肖宏偉, 王浩宇, 葛真真, 趙建強(qiáng), 周鳴強(qiáng)*, 袁偉成,*

(1. 中國(guó)科學(xué)院 成都有機(jī)化學(xué)研究所 手性藥物國(guó)家工程研究中心,四川 成都 610041；2. 成都大學(xué) 高等研究院手性藥物創(chuàng)新研究中心,四川 成都 610106； 3. 中國(guó)科學(xué)院大學(xué),北京 100049)

色胺酮(Tryptanthrin)是一種具有吲哚喹唑啉結(jié)構(gòu)的生物堿,主要存在于蓼藍(lán)等產(chǎn)藍(lán)植物中[1-2]。相關(guān)研究[3-6]表明,色胺酮及其衍生物具有廣泛的生物活性(Chart 1)。如Phaitanthrin A和Phaitanthrin B是從Phaiusmishmensis中分離出的新型吲哚喹唑啉生物堿,其對(duì)MCF-7、 NCI-H460和SF-268細(xì)胞株顯示出良好的細(xì)胞毒性。Cruciferane是從Isatisindigotica的根中分離出的吡咯并吲哚喹唑啉生物堿,其對(duì)WB-F344細(xì)胞中半乳糖胺誘導(dǎo)的細(xì)胞毒性具有抑制作用。因此,通過(guò)直接對(duì)色胺酮進(jìn)行結(jié)構(gòu)修飾,將得到各種新穎的吲哚喹唑啉衍生物,進(jìn)一步為生物活性篩選提供物質(zhì)基礎(chǔ),對(duì)制藥行業(yè)有著重要的潛在應(yīng)用價(jià)值[7-11]。另一方面,螺環(huán)氧化吲哚是許多生物活性化合物的基本骨架,如(S)-(-)-Spirobrassinin[12]和(+)-Alantrypinone[13](Chart 1)。3-異硫氰酸酯氧化吲哚是本課題組發(fā)展的一種高活性親核試劑,其已被證明是一種高效且多用途的3C合成子,可通過(guò)不對(duì)稱串聯(lián)反應(yīng)構(gòu)建結(jié)構(gòu)多樣的螺環(huán)氧化吲哚[14-19]。

Chart 1

本文以3-異硫氰酸酯氧化吲哚為反應(yīng)底物,在催化劑Et3N作用下,與色胺酮發(fā)生aldol加成環(huán)化反應(yīng),10～20 min即可反應(yīng)完全,合成了13個(gè)結(jié)構(gòu)新穎的含雙螺環(huán)骨架的氧化吲哚類化合物3a～3m,收率為63～93%,dr值>19 ∶1(Scheme 1)。其結(jié)構(gòu)經(jīng)1H NMR、13C NMR和HR-MS(ESI-TOF)表征及熔點(diǎn)測(cè)試。該化合物同時(shí)含有色胺酮和螺環(huán)氧化吲哚骨架,且含有兩個(gè)連續(xù)的螺環(huán)季碳中心,可為后續(xù)生物活性評(píng)價(jià)提供物質(zhì)基礎(chǔ)。

Scheme 1

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

BüchiB-545型熔點(diǎn)儀；Bruker-300 MHz型核磁共振儀(DMSO-d6為溶劑,TMS為內(nèi)標(biāo))；Bruker Q TOF型高分辨質(zhì)譜儀。

1.2 化合物3a～3m的合成

(1)3a～3e,3g,3k～3m的合成

以合成3a為例:在反應(yīng)管中依次加入N-甲基-3-異硫氰酸酯氧化吲哚(1a) 25 mg(0.12 mmol),色胺酮(2a) 25 mg(0.1 mmol), 2 mL二氯甲烷和三乙胺2.8 μL(20 mol/mol, 0.02 mmol)。室溫?cái)嚢璺磻?yīng)10 min(TLC檢測(cè)),析出固體,過(guò)濾,濾餅用二氯甲烷洗滌,得白色固體3a42 mg。

(2)3f,3h～3j的合成

以合成3f為例:在反應(yīng)管中依次加入N-甲基-3-異硫氰酸酯氧化吲哚(1a) 25 mg(0.12 mmol),9-氟色胺酮(2g) 27 mg(0.1 mmol), 2 mL二氯甲烷和三乙胺2.8 μL(20 mol%, 0.02 mmol)。室溫?cái)嚢璺磻?yīng)10 min(TLC檢測(cè)),未析出固體。攪拌下緩慢滴加3 mL正己烷,析出固體,攪拌5 min,過(guò)濾,濾餅用乙酸乙酯洗滌,得白色固體3f39 mg。

