新型吡唑啉酮-六氫山酮素-氧化吲哚衍生物的合成

姜維艷, 岳 靜, 劉雄利, 鄧國棟*

(1. 貴州裝備制造職業(yè)學(xué)院，貴州 貴陽 550025;2. 貴州大學(xué) 貴州省藥食同源植物資源開發(fā)工程技術(shù)研究中心，貴州 貴陽 550025)

把兩個或多個有生物活性的骨架拼接成具有潛在生物活性的多骨架分子，是重要的新化合物構(gòu)造策略[1-2]。六氫山酮素骨架在廣泛存在于藥物和天然產(chǎn)物分子中。如天然產(chǎn)物分子Diversonol， Desoxydiversonol， Ergochrome DD和Isocochlioquinone A共有一個六氫山酮素骨架單元，這類化合物具有良好的鎮(zhèn)痛作用[3-5]。螺六元碳環(huán)氧化吲哚主要存在于天然產(chǎn)物和合成藥物分子中[6-8]，如天然產(chǎn)物分子Satavaptan表現(xiàn)出明顯的生物活性。螺環(huán)吡唑啉酮是重要的天然產(chǎn)物和藥物分子[9-11]，在生物制藥領(lǐng)域有重要應(yīng)用價值。因此，將螺環(huán)吡唑啉酮和六氫山酮素骨架拼接到螺環(huán)氧化吲哚骨架上，有望合成一系列具有多樣性特征的新化合物，為生物活性篩選提供化合物源。目前合成六氫山酮素骨架的方法主要為：以3-吸電子基團(tuán)的色酮為起始原料[12-14]，經(jīng)4+2環(huán)加成反應(yīng)合成，反應(yīng)存在底物局限性。

Scheme 1

本文以色酮-吡唑啉酮合成子(1)與3-烯鍵氧化吲哚(2)[15]為原料，DABCO為催化劑，氯仿為溶劑，于室溫發(fā)生分子間Michael加成反應(yīng)后再發(fā)生分子內(nèi)環(huán)化反應(yīng)，合成了14個新型的吡唑啉酮六氫山酮素骨架拼接氧化吲哚3a～3n，產(chǎn)率75%～89%，dr值7/1～11/1,其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-MS(ESI-TOF)表征。

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

WRS-1B型數(shù)字熔點(diǎn)儀；Bruker-500 MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo));MicroTMQ-TOF型高分辨質(zhì)譜儀。

所用試劑均為分析純。

1.2 3a～3n的合成(以3a為例)

在反應(yīng)管中依次加入吡唑啉酮-色酮合成子(1a)66.4 mg(0.20 mmol)， 3-烯鍵氧化吲哚(2a)8.03 mg(0.25 mmol)， 10 mol%DABCO 2.24 mg(0.02 mmol)和氯仿2.0 mL，攪拌下于室溫反應(yīng)約3 d(TLC檢測)。經(jīng)硅膠柱層析[洗脫劑：V(石油醚)/V(乙酸乙酯)=5/1]純化得化合物3a113.7 mg。

用類似的方法合成3b～3n。

3a: 白色固體,產(chǎn)率87%, m.p.160.4～161.3 ℃, 7/1dr;1H NMRδ: 0.93(s, 9H), 2.19(s, 3H), 2.42～2.47(m, 1H), 2.49～2.53(m, 1H), 2.77(s, 3H), 3.79～3.84(m, 2H), 5.93(d,J=9.6 Hz, 1H), 6.93(d,J=5.6 Hz, 1H), 7.02～7.04(m, 1H), 7.23～7.25(m, 1H), 7.38～7.42(m, 2H), 7.44～7.47(m, 2H), 7.85～7.86(m, 1H), 7.97(d,J=5.2 Hz, 2H), 8.07(s, 1H), 8.30(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 25.9, 26.7, 27.0, 38.3, 52.1, 52.9, 53.6, 80.2, 83.6, 116.9, 117.8, 119.2, 120.2, 122.3, 125.4, 127.1, 127.3, 128.9, 129.4, 129.8, 131.2, 136.3, 138.0, 140.1, 159.9, 160.3, 165.8, 170.4, 175.2, 178.7, 192.0; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7ClNa{[M+Na]+}676.1821, found 676.1827。

