CN104086477B - Preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof - Google Patents

Preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof Download PDF

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CN104086477B
CN104086477B CN201410336580.1A CN201410336580A CN104086477B CN 104086477 B CN104086477 B CN 104086477B CN 201410336580 A CN201410336580 A CN 201410336580A CN 104086477 B CN104086477 B CN 104086477B
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methyl
indole
phenyl
phenyl sulfonyl
arylsulfonyl
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CN104086477A (en
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刘全忠
李献静
刘泽水
康泰然
何龙
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China West Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention relates to a synthesis method of optical-activity spiropentylindole, particularly a preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof. Arylsulfonyl indole and vinyl cyclopropane used as raw materials react by using tetrahydrofuran as a solvent and chiral phosphine ligand-palladium complex as a catalyst for 2-96 hours. The optical-activity spiropentyl-1,3'-indole is synthesized from the arylsulfonyl indole and vinyl cyclopropane under the catalytic action of the metal palladium and chiral ligand; the yield is 65-95%, and the optical purity of the product is 78-97%ee; and compared with the existing method, the method provided by the invention has the advantages of high yield and simple preparation process.

Description

The preparation method of optical activity spiro cyclopentane -1,3 '-indole and its derivant
Technical field
The present invention relates to a kind of synthetic method of optical activity spiro cyclopentane indole, specially optical activity spiro cyclopentane- 1, the preparation method of 3 '-indole and its derivant.
Background technology
Indole derivativeses are especially many natural products and drug molecule in 3 indole containing spirocyclic ring scaffold of indole Important component part, therefore such compound has very important bio-pharmacology activity.Current spiro indole compound Primary synthetic methods are had and are transformed using oxoindole derivative, the pi-allyl chemical combination that chiral iridium catalyst indole replaces The intramolecular asymmetric allylation of thing is also the important method of synthesis of chiral spiro indole.But these methods need many Step conversion, or need to make the indole derivativeses of pi-allyl replacement in advance, cause preparation process complexity, low yield.
The content of the invention
The purpose of the present invention is to overcome the deficiencies in the prior art, there is provided the optical activity spiral shell that a kind of process is simple, yield is high The product of ring indole preparation method and its gained.
Specifically technical scheme is：
Optical activity spiro cyclopentane -1,3 '-indole, it is characterised in that：Its chemical structural formula is,
Wherein Ar is aryl, and R ', R ", R " ' are one or more of alkyl, aryl or hydrogen, R ', R ", R " ' can with identical, Can also be different.
Optical activity spiro cyclopentane -1,3 '-indole is obtained by following methods：
With arylsulfonyl indole and vinylcyclopropane as raw material, tetrahydrofuran as solvent, by arylsulfonyl indole and Vinylcyclopropane, tetrahydrofuran are with ratio 1mmol: 2-4mmol: 6-10mL mixed dissolution, and the amount for adding material is aryl sulphur The Pd (dba) of acyl indole 5-15mol%2With the chiral phosphine ligand of 10-30mol% as catalyst；2-96h is stirred at room temperature Until reaction is finished, react the mixture for finishing and add saturation NH4Cl aqueous solutions, are extracted, the organic faciess of gained with ethyl acetate, Jing anhydrous sodium sulfate dryings；Jing column chromatographic isolation and purifications after solvent are steamed, optical activity spiro cyclopentane -1,3 '-indole is obtained Compound.
Course of reaction is：
In above-listed reaction equation, Ar is aryl, and R ', R ", R " ' are one or more in alkyl, aryl or hydrogen, Ke Yixiang Together, it is also possible to different.
Obtained with optically active spiro cyclopentane -1,3 '-indole as catalyst with chiral phosphine ligand and palladium complex.
Described chiral phosphine ligand is one or more mixing in BINAP, DIOP, chiral phosphoramide part Thing.
