CN111499558B - 手性螺环双硼催化取代吡啶的不对称还原方法及其应用 - Google Patents

手性螺环双硼催化取代吡啶的不对称还原方法及其应用 Download PDF

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CN111499558B
CN111499558B CN202010408862.3A CN202010408862A CN111499558B CN 111499558 B CN111499558 B CN 111499558B CN 202010408862 A CN202010408862 A CN 202010408862A CN 111499558 B CN111499558 B CN 111499558B
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王晓晨
杨钊英
田俊杰
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Nankai University
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Abstract

本发明提供了一种手性螺环双硼催化取代吡啶的不对称还原方法，包括制备手性螺环双硼催化剂：在充满氮气的手套箱中，向反应瓶中依次加入手性螺环双烯和二芳基硼氢化合物，向反应瓶中加入溶剂，搅拌，使其充分反应，得到手性螺环双硼催化剂；催化还原吡啶：向上述反应瓶中加入吡啶、二级胺、三正丁基苄基氯化铵、频那醇硼烷和所述溶剂，在氮气氛围中搅拌至反应结束；减压蒸馏除去溶剂，柱层析分离得到手性哌啶。该方法反应条件温和、催化剂用量低、选择性好、官能团兼容性广，且不需借助过渡金属催化剂，解决了药物中间体合成中重金属残留的问题。

Description

手性螺环双硼催化取代吡啶的不对称还原方法及其应用
技术领域
本发明涉及化学合成领域，特别是涉及一种手性螺环双硼催化取代吡啶的不对称还原方法及其应用。
背景技术
哌啶结构的化合物广泛存在于天然产物和药物分子中，吡啶的不对称氢化或转移氢化反应是构建手性哌啶化合物最直接有效的方法。然而，由于吡啶去芳构化的能垒较高，且吡啶的氮原子对催化剂具有毒化作用，其不对称还原存在一定挑战。
为了解决这一问题，科学家目前提出两种策略，其一是通过对吡啶底物进行成盐活化，实现了温和条件下过渡金属催化的吡啶的不对称氢化(Legault，C.Y.；Charette，A.B.J.Am.Chem.Soc.2005，127，8966；Chang，M.；Huang，Y.；Liu，S.；Chen，Y.；Krska，S.W.；Davies，I.W.；Zhang，X.Angew.Chem.Int.Ed.2014，53，12761；Chen，M.-W.；Ji，Y.；Wang，J.；Chen，Q.-A.；Shi，L.；Zhou，Y.-G.Org.Lett.2017，19，4988.)：
a)Metal-catalyzed enantioselective pyridine hydrogenations：
Figure GDA0003833294290000011
其二是采用有机小分子催化体系如手性磷酸催化，为吡啶的不对称还原提供了新的解决方案(Rueping，M.；Antonchick，A.P.Angew.Chem.Int.Ed.2007，46，4562.)：
b)Phosphoric acid-catalyzed enatioselective transfer hydrogenation ofpyridines：
Figure GDA0003833294290000012
但上述这些方法的底物局限性比较大，只兼容一些惰性基团，而一些特殊基团，如烯烃是不能够保留的，限制了产物的后续转化。
手性硼烷催化的不对称还原反应在亚胺和喹啉还原中均有所突破，且表现出很好的化学选择性。但由于吡啶底物的特殊性，手性硼烷催化吡啶的不对称还原反应一直没有进展。
发明内容
本发明的一个目的是提供一种手性螺环双硼催化取代吡啶的不对称还原方法，该方法反应条件温和、对映选择性高、无需使用贵金属催化剂且官能团兼容性较好。
本发明的另一目的是提供一种手性螺环双硼催化剂在催化吡啶的不对称还原反应中的应用。
为此，本发明的技术方案如下：
一种手性螺环双硼催化取代吡啶的不对称还原方法，包括以下步骤：
S1，制备手性螺环双硼催化剂：
在充满氮气的手套箱中，向反应瓶中依次加入手性螺环双烯和二(五氟苯基)硼氢，向反应瓶中加入溶剂，搅拌，使其充分反应，得到手性螺环双硼催化剂，其中所述手性螺环双烯的结构式如下：
Figure GDA0003833294290000021
所述手性螺环双硼催化剂的结构式如下：
Figure GDA0003833294290000022
S2，催化还原吡啶：
向上述反应瓶中加入吡啶类化合物、二级胺3,5-双(三氟甲基)乙酰苯胺、三正丁基苄基氯化铵、频那醇硼烷和所述溶剂，在氮气氛围中搅拌至反应结束；减压蒸馏除去溶剂，柱层析分离得到手性哌啶类化合物，其中，所述吡啶类化合物和手性哌啶类化合物的结构式分别如下：
