CN102180828A - Chiral indolinone spiropentacyclic skeleton compounds and asymmetric synthesis thereof - Google Patents

Chiral indolinone spiropentacyclic skeleton compounds and asymmetric synthesis thereof Download PDF

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CN102180828A
CN102180828A CN2011100797636A CN201110079763A CN102180828A CN 102180828 A CN102180828 A CN 102180828A CN 2011100797636 A CN2011100797636 A CN 2011100797636A CN 201110079763 A CN201110079763 A CN 201110079763A CN 102180828 A CN102180828 A CN 102180828A
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indolinone
arbitrarily
chiral
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nmr
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陈应春
彭景�
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Sichuan University
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Sichuan University
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Abstract

The invention provides a method for efficiently synthesizing chiral indolinone spiropentacyclic skeleton compounds. In the method, a series of 3+2 ring addition chiral products with multifunctional functional groups are synthesized by indolinone morita-baylis-hillman (MBH) carbonate ester and various dipole philic compounds (such as propargyl sulfone, butyne diester, succimide and the like) by effectively using chiral ammonia, particularly a derivative of beta-ICD((3S,8R,9S)-10,11-dihydro-3,9epoxy-6'-hydroxyl cinchona alkane) derived from quinine as a catalyst and a 4-molecular sieve as an additive in high efficiency and high enantioselectivitiy. The asymmetric synthesis method is reported for the first time, and has the advantages of readily available catalyst, high catalytic activity, mild reaction condition, simple operation, wide application range of a substrate, large product area and high enantioselectivitiy. The obtained various indolinone-containing spiral ring or multi-ring skeletons may have special physiological activity or become important synthetic intermediates for natural products.

Description

Chirality indolinone spiral shell five rings framework compound and asymmetric synthesis
Technical field
The present invention relates to a kind ofly have the cycloaddition product of multi-functional functional group spiral shell Pentacyclic indole quinoline ketone by the synthetic class of Chiral Amine catalyzing indole quinoline ketone MBH (Morita-Baylis-Hillman) carbonic ether and all kinds of dipolarophile body compound, it is active or become the important synthetic intermediate of natural product that this multi-functional functional group product may have special physiological.
Background technology
Volution indolinone skeleton, especially optically pure this class 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) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,2209. (b) Trost, B. M.; Brennan, M. K. Synthesis 2009,3003. (c) Zhou, F.; Liu, Y.; Zhou, J. Adv. Synth. Catal. 2010,352,1381.] wherein adopt the cycloaddition method to construct the volution skeleton to have obtained great development [(a) Corey, E. J. Angew. Chem., Int. Ed. 2002 especially in recent years, 41,1650. (b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,122,5666. (c) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007,129,12396. (d) Bencivenni, G.; Wu, L.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,48,7200. (e) Chen, X.; Wei, Q.; Luo, S.; Xiao, H.; Gong, L. J. Am. Chem. Soc. 2009,131,13819. (f) Wei, Q.; Gong, L. Org. Lett. 2010,12,1008] simultaneously, in this field, we have also developed with chirality Prolinol silicon ether and have constructed volution indolinone structure product [(a) Jiang, K. as a series of cascade reactions of catalyst; Jia, Z-J.; Chen, S.; Wu, L.; Chen, Y-C. Chem. Eur. J. 2010,16,2852. (b) Jiang, K.; Jia, Z-J.; Yin, X.; Wu, L.; Chen, Y-C. Org. Lett. 2010,12,2766.] and chirality quinine deutero-tertiary amine as the indolinone C-3 position electrophilic addition of catalyst after the intramolecularly Michael reaction construct spirane structure [Peng, J.; Huang, X.; Cui, H-L.; Chen, Y-C. Org. Lett. 2010,12,4260.].But up till now for this reason, can be effectively in the document to obtain the asymmetric reaction of optical purity indolone volution amylene by cycloaddition reaction considerably less.Therefore, develop a kind of easy and simple to handle, environmental friendliness, and high enantioselectivity synthetic a kind of has the cycloaddition product of multi-functional functional group and then makes up a series of methods that contain indolinone volution skeleton 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 cycloaddition product that contains multi-functional functional group.