3b: 白色固體,產(chǎn)率80%, m.p.123.2～124.7 ℃, 8/1dr;1H NMRδ: 0.88(s, 9H), 2.19(s, 3H), 2.34(s, 3H), 2.41～2.45(m, 1H), 2.52～2.56(m, 1H), 2.76(s, 3H), 3.80～3.86(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.72(d,J=5.6 Hz, 1H), 6.99～7.02(m, 1H), 7.18～7.20(m, 1H), 7.22～7.25(m, 1H), 7.38～7.41(m, 1H), 7.44～7.47(m, 2H), 7.78(s, 1H), 7.84～7.86(m, 1H), 7.96～7.98(m, 2H), 8.20(d,J=5.6 Hz, 1H);13C NMRδ: 13.2, 21.4, 25.8, 26.8, 26.9, 38.4, 52.3, 53.0, 53.5, 80.3, 83.0, 115.5, 117.9, 119.3, 120.3, 122.0, 125.2, 127.2, 127.3, 127.9, 128.8, 129.7, 135.5, 136.1, 138.2, 139.2, 160.2, 160.4, 166.0, 170.5, 175.2, 179.5, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C37H35N3O7Na{[M+Na]+}656.236, found 656.2361。

3c: 白色固體,產(chǎn)率80%, m.p.126.3～127.4 ℃, 11/1dr;1H NMRδ: 0.88(s, 9H), 1.19(s, 3H), 1.20(s, 3H), 2.18(s, 3H), 2.34(s, 3H), 2.41～2.45(m, 1H), 2.50～2.54(m, 1H), 2.75(s, 3H), 2.83～2.88(m, 1H), 3.78～3.83(m, 2H), 5.91(d,J=9.6 Hz, 1H), 6.66(d,J=5.6 Hz, 1H), 7.19(d,J=5.6 Hz, 1H), 7.22～7.24(m, 1H), 7.26～7.29(m, 1H), 7.44～7.46(m, 2H), 7.69(s, 1H), 7.77(s, 1H), 7.97(d,J=5.2 Hz, 2H), 8.19(d,J=5.6 Hz, 1H);13C NMRδ: 13.2, 21.4, 23.9, 25.9, 26.8, 26.9, 33.3, 38.5, 52.2, 53.0, 53.5, 80.4, 83.0, 115.5, 117.8, 119.3, 119.9, 124.4, 125.2, 127.2, 128.0, 128.8, 129.6, 134.8, 135.5, 138.2, 139.2, 142.7, 158.5, 160.4, 166.1, 170.5, 175.2, 179.5, 192.7; HR-MS(ESI-TOF)m/z: Calcd for C40H41N3O7Na{[M+Na]+}698.2837, found 698.2839。

3d: 白色固體,產(chǎn)率89%, m.p.131.4～132.7 ℃, 9/1dr;1H NMRδ: 0.92(s, 9H), 1.20(s, 3H), 1.21(s, 3H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.76(s, 3H), 2.84～2.89(m, 1H), 3.77～3.82(m, 2H), 5.84(d,J=9.6 Hz, 1H), 6.67(d,J=5.6 Hz, 1H), 7.22～7.25(m, 2H), 7.29～7.31(m, 1H), 7.43～7.46(m, 2H), 7.70(s, 1H), 7.93(d,J=5.2 Hz, 2H), 7.97(d,J=5.6 Hz, 1H), 8.40(s, 1H);13C NMRδ: 13.1, 23.9, 26.0, 26.7, 27.0, 33.3, 38.3, 52.0, 52.8, 53.4, 80.3, 83.4, 116.3, 117.7, 119.5, 119.9, 124.2, 125.4, 125.8, 126.5, 127.8, 128.9, 135.0, 135.1, 138.0, 142.4, 143.0, 158.3, 160.4, 165.9, 170.4, 175.4, 179.0, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C39H38N3O7ClNa{[M+Na]+}718.2290, found 718.2294。