3a:白色固體,收率93%, m.p.213.1～213.9 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 10.98(s, 1H), 8.22(dd,J=8.0 Hz, 3.1 Hz, 2H), 7.99(s, 2H), 7.87～7.66(m, 2H), 7.65～7.53(m, 1H), 7.53～7.39(m, 1H), 7.32～7.13(m, 1H), 6.95(d,J=7.6 Hz, 1H), 6.88(d,J=8.0 Hz, 1H), 6.77～6.59(m, 1H), 2.94(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.19, 172.23, 158.09, 153.76, 145.30, 144.19, 139.89, 135.53, 133.07, 131.70, 128.86, 128.19, 126.80, 126.67, 126.47, 125.44, 122.80, 121.74, 120.98, 119.15, 116.10, 109.77, 89.97, 72.73, 26.22; HR-MS(ESI-TOF)m/z: Calcd for C25H17N4O3S{[M+H]+}453.1016, found 453.1025。

3b:白色固體,收率89%, m.p.204.9～205.7 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 10.97(s, 1H), 8.20(d,J=7.9 Hz, 1H), 8.05(d,J= 8.3 Hz, 1H), 7.98(s, 2H), 7.77～7.63(m, 1H), 7.56(s, 1H), 7.38(d,J=8.3 Hz, 1H), 7.29～7.13(m, 1H), 6.91(dd,J=13.0 Hz, 7.7 Hz, 2H), 6.74～6.58(m, 1H), 2.95(s, 3H), 2.37(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.25, 172.29, 157.90, 153.85, 145.35, 144.21, 137.57, 136.55, 135.45, 133.30, 131.69, 128.83, 128.19, 126.78, 126.62, 125.43, 122.79, 121.74, 121.01, 119.15, 115.80, 109.76, 89.94, 72.78, 26.17, 20.79; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O3S{[M+H]+}467.1172, found 467.1177。

3c:灰白色固體,收率81%, m.p.218.7～219.4 ℃,dr>19 ∶1；1H NMR(400 MHz, DMSO-d6)δ: 11.01(s, 1H), 8.21(d,J=8.0 Hz, 1H), 8.09(d,J=8.9 Hz, 1H), 7.98(s, 2H), 7.70(ddd,J=8.1 Hz, 5.5 Hz, 2.8 Hz, 1H), 7.30(d,J=2.7 Hz, 1H), 7.27～7.20(m, 1H), 7.14(dd,J=8.9 Hz, 2.7 Hz, 1H), 6.93(dd,J=11.5 Hz, 7.9 Hz, 2H), 6.74～6.63(m, 1H), 3.82(s, 3H), 2.99(s, 3H);13C NMR(101 MHz, DMSO-d6)δ: 190.11, 172.27, 157.80, 157.71, 153.88, 145.31, 144.22, 135.35, 133.11, 131.75, 128.82, 128.19, 126.54, 125.50, 122.91, 122.41, 121.78, 119.07, 118.41, 117.23, 111.71, 109.89, 89.77, 72.74, 55.85, 26.29; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O4S{[M+H]+}483.1122, found 483.1121。

3d:淡黃色固體,收率75%, m.p.215.8～216.6 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 10.92(s, 1H), 8.22(d,J=7.4 Hz, 1H), 8.09～7.89(m, 2H), 7.81(d,J=2.5 Hz, 1H), 7.71(ddd,J=8.2 Hz, 6.0 Hz, 2.4 Hz, 1H), 7.66(d,J=8.8 Hz, 1H), 7.29～7.18(m, 1H), 7.03～6.95(m, 2H), 6.92(d,J=7.9 Hz, 1H), 6.77～6.62(m, 1H), 3.82(s, 3H), 2.99(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.21, 172.40, 162.56, 158.18, 154.20, 145.27, 144.33, 141.50, 135.63, 131.66, 128.95, 128.24, 127.69, 126.70, 125.60, 122.86, 121.69, 119.34, 112.28, 112.16, 109.87, 102.34, 89.91, 72.35, 55.79, 26.32; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O4S{[M+H]+}483.1122, found 483.1126。

