CN109666043B - Chiral monophosphine ligand CF-Phos with pyridine skeleton and preparation method and application thereof - Google Patents

Chiral monophosphine ligand CF-Phos with pyridine skeleton and preparation method and application thereof Download PDF

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CN109666043B
CN109666043B CN201811586531.8A CN201811586531A CN109666043B CN 109666043 B CN109666043 B CN 109666043B CN 201811586531 A CN201811586531 A CN 201811586531A CN 109666043 B CN109666043 B CN 109666043B
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CN109666043A (en
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张俊良
陈晓峰
周璐佳
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Suzhou Kerroli New Material Technology Co ltd
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East China Normal University
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

The invention discloses a chiral monophosphine ligand CF-Phos with a pyridine skeleton, a preparation method and application thereof, wherein the monophosphine ligand is compound 1 or an enantiomer, a racemate and a diastereoisomer of the compound 1; the ligand is prepared by a method of using the compound
Figure DDA0001919193330000011
And
Figure DDA0001919193330000012
performing condensation reaction, substitution reaction, hydrolysis reaction and addition reaction on the raw materials to prepare the monophosphine ligand; or with compounds
Figure DDA0001919193330000013
And
Figure DDA0001919193330000014
as raw material, carrying out condensation reaction with
Figure DDA0001919193330000015
Or
Figure DDA0001919193330000016
And carrying out addition reaction to prepare the monophosphine ligand. The invention is achieved by using compounds of two configurations
Figure DDA0001919193330000017
The chiral monophosphine ligand is obtained by addition reaction of the chiral monophosphine ligand and different types of metal reagentsCompound 1(S, R)s)、1(R,Rs)、1(S,Ss) And 1(R, S)s) The four full configurations of (a) are optically pure. The invention also discloses application of the ligand in asymmetric lactonization reaction of unsaturated carboxylic acid catalyzed by copper, and the ligand has wide application value.

Description

Chiral monophosphine ligand CF-Phos with pyridine skeleton and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemistry, relates to a novel chiral monophosphine ligand, a preparation method and application thereof, and particularly relates to a novel chiral monophosphine ligand CF-Phos with a modified pyridine skeleton, a preparation method and application thereof.
Background
Chirality is a basic property that exists widely in nature, and two substances that are chiral to each other can exhibit completely different properties, and common living substances such as proteins (composed of L-type amino acids), DNA and RNA (composed of D-configuration ribose) and the like all have specific chirality. It can be seen that the study of chiral compounds is an urgent and important task. Hitherto, methods for obtaining optically pure compounds have various modes such as chiral resolution, induced conversion of chiral compounds, asymmetric catalysis and the like, and asymmetric catalysis has the advantages of mild reaction conditions, good stereoselectivity, economy, practicability, environmental protection and the like, and is popular among chemists. Therefore, the design and synthesis of chiral catalysts have been the hot spot and the leading edge of chemical research for decades.
Phosphorus (P) is an important chemical element widely present in animals and plants, and phosphorus-containing compounds have attracted much attention from chemists because of its important role in agriculture and industry, drug molecules, and living bodies. Further research shows that the construction of the phosphorus ligand of the C-chiral center provides a new choice for asymmetric catalytic reaction, and the phosphorus ligand has outstanding performances in asymmetric hydrogenation, formation of chiral C-C bonds and C-X bonds and other reactions. Through the development of recent decades, more and more chiral phosphine ligands with different configurations are reported, and the generation of chiral phosphine ligands with central chirality, axial chirality, surface chirality, spiro and other frameworks solves one more problem for asymmetric catalysis. However, there have been few reports on the preparation methods and applications of S-chiral and C-central chiral monophosphine ligands based on pyridine skeletons.
The design and synthesis of novel chiral phosphine ligands are the focus of research from the past. A class of C-centered chiral monophosphine ligands (catalysts) Ming-Phos (angelw.chem.int.ed.2014, 53,4350) was successfully synthesized as early as 2014 based on sulfenamide structure, and in the following years, many new C-centered chiral monophosphine ligands (catalysts) such as Xiao-Phos (angelw.chem.int.ed.2015, 54,6874), Wei-Phos (angelw.chem.int.ed.2015, 54,14853) and Peng-Phos (angelw.chem.int.ed.2016, 55,13316) were successively and successfully developed.
Disclosure of Invention
The invention aims to provide a novel chiral monophosphine ligand CF-Phos and a preparation method and application thereof, overcomes the defects of expensive raw materials, complex synthetic route, great harm of reaction reagents and the like in the existing synthesis research technology of phosphine-containing chiral ligands (catalysts), and can prepare the chiral monophosphine ligand CF-Phos with all three-dimensional configurations efficiently, with high selectivity and at low cost by using different metal reagents.
The chiral monophosphine ligand CF-Phos provided by the invention is a C-center chiral monophosphine ligand, and is a compound 1 shown as the following formula or an enantiomer, a racemate or a diastereoisomer of the compound 1:
Figure GDA0001998588640000021
wherein R is1、R2、R5Are each independently selected from C1～C12Alkyl of (A), C1～C10Alkoxy group of,
Figure GDA0001998588640000022
Figure GDA0001998588640000023
R、R3、R4Are 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～C10A sulfonate group of,
Figure GDA0001998588640000024
ORwOr SRw(ii) a Wherein: rxAnd Rx′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 (1), C1～C10A sulfonate group of (a); ry、Ry′、Ry〃、Rz、Rz′And RwAre each independently selected from C1～C12Alkyl of (A), C1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10A sulfonate group of (a).
As a preferable mode, R in the above compound 11、R2Are simultaneously selected from C1～C12An alkyl group of,
Figure GDA0001998588640000025
Figure GDA0001998588640000026
R、R3、R4Are respectively and independently selected from hydrogen and C1～C12Alkyl of (A), C1～C10Siloxane group of (A), C1～C10Ester group of
Figure GDA0001998588640000027
R5Is selected from C1～C12An alkyl group of,
Figure GDA0001998588640000028
Wherein R isxAnd Rx′Are respectively and independently selected from hydrogen,Halogen, C1～C12Alkyl of (A), C1～C10Alkoxy group of (C)1～C10Siloxane group of (A), C1～C10Alkanoyl of (2), C1～C10Ester group of (1), C1～C10A sulfonate group of (a); "+" represents a chiral center.
As a preferred embodiment, R in compound 1 is selected from hydrogen; r1、R2Are simultaneously selected from C1～C12An alkyl group of,
Figure GDA0001998588640000029
R3Selected from hydrogen; r4Is selected from C1～C12Alkyl of (A) or (B)
Figure GDA00019985886400000210
R5Selected from tert-butyl; wherein R isxAnd Rx′Are respectively and independently selected from hydrogen and C1～C12Alkyl of (A), C1～C10Alkoxy group of (C)1～C10A siloxane group of (a).
