7,29.3,29.1,26.7,26.0,25.92,25.90,22.5,13.9.

Embodiment 11

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0710 g,0.06mmol),K₂CO₃(0.2761g,2mmol),NMP(5mL),(R_a*,S*)-1i(0.2947g,1 mmol)/NMP (2.5mL), diethyl malonate (2c) (0.3204g, 2mmol)/NMP (2.5mL) react 16 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3ic(0.3155g, 80%):98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=200/1, 1.0mL/min, λ=214nm, t_R(major)=8.9min, t_R(minor)=9.4min)；[α]_D ²⁰=-34.0 (c= 1.035,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.18-5.04 (m, 2H ,=CH × 2), 4.29-4.08 (m, 4H, CH₂ × 2), 3.36 (d, J=9.3Hz, 1H, CH), 2.85-2.70 (m, 1H, CH), 2.04-1.89 (m, 2H, CH₂),1.53-1.17 (m,26H,CH₂×10and CH₃×2),0.94-0.81(m,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ203.8, 168.5, 168.3,92.5,91.5,61.2,61.0,57.1,39.0,32.6,31.8,31.7,29.3,29.11,29.08, 28.9, 26.8,22.6,22.5,14.03,13.98；IR(neat)ν(cm^-1)2927,2856,1963,1735,1463,1370, 1301,1249,1154,1034；MS (70ev, EI) m/z (%) 394 (M⁺,16.74),43(100)；HRMS calcd.for C₂₄H₄₂O₄[M⁺]:394.3083,found:394.3087.

Embodiment 12

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1b(0.3329g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3201g, 2mmol)/NMP (2.5mL) react 15 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=50/1) obtain the chiral connection ene product (R of liquid_a,S)-3bc(0.3032g, 70%):98%ee (HPLC conditions:Chiralcel PC-2 column, n-hexane/i-PrOH=250/1, 1.0mL/min, λ=214nm, t_R(major)=9.6min, t_R(minor)=16.5min)；[α]_D ²⁰=-35.5 (c= 1.03,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.89-5.72 (m, 1H ,=CH), 5.19-5.06 (m, 2H ,=CH × 2), 5.04-4.88 (m, 2H ,=CH₂), 4.27-4.08(m,4H,CH₂× 2), 3.35 (d, J=9.3Hz, 1H, CH), 2.86- 2.70 (m, 1H, CH), 2.03 (q, J=7.0Hz, 2H, CH₂),1.99-1.85(m,1H,CH),1.79-1.56(m,5H,five proton from Cy),1.52-0.97(m,25H,five proton from Cy,CH₃×2,and CH₂×7)；¹³C NMR (75MHz,CDCl₃)δ202.4,168.5,168.2,139.0,114.0,98.5,92.4,61.1,61.0,57.0, 38.9, 37.3,33.7,33.0,32.9,32.7,29.4,29.34,29.30,29.0,28.8,26.7,26.0,25.95, 25.92, 14.0；IR(neat)ν(cm^-1)3076,2979,2925,2853,1961,1755,1736,1640,1464, 1448,1368, 1303,1243,1175,1154,1096,1035；MS (70ev, EI) m/z (%) 432 (M⁺, 20.74),134(100)；HRMS calcd.for C₂₇H₄₄O₄[M⁺]:432.3240,found:432.3241.

Embodiment 13

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0707 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1j(0.3952g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3200g, 2mmol)/NMP (2.5mL) react 14 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3jc(0.3861g, 78%):97%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=200/1, 1.0mL/min, λ=214nm, t_R(major)=8.9min, t_R(minor)=7.6min)；[α]_D ²⁰=-33.9 (c=1.02, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.13-5.00 (m, 2H ,=CH × 2), 4.23-4.02 (m, 4H, CH₂×2), 3.53 (t, J=6.6Hz, 2H, CH₂), 3.30 (d, J=9.3Hz, 1H, CH), 2.80-2.65 (m, 1H, CH), 1.96-1.78 (m,1H,CH),1.76-1.51(m, 5H,5H from Cy),1.51-0.89(m,19H,5H from Cy,CH₂×4,and CH₃×2),0.83(s,9H, CH₃×3),-0.01(s,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ202.4,168.4, 168.1, 98.5,92.3,63.0,61.1,61.0,56.9,38.9,37.2,32.93,32.86,32.7,32.6,26.6, 26.0, 25.91,25.88,25.8,25.6,18.2,14.0,-5.4；IR(neat)ν(cm^-1)2928,2855,1961,1755, 1737,1733,1463,1448,1389,1368,1254,1175,1098,1035；MS (70ev, EI) m/z (%) 494 (M⁺, 4.42),217(100)；HRMS calcd.for C₂₈H₅₀O₅Si[M⁺]:494.3428,found: 494.3432.

Embodiment 14

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1k(0.3221g,1 mmol)/NMP (2.5mL), diethyl malonate (2c) (0.3203g, 2mmol)/NMP (2.5mL) react 20 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=10/1) obtain the chiral connection ene product (R of liquid_a,S)-3kc(0.3252g, 77%):98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=97/3, 1.0mL/min, λ=214nm, t_R(major)=24.4min, t_R(minor)=30.3min)；[α]_D ²⁰=-41.1 (c= 1.05,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.17-5.07 (m, 2H ,=CH × 2), 4.27-4.10 (m, 4H, CH₂× 2), 4.04 (t, J=6.6Hz, 2H, CH₂), 3.35 (d, J=9.0Hz, 1H, CH), 2.85-2.71 (m, 1H, CH), 2.04 (s, 3H,CH₃),2.00-1.86(m,1H, CH),1.80-1.54(m,7H,5H from Cy and CH₂),1.54-0.92(m, 17H,5H from Cy,CH₂×3,and CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ202.4,171.0,168.3,168.1, 98.5, 92.1,64.3,61.1,61.0,56.8,38.8,37.2,32.9,32.8,32.5,28.3,26.4,25.92, 25.87,25.8, 25.6,20.8,13.9；IR(neat)ν(cm^-1)2979,2927,2853,1960,1738,1732,1464, 1448, 1388,1367,1303,1239,1175,1155,1096,1034；MS (70ev, EI) m/z (%) 423 (M⁺+1, 5.29),422(M⁺,4.09),43(100)；HRMS calcd.for C₂₄H₃₈O₆[M⁺]:422.2668,found: 422.2665.

Embodiment 15

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0135g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1l(0.2775g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3201g, 2mmol)/NMP (2.5mL) react 17 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3lc(0.2951g, 78%):>99%ee (SFC conditions:Chiralcel IE column, n-hexane/i-PrOH=97/3, 1.3mL/min, λ=214nm, t_R(major)=13.5min, t_R(minor)=14.4min)；[α]_D ²⁰=-35.4 (c= 0.98,CHCl₃)；¹HNMR(300MHz,CDCl₃) δ 5.19 (t, 1H, J=7.1Hz ,=CH), 4.96 (t, J=7.7Hz, 1H, =CH), 4.30-4.10 (m, 4H, CH₂× 2), 3.36 (d, J=9.3Hz, 1H, CH), 2.87-2.70 (m, 1H, CH), 1.52- 1.12(m,23H,CH,CH₂×8,and CH₃× 2), 0.88 (t, J=6.6Hz, 3H, CH₃),0.73-0.63(m,2H,CH₂), 0.38-0.28(m,2H, CH₂)；¹³C NMR(75MHz,CDCl₃)δ203.3,168.4,168.2,96.7,93.3,61.1, 61.0,57.0, 39.2,32.6,31.8,29.4,29.3,29.2,26.8,22.6,14.0,9.5,6.6,6.5；IR(neat)ν (cm^-1) 3082,2980,2956,2926,2855,1961,1755,1737,1465,1447,1368,1301,1244,1175, 1154,1096,1034；MS (70ev, EI) m/z (%) 378 (M⁺,1.63),93(100)；HRMS calcd.for C₂₃H₃₈O₄[M⁺]:378.2770,found:378.2773.

