CN114516881B - 一种氮杂环卡宾催化的含吡唑并吡喃骨架手性化合物及制备方法 - Google Patents

一种氮杂环卡宾催化的含吡唑并吡喃骨架手性化合物及制备方法 Download PDF

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CN114516881B
CN114516881B CN202210220563.6A CN202210220563A CN114516881B CN 114516881 B CN114516881 B CN 114516881B CN 202210220563 A CN202210220563 A CN 202210220563A CN 114516881 B CN114516881 B CN 114516881B
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金智超
杨小群
孙俊
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Guizhou University
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Abstract

本发明公开一类手性化合物吡唑并吡喃衍生物，其特征在于：所述的衍生物如下述通式(1)表示：其中标有*的碳原子为手性碳原子，R1为烷基、卤原子，R2为卤原子、烷基、烷氧基或苯基，R3为烷基、氢原子、羰基，R3为烷基、苯基或取代苯基。本发明公开的α‑氯代醛和吲哚取代的吡唑酮的不对称环化反应制备吲哚螺环骨架手性化合物吡唑并吡喃衍生物，其衍生物普适性好，具有良好的产率高达99％、对映选择性高达99:1和良好的放大反应。

Description

一种氮杂环卡宾催化的含吡唑并吡喃骨架手性化合物及制备 方法
技术领域
本发明涉及一种氮杂环卡宾有机小分子催化合成含吡唑并吡喃骨架手性化合物的制备方法研究。
背景技术
吡唑并吡喃类衍生物常存在于天然产物和非天然化合物中，具有良好的生物活性。含吡唑并吡喃核的各种分子在抗病毒、抗菌、抗真菌、抗癌和农药等方面得到了广泛的研究。因此，吡唑并吡喃类化合物的合成受到了广泛的关注。开发高效、高立体选择性的手性吡唑并吡喃衍生物的制备方法具有重要的应用价值。
发明内容
本发明的目的是为了设计合成出一类结构新颖、底物普适性好和高对映选择性的吡唑并吡喃骨架手性化合物。
本发明的技术方案：一类手性化合物吡唑并吡喃衍生物，如下述通式(1)表示：
其中标有*的碳原子为手性碳原子，R1为烷基、卤原子，R2为卤原子、烷基、烷氧基或苯基，R3为烷基、氢原子、羰基，R4为烷基、苯基或取代苯基。
所述的取代苯基为苯环的取代基为卤素、甲基、甲氧基或萘基。
所述卤原子为氟、氯、溴。
通过采用上述技术方案，本发明以吡唑并吡喃类化合物为基础，将能够提高目标化合物生物活性的氮杂环基引入到此体系中，合成一系列含吡唑并吡喃骨架类化合物，且发现该化合物对致病病原细菌具有良好的抑制作用，针对病原细菌柑橘溃疡病菌(Xanthomonas axonopodis pv.citri,Xac)具有良好的抑制效果，为新农药的研发和创制提供重要的科学基础。
所述的手性化合物吡唑并吡喃衍生物的制备方法，其特征在于：包括以下步骤：
(1)取代α-氯代醛与手性卡宾催化剂反应得到中间体I,氯原子离去得到酰基唑鎓中间体II,进一步在碱性条件下得到烯醇式中间体ⅠII；
(2)由吲哚取代的吡唑酮和中间体III发生加成反应，得到中间体IV；
(3)步骤(2)发生分子内酯化反应，卡宾催化剂离去生成手性化合物吡唑并吡喃衍生物。
反应通式及过程如下：
所述的吲哚取代的吡唑酮类底物的合成路线如下：将取代的靛红S1溶解于N,N-二甲基甲酰胺中，0℃下缓慢加入氢化钠，然后滴加碘甲烷，转至常温反应，TLC监测反应完毕后，加饱和氯化铵溶液调节体系PH至中性，乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，抽滤旋干得到产物S2；将S2溶解于乙酸溶液中，加入乙酸钠和吡唑酮，回流反应，监测反应情况，反应完毕后，乙酸乙酯萃取3次，有机层用无水硫酸钠干燥，抽滤，滤液旋干，用石油醚:乙酸乙酯作洗脱剂过柱纯化即得S3；
本发明的具体制备内容如下：
(1)催化合成的手性化合物吡唑并吡喃衍生物
(2)对合成的吡唑并吡喃衍生物进行放大及转化反应研究
本发明的有益效果：以常见的α-氯代醛和修饰的吡唑酮为原料，通过氮杂环卡宾(NHC)催化合成了一系列具有高立体选择性的手性吡唑并吡喃类化合物，发现其有很好的普适性和良好的转化性。利用有机小分子催化合成这一类吡唑并吡喃骨架是一种全新的、高效的手性合成方法，在新农药创制及绿色手性农药创制方面具有潜在的应用前景，对于新结构在农药上的开发，我们提供了一种全新高效的解决方案和合成策略。
具体制备实施方式
以下介绍本发明的实施例，介绍26个制备实施例及放大转化反应研究，并对一系列制备化合物进行抗菌活性评估。
总实施例
(1)制备吡唑并吡喃衍生物的合成路线：
制备实施方法和条件如下：
分别称取0.12mmol取代α-氯代醛1、0.10mmol取代吡唑酮2、0.05mmol的氮杂环卡宾催化剂，加入放有磁力搅拌子的4mL反应瓶中，于抽真空且充满氮气的手套箱加入2mL溶剂1，4-二氧六环和0.12mmol碳酸铯，轻轻晃动反应瓶，使其充分混匀，盖上瓶盖，取出手套箱并置于30℃油浴中充分搅拌反应12h。TLC监测反应完毕后，旋干，少量二氯甲烷充分溶解后湿法上样，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝4:1得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪NMR，高分辨质谱仪HRMS和高效液相色谱仪HPLC予以表征。
