CN111574450B - Novel chiral biphenyl quaternary ammonium salt phase transfer catalyst and preparation method and application thereof - Google Patents

Novel chiral biphenyl quaternary ammonium salt phase transfer catalyst and preparation method and application thereof Download PDF

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CN111574450B
CN111574450B CN202010361043.8A CN202010361043A CN111574450B CN 111574450 B CN111574450 B CN 111574450B CN 202010361043 A CN202010361043 A CN 202010361043A CN 111574450 B CN111574450 B CN 111574450B
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tert
butyl
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diaryl
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CN111574450A (en
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刘艳
柯翠连
徐伟平
徐亮
蔡祥
丸岡啓二
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Foshan Yiansai Pharmaceutical Technology Co ltd
Guangdong University of Technology
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Guangdong University of Technology
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Abstract

The invention discloses a novel chiral biphenyl quaternary ammonium salt phase transfer catalyst, and a preparation method and application thereof. The catalyst comprises a compound A and a compound B, wherein the molecular structure of the compound A is shown as a formula (I), and the molecular structure of the compound B is shown as a formula (II): wherein R is1Is methoxy or hydroxy; r2Is tert-butyl or hydrogen; r3Is 3, 5-bis (trifluoromethyl) phenyl or 3,4, 5-trifluorophenyl. The biphenyl catalyst has high optical purity, belongs to quaternary ammonium salt phase transfer catalysts, and can effectively catalyze asymmetric alkylation reactionThe catalyst-mediated asymmetric catalysis method has the advantages of mild reaction conditions, high yield, simple operation steps, safety, reliability, environmental protection, high yield of 97 percent and high selectivity of diastereoisomers and enantiomers of 93 percent.
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Description

Novel chiral biphenyl quaternary ammonium salt phase transfer catalyst and preparation method and application thereof
Technical Field
The invention belongs to the technical field of synthetic chemistry and catalytic chemistry, and particularly relates to a chiral biphenyl quaternary ammonium salt phase transfer catalyst, a preparation method thereof and application thereof in asymmetric catalytic reaction.
Background
Phase-transfer catalysis (PTC) has been applied in academic and industrial production due to its advantages of mild reaction conditions, simple operation, environmental friendliness, availability of aqueous solutions, and easy mass production. The asymmetric phase transfer catalysis provides a convenient and effective method for the construction of chiral functional molecules such as chiral drugs, natural product chiral core structures, chiral fine chemicals and the like. Therefore, attention has been paid in recent years. Chiral phase transfer catalysts play a very critical role in achieving asymmetric phase transfer catalysis. The Maruoka group developed a chiral quaternary ammonium salt type phase transfer Catalyst (Maruoka Catalyst) comprising: "Spiro-type Maruoka phase transfer Catalyst" (Spiro-type Maruoka Catalyst) based on a chiral binaphthol skeleton, "Simplified Maruoka phase transfer Catalyst" (Simplified Maruoka Catalyst) based on a chiral binaphthol skeleton, and "Modified Maruoka phase transfer Catalyst" (Modified Maruoka Catalyst) based on a chiral biphenyl skeleton. The series of phase transfer catalysts have been successfully applied to catalyzing asymmetric alkylation reactions, asymmetric Michael addition reactions, asymmetric Mannich reactions, asymmetric aldol condensation reactions, asymmetric Darcy reactions, asymmetric epoxidation reactions, asymmetric Sterlock reactions and other reaction types. The improved Maruoka phase transfer catalyst based on a biphenyl skeleton shows higher catalytic activity (0.01-1 mol% of catalyst dosage) and excellent stereoselectivity in the asymmetric alkylation reaction, and provides a using method for the synthesis of alpha-alkyl substituted-alpha-amino acid. The optically pure biphenyl skeleton is crucial to the development of chiral biphenyl phase transfer catalysts. The Maruoka group carries out chiral resolution on biphenyl derivatives (6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol) in the early period, uses (R, R) -diphenylethylenediamine as a resolving agent, and carries out chemical resolution on the biphenyl derivatives by carrying out salt forming reaction on the biphenyl derivatives with axial chirality, wherein the ee value of the resolved single biphenyl derivatives is more than 99%, however, the (R, R) -diphenylethylenediamine as the resolving agent is expensive, so that the 'improved Maruoka phase transfer catalyst' of the chiral biphenyl skeleton is limited in industrial production.
Disclosure of Invention
In order to overcome the defects and defects of the prior art, the invention provides a chemical resolution method for constructing a biphenyl skeleton based on cheap and easily-obtained (R) -methoxyphenylacetic acid as a resolving agent, and further a series of chiral biphenyl quaternary ammonium salt phase transfer catalysts are prepared. The catalyst has simple preparation process and high total yield. The catalyst has high catalytic efficiency and good selectivity. For traditional toxic transition metal catalysis, a catalytic system based on the novel catalyst is green and environment-friendly, has mild reaction conditions, and is beneficial to industrial production.
The invention also aims to provide a preparation method of the chiral biphenyl quaternary ammonium salt phase transfer catalyst. The method has the advantages of mild reaction conditions, simplicity in operation, environmental friendliness and the like, and can efficiently synthesize the chiral biphenyl skeleton-containing quaternary ammonium salt catalyst.
The invention further aims to provide the catalytic application of the asymmetric reaction of the chiral biphenyl quaternary ammonium salt phase transfer catalyst.
The above purpose is realized by the following technical scheme:
a chiral biphenyl quaternary ammonium salt phase transfer catalyst comprises a compound A and a compound B, wherein the molecular structure of the compound A is shown as a formula (I), and the molecular structure of the compound B is shown as a formula (II):
Figure BDA0002474022800000021
wherein R is1Are methoxy and hydroxy; r2Is tert-butyl and hydrogen; r3Are 3, 5-bis (trifluoromethyl) phenyl and 3,4, 5-trifluorophenyl.
Preferably, the molecular structure of the catalyst is one of the following structural formulas:
Figure BDA0002474022800000031
preferably, the method comprises the following steps:
s1, dissolving 5-methyl-2-tert-butyl phenol and tetrabutylammonium tribromide in a mixed solvent of dichloromethane and methanol, and reacting at normal temperature for 1 hour to obtain 4-bromo-2-tert-butyl-5-methylphenol.
S2, dissolving 4-bromo-2-tert-butyl-5-methylphenol and tetramethylethylenediamine in dichloromethane, and reacting for 6 hours at normal temperature by using cuprous chloride as a catalyst to obtain 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol.
S3, dissolving 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol and sodium hydride in anhydrous tetrahydrofuran, deprotonating for 3 hours, dropwise adding the prepared (R) -2-methoxybenzene acetyl chloride into the system, and continuing to react for 1 hour to obtain a mono-esterification product and a di-esterification product.