3e: 白色固體,產(chǎn)率83%, m.p.128.3～129.6 ℃, 8/1dr;1H NMRδ: 0.92(s, 9H), 1.20(s, 3H), 1.21(s, 3H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.76(s, 3H), 2.84～2.89(m, 1H), 3.77～3.82(m, 2H), 5.84(d,J=5.2 Hz, 1H), 6.68(d,J=5.6 Hz, 1H), 7.23～7.25(m, 1H), 7.29～7.31(m, 1H), 7.38～7.40(m, 1H), 7.43～7.46(m, 2H), 7.70(s, 1H), 7.92～7.94(m, 3H), 8.56(s, 1H);13C NMRδ: 13.1, 23.9, 26.0, 26.7, 27.0, 33.3, 38.3, 52.0, 52.8, 53.5, 80.2, 83.4, 117.7, 119.0, 119.5, 119.9, 123.1, 124.2, 125.5, 127.1, 128.2, 128.8, 128.9, 135.0, 138.0, 142.5, 143.0, 158.3, 160.4, 165.9, 170.4, 175.4, 178.9, 192.4; HR-MS(ESI-TOF)m/z: Calcd for C39H38N3O7BrNa{[M+Na]+}762.1785, found 762.1784。

3f: 白色固體,產(chǎn)率75%, m.p.120.6～121.7 ℃, 9/1dr;1H NMRδ: 0.87(s, 9H), 2.18(s, 3H), 2.43～2.52(m, 2H), 2.77(s, 3H), 3.81～3.86(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.69～6.71(m, 1H), 7.10～7.13(m, 1H), 7.22～7.26(m, 2H), 7.39～7.42(m, 1H), 7.43～7.46(m, 2H), 7.49～7.51(m, 1H), 7.94(d,J=5.2 Hz, 2H), 7.98(d,J=5.2 Hz, 1H), 8.33(d,J=5.2 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.8, 26.9, 38.4, 52.3, 52.9, 53.4, 80.6, 83.2, 112.2 (d,JCF=24.3 Hz), 115.7, 119.5, 119.6, 123.6 (d,JCF=24.0 Hz), 125.4, 125.9, 126.8, 127.8, 128.9, 129.4, 138.0, 141.5, 156.3, 157.6 (d,JCF=241.5 Hz), 160.3, 165.9, 170.5, 175.3, 179.3, 191.6; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7FNa{[M+Na]+}660.2116, found 660.2118。

3g: 白色固體,產(chǎn)率84%, m.p.118.0～119.3 ℃, 7/1dr;1H NMRδ: 0.92(s, 9H), 2.18(s, 3H), 2.45～2.50(m, 1H), 2.77(s, 3H), 3.78～3.83(m, 2H), 5.89(d,J=9.6 Hz, 1H), 6.72～6.75(m, 1H), 7.13～7.16(m, 1H), 7.23～7.26(m, 2H), 7.44～7.47(m, 2H), 7.49～7.51(m, 1H), 7.92～7.96(m, 3H), 8.40(s, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.3, 52.1, 52.8, 53.3, 80.5, 83.5, 112.3(d,JCF=22.5 Hz), 116.3, 119.6, 120.8, 123.8(d,JCF=25.5 Hz), 125.6, 125.9, 126.3, 127.9, 128.9, 135.3, 137.9, 142.3, 156.2, 157.8(d,JCF=231.8 Hz), 160.2, 165.8, 170.4, 175.3, 178.9, 191.4; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FClNa{[M+Na]+}694.1727, found 694.1732。

3h: 白色固體,產(chǎn)率82%, m.p.105.3～106.4 ℃, 10/1dr;1H NMRδ: 0.92(s, 9H), 2.18(s, 3H), 2.45～2.49(m, 2H), 2.77(s, 3H), 3.78～3.83(m, 2H), 5.88(d,J=9.6 Hz, 1H), 6.73～6.75(m, 1H), 7.13～7.16(m, 1H), 7.24～7.26(m, 1H), 7.39～7.41(m, 1H), 7.44～7.47(m, 2H), 7.49～7.51(m, 1H), 7.89～7.93(m, 3H), 8.55(s, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.3, 52.1, 52.8, 53.3, 80.4, 83.5, 112.3 (d,JCF=22.5 Hz), 119.1, 119.6, 123.3, 123.8(d,JCF=24.0 Hz), 125.6, 126.8, 128.2, 128.9, 137.9, 142.4, 156.2, 157.3 (d,JCF=246.0 Hz), 160.2, 165.7, 170.4, 175.3, 178.8, 191.4; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FBrNa{[M+Na]+}738.1222, found 738.1222。