Optical activity spiro cyclopentane -1,3 '-indole obtains having four handss in alkalescence condition stereo selectivity decarboxylic reaction Spiro cyclopentane -1 of property Stereocenter, 3 '-indole derivativeses, derivant method only provided by the present invention just can be obtained, Structural formula is as follows：
Wherein Ar is aryl, and R ', R ", R " ' are one or more of alkyl, aryl or hydrogen, can be with identical, it is also possible to no Together.
Hydrolytic process is：
Optical activity spiro cyclopentane -1 that the present invention is provided, 3 '-indole and preparation method thereof, with arylsulfonyl indole and second Thiazolinyl cyclopropane synthesizes under Metal Palladium and chiral phosphine ligand catalysis, and between 65-95%, product optical purity is its yield 78-97%ee, is difficult to synthesize with additive method, and this preparation process is simple.
Specific embodiment
The specific embodiment of the present invention is illustrated by the following examples.
Embodiment 1
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1a, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [phenyl (phenyl sulfonyl) methyl] -1H- indole 4a (36.1mg, 0.1mmol), displacement is wherein Air after, add anhydrous and oxygen-free tetrahydrofuran (1mL), after 30min is stirred at room temperature, thereto inject vinylcyclopropane two Methyl formate 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture addition 5mL Saturation NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, and Jing anhydrous sodium sulfates are done It is dry.Steam Jing column chromatographic isolation and purifications after solvent (petroleum ether: ethyl acetate=10: 1), obtain (1R, 2S, 5R) -2 '-methyl - 2- phenyl -5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dimethyl dicarboxylate 1a.Yield 71%, colourless oil liquid, 96%ee (AD-H, normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=8.7min, tminor= 15.1min).[α]D 26=52.8 °. (c=0.14, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.16 (d, J=6.9Hz, 1H), 7.38-7.26 (m, 3H), 7.04-6.94 (m, 3H), 62.84 (d, J= 7.3Hz, 2H), 5.05-4.91 (m, 3H), 4.77 (dd, J=9.7Hz, 2.4Hz, 1H), 3.84 (s, 3H), 3.67 (t, J= 13.9Hz, 1H), 3.23 (s, 3H), 3.13-3.06 (m, 1H), 2.55 (dd, J=14.4Hz, 6.6Hz, 1H), 2.42 (s, 3H) .13C NMR (100MHz, CDCl3, ppm)：δ 181.9,173.2,170.8,155.2,136.6,135.2,133.6,129.3, 128.3,127.7,127.4,125.7,124.6,120.2,117.4,73.8,63.8,56.1,53.4,52.3,49.6,39.6, 15.8。
Embodiment 2
Optical activity spiro cyclopentane -1, the synthesis of 3 '-benzazolyl compounds 1a, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), DIOP (7.5mg, 0.015mmol) and 2- Methyl -3- [(1 '-phenyl sulfonyl) methyl] -1H- indole 4a (36.1mg, 0.1mmol), after replacing air therein, The tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after stirring 30min, vinylcyclopropane dicarboxylic acid methyl ester 3 is injected thereto (55.3mg, 0.30mmol).Said mixture is stirred at room temperature until reaction 2d, reactant mixture addition saturation NH4Cl water Solution (5mL), with ethyl acetate extractive reaction liquid three times, each 10mL, merges organic faciess, Jing anhydrous sodium sulfate dryings.Steam (petroleum ether: ethyl acetate=10: 1) obtains (1R, 2S, 5R) -2- (1,-phenyl) -2 '-first to Jing column chromatographic isolation and purifications after solvent Base -5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1a, yield 45%, colourless oil liquid, 11%ee (AD-H, normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=8.5min, tminor= 15.5min).[α]D 26=12.0 °. (c=0.10, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.16 (d, J=6.9Hz, 1H), 7.38-7.26 (m, 3H), 7.04-6.94 (m, 3H), 62.84 (d, J= 7.3Hz, 2H), 5.05-4.91 (m, 3H), 4.77 (dd, J=9.7Hz, J=2.4Hz, 1H), 3.84 (s, 3H), 3.67 (t, J= 13.9Hz, 1H), 3.23 (s, 3H), 3.13-3.06 (m, 1H), 2.55 (dd, J=14.4Hz, J=6.6Hz, 1H), 2.42 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 181.9,173.2,170.8,155.2,136.6,135.2,133.6, 129.3,128.3,127.7,127.4,125.7,124.6,120.2,117.4,73.8,63.8,56.1,53.4,52.3, 49.6,39.6,15.8.