As a further preferable embodiment, R in Compound 11、R2Are simultaneously selected from C1～C12Alkyl of (A) or (B)
Figure GDA00019985886400000211
As a further preferred embodiment, R in the compound 1 is selected from hydrogen or C1～C12An alkyl group of (1).
As a further preferred embodiment, the chiral monophosphine ligand CF-Phos is selected from the following compounds or enantiomers, racemates or diastereomers of said compounds, as shown below:
Figure GDA0001998588640000031
wherein: cy is cyclohexyl.
The invention also provides a preparation method of the chiral monophosphine ligand CF-Phos, which comprises the following two schemes:
the first scheme is as follows:
the first step is as follows: in a solvent, under the action of a condensing agent, a compound 2 and ethylene glycol are subjected to condensation reaction at a certain temperature to protect aldehyde groups, so that a compound 3 is synthesized, wherein the reaction process is shown as the following reaction formula (I):
Figure GDA0001998588640000032
wherein each group in formula (I) is as defined for compound 1, and X is halogen.
The solvent is selected from dried 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; preferably, it is dry toluene.
The temperature of the condensation reaction is between room temperature and 150 ℃; preferably, the temperature is 120-150 ℃.
The time of the condensation reaction is 1 to 12 hours; preferably, it is 5 to 6 hours.
The molar ratio of the compound 2 to the glycol to the condensing agent is (1-100) to (1-10); preferably, it is 1: 3: 0.1.
The condensing agent is used for promoting the condensation reaction and is selected from sulfuric acid, p-toluenesulfonic acid (TsOH) and hydrochloric acid; preferably, TsOH.
The second step is that: in a solvent, at a certain temperature, compound 3 is mixed with KPR1R2Substitution reaction is carried out to obtain a compound 4, and the reaction process is shown as the following reaction formula (II):
Figure GDA0001998588640000041
wherein each group in formula (II) is as defined for compound 1, and X is halogen.
The solvent is selected from dried 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; preferably, it is dry tetrahydrofuran.
The temperature of the substitution reaction is-78-50 ℃; preferably-50 to 0 ℃.
The time of the substitution reaction is 10 minutes to 24 hours; preferably, it is 12 hours.
The compound 3, KPR1R2The molar ratio of (1-10) to (1-10); preferably, it is 1: 1.2.
The third step: in a solvent, compound 4 is hydrolyzed under the action of acid at a certain temperature to remove a protecting group, and the reaction process is shown as the following reaction formula (III):
Figure GDA0001998588640000042
wherein each group in the formula (III) is as defined for compound 1.
The solvent is selected from mixed solution of dichloromethane and water, diethyl ether and water, dibutyl ether and water, methyl tert-butyl ether and water, ethylene glycol dimethyl ether and water, 1, 4-dioxane and water, tetrahydrofuran and water, 2-methyltetrahydrofuran and water, toluene and water, xylene and water, benzene and water, chlorobenzene and water, fluorobenzene and water, chloroform and water, normal hexane and water or acetone and water; preferably, it is a mixed solution of acetone and water. The volume ratio of acetone to water is (1-10) to (1-10); preferably, it is 1: 1.5.
The temperature of the hydrolysis reaction is-50 to 100 ℃; preferably, the temperature is 60-80 ℃.
The time of the hydrolysis reaction is 10 minutes to 24 hours; preferably, it is 10 hours.
The molar ratio of the compound 4 to the acid is (1-10) to (1-10); preferably, it is 5: 1.
The acid is used for promoting the hydrolysis reaction and is selected from sulfuric acid, p-toluenesulfonic acid (TsOH) and hydrochloric acid; preferably, TsOH.
The fourth step: in a solvent, under the action of a condensing agent at a certain temperature, the compound 5 is respectively reacted with the compound 6 (R)s) Compound 6 (S)s) Condensation reaction is carried out to obtain a compound 7 (R)s) Compound 7 (S)s) See literature (angelw.chem.int.ed.2014, 53,4350) for specific operation, the reaction process is shown in the following reaction formula (IV):
Figure GDA0001998588640000051
wherein each group in formula (IV) is as defined for compound 1;
the solvent is selected from dried 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; preferably, it is dry tetrahydrofuran.
The temperature of the condensation reaction is-50 to 100 ℃; preferably, the temperature is 50-70 ℃.
The time of the condensation reaction is 10 minutes to 48 hours; preferably, it is 8 hours.
The compound 5 and the compound 6 (R)s) (or 6 (S)s) The molar ratio of the (a) to the condensing agent is (1-10) to (1-100); preferably, it is 1: 1.2: 2.5.
The condensing agent is used for promoting the condensation reaction and is selected from tetraethyl titanate (Ti (OEt)4) Tetraisopropyl titanate, tetramethyl titanate; preferably, it is Ti (OEt)4。
The fifth step: compound 7 (R)s) Compound 7 (S)s) Dissolving in dry solvent, and reacting with metal reagent R at certain temperature3MgX or R3Li is subjected to addition reaction and then reacts with R under the action of BuLi4OTf is substituted to obtain chiral monophosphine ligand CF-Phos, namely the compound 1(R, R)s) Compound 1(S, R)s) To transform intoCompound 1(R, S)s) Compound 1(S, S)s) The reaction process is shown in the following reaction formula (V):
Figure GDA0001998588640000061
wherein each group in formula (V) is as defined for compound 1, and X is halogen.
The solvent is selected from dried 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; preferably, it is dry tetrahydrofuran.
The temperature of the addition substitution reaction is-78-30 ℃; preferably-78 to-40 ℃.
The time of the addition substitution reaction is 10 minutes to 48 hours; preferably, the time is 8 to 12 hours.
The compound 7 (R)s) (or 7 (S)s))、R3MgX (or R)3Li), BuLi and R4The mol ratio of OTf is (10-1): (1-50): (1-10); preferably, it is 1: 1.5: 1.2: 2.
The BuLi includes n-BuLi, s-BuLi and t-BuLi, and preferably n-BuLi.
The compound R3MgX (or R)3Li) has the effect of being equal to 7 (R)s) (or 7 (S)s) ) to carry out an addition reaction.
