CN111704586A - 一种合成手性四取代联烯类化合物的新方法 - Google Patents

一种合成手性四取代联烯类化合物的新方法 Download PDF

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CN111704586A
CN111704586A CN202010650860.5A CN202010650860A CN111704586A CN 111704586 A CN111704586 A CN 111704586A CN 202010650860 A CN202010650860 A CN 202010650860A CN 111704586 A CN111704586 A CN 111704586A
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李文军
刘小红
梁帅
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Qingdao University
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Abstract

本发明公开了一种合成手性四取代联烯类化合物的新方法，是在反应溶剂中，以β,γ‑炔基‑α‑亚氨基酯和异噁唑啉酮为反应原料，以手性磷酸为催化剂，反应得手性四取代联烯类化合物。本发明反应条件温和，原料易得价廉，反应操作简单，产率较高，为很多天然产物和药物的合成提供关键的骨架结构，可以广泛适用于工业化规模生产。

Description

一种合成手性四取代联烯类化合物的新方法
技术领域
本发明具体涉及一种制备手性四取代联烯类化合物的合成方法，属于有机化合物工艺应用技术领域。
背景技术
手性四取代联烯类化合物是一类非常重要医药化工中间体，存在于诸多的天然产物、药物分子以及先进功能材料分子结构中，也是有机合成中非常实用的合成前体、配体以及催化剂，具有非常高的应用价值。如下所示：
Figure 678204DEST_PATH_IMAGE002
合成手性四取代联烯类化合物的传统方法主要是通过手性拆分消旋联烯化合物、手性转移光学纯炔丙醇及其衍生物以及过渡金属催化构建。但是，自生转化的成本高和重金属的使用会对环境造成严重污染，使传统方法的应用受到制约。
发明内容
本发明克服现有技术的以上缺陷，首次创新地提出了一种绿色环保，简单高效制备四取代联烯类化合物的新方法，通过使用手性磷酸为催化剂，可以高效地实现反应的转化。本发明利用β,γ-炔基-α-亚氨基酯和异噁唑啉酮作为反应起始原料，以手性磷酸为催化剂，在反应溶剂中进行反应，合成四取代联烯类化合物。
本发明中，R可以是烷基、芳香基、取代的芳环、芳杂环和各类侧链。
本发明中，所述起始原料丙炔衍生物和噻唑酮的用量比例为1:1-1:5。优选地，两者用量比例为1:1.2。
本发明中，所述催化剂是手性磷酸；所述催化剂的用量为1-100％。所述催化剂的用量为原料β,γ-炔基-α-亚氨基酯的1-100 mol％。优选地，所述催化剂用量为1 mol％。
本发明中，所述反应溶剂是二氯甲烷、氯仿、乙腈、甲苯、1,4-二氧六环、四氢呋喃、甲醇、1,2-二氯乙烷。所述反应溶剂包括但不局限于以上，还可以是乙醚、乙酸乙酯、三氟甲苯、二甲苯类化合物或苯甲醚。
本发明中，所述合成反应是在0-80℃温度下进行。优选地，是在25 ℃温度下进行反应。
具体地，本发明合成反应是在反应瓶A中，将β,γ-炔基-α-亚氨基酯(底物1，Xmmol)和异噁唑啉酮(底物2，Y mmol)溶解在Z mL反应溶剂中，室温下，加入手性磷酸(Wmmol)。反应在25 ℃下反应1个小时，用TLC检测反应进程。反应完毕后，直接加硅胶，旋干柱层析，分离得到目标产物3。
本发明合成反应的优点包括：本发明合成方法所使用的各原料非常简单，均为工业化商品，简单易得，来源广泛，并且性能非常稳定，不需要特殊保存条件。本发明所用的各种催化剂也都是常用的商品化试剂，非常稳定。合成手性四取代联烯类化合物的传统方法一般是使用金属催化的丙炔衍生物与其它底物的反应来实现。但是，由于丙炔衍生物的适应性不够广泛，重金属的使用会对环境造成严重污染，对工业化生产造成很大的限制。本发明以简单易得的β,γ-炔基-α-亚氨基酯和异噁唑啉酮为反应原料，在手性磷酸作用下，反应得到手性四取代联烯类化合物。本方法的反应操作比较简单，反应条件温和，产率较高，适合大规模工业化生产。本发明合成的手性四取代联烯类化合物是很多天然产物和活性药物分子的核心骨架，本发明创新设计的反应路线为合成这类化合物提供了一个广泛适用的制备方法。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁共振鉴定。
实施例1
Figure 31562DEST_PATH_IMAGE004
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色固体3aa (73%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.23 (d, J = 8.0 Hz, 2H), 7.54-7.51 (m, 1H), 7.49-7.46 (m, 2H), 7.36-7.35 (m,1H), 7.27-7.23 (m, 3H), 7.14-7.11 (m, 1H), 7.03-7.00 (m, 2H), 6.98-6.96 (m,2H), 6.89 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 4.0 Hz, 2H), 6.45 (s, 1H), 5.69-5.68 (m, 1H), 3.58-3.55 (m, 1H), 3.47-3.36 (m, 3H), 3.31-3.23 (m, 2H), 2.24(m, 3H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.4, 177.0, 165.3,164.3, 151.5, 140.3, 140.0, 137.3, 133.6, 131.7, 130.1, 129.6, 129.0, 128.6,128.4, 128.1, 127.9, 127.8, 126.8, 126.7, 125.0, 124.8, 114.2, 110.0, 105.6,81.2, 78.7, 60.8, 41.0, 39.6, 39.1, 28.3, 21.1. HRMS (ESI): exact masscalculated for [M+Na]+ (C41H38N2O6Na) requires m/z 677.2622, found m/z 677.2620.