Purpose of the present invention or a kind of synthetic method that contains the cycloaddition product of multi-functional functional group is provided.
The cycloaddition product of multi-functional functional group of the present invention, it is just like graph structure:
Figure 2011100797636100002DEST_PATH_IMAGE001
, wherein * is a chiral carbon atom, PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; R 1Be selected from alkyl, aryl arbitrarily; The indolinone aryl
Figure 151618DEST_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; EWG is selected from the benzene sulfuryl arbitrarily, heterocycle sulfuryl and various carbonyl (ester, ketone, imide etc.); On behalf of ethanoyl, Boc, wherein said Ac represent tertbutyloxycarbonyl, Bz to represent benzoyl, Cbz to represent carbobenzoxy-(Cbz), Me represent methylidene.
The cycloaddition product of multi-functional functional group of the present invention is to be raw material with indolinone MBH carbonic ether and all kinds of dipolarophile body compound, in the presence of organic solvent, quinine deutero-beta-ICD derivative with chirality makes as catalyst reaction, and available following reaction formula is represented:
Figure 2011100797636100002DEST_PATH_IMAGE003
Further describing of this reaction is 25 at the organic solvent neutral temperature oC, with indolinone MBH carbonic ether and all kinds of dipolarophile body compound (as, propargyl sulfone, butine diester, succimide or the like) be raw material, with the derivative of the quinine deutero-beta-ICD of chirality as catalyst reaction 12 hours to 24 hours; The mol ratio of the quinine deutero-beta-ICD derivative of wherein said indolinone MBH carbonic ether, all kinds of dipolarophile body compound and chirality is 1 ~ 2:1:0.05 ~ 0.1.
The structural formula of indolinone MBH carbonic ether is:
Figure 36398DEST_PATH_IMAGE004
, wherein: PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; The indolinone aryl
Figure 365748DEST_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 dipolarophile body compounds is: , wherein: R 1Be selected from alkyl, aryl arbitrarily; EWG is selected from the benzene sulfuryl arbitrarily, heterocycle sulfuryl and various carbonyl (ester, ketone, imide etc.).
The general structure of catalyzer is (be any optically pure structure, not limit by diagram): , wherein R is selected from H arbitrarily; CH 3O, BnO, CH 3OCH 2O, BnOCH 2Various alkoxyl groups such as O; Various substituted aryls or heterocyclic base; Various ester groups are as the trifluoro sulphonate; Various secondary amine or nitrogen heterocyclic ring are as 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, tetrahydrofuran (THF) etc.
Adopt the prepared product of the present invention to be separated through the method for column chromatography.Used developping agent and eluent are the mixed solvent of polar solvent and non-polar solvent.Recommend solvent: sherwood oil-ethyl acetate.
The invention provides a kind of effectively with the quinine deutero-beta-ICD derivative of chirality as catalyzer, by indolinone MBH carbonic ether and all kinds of dipolarophile body compound (as, the propargyl sulfone, butine diester, succimide or the like) synthetic a kind of method of high-level efficiency, high enantioselectivity with cycloaddition product of multi-functional functional group spiral shell Pentacyclic indole quinoline ketone.This method not only catalyzer is easy to get, the catalytic activity height, and the reaction conditions gentleness, simple to operate, wide application range of substrates, also better (being generally 37%-94%) enantioselectivity height (being generally 76%-99%) of productive rate.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment: the indolinone MBH carbonic ether of chirality quinine deutero-beta-ICD derivatives catalysis and the cycloaddition reaction of all kinds of dipolarophile body compounds
In a clean reaction tubes, add chirality quinine deutero-beta-ICD derivative catalyst (0. 01mmol) successively, indolinone MBH carbonic ether (0.12mmol), dipolarophile body compound (0.1mmol), with m-xylene 0.1 mL, the corresponding time of stirring reaction under 25 ° of C.Column chromatography for separation gets product.
