CN116655691A - Synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand - Google Patents

Synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand Download PDF

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CN116655691A
CN116655691A CN202310694973.9A CN202310694973A CN116655691A CN 116655691 A CN116655691 A CN 116655691A CN 202310694973 A CN202310694973 A CN 202310694973A CN 116655691 A CN116655691 A CN 116655691A
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chiral
phosphite
chromane
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indan
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谢建华
张洋铭
郭淑敏
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Nankai University
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Abstract

The invention relates to a chiral spiro [ chromane-4, 1' -indane]Synthesis and use of phosphite monophosphorus ligands. To achieve%R/S) -2-oxo-spiro [ chromane-4, 1' -indane]The 7 '-phenol is used as an initial raw material and can react with disubstituted phosphorus chloride under the action of an acid binding agent or react with alcohol phenol after being treated by phosphorus trichloride to obtain spiro [ chromane-4, 1' -indane ]]Phosphite monophosphorus ligands. The ligand synthesis method is simple and economical, and the chiral monophosphorus ligand is obtainedThe catalyst can be applied to various asymmetric catalytic reactions, such as asymmetric catalytic hydrogenation reaction of rhodium catalytic dehydrogenation amino acid ester, can obtain excellent enantioselectivity, and has important application value and potential in synthesis of chiral drugs and essence and spices.

Description

Synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand
Technical Field
The invention relates to synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand. The ligand can be used as a chiral ligand for asymmetric catalytic reactions such as asymmetric hydrogenation of rhodium catalytic dehydrogenation amino acid ester, has high application value in the field of asymmetric catalysis, and belongs to the field of asymmetric catalysis.
Background
Asymmetric catalytic synthesis is a green and efficient means for obtaining chiral fine chemicals, such as the efficient preparation of chiral drugs by hydrogenation of rhodium catalyzed dehydrogenated amino acidsL-DOPA（Knowles, W. S.;Sabacky,M.J.;Vineyard, B. D.; Weinkauff, D. J. J. Am. Chem. Soc. 1975, 97, 2567-2568). The creation of chiral catalyst is one of the most central problems in the field of asymmetric catalytic synthesis, and the design and synthesis of brand new catalyst involve the opportunity of solving the problem that partial asymmetric catalytic reaction at present lacks efficient and high-selectivity catalyst. Among the existing Chiral Catalysts, the catalyst with a Chiral spiro structure is one of the most efficient organometallic homogeneous Catalysts so far, and Chiral spiro frameworks are a typical class of "dominant ligand frameworks" (Yoon, t.p.; jacobsen, e.n. driven Chiral Catalysts.Science 2003, 2991691-1693.), thus developing new chiral spiro ligands helps to develop asymmetric catalytic new reactions, providing a more green and efficient chiral fine chemical synthesis method.
Chinese patent CN 109970697B discloses a synthesis method of chiral spiro [ chromane-4, 1 '-indan ] molecules, which has important significance for researching and finding the practical application and application value of chiral spiro [ chromane-4, 1' -indan ] molecules.
Chiral monophosphorus ligands are a very important class of chiral ligands (Guo Gongchao; ding Kuiling; dai Lixin. New developments in asymmetric catalytic hydrogenation-rendition of monodentate phosphorus ligands. Science bulletins 2004,49(16) 1575-7588.) chiral phosphite monophosphorus ligands are very rare and catalyzed asymmetric reactions can only achieve moderate to good selectivity and yield due to lack of a suitable chiral ligand backbone (Park, h.; rajanBabu, t.v.J. Am. Chem. S℃. 2002, 124, 734–735.；Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron Asymmetry2007, 18
, 251-259.). Therefore, the development of chiral spiro phosphite monophosphate ligand with brand new skeleton by chiral spiro [ chromane-4, 1' -indan ] phenol has important meaning and value.
Disclosure of Invention
The invention aims to provide a chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand which has the structure shown in the following general formula (I):
in the general formula (I):
R 1 is an alkyl group, an alkoxy group, an aryl group, an aryloxy group, or a hydrogen atom.
The above term alkyl is preferably methyl, ethyl, propyl, butyl, and the like.
The alkoxy group is preferably methoxy, ethoxy, propoxy, butoxy, or the like.
Aryl is preferably phenyl or the like substituted or unsubstituted with alkyl or alkoxy, the alkyl and alkoxy being as defined above.
The present invention provides two methods for synthesizing the foregoing compounds, by the following routes:
the method comprises the following specific steps: chiral spiro chromane indanol as initial materialR) -a or%S) A, reacting alkali serving as an acid binding agent with disubstituted phosphorus chloride in an organic solvent at a temperature of between 0 and 110 ℃ to obtain chiral phosphite ligands; the organic solvent is one or more of dichloromethane, toluene and tetrahydrofuran; the base is triethylamine, diisopropylethylamine, potassium carbonate, 1, 4-diazabicyclo [2.2.2 ]]Octane, 1, 8-diazabicyclo [5.4.0]Undec-7-ene, dimethylaminopyridine, and the disubstituted phosphorus chloride is diaryl phosphorus chloride or dialkyl phosphorus chloride.
