CN103408530B - Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof - Google Patents

Abstract

The invention relates to a coumarin skeleton polycyclic compound with biological activity as well as a preparation method and use thereof. The general formula structure of the compound is shown in the specification, wherein, * represents a chiral carbon atom, R1 and R2 are respectively any one of C1-C16 alkyl, heteroaromatic ring or substituted aromatic ring; R3 is any one of H or C1-C16 alkyl or aryl; R4-R7 are respectively any one of H, F, Cl, Br, ester group, cyano, sulfuryl, nitro, heteroaromatic ring, C1-C16 oxyl, C1-C16 alkyl or substituted aromatic ring, and X is any one of O, X N, S atoms or imine, ketoxime and aromatic hydrazone. The compound has excellent region and stereoselectivity and a plurality of special physiological activities and tumor cell proliferation inhibition activities, and can be used for researching and developing antitumor drugs.

Description

There is bioactive coumarin skeleton polynuclear compound and preparation method and purposes

Technical field

The present invention relates to a kind of medicinal chemistry arts, particularly one has bioactive coumarin skeleton polynuclear compound and preparation method and purposes.

Background technology

Coumarin skeleton, the polynuclear compound especially based on this type of skeleton structure is extensively present in natural product and pharmaceutical intermediate, this compounds pharmaceutically vital role caused the interest of increasing chemist.Modify the substituting group of this compounds, synthesis and the bioactive research thereof of analog become study hotspot.[a)S.M.Sethna,N.M.Shah,Chem.Rev.1945,36,1;b)S.V.Ukhov,M.E.Kon’shin,T.F.Odegova,Pharm.Chem.J.2001,35,364;c)B.Musicki,A.M.Periers,P.Laurin,D.Ferroud,Y.Benedetti,S.Lachaud,F.Chatreaux,J.L.Haesslein,A.Iltis,C.Pierre,J.Khider,N.Tessot,M.Airault,J.Demassey,C.Dupuis-Hamelin,P.Lassaigne,A.Bonnefoy,P.Vicat,M.Klich,Bioorg.Med.Chem.Lett.2000,10,1695;d)S.Chimichi,M.Boccalini,B.Cosimelli,G.Viola,D.Vedaldi,F.Dall’Acqua,Tetrahedron Lett.2002,43,7473;e)N.S.Reddy,K.Gumireddy,M.R.Mallireddigari,S.C.Cosenza,P.Venkatapuram,S.C.Bell,E.P.Reddy,M.V.R.Reddy,Bioorg.Med.Chem.2005,13,3141;f)F.Uchiumi,T.Hatano,H.Ito,T.Yoshida,S.Tanuma,Antiviral Res.2003,58,89;g)R.Fre′de′rick,S.Robert,C.Charlier,J.de Ruyck,J.Wouters,B.Pirotte,B.Masereel,L.Pochet,J.Med.Chem.2005,48,7592;h)S.Robert,C.Bertolla,B.Masereel,J.-M.Dogne,L.Pochet,J.Med.Chem.2008,51,3077;i)I.E.Bylov,M.V.Vasylyev,Y.V.Bilokin,Eur.J.Med.Chem.1999,34,997.]。But prepared the correlative study of chirality tonka bean camphor polynuclear compound by asymmetry catalysis method, the organocatalysis mode especially by environmental protection does not also have relevant report at present.Therefore, development is a kind of easy and simple to handle, environmental friendliness, and the synthesis of high enantioselectivity has coumarin skeleton diversity and the method with the chipal compounds storehouse of potential medical active has great significance.

Summary of the invention

The object of this invention is to provide a kind of coumarin skeleton polynuclear compound with multiple potential source biomolecule activity, described compound has outstanding regioselectivity and stereoselectivity, and it is active to have multiple special physiological, find that this compounds has inhibition tumor cell proliferation activity through cytotoxicity experiment, can be used as the research and development of lead compound for new type antineoplastic medicine.

Of the present invention have bioactive coumarin skeleton polynuclear compound, has following formula:

Wherein, * is chiral carbon atom, R₁, R₂be independently of one another the alkyl of C1-C16, fragrant heterocycle orany one of aromatic ring replaced; R₃for any one in the alkyl of H or C1-C16 or aryl; R₄, R₅, R₆, R₇be independently of one another H, F, Cl, Br, ester group, cyano group, sulfuryl, nitro, fragrant heterocycle, the-oxyl of C1-C16, the alkyl of C1-C16 orany one of aromatic ring replaced, X is any one in O, N, S atom or imines, ketoxime, aryl hydrazone.

