CN115108937A - 含三级立体中心的α-叠氮酮的合成方法 - Google Patents

含三级立体中心的α-叠氮酮的合成方法 Download PDF

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CN115108937A
CN115108937A CN202210854830.5A CN202210854830A CN115108937A CN 115108937 A CN115108937 A CN 115108937A CN 202210854830 A CN202210854830 A CN 202210854830A CN 115108937 A CN115108937 A CN 115108937A
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郭文岗
周英
乐鑫
江枫
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Changzhou University
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Abstract

本发明属于有机合成技术领域，具体公开一种含三级手性中心的α‑叠氮酮的合成方法。在手性催化剂的作用下，对氧化锍叶立德衍生物进行不对称H‑N3插入反应，反应具有良好的收率和对映体选择性。这一有机催化的方法克服了先前文献中报道的α‑叠氮化方法的不足：仅限于构建α‑四级碳手性中心，且主要用于1,3‑二羰基化合物，而本方法则可以用于合成具有三级立体中心的α‑叠氮酮。本发明反应条件温和且无需金属，其不仅可以弥补基于重氮基类羰基化合物无法合成该类重要手性叠氮化合物的不足，而且所获得的产物在有机合成中可以作为重要的手性砌块去合成其他重要的生物活性物质。

Description

含三级立体中心的α-叠氮酮的合成方法
技术领域
本发明所获得的手性产物能够作为有用的有机合成砌块，用于制备生物活性分子、杂环和手性配体，具体涉及一种含三级手性中心的α-叠氮酮的合成方法。
背景技术
有机叠氮化物是一种高附加值的合成砌块，在化学生物学、材料科学和药物化学等领域有着广泛的应用。因此，在过去几十年里，有机叠氮化合物的合成及应用引起了化学工作者极大的研究兴趣。然而目前为止，文献中报道的通过手性催化方法合成的α-羰基叠氮化合物均具有季碳手性中心，含三级手性中心的α-叠氮酮的不对称催化合成方法目前为止仍未有相关的文献报道。这种局限性来源于三级手性中心在羰基及叠氮基团的吸电子诱导效应存在下极易通过烯醇互变异构而消旋化，因此含该类手性中心的α-叠氮酮对酸、碱手性催化剂皆很敏感，进一步造成了其通过不对称催化合成的难度。
虽然Corey课题组在2019年报道了碱性条件下利用手性相转移催化方法合成含三级手性中心的α-叠氮酮(J.Am.Chem.Soc.2019,141,20058–20061)，但其是通过手性中间体的水解而间接获得的。受限于上述提到的稳定性因素，直接通过催化不对称合成方法来获得该类手性化合物目前仍未有相关的文献报道。
发明内容
本申请的目的在于提供一种含三级立体中心α-叠氮酮的合成方法。
含三级立体中心的α-叠氮酮的结构式如下：
Figure BDA0003751555170000021
其中Ar1＝
Figure BDA0003751555170000022
中的任意一种；
X＝Me、OMe、F、
Figure BDA0003751555170000023
中的任意一种取代基；
Figure BDA0003751555170000024
中的任意一种；
Y＝Ph、Me、F、Br、Cl、
Figure BDA0003751555170000025
中的任意一种取代基。
合成方法包括：在催化剂(例如SQ3)的作用下，氧化锍叶立德衍生物与通过原位产生的叠氮化试剂HN3反应生成所述的α-叠氮酮，氧化锍叶立德衍生物(α-羰基氧化锍叶立德)的结构式为
Figure BDA0003751555170000026