Embodiment 3
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1b, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [4 '-chlorphenyl (phenyl sulfonyl) methyl] -1H- indole 4b (39.6mg, 0.1mmol), put After changing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring is injected thereto Propane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture Add 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, the anhydrous sulfur of Jing Sour sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (4- chlorphenyls) -2 '-methyl -5- ethylene Base spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1b, yield 63%, colourless oil liquid, 97%ee (AD-H, just Hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=9.1min, tminor=11.7min). [α]D 26 =33.4 °. (c=0.14, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ8.12 (d, J=7.4Hz, 1H), 7.39-7.26 (m, 3H), 6.94 (d, J=8.5Hz, 2H), 6.77 (d, J=8.6Hz, 2H), 5.05- 4.91 (m, 3H), 4.77 (dd, J=9.4Hz, J=2.3Hz, 1H), 3.84 (s, 3H), 3.65 (t, J=13.9Hz, 1H), 3.28 (s, 3H), 3.12-3.05 (m, 1H), 2.56 (dd, J=14.3Hz, J=6.6Hz, 1H), 2.40 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 181.7,173.1,170.6,155.2,136.2,133.7,133.5,133.4,130.6, 128.5,127.9,125.6,124.8,120.3,117.5,73.6,63.6,55.4,53.5,52.5,49.5,39.6,15.7.
Embodiment 4
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1c, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) and 2- methyl -3- [4 '-methoxyphenyl (phenyl sulfonyl) methyl] -1H- indole 4c (39.1mg, 0.1mmol), the tetrahydrofuran (1mL) that anhydrous and oxygen-free is added after air therein is replaced, after 30min is stirred at room temperature, thereto Injection vinylcyclopropane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture adds 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge Organic faciess, Jing anhydrous sodium sulfate dryings.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (4- methoxyl groups Phenyl) -2 '-methyl -5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1c, yield 75%, colorless oil Liquid, 95%ee (AD-H, normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=11.1min, Tminor=20.5min). [α]D 27=50.6 °. (c=0.16, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.16 (d, J=8.0Hz, 1H), 7.38 (d, J=8.6Hz, 1H), 7.34-7.25 (m, 2H), 6.78-6.74 (m, 2H), 6.51-6.47 (m, 2H), 5.05-4.90 (m, 3H), 4.78-4.75 (m, 1H), 3.84 (s, 3H), 3.27 (s, 3H), 3.11-3.04 (m, 1H), 2.54 (dd, J=14.3Hz, J=6.5Hz, 1H), 2.41 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.1,173.3,170.9,158.7,155.3,136.7,133.7,130.3,128.2, 127.2,125.7,124.6,120.2,117.3,113.1,73.9,63.7,55.5,55.0,53.3,52.5,49.5,39.6, 15.8。
Embodiment 5
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1d, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) and 2- methyl -3- [3 '-methoxyphenyl (phenyl sulfonyl) methyl] -1H- indole 4d (39.1mg, 0.1mmol), the tetrahydrofuran (1mL) that anhydrous and oxygen-free is added after air therein is replaced, after 30min is stirred at room temperature, thereto Injection vinylcyclopropane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture adds 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge Organic faciess, Jing anhydrous sodium sulfate dryings.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (3- methoxyl groups Phenyl) -2 '-methyl -5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1d, yield 67%, colorless oil Liquid, 95%ee (AD-H, normal hexane: ethanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=6.5min, Tminor=11.2min). [α]D 27=40.2 °. (c=0.1, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.20 (d, J=7.1Hz, 1H), 7.39 (d, J=7.5Hz, 1H), 7.34-7.26 (m, 2H), 6.91 (t, J=7.9Hz, 1H), 6.57 (dd, J=11.4Hz, J=2.2Hz, 2H), 6.29 (s, 1H), 5.06-4.92 (m, 3H), 4.77 (dd, J=9.3Hz, J=2.0Hz, 1H), 3.84 (s, 3H), 3.67 (t, J=13.9Hz, 1H), 3.39 (s, 3H), 3.24 (s, 3H), 3.13-3.06 (m, 1H), 2.55 (dd, J=14.3Hz, J=6.5Hz, 1H), 2.41 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.0,173.2,170.8,158.8,155.4,136.8,136.6,133.6,128.7, 128.3,125.7,124.6,122.1,120.3,117.4,114.1,113.4,73.7,63.8,56.0,54.9,53.4, 52.4,49.6,39.6,15.8.
