CN102584800A - Compound containing framework of chiral indolone and angelica lactone and asymmetric synthesis method - Google Patents

Compound containing framework of chiral indolone and angelica lactone and asymmetric synthesis method Download PDF

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CN102584800A
CN102584800A CN2011104234565A CN201110423456A CN102584800A CN 102584800 A CN102584800 A CN 102584800A CN 2011104234565 A CN2011104234565 A CN 2011104234565A CN 201110423456 A CN201110423456 A CN 201110423456A CN 102584800 A CN102584800 A CN 102584800A
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indolone
angelica lactone
chiral
arbitrarily
nmr
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陈应春
黄鑫
蕫琳
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Sichuan University
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Sichuan University
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Abstract

The invention provides a high-efficiency synthesis method of a compound containing a chiral indolone and angelica lactone framework, which is an effective method of synthetizing a series of allyl alkylate chiral product with multifunction functional groups in high-efficiency high- enantioselectivity mode through indolone MBH (Morit-Baylis-Hill1man) carbonic ester and various angelica lactone compounds with chiral amines, especially derivatives of b-1CD ((3 S, 8R, 9S) -10, 11- dihydro -3,9 epoxy-6'- oxhydryl quinine alkyl) derived by cinchona alkaloid as catalysts, with 4 molecular sieve and R-BINOL as additives. The asymmetric synthesis method is reported for the first time, the catalysts are easy to obtain and high in catalytic activity, the asymmetric synthesis method is mild in reaction conditions, simple in operation, wide in substrate application range and high in product area and enantioselectivity. In addition, various obtained compounds containing the framework of indolone and angelica lactone can possibly have special physiological activity or become important synthesis intermediates of natural product.

Description

Chirality indolone and angelica lactone framework compound and asymmetric synthesis
Technical field
The present invention relates to a kind ofly have the allyl group alkylated compound of multi-functional functional group for synthetic one type by Chiral Amine catalyzing indole ketone MBH (Morit-Baylis-Hillman) carbonic ether and all kinds of angelica lactone compound, it is active or become the important synthetic intermediate of natural product that this multi-functional functional group product possibly have special physiological.
Background technology
Indolone and angelica lactone skeleton, especially optically pure this type skeleton extensively is present in natural product and the pharmaceutical intermediate, in view of this compounds pharmaceutically vital role, caused increasing chemist's interest.[(a) X. Z. Wearing and J. M. Cook, Org. Lett., 2002,4,4237; (b) B. K. Albrecht and R. M. Williams, Org. Lett., 2003,5,197; (c) S. E. Reisman, J. M. Ready, M. M. Weiss, A. Hasuoka, M. Hirata, K. Tamaki, T. V. Ovaska, C. J. Smith and J. L. Wood, J. Am. Chem. Soc., 2008,130,2087; (d) K. C. Nicolaou, P. B. Rao, J. Hao, M. V. Reddy, G. Rassias, X. Huang, D. Y.-K. Chen and S. A. Snyder, Angew. Chem., Int. Ed., 2003,42,1753; (e) K. Ding, Y. Lu, Z. Nikolovska-Coleska, S. Qiu; Y. Ding, W. Gao, J. Stuckey, K. Krajewski; P. Roller, Y. Tomita, D. A. Parrish, J. R. Deschamps and S. Wang; J. Am. Chem. Soc., 2005,127,10130; (f) F. Q. Alali, X.-X.Liu and J. L. McLaughlin, J. Nat. Prod.; 1999,62,504.] in the past several years; Obtain optically purely 3 through catalyzed reaction, 3-disubstituted indole ketone compound has also obtained broad research.[(a) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura and M. Sedeoka, J. Am. Chem. Soc., 2005,127,10164; (b) K. Jiang, J. Peng, H.-L. Cui and Y.-C. Chen Chem. Commun., 2009,3955; (c) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B. Giannichi, L. Sambri, G. Bartoli and P. Melchiorre, Chem.-Eur. J. 2009,15,7846; (d) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009,131,9168; (e) R. He, S. Shirakawa and K. Maruoka, J. Am. Chem. Soc., 2009,131,16620; (f) T. Bui, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2010,132,5574; (g) for a review; See:F. Zhou, Y. Liu and J. Zhou, Adv. Synth. Catal.; 2010; 352,1381.] simultaneously, we have developed a kind of method of constructing 3 quaternary carbon structures of indolone with chirality quinine deutero-tertiary amine as the indolone C-3 position cationoid reaction of catalyst.[(a) J. Peng, X. Huang, H.-L. Cui and Y.-C. Chen, Org. Lett., 2010,12,4260; (b) J. Peng, X. Huang, L. Jiang, H.-L. Cui and Y.-C. Chen, Org. Lett., 2011,13,4584.] still, the reactant type of this type reaction receives certain restriction.Therefore; Develop a kind of easy and simple to handle; Environmental friendliness, and high enantioselectivity synthetic a kind of has the allyl group alkylated product of multi-functional functional group and then makes up a series of methods that contain indolone and angelica lactone skeleton simultaneously and have an active compound of potential drug and have great significance.