The method comprises the following specific steps: chiral spiro chromane indanol as initial materialR) -a or%S) A, reacting alkali serving as an acid binding agent with phosphorus trichloride in an organic solvent at a temperature of between 0 and 110 ℃; subsequent removal of the trichlorination under reduced pressureReacting phosphorus with phenol or alcohol in an organic solvent at a temperature of between 0 and 110 ℃ by taking alkali as an acid binding agent to obtain chiral phosphite ligands; the organic solvent is one or more of dichloromethane, toluene and tetrahydrofuran, and the alkali is triethylamine, diisopropylethylamine, potassium carbonate, 1, 4-diazabicyclo [2.2.2 ]]Octane, 1, 8-diazabicyclo [5.4.0]Undec-7-ene and dimethylaminopyridine.
It is another object of the present invention to provide the use of the aforementioned ligands in asymmetric catalytic reactions including hydrogenation, hydroformylation, hydrosilation, hydroboration, hydrohydroxylation, hydroammoniation, hydrocyanation, isomerisation formylation, hydroaminomethylation, transfer hydrogenation, allylation, olefin metathesis, cycloisomerisation, diels-Alder reactions, asymmetric coupling reactions, aldol reactions, michael addition reactions, asymmetric epoxidation reactions, kinetic resolution and [ m+n ] cyclization reactions; according to the application, the chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand has high activity and enantioselectivity on hydrogenation reaction of rhodium catalytic dehydrogenation amino acid ester in an organic solvent; the synthesis process for the aforementioned applications is preferably as follows:
in the general formula (II):
R 2 ，R 3 is an alkyl group, an aryl group, or a hydrogen atom.
The above term alkyl is preferably methyl, ethyl, propyl, butyl, and the like.
Aryl is preferably phenyl or the like substituted or unsubstituted with an alkyl group, an alkoxy group, a halogen atom, etc., and the alkyl group is preferably methoxy, ethoxy, propoxy, butoxy, etc., as defined above.
R 4 The amino protecting group is preferably an acetyl group, an alkoxycarbonyl group, a p-toluenesulfonyl group, a benzyl group or the like.
The specific catalytic asymmetric hydrogenation reaction route is as follows:
under the protection of argon or nitrogen, adding dehydroamino acid ester, ligand, rhodium metal precursor and organic solvent into a hydrogenation kettle, stirring and dissolving, then filling hydrogen, and stirring and reacting for 3-48 hours at a proper temperature and pressure to obtain optically active amino acid ester; wherein the rhodium metal precursor is [ Rh (cod) Cl] 2 (cod=cyclooctadiene), [ Rh (cod) 2 ]BF 4 、[Rh(cod) 2 ]PF 6 、[Rh(cod) 2 ]SbF 6 、[Rh(cod) 2 ]OTf); the organic solvent is one or more of dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.
The invention provides synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand, which has the following beneficial effects on the prior art:
(1) The chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand has central chirality, so that the chiral spiro [ chroman-4, 1' -indan ] phosphorus ligand and the chiral spiro [ chroman-4, 1' -indan ] phosphorus ligand are provided, and the racemized chiral spiro [ chroman-4, 1' -indan ] phosphorus ligand can be synthesized by taking racemized spiro [ chroman-4, 1' -indan ] monophenol as raw materials.
(2) The ligand can be used as a chiral catalyst in asymmetric hydrogenation, has high activity and enantioselectivity for hydrogenation of dehydrogenated amino acid ester in an organic solvent, and can obtain excellent enantioselectivity in asymmetric catalytic hydrogenation reaction of rhodium catalytic dehydrogenated amino acid ester, and the yield is 99 percent, 88 percent ee-95 percent ee.
(3) The synthesis method of the chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand is simple and economical, and the obtained chiral monophosphorus ligand has important application value and great potential in the synthesis of chiral medicines, essence and spices.
Description of the embodiments
The invention is further illustrated by the following examples, which are merely helpful in further understanding the invention and are not intended to limit the scope of the invention. The experimental methods for which specific conditions are not specified in the examples are generally as described in conventional conditions and handbooks, or as suggested by the manufacturer; the general equipment, materials, reagents, etc. used, unless otherwise indicated, are all commercially available.
Example 1: (R) -7-bis- (3, 5-dimethyl) -phenylphosphinyloxy-2 ',3' -dihydrospiro [ chromane-4, 1' -indene]-synthesis of 2-ketone:
to a 25mL dry Schlenk tube, addR) -spiro [ chromane-4, 1' -indane]Monophenol a (133.1 mg,0.5 mmol), under argon, was added 4mL of anhydrous toluene, followed by the corresponding bis- (3, 5-dimethyl) -phenylphosphine chloride (110.3 mg,0.5 mmol), and cooled to 0 ℃; triethylamine (162 μl, 1.25 mmol) was slowly added dropwise at 0 ℃, sealed and placed in an oil bath at 110 ℃ for reflux reaction for 14 hours, desolventized under reduced pressure, column chromatographed (petroleum ether/ethyl acetate=50:1 to 20:1), separated to give ligand, 218 mg, yield 89%, optical rotation: [ a ]]28D = –37 (c =1, CHCl 3 ) Melting point: 54-55 ℃. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.27–7.20 (m, 2H), 7.10–6.93 (m, 5H), 6.92–6.84 (m, 3H), 6.80 (dd, J = 7.7, 1.6 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H), 3.38 (d, J = 15.7 Hz, 1H), 2.97 (t, J = 7.5 Hz, 2H), 2.69 (d, J = 15.7 Hz, 1H), 2.21 (d, J = 14.9 Hz, 12H). 13 C NMR (101 MHz, CDCl 3 ) δ: 168.2, 154.4, 154.3, 150.4, 146.6, 140.1, 140.0, 139.9, 139.8, 138.1, 138.0, 137.7, 137.6, 132.0, 131.4, 130.1, 130.0, 128.2, 128.1, 128.0, 127.7, 127.4, 126.2, 124.5, 118.7, 117.0, 115.8, 115.6, 49.7, 40.1, 39.1, 30.5, 21.3, 21.3. 31 P NMR (162 MHz, CDCl 3 ) δ 111.5. HRMS (ESI) Calcd for C 33 H 32 O 3 P + : ([M+H] + ): 507.2084; Found: 507.2088.