Embodiment 6
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1e, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [1 '-naphthyl (phenyl sulfonyl) methyl] -1H- indole 4e (41.1mg, 0.1mmol), displacement After air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring third is injected thereto Alkane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred until reacting 3.5d, reactant mixture adds at 0 DEG C Enter 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, Jing anhydrous slufuric acids Sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (1 '-naphthyl) -2 '-methyl -5- vinyls Spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1e, yield 57%, colourless oil liquid, 78%ee (AD-H, just oneself Alkane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=8.3min, tminor=19.6min). [α]D 26 =-19.1 °. (c=0.18, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1HNMR (400MHz, CDCl3, ppm)：δ8.73 (d, J=8.8Hz, 1H), 8.25 (t, J=3.6Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.63 (dd, J=8.2Hz, 1.1Hz, 1H), 7.53 (dd, J=6.0Hz, 3.2Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.33 (dd, J=10.3Hz, 4.6Hz, 3H), 6.92-6.87 (m, 2H), 6.11 (s, 1H), 5.03-4.96 (m, 2H), 4.81-4.78 (m, 1H)；3.30- 3.24 (m, 1H), 3.08 (s, 3H), 2.58 (dd, J=14.3Hz, 6.4Hz, 1H), 2.43 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.0,173.7,170.9,155.4,136.8,133.9,133.6,132.5,131.5,129.0, 128.3,128.1,126.6,126.4,126.0,125.2,124.6,124.0,123.2,120.2,117.5,74.6,64.3, 53.5,52.2,49.6,48.2,40.2,16.2.
Embodiment 7
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1f its, reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [(3 '-chlorphenyl phenyl sulfonyl) methyl] -1H- indole 4f (39.6mg, 0.1mmol), put After changing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring is injected thereto Propane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture Add 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, the anhydrous sulfur of Jing Sour sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (3 '-chlorphenyl) -2 '-methyl -5- second Thiazolinyl spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1f, yield 71%, colourless oil liquid, 96%ee (AD-H, Normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=7.9min, tminor=14.7min). [α]D 26=30.4 °. (c=0.58, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.12 (d, J=7.8Hz, 1H), 7.39 (d, J=7.2Hz, 1H), 7.35-7.29 (m, 2H), 7.03-7.01 (m, 1H), 6.88 (t, J=7.9Hz, 2H), 6.69 (d, J=8.0Hz, 1H), 5.03-4.92 (m, 3H), 4.80-4.77 (m, 1H)；3.85 (s, 3H), 3.66 (t, J=13.9Hz, 1H), 3.29 (s, 3H), 3.13-3.06 (m, 1H), 2.56 (dd, J=14.4Hz, 6.5Hz, 1H), 2.42 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 181.6,173.0,170.5,155.2,137.2,136.1, 133.5,133.4,129.6,128.9,128.5,127.6,127.3,125.6,124.8,120.3,117.6,73.6,63.7, 55.5,53.5,52.5,49.5,39.6,15.8.