Scheme II:
the first step is as follows: dissolving compound 8 in solvent, reacting with compound 6 (R) at certain temperatures) Compound 6 (S)s) Condensation reaction is carried out under the action of a condensing agent to obtain a compound 9 (R)s) Compound 9 (S)s) The concrete operation is the same as the fourth step of the first scheme, and the reaction process is shown as the following reaction formula (VI):
Figure GDA0001998588640000071
wherein each group in formula (VI) is as defined for compound 1;
the solvent is selected from dried 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; preferably, it is dry tetrahydrofuran.
The temperature of the condensation reaction is-50 to 100 ℃; preferably, the temperature is 50-70 ℃.
The time of the condensation reaction is 10 minutes to 48 hours; preferably, it is 8 hours.
The compound 8 and the compound 6 (R)s) Or 6 (S)s) The molar ratio of the condensing agent is (1-10) to (1-100); preferably, it is 1: 1.5: 2.5.
The condensing agent is used for promoting the condensation reaction and is selected from tetraethyl titanate (Ti (OEt)4) Tetraisopropyl titanate, tetramethyl titanate; preferably, it is Ti (OEt)4。
The second step is that: in a solvent at a certain temperature
Figure GDA0001998588640000072
With ClPR under the action of BuLi1R2Carrying out a substitution reaction to produce an intermediate compound 10
Figure GDA0001998588640000073
The reaction process is shown as a reaction formula (VII):
Figure GDA0001998588640000074
wherein each group in formula (VII) is as defined for compound 1, and X is halogen.
The solvent is selected from dried 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; preferably, it is dry dichloromethane.
The temperature of the substitution reaction is-78-30 ℃; preferably-78 to-50 ℃.
The time of the substitution reaction is 10 minutes to 12 hours; preferably, it is 6 hours.
Said compounds
Figure GDA0001998588640000081
BuLi、ClPR1R2The molar ratio of (1-10) to (1-10); preferably, it is 1: 1.
The BuLi is used for exchanging with halogen X and carrying out substitution reaction; the BuLi includes n-BuLi, s-BuLi and t-BuLi, and preferably n-BuLi.
The third step: in a solvent, under the action of BuLi (or Mg) at a certain temperature, the intermediate compound 10 generates an intermediate
Figure GDA0001998588640000082
(or
Figure GDA0001998588640000083
) Reaction of Compound 9 (R)s) Compound 9 (S)s) Dissolving in solvent, and reacting with intermediate
Figure GDA0001998588640000084
(or
Figure GDA0001998588640000085
) Performing addition reaction with R under the action of BuLi4OTf is substituted to obtain chiral monophosphine ligand CF-Phos, namely the compound 1(R, R)s) Compound 1(S, S)s) Compound 1(S, R)s) Compound 1(R, S)s) The reaction process is shown in the following reaction formula (VIII):
Figure GDA0001998588640000086
wherein each group in the formula (VIII) is as defined for compound 1, and X is halogen.
The solvent is selected from dried 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; preferably, it is dry tetrahydrofuran.
The temperature of the addition substitution reaction is-78-30 ℃; preferably-78 to-50 ℃.
The time of the addition substitution reaction is 10 minutes to 24 hours; preferably, it is 12 hours.
The compound 9 (R)s) (or 9 (S)s))、
Figure GDA0001998588640000091
(or
Figure GDA0001998588640000092
) BuLi and R4The mol ratio of OTf is (10-1): (1-50): (1-10); preferably, it is 1.5: 1: 1.5: 2.
The BuLi includes n-BuLi, s-BuLi and t-BuLi, and preferably n-BuLi.
In the process of the invention, the compounds
Figure GDA0001998588640000093
And ethylene glycol as raw material, condensation reaction with KPR1R2By substitution reaction followed by hydrolysis reaction with a compound
Figure GDA0001998588640000094
Carrying out a condensation reaction with a compound of formula R3MgX or R3Addition reaction of Li compound and R4OTf is subjected to substitution reaction to prepare the compound 1, namely chiral monophosphine ligand CF-Phos; or a compound
Figure GDA0001998588640000095
And compounds
Figure GDA0001998588640000096
As raw material, condensation reaction is carried out, and the raw material and the compound are
Figure GDA0001998588640000097
(or
Figure GDA0001998588640000098
) Carrying out addition reaction with R4OTf is subjected to substitution reaction to prepare the compound 1, namely chiral monophosphine ligand CF-Phos.
The invention can conveniently obtain four full-configuration 1(S, R) of chiral monophosphine ligand CF-Phos by using two chiral sulfinamide 6 configurations and different types of metal reagents for additions)、1(R,Rs)、1(S,Ss) And 1(R, S)s) The optically pure compound of (1).
The invention also provides the application of the chiral monophosphine ligand CF-Phos in copper-catalyzed lactonization of unsaturated carboxylic acids, wherein the chiral monophosphine ligand CF-Phos is provided with the compound 1 or an enantiomer, a racemate or a diastereoisomer of the compound 1.
The invention also provides a method for producing carbon chiral centers by lactonization of the unsaturated carboxylic acids, which comprises the steps of forming CF-PhosMX complex solution by the chiral monophosphine ligand CF-Phos and transition metal salt, and then catalyzing lactonization of the unsaturated carboxylic acids to synthesize the carbon chiral center compounds. The chiral monophosphine ligand CF-Phos is compound 1 or an enantiomer, a racemate or a diastereoisomer of the compound 1.
The use of a chiral monophosphine ligand CF-Phos as described above for catalysing the asymmetric lactonization of an unsaturated carboxylic acid, and in a process for the asymmetric lactonization of an unsaturated carboxylic acid into said carbon chiral centre compound:
as a preferred variant, the chiral monophosphine ligand CF-Phos is first reacted with a transition metal salt to form a CF-PhosMX complex, which is then used to catalyze the asymmetric lactonization of the unsaturated carboxylic acid. The reaction process is shown in the following reaction formula (IX):
Figure GDA0001998588640000101
as a further preferred embodiment, the preparation of the complex comprises the steps of: under inert atmosphere, the chiral monophosphine ligand CF-Phos and the transition metal salt are added into an organic solvent and react for 0.1-20 hours at-10-50 ℃ to form a CF-phosMX complex solution.
The molar ratio of the monophosphine ligand CF-Phos to the transition metal salt is (1-100) to 1.
The transition metal salt is a copper salt.
Said copper salt comprises Cu (OTf)2、Cu(OAc)2、CuCl2Or CuOAc.
The inert atmosphere is argon atmosphere 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.
The operation of using the complex for catalyzing asymmetric lactonization of unsaturated carboxylic acids is as follows: under inert atmosphere, adding unsaturated carboxylic acid and morpholine derivatives into a CF-PhosMX complex solution, and carrying out asymmetric lactonization reaction at-10-100 ℃.