Wherein%R) -spiro [ chromane-4, 1' -indane]The monophenol a is prepared by referring to Chinese patent CN 109970697B, and the specific synthetic route is as follows:
step one: to a dry 2000 mL reaction flask was weighed 3- (3-hydroxyphenyl) propionic acid (37.3 g, 224 mmol), methylene chloride (300 mL) and acetonitrile (150 mL) were added and dissolved by stirring at room temperature. The system was cooled to below 5 ℃ using an ice-water bath, followed by dropwise addition of bromine in dichloromethane (11.5 mL Br) using a constant pressure dropping funnel 2 150 mL dichloromethane) was added thereto, and the dropwise addition was completed for 1 hour. The reaction was then continued under stirring for 1.5 hours in an ice-water bath. After the nuclear magnetism hydrogen spectrum monitoring reaction is finished, adding a saturated sodium thiosulfate solution quenching system, decompressing and desolventizing, adding ethyl acetate (500 mL) for dissolution and dilution, separating liquid, extracting a water phase by using ethyl acetate (150 mL multiplied by 2), combining organic phases, drying by using anhydrous magnesium sulfate, leaching and desolventizing to obtain 3- (2-bromo-5-hydroxyphenyl) -propionic acid: pale yellow solid, 54.3 g, 99% yield, melting point: 152-155 ℃ (which can be used directly in the next reaction without purification). 1 H NMR (400 MHz, CD 3 OD) δ: 7.30 (d, J = 8.6 Hz, 1H), 6.77 (s, 1H), 6.57 (d, J = 8.7 Hz, 1H), 5.02 (brs, 2H), 2.94 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H). 13 C NMR (101 MHz, CD 3 OD) δ 175.0, 156.8, 140.6, 133.0, 116.9, 115.0, 112.5, 33.5, 31.1.。
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Step two: to a 3000 mL dry reaction flask was added 3- (2-bromo-5-hydroxyphenyl) -propionic acid (40 g, 163 mmol) and carbonyldiimidazole CDI (28.6 g, 176 mmol) and tetrahydrofuran (700 mL) was added for dissolution. The reaction was stirred at room temperature for 8 hours under argon atmosphere. A solution of magnesium monoethylmalonate (39 g, 253 mmol) in tetrahydrofuran (300 mL) was added to the reaction system and the reaction was continued at room temperature with stirring for 12 hours, with TLC monitoring the completion of the reaction. To the system was added 1N HCl for acidification, diethyl ether (2×150 mL) extraction, the organic phases were combined, then washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Adding diatomite for suction filtration, decompressing and desolventizing, and carrying out column chromatography (petroleum ether/ethyl acetate=5:1) to obtain 5- (2-bromo-5-hydroxyphenyl) -3-carbonyl ethyl valerate b: pale yellow foamy solid, 39 g, 76% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 3.0 Hz, 1H), 6.50 (dd, J = 8.7, 3.1 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.63 (s, 3H), 3.31 (s, 2H), 2.84 (ddd, J = 9.3, 7.4, 2.1 Hz, 2H), 2.78–2.72 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.4, 167.5, 155.5, 140.7, 133.6, 117.6, 115.5, 114.2, 61.7, 49.3, 42.7, 30.0, 14.1.。
Step three: to a 1000 mL dry reaction flask was added ethyl 5- (2-bromo-5-hydroxyphenyl) -3-oxopentanoate b (17.8 g, 56.5 mmol) and dichloromethane (300 mL) was added for dissolution. The replacement system is in argon atmosphere, and the temperature in the system is controlled to be below 5 ℃ by using ice water bath. Then trifluoromethanesulfonic acid (15.0. 15.0 mL, 169 mmol) was slowly added dropwise. After the addition was completed, the ice bath was removed, and the system was allowed to stir at room temperature for 0.5 hours, and TLC monitored complete conversion of the starting materials and a large amount of yellow solid was precipitated in the system. Resorcinol (6.2 g, 56.5 mmol) was added to the reaction and the reaction stirred at room temperature for 1 hour, TLC monitored complete conversion of the intermediate. The reaction was quenched with ice water, extracted with ethyl acetate (2×150 mL), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered through celite, desolventized under reduced pressure, and chromatographed on a column (petroleum ether/ethyl acetate=5:1). To give 4' -bromo-5-hydroxy-7 ' -hydroxy-spiro [ chromane-4, 1' -indan ] -2-one c: yellow foamy solid, 16.9, g, yield 83%.1H NMR (400 MHz, CDCl 3) delta 7.38 (d, J=8.9 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.39-6.33 (dd, 1H), 3.42 (d, J=15.8 Hz, 1H), 3.30-3.13 (m, 1H), 2.94-2.83 (m, 2H), 2.78 (d, J=15.9 Hz, 1H), 2.56-2.49 (m, 1H), 2.28 (m, 1H) 13C NMR (101 MHz, CDCl 3) delta 170.5, 158.8, 155.2, 152.4, 146.9, 133.3, 132.8, 127.5, 121.5, 117.1, 108.7, 8.7, 8.104, 8.54.33, 40.40.4, 4.40.12, 4.15.8.4, 4.12.40.12, 4.40.51.
