Synthesis and Application of Chiral Spiro[chroman-4,1′-indane] Phosphite Monophosphorus Ligands

Abstract

The present invention relates to the synthesis and application of a chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand. R / S )-2-oxospiro[chroman-4,1'-dihydroindene]-7'-phenol is used as the starting material. In the presence of an acid-binding agent, it can react with a disubstituted phosphorus chloride, or after treatment with phosphorus trichloride and then with an alcohol-phenol, to obtain a spiro[chroman-4,1'-dihydroindene] phosphite monophosphorus ligand. This ligand synthesis method is simple and economical. The resulting chiral monophosphorus ligand can be used in a variety of asymmetric catalytic reactions, such as achieving excellent enantioselectivity in the rhodium-catalyzed asymmetric catalytic hydrogenation of dehydrogenated amino acid esters. It has important application value and potential in the synthesis of chiral pharmaceuticals and flavors and fragrances.

Description

Technical Field

[0001] The present invention relates to the synthesis and application of a chiral spiro[chroman-4,1′-dihydroindene]phosphite monophosphorus ligand. This ligand can be used as a chiral ligand in asymmetric catalytic reactions, such as the rhodium-catalyzed asymmetric hydrogenation of dehydrogenated amino acid esters. It has high application value in the field of asymmetric catalysis and belongs to the field of asymmetric catalysis. Background Art

[0002] Asymmetric catalytic synthesis is a green and efficient means of obtaining chiral fine chemicals. For example, the chiral drug L-DOPA can be efficiently prepared through the rhodium-catalyzed hydrogenation of dehydrogenated amino acids (Knowles, WS; Sabacky, MJ; Vineyard, BD; Weinkauff, DJ, J Am. Chem. Soc. 1975, 97, 2567-2568). The development of chiral catalysts is one of the most core challenges in asymmetric catalytic synthesis. The design and synthesis of novel catalysts offers the opportunity to address the current lack of efficient and selective catalysts for some asymmetric reactions. Among existing chiral catalysts, catalysts with chiral spirocyclic structures are among the most efficient organometallic homogeneous catalysts to date. Chiral spirocyclic skeletons are a typical type of "privileged ligand skeleton" (Yoon, TP; Jacobsen, EN Privileged Chiral Catalysts. Science 2003, 299, 1691-1693.). Therefore, the development of new chiral spirocyclic ligands will help develop new asymmetric catalytic reactions, thereby providing greener and more efficient methods for the synthesis of chiral fine chemicals.

[0003] Chinese patent CN 109970697 B discloses a method for synthesizing chiral spiro[chroman-4,1′-dihydroindene] molecules, which is of great significance for studying and discovering the practical uses and application values of chiral spiro[chroman-4,1′-dihydroindene] molecules.

[0004] Chiral monophosphorus ligands are a very important class of chiral ligands (Guo Hongchao; Ding Kuiling; Dai Lixin. New progress in asymmetric catalytic hydrogenation - the revival of monodentate phosphorus ligands. Science Bulletin 2004, 49(16), 1575-7588.). Due to the lack of suitable chiral ligand skeletons, chiral phosphite monophosphorus ligands are very rare and the asymmetric reactions catalyzed by them can only achieve moderate to good selectivity and yield (Park, H.; Rajan Babu, TV J Am. Chem. S ℃. 2002, 124, 734-735.; Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron Asymmetry 2007, 18, 251-259.). Therefore, the development of chiral spirocyclic phosphite monophosphorus ligands with a new skeleton based on chiral spiro[chroman-4,1′-dihydroindan]phenol is of great significance and value. Summary of the Invention

[0005] The present invention aims to provide a chiral spiro[chroman-4,1′-dihydroindene]phosphite monophosphorus ligand having the following general formula (I):

[0006]

[0007] In the general formula (I):

[0008] R 1 is an alkyl group, an alkoxy group, an aryl group, an aryloxy group or a hydrogen atom.

[0009] The above term alkyl is preferably methyl, ethyl, propyl, butyl and the like.

[0010] The alkoxy group is preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like.

[0011] The aryl group is preferably a phenyl group which may be substituted or unsubstituted by an alkyl group or an alkoxy group, and the alkyl group and the alkoxy group are as defined above.

[0012] The present invention provides two methods for synthesizing the aforementioned compounds, which are synthesized by the following routes:

[0013]

[0014]

[0015] The specific steps of the first method are as follows: a starting material, chiral spirochroman dihydroindanol (R)-a or (S)-a, is reacted with a disubstituted phosphorus chloride in an organic solvent at a temperature within the range of 0 to 110° C. using a base as an acid-binding agent to obtain a chiral phosphite ligand; 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, or dimethylaminopyridine; and the disubstituted phosphorus chloride is a diarylphosphine chloride or a dialkylphosphine chloride.