3i: 白色固體,產(chǎn)率82%, m.p.139.1～140.4 ℃, 9/1dr;1H NMRδ: 0.87(s, 9H), 2.18(s, 3H), 2.42～2.47(m, 1H), 2.49～2.53(m, 1H), 2.77(s, 3H), 3.82～3.86(m, 2H), 5.96(d,J=9.6 Hz, 1H), 6.69(d,J=6.0 Hz, 1H), 7.23～7.26(m, 2H), 7.33～7.35(m, 1H), 7.39～7.42(m, 1H), 7.44～7.46(m, 2H), 7.80(s, 1H), 7.95(d,J=5.2 Hz, 2H), 7.98(d,J=4.8 Hz, 1H), 8.32(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.8, 26.9, 38.3, 52.3, 52.8, 53.4, 80.6, 83.2, 115.7, 119.5, 119.6, 121.0, 125.4, 126.0, 126.6, 126.8, 127.7, 128.9, 129.4, 136.0, 138.0, 141.5, 158.5, 160.2, 165.9, 170.5, 175.2, 179.3, 191.3; HR-MS(ESI-TOF)m/z: Calcd for C36H32N3O7ClNa{[M+Na]+}676.1821, found 676.1827。

3j: 白色固體,產(chǎn)率84%, m.p.128.5～129.4 ℃, 10/1dr;1H NMRδ: 0.93(s, 9H), 2.19(s, 3H), 2.42～2.52(m, 2H), 2.76(s, 3H), 3.78～3.84(m, 2H), 5.95(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.23～7.26(m, 1H), 7.35～7.40(m, 2H), 7.45～7.47(m, 2H), 7.81(s, 1H), 7.96(d,J=5.2 Hz, 2H), 8.05(s, 1H), 8.29(d,J=6.0 Hz, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.2, 52.2, 52.9, 53.5, 80.4, 83.7, 117.0, 119.2, 119.6, 121.0, 125.4, 126.6, 127.1, 127.9, 128.9, 129.5, 129.6, 131.3, 136.1, 138.0, 140.0, 158.3, 160.1, 165.6, 170.3, 175.1, 178.5, 191.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7Cl2Na{[M+Na]+}710.1431, found 710.1436。

3k: 白色固體,產(chǎn)率87%, m.p.127.6～128.7 ℃, 7/1dr;1H NMRδ: 0.92(s, 9H), 2.19(s, 3H), 2.45～2.48(m, 2H), 2.76(s, 3H), 3.80～3.85(m, 2H), 5.92(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.10～7.13(m, 1H), 7.24～7.26(m, 1H), 7.35～7.37(m, 1H), 7.44～7.47(m, 2H), 7.81(s, 1H), 7.84～7.86(m, 1H), 7.95(d,J=5.2 Hz, 2H), 8.32～8.34(m, 1H);13C NMRδ: 13.1, 25.8, 26.7, 27.0, 38.2, 52.1, 52.8, 53.6, 80.5, 83.5, 114.6, 114.8, 115.9, 116.0, 117.1, 119.4, 119.5, 121.0, 125.5, 126.6, 127.9, 128.9, 129.7, 136.1, 137.6, 137.9, 158.3, 159.7, 160.2, 161.3, 165.7, 170.3, 175.3, 178.8, 191.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7FClNa{[M+Na]+}694.1727, found 694.1727。

3l: 白色固體,產(chǎn)率84%, m.p.146.5～147.3 ℃, 7/1dr;1H NMRδ: 0.97(s, 9H), 2.21(s, 3H), 2.46～2.53(m, 2H), 2.78(s, 3H), 3.79～3.86(m, 2H), 5.98(d,J=11.2 Hz, 1H), 6.72(d,J=7.2 Hz, 1H), 7.25～7.28(m, 1H), 7.37～7.40(m, 1H), 7.46～7.50(m, 2H), 7.56～7.58(m, 1H), 7.83(s, 1H), 7.99(d,J=6.4 Hz, 2H), 8.21(s, 1H), 8.25(d,J=7.2 Hz, 1H);13C NMRδ: 13.0, 25.8, 26.5, 27.0, 38.2, 52.3, 52.9, 53.5, 80.4, 83.7, 117.3, 118.9, 119.2, 119.5, 121.1, 125.4, 126.6, 127.9, 128.8, 129.9, 130.0, 132.4, 136.0, 138.0, 140.5, 158.3, 160.0, 165.6, 170.2, 175.1, 178.4, 190.8; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7ClBrNa{[M+Na]+}754.0926, found 754.0922。

