姜維艷, 岳 靜, 劉雄利, 鄧國(guó)棟*

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

把兩個(gè)或多個(gè)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(gè)六氫山酮素骨架單元，這類(lèi)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(jià)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(gè)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(cè))。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(lèi)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(shí)間和產(chǎn)率對(duì)反應(yīng)的影響，結(jié)果見(jiàn)表1。

表1 反應(yīng)條件的優(yōu)化

由表1可見(jiàn)，無(wú)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(jí)胺類(lèi)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(bào)道基礎(chǔ)上，我們推測(cè)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(gè)未見(jiàn)文獻(xiàn)報(bào)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。化合物骨架含有連續(xù)5個(gè)立體中心(含兩個(gè)螺環(huán)季碳中心)，有望為生物活性篩選提供化合物基礎(chǔ)。