CN109851634B - Chiral monophosphine ligand Yu-Phos and preparation method and application of full configuration thereof - Google Patents

Abstract

The invention discloses a chiral monophosphine ligand Yu-Phos and a preparation method and application of a full configuration thereof, wherein the ligand is compound 1 or an enantiomer, a racemate and a diastereoisomer of the compound 1; wherein "+" denotes a chiral center; n is an integer of 0 to 6; the invention also discloses a preparation method of the ligand complete configuration, and a compound

And Compound 4

Preparing the ligand by using the raw material through steps of substitution reaction, addition reaction, condensation reaction and the like; the chiral monophosphine ligand 1(S, R) can be obtained by performing addition reaction by using two configurational compounds 4 and different types of metal reagents_s)、1(R,R_s)、1(S,S_s) And 1(R, S)_s) The four full configurations of (a) are optically pure. The invention also discloses application of the ligand in catalyzing asymmetric cycloaddition reaction between eneynone molecules, and the ligand has the advantages ofGood reaction activity and stereoselectivity, and wide application value.

Description

Preparation method and application of chiral monophosphine ligand Yu-Phos and its full configuration

technical field

The invention belongs to the technical field of organic chemistry, and relates to a novel chiral monophosphine ligand and a preparation method and application thereof.

Background technique

Human understanding of chiral compounds can be traced back to the middle of the 19th century. In 1848, the young French chemist and microbiologist Li Pasteur discovered that the slow evaporation and crystallization of racemic potassium ammonium tartrate aqueous solution can obtain two kinds of mirror images of each other. The crystal form of chiral compounds has since opened the curtain on the research of chiral compounds. After continuous research and exploration, scientists have found that in the synthesis of asymmetric compounds, compared with chiral resolution, the induction of chiral sources (such as chiral prosthetic groups), asymmetric catalysis has very obvious advantages, because it does not Resolving reagents and complex resolution processes are required, and there is no requirement for substrates, and the conversion from racemic compounds to optically pure compounds can be efficiently accomplished with a small amount of catalyst. In the past 30 years since the end of the twentieth century, the field of asymmetric catalysis has developed and expanded rapidly. Over time, economical, safe, environmentally friendly, and resource- and energy-saving chemistry has become the latest requirement in the field of organic synthesis. In this regard, chemists in the field of asymmetric catalysis are also working tirelessly to achieve "perfect chemical reactions with 100% selectivity and 100% yield without by-products." However, there are still many challenging problems in this field, such as the stereoselectivity, activity and production efficiency of three-dimensional space. The laws of transfer, induction and amplification during the transformation of chiral compounds are revealed from a deeper level. Through the unremitting efforts of organic chemists in asymmetric catalysis and chiral synthesis, the initial random empirical exploration has gradually risen to a scientific and theoretical guidance with good application background and development prospects. system. At the same time, the rapid development of asymmetric catalysis and chirality science has also provided scientific basis and technical support for the research and development in the fields of medicine and pesticides. Other scientific fields such as chiral separation provide scientific basis and material support. In 2001, William Standish Knowles, Ryoji Noyori, and Barry Sharpless shared the Nobel Prize in Chemistry for their contributions to chiral catalysis, highlighting the importance of research in this field and the achievements in this field. significant progress. It can be said that the discovery and development of asymmetric catalytic reactions is one of the most important achievements in the field of chemistry and even the entire natural sciences in the 20th century.

A molecule has chirality if it does not coincide with its mirror image, just as the right hand and the left hand cannot overlap. The chirality of molecules is usually caused by asymmetric carbons, which are usually identified by (DL), (±) and (RS). Chirality exists widely in nature and is a universal feature of the universe. Human life activities are inseparable from chirality. For example, biological macromolecules such as nucleic acids, proteins and enzymes, which are the important basis of life activities, are almost all chiral, and most of these biological macromolecules have important physiological functions in the human body.

Generally speaking, there are mainly the following methods to obtain optically pure chiral molecules: (1) Extraction from natural products; (2) Resolution of racemates, mainly achieved by chemical resolution or enzymatic resolution; ( 3) Chiral prosthetic group method; (4) Asymmetric catalytic synthesis. Ryoji Noyori's discovery of a new method for enantiocatalyzed oxidization with transition metals, and ultimately the effective enantiomer, was quickly applied to the production of a drug for the treatment of Parkinson's disease. Compared with traditional methods, asymmetric catalytic synthesis has broad development prospects, and optically pure chiral molecules can be synthesized with catalytic amount or even a very small amount of catalyst, which has potential industrial application value. The chiral ligand is an important part of the catalyst in metal-organocatalysis and is the core of inducing the chirality of the product.

Phosphine ligands are a large family of chiral ligands. Due to their structural characteristics such as good coordination ability with metals and easy modification, they have received extensive attention from chemists and have been the focus of research by chemists in recent years. one. Chiral phosphine ligands can be roughly divided into carbon center, sulfur center, phosphine center chiral phosphine ligands and so on according to their chiral centers. Among them, carbon-centered chiral phosphine ligands have developed rapidly in recent years due to the extensive carbon centers, diverse structures, easy modification, and good application effects. At the same time, thiochiral phosphine ligands have also been well developed and applied in many systems. However, according to research, it can be seen that ligands containing both carbon centers and sulfur centers in the same chiral phosphine ligand are rare. There are reports. Therefore, the design and synthesis of a class of phosphine ligands with both chiral carbon centers and chiral sulfur centers has potential application value.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a kind of chiral monophosphine ligand Yu-Phos and the preparation method and application of its full configuration, which can prepare all stereoconfigurations with high efficiency, high selectivity and low cost by using different metal reagents. The chiral monophosphine ligand Yu-Phos.

The concrete technical scheme that realizes the object of the present invention is:

A class of chiral monophosphine ligands, Yu-Phos, is characterized in that the monophosphine ligands are compound 1 or an enantiomer, racemate or diastereomer of compound 1 shown in the following formula:

R¹、R²、R⁴分别独立选自C₁～C₁₂的烷烃基、C₁～C₁₀的烷氧基、

R³、R⁵分别独立选自氢、C₁～C₁₂的烷烃基、C₁～C₁₀的硅氧基、C₁～C₁₀的烷酰基、C₁～C₁₀的酯基、C₁～C₁₀的磺酸酯基、

OR^W或SR^W；其中：“*”代表手性中心、R^x和R^x′分别独立选自氢、卤素、C₁～C₁₂的烷烃基、C₁～C₁₀的烷氧基、C₁～C₁₀的硅氧基、C₁～C₁₀的烷酰基、C₁～C₁₀的酯基、C₁～C₁₀的磺酸酯基；R^y、R^y′、R^y〃、R^z、R^z′和R^w分别独立选自C₁～C₁₂的烷烃基、C₁～C₁₀的烷氧基、C₁～C₁₀的硅氧基、C₁～C₁₀的烷酰基、C₁～C₁₀的酯基或C₁～C₁₀的磺酸酯基；“*”表示手性中心；n取值范围为0～6的整数；wherein R and R ⁰ are independently selected from hydrogen, C ₁ -C ₁₂ alkane, C ₁ -C ₁₀ alkoxy,

R ¹ , R ² and R ⁴ are independently selected from C ₁ -C ₁₂ alkane groups, C ₁ -C ₁₀ alkoxy groups,

R ³ and R ⁵ are independently selected from hydrogen, C ₁ -C ₁₂ alkane group, C ₁ -C ₁₀ siloxy group, C ₁ -C ₁₀ alkanoyl group, C ₁ -C ₁₀ ester group, C ₁ ～C ₁₀ sulfonate group,