Embodiment 16

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0708 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1m(0.3423g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3204g, 2mmol)/NMP (2.5mL) react 16 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product afforded (R of liquid_a,S)-3mc (0.3669g, 83%):96%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH= 200/1,0.6mL/min, λ=214nm, t_R(major)=16.3min, t_R(minor)=17.8min)；[α]_D ²⁰=-43.1 (c=1.005, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 7.32-7.23(m,2H,ArH),7.22-7.13(m,3H, ), ArH 5.23-5.06 (m, 2H ,=CH × 2), 4.26-4.09 (m, 4H, CH₂× 2), 3.34 (d, J=9.0Hz, 1H, CH), 2.86-2.64(m,3H,CH and CH₂),2.36-2.21(m,2H,CH₂),1.50-1.15(m,22H,CH₂×8and CH₃× 2), 0.88 (t, J=6.8Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ203.9,168.4,168.2,141.6, 128.4, 128.2,125.8,92.0,91.7,61.2,61.1,57.0,39.0,35.4,32.6,31.8,30.6,29.5, 29.4,29.2, 26.8,22.6,14.0；IR(neat)ν(cm^-1)2926,2855,1963,1734,1457,1370,1301, 1243, 1153,1033；MS (70ev, EI) m/z (%) 443 (M⁺+1,24.93),442(M⁺,5.11),282 (100)；HRMS calcd.for C₂₈H₄₂O₄[M⁺]:442.3083,found:442.3081.

Embodiment 17

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0133g,0.025mmol),(S)-L5a(0.0707 g,0.06mmol),K₂CO₃(0.2761g,2mmol),NMP(5mL),(R_a*,S*)-1h(0.2917g,1 mmol)/NMP(5mL) Reacted 12 hours with fluorobis (phenylsulfonyl) methane (2b) (0.6295g, 2mmol).Rapid column chromatography (leaching Lotion:Petroleum ether (60~90 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (S of oily_a,R)-3hb(0.4261g, 78%):97%ee (HPLC conditions:Chiralcel PC-4 column, n-hexane/i-PrOH=95/5, 1.0mL/min, λ=214nm, t_R(major)=22.6min, t_R(minor)=19.3min)；[α]_D ²⁰=+82.0 (c= 1.03,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.92 (d, J=8.4Hz, 2H, ArH), 7.84 (d, J=8.4Hz, 2H, ), ArH 7.68 (t, J=7.5Hz, 2H, ArH), 7.60-7.43 (m, 4H, ArH), 5.26-5.17 (m, 1H ,=CH), 5.05 (t, J=6.3Hz, 1H ,=CH), 3.06-2.90 (m, 1H, CH), 2.42-2.25 (m, 1H, CH), 1.99-1.72 (m, 2H, CH₂),1.69-1.39(m, 6H,1H from CH₂and 5H from Cy),1.40-0.96(m,12H,1H from CH₂,5H from Cy and CH₂×3),0.95-0.71(m,5H,CH₂and CH₃)；¹³C NMR(75MHz,CDCl₃)δ205.2, 136.7,135.3,134.9,134.8,131.0,130.9,128.8,128.5,115.5 (d, J=264.8Hz), 98.0, 87.7 (d, J=6.9Hz), 45.8 (d, J=16.6Hz), 36.9,32.7,32.5,31.7,29.1,28.9,28.3,28.1 (d, J=2.8Hz), 25.89,25.86,22.5,14.0；¹⁹F NMR(282MHz,CDCl₃)δ-128.5； IR(neat)ν(cm^-1)3066,2925,2853,1963,1584,1463,1448,1348,1313,1290,1167, 1152,1079；MS(70ev, EI the) (M of m/z (%) 547⁺+1,2.36),546(M⁺,1.05),125(100)； HRMS calcd.for C₃₀H₃₉O₄S₂F[M⁺]: 546.2274,found:546.2276.

Embodiment 18

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(S)-L5a(0.0709g, 0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1h(0.2921g,1 mmol)/NMP(2.5mL) Reacted 12 hours with diethyl malonate (2c) (0.3203g, 2mmol)/NMP (2.5mL).Rapid column chromatography (eluent: Petroleum ether (30~60 DEG C)/ether=20/1) obtain the chiral connection ene product (S of liquid_a, R) and -3hc (0.2865g, 73%):99%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=200/1,1.2mL/min, λ= 214nm,t_R(major)=8.1min, t_R(minor)=5.6min)；[α]_D ²⁰=+42.0 (c=0.96, CHCl₃)；¹H NMR (300MHz,CDCl₃) δ 5.21-5.05 (m, 2H ,=CH × 2), 4.28-4.08 (m, 4H, CH₂× 2), 3.36 (d, J=9.3Hz, 1H, CH),2.86-2.69(m,1H,CH),2.01-1.85(m,1H,CH),1.80-1.55(m,5H,5H from Cy), 1.55-0.97(m,23H,5H from Cy,CH₂×6,and CH₃× 2), 0.88 (t, J=6.6Hz, 3H, CH₃)；¹³C NMR (75MHz,CDCl₃)δ202.5,168.4,168.2,98.5,92.4,61.1,61.0,57.0,38.9, 37.3,33.0, 32.9,32.7,31.7,29.3,29.1,26.7,26.0,25.94,25.91,22.5,14.0；IR(neat)ν (cm^-1)2926, 2853,1961,1755,1738,1732,1464,1448,1368,1303,1247,1177, 1155,1114,1096,1035； MS (70ev, EI) m/z (%) 392 (M⁺,19.01),134(100)；HRMS calcd.for C₂₄H₄₀O₄[M⁺]:392.2927, found:392.2929.

Embodiment 19

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0133g,0.025mmol),(S)-L5a(0.0708g, 0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1i(0.2943g,1 mmol)/NMP(2.5mL) Reacted 16 hours with diethyl malonate (2c) (0.3202g, 2mmol)/NMP (2.5mL).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (S of liquid_a, R) and -3ic (0.3083g, 78%):97%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=200/1,1.0mL/min, λ= 214nm,t_R(major)=9.5min, t_R(minor)=8.6min)；[α]_D ²⁰=+34.2 (c=1.03, CHCl₃)；¹H NMR (300MHz,CDCl₃) δ 5.18-5.03 (m, 2H ,=CH × 2), 4.29-4.08 (m, 4H, CH₂× 2), 3.36 (d, J= 9.0Hz,1H,CH), 2.86-2.69(m,1H,CH),2.04-1.88(m,2H,CH₂),1.52-1.15(m,26H,CH₂× 10and CH₃×2),0.95-0.78(m,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ203.8,168.5, 168.3, 92.6,91.4,61.2,61.1,57.1,39.0,32.6,31.8,31.7,29.3,29.1,28.9,26.8,22.6, 22.5, 14.03,13.99；IR(neat)ν(cm^-1)2927,2856,1963,1735,1463,1370,1301, 1250,1155,1034； MS (70ev, EI) m/z (%) 394 (M⁺,20.98),43(100)；HRMS calcd. for C₂₄H₄₂O₄[M⁺]:394.3083, found:394.3082.