Figure GDA0003833294290000023
其中，所述R1为烯基、烷基、芳基或杂芳基。
所述R2为芳基或烷基，优选的是，所述芳基为苯基。
上述的烷基可以是甲基、乙基、丙基、苄基等；所述芳基可以是苯基、萘基等；所述杂芳基可以是呋喃基、噻吩基等。
优选的是，所述手性螺环双烯、二(五氟苯基)硼氢与吡啶的摩尔比为(0.5–5):(1–10):100。
优选的是，所述频那醇硼烷与吡啶类化合物的当量比为(3–6):1。
优选的是，所述3,5-双(三氟甲基)乙酰苯胺与吡啶类化合物的当量比为(2–4):1。
优选的是，所述三正丁基苄基氯化铵与吡啶类化合物的摩尔比为(5–10):100。
步骤S1、S2中所述溶剂为芳香溶剂、二氯甲烷或正己烷，优选的是，所述芳香溶剂为三氟甲苯。
上述催化还原吡啶的反应中，反应温度为-20–60℃，反应时间为6–48小时。
本发明以手性螺环双硼为催化剂，以频那醇硼烷和二级胺为还原剂，实现了吡啶的不对称还原反应，合成了一系列手性哌啶产物。其中，手性螺环双硼催化剂由二芳基硼氢化合物与手性螺环双烯现场制备而成。
与现有技术相比，本发明具有以下有益效果：
1.本发明的方法能够以较高的反应活性、化学选择性和对映选择性实现取代吡啶类衍生物的不对称还原反应，其底物范围广、官能团兼容性强。
2.本发明采用硼催化剂替代过渡金属，不仅节约了生产成本，还解决了药物中间体合成中重金属残留的问题。
3.本发明的螺环双硼催化剂的用量低(0.5mol％或更低)，并且进行了克量级实验，反应适合大量生产。
具体实施方式
下面结合具体实施例对本发明的方法进行详细说明。需要强调的是，本发明不限于以下实施例所表示内容。以下实施例显示了本发明的不同侧面。所给出的数据包括具体操作和反应条件及产物，产物纯度通过核磁鉴定。
以下实施例中使用的手性螺环双烯(手性螺环二烯)，其制备方法记载在公开号为CN109575060A的中国发明专利申请文件中，并作为本发明申请文件的一部分。
手性螺环双烯L与二(五氟苯基)硼氢HB(C6F5)2反应生成手性螺环双硼催化剂的反应式如下：
Figure GDA0003833294290000041
以下实施例中，上述R2均为苯基。
实施例1：2-苯乙烯基哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 7.2mg(0.028mmol,0.5mol％)和二(五氟苯基)硼氢HB(C6F5)2 20mg(0.056mmol,1mol％)加入到15mL小试管中，加入3mL三氟甲苯溶解，在40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，然后将该溶液转移到100mL耐压管中，补加27mL三氟甲苯，再依次加入原料2-苯乙烯基吡啶1a 1.01g(5.6mmol)，3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)4.5g(16.8mmol,3.0equiv)、三正丁基苄基氯化铵nBu3BnNCl 87mg(0.028mmol,5.0mol％)和频那醇硼烷HBPin 3.6g(28mmol,5.0equiv)，在25℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-苯乙烯基哌啶(Benzyl(S,E)-2-styrylpiperidine-1-carboxylate)2a，其为白色固体，收率为88％。
产物对映选择性的测定：
将上述还原产物2a 37.4mg(0.2mmol)置于25mL圆底瓶中，加入乙醚2.0mL和2M氢氧化钠溶液0.3mL，冰浴冷却下慢慢滴加氯甲酸苄酯CbzCl 34mg(0.2mmol)。恢复室温搅拌至哌啶产物消耗完，加水2mL猝灭并稀释，用乙酸乙酯萃取(5mL×3次)，将有机相合并，再用无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化，得到苄氧羰基保护的还原产物3a，其为无色油状液体，收率94％，对映选择性为91％ee。[α]25 D＝-157.3(c＝0.40,CHCl3).1H NMR(400MHz,CDCl3)δ7.39-7.27(m,9H),7.25-7.20(m,1H),6.40(d,J＝16.2Hz,1H),6.20(dd,J＝16.2,4.8Hz,1H),5.17(dd,J＝19.4,12.4Hz,2H),5.07(s,1H),4.10(d,J＝12.8Hz,1H),3.00(t,J＝12.8Hz,1H),1.90-1.71(m,2H),1.70-1.56(m,3H),1.54-1.43(m,1H).13C NMR(101MHz,CDCl3)δ155.9,137.0,136.9,131.3,128.6,128.6,128.3,128.0,127.9,127.6,126.4,67.2,52.5,40.3,29.6,25.6,19.7.