S4, dissolving the mono-esterification product and the di-esterification product in anhydrous tetrahydrofuran, and reacting for 1 hour by using lithium aluminum hydride as a reducing agent to obtain chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol.
S5, dissolving chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -dibromo-2, 2' -biphenol in a toluene solution, and using trifluoromethanesulfonic acid as an oxidant to obtain the chiral 6,6' -dimethyl-5, 5' -dibromo-2, 2' -biphenol.
S6, dissolving the product obtained in the S4 or S5, tetrakis (triphenylphosphine) palladium, sodium carbonate and phenylboronic acid compounds in a mixed system of ethylene glycol dimethyl ether (DME) and water, and reacting overnight at the temperature of 95 ℃ under argon to obtain chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -biphenol or chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -biphenol.
S7, dissolving chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-diaryl-2, 2' -biphenol or chiral 6,6 '-dimethyl-5, 5' -diaryl-2, 2 '-biphenol, methyl iodide and potassium carbonate in acetone, and reacting overnight under the reflux condition to obtain chiral 6,6' -dimethyl-3, 3 '-di-tert-butyl-5, 5' -diaryl-2, 2 '-dimethoxybiphenyl or chiral 6,6' -dimethyl-5, 5 '-diaryl-2, 2' -dimethoxybiphenyl.
S8, dissolving chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-diaryl-2, 2' -dimethoxybiphenyl or chiral 6,6 '-dimethyl-5, 5' -diaryl-2, 2 '-dimethoxybiphenyl, azobisisobutyronitrile and N-bromosuccinimide in benzene, and reacting for 4 hours under the reflux condition to obtain chiral 3,3' -di-tert-butyl-5, 5 '-diaryl-6, 6' -dibromomethyl-2, 2 '-dimethoxybiphenyl or 5,5' -diaryl-6, 6 '-dibromomethyl-2, 2' -dimethoxybiphenyl.
S9, dissolving chiral 3,3' -di-tert-butyl-5, 5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl or 5,5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl, potassium carbonate and n-dibutylamine in acetonitrile, and reacting at 85 ℃ overnight to obtain a chiral catalyst compound A and a chiral catalyst compound B, wherein R is1Is a methoxy group; r2Is tert-butyl and hydrogen; r3Are 3, 5-bis (trifluoromethyl) phenyl and 3,4, 5-trifluorophenyl.
S10, dissolving the chiral methoxy catalyst in anhydrous dichloromethane, dropwise adding 1M boron tribromide at-78 ℃, and reacting at room temperature for 4 hours to obtain the chiral hydroxy catalyst, wherein R1Is a hydroxyl group; r2Is tert-butyl and hydrogen; r3Are 3, 5-bis (trifluoromethyl) phenyl and 3,4, 5-trifluorophenyl, as exemplified by the examples of this invention, the above scheme being the last step in FIGS. 2 and 3, namely: (S) -15 from (S) -13, (S) -16 from (S) -14, (R) -25 from (R) -23, and (R) -26 from (R) -24.
Preferably, the mono-esterification product and the di-esterification product obtained in step S3 are subjected to primary separation by silica gel column chromatography, and then are recrystallized to obtain the stereoselectivity of more than 99%, namely ee of more than 99%.
Preferably, the (R) -2-methoxybenzene acetyl chloride prepared in step S3 is prepared by dissolving (R) -2-methoxybenzene acetic acid and 2M oxalyl chloride in anhydrous dichloromethane, and reacting for 6 hours at 0 ℃ to room temperature under the catalysis of N, N-dimethylformamide and under the protection of argon.
Preferably, the phenylboronic acid-based compounds used in step S6 are 3, 5-bis (trifluoromethyl) phenylboronic acid and 3,4, 5-trifluorophenylboronic acid, respectively.
Preferably, the mass ratio of the 5-methyl-2-tert-butylphenol, the tetrabutylammonium tribromide, the dichloromethane and the methanol in the step S1 is 1:3:11: 4.4.
Preferably, the mass ratio of the 4-bromo-2-tert-butyl-5-methylphenol, the tetramethylethylenediamine, the cuprous chloride and the dichloromethane in the step S2 is 121.5:8.5:5: 1.3.
Preferably, the mass ratio of the 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol, the sodium hydride, the (R) -2-methoxybenzeneacetyl chloride and the anhydrous tetrahydrofuran in the step S3 is 20:5:3: 40.
Preferably, the mass ratio of the mono-esterification product, the lithium aluminum hydride and the anhydrous tetrahydrofuran in the step S4 is 0.6:2.1: 2; the mass ratio of the double esterification product to the lithium aluminum hydride to the anhydrous tetrahydrofuran is 1:4: 2.3.
Preferably, the mass ratio of the chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol, the trifluoromethanesulfonic acid and the toluene solution in step S5 is 1.4:1: 12.9.
Preferably, the mass ratio of the product obtained in S4 and S5 in the step S6, the tetrakis (triphenylphosphine) palladium, the sodium carbonate, the phenylboronic acid compound, the ethylene glycol dimethyl ether (DME) and the water is (3.1-4.1): 1:3.5 (3.7-5.2): 28.9: 16.7.
Preferably, the chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -biphenol and the chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -biphenol according to step S7 are present in a mass ratio of 1.6:1.2:1.3: 1; the mass ratio of methyl iodide to potassium carbonate to acetone is 1:2.1: 5.2.
Preferably, the chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -dimethoxybiphenyl and the chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -dimethoxybiphenyl are mixed in step S8 at a mass ratio of 1.5:1.2:1.3: 1; the mass ratio of the azodiisobutyronitrile to the N-bromosuccinimide to the benzene is 22:1: 460.
Preferably, the chiral 3,3' -di-tert-butyl-5, 5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl and the chiral 5,5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl are mixed in step S9 at a mass ratio of 1.4:1.2:1.2: 1; the mass ratio of the potassium carbonate to the n-dibutylamine to the acetonitrile is 16:1: 78.
Preferably, the mass ratio of the chiral methoxy-based catalyst in the step S10 is 1.4:1.1:1.2: 1; the mass ratio of boron tribromide to anhydrous dichloromethane is 22: 13.
Compared with the prior art, the invention has the following beneficial effects:
1. the chiral biphenyl quaternary ammonium salt phase transfer catalyst has high optical purity, can effectively catalyze a plurality of asymmetric reactions such as alkylation and the like, and has the yield of 97 percent and the enantiomer selectivity of 93 percent.