[0016] The specific steps of the second method are as follows: the starting material chiral spirochroman dihydroindanol (R)-a or (S)-a reacts with phosphorus trichloride in an organic solvent at a temperature between 0 and 110° C. using a base as an acid-binding agent; the phosphorus trichloride is subsequently removed under reduced pressure, and the chiral phosphite ligand is reacted with a phenol or alcohol in an organic solvent at a temperature between 0 and 110° C. using a base as an acid-binding agent; the organic solvent is one or more of dichloromethane, toluene, and tetrahydrofuran, and the base is triethylamine, diisopropylethylamine, potassium carbonate, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or dimethylaminopyridine.

[0017] Another object of the present invention is to provide the use of the aforementioned ligand in asymmetric catalytic reactions, including hydrogenation, hydroformylation, hydrosilylation, hydroboration, hydrohydroxylation, hydroamination, hydrocyanation, isomerization formylation, hydroaminomethylation, transfer hydrogenation, allylation, olefin metathesis, cycloisomerization, Diels-Alder reaction, asymmetric coupling reaction, Aldol reaction, Michael addition reaction, asymmetric epoxidation, kinetic resolution and [m+n] cyclization reaction; according to the aforementioned application, the chiral spiro[chroman-4,1′-dihydroindane]phosphite monophosphorus ligand has high activity and enantioselectivity for the rhodium-catalyzed dehydrogenation of amino acid esters in an organic solvent; the preferred synthesis process of the aforementioned application is as follows:

[0018]

[0019] In the general formula (II):

[0020] R 2 , R 3 is an alkyl group, an aryl group, or a hydrogen atom.

[0021] The above term alkyl is preferably methyl, ethyl, propyl, butyl and the like.

[0022] The aryl group is preferably a phenyl group which is substituted or unsubstituted by an alkyl group, an alkoxy group or a halogen atom. The alkyl group is as defined above, and the alkoxy group is preferably a methoxy group, an ethoxy group, a propoxy group or a butoxy group.

[0023] R 4 is an amino protecting group, preferably an acetyl group, an alkoxycarbonyl group, a p-toluenesulfonyl group, a benzyl group or the like.

[0024] The specific catalytic asymmetric hydrogenation reaction route is:

[0025] Under argon or nitrogen protection, dehydrogenated amino acid ester, ligand, rhodium metal precursor and organic solvent are added to a hydrogenation kettle, stirred and dissolved, and then hydrogen is introduced and stirred and reacted at a suitable temperature and pressure for 3 to 48 hours to obtain an optically active amino acid ester; wherein the rhodium metal precursor is [Rh(cod)Cl]2 (cod=cyclooctadiene), [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Rh(cod)2]SbF6, [Rh(cod)2]OTf); and the organic solvent is one or more of dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.

[0026] The present invention provides a synthesis and application of a chiral spiro[chroman-4,1′-dihydroindene]phosphite monophosphorus ligand, which has the following beneficial effects on the prior art:

[0027] (1) The chiral spiro[chroman-4,1′-dihydroindene]phosphite monophosphite ligand has central chirality, and thus there are left-handed chiral spiro[chroman-4,1′-dihydroindene]phosphite ligands and right-handed chiral spiro[chroman-4,1′-dihydroindene]phosphite ligands. The racemic chiral spiro[chroman-4,1′-dihydroindene]phosphite ligand can be synthesized by using racemic spiro[chroman-4,1′-dihydroindene]monophenol as a raw material.

[0028] (2) The present invention can be used as a chiral catalyst in asymmetric hydrogenation. The ligand has high activity and enantioselectivity for the hydrogenation of dehydrogenated amino acid esters in organic solvents. For example, in the rhodium-catalyzed asymmetric catalytic hydrogenation reaction of dehydrogenated amino acid esters, excellent enantioselectivity can be achieved, with a yield of 99%, 88% ee-95% ee.

[0029] (3) The synthesis method of the chiral spiro[chroman-4,1′-dihydroindene]phosphite monophosphorus ligand is simple and economical. The obtained chiral monophosphorus ligand has important application value and great potential in the synthesis of chiral drugs, flavors and fragrances. DETAILED DESCRIPTION

[0030] The present invention is further illustrated by the following examples, which are intended only to facilitate a further understanding of the present invention and are not intended to limit the scope of the present invention. Experimental procedures not specifically specified in the examples were generally performed under conventional conditions, those described in the manual, or as recommended by the manufacturer. General equipment, materials, and reagents used were commercially available unless otherwise specified.