3e:白色固體,收率80%, m.p.220.5～221.3 ℃,dr>19 ∶1 ；1H NMR(300 MHz, DMSO-d6)δ: 11.01(s, 1H), 8.18(d,J=8.1 Hz, 1H), 8.07(dd,J=8.5 Hz, 4.9 Hz, 1H), 7.96～7.81(m, 2H), 7.75(d,J=7.7 Hz, 1H), 7.70～7.53(m, 1H), 7.52～7.37(m, 1H), 7.32～7.12(m, 1H), 6.91(dd,J=12.9 Hz, 7.8 Hz, 2H), 6.79～6.60(m, 1H), 2.94(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.20, 172.24, 161.34(d,JCF=248.3 Hz), 157.43(d,JCF=3.4 Hz), 153.38, 144.22, 142.21, 139.75, 133.18, 131.79, 131.16(d,JCF=8.7 Hz), 127.07, 126.55, 125.50, 123.73(d,JCF=23.2 Hz), 123.53(d,JCF=8.3 Hz), 122.99, 121.13, 119.12, 116.21, 111.90(d,JCF=24.1 Hz), 109.89, 89.93, 72.79, 26.30; HR-MS(ESI-TOF)m/z: Calcd for C25H16FN4O3S{[M+H]+}471.0922, found 471.0924。

3f:白色固體,收率83%, m.p.221.5～222.3 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.01(s, 1H), 8.22(d,J=7.4 Hz, 1H), 8.08～7.99(m, 2H), 7.97(dd,J=9.3 Hz, 2.4 Hz, 1H), 7.78(dd,J=8.8 Hz, 5.6 Hz, 1H), 7.75～7.67(m, 1H), 7.36～7.28(m, 1H), 7.28～7.19(m, 1H), 6.94(dd,J=10.6 Hz, 7.8 Hz, 2H), 6.76～6.63(m, 1H), 2.98(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 189.99, 172.18, 163.99(d,JCF=249.4 Hz), 158.07, 153.73, 145.18, 144.16, 141.32(d,JCF=12.8 Hz), 135.72, 131.71, 129.00, 128.54(d,JCF=10.2 Hz), 128.25, 126.70, 125.50, 122.86, 121.52, 119.06, 117.16(d,JCF=2.5 Hz), 113.68(d,JCF=23.2 Hz), 109.87, 104.27(d,JCF=29.4 Hz), 89.40, 72.58, 26.24; HR-MS(ESI-TOF)m/z: Calcd for C25H16FN4O3S{[M+H]+}471.0922, found 471.0929。

3g:淡黃色固體,收率85%, m.p.223.7～224.5 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.02(s, 1H), 8.26～8.17(m, 2H), 8.06～7.94(m, 2H), 7.79～7.67(m, 2H), 7.54(dd,J=8.4 Hz, 2.0 Hz, 1H), 7.30～7.20(m, 1H), 6.94(dd,J=11.4 Hz, 7.8 Hz, 2H), 6.76～6.64(m, 1H), 2.98(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 189.95, 172.12, 158.16, 153.50, 145.20, 144.16, 140.97, 137.15, 135.76, 131.78, 129.04, 128.27, 128.00, 126.80, 126.74, 125.52, 122.91, 121.54, 120.06, 119.01, 116.03, 109.96, 89.39, 72.61, 26.28; HR-MS(ESI-TOF)m/z: Calcd for C25H16ClN4O3S{[M+H]+}487.0626, found 487.0630。

3h:白色固體,收率85%, m.p.196.7～197.6 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 10.98(s, 1H), 8.21(dd,J=7.9 Hz, 3.3 Hz, 2H), 7.99(s, 2H), 7.78(d,J=7.7 Hz, 1H), 7.70(ddd,J=8.2 Hz, 5.5 Hz, 2.9 Hz, 1H), 7.66～7.56(m, 1H), 7.50～7.37(m, 1H), 7.30～7.12(m, 1H), 7.02～6.82(m, 2H), 6.75～6.54(m, 1H), 3.65(dq,J=13.9 Hz, 7.1 Hz, 1H), 3.44(dq,J=13.9 Hz, 7.1 Hz, 1H), 0.82(t,J=7.1 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.19, 171.81, 158.11, 153.83, 145.29, 143.24, 139.87, 135.54, 132.96, 131.75, 128.86, 128.18, 126.79(2C), 126.67, 125.69, 122.60, 121.73, 121.03, 119.35, 116.06, 109.72, 90.01, 72.64, 34.44, 11.96; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O3S{[M+H]+}467.1172, found 467.1177。