(2)对合成的手性吡唑并吡喃衍生物进行放大及转化反应研究：
得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪NMR，高分辨质谱仪HRMS和高效液相色谱仪HPLC予以表征。
对合成的化合物实验表征如下：
[α]25 D ＝-101.4(c＝0.5in CHCl3)；8:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.6Hz,2H),7.48–7.38(m,3H),7.30(d,J＝7.4Hz,1H),7.23–7.08(m,6H),7.03(d,J＝6.8Hz,3H),6.92(d,J＝7.8Hz,1H),3.87(dd,J＝7.8,5.7Hz,1H),3.12(s,3H),3.03(dd,J＝14.4,8.0Hz,1H),2.31(dd,J＝14.4,5.7Hz,1H),1.83(s,3H).
13CNMR(101MHz,CDCl3)δ174.9,167.3,146.9,144.3,142.9,137.4,137.0,129.7,129.3,129.2,128.2,127.7,126.8,124.1,123.7,121.1,108.8,98.4,49.7,47.3,32.5,26.6,12.4.
HRMS(ESI,m/z):calcd.for C28H23N3O3H+[M+H]+:450.1812,found 450.1807；
HPLC analysis:>99:1 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝30.6min,Rt(minor)＝24.9min.
[α]13 D ＝-6.2(c＝0.5in CHCl3)；1:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ9.21(d,J＝12.8Hz,1H),7.78–7.75(m,2H),7.49–7.45(m,1H),7.39(dd,J＝10.8,5.2Hz,2H),7.31(dd,J＝8.6,5.6Hz,2H),7.22(dd,J＝11.2,4.4Hz,2H),7.00–6.92(m,3H),5.37(d,J＝12.8Hz,1H),3.38–3.34(m,1H),3.36(s,3H).2.70(d,J＝13.8Hz,1H),1.38(s,3H).
13C NMR(101MHz,CDCl3)δ178.0,162.4(d,J＝247.5Hz),147.9,145.4,144.2,138.2,133.1(d,J＝8.1Hz),130.1,129.3,128.9,128.75(d,J＝3.0Hz),127.4,126.0,124.0,120.9,114.86(d,J＝21.2Hz),108.9,101.0,94.4,70.1,56.8,39.0,27.1,12.5.
19F NMR(377MHz,CDCl3)δ-114.91.
HRMS(ESI,m/z):calcd.for C28H22FN3O3H+[M+H]+:468.1718,found 468.1725；
HPLC analysis:88:12 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝60.5min,Rt(minor)＝39.3min.
[α]13 D ＝10.7(c＝0.5in CHCl3)；2:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.49–7.40(m,3H),7.29(dd,J＝7.0,4.2Hz,2H),7.22(t,J＝7.4Hz,1H),7.13(d,J＝8.4Hz,2H),6.97(dd,J＝19.1,8.0Hz,3H),3.39(dd,J＝8.8,2.4Hz,1H),3.27(s,3H),3.09(dd,J＝14.0,8.8Hz,1H),2.21(dd,J＝14.0,2.4Hz,1H),1.49(s,3H).
13CNMR(101MHz,CDCl3)δ175.0,166.4,147.6,144.9,144.6,137.4,137.2,132.4,130.4,130.2,129.2,128.4,127.0,126.9,124.0,123.7,121.2,109.2,97.4,50.3,49.2,30.5,26.6,12.7.
HRMS(ESI,m/z):calcd.for C28H22ClN3O3H+[M+H]+:484.1422,found 484.1424.
HPLC analysis:91:9er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝52.6min,Rt(minor)＝37.8min.
[α]13 D ＝-18.2(c＝1.0in CHCl3)；2:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.2Hz,2H),7.45–7.36(m,3H),7.31(dd,J＝10.9,8.0Hz,2H),7.22–7.01(m,4H),6.90(t,J＝8.6Hz,2H),3.87–3.81(m,1H),3.13(d,J＝13.2Hz,3H),3.05–3.93(m,1H),2.33–2.23(m,1H),1.83(s,3H).
