CN115215779B - 一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法 - Google Patents
一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法 Download PDFInfo
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法，涉及有机化学合成技术领域。该方法是以螺环酮类硒、硫芳基为底物，通过不同的进一步衍生化，得到不同取代基取代的螺环类衍生催化剂。本发明合成的手性螺环类化合物具有良好的催化活性，可以应用于有机手性催化反应，收率好；并且手性螺环类化合物制备原料易得、合成路线简单、可重复性好、产物具有多样性、应用前景广阔。
Description
技术领域
本发明属于有机化学合成技术领域，具体涉及一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法。
背景技术
单苯并螺环类结构占据了螺环类中的很大一部分，此类结构也存在于具有生物活性的天然产物和药物分子中（Eur. J. Org. Chem. 2003, 2209.）。而螺环类催化剂作为催化剂领域中的一重大分支，在催化领域占据着举足轻重的地位。对比现有常用的SPINOL类螺环催化剂的成熟开发与应用，此类单苯类螺环结构作为催化剂的发展与应用还是比较少的。同时特殊的螺环辛醇骨架作为核心骨架具有很高的潜力，可用于开发相关化合物，从而合成药物分子（Angew. Chem., Int. Ed. 2007, 46, 8748.）。
对于单苯并酮类螺环骨架的合成目前为止有不少的化学家对其进行了合成研究（J. Am. Chem. Soc. 2009, 131, 13819.），能以较高的收率和对映选择性得到较各种取代的相对应螺环产物。尤其国内的周其林课题组在这个方面做了很多贡献（Acc. Chem. Res. 2017, 50, 2621.）。2019年涂永强课题组发表了不对称硫芳基/频哪醇重排反应研究（Angew. Chem. Int. Ed. 2019, 58, 12491.），以高收率和高对映选择性构建了硫芳基取代的单苯并螺环酮类化合物。本发明以此类产物为基础，进一步衍生化构建了不同取代基的螺环类手性催化剂。同时将此类催化剂应用在了有机小分子催化反应中，并体现出了一定的催化活性。
发明内容
本发明的目的在于提供一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法，该手性螺环类化合物具有良好的催化活性，可以应用于有机手性催化反应，收率好；并且手性螺环类化合物制备原料易得、合成路线简单、可重复性好、产物具有多样性、应用前景广阔。
本发明为实现上述目的所采取的技术方案为：
一类基于螺环酮类骨架的手性螺环类化合物，其化学结构通式如式I或式II或式III所示：
其中，R1选自氧或N-OH；R2选自羟基或OTBs；X选自Se或S。本发明提供了一类基于螺环酮类骨架的手性螺环类催化剂，具有良好的催化活性，能够很好地应用于有机手性催化反应，制备得到具有季碳中心的硫芳基取代的五元环内酯产物，且产物的收率高；同时还能够催化其它有机小分子反应的发生，具有广阔的应用前景。与现有催化剂催化某些有机小分子反应的催化活性相比，该类催化剂具有较高的催化活性，并且可以作为一类新的催化剂类型来发展应用。
进一步的，手性螺环类化合物的化学结构选自式A~式F中的一种：
本发明又公开了上述基于螺环酮类骨架的手性螺环类化合物的合成方法，包括：从螺环酮类底物出发，通过进一步的衍生化，生成不同的手性螺环类化合物。本发明提供的合成方法克服了现有技术存在的缺陷而提供一种反应步骤简单、条件温和，所使用原料易制且基本无毒，可重复性好，制备的产物具有多样性，且产率和收率高，同时获得的螺环衍生的硒/硫芳基化物经济性好。
具体的，上述基于螺环酮类骨架的手性螺环类化合物的合成方法，包括：将酮类螺环底物溶于不同的溶剂，加入不同的需要衍生的反应底物，后经过常温或者加热回流反应，TLC监测反应是否完成；后经减压蒸馏、柱色谱提纯，得到不同衍生化的螺环化合物。
于具体实施方式中，上述手性螺环类化合物的合成路线为：
其中，R1选自N-OH；R2选自羟基或OTBs；X选自Se或S。
于具体实施方式中，螺环酮类底物的化学结构如式IV所示：
本发明的又一目的在于，还公开了上述基于螺环酮类骨架的手性螺环类化合物在催化有机手性催化反应中的应用。