2. The structure-activity relationship research of the chiral biphenyl quaternary ammonium salt phase transfer catalyst disclosed by the invention discovers that: (1) after methylation is carried out on the hydroxyl at the 2-position and the 2' -position, the yield is not changed greatly, and the ee value is slightly improved; (2) the substituents at the 3-position and the 3' -position have a large influence on the reactivity and the selectivity. When the 3-position and the 3' -position are H and a small steric hindrance substituent methoxyl group, the catalytic activity and the selectivity are high, the yield is 95-97%, and the ee value is 91-98%. When the substituent was a 3,4, 5-trifluorophenyl substituent, the yield was 94%, the ee value was 86%, and the reactivity and the selectivity were decreased. When tertiary butyl large steric hindrance groups are introduced into the 3-position and the 3' -position, the reaction activity and the selectivity of the catalyst are greatly reduced. (3) The substituents at the 5-position and the 5' -position play a very crucial role in influencing the reactivity and selectivity of the Maruoka phase transfer catalyst. The substituent at the position assists the catalyst matrix framework to construct a chiral catalytic cavity on one hand, and plays an important role in the electron distribution of the matrix framework on the other hand.
3. The method takes (R) -methoxyphenylacetic acid as a resolving agent, has low price and easily obtained raw materials. The synthetic reaction has the advantages of simple operation steps, high yield, safety, reliability, greenness and environmental protection, and is suitable for synthesizing various catalysts with different substituent groups. The catalyst is expected to develop more novel asymmetric catalytic reactions and has more chiral catalytic potentials.
4. The development of the chiral biphenyl quaternary ammonium salt phase transfer catalyst and the asymmetric catalytic reaction system provides an effective method for synthesizing chiral functional molecules such as chiral drugs and drug intermediates, preparing chiral fine chemicals, chiral materials and the like, and synthesizing a core structure of a chiral natural product.
Description of the drawings:
FIG. 1 is a construction flow chart of axial chirality of (R)/(S) -3 and (R)/(S) -6 biphenyl compounds.
FIG. 2 is a synthesis scheme of (S) -13, (S) -14, (S) -15, and (S) -16 catalysts.
FIG. 3 is a synthesis scheme of (R) -23, (R) -24, (R) -25, and (R) -26 catalysts.
Detailed Description
The following description and specific examples, taken in conjunction with the accompanying drawings, further illustrate the present invention and should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
EXAMPLE 15 preparation of methyl-2-tert-butyl-4-bromophenol (2)
To a mixed solution (100mL, volume ratio 2:3) of 5-methyl-2-tert-butylphenol (13.6mL,80.0mmol) in methanol and dichloromethane was added dropwise a mixed solution (80mL, volume ratio 2:3) of tetrabutylammonium tribromide (38.6g,80.0 mmol) in methanol and dichloromethane at room temperature, after vigorously stirring for 1h, water was added for quenching, extraction was carried out three times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1: 40-1: 10) to obtain 19.2g of a target compound of yellow oily liquid with the yield of 99%.
And (3) testing the structure:1H NMR(400MHz,CDCl3)δ:7.38(s,1H),6.56(s,1H),4.82(s, 1H),2.30(s,3H),1.39(s,9H)；13C NMR(100MHz,CDCl3)δ:153.4,136.3,136.0, 130.9,119.0,115.5,34.5,29.6,22.2.
EXAMPLE 26 preparation of 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol (3)
After compound 2(243.1mg,1.0mmol), cuprous chloride (9.90mg,0.1mmol) and tetramethylethylenediamine (22 μ L,0.15mmol) were vigorously stirred in dichloromethane (2mL) at room temperature for reaction overnight, water was added to quench, the system was extracted three times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent n-hexane) to give 123.5mg of the target product as a white solid in 51% yield.
And (3) testing the structure:1H NMR(400MHz,CDCl3)δ:7.55(s,2H),4.88(s,2H),2.00(s,6H), 1.40(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8,135.5,132.0,121.8, 116.4,35.0,29.4,19.9.
EXAMPLE 3 preparation of the Mono-and di-esterification products (R, R, R) -4 and (R, R) -5
(R) -2-methoxy-2-phenylacetyl chloride: in a two-necked flask (250mL), compound (R) -2-methoxy-2-phenylacetic acid (7.98g,48mmol) was added, purged with argon three times. At 0 deg.C, anhydrous dichloromethane (70mL) was added, and 2M oxalyl chloride (24mL,48mmol) and anhydrous N, N-dimethylformamide (800. mu.L) were slowly added dropwise, after 15 minutes of reaction, the reaction was continued at room temperature for 6 h. Concentrating, and draining for 15 minutes to obtain (R) -2-methoxy-2-phenylacetyl chloride.
To a mixture of sodium hydride (1.44g,36mmol) and dry tetrahydrofuran (80 mL) at 0 ℃ under an argon atmosphere, a solution of compound 3(5.81g,12mmol) in dry tetrahydrofuran (50mL) was slowly added dropwise, and after the addition was complete, the reaction mixture was stirred at room temperature for further reaction for 3 hours. (R) -2-methoxy-2-phenylacetyl chloride (8.86g,48mmol), which is prepared in the prior art, is dropwise added into the reaction system, the reaction system is stirred vigorously for 1h, the reaction system is slowly poured into ice water, dichloromethane is extracted for three times, and the combined organic phase is dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. And separating and purifying the obtained crude product by silica gel column chromatography (ethyl acetate/dichloromethane/n-hexane, 1:1: 90-1: 1:50) to obtain white solid target substances (R, S) -4 and (R, R, R) -5.
(R, S) -4: white solid Compound, 3.72g, yield 49%, after recrystallization (dichloromethane/n-hexane, 1:2), ee>99％.1H NMR(400MHz,CDCl3)δ:7.60(s,1H),7.41(s,1H),7.33～7.35(m, 3H),7.25～7.23(m,1H),5.05(s,1H),4.17(s,1H),3.02(s,3H),2.01(s,3H),1.94(s, 3H),1.35(s,9H),0.97(s,9H)；13C NMR(100MHz,CDCl3)δ:169.6,151.7,147.7, 142.2,138.0,137.1,134.7,134.0,131.9,131.5,130.7,129.2,128.8,127.8,126.6, 123.4,116.2,82.9,57.6,34.9,34.4,29.6,29.4,20.0,19.8.