Summary of the invention
The purpose of this invention is to provide a kind of allyl group alkylated product that contains multi-functional functional group.
The object of the invention or a kind of compound method that contains the allyl group alkylated product of multi-functional functional group is provided.
The allyl group alkylated product of multi-functional functional group of the present invention, it has following structure:
Figure 2011104234565100002DEST_PATH_IMAGE001
Wherein * is a chiral carbon atom, and PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; R 1Be selected from alkyl or hydrogen arbitrarily; R 2Be selected from-oxyl, aryloxy, the benzyloxy of methyl, C1-C16 arbitrarily; The indolone aryl
Figure 2011104234565100002DEST_PATH_IMAGE002
Replace wherein R 2, R 3, R 4Or R 5Be selected from the-oxyl of H, F, Cl, Br, C1-C16 arbitrarily, the alkyl of C1-C16.On behalf of ethanoyl, Boc, wherein said Ac represent tertbutyloxycarbonyl, Bz to represent benzoyl-, Cbz to represent carbobenzoxy-(Cbz), Me represent methylidene.The allyl group alkylated product of multi-functional functional group of the present invention is to be raw material with indolone MBH carbonic ether and all kinds of angelica lactone compound; In the presence of organic solvent; Quinine deutero-b-ICD verivate with chirality makes as catalyst reaction, and available following reaction formula is represented:
Figure 2011104234565100002DEST_PATH_IMAGE003
Further describing of this reaction is-10 at the organic solvent neutral temperature oC is a raw material with indolone MBH carbonic ether and all kinds of angelica lactone compound, with the verivate of the quinine deutero-b-ICD of chirality as catalyst reaction 24 h ~ 72 hours.The mol ratio of the quinine deutero-b-ICD verivate of wherein said indolone MBH carbonic ether, all kinds of angelica lactone compound and chirality is 1:1 ~ 2:0.05 ~ 0.1.
The structural formula of indolone MBH carbonic ether is:
Figure 2011104234565100002DEST_PATH_IMAGE004
, wherein: PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; R 2Be selected from-oxyl, aryloxy, the benzyloxy of methyl, C1-C16 arbitrarily; The indolone aryl
Figure 613980DEST_PATH_IMAGE002
Replace wherein R 2, R 3, R 4Or R 5Be selected from the-oxyl of H, F, Cl, Br, C1-C16 arbitrarily, the alkyl of C1-C16; The structural formula of all kinds of angelica lactone compounds is:
Figure 2011104234565100002DEST_PATH_IMAGE005
, wherein: R 1Be selected from alkyl or hydrogen arbitrarily.
The general structure of catalyzer is (be any optically pure structure, do not receive to limit shown in the chemical formula):
Figure 113805DEST_PATH_DEST_PATH_IMAGE007A
, wherein R is selected from H arbitrarily; CH 3O, BnO, CH 3OCH 2O, BnO, CH 2Various alkoxyl groups such as O; Various substituted aryls or heterocyclic base; Various ester groups are like the trifluoro sulphonate; Various secondary amine or nitrogen heterocyclic ring are like morpholine, piperidines etc.
