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CN107827897A - Synthesis method of chiral hepta-spiro indolone compound - Google Patents

Synthesis method of chiral hepta-spiro indolone compound Download PDF

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CN107827897A
CN107827897A CN201710990603.4A CN201710990603A CN107827897A CN 107827897 A CN107827897 A CN 107827897A CN 201710990603 A CN201710990603 A CN 201710990603A CN 107827897 A CN107827897 A CN 107827897A
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李文军
石振艳
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Qingdao University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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  • Organic Chemistry (AREA)
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Abstract

本发明公开了一种手性七元螺环吲哚酮类化合物的合成方法，是在反应溶剂中，以对位醌的亚甲基化合物和α,β‑不饱和醛为反应原料，以卡宾为催化剂，反应得手性七元螺环吲哚酮类化合物。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。The invention discloses a method for synthesizing a chiral seven-membered spirocyclic indole ketone compound, wherein a methylene compound of a para-quinone and an α,β-unsaturated aldehyde are used as reaction raw materials in a reaction solvent, and a carbene is used as a catalyst to react and obtain a chiral seven-membered spirocyclic indole ketone compound. The invention has mild reaction conditions, readily available and inexpensive raw materials, simple reaction operation, and high yield, and provides a key skeleton structure for the synthesis of many natural products and drugs, and can be widely applied to industrial-scale production.

Description

一种手性七元螺环吲哚酮类化合物的合成方法A kind of synthetic method of chiral seven-membered spiro ring indolinone compound

技术领域technical field

本发明具体涉及一种制备手性七元螺环吲哚酮类化合物的合成方法，属于有机化合物工艺应用技术领域。The invention specifically relates to a synthesis method for preparing chiral seven-membered spiro-indolinone compounds, which belongs to the technical field of organic compound technology application.

背景技术Background technique

手性七元螺环吲哚酮类化合物是一类非常重要医药化工中间体，具有非常高的应用价值。很多药物和生物活性分子都具有七元螺环吲哚酮的骨架。Chiral seven-membered spirocyclic indolinone compounds are a very important class of pharmaceutical and chemical intermediates with very high application value. Many drugs and bioactive molecules have a seven-membered spirocyclic indolinone backbone.

发明内容Contents of the invention

本发明首次创新地提出了一种绿色环保，简单高效制备手性七元螺环吲哚酮类化合物的新方法，通过使用卡宾为催化剂，可以高效地实现反应的转化。如以上式(I)所示，本发明利用对位醌的亚甲基化合物和α,β-不饱和醛为反应原料，以卡宾为催化剂，在反应溶剂中进行反应，合成手性七元螺环吲哚酮类化合物。The present invention for the first time innovatively proposes a green, environmentally friendly, simple and efficient new method for preparing chiral seven-membered spiro indolinone compounds. By using carbene as a catalyst, the conversion of the reaction can be realized efficiently. As shown in the above formula (I), the present invention utilizes the methylene compound of p-quinone and α, β-unsaturated aldehydes as reaction raw materials, and uses carbene as a catalyst to react in a reaction solvent to synthesize a chiral seven-membered spiro Cycloindolinone compounds.

本发明中，R是烷基、芳香基或取代的芳环。In the present invention, R is an alkyl group, an aryl group or a substituted aromatic ring.

本发明中，所述起始原料对位醌的亚甲基化合物和α,β-不饱和醛的用量比例为1:1-1:5。优选地，两者用量比例为1.2:1。In the present invention, the amount ratio of the starting material p-quinone methylene compound and α,β-unsaturated aldehyde is 1:1-1:5. Preferably, the dosage ratio of the two is 1.2:1.

本发明中，所述催化剂是卡宾；所述催化剂的用量为原料对位醌的亚甲基化合物的1-20 mol％。优选地，所述催化剂用量为10 mol％。In the present invention, the catalyst is carbene; the dosage of the catalyst is 1-20 mol% of the methylene compound of p-quinone as the raw material. Preferably, the catalyst is used in an amount of 10 mol%.