(R, R, R) -5: white solid compound, 2.99g, yield 30%. After recrystallization (dichloromethane/n-hexane, 1:3), ee>99％.1H NMR(400MHz,CDCl3)δ:7.60(s,2H),7.44～7.34(m, 10H),3.98(s,2H),2.99(s,6H),2.14(s,6H),0.94(s,18H)；13C NMR(100MHz, CDCl3)δ:168.0,146.9,141.6,138.0,135.0,132.3,131.3,129.1,128.6,127.8,123.6, 82.2,58.0,34.2,29.9,20.4。
EXAMPLE 4 preparation of chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol (S) -3, (R) -3
(S) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol (S) -3: to a solution of (R, S) -4(556.5mg,0.88mmol) in anhydrous tetrahydrofuran (1.8mL) at 0 ℃ under argon protection, 1M lithium aluminum hydride (1.8mL, 1.76mmol) was slowly added dropwise, the reaction was reacted for 1h, the reaction was slowly poured into a mixture of ice and water, dichloromethane was extracted three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was separated and purified by silica gel column chromatography (n-hexane) to obtain 409.3mg of the target (S) -3 as a white solid with a yield of 96%.1H NMR(400MHz,CDCl3)δ:7.54(s,2H),4.87(s,2H), 1.99(s,6H),1.39(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8,135.5, 132.0,121.7,116.4,35.0,29.4,19.9.
(R) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol (R) -3 Synthesis procedure same as (S) -3, white solid, 669.3mg, 96% yield.1H NMR(400MHz,CDCl3)δ:7.54(s,2H), 4.87(s,2H),1.99(s,6H),1.39(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8, 135.5,132.0,121.7,116.4,35.0,29.4,19.9.
EXAMPLE 5 preparation of chiral 6,6' -dimethyl-5, 5' -dibromo-2, 2' -biphenol (S) -6, (R) -6
(S) -6,6' -dimethyl-5, 5' -dibromo-2, 2' -biphenol (S) -6 to a solution of (S) -3(377.7mg,0.78mmol) in toluene (4mL) was slowly added dropwise trifluoromethanesulfonic acid (158.0. mu.L, 1.79mmol) at 0 ℃ under argon protection, stirring was continued for 15min, the reaction was poured into an ice-water mixture, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:10) to give 272.8mg of a white solid as the target (S) -6 in 94% yield and ee>99％。1H NMR(400MHz,CDCl3)δ:7.54(d,J＝8.4Hz,2H),6.81 (d,J＝8.8Hz,2H),4.76(s,2H),2.07(s,6H)；13C NMR(100MHz,CDCl3)δ:153.1, 138.3,134.3,121.7,116.6,115.3,20.3；HPLC：Diacel Chiralpak AD-H(5μm,4.6 mm×250mm),hexane/EtOH＝20/1(V/V),flow rate＝1.0mL/min,λ＝290nm, retention time:25.1min((S)-enantiomer)and 55.5min((R)-enantiomer).
(R) -6,6' -dimethyl-5, 5' -dibromo-2, 2' -biphenol (R) -6 Synthesis procedure same as (S) -6, white solid, 349.7mg, yield 94%, ee>99％。1H NMR(400MHz,CDCl3)δ:7.54(d,J＝8.4Hz, 2H),6.81(d,J＝8.8Hz,2H),4.76(s,2H),2.07(s,6H).13C NMR(100MHz,CDCl3) δ:153.1,138.3,134.3,121.7,116.6,115.3,20.3；HPLC：Diacel Chiralpak AD-H(5 μm,4.6mm×250mm),hexane/EtOH＝20/1(V/V),flow rate＝1.0mL/min,λ＝290 nm,retention time:24.6min((S)-enantiomer)and 54.6min((R)-enantiomer).
EXAMPLE 6 preparation of chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -biphenol (S) -7, (S) -8 and chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -biphenol (R) -17, (R) -18
(S) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5'- (3, 5-bis (trifluoromethyl) phenyl) -2,2' -biphenol (S) -7: a mixed solution of (S) -3(368.0mg,0.76mmol), 3, 5-bis (trifluoromethyl) phenylboronic acid (469.4mg,1.82mmol), palladium tetrakistriphenylphosphine (87.8mg,0.076mmol) and sodium carbonate (322.2mg, 3.04mmol) in ethylene glycol dimethyl ether (3mL) and water (1.5mL) was reacted at 90 ℃ overnight under argon. After cooling the system to room temperature, saturated ammonium chloride solution (10mL) was slowly added, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was separated and purified by silica gel column chromatography (using n-hexane as eluent) to obtain 553.1mg of the target (S) -7 as a white solid with a yield of 97%.1H NMR(500MHz,CDCl3)δ:7.87(s,2H),7.80(s,4H),7.24(s,2H),5.19 (s,2H),1.86(s,6H),1.45(s,18H).13C NMR(125MHz,CDCl3)δ:152.8,144.3, 135.2,133.4,132.2,131.7(q,J C-F＝33Hz),129.86～129.84(m),129.7,123.5(q,J C-F＝271.1Hz),121.2,120.8～120.7(m),35.0,29.5,17.3。
(S) -6,6' -dimethyl-5, 5' -bis (3, 5-bis (trifluoromethyl) phenyl) -2,2' -biphenol (S) -8: the synthesis procedure was the same as (S) -7, white solid, 632.0mg, yield 94%.1H NMR(400MHz,CDCl3)δ:7.88 (s,2H),7.81(s,4H),7.28(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),5.17(s,2H), 1.97(s,6H).13C NMR(100MHz,CDCl3)δ:154.1,143.7,136.3,133.0,132.2,131.8 (q,JC-F＝33.1Hz),129.84～129.82(m),123.5(q,JC-F＝271.1Hz),121.0, 121.96～120.90(m),114.1,17.7.
(R) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-bis (3,4, 5-trifluorophenyl) -2,2' -biphenol (R) -17: the synthetic procedure was the same as for (S) -7, white solid, 232.7mg, 93% yield.1H NMR(400MHz,CDCl3) δ:7.20(s,2H),6.96(dd,J＝8.4,6.4Hz,4H),5.12(s,2H),1.86(s,6H),1.44(s,18H)；13C NMR(100MHz,CDCl3)δ:152.4,150.96(ddd,JC-F＝250,10,4Hz),138.9(dt, JC-F＝250,15Hz),138.2～138.4(m),134.8,133.2,132.3,129.4,121.1,113.9(dd, JC-F＝15.2,5.6Hz),34.9,29.6,17.2.
(R) -6,6' -dimethyl-5, 5' -bis (3,4, 5-trifluorophenyl) -2,2' -biphenol (R) -18: the synthetic procedure was the same as for (S) -7, white solid, 331.0mg, yield 95%.1H NMR(400MHz,Acetone)δ:7.86(s,2H), 7.12～7.16(m,6H),6.91(d,J＝8.4Hz,2H),1.96(s,6H).13C NMR(100MHz, Acetone)δ:155.8,151.4(ddd,JC-F＝246,10,4Hz),140.1～140.3(m),139.1(dt,JC-F＝247,15Hz),136.5,132.0,130.8,125.2,114.7(dd,JC-F＝15.3,5.4Hz),114.1,17.9.