3i:白色固體,收率90%, m.p.200.8～201.7 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.02(s, 1H), 8.21(dd,J=8.1 Hz, 3.6 Hz, 2H), 8.00(d,J=3.9 Hz, 2H), 7.78(d,J=7.8 Hz, 1H), 7.74～7.66(m, 1H), 7.66～7.56(m, 1H), 7.52～7.36(m, 1H), 7.28～7.12(m, 1H), 6.96(dd,J=7.8 Hz, 4.5 Hz, 2H), 6.73～6.58(m, 1H), 3.57(dt,J=14.4 Hz, 7.5 Hz, 1H), 3.30(dt,J=14.4 Hz, 7.5 Hz, 1H), 1.46～1.15(m, 2H), 0.58(t,J=7.3 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.13, 172.13, 158.16, 153.88, 145.28, 144.06, 139.90, 135.56, 133.01, 131.74, 128.88, 128.21, 126.93, 126.86, 126.69, 125.72, 122.60, 121.77, 121.13, 119.24, 116.03, 109.95, 90.01, 72.54, 41.20, 20.13, 10.82; HR-MS(ESI-TOF)m/z: Calcd for C27H21N4O3S{[M+H]+}481.1329, found 481.1337。

3j:白色固體,收率77%, m.p.204.3～205.1 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.09(s, 1H), 8.35～8.13(m, 2H), 8.00(d,J=4.1 Hz, 2H), 7.79(d,J=7.7 Hz, 1H), 7.75～7.59(m, 2H), 7.45～7.32(m, 1H), 7.31～7.17(m, 3H), 7.17～7.07(m, 1H), 7.01(d,J=7.6 Hz, 1H), 6.84(d,J=5.4 Hz, 2H), 6.75～6.54(m, 2H), 4.89(d,J=16.0 Hz, 1H), 4.63(d,J=16.0 Hz, 1H);13C NMR(75 MHz, DMSO-d6)δ: 190.02, 172.29, 158.12, 153.83, 145.21, 143.41, 139.93, 135.51, 134.65, 133.00, 131.63, 128.86, 128.52(2C), 128.16, 127.40, 127.07, 126.96, 126.77(2C), 126.64, 125.85, 122.88, 121.73, 121.25, 119.36, 116.07, 110.37, 90.00, 72.75, 42.99; HR-MS(ESI-TOF)m/z: Calcd for C31H21N4O3S{[M+H]+}529.1329, found 529.1333。

3k:白色固體,收率85%, m.p.213.8～214.5 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.01(s, 1H), 8.20(dd,J=11.3 Hz, 8.0 Hz, 2H), 8.02(d,J=4.1 Hz, 2H), 7.79～7.67(m, 2H), 7.66～7.53(m, 1H), 7.50～7.35(m, 1H), 7.00(d,J=7.9 Hz, 1H), 6.81～6.65(m, 2H), 2.87(s, 3H), 1.63(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.19, 172.07, 158.05, 153.78, 145.29, 141.68, 139.74, 135.52, 133.03, 131.74, 131.60, 128.85, 128.04, 126.78, 126.64, 126.50(2C), 121.76, 121.12, 119.24, 116.08, 109.39, 90.13, 73.07, 26.24, 19.88; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O3S{[M+H]+}467.1172, found 467.1175。

3l:白色固體,收率69%, m.p.188.9～189.6 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 11.01(s, 1H), 8.20(d,J=8.1 Hz, 2H), 8.08～7.86(m, 2H), 7.82～7.65(m, 2H), 7.65～7.54(m, 1H), 7.52～7.35(m, 1H), 6.95(d,J=7.8 Hz, 1H), 6.85(d,J=7.7 Hz, 1H), 6.65～6.42(m, 1H), 3.19(s, 3H), 2.28(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.26, 172.91, 158.20, 153.78, 145.32, 141.92, 139.98, 135.60, 135.32, 133.13, 128.93, 128.24, 126.88, 126.72, 126.55, 123.50, 122.66, 121.78, 121.08, 121.02, 119.77, 116.16, 90.12, 72.32, 29.37, 18.23; HR-MS(ESI-TOF)m/z: Calcd for C26H19N4O3S{[M+H]+}467.1172, found 467.1175。

3m:白色固體,收率63%, m.p.203.9～204.9 ℃,dr>19 ∶1；1H NMR(300 MHz, DMSO-d6)δ: 10.99(s, 1H), 8.24(d,J=8.1 Hz, 2H), 7.98(s, 2H), 7.73(d,J=7.9 Hz, 2H), 7.67～7.56(m, 1H), 7.53～7.36(m, 1H), 7.08～6.81(m, 2H), 6.67～6.46(m, 1H), 2.95(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 190.04, 172.56, 164.07(d,JCF=247.7 Hz), 158.10, 153.69, 146.30(d,JCF=12.7 Hz), 145.25, 139.94, 135.51, 133.14, 128.90, 128.21, 127.32(d,JCF=10.3 Hz), 126.84, 126.69, 126.45, 121.75, 120.85, 116.18, 114.95(d,JCF=2.5 Hz), 109.14(d,JCF=22.8 Hz), 98.86(d,JCF=28.2 Hz), 89.77, 72.28, 26.50; HR-MS(ESI-TOF)m/z: Calcd for C25H16FN4O3S{[M+H]+}471.0922, found 471.0933。