Embodiment 8
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1g, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [(4 '-methyl phenyl phenyl sulfonyl) methyl] -1H- indole 4g (37.5mg, 0.1mmol), After replacing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, vinyl is injected thereto Ethylene-malonic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reaction mixing Thing adds 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, and Jing is anhydrous Sodium sulfate is dried.Steam Jing column chromatographic isolation and purifications after solvent obtain (1R, 2S, 5R) -2- (4 '-aminomethyl phenyl) -2 '-methyl - 5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1g, yield 69%, colourless oil liquid, 96%ee (AD-H, normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=7.9min, tminor= 13.2min).[α]D 27=30.9 °. (c=0.16, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.16 (d, J=6.9Hz, 1H), 7.36 (d, J=7.2Hz, 1H), 7.33-7.29 (m, 1H), 7.26 (dd, J =7.4Hz, 1.5Hz, 1H), 6.74 (dd, J=19.5Hz, J=8.1Hz, 4H), 5.04-4.90 (m, 3H), 4.78-4.74 (m, 1H), 3.83 (s, 3H), 3.66 (t, J=13.8Hz, 1H), 3.26 (s, 3H), 3.12-3.05 (m, 1H), 2.55 (dd, J= 14.3Hz, 6.6Hz, 1H), 2.41 (s, 3H), 2.13 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.0,173.3, 170.9,155.2,137.0,136.7,133.7,132.0,129.1,128.4,128.2,125.7,124.6,120.1, 117.3,73.9,63.7,56.0,53.3,52.4,49.5,39.6,20.9,15.8.
Embodiment 9
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1h, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2,5- dimethyl -3- (phenyl sulfonyl) Methyl-1H-indole 4h (37.5mg, 0.1mmol), it is replaced In air after, add anhydrous and oxygen-free tetrahydrofuran (1mL), after 30min is stirred at room temperature, vinylcyclopropane is injected thereto Dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture addition 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, Jing anhydrous sodium sulfates It is dried.Steam Jing column chromatographic isolation and purifications after solvent obtain (1R, 2S, 5R) -2- phenyl -2 ', 5 '-dimethyl -5- vinyl spiral shells [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1h, yield 65%, colourless oil liquid, 92%ee (AD-H, normal hexane: Isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=10.3min, tminor=13.0min). [α]D 27= 54.5 °. (c=0.2, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 7.95 (s, 1H), 7.24 (d, J=7.8Hz, 1H), 7.11 (d, J=7.8Hz, 1H), 7.04-6.95 (m, 3H), 6.85 (d, J=7.3Hz, 2H), 5.07-4.91 (m, 3H), 4.77 (dd, J=9.9Hz, J=1.8Hz, 1H), 3.84 (s, 3H), 3.66 (t, J= 14.0Hz, 1H), 3.23 (s, 3H), 3.10-3.04 (m, 1H), 2.55 (t, J=6.5Hz, 1H), 2.51 (s, 3H), 2.40 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 180.6,173.3,170.7,153.1,136.7,135.3,134.1, 133.8,129.3,128.8,127.7,127.4,126.5,119.6,117.3,73.7,63.8,56.1,53.4,52.3, 49.6,39.7,21.9,15.7.
Embodiment 10
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1i, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- (2 '-chlorphenyl phenyl sulfonyl) Methyl-1H-indole 4i (39.5mg, 0.1mmol), displacement After air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring third is injected thereto Alkane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred until reacting 3.5d, reactant mixture adds at 0 DEG C Enter 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, Jing anhydrous slufuric acids Sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (2 '-chlorphenyl) -2 '-dimethyl -5- second Thiazolinyl spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1i, yield 43%, colourless oil liquid, 91%ee (AD-H, Normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=8.8min, tminor=14.9min). [α]D 30=14.4 °. (c=0.07, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 7.98 (d, J=7.0Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 7.30-7.20 (m, 3H), 6.94-6.90 (m, 1H), 6.74 (dd, J=8.0Hz, 1.7Hz, 1H), 6.71-6.66 (m, 1H), 5.86 (s, 1H), 5.07-4.94 (m, 2H), 4.80-4.77 (m, 1H)；3.86 (s, 3H), 3.67 (t, J=13.8Hz, 1H), 3.26 (s, 3H), 3.24-3.17 (m, 1H), 2.60-2.54 (m, 4H).13C NMR (100MHz, CDCl3, ppm)：δ 182.6,172.9,170.7,155.4,136.2,135.0,133.5, 133.1,130.5,129.6,128.4,128.3,125.8,125.1,124.4,120.2,117.5,74.0,63.9,53.5, 52.3,49.9,49.1,40.3,16.5.