Embodiment 20

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(S)-L5a(0.0708g, 0.06mmol),K₂CO₃(0.2761g,2mmol),NMP(5mL),(R_a*,S*)-1j(0.3948g,1 mmol)/NMP(2.5mL) Reacted 14 hours with diethyl malonate (2c) (0.3202g, 2mmol)/NMP (2.5mL).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (S of liquid_a, R) and -3jc (0.3710g, 75%):97%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=200/1,1.0mL/min, λ= 214nm,t_R(major)=8.3min, t_R(minor)=9.1min)；[α]_D ²⁰=+32.7 (c=1.04, CHCl₃)；¹H NMR (300MHz,CDCl₃) δ 5.14-5.01 (m, 2H ,=CH × 2), 4.21-4.04 (m, 4H, CH₂× 2), 3.54 (t, J= 6.6Hz,2H,CH₂), 3.31 (d, J=9.0Hz, 1H, CH), 2.81-2.65 (m, 1H, CH), 1.95-1.80 (m, 1H, CH), 1.75-1.52(m, 5H,5H from Cy),1.52-0.91(m,19H,5H from Cy,CH₂×4,and CH₃×2),0.84 (s,9H, CH₃×3),-0.01(s,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ202.5,168.4,168.1, 98.5, 92.3,63.0,61.1,61.0,56.9,38.9,37.3,33.0,32.9,32.74,32.66,26.6,26.0, 25.93, 25.89,25.8,25.6,18.2,14.0,-5.4；IR(neat)ν(cm^-1)2928,2855,1961,1755, 1737,1463, 1448,1368,1303,1254,1175,1153,1098,1035；MS (70ev, EI) m/z (%) 494 (M⁺,3.52),217 (100)；HRMS calcd.for C₂₈H₅₀O₅Si[M⁺]:494.3428,found: 494.3423.

Embodiment 21

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(S)-L5a(0.0710 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1k(0.3220g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3203g, 2mmol)/NMP (2.5mL) react 20 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=10/1) obtain the chiral connection ene product (S of liquid_a,R)-3kc(0.3172g, 75%):98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=97/3, 1.0mL/min, λ=214nm, t_R(major)=27.9min, t_R(minor)=23.9min)；[α]_D ²⁰=+41.1 (c= 1.005,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.19-5.05 (m, 2H ,=CH × 2), 4.29-4.09 (m, 4H, CH₂ × 2), 4.04 (t, J=6.6Hz, 2H, CH₂), 3.35 (d, J=9.0Hz, 1H, CH), 2.87-2.69 (m, 1H, CH), 2.04 (s,3H,CH₃), 2.00-1.85(m,1H,CH),1.80-1.54(m,7H,5H from Cy and CH₂),1.54-0.93(m, 17H, 5H from Cy,CH₂×3,and CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ202.5,171.0, 168.3, 168.1,98.5,92.1,64.3,61.1,61.0,56.9,38.9,37.2,32.9,32.8,32.5,28.4,26.4, 25.93,25.88,25.85,25.6,20.8,13.9；IR(neat)ν(cm^-1)2979,2927,2853,1960,1738, 1732,1464,1448,1388,1367,1303,1239,1175,1155,1096,1034；MS (70ev, EI) m/z (%) 423 (M⁺+1,7.81),422(M⁺,7.36),43(100)；HRMS calcd.for C₂₄H₃₈O₆ [M⁺]:422.2668,found: 422.2672.

Embodiment 22

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(S)-L5a(0.0707g, 0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1m(0.3424g,1 mmol)/NMP(2.5mL) Reacted 16 hours with diethyl malonate (2c) (0.3203g, 2mmol)/NMP (2.5mL).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (S of liquid_a, R) and -3mc (0.3587g, 81%):98%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=200/1,0.6mL/min, λ= 214nm,t_R(major)=17.7min, t_R(minor)=16.2min)；[α]_D ²⁰=+43.6 (c=1.035, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 7.32-7.22 (m, 2H, ArH), 7.22-7.13 (m, 3H, ArH), 5.23-5.06 (m, 2H ,= CH×2), 4.27-4.08(m,4H,CH₂× 2), 3.34 (d, J=8.7Hz, 1H, CH), 2.86-2.63 (m, 3H, CH and CH₂),2.38-2.19(m,2H,CH₂),1.52-1.15(m,22H,CH₂×8and CH₃× 2), 0.88 (t, J=6.9Hz, 3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ203.9,168.4,168.2,141.6,128.3, 128.2,125.8,92.0, 91.7,61.1,61.0,56.9,39.0,35.4,32.6,31.8,30.6,29.5,29.4,29.2, 26.8,22.6,14.0； IR(neat)ν(cm^-1)2926,2855,1963,1733,1603,1495,1456,1369, 1301,1245,1153,1033；MS (the M of (70ev, EI) m/z (%) 443⁺+1,12.09),442(M⁺,2.82), 282(100),91(100)；HRMS calcd.for C₂₈H₄₂O₄[M⁺]:442.3083,found:442.3084.

Embodiment 23

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0133g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2761g,2mmol),NMP(5mL),(R_a*,S*)-1n(0.3360g,1 mmol)/NMP(5mL) Reacted 36 hours with bis (phenylsulfonyl) methane (2a) (0.6044g, 1mmol).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (R of oily_a, S) and -3na (0.3151g, 55%): 97%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=85/15,1.0mL/ Min, λ=214nm, t_R(major)=9.9min, t_R(minor)=17.8min)；[α]_D ²⁰=-34.9 (c=0.99, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ7.97-7.85 (m,4H,ArH),7.70-7.59(m,2H,ArH),7.58-7.45 (m, 4H, ArH), 5.35-5.24 (m, 1H ,=CH), 4.67 (d, J=1.5Hz, 1H, CH), 3.08-2.94 (m, 1H, CH), 1.99-1.79(m,3H,1H from CH₂and CH₂),1.74-1.57(m,4H,1H from CH₂and CH₃),1.50- 1.00(m,22H, CH₂×11),0.86-0.81(m,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃)δ201.4,140.2, 138.6,134.3,134.0,129.4,128.91,128.85,101.7,90.8,87.6,40.8,33.7,31.8,31.4, 30.0,29.5,29.4,29.2,28.9,28.3,27.2,22.6,22.5,18.7,14.02,13.99；IR(neat)ν (cm^-1) 3067,2925,2855,1963,1685,1584,1463,1447,1336,1311,1158,1080, 1024；MS(70ev,EI) (the M of m/z (%) 573⁺+1,3.04),572(M⁺,2.44),291(100)；HRMS calcd.for C₃₃H₄₈O₄S₂[M⁺]: 572.2994,found:572.2994.

Embodiment 24

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0706 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1o(0.3904g,1 mmol)/NMP(5mL) Reacted 41 hours with bis (phenylsulfonyl) methane (2a) (0.6040g, 1mmol).Rapid column chromatography (eluent: Petroleum ether (60~90 DEG C)/ethyl acetate=9/1) obtain the chiral connection ene product (R of oily_a, S) and -3oa (0.3820g, 61%): 97%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=85/15,1.0mL/ Min, λ=214nm, t_R(major)=8.8min, t_R(minor)=13.7min)；[α]_D ²⁰=-35.7 (c=1.01, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ7.97-7.85 (m,4H,ArH),7.68-7.56(m,2H,ArH),7.56-7.42 (m, 4H, ArH), 5.90-5.72 (m, 1H ,=CH), 5.36-5.24 (m, 1H ,=CH), 5.05-4.89 (m, 2H ,=CH₂), 4.67 (d, J=1.2Hz, 1H, CH), 3.07-2.95 (m, 1H, CH), 2.04 (q, J=7.0Hz, 2H, CH₂),1.98-1.79 (m,3H,1H from CH₂and CH₂),1.74-1.58(m,4H,1H from CH₂and CH₃),1.45-0.99(m,26H, CH₂× 13), 0.88 (t, J=6.8Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ201.5,140.3, 139.0,138.6, 137.5,134.2,134.0.129.4,128.92,128.87,128.8,114.1,101.7,90.8, 87.6,40.8, 33.73,33.70,31.8,30.0,29.5,29.36,29.29,29.26,29.0,28.9,28.8,28.3, 27.6,22.6, 18.7,14.0；IR(neat)ν(cm^-1)3070,2925,2854,1965,1640,1585,1464, 1448,1335,1312, 1158,1080；MS (70ev, EI) m/z (%) 627 (M⁺+1,2.18),626(M⁺, 2.12),231(100)；HRMS calcd.for C₃₇H₅₄O₄S₂[M⁺]:626.3464,found:626.3461.