13C NMR(101MHz,CDCl3)δ174.9,167.2,146.8,144.2,142.8,137.3,137.0,136.0,131.2,129.8,129.3,128.2,127.5,126.9,124.1,123.8,121.1,108.9,98.3,49.7,47.2,32.1,26.6,12.5.
HRMS(ESI,m/z):calcd.for C28H22BrN3O3H+[M+H]+:528.0917,found 528.0920.
HPLC analysis:>99:1er(IF column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝42.3min,Rt(minor)＝47.6min.
率,35.6mg,熔点98-99℃.
[α]14 D ＝-30.0(c＝1.0in CHCl3)；3:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.45–7.36(m,3H),7.29(d,J＝7.4Hz,1H),7.14–7.07(m,2H),6.91(dd,J＝8.1,5.8Hz,3H),6.74(d,J＝8.6Hz,2H),3.81(dd,J＝7.8,5.8Hz,1H),3.75(s,3H),3.13(s,3H),2.97(dd,J＝14.5,7.8Hz,1H),2.27(dd,J＝14.5,5.8Hz,1H),1.83(s,3H).
13C NMR(101MHz,CDCl3)δ175.0,167.4,158.4,147.0,144.0,143.0,137.4,130.4,129.6,129.2,128.9,127.7,126.8,124.1,123.7,121.1,113.6,108.8,98.4,55.3,49.7,47.5,31.7,26.6,12.5.
HRMS(ESI,m/z):calcd.for C29H25N3O4H+[M+H]+:480.1918,found 480.1924.
HPLC analysis:97:3 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝65.3min,Rt(minor)＝56.6min.
[α]14 D ＝-50.7(c＝1.0in CHCl3)；9:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.46–7.40(m,3H),7.30(d,J＝7.4Hz,1H),7.18–7.09(m,3H),6.97–6.90(m,3H),6.78(t,J＝7.6Hz,1H),4.00(t,J＝7.0Hz,1H),3.18(dd,J＝14.7,7.0Hz,1H),3.04(s,3H),2.40(dd,J＝14.6,7.2Hz,1H),1.81(s,3H).
13C NMR(101MHz,CDCl3)δ174.6,167.3,161.59(d,J＝247.5Hz),146.8,144.3,143.0,137.3,131.52(d,J＝4.0Hz),129.7,129.3,128.92(d,J＝8.1Hz),127.4,126.8,124.1,123.86(d,J＝5.0Hz),123.7,123.55(d,J＝4.0Hz),121.1,115.30(d,J＝21.2Hz),108.9,98.2,49.4,45.2,26.6,26.5,12.5.
19F NMR(377MHz,CDCl3)δ-115.63.
HRMS(ESI,m/z):calcd.for C28H22FN3O3H+[M+H]+:468.1718,found 468.1719.
HPLC analysis:>99:1 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝45.7min,Rt(minor)＝41.7min.
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.4Hz,2H),7.45–7.37(m,3H),7.20–7.36(m,1H),7.15–7.12(m,2H),7.07(d,J＝4.0Hz,2H),6.97–6.93(m,1H),6.88(d,J＝7.8Hz,1H),6.62(d,J＝7.4Hz,1H),3.96(t,J＝7.2Hz,1H),3.17(dd,J＝14.4,6.8Hz,1H),2.97(s,3H),2.44(dd,J＝14.8,7.6Hz,1H),2.20(s,3H),1.80(s,3H).
13C NMR(101MHz,CDCl3)δ174.7,167.5,146.9,144.3,143.1,137.4,137.4,134.4,130.5,130.3,129.7,129.3,127.8,127.2,126.8,125.4,124.2,123.6,121.1,109.0,98.4,49.5,44.7,30.6,26.4,19.4,12.5.
HRMS(ESI,m/z):calcd.for C29H24N3O3Na+[M+Na]+:486.1788,found 486.1789.
HPLC analysis:>99:1 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝47.5min,Rt(minor)＝31.8min.
氢吲哚-3,4'-吡喃并[2,3-c]吡唑]-2,6'(5'氢)-二酮
取代基R1为苯氢,R2为间氯，R3为甲基,R4为苯基，制备实施方法和条件同实施例I；白色固体,>99％产率,48.2mg,熔点120-121℃.
[α]14 D ＝5.9(c＝1.0in CHCl3)；>20:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.70–7.67(m,2H),7.45–7.38(m,4H),7.29(d,J＝7.4Hz,1H),7.16–7.11(m,3H),6.95–6.90(m,3H),3.85(dd,J＝7.6,5.8Hz,1H),3.15(s,3H),3.00(dd,J＝14.4,7.8Hz,1H),2.27(dd,J＝14.6,6.0Hz,1H),1.83(s,3H).
13C NMR(101MHz,CDCl3)δ174.8,167.2,146.8,144.3,142.8,139.1,137.3,133.8,129.9,129.5,129.3,129.2,127.6,127.4,127.1,126.9,124.0,123.9,121.1,109.0,98.4,49.7,47.1,32.2,26.6,12.4.
HRMS(ESI,m/z):calcd.for C32H25N3O3H+[M+H]+:484.1422,found 484.1420.