实施例2
Figure 811300DEST_PATH_IMAGE006
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2b、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ab (67%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.23-8.21 (m, 2H), 7.54-7.46 (m, 3H), 7.36-7.34 (m, 1H), 7.30-7.28 (m, 1H),7.25-7.24 (m, 2H), 7.22-7.19 (m, 2H), 7.16-7.12 (m, 1H), 7.05-7.01 (m, 2H),6.98-6.95 (m, 2H), 6.49-6.46 (m, 3H), 5.70-5.66 (m, 1H), 3.56-3.51 (m, 1H),3.46-3.45 (m, 1H), 3.42-3.35 (m, 2H), 3.29-3.24 (m, 2H), 1.57 (s, 9H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.4, 176.8, 165.0, 164.2, 151.6, 140.3, 140.1,133.4, 132.4, 132.0, 131.5, 129.2, 128.7, 128.6, 128.0, 127.9, 127.8, 126.9,126.8, 125.0, 124.9, 124.7, 122.0, 114.0, 105.8, 81.4, 78.9, 60.5, 40.6,39.6, 39.3, 28.3. HRMS (ESI): exact mass calculated for [M+Na]+ (C40H35N2O6BrNa)requires m/z 741.1571, found m/z 741.1572.
实施例3
Figure 144192DEST_PATH_IMAGE008
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2c、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ac (66%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.24-8.22 (m, 2H), 7.53-7.45 (m, 3H), 7.37-7.35 (m, 1H), 7.28-7.23 (m, 3H),7.15-7.11 (m, 1H), 7.04-6.96 (m, 4H), 6.63-6.56 (m, 4H), 6.46 (s, 1H), 5.70-5.67 (m, 1H), 3.72 (s, 3H), 3.59-3.54 (m, 1H), 3.46-3.35 (m, 3H), 3.30-3.22(m, 2H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.5, 177.1, 165.3,164.4, 159.0, 151.6, 140.4, 140.1, 133.6, 131.8, 130.9, 129.1, 128.6, 128.5,128.1, 127.9, 127.8, 126.9, 126.8, 125.2, 125.0, 124.8, 114.2, 113.7, 105.6,81.3, 78.8, 60.8, 55.1, 40.6, 39.6, 39.2, 28.3. HRMS (ESI): exact masscalculated for [M+Na]+ (C41H38N2O7Na) requires m/z 693.2571, found m/z 693.2575.
实施例4
Figure 896247DEST_PATH_IMAGE010
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2d、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ad (60%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.24-8.21 (m, 2H), 7.95-7.92 (m, 2H), 7.59-7.55 (m, 1H), 7.52-7.48 (m, 2H),7.36-7.27 (m, 4H), 7.17-7.13 (m, 1H), 7.07-7.03 (m, 2H), 6.98-6.96 (m, 2H),6.74 (d, J = 8.0 Hz, 2H), 6.48 (s, 1H), 5.71-5.67 (m, 1H), 3.60-3.57 (m, 1H),3.54-3.46 (m, 2H), 3.43-3.35 (m, 2H), 3.31-3.27 (m, 1H), 1.58 (s, 9H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.3, 176.5, 164.8, 164.1, 151.6, 147.5, 141.0,140.2, 133.1, 132.3, 130.8, 129.4, 128.7, 127.9, 127.7, 127.6, 127.5, 126.9,126.8, 125.0, 124.9, 123.5, 113.8, 106.0, 81.5, 79.0, 60.3, 40.8, 39.6, 39.4,28.3. HRMS (ESI): exact mass calculated for [M+Na]+ (C40H35N3O8Na) requires m/z708.2316, found m/z 708.2315.