Embodiment 11
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1j, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- (4 '-nitrobenzophenone phenyl sulfonyl) Methyl-1H-indole 4j (40.6mg, 0.1mmol), put After changing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring is injected thereto Propane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture Add 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, the anhydrous sulfur of Jing Sour sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (4 '-nitrobenzophenone) -2 '-methyl -5- Vinyl spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1j, yield 56%, colourless oil liquid, 92%ee (AD- H, normal hexane: isopropanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=37.0min, tminor=16.2min). [α]D 27=50.8 °. (c=0.2, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.10 (d, J=7.3Hz, 1H), 7.83 (d, J=8.8Hz, 2H), 7.39-7.30 (m, 3H), 7.01 (d, J=8.8Hz, 2H), 5.10 (s, 1H), 5.06-4.93 (m, 2H), 4.81-4.79 (m, 1H), 3.86 (s, 3H), 3.67 (t, J=13.9Hz, 1H), 3.27 (s, 3H), 3.16-3.10 (m, 1H), 2.60 (dd, J=14.4Hz, 6.6Hz, 1H), 2.41 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 181.1,172.8,170.2,155.2,147.1,142.9,135.7,133.1,130.2, 128.8,125.5,125.1,122.8,120.6,117.9,73.5,63.7,55.5,53.7,52.6,49.6,39.6,15.7.
Embodiment 12
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1k, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- (3 '-methyl phenyl phenyl sulfonyl) Methyl-1H-indole 4k (37.5mg, 0.1mmol), put After changing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring is injected thereto Propane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture Add 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, the anhydrous sulfur of Jing Sour sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (3 '-aminomethyl phenyl) -2 '-methyl -5- Vinyl spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1k, yield 65%, colourless oil liquid, 95%ee (AD- H, normal hexane: ethanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=7.4min, tminor=16.5min). [α]D 27=-21.8 °. (c=0.08, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.15 (dd, J=6.8Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 7.31 (dd, J=7.3Hz, 1.5Hz, 1H), 7.26 (dd, J =7.3Hz, 1.5Hz, 1H), 6.81 (t, J=4.9Hz, 2H), 6.68 (s, 1H), 6.60-6.57 (m, 1H), 5.03-4.91 (m, 3H), 4.78-4.75 (m, 1H), 3.84 (s, 3H), 3.67 (t, J=13.9Hz, 1H), 3.24 (s, 3H), 3.12-3.06 (m, 1H), 2.54 (dd, J=14.3Hz, 6.6Hz, 1H), 2.42 (s, 3H), 2.08 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.0,173.3,170.8,155.2,137.2,136.7,135.0,133.7,130.3,128.2,128.1, 127.5,126.1,125.8,124.5,120.1,117.3,73.9,63.7,56.1,53.4,52.3,49.5,39.7,21.2, 15.8.