HPLC analysis:98:2er(IB column,25℃,hexanes/iso-propanol＝82:18,0.5mL/min,λ＝254nm)Rt(major)＝19.7min,Rt(minor)＝22.5min.
[α]14 D ＝-71.3(c＝1.0in CHCl3)；14:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.70–7.67(m,2H),7.45–7.38(m,3H),7.31–7.29(m,2H),7.15–7.00(m,5H),6.95(d,J＝7.8Hz,1H),3.85(dd,J＝7.6,6.0Hz,1H),3.14(s,3H),3.01(dd,J＝14.5,7.6Hz,1H),2.27(dd,J＝14.6,6.0Hz,1H),1.83(s,3H).
13C NMR(101MHz,CDCl3)δ174.8,167.2,146.8,144.3,142.7,139.3,137.3,132.4,130.0,129.8,129.8,129.3,128.1,127.4,126.9,124.0,123.8,122.0,121.1,109.0,98.3,49.6,47.0,32.3,26.6,12.4.
HRMS(ESI,m/z):calcd.for C28H22BrN3O3H+[M+H]+:528.0917,found 528.0918.
HPLC analysis:92:8er(IF column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝24.0min,Rt(minor)＝22.8min.
[α]14 D ＝-9.2(c＝0.2in CHCl3)；6:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.59(d,J＝7.4Hz,2H),7.36–7.27(m,4H),7.21–7.17(m,2H),7.05–6.98(m,3H),6.88(d,J＝7.6Hz,1H),6.81(d,J＝7.8Hz,1H),6.75–6.70(m,2H),3.78(dd,J＝7.8,5.6Hz,1H),3.01(s,3H),2.90(dd,J＝14.4,7.8Hz,1H),2.22–2.11(m,2H),2.17(s,3H),1.74(s,3H).
13C NMR(101MHz,CDCl3)δ175.0,167.4,147.0,144.3,142.9,137.7,137.4,136.9,130.1,129.7,129.3,128.1,127.7,127.6,126.9,126.5,124.1,123.7,121.1,108.8,98.4,49.7,47.3,32.5,26.5,21.3,12.4.
HRMS(ESI,m/z):calcd.for C29H25N3O3H+[M+H]+:464.1969,found 464.1970.
HPLC analysis:94:6er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝48.0min,Rt(minor)＝34.6min.
产率,46.2mg,熔点92-93℃.
[α]14 D ＝92.4(c＝1.0in CHCl3)；>20:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.8Hz,2H),7.36–7.28(m,3H),7.20–7.16(m,2H),7.04–6.98(m,3H),6.81(d,J＝7.8Hz,1H),6.63–6.60(m,1H),6.52–6.46(m,2H),3.79(dd,J＝7.6,5.8Hz,1H),3.64(s,3H),3.02(s,3H),2.93(dd,J＝14.4,7.6Hz,1H),2.20(dd,J＝14.4,6.0Hz,1H),1.74(s,3H).
13C NMR(101MHz,CDCl3)δ174.9,167.4,159.4,147.0,144.3,142.9,138.5,137.4,129.7,129.3,129.2,127.6,126.8,124.1,123.7,121.6,121.1,114.6,112.7,108.9,98.4,55.1,49.7,47.2,32.6,26.5,12.5.
HRMS(ESI,m/z):calcd.for C32H25N3O3H+[M+H]+:502.1737,found 502.1733.
HPLC analysis:>99:1er(IF column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝32.3min,Rt(minor)＝37.9min.
[α]3 D ＝215.3(c＝1.0in CHCl3)；4:1dr(reaction mixture).
1H NMR(400MHz,Chloroform-d)δ7.83–7.78(m,2H),7.71–7.68(m,3H),7.47–7.39(m,5H),7.29–7.25(m,2H),7.17(d,J＝4.0,2H),7.03(d,J＝7.0Hz,1H),6.87(d,J＝7.8Hz,1H),4.16(t,J＝7.0Hz,1H),3.56(dd,J＝14.8,1H),2.95(s,3H),2.90(dd,J＝14.8,7.0Hz,1H),1.79(s,3H).
13C NMR(101MHz,Chloroform-d)δ174.4,167.5,146.9,144.2,143.1,137.4,133.7,132.3,131.9,129.8,129.3,128.9,128.4,128.1,127.6,126.9,126.4,125.6,124.9,124.1,123.8,123.3,121.1,109.0,98.6,49.5,45.8,29.8,26.4,12.4.
HRMS(ESI,m/z):calcd.for C32H25N3O3Na+[M+Na]+:522.1788,found 522.1790.
HPLC analysis:>99:1er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝71.3min,Rt(minor)＝52.8min.
[α]15 D ＝12.2(c＝1.0in CHCl3)；8:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.76–7.74(m,1H),7.69(t,J＝8.2Hz,3H),7.64–7.61(m,1H),7.44–7.36(m,6H),7.27(d,J＝7.4Hz,1H),7.21(s,1H),7.16–7.10(m,2H),6.81(d,J＝7.8Hz,1H),4.00(t,J＝7.0Hz,1H),3.30–3.21(m,1H),2.76(s,3H),2.52(dd,J＝14.4,6.8Hz,1H),1.79(s,3H).