本发明中，所述反应溶剂是二氯甲烷、氯仿、四氯化碳、DCE、甲苯、苯甲醚、二甲苯类化合物或乙腈。In the present invention, the reaction solvent is dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, anisole, xylene compounds or acetonitrile.

本发明中，所述合成反应是在20-80℃温度下进行。优选地，是在25℃温度下进行反应。In the present invention, the synthesis reaction is carried out at a temperature of 20-80°C. Preferably, the reaction is carried out at a temperature of 25°C.

具体地，本发明合成反应是在反应瓶A中，将α,β-不饱和醛(底物1，X mmol)和对位醌的亚甲基化合物(底物2，Y mmol)溶解在Z mL反应溶剂中，室温下，加入卡宾(W mmol)。反应在25℃下反应48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。Specifically, the synthesis reaction of the present invention is to dissolve the methylene compound of α,β-unsaturated aldehyde (substrate 1, X mmol) and p-quinone (substrate 2, Y mmol) in reaction bottle A in Z In mL reaction solvent, add carbene (W mmol) at room temperature. The reaction was carried out at 25°C for 48 hours. The progress of the reaction was checked by TLC. After the reaction was completed, silica gel was added directly, spin-drying column chromatography, and the target product 3 was isolated and obtained.

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。本发明以简单易得的对位醌的亚甲基化合物和α,β-不饱和醛为反应原料，在卡宾作用下，反应得到手性七元螺环吲哚酮类化合物。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。本发明合成的手性七元螺环吲哚酮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。The advantages of the synthesis reaction of the present invention include: the raw materials used in the synthesis method of the present invention are very simple, all are industrial commodities, easy to obtain, wide in source, very stable in performance, and do not require special storage conditions. The invention uses simple and easy-to-obtain methylene compounds of p-quinone and α, β-unsaturated aldehydes as reaction raw materials, and reacts under the action of carbene to obtain chiral seven-membered spiro-indolinone compounds. The reaction operation is relatively simple, the reaction conditions are mild, the yield is high, and the method is suitable for large-scale industrial production. The chiral seven-membered spiro indolinone synthesized by the invention is the core skeleton of many natural products and active drug molecules, and the innovatively designed reaction route of the invention provides a widely applicable preparation method for synthesizing this type of compound.

具体实施方式Detailed ways

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。In conjunction with the following specific examples, the present invention will be further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope. The process, conditions, reagents, experimental methods, etc. for implementing the present invention are general knowledge and common knowledge in the art except for the content specifically mentioned below, and the present invention has no special limitation content. The data given in the following examples include specific operating and reaction conditions and products. Product purity was identified by NMR.

实施例1Example 1

在25 mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3aa (78%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.59 (d, J = 5.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.38-7.35 (m, 1H), 7.27-7.20 (m, 5H), 7.08-7.02 (m, 4H), 6.99 (s, 2H), 6.44-6.42(m, 1H), 5.29 (d, J = 15.0 Hz, 1H), 5.08 (s, 1H), 4.76 (s, 1H), 4.16 (d, J =15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.36 (d, J = 15.0 Hz, 1H), 1.32 (s,18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.9, 168.8, 152.9, 151.0, 141.1,135.3, 135.2, 130.7, 129.9, 129.6, 128.8, 128.6, 128.4, 127.7, 127.2, 127.1,125.9, 124.7, 123.4, 122.8, 119.6, 109.1, 56.6, 51.2, 43.8, 39.9, 34.2, 30.3.HRMS计算值为M+ (C38H40NO4) m/z 574.2957,实际值574.2959. The enantiomeric ratiowas determineδto be 98:2 by HPLC. [IC column, 254 nm, n-hexane:IPA = 96:4,0.8 mL/min]: 14.5 min (minor), 16.7 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3aa (78%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.59 (d, J = 5.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.38-7.35 (m, 1H), 7.27-7.20 (m , 5H), 7.08-7.02 (m, 4H), 6.99 (s, 2H), 6.44-6.42(m, 1H), 5.29 (d, J = 15.0 Hz, 1H), 5.08 (s, 1H), 4.76 ( s, 1H), 4.16 (d, J =15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.36 (d, J = 15.0 Hz, 1H), 1.32 (s,18H). 13 C NMR (CDCL 3 , 125 MHz): Δ (PPM) 175.9, 168.8, 152.9, 151.0, 141.1,135.3, 135.2, 130.7, 129.9, 129.6, 128.6, 127.2, 127.1,125.9, 123.4, 123.4, 123.4 , 122.8, 119.6, 109.1, 56.6, 51.2, 43.8, 39.9, 34.2, 30.3. The HRMS calculated value is M + (C 38 H 40 NO 4 ) m/z 574.2957, the actual value is 574.2959. The enantiomeric ratio was determineδ2to be 98: by HPLC. [IC column, 254 nm, n -hexane:IPA = 96:4,0.8 mL/min]: 14.5 min (minor), 16.7 min (major).