Figure 2011100797636100002DEST_PATH_IMAGE007
P1,84% yield; [α] D 20=-35.0 ( c=0.5 in CHCl 3); 99% 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)=6.583 min, t (minor)=14.473 min]; 1H NMR (400 MHz, CDCl 3): δ=7.97-7.92 (m, 3H), 7.68 (t, J=7.2 Hz, 1H), 7.59 (t, J=7.6 Hz, 2H), 7.51 (s, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.10 (t, J=7.2 Hz, 1H), 6.68 (d, J=6.8 Hz, 1H), 3.59 (s, 3H), 2.06 (s, 3H), 1.63 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.3,161.3,161.1,148.6,141.8,141.4,141.3,140.5,138.9,134.0,129.8,129.6,127.2,125.0,122.6,122.4,116.2,85.1,72.1,51.9,28.0,12.2 ppm; High resolution mass spectrum calculating value: (C 26H 25NO 7S+Na) m/z 518.1249, measured value: 518.1247.
Figure 2011100797636100002DEST_PATH_IMAGE009
P2,34% yield; [α] D 20=-20.1 ( c=1.1 in CHCl 3); 94% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak IB, n-hexane/ i-PrOH=60/40,1.0 mL/min, λ=254 nm, t (major)=6.263 min, t (minor)=11.921 min]; 1H NMR (400 MHz, CDCl 3): δ=8.29 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.69 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.50 (s, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12 (t, J=7.2 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 3.59 (s, 3H), 2.63 (s, 3H), 2.05 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=171.4,170.4,161.4,160.8,141.8,140.5,139.1,134.2,130.1,129.7,127.3,125.8,122.9,122.2,117.7,72.4,52.1,26.5,12.2 ppm; High resolution mass spectrum calculating value: (C 23H 19NO 6S+Na) m/z 460.0831, measured value: 460.0833.
Figure 2011100797636100002DEST_PATH_IMAGE011
P3,87% yield; [α] D 20=-65.9 ( c=1.2 in CHCl 3); 98% 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)=7.764 min, t (minor)=13.027 min]; 1H NMR (400 MHz, CDCl 3): δ=7.97 (d, J=7.6 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.54 (s, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.69 (d, J=7.6 Hz, 1H), 3.57 (s, 3H), 3.30 (s, 3H), 2.00 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=161.4,161.2,145.2,141.9,141.1,140.7,137.9,133.9,129.7,129.6,128.7,127.2,123.8,123.3,122.7,105.8,51.8,27.5,27.2,12.0 ppm; High resolution mass spectrum calculating value: (C 22H 19NO 5S+Na) m/z 432.0882, measured value: 432.0884.
Figure 2011100797636100002DEST_PATH_IMAGE013
P4,94% yield; [α] D 20=-40.8 ( c=1.3 in CHCl 3); 98% 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)=6.209 min, t (minor)=12.361 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.2 Hz,, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.50 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 3.59 (s, 3H), 2.25 (s, 3H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.5,161.4,161.3,148.6,141.8,141.2,140.5,139.0,138.9,134.8,134.0,130.4,129.6,127.3,122.9,122.5,115.9,85.0,72.3,51.9,28.0,20.9,12.3 ppm; High resolution mass spectrum calculating value: (C 27H 27NO 7S+Na) m/z 534.1406, measured value: 534.1402.
Figure 2011100797636100002DEST_PATH_IMAGE015
P5,93% yield; [α] D 20=-26.0 ( c=0.1 in CHCl 3); 99% 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)=9.838 min]; 1H NMR (400 MHz, CDCl 3): δ=7.95 (d, J=8.0 Hz, 2H), 7.84 (d, J=9.2 Hz, 1H), 7.66 (t, J=7.6 Hz,, 1H), 7.58 (t, J=7.6 Hz, 2H), 7.50 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 3.71 (s, 3H), 3.59 (s, 3H), 2.06 (s, 3H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.4,161.3,157.0,148.7,142.0,141.4,140.8,140.6,138.9,134.6,134.0,129.6,127.3,123.9,117.2,114.9,108.1,85.0,72.3,55.6,52.0,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 27H 27NO 8S+Na) m/z 548.1355, measured value: 548.1357.