13C NMR(101MHz,CDCl3)δ174.9,167.4,146.9,144.3,142.9,137.4,134.1,133.1,132.5,129.7,129.3,128.2,127.8,127.7,127.6,127.6,127.5,126.9,126.1,125.8,124.1,123.7,121.1,108.9,98.4,49.7,46.6,33.0,26.3,12.4.
HRMS(ESI,m/z):calcd.for C32H25N3O3H+[M+H]+:500.1969,found 500.1970.
HPLC analysis:>99:1 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝63.2min,Rt(minor)＝49.4min.
[α]1 D＝134.0(c＝0.5in CHCl3)；2:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.6Hz,3H),7.49(t,J＝7.8Hz,3H),7.35–7.28(m,2H),7.11(t,J＝7.6Hz,3H),6.87(d,J＝7.4Hz,2H),6.67(d,J＝7.8Hz,1H),4.56(s,1H),3.01(s,3H),1.83(s,3H).
13C NMR(101MHz,CDCl3)δ174.9,165.5,147.4,144.7,142.9,137.5,130.6,130.3,130.0,129.7,129.6,129.3,128.5,127.9,127.1,126.9,124.7,123.2,121.2,53.3,51.7,26.4,12.7.
HRMS(ESI,m/z):calcd.for C27H21N3O3Na+[M+Na]+:458.1475,found 458.1476.
HPLC analysis:95:5 er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝27.3min,Rt(minor)＝61.6min.
mg,熔点111-112℃.
[α]25 D ＝-21.3(c＝1.0in CHCl3)；>20:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.43(t,J＝8.0Hz,2H),7.30(d,J＝7.2Hz,1H),7.23–7.14(m,4H),7.05(d,J＝6.8Hz,2H),6.87(s,1H),6.80(d,J＝8.0Hz,1H),3.86(dd,J＝7.9,5.4Hz,1H),3.11(s,3H),3.01(dd,J＝14.4,7.6Hz,1H),2.33(s,3H),2.37–2.27(m,1H),1.84(s,3H).
13C NMR(101MHz,CDCl3)δ174.8,167.5,146.9,144.3,140.4,137.4,137.2,133.5,130.0,129.3,129.2,128.2,127.7,126.8,124.7,121.1,108.6,98.6,49.8,47.4,32.5,26.6,21.1,12.4.
HRMS(ESI,m/z):calcd.for C29H25N3O3H+[M+H]+:464.1969,found 464.1965；
HPLC analysis:>99:1er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝32.3min,Rt(minor)＝41.7min.
[α]25 D ＝-38.8(c＝1.0in CHCl3)；6:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.4Hz,3H),7.34(dd,J＝14.3,7.6Hz,3H),7.23–7.19(m,1H),7.15–7.04(m,5H),6.99–6.84(m,5H),6.69(dd,J＝19.8,6.2Hz,2H),3.79(dd,J＝7.5,6.2Hz,1H),3.00(dd,J＝14.5,7.6Hz,1H),2.95(s,3H),2.22(dd,J＝14.6,6.2Hz,1H),1.73(s,3H).
13C NMR(101MHz,CDCl3)δ174.8,166.8,151.33(dd,J＝251.5,14.1Hz),147.12(dd,J＝246.4,13.1Hz),146.8,144.1,139.30(dd,J＝9.1,2.6Hz),137.2,136.5,129.3,129.3,128.3,127.04(d,J＝3.1Hz),123.0(d,J＝5.1Hz),121.2,121.2,113.99(d,J＝20.3Hz),99.4,97.6,49.6,47.0,32.6,26.8,12.4.
19F NMR(377MHz,CDCl3)δ-143.6(d,J＝22.62Hz),-133.8(d,J＝18.58Hz).
HRMS(ESI,m/z):calcd.for C28H21F2N3O3H+[M+H]+:486.1624,found 486.1620.
HPLC analysis:92:8er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝20.6min,Rt(minor)＝34.1min.
[α]25 D ＝29.8(c＝1.0in CHCl3)；8:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.6Hz,2H),7.43(dd,J＝10.8,5.1Hz,2H),7.30–7.27(m,1H),7.24–7.13(m,4H),7.06–6.93(m,4H),3.86(dd,J＝7.6,6.0Hz,1H),3.06(s,3H),3.08–3.02(m,1H),2.29(dd,J＝14.5,6.0Hz,1H),1.82(s,3H).
13C NMR(101 MHz,CDCl3)δ174.8,167.0,146.9,144.2,144.2,137.3,136.7,129.3,129.3,128.3,127.0,126.9,126.6,126.5,125.4,123.3,121.1,112.4,97.8,49.5,47.1,32.6,26.7,12.5.