Step four: to a 250 mL dry reaction flask was added 4' -bromo-5-hydroxy-7 ' -hydroxy-spiro [ chromane-4, 1' -indan ] -2-one c (6.8 g, 18.8 mmol), dichloromethane (120 mL) was added for dissolution, and then pyridine (3.0 mL, 37.6 mmol) was added. The system was placed in an ice-water bath to bring the temperature within the system to below 5.5 oC, and then triflic anhydride (3.2 mL, 18.8 mmol) was slowly added dropwise. After the addition was completed, the ice bath was removed and the system was allowed to react with stirring at room temperature for 12 hours, and TLC monitored complete conversion of the starting material. The reaction was quenched with ice water, extracted with ethyl acetate (2×50 mL), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered through celite, desolventized under reduced pressure, and chromatographed on a column (petroleum ether/ethyl acetate=10:1). To give 4' -bromo-5-trifluoromethanesulfonyl-7 ' -hydroxy-spiro [ chromane-4, 1' -indan ] -2-one d: yellow foamy solid, 7.0 g, 76% yield. 1H NMR (400 MHz, CDCl 3) delta 7.35 (d, j=8.4 Hz, 1H), 7.06 (d, j=2.4 Hz, 1H), 6.95 (dd, j=8.6, 2.5 Hz, 1H), 6.87 (d, j=8.6 Hz, 1H), 6.58 (dd, j=8.5, 0.8 Hz, 1H), 5.55 (s, 1H), 3.58 (d, j=16.0 Hz, 1H), 3.11-2.96 (m, 2H), 2.87 (d, j=16.0 Hz, 1H), 2.36 (m, j=13.3, 8.6, 6.9 Hz, 1H), 2.25-2.16 (m, 1H) < 13C NMR (101 MHz, 3) delta 167.3, 151.9, 150.9, 148.6, 146.2.129.3, 130.11-2.96 (m, 2H), 2.87 (d, 2.33.6, 2H), 2.37, 3.35, 1H, 2.25-2.16 (m, 1H), 2.25-2.36 (m, 1H), 13C NMR (167.3, 35, 151.9, 3.9, 150.9, 148.6, 146.35, 2.35, 3.35, 3.7, 3.116, 3.15, 3.7.15, 3.116, 3.0.116, 4.0.116, 3.7.15, 120.0.116.6, 1H.
Step five: to a 500 mL dry reaction flask was added 4' -bromo-5-trifluoromethanesulfonyl-7 ' -hydroxy-spiro [ chromane-4, 1' -indan-2-one d (19.6 g, 39.7 mmol), dissolved in absolute ethanol (230 mL), then triethylamine (14 mL, 100 mmol) and 10% Pd/C (2.0 g, 1.9 mmol) were added to displace the H2 atmosphere. The reaction was completed by nuclear magnetic resonance hydrogen spectroscopy at room temperature under 1 atm H2 conditions for 48 hours. Desolventizing under reduced pressure, dissolving and diluting with ethyl acetate (200 mL), and acidifying with 1N HCl until insoluble substances disappear. The aqueous phase was separated, the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered through celite, desolventized, and the solid was washed with diethyl ether (3×20 mL) to give (rac) -2-oxospiro [ chroman-4, 1 '-indan ] -7' -ol (rac) -a,9.6 g in 91% yield. 1H NMR (400 MHz, CDCl 3) delta 7.27 (m, 1H), 7.21 (t, j=7.7 Hz, 1H), 7.12 (dd, j=8.2, 1.2 Hz, 1H), 7.03 (td, j=7.5, 1.3 Hz, 1H), 6.92 (dd, j=7.5, 1.0 Hz, 1H), 6.82 (dd, j=7.7, 1.6 Hz, 1H), 6.67-6.62 (m, 1H), 4.90 (s, 1H), 3.54 (d, j=15.9 Hz, 1H), 3.00 (t, j=7.3 Hz, 2H), 2.84 (d, j=15.9 Hz, 1H), 2.33 (dt, j=12.8, 7.4 Hz, 1H), 2.24-2.13 (m, 1H) 13C NMR (101 MHz, CDCl 3) delta 168.4, 152.4, 150.7, 146.7, 130.0, 128.7, 125.6, 124.8, 117.7, 117.3, 114.4, 49.3, 40.4, 39.2, 30.6.
Step six: (rac) -2-oxospiro [ chroman-4, 1 '-indan ] -7' -phenol (rac) -a (7.0 g, 26.3 mmol) and N-benzyl-chlorinated cinchonidine e (3.2 g, 7.5 mmol) were weighed into a 250 mL dry reaction flask in sequence, placed in a stirrer, and dried tert-butyl methyl ether (130 mL) was added. The reaction system was placed in an oil bath heated to 60℃in advance for reflux, and the stirrer was set to a magnetic stirring speed of 1000 r/min and stirred continuously for 24 hours. A large amount of white insoluble substances are generated in the system, and filtrate and insoluble substances are separated after the system is cooled to room temperature and filtered. Mother liquor recovery: washing insoluble substances with ethyl acetate (3×20 mL), mixing filtrate and washing solution, and removing solvent under reduced pressure to obtain (S) -a which is not bound with resolution agent. Yield: 62%,62% ee. And (3) dissociation of inclusion compound: the insoluble material was placed in a 250 mL beaker, diluted with ethyl acetate (80 mL) and 1N HCl was added thereto continuously until no insoluble material was present. Separating with separating funnel, extracting water phase with ethyl acetate (2×50 mL), mixing organic phases, drying with anhydrous magnesium sulfate, filtering with diatomite, and removing solvent under reduced pressure to obtain (R) -a with inclusion of resolution agent. Yield: 40%,95% ee.