Figure 2011100797636100002DEST_PATH_IMAGE017
P6,88% yield; [α] D 20=-76.8 ( c=1.3 in CHCl 3); 96% 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)=6.201 min, t (minor)=7.599 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.6 Hz, 2H), 7.67 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 2H), 7.50 (s, 1H), 6.97 (s, 1H), 6.31 (s, 1H), 3.57 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.60 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=169.8,161.3,161.3,148.6,141.5,141.1,140.6,139.2,137.8,134.8,134.0,133.4,129.6,127.3,125.0,123.9,120.5,85.0,72.7,52.0,27.8,20.8,19.7,12.3 ppm; High resolution mass spectrum calculating value: (C 28H 29NO 7S+Na) m/z 546.1562, measured value: 546.1567.
Figure 2011100797636100002DEST_PATH_IMAGE019
P7,72% yield; [α] D 20=-38.3 ( c=0.8 in CHCl 3); 95% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=70/30,1.0 mL/min, λ=254 nm, t (major)=5.387 min, t (minor)=9.396 min]; 1H NMR (400 MHz, CDCl 3): δ=7.98-7.93 (m, 3H), 7.68 (t, J=7.6 Hz,, 1H), 7.60 (t, J=8.0 Hz,, 2H), 7.51 (s, 1H), 7.08 (td, J=8.8 Hz, 2.8 Hz, 1H), 6.42 (dd, J=7.2 Hz, 2.4 Hz, 1H), 3.62 (s, 3H), 2.08 (s, 3H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.9,160.8 (d, 1 J C, F =244.5 Hz), 160.5,148.6,142.2,141.9,140.4,139.2,138.6,134.2,129.7,129.6,127.3,124.5,117.6 (d, 3 J C, F =8.0 Hz), 116.5 (d, 2 J C, F =22.5 Hz), 110.0 (d, 2 J C, F =24.3 Hz), 85.4,72.0,52.1,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 26H 24FNO 7S+Na) m/z 536.1155, measured value: 536.1157.
Figure 2011100797636100002DEST_PATH_IMAGE021
P8,74% yield; [α] D 20=-25.2 ( c=1.2 in CHCl 3); 97% 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)=6.159 min, t (minor)=12.128 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.6 Hz, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.67 (t, J=7.6 Hz,, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.50 (s, 1H), 7.34 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 3.62 (s, 3H), 2.08 (s, 3H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.7,161.2,160.4,148.4,142.1,142.0,140.4,140.0,138.6,134.2,130.4,130.0,129.7,127.3,124.4,122.6,117.4,85.6,74.0,52.1,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 26H 24ClNO 7S+Na) m/z 552.0860, measured value: 552.0864.
Figure 2011100797636100002DEST_PATH_IMAGE023
P9,63% yield; [α] D 20=-14.6 ( c=1.6 in CHCl 3); 97% 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)=6.848 min, t (minor)=13.491 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.49 (s, 1H), 7.49 (dd, J=8.8 Hz, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 3.62 (s, 3H), 2.08 (s, 3H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.6,161.2,160.3,148.4,142.1,142.0,140.4,140.3,138.6,134.2,132.8,130.4,127.6,127.3,125.4,124.8,117.8,85.6,71.7,52.1,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 26H 24BrNO 7S+Na) m/z 596.0355, measured value: 596.0357.
P10,81% yield; [α] D 20=-54.0 ( c=0.3 in CHCl 3); 97% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak AD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=10.899 min, t (minor)=7.981 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.6 Hz, 2H), 7.73-7.67 (m, 3H), 7.60 (t, J=7.6 Hz, 2H), 7.49 (s, 1H), 6.94 (s, 1H), 3.62 (s, 3H), 2.07 (s, 3H), 1.61 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.7,161.2,160.4,148.4,142.1,142.0,140.4,140.0,138.6,134.2,130.4,130.0,129.7,127.3,124.4,122.6,117.4,85.6,74.0,52.1,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 26H 24ClNO 7S+Na) m/z 552.0860, measured value: 552.0864.
Figure 734992DEST_PATH_IMAGE026
P11,83% yield; [α] D 20=-37.2 ( c=0.6 in CHCl 3); 97% 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)=5.648 min, t (minor)=11.535 min]; 1H NMR (400 MHz, CDCl 3): δ=8.02-7.95 (m, 3H), 7.69 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 6.52 (s, 1H), 3.62 (s, 3H), 2.08 (s, 3H), 1.63 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.7,161.2,160.2,148.4,146.0,142.2,140.4,139.9,138.6,134.4,134.2,129.2,128.9,127.3,122.6,117.4,115.6,85.7,71.9,71.6,52.1,48.4,28.0,12.3 ppm; High resolution mass spectrum calculating value: (C 27H 24F 3NO 8S+K) m/z 618.0812, measured value: 618.0814.