于具体实施方式中，上述有机手性催化反应制备得到的是具有季碳中心的硫芳基取代的五元环内酯产物。
具体的，上述有机手性催化反应的合成路线如下：
于具体实施方式中，上述有机手性催化反应的合成过程包括：以易制的苯烯羧酸和糖精类硫芳基试剂为原料，在催化剂和对甲基苯磺酸的作用下，于低温下反应一段时间，制得具有季碳中心的硫芳基取代的五元环内酯产物。
进一步的，上述手性螺环类化合物的应用场景还包括，合成路线如下：
于具体实施方式中，上述合成路线的合成过程包括：以易得的萘基苯醇和糖精类硫芳基试剂为原料，在催化剂和对甲基苯磺酸的作用下，于低温下反应一段时间制得硫芳基取代的产物。
相比于现有技术，本发明具有如下有益效果：
本发明方法通过同一类型的酮类单苯并螺环底物，首次实现了不同类型取代的手性螺环类催化剂合成。其中，本发明提供的合成方法采用一步法制得手性的螺环类催化剂，反应过程避免了复杂的路线合成，能够有效提高生产效率，增加收率；同时，本发明提供的合成方法制备的产物具有多样性，可以合成具有多种取代基衍生的螺环催化剂，并具有一定的催化活性，具有巨大的应用前景。
因此，本发明提供了一类基于螺环酮类骨架合成不同手性螺环类化合物的合成方法，该手性螺环类化合物具有良好的催化活性，可以应用于有机手性催化反应，收率好；并且手性螺环类化合物制备原料易得、合成路线简单、可重复性好、产物具有多样性、应用前景广阔。
附图说明
图1为本发明实施例中手性螺环催化剂A的核磁氢谱图；
图2为本发明实施例中手性螺环催化剂A的核磁碳谱图；
图3为本发明实施例中手性螺环催化剂B的核磁氢谱图；
图4为本发明实施例中手性螺环催化剂B的核磁碳谱图；
图5为本发明实施例中手性螺环催化剂C的核磁氢谱图；
图6为本发明实施例中手性螺环催化剂C的核磁碳谱图；
图7为本发明实施例中手性螺环催化剂D的核磁氢谱图；
图8为本发明实施例中手性螺环催化剂D的核磁碳谱图；
图9为本发明实施例中手性螺环催化剂E的核磁氢谱图；
图10为本发明实施例中手性螺环催化剂E的核磁碳谱图；
图11为本发明实施例中手性螺环催化剂F的核磁氢谱图；
图12为本发明实施例中手性螺环催化剂F的核磁碳谱图；
图13为本发明实施例7中产物I消旋结构的HPLC图；
图14为本发明实施例7中产物I的HPLC图；
图15为本发明实施例8中产物K消旋结构的HPLC图；
图16为本发明实施例8中产物K的HPLC图。
具体实施方式
以下结合具体实施方式对本发明的技术方案作进一步详细描述，但是应当理解，这些实施例仅用于举例说明本发明以帮助理解的本发明的公开内容，而不是对本发明范围的限制，并且本发明的保护范围也不限于下述的实施例。
本发明对下述实施例中原料的来源没有特别限制，以本领域技术人员熟知的制备方法制备或市售购买均可。
本发明实施例中所用部分原料结构及CAS号如表1所示：
表1 原料结构
本发明实施方式中，化合物的氢核磁共振谱（1H NMR、13C NMR）由Bruker AVANCEIII HD 400测定，溶剂为氘代氯仿。化学位移（δ）以ppm为单位引用，以四甲基硅烷作为内标，多重性如下所示：s=单重态，d=双重态，t=三重态，q=四重态，m=多重态。
实施例1：
一种手性螺环类化合物（式A所示结构）的制备路线如下：
具体合成方法为：
无水无氧条件下，将底物(0.05 mmol, 1.0 equiv)和邻苯二甲酰胺类硒芳基试剂(0.06 mmol, 1.2 equiv)称于反应管中的乙酸乙酯(1 mL)中，室温下向其中加入消旋的磷酸(rac-CPA，0.005 mmol, 0.1 equiv)，室温下搅拌反应12h；后经减压蒸馏旋干，色谱柱提纯，得到消旋的螺环酮类硒苯基化物A，收率为76%，之后进行手性拆分（制备液相，v/v，n-hexane:i-PrOH=97:3，过大赛璐手性柱AD-H）得到手性螺环化合物A。核磁表征如图1-2所示：1H NMR (400 MHz, Chloroform-d) δ 7.62 (dd, J = 6.5, 3.1 Hz, 2H), 7.34 –7.27 (m, 3H), 7.27 – 7.06 (m, 4H), 3.78 (dd, J = 10.3, 8.1 Hz, 1H), 3.62 (dd,J = 15.6, 10.3 Hz, 1H), 3.36 (dd, J = 15.6, 8.1 Hz, 1H), 2.64 – 2.30 (m, 4H),2.29 – 2.09 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 218.01, 145.53, 143.26,133.80, 130.85, 129.26, 127.76, 127.51, 127.10, 124.65, 122.39, 64.72, 51.85,40.77, 38.37, 35.62, 20.44。