HRMS(ESI,m/z):calcd.for C28H22BrN3O3H+[M+H]+:528.0917,found 528.0916；
HPLC analysis:>99:1 er(IF column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝28.0min,Rt(minor)＝24.1min.
[α]25 D ＝-30.0(c＝1.0in CHCl3)；3:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.43(t,J＝8.0Hz,2H),7.29(d,J＝7.6Hz,1H),7.24–7.17(m,3H),7.11(d,J＝7.6Hz,1H),7.04–6.98(m,3H),6.90(d,J＝7.0Hz,1H),3.86(dd,J＝7.8,5.7Hz,1H),3.37(s,3H),3.01(dd,J＝14.5,8.0Hz,1H),2.60(s,3H),2.30(dd,J＝14.5,5.6Hz,1H),1.86(s,3H).
13C NMR(101MHz,CDCl3)δ175.8,167.4,146.9,144.3,140.6,137.4,137.1,133.3,129.4,129.22,128.3,128.1,126.8,126.8,123.6,122.0,121.1,120.5,98.7,49.2,47.4,32.6,29.9,19.1,12.5.
HRMS(ESI,m/z):calcd.for C29H25N3O3H+[M+H]+:464.1969,found 464.1964；
HPLC analysis:>99:1 er(IB column,25℃,hexanes/iso-propanol＝95:5,0.5mL/min,λ＝254nm)Rt(major)＝48.1min,Rt(minor)＝38.1min.
1H NMR(400MHz,CDCl3)δ7.74(t,J＝1.8Hz,1H),7.61(dd,J＝8.1,1.2Hz,1H),7.41–7.37(m,1H),7.23–7.15(m,6H),7.00(d,J＝7.2Hz,2H),6.91(d,J＝7.8Hz,1H),3.86(dd,J＝7.7,6.0Hz,1H),3.09(s,3H),3.02(dd,J＝14.5,7.8Hz,1H),2.30(dd,J＝14.5,5.8Hz,1H),1.80(s,3H).
13C NMR(101MHz,CDCl3)δ174.8,167.0,147.2,145.0,142.8,138.3,136.9,135.0,130.3,129.8,129.3,128.2,127.4,126.9,126.8,124.1,123.8,121.0,118.7,109.0,98.8,49.7,47.2,32.5,26.6,12.4.
HRMS(ESI,m/z):calcd.for C28H22ClN3O3H+[M+H]+:484.1422,found 484.1416；
HPLC analysis:>99:1 er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝45.8min,Rt(minor)＝49.5min.
[α]25 D ＝-53.4(c＝1.0in CHCl3)；6:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.39–7.35(m,1H),7.22–7.14(m,3H),7.04–6.96(m,4H),6.89(d,J＝7.8Hz,1H),3.77(dd,J＝7.8,5.8 Hz,1H),3.67(s,3H),3.08(s,3H),3.00(dd,J＝14.5,7.8Hz,1H),2.28(dd,J＝14.5,5.6Hz,1H),1.73(s,3H).
13C NMR(101MHz,CDCl3)δ175.1,167.6,147.5,142.8,142.6,137.1,129.5,129.3,128.3,128.1,126.8,124.0,123.5,108.7,96.3,49.8,47.5,33.8,26.5,12.3.
HRMS(ESI,m/z):calcd.for C23H21N3O3H+[M+H]+:388.1656,found 388.1644.
HPLC analysis:>99:1 er(IF column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝47.7min,Rt(minor)＝113.1min.
[α]11 D ＝175.4(c＝1.0in CHCl3)；4:1 dr(reaction mixture).
1H NMR(400 MHz,CDCl3)δ9.56(s,1H),7.69(d,J＝7.6Hz,2H),7.42(t,J＝8.0Hz,2H),7.31–7.28(m,1H),7.20–7.09(m,8H),6.98(d,J＝7.8Hz,1H),3.78(dd,J＝9.0,4.0Hz,1H),2.92(dd,J＝14.3,9.0Hz,1H),2.44(dd,J＝14.3,3.8Hz,1H),1.95(s,3H).
13C NMR(101MHz,CDCl3)δ178.2,167.0,147.2,144.5,140.1,137.5,137.3,129.8,129.3,129.3,128.3,128.0,127.0,126.9,124.4,123.9,121.2,111.0,98.1,50.7,48.2,32.2,12.6.
HRMS(ESI,m/z):calcd.for C27H21N3O3Na+[M+Na]+:458.1475,found:458.1469.
HPLC analysis:98:2 er(AD-H column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝46.1min,Rt(minor)＝30.5min.
[α]25 D ＝51.2(c＝1.0in CHCl3)；16:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.2Hz,1H),7.68(d,J＝8.0Hz,2H),7.46–7.40(m,3H),7.29(t,J＝7.4Hz,1H),7.23–7.17(m,4H),7.10(d,J＝6.8Hz,1H),7.01(d,J＝6.4Hz,2H),3.88(dd,J＝7.9,5.8Hz,1H),3.07(dd,J＝14.4,8.0Hz,1H),2.42(dd,J＝14.4,5.8Hz,1H),1.89(s,3H),1.63(s,9H).