In the asymmetric lactonization reaction, the molar ratio of the unsaturated carboxylic acid to the morpholine derivative to the CF-PhosMX complex is (10-100) to 1; preferably, the molar ratio of the unsaturated carboxylic acid, the morpholine derivative and the CF-PhosMX complex is 20: 1.
The unsaturated carboxylic acid may be of the structure shown in compound 11:
Figure GDA0001998588640000102
in the above compound 11: r1、R2Selected from hydrogen, halogen, nitro, cyano, alkynyl, C1～C10Alkyl of (A), C1～C10Alkoxy group of (C)1～C10Alkanoyl or C1～C10An ester group of (a);
further preferably, R1、R2Selected from hydrogen, halogen, nitro, cyano, alkynyl, C1～C10Alkyl or C1～C10Alkoxy group of (2).
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention provides a novel chiral monophosphine ligand, and reports that the chiral monophosphine ligand is used for asymmetric lactonization of unsaturated carboxylic acid after forming a complex with transition metal salt for the first time, so that the chiral monophosphine ligand has high reaction activity and good stereoselectivity, and can ensure that a lactonization product:
Figure GDA0001998588640000103
(wherein ". sup." represents a chiral center.) the yield was 20% to 85%, and the enantiomeric excess (ee) was 15% to 31%.
(2) The preparation method of the chiral monophosphine ligand overcomes the defects of expensive raw materials, long synthetic route, high toxicity of reaction reagents, high difficulty in synthesis of enantiomers, low yield and the like when the chiral ligand containing phosphine is synthesized in the prior art, is diversified, short in route, simple to operate, suitable for large-scale production and has practical value, and the yield is 37% -85%.
In the invention:
n-BuLi is n-butyl lithium; ClPPh2Is diphenyl phosphonium chloride; DMF is N, N-dimethylformamide; ti (OEt)4Is tetraethyl titanate.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The following examples provide all two synthetic schemes for the chiral monophosphine ligand described above, compound 1, specifically:
example 1
Figure GDA0001998588640000111
Synthesis of a-1(R, Rs) (cf. scheme I)
The first step is as follows: into a 250mL single-neck flask, add
Figure GDA0001998588640000112
(20mmol,3.72g), ethylene glycol (3.0eq.,3.72g), TsOH (0.1eq.,0.38g) and 50mL Toluene, installing a water separation device, heating and refluxing at 150 ℃ for 5 hours, slowly cooling to room temperature, separating liquid, extracting a water layer with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride respectively, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain the active ingredient
Figure GDA0001998588640000113
The yield was 95%.
Wherein TsOH is p-toluenesulfonic acid, and Toluene is Toluene.
The second step is that: prepared in the first step
Figure GDA0001998588640000114
(10mmol,2.3g) was added to a 100mL dry reaction flask under argon protection, 30mL THF was added, and KPPh was added at-50 deg.C2(1.2eq.,24mL,0.5M in THF), stirring for 1 hour, naturally heating, stirring overnight, adding saturated ammonium chloride, quenching, separating, extracting water layer with ethyl acetate for three times, mixing organic phases, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain the final product
Figure GDA0001998588640000115
The yield was 80%.
Wherein THF is tetrahydrofuran.
The third step: prepared in the second step
Figure GDA0001998588640000121
(20mmol, 6.71g), TsOH (0.2eq, 0.76g), 20mL of water and 30mL of Toluene, heating and refluxing for 8 hours at 80 ℃ under nitrogen atmosphere, slowly cooling to room temperature, separating liquid, extracting a water layer with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride respectively, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain the compound
Figure GDA0001998588640000122
The yield was 90%.
Wherein TsOH is p-toluenesulfonic acid, and Toluene is Toluene.
The fourth step: prepared by the third step
Figure GDA0001998588640000123
(2.91g,10mmol) and
Figure GDA0001998588640000124
(1.2eq.,1.45g) into a 100mL three-necked flask, 50mL of THF under nitrogen, Ti (OEt)2(2.5eq.,7.4mL), stirring at 50 deg.C for 24 hr, separating, extracting water layer with ethyl acetate for three times, mixing organic phases, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, spin drying, and purifying by column chromatography to obtain the final product
Figure GDA0001998588640000125
The yield was 85%.1H NMR(400MHz,CDCl3)δ8.62(s,1H),7.86(d,J＝8.0Hz,1H),7.61–7.53(m,1H),7.38–7.32(m,4H),7.31–7.23(m,6H),7.13(d,J＝4.0Hz,1H),1.19(s,9H)；31P NMR(122MHz,CDCl3)δ-3.78；13C NMR(101MHz,CDCl3)δ164.82,164.31,153.1,152.99,136.29(d,J＝3.0Hz),135.78(d,J＝11.1Hz),134.24(dd,J＝20.2,9.1Hz),129.98,129.80,129.25(d,J＝7.1Hz),128.68(dd,J＝8.1,5.1Hz),120.87,58.10,22.76.HRMS(ESI)calculated for[C22H24N2OPS][M+H]+:395.1334；found:395.1341.
WhereinTHF is tetrahydrofuran; ti (OEt)4Is tetraethyl titanate.