实施例5
Figure 718710DEST_PATH_IMAGE012
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2e、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ae (74%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.23-8.21 (m, 2H), 7.56-7.47 (m, 3H), 7.37-7.34 (m, 1H), 7.29-7.26 (m, 1H),7.25-7.24 (m, 2H), 7.16-7.12 (m, 1H), 7.08-7.01 (m, 3H), 6.97-6.95 (m, 2H),6.88-6.84 (m, 1H), 6.46-6.44 (m, 2H), 6.35-6.31 (m, 1H), 5.71-5.66 (m, 1H),3.58-3.57 (m, 1H), 3.50-3.35 (m, 3H), 3.31-3.22 (m, 2H), 1.57 (s, 9H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.3, 176.8, 165.1, 164.3, 162.3 (d, J = 980.0Hz), 151.6, 140.3, 140.1, 135.7 (d, J = 28.0 Hz), 133.4, 132.0, 129.9 (d, J =36.0 Hz), 129.2, 128.6, 128.5, 128.0, 127.8, 127.0, 126.9 (d, J = 36.0 Hz),125.5, 125.0, 124.8, 124.7, 116.7 (d, J = 84.0 Hz), 114.7 (d, J = 84.0 Hz),114.0, 105.7, 81.4, 78.9, 60.5, 40.8, 39.6, 39.2, 28.3. HRMS (ESI): exactmass calculated for [M+Na]+ (C40H35N2O6FNa) requires m/z 681.2371, found m/z681.2371.
实施例6
Figure 923426DEST_PATH_IMAGE014
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2f、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3af (84%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.22-8.20 (m, 2H), 7.55-7.47 (m, 3H), 7.37-7.35 (m, 1H), 7.29-7.26 (m, 1H),7.25-7.23 (m, 2H), 7.16-7.12 (m, 2H), 7.05-7.01 (m, 3H), 6.97-6.95 (m, 2H),6.57-6.56 (m, 2H), 6.46 (s, 1H), 5.71-5.66 (m, 1H), 3.58-3.53 (m, 1H), 3.46-3.35 (m, 3H), 3.28-3.22 (m, 2H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d(ppm) 202.3, 176.8, 165.1, 164.2, 151.6, 140.3, 140.1, 135.4, 134.0, 133.4,132.0, 129.9, 129.6, 129.2, 128.7, 128.6, 128.0, 127.9, 127.8, 127.0, 126.9,126.8, 125.0, 124.8, 124.7, 114.0, 105.7, 81.4, 78.9, 60.5, 40.7, 39.6, 39.2,28.3. HRMS (ESI): exact mass calculated for [M+Na]+ (C40H35N2O6ClNa) requires m/z 697.2076, found m/z 697.2075.
实施例7
Figure 558545DEST_PATH_IMAGE016
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2g、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ag (78%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.22-8.20 (m, 2H), 7.56-7.50 (m, 3H), 7.39-7.37 (m, 1H), 7.28-7.27 (m, 1H),7.26-7.23 (m, 2H), 7.15-7.11 (m, 1H), 7.04-7.00 (m, 2H), 6.98-6.96 (m, 4H),6.49-6.46 (m, 2H), 6.46 (s, 1H), 5.71-5.67 (m, 1H), 3.61-3.56 (m, 1H), 3.48-3.47 (m, 1H), 3.43-3.36 (m, 2H), 3.31-3.22 (m, 2H), 2.13 (s, 3H), 1.58 (s,9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.4, 177.1, 165.3, 164.4, 151.6,140.4, 140.1, 137.8, 133.6, 133.2, 131.7, 130.5, 129.0, 128.6, 128.5, 128.4,128.3, 128.2, 128.0, 127.9, 126.9, 126.8, 125.0, 124.8, 124.7, 114.2, 105.6,81.3, 78.8, 60.7, 41.2, 39.6, 39.1, 28.4, 21.3. HRMS (ESI): exact masscalculated for [M+Na]+ (C41H38N2O6Na) requires m/z 677.2622, found m/z 677.2619.
实施例8
Figure 227423DEST_PATH_IMAGE018
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2h、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ah (80%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.26-8.24 (m, 2H), 7.53-7.44 (m, 3H), 7.36-7.34 (m, 1H), 7.26-7.22 (m, 3H),7.16-7.11 (m, 1H), 7.05-7.03 (m, 2H), 7.01-6.93 (m, 5H), 6.77-6.75 (m, 1H),6.48 (s, 1H), 5.70-5.66 (m, 1H), 3.58-3.53 (m, 3H), 3.47-3.36 (m, 2H), 3.27-3.22 (m, 1H), 1.90 (s, 3H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm)202.6, 177.4, 165.5, 164.4, 151.6, 140.3, 139.9, 137.2, 133.5, 131.9, 131.8,130.8, 129.7, 129.0, 128.6, 128.5, 128.2, 128.1, 128.0, 127.6, 126.9, 126.8,125.8, 125.0, 124.7, 114.7, 105.8, 81.3, 78.8, 60.2, 39.6, 39.1, 36.9, 28.3,19.2. HRMS (ESI): exact mass calculated for [M+Na]+ (C41H38N2O6Na) requires m/z677.2622, found m/z 677.2622.