实施例2：
式B所示的手性螺环类化合物的制备路线如下：
具体合成方法为：
无氧条件下，螺环酮类硫芳基底物(1.36 mmol, 1.0 equiv)溶于甲醇(7 mL)，-78℃下向其中加入CeCl3•7H2O(1.63 mmol, 1.2 equiv)，2min后向体系中加入NaBH4(1.50mmol, 1.1 equiv)，将体系缓慢升至室温，搅拌反应五分钟后TLC板监测反应；反应完成后处理为：向体系中加入乙醚和水进行萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏旋干，硅胶柱纯化，得到手性螺环化合物B，收率为85%。核磁表征如图3-4所示：1HNMR (400 MHz, Chloroform-d) δ 7.49 – 7.40 (m, 2H), 7.39 – 7.31 (m, 2H), 7.29(t, J = 1.4 Hz, 1H), 7.28 – 7.18 (m, 3H), 7.05 (dd, J = 5.7, 2.8 Hz, 1H),4.42 (dd, J = 6.4, 2.1 Hz, 1H), 3.98 (dd, J = 5.3, 2.0 Hz, 1H), 3.67 – 3.31(m, 2H), 3.05 (dd, J = 16.0, 1.9 Hz, 1H), 2.42 (dddd, J = 14.5, 10.5, 6.3,3.9 Hz, 1H), 2.28 – 2.14 (m, 1H), 2.13 – 2.03 (m, 1H), 1.96 (m, 1H), 1.80 –1.54 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 147.12, 141.10, 135.08, 131.20,129.23, 127.20, 127.10, 126.82, 125.51, 122.84, 78.19, 64.37, 58.64, 39.40,36.22, 34.13, 21.27。
本实施例涉及的螺环酮类硫芳基底物的制备方法与实施例1中手性螺环类化合物的合成方法相同，区别仅在，邻苯二甲酰胺类硒芳基试剂的化学结构为：
实施例3：
式C所示的手性螺环类化合物的制备路线如下：
具体合成方法为：
无氧条件下，取手性螺环化合物A(0.59 mmol, 1.0 equiv)溶于甲醇(3 mL)，-78℃下向其中加入CeCl3•7H2O(0.71 mmol, 1.2 equiv)，两分钟后向体系中加入NaBH4(0.65mmol, 1.1 equiv)，将体系缓慢升至室温，搅拌反应五分钟后TLC板监测反应；反应完成后处理为：向体系中加入乙醚和水进行萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏旋干，硅胶柱纯化，得到手性螺环化合物C，收率为95%。核磁表征如图5-6所示：1HNMR (400 MHz, Chloroform-d) δ 7.63 – 7.50 (m, 2H), 7.35 – 7.27 (m, 3H), 7.22(m, 3H), 7.08 – 6.98 (m, 1H), 4.33 (dt, J = 6.0, 2.8 Hz, 1H), 3.92 (dd, J =5.5, 2.8 Hz, 1H), 3.51 (dd, J = 16.2, 5.4 Hz, 1H), 3.36 – 3.10 (m, 2H), 2.50– 2.29 (m, 1H), 2.23 – 2.12 (m, 1H), 2.11 – 1.88 (m, 2H), 1.81 – 1.64 (m,2H); 13C NMR (101 MHz, CDCl3) δ 147.61, 141.62, 134.02, 130.19, 129.31,127.66, 127.15, 126.79, 125.32, 122.76, 79.17, 64.67, 55.63, 40.69, 35.75,34.19, 21.51。
实施例4：
式D所示的手性螺环类催化剂的制备路线如下：
具体合成方法为：