The alkyl that the present invention mentioned,-oxyls etc. unless otherwise indicated, all are recommended as carbon number and are 1 ~ 16 group, and further recommending carbon number is 1 ~ 10 group, and especially recommending carbon number is 1 ~ 4 group.The aryl that the present invention mentioned unless otherwise indicated, all refers to phenyl or naphthyl, is recommended as phenyl.The heterocyclic base that the present invention mentioned unless otherwise indicated, all is recommended as the N that contains of C5 ~ C10, O, and the heterocyclic radical of S is especially recommended benzothiazolyl.The carbonyl that the present invention mentioned all is recommended as carbon number and is 1 ~ 16 group, and further recommending carbon number is 1 ~ 10 group; Especially recommending carbon number is 1 ~ 4 group, unless otherwise indicated, and the equal nail ester group of ester group; Ketone all refers to benzoyl-, and imide all refers to N-phenyl butylene imide.
Organic solvent of the present invention can be polar solvent or non-polar solvent, as: methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, toluene, m-xylene, sym-trimethylbenzene, phenylfluoroform, 1,4-dioxane, THF etc.
The method that adopts the prepared product of the present invention can pass through column chromatography is separated.Used developping agent and eluent are the mixed solvent of polar solvent and non-polar solvent.Recommend solvent: sherwood oil-ETHYLE ACETATE.
The invention provides a kind of effectively with the quinine deutero-b-ICD verivate of chirality as catalyzer, by synthetic a kind of method of indolone MBH carbonic ether and all kinds of angelica lactone compound high-level efficiency, high enantioselectivity with the allyl group alkylated product of multi-functional functional group.This method not only catalyzer is easy to get, and catalytic activity is high, and reaction conditions is gentle, and is simple to operate, wide application range of substrates, also better (being generally 70%-91%) enantioselectivity of productive rate high (being generally 80%-92%).
The resulting allyl group alkylated product with multi-functional functional group of the present invention can be used for the compound of synthetic following structure:
1
Figure 2011104234565100002DEST_PATH_IMAGE007
, PG wherein, R 1And R 2As noted earlier, available following equation is represented:
Figure 2011104234565100002DEST_PATH_IMAGE008
2
Figure 2011104234565100002DEST_PATH_IMAGE009
, PG wherein, R 1And R 2As noted earlier, available following equation is represented:
Figure 2011104234565100002DEST_PATH_IMAGE010
3
Figure 2011104234565100002DEST_PATH_IMAGE011
, PG wherein, R 1And R 2As noted earlier, available following equation is represented:
Figure 2011104234565100002DEST_PATH_IMAGE012
Embodiment
To help to understand the present invention through following embodiment, but not limit content of the present invention.
  
Embodiment 1: the indolone MBH carbonic ether of chirality quinine deutero-b-ICD derivatives catalysis and the allyl group alkylated reaction of all kinds of angelica lactone compounds
In a clean reaction tubes, add chirality quinine deutero-b-ICD derivative catalyst (0. 01mmol) successively, indolone MBH carbonic ether (0.10mmol), angelica lactone compound (0.20mmol) and sym-trimethylbenzene 0.1 mL are-10 oThe corresponding time of stirring reaction under the C.Column chromatography for separation gets product.
  
Figure 2011104234565100002DEST_PATH_IMAGE013
P1,80% yield; [α] D 20=+8.5 ( c=0.4 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=26.532 min, t (minor)=18.793 min ,]; 1H NMR (400 MHz, CDCl 3): δ=7.26 (t, J=7.6 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.06 (d, J=5.6 Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.75 (s, 1H), 5.70 (d, J=5.6 Hz, 1H), 3.62 (s, 3H), 3.29 (s, 3H), 1.88 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.6,171.6,165.6,157.1,143.6,136.9,131.1,129.2,127.1,125.0,122.7,122.4,108.1,89.7,59.9,52.3,26.6,19.1 ppm; High resolution mass spectrum calculating value: (C 18H 17NO 5+ Na) m/z 350.1004, measured value: 350.1002.