OR ^W or SR ^W ; wherein: "*" represents a chiral center, R ^x and R ^x' are independently selected from hydrogen, halogen, C ₁ -C ₁₂ alkane, C ₁ -C ₁₀ alkoxy, C Siloxy group of ₁ -C ₁₀ , alkanoyl group of C ₁ -C ₁₀ , ester group of C ₁ -C ₁₀ , sulfonate group of C ₁ -C ₁₀ ; R ^y , R ^y′ , R ^y″ , R ^z , R ^z′ and R ^w are independently selected from C ₁ -C ₁₂ alkane group, C ₁ -C ₁₀ alkoxy group, C ₁ -C ₁₀ siloxy group, C ₁ -C ₁₀ alkanoyl group, C ₁ -C ₁₀ ester group or C ₁ -C ₁₀ sulfonate group; "*" represents a chiral center; n is an integer ranging from 0 to 6;

R¹、R²同时选自C₁～C₁₂的烷烃基、

R³、R⁵分别独立选自氢、C₁～C₁₂的烷烃基、C₁～C₁₀的硅氧基、C₁～C₁₀的酯基或

R⁴选自C₁～C₁₂的烷烃基、

其中R^x和R^x′分别独立选自氢、卤素、C₁～C₁₂的烷烃基、C₁～C₁₀的烷氧基、C₁～C₁₀的硅氧基、C₁～C₁₀的烷酰基、C₁～C₁₀的酯基、C₁～C₁₀的磺酸酯基；“*”代表手性中心；n取值范围为1-4的整数；As a preferred solution, R and R ⁰ in compound 1 are independently selected from hydrogen, C ₁ -C ₁₂ alkane groups,

R ¹ and R ² are simultaneously selected from C ₁ -C ₁₂ alkane groups,

R ³ and R ⁵ are independently selected from hydrogen, C ₁ -C ₁₂ alkane group, C ₁ -C ₁₀ siloxy group, C ₁ -C ₁₀ ester group or

R ⁴ is selected from C ₁ -C ₁₂ alkane groups,

wherein R ^x and R ^x' are independently selected from hydrogen, halogen, C ₁ -C ₁₂ alkane, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ siloxy, C ₁ -C ₁₀ Alkanoyl group, C ₁ -C ₁₀ ester group, C ₁ -C ₁₀ sulfonate group; "*" represents a chiral center; n is an integer ranging from 1 to 4;

R¹、R²同时选自C₁～C₁₂的烷烃基、

R³选自C₁～C₁₂的烷烃基或

R⁴选自叔丁基；R⁵选自氢、C₁～C₁₂的烷烃基、C₁～C₁₀的硅氧基；其中R^x和R^x′分别独立选自氢、C₁～C₁₂的烷烃基、C₁～C₁₀的烷氧基或C₁～C₁₀的硅氧基；“*”代表手性中心；n取值范围为1-3的整数；As a preferred solution, R and R ⁰ in compound 1 are independently selected from hydrogen, C ₁ -C ₁₂ alkane groups,

R ¹ and R ² are simultaneously selected from C ₁ -C ₁₂ alkane groups,

R ³ is selected from C ₁ -C ₁₂ alkane groups or

R ⁴ is selected from tert-butyl group; R ⁵ is selected from hydrogen, C ₁ -C ₁₂ alkane, C ₁ -C ₁₀ siloxy; wherein R ^x and R ^x' are independently selected from hydrogen, C ₁ -C ₁₂ alkane group, C ₁ -C ₁₀ alkoxy group or C ₁ -C ₁₀ siloxy group; "*" represents a chiral center; n is an integer ranging from 1 to 3;

As a further preferred solution, n in compound 1 ranges from an integer of 1-2.

As a further preferred solution, R and R ⁰ in compound 1 are respectively selected from hydrogen and C ₁ -C ₁₂ alkane groups, respectively,

As a further preferred solution, R ¹ and R ² in compound 1 are simultaneously selected from C ₁ -C ₁₂ alkane groups,

As a further preferred solution, R ⁵ in compound 1 is selected from hydrogen or a C ₁ -C ₁₂ alkane group.

As a further preferred solution, the chiral monophosphine ligand Yu-Phos is selected from the following compounds or

Enantiomers, racemates or diastereomers, as follows:

Wherein: Ph is phenyl, ^tBu is tert-butyl, and Cy is cyclohexyl.

The present invention also provides a method for preparing the chiral monophosphine ligand Yu-Phos compound 1, which comprises the following steps:

The first step: in a solvent, at a certain temperature:

1) Addition and substitution reaction of compound 2 with DMF and PBr ₃ to generate an intermediate

与乙二醇脱水缩合生成中间体

2) Then the intermediate

Dehydration condensation with ethylene glycol to form intermediates

在BuLi作用下与ClPR¹R²(即

)进行取代反应，生成中间体

3) Subsequent intermediates

Under the action of BuLi with ClPR ¹ R ² (ie

) undergoes a substitution reaction to generate an intermediate

在对甲苯磺酸的存在下通过水解得到式3化合物。反应过程如下反应式(I)所示：4) Subsequent intermediates

The compound of formula 3 is obtained by hydrolysis in the presence of p-toluenesulfonic acid. The reaction process is shown in the following reaction formula (I):

The definition of each group is the same as the definition of each group of compound 1.

The solvent is selected from dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, Xylene, benzene, chlorobenzene, fluorobenzene, chloroform or n-hexane; preferably, dry tetrahydrofuran.

The temperature of the substitution reaction with the participation of BuLi is -78～30°C; preferably, it is -78～-50°C.

The time for the substitution reaction under the participation of the BuLi is 10 minutes to 10 hours; preferably, it is 1 to 2 hours.

The molar ratio of the compound 2, DMF in step 1), PBr ₃ , ethylene glycol in step 2), BuLi in step 3), ClPR ¹ R ² , and p-toluenesulfonic acid in step 4) is (1-30) :(1-30):(1-30):(1-30):(1-30):(1-30):(1-30); preferably 10:30:26:25:11 :12:2.

The function of the BuLi is to exchange with the halogen Br and perform a substitution reaction; the BuLi includes n-BuLi, s-BuLi, and t-BuLi.

The second step: in a solvent, at a certain temperature, under the action of a condensing agent, compound 3 is respectively subjected to a condensation reaction with compound 4 (R _s ) and compound 4 (S _s ) to obtain compound 5 (R _s ), compound 5(S _s ), the reaction process is shown in the following reaction formula (II):

The definition of each group in the formula is the same as that of each group of compound 1.

The solvent is selected from dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, Xylene, benzene, chlorobenzene, fluorobenzene, chloroform or n-hexane; preferably, dry tetrahydrofuran.

The temperature of the condensation reaction is -50-100°C; preferably, it is 50-70°C.

The time of the condensation reaction is 10 minutes to 48 hours; preferably, it is 8 hours.

The molar ratio of the compound 3, the compound 4 (R _s ) or the compound 4 (S _s ) and the condensing agent is (1-10):(1-10):(1-10); preferably, it is 1:1 : 2.5.

The function of the condensing agent is to promote the condensation reaction, and is selected from tetraethyl titanate (Ti(OEt) ₄ ), tetraisopropyl titanate Ti(O ⁱ Pr) ₄ or tetramethyl titanate; preferably , which is tetraisopropyl titanate Ti(O ⁱ Pr) ₄ .