EXAMPLE 7 preparation of chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -dimethoxybiphenyl (S) -9, (S) -10 and chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -dimethoxybiphenyl (R) -19, (R) -20
(S) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5'- (3, 5-bis (trifluoromethyl) phenyl) -2,2' -dimethoxybiphenyl (S) -9: methyl iodide (846. mu.L, 13.6mmol) was slowly added dropwise to a mixture (6.0mL) of compound (S) -7(510.4mg,0.68mmol) and potassium carbonate (939.7mg,6.8mmol) in acetone, the reaction was refluxed overnight, the reaction was cooled to room temperature, water was added to terminate the reaction, extraction was carried out three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfateThe crude product was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:100) to give 524.2mg of the target (S) -9 as a white solid with a yield of 99%.1H NMR(400MHz, CDCl3)δ:7.87(s,2H),7.79(s,4H),7.20(s,2H),3.31(s,6H),1.94(s,9H),1.43(s, 18H)；13C NMR(100MHz,CDCl3)δ:157.9,145.0,141.3,134.6,133.7,132.9,131.6 (q,J C-F＝33.1Hz),129.8～129.7(m),128.0,123.6(q,J C-F＝271.1Hz),120.8～120.7 (m),59.6,35.1,30.8,18.1.
(S) -6,6' -dimethyl-5, 5' -bis (3, 5-bis (trifluoromethyl) phenyl) -2,2' -dimethoxybiphenyl (S) -10: the synthesis steps are the same as those of (S) -9, wherein 528.2mg of white solid is obtained, and the yield is 99% m.p.39-41 ℃; [ alpha ] to]25D＝+2.8 (c＝0.54,CHCl3)；1H NMR(400MHz,CDCl3)δ:7.76(s,2H),7.74(s,4H),7.16(d, J＝8.4Hz,2H),6.87(d,J＝8.8Hz,2H),3.71(s,6H),1.79(s,6H).13C NMR(100 MHz,CDCl3)δ:157.2,144.5,135.5,132.25,131.5(q,J C-F＝33.1Hz),130.1, 129.96～129.93(m),127.2,123.6(q,JC-F＝216.9Hz),120.6～120.4(m),108.8,56.08, 17.6.
(R) -6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-bis (3,4, 5-trifluorophenyl) -2,2' -dimethoxybiphenyl (R) -19: the synthetic procedure was the same as (S) -9, white solid, 229.4mg, 99% yield.1H NMR(400MHz, CDCl3)δ:7.08(s,2H),6.86(dd,J＝8,6.8Hz,4H),3.17(s,6H),1.85(s,6H),1.31(s, 18H)；13C NMR(100MHz,CDCl3)δ:157.6,151.0(ddd,JC-F＝250,10,4Hz),141.0 (s),138.8～139.0(m),138.9(dt,JC-F＝249,15Hz),134.7,133.7,132.8,127.8,113.8 (dd,JC-F＝15.2,5.5Hz),59.4,35.0,30.8,18.1.
(R) -6,6' -dimethyl-5, 5' -bis (3,4, 5-trifluorophenyl) -2,2' -dimethoxybiphenyl (R) -20: the synthetic procedure was the same as (S) -9, white solid, 386.9mg, 99% yield.1H NMR(400MHz,CDCl3)δ:7.18 (d,J＝8.4Hz,2H),6.96(t,J＝7.4Hz,4H),6.89(d,J＝8.4Hz,2H),3.76(s,6H), 1.83(s,6H).13C NMR(100MHz,CDCl3)δ:156.9,150.86(ddd,JC-F＝250,10,4Hz), 138.6(dt,JC-F＝249,15Hz),138.4～138.6(m),135.4,132.4,129.7,127.0,113.9(dd, JC-F＝15.3,5.5Hz),108.5,55.9,17.6.
EXAMPLE 8 preparation of chiral 3,3' -di-tert-butyl-5, 5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl (S) -11, (S) -12 and chiral 5,5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl (R) -21, (R) -22
(S) -3,3 '-di-tert-butyl-5, 5' - (3, 5-bis (trifluoromethyl) phenyl) -6,6 '-dibromomethyl-2, 2' -dimethoxybiphenyl (S) -11: to a mixed solution of compound (S) -9(420.5mg,0.54mmol) and N-bromosuccinimide (673.0mg, 3.78mmol) in benzene (5mL) was added azobisisobutyronitrile (26.6mg,30 mol%), and reacted under reflux for 4 h. The reaction system was cooled to room temperature, diluted with ether, filtered, and the filtrate was concentrated to give a crude product which was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:100) to give 476.9mg of a yellow solid target with a yield of 94%.1H NMR(400MHz,CDCl3)δ:7.85(s,2H),7.83(s, 2H),7.20(s,2H),4.14(d,J＝10.8Hz,2H),4.00(d,J＝10.4Hz,2H),3.38(s,6H), 1.34(s,18H)；13C NMR(100MHz,CDCl3)δ:157.0,144.9,143.2,136.4,133.5, 131.7(q,JC-F＝33.4Hz),130.8,130.2,129.81～129.78(m),123.5(q,JC-F＝271.1Hz), 121.6～121.5(m),60.0,35.5,30.6,30.1.
(S) -5,5' -bis (3, 5-bis (trifluoromethyl) phenyl) -6,6' -dibromomethyl-2, 2' -dimethoxybiphenyl (S) -12: the synthetic procedure was the same as (S) -11, yellow solid, 595.5mg, 96% yield.1H NMR(400MHz,CDCl3) δ:7.94(s,2H),7.83(s,2H),7.24(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),3.94(q, J＝10.4Hz,2H),3.72(s,6H)；13C NMR(100MHz,CDCl3)δ:157.5,142.6,134.7, 133.0,131.7,131.6(q,J C-F＝33.2Hz),129.92～129.90(m),125.8,123.5(q,J C-F＝ 271.2.Hz),121.47～121.4(m),111.5,56.0,30.0.
(R) -3,3 '-di-tert-butyl-5, 5' -bis (3,4, 5-trifluorophenyl) -6,6 '-dibromomethyl-2, 2' -biphenol phenol (R) -21: the synthetic procedure was the same as (S) -11, yellow solid, 224.3mg, 78% yield.1H NMR(400MHz, CDCl3)δ:7.24(s,2H),7.09(dd,J＝8.0,6.4Hz,4H),4.26(d,J＝10.8Hz,2H),4.17 (d,J＝10.4Hz,2H),3.42(s,6H),1.42(s,18H)；13C NMR(100MHz,CDCl3)δ: 156.6,151.0(ddd,JC-F＝249,10,4Hz),144.5,139.4(dt,JC-F＝250,15Hz), 136.9～137.1(m),136.4,133.3,130.7,130.0,113.8(dd,JC-F＝15.4,5.7Hz),59.8, 35.4,30.6,30.3.