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Recrystallizing both by using n-hexane-methyl tertiary butyl ether as a solvent to obtain the product respectivelyS) -a, yield: 36%, ee value:>99%；(R) -a, yield: 34%,>99% ee. HPLC conditions: chiralcel IC-3 column (25 cm X0.46 cm ID);n-hexane/2-propanol = 85:15; temp, rt; flow rate = 1.0 mL/min; 88 bars; 220 nm UV detector。
example 2: (R) -7-diphenylphosphinyloxy-2 ',3' -dihydrospiro [ color ]Manchurian 4,1' -indene]-synthesis of 2-ketone:
the procedure is as in example 1, with a white solid, 75.5. 75.5 mg, yield 42%, melting point 58-60 ℃ [ a ]]28D –58.6 (c 1.0, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ) δ: 7.36–7.20 (m, 8H), 7.19–7.13 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 7.06–6.94 (m, 5H), 6.84 (d, J = 7.6 Hz, 1H), 3.29 (d, J = 15.7 Hz, 1H), 3.00 (t, J = 7.4 Hz, 2H), 2.70 (d, J = 15.7 Hz, 1H), 2.38–2.25 (m, 1H), 2.24–2.09 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ: 168.1, 154.1, 154.0, 150.6, 146.7, 140.2, 140.0, 140.0, 139.9, 132.6, 132.6, 130.7, 130.4, 130.2, 130.1, 130.0, 129.9, 129.5, 128.7, 128.6, 128.3, 128.3, 126.4, 124.6, 119.0, 116.9, 115.7, 115.5, 49.7, 40.0, 39.0, 30.5. 31 P NMR (162 MHz, CDCl 3 ) δ:110.1. HRMS (ESI) Calcd for C 29 H 23 NaO 3 P + ([M+Na] + ): 473.1277; Found: 473.1280.。
Example 3: (R) -7-bis- (4-methylphenyl) -phosphinoxy-2 ',3' -dihydrospiro [ chromane-4, 1' -indene]-synthesis of 2-ketone:
the procedure is as in example 1, with 84.2. 84.2 mg as oily liquid, 44% yield, [ a ]]28D –33 (c 1.0, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (td, J = 8.2, 1.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.15–7.06 (m, 5H), 7.06–6.99 (m, 2H), 6.97 (dd, J = 6.9, 4.6 Hz, 3H), 6.86 (t, J = 7.8 Hz, 2H), 6.82 (dd, J = 7.7, 1.4 Hz, 1H), 3.30 (d, J = 15.7 Hz, 1H), 2.98 (t, J = 7.3 Hz, 2H), 2.67 (d, J = 15.7 Hz, 1H), 2.35–2.25 (m, 7H), 2.18–2.10 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.3, 154.2, 154.1, 150.6, 146.6, 140.4, 139.5, 136.9, 136.9, 136.8, 136.7, 132.5, 132.5, 130.8, 130.6, 130.2, 130.1, 130.0, 129.4, 129.3, 129.1, 129.0, 128.3, 126.4, 124.6, 118.8, 116.9, 115.6, 115.4, 49.7, 40.0, 39.0, 30.5, 29.7, 21.5, 21.4. 31 P NMR (162 MHz, CDCl 3 ) δ 110.7. HRMS (ESI) Calcd for C 31 H 27 NaO 3 P + ([M+Na] + ): 501.1590; Found: 501.1594.。
Example 4: (R) -7-bis- (3, 5-di-tert-butyl) -phenylphosphinyloxy-2 ',3' -dihydrospiro [ chromane-4, 1' -indene]-synthesis of 2-ketone:
to 25mL dry Schlenk tube, addR) -2-oxo-spiro [ chromane-4, 1' -indane]-7' -phenol ]R) -a (107 mg,0.4 mmol), 1, 4-diazabicyclo [2.2.2 ]]Octane (112 mg,1.0 mmol), anhydrous toluene 4mL was added under argon, cooled to 0 ℃, and then di- (3, 5-di-t-butyl) phenylphosphine chloride (178 mg,0.4 mmol) was added, sealed and placed in room temperature with stirring for reaction for 14 hours. Desolventizing under reduced pressure, column chromatography (petroleum ether/ethyl acetate=50:1 to 20:1), separation to give ligand, 122 mg, yield 45%, optical rotation [ a]28D –48 (c 0.5, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 17.82 Hz, 2H), 7.18 – 7.14 (m, 1H), 7.12 (dd, J = 8.76, 1.86 Hz, 2H), 7.07 (dd, J = 8.67, 1.85 Hz, 2H), 7.05–6.97 (m, 2H), 6.90 (d, J= 7.42 Hz, 1H), 6.87 – 6.78 (m, 2H), 6.57 – 6.48 (m, 1H), 3.32 (d, J = 15.55 Hz, 1H), 2.84 (td, J = 7.87, 6.35, 4.13 Hz, 2H), 2.53 (d, J = 15.53 Hz, 1H), 2.16 (dt, J = 12.86, 8.34 Hz, 1H), 2.06–1.96 (m, 1H), 1.14 (d, J = 2.89 Hz, 36H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.2, 150.9, 150.8, 150.5, 150.4, 150.2, 146.8, 138.9, 138.8, 138.7, 138.5, 131.8, 131.7, 130.0, 129.9, 128.0, 125.5, 125.4, 125.2, 124.4, 124.1, 123.7, 118.6, 117.0, 116.1, 115.9, 49.5, 40.3, 39.7, 34.9, 31.4, 31.3, 30.2. 31 P NMR (162 MHz, CDCl 3 ) δ 113.6. HRMS (ESI) Calcd for C 45 H 56 O 3 P + ([M+H] + ): 675.3962; Found: 675.3962.。
Example 5: (R) -7 '-diphenoxyphosphinoxy-2', 3 '-dihydrospiro [ chromane-4, 1' -indene]-synthesis of 2-ketone:
to 25mL dry Schlenk tube, addR) -2-oxo-spiro [ chromane-4, 1' -indane]-7' -phenol ]R) -a (133.1 mg,0.5 mmol), dissolved by adding anhydrous dichloromethane (4 mL) under argon, then adding a dichloromethane solution of phosphorus trichloride (1.25 mL, 2.0 m,2.5 mmol) dissolved with stirring and cooled to 0 ℃. 0. Triethylamine (649. Mu.L, 5 mmol) was slowly added dropwise at C, and the reaction was carried out at room temperature for 30 min at natural temperature. Solvent and excess phosphorus trichloride were removed under reduced pressure using a high vacuum pump, anhydrous dichloromethane (3 mL) was added again for dissolution, and corresponding phenol (94 mg,1.0 mmol) was added, cooled to 0deg.C, triethylamine (649. Mu.L, 5 mmol) was slowly added dropwise at 0deg.C, naturally warmed to room temperature for reaction for 14 hours, desolventized under reduced pressure, column chromatography (petroleum ether/ethyl acetate=50:1 to 20:1), and the target ligand was isolated, 133 mg, yield 55%, melting point: 158-159 ℃, optically active: [ a ]]27D = –33 (c =1, CHCl 3 ) 1 H NMR (400 MHz, CDCl 3 ) δ 7.32–7.20 (m, 4H), 7.20–7.02 (m, 8H), 7.00–6.90 (m, 3H), 6.71 (d, J = 8.5 Hz, 2H), 6.62 (dd, J = 7.7, 1.6 Hz, 1H), 3.15 (d, J = 15.7 Hz, 1H), 3.03–2.86 (m, 2H), 2.61 (d, J = 15.7 Hz, 1H), 2.32–2.19 (m, 1H), 2.17–2.04 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.1, 151.3, 151.3, 151.1, 150.6, 149.7, 149.6, 147.8, 132.8, 132.8, 130.1, 129.9, 129.6, 129.6, 128.4, 125.8, 124.6, 124.5, 120.8, 120.7, 120.6, 120.6, 117.4, 117.2, 49.8, 40.3, 39.3, 30.5 . 31 P NMR (162 MHz, CDCl 3 ) δ 126.2. HRMS (ESI) Calcd for C 29 H 24 O 5 P + ([M+H] + ): 483.1356; Found: 483.1359.。
Example 6: (R) -7'- (2, 2-diphenyl) oxyphosphinyloxy-2', 3 '-dihydrospiro [ chromane-4, 1' -indene ]]-synthesis of 2-ketone:
the procedure is as in example 5, oily liquid, 151 mg, yield 63%, melting point: 93-95 ℃, optically active: [ a ]]27D = –36 (c = 0.5, CHCl 3 )， 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (dt, J = 6.7, 2.0 Hz, 2H), 7.34–7.18 (m, 7H), 7.14 (t, J = 8.2 Hz, 2H), 7.10–6.98 (m, 2H), 6.70 (dd, J = 7.7, 1.5 Hz, 1H), 6.48–6.37 (m, 1H), 3.35 (d, J = 15.7 Hz, 1H), 2.99 (t, J = 7.4 Hz, 2H), 2.67 (d, J = 15.7 Hz, 1H), 2.30 (dt, J = 12.9, 7.7 Hz, 1H), 2.15 (dt, J = 13.3, 6.9 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 168.0, 150.6, 149.2, 149.2, 148.8, 148.8, 148.7, 148.7, 147.6, 133.3, 133.3, 131.0, 130.9, 130.8, 130.8, 130.1, 130.0, 129.9, 129.7, 129.2, 129.1, 128.5, 126.0, 125.5, 124.7, 121.8, 121.7, 120.9, 117.9, 117.7, 117.1, 49.7, 40.2, 39.3, 30.5. 31 P NMR (162 MHz, CDCl 3 ) δ 144.32. HRMS (ESI) Calcd for C 29 H 22 O 5 P + ([M+H] + ): 481.1199; Found: 481.1196.。
Example 7:Nasymmetric catalytic hydrogenation of methyl acetamido-3-phenylacrylate:
in a glove box, takeNAcetamido-3-phenyl methyl acrylate (55 mg, 0.25 mmol), ligandR) -7-bis- (3, 5-dimethyl) -phenylphosphinyloxy-2 ',3' -dihydrospiro [ chromane-4, 1' -indene]-2-Ketone ]2.5 mg, 0.005 mmol) and Rh (COD) 2 BF 4 (1.02 mg, 0.0025 mmol) in a dry clean hydrogenation inner tube and sealing and taking out. The hydrogenation inner tube was placed in an autoclave, the atmosphere in the autoclave was replaced with nitrogen, and anhydrous dichloromethane (5 mL) was added thereto and dissolved with stirring. The atmosphere in the kettle is replaced by hydrogen for three times, and 20 atm of hydrogen is filled, the kettle is sealed, and the kettle is placed at the temperature of 0 ℃ for stirring reaction. After reaction 24 and h, hydrogen in the reaction kettle is slowly released, and after desolventizing, the conversion rate is measured by nuclear magnetism. The crude product is subjected to column chromatography to obtain a hydrogenated product. The enantioselectivity of the product was determined by chiral GC, GC (Varian Chirasil-L-Val column 25m X0.25 mm X0.12 μm; N 2 1.8 mL/min; 90℃ then 4℃/min to 220℃) t R = 18.9 min, t S =19.3 min, yield 99%,92% ee. 1 H NMR (400 MHz, CDCl 3 ) δ 7.40–7.22 (m, 3H), 7.09 (d, J = 6.9 Hz, 2H), 5.88 (s, 1H), 4.89 (q, J = 5.9 Hz, 1H), 3.73 (s, 3H), 3.24–3.01 (m, 2H), 1.99 (s, 3H).。