Work as R₁, R₂fortime, R¹, R², R³, R⁴or R⁵be independently of one another H, F, Cl, Br, ester group, cyano group, sulfuryl, nitro, the-oxyl of C1-C16, the alkyl of C1-C16 any one.

Work as R₄, R₅, R₆, R₇fortime, wherein R¹, R², R³, R⁴or R⁵be any one in the alkyl of the-oxyl of H, F, Cl, Br, C1-C16, C1-C16 independently of one another.

Second object of the present invention is to provide a kind of preparation method with the active coumarin skeleton polynuclear compound of multiple potential source biomolecule, and the method catalyzer is easy to get, and catalytic activity is high, and reaction conditions is gentle, simple to operate.

There is the preparation method of bioactive coumarin skeleton polynuclear compound, have following steps:

One kettle way, under acid additives, in organic solvent, under the condition of-20 DEG C ~ 50 DEG C, 3-ethanoyl coumarin compound [Xu Cuilian, Chen Gang, Xia Baigen, Su Hui, Jiang Zhihong, Deng Shuguang, Yang Nan, chemistry circular .2009, 9, 815-819.] and two olefine aldehydr [Z.-J.Jia, Q.Zhou, Q.-Q.Zhou, P.-Q.Chen, Y.-C.Chen, Angew.Chem.Int.Ed.2011, 50, 8638] be raw material, chiral alpha, α-diaryl Prolinol silicon ether [J.-L.Li, S.-L.Zhou, P.-Q.Chen, L.Dong, T.-Y.Liu, Y.-C.Chen, Chem.Sci.2012, 3, 1879.] Diels-Alder reaction is carried out as catalyzer, 20 ~ 120 hours reaction times, DBU is added at 25 DEG C, series connection Diels-Alder/Aldol reacts 2 hours, reaction expression is as follows:

at 0 DEG C, MsCl, TEA dehydration reaction obtains target product in 15 minutes.

The good technical scheme of the present invention is; one kettle way, under acid additives, in organic solvent at 0 DEG C; with 3-ethanoyl coumarin compound and two olefine aldehydrs for raw material; chiral alpha, the Diels-Alder reaction that α-diaryl Prolinol silicon ether carries out as catalyzer, 20 ~ 120 hours reaction times is not etc.; after TLC monitoring reacts completely; add DBU, at 25 DEG C, carry out Aldol react 2 hours, finally add MsCl, TEA dehydration reaction at 0 DEG C and obtain target product in 15 minutes.

The structural formula of the coumarin compound of 3-ethanoyl described in above-mentioned method is:wherein: R⁴, R⁵, R⁶, R⁷be selected from arbitrarily H, F, Cl, Br, ester group, cyano group, sulfuryl, nitro, fragrant heterocycle, the-oxyl of C1-C16, the alkyl of C1-C16 orthe aromatic ring replaced, wherein R¹, R², R³, R⁴or R⁵be selected from arbitrarily the-oxyl of H, F, Cl, Br, C1-C16, the alkyl of C1-C16;

The structural formula of two olefine aldehydrs described in above-mentioned method is:wherein: R₁, R₂be selected from arbitrarily fragrant heterocycle, C1-C16 alkyl orthe aromatic ring replaced, wherein R¹, R², R³, R⁴or R⁵be selected from arbitrarily the-oxyl of H, F, Cl, Br, C1-C16, the alkyl of C1-C16, ester group, cyano group, sulfuryl, nitro, R₃be selected from arbitrarily alkyl or the aryl of H, C1-C16;

Chiral alpha described in above-mentioned method, the general structure of α-diaryl Prolinol silicon ether catalyst is (any optically pure structure not limit by diagram):

wherein: R¹, R²be selected from H, CH arbitrarily₃, tBu, OCH₃, R³be selected from TMS, TES, TBS arbitrarily, R⁴be selected from H arbitrarily, OTBS.

Described in above-mentioned method, acid additives is selected from protonic acid arbitrarily; Described DBU is 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Described MsCl is methane sulfonyl chloride; Described TEA is triethylamine.