实施例9
Figure 158470DEST_PATH_IMAGE020
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2i、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ai (66%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.23-8.21 (m, 2H), 7.74-7.72 (m, 1H), 7.59-7.55 (m, 3H), 7.53-7.49 (m, 2H),7.42-7.38 (m, 3H), 7.32-7.27 (m, 3H), 7.16-7.10 (m, 2H), 7.05-7.03 (m, 1H),7.01-6.98 (m, 3H), 6.79-6.76 (m, 1H), 6.49 (s, 1H), 5.74-5.69 (m, 1H), 3.67-3.60 (m, 2H), 3.51-3.44 (m, 2H), 3.42-3.38 (m, 1H), 3.30-3.22 (m, 1H), 1.59(s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.5, 177.1, 165.3, 164.4, 151.6,140.4, 140.1, 133.9, 133.5, 133.1, 132.7, 131.8, 130.9, 129.1, 129.0, 128.8,128.6, 128.5, 128.3, 128.0, 127.9, 127.8, 127.6, 126.9, 126.8, 126.0, 125.9,125.0, 124.8, 114.2, 105.7, 81.3, 78.9, 60.8, 41.4, 39.6, 39.2, 28.4. HRMS(ESI): exact mass calculated for [M+Na]+ (C44H38N2O6Na) requires m/z 713.2622,found m/z 713.2619.
实施例10
Figure 850483DEST_PATH_IMAGE022
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2j、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3aj (85%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.25-8.23 (m, 2H), 7.54-7.46 (m, 3H), 7.38-7.36 (m, 1H), 7.30-7.27 (m, 1H),7.25-7.24 (m, 2H), 7.17-7.08 (m, 4H), 7.05-6.97 (m, 4H), 6.68-6.66 (m, 2H),6.48 (s, 1H), 5.72-5.67 (m, 1H), 3.61-3.56 (m, 1H), 3.53-3.49 (m, 1H), 3.48-3.37 (m, 2H), 3.36-3.33 (m, 1H), 3.28-3.23 (m, 1H), 1.58 (s, 9H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.5, 177.0, 165.2, 164.4, 151.6, 140.4, 140.1,133.6, 133.3, 131.8, 129.8, 129.1, 128.6, 128.5, 128.4, 128.2, 128.0, 127.8,127.7, 126.9, 126.8, 125.0, 124.8, 114.2, 105.7, 81.3, 78.8, 60.7, 41.3,39.6, 39.2, 28.4. HRMS (ESI): exact mass calculated for [M+Na]+ (C40H36N2O6Na)requires m/z 663.2466, found m/z 663.2462.
实施例11
Figure 587495DEST_PATH_IMAGE024
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2k、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色固体3ak (76%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.25-8.23 (m, 2H), 7.49-7.42 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.23-7.21 (m,3H), 7.15-7.11 (m, 1H), 7.03-6.99 (m, 2H), 6.93-6.91 (m, 2H), 6.43 (s, 1H),5.67-5.62 (m, 1H), 3.52-3.47 (m, 1H), 3.41-3.38 (m, 1H), 3.37-3.32 (m, 1H),3.17-3.12 (m, 1H), 1.71 (s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3, 100 MHz): d(ppm) 202.7, 178.1, 167.4, 164.3, 151.5, 140.4, 139.9, 133.6, 131.9, 129.0,128.6, 128.5, 127.9, 127.7, 127.2, 126.9, 126.7, 125.0, 124.6, 114.5, 105.6,81.2, 78.6, 53.7, 39.6, 38.8, 28.3, 22.4. HRMS (ESI): exact mass calculatedfor [M+Na]+ (C34H32N2O6Na) requires m/z 587.2153, found m/z 587.2153.
实施例12
Figure 48563DEST_PATH_IMAGE026
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2l、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3al (58%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.24 (d, J = 8.0 Hz, 2H), 7.50-7.48 (m, 1H), 7.47-7.43 (m, 2H), 7.36 (d, J =8.0 Hz, 1H), 7.25-7.21 (m, 3H), 7.14-7.10 (m, 1H), 7.01-6.97 (m, 2H), 6.91-6.89 (m, 2H), 6.42 (s, 1H), 5.67-5.63 (m, 1H), 3.53-3.48 (m, 1H), 3.42-3.40(m, 1H), 3.38-3.32 (m, 1H), 3.17-3.12 (m, 1H), 2.21-2.13 (m, 1H), 2.05-1.98(m, 1H), 1.56 (s, 9H), 1.15-1.04 (m, 2H), 0.80 (t, J = 8.0 Hz, 3H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.4, 177.8, 166.0, 164.4, 151.5, 140.4, 139.9,133.7, 131.9, 129.0, 128.5, 128.4, 127.9, 127.6, 127.6, 126.9, 126.7, 125.0,124.6, 114.3, 105.3, 81.1, 78.6, 59.2, 39.6, 38.9, 37.2, 28.3, 17.7, 13.9.HRMS (ESI): exact mass calculated for [M+Na]+ (C36H36N2O6Na) requires m/z615.2466, found m/z 615.2462.