Example 8:Nasymmetric catalytic hydrogenation of acetamido-3-phenylacrylate:
the operation was the same as in example 7, 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (q, J = 6.43, 5.36 Hz, 3H), 7.04 (d, J = 7.25 Hz, 2H), 6.08 (d, J = 7.84 Hz, 1H), 4.78 (q, J = 6.55 Hz, 1H), 4.08 (q, J = 7.14 Hz, 2H), 3.13 – 2.90 (m, 2H), 1.89 (s, 3H), 1.16 (t, J = 7.17 Hz, 3H). Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 90:10; temp, 20 ℃; flow rate = 1.0 mL/min; 50 bars; 210 nm UV detector; t 1 (major) = 8.6 min; t 2 (minor) =12.9 min. Yield 99%,94% ee..
Example 9:Nasymmetric catalytic hydrogenation of methyl acetamido-3-p-methylphenyl acrylate:
the operation was the same as in example 7, 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (q, J = 6.43, 5.36 Hz, 3H), 7.04 (d, J = 7.25 Hz, 2H), 6.08 (d, J =7.84 Hz, 1H), 4.78 (q, J = 6.55 Hz, 1H), 4.08 (q, J =7.14 Hz, 2H), 3.13 – 2.90 (m,2H), 1.89 (s,3H), 1.16 (t, J =7.17 Hz, 3H). HPLC condition:Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 90:10; temp, 20 ℃; flow rate =1.0 mL/min; 50 bars; 230 nm UV detector; t 1 (major) =9.5 min; t 2 (minor) =12.8 min. Yield 99%,89% ee..
Example 10:Nasymmetric catalytic hydrogenation of methyl acetamido-3-p-chlorophenyl acrylate:
the operation was the same as in example 7, 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 – 7.23 (m, 2H), 7.07 – 6.96 (m, 2H), 6.03 – 5.79 (m, 1H), 4.87 (dt, J = 7.96, 5.81 Hz, 1H), 3.73 (d, J = 1.02 Hz, 3H), 3.10 (qd, J = 13.93, 5.70 Hz, 2H), 1.99 (d, J = 0.97 Hz, 3H). HPLC condition: Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 90:10; temp, 20 ℃; flow rate = 1.0 mL/min; 50 bars; 230 nm UV detector; t 1 (major) = 10.9 min; t 2 (minor) =13.3 min.99% yield, 90% ee.
Example 11:Nasymmetric catalytic hydrogenation of methyl acetamido-3-m-methylphenyl acrylate:
the procedure was carried out in the same manner as in example 7, except that the yield was 99%,89% ee, 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (d, J = 15.05 Hz, 1H), 7.05 (d, J = 7.66 Hz, 1H), 6.95 – 6.80 (m, 2H), 6.01 (d, J= 6.15 Hz, 1H), 4.85 (dt, J = 8.04, 5.89 Hz, 1H), 3.71 (s, 3H), 3.06 (qd, J = 13.83, 5.85 Hz, 2H), 2.31 (s, 3H), 1.97 (s, 3H). HPLC condition: Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 90:10; temp, 20 ℃; flow rate = 1.0 mL/min; 50 bars; 210 nm UV detector; t 1 (major) = 6.5 min; t 2 (minor) = 11.4 min.。
example 12:Nasymmetric catalytic hydrogenation of methyl acetamido-3-o-methylphenyl acrylate:
the procedure was carried out in the same manner as in example 7, except that the yield was 99%, 88% ee, 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 – 7.17 (m, 3H), 7.12 (d, J = 7.32 Hz, 1H), 6.19 (d, J = 8.15 Hz, 1H), 4.95 (q, J = 7.16 Hz, 1H), 3.77 (s, 3H), 3.24 (dd, J = 14.08, 6.64 Hz, 1H), 3.12 (dd, J = 14.12, 7.02 Hz, 1H), 2.42 (s, 3H), 2.05 (s, 3H). HPLC condition: Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 90:10; temp, 20 ℃; flow rate = 1.0 mL/min; 50 bars; 210 nm UV detector; t 1 (major) = 8.1 min; t 2 (minor) = 11.5 min.。
example 13:Nasymmetric catalytic hydrogenation of acetamido-3- (2-naphthyl) -acrylic acid methyl ester:
the procedure was carried out in the same manner as in example 7, except that the yield was 99%,89% ee, 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 – 7.73 (m, 3H), 7.56 (s, 1H), 7.51 – 7.41 (m, 2H), 7.22 (dd, J = 8.44, 1.72 Hz, 1H), 6.09 (d, J = 7.90 Hz, 1H), 4.97 (dt, J = 8.08, 5.91 Hz, 1H), 3.72 (s, 3H), 3.27 (qd, J = 13.90, 5.90 Hz, 2H), 1.96 (s, 3H). HPLC condition: Chiralcel AD-H column (25 cm × 0.46 cm ID); n-hexane/2-propanol = 95:5; temp, 20 ℃; flow rate = 1.0 mL/min; 45 bars; 254 nm UV detector; t 1 (major) = 14.5 min; t 2 (minor) = 21.7 min.。

Claims (8)

1. a chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand which is either optical or racemic, having the structure of the general formula (I):
in the general formula (I): r is R 1 Is an alkyl group, an alkoxy group, an aryl group, an aryloxy group, or a hydrogen atom.