上述反应过程如下：
Figure GDA0003833294290000051
实施例2：2-(对乙酰氧基)苯乙烯基哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 12.2mg(0.045mmol,1.0mol％)和二(五氟苯基)硼氢HB(C6F5)2 31mg(0.09mmol,2.0mol％)加入到15mL小试管中，加入3mL三氟甲苯溶解，40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，然后将该溶液转移到100mL耐压管中，补加27mL三氟甲苯，再依次加入原料2-(对乙酰氧基)苯乙烯基吡啶1b 1.06g(4.5mmol)、3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)3.7g(13.5mmol,3.0equiv)，三正丁基苄基氯化铵nBu3BnNCl70mg(0.225mmol,5mol％)和频那醇硼烷HBPin 2.9g(22.5mmol,5.0equiv)，在25℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-(对乙酰氧基)苯乙烯基哌啶(Benzyl(S,E)-2-(4-acetoxystyryl)piperidine-1-carboxylate)2b，其为白色固体，收率为93％。
产物对映选择性的测定：
将上述还原产物2b 49.2mg(0.2mmol)置于25mL圆底瓶中，加入乙醚2.0mL和2M氢氧化钠溶液0.3mL，冰浴冷却下慢慢滴加氯甲酸苄酯CbzCl 34mg(0.2mmol)。恢复室温搅拌至哌啶产物消耗完，加水2mL猝灭并稀释，用乙酸乙酯萃取(5mL×3次)，将有机相合并，无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到苄氧羰基保护的还原产物3b，其为无色油状液体，收率95％，对映选择性为91％ee。[α]25 D＝-102.8(c＝0.80,CHCl3).1H NMR(400MHz,CDCl3)δ7.39-7.28(m,7H),7.03(d,J＝8.6Hz,2H),6.37(d,J＝16.1Hz,1H),6.14(dd,J＝16.1,4.8Hz,1H),5.16(dd,J＝20.3,12.4Hz,2H),5.05(s,1H),4.09(d,J＝13.5Hz,1H),2.97(t,J＝12.0Hz,1H),2.29(s,3H),1.89-1.72(m,2H),1.66-1.59(m,2H),1.59-1.35(m,2H).13C NMR(101MHz,CDCl3)δ169.6,155.9,150.1,137.0,134.8,130.3,128.6,128.6,128.0,127.9,127.3,121.8,67.2,52.5,40.4,29.6,25.6,21.2,19.7.HRMS(ESI):calcd for C23H26NO4 +(M+H)+:380.1856,found:380.1861.