实施例13
Figure 478407DEST_PATH_IMAGE028
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2m、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油3am (63%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.28-8.24 (m, 2H), 7.55-7.36 (m, 2H), 7.29-7.27 (m, 1H), 7.25-7.23 (m, 2H),7.18-7.14 (m, 3H), 7.13-7.09 (m, 2H), 7.06-7.03 (m, 2H), 6.97-6.95 (m, 2H),6.68-6.66 (m, 2H), 6.50 (s, 1H), 5.71-5.67 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.44 (m, 2H), 3.42-3.33 (m, 2H), 3.28-3.23 (m, 1H), 1.59 (s, 9H). 13C NMR(CDCl3, 100 MHz): d (ppm) 202.5, 176.9, 164.8 (d, J = 1008.0 Hz), 164.2,151.7, 140.3, 140.0, 133.9, 133.4, 133.2, 131.9, 130.2 (d, J = 36.0 Hz),129.7, 128.8, 128.7, 128.6, 128.4, 127.9, 127.8, 127.1, 126.8 (d, J = 44.0Hz), 124.9 (d, J = 72.0 Hz), 124.8, 124.4 (d, J = 16.0 Hz), 116.3 (d, J =84.0 Hz), 114.1, 105.8, 81.4, 78.9, 60.6, 41.4, 39.6, 39.2, 28.4. HRMS (ESI):exact mass calculated for [M+Na]+ (C40H35N2O6FNa) requires m/z 681.2371, foundm/z 681.2371.
实施例14
Figure 156251DEST_PATH_IMAGE030
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2n、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3an (59%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.20-8.17 (m, 2H), 7.37-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.25-7.23 (m, 2H),7.17-7.15 (m, 1H), 7.13-7.08 (m, 3H), 7.04-7.01 (m, 2H), 7.00-6.95 (m, 4H),6.68 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.71-5.66 (m, 1H), 3.88 (s, 3H),3.60-3.55 (m, 1H), 3.48-3.35 (m, 3H), 3.33-3.29 (m, 1H), 3.28-3.23 (m, 1H),1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.4, 177.1, 164.7, 164.4,162.2, 151.6, 140.4, 140.1, 133.6, 133.4, 129.8, 129.6, 128.6, 128.5, 128.3,128.0, 127.7, 126.9, 126.8, 125.0, 124.8, 120.6, 114.4, 105.6, 81.2, 78.8,60.8, 55.3, 41.5, 39.6, 39.2, 28.3. HRMS (ESI): exact mass calculated for [M+H]+ (C41H39N2O7) requires m/z 671.2745, found m/z 671.2743.
实施例15
Figure 369058DEST_PATH_IMAGE032
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2o、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ao (64%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.74-8.70 (m, 1H), 7.54-7.49 (m, 1H), 7.40-7.35 (m, 2H), 7.29-7.27 (m, 1H),7.25-7.22 (m, 2H), 7.18-7.10 (m, 5H), 7.07-7.03 (m, 2H), 7.00-6.98 (m, 2H),6.67-6.65 (m, 2H), 6.47 (s, 1H), 5.71-5.66 (m, 1H), 3.59-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.43-3.40 (m, 1H), 3.38-3.32 (m, 2H), 3.27-3.22 (m, 1H), 1.57(s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.5, 176.3, 164.2, 162.4, 160.1(d, J = 1044.0 Hz), 151.6, 140.3, 140.0, 133.3, 133.2, 133.1, 131.4, 129.5,128.7, 128.6, 128.5, 127.9, 127.8, 127.0, 126.8 (d, J = 52.0 Hz), 124.9 (d, J= 84.0 Hz), 124.8 (d, J = 16.0 Hz), 124.7, 117.0 (d, J = 84.0 Hz), 116.3 (d,J = 40.0 Hz), 114.2, 105.8, 81.3, 78.9, 61.0, 41.2, 39.6, 39.1, 28.4. HRMS(ESI): exact mass calculated for [M+Na]+ (C40H35N2O6FNa) requires m/z 681.2363,found m/z 681.2363.