[0031] Example 1: Synthesis of (R)-7-bis-(3,5-dimethyl)-phenylphosphinooxy-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0032]

[0033] To a 25 mL dry Schlenk tube, (R)-spiro[chroman-4,1′-dihydroindene]monophenol a (133.1 mg, 0.5 mmol) was added. 4 mL of anhydrous toluene was added under argon, followed by the corresponding di-(3,5-dimethyl)-phenylphosphonium chloride (110.3 mg, 0.5 mmol). The tube was cooled to 0°C; triethylamine (162 μL, 1.25 mmol) was slowly added dropwise at 0°C. The tube was sealed and refluxed in an oil bath at 110°C for 14 hours. The solvent was removed under reduced pressure and the ligand was isolated by column chromatography (petroleum ether / ethyl acetate = 50:1 to 20:1) to obtain 218 mg of the ligand in a yield of 89%. Optical rotation: Melting point: 54-55℃. 1 H NMR(400MHz, CDCl3)δ:7.27-7.20(m,2H),7.10-6.93(m,5H),6.92-6.84(m,3H),6.80(dd,J=7.7,1.6Hz,1H),6.72 (d,J=8.3Hz,2H),3.38(d,J=15.7Hz,1H),2.97(t,J=7.5Hz,2H),2.69(d,J=15.7Hz,1H),2.21(d,J=14.9Hz,12H). 13 C NMR(101MHz, CDCl3)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. 31P NMR(162MHz,CDCl3)δ111.5.HRMS(ESI)Calcdfor C 33 H 32 O3P + :([M+H] + ):507.2084;Found:507.2088.

[0034] Among them, (R)-spiro[chroman-4,1′-dihydroindene]monophenol a was prepared according to Chinese patent CN 109970697 B. The specific synthetic route is as follows:

[0035]

[0036] Step 1: Weigh 3-(3-hydroxyphenyl)propionic acid (37.3 g, 224 mmol) into a dry 2000 mL reaction flask. Add dichloromethane (300 mL) and acetonitrile (150 mL) and stir at room temperature to dissolve. Cool the system to below 5°C using an ice-water bath. Then, using a constant pressure dropping funnel, add a dichloromethane solution of bromine (11.5 mL Br2 in 150 mL dichloromethane) dropwise over 1 hour. Continue stirring in an ice-water bath for 1.5 hours. After the reaction was completed, the system was quenched by hydrogen nuclear magnetic spectrum monitoring, and saturated sodium thiosulfate solution was added to quench the system. The solvent was removed under reduced pressure, and ethyl acetate (500 mL) was added to dissolve and dilute. The liquids were separated, and the aqueous phase was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and removed to obtain 3-(2-bromo-5-hydroxyphenyl)-propionic acid: a light yellow solid, 54.3 g, a yield of 99%, and a melting point of 152-155 ° C. (can be directly used in the next reaction without purification). 1 H NMR (400MHz, CD3OD) δ: 7.30 (d, J = 8.6Hz, 1H), 6.77 (s, 1H), 6.57 (d, J = 8.7Hz, 1H), 5.02 (brs, 2H), 2.94 (t, J = 7.8Hz, 2H), 2.59 (t, J = 7.8Hz, 2H). 13 C NMR (101MHz, CD3OD) δ175.0,156.8,140.6,133.0,116.9,115.0,112.5,33.5,31.1.

[0037] Step 2: To a 3000 mL dry reaction flask, add 3-(2-bromo-5-hydroxyphenyl)-propionic acid (40 g, 163 mmol) and carbonyldiimidazole (CDI) (28.6 g, 176 mmol). Dissolve the mixture in tetrahydrofuran (700 mL). Replace the atmosphere with argon and stir at room temperature for 8 hours. Add a solution of magnesium malonate monoethyl ester (39 g, 253 mmol) in tetrahydrofuran (300 mL) to the reaction system. Stir at room temperature for 12 hours. Complete reaction is monitored by TLC. Acidify the reaction with 1N HCl and extract with diethyl ether (2 x 150 mL). Combine the organic phases, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Filter through celite, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 5-(2-bromo-5-hydroxyphenyl)-3-oxopentanoic acid ethyl ester b as a light yellow foamy solid (39 g, 76% yield). 1 H NMR (400MHz, CDCl3) δ7.25(d,J=8.7Hz,1H),6.66(d,J=3.0Hz,1H),6.50(dd,J=8.7,3.1Hz,1H),4.04(q,J=7.2 Hz,2H),3.63(s,3H),3.31(s,2H),2.84(ddd,J=9.3,7.4,2.1Hz,2H),2.78-2.72(m,2H),1.13(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ202.4,167.5,155.5,140.7,133.6,117.6,115.5,114.2,61.7,49.3,42.7,30.0,14.1.