2. Chiral spiro [ chromane-4, 1' -indanes ] according to claim 1]Phosphite monophosphorus ligands, characterized by R 1 Methyl, ethyl, propyl, butyl; alkoxy is methoxy, ethoxy, propoxy, butoxy; aryl is phenyl substituted or unsubstituted with alkyl or alkoxy, alkyl and alkoxy being as defined above.
3. A method of synthesizing a chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand of claim 1, comprising the steps of:
chiral of starting materialR/S) -2-oxo-spiro [ chromane-4, 1' -indane]-7' -phenol ]R/S) A, reacting alkali serving as an acid binding agent with disubstituted phosphorus chloride in an organic solvent at a temperature of between 0 and 110 ℃ to obtain chiral phosphite ligands; the organic solvent is one or more of dichloromethane, toluene and tetrahydrofuran, and the alkali is triethylamine, diisopropylethylamine, potassium carbonate, 1, 4-diazabicyclo [2.2.2 ]]Octane, 1, 8-diazabicyclo [5.4.0]Undec-7-ene, dimethylaminopyridine, and the disubstituted phosphorus chloride is diaryl phosphorus chloride or dialkyl phosphorus chloride.
4. A method of synthesizing a chiral spiro [ chroman-4, 1' -indan ] phosphite monophosphorus ligand of claim 1, comprising the steps of:
starting materials [ (]R/S) -2-oxo-spiro [ chromane-4, 1' -indane]-7' -phenol ]R/S) -a reacting with phosphorus trichloride in an organic solvent at 0 ℃ with a base as an acid-binding agent; then removing phosphorus trichloride under reduced pressure, and reacting alkali serving as an acid binding agent with phenol or alcohol in an organic solvent at a temperature of between 0 and 110 ℃ to obtain chiral phosphite ligands; the organic solvent is one or more of dichloromethane, toluene and tetrahydrofuran, and the alkali is triethyleneAmines, diisopropylethylamine, potassium carbonate, 1, 4-diazabicyclo [2.2.2]Octane, 1, 8-diazabicyclo [5.4.0]Undec-7-ene and dimethylaminopyridine.
5. A process for the rhodium-catalyzed asymmetric hydrogenation of amino acid esters, characterized in that: carrying out asymmetric catalytic hydrogenation on dehydrogenated amino acid ester in an organic solvent in the presence of the chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand and iridium precursor to obtain optically active chiral amino acid ester; the hydrogenation reaction process is as follows:
the specific reaction steps are as follows: under the protection of argon or nitrogen, adding dehydroamino acid ester and chiral spiro [ chromane-4, 1' -indan into organic solvent]Phosphite ester monophosphorus ligand and rhodium precursor are filled with hydrogen and stirred at 0-60 ℃ for reaction for 3-48 hours to obtain optically active amino acid ester;
in the general formula (II):
R 2 ，R 3 is an alkyl group, an aryl group, or a hydrogen atom; r is R 4 Is an amino protecting group;
the configuration of the obtained chiral amino acid ester with the general formula II is [ ]R) -configuration or%S) -configuration.
6. The hydrogenation process according to claim 5, wherein said alkyl group is methyl, ethyl, propyl, butyl; the aryl is phenyl substituted or unsubstituted by alkyl, alkoxy and halogen atoms, and the alkyl is defined as above; alkoxy is methoxy, ethoxy, propoxy, butoxy; the amino protecting group is acetyl, alkoxycarbonyl, p-toluenesulfonyl or benzyl.
7. The hydrogenation process according to claim 5, wherein said organic solvent is one or more of methylene chloride, toluene, tetrahydrofuran, methanol, ethanol, isopropanol and t-butanol.
8. A hydrogenation process according to claim 5 wherein said rhodium metal precursor is [ Rh (cod) Cl] 2 (cod=cyclooctadiene), [ Rh (cod) 2 ]BF 4 、[Rh(cod) 2 ]PF 6 、[Rh(cod) 2 ]SbF 6 、[Rh(cod) 2 ]OTf）。
CN202310694973.9A 2023-06-13 2023-06-13 Synthesis and application of chiral spiro [ chromane-4, 1' -indan ] phosphite monophosphorus ligand Pending CN116655691A (en)

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