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化

在該加成反應(yīng)中,以N-甲基-3-異硫氰酸酯氧化吲哚1a和色胺酮2a的反應(yīng)為模型反應(yīng),對(duì)反應(yīng)條件進(jìn)行篩選,結(jié)果如表1所示。首先以二氯甲烷(DCM)為溶劑,考察堿對(duì)反應(yīng)的影響。在不加堿的情況下,反應(yīng)依然能進(jìn)行,但反應(yīng)時(shí)間較長(zhǎng),收率僅有78%,非對(duì)映選擇性較差。在堿的催化下,反應(yīng)時(shí)間大大縮短。結(jié)果表明,有機(jī)堿的催化效果比無(wú)機(jī)堿更好。有機(jī)堿中,叔胺比仲胺的催化效果更好。對(duì)于叔胺,當(dāng)使用大位阻的N,N-二環(huán)己基甲胺(Cy2NMe)時(shí),反應(yīng)較慢,收率僅有75%。其它叔胺的催化效果大致相當(dāng),因此選擇廉價(jià)易得的三乙胺(Et3N)作為堿,進(jìn)一步對(duì)反應(yīng)溶劑進(jìn)行了篩選。結(jié)果表明,該反應(yīng)在鹵代烴類溶劑中的效果最好,其余溶劑中的反應(yīng)時(shí)間均有不同程度的延長(zhǎng)且收率較低。對(duì)于鹵代烴類溶劑,氯仿(CHCl3)與二氯甲烷(DCM)在反應(yīng)時(shí)間上相當(dāng),但收率稍低,而1,2-二氯乙烷(1,2-DCE)與二氯甲烷(DCM)在收率上相當(dāng),但反應(yīng)時(shí)間稍長(zhǎng)。綜上,3-異硫氰酸酯氧化吲哚和色胺酮反應(yīng)的最優(yōu)條件是:3-異硫氰酸酯氧化吲哚(1.2 eq.)和色胺酮(1.0 eq. ),在三乙胺(20 mol/mol)的催化下,二氯甲烷(2 mL)作溶劑,室溫反應(yīng)10 min。

表1 反應(yīng)條件的優(yōu)化a

2.2 底物擴(kuò)展

在確定了最優(yōu)的反應(yīng)條件后,對(duì)底物的適用性進(jìn)行了考察,結(jié)果如Scheme 1所示。所有產(chǎn)物dr值均大于19 ∶1。首先考察了色胺酮上R3和R4取代基對(duì)反應(yīng)的影響。當(dāng)色胺酮苯環(huán)上不同位置被給電子基(如-Me,-OMe)取代時(shí),除9-OMe取代的底物反應(yīng)時(shí)間稍長(zhǎng)且收率稍低外,8-Me和8-OMe取代的底物在10 min內(nèi)即可反應(yīng)完全,以89%和81%的收率分別得到目標(biāo)產(chǎn)物3b和3c。當(dāng)色胺酮苯環(huán)上不同位置被吸電子基(如—F, —Cl)取代時(shí),反應(yīng)在10 min內(nèi)均可完成,以80%～85%的收率得到目標(biāo)產(chǎn)物3e～3g。隨后考察了3-異硫氰酸酯氧化吲哚上R1和R2取代基對(duì)反應(yīng)的影響。對(duì)于R1,當(dāng)其為更長(zhǎng)的烷基(如Et和nPr)時(shí),能以85%和90%的收率分別得到目標(biāo)產(chǎn)物3h和3i,而當(dāng)其為芐基時(shí),收率下降至77%。對(duì)于R2,當(dāng)其為Me時(shí),C5-取代的底物在反應(yīng)收率和反應(yīng)性上都優(yōu)于C7-取代的底物,而當(dāng)其為6-F時(shí),反應(yīng)收率大幅降低且反應(yīng)時(shí)間較長(zhǎng)。

3 結(jié)論

在有機(jī)堿Et3N作用下,3-異硫氰酸酯氧化吲哚與色胺酮發(fā)生[3+2]環(huán)加成反應(yīng),構(gòu)建了一系列含雙螺環(huán)骨架的氧化吲哚類化合物3a～3m,產(chǎn)率63%～93%,dr值>19:1。該化合物含有色胺酮骨架和螺環(huán)氧化吲哚骨架,且含有兩個(gè)連續(xù)的螺環(huán)季碳中心,可為后續(xù)生物活性篩選提供候選化合物。