Embodiment 25

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0706 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1p(0.3085g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3201g, 2mmol)/NMP (2.5mL) react 18 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3pc(0.1840g, 45%):95%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=400/1, 0.8mL/min, λ=214nm, t_R(major)=20.4min, t_R(minor)=22.3min)；[α]_D ²⁰=+5.4 (c= 1.07,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.09-4.96 (m, 1H ,=CH), 4.27-4.10 (m, 4H, CH₂×2), 3.35 (d, J=9.6Hz, 1H, CH), 2.83-2.67 (m, 1H, CH), 2.01-1.80 (m, 2H, CH₂), 1.63 (d, J= 2.7Hz,3H,CH₃),1.51-1.15(m, 26H,CH₂×10and CH₃×2),0.94-0.81(m,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃) δ201.1,168.7,168.4,101.3,90.8,61.2,61.1,57.1,39.2,34.0,32.8, 31.8,31.6,29.52, 29.46,29.2,27.2,26.7,22.6,22.5,18.9,14.1；IR(neat)ν(cm^-1)2957, 2927,2856, 1966,1757,1736,1465,1368,1302,1240,1174,1153,1035；MS(70ev,EI)m/z (%) 408 (M⁺,13.57),136(100)；HRMS calcd.for C₂₅H₄₄O₄[M⁺]:408.3240,found: 408.3239.

Embodiment 26

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(R)-L5a(0.0710 g,0.06mmol),K₂CO₃(0.2763g,2mmol),NMP(5mL),(R_a*,S*)-1n(0.3362g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3205g, 2mmol)/NMP (2.5mL) react 40 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=30/1) obtain the chiral connection ene product (R of liquid_a,S)-3nc(0.2001g, 46%):99%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=400/1, 1.0mL/min, λ=214nm, t_R(major)=10.5min, t_R(minor)=18.7min)；[α]_D ²⁰=+7.1 (c= 1.015,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.08-4.97 (m, 1H ,=CH), 4.27-4.09 (m, 4H, CH₂× 2), 3.35 (d, J=9.6Hz, 1H, CH), 2.83-2.69 (m, 1H, CH), 2.01-1.81 (m, 2H, CH₂), 1.63 (d, J= 2.7Hz,3H,CH₃), 1.50-1.16(m,30H,CH₂×12and CH₃×2),0.97-0.82(m,6H,CH₃×2)；¹³C NMR (75MHz,CDCl₃)δ201.0,168.6,168.2,101.2,90.7,61.03,60.93,57.0,39.1,33.9, 32.7,31.8,31.5,29.51,29.48,29.37,29.2,27.1,26.6,22.6,22.4,18.8,14.0；IR(neat) ν(cm^-1)2956,2926,2855,1966,1757,1737,1465,1368,1301,1239,1174,1153, 1096,1035； MS (70ev, EI) m/z (%) 436 (M⁺,35.72),93(100)；HRMS calcd.for C₂₇H₄₈O₄[M⁺]:436.3553, found:436.3557.

Embodiment 27

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0134g,0.025mmol),(S)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2762g,2mmol),NMP(5mL),(R_a*,S*)-1p(0.3084g,1 mmol)/NMP (2.5mL) and diethyl malonate (2c) (0.3201g, 2mmol)/NMP (2.5mL) react 18 hours.Rapid column chromatography (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (S of liquid_a,R)-3pc(0.1798g, 44%):95%ee (HPLC conditions:Chiralcel IC column, n-hexane/i-PrOH=400/1, 0.8mL/min, λ=214nm, t_R(major)=23.9min, t_R(minor)=21.2min)；[α]_D ²⁰=-5.3 (c= 0.94,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.08-4.97 (m, 1H ,=CH), 4.28-4.10 (m, 4H, CH₂×2), 3.35 (d, J=9.6Hz, 1H, CH), 2.83-2.68 (m, 1H, CH), 2.00-1.81 (m, 2H, CH₂), 1.63 (d, J= 3.0Hz,3H,CH₃),1.54-1.15(m, 26H,CH₂×10and CH₃×2),0.95-0.80(m,6H,CH₃×2)；¹³C NMR(75MHz,CDCl₃) δ201.1,168.7,168.4,101.3,90.8,61.2,61.1,57.1,39.2,34.0,32.8, 31.8,31.6,29.51, 29.45,29.2,27.2,26.7,22.6,22.5,18.9,14.0；IR(neat)ν(cm^-1)2957, 2927,2856, 1966,1757,1737,1465,1368,1302,1241,1174,1153,1035；MS(70ev,EI)m/z (%) 408 (M⁺,12.56),136(100)；HRMS calcd.for C₂₅H₄₄O₄[M⁺]:408.3240,found: 408.3243.

Embodiment 28

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L5a(0.0142 g,0.012mmol),K₂CO₃(0.0551g,0.4mmol),NMP(1mL),(R_a,S)-1h(0.0584g,0.2 mmol)/NMP (0.5mL) and diethyl malonate (2c) (0.0642g, 0.4mmol)/NMP (0.5mL) react 12 hours.Flash column Analyse (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3hc(0.0601g, 76%):99%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=200/1, 1.2mL/min, λ=214nm, t_R(major)=10.0min, t_R(minor)=14.0min)；¹H NMR(300MHz, CDCl₃) δ 5.19-5.06 (m, 2H ,=CH × 2), 4.27-4.08 (m, 4H, CH₂× 2), 3.35 (d, J=9.3Hz, 1H, CH), 2.86-2.71(m,1H,CH), 2.02-1.85(m,1H,CH),1.78-1.56(m,5H,5H from Cy),1.53-0.97 (m,23H,5H from Cy,CH₂×6,and CH₃× 2), 0.87 (t, J=6.6Hz, 3H, CH₃)；¹³C NMR(75MHz, CDCl₃) δ202.4,168.4,168.1,98.5,92.4,61.1,60.9,56.9,38.9,37.3,32.94,32.88, 32.7,31.7, 29.3,29.1,26.7,26.0,25.92,25.89,22.5,13.9.

Embodiment 29

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L5a(0.0142 g,0.012mmol),K₂CO₃(0.0554g,0.4mmol),NMP(1mL),(S_a,R)-1h(0.0580g,0.2 mmol)/NMP (0.5mL) and diethyl malonate (2c) (0.0637g, 0.4mmol)/NMP (0.5mL) react 12 hours.Flash column Analyse (eluent:Petroleum ether (60~90 DEG C)/ether=20/1) obtain the chiral connection ene product (R of liquid_a,S)-3hc(0.0616g, 79%):98%ee (HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=200/1, 1.2mL/min, λ=214nm, t_R(major)=9.2min, t_R(minor)=12.1min)；¹H NMR(300MHz,CDCl₃) δ 5.19-5.06 (m, 2H ,=CH × 2), 4.28-4.08 (m, 4H, CH₂× 2), 3.36 (d, J=9.0Hz, 1H, CH), 2.85- 2.71(m,1H,CH), 2.00-1.85(m,1H,CH),1.81-1.57(m,5H,5H from Cy),1.52-0.97(m,23H, 5H from Cy,CH₂×6,and CH₃× 2), 0.88 (t, J=6.6Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃) δ 202.5,168.5,168.2,98.5,92.4,61.1,61.0,57.0,39.0,37.3,33.0,32.9,32.8,31.7, 29.3,29.1,26.8,26.01,25.96,25.9,22.5,14.0.