随后在n-BuLi作用下与R⁵OTf进行取代反应，得到手性单膦配体Yu-Phos即化合物1(S,R_s)、1(R,R_s)、1(S,S_s)、1(R,S_s)，反应过程如下反应式(III)所示：The third step: compound 5 (R _s ) and compound 5 (S _s ) are dissolved in a dry solvent, and at a certain temperature, they are respectively subjected to an addition reaction with the metal reagent R ³ MgX or R ³ Li compound to obtain intermediate 5.1

Subsequent substitution reaction with R ⁵ OTf under the action of n-BuLi yields the chiral monophosphine ligand Yu-Phos, namely compounds 1(S,R _s ), 1(R,R _s ), 1(S,S _s ) , 1(R, S _s ), the reaction process is shown in the following reaction formula (III):

The definition of each group in the formula is the same as the definition of each group of compound 1; X is halogen.

The solvent is selected from dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, Xylene, benzene, chlorobenzene, fluorobenzene, chloroform or n-hexane; preferably, dry tetrahydrofuran.

The temperature of the addition reaction is -78 to 30°C; preferably, it is -78 to -40°C.

The time of the addition reaction is 10 minutes to 48 hours; preferably, it is 8 to 12 hours.

The molar ratio of compound 5(R _s ) or compound 5(S _s )), R ³ MgX or R ³ Li, n-BuLi, R ⁵ OTf is 1:(1-5):(1-5): (1-5); preferably, it is 1:(1-2):(1-2):(1-2).

The role of the R ⁴ MgX (or R ⁴ Li) is to react with 5(R _s ) (or 5(S _s )), and the role of R ⁵ OTf is to perform a substitution reaction with the compound 5.1.

和化合物4：

为原料，取代反应、加成反应、缩合反应形成中间体化合物5

与式R⁴MgX或者R⁴Li化合物进行反应制备中间体5.1

在BuLi作用下化合物5.1再与R⁵OTf进行取代反应，生成Yu-Phos化合物1

“*”表示手性中心；n取值范围为0～6的整数；。In the method of the present invention, compound 2 is used:

and compound 4:

As raw material, substitution reaction, addition reaction, condensation reaction form intermediate compound 5

Reaction with compounds of formula R ⁴ MgX or R ⁴ Li to prepare intermediate 5.1

Compound 5.1 undergoes substitution reaction with R ⁵ OTf under the action of BuLi to form Yu-Phos compound 1

"*" represents a chiral center; n is an integer ranging from 0 to 6;

In the present invention, four full configurations 1(S, R _s ) of the chiral monophosphine ligand Yu-Phos can be conveniently obtained by using the addition of two configurations of compound 4 chiral sulfinamide and different types of metal reagents. , 1(R,Rs), 1( _S , _Ss ) and 1(R, _Ss ) optically pure compounds.

The present invention also provides the application of the chiral monophosphine ligand Yu-Phos in the intermolecular asymmetric cycloaddition reaction of enynone and 1,3-diphenylisobenzofuran, the chiral monophosphine Ligand Yu-Phos is an enantiomer, racemate or diastereomer with Compound 1 or said Compound 1.

The present invention also provides a method for synthesizing oxygen-bridged polyaromatic heterocyclic compounds by intermolecular asymmetric cycloaddition reaction between the enynone and 1,3-diphenylisobenzofuran. The monophosphine ligand Yu-Phos forms a Yu-PhosMX complex with a transition metal salt, which is then anion-exchanged with AgY to form a Yu-PhosMY complex solution, which then catalyzes the enynone with 1,3-diphenylisobenzene. And furan intermolecular asymmetric cycloaddition reaction, synthesis of oxygen-bridged polyaromatic heterocyclic compounds. The chiral monophosphine ligand Yu-Phos is compound 1 or an enantiomer, racemate or diastereomer of the compound 1.

The above-mentioned chiral monophosphine ligand Yu-Phos is used to catalyze the intermolecular asymmetric cycloaddition of enynone and 1,3-diphenylisobenzofuran, as well as enynone and 1,3- Method for synthesizing oxygen-containing bridged polyaromatic heterocyclic compounds by intermolecular asymmetric cycloaddition reaction of diphenylisobenzofuran:

As a preferred solution, the chiral monophosphine ligand Yu-Phos is formed with transition metal salts to form Yu-PhosMX complexes, and then anion-exchanged with silver salts to form Yu-PhosMY, which is then used to catalyze enynone molecules with Asymmetric cycloaddition between 1,3-diphenylisobenzofurans. The reaction process is shown in the following reaction formula (X):

As a further preferred solution, the preparation of the complex includes the following steps: under an inert atmosphere, adding the chiral monophosphine ligand Yu-Phos and transition metal salt into an organic solvent, stirring at -10 to 50 °C, React for 0.1 to 20 hours to form a Yu-PhosMX complex, then add AgY and stir at -10 to 50°C for 0.1 to 20 hours to perform anion exchange to form a Yu-PhosMY complex solution.

As a further preferred solution, the molar ratio of the chiral monophosphine ligand Yu-Phos, transition metal salt and AgY is (1-100):(1-10):1, and (1-5):1: 1 Best.

As a further preferred solution, the transition metal salt is an Au salt.

As a further preferred solution, the Au salts include AuCl, AuOTf, AuSbF ₆ , AuBF ₄ , AuNTf ₂ , AuOTs, AuOPNB, Au(SMe ₂ )Cl, Au(OTf) ₃ , Au(SbF ₆ ) ₃ , Au( BF ₄ ) ₃ and Au(NTf ₂ ) ₃ .

The AgY is selected from AgOTf, AgSbF ₆ , AgBF ₄ , AgNTf ₂ , AgOTs or AgOPNB.

As a further preferred solution, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere; the organic solvent is selected from methylene chloride, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene or chloroform.

The operation of using the complex to catalyze the intermolecular asymmetric cycloaddition reaction is as follows: under an inert atmosphere, add the prepared Yu-PhosAuY complex solution to enynone and 1,3-diphenylisobenzene And in furan, the cycloaddition reaction is carried out under the condition of -90～90℃.

In the asymmetric cyclization reaction, the molar ratio of the enynone substrate to the Yu-PhosAuY complex is (10-10000):1; preferably, the enynone substrate and the Yu-PhosAuY The molar ratio of the complex is (10-1000):1.

The enynone substrate can be a compound whose structure is shown in compound 8:

优选地，R⁶、R⁷、R⁸分别独立选自氢、C₁～C₅的烷烃基、C₁～C₅的烷氧基、

In the above compound 8: R ⁶ , R ⁷ and R ⁸ are independently selected from hydrogen, C ₁ -C ₁₀ alkane, C ₁ -C ₁₀ alkoxy,

Preferably, R ⁶ , R ⁷ and R ⁸ are independently selected from hydrogen, C ₁ -C ₅ alkane, C ₁ -C ₅ alkoxy,

R⁷、R⁸分别独立选自

Further preferably, R ⁶ is selected from hydrogen, C ₁ -C ₅ alkane group,

R ⁷ and R ⁸ are independently selected from

Compared with the prior art, the present invention has the following beneficial effects:

(“*”代表手性中心)的产率为65％-76％，非対映异构体(endo:exo)比例为(6.5～10)：1，对映体过量(ee)为65％-73％。(1) The present invention provides a class of chiral monophosphine ligands. It is reported for the first time that the chiral monophosphine ligands form complexes with transition metal salts and then exchange with AgY anions for intermolecular asymmetric cycloaddition The reaction has good reactivity and stereoselectivity, and can make the cyclized product:

("*" represents a chiral center), the yields are 65%-76%, the ratio of diastereoisomers (endo:exo) is (6.5-10):1, and the enantiomeric excess (ee) is 65% -73%.

(2) The preparation method of the chiral monophosphine ligand provided by the present invention overcomes the problems of expensive raw materials, lengthy synthesis route, high toxicity of reagents, and high concentration of enantiomers when synthesizing phosphine-containing chiral ligands in the prior art. The synthesis is difficult and the yield is low. The preparation method of the invention is clear, simple to operate, and the yield is 71%-88%, which is suitable for large-scale production and has practical value.