无水无氧条件下，手性螺环化合物B(0.68 mmol, 1.0 equiv)溶于超干DMF(3.5mL)，将咪唑(1.89 mmol, 2.8 equiv)、4-二甲氨基吡啶(0.14 mmol, 0.2 equiv)、叔丁基二甲基氯硅烷(0.95 mmol, 1.4 equiv)依次加入反应体系中。将反应体系升至60℃后搅拌反应7h，点板反应完成后将体系降至室温，利用棉花和硅藻土过滤得滤液，向滤液中加入饱和碳酸氢钠搅拌五分钟后，再次向其中加入乙醚和正己烷萃取，利用饱和食盐水洗涤，分离得有机相后利用无水硫酸钠干燥，减压蒸馏旋干，硅胶过柱纯化得手性螺环化合物D，收率为54%。核磁表征如图7-8所示：1H NMR (400 MHz, Chloroform-d) δ 7.55 – 7.45 (m,2H), 7.37 – 7.30 (m, 2H), 7.29 – 7.14 (m, 5H), 4.18 (dd, J = 8.9, 6.9 Hz,1H), 3.76 (dd, J = 9.7, 7.8 Hz, 1H), 3.54 – 3.35 (m, 1H), 3.29 (dd, J = 15.4,7.8 Hz, 1H), 2.37 – 2.15 (m, 3H), 2.15 – 1.97 (m, 2H), 1.84 – 1.66 (m, 1H),0.92 (s, 9H), -0.03 (s, 3H), -0.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 150.23,142.08, 140.27, 129.88, 128.90, 126.98, 126.79, 125.77, 124.00, 122.02,86.19, 60.87, 59.50, 41.14, 37.74, 35.21, 26.04, 22.01, 18.07, -4.82, -5.29。
实施例5：
式E所示的手性螺环类催化剂的制备路线如下：
具体合成方法为：
无水无氧条件下，冰浴下将螺环酮类硫芳基底物(0.17 mmol, 1.0 equiv)溶于超干THF (2 mL)，向其中加入LiHMDS (0.2 mmol, 1.2 equiv)，冰浴下搅拌反应30min后，向其中加入N-苯基双(三氟甲烷磺酸)亚胺（0.26 mmol, 1.5 equiv），将体系缓慢升至室温搅拌过夜。反应完成后将体系置于冰浴下，缓慢向其中加入饱和氯化铵的水溶液淬灭反应，向体系中加入乙酸乙酯后水进行萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液旋干利用硅胶柱纯化得到手性螺环化合物E，收率为90%。核磁表征如图9-10所示：1HNMR (400 MHz, Chloroform-d) δ 7.60 – 7.46 (m, 2H), 7.38 – 7.28 (m, 3H), 7.25– 7.14 (m, 4H), 5.76 (t, J = 2.6 Hz, 1H), 3.89 (dd, J = 11.0, 8.1 Hz, 1H),3.27 (dd, J = 15.7, 8.1 Hz, 1H), 3.16 – 3.04 (m, 1H), 2.70 – 2.34 (m, 3H),2.30 – 2.13 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 151.48, 144.40, 141.66,135.47, 132.03, 129.17, 128.44, 127.53, 127.29, 124.40, 123.80, 115.95,63.08, 58.05, 39.61, 34.96, 26.86。
实施例6：
式F所示的手性螺环类催化剂的制备路线如下：
具体合成方法为：
无水无氧条件下，螺环酮类硫芳基底物(0.75 mmol, 1.0 equiv)溶于超干甲醇(4mL)，向体系中依次加入乙酸钠(3.0 mmol, 4.0 equiv)和盐酸羟胺 (2.24 mmol, 3.0equiv)后，将体系升温至回流反应，搅拌反应5h；TLC监测反应完成后，将体系旋干，向其中加入饱和碳酸氢钠溶液和乙酸乙酯进行萃取，合并有机相，利用饱和食盐水洗涤后，最后用硫酸钠干燥有机相后过滤得滤液，将滤液旋干后硅胶柱纯化，得到手性螺环化合物F，收率为99%。核磁表征如图11-12所示：1H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.38 (m,2H), 7.29 (dd, J = 8.4, 6.7 Hz, 2H), 7.25 – 7.10 (m, 5H), 3.91 (t, J = 7.9Hz, 1H), 3.45 – 3.23 (m, 2H), 2.73 (ddd, J = 18.7, 8.7, 7.0 Hz, 1H), 2.56(ddd, J = 18.7, 8.9, 5.7 Hz, 1H), 2.22 (m, 2H), 2.13 – 2.06 (m, 1H), 1.99 (m,1H); 13C NMR (101 MHz, CDCl3) δ 168.36, 146.95, 141.54, 136.75, 131.09,129.07, 127.57, 127.28, 126.68, 124.52, 123.16, 61.22, 58.74, 40.25, 39.60,28.09, 22.53。