3-ethanoyl coumarin compound described in above-mentioned method, two olefine aldehydrs, chiral alpha, the mol ratio of α-diaryl Prolinol silicon ether, acid additives, DBU, MsCl, TEA is 1:2:0.2:0.2:0.5:2:5.

Organic solvent described in above-mentioned method is polar solvent or non-polar solvent, and described polar solvent is toluene, methylene dichloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ethyl acetate; Non-polar solvent is benzene, sherwood oil.Water described in the present invention is distilled water.

The product obtained by the present invention is adopted to be separated through the method for column chromatography.Developping agent used and eluent are the mixed solvent of polar solvent and non-polar solvent, and good solvent is sherwood oil/acetone.

Alkyl of the present invention,-oxyl etc., unless otherwise indicated, be all recommended as the group that carbon number is 1-16, recommends carbon number to be the group of 1-10 further, especially recommends carbon number to be the group of 1-4.

Aryl of the present invention, unless otherwise indicated, all refers to phenyl or naphthyl, is recommended as phenyl, described heterocycle be C5-C10 containing N, O, S heterocyclic radical.

Coumarin skeleton polynuclear compound of the present invention can be used for preparing Hepatoma therapy medicine, treatment kidney medicine, treatment cervical cancer medicine, treatment prostate cancer medicine, treatment lymphoid tumor medicament etc.

The present invention is with the α of chirality; α-diaryl Prolinol silicon ether is as catalyzer; be raw material by 3-ethanoyl coumarin compound and two olefine aldehydrs, a kind of method with the coumarin skeleton polynuclear compound of multiple lateral reactivity of the synthesis of high-level efficiency, highly-solid selectively.The method catalyzer is easy to get, catalytic activity is high, reaction conditions is gentle, simple to operate, wide application range of substrates, product structure is various, Atom economy good (atom in raw molecule is all transformed into product, does not produce by product or refuse), has environment friendly, yield high (ranging up to 95% yield), cis-selectivity higher (P1 ~ P11 is all greater than 95% de), enantioselectivity high (P1-(3aR, 7aS, 13bR)-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 90%ee; P2-(3aR, 7aS, 13bR)-12-bromo-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 87%ee; P3-(3aR, 7aS, 13bR)-12-chloro-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 87%ee; P4-(4aS, 12cR, 15aR)-15-phenyl-1,12c, 13,15a-tetrahydro benzo [f] naphtho-[8a, 1-c] chromene-4,5-diketone: 87%ee; P5-(3aR, 7aS, 13bR)-10-methoxyl group-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 96%ee; P6-(3aR, 7aS, 13bR)-10-oxyethyl group-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 94%ee; P7-(3aR, 7aS, 13bR)-7,8-dioxy-3-phenyl-1,3a, 4,7,8,13b-hexahydro naphthalene also [8a, 1-c] chromene-12-acetic ester: 89%ee; P8-(3aR, 7aS, 13bR)-12-methoxyl group-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 93%ee; P9-(3aR, 7aS, 13bR)-12-phenyl-3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 92%ee; P10-(3aR, 7aS, 13bR)-10,12-dichloro--3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 73%ee; P11-(3aR, 7aS, 13bR)-3-ethyl-10-methoxyl group--3-phenyl-1,3a, 4,13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7,8-diketone: 86%ee).Test through cytotoxicity, find P1:(3aR, 7aS, 13bR)-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, P3:(3aR, 7aS, 13bR) the chloro-3-phenyl-1 of-12-, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, P5:(3aR, 7aS, 13bR)-10-methoxyl group-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, the compound on tumor cells such as 8-diketone have proliferation inhibition activity, the lead compound be expected to as new type antineoplastic medicine is studied further.

To contribute to understanding the present invention by following embodiment, but not limit content of the present invention.

Embodiment

Reagent:

3-ethanoyl coumarin compound [Xu Cuilian, Chen Gang, Xia Baigen, Su Hui, Jiang Zhihong, Deng Shuguang, Yang Nan, chemistry circular .2009,9,815-819.];

Two olefine aldehydrs [Z.-J.Jia, Q.Zhou, Q.-Q.Zhou, P.-Q.Chen, Y.-C.Chen, Angew.Chem.Int.Ed.2011,50,8638];

Chiral alpha, α-diaryl Prolinol silicon ether [J.-L.Li, S.-L.Zhou, P.-Q.Chen, L.Dong, T.-Y.Liu, Y.-C.Chen, Chem.Sci.2012,3,1879.]