In the present invention:

n-BuLi is n-butyl lithium; ClPPh ₂ is diphenylphosphine chloride; DMF is N,N-dimethylformamide.

Detailed ways

The present invention will be further described in detail with reference to the following specific embodiments. Except for the content specifically mentioned below, the process, conditions, experimental methods, etc. for implementing the present invention are all common knowledge and common knowledge in the field, and the present invention is not particularly limited.

The following examples provide the synthesis scheme of the above-mentioned chiral monophosphine ligand compound 1, specifically:

a-1(S,R_s)的合成Example 1

Synthesis of a-1(S,R _s )

(205mmol.,18.2mL)，继续搅拌0.5小时后，关闭冷阱，缓慢升至室温后继续搅拌8小时，反应完全加NaOH淬灭，乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为71％。其中，DMF为N,N-二甲基甲酰胺。The first step: in a 500mL dry three-necked flask, add DMF (615mmol, 47.5mL) and 300mL DCM under nitrogen atmosphere, stir at 0°C for 10 minutes, add phosphorus tribromide (532mmol, 50.0mL) ), continue stirring at 0°C for 0.5-2.0 hours, then add dropwise

(205mmol., 18.2mL), after continuing to stir for 0.5 hours, close the cold trap, slowly rise to room temperature and continue to stir for 8 hours, the reaction is completely quenched by adding NaOH, extracted three times with ethyl acetate, and the organic phases are combined, respectively, with water and saturated chlorine Washed with sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain

The yield was 71%. Wherein, DMF is N,N-dimethylformamide.

(145mmol,23.4g)、对甲苯磺酸(2mol％,0.5g)和乙二醇(2.0eq.,18.0g)加入500mL的三颈瓶中，在氮气的氛围下加入300mL甲苯，在130℃下搅拌回流3.0-5.0小时，停止加热用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为60％。The second step: the first step prepared

(145mmol, 23.4g), p-toluenesulfonic acid (2mol%, 0.5g) and ethylene glycol (2.0eq., 18.0g) were added to a 500mL three-necked flask, 300mL of toluene was added under a nitrogen atmosphere, and the temperature was 130°C. Stir under reflux for 3.0-5.0 hours, stop heating and extract with ethyl acetate three times, combine the organic phases, wash with water and saturated sodium chloride, dry with anhydrous sodium sulfate, filter, spin dry, and purify by column chromatography to obtain

Yield was 60%.

(100mmol,21.9g)和300mL THF，在-78℃下搅拌10分钟后，滴加n-BuLi(1.1eq.,43.6mL,2.5M)，继续搅拌1.5小时，滴加ClPPh₂(1.3eq.,23.0mL)，再搅拌1小时，缓慢升至室温后继续搅拌1小时，加饱和氯化铵淬灭，用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为42％。The third step: in a 250mL dry three-necked bottle, add the prepared product in the second step under a nitrogen atmosphere.

(100mmol, 21.9g) and 300mL THF, after stirring at -78°C for 10 minutes, n-BuLi (1.1eq., 43.6mL, 2.5M) was added dropwise, stirring was continued for 1.5 hours, and ClPPh ₂ (1.3eq. , 23.0 mL), stirred for another 1 hour, slowly raised to room temperature and continued to stir for 1 hour, quenched by adding saturated ammonium chloride, extracted three times with ethyl acetate, combined the organic phases, washed with water and saturated sodium chloride, respectively, anhydrous Dry over sodium sulfate, filter, spin dry, and purify by column chromatography to obtain

Yield 42%.

(13.3g,41mmol)加入到干燥的250mL的三支口反应瓶中，氮气保护，加入对甲苯磺酸(0.2eq.,1.4g)，水：丙酮＝1:3的混合溶剂250mL，在80℃下，搅拌3-5小时，降温，加水淬灭，乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为80％。The fourth step: the third step prepared

(13.3g, 41mmol) was added to a dry 250mL three-necked reaction flask, nitrogen protection, added p-toluenesulfonic acid (0.2eq., 1.4g), water: acetone = 1:3 mixed solvent 250mL, at 80 At ℃, stirred for 3-5 hours, cooled, quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, washed with water and saturated sodium chloride respectively, dried over anhydrous sodium sulfate, filtered, spin-dried, purified by column chromatography, have to

Yield was 80%.

(40mmol,11.3g)和

(1.1eq.,5.38g)加入500mL的三颈瓶中，在氮气的氛围下加入200mL THF，加Ti(OⁱPr)₄(2.5eq.,30mL)，在50℃下搅拌24小时，加饱和氯化铵淬灭，用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为83％。¹H NMR(300MHz,CDCl₃):δ9.03(d,J＝3.9Hz,1H),7.43-7.30(m,10H),3.02-2.69(m,2H),2.54-2.39(m,2H),2.00-1.85(m,2H),1.20(s,9H).；³¹P NMR(160MHz,CDCl₃):δ-21.81；HRMS(ESI)calculated for[C₂₂H₂₆NOPS][M+Na]⁺:406.1365；found:406.1353.Step 5: Prepare the first step

(40mmol, 11.3g) and

(1.1eq., 5.38g) was added to a 500mL three-neck flask, 200mL of THF was added under a nitrogen atmosphere, Ti(O ⁱ Pr) ₄ (2.5eq., 30mL) was added, and the mixture was stirred at 50°C for 24 hours. Quenched with saturated ammonium chloride, extracted three times with ethyl acetate, combined the organic phases, washed with water and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain

The yield was 83%. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.03 (d, J=3.9 Hz, 1H), 7.43-7.30 (m, 10H), 3.02-2.69 (m, 2H), 2.54-2.39 (m, 2H) , 2.00-1.85(m, 2H), 1.20(s, 9H).; ³¹ P NMR (160MHz, CDCl ₃ ): δ-21.81; HRMS(ESI) calculated for [C ₂₂ H ₂₆ NOPS][M+Na] ⁺ :406.1365;found:406.1353.

Wherein, THF is tetrahydrofuran; Ti(O ⁱ Pr) ₄ is tetraisopropyl titanate.

(0.77g，2mmol)加入到干燥的50mL的单支口茄形反应瓶中，氮气保护，加入10mL THF。在-78℃下，加入苯基溴化镁(2eq.,4mL,1Min THF)，搅拌1小时后，自然升温，搅拌过夜，加饱和氯化铵淬灭，分液，水层用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

a-1(S,R_s)，产率为88％。¹H NMR(400MHz,CDCl₃)δ7.53-7.46(m,2H),7.37-7.23(m,13H),6.31(dd,J＝7.6,2.4Hz,1H),3.68(d,J＝2.4Hz,1H),2.65-2.50(m,1H),2.37-2.10(m,3H),1.80-1.68(m,2H),1.28(s,9H).；¹³C NMR(100MHz,CDCl₃)δ156.1,155.9,140.9,137.2,137.1,137.0,136.9,136.8,136.7,133.7,133.5,132.8,132.6,128.5,128.4,128.34,128.28,128.2,128.0,127.6,127.1,57.4,57.2,55.8,35.0,34.9,32.71,32.65,22.8,22.5.；³¹P NMR(160MHz，CDCl₃)δ-27.45；HRMS(ESI)calculated for[C₂₈H₃₃NOPS][M+H]⁺:462.2015；found:462.2007。Step 6: Prepare the