[0038] Step 3: Add 5-(2-bromo-5-hydroxyphenyl)-3-oxopentanoic acid ethyl ester b (17.8g, 56.5mmol) to a 1000mL dry reaction bottle and dissolve it in dichloromethane (300mL). Replace the system with argon atmosphere and use an ice-water bath to control the temperature in the system to below 5°C. Then slowly add trifluoromethanesulfonic acid (15.0mL, 169mmol) dropwise. After the addition is complete, remove the ice bath and stir the system at room temperature for 0.5 hours. TLC monitoring shows that the raw materials are completely converted and a large amount of yellow solid precipitates in the system. Add resorcinol (6.2g, 56.5mmol) to the reaction system and continue stirring at room temperature for 1 hour. TLC monitoring shows that the intermediate is completely converted. The reaction was quenched with ice water and extracted with ethyl acetate (2 × 150 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered through celite, and desolvated under reduced pressure. Column chromatography (petroleum ether / ethyl acetate = 5:1) was performed to obtain 4'-bromo-5-hydroxy-7'-hydroxy-spiro[chroman-4,1'-dihydroindane]-2-one c: a yellow foamy solid (16.9 g, 83% yield). 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.9Hz,1H),6.79(d,J=9.0Hz,1H),6.65(d,J=8.5Hz,1H),6.55(d,J=2.3Hz,1H),6.39-6.33(d d,1H),3.42(d,J=15.8Hz,1H),3.30-3.13(m,1H),2.94-2.83(m,2H),2.78(d,J=15.9Hz,1H),2.56-2.49(m,1H),2.28(m,1H). 13 C NMR (101MHz, CDCl3) δ170.5,158.8,155.2,152.4,146.9,133.3,132.8,127.5,121.5,117.1,112.7,108.8,104.7,54.8,51.4,40.9,40.8,33.1.

[0039] Step 4: To a 250 mL dry reaction flask, add 4'-bromo-5-hydroxy-7'-hydroxy-spiro[chroman-4,1'-dihydroindene]-2-one c (6.8 g, 18.8 mmol). Dissolve the mixture in dichloromethane (120 mL), followed by pyridine (3.0 mL, 37.6 mmol). Place the reaction mixture in an ice-water bath to cool the temperature to below 5°C, then slowly add trifluoromethanesulfonic anhydride (3.2 mL, 18.8 mmol) dropwise. After the addition is complete, remove the ice bath and stir the reaction at room temperature for 12 hours. Complete conversion of the starting material is monitored by TLC. Quench the reaction with ice water and extract with ethyl acetate (2 x 50 mL). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, filter over celite, remove the solvent under reduced pressure, and perform column chromatography (petroleum ether / ethyl acetate = 10:1). 4'-Bromo-5-trifluoromethanesulfonyloxy-7'-hydroxy-spiro[chroman-4,1'-dihydroindane]-2-one d was obtained as a yellow foamy solid, 7.0 g, with a yield of 76%. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.4Hz,1H),7.06(d,J=2.4Hz,1H),6.95(dd,J=8.6,2.5Hz,1H),6.87(d,J=8.6Hz,1H),6.58(dd,J=8.5,0.8H z,1H),5.55(s,1H),3.58(d,J=16.0Hz,1H),3.11-2.96(m,2H),2.87(d,J=16.0Hz,1H),2.36(m,J=13.3,8.6,6.9Hz,1H),2.25-2.16(m,1H). 13 C NMR (101MHz, CDCl3) δ167.3,151.9,150.9,148.6,146.2,133.0,130.2,129.6,127.3,120.2,117.4,116.4,110.8,110.7,50.4,39.3,39.0,32.3.

[0040] Step 5: To a 500 mL dry reaction flask, add 4'-bromo-5-trifluoromethanesulfonyloxy-7'-hydroxy-spiro[chroman-4,1'-dihydroindane]-2-one d (19.6 g, 39.7 mmol). Dissolve in anhydrous ethanol (230 mL). Then, add triethylamine (14 mL, 100 mmol) and 10% Pd / C (2.0 g, 1.9 mmol) to displace the H₂ atmosphere. Reaction was allowed to proceed at room temperature under 1 atm H₂ for 48 hours. Completion of the reaction was monitored by H₄NMR spectroscopy. Remove the solvent under reduced pressure, dissolve and dilute with ethyl acetate (200 mL), and acidify with 1N HCl until the insoluble matter disappears. The liquids were separated, the aqueous phase was extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, filtered through celite, desolvated, and the solid was washed with ether (3×20 mL) to obtain (rac)-2-oxospiro[chroman-4,1′-dihydroindene]-7′-phenol (rac)-a, 9.6 g, yield 91%. 1 H NMR (400MHz, CDCl3) δ7.27(m,1H),7.21(t,J=7.7Hz,1H),7.12(dd,J=8.2,1.2Hz ,1H),7.03(td,J=7.5,1.3Hz,1H),6.92(dd,J=7.5,1.0Hz,1H),6.82(dd,J=7.7,1 .6Hz,1H),6.67-6.62(m,1H),4.90(s,1H),3.54(d,J=15.9Hz,1H),3.00(t,J=7.3 Hz,2H),2.84(d,J=15.9Hz,1H),2.33(dt,J=12.8,7.4Hz,1H),2.24-2.13(m,1H). 13 C NMR (101MHz, CDCl3) δ168.4,152.4,150.7,146.7,130.0,128.7,125.6,124.8,117.7,117.3,114.4,49.3,40.4,39.2,30.6.