实施例7：
式B所示的手性螺环类化合物的应用
催化有机手性催化反应，其合成路线为：
具体合成方法为：
无水无氧条件下，将底物G (0.1 mmol，1.0 equiv)和硫芳基试剂H (0.12 mmol，1.2 equiv)称于反应管中，向其中加入催化剂B (0.01 mmol，0.1 equiv)和对甲基苯磺酸(0.01 mmol，0.1 equiv)，将反应管置于-20℃下，向其中加入超干二氯甲烷（1 mL），反应在-20℃色固体产物I（76% yield）。其中，数据表征如图13-14所示，通过HPLC分离对映异构体，色谱柱：Chiralcel®Column OD-H，柱温：30℃，n-hexane:i-PrOH（v/v）=90:10，流速：1mL/min，次要保留时间：13.20 min，主要保留时间：11.70 min，er=44:56。
实施例8：
式E所示的手性螺环类化合物的应用
催化有机小分子反应，其合成路线为：
具体合成方法为：
无水无氧条件下，将底物J (0.1 mmol，1.0 equiv)和硫芳基试剂H (0.12 mmol，1.2 equiv)称于反应管中，向其中加入催化剂E (0.01 mmol，0.1 equiv)和对甲基苯磺酸（0.01 mmol，0.1 equiv），将反应管置于-20℃行硅胶柱纯化，得到白色固体产物K (87%yield)。其中，数据表征如图15-16所示，通过HPLC分离对映异构体，色谱柱：Chiralcel®Column OJ-H，柱温：30℃，n-hexane:i-PrOH（v/v）=70:30，流速：1 mL/min；次要保留时间：16.12 min，主要保留时间：20.20 min，er=45.4:54.6。
上述实施例中的常规技术为本领域技术人员所知晓的现有技术，故在此不再详细赘述。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发的保护范围应以所述权利要求的保护范围为准。
Claims (4)
1.一类基于螺环酮类骨架的手性螺环类化合物，其化学结构如式B或式E所示：
2. 权利要求1所述的一类基于螺环酮类骨架的手性螺环类化合物的合成方法，包括：无氧条件下，螺环酮类硫芳基底物1.36 mmol，溶于7 mL甲醇，-78℃下向其中加入CeCl3•7H2O 1.63 mmol，2min后向体系中加入NaBH4 1.50 mmol，将体系缓慢升至室温，搅拌反应五分钟后TLC板监测反应；反应完成后处理为：向体系中加入乙醚和水进行萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏旋干，硅胶柱纯化，得到手性螺环化合物B；或，
无水无氧条件下，冰浴下将螺环酮类硫芳基底物0.17 mmol，溶于2 mL超干THF，向其中加入LiHMDS 0.2 mmol，冰浴下搅拌反应30min后，向其中加入N-苯基双(三氟甲烷磺酸)亚胺0.26 mmol，将体系缓慢升至室温搅拌过夜；反应完成后将体系置于冰浴下，缓慢向其中加入饱和氯化铵的水溶液淬灭反应，向体系中加入乙酸乙酯后水进行萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液旋干利用硅胶柱纯化得到手性螺环化合物E；
所述螺环酮类硫芳基底物如式IV所示：
3.权利要求1所述的一类基于螺环酮类骨架的手性螺环类化合物在催化有机手性催化反应中的应用，所述有机手性催化反应制备得到的是具有季碳中心的硫芳基取代的五元环内酯产物，其合成路线如下：
其中，反应所用催化剂为式B所示化合物；所述反应在对甲基苯磺酸的作用下进行。
4.权利要求1所述的一类基于螺环酮类骨架的手性螺环类化合物的应用，包括催化如下合成路线的反应：
其中，反应所用催化剂为式E所示化合物；所述反应在对甲基苯磺酸的作用下进行。
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