(0.77 g, 2 mmol) was added to a dry 50 mL single-mouth eggplant-shaped reaction flask, under nitrogen protection, and 10 mL of THF was added. At -78°C, phenylmagnesium bromide (2eq., 4mL, 1Min THF) was added, and after stirring for 1 hour, the temperature was naturally raised, stirred overnight, quenched by adding saturated ammonium chloride, and the layers were separated. The aqueous layer was washed with ethyl acetate. Extract three times, combine the organic phases, wash with water and saturated sodium chloride respectively, dry over anhydrous sodium sulfate, filter, spin dry, and purify by column chromatography to obtain

a-1 (S, R _s ) in 88% yield. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.53-7.46 (m, 2H), 7.37-7.23 (m, 13H), 6.31 (dd, J=7.6, 2.4Hz, 1H), 3.68 (d, J=2.4 Hz, 1H), 2.65-2.50(m, 1H), 2.37-2.10(m, 3H), 1.80-1.68(m, 2H), 1.28(s, 9H).; ¹³ C NMR (100MHz, CDCl ₃ )δ156 .1,155.9,140.137.2,137.1,137.0,136.9,136.7,133.7,133.5,132.6,128.4,128.34,128.28.0, 127.6,57.5.5.5.5.5.5. , 32.71, 32.65, 22.8, 22.5.; ³¹ P NMR (160 MHz, CDCl ₃ ) δ-27.45; HRMS (ESI) calculated for [C ₂₈ H ₃₃ NOPS][M+H] ⁺ : 462.2015; found: 462.2007.

a-1(R,R_s)的合成Example 2

Synthesis of a-1(R,R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to phenyllithium, and the yield is 86%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.37 (m, 2H), 7.38-7.21 (m, 13H), 6.13 (t, J=6.4Hz, 1H), 3.74 (d, J=6.4Hz, 1H), 2.77-2.55 (m, 1H), 2.49-2.14 (m, 3H), 1.88-1.71 (m, 2H), 1.24 (s, 9H).; ¹³ CNMR (100MHz, CDCl ₃ ) δ 157.3, 157.0, 140.2, 136.9, 136.8, 136.64,136.55,135.4,135.2,133.133.1,133.0, 128.39,128.3,127.4,58.7.5,56.2,34,334,34,34,34,34,34,33,34,34,334,34,334,34,34,34,34,34,34,34,34,34,34,34,34,34,34,34,34,34,34,34,35,35,35,35,35.2,35,35.2,35,35,35.2,35.2,35. 22.6.; ^31P NMR (160 MHz, _CDCl3 ) delta-27.32; HRMS (ESI) calculated for [ _C28H33NOPS ][M+H] ⁺ : _462.2015 ; found: 462.2007.

b-1(S,R_s)的合成Example 3

Synthesis of b-1(S,R _s )

The specific operation is the same as in Example 1, except that the used metal reagent is changed to tert-butylmagnesium bromide, and the yield is 83%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.20 (m, 10H), 4.97 (dd, J=8.0, 4.4 Hz, 1H), 3.37 (d, J=4.0 Hz, 1H), 2.61-2.40 (m ,2H),2.40-2.25(m,2H),1.93-1.79(m,2H),1.18(d,J=13.2Hz,9H),1.00(d,J=9.2Hz,9H).; ¹³ C NMR (100MHz,CDCl ₃ )δ157.30,157.02,138.03,137.89,137.62,137.53,136.95,136.85,133.30,133.12,133.10,132.91,128.23,128.16,128.08,128.05,127.94,62.77,62.52,55.58,41.99,35.28, 35.18, 35.12, 34.36, 34.31, 29.70, 27.78, 27.02, 25.01, 24.09, 22.65.; ³¹ P NMR (160MHz, CDCl ₃ )δ-27.79; HRMS(ESI) calculated for [C ₂₆ H ₃₇ NOPS][M+ H] ⁺ :442.2328, found:442.2321.

b-1(R,R_s)的合成Example 4

Synthesis of b-1(R,R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to tert-butyllithium reagent, and the total yield is 86%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54-7.19 (m, 10H), 4.81 (dd, J=11.2, 8.0 Hz, 1H), 3.32 (d, J=10.4 Hz, 1H), 2.69 (dd, J=14.4, 8.0Hz, 1H), 2.53-2.12 (m, 3H), 1.93-1.80 (m, 2H), 1.24 (d, J=6.4Hz, 9H), 1.02 (d, J=12.4Hz, 9H) ).; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.6, 158.3, 137.6, 137.5, 136.64, 136.55, 136.3, 136.2, 134.1, 133.9, 132.3, 132.2, 128.5, 128.29, 128.25, 128, .2, 127.5. 64.7, 56.4, 35.7, 34.9, 34.4, 27.8, 27.5, 24.0, 22.6.; ³¹ P NMR (160MHz, CDCl ₃ )δ-27.90; HRMS(ESI) calculated for [C ₂₆ H ₃₇ NOPS][M+H] ⁺ :442.2328,found:442.2321.

c-1(S,R_s)的合成Example 5

Synthesis of c-1(S,R _s )

The specific operation is the same as in Example 1, except that the used metal reagent is changed to 4-chlorophenylmagnesium bromide reagent, and the total yield is 77%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.52-7.42 (m, 2H), 7.36-7.21 (m, 12H), 6.26 (dd, J=7.8, 2.8Hz, 1H), 3.64 (d, J=2.8 Hz, 1H), 2.64-2.45(m, 1H), 2.38-2.12(m, 3H), 1.82-1.65(m, 2H), 1.26(d, J=12.4Hz, 9H).; ¹³ C NMR (100MHz) ,CDCl ₃ )δ155.4,155.2,139.4,137.7,137.6,136.8,136.69,136.66,136.6,133.6,133.4,133.3,132.7,132.6,128.7,128.43,128.41,128.34,128.29,128.2,128.1,57.0,56.7, 55.9, 35.1, 35.0, 32.7, 32.6, 22.8, 22.5.; ³¹ PNMR(160MHz, CDCl ₃ )δ-27.46.HRMS(ESI)calculated for[C ₂₈ H ₃₂ ClNOPS][M+H] ⁺ :496.1625,found :496.1622.

c-1(R,R_s)的合成Example 6

Synthesis of c-1(R,R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to 4-chlorophenyllithium reagent, and the total yield is 80%. ¹ H NMR (CDCl ₃ , 400MHz): δ 7.44-7.37 (m, 2H), 7.37-7.19 (m, 12H), 6.09 (t, J=6.0Hz, 1H), 3.72 (d, J=5.6Hz) , 1H), 2.75-2.55(m, 1H), 2.43-2.12(m, 3H), 1.92-1.62(m, 2H), 1.24(s, 9H).; ¹³ C NMR (CDCl ₃ , 100MHz): δ156 .4,156.1,138.8,136.7,136.6,136.4,136.3,135.9,135.8,133.2,133.0,133.0,128.7,128.5,128.44,128.40,128.38,128.34,128.31,58.0,57.8,56.2,35.5,35.4,33.6,33.5 , 22.7, 22.6.; ³¹ P NMR (CDCl ₃ , 160 MHz): δ-27.39. HRMS (ESI) calculated for [C ₂₈ H ₃₂ ClNOPS][M+H] ⁺ : 496.1625, found: 496.1622.

d-1(S,R_s)的合成Example 7

Synthesis of d-1(S,R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to 4-methoxyphenylmagnesium bromide reagent, and the total yield is 77%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.40 (m, 2H), 7.37-7.22 (m, 10H), 6.81 (d, J=8.6 Hz, 2H), 6.25 (dd, J=7.2, 2.0 Hz, 1H), 3.78(s, 3H), 3.61(d, J=11.6Hz, 1H), 2.66-2.53(m, 1H), 2.40-2.12(m, 3H), 1.80-1.66(m, 2H) , 1.27(s, 9H). ¹³ C NMR (100MHz, CDCl ₃ )δ159.0, 156.5, 156.2, 137.1, 137.0, 136.9, 136.6, 136.5, 133.7, 133.5, 133.1, 132.7, 132.6, 128.3, 128.24, 128.9. , 113.9, 56.9, 56.6, 55.7, 55.29, 55.26, 35.0, 34.9, 32.8, 32.7, 22.8, 22.5.; ³¹ P NMR(160MHz, CDCl ₃ )δ-27.39.HRMS(ESI) calculated for [C ₂₉ H ₃₅ NO ₂ PS][M+H] ⁺ :492.2121,found:492.2118.