上述反应过程如下：
Figure GDA0003833294290000061
实施例3：2-(对乙酰基)苯乙烯基哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 1.1mg(0.004mmol,2.0mol％)和二(五氟苯基)硼氢HB(C6F5)2 2.76mg(0.008mmol,4.0mol％)加入到15mL耐压管中，加入1mL三氟甲苯溶解，在40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，补加3mL三氟甲苯，再依次加入原料2-(对乙酰基)苯乙烯基吡啶1c 44.6mg(0.2mmol)，3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)135.5mg(0.5mmol,2.5equiv)，三正丁基苄基氯化铵nBu3BnNCl 3.11mg(0.01mmol,5mol％)和频那醇硼烷HBPin 127mg(1.0mmol,5.0equiv)，在25℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-(对乙酰基)苯乙烯基哌啶(Benzyl(S,E)-2-(4-acetylstyryl)piperidine-1-carboxylate)2c，其为白色固体，收率为81％。
产物对映选择性的测定：
将分离得到的产物2c置于25mL圆底瓶中，加入乙醚2mL和2M氢氧化钠溶液0.3mL，冰浴冷却下慢慢滴加氯甲酸苄酯CbzCl 34mg(0.2mmol)。恢复室温搅拌至哌啶产物消耗完，加水2.0mL猝灭并稀释，用乙酸乙酯萃取(5mL×3次)，有机相合并，无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到苄氧羰基保护的还原产物3c，其为无色油状液体，收率为95％，对映选择性为96％ee。[α]25 D＝-124.6(c＝0.50,CHCl3).1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.3Hz,2H),7.47-7.28(m,7H),6.42(d,J＝16.2Hz,1H),6.33(dd,J＝16.1,4.4Hz,1H),5.18(dd,J＝21.9,12.4Hz,2H),5.09(s,1H),4.11(d,J＝13.0Hz,1H),3.04-2.91(m,1H),2.59(s,3H),1.91-1.75(m,2H),1.72-1.45(m,4H).13C NMR(101MHz,CDCl3)δ197.6,155.9,141.6,136.9,136.1,131.6,130.3,128.8,128.6,128.1,127.9,126.5,67.2,52.6,40.4,29.5,26.7,25.5,19.8.HRMS(ESI)calcd.for C23H26NO3 +(M+H)+:364.1907,Found:364.1911.
上述反应过程如下：
Figure GDA0003833294290000071
实施例4：2-(2-噻吩乙烯基)哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 0.54mg(0.002mmol,1.0mol％)和二(五氟苯基)硼氢HB(C6F5)2 1.38mg(0.004mmol,2.0mol％)加入到15mL耐压管中，加入1mL三氟甲苯溶解，40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，补加2mL三氟甲苯，再依次加入原料2-(2-噻吩乙烯基)吡啶1d37.5mg(0.2mmol)，3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)163.2mg(0.6mmol,3.0equiv)，三正丁基苄基氯化铵nBu3BnNCl 3.11mg(0.01mmol,5mol％)和频那醇硼烷HBPin 127mg(1.0mmol,5.0equiv)，25℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-2-噻吩乙烯基)哌啶(Benzyl(S,E)-2-(2-(thiophen-2-yl)vinyl)piperidine-1-carboxylate)2d，其为白色固体，收率为80％。
产物对映选择性的测定：
将分离得到的产物2d置于25mL圆底瓶中，加入乙醚2.0mL和2M氢氧化钠溶液0.3mL，冰浴冷却下慢慢滴加氯甲酸苄酯CbzCl 34mg(0.2mmol)。恢复室温搅拌至哌啶产物消耗完，加水2mL猝灭并稀释，用乙酸乙酯萃取(5mL×3次)，有机相合并，无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到苄氧羰基保护的还原产物3d，无色油状液体，收率95％，对映选择性为91％ee。[α]25 D＝-127.7(c＝0.64,CHCl3).1H NMR(400MHz,CDCl3)δ7.40-7.29(m,5H),7.14(d,J＝4.9Hz,1H),6.96(t,J＝4.0Hz,1H),6.90(s,1H),6.53(d,J＝15.8Hz,1H),6.04(dd,J＝15.9,4.8Hz,1H),5.17(dd,J＝19.2,12.4Hz,2H),5.04(s,1H),4.09(d,J＝12.7Hz,1H),2.98(t,J＝12.7Hz,1H),1.88-1.73(m,2H),1.70-1.39(m,4H).13C NMR(101MHz,CDCl3)δ155.8,142.1,137.0,128.6,128.0,128.0,127.9,127.5,125.7,124.7,124.1,67.2,52.4,40.3,29.5,25.6,19.7.HRMS(ESI):calcdfor C19H22NO2S+(M+H)+:328.1366,found:328.1364.