Embodiment 13
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1l, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl -3- [(1 '-furan phenyl sulfonyl) methyl] -1H- indole 4l (35.1mg, 0.1mmol), displacement After air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring third is injected thereto Alkane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred until reacting 3.5d, reactant mixture adds at 0 DEG C Enter 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, Jing anhydrous slufuric acids Sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- (1 '-furan) -2 '-dimethyl -5- ethylene Base spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1l, yield 58%, colourless oil liquid, 85%ee (AD-H, just Hexane: ethanol=95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=9.6min, tminor=17.8min). [α]D 27= 12.1 °. (c=0.19, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 7.95 (d, J =7.5Hz, 1H), 7.43 (d, J=7.5Hz, 1H), 7.35-7.31 (m, 1H), 7.25-7.21 (m, 1H), 7.05 (dd, J= 1.7Hz, 0.6Hz, 1H), 5.93 (dd, J=3.2Hz ,=1.8Hz, 1H), 5.33 (d, J=3.3Hz, 1H), 5.22 (s, 1H), 4.97-4.91 (m, 2H)；4.79-4.76 (m, 1H), 3.87 (s, 3H), 3.57 (t, J=13.9Hz, 1H), 3.40 (s, 3H), 3.10-3.01 (m, 1H), 2.49 (dd, J=14.3Hz, J=6.4Hz, 1H), 2.42 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 181.6,172.9,170.2,155.1,149.3,141.5,136.7,133.3,128.3,125.5, 124.6,120.0,117.6,110.1,108.1,72.3,63.0,53.6,52.9,49.3,49.0,39.5,15.6.
Embodiment 14
Optically active spiro cyclopentane -1, the synthesis of 3 '-indole 1m, its reaction equation is：
Pd (dba) is added in one test tube being dried2(5.8mg, 0.01mmol), chiral phosphoramide part (16.2mg, 0.03mmol) with 2- methyl-5-chloro -3- [(phenyl sulfonyl) methyl] -1H- indole 4m (39.6mg, 0.1mmol), put After changing air therein, the tetrahydrofuran (1mL) of anhydrous and oxygen-free is added, after 30min is stirred at room temperature, ethylene basic ring is injected thereto Propane dicarboxylic acid methyl ester 3 (55.3mg, 0.3mmol).Said mixture is stirred at 0 DEG C until reaction 3.5d, reactant mixture Add 5mL saturations NH4Cl aqueous solutions, with ethyl acetate extractive reaction liquid three times, each 10mL, merge organic faciess, the anhydrous sulfur of Jing Sour sodium is dried.Steam Jing column chromatographic isolation and purifications after solvent and obtain (1R, 2S, 5R) -2- phenyl -2 '-methyl -5 '-chloro- 5- ethylene Base spiral shell [Pentamethylene. -1,3 '-indole] -3,3- dicarboxylic acid methylester 1m, yield 57%, colourless oil liquid, 80%ee (AD-H, just Hexane: ethanol=98: 2, wavelength 254nm, flow velocity 1mL/min, tmajor=7.8min, tminor=9.8min). [α]D 26= 118.0 °. (c=0.15, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.20 (d, J=1.4Hz, 1H), 7.31-7.26 (m, 2H), 7.07-6.98 (m, 3H), 6.84 (d, J=8.5Hz, 2H), 5.06-4.92 (m, 3H), 4.82-4.79 (m, 1H), 3.84 (s, 3H), 3.59 (t, J=13.9Hz, 1H), 3.26 (s, 3H), 3.12-3.06 (m, 1H), 2.57 (dd, J=14.5Hz, 6.6Hz, 1H), 2.41 (s, 3H).13C NMR (100MHz, CDCl3, ppm)：δ 182.6, 173.1,170.6,153.8,138.5,134.8,133.2,130.6,129.2,128.5,128.0,127.6,126.0, 120.9,117.8,74.3,63.7,56.1,53.5,52.5,49.6,39.6,15.9.