本发明采用TMSN3与苯甲酸原位反应来产生叠氮化试剂HN3，其他可原位产生HN3的方法应用于与锍叶立德反应来合成手性α-羰基叠氮化合物均属于本发明内容的逻辑拓展。例如，原位产生的叠氮化试剂HN3的质子源可以为苯甲酸、N-Boc-L-Proline、N-Boc-D-Proline、N-Boc-L-Leucine、N-Boc-D-Leucine、N-Boc-L-tert-Leucine、N-Boc-D-tert-Leucine、N-Boc-L-Valine、N-Boc-D-Valine、H2O、MeOH、HFIP、AcOH、(p-OH)C6H4CO2H、(p-Cl)C6H4CO2H中的任意一种。
本发明的氧化锍叶立德衍生物被原位产生的HN3质子化而形成不稳定的锍鎓离子中间体1'，应用其他稳定的锍鎓离子与叠氮试剂来合成手性α-羰基叠氮化合物均属于本发明内容的逻辑拓展，锍鎓离子中间体1'的结构式为：
Figure BDA0003751555170000031
所用催化剂SQ3为本发明的较优催化剂，结构为：
Figure BDA0003751555170000032
其中Ar＝1-pyrenyl，包括其相应的对应异构体。针对于最优催化剂的结构修饰所获得的任意变种催化剂并应用于氧化锍叶立德衍生物的不对称叠氮化来合成手性叠氮化合物均属于本发明内容的逻辑拓展。
进一步的，还包括如下步骤：将添加有氧化锍叶立德衍生物、质子源、方酸酰胺催化剂和CHCl3的体系冷却至-15～0℃(-15～0℃可以获得收率范围50-95％，ee范围80-95％)；在相同温度下持续搅拌，并加入TMSN3，然后继续在相同的温度下搅拌至反应结束。
从收率和选择性及经济性的角度，进一步优选的，质子源与氧化锍叶立德衍生物的摩尔比为1～2:1，TMSN3与氧化锍叶立德衍生物的摩尔比为1～4:1。
更优选的，更优的反应温度为-15℃，质子源与氧化锍叶立德衍生物的摩尔比为1.1:1；TMSN3与氧化锍叶立德衍生物的摩尔比为2:1。
以质子源为苯甲酸的具体优选制备方法，包括如下步骤：以下式所示的氧化锍叶立德衍生物1、TMSN3和苯甲酸作为原料，在方酸酰胺作为催化剂的条件下合成具有三级立体中心的α-叠氮酮2，反应式如下：
Figure BDA0003751555170000033
具体操作步骤如下：
根据上述反应式，在一个装有磁力搅拌子的4mL玻璃小瓶中，加入氧化锍叶立德衍生物1、苯甲酸、方酸酰胺催化剂和CHCl3。小瓶用可刺穿的螺帽和电工胶带小心密封，然后冷却至-15℃(此温度下可以得到最佳的选择性和收率。温度升高，不影响收率，但是影响ee；温度进一步降低，对Ee有利，但是收率会降低)。在相同温度下搅拌5分钟，加入TMSN3。然后继续在相同的温度下搅拌反应，并用薄层色谱(TLC)监测反应过程。反应完成后，直接进行硅胶柱层析(洗脱液:正己烷/乙酸乙酯＝20:1)，得到所需产物2；
氧化锍叶立德衍生物的用量为0.2mmol；苯甲酸的用量为0.22mmol；方酸酰胺催化剂衍生物的用量为氧化锍叶立德的20mol％；TMSN3的用量为0.4mmol；CHCl3的用量约为1mL。
本发明有以下优点：
1.反应条件温和；
2.反应操作简单，且收率和对映选择性很好；
3.除了上述基础研究价值外，本发明获得的手性产物在配体合成、生物活性化合物的合成方面也具有一定的应用价值。
具体实施方式
在一个装有磁力搅拌子的4毫升小瓶中，加入氧化锍叶立德1(0.2mmol,1.0equiv)、苯甲酸(0.22mmol,1.1equiv)、最优手性催化剂(代号SQ3,27.6mg,0.04mmol,20mol％)和CHCl3(1.0mL)。小瓶用可刺穿的螺帽和电气胶带小心密封，然后冷却至-15℃。在相同温度下搅拌5分钟，加入TMSN3(52.6μL,0.4mmol,2.0equiv)。然后，在相同温度下搅拌，用薄层色谱(TLC)监测反应过程。反应完成后，直接进行硅胶柱层析(洗脱液:正己烷/乙酸乙酯＝20:1)，得到所需产物2。
实施例1：
Figure BDA0003751555170000051
产物为淡黄色油状物(120h,39.4mg,83％yield,90％ee)。
表征数据如下：
[α]D 25:+145.1(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000054
OD-H column；1％i-PrOH in n-hexane；0.5mL/min；retentiontimes:29.3min(major),45.7min(minor).
1H NMR(400MHz,CDCl3)δ7.88(d,J＝7.4Hz,2H),7.50(t,J＝7.4Hz,1H),7.39–7.35(m,7H),5.73(s,1H)ppm.