上述反应过程如下：
Figure GDA0003833294290000081
实施例5：2-苄乙烯基哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 1.1mg(0.004mmol,2.0mol％)和二(五氟苯基)硼氢HB(C6F5)2 2.76mg(0.008mmol,4.0mol％)加入到15mL耐压管中，加入1mL三氟甲苯溶解，40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，补加4mL三氟甲苯，再依次加入原料2-苄乙烯基吡啶1e 39.1mg(0.2mmol)，3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)135.5mg(0.5mmol,2.5equiv)，三正丁基苄基氯化铵nBu3BnNCl 3.11mg(0.01mmol,5mol％)和频那醇硼烷HBPin127mg(1.0mmol,5.0equiv)，在30℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-苄乙烯基哌啶(Benzyl(S,E)-2-(3-phenylprop-1-en-1-yl)piperidine-1-carboxylate)2e，其为白色固体，收率为65％。
产物对映选择性的测定：
将分离得到的产物2e置于25mL圆瓶中，加入乙醚2mL和2M氢氧化钠溶液0.3mL，冰浴下慢慢滴加氯甲酸苄酯CbzCl(34mg,0.2mmol)。恢复室温搅拌至哌啶产物消耗完，加水2mL猝灭并稀释，用乙酸乙酯萃取(5mL×3次)，有机相合并，无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到苄氧羰基保护的还原产物3e，无色油状液体，收率92％，对映选择性为93％ee。[α]25 D＝-33.1(c＝0.80,CHCl3).1H NMR(400MHz,CDCl3)δ7.36-7.23(m,7H),7.18(dd,J＝19.4,7.2Hz,3H),5.69-5.60(m,1H),5.51(dd,J＝15.6,4.6Hz,1H),5.12(dd,J＝18.6,12.5Hz,2H),4.89(s,1H),4.02(d,J＝13.5Hz,1H),3.37(d,J＝6.6Hz,2H),2.91(td,J＝13.0,2.8Hz,1H),1.77-1.66(m,2H),1.65-1.57(m,2H),1.55-1.37(m,2H).13C NMR(101MHz,CDCl3)δ155.8,140.4,137.1,130.8,129.7,128.6,128.5,128.0,127.9,126.2,67.1,52.2,40.2,38.9,29.5,25.7,19.6.HRMS(ESI)calcd.forC22H26NO2 +(M+H)+:336.1958,found:336.1962.
上述反应过程如下：
Figure GDA0003833294290000091
实施例6：2-环己烯甲基哌啶的合成
在充满氮气的手套箱中，二苯基取代的手性螺环双烯L1 2.72mg(0.01mmol,5.0mol％)和二(五氟苯基)硼氢HB(C6F5)2 6.9mg(0.02mmol,10.0mol％)加入到15mL耐压管中，加入1mL三氟甲苯溶解，40℃下反应15分钟，得到手性螺环双硼催化剂。
体系冷却至室温，补加4mL三氟甲苯，再依次加入原料2-环己烯甲基吡啶1f34.7mg(0.2mmol)，3,5-双(三氟甲基)乙酰苯胺3,5-(CF3)2C6H3(Ac)NH(PD)162.6mg(0.6mmol,3.0equiv)，三正丁基苄基氯化铵nBu3BnNCl 3.11mg(0.01mmol,5mol％)频那醇硼烷HBPin 127mg(1.0mmol,5.0equiv)，30℃反应24小时。反应完成后，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到还原产物2-环己烯甲基哌啶((S)-2-(Cyclohexylidenemethyl)-1-((4-nitrophenyl)sulfonyl)piperidine)2f，其为白色固体，收率为88％。
产物对映选择性的测定：
将分离得到的产物2f置于25mL圆瓶中，加入二氯甲烷2mL,三乙胺54.6mg(0.6mmol,3.0equiv)和4-二甲氨基吡啶0.25mg(0.002mmol,1.0mol％)，冰浴冷却下慢慢加入对硝基苯磺酰氯NsCl 60.6mg(0.3mmol)。恢复室温搅拌至哌啶产物消耗完，加水2mL猝灭并稀释，用二氯甲烷萃取(5mL×3次)，有机相合并，无水硫酸钠干燥，过滤，旋蒸除去溶剂，残余物通过硅胶柱层析分离纯化得到对硝基苯磺酰基保护的还原产物3f，白色固体，收率93％，对映选择性为87％ee。[α]25 D＝88.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ8.28(d,J＝8.8Hz,2H),7.89(d,J＝8.8Hz,2H),4.98(d,J＝9.2Hz,1H),4.93-4.84(m,1H),3.75(d,J＝13.3Hz 1H),2.91(td,J＝12.3,2.9Hz,1H),2.24-2.14(m,1H),2.12-2.02(m,1H),1.87-1.68(m,4H),1.61-1.41(m,10H).13C NMR(101MHz,CDCl3)δ149.8,146.1,142.8,128.8,123.8,116.1,51.0,41.9,37.0,32.3,29.2,28.3,27.7,26.6,25.5,18.8.HRMS(ESI)calcd.for C18H25N2O4S+(M+H)+:365.1530,found:365.1536.