[0041] Step 6: (rac)-2-oxospiro[chroman-4,1′-dihydroindene]-7'-ol (rac)-a (7.0 g, 26.3 mmol) and N-benzylchlorocinchonidin e (3.2 g, 7.5 mmol) were weighed sequentially into a 250 mL dry reaction flask, a stirrer was placed, and dry tert-butyl methyl ether (130 mL) was added. The reaction system was refluxed in an oil bath preheated to 60°C with a magnetic stirrer set to 1000 rpm and stirred continuously for 24 hours. A large amount of white insoluble material was formed. After the system was cooled to room temperature, the filtrate was filtered and the insoluble material was separated. The mother liquor was recovered: the insoluble material was washed with ethyl acetate (3 × 20 mL). The filtrate and washings were combined and desolvated under reduced pressure to obtain (S)-a, which was not bound to the resolving agent. Yield: 62%, 62% ee. Dissociation of the Inclusion Complex: Place the insoluble material in a 250 mL beaker and dilute with ethyl acetate (80 mL). Continue adding 1N HCl until no insoluble material remains. Separate the mixture using a separatory funnel. Extract the aqueous phase with ethyl acetate (2 x 50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter over celite, and remove the solvent under reduced pressure to obtain (R)-a, which is complexed with the resolving agent. Yield: 40%, 95% ee.

[0042] Both products were recrystallized from n-hexane-methyl tert-butyl ether to afford (S)-a in 36% yield and >99% ee, and (R)-a in 34% yield and >99% ee, respectively. HPLC conditions: Chiralcel IC-3 column (25 cm × 0.46 cm ID); n-hexane / 2-propanol ratio = 85:15; temp, rt; flow rate = 1.0 mL / min; 88 bars; 220 nm UV detector.

[0043] Example 2: Synthesis of (R)-7-diphenylphosphinoyl-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0044]

[0045] The operation was the same as in Example 1, white solid, 75.5 mg, yield 42%, melting point 58-60 ℃. 1H NMR(400MHz, CDCl3)δ:7.36-7.20(m,8H),7.19-7.13(m,2H),7.10(d,J=8.1Hz,1H),7.06-6.94(m,5H),6.84(d,J=7.6 Hz,1H),3.29(d,J=15.7Hz,1H),3.00(t,J=7.4Hz,2H),2.70(d,J=15.7Hz,1H),2.38-2.25(m,1H),2.24-2.09(m,1H). 13 C NMR(101MHz, CDCl3)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(162MHz,CDCl3)δ:110.1.HRMS(ESI)Calcd for C 29 H 23 NaO3P + ([M+Na] + ):473.1277;Found:473.1280.

[0046] Example 3: Synthesis of (R)-7-di-(4-methylphenyl)-phosphinoyl-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0047]

[0048] The operation was the same as in Example 1, the oily liquid, 84.2 mg, yield 44%, 1H NMR (400MHz, CDCl3) δ7.27(td,J=8.2,1.5Hz,1H),7.22(t,J=7.8Hz,1H),7.15-7.06(m,5H),7.06-6.99(m,2H),6.97(dd,J=6.9,4.6Hz,3H),6.86(t,J =7.8Hz,2H),6.82(dd,J=7.7,1.4Hz,1H),3.30(d,J=15.7Hz,1H),2.98(t,J =7.3Hz,2H),2.67(d,J=15.7Hz,1H),2.35-2.25(m,7H),2.18-2.10(m,1H). 13 C NMR (101MHz, CDCl3) δ168.3,154.2,154.1,150.6,146.6,140.4,139.5,136.9,136.9,136.8,136.7,132.5,132.5,130.8,130.6,130.2 ,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(162MHz,CDCl3)δ110.7.HRMS(ESI)Calcd for C 31 H 27 NaO3P + ([M+Na] + ):501.1590;Found:501.1594.

[0049] Example 4: Synthesis of (R)-7-di-(3,5-di-tert-butyl)-phenylphosphinoyl-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0050]

[0051] To a 25 mL dry Schlenk tube, add (R)-2-oxospiro[chroman-4,1′-dihydroindene]-7′-phenol(R)-a (107 mg, 0.4 mmol) and 1,4-diazabicyclo[2.2.2]octane (112 mg, 1.0 mmol). 4 mL of anhydrous toluene was added under argon and cooled to 0°C. Then, di-(3,5-di-tert-butyl)phenylphosphonium chloride (178 mg, 0.4 mmol) was added. The tube was sealed and stirred at room temperature for 14 hours. The solvent was removed under reduced pressure and column chromatography (petroleum ether / ethyl acetate = 50:1 to 20:1) was performed to isolate the ligand, 122 mg, 45% yield, optically active. 1 H NMR (400MHz, CDCl3) δ7.29 (d, J=17.82Hz, 2H), 7.18-7.14 (m, 1H), 7.12 (dd, J=8.76, 1.86Hz, 2 H),7.07(dd,J=8.67,1.85Hz,2H),7.05-6.97(m,2H),6.90(d,J=7.42Hz,1H),6.87-6.78(m,2 H),6.57-6.48(m,1H),3.32(d,J=15.55Hz,1H),2.84(td,J=7.87,6.35,4.13Hz,2H),2.53(d, J=15.53Hz,1H),2.16(dt,J=12.86,8.34Hz,1H),2.06-1.96(m,1H),1.14(d,J=2.89Hz,36H). 13 C NMR (101MHz, CDCl3) δ168.2,150.9,150.8,150.5,150.4,150.2,146.8,138.9,138.8,138.7,138.5,131.8,131.7,130.0,12 9.9,128.0,125.5,125.4,125.2,124.4,124.1,123.7,118.6,117.0,116.1,115.9,49.5,40.3,39.7,34.9,31.4,31.3,30.2. 31 P NMR(162MHz,CDCl3)δ113.6.HRMS(ESI)Calcd for C 45 H 56 O3P + ([M+H] + ):675.3962;Found:675.3962.