(R) -5,5' -bis (3,4, 5-trifluorophenyl) -6,6' -dibromomethyl-2, 2' -biphenol phenol (R) -22: the synthetic procedure was the same as (S) -11, yellow solid, 194.9mg, 96% yield.1H NMR(400MHz,CDCl3)δ:7.17 (d,J＝8.4Hz,2H),7.16(dd,J＝8.4,6.8Hz,4H),7.04(d,J＝8.4Hz,2H),4.08(s, 4H),3.78(s,6H).13C NMR(100MHz,CDCl3)δ:157.16(s),150.8(ddd,JC-F＝249, 10,4Hz),139.3(dt,JC-F＝250,15Hz),136.6～136.4(m),134.5,133.0,131.5,125.7, 114.0(dd,JC-F＝15.4,5.6Hz),111.3,55.9,30.2.
Example 9 preparation of chiral methoxy-based catalyst (S) -13, (S) -14, (R) -23, and (R) -24 catalyst (S) -13: according to the literature method, to a solution of optically pure catalyst intermediate (S) -11(355.9mg, 0.38mmol) in acetonitrile (4.0mL) at room temperature, n-dibutylamine (57.6. mu.L, 0.342mmol) and potassium carbonate (655mg,3.8mmol) were added and reacted at 85 ℃ overnight. After the reaction was completed, the reaction system was cooled to room temperature, diluted with dichloromethane, and filtered through celite. And (3) separating and purifying a crude product obtained after the filtrate is concentrated by silica gel column chromatography (methanol/dichloromethane, 1: 80-1: 20) to obtain 245.4mg of a yellow solid chiral quaternary ammonium salt target compound with the yield of 66%.1H NMR(400MHz,Acetone)δ:8.48(br s,4H),8.12(s,2H),7.51(s,2H),4.61 (d,J＝14Hz,2H),4.42(d,J＝14Hz,2H),3.36(s,6H),3.28～3.22(m,2H),2.82(td, J＝13.2,4.0Hz,2H),1.50(s,18H),1.30～1.34(m,2H),1.08～1.17(m,2H), 0.84～0.89(m,2H),0.61(t,J＝7.2Hz,6H),0.57～0.51(m,2H).13C NMR(100MHz, Acetone)δ:160.0,146.1,143.9,136.4,132.2,131.2,125.5,124.41(q,J C-F＝270.9 Hz),122.6～122.3(m),61.8,59.2,58.2,36.1,30.6,24.9,19.7,13.9.
Catalyst (S) -14: synthesis procedureThe same as catalyst (S) -13, chiral quaternary ammonium salt as a yellow solid, 488.1mg, yield 82%.1H NMR(400MHz,CDCl3)δ:7.95(s,6H),7.48(d,J＝8.8Hz,2H),7.32 (d,J＝8.8Hz,2H),4.54(d,J＝14Hz,2H),3.94(s,6H),3.90(d,J＝14Hz,2H), 3.14(t,J＝12.8Hz,2H),2.68(td,J＝12.8,4.0Hz,2H),1.04～1.02(m,4H), 0.82～0.76(m,2H),0.58(t,J＝7.2Hz,6H),0.22～0.16(m,2H)；13C NMR(100MHz, CDCl3)δ:157.4,141.4,133.0,132.4,130.0～129.8(m),126.6,124.8,122.7(q,J C-F＝ 271.4Hz),121.5～121.4(m),113.8,57.3,57.2,56.1,24.2,18.9,13.1.
Catalyst (R) -23: the synthesis procedure was identical to catalyst (S) -13, chiral quaternary ammonium salt as yellow solid, 189.2mg, 80% yield.1H NMR(400MHz,Acetone)δ:7.66(br s,4H),7.46(s,2H),4.81(d,J＝ 14Hz,2H),4.04(d,J＝14Hz,2H),3.27(s,6H),3.23～3.17(m,2H),2.91～2.84(m, 2H),1.47(s,18H),1.30～1.33(m,2H),1.20～1.10(m,2H),0.95～1.04(m,2H),0.71(t, J＝7.2Hz,6H),0.42～0.53(m,2H)；13C NMR(100MHz,Acetone)δ:159.4, 153.3～152.3(m),150.6～150.0(m),145.9,140.1(dt,JC-F＝249,15Hz),137.5～137.3 (m),136.5,132.0,130.5,125.3,117.0～115.1(m),61.4,58.4,57.9,35.9,30.4,25.1, 19.9,13.6.
Catalyst (R) -24: the synthesis procedure was identical to catalyst (S) -13, yellow solid chiral quaternary ammonium salt, 337.2mg, 81% yield.1H NMR(400MHz,CDCl3)δ:7.41(d,J＝8.8Hz,2H),7.24(d,J＝8.8 Hz,2H),7.17(br s,4H),4.74(d,J＝14Hz,2H),3.89(s,6H),3.64(d,J＝14Hz,2H), 3.18(t,J＝12.8Hz,2H),2.72～2.67(m,2H),1.10～1.09(m,4H),0.99～0.95(m,2H), 0.72(t,J＝6.8Hz,6H),0.29～0.26(m,2H)；13C NMR(100MHz,CDCl3)δ:156.9, 152.2～152.0(m),149.8～149.5(m),139.3(dt,JC-F＝252,15Hz),135.0～134.8(m), 132.5,132.0,126.4,125.1,115.0～113.9(m),113.3,57.2,56.9,55.9,24.3,19.1,13.0.
EXAMPLE 10 preparation of chiral hydroxy catalysts (S) -15, (S) -16, (R) -25, and (R) -26
Catalyst (S) -15: to catalyst (S) -13(118.2mg, 0) was added under argon at-78 ℃.12mmol) was added dropwise to a solution of 1M boron tribromide (0.84mL,0.84 mmol) in anhydrous dichloromethane (1.0mL), and the reaction system was warmed to room temperature and then reacted at room temperature for 4 hours. The reaction was poured into ice water, extracted three times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product is separated and purified by silica gel column chromatography (methanol/dichloromethane, 1: 40-1: 5) to obtain 97.5mg of white solid chiral quaternary ammonium salt with the yield of 81%.1H NMR(400MHz,Acetone-d6)δ:8.35(s,2H),8.22(s, 2H),8.07(s,2H),7.36(s,2H),4.54(d,J＝13.6Hz,2H),3.67(d,J＝13.2Hz,2H), 3.05～2.98(m,2H),2.82(td,J＝13.2,4.4Hz,2H),1.53(s,18H),1.25～1.19(m,2H), 1.11～1.02(m,2H),0.93～0.86(m,2H),0.61(t,J＝7.2Hz,6H),0.47～0.35(m,2H). 13C NMR(100MHz,Acetone-d6)δ:159.8,145.3,142.8,131.9～131.7(m),131.5, 131.3～131.1(m),130.3,129.7,124.43,124.40(q,J C-F＝270.6Hz),121.5～121.3(m), 58.6,57.4,35.9,30.0,24.96,19.7,13.7.