13C NMR(100MHz,CDCl3)δ194.4,134.3,133.8(two C),129.6,129.4,128.9,128.8,128.3,67.9ppm.
HRMS(ESI-TOF)Calcd for C14H11N3NaO[M+Na]+:260.0800,found:260.0796.
实施例2：
Figure BDA0003751555170000052
产物为白色固体(120h,60.2mg,96％yield,85％ee)。
表征数据如下：
[α]D 25:+133.0(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000053
IC column；3％i-PrOH in n-hexane；1.0mL/min；retention times:13.3min(major),15.5min(minor).
1H NMR(400MHz,acetone-d6)δ7.90(d,J＝8.3Hz,2H),7.56(d,J＝8.0Hz,2H),7.48–7.41(m,5H),7.33–7.26(m,4H),7.21–7.17(m,1H),6.11(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm.
HRMS(ESI-TOF)Calcd for C20H15N3NaO[M+Na]+:336.1113,found:336.1106.
实施例3：
Figure BDA0003751555170000061
产物为白色固体(120h,59.4mg,88％yield,90％ee)。
表征数据如下：
[α]D 25:+133.0(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000062
IC column；3％i-PrOH in n-hexane；1.0mL/min；retention times:13.3min(major),15.5min(minor).
1H NMR(400MHz,acetone-d6)δ7.90(d,J＝8.3Hz,2H),7.56(d,J＝8.0Hz,2H),7.48–7.41(m,5H),7.33–7.26(m,4H),7.21–7.17(m,1H),6.11(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.5,141.8,139.8,134.6,133.9,133.4,129.1,128.94,128.91,128.88,127.9,127.8,126.9,66.9ppm.
HRMS(ESI-TOF)Calcd for C20H15N3NaO[M+Na]+:336.1113,found:336.1106.
实施例4：
Figure BDA0003751555170000063
合成过程见式3(120h,44.7mg,89％yield,88％ee)，产物为淡黄色油状物。表征数据如下：
[α]D 25:+100.5(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000071
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retentiontimes:13.1min(major),19.8min(minor).
1H NMR(400MHz,acetone-d6)δ7.87–7.84(m,2H),7.44–7.40(m,1H),7.32–7.29(m,2H),7.22–7.20(m,2H),7.10–7.08(m,2H),6.00(s,1H),2.13(s,3H)ppm.
13C NMR(100MHz,acetone-d6)δ194.6,139.2,134.6,133.7,131.4,130.1,128.83,128.80,128.4,67.0,20.3ppm.
HRMS(ESI-TOF)Calcd for C15H13N3NaO[M+Na]+:274.0956,found:274.0951.
实施例5：
Figure BDA0003751555170000072
产物为无色油状物(120h,48.8mg,92％yield,85％ee)。
表征数据如下：
[α]D 25:+172.5(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000073
IC column；2％i-PrOH in n-hexane；1.0mL/min；retention times:9.1min(major),11.9min(minor).
1H NMR(400MHz,acetone-d6)δ7.88–7.86(m,2H),7.46–7.42(m,1H),7.34–7.30(m,2H),6.94(s,2H),6.88(s,1H),5.94(s,1H),2.13(s,6H)ppm.
13C NMR(100MHz,acetone-d6)δ194.5,139.0,134.6,134.2,133.7,130.8,128.83,128.79,126.1,67.2,20.4ppm.
HRMS(ESI-TOF)Calcd for C16H15N3NaO[M+Na]+:288.1113,found:288.1109.
实施例6：
Figure BDA0003751555170000081
产物为无色油状物(168h,37.3mg,73％yield,94％ee)。
表征数据如下：
[α]D 25:+119.9(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000082
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retention times:15.6min(major),23.2min(minor).
1H NMR(400MHz,acetone-d6)δ7.88–7.86(m,2H),7.47–7.31(m,5H),7.09–7.04(m,2H),6.13(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.4,163.0(d,1JC-F＝246Hz),134.5,133.9,130.723(d,3JC-F＝8Hz),130.716,128.9(2C),116.3(d,2JC-F＝22Hz),66.3ppm.
19F NMR(376MHz,acetone-d6)δ-113.5ppm.
HRMS(ESI-TOF)Calcd for C14H10FN3NaO[M+Na]+:278.0706,found:278.0702.