Acid additives, DBU, MsCl, TEA are commercially available analytical pure.

Water described in the present invention is distilled water, and described organic solvent is commercially available analytically pure polar solvent or non-polar solvent, as: benzene, toluene, methylene dichloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), sherwood oil, ethyl acetate etc.

Embodiment 1-11 all adopts one kettle way.

Embodiment 1

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 3-ethanoyl tonka bean camphor (0.1mmol, 18.8mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 42 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 1 by column chromatography for separation and is called (3aR, 7aS, 13bR)-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 87%, structural formula is as follows:

[α]_d²⁰=+152.4 (c=0.42in CHCl₃); 90%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=18.53min, t (minor)=11.84min];

¹H NMR(400MHz,CDCl₃):δ=7.43-7.41(m,2H),7.37-7.33(m,2H),7.30-7.29(m,2H),7.18-7.16(m,1H),7.15-7.07(m,2H),6.90-6.86(m,1H),5.97(dd,J=10.0,1.6Hz,1H),5.78(t,J=4.0Hz,1H),3.95-3.94(m,1H),3.52(t,J=8.0Hz,1H),2.89-2.80(m,1H),2.71(dt,J=20.0,5.6Hz,1H),2.40-2.28(m,2H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.7,167.8,151.1,148.5,140.3,140.1,128.7,128.5,127.6,127.3,126.5,126.3,125.6,124.5,121.4,116.9,56.5,36.9,32.9,32.0,30.4ppm;

High resolution mass spectrum calculating value: C₂₃h₁₈o₃+ H343.1334, measured value: 343.1336.

Embodiment 2

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-bromo-3-ethanoyl tonka bean camphor (0.1mmol, 26.7mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 72 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 2 by column chromatography for separation and is called: (3aR, 7aS, 13bR) the bromo-3-phenyl-1 of-12-, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 76%, structural formula is as follows:

[α]_d²⁰=+162.9 (c=0.80in CHCl₃); 87%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=19.07min, t (minor)=17.72min];

¹H NMR(400MHz,CDCl₃):δ=7.43-7.40(m,3H),7.37-7.34(m,2H),7.32-7.30(m,1H),7.27-7.26(m,1H),7.06-7.04(m,1H),6.93-6.88(m,1H),5.99-5.97(m,1H),5.77(t,J=4.0Hz,1H),3.98-3.95(m,1H),3.46(t,J=8.4Hz,1H),2.84(dq,J=20.0,4.0Hz,1H),2.72(dt,J=20.0,5.2Hz,1H),2.38-2.23(m,2H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.4,167.2,150.3,148.7,140.4,139.9,131.8,129.5,128.6,127.7,127.4,126.4,121.0,118.8,116.9,56.3,36.9,32.9,31.9,30.4ppm;

High resolution mass spectrum calculating value: C₂₃h₁₇brO₃+ H421.0439, measured value: 421.0437.

Embodiment 3

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-chloro-3-ethanoyl tonka bean camphor (0.1mmol, 22.2mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 12 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 3 by column chromatography for separation and is called: (3aR, 7aS, 13bR) the chloro-3-phenyl-1 of-12-, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 83%, structural formula is as follows:

[α]_d²⁰=+204.4 (c=0.78in CHCl₃); 87%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=20.04min, t (minor)=18.11min];

¹H NMR(400MHz,CDCl₃):δ=7.43-7.41(m,2H),7.37-7.34(m,2H),7.32-7.25(m,2H),7.13-7.09(m,2H),6.92-6.88(m,1H),5.98-5.96(m,1H),5.77(t,J=3.6Hz,1H),3.96-3.95(m,1H),3.47(t,J=8.4Hz,1H),2.84(dq,J=20.0,4.0Hz,1H),2.71(dt,J=20.0,5.6Hz,1H),2.38-2.23(m,2H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.4,167.2,149.7,148.8,140.4,139.9,129.4,128.8,128.6,127.7,127.3,126.6,126.3,121.0,118.3,56.2,36.9,32.9,31.8,30.1ppm;

High resolution mass spectrum calculating value: C₂₃h₁₇clO₃+ H377.0944, measured value: 377.0948.