The fifth step: prepared by the fourth step
Figure GDA0001998588640000126
(0.79g,2.0mmol) was added to a dry 50mL single-necked eggplant-shaped reaction flask under argon and 15mL of THF was added. Adding methyl magnesium bromide (1.5eq.,3mL,1M in THF) at-78 deg.C, stirring for 5 hr, naturally heating, stirring overnight, adding saturated ammonium chloride, quenching, separating, extracting water layer with ethyl acetate for three times, mixing organic phases, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, spin drying, and purifying by column chromatography to obtain final product
Figure GDA0001998588640000127
a-1(R, Rs), 70% yield.1H NMR(300MHz,CDCl3)δ7.56–7.49(m,1H),7.46–7.34(m,10H),7.16(d,J＝76.0Hz,1H),7.03(d,J＝9.0Hz,1H),5.00(s,1H),4.60(d,J＝6.0Hz,1H),1.48(d,J＝9.0Hz,3H),1.11(s,9H)；31P NMR(122MHz,CDCl3)δ-3.08；13C NMR(101MHz,CDCl3)δ162.77(d,J＝2.0Hz),162.05,161.96,136.51–136.33(m),136.28,134.31(dd,J＝20.2,18.2Hz),129.03(d,J＝13.1Hz),128.57(dd,J＝7.1,2.0Hz),126.75,126.54,119.47,55.46,54.52,23.36,22.66.HRMS(ESI)calculated for[C23H28N2OPS][M+H]+:411.1653；found:411.1654。
Example 2
Figure GDA0001998588640000131
a-1(S,Ss) Synthesis of (see scheme one)
The specific operation was the same as in example 1, and the raw materials used were changed to
Figure GDA0001998588640000132
The yield was 76%.1H NMR(300MHz,CDCl3)δ7.52–7.43(m,1H),7.42–7.30(m,10H),7.10(d,J＝76.0Hz,1H),7.02(d,J＝9.0Hz,1H),4.92(s,1H),4.56(d,J＝6.0Hz,1H),1.40(d,J＝9.0Hz,3H),1.30(s,9H)；31P NMR(122MHz,CDCl3)δ-3.09；13C NMR(101MHz,CDCl3)δ163.77(d,J＝2.4Hz),162.50,161.96,136.60–136.40(m),136.28,134.20,129.03(d,J＝13.6Hz),128.60,127.65,126.34,118.45,54.45,52.50,23.32,21.64.HRMS(ESI)calculated for[C23H28N2OPS][M+H]+:411.1655；found:411.1656。
Example 3
Figure GDA0001998588640000133
b-1(R,Rs) Synthesis of (see scheme one)
The procedure was as in example 1, except that t-butylmagnesium bromide (4eq.,4mL,1M in THF) was used as the metal reagent, and the yield was 63%.1H NMR(400MHz,CDCl3)δ7.41(td,J＝8.0,2.4Hz,1H),7.38–7.20(m,10H),7.04(dd,J＝8.0,2.0Hz,1H),6.98(d,J＝8.0Hz,1H),5.07(d,J＝8.0Hz,1H),3.93(d,J＝8.0Hz,1H),1.03(s,9H),0.72(s,9H)；31P NMR(122MHz,CDCl3)δ-2.70；13C NMR(101MHz,CDCl3)δ161.62,159.76(d,J＝8.1Hz),136.57(d,J＝9.1Hz),135.96(d,J＝9.1Hz),135.29(d,J＝5.12Hz),134.90,134.70,134.10,133.91,129.09,128.76–128.29(m),127.22,126.95,122.52,68.32,56.00,36.47,26.58,22.99.HRMS(ESI)calculated for[C26H34N2OPS][M+H]+:453.2124；found:453.2116。
Example 4
Figure GDA0001998588640000134
b-1(S,Rs) Synthesis of (see scheme one)
The procedure was carried out in the same manner as in example 1 except that the metal reagent used was changed to t-butyllithium reagent, whereby the yield was 58%.1H NMR(400MHz,CDCl3)δ7.45–7.39(m,1H),7.32–7.24(m,10H),7.05(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,1H),4.57(d,J＝8.0Hz,1H),3.98(d,J＝8.0Hz,1H),0.82(s,9H),0.81(s,9H)；31P NMR(122MHz,CDCl3)δ-2.90；13C NMR(101MHz,CDCl3)δ162.45,159.53(d,J＝9.1Hz),136.03,135.12,134.35(dd,J＝19.2,10.1Hz),132.20(d,J＝10.1Hz),129.10(d,J＝9.1Hz),128.50(d,J＝5.1Hz),126.90,126.67,122.23,69.21,56.06,36.07,26.76,22.20.HRMS(ESI)calculated for[C26H34N2OPS][M+H]+:453.2124；found:453.2125。
Example 5
Figure GDA0001998588640000141
Synthesis of c-1(R, Rs) (cf. scheme II)
The first step is as follows: will be provided with
Figure GDA0001998588640000142
(20mmol,2.24g) and
Figure GDA0001998588640000143
(1.5eq.,3.62g) into a 100mL three-necked flask, 50mL of THF under nitrogen, Ti (OEt)2(2.5eq.,11.5mL), stirring at 50 deg.C for 24 hr, separating, extracting water layer with ethyl acetate for three times, mixing organic phases, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, spin drying, and purifying by column chromatography to obtain the final product
Figure GDA0001998588640000144
The yield was 93%.
Wherein THF is tetrahydrofuran; ti (OEt)4Is tetraethyl titanate.
The second step is that: into a dry 100mL single-necked eggplant-shaped reaction flask, add
Figure GDA0001998588640000145
(20mmol,4.74g), under argon, 50mL of dry DCM was added. n-BuLi (1.0eq.,12.5mL,1.6M in THF) was added at-78 deg.C, stirred for 1 hour, and then Ph was slowly added dropwise2PCl (1.0eq.,3.6mL) is stirred at 78 ℃ for 2 hours, then the temperature is naturally raised, the stirring is carried out overnight, saturated ammonium chloride is added for quenching, liquid separation is carried out, an aqueous layer is extracted by ethyl acetate for three times, organic phases are combined, water and saturated sodium chloride are respectively used for washing, anhydrous sodium sulfate is used for drying, filtering, spin-drying and column chromatography purification are carried out, and the product is obtained
Figure GDA0001998588640000146
The yield was 70%.
Wherein DCM is dichloromethane; n-BuLi is an n-butyl lithium reagent; ph2PCl is diphenyl phosphine chloride; THF is tetrahydrofuran.