实施例7：
Figure BDA0003751555170000083
产物为无色油状物(168h,40.2mg,74％yield,92％ee)。
表征数据如下：
[α]D 25:+83.2(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000084
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retention times:16.4min(major),23.9min(minor).
1H NMR(400MHz,acetone-d6)δ8.05(d,J＝7.4Hz,2H),7.67–7.63(m,1H),7.56–7.51(m,6H),6.33(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.3,134.7,134.4,133.9,133.4,130.2,129.5,128.9(two C),66.3ppm.
HRMS(ESI-TOF)Calcd for C14H1CClNO[M-N3]+:229.0415,found:229.0417.
实施例8：
Figure BDA0003751555170000091
产物为无色油状物(168h,35.4mg,56％yield,91％ee)。
表征数据如下：
[α]D 25:+90.5(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000092
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retention times:16.5min(major),24.4min(minor).
1H NMR(400MHz,acetone-d6)δ8.05–8.03(m,2H),7.67–7.62(m,3H),7.53–7.46(m,4H),6.30(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.2,134.4,133.94,133.90,132.5,130.5,128.9(2C),123.0,66.4ppm.
HRMS(ESI-TOF)Calcd for C14H10BrO[M-N3]+:272.9910,found:272.9911.
实施例9：
Figure BDA0003751555170000093
产物为无色油状物(168h,31.6mg,50％yield,84％ee)。
表征数据如下：
[α]D 25:+68.9(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000094
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retention times:16.8min(major),24.8min(minor).
1H NMR(400MHz,acetone-d6)δ7.92–7.89(m,2H),7.59–7.58(m,1H),7.51–7.44(m,2H),7.39–7.25(m,4H),6.17(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.1,137.0,134.4,134.0,132.3,131.4,131.3,128.94,128.91,127.2,122.7,66.3ppm.
HRMS(ESI-TOF)Calcd for C14H10BrO[M-N3]+:272.9910,found:274.9892.
实施例10：
Figure BDA0003751555170000101
产物为无色油状物(168h,36.1mg,67％yield,96％ee)。
表征数据如下：
[α]D 25:+97.8(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000102
OD-H column；3％i-PrOH in n-hexane；1.0mL/min；retention times:8.6min(major),10.6min(minor).
1H NMR(400MHz,acetone-d6)δ7.78–7.76(m,2H),7.41–7.38(m,2H),7.15–7.05(m,4H),6.08(s,1H),2.20(s,3H)ppm.
13C NMR(100MHz,acetone-d6)δ194.0,163.0(d,1JC-F＝245Hz),144.9,131.9,130.9(d,4JC-F＝3Hz),130.7(d,3JC-F＝9Hz),129.5,129.0,116.2(d,2JC-F＝22Hz),66.1,20.7ppm.
19F NMR(376MHz,acetone-d6)δ-113.7ppm.
HRMS(ESI-TOF)Calcd for C15H12FN3NaO[M+Na]+:292.0862,found:292.0859.
实施例11：
Figure BDA0003751555170000111
产物为无色油状物(168h,47.4mg,83％yield,94％ee)。
表征数据如下：
[α]D 25:+107.9(c＝2.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000112
IC column；10％i-PrOH in n-hexane；1.0mL/min；retention times:10.4min(major),13.6min(minor).
1H NMR(400MHz,acetone-d6)δ7.87–7.83(m,2H),7.41–7.38(m,2H),7.08–7.04(m,2H),6.85–6.81(m,2H),6.02(s,1H),3.69(s,3H)ppm.
13C NMR(100MHz,acetone-d6)δ192.8,164.2,163.0(d,1JC-F＝245Hz),131.3,131.2(d,4JC-F＝3Hz),130.6(d,3JC-F＝8Hz),127.1,116.2(d,2JC-F＝22Hz),114.1,65.8,55.2ppm.
19F NMR(376MHz,acetone-d6)δ-113.7ppm.
HRMS(ESI-TOF)Calcd for C15H12FN3NaO2[M+Na]+:308.0811,found:308.0809.
实施例12：
Figure BDA0003751555170000113
产物为无色油状物(168h,53.1mg,87％yield,96％ee)。
表征数据如下：
[α]D 25:+100.6(c＝1.5,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000114
IC column；3％i-PrOH in n-hexane；1.0mL/min；retention times:12.3min(major),15.9min(minor).