Embodiment 4

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 5, 6-naphthalene-3-ethanoyl tonka bean camphor (0.1mmol, 23.8mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 60 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 4 by column chromatography for separation and is called (4aS, 12cR, 15aR)-15-phenyl-1, 12c, 13, 15a-tetrahydro benzo [f] naphtho-[8a, 1-c] chromene-4, 5-diketone, recovery rate is 76%, structural formula is as follows:

[α]_d²⁰=+300.0 (c=0.62in CHCl₃); 87%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=34.08min, t (minor)=25.69min];

¹H NMR(400MHz,CDCl₃):δ=7.91-7.85(m,2H),7.81(d,J=8.8Hz,1H),7.57-7.52(m,3H),7.47-7.43(m,1H),7.40-7.30(m,4H),6.93-6.89(m,1H),5.86-5.81(m,2H),4.18-4.11(m,2H),3.10(dq,J=20.0,4.0Hz,1H),2.80(dt,J=20.0,5.6Hz,1H),2.54-2.46(m,1H),2.32-2.24(m,1H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.6,167.8,148.9,148.5,140.8,140.1,130.9,129.2,129.0,128.6,127.7,127.1,127.0,126.4,124.9,121.8,120.7,119.0,117.6,56.1,37.4,32.1,30.9,28.9ppm;

High resolution mass spectrum calculating value: C₂₇h₂₀o₃+ H393.1491, measured value: 393.1492.

Embodiment 5

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 8-methoxyl group-3-ethanoyl tonka bean camphor (0.1mmol, 21.8mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 60 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 5 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-10-methoxyl group-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 95%, structural formula is as follows:

[α]_d²⁰=+277.5 (c=0.40in CHCl₃); 96%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=26.51min, t (minor)=32.86min];

¹H NMR(400MHz,CDCl₃):δ=7.41-7.39(m,2H),7.35-7.31(m,2H),7.29-7.26(m,1H),7.05-7.00(m,1H),6.91-6.83(m,2H),6.73-6.70(m,1H),5.96(d,J=11.2Hz,1H),5.77(t,J=3.6Hz,1H),3.92(s,3H),3.92-3.89(m,1H),3.51(t,J=8.0Hz,1H),2.82(ddd,J=20.0,7.2,4.0Hz,1H),2.68(dt,J=20.0,5.2Hz,1H),2.38-2.28(m,2H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.6,167.1,148.3,147.5,140.2,128.5,127.5,127.4,126.6,126.4,124.6,121.4,118.1,112.0,56.2,36.8,33.1,30.3,25.3ppm;

High resolution mass spectrum calculating value: C₂₄h₂₀o₄+ Na395.1259, measured value: 395.1258.

Embodiment 6

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 8-oxyethyl group-3-ethanoyl tonka bean camphor (0.1mmol, 23.2mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 96 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 6 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-10-oxyethyl group-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate 88%, structural formula is as follows:

[α]_d²⁰=+195.2 (c=0.52in CHCl₃); 94%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=14.73min, t (minor)=16.96min];

¹H NMR(400MHz,CDCl₃):δ=7.41-7.39(m,2H),7.36-7.32(m,2H),7.30-7.27(m,1H),7.02-6.98(m,1H),6.91-6.83(m,2H),6.72-6.69(m,1H),5.96(d,J=10.0Hz,1H),5.76(dd,J=4.0,3.6Hz,1H),4.21-4.01(m,2H),3.93-3.91(m,1H),3.50(dd,J=8.0,7.6Hz,1H),2.81(ddd,J=20.0,7.6,4.0Hz,1H),2.69(dt,J=20.0,5.6Hz,1H),2.38-2.29(m,2H),1.48(t,J=6.8Hz,3H)ppm;

¹³C NMR(100MHz,CDCl₃):δ=194.6,167.2,148.3,146.9,140.3,128.6,128.5,127.4,126.7,126.4,124.5,121.6,118.2,113.9,65.2,36.9,33.2,32.0,30.4,14.8ppm;

High resolution mass spectrum calculating value: C₂₅h₂₂o₄+ Na409.1416, measured value: 409.1412.