The third step: in a 50mL dry single-neck eggplant-shaped reaction flask, the mixture was added under argon atmosphere
Figure GDA0001998588640000147
(0.68g,2.0mmol) and 10mL of dry THF, stirring at-78 deg.C for 10 minutes, then n-BuLi (1.2eq.,12.5mL,1.6M in THF) was added dropwise, and stirring continued for 1.5 hours to form the compound
Figure GDA0001998588640000148
Then will be
Figure GDA0001998588640000149
(1.5eq.,0.65g) is dissolved in 5mL of dry THF solution, slowly dropped into a reaction bottle, stirred for 3 hours at-78 ℃, naturally warmed, stirred overnight, quenched by saturated ammonium chloride, separated, the water layer is extracted three times by ethyl acetate, the organic phases are combined, washed by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, filtered, dried by spinning, and purified by column chromatography to obtain the product
Figure GDA0001998588640000151
c-1(R,Rs) The yield was 50%.1H NMR(400MHz,CDCl3)δ7.43(m,1H),7.32–7.24(m,11H),6.95(t,J＝8.0Hz,2H),4.39(s,1H),4.10(t,J＝8.0Hz,1H),1.74–1.47(m,7H),1.12–0.98(m,4H),0.92(s,9H)；31P NMR(122MHz,CDCl3)δ-3.89；13C NMR(101MHz,CDCl3)δ162.94,160.55,160.45,134.24(dd,J＝20.0,16.1Hz),129.05,128.52(d,J＝7.0Hz),126.67,126.47,121.13,65.75,56.08,44.47,29.43,29.07,26.26,26.12,22.40.HRMS(ESI)calculated for[C28H36N2OPS][M+H]+:479.2280；found:479.2273。
Example 6
Figure GDA0001998588640000152
d-1(R,Rs) Synthesis of (see scheme two)
The specific operation was the same as in example 5, and the raw materials used were changed to
Figure GDA0001998588640000153
The yield was 65%.1H NMR(300MHz,CDCl3)δ7.48–7.26(m,20H),7.04(dd,J＝6.0,3.0Hz,1H),6.69(d,J＝9.0Hz,1H),5.74(d,J＝6.0Hz,1H),5.15(d,J＝6.0Hz,1H),1.06(s,9H)；31P NMR(122MHz,CDCl3)δ-3.11；13C NMR(126MHz,CDCl3)δ162.85,160.32(d,J＝8.8Hz),141.18,141.02,139.52,136.15(d,J＝5.0Hz),134.30(dd,J＝20.2,12.6Hz),129.88,129.77,129.08,128.66–128.47(m),128.35,128.09,127.26(d,J＝8.8Hz),126.83,126.64,120.62,58.63,56.40,30.96,22.47.HRMS(ESI)calculatedfor[C34H34N2OPS][M+H]+:549.2124；found:549.2140。
Example 7
Figure GDA0001998588640000154
e-1(R,Rs) Synthesis of (see scheme two)
The specific operation was the same as in example 5, and the raw materials used were changed to
Figure GDA0001998588640000155
The yield was 68%.1H NMR(300MHz,CDCl3)δ7.42–7.08(m,18H),6.89(d,J＝6.0Hz,1H),6.45(d,J＝9.0Hz,1H),5.60(d,J＝6.0Hz,1H),5.32(s,1H),1.27(s,18H),0.90(s,9H)..31P NMR(122MHz,CDCl3)δ-3.12(s)；13C NMR(126MHz,CDCl3)δ162.78,160.13(d,J＝8.8Hz),150.72,142.13,140.28,139.55,134.29(t,J＝20.2Hz),129.68,129.09,128.55(dd,J＝7.6,2.5Hz),127.83,127.05,124.19,120.88,120.71,58.48,56.37,35.03,31.58,22.41.HRMS(ESI)calculated for[C42H50N2OPS][M+H]+:661.3376；found:661.3371。
Example 8
Figure GDA0001998588640000161
f-1(R,Rs) Synthesis of (see scheme two)
The specific operation was the same as in example 5, and the raw materials used were changed to
Figure GDA0001998588640000162
The yield was 74%.1H NMR(300MHz,CDCl3)δ7.94(s,1H),7.85(s,2H),7.54–7.32(m,15H),7.20–7.15(m,1H),7.03(d,J＝9.0Hz,1H),6.70(d,J＝6.0Hz,1H),5.46(s,1H),1.05(s,9H)；31P NMR(122MHz,CDCl3)δ-2.91；19F NMR(282MHz,CDCl3)δ-62.60；13C NMR(101MHz,CDCl3)δ163.53,159.37,159.28,143.08,138.23,134.33(dd,J＝20.0,16.0Hz),131.63,131.30,130.06,129.82,129.66,129.32,129.16(d,J＝6.0Hz),128.58(t,J＝7.1Hz),127.80,126.84,126.63,124.65,121.94,121.32,120.31,59.21,56.49,22.32.HRMS(ESI)calculated for[C36H32F6N2OPS][M+H]+:685.1872；found:685.1874。
Example 9
Figure GDA0001998588640000163
g-1(R,Rs) Synthesis of (see scheme one)
The procedure was carried out in the same manner as in example 1, except that 4-methoxyphenylmagnesium bromide (4eq.,4mL,1M in THF) was used as the starting material in a yield of 40%.1H NMR(400MHz,CDCl3)δ7.39–7.33(m,5H),7.31–7.26(m,6H),7.16–7.11(m,2H),6.98(dd,J＝8.0,4.0Hz,1H),6.81–6.74(m,3H),5.67(s,1H),5.47(s,1H),3.71(s,3H),0.96(s,9H)；31P NMR(122MHz,CDCl3)δ-2.60；13C NMR(101MHz,CDCl3)δ162.34,160.31,160.23,159.24,136.30-136.05(m),134.35(dd,J＝20.2,14.1Hz),133.72,129.65,129.12,128.60(d,J＝6.1Hz),126.87,126.63,120.98,113.99,60.78,55.53,55.25(d,J＝3.0Hz),22.64.HRMS(ESI)calculated for[C29H32N2O2PS][M+H]+:503.1917；found:503.1913。
Example 10
Figure GDA0001998588640000171
g-1(S,Rs) Synthesis of (see scheme one)
The procedure was carried out in the same manner as in example 1 except that the metal reagent used was changed to 4-methoxyphenyllithium reagent, whereby the yield was 42%.1H NMR(300MHz,CDCl3)δ7.34–7.23(m,11H),7.16(d,J＝9.0Hz,2H),7.02(d,J＝9.0Hz,1H),6.92(d,J＝9.0Hz,1H),6.72(d,J＝9.0Hz,1H),5.47(d,J＝6.0Hz,1H),5.03(s,1H),3.68(s,3H),1.00(s,9H)；31P NMR(122MHz,CDCl3)δ-3.28；13C NMR(101MHz,CDCl3)δ162.92,160.47(d,J＝11.1Hz),159.08,136.37,134.46–134.05(m),129.07(d,J＝3.0Hz),128.94,128.54(d,J＝5.1Hz),126.69(d,J＝21.2Hz),120.73,114.01,61.20,56.36,55.25(d,J＝4.0Hz),22.61.HRMS(ESI)calculated for[C29H32N2O2PS][M+H]+:503.1916；found:503.1917。