Figure 2011104234565100002DEST_PATH_IMAGE014
P2, 90% yield; [α] D 20=+41.0 ( c=0.4 in CHCl 3); 91% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=15.910 min, t (minor)=8.967 min]; 1H NMR (400 MHz, CDCl 3): δ=7.04 (d, J=5.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 5.69 (d, J=5.6 Hz, 1H), 3.62 (s, 3H), 3.26 (s, 3H), 2.24 (s, 3H), 1.87 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.5,171.6,165.7,157.2,141.1,137.0,132.3,131.0,129.5,127.1,125.8,122.4,107.8,89.7,60.0,52.3,26.6,21.0,19.1 ppm; High resolution mass spectrum calculating value: (C 19H 19NO 5+ Na) m/z 364.1161, measured value: 364.1156.
Figure 2011104234565100002DEST_PATH_IMAGE015
P3,90% yield; [α] D 20=+26.8 ( c=0.5 in CHCl 3); 89% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=18.740 min, t (minor)=11.663 min]; 1H NMR (400 MHz, CDCl 3): δ=7.03 (d, J=5.6 Hz, 1H), 6.81 (s, 1H), 6.77 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.74 (s, 1H), 6.72 (d, J=2.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 5.70 (d, J=5.6 Hz, 1H), 3.69 (s, 3H), 3.61 (s, 3H), 3.24 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.2,171.7,165.6,157.3,155.7,136.9,131.2,128.3,122.4,114.7,111.3,108.6,89.6,60.2,55.7,52.3,26.7,19.1 ppm; High resolution mass spectrum calculating value: (C 19H 19NO 6+ Na) m/z 380.1110, measured value: 380.1109.
Figure 2011104234565100002DEST_PATH_IMAGE016
P4, 88% yield; [α] D 20=+27.2 ( c=0.5 in CHCl 3); 92% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=12.660 min, t (minor)=6.586 min]; 1H NMR (400 MHz, CDCl 3): δ=7.05 (d, J=5.6 Hz, 1H), 6.80 (s, 1H), 6.76 (d, J=2.8 Hz, 2H), 5.70 (d, J=5.6 Hz, 1H), 3.63 (s, 3H), 3.52 (s, 3H), 2.49 (s, 3H), 2.18 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=176.2,171.6,165.7,157.3,138.8,137.2,133.5,131.9,130.8,127.6,123.7,122.3,119.1,89.7,59.5,52.2,23.0,20.6,19.2,18.8 ppm; High resolution mass spectrum calculating value: (C 20H 21NO 5+ Na) m/z 378.1317, measured value: 378.1316.
P5,80% yield; [α] D 20=+8.0 ( c=0.2 in CHCl 3); 92% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=13.872 min, t (minor)=8.391 min]; 1H NMR (400 MHz, CDCl 3): δ=7.06 (d, J=5.6 Hz, 1H), 6.96 (td, J=8.8 Hz, 2.4 Hz, 1H), 6.89 (dd, J=8.0 Hz, 2.4Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.73 (dd, J=8.4 Hz, 4.0 Hz, 1H), 5.75 (d, J=5.6 Hz, 1H), 3.64 (s, 3H), 3.27 (s, 3H), 1.87 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.2,171.2,165.5,158.8 (d, 1 J C, F =240.8 Hz), 157.0,139.6,136.6,131.6,128.8 (d, 3 J C, F =8.4 Hz), 122.5,115.6 (d, 2 J C, F =23.6 Hz), 113.2 (d, 2 J C, F =25.0 Hz), 108.6 (d, 3 J C, F =8.0 Hz), 89.4,60.1,52.4,26.8,19.2 ppm; High resolution mass spectrum calculating value: (C 18H 16FNO 5+ Na) m/z 368.0910, measured value: 368.0903.