Embodiment 15
Optical activity spiro cyclopentane -1, the synthesis of 3 '-indole selectivity decarboxylate 5：
Optically active spiro cyclopentane -1 of 43.7mg (0.1mmol), 3 '-indole 1f is dissolved in 2mL MeOH, adds 2mL's 2mol/L NaOH solutions.Said mixture is stirred at room temperature after 2-4h, faintly acid is acidified to 6mol/L HCl, with acetic acid Ethyl ester extractive reaction mixture, combining extraction liquid and with 5mL saturated common salts water washing 3 times, Jing anhydrous Nas2SO4Steam after drying molten Agent.Isolated (1R, 2S, 3R, the 5R) -2- (3- chlorphenyls) -2 of crude by column chromatography '-methyl -5- vinyl spiral shell [rings penta Alkane -1,3 '-indole] -3- carboxylate methyl esters 5, white solid, yield 98%, optical purity 96%ee (AD-H, normal hexane: ethanol= 95: 5, wavelength 254nm, flow velocity 1mL/min, tmajor=8.5min, tminor=14.7min). [α]D 27=24.4 °. (c= 0.2, CH2Cl2). the nuclear magnetic resoance spectrum of the product is：1H NMR (400MHz, CDCl3, ppm)：δ 8.15 (d, J=76.8Hz, 1H), 7.50 (t, J=8.7Hz, 1H), 7.38-7.32 (m, 2H), 7.05-7.02 (m, 1H), 6.92-6.88 (m, 2H), 6.71 (d, J=8.1Hz, 1H), 5.02-4.95 (m, 3H), 4.82-4.79 (m, 1H), 3.70 (t, J=13.8Hz, 1H), 3.32 (s, 3H), 3.20-3.14 (m, 1H), 6.74 (dd, J=14.4Hz, 6.6Hz, 2H), 2.47 (s, 3H).

Claims (1)

1. optical activity spiro cyclopentane -1, the preparation method of 3 '-indole, optical activity spiro cyclopentane -1,3 '-indole chemistry Structural formula is,
Wherein Ar is phenyl, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 3- methoxyphenyls, 4- methoxyphenyls, 3- methyl Phenyl, 4- nitrobenzophenones, R ' is methyl, R " be methyl, R " ' it is hydrogen；
Characterized in that, comprising the following steps：With arylsulfonyl indole and vinylcyclopropane as raw material, tetrahydrofuran is used as molten Agent, by arylsulfonyl indole and vinylcyclopropane, tetrahydrofuran with ratio 1mmol: 2-4mmol: 6-10mL mixed dissolution, plus Enter the Pd (dba) of the amount for arylsulfonyl indole 5-15mol% of material2With the chiral phosphine ligand of 10-30mol% as catalysis Agent；2-96h is stirred at room temperature and finishes until reacting, react the mixture for finishing and add saturation NH4Cl aqueous solutions, with acetic acid second Ester is extracted, the organic faciess of gained, Jing anhydrous sodium sulfate dryings；Jing column chromatographic isolation and purifications after solvent are steamed, optical activity is obtained Spiro cyclopentane -1,3 '-benzazolyl compounds；
Described chiral phosphine ligand is
Described arylsulfonyl indole is following one kind：2- methyl -3- [phenyl (phenyl sulfonyl) methyl] -1H- indole, 2- Methyl -3- [4 '-chlorphenyl (phenyl sulfonyl) methyl] -1H- indole, 2- methyl -3- [4 '-methoxyphenyl (phenylSulphons Base) methyl] -1H- indole, 2- methyl -3- [3 '-methoxyphenyl (phenyl sulfonyl) methyl] -1H- indole, 2- methyl -3- [1 '-naphthyl (phenyl sulfonyl) methyl] -1H- indole, 2- methyl -3- [(3 '-chlorphenyl phenyl sulfonyl) methyl] -1H- Yin Diindyl, 2- methyl -3- [(4 '-methyl phenyl phenyl sulfonyl) methyl] -1H- indole, 2- methyl -3- (2 '-chlorphenyl phenylSulphons Base) Methyl-1H-indole, 2- methyl -3- (4 '-nitrobenzophenone phenyl sulfonyl) Methyl-1H-indole, 2- methyl -3- (3 '-first Base phenyl sulfonyl) Methyl-1H-indole, 2- methyl -3- [(1 '-furan phenyl sulfonyl) methyl] -1H- indole；
Described vinylcyclopropane is vinylcyclopropane dicarboxylic acid methyl ester.
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