Example 11
Figure GDA0001998588640000172
h-1(R,Rs) Synthesis of (see scheme one)
The operation was carried out in the same manner as in example 1 except that potassium dicyclohexylphosphate was used as the phosphine source, whereby the yield was 37%.1H NMR(400MHz,CDCl3)δ7.30–7.22(m,4H),7.16–7.11(m,2H),6.98(dd,J＝8.0,4.0Hz,1H),5.45(s,1H),5.27(s,1H),3.80(s,3H),1.58-1.41(m,22H),0.98(s,9H)；31P NMR(122MHz,CDCl3)δ-2.50；13CNMR(101MHz,CDCl3)δ160.34,158.36-158.28(m),135.40,134.35(dd,J＝20.2,14.1Hz),130.72,127.60(d,J＝6.0Hz),126.65,122.12,113.99,63.75,61.03,34.82,31.31,29.05,25.51,24.64.HRMS(ESI)calculated for[C29H44N2O2PS][M+H]+:515.1921；found:515.2918。
Example 12
Figure GDA0001998588640000173
i-1(R,Rs) Synthesis of (see scheme one)
In the same manner as in example 1, n-BuLi (1.5eq.,1.9mL,1.6M in THF) was added to the reaction, and after stirring for 1 hour, MeOTf (2.0eq.,0.98g) was slowly added dropwise, and the reaction was stirred for 3 hours, followed by column chromatography separation, whereby the yield was 83%.1H NMR(400MHz,CDCl3)δ7.38–7.36(m,5H),7.31–7.26(m,6H),7.15–7.11(m,2H),6.89(dd,J＝8.0,4.0Hz,1H),6.78–6.72(m,3H),5.45(s,1H),3.81(s,3H),2.90(s,3H),0.96(s,9H)；31P NMR(122MHz,CDCl3)δ-2.58；13C NMR(101MHz,CDCl3)δ161.34,160.28,160.09,158.80,136.20-136.05(m),134.40(dd,J＝20.2,14.1Hz),132.73,129.80,129.20,127.96(d,J＝6.0Hz),126.58,125.90,120.09,113.80,60.80,56.60,55.24(d,J＝3.0Hz),45.30,22.62.HRMS(ESI)calculated for[C30H34N2O2PS][M+H]+:517.2012；found:517.2018。
EXAMPLE 13 asymmetric lactonization of unsaturated Carboxylic acids
The chiral monophosphine ligand g-1(R, R) obtained in example 1s)：
Figure GDA0001998588640000181
The complex formed with the copper salt is used for catalyzing the reaction, and the specific operation is as follows: under argon atmosphere, chiral monophosphine ligand g-1(R, R)s) (0.05mmol) and Cu (OAc)2(0.02mmol) was added to the reaction tube which had been treated with anhydrous and oxygen-free water, and then an anhydrous 1, 2-dichloroethane solution (2mL) was added and stirred at room temperature for 15 min. Then, the unsaturated carboxylic acid and the morpholine derivative were added to the reaction system, followed by stirring at 80 ℃ for 20 hours, and the reaction was checked by TLC. After the reaction is finished, the temperature is reduced to room temperature, the filtrate is concentrated to 1mL, the yield is analyzed by column chromatography, and the enantiomeric excess value (ee) is analyzed by HPLC.
The specific catalytic reaction is shown in the following formula (13):
Figure GDA0001998588640000182
wherein ". sup." represents a chiral center.
Column chromatography analysis revealed that: yield of target product 85%: HPLC analysis gave: ee is 31%.
Of the target product1H NMR(400MHz,CDCl3):δ7.84(d,J＝7.5Hz,1H),7.61(t,J＝7.5Hz,1H),7.48(t,J＝7.5Hz,1H),7.38(d,J＝7.5Hz,1H),3.50-3.46(m,2H),3.42-3.38(m,2H),2.80(d,J＝14.3Hz,1H),2.63(d,J＝14.3Hz,1H),2.45-2.40(m,2H),2.36-2.32(m,2H),1.62(s,3H)。
Examples 14 to 26
Examination of the chiral monophosphine ligands CF-Phos and Cu (OAc) described in the present invention2The complex formed, ligand R3The effect of substituents, temperature and solvent on the lactonization reaction, the detailed procedure and the rest of the conditions are described in example 19. The reaction conditions and experimental results of the examples are shown in Table 1.
TABLE 1 reaction conditions and results of examples 14-26
Figure GDA0001998588640000183
Figure GDA0001998588640000191
The title product was obtained in 85% yield and 31% ee by way of examples 14-16, indicating that 80 ℃ was the most suitable temperature; by way of examples 14, 17-23, g-1(R, R)s) The most suitable phosphine ligand gave the desired product in 85% yield, 31% ee; by way of examples 14, 24-26, showing that 1, 2-dichloroethane is the most suitable solvent, the desired product is obtained in 85% yield, 31% ee.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.

Claims (7)

1. A chiral monophosphine ligand CF-Phos with pyridine skeleton is characterized in that the monophosphine ligand is compound 1 or enantiomer, racemate or diastereoisomer of compound 1 shown as the following formula:
Figure FDA0002944146300000011
wherein R is hydrogen; r1、R2Each is independently selected from phenyl or cyclohexyl; r3Is selected from C1～C12Alkyl, cyclohexyl or
Figure FDA0002944146300000012
Wherein R isxAnd Rx′Are respectively and independently selected from hydrogen, halogen and C1～C12Alkyl or C1～C10Alkoxy group of (a); r4Selected from hydrogen or methyl; r5Is tert-butyl; "+" represents a chiral center.