[0052] Example 5: Synthesis of (R)-7′-diphenoxyphosphinyloxy-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0053]

[0054] To a 25 mL dry Schlenk tube, add (R)-2-oxospiro[chroman-4,1′-dihydroindane]-7'-phenol (R)-a (133.1 mg, 0.5 mmol). Dissolve in anhydrous dichloromethane (4 mL) under argon. Then, add a dichloromethane solution of phosphorus trichloride (1.25 mL, 2.0 M, 2.5 mmol) and stir to dissolve. Cool to 0°C. Slowly add triethylamine (649 μL, 5 mmol) dropwise at 0°C and allow to warm to room temperature for 30 min. The solvent and excess phosphorus trichloride were removed under reduced pressure using a high vacuum pump, and anhydrous dichloromethane (3 mL) was added to dissolve the mixture. The corresponding phenol (94 mg, 1.0 mmol) was added and cooled to 0°C. Triethylamine (649 μL, 5 mmol) was slowly added dropwise at 0°C. The mixture was naturally warmed to room temperature and reacted for 14 hours. The solvent was removed under reduced pressure and the target ligand was isolated by column chromatography (petroleum ether / ethyl acetate = 50:1 to 20:1). The yield was 55%, 133 mg, melting point: 158-159°C, optical rotation: 1 H NMR (400MHz, CDCl3) δ7.32-7.20(m,4H),7.20-7.02(m,8H),7.00-6.90(m,3H),6.71(d,J=8.5Hz,2H),6.62(dd,J=7.7 ,1.6Hz,1H),3.15(d,J=15.7Hz,1H),3.03-2.86(m,2H),2.61(d,J=15.7Hz,1H),2.32-2.19(m,1H),2.17-2.04(m,1H). 13 C NMR (101MHz, CDCl3) δ168.1,151.3,151.3,151.1,150.6,149.7,149.6,147.8,132.8,132.8,130.1,129.9,1 29.6,129.6,128.4,125.8,124.6,124.5,120.8,120.7,120.6,120.6,117.4,117.2,49.8,40.3,39.3,30.5. 31 P NMR(162MHz,CDCl3)δ126.2.HRMS(ESI)Calcd for C 29 H 24 O5P + ([M+H] +):483.1356;Found:483.1359.

[0055] Example 6: Synthesis of (R)-7′-(2,2-biphenyl)oxyphosphinyloxy-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one:

[0056]

[0057] The operation was the same as in Example 5, oily liquid, 151 mg, yield 63%, melting point: 93-95 ° C, optical rotation: 1 H NMR (400MHz, CDCl3) δ7.39(dt,J=6.7,2.0Hz,2H),7.34-7.18(m,7H),7.14(t,J=8.2Hz,2H),7.10-6.98(m,2H),6.70(dd,J=7.7,1.5Hz,1H),6.48 -6.37(m,1H),3.35(d,J=15.7Hz,1H),2.99(t,J=7.4Hz,2H),2.67(d,J=15.7Hz,1H),2.30(dt,J=12.9,7.7Hz,1H),2.15(dt,J=13.3,6.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ168.0,150.6,149.2,149.2,148.8,148.8,148.7,148.7,147.6,133.3,133.3,131.0,130.9,130.8,130.8,130. 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(162MHz,CDCl3)δ144.32.HRMS(ESI)Calcd for C 29 H 22 O5P + ([M+H] + ):481.1199;Found:481.1196.