3m: 白色固體,產(chǎn)率80%, m.p.121.2～122.4 ℃, 10/1dr;1H NMRδ: 0.88(s, 9H), 2.18(s, 3H), 2.34(s, 3H), 2.40～2.44(m, 1H), 2.50～2.54(m, 1H), 2.76(s, 3H), 3.80～3.85(m, 2H), 5.97(d,J=9.6 Hz, 1H), 6.70(d,J=6.0 Hz, 1H), 7.19(d,J=5.6 Hz, 1H), 7.23～7.25(m, 1H), 7.33～7.35(m, 1H), 7.44～7.47(m, 2H), 7.76(s, 1H), 7.80(s, 1H), 7.96(d,J=5.2 Hz, 2H), 8.19(d,J=5.6 Hz, 1H);13C NMRδ: 13.1, 21.4, 25.7, 26.8, 26.9, 38.4, 52.4, 53.0, 53.3, 80.5, 83.1, 115.6, 119.3, 119.6, 121.1, 125.3, 126.5, 127.2, 127.6, 128.9, 129.8, 135.6, 135.9, 138.1, 139.2, 158.6, 160.2, 165.9, 170.4, 175.2, 179.4, 191.3; HR-MS(ESI-TOF)m/z: Calcd for C37H34N3O7ClNa{[M+Na]+}690.1977, found 690.1971。

Scheme 2

3n: 白色固體,產(chǎn)率86%, m.p.112.9～113.4 ℃, 7/1dr;1H NMRδ: 0.83(s, 9H), 2.08(s, 3H), 2.32～2.42(m, 2H), 2.67(s, 3H), 3.69～3.74(m, 2H), 5.81(d,J=9.6 Hz, 1H), 6.63(d,J=6.0 Hz, 1H), 7.14～7.17(m, 1H), 7.26～7.28(m, 1H), 7.30～7.32(m, 1H), 7.35～7.37(m, 2H), 7.72(s, 1H), 7.79～7.83(m, 3H), 8.46(s, 1H);13C NMRδ: 12.1, 24.7, 25.7, 26.0, 37.2, 51.1, 51.7, 52.3, 79.4, 82.5, 118.0, 118.5, 120.0, 122.3, 124.5, 125.6, 125.7, 126.9, 127.2, 127.9, 135.1, 136.9, 141.4, 157.3, 159.1, 164.7, 169.3, 174.2, 177.7, 190.0; HR-MS(ESI-TOF)m/z: Calcd for C36H31N3O7ClBrNa{[M+Na]+}754.0926, found 754.0928。

2 結(jié)果與討論

2.1 合成

以3a的合成為例，研究了催化劑、反應(yīng)時間和產(chǎn)率對反應(yīng)的影響，結(jié)果見表1。

表1 反應(yīng)條件的優(yōu)化

由表1可見，無催化劑存在，反應(yīng)不能進(jìn)行，在10 mol%DABCO催化下，3 d內(nèi)可反應(yīng)完全，產(chǎn)率達(dá)到87%。在其它堿性三級胺類催化劑作用下(DBU, Et3N和DMAP)，產(chǎn)率明顯降低，且伴有少量副產(chǎn)物生成。

2.2 反應(yīng)機(jī)理

在實(shí)驗(yàn)結(jié)果和文獻(xiàn)[16-20]報道基礎(chǔ)上，我們推測了可能的反應(yīng)機(jī)理(Scheme 2)：在DABCO的催化作用下，1與2先發(fā)生分子間Michael加成，再發(fā)生分子內(nèi)環(huán)化反應(yīng)轉(zhuǎn)化為目標(biāo)產(chǎn)物3。

合成了14個未見文獻(xiàn)報道的吡唑啉酮六氫山酮素骨架拼接氧化吲哚，產(chǎn)率75%～89%,dr值7/1～11/1?；衔锕羌芎羞B續(xù)5個立體中心(含兩個螺環(huán)季碳中心)，有望為生物活性篩選提供化合物基礎(chǔ)。