2. A process for the preparation of the chiral monophosphine ligand CF-Phos according to claim 1, characterized in that it comprises the following specific steps:
the first step is as follows: in a solvent, a compound 2 and ethylene glycol are subjected to condensation reaction under the action of a condensing agent to protect aldehyde groups, so that a compound 3 is synthesized, wherein the reaction process is shown as the following reaction formula (I):
Figure FDA0002944146300000013
the solvent is selected from dried 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;
the temperature of the condensation reaction is between room temperature and 150 ℃;
the time of the condensation reaction is 1 to 12 hours;
the molar ratio of the compound 2 to the glycol to the condensing agent is (1-100) to (1-10);
the condensing agent is selected from sulfuric acid, p-methyl benzenesulfonic acid (TsOH) or hydrochloric acid;
the second step is that: in a solvent, compound 3 is reacted with KPR1R2Substitution reaction is carried out to obtain a compound 4, and the reaction process is shown as the following reaction formula (II):
Figure FDA0002944146300000014
the solvent is selected from dried 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;
the temperature of the substitution reaction is-78-50 ℃;
the time of the substitution reaction is 10 minutes to 24 hours;
the compound 3 and KPR1R2The molar ratio of (1-10) to (1-10);
the third step: in a solvent, the compound 4 is subjected to hydrolysis reaction under the action of acid to remove a protecting group, so as to obtain a compound 5, wherein the reaction process is shown as the following reaction formula (III):
Figure FDA0002944146300000021
the solvent is selected from mixed solution of dichloromethane and water, diethyl ether and water, dibutyl ether and water, methyl tert-butyl ether and water, ethylene glycol dimethyl ether and water, 1, 4-dioxane and water, tetrahydrofuran and water, 2-methyltetrahydrofuran and water, toluene and water, xylene and water, benzene and water, chlorobenzene and water, fluorobenzene and water, chloroform and water, normal hexane and water or acetone and water;
the temperature of the hydrolysis reaction is-50 to 100 ℃;
the time of the hydrolysis reaction is 10 minutes to 24 hours;
the molar ratio of the compound 4 to the acid is (1-10) to (1-10);
the acid is selected from sulfuric acid, p-toluenesulfonic acid (TsOH) or hydrochloric acid;
the fourth step: in a solvent, under the action of a condensing agent, the compound 5 is respectively reacted with the compound 6 (R)s) Compound 6 (S)s) Condensation reaction is carried out to obtain a compound 7 (R)s) Compound 7 (S)s) The reaction process is shown in the following reaction formula (IV):
Figure FDA0002944146300000022
the solvent is selected from dried 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;
the temperature of the condensation reaction is-50 to 100 ℃;
the time of the condensation reaction is 10 minutes to 48 hours;
the compound 5 and the compound 6 (R)s) Or 6 (S)s) The molar ratio of the condensing agent to the condensing agent is (1-10) to (1-100);
the condensing agent is selected from tetraethyl titanate, tetraisopropyl titanate or tetramethyl titanate;
the fifth step: compound 7 (R)s) Compound 7 (S)s) Dissolved in a solvent and respectively reacted with a metal reagent R3MgX or R3Li is subjected to addition reaction and then reacts with R under the action of BuLi4OTf is substituted to obtain chiral monophosphine ligand CF-Phos, namely the compound 1(R, R)s) Compound 1(S, R)s) Compound 1(R, S)s) And Compound 1(S, S)s) The reaction process is shown in the following reaction formula (V):
Figure FDA0002944146300000031
the solvent is selected from dried 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;
the temperature of the addition substitution reaction is-78-30 ℃;
the time of the addition substitution reaction is 10 minutes to 48 hours;
the compound 7 (R)s) Or 7 (S)s)、R3MgX or R3Li, BuLi and R4The mol ratio of OTf is (10-1): (1-50): (1-10);
the BuLi is n-BuLi, s-BuLi or t-BuLi;
wherein R is hydrogen; r1、R2Each is independently selected from phenyl or cyclohexyl; r3Is selected from C1～C12Alkyl, cyclohexyl or
Figure FDA0002944146300000032
Wherein R isxAnd Rx′Are respectively and independently selected from hydrogen, halogen and C1～C12Alkyl or C1～C10Alkoxy group of (a); r4Selected from hydrogen or methyl; r5Is tert-butyl; x is halogen.
3. A process for the preparation of the chiral monophosphine ligand CF-Phos according to claim 1, characterized in that it comprises the following specific steps:
the first step is as follows: dissolving compound 8 in solvent, and reacting with compound 6 (R)s) Compound 6 (S)s) Condensation reaction is carried out under the action of a condensing agent to obtain a compound 9 (R)s) Compound 9 (S)s) The reaction process is shown in the following reaction formula (VI):
Figure FDA0002944146300000041
the solvent is selected from dried 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;
the temperature of the condensation reaction is-50 to 100 ℃;
the time of the condensation reaction is 10 minutes to 48 hours;
the compound 8 and the compound 6 (R)s) Or 6 (S)s) The molar ratio of the condensing agent is (1-10) to (1-100);
the condensing agent is selected from tetraethyl titanate, tetraisopropyl titanate or tetramethyl titanate;
the second step is that: in a solvent, a compound
Figure FDA0002944146300000042
With ClPR under the action of BuLi1R2Carrying out a substitution reaction to generate an intermediate compound 10, wherein the reaction process is shown as a reaction formula (VII):
Figure FDA0002944146300000043
the solvent is selected from dried 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;
the temperature of the substitution reaction is-78-30 ℃;
the time of the substitution reaction is 10 minutes to 12 hours;
said compounds
Figure FDA0002944146300000044
BuLi and ClPR1R2The molar ratio of (1-10) to (1-10);
the BuLi is n-BuLi, s-BuLi or t-BuLi;
the third step: in a solvent, the intermediate compound 10 generates an intermediate under the action of BuLi or Mg
Figure FDA0002944146300000051
Figure FDA0002944146300000052
Reacting compound 9 (R)s) Compound 9 (S)s) Dissolving in solvent, and reacting with intermediate
Figure FDA0002944146300000053
Figure FDA0002944146300000054
Performing addition reaction with R under the action of BuLi4OTf is substituted to obtain chiral monophosphine ligand CF-Phos, namely the compound 1(R, R)s) Compound 1(S, S)s) Compound 1(S, R)s) Compound 1(R, S)s) The reaction process is shown in the following reaction formula (VIII):
Figure FDA0002944146300000055
the solvent is selected from dried 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;
the temperature of the addition substitution reaction is-78-30 ℃;
the time of the addition substitution reaction is 10 minutes to 24 hours;
the above-mentioned 9 (R)s) Or 9 (S)s)、
Figure FDA0002944146300000061
BuLi and R4The mol ratio of OTf is (10-1): (1-50): (1-10);
the BuLi is n-BuLi, s-BuLi or t-BuLi;
wherein R is hydrogen; r1、R2Each is independently selected from phenyl or cyclohexyl; r3Is selected from C1～C12Alkyl, cyclohexyl or
Figure FDA0002944146300000062
Wherein R isxAnd Rx′Are respectively and independently selected from hydrogen, halogen and C1～C12Alkyl or C1～C10Alkoxy group of (a); r4Selected from hydrogen or methyl; r5Is tert-butyl; x is halogen.
4. Use of the chiral monophosphine ligand CF-Phos of claim 1 to construct a carbon chiral center in a lactonization reaction of an unsaturated carboxylic acid catalyzed by a copper salt of a transition metal.
5. The use according to claim 4, wherein the chiral monophosphine ligand CF-Phos is reacted with a copper salt of a transition metal to form a solution of a CF-PhosCuX complex, and then the solution is used to catalyze the asymmetric lactonization of an unsaturated carboxylic acid, specifically comprising:
under inert atmosphere, adding the chiral monophosphine ligand CF-Phos and a transition metal copper salt into an organic solvent, reacting for 0.1-20 hours at-10-50 ℃ to form a CF-phosCuX complex solution, adding unsaturated carboxylic acid and N-benzoyloxymorphone into a reaction system, and carrying out asymmetric lactonization reaction at-10-100 ℃; wherein:
the molar ratio of the unsaturated carboxylic acid to the N-benzoyloxymorphone to the CF-PhosCuX complex is (10-100) to 1;
the molar ratio of the chiral monophosphine ligand CF-Phos to the transition metal copper salt is (1-100) to 1.
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 4 or 5, wherein the copper salt of a transition metal is selected from Cu (OTf)2、Cu(OAc)2、CuCl2Or CuOAc.
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