13C NMR(101MHz,CDCl3)δ173.7,166.9,148.4,146.6,144.3,139.0,137.3,136.6,129.9,129.44,129.3,128.3,127.1,127.0,126.5,125.4,124.0,121.1,115.5,98.9,85.1,50.5,48.0,32.8,28.1,12.6.
HRMS(ESI,m/z):calcd.for C32H29N3O5H+[M+H]+:536.2180,found:536.2174.
HPLC analysis:>99:1 er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝24.5min,Rt(minor)＝13.9min.
[α]25 D ＝13.7(c＝1.0in CHCl3)；10:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.59(d,J＝8.2Hz,1H),7.45–7.38(m,3H),7.29(t,J＝7.4Hz,1H),7.24–7.18(m,4H),7.12(dd,J＝13.4,7.0Hz,3H),3.79(dd,J＝9.3,3.6Hz,1H),2.92(dd,J＝14.3,9.2Hz,1H),2.44(dd,J＝14.3,3.4Hz,1H),1.92(s,3H),1.46(s,9H).
13C NMR(101MHz,CDCl3)δ181.4,175.0,166.5,146.9,144.3,140.3,137.4,137.3,129.8,129.3,129.1,128.6,127.6,127.0,127.0,125.5,124.2,121.1,115.5,98.5,51.2,49.3,43.5,32.4,26.7(3C),13.0.
HRMS(ESI,m/z):calcd.for C32H29N3O4H+[M+H]+:520.1292,found:520.1287.
HPLC analysis:>99:1 er(IA column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝17.9min,Rt(minor)＝10.9min.
[α]13 D ＝22.3(c＝1.0in CHCl3)；9:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.2Hz,1H),7.71(d,J＝7.6Hz,2H),7.48–7.43(m,3H),7.34–7.27(m,2H),7.20–7.18(m,3H),7.11(d,J＝7.6Hz,1H),6.87(dd,J＝5.4,4.0Hz,2H),3.95(dd,J＝8.6,5.8Hz,1H),3.34(dd,J＝14.7,5.8Hz,1H),2.41–2,35(m,1H),2.37(s,3H),1.82(s,3H).
13C NMR(101MHz,CDCl3)δ175.5,169.4,165.9,145.6,143.3,138.6,136.4,135.1,129.2,128.8,128.5,127.6,126.6,126.2,126.0,125.4,123.0,120.3,116.5,97.9,49.5,46.8,32.1,25.7,11.9.
HRMS(ESI,m/z):calcd.for C29H23N3O4H+[M+H]+:478.1761,found:478.1755.
HPLC analysis:>99:1 er(IF column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝10.9min,Rt(minor)＝9.7min.
[α]25 D ＝-92.0(c＝1.0in CHCl3)；12:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.70–7.67(m,2H),7.44–7.40(m,4H),7.33–7.26(m,7H),7.23(s,1H),7.13(d,J＝8.4Hz,2H),7.08(d,J＝4.8Hz,2H),6.97(d,J＝8.0Hz,1H),4.88–4.84(m,2H),3.83(dd,J＝9.0,3.7Hz,1H),2.86(dd,J＝14.3,9.0Hz,1H),2.29(dd,J＝14.3,3.6Hz,1H),1.78(s,3H).
13C NMR(101MHz,CDCl3)δ175.3,167.1,147.2,144.4,142.2,137.7,137.4,135.3,129.6,129.3,129.0,128.4,128.2,128.1,127.7,127.6,126.8,126.5,124.3,123.8,121.1,109.9,98.3,50.0,48.6,44.8,32.2,12.8.
HRMS(ESI,m/z):calcd.for C34H27N3O3H+[M+H]+:526.2125,found 526.2120.
HPLC analysis:>99:1 er(IF column,25℃,hexanes/iso-propanol＝80:20,0.5mL/min,λ＝254nm)Rt(major)＝46.7min,Rt(minor)＝59.1min.
[α]14 D ＝138.3(c＝1.0in CHCl3)；>20:1 dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ7.69(d,J＝6.4Hz,2H),7.45–7.41(m,2H),7.29(d,J＝5.8Hz,1H),7.24–7.15(m,3H),7.06(d,J＝3.6Hz,2H),6.90(s,1H),6.68(s,1H),3.85(dd,J＝8.0,5.4Hz,1H),3.36(s,3H),3.00(dd,J＝14.4,8.0Hz,1H),2.55(s,3H),2.30(dd,J＝14.4,5.2Hz,1H),2.26(s,3H),1.86(s,3H).
13C NMR(101MHz,CDCl3)δ175.7,167.6,146.8,144.3,138.1,137.4,137.3,133.8,133.3,129.4,129.2,128.4,128.1,126.8,126.8,122.5,121.1,120.2,98.9,49.3,47.5,32.5,29.9,20.8,19.0,12.5.
HRMS(ESI,m/z):calcd.for C32H25N3O3H+[M+H]+:500.1945,found 500.1938.