Figure 2011104234565100002DEST_PATH_IMAGE018
P6,83% yield; [α] D 20=+45.2 ( c=0.4 in CHCl 3); 92% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=28.473 min, t (minor)=16.415 min]; 1H NMR (400 MHz, CDCl 3): δ=7.23 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.05 (d, J=5.6 Hz, 1H), 6.84 (s, 1H), 6.78 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.76 (d, J=5.6 Hz, 1H), 3.64 (s, 3H), 3.27 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.2,171.1,165.5,156.8,142.2,136.5,131.7,129.2,128.8,128.0,125.4,122.7,109.0,89.3,52.4,26.8,25.3,19.2 ppm; High resolution mass spectrum calculating value: (C 18H 16ClNO 5+ Na) m/z 384.0615, measured value: 384.0612.
Figure 2011104234565100002DEST_PATH_IMAGE019
P7,91% yield; [α] D 20=+61.0 ( c=0.5 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=21.370 min, t (minor)=11.016 min]; 1H NMR (400 MHz, CDCl 3): δ=7.36 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.03 (d, J=5.6 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.74 (d, J=5.6 Hz, 1H), 3.62 (s, 3H), 3.24 (s, 3H), 1.84 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.1,171.1,165.5,156.7,142.7,136.5,132.1,131.7,129.1,128.1,122.7,115.2,109.5,89.2,60.0,52.4,26.7,19.1 ppm; High resolution mass spectrum calculating value: (C 18H 16BrNO 5+ Na) m/z 428.0110, measured value: 428.0112.
Figure 2011104234565100002DEST_PATH_IMAGE020
P8,90% yield; [α] D 20=+60.6 ( c=0.5 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=20.384 min, t (minor)=10.854 min]; 1H NMR (400 MHz, CDCl 3): δ=7.58 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.04 (d, J=5.6 Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.58 (d, J=8.4 Hz, 1H), 5.76 (d, J=5.6 Hz, 1H), 3.64 (s, 3H), 3.26 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.0,171.1,165.5,156.6,143.4,138.1,136.5,133.6,131.7,129.3,122.8,110.1,89.2,85.0,52.4,26.7,19.1 ppm; High resolution mass spectrum calculating value: (C 18H 16INO 5+ Na) m/z 475.9971, measured value: 475.9981.
Figure 2011104234565100002DEST_PATH_IMAGE021
P9, 83% yield; [α] D 20=+12.0 ( c=0.2 in CHCl 3); 86% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=15.291 min, t (minor)=8.201 min]; 1H NMR (400 MHz, CDCl 3): δ=7.13 (d, J=8.4 Hz, 1H), 7.03 (d, J=5.6 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.77 (s, 1H), 5.74 (d, J=5.6 Hz, 1H), 3.63 (s, 3H), 3.28 (s, 3H), 1.85 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.3,170.9,165.6,156.7,144.4,142.3,136.4,131.8,128.7,122.6,122.5,119.0,108.5,89.2,60.0,52.4,26.8,19.2 ppm; High resolution mass spectrum calculating value: (C 19H 16F 3NO 6+ Na) m/z 434.0827, measured value: 434.0828.
Figure 2011104234565100002DEST_PATH_IMAGE022
P10,75% yield; [α] D 20=+27.0 ( c=0.2 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=9.237 min, t (minor)=7.006 min]; 1H NMR (400 MHz, CDCl 3): δ=7.09 (d, J=5.6 Hz, 1H), 6.99-6.88 (m, 3H), 6.83 (s, 1H), 6.76 (s, 1H), 5.75 (d, J=5.6 Hz, 1H), 3.65 (s, 3H), 3.49 (d, J H, F =2.4 Hz, 3H), 1.87 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.2,171.4,165.6,156.9,147.4 (d, 1 J C, F =242.3 Hz), 136.7,131.5,130.2,129.9,123.1 (d, 3 J C, F =6.4 Hz), 122.6,120.8 (d, 4 J C, F =3.1 Hz), 117.2 (d, 2 J C, F =19.6 Hz), 89.4,60.1,52.4,29.1 (d, 4 J C, F =6.1 Hz), 19.0 ppm; High resolution mass spectrum calculating value: (C 18H 16FNO 5+ H) m/z 346.1091, measured value: 346.1084.