实施例16
Figure 12529DEST_PATH_IMAGE034
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2p、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油3ap (60%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.79-8.77 (m, 1H), 7.55-7.49 (m, 2H), 7.46-7.42 (m, 1H), 7.38-7.36 (m, 1H),7.30-7.27 (m, 2H), 7.25-7.24 (m, 1H), 7.21-7.16 (m, 2H), 7.15-7.11 (m, 2H),7.07-7.05 (m, 1H), 7.04-7.00 (m, 3H), 6.63-6.61 (m, 2H), 6.47 (s, 1H), 5.71-5.67 (m, 1H), 3.60-3.56(m, 1H), 3.47-3.42 (m, 1H), 3.41-3.34 (m, 1H), 3.31-3.23 (m, 3H), 1.56 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.4, 176.2,164.3, 163.2, 151.5, 140.4, 140.0, 133.7, 133.1, 132.3, 132.0, 131.8, 129.5,128.8, 128.7, 128.6, 128.0, 127.7, 127.5, 127.0, 126.8, 126.3, 125.1, 124.8,114.5, 105.7, 81.3, 79.0, 61.5, 40.5, 39.6, 39.1, 28.4. HRMS (ESI): exactmass calculated for [M+Na]+ (C40H35N2O6ClNa) requires m/z 697.2069, found m/z697.2069.
实施例17
Figure 285378DEST_PATH_IMAGE036
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1b、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ba (78%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.23-8.21 (m, 2H), 7.57-7.53 (m, 1H), 7.51-7.47 (m, 2H), 7.40-7.38 (m, 1H),7.30-7.27 (m, 3H), 6.91-6.86 (m, 4H), 6.69-6.65 (m, 2H), 6.56 (d, J = 8.0 Hz,2H), 6.47 (s, 1H), 5.72-5.68 (m, 1H), 3.63-3.58 (m, 1H), 3.46-3.45 (m, 1H),3.43-3.36 (m, 2H), 3.31-3.28 (m, 1H), 3.24-3.20 (m, 1H), 2.24 (s, 3H), 1.58(s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.5, 177.0, 165.2, 164.2, 162.6(d, J = 984.0 Hz), 151.6, 140.5, 140.0, 137.4, 131.9, 130.1, 129.9 (d, J =36.0 Hz), 129.6, 129.2, 129.1, 128.1, 127.8, 127.0, 126.9 (d, J = 60.0 Hz),125.1, 124.8, 124.7, 115.6 (d, J = 88.0 Hz), 113.2, 105.6, 81.4, 78.9, 61.0,40.8, 39.8, 39.1, 28.3, 21.1. HRMS (ESI): exact mass calculated for [M+Na]+(C41H37N2O6FNa) requires m/z 695.2528, found m/z 695.2529.
实施例18
Figure 14300DEST_PATH_IMAGE038
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1c、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色固体3ca (69%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.21-8.18 (m, 2H), 7.56-7.52 (m, 1H), 7.49-7.45 (m, 2H), 7.38-7.36 (m, 1H),7.26-7.24 (m, 4H), 6.98-6.95 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.86-6.83 (m,2H), 6.54 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.71-5.67 (m, 1H), 3.60-3.55 (m,1H), 3.45-3.44 (m, 1H), 3.41-3.34 (m, 2H), 3.29-3.26 (m, 1H), 3.23-3.18 (m,1H), 2.24 (m, 3H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.6,176.9, 165.2, 164.1, 151.6, 140.4, 140.0, 137.4, 134.5, 132.0, 131.9, 129.9,129.6, 129.3, 129.1, 129.0, 128.8, 128.0, 127.7, 126.9, 126.8, 125.1, 124.8,113.2, 105.9, 81.4, 78.9, 60.7, 40.9, 39.7, 39.1, 28.3, 21.1. HRMS (ESI):exact mass calculated for [M+Na]+ (C41H37N2O6ClNa) requires m/z 711.2232, foundm/z 711.2230.
实施例19
Figure 30797DEST_PATH_IMAGE040
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1d、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色固体3da (63%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.20-8.18 (m, 2H), 7.56-7.52 (m, 1H), 7.50-7.46 (m, 2H), 7.38-7.36 (m, 1H),7.27-7.24 (m, 4H), 7.13-7.10 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.80-6.77 (m,2H), 6.54 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.71-5.67 (m, 1H), 3.59-3.55 (m,1H), 3.45-3.44 (m, 1H), 3.41-3.34 (m, 2H), 3.29-3.26 (m, 1H), 3.23-3.18 (m,1H), 2.24 (m, 3H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.6,176.9, 165.2, 164.1, 151.6, 140.4, 140.0, 137.4, 132.5, 131.9, 131.8, 129.9,129.6, 129.5, 129.2, 129.1, 128.0, 127.7, 126.9, 126.8, 125.1, 124.8, 122.9,113.2, 105.9, 81.5, 78.9, 60.7, 40.9, 39.7, 39.1, 28.3, 21.1. HRMS (ESI):exact mass calculated for [M+Na]+ (C41H37N2O6BrNa) requires m/z 755.1727, foundm/z 755.1723.