Embodiment 7

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-acetoxy-3-ethanoyl tonka bean camphor (0.1mmol, 24.6mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 72 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 7 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-7, 8-dioxy-3-phenyl-1, 3a, 4, 7, 8, 13b-hexahydro naphthalene also [8a, 1-c] chromene-12-acetic ester, recovery rate is 73%, structural formula is as follows:

[α]_d²⁰=+142.6 (c=0.74in CHCl₃); 89%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=60/40,1.0mL/min, λ=254nm, t (major)=25.61min, t (minor)=21.18min];

¹H NMR(400MHz,CDCl₃):δ=7.41-7.39(m,2H),7.37-7.32(m,2H),7.31-7.28(m,1H),7.17-7.15(m,1H),7.04-7.01(m,1H),6.93-6.85(m,2H),5.97(d,J=10.0Hz,1H),5.77(t,J=3.6Hz,1H),3.92(bs,1H),3.50(dd,J=7.6,7.2Hz,1H),2.84(ddd,J=20.0,7.6,4.0Hz,1H),2.69(dt,J=20.0,5.2Hz,1H),2.38-2.29(m,2H),2.27(s,3H)pp；

¹³C NMR(100MHz,CDCl₃):δ=194.4,169.2,167.5,148.5,146.8,140.2,140.0,128.5,127.6,127.4,126.4,126.3,121.6,119.7,117.8,56.2,36.8,33.0,30.3,21.1ppm；

High resolution mass spectrum calculating value: C₂₅h₂₀o₅+ Na423.1208, measured value: 423.1209.

Embodiment 8

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-methoxyl group-3-ethanoyl tonka bean camphor (0.1mmol, 21.8mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 120 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 8 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-12-methoxyl group-3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 86%, structural formula is as follows:

[α]_d²⁰=+152.8 (c=0.68in CHCl₃); 93%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=60/40,1.0mL/min, λ=254nm, t (major)=22.40min, t (minor)=20.20min];

¹H NMR(400MHz,CDCl₃):δ=7.43-7.40(m,2H),7.37-7.28(m,3H),7.10(d,J=9.2Hz,1H),6.90-6.85(m,1H),6.80(dd,J=8.8,2.8Hz,1H),6.67(d,J=2.8Hz,1H),5.97(d,J=10.0Hz,1H),5.78(dd,J=4.0,3.2Hz,1H),3.96-3.94(m,1H),3.78(s,3H),3.46(dd,J=7.6,7.2Hz,1H),2.83(ddd,J=20.0,7.2,4.0Hz,1H),2.70(dt,J=20.0,5.2Hz,1H),2.38-2.27(m,2H)ppm；

¹³C NMR(100MHz,CDCl₃):δ=194.8,167.9,156.1,148.4,144.9,140.2,128.5,127.6,127.5,126.5,126.4,121.4,117.7,112.8,112.5,55.5,36.9,33.2,31.8,30.4ppm；

High resolution mass spectrum calculating value: C₂₄h₂₀o₄+ Na395.1259, measured value: 395.1257.

Embodiment 9

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-phenyl-3-ethanoyl tonka bean camphor (0.1mmol, 26.4mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 120 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 9 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-3, 12-phenylbenzene-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 89%, structural formula is as follows:

[α]_d²⁰=+142.6 (c=0.74in CHCl₃); 92%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=60/40,1.0mL/min, λ=254nm, t (major)=31.13min, t (minor)=21.76min];

¹H NMR(400MHz,CDCl₃):δ=7.54-7.50(m,4H),7.44-7.40(m,4H),7.37-7.22(m,5H),6.91-6.87(m,1H),5.98(d,J=10.0Hz,1H),5.79(t,J=3.6Hz,1H),3.99-3.98(m,1H),3.56(dd,J=8.0,7.6Hz,1H),2.89(ddd,J=19.6,7.6,4.0Hz,1H),2.72(dt,J=19.6,5.2Hz,1H),2.41-2.32(m,2H)ppm；

¹³C NMR(100MHz,CDCl₃):δ=194.7,167.7,150.6,148.5,140.4,140.1,140.0,137.7,128.8,128.5,127.6,127.5,127.3,126.9,126.4,125.9,125.3,121.3,117.3,56.6,37.1,33.2,32.2,30.5ppm；

High resolution mass spectrum calculating value: C₂₉h₂₂o₃+ K457.1206, measured value: 457.1207.