1H NMR(400MHz,acetone-d6)δ7.79(s,1H),7.14–7.11(m,2H),7.07–7.01(m,2H),6.76–6.66(m,4H),6.33–6.28(m,2H),5.59(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.6,163.0(d,1JC-F＝246Hz),135.7,132.4,131.7,131.2,130.84,130.75(d,3JC-F＝9Hz),129.7,129.2,128.8,127.8,127.2,123.9,116.3(d,2JC-F＝22Hz),66.3ppm.
19F NMR(376MHz,acetone-d6)δ-113.4ppm.
HRMS(ESI-TOF)Calcd for C18H12FN3NaO[M+Na]+:328.0862,found:328.0858.
实施例13：
Figure BDA0003751555170000121
产物为无色油状物(168h,52.7mg,79％yield,91％ee)。
表征数据如下：
[α]D 25:+164.9(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000122
OD-H column；1％i-PrOH in n-hexane；1.0mL/min；retention times:13.0min(major),23.6min(minor).
1H NMR(400MHz,acetone-d6)δ7.67–7.66(m,2H),7.59–7.54(m,2H),7.25–7.21(m,3H),6.27(s,1H),2.32(s,6H)ppm.
13C NMR(100MHz,acetone-d6)δ194.7,163.0(d,1JC-F＝246Hz),138.6,135.4,134.7,130.9(d,4JC-F＝3Hz),130.7(d,3JC-F＝9Hz),126.6,116.2(d,2JC-F＝22Hz),66.1,20.2ppm.
19F NMR(282MHz,acetone-d6)δ-113.6ppm.
HRMS(ESI-TOF)Calcd for C16H14FO[M-N3]+:241.1023,found:241.1026.
实施例14：
Figure BDA0003751555170000131
产物为无色油状物(168h,40.2mg,54％yield,87％ee)。
表征数据如下：
[α]D 25:+80.9(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000132
IC column；1％i-PrOH in n-hexane；1.0mL/min；retention times:16.7min(major),18.2min(minor).
1H NMR(400MHz,acetone-d6)δ8.07–8.05(m,2H),7.66–7.64(m,2H),7.59–7.49(m,6H),7.46–7.43(m,3H),6.33(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ193.5,134.8,133.7,133.3,131.7,131.6,130.3,130.0,129.2,129.1,128.7,128.6,122.3,92.9,88.1,66.4ppm.
HRMS(ESI-TOF)Calcd for C22H14ClO[M-N3]+:329.0728,found:329.0727.
实施例15：
Figure BDA0003751555170000133
产物为无色油状物(168h,39.9mg,82％yield,88％ee)。
表征数据如下：
[α]D 25:+140.6(c＝1.0,CH2Cl2).HPLC analysis of the product:Daicel
Figure BDA0003751555170000134
OD-H column；5％i-PrOH in n-hexane；1.0mL/min；retention times:11.2min(major),13.7min(minor).
1H NMR(400MHz,acetone-d6)δ7.81–7.78(m,2H),7.41–7.39(m,2H),7.35–7.26(m,3H),7.04–7.02(m,1H),5.92(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ187.5,141.0,135.7,134.8,134.3,129.4,129.3,128.7,128.3 67.5ppm.
HRMS(ESI-TOF)Calcd for C12H9OS[M-N3]+:201.0369,found:201.0374.
实施例16：
Figure BDA0003751555170000141
产物为无色油状物(168h,25.5mg,52％yield,89％ee)。
表征数据如下：
[α]D 25:+77.6(c＝0.5,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000142
OD-H column；3％i-PrOH in n-hexane；1.0mL/min；retention times:9.5min(major),11.3min(minor).
1H NMR(400MHz,acetone-d6)δ7.91–7.90(m,1H),7.61–7.58(m,2H),7.51(d,J＝6.4Hz,1H),7.29–7.24(m,2H),6.71–6.69(m,1H),6.01(s,1H)ppm.13C NMR(100MHz,acetone-d6)δ182.5,163.1(d,1JC-F＝245Hz),150.2,148.4,130.7(d,4JC-F＝3Hz),130.6(d,3JC-F＝9Hz),120.1,116.1(d,2JC-F＝22Hz),112.7,65.9ppm.
19F NMR(282MHz,acetone-d6)δ-113.7ppm.
HRMS(ESI-TOF)Calcd for C12H8FO2[M-N3]+:203.0503,found:203.0506.