实施例20
Figure 959134DEST_PATH_IMAGE042
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1e、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油3ea (67%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.19 (d, J = 8.0 Hz, 2H), 7.55-7.51 (m, 1H), 7.49-7.45 (m, 2H), 7.35-7.33 (m,1H), 7.25-7.22 (m, 3H), 7.01-6.96 (m, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.85-6.79 (m, 2H), 6.74-6.72 (m, 1H), 6.52 (d, J = 8.0 Hz, 2H), 6.48 (s, 1H),5.71-5.66 (m, 1H), 3.56-3.51 (m, 1H), 3.47-3.44 (m, 1H), 3.42-3.35 (m, 2H),3.29-3.22 (m, 2H), 2.24 (s, 3H), 1.58 (s, 9H). 13C NMR (CDCl3, 100 MHz): d(ppm) 203.0, 177.0, 165.2, 164.1, 162.3 (d, J = 984.0 Hz), 151.6, 140.2,140.0, 137.4, 135.7 (d, J = 32.0 Hz), 131.9, 130.3 (d, J = 32.0 Hz), 129.9,129.6, 129.1 (d, J = 16.0 Hz), 127.9, 127.7, 126.9, 126.8, 124.9, 124.8,123.4 (d, J = 16.0 Hz), 115.7, 115.5, 115.2 (d, J = 92.0 Hz), 113.3, 106.1,81.5, 78.9, 60.5, 41.2, 39.5, 39.2, 28.3, 21.1. HRMS (ESI): exact masscalculated for [M+Na]+ (C41H37N2O6FNa) requires m/z 695.2528, found m/z695.2527.
实施例21
Figure 730780DEST_PATH_IMAGE044
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1f、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油3fa (59%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.18-8.15 (m, 2H), 7.54-7.51 (m, 1H), 7.49-7.45 (m, 2H), 7.34-7.32 (m, 1H),7.28-7.27 (m, 2H), 7.25-7.21 (m, 3H), 6.91-6.85 (m, 4H), 6.51 (d, J = 8.0 Hz,2H), 6.47 (s, 1H), 5.69-5.66 (m, 1H), 3.49-3.43 (m, 2H), 3.41-3.36 (m, 2H),3.27-3.23 (m, 2H), 2.23 (s, 3H), 1.58 (s, 9H). 13C NMR (CDCl3, 100 MHz): d(ppm) 203.1, 177.0, 165.2, 164.1, 151.6, 140.2, 140.0, 137.4, 135.7, 131.9,131.6, 131.3, 130.2, 129.8, 129.6, 129.1, 129.0, 127.8, 127.7, 126.9, 126.8,126.0, 124.9, 124.7, 122.5, 113.0, 106.3, 81.5, 78.8, 60.4, 41.2, 39.4, 39.2,28.3, 21.1. HRMS (ESI): exact mass calculated for [M+Na]+ (C41H37N2O6BrNa)requires m/z 755.1721, found m/z 755.1721.
实施例22
Figure 619102DEST_PATH_IMAGE046
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1g、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ga (80%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.18 (d, J = 4.0 Hz, 2H), 7.50-7.46 (m, 1H), 7.43-7.39 (m, 2H), 7.33-7.31 (m,1H), 7.24-7.18 (m, 4H), 7.08-7.02 (m, 2H), 6.97-6.93 (m, 1H), 6.88 (d, J =8.0 Hz, 2H), 6.60 (d, J = 8.0 Hz, 2H), 6.36 (s, 1H), 5.68-5.63 (m, 1H), 3.80-3.76 (m, 1H), 3.44-3.42 (m, 2H), 3.38-3.33 (m, 2H), 3.25-3.20 (m, 1H), 2.23(s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 204.5, 177.0, 165.1,164.2, 151.4, 140.2, 140.0, 137.2, 133.2, 131.8, 131.6, 130.3, 130.2, 129.8,129.7, 129.5, 129.0, 128.7, 128.1, 128.0, 126.9, 126.8, 124.8, 124.7, 110.3,106.2, 81.2, 78.4, 60.5, 41.0, 39.4, 39.2, 28.3, 21.1. HRMS (ESI): exact masscalculated for [M+Na]+ (C41H37N2O6ClNa) requires m/z 711.2232, found m/z711.2229.