上述反应过程如下：
Figure GDA0003833294290000092

Claims (8)

1.一种手性螺环双硼催化取代吡啶的不对称还原方法，包括以下步骤：
S1，制备手性螺环双硼催化剂：
在充满氮气的手套箱中，向反应瓶中依次加入手性螺环双烯和二（五氟苯基）硼氢，向反应瓶中加入溶剂，搅拌，使其充分反应，得到手性螺环双硼催化剂，其中所述手性螺环双烯的结构式如下：
Figure 832728DEST_PATH_IMAGE001
；
所述手性螺环双硼催化剂的结构式如下：
Figure 31628DEST_PATH_IMAGE002
；
S2，催化还原吡啶：
向上述反应瓶中加入吡啶类化合物、3,5-双(三氟甲基)乙酰苯胺、三正丁基苄基氯化铵、频那醇硼烷和溶剂，在氮气氛围中搅拌至反应结束；减压蒸馏除去溶剂，柱层析分离得到手性哌啶类化合物，其中，所述吡啶类化合物和手性哌啶类化合物的结构式分别如下：
Figure 638190DEST_PATH_IMAGE003
,
Figure 631554DEST_PATH_IMAGE004
；
所述R1为烯基、烷基、芳基或杂芳基；所述R2为芳基、烷基。
2.根据权利要求1所述的不对称还原方法，其特征在于：所述芳基为苯基。
3.根据权利要求1所述的不对称还原方法，其特征在于：所述手性螺环双烯、二（五氟苯基）硼氢与吡啶类化合物的摩尔比为(0.5–5):(1–10):100。
4.根据权利要求1所述的不对称还原方法，其特征在于：所述频那醇硼烷与吡啶类化合物的当量比为(3–6):1。
5.根据权利要求1所述的不对称还原方法，其特征在于：所述3,5-双(三氟甲基)乙酰苯胺与吡啶类化合物的当量比为(2–4):1。
6.根据权利要求1所述的不对称还原方法，其特征在于：所述三正丁基苄基氯化铵与吡啶类化合物的摩尔比为(5–10):100。
7.根据权利要求1所述的不对称还原方法，其特征在于：步骤S1、S2中所述溶剂为芳香溶剂、二氯甲烷或正己烷。
8.根据权利要求7所述的不对称还原方法，其特征在于：所述芳香溶剂为三氟甲苯。
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WO2000013682A2 (en) * 1998-09-04 2000-03-16 Vernalis Research Limited 4-quinolinemethanol derivatives as purine receptor antagonists.(ii)
CN107973781A (zh) * 2017-12-16 2018-05-01 河南师范大学 具有逆转肿瘤细胞耐药活性的新型喹啉类化合物及其合成方法和应用
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CN109046447A (zh) * 2018-08-27 2018-12-21 南开大学 C2-对称的双环双硼催化剂的合成
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* Cited by examiner, † Cited by third party
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WO2000013682A2 (en) * 1998-09-04 2000-03-16 Vernalis Research Limited 4-quinolinemethanol derivatives as purine receptor antagonists.(ii)
CN107973781A (zh) * 2017-12-16 2018-05-01 河南师范大学 具有逆转肿瘤细胞耐药活性的新型喹啉类化合物及其合成方法和应用
CN108329297A (zh) * 2018-04-19 2018-07-27 河南师范大学 具有抗肿瘤活性的氟苯喹啉取代甲醇衍生物及其合成方法和应用
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