实施例17：
Figure BDA0003751555170000143
产物为无色油状物(120h,43.7mg,76％yield,77％ee)。
表征数据如下：
1H NMR(400MHz,acetone-d6)δ8.09–8.07(m,2H),8.03–8.00(m,2H),7.96–7.91(m,2H),7.65–7.63(m,1H),7.58–7.52(m,3H),7.47–7.44(m,2H),6.42(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ194.5,134.6,133.8,133.43,133.42,132.0,129.5,128.9,128.8,128.2,128.0,127.8,127.0,126.8,125.7,67.4ppm.
HRMS(ESI-TOF)Calcd for C18H13N3NaO[M+Na]+:310.0956,found:310.0954.
实施例18：
Figure BDA0003751555170000151
产物为无色油状物(168h,23.5mg,46％yield,67％ee)。
表征数据如下：
[α]D 25:+58.3(c＝1.0,CHCl3).HPLC analysis of the product:Daicel
Figure BDA0003751555170000152
OD-H column；3％i-PrOH in n-hexane；1.0mL/min；retention times:9.8min(major),11.4min(minor).
1H NMR(400MHz,acetone-d6)δ8.13–8.08(m,2H),7.50–7.39(m,5H),7.26–7.21(m,2H),6.21(s,1H)ppm.
13C NMR(100MHz,acetone-d6)δ193.1,165.8(d,1JC-F＝253Hz),134.3,131.9(d,3JC-F＝9Hz),131.2(d,4JC-F＝3Hz),129.5,129.3,128.5,115.8(d,2JC-F＝22Hz),67.2ppm.
19F NMR(376MHz,acetone-d6)δ-105.8ppm.
HRMS(ESI-TOF)Calcd for C14H10FO[M-N3]+:213.0710,found:213.0713.
应用例：
Figure BDA0003751555170000161
手性氨基醇是一类重要的医药中间体，同时也是一种重要的手性配体广泛地应用于手性合成化学(Chem.Rev.1996,96,835-875；J.Med.Chem.2005,48,4220-4223)。为了展示本发明获得的手性叠氮化合物可以转化为此类重要的化合物，本发明采用以下应用例进行说明：
1)按照上图所示，首先制备2.0mmol级别的α-叠氮酮(R)-2b。
2)通过Pd/C催化加氢和Boc保护形成α-氨基酮3。向25mL圆底烧瓶中添加2b(62mg,0.2mmol,95％ee after re-crystallization)，Pd/C(10％on charcoal wetted withca.55％water,12.4mg,20wt％)和乙酸乙酯(2.0mL)。使用真空泵将混合物脱气三次，充入N2。然后，通过注射器将Boc2O(56mL，0.24mmol，1.2equiv)添加到反应混合物中。将所得悬浮液在0℃下搅拌10分钟，将反应气氛更改为H2(气球)并搅拌1小时。接下来，通过硅藻土过滤，并用乙酸乙酯(10mL)清洗滤饼。减压下浓缩滤液、通过硅胶柱层析法纯化(洗脱液：正己烷/乙酸乙酯＝20:1至10:1)，获得无色固体产物3(67.4mg,87％yield,93％ee)。值得注意的是，经化合物3的单晶衍射可确定本发明产物的绝对构型。
3)进一步非对映选择还原3生成氨基醇4。在-20℃的N2条件下，向手性α-氨基酮3(0.2mmol，77.5mg，93％ee)的无水甲醇(2.0mL)溶液中缓慢加入NaBH4(0.6mmol，22.7mg，3.0equiv)。在相同温度下搅拌，直到氨基酮3完全转化(约5小时)。然后，通过缓慢添加水(5.0mL)小心地淬灭反应混合物，并用乙酸乙酯萃取三次(3*10mL)，再用饱和NaCl水溶液(5mL)洗涤合并的有机层，并用无水Na2SO4进行干燥。过滤后，浓缩滤液以获得粗产物，并通过1H NMR分析确定d.r.值，最后通过硅胶柱层析进一步纯化粗产物，得到1,2-氨基醇产物4(60.8mg,78％yield,91％ee)。
本发明所获得的手性叠氮化合物经铜催化的click反应可转化成相应的手性三氮唑类杂环化合物。值得注意的是研究证明含三级手性中心的α-羰基三氮唑类化合物具有一定的抗肿瘤活性(Eur.J.Med.Chem.2010,45,5044-5050；ARKIVOC 2012,279-296)，但受限于相关不对称催化合成方法的制约，目前为止尚未有含三级手性中心的α-羰基三氮唑类化合物的手性合成报道，故人们无法进一步探究手性中心的构型与药物活性之间的关系。基于此，本发明展示了所获得的手性叠氮化合物可以转化成相关的手性三氮唑杂环化合物：