Figure 292137DEST_PATH_IMAGE028
P12,71% yield; [α] D 20=-37.1 ( c=0. 9 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)=8.105 min, t (minor)=10.717 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=7.6 Hz, 2H), 7.68 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.17-7.08 (m, 2H), 6.52 (d, J=7.6 Hz, 1H), 3.59 (s, 3H), 2.06 (s, 3H), 1.60 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.0,161.1,160.1,150.3,147.8,146.9,142.2,141.9,140.4,138.6,134.1,129.7,127.3,126.2 (d, 3 J C, F =6.9 Hz), 118.4 (d, 4 J C, F =3.5 Hz),, 118.2, (d, 2 J C, F =20.4 Hz), 85.7,72.4,52.1,27.7,12.3 ppm; High resolution mass spectrum calculating value: (C 26H 24FNO 7S+Na) m/z 536.1155, measured value: 536.1159.
Figure 108784DEST_PATH_IMAGE030
P13,82% yield; [α] D 20=-36.1 ( c=1.2 in CHCl 3); 96% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak AD, n-hexane/ i-PrOH=70/30,1.0 mL/min, λ=254 nm, t (major)=10.846 min, t (minor)=12.262 min]; 1H NMR (400 MHz, CDCl 3): δ=7.97 (d, J=8.0 Hz, 2H), 7.68 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.53 (s, 1H), 7.48 (dd, J=8.4 Hz, 1.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 3.61 (s, 3H), 3.29 (s, 3H), 2.02 (s, 3H) ppm; 13C NMR (100 MHz, CDCl 3): δ=161.3,160.3,144.3,142.1,140.6,137.6,134.1,132.6,130.2,129.6,128.2,127.3,125.9,115.7,110.6,51.9,31.6,27.4,12.1 ppm; High resolution mass spectrum calculating value: (C 22H 18BrNO 5S+Na) m/z 509.9987, measured value: 509.9984.
Figure 845795DEST_PATH_IMAGE032
P14,91% yield; [α] D 20=-18.6 ( c=1.0 in CHCl 3); 97% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralcel OD, n-hexane/ i-PrOH=70/30,1.0 mL/min, λ=254 nm, t (major)=7.417 min, t (minor)=10.620 min]; 1H NMR (400 MHz, CDCl 3): δ=8.76 (d, J=4.4 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.99 (td, J=7.6 Hz, 1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.57 (ddd, J=7.6 Hz, 4.8 Hz, 1.2 Hz, 1H), 7.37 (td, J=7.6 Hz, 1.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.72 (d, J=6.8 Hz, 1H), 3.61 (s, 3H), 2.10 (s, 3H), 1.64 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.2,164.2,161.4,158.2,150.6,148.6,142.6,141.4,139.3,138.3,138.3,129.8,127.6,124.9,122.7,122.4,121.8,116.1,85.1,72.2,51.9,28.0,12.6 ppm; High resolution mass spectrum calculating value: (C 25H 24N 2O 7S+Na) m/z 519.1202, measured value: 519.1205.
Figure 431498DEST_PATH_IMAGE034
P15,35% yield; [α] D 20=-5.0 ( c=0.5 in CHCl 3); 92% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak IB, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=7.524 min, t (minor)=9.509 min]; 1H NMR (400 MHz, CDCl 3): δ=8.26 (d, J=8.0 Hz, 1H), 8.05 (dd, J=8.0 Hz, 1.2Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.69 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.64 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.33 (td, J=8.0 Hz, 1.2 Hz, 1H), 7.10-7.00 (m, 4H), 6.80 (d, J=7.2 Hz, 2H), 6.65 (d, J=7.6 Hz, 1H), 4.69 (d, J=16.0 Hz, 1H), 3.58 (s, 3H), 3.50 (d, J=16.0 Hz, 1H), 1.50 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=168.2,164.2,164.0,148.2,147.7,141.6,141.0,140.2,134.9,134.0,129.9,129.8,128.4,128.2,127.9,127.3,125.8,124.7,122.9,122.4,116.1,84.2,72.0,52.0,34.1,27.9 ppm; High resolution mass spectrum calculating value: (C 32H 29NO 7S+K) m/z 667.0975, measured value: 667.0971.