Figure 2011104234565100002DEST_PATH_IMAGE023
P11,80% yield; [α] D 20=+29.2 ( c=0.5 in CHCl 3); 92% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel AS, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=31.230 min, t (minor)=21.196 min]; 1H NMR (400 MHz, CDCl 3): δ=7.22 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.09 (s, 1H), 7.05 (d, J=5.6 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.91 (td, J=7.6 Hz, 1.2 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 5.68 (d, J=5.6 Hz, 1H), 3.28 (s, 3H), 2.30 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=198.0,176.0,171.6,157.2,146.2,143.6,131.3,129.1,127.2,124.6,122.5,122.3,108.1,89.6,77.2,26.6,25.9,19.0 ppm; High resolution mass spectrum calculating value: (C 18H 17NO 4+ Na) m/z 334.1055, measured value: 334.1054.
P12,73% yield; [α] D 20=+6.5 ( c=0.4 in CHCl 3); 91% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel AD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=14.320 min, t (minor)=10.904 min]; 1H NMR (400 MHz, CDCl 3): δ=7.06 (d, J=5.6 Hz, 1H), 6.94 (td, J=8.4 Hz, 2.4 Hz, 1H), 6.81 (dd, J=12.0 Hz, 2.4 Hz, 1H), 6.71 (dd, J=8.4 Hz, 4.0 Hz, 1H), 6.64 (s, 1H), 5.74 (d, J=5.6 Hz, 1H), 3.28 (s, 3H), 2.32 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=198.0,175.7,171.3,158.7 (d, 1 J C, F =240.5 Hz), 157.0,145.9,139.6,131.8,128.9,122.5,115.4 (d, 2 J C, F =23.1 Hz), 112.8 (d, 2 J C, F =25.4 Hz), 108.6 (d, 3 J C, F =7.9 Hz), 89.3,26.8,25.9,24.4,19.1 ppm; High resolution mass spectrum calculating value: (C 18H 16FNO 4+ Na) m/z 352.0961, measured value: 352.0960.
P13,80% yield; [α] D 20=+2.2 ( c=0.4 in CHCl 3); 91% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel AD, n-hexane/ i-PrOH=60/40,1.0 mL/min, λ=254 nm, t (major)=11.253 min, t (minor)=8.685 min]; 1H NMR (400 MHz, CDCl 3): δ=7.12 (d, J=5.2 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J=5.6 Hz, 1H), 6.95 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 5.74 (d, J=5.6 Hz, 1H), 3.30 (s, 3H), 2.32 (s, 3H), 1.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=198.0,175.8,170.9,156.8,145.8,142.3,132.0,128.8,122.6,122.3,118.7,108.5,89.2,77.2,59.7,26.9,25.9,19.1 ppm; High resolution mass spectrum calculating value: (C 19H 16F 3NO 5+ Na) m/z 418.0878, measured value: 418.0878.
P14,70% yield; [α] D 20=+30.4 ( c=0.5 in CHCl 3); 80% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel AD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=5.937 min, t (minor)=5.417 min]; Dr=83:17 (by 1H NMR analysis); Major isomer: 1H NMR (400 MHz, CDCl 3): δ=7.25 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.96 (t, J=8.0 Hz, 1H), 6.94 (d, J=5.6 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 5.73 (d, J=5.6 Hz, 1H), 3.62 (s, 3H), 3.28 (s, 3H), 2.58-2.42 (m, 2H), 1.34-1.24 (m, 2H), 0.94-0.89 (m, 2H), 0.86 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.7,172.1,165.8,155.6,143.5,137.0,131.1,129.2,127.3,125.0,123.6,122.7,108.0,92.4,60.5,52.3,29.4,26.6,25.2,22.6,13.9 ppm; High resolution mass spectrum calculating value: (C 21H 23NO 5+ Na) m/z 392.1474, measured value: 392.1475.