Embodiment 10

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6, 8-bis-chloro-3-ethanoyl tonka bean camphor (0.1mmol, 25.7mg), 4-phenyl-2, 4-sorbic aldehyde (0.2mmol, 34mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 20 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 10 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-10, 12-dichloro--3-phenyl-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 61%, structural formula is as follows:

[α]_d²⁰=+150.2 (c=0.44in CHCl₃); 73%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=10.52min, t (minor)=12.40min];

¹H NMR(400MHz,CDCl₃):δ=7.43-7.40(m,2H),7.38-7.28(m,4H),7.02(d,J=2.0Hz,1H),6.94-6.89(m,1H),5.98(dd,J=10.4,1.6Hz,1H),5.77(t,J=4.0,3.6Hz,1H),3.98-3.95(m,1H),3.46(dd,J=8.8,8.4Hz,1H),2.84(dq,J=20.0,4.0Hz,1H),2.72(dt,J=20.0,5.6Hz,1H),2.37-2.23(m,2H)ppm；

¹³C NMR(100MHz,CDCl₃):δ=193.9,166.0,149.0,146.0,140.4,139.8,130.9,129.3,129.2,128.8,128.6,128.5,127.8,127.3,126.3,125.1,122.8,120.7,56.0,36.9,33.4,31.7,30.4ppm；

High resolution mass spectrum calculating value: C₂₃h₁₆o₃+ H411.0555, measured value: 411.0555.

Embodiment 11

In a clean 10ml reaction tubes, add chiral Prolinol silicon ether catalyst (0.02mmol successively, 14.8mg), 6-methoxyl group-3-ethanoyl tonka bean camphor (0.1mmol, 21.8mg), 4-ethyl-2, 4-sorbic aldehyde (0.2mmol, 25mg), L-Boc-2-phenylglycocoll (0.02mmol, 5mg) with chloroform (0.5mL), stirring reaction 72 hours at 0 DEG C, after TLC monitoring reaction terminates, add DBU(0.05mmol, 7.5 μ L), 25 DEG C are stirred 2 hours, add TEA(0.5mmol successively at 0 DEG C afterwards, 70 μ L) and MsCl(0.2mmol, 15.5 μ L) stir 15 minutes after, decompression and solvent recovery, residuum obtains product P 11 by column chromatography for separation and is called: (3aR, 7aS, 13bR)-3-ethyl-10-methoxyl group-1, 3a, 4, 13b-tetrahydrochysene naphtho-[8a, 1-c] chromene-7, 8-diketone, recovery rate is 65%, structural formula is as follows:

[α]_d²⁰=+38.3 (c=0.60in CHCl₃); 86%ee, chirality test condition HPLC analysis [Daicel chiralpak AD, n-hexane/i-PrOH=80/20,1.0mL/min, λ=254nm, t (major)=13.16min, t (minor)=8.47min];

¹H NMR(400MHz,CDCl₃):δ=7.01(dd,J=8.4,7.6Hz,1H),6.92(ddd,J=10.0,5.2,3.2Hz,1H),6.88(d,J=8.4Hz,1H),6.68(d,J=7.6Hz,1H),5.95(d,J=10.0Hz,1H),5.33-5.32(m,1H),3.91(s,3H),3.45(t,J=8.0Hz,1H),3.27(dd,J=8.8,6.0Hz,1H),2.84(dt,J=20.0,5.2Hz,1H),2.67-2.60(m,1H),2.39-2.30(m,1H),2.18-2.08(m,3H),1.04(t,J=7.2Hz,3H)ppm；

¹³C NMR(100MHz,CDCl₃):δ=194.9,167.1,147.9,147.4,130.9,128.8,127.6,126.9,124.4,118.0,116.9,111.8,56.2,36.8,33.3,30.5,29.9,27.9,11.8ppm；

High resolution mass spectrum calculating value: C₂₀h₂₀o₄+ Na347.1259, measured value: 347.1259.

Embodiment 12

Cytotoxicity is tested: CCK-8 method measures the impact of compound on tumor cell proliferation

(1) cell strain: choose human foetus liver cell L02, hepatocellular carcinoma cells HepG2, Huh7, vascular endothelial cell EA.hy926, cervical cancer cell HeLa, renal epithelial cell HEK293, kidney cancer cell ACHN, lymphoma cell Jeko, Namalwa, prostate cancer cell DU145 totally 10 kinds of clones test.