P16,88% yield; [α] D 20=-16.6 ( c=0.9 in CHCl 3); 93% 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)=6.220 min, t (minor)=13.943 min]; 1H NMR (400 MHz, CDCl 3): δ=7.96 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.35 (td, J=8.0 Hz, 0.8 Hz, 1H), 7.05 (td, J=8.0 Hz, 0.8 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H), 3.60 (s, 3H), 1.65 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.5,174.8,173.2,172.1,161.7,140.5,140.2,139.5,130.1,129.2,128.9,125.9,124.4,123.0,115.8,84.9,52.9,52.7,52.4,28.1 ppm; High resolution mass spectrum calculating value: (C 23H 23NO 9+ Na) m/z 480.1271, measured value: 480.1274.
Figure 165284DEST_PATH_IMAGE038
P17,84% yield, dr=86:14; [α] D 20=+12.4 ( c=1.1 in CHCl 3); 76% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak AD, n-hexane/ i-PrOH=80/20,1.0 mL/min, λ=254 nm, t (major)=11.475 min, t (minor)=7.737 min]; 1H NMR (400 MHz, CDCl 3): δ=7.59 (d, J=8.0 Hz, 1H), 7.43-7.39 (m, 1H), 7.35-7.22 (m, 5H), 7.19 (d, J=2.8 Hz, 1H), 7.14-7.10 (m, 2H), 5.06 (dd, J=6.4 Hz, 2.8 Hz, 1H), 4.72 (d, J=6.4 Hz, 1H), 3.82 (s, 3H), 3.52 (s, 3H), 1.44 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=175.6,173.9,172.8,161.8,161.7,148.7,140.9,140.6,135.1,129.8,129.5,128.8,128.4,128.0,124.4,123.2,115.4,84.8,62.0,52.9,52.6,52.3,43.0,28.1 ppm; High resolution mass spectrum calculating value: (C 28H 27NO 8+ Na) m/z 528.1634, measured value: 528.1636.
Figure 440408DEST_PATH_IMAGE040
P18,84% yield, dr〉95:5; [α] D 20=+133.2 ( c=0.5 in CHCl 3); 97% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak AD, n-hexane/ i-PrOH=60/40,1.0 mL/min, λ=254 nm, t (major)=11.729 min, t (minor)=9.823 min]; 1H NMR (400 MHz, CDCl 3): δ=7.92 (d, J=8.0 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.40-7.35 (m, 2H), 7.23 (d, J=3.2 Hz, 1H), 7.19 (d, J=7.2 Hz, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.83 (d, J=7.2 Hz, 1H), 4.45 (dd, J=8.4 Hz, 3.2 Hz, 1H), 4.10 (d, J=8.4 Hz, 1H), 3.60 (s, 3H), 1.67 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=167.9,163.0,161.2,160.9,149.0,144.4,144.1,143.7,142.0,141.7,129.7,124.4,122.2,121.6,116.3,111.1,84.7,72.4,52.8,52.5,52.2,28.0 ppm; High resolution mass spectrum calculating value: (C 27H 24N 2O 7+ Na) m/z 511.1481, measured value: 511.1485.
Figure 647660DEST_PATH_IMAGE042
P19,80% yield, dr〉95:5; [α] D 20=+56.3 ( c=0.5 in CHCl 3); 95% ee, the chirality test condition: determined by HPLC analysis [Daicel Chiralpak AD, n-hexane/ i-PrOH=60/40,1.0 mL/min, λ=254 nm, t (major)=11.010 min, t (minor)=13.958 min]; 1H NMR (400 MHz, CDCl 3): δ=7.82 (d, J=8.8 Hz, 1H), 7.48-7.44 (m, 3H), 7.39 (t, J=6.8 Hz, 1H), 7.21-7.19 (m, 3H), 6.97 (s, 1H), 4.41 (dd, J=8.8 Hz, 2.8 Hz, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.61 (s, 3H), 1.64 (s, 9H) ppm; 13C NMR (100 MHz, CDCl 3): δ=174.5,172.8,171.9,161.4,148.3,141.0,139.1,138.8,132.8,130.8,129.2,128.9,128.5,126.0,125.7,117.3,117.2,85.1,62.0,52.9,52.7,52.4,27.9 ppm; High resolution mass spectrum calculating value: (C 27H 23BrN 2O 7+ Na) m/z 589.0586, measured value: 589.0584.