d-1(R,R_s)的合成Example 8

Synthesis of d-1(R,R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to 4-methoxyphenyllithium reagent, and the total yield is 71%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.47-7.36 (m, 2H), 7.36-7.27 (m, 8H), 7.26-7.21 (m, 2H), 6.80 (t, J=8.2Hz, 2H), 6.07(t,J＝6.4Hz,1H),3.77(d,J＝7.2Hz,3H),3.70(dd,J＝11.2,6.4Hz,1H),2.77-2.57(m,1H),2.43-2.10 (m, 3H), 1.89-1.65 (m, 2H), 1.23 (s, 9H).; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.9, 157.5, 157.2, 137.0, 136.9, 136.7, 136.6, 134.9, 134.7, 133.24, ^133.18 , 133.1, 133.00, 132.2, 128.44, 128.36, 128.29, 128.26, 128.2, 113.8, 58.1, 57.9, 56.1, 55.27, 55.25, 35.40, 35.35, 33.64, 33.2 MHz , CDCl ₃ )δ-27.30.HRMS(ESI) calculated for [C ₂₉ H ₃₅ NO ₂ PS][M+H] ⁺ : 492.2121, found: 492.2118.

e-1(S，R_s)的合成Example 9

Synthesis of e-1(S, R _s )

The specific operation is the same as that in Example 1, except that the used metal reagent is changed to 3,5-di-tert-butylphenylmagnesium bromide reagent, and the total yield is 71%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60-7.47 (m, 2H), 7.42-7.21 (m, 11H), 6.38 (dd, J=8.0, 2.0 Hz, 1H), 3.69 (d, J=1.7 Hz, 1H), 2.80-2.57(m, 1H), 2.51-2.11(m, 3H), 1.87-1.73(m, 2H), 1.33(s, 9H), 1.29(s, 18H).; ¹³ C NMR (100MHz, CDCl ₃ )δ156.5, 156.3, 150.9, 140.1, 137.24, 137.22, 137.1, 137.0, 136.9, 136.8, 133.7, 133.5, 132.7, 132.5, 128.33, 128.27, 128.24, 128.27, 128.24, 128.27, 128.24, 128.27, 128.8 57.7, 57.4, 55.7, 35.0, 34.84, 34.80, 32.7, 32.6, 31.5, 31.4, 22.9, 22.6.; ³¹ P NMR(160MHz, CDCl ₃ )δ-27.71.HRMS(ESI) calculated for [C ₃₆ H ₄₉ NOPS ][M+H] ⁺ :574.3267, found:574.3260.

f-1(R，R_s)的合成Example 10

Synthesis of f-1(R, R _s )

用

替换，所用金属试剂改为苯基锂试剂，总产率为78％。¹H NMR(400MHz,CDCl₃)δ7.56-7.21(m,15H),6.81-6.65(m,1H),3.76(d,J＝8.4Hz,1H),2.60-2.35(m,1H),2.05-1.85(m,3H),1.75-1.45(m,4H),1.30(s,9H).；¹³C NMR(100MHz,CDCl₃)δ157.5,157.3,140.5,137.2,137.1,136.94,136.85,138.4,138.2,136.3,136.1,136.1,136.0,128.69,128.66,131.3,131.2,130.4,130.2,59.0,58.8,58.6,56.3,35.44,35.38,33.7,33.6,22.8,22.7.；³¹P NMR(160MHz,CDCl₃)δ-15.113.HRMS(ESI)calculated for[C₂₉H₃₅NOPS][M+H]⁺:476.2177,found:476.2179。The specific operation is the same as in Example 1, only the

use

Instead, the metal reagent used was changed to phenyllithium reagent, and the overall yield was 78%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.56-7.21 (m, 15H), 6.81-6.65 (m, 1H), 3.76 (d, J=8.4Hz, 1H), 2.60-2.35 (m, 1H), 2.05-1.85 (m, 3H), 1.75-1.45 (m, 4H), 1.30 (s, 9H).; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 157.5, 157.3, 140.5, 137.2, 137.1, 136.94, 136.85, 138.4 ^3MHz P NMR( CDCl ₃ )δ-15.113.HRMS(ESI) calculated for [C ₂₉ H ₃₅ NOPS][M+H] ⁺ : 476.2177, found: 476.2179.

g-1(S,R_s)的合成Example 11

Synthesis of g-1(S,R _s )

The specific operation is the same as that of Example 1, except that the used ClPPh ₂ is replaced with ClPCy ₂ , and the total yield is 80%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 2H), 7.29-7.27 (m, 1H), 7.24-7.17 (m, 2H), 6.84-6.80 (m, 1H), 3.85 (d , J=5.2Hz, 1H), 2.86-2.66(m, 1H), 2.46-2.22(m, 3H), 1.96-1.53(m, 12H), 1.28-1.04(m, 21H).; ¹³ C NMR( 100MHz, CDCl ₃ )δ128.71,128.2,128.1,127.88,127.13,126.54,59.6,58.9,55.8,35.4,35.3,34.7,34.6,33.7,30.6,30.5,30.4,30.3,229.7,2,7.2093. , 27.15, 27.10, 27.09, 27.04, 26.99, 26.95, 26.3, 26.2, 22.8, 22.7.; ³¹ PNMR(160MHz, CDCl ₃ )δ-17.57.HRMS(ESI)calculated for[C ₂₈ H ₄₅ NOPS][M+ H] ⁺ :474.2959,found:474.2961.

h-1(R,S_s)的合成Example 12

Synthesis of h-1(R,S _s )

(40mmol,11.3g)和

(1.1eq.,5.38g)加入500mL的三颈瓶中，在氮气的氛围下加入200mL THF，加Ti(OⁱPr)₄(2.5eq.,30mL)，在50℃下搅拌24小时，加饱和氯化铵淬灭，用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为86％。¹H NMR(300MHz，CDCl₃):δ9.03(d，J＝3.9Hz，1H)，7.43-7.30(m，10H)，3.02-2.69(m，2H)，2.54-2.39(m，2H)，2.00-1.85(m，2H),1.26(s,9H).；³¹P NMR(160MHz,CDCl₃):δ-21.76；HRMS(ESI)calculated for[C₂₂H₂₆NNaOPS][M+Na]⁺:406.1365；found:406.1353.Steps: The first step: the prepared

(40mmol, 11.3g) and

(1.1eq., 5.38g) was added to a 500mL three-neck flask, 200mL of THF was added under a nitrogen atmosphere, Ti(O ⁱ Pr) ₄ (2.5eq., 30mL) was added, and the mixture was stirred at 50°C for 24 hours. Quenched with saturated ammonium chloride, extracted three times with ethyl acetate, combined the organic phases, washed with water and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain

The yield was 86%. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.03 (d, J=3.9 Hz, 1H), 7.43-7.30 (m, 10H), 3.02-2.69 (m, 2H), 2.54-2.39 (m, 2H) , 2.00-1.85(m, 2H), 1.26(s, 9H).; ³¹ P NMR (160MHz, CDCl ₃ ): δ-21.76; HRMS(ESI) calculated for [C ₂₂ H ₂₆ NNaOPS][M+Na] ⁺ :406.1365;found:406.1353.