(2) testing method (CCK-8 method): 2000, the cell in vegetative period of taking the logarithm is inoculated in 96 orifice plates, every hole 100ul, is divided into blank group and compound group.After cell normally cultivates 12h, in cell culture medium by 0,1.25,2.5,5,10,20,40 μm of ol/L totally 7 concentration gradients add compound, often group establishes 3 multiple holes.After cellar culture 48-72h, by centrifugal for every hole, abandon supernatant, respectively add the CCK8 of RPMI-1640 containing 10%FBS and 10 μ l, in 37 DEG C, hatch 1 hour in 5%CO2 incubator, microplate reader is determined at the absorption photometric value (A value) under 450nm wavelength, then calculates the growth-inhibiting situation of compound on intracellular, using half-inhibition concentration (IC50) as Testing index.

(3) measurement result: in table 1.Compound all has proliferation inhibition activity (LO2: human foetus liver cell, Huh7, HepG2: human liver cancer cell to 10 kinds of cells; EA.hy926: human vascular endothelial; HeLa: human cervical carcinoma cell; HEK293: HEKC; ACHN: human renal carcinoma cell; Jeko: people's lymphoma mantle cell cell; Namalwa: human B cell lymphoma cell; DU145: prostate cancer cell).

Table 1 compound half-inhibition concentration (μm ol/L)

Conclusion a: class of the inventive method synthesis has the novel coumarin framework compound of multichiral center, has outstanding regioselectivity and stereoselectivity.It is active that such chipal compounds has multiple special physiological, and yield is waited until very well (reaching as high as 95%yield) in can reaching, cis-selectivity higher (being greater than 95%de), enantioselectivity high (being up to 96%ee).Show that this compounds has inhibition tumor cell proliferation activity through cytotoxicity experiment, the research and development of new type antineoplastic medicine may be used for as lead compound.

Claims (11)

1. there is a bioactive coumarin skeleton polynuclear compound, it is characterized in that, there is following formula:

Wherein, * is chiral carbon atom, R₁for phenyl, R₂-R₃, R₅for H, R₄for H or Cl, R₆for H or methoxyl group, X is O.

2. the preparation method of compound according to claim 1, is characterized in that, has following steps:

Under one kettle way acid additives; in organic solvent; under the condition of-20 DEG C ~ 50 DEG C, 3-ethanoyl coumarin compound and two olefine aldehydrs are raw material, chiral alpha; α-diaryl Prolinol silicon ether carries out Diels-Alder reaction as catalyzer; in 20 ~ 120 hours reaction times, add DBU at 25 DEG C, series connection Diels-Alder/Aldol reacts 2 hours; at 0 DEG C, MsCl, TEA dehydration reaction obtains target product in 15 minutes.

3. method according to claim 2, is characterized in that: described chiral alpha, and the general structure of α-diaryl Prolinol silicon ether catalyst is:wherein: R¹, R²be selected from H, CH arbitrarily₃, tBu, OCH₃, R³be selected from TMS, TES, TBS arbitrarily, R⁴be selected from H arbitrarily, OTBS.

4. method according to claim 2, is characterized in that: described acid additives is selected from protonic acid arbitrarily; Described DBU is 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Described MsCl is methane sulfonyl chloride; Described TEA is triethylamine.

5. method according to claim 2, is characterized in that: described 3-ethanoyl coumarin compound, two olefine aldehydrs, chiral alpha, and the mol ratio of α-diaryl Prolinol silicon ether, acid additives, DBU, MsCl, TEA is 1:2:0.2:0.2:0.5:2:5.

6. method according to claim 2, is characterized in that: described organic solvent is polar solvent or non-polar solvent, and described polar solvent is toluene, methylene dichloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ethyl acetate; Non-polar solvent is benzene, sherwood oil.

7. coumarin skeleton polynuclear compound according to claim 1 is for the preparation of the purposes in Hepatoma therapy medicine.

8. coumarin skeleton polynuclear compound according to claim 1 is for the preparation of the purposes in treatment kidney medicine.

9. coumarin skeleton polynuclear compound according to claim 1 is for the preparation of the purposes in treatment cervical cancer medicine.

10. coumarin skeleton polynuclear compound according to claim 1 is for the preparation of the purposes in treatment prostate cancer medicine.

11. coumarin skeleton polynuclear compounds according to claim 1 for the preparation for the treatment of lymphoid tumor medicament in purposes.