4)手性三唑5的合成：在25mL单颈圆底烧瓶中加入2b(62mg,0.2mmol,87％ee)和MeOH(1.0mL)。将得到的悬浮液冷却到0℃。再加入一份NaBH4(9.1mg,0.24mmol,1.2equiv)。反应混合物在相同温度下搅拌，直到2b完全转化。反应完成后(1.0h)，加入几滴HCl(1M)以淬灭反应，并用Et2O(3×10mL)萃取混合物。将组合的有机层用盐水(10ml)洗涤，在无水Na2SO4上干燥，过滤，真空浓缩，得到粗制的β-叠氮醇，无需进一步纯化，直接用于下一步。
在N2条件下，将粗制的β-叠氮醇(0.2mmol)、CuSO4·5H2O(10.0mg,0.04mmol,20mol％)、抗坏血酸钠(16.0mg,0.08mmol,0.4equiv)、tBuOH(1.6mL)和H2O(0.8mL)装入10mL小瓶。在剧烈搅拌下，加入苯基乙炔(24.4mg,0.24mmol,1.2equiv)。在此期间，反应混合物的颜色变成黄色。反应混合物在40℃下搅拌24小时，然后用DCM(10mL)稀释，硅藻土过过滤、DCM(10mL)洗涤滤饼，将合并的有机层浓缩得到β-羟基三唑中间体，直接用于下一步操作，无需进一步纯化。
将粗制的β-羟基三唑(0.2mmol)溶于无水DCM(2.0mL)中，冷却至0℃。再加入DMP(127mg,0.3mmol,1.5equiv)。在相同温度下搅拌反应混合物，直到β-羟基三氮唑完全转化。反应完成后(约3小时)，加入NaHCO3水溶液(10mL,1.0M)，使反应淬灭。然后用DCM(3×5mL)萃取反应混合物。将合并的有机层用盐水(10mL)洗涤，用Na2SO4干燥，过滤，浓缩，得到粗产物。粗产品经硅胶柱层析法纯化(洗脱液:正己烷/乙酸乙酯＝5:1至3:1)，得到无色固体5(58.2mg，70％yield，86％ee)。
比较例：
例1：其他类型催化剂对本发明反应结果的影响—手性磷酸
Figure BDA0003751555170000181
Figure BDA0003751555170000182
a Determined by crude 1H NMR anaylsis using CH2Br2 as an internalstandard.All the reactions described above provided clean conversion.bDetermined by Chiral HPLC analysis.
例2：其他类型催化剂对本发明反应结果的影响—其他氢键催化剂
Figure BDA0003751555170000191
Figure BDA0003751555170000192
a Determined by crude 1H NMR anaylsis using CH2Br2 as an internalstandard.b Determined by Chiral HPLC analysis.c The reaction gave a messymixture,likely due to the incompatibility of the reaction with the basiccinchona alkaloid functionality.
从以上两则比较例可以看出，本发明中采用的SQ3催化剂在对目标反应的立体选择性控制中具有显著的优势；同时由于本发明反应条件比较温和，产物的光学纯度不会受到消旋化的影响(产物由于受羰基以及叠氮基的吸电子性影响，对酸碱敏感而易消旋化)。
例3：手性质子源对本发明反应结果的影响—氨基酸作为手性质子
Figure BDA0003751555170000201
Figure BDA0003751555170000202
a Determined by crude 1H NMR analysis using CH2Br2 as an internalstandard.b Determined by chiral HPLC analysis.c ent-SQ3 was used as thecatalyst.
例4：其他非手性质子源对本发明反应结果的影响—醇、羧酸作为质子源
Figure BDA0003751555170000211
Figure BDA0003751555170000212
Reaction scale:1a(0.1mmol),TMSN3(0.2mmol),proton source(0.11mmol),SQ3(0.01mmol),solvent(0.5mL),24h.Yield was determined by 1H NMR spectra of thecrude mixture using CH2Br2as an internal standard.Ee was determined by HPLC ona chiral stationary phase.