Wherein, THF is tetrahydrofuran; Ti(O ⁱ Pr) ₄ is tetraisopropyl titanate.

(0.77g，2mmol)加入到干燥的50mL的单支口茄形反应瓶中，氮气保护，加入10mL THF。在-78℃下，加入苯基溴化锂(2eq.,4mL,1Min THF)，搅拌1小时后，自然升温，搅拌过夜，加饱和氯化铵淬灭，分液，水层用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

a-1(R,S_s)，产率为86％。The second step: the first step prepared

(0.77 g, 2 mmol) was added to a dry 50 mL single-mouth eggplant-shaped reaction flask, under nitrogen protection, and 10 mL of THF was added. At -78°C, add phenyllithium bromide (2eq., 4mL, 1Min THF), stir for 1 hour, then heat up naturally, stir overnight, add saturated ammonium chloride to quench, separate the layers, and extract the aqueous layer three times with ethyl acetate , the organic phases were combined, washed with water and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain

a-1 (R,S _s ) in 86% yield.

(0.92g，2mmol)加入到干燥的50mL的单支口茄形反应瓶中，氮气保护，加入20mL THF，在-40℃下搅拌10分钟后，滴加n-BuLi(1.1eq.,0.9mL,2.5M)，继续搅拌1.5小时，滴加R⁵OTf(1.5eq.,3mmol)，再搅拌1小时，缓慢升至室温后继续搅拌1小时，加饱和氯化铵淬灭，用乙酸乙酯萃取三次，合并有机相，分别用水、饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干，柱层析纯化，得

产率为81％。¹H NMR(400MHz,CDCl₃)δ7.47-7.37(m,2H),7.38-7.21(m,13H),6.13(t,J＝6.4Hz,1H),3.74(d,J＝6.4Hz,1H),2.87(s,3H),2.49-2.14(m,3H),1.88-1.71(m,2H),1.24(s,9H).¹³C NMR(100MHz,CDCl₃)δ157.3,157.0,140.2,136.9,136.8,136.64,136.55,135.4,135.2,133.3,133.1,133.1,133.0,128.39,128.36,128.3,128.2,127.4,127.2,58.7,58.5,56.2,41.1,35.34,35.28,33.6,33.5,22.7,22.6.；³¹P NMR(160MHz,CDCl₃)δ-27.22.；HRMS(ESI)calculated for[C₂₉H₃₅NOPS][M+Na]⁺:476.2177；found:476.2179。The third step: the second step prepared

(0.92g, 2mmol) was added to a dry 50mL single-mouth eggplant-shaped reaction flask, nitrogen protection, 20mL THF was added, and after stirring at -40 ° C for 10 minutes, n-BuLi (1.1eq., 0.9mL) was added dropwise. , 2.5M), continue to stir for 1.5 hours, add R ⁵ OTf (1.5eq., 3mmol) dropwise, stir for another 1 hour, slowly warm to room temperature and continue to stir for 1 hour, add saturated ammonium chloride to quench, use ethyl acetate Extract three times, combine the organic phases, wash with water and saturated sodium chloride respectively, dry over anhydrous sodium sulfate, filter, spin dry, and purify by column chromatography to obtain

The yield was 81%. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.47-7.37 (m, 2H), 7.38-7.21 (m, 13H), 6.13 (t, J=6.4Hz, 1H), 3.74 (d, J=6.4Hz, 1H), 2.87(s, 3H), 2.49-2.14(m, 3H), 1.88-1.71(m, 2H), 1.24(s, 9H). ¹³ C NMR(100MHz, CDCl ₃ )δ157.3,157.0,140.2, 136.9,136.8,136.64,136.55,135.4,135.2,133.3,133.1,133.1,133.0,128.39,128.36,128.3,128.2,127.4,127.2,58.7,58.5,56.2,41.1,2.6,3.34 22.6.; ^31P NMR (160 MHz, _CDCl3 ) delta-27.22.; HRMS (ESI) calculated for [ _C29H35NOPS ][M+Na] ⁺ : _476.2177 ; found: 476.2179.

Example 13 Asymmetric intermolecular cycloaddition reaction of enynone

a-1(S,Rs)与Au盐形成的配合物再与Ag盐进行阴离子交换后用于反应的催化，具体操作为：在氩气气氛中，将手性单膦配体a-1(S,R_s)(0.05mmol)和AuCl(SMe₂)(0.05mmol)加入经无水无氧处理过的反应管中，然后加入无水二氯甲烷溶液(2mL)，室温搅拌2h后，加入AgNTf₂，避光搅拌15min。然后，在-50℃下，加入烯炔酮，维持在室温，通过TLC检测，底物全部转化后，过滤，滤液浓缩至1mL，柱层析分析其产率，HPLC分析其对映体过量值(ee)。The chiral monophosphine ligand obtained in Example 1

The complex formed by a-1(S, Rs) and Au salt is used for the catalysis of the reaction after anion exchange with Ag salt. The specific operation is: in an argon atmosphere, the chiral monophosphine ligand a-1( S, R _s ) (0.05 mmol) and AuCl (SMe ₂ ) (0.05 mmol) were added to the reaction tube treated with anhydrous and anoxic, then anhydrous dichloromethane solution (2 mL) was added, and after stirring at room temperature for 2 h, added AgNTf ₂ , and stirred in the dark for 15 min. Then, at -50°C, enynone was added, maintained at room temperature, detected by TLC, after the substrate was completely converted, filtered, the filtrate was concentrated to 1 mL, the yield was analyzed by column chromatography, and the enantiomeric excess value was analyzed by HPLC (ee).

The specific catalytic reaction is shown in the following formula (16):

Column chromatography analysis showed that the yield of the target product was 84%; HPLC analysis showed that ee=71%.

Examples 14-31

After the complex formed by the chiral monophosphine ligand Yu-Phos 1 described in the present invention and the Au salt AuCl(SMe ₂ ) is exchanged with the Ag salt, the anion, the ligand R ⁴ substituent, the reaction temperature and the solvent will affect the cyclization The influence of the reaction, the specific operation and the remaining conditions are all described with reference to Example 19. The reaction conditions and experimental results of each embodiment are shown in Table 1.

Table 1 Reaction conditions and reaction results of Examples 16-31

According to Examples 14-20, e-1(S, R _s ) is the most suitable ligand, and the target product is obtained with 72% yield, endo:exo=1.3:1, 51%ee; through Example 18, 21, 22, show that AgSbF ₆ is the most suitable silver salt, and obtain the target product with 70% yield, endo:exo=1.5:1, 52% ee; through Examples 21, 23-25, it is shown that toluene is the most suitable Solvent, with 73% yield, endo:exo=3.1:1, 60% ee to obtain the target product; through Examples 25-29, it is shown that -30°C is the most suitable temperature, with 74% yield, endo:exo= 7.0:1,71%ee to obtain the target product.

(S)-L2:

Where: (S, R, R)-L1:

(S)-L2:

Examples 30-36

To investigate the universality of the substrate of the present invention, the specific operation and other conditions are all described in Example 29. The reaction conditions and experimental results of each embodiment are shown in Table 2.

The catalytic reaction is shown in the following formula (17):

Note: "*" indicates chiral center

Table 2 Reaction conditions and reaction results of Examples 30-36

Example R⁶/R⁷/R⁸ Yield(%) Endo:exo ee(%) 30 Me/4-OMe/4-Cl 70 6.5:1 69 31 Me/4-Cl/4-OMe 72 7.1:1 70 32 Me/4-NO₂/4-OMe 76 10.2:1 73 33 Me/4-NO₂/4-Cl 69 8.6:1 71 34 Ph/Ph/Ph 65 7.3:1 65

Through Examples 30-34, in catalyzing the asymmetric cycloaddition reaction of enynone molecules, the ligand has good substrate universality, and has good reactivity and stereoselectivity.