Embodiment 2: the conversion (application example 1) with multi-functional functional group
Figure 2011104234565100002DEST_PATH_IMAGE027
With P1 (65.4 mg, 0.20 mmol) and BnNH 2(110 μ L, 1.00 mmol) are dissolved in CF 3CH 2Among the OH (0.5 mL), 80 oC is stirred to thin-layer chromatography and detects the P1 disappearance.Under room temperature, add Boc 2O (436 mg, 2.00 mmol) is to eliminate unreacted BnNH completely 2Column chromatography for separation (petrol ether/ethyl acetate: 2/1) must be like topic compound colorless oil.(61.0 mg, 70% yield). [α] D 20=-9.2 ( c=0.9 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel AD, n-hexane/ i-PrOH=70/30,1.0 mL/min, λ=254 nm, t (major)=15.195 min, t (minor)=14.046 min]; 1H NMR (400 MHz, CDCl 3): δ=7.54 (d, J=7.2 Hz, 1H), 7.41-7.30 (m, 6H), 6.97 (td, J=7.6 Hz, 0.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.71 (dd, J=7.2 Hz, 6.0 Hz, 1H), 3.66 (d, J=13.6 Hz, 1H), 3.35 (d, J=5.6 Hz, 1H), 3.29 (dd, J=12.4 Hz, 7.2 Hz, 1H), 3.28 (s, 3H), 3.23 (s, 3H), 3.05 (dd, J=12.4 Hz, 6.0 Hz, 1H), 2.83 (d, J=18.0 Hz, 1H), 2.66 (dd, J=18.0 Hz, 5.6 Hz, 1H), 0.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=198.0,175.8,170.9,156.8,145.8,142.3,132.0,128.8,122.6,122.3,118.7,108.5,89.2,77.2,59.7,26.9,25.9,19.1 ppm; High resolution mass spectrum calculating value: (C 25H 26N 2O 5+ H) m/z 435.1920, measured value: 435.1920.
Embodiment 3: the conversion (application example 2) with multi-functional functional group
Figure 2011104234565100002DEST_PATH_IMAGE028
With P1 (50.0 mg, 0.15 mmol), MeNO 2(1.50 mmol, 80 μ L) and DBU (0.07 mmol, 11.4 mg) are dissolved in CH 3Among the CN (0.5 mL), 70 oC is stirred to thin-layer chromatography detection P1 no longer to be continued to transform.Column chromatography for separation (petrol ether/ethyl acetate: 2/1) get white solid.(23.0 mg, 40% yield). [α] D 20=+5.5 ( c=0.9 in CHCl 3); 90% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=60/40,1.0 mL/min, λ=254 nm, t (major)=26.963 min, t (minor)=19.554 min]; 1H NMR (400 MHz, CDCl 3): δ=7.42 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.76 (m, 1H), 3.56 (dd, J=12.8 Hz, 5.6 Hz, 1H), 3.46 (s, 3H), 3.29 (s, 3H), 3.11 (dd, J=10.8 Hz, 6.8 Hz, 1H), 2.86-2.80 (m, 2H), 2.97 (dd, J=18.0 Hz, 6.8 Hz, 1H), 2.70 (d, J=18.0 Hz, 1H), 1.10 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=174.2,172.7,169.8,145.0,129.8,126.5,124.5,122.7,109.0,86.0,85.8,53.3,52.4,42.9,42.2,35.4,27.1,26.7,22.7 ppm; High resolution mass spectrum calculating value: (C 19H 20N 2O 7+ Na) m/z 411.1168, measured value: 411.1167.