HPLC analysis:>99:1 er(IF column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝30.9min,Rt(minor)＝46.1min.
℃.
[α]2 D ＝-92.2(c＝1.0in CHCl3)；3:1dr(reaction mixture).
1H NMR(400MHz,CDCl3)δ11.18(s,1H),8.32(d,J＝6.8Hz,1H),7.87–7.84(m,2H),7.69(d,J＝7.8Hz,2H),7.39–7.37(m,2H),7.28–7.26(m,2H),7.14–7.84(m,2H),7.04(d,J＝7.0Hz,1H),6.83–6.79(m,2H),4.44(dd,J＝11.6,4.4Hz,1H),3.49–3.46(m,1H),3.29(s,3H),2.89(s,3H),2.36(dd,J＝12.8,7.2Hz,1H),1.80(s,3H).
13C NMR(101MHz,CDCl3)δ175.1,172.4,156.6,142.9,138.7,129.7,129.4,129.1,129.0,128.8,128.4,128.1,126.7,126.5,125.6,123.3,123.2,119.4,108.4,52.2,51.1,50.7,32.6,26.4,16.2.
HRMS(ESI,m/z):calcd.for C29H27N3O4Na+[M+Na]+:504.1894,found 504.1893.
HPLC analysis:94:6er(ADH column,25℃,hexanes/iso-propanol＝90:10,1mL/min,λ＝254nm)Rt(major)＝17.1min,Rt(minor)＝13.8min.
(3)药理实施例:
采用浊度法测试目标化合物对植物病原菌的抑制率，试验对象为柑橘溃疡病菌(Xac)，DMSO溶解在培养基中作为空白对照。将柑橘溃疡病菌(柑橘溃疡病菌在M210固体培养基)放到NB培养基中，在28℃、180rpm恒温摇床中振荡培养到对数生长期备用；将药剂(化合物)配置成不同浓度(例：100,50μg/mL)的含毒NB液体培养基5mL加入到试管中，分别加入40μL含有植病细菌的NB液体培养基，在28-30℃、180rpm恒温摇床中振荡，柑橘溃疡病菌培养48h。将各个浓度的菌液在分光光度计上测定OD595值，并且另外测定对应浓度的含毒无菌NB液体培养基的OD595值。
本申请化合物对植物病原细菌的抑制活性数据如下表所示：
从本申请所合成化合物对病原细菌柑橘溃疡病菌(Xanthomonas axonopodispv.citri,Xac)抑制活性数据表中可以看出，编号为3g、3i、3k、3l、3o、3p、3s、3t、4的化合物均对Xac表现出优于常规商品药噻菌酮的抑制活性，其中化合物3i和3l抑制效果最佳，该类分子骨架为新农药的研发和创制提供了重要的科学基础。
综上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，任何未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (7)

1.一类手性化合物吡唑并吡喃衍生物，其特征在于：所述的衍生物如下述通式(1)表示：
其中标有*的碳原子为手性碳原子，R1为烷基或卤原子，R2为卤原子、烷基、烷氧基或苯基，R3为烷基、氢原子或羰基，R4为烷基、苯基或取代苯基；所述的取代苯基为苯环的取代基为卤素、甲基、甲氧基或萘基。
2.根据权利要求1所述的一类手性化合物吡唑并吡喃衍生物，其特征在于：所述卤原子为氟、氯或溴。
3.一种如权利要求1所述的手性化合物吡唑并吡喃衍生物的制备方法，其特征在于：包括以下步骤：
(1)取代α-氯代醛与手性卡宾催化剂反应得到中间体I，进一步在碱性条件下得到烯醇式中间体III；
(2)由吲哚取代的吡唑酮和III中间体1,4加成反应，得到中间体IV；
(3)步骤(2)发生分子内酯化加成，卡宾催化剂离去生成手性化合物吡唑并吡喃衍生物；
反应通式及过程如下：
4.根据权利要求3所述的一类手性化合物吡唑并吡喃衍生物的制备方法，其特征在于：所述的吲哚取代的吡唑酮的合成路线如下：将取代的靛红S1溶解于N,N-二甲基甲酰胺中，0℃下缓慢加入氢化钠，然后滴加碘甲烷，转常温反应，TLC监测反应完毕后，加饱和氯化铵溶液调节体系pH至中性，乙酸乙酯萃取，有机相通过无水硫酸钠干燥，抽滤旋干得到产物S2；将S2溶解于乙酸溶液中，加入乙酸钠和吡唑酮，回流反应，监测反应情况，反应完毕后，乙酸乙酯萃取，有机层用无水硫酸钠干燥，抽滤，滤液旋干，用石油醚:乙酸乙酯作洗脱剂过柱纯化即得S3；
5.如权利要求1所述的衍生物在防治农业病虫害中的应用。
6.根据权利要求5所述的应用，其特征在于：所述的农业病虫害为植物细菌性病害。
7.根据权利要求6所述的应用，其特征在于：所述的植物细菌性病害为柑桔溃疡病菌。
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