The protection content of the present invention is not limited to the above embodiments. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the appended claims are the scope of protection.

Claims (8)

1. A chiral monophosphine ligand Yu-Phos, which is characterized in that the monophosphine ligand is a compound 1 shown as the following formula or an enantiomer, a racemate and a diastereoisomer of the compound 1:

in Compound 1, R, R⁰Are respectively and independently selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy or

R¹、R²、R⁴Are each independently selected from C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy or

R³、R⁵Are respectively and independently selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Siloxane group of (A), C₁～C₁₀Alkanoyl of (2), C₁～C₁₀Ester group of (1), C₁～C₁₀Sulfonate of (A) or (B)

Wherein R is^xAnd R^x′Are respectively and independently selected from hydrogen, halogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy group of (C)₁～C₁₀Siloxane group of (A), C₁～C₁₀Alkanoyl of (2), C₁～C₁₀Ester group of (A) or (C)₁～C₁₀A sulfonate group of (a); "+" indicates a chiral center; n is an integer ranging from 1 or 2.

2. The chiral monophosphine ligand Yu-Phos according to claim 1, wherein in compound 1, R, R⁰Simultaneously selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy or

R¹、R²Are simultaneously selected from C₁～C₁₂Alkyl of (A) or (B)

R³、R⁵Are respectively and independently selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Siloxane group of (A), C₁～C₁₀Ester group of

R⁴Is selected from C₁～C₁₂Alkyl of (A) or (B)

R^xAnd R^x′Are respectively and independently selected from hydrogen, halogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy group of (C)₁～C₁₀Siloxane group of (A), C₁～C₁₀Alkanoyl of (2), C₁～C₁₀Ester group of (A) or (C)₁～C₁₀A sulfonate group of (a); "+" indicates a chiral center; n is an integer ranging from 1 or 2.

3. A method for preparing the chiral monophosphine ligand Yu-Phos according to claim 1, comprising the following specific steps:

the first step is as follows: in a solvent, 1) mixing the compound 2 with DMF and PBr₃Carrying out a substitution reaction to generate an intermediate compound

2) Then intermediate compound

Dehydrating and condensing with ethylene glycol to generate intermediate compound

3) Intermediate compound

With ClPR under the action of BuLi¹R²Carrying out a substitution reaction to generate an intermediate compound

4) Intermediate compoundsArticle (A)

Then hydrolyzing to obtain a compound 3, wherein the reaction process is shown as the following reaction formula (I):

the solvent is selected from dried methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform or N-hexane;

the reaction temperature is-78-120 ℃;

the reaction time is 1-12 hours;

the compound 2, DMF and PBr in the step 1)₃Ethylene glycol of step 2), BuLi and ClPR of step 3)¹R²And the mol ratio of the p-toluenesulfonic acid obtained in the step 4) is (1-30) to (1-30);

the BuLi is n-BuLi, s-BuLi or t-BuLi;

the second step is that: in a solvent, under the action of a condensing agent, the compound 3 is respectively reacted with the compound 4 (R)_s) Compound 4 (S)_s) Condensation reaction is carried out to obtain a compound 5 (R)_s) Compound 5 (S)_s) The reaction process is shown in the following reaction formula (II):

wherein the solvent is selected from the group consisting of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform, and n-hexane;

the temperature of the condensation reaction is-50 to 100 ℃;

the time of the condensation reaction is 10 minutes to 48 hours;

the compound 3 and the compound 4 (R)_s) Or 4 (S)_s) The mol ratio of the condensing agent to the condensing agent is (1-10) to (1-10);

the condensing agent is selected from tetraethyl titanate (Ti (OEt)₄) Tetraisopropyl titanate or tetramethyl titanate;

the third step: compound 5 (R)_s) Compound 5 (S)_s) Dissolved in a solvent and respectively reacted with a metal reagent, i.e. a compound R³MgX or R³Addition reaction of Li with R under action of n-BuLi⁵OTf is substituted to obtain chiral monophosphine ligand Yu-Phos, namely the compound 1(S, R)_s) Compound 1(R, R)_s) Compound 1(S, S)_s) Compound 1(R, S)_s) The reaction process is shown in the following reaction formula (III):

wherein the solvent is selected from the group consisting of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform, and n-hexane;

the reaction temperature is-78-30 ℃;

the reaction time is 10 minutes to 48 hours;

the compound 5 (R)_s) Or Compound 5 (S)_s) Metal reagent, n-BuLi, R⁵The mol ratio of OTf is (1-10): (1-10);

r, R therein⁰Are respectively and independently selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy or

R¹、R²、R⁴Are each independently selected from C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy or

R³、R⁵Are respectively and independently selected from hydrogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Siloxane group of (A), C₁～C₁₀Alkanoyl of (2), C₁～C₁₀Ester group of (1), C₁～C₁₀Sulfonate of (A) or (B)

Wherein R is^xAnd R^x′Are respectively and independently selected from hydrogen, halogen and C₁～C₁₂Alkyl of (A), C₁～C₁₀Alkoxy group of (C)₁～C₁₀Siloxane group of (A), C₁～C₁₀Alkanoyl of (2), C₁～C₁₀Ester group of (A) or (C)₁～C₁₀A sulfonate group of (a); n is an integer ranging from 1 or 2.

4. An application of the chiral monophosphine ligand Yu-Phos of claim 1 in catalyzing asymmetric cycloaddition reaction between an enynone substrate and 1, 3-diphenyl isobenzofuran molecules to synthesize an oxygen-containing bridge polyaryl heterocyclic compound.

5. The application of claim 4, wherein the chiral monophosphine ligand Yu-Phos and the transition metal salt form Yu-phosMX complex, then the complex and AgY are subjected to anion exchange to form a Yu-phosMY complex solution, and then the Yu-phosMY complex solution catalyzes intermolecular asymmetric cycloaddition reaction of eneynone and 1, 3-diphenyl isobenzofuran to synthesize the oxygen bridge-containing polyaromatic heterocyclic compound, which specifically comprises the following steps:

adding a chiral monophosphine ligand Yu-Phos and a transition metal salt into an organic solvent in an inert atmosphere, reacting for 0.1-20 hours at-10-50 ℃ to form a Yu-phosMX complex, adding AgY, stirring at-10-50 ℃, reacting for 0.1-20 hours, carrying out anion exchange to form a Yu-phosMY complex solution, adding enealkynone and 1, 3-diphenyl isobenzofuran into the Yu-phosMY complex solution, and carrying out intermolecular asymmetric cycloaddition reaction at-90 ℃ to synthesize the oxo-bridge-containing polyaromatic heterocyclic compound; wherein:

the molar ratio of the eneynone to the 1, 3-diphenyl isobenzofuran to the Yu-PhosMY complex is (10-10000) to 1;

the molar ratio of the chiral monophosphine ligand to the transition metal salt to AgY is (1-100) to (1-10).

6. Use according to claim 5, wherein the inert atmosphere is an argon or nitrogen atmosphere; the organic solvent is selected from dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene or chloroform.

7. Use according to claim 5, wherein the transition metal salt is an Au salt selected from AuOTf, AuSbF₆、AuBF₄、AuNTf₂、AuOTs、AuOPNB、AuCl(SMe₂)、Au(OTf)₃、Au(SbF₆)₃、Au(BF₄)₃Or Au (NTf)₂)₃。

8. Use according to claim 5, wherein AgY is selected from AgOTf, AgSbF₆、AgBF₄、AgNTf₂AgOTs or AgOPNB.