Embodiment 4: the conversion (application example 3) with multi-functional functional group
Figure DEST_PATH_IMAGE029
This nitro-compound (44.0 mg, 0.11 mmol) and Pd/C (10%, 5.0 mg) are dissolved among the MeOH (0.5mL), and stirring at room to thin-layer chromatography detects the P1 disappearance under argon atmospher.Column chromatography for separation (methylene chloride: 50/1) get white solid.(27.5 mg, 70% yield). [α] D20=+ 16.0 (c=0.1 in CHCl3); 90% ee, chirality test condition: determined by HPLC analysis [Daicel Chiralcel AD, n-hexane/i-PrOH=60/40; 1.0 mL/min; λ=254 nm, t (major)=14.526 min, t (minor)=8.835 min]; 1H NMR (400 MHz, CDCl3): δ=7.51 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.04 (t; J=7.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.88 (bs, 1H), 3.57 (dd; J=14.0 Hz, 4.0 Hz, 1H), 3.41 (s, 3H), 3.27 (s, 3H), 2.92-2.84 (m; 2H), and 2.71-2.58 (m, 3H), 2.35 (dt, J=8.8 Hz, 4.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ=175.3,175.0,171.4,145.0,129.2,127.8,124.9,122.5,108.5,86.8,60.8,53.9,52.0,43.1,40.2,36.2,26.6,26.3,21.8 ppm; High resolution mass spectrum calculating value: (C 19H 22N 2O 5+ K) m/z 397.1166, measured value: 397.1164.

Claims (3)

1. one type of allyl group alkylated product that contains multi-functional functional group, it is the optical pure compound with following structure: , wherein * is a chiral carbon atom, PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; R 1Be selected from alkyl or hydrogen arbitrarily; R 2Be selected from-oxyl, aryloxy, the benzyloxy of methyl, C1-C16 arbitrarily; The indolone aryl
Figure 70564DEST_PATH_IMAGE002
Replace wherein R 2, R 3, R 4Or R 5Be selected from the-oxyl of H, F, Cl, Br, C1-C16 arbitrarily, the alkyl of C1-C16; On behalf of ethanoyl, Boc, wherein said Ac represent tertbutyloxycarbonyl, Bz to represent benzoyl-, Cbz to represent carbobenzoxy-(Cbz), Me represent methylidene.
2. the compound method by the allyl group alkylated product of the described multi-functional functional group of claim 1 is characterized in that-10 oC ~ 50 oIn organic solvent, be raw material under the condition of C with indolone MBH carbonic ether and all kinds of angelica lactone compound, with 4 molecular sieves with R-BINOL is as additive; With Chiral Amine; The verivate of quinine deutero-b-ICD particularly, as the reaction that catalyzer carries out, wherein the mol ratio of the verivate of indolone MBH carbonic ether, angelica lactone compound and quinine deutero-b-ICD is 1:1 ~ 2:0.05 ~ 0.1; The structure of the quinine deutero-b-ICD derivative catalyst of wherein said chirality is:
Figure 81DEST_PATH_IMAGE003
, wherein R is selected from H arbitrarily; CH 3O, BnO, CH 3OCH 2O, BnO, CH 2Various alkoxyl groups such as O; Various substituted aryls or heterocyclic base; Various ester groups are like the trifluoro sulphonate; Various secondary amine or nitrogen heterocyclic ring are like morpholine, piperidines etc.
3. the method for the allyl group alkylated product of synthetic multi-functional functional group according to claim 2; It is characterized in that said solvent is arranged is methylene dichloride; Chloroform, tetracol phenixin, 1; 2-ethylene dichloride, toluene, m-xylene, sym-trimethylbenzene, phenylfluoroform, 1,4-dioxane, THF.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104844613A (en) * 2015-04-10 2015-08-19 昆明理工大学 Quinidine derivative and preparation method thereof
CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof

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EP1772151A2 (en) * 1990-02-01 2007-04-11 Emory University Method and compositions for the synthesis of bch-189 and related compounds
CN101723893A (en) * 2009-12-04 2010-06-09 中国科学院上海有机化学研究所 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof
CN102180828A (en) * 2011-03-31 2011-09-14 四川大学 Chiral indolinone spiropentacyclic skeleton compounds and asymmetric synthesis thereof

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CN101723893A (en) * 2009-12-04 2010-06-09 中国科学院上海有机化学研究所 2,3-disubstituted-2,3-dihydro quinoline ketone chiral compound as well as preparation method and application thereof
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CN104844613A (en) * 2015-04-10 2015-08-19 昆明理工大学 Quinidine derivative and preparation method thereof
CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof

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