[0058] Example 7: Asymmetric catalytic hydrogenation of methyl N-acetylamino-3-phenylacrylate:

[0059]

[0060] In a glove box, place methyl N-acetylamino-3-phenylacrylate (55 mg, 0.25 mmol), the ligand (R)-7-di-(3,5-dimethyl)-phenylphosphinoyl-2′,3′-dihydrospiro[chroman-4,1′-indene]-2-one (2.5 mg, 0.005 mmol), and Rh(COD)2BF4 (1.02 mg, 0.0025 mmol) into a clean, dry hydrogenation inner tube, seal the tube, and remove. The inner tube was placed in an autoclave, the atmosphere replaced with nitrogen, and anhydrous dichloromethane (5 mL) was added and stirred to dissolve. The atmosphere in the autoclave was replaced with hydrogen three times, and then flushed with 20 atm of hydrogen. The tube was sealed and stirred at 0°C. After 24 hours of reaction, the hydrogen in the reactor was slowly released. After desolvation, the conversion was determined by nuclear magnetic resonance. The crude product was purified by column chromatography to obtain the hydrogenated product. The enantioselectivity of the product was determined by chiral GC (Varian Chirasil-L-Val column 25m×0.25mm×0.12μm; N2 1.8mL / min; 90℃then 4℃ / min to 220℃)t R =18.9min,t S =19.3 min., yield 99%, 92% ee. 1 H NMR (400MHz, CDCl3) δ7.40-7.22(m,3H),7.09(d,J=6.9Hz,2H),5.88(s,1H),4.89(q,J=5.9Hz,1H),3.73(s,3H),3.24-3.01(m,2H),1.99(s,3H).

[0061] Example 8: Asymmetric catalytic hydrogenation of ethyl N-acetylamino-3-phenylacrylate:

[0062]

[0063] The operation is the same as in Example 7. 1H NMR (400MHz, CDCl3) δ7.20(q,J=6.43,5.36Hz,3H),7.04(d,J=7.25Hz,2H),6.08(d,J=7.84Hz,1H),4.78(q ,J=6.55Hz,1H),4.08(q,J=7.14Hz,2H),3.13-2.90(m,2H),1.89(s,3H),1.16(t,J=7.17Hz,3H).Chiralcel AD-H column (25cm×0.46cm ID); n-hexane / 2-propanol=90:10; temp, 20℃; flow rate=1.0mL / min; 50bars; 210nm UV detector; t1(major)=8.6min; t2(minor)=12.9min. Yield 99%, 94% ee.

[0064] Example 9: Asymmetric catalytic hydrogenation of N-acetylamino-3-p-methylphenyl acrylate:

[0065] The operation is the same as in Example 7. 1 H NMR (400MHz, CDCl3) δ7.20(q,J=6.43,5.36Hz,3H),7.04(d,J=7.25Hz,2H),6.08(d,J=7.84Hz,1H),4.78 (q,J=6.55Hz,1H),4.08(q,J=7.14Hz,2H),3.13-2.90(m,2H),1.89(s,3H),1.16(t,J=7.17Hz,3H).HPLC condition: ChiralcelAD-Hcolumn (25cm×0.46cm ID); n-hexane / 2-propanol=90:10; temp, 20℃; flow rate=1.0mL / min; 50bars; 230nm UV detector; t1(major)=9.5min; t2(minor)=12.8min. Yield 99%, 89% ee.

[0066] Example 10: Asymmetric catalytic hydrogenation of N-acetylamino-3-(p-chlorophenyl)acrylate

[0067] The operation is the same as in Example 7. 1H NMR (400MHz, CDCl3) δ7.29-7.23(m,2H),7.07-6.96(m,2H),6.03-5.79(m,1H),4.87(dt,J=7.96, 5.81Hz,1H),3.73(d,J=1.02Hz,3H),3.10(qd,J=13.93,5.70Hz,2H),1.99(d,J=0.97Hz,3H).HPLC condition: Chiralcel AD-H column (25cm×0.46cm ID); n-hexane / 2-propanol=90:10; temp, 20℃; flow rate=1.0mL / min; 50bars; 230nm UV detector; t1(major)=10.9min; t2(minor)=13.3min. 99% yield, 90% ee.

[0068] Example 11: Asymmetric catalytic hydrogenation of N-acetylamino-3-methylphenyl acrylate:

[0069] The operation was the same as in Example 7, with a yield of 99%, 89% ee, 1 H NMR (400MHz, CDCl3) δ7.16(d,J=15.05Hz,1H),7.05(d,J=7.66Hz,1H),6.95-6.80(m,2H),6.01(d,J=6.15Hz,1 HPLC condition: Chiralcel AD-H column (25cm×0.46cm ID); n-hexane / 2-propanol=90:10; temp, 20℃; flow rate=1.0mL / min; 50bars; 210nm UV detector; t1 (major) = 6.5min; t2 (minor) = 11.4min.

[0070] Example 12: Asymmetric catalytic hydrogenation of methyl N-acetylamino-3-o-methylphenylacrylate:

[0071] The operation was the same as in Example 7, with a yield of 99%, 88% ee, 1H NMR (400MHz, CDCl3) δ7.28-7.17(m,3H),7.12(d,J=7.32Hz,1H),6.19(d,J=8.15Hz,1H),4.95(q,J=7.16Hz,1H ),3.77(s,3H),3.24(dd,J=14.08,6.64Hz,1H),3.12(dd,J=14.12,7.02Hz,1H),2.42(s,3H),2.05(s,3H).HPLC condition: Chiralcel AD-H column (25cm×0.46cm ID); n-hexane / 2-propanol=90:10; temp, 20℃; flow rate=1.0mL / min; 50bars; 210nm UV detector; t1 (major) = 8.1min; t2 (minor) = 11.5min.