从以上两则比较例可以看出，质子源的种类只影响反应的收率(或者转化率)，而对产物的立体选择性没有明显影响，从侧面证明了质子源只是与TMSN3反应来产生HN3，而不参与立体化学控制过程。

Claims (4)

1.一种含三级立体中心的α-叠氮酮的合成方法，其特征在于，所述的α-叠氮酮具有一个手性中心，结构式如下：
Figure FDA0003751555160000011
其中
Figure FDA0003751555160000012
Figure FDA0003751555160000013
中的任意一种；
X＝Me、OMe、F、
Figure FDA0003751555160000014
中的任意一种取代基；
Figure FDA0003751555160000015
中的任意一种；
Y＝Ph、Me、F、Br、Cl、
Figure FDA0003751555160000016
中的任意一种取代基；
合成方法包括：在方酸酰胺催化剂的作用下，氧化锍叶立德衍生物与通过原位产生的叠氮化试剂HN3反应生成所述的α-叠氮酮，所述方酸酰胺催化剂结构式为
Figure FDA0003751555160000017
其中Ar＝1-pyrenyl，包括其相应的对应异构体；
氧化锍叶立德衍生物的结构式为
Figure FDA0003751555160000018
2.根据权利要求1所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，原位产生的叠氮化试剂HN3的质子源为苯甲酸、N-Boc-L-Proline、N-Boc-D-Proline、N-Boc-L-Leucine、N-Boc-D-Leucine、N-Boc-L-tert-Leucine、N-Boc-D-tert-Leucine、N-Boc-L-Valine、N-Boc-D-Valine、H2O、MeOH、HFIP、AcOH、(p-OH)C6H4CO2H、(p-Cl)C6H4CO2H中的任意一种。
3.根据权利要求2所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，还包括如下步骤：将添加有氧化锍叶立德衍生物、质子源、方酸酰胺催化剂和CHCl3的体系冷却至-15～0℃；在相同温度下持续搅拌，并加入TMSN3，然后继续在相同的温度下搅拌至反应结束。
4.根据权利要求3所述的含三级立体中心的α-叠氮酮的合成方法，其特征在于，质子源与氧化锍叶立德衍生物的摩尔比为1～2:1；TMSN3与氧化锍叶立德衍生物的摩尔比为1～4:1。
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WO2024017221A1 (zh) * 2022-07-18 2024-01-25 常州大学 含三级立体中心的α-叠氮酮的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821277A (en) * 1964-10-30 1974-06-28 Basf Ag Ypsilon-methoxy-ypsilon-carbanilino-alpha,omega-dicyanopentane

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115108937B (zh) * 2022-07-18 2023-08-22 常州大学 含三级立体中心的α-叠氮酮的合成方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3821277A (en) * 1964-10-30 1974-06-28 Basf Ag Ypsilon-methoxy-ypsilon-carbanilino-alpha,omega-dicyanopentane

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DAVID PHILIP DAY等: "Direct Synthesis of α‐Fluoro-α-Triazol-1-yl Ketones from Sulfoxonium Ylides: A One-Pot Approach", 《J. ORG. CHEM.》, vol. 86, pages 12427 *
HU ZHANG等: "Enantioselective Selenocyclization via Dynamic Kinetic Resolution of Seleniranium Ions by Hydrogen-Bond Donor Catalysts", 《J. AM. CHEM. SOC.》, vol. 136, pages 16485 *
M.VENKAT RAM REDDY等: "A One Step Conversion of Olefins into a-Azidoketones using Azidotrimethylsilane-Chromium Trioxide Reagent System", 《TETRAHEDRON LETTERS》, vol. 36, no. 37, pages 6751 - 6754, XP027445924, DOI: 10.1016/00404-0399(50)1332-C *
MOHAMMAD NAVID SOLTANI RAD等: "A simple one-pot procedure for the direct conversion of alcohols into azides using TsIm", 《TETRAHEDRON LETTERS》, vol. 48, pages 3445, XP022031974, DOI: 10.1016/j.tetlet.2007.03.049 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024017221A1 (zh) * 2022-07-18 2024-01-25 常州大学 含三级立体中心的α-叠氮酮的合成方法

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