Embodiment 30

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0135g,0.025mmol),(R)-L5a(0.0709 g,0.06mmol),K₂CO₃(0.2763g, 2mmol), NMP (5mL), 1f (0.3508g, 1mmol)/NMP (5mL) and bis (phenylsulfonyl) methane (2a) (0.6103g, 2mmol) reacts 24 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ethyl acetate=6/1) obtain the chiral connection ene product (R of oily_a, S) and -3fa (0.1705g, 58%yield based on(R_a*,S*)-1f,d.r.>99:1as determined by ¹H NMR of isolated product):97% ee(HPLC conditions:Chiralcel AD-H column, n-hexane/i-PrOH=80/20,1.0mL/min, λ =214nm, t_R(major)=10.7min, t_R(minor)=12.4min)；[α]_D ²⁰=-230.5 (c=0.99, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 7.97-7.88(m,2H,ArH),7.88-7.79(m,2H,ArH),7.71-7.57(m,2H, ), ArH 7.57-7.37 (m, 6H, ArH), 7.15 (d, J=8.1Hz, 2H, ArH), 6.18 (dd, J₁=6.5Hz, J₂=2.6Hz, 1H ,=CH), 5.89 (t, J=6.6Hz, 1H ,=CH), 4.72 (d, J=1.2Hz, 1H, CH), 3.28-3.14 (m, 1H, CH),2.02-1.83(m,1H,1H from CH₂),1.77-1.57(m,1H,1H from CH₂),1.41-1.00 (m,8H, CH₂× 4), 0.84 (t, J=7.1Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ205.4, 139.6,138.7,134.5, 134.3,132.7,131.7,129.5,129.2,129.03,129.00,128.6,120.9, 96.2,95.4,86.2,39.5, 31.5,31.1,28.6,28.1,22.4,14.0.

Embodiment 31

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0135g,0.025mmol),(S)-L5a(0.0709g, 0.06mmol),K₂CO₃(0.1377g, 1mmol), NMP (5mL), 1i (0.2943g, 1mmol)/NMP (5 mL) and bis (phenylsulfonyl) methane (2a) (0.3050g, 1mmol) reacts 18 hours.Rapid column chromatography (eluent:Petroleum ether (30~60 DEG C)/ethyl acetate=8/1) obtain the chiral connection ene product (S of oily_a, R) and -3ia (0.1301g, 50%yield based on(R_a*,S*)-1i,d.r.>99:1as determined by ¹H NMR of isolated product):95% ee(HPLC conditions:Chiralcel OZ-H column, n-hexane/i-PrOH=90/10,1.0mL/min, λ =214nm, t_R(major)=15.6min, t_R(minor)=10.2min)；[α]_D ²⁰=+66.3 (c=0.98, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ 7.98-7.84(m,4H,ArH),7.70-7.59(m,2H,ArH),7.59-7.45(m,4H, ), ArH 5.44-5.33 (m, 1H ,=CH), 5.16 (qd, J₁=6.6Hz, J₂=2.0Hz, 1H ,=CH), 4.68 (d, J= 1.5Hz,1H, CH),3.13-3.00(m,1H,CH),2.02-1.79(m,3H,1H from CH₂and CH₂),1.79-1.60 (m, 1H,1H from CH₂),1.46-1.00(m,18H,CH₂×9),0.98-0.79(m,6H,CH₃×2)；¹³C NMR (75MHz,CDCl₃)δ203.9,140.0,138.6,134.3,134.1,129.4,128.90,128.87, 93.2,91.3, 87.1,40.0,31.6,31.5,30.3,29.1,29.01,28.97,28.6,28.4,28.1,22.5,22.4, 13.94, 13.89；IR(neat)ν(cm^-1)3067,2956,2926,2856,1961,1584,1463,1448, 1335,1312,1157, 1079；MS (70ev, EI) m/z (%) 530 (M⁺,1.22),207(100)；HRMS calcd.for C₃₀H₄₂O₄S₂[M⁺]: 530.2525,found:530.2524.

Embodiment 32

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L1a(0.0076 g,0.012mmol),K₂CO₃(0.0553g,0.4mmol),(R_a*, S*) -1a (0.0555g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1235g, 0.4mmol) reacts 14 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (R_a, S) and -3aa (51%NMR yield, d.r.>99:1,88.6%ee), there is 35% raw material (R_a*, S*) -1a remains It is remaining.

Embodiment 33

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(S)-L2a(0.0085g, 0.012mmol),K₂CO₃(0.0553g,0.4mmol),(R_a*, S*) -1a (0.0555g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1233g, 0.4mmol) reacts 12 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (S_a, R) and -3aa (68%NMR yield, d.r.=99:2,91.0%ee).

Embodiment 34

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L3a(0.0078 g,0.012mmol),K₂CO₃(0.0552g,0.4mmol),(R_a*, S*) -1a (0.0554g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1232g, 0.4mmol) reacts 24 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (R_a, S) and -3aa (59%NMR yield, d.r.>99:1,92.9%ee), there is 24% raw material (R_a*,S*)-1a It is remaining.

Embodiment 35

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L4a(0.0144 g,0.012mmol),K₂CO₃(0.0553g,0.4mmol),(R_a*, S*) -1a (0.0554g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1235g, 0.4mmol) reacts 37 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (R_a, S) and -3aa (30%NMR yield, d.r.>99:1,64.0%ee), there is 17% raw material (R_a*,S*)-1a It is remaining.

Embodiment 36

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L4b(0.0072 g,0.012mmol),K₂CO₃(0.0553g,0.4mmol),(R_a*, S*) -1a (0.0557g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1234g, 0.4mmol) reacts 14 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (R_a, S) and -3aa (53%NMR yield, d.r.>99:1,94.3%ee), there is 34% raw material (R_a*,S*)-1a It is remaining.

Embodiment 37

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.0027g,0.005mmol),(R)-L5a(0.0142 g,0.012mmol),K₂CO₃(0.0553g,0.4mmol),(R_a*, S*) -1a (0.0554g, 0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.1234g, 0.4mmol) reacts 12 hours for 40 DEG C in DMF (2.0mL), goes smoothly Property connection ene product (R_a, S) and -3aa (67%NMR yield, d.r.>99:1,94.7%ee).

Embodiment 38

Operation is the same as embodiment 1.[Pd(π-cinnamyl)Cl]₂(0.005mmol),(R)-L5b(0.012mmol), K₂CO₃ (0.4mmol),(R_a*, S*) -1a (0.2mmol) and bis (phenylsulfonyl) methane (2a) (0.4 mmol) be in DMF 40 DEG C are reacted 13 hours in (2.0mL), obtain chiral ene product (R_a, S) and -3aa (64% NMR yield, d.r.>99:1, 94.1%ee).

To prove the practicality of the present invention, example 3 below 9~44 is to have axial chirality and center concurrently prepared by the present invention Chirality connection ene product is used for the application for preparing other compounds.