Catalyst (S) -16: the synthesis procedure was the same as for catalyst (S) -15, yellow solid chiral quaternary ammonium salt, 72mg, 85% yield.1H NMR(400MHz,MeOD-d4)δ:8.09(s,6H),7.44(d,J＝8.4Hz,2H), 7.29(d,J＝8.8Hz,2H),4.42(d,J＝14Hz,2H),3.73(d,J＝13.6Hz,2H),2.92～2.86 (m,2H),2.62(td,J＝12.8,4.4Hz,2H),1.11～0.92(m,4H),0.85～0.72(m,2H),0.60 (t,J＝7.2Hz,6H),0.24～0.11(m,2H)；13C NMR(100MHz,MeOD-d4)δ:157.0, 143.8,133.9,133.4,131.7,126.7,126.5,124.6(q,J C-F＝270.6Hz),122.7～122.5(m), 119.8,58.2,58.0,25.4,20.1,13.8.
Catalyst (R) -25: the synthesis procedure was the same as for catalyst (S) -15, yellow solid chiral quaternary ammonium salt, 45.1mg, 57% yield.1H NMR(400MHz,Acetone-d6)δ:7.53(br s,2H),7.32(br s,2H),7.25 (s,2H),4.63(d,J＝13.2Hz,2H),3.42(d,J＝13.2Hz,2H),3.02(t,J＝12.4Hz,2H), 2.87(td,J＝12.8,4.4Hz,2H),1.50(s,18H),1.22～1.06(m,6H),0.73(t,J＝7.2Hz, 6H),0.45～0.37(m,2H).13C NMR(100MHz,Acetone-d6)δ:159.9,152.5～151.5(m), 150.0～149.0(m),141.3,138.8～138.6(m),138.6(dt,JC-F＝247.6,15Hz),130.5, 128.7,128.0,123.3,115.2～14.3(m),35.0,29.1,24.3,19.1,12.7.
Catalyst (R) -26: the synthesis procedure was the same as for catalyst (S) -15, yellow solid chiral quaternary ammonium salt, 34.0mg, 50% yield.1H NMR(400MHz,MeOD-d4)δ:7.38(d,J＝8.8Hz,4H),7.22(d,J＝8.8 Hz,4H),4.56(d,J＝13.6Hz,2H),3.54(d,J＝13.6Hz,2H),2.92(t,J＝12.8Hz, 2H),2.67(td,J＝12.8,4.4Hz,2H),1.15～1.03(m,4H),1.01～0.90(m,2H),0.75(t,J ＝7.2Hz,6H),0.25～0.19(m,2H)；13C NMR(100MHz,MeOD-d4)δ:156.6, 153.9～153.4(m),151.4～150.9(m),140.6(dt,JC-F＝250,15Hz),137.8～137.6(m), 133.6,133.2,126.8,126.4,119.5,116.1～115.7(m),57.95,57.9,25.5,20.3,13.6.
Application example
The catalysts prepared in examples 9 and 10 were used in the asymmetric alkylation starting from tert-butyl N- (diphenylmethylene) glycinate 27, the reaction scheme of which is shown below. The enantiomeric excess of the product was determined by HPLC analysis using a chiralpak OD-H column, as shown in Table 1.
Figure BDA0002474022800000151
TABLE 1 adaptive results of chiral biphenyl quaternary ammonium salt catalysts in asymmetric alkylation
Figure BDA0002474022800000152
aYield of internal standard, internal standard is p-nitroacetophenone.
As can be seen from Table 1, in a two-phase solvent at 0 ℃, the improved Maruoka phase transfer catalyst can effectively catalyze the benzylation reaction of N-diphenylmethylene glycine tert-butyl ester 27, the reaction yield is 70-97%, and the ee value of the target product is 61-95%. The structure-activity relationship research on the series of improved Maruoka phase transfer catalysts discovers that: (1) after methylation is carried out on the hydroxyl at the 2-position and the 2' -position, the yield is not changed greatly, and the ee value is slightly improved; (2) the substituents at the 3-position and the 3' -position have a large influence on the reactivity and the selectivity. When the 3-position and the 3' -position are H and a small steric hindrance substituent methoxy, the catalytic activity and the selectivity are high, the yield is 95-97%, and the ee value is 91-98% ( Entry 2,4,6, 8). When tertiary butyl large steric hindrance groups are introduced into the 3-position and the 3' -position, the reaction activity and the selectivity of the catalyst are greatly reduced ( Entry 1,3,5 and 7). (3) The substituents at the 5-position and the 5' -position play a very crucial role in influencing the reactivity and selectivity of the Maruoka phase transfer catalyst. The substituent at the position assists the catalyst matrix framework to construct a chiral catalytic cavity on one hand, and plays an important role in the electron distribution of the matrix framework on the other hand. Based on the research results of the classical Maruoka catalyst and the simplified Maruoka catalyst for catalyzing asymmetric alkylation, 3,4, 5-trifluorophenyl and 3, 5-bis (trifluoromethyl) phenyl are favorable for the selectivity of the reaction, so that 3,4, 5-trifluorophenyl and 3, 5-bis (trifluoromethyl) phenyl are introduced into the 5-position and the 5' -position of the improved Maruoka phase transfer catalyst. After structural modification, the catalyst containing the two substituent groups shows better reaction activity and selectivity ( Entry 2,4,6,8), and a chiral cavity constructed by the 3,4, 5-trifluorophenyl is beneficial to improving diastereoselectivity.