[0072] Example 13: Asymmetric catalytic hydrogenation of N-acetylamino-3-(2-naphthyl)-methyl acrylate:

[0073] The operation was the same as in Example 7, with a yield of 99%, 89% ee, 1 H NMR (400MHz, CDCl3) δ7.85-7.73(m,3H),7.56(s,1H),7.51-7.41(m,2H),7.22(dd,J=8.44,1.72Hz,1H),6.09(d ,J=7.90Hz,1H),4.97(dt,J=8.08,5.91Hz,1H),3.72(s,3H),3.27(qd,J=13.90,5.90Hz,2H),1.96(s,3H).HPLC condition: Chiralcel AD-H column (25cm×0.46cm ID); n-hexane / 2-propanol=95:5; temp, 20℃; flow rate=1.0mL / min; 45bars; 254nm UV detector; t1 (major) = 14.5min; t2 (minor) = 21.7min.

Claims

1. A chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand, the compound is R The chiral ligand has the following general formula (I): , R 1 is alkyl, alkoxy, aryl, aryloxy; the alkyl is methyl, ethyl, propyl, butyl; the alkoxy is methoxy, ethoxy, propoxy, butoxy; The aryl group is a phenyl group which is substituted or unsubstituted by an alkyl group or an alkoxy group, wherein the alkyl group substituted is a methyl group, an ethyl group, a propyl group or a butyl group, and the alkoxy group substituted is a methoxy group, an ethoxy group, a propoxy group or a butoxy group.

2. A method for synthesizing the chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand according to claim 1, characterized in that The steps include: , Chirality of starting materials ( R )-2-oxospiro[chroman-4,1'-dihydroindene]-7'-phenol( R )-a reacts with a disubstituted phosphorus chloride in an organic solvent at a temperature between 0 and 110°C using a base as an acid-binding agent to obtain a chiral phosphite ligand; 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, or dimethylaminopyridine; and the disubstituted phosphorus chloride is a diarylphosphine chloride; R 1 Same as in general formula (I).

3. A method for synthesizing the chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand according to claim 1, characterized in that The steps include: , Starting material ( R )-2-oxospiro[chroman-4,1'-dihydroindene]-7'-phenol( R )-a reacts with phosphorus trichloride in an organic solvent at 0°C with a base as an acid-binding agent; subsequently, the phosphorus trichloride is removed under reduced pressure, and the reaction is carried out with a phenol or alcohol in an organic solvent at 0-110°C with a base as an acid-binding agent to obtain a chiral phosphite ligand; the organic solvent is one or more of dichloromethane, toluene, and tetrahydrofuran, and the base is triethylamine, diisopropylethylamine, potassium carbonate, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or dimethylaminopyridine; R 1 Same as in general formula (I).

4. A method for the asymmetric hydrogenation of rhodium-catalyzed dehydrogenation of amino acid esters, characterized in that: In the presence of the chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand and a rhodium precursor as claimed in claim 1, a dehydrogenated amino acid ester is subjected to asymmetric catalytic hydrogenation in an organic solvent to obtain an optically active chiral amino acid ester; the hydrogenation reaction process is: ， In the general formula (II): R 2 , R 3 is an alkyl group, an aryl group, or a hydrogen atom; the alkyl group is a methyl group, an ethyl group, a propyl group, or a butyl group; The aryl group is a phenyl group which is substituted or unsubstituted by an alkyl group or an alkoxy group, wherein the alkyl group substituted is a methyl group, an ethyl group, a propyl group or a butyl group, and the alkoxy group substituted is a methoxy group, an ethoxy group, a propoxy group or a butoxy group; R 4 Amino protecting groups: acetyl, alkoxycarbonyl, p-toluenesulfonyl, benzyl; The configuration of the chiral amino acid ester of formula II is ( R )-configuration.

5. The hydrogenation process according to claim 4, characterized in that The reaction steps are as follows: under argon or nitrogen protection, adding dehydrogenated amino acid ester, chiral spiro[chroman-4,1'-dihydroindene]phosphite monophosphorus ligand, and rhodium precursor to an organic solvent, injecting hydrogen, and stirring the reaction at 0-60°C for 3-48 hours to obtain an optically active amino acid ester.

6. The hydrogenation process according to claim 4, characterized in that The organic solvent is one or more of dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, and tert-butanol.

7. The hydrogenation process according to claim 4, characterized in that The rhodium metal precursor is [Rh(cod)Cl]2, [Rh(cod)2]BF4, [Rh(cod)2]PF6, [Rh(cod)2]SbF6, [Rh(cod)2]OTf; and the (cod) is cyclooctadiene.

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