Embodiment 39

Nitrogen protection under, sequentially added in the Schlenk reaction tubes dry toward one magnesium chips (0.2402g, 10 mmol) and Methanol (4mL), reaction tube is placed in ice-water bath, and (R is then added at 0 DEG C_a, S) and -3hb (0.2734 g, 0.5mmol) and four Hydrogen furans (1mL), stirring, and make its clear-cutting forestland room temperature.After 3 hours, thin-layer chromatography monitoring reaction is completed.Add into reaction tube Enter ether (5mL) dilute reaction solution, gained mixing liquid is filtered with a short column, ether elution (10mL × 3).Filtrate is rotated dense Contracting, residue is through rapid column chromatography (eluent：Petroleum ether (60~90 DEG C)) separate to obtain liquid chirality allenic compound (R_a, S) -4 (0.1065g, 80%):96%ee (HPLC conditions:Chiralcel IF-3column,n-hexane, 0.5mL/min, λ=214nm, t_R(major)=10.1min, t_R(minor)=11.2min)；[α]_D ²⁰=-42.3 (c= 0.96,CHCl₃)；¹H NMR(300MHz,CDCl₃)δ5.15(td,J₁=6.2Hz, J₂=2.3Hz, 1H ,=CH), 5.03 (td, J₁=6.6Hz, J₂=3.0Hz, 1H ,=CH), 4.39 (ddd, J₁=23.9Hz, J₂=8.7Hz, J₂=5.7Hz, 1H, 1H from CH₂),4.23(ddd,J₁=24.0Hz, J₂=8.7Hz, J₂=6.0Hz, 1H, 1H from CH₂), 2.49-2.24(m, 1H,CH),2.05-1.86(m,1H,CH),1.84-0.97(m,22H,CH₂× 11), 0.88 (t, J=6.9Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃) δ 202.8,98.2,91.5 (d, J=8.3Hz), 86.5 (d, J=170.3Hz), 39.9 (d, J =18.6Hz), 37.2,33.0,31.8,30.8 (d, J=4.9Hz), 29.7,29.2,26.9,26.13,26.05,22.6, 14.1；¹⁹F NMR(282MHz,CDCl₃)δ-221.2(td,J₁=47.5Hz, J₂=18.0Hz)；IR(neat)ν(cm^-1) 2924,2853,1961,1714,1450,1380, 1010；MS (70ev, EI) m/z (%) 266 (M⁺,8.99),168(100)； HRMS calcd.for C₁₈H₃₁F [M⁺]:266.2410,found:266.2414.

Embodiment 40

In glove box, in the Schlenk reaction tubes dry toward one add LiCl (0.0521g, 1.2mmol, 98%) H, is then once added under nitrogen protection₂O (28.8 μ L, d=1.00g/mL, 0.0288g, 1.6 mmol), (R_a,S)- 3hc and DMSO (2mL).Reaction tube is placed in into one to be previously heated in 180 DEG C of oil bath, stirring reaction, thin-layer chromatography monitoring 4 is small When after react complete.Reaction tube is proposed from oil bath, and naturally cools to room temperature, adds ether (10mL) dilute reaction solution, Gained mixed liquor is washed (5mL × 3) with saturated common salt.Organic phase is separated, aqueous phase is extracted once again with ether (10mL).Merge All organic phases, anhydrous sodium sulfate drying.Filtering, concentrated by rotary evaporation, residue is through rapid column chromatography (eluent：Petroleum ether (60 ~90 DEG C)/ether=40/1) separate to obtain liquid chirality allenic compound (R_a, R) and -5 (0.0872g, 68%):98%ee (determined by the corresponding reduction product(R_a,R)-8)；[α]_D ²⁰=-45.7 (c= 1.055,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.20-5.04 (m, 2H ,=CH × 2), 4.12 (q, J=7.1Hz, 2H, CH₂), 2.62-2.45 (m, 1H, CH), 2.32 (d, J=6.9Hz, 2H, CH₂),2.02-1.84 (m,1H,CH),1.84-1.54 (m,5H,5H from Cy),1.50-0.96(m,20H,5H from Cy and CH₂×6and CH₃), 0.88 (t, J= 6.6Hz,3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ201.7, 172.8,98.6,95.0,60.1,39.8,37.2,35.4, 35.1,33.03,32.98,31.8,29.5,29.2,26.8, 26.1,26.0,22.6,14.2,14.0；IR(neat)ν(cm^-1) 2925,2853,1960,1738,1463,1448, 1370,1157,1035；MS (70ev, EI) m/z (%) 320 (M⁺, 22.35),55(100)；HRMS calcd. for C₂₁H₃₆O₂[M⁺]:320.2715,found:320.2719.

Embodiment 41

Under nitrogen protection, (R is sequentially added into a Schlenk reaction tube_a,S)-3hc(0.3928g,1.0mmol) With MeOH (3mL), the NaOH aqueous solution (0.1601gNaOH is dissolved in 1.8mL water).Reaction tube then is placed in into one to be previously heated to In 100 DEG C of oil bath, stirring reaction, thin-layer chromatography monitors reaction in 2.5 hours and completed.Reaction tube is proposed from oil bath, it is natural Room temperature is cooled to, reaction solution PH=1 is adjusted with hydrochloric acid (concentration 1.0M).Ether extracts (10mL × 3), merges organic phase, satisfies (20mL) is washed with salt, anhydrous sodium sulfate drying.Filtering, concentrated by rotary evaporation, residue is directly used in react in next step.

The residue obtained by acetic acid (4.0mL) dissolving previous step, under nitrogen protection, is added to another drying In Schlenk reaction tubes, reaction tube is then placed in one and is previously heated in 120 DEG C of oil bath, stirring reaction, thin-layer chromatography prison React and complete after surveying 41 hours.Reaction tube is proposed from oil bath, naturally cools to room temperature.Reaction solution is transferred in round-bottomed bottle, Concentrated by rotary evaporation, residue is through rapid column chromatography (eluent：Petroleum ether (60~90 DEG C)/ethyl acetate=20/1 (400mL)~ 10:1) liquid chirality allenic compound (R is separated to obtain_a, R) and -6 (0.2541g, 87%):98%ee (determined by the corresponding cyclization product(4R,5S)-7and reduction product(R_a,R)-8)； [α]_D ²⁰=-50.2 (c=1.045, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ11.21(s,1H,COOH),5.22-5.03 (m, 2H ,=CH × 2), 2.63-2.44 (m, 1H, CH), 2.38 (d, J=6.9Hz, 2H, CH₂),2.03-1.84(m,1H, CH), 1.83-1.55(m,5H,5H from Cy),1.49-0.97(m,17H,5H from Cy and CH₂×6),0.88 (t, J=6.6Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ201.8,179.7,98.8,94.7,39.6, 37.2, 35.3,35.1,33.01,32.95,31.8,29.5,29.2,26.8,26.1,26.0,22.6,14.0；IR(neat)ν (cm^-1) 2924,2852,1961,1708,1447,1412,1288；MS (70ev, EI) m/z (%) 293 (M⁺, 7.92),41(100)； HRMS calcd.for C₁₉H₃₂O₂[M⁺]:292.2402,found:292.2401.