实施例23
Figure 501607DEST_PATH_IMAGE048
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1h、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ha (74%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.09-8.07 (m, 2H), 7.43-7.31 (m, 4H), 7.21-7.17 (m, 3H), 7.11-7.08 (m, 1H),7.06-7.01 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.61-6.55 (m, 2H), 6.42 (s, 1H), 5.69-5.64 (m, 1H), 3.63-3.60 (m, 1H), 3.56-3.46(m, 2H), 3.43-3.41 (m, 1H), 3.39 (s, 3H), 3.38-3.34 (m, 1H), 3.17-3.12 (m,1H), 2.22 (s, 3H), 1.58 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 203.3,177.1, 165.3, 164.5, 156.7, 151.6, 140.5, 140.1, 137.1, 132.3, 131.0, 130.6,129.7, 128.9, 128.4, 128.3, 127.8, 126.8, 126.6, 124.8, 124.6, 122.9, 120.4,112.5, 110.7, 105.1, 81.1, 78.1, 59.8, 54.2, 42.5, 39.5, 38.9, 28.3, 21.1.HRMS (ESI): exact mass calculated for [M+Na]+ (C40H40N2O7Na) requires m/z707.2728, found m/z 707.2725.
实施例24
Figure 791774DEST_PATH_IMAGE050
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1i、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油3ia (80%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.21-8.19 (m, 2H), 7.54-7.44 (m, 3H), 7.31-7.29 (m, 2H), 7.25-7.20 (m, 2H),7.04-7.02 (m, 1H), 6.92-6.87 (m, 3H), 6.74-6.73 (m, 1H), 6.52-6.48 (m, 3H),5.70-5.65 (m, 1H), 3.53-3.44 (m, 2H), 3.41-3.35 (m, 2H), 3.31-3.20 (m, 2H),2.24 (s, 3H), 1.57 (s, 9H). 13C NMR (CDCl3, 100 MHz): d (ppm) 202.8, 177.1,165.9, 164.2, 151.6, 140.3, 140.1, 137.4, 133.1, 131.8, 130.0, 129.6, 129.1,129.0, 128.0, 127.7, 127.3, 126.9, 126.8, 125.8, 125.0, 124.9, 123.8, 110.4,105.6, 81.3, 78.9, 60.3, 40.9, 39.5, 39.2, 28.3, 21.2. HRMS (ESI): exact masscalculated for [M+Na]+ (C39H36N2O6SNa) requires m/z 683.2186, found m/z683.2186.
实施例25
Figure 672006DEST_PATH_IMAGE052
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1j、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到白色油3ja (72%)。1H NMR (CDCl3, 400 MHz): d (ppm)8.17-8.15 (m, 2H), 7.55-7.45 (m, 3H), 7.32-7.28 (m, 1H), 7.26-7.23 (m, 1H),7.22-7.17 (m, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.55-6.53 (m, 2H), 6.42 (s, 1H),5.66-5.61 (m, 1H), 3.40-3.34 (m, 4H), 3.17-3.10 (m, 2H), 2.22 (s, 3H), 1.54(s, 9H), 1.02-0.96 (m, 1H), 0.46-0.35 (m, 3H), 0.12-0.08 (m, 1H) . 13C NMR(CDCl3, 100 MHz): d (ppm) 197.7, 177.6, 165.9, 164.4, 151.5, 140.3, 139.9,137.1, 131.8, 130.6, 129.5, 129.1, 129.0, 128.0, 127.6, 126.9, 126.7, 124.9,124.6, 116.5, 106.3, 81.0, 78.3, 60.9, 40.1, 39.6, 38.9, 28.3, 21.1, 11.5,8.3, 5.7. HRMS (ESI): exact mass calculated for [M+Na]+ (C38H38N2O6Na) requiresm/z 641.2622, found m/z 641.2615。

Claims (5)

1.一种合成手性四取代联烯类化合物的新方法，其特征在于，以化合物1和2为反应原料，以手性磷酸为催化剂，一定温度下在反应溶剂中反应得到手性四取代联烯类化合物；其中，所述温度为0-80℃；反应过程如式(I)所示；
Figure 274934DEST_PATH_IMAGE002
其中 R1, R2, R3 ，R4和R5是烷基、芳香基、取代的芳环、芳杂环和各类侧链。
2.如权利要求1所述的手性四取代联烯类化合物的合成方法，其特征在于，所述催化剂是手性磷酸；所述催化剂的用量为1-100％。
3.如权利要求1所述的手性四取代联烯类化合物的合成方法，其特征在于，所述反应溶剂是二氯甲烷、氯仿、四氢呋喃、甲醇、1,2-二氯乙烷、乙腈、甲苯、1,4-二氧六环、乙醚、乙酸乙酯、三氟甲苯、二甲苯类化合物或苯甲醚。
4.如权利要求1所述的手性四取代联烯类化合物的合成方法，其特征在于，所述化合物1和化合物2的比例为1:1.2。
5.一种手性四取代联烯类化合物的合成方法，反应过程如以下反应式所示；
Figure 131769DEST_PATH_IMAGE004
在10 mL的试管反应器中，加入0.3 mL的氯仿，将0.05 mmol底物1a、0.06 mmol底物2a、0.0005 mmol CPA依次加入反应管；将反应体系在25 oC下反应1小时；TLC检测反应结束后，直接加硅胶，旋干柱层析，得到3aa。
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