The following is product 28 prepared in table 1:
to a mixture of tert-butyl N- (diphenylmethylene) glycinate 27(90.4mg, 0.3mmol) and chiral phase transfer catalyst (0.003mmol) in toluene (1.5mL) at 0 ℃ under argon protection, benzyl bromide (109. mu.L, 0.9mmol) and 50% aqueous KOH (0.5mL) were added dropwise and the catalytic reaction was carried out with vigorous stirring. After completion of the reaction, the reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. And separating and purifying the obtained crude product by silica gel column chromatography (normal hexane/dichloromethane/ethyl acetate, 100:1: 1-70: 1:1) to obtain the target compound N- (diphenylmethylene) -2-benzylglycine tert-butyl ester 28. HPLC: diacel Chiralpak OD-H (5 μm,4.6 mm. times.250 mm), hexane/i-PrOH 100/1(V/V), flow rate 0.3mL/min, λ 254nm, retentivity time 21.7min ((R) -antagonist) and 31.0min ((S) -antagonist);1H NMR(400MHz, CDCl3)δ:7.58～7.56(m,2H),7.38～7.25(m,6H),7.21～7.13(m,3H),7.06～7.04(m, 2H),6.60(d,J＝6.8Hz,2H),4.11(dd,J＝9.2,4.4Hz,1H),3.23(dd,J＝13.6,4.4 Hz,1H),3.16(dd,J＝13.2,9.2Hz,1H),1.44(s,9H).13C NMR(100MHz,CDCl3)δ: 171.0,170.4,139.7,138.5,136.5,130.2,130.0,128.9,128.3,128.2,128.2,128.1, 127.8,126.3,81.3,68.1,39.7,28.2。

Claims (6)

1. a preparation method of a chiral biphenyl quaternary ammonium salt phase transfer catalyst is characterized by comprising the following steps:
s1, dissolving 5-methyl-2-tert-butylphenol and tetrabutylammonium tribromide in a mixed solvent of dichloromethane and methanol, and reacting at normal temperature for 1 hour to obtain 4-bromo-2-tert-butyl-5-methylphenol;
s2, dissolving 4-bromo-2-tert-butyl-5-methylphenol and tetramethylethylenediamine in dichloromethane, reacting for 6 hours at normal temperature by using cuprous chloride as a catalyst to obtain 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol;
s3, dissolving 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol and sodium hydride in anhydrous tetrahydrofuran, deprotonating for 3 hours, dropwise adding the prepared (R) -2-methoxybenzene acetyl chloride into the system, and continuously reacting for 1 hour to obtain a mono-esterification product and a di-esterification product;
s4, preliminarily separating the obtained mono-esterification product and the obtained di-esterification product through silica gel column chromatography, dissolving the mono-esterification product or the di-esterification product in anhydrous tetrahydrofuran, and reacting for 1 hour by using lithium aluminum hydride as a reducing agent to obtain chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol;
s5, chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -dibromo-2, 2' -biphenol is dissolved in a toluene solution, and trifluoromethanesulfonic acid is used as an oxidant to obtain chiral 6,6' -dimethyl-5, 5' -dibromo-2, 2' -biphenol;
s6, dissolving the product obtained in the S4 or S5, tetrakis (triphenylphosphine) palladium, sodium carbonate and phenylboronic acid compounds in a mixed system of ethylene glycol dimethyl ether and water, and reacting overnight at the temperature of 95 ℃ under argon to obtain chiral 6,6' -dimethyl-3, 3' -di-tert-butyl-5, 5' -diaryl-2, 2' -biphenol or chiral 6,6' -dimethyl-5, 5' -diaryl-2, 2' -biphenol;
s7, dissolving chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-diaryl-2, 2' -biphenol or chiral 6,6 '-dimethyl-5, 5' -diaryl-2, 2 '-biphenol, methyl iodide and potassium carbonate in acetone, and reacting overnight under the reflux condition to obtain chiral 6,6' -dimethyl-3, 3 '-di-tert-butyl-5, 5' -diaryl-2, 2 '-dimethoxybiphenyl or chiral 6,6' -dimethyl-5, 5 '-diaryl-2, 2' -dimethoxybiphenyl;
s8, dissolving chiral 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-diaryl-2, 2' -dimethoxybiphenyl or chiral 6,6 '-dimethyl-5, 5' -diaryl-2, 2 '-dimethoxybiphenyl, azobisisobutyronitrile and N-bromosuccinimide in benzene, and reacting for 4 hours under the reflux condition to obtain chiral 3,3' -di-tert-butyl-5, 5 '-diaryl-6, 6' -dibromomethyl-2, 2 '-dimethoxybiphenyl or 5,5' -diaryl-6, 6 '-dibromomethyl-2, 2' -dimethoxybiphenyl;
s9, dissolving chiral 3,3' -di-tert-butyl-5, 5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl or 5,5' -diaryl-6, 6' -dibromomethyl-2, 2' -dimethoxybiphenyl, potassium carbonate and n-dibutylamine in acetonitrile, and reacting at 85 ℃ overnight to obtain the chiral methoxy catalyst, wherein R is1Is a methoxy group; r2Is tert-butyl and hydrogen; r3Are 3, 5-bis (trifluoromethyl) phenyl and 3,4, 5-trifluorophenyl;
s10, dissolving the chiral methoxy catalyst in anhydrous dichloromethane, dropwise adding 1M boron tribromide at-78 ℃, and heating to room temperature to react for 4 hours to obtain the chiral hydroxy catalyst, wherein R is1Is a hydroxyl group; r2Is tert-butyl and hydrogen; r3Are 3, 5-bis (trifluoromethyl) phenyl and 3,4, 5-trifluorophenyl;
the structural formula of the chiral biphenyl quaternary ammonium salt phase transfer catalyst is as follows:
Figure FDA0003128457020000021
wherein R is1Is methoxy or hydroxy; r2Is tert-butyl or hydrogen; r3Is 3, 5-bis (trifluoromethyl) phenyl or 3,4, 5-trifluorophenyl.
2. The method for preparing a chiral biphenyl quaternary ammonium salt phase transfer catalyst according to claim 1, wherein the mono-esterification product and the di-esterification product obtained in step S3 are subjected to primary separation by silica gel column chromatography, and then recrystallized to obtain stereoselectivity of more than 99%, namely ee of more than 99%.
3. The method for preparing a chiral biphenyl quaternary ammonium salt phase transfer catalyst according to claim 1, wherein the (R) -2-methoxybenzeneacetyl chloride prepared in step S3 is prepared by dissolving (R) -2-methoxybenzeneacetic acid and 2M oxalyl chloride in anhydrous dichloromethane, and reacting under the catalysis of N, N-dimethylformamide and under the protection of argon at 0 ℃ to room temperature for 6 hours.
4. The method for preparing the chiral biphenyl quaternary ammonium salt phase transfer catalyst according to claim 1, wherein the mass ratio of the 5-methyl-2-tert-butylphenol, tetrabutylammonium tribromide, dichloromethane and methanol in step S1 is 1:3:11: 4.4.
5. The method for preparing a chiral biphenyl quaternary ammonium salt phase transfer catalyst according to claim 1, wherein the mass ratio of the 4-bromo-2-tert-butyl-5-methylphenol, the tetramethylethylenediamine, the cuprous chloride and the dichloromethane in step S2 is 121.5:8.5:5: 1.3.
6. The method for preparing a chiral biphenyl quaternary ammonium salt phase transfer catalyst according to claim 1, wherein the mass ratio of the 6,6 '-dimethyl-3, 3' -di-tert-butyl-5, 5 '-dibromo-2, 2' -biphenol, the sodium hydride, the (R) -2-methoxybenzeneacetyl chloride and the anhydrous tetrahydrofuran in step S3 is 20:5:3: 40.
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