Embodiment 42

In glove box, in the Schlenk reaction tubes dry toward one, Au (PPh are sequentially added₃)Cl(0.0074 g, 0.015mmol) and AgOTs (0.0044g, 0.015mmol, 98%).The lower room temperature of nitrogen protection adds CHCl₃(1.5mL), room Temperature stirring 30 minutes.(R is then added under -20 DEG C of cryostats_a, R) and -6 (0.0874g, 0.3mmol) and CHCl₃(1.5mL), and Continue the stirring reaction at -20 DEG C, thin-layer chromatography reacts after monitoring 12 hours to be completed.Reaction solution is filtered with a short column, second Ether elutes (10mL × 3), filtrate concentrated by rotary evaporation, crude product warp¹H NMR analyze double bond E/Z ratios be 96:4.Through flash column Analyse (eluent：Petroleum ether (60~90 DEG C)/ethyl acetate=30/1) separation after, obtain liquid chiral ring product (4R, 5S) -7 (0.0768g,E/Z>99:1,88%):98%ee (HPLC conditions:Chiralcel PC-4column,n- Hexane/i-PrOH=95/5,1.0mL/min, λ=214nm, t_R(major)=12.3min, t_R(minor)= 13.7min)；[α]_D ²⁰=+42.1 (c=1.00, CHCl₃)；¹H NMR(300MHz,CDCl₃)δ5.74(dd,J₁=15.3Hz, J₂=6.6Hz, 1H ,=CH), 5.39 (ddd, J₁=15.3Hz, J₂=7.8Hz, J₃=1.2Hz, 1H ,=CH), 4.91 (t, J =7.2Hz, 1H, CH), 2.64-2.45 (m, 2H, CH₂),2.34-2.16(m,1H,CH),2.10-1.93(m,1H, CH), 1.79-1.58(m,5H,5H from Cy),1.50-0.99(m,17H,5H from Cy and CH₂× 6), 0.88 (t, J= 6.9Hz,3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ176.7,141.8,121.0,83.8, 40.3,39.6,33.8, 32.5,32.4,31.6,29.39,29.37,29.0,27.4,25.9,25.7,22.5,13.9；IR (neat)ν(cm^-1)2924, 2853,1778,1668,1450,1309,1165；MS (70ev, EI) m/z (%) 292 (M⁺,5.76),121(100)；HRMS calcd.for C₁₉H₃₂O₂[M⁺]:292.2402, found:292.2401.

Embodiment 43

Under nitrogen protection, in the Schlenk reaction tubes dry toward one, LiAlH is sequentially added₄(0.0392g,1.0 ) and ether (4mL) mmol.(R is then added at 0 DEG C_a, R) -6 diethyl ether solution (4mL), and be kept at this temperature stirring Reaction.Thin-layer chromatography reacts complete after monitoring 4 hours, adds water (5mL) and reaction is quenched.Gained mixed liquor is extracted with ether (10mL × 3), merge organic phase, anhydrous sodium sulfate drying.Filtering, concentrated by rotary evaporation, residue is through rapid column chromatography (eluent： Petroleum ether (60~90 DEG C)/ethyl acetate=10/1) separate to obtain liquid chirality allenic compound (R_a,R)-8(0.1275g, 92%):98%ee (HPLC conditions:Chiralcel OD-H column, n-hexane/i-PrOH=100/1, 1.0mL/min, λ=214nm, t_R(major)=14.7min, t_R(minor)=13.4min)；[α]_D ²⁰=-73.0 (c= 0.985,CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.16-5.05 (m, 1H ,=CH), 5.03-4.92 (m, 1H ,=CH), 3.79-3.62(m,2H,CH₂),2.19-2.03(m,1H,CH),2.03-1.87(m,1H,CH),1.84-1.46(m, 8H,5H from Cy and CH₂and OH),1.45-0.98(m,17H,5H from Cy and CH₂× 6), 0.88 (t, J= 6.6Hz,3H,CH₃)；¹³C NMR(75MHz,CDCl₃)δ202.0,97.6,95.6,61.4, 37.9,37.4,36.4,35.8, 33.2,33.1,31.8,29.6,29.3,27.0,26.1,26.03,26.01,22.6,14.0； IR(neat)ν(cm^-1)3364, 2925,2853,1957,1463,1448,1378,1348,1050；MS (70ev, EI) m/z (%) 279 (M⁺,6.92),135 (100)；HRMS calcd.for C₁₉H₃₄O[M⁺]:278.2610, found:278.2614.

Embodiment 44

Under nitrogen protection, in the Schlenk reaction tubes dry toward one, (R is sequentially added_a,R)-8(0.1669g,0.6 mmol)/DCM(6mL),PPh₃(0.1888g, 0.72mmol), imidazole (0.0497,0.72mmol, 99%) and I₂ (0.1830g,0.72mmol).After being stirred at room temperature 1 hour, thin-layer chromatography monitoring reaction is complete.After reaction solution concentrated by rotary evaporation, through fast Fast column chromatography (eluent：Petroleum ether (30~60 DEG C)) crude product is separated to obtain, it is directly used in and reacts in next step.

Nitrogen protection under, toward another dry Schlenk reaction tubes in, sequentially add NaH (0.0289g, 0.72mmol), DMF (1mL) and diethyl malonate (0.1932g, 1.2mmol)/DMF (1mL).It is stirred at room temperature 30 minutes Afterwards, the crude product of previous step is dissolved in DMF (4mL), be slowly added drop-wise in 5 minutes in the reaction solution of stirring, continue room temperature Stirring reaction.After thin-layer chromatography monitors 12 hours, reaction is complete, adds saturation NH₄The Cl aqueous solution (10mL) and water (10mL) are quenched Go out reaction.Mixed liquor is extracted (20mL × 3) with ether, merges organic phase, saturated common salt washing (10mL), anhydrous sodium sulfate is done It is dry.Filtering, concentrated by rotary evaporation, residue is through rapid column chromatography (eluent：Petroleum ether (60~90 DEG C)/ether=20/1) separate The chiral connection ene product (R of liquid_a, R) and -9 (0.2115g, 84%):96%ee (SFC conditions:Chiralcel AD-H Column, n-hexane/i-PrOH=95/5,1.3mL/min, λ=214nm, t_R(major)=7.0min, t_R(minor)= 7.8min)；[α]_D ²⁰=-49.3 (c=1.03, CHCl₃)；¹H NMR(300MHz,CDCl₃) δ 5.12-5.04 (m, 1H ,= ), CH 4.96-4.87 (m, 1H ,=CH), 4.29-4.10 (m, 4H, CH₂× 2), 3.30 (t, J=7.7 Hz, 1H, CH), 2.10- 1.80(m,4H,CH₂and CH×2),1.80-1.55(m,5H,5H from Cy), 1.51-0.96(m,25H,5H from Cy,CH₂×7,and CH₃× 2), 0.88 (t, J=6.8Hz, 3H, CH₃)；¹³C NMR(75MHz,CDCl₃)δ202.1,169.3, 97.3,95.3,61.0,51.9,39.2,37.3,33.1, 33.0,31.7,29.5,29.2,26.9,26.5,26.0,25.94, 25.92,22.5,13.9；IR(neat)ν(cm^-1) 2925,2853,1958,1754,1737,1463,1449,1369,1336, 1300,1244,1221,1177,1150, 1097,1032；MS (70ev, EI) m/z (%) 421 (M⁺+1,4.15),420(M⁺, 1.36),173(100)； HRMS calcd.for C₁₉H₃₄O[M⁺]:420.3244,found:420.3240.

The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect Protect scope.

Claims

1. a kind of method that direct construction has the high optical activity allenic compound of axial chirality and central chirality concurrently, its feature exist In, in the presence of palladium catalyst, chiral diphosphine ligand and alkali, 2,3- connection alkenyl-functional groups compounds and formula shown in formula (1) (2) nucleopilic reagent shown in carries out transition metal-catalyzed asymmetric connection olefination in organic solvent, and step generation is simultaneous There is the high optical activity allenic compound of axial chirality and central chirality, course of reaction is reacted shown in formula (I) as follows：

Wherein, R¹For alkyl, the alkyl with functional group, phenyl, aryl or heterocyclic radical；R²For hydrogen atom, alkyl, with official The alkyl that can be rolled into a ball, phenyl, aryl or heterocyclic radical；R³For alkyl, the alkyl with functional group, phenyl or aryl；LG is vinegar Acid esters, carbonic ester, phosphate, phosphite ester, sulphonic acid ester or halogen atom；R is hydrogen atom, halogen atom, alkyl, phenyl or Person's aryl；E is drawing electron group, is one kind in ester group, sulfonyl, cyano group, acyl group；The aryl is o-, m-, contraposition has suction The phenyl of electronics or electron substituent, the heterocyclic radical are thiophene, furans or pyridine or have electrophilic or electron substitution Thiophene, furans or the pyridine of base.

2. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that R¹For C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl, or heterocycle Base；R²For hydrogen atom, C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For C1-C20 alkyl, end carry the C1-C20 alkyl of functional group, phenyl or aryl；LG is acetate, carbonic ester, phosphate, Or halogen atom；R is hydrogen atom, halogen atom, C1-C20 alkyl, phenyl or aryl；E is drawing electron group, is ester group, sulphur One kind in acyl group, cyano group, acyl group；Wherein, in C1-C20 alkyl of the end with functional group, the functional group is selected from carbon-to-carbon Double bond, the key of carbon-to-carbon three, hydroxyl, oxyl, silicon ether, ester group, acyl group, acyloxy, amide groups, sulfonic group, halogen, sulfonyl, Carboxyl, cyano group, nitro, the amino of alkyl substitution, the amino of acyl group substitution；The aryl be it is o-, m-, contraposition have electrophilic or to Electronics substitution phenyl, the heterocyclic radical be thiophene, furans or pyridine or have the thiophene of electrophilic or electron substituent, Furans or pyridine, the electron-withdrawing substituent include halogen, nitro, ester group, carboxyl, acyl group, amide groups, sulfonyl, sulfonic group, Cyano group, the electron substituent include alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, amino, acyloxy, alkyl substitution Amino, acyl group substitution amino.

3. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that the described method comprises the following steps：

1) in oil bath, palladium catalyst, chiral diphosphine ligand and alkali is put into successively into dry reaction tube, reaction tube is taken Go out, add the organic solvent of certain volume in a nitrogen atmosphere；Reaction tube is placed in the oil bath for being previously heated to 20-50 DEG C, Stir 5-60 minutes；Wherein, the organic solvent of the certain volume refers to join alkenyl-functional groups chemical combination with 2,3- shown in formula (1) On the basis of the dosage of thing, the dosage of the organic solvent is 0.5-10.0mL/mmol；

2) after the completion for the treatment of step 1), reaction tube is proposed from oil bath, 2, the 3- connection alkenyls shown in formula (1) are added under nitrogen atmosphere The organic solvent of functional compounds, nucleopilic reagent and certain volume, then reaction tube is put back in oil bath and heated, stirring reaction； Wherein, the organic solvent of the certain volume refers to the dosage with 2, the 3- connection alkenyl-functional groups compounds shown in formula (1) for base Standard, the dosage of the organic solvent is 0.5-10.0mL/mmol；

3) after step 2) reaction completely, the ethyl acetate of certain volume is added into reaction tube, gained mixed liquor is eaten with saturation Salt is washed 3 times, separates organic phase, and the ether of aqueous phase certain volume extracts 1 time, merges all organic phases, use anhydrous slufuric acid Sodium is dried, and is filtered, and concentration, rapid column chromatography must have the high optical activity allenic compound of axial chirality and central chirality concurrently；Wherein, The ethyl acetate of the certain volume refer to shown in formula (1) 2,3- connection alkenyl-functional groups compound dosage on the basis of, institute The dosage for stating ethyl acetate is 1.0-100mL/mmol, and the ether of the certain volume refers to join alkene with 2,3- shown in formula (1) On the basis of the dosage of base functional compounds, the dosage of the ether is 1.0-100mL/mmol.

4. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that described palladium catalyst is two (cinnamyl palladium bichlorides), two (allyl palladium chlorides), four (triphenyls Phosphine) palladium, three (dibenzalacetone) two palladium, two (dibenzalacetone) one palladium, palladium bichloride, palladium, two (triphenylphosphine) chlorine Change palladium, two (acetonitrile) palladium bichlorides any one or more.

5. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that described chiral diphosphine ligand is selected from (R)-L1~(the R)-L5 and its enantiomter of following structure (S)-L1~(S)-L5 one or more；Wherein, Ar is phenyl, aryl or heterocyclic radical, and the aryl is o-, m-, contraposition There are alkyl or the phenyl of oxyl substitution；The heterocyclic radical is thiophene, furans or pyridine；

6. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that described chiral diphosphine ligand is selected from (R)-L5a, (R)-L5b and its enantiomter (S)-L5a, (S) one or more in-L5b；Wherein, described (R)-L5a, (R)-L5b structure are as follows：

7. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that described alkali is selected from potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium hydroxide, Sodium hydroxide, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide, any one or more in sodium hydride.

8. direct construction according to claim 1 has the high optical activity allenic compound of axial chirality and central chirality concurrently Method, it is characterised in that described organic solvent is selected from 1-METHYLPYRROLIDONE, DMF, N, N- dimethyl Acetamide, dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, acetonitrile, ether, butyl ether, methyl tertiary butyl ether(MTBE) any one or It is a variety of.

9. one kind has the high optical activity allenic compound of axial chirality and central chirality concurrently, it is characterised in that the following (R of its structure_a, S)-3,(S_a, R) and shown in -3：

Wherein, R¹For alkyl, the alkyl with functional group, phenyl, aryl or heterocyclic radical；R²For hydrogen atom, alkyl, with official The alkyl that can be rolled into a ball, phenyl, aryl or heterocyclic radical；R³For alkyl, the alkyl with functional group, phenyl or aryl；LG is vinegar Acid esters, carbonic ester, phosphate, phosphite ester, sulphonic acid ester or halogen atom；R is hydrogen atom, halogen atom, alkyl, phenyl or Person's aryl；E is drawing electron group, is one kind in ester group, sulfonyl, cyano group, acyl group；Wherein, the aryl is o-, m-, right There is the phenyl of electrophilic or electron substituent position；The heterocyclic radical is thiophene, furans or pyridine or has electrophilic or to electricity Thiophene, furans or the pyridine of sub- substituent.

10. the high optical activity allenic compound for having axial chirality and central chirality concurrently according to claim 8 or claim 9, it is special Sign is, R¹For C1-C20 alkyl, end carries the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical；R²It is former for hydrogen Son, C1-C20 alkyl, end carry the C1-C20 alkyl of functional group, phenyl, aryl or heterocyclic radical；R³For C1-C20 alkyl, End carries the C1-C20 alkyl of functional group, phenyl or aryl；LG is that acetate, carbonic ester, phosphate, or halogen are former Son；R is hydrogen atom, halogen atom, C1-C20 alkyl, phenyl or aryl；E is drawing electron group, be ester group, sulfonyl, cyano group, One kind in acyl group；Wherein, in C1-C20 alkyl of the end with functional group, the functional group is selected from carbon-to-carbon double bond, carbon-to-carbon Three key, hydroxyl, oxyl, silicon ether, acyloxy, ester group, acyl group, amide groups, sulfonic group, halogen, sulfonyl, carboxyl, cyano group, Nitro, the amino of alkyl substitution, the amino of acyl group substitution；The aryl is o-, m-, contraposition has electrophilic or electron substitution Phenyl；The heterocyclic radical is thiophene, furans or pyridine or has the thiophene, furans or pyridine of electrophilic or electron substituent, The electron-withdrawing substituent includes halogen, nitro, ester group, carboxyl, acyl group, amide groups, sulfonyl, sulfonic group, cyano group, described to give Electron substituent group includes alkyl, alkenyl, alkynyl, phenyl, oxyl, hydroxyl, amino, acyloxy, amino, the acyl group of alkyl substitution Substituted amino.

11. according to claim 9 or 10 have axial chirality concurrently and the high optical activity allenic compound of central chirality is being made Standby single fluoromethylation connection alkene, γ-connection olefin(e) acid ester, γ-connection olefin(e) acid, γ-connection enol, gamma-butyrolacton containing multiple chiral centers The application of compound.