Claims (4)

1. a class contains the cycloaddition product of multi-functional functional group volution indolinone, and it is the optical pure compound with following structure:
Figure 2011100797636100001DEST_PATH_IMAGE001
, wherein * is a chiral carbon atom, PG is selected from Ac, Boc, Bz, Cbz, Me or H arbitrarily; R 1Be selected from alkyl, aryl arbitrarily; The indolinone aryl replaces
Figure 2011100797636100001DEST_PATH_IMAGE002
R wherein 2, R 3, R 4Or R 5Be selected from the-oxyl of H, F, Cl, Br, C1-C16 arbitrarily, the alkyl of C1-C16; EWG is selected from the benzene sulfuryl arbitrarily, heterocycle sulfuryl and various carbonyl (ester, ketone, imide etc.).
2. on behalf of ethanoyl, Boc, wherein said Ac represent tertbutyloxycarbonyl, Bz to represent benzoyl, Cbz to represent carbobenzoxy-(Cbz), Me represent methylidene.
3. synthetic method by the cycloaddition product of the described multi-functional functional group of claim 1 volution indolinone, it is characterized in that under-10 ~ 50 degrees centigrade condition in organic solvent, with indolinone Morita-Baylis-Hillman (MBH) carbonic ether and all kinds of dipolarophile body compound (as, the propargyl sulfone, the butine diester, succimide or the like) is raw material, with 4 molecular sieves as additive, with Chiral Amine, the derivative of quinine deutero-beta-ICD particularly, the indolone cycloaddition reaction of carrying out as catalyzer, wherein indolinone MBH carbonic ether, the mol ratio of the derivative of dienophile compound and quinine deutero-beta-ICD is 1 ~ 2:1:0.05 ~ 0.1; The structure of the quinine deutero-beta-ICD derivative catalyst of wherein said chirality is: Wherein R is selected from H, CH arbitrarily 3O, BnO, CH 3OCH 2O, BnOCH 2Various alkoxyl groups such as O; Various substituted aryls or heterocyclic base; Various ester groups are as the trifluoro sulphonate; Various secondary amine or nitrogen heterocyclic ring are as morpholine, piperidines etc.
4. the method for the cycloaddition product of synthetic multi-functional functional group according to claim 2 volution indolinone, it is characterized in that described solvent is arranged is methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, toluene, m-xylene, sym-trimethylbenzene, phenylfluoroform, 1,4-dioxane, tetrahydrofuran (THF).
CN2011100797636A 2011-03-31 2011-03-31 Chiral indolinone spiropentacyclic skeleton compounds and asymmetric synthesis thereof Pending CN102180828A (en)

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CN104086477A (en) * 2014-07-15 2014-10-08 西华师范大学 Preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof
CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof
CN107226816A (en) * 2017-05-27 2017-10-03 重庆文理学院 A kind of preparation method of indoline spiro-compound
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CN102584800A (en) * 2011-12-16 2012-07-18 四川大学 Compound containing framework of chiral indolone and angelica lactone and asymmetric synthesis method
CN104086477A (en) * 2014-07-15 2014-10-08 西华师范大学 Preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof
CN104086477B (en) * 2014-07-15 2017-04-12 西华师范大学 Preparation method of optical-activity spiropentyl-1,3'-indole and derivatives thereof
CN104860939A (en) * 2015-04-10 2015-08-26 昆明理工大学 Cinchona alkaloids compound and preparation method thereof
CN107226816A (en) * 2017-05-27 2017-10-03 重庆文理学院 A kind of preparation method of indoline spiro-compound
CN113149890A (en) * 2021-04-27 2021-07-23 华东理工大学 Method for synthesizing 3-spiro-2-indolone compounds

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