实施例2Example 2

在25 mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2b (0.05 mmol, 16.4 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ab (69%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.49-7.48 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.19 (m,4H), 7.06-7.03 (m, 5H), 6.97 (s, 2H), 6.43-6.42 (m, 1H), 5.26 (d, J = 15.0Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.17 (d, J = 15.0 Hz, 1H), 3.46 (d, J =15.0 Hz, 1H), 2.37 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13C NMR (CDCl3, 125MHz): δ(ppm) 175.8, 168.5, 159.9 (d, J = 970.0 Hz), 153.2, 146.9, 141.2,135.5, 135.0, 131.8 (d, J = 35.0 Hz), 130.5, 128.8, 128.6, 127.7, 127.1,127.0, 124.2, 123.4, 122.9, 120.9 (d, J = 35.0 Hz), 117.2 (d, J = 100.0 Hz),115.2 (d, J = 95.0 Hz), 109.2, 56.4, 51.2, 43.8, 39.7, 34.3, 30.3. HRMS计算值为M+ (C38H39FNO4) m/z 592.2863,实际值592.2866. The enantiomeric ratio wasdetermineδto be 98:2 by HPLC. [IC column, 254 nm, n-hexane:IPA = 96:4, 0.8mL/min]: 13.9 min (minor), 16.3 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2b (0.05 mmol, 16.4 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ab (69%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.49-7.48 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.19 (m,4H), 7.06-7.03 (m, 5H) , 6.97 (s, 2H), 6.43-6.42 (m, 1H), 5.26 (d, J = 15.0Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.17 (d, J = 15.0 Hz, 1H), 3.46 (d, J =15.0 Hz, 1H), 2.37 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13 C NMR (CDCl 3 , 125MHz): δ(ppm) 175.8, 168.5, 159.9 (d, J = 970.0 Hz), 153.2, 146.9, 141.2, 135.5, 135.0, 131.8 (d, J = 35.0 Hz), 130.5, 128.8, 128.6, 127.7, 124.02, 2, 127 122.9, 120.9 (d, J = 35.0 Hz), 117.2 (d, J = 100.0 Hz), 115.2 (d, J = 95.0 Hz), 109.2, 56.4, 51.2, 43.8, 39.7, 34.3, 30.3. HRMS calculations are M + (C 38 H 39 FNO 4 ) m/z 592.2863, actual value 592.2866. The enantiomeric ratio was determinedδto be 98:2 by HPLC. [IC column, 254 nm, n -hexane:IPA = 96:4, 0.8mL/ min]: 13.9 min (minor), 16.3 min (major).

实施例3Example 3

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2c (0.05 mmol, 17.2 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄白色固体3ac (67%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.60 (s, 1H), 7.49-7.47 (m, 1H), 7.34-7.31 (m, 1H),7.25-7.21 (m, 3H), 7.18-7.16 (d, J = 10.0 Hz, 1H), 7.06-7.03 (m, 4H), 6.96(s, 2H), 6.42-6.41 (m, 1H), 5.23 (d, J = 20.0 Hz, 1H), 5.12 (s, 1H), 4.68 (s,1H), 4.18 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.38 (d, J = 15.0Hz, 1H), 1.32 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.7, 168.1, 153.2,149.5, 141.2, 135.5, 135.0, 131.4, 131.3, 130.4, 130.3, 128.8, 128.6, 128.5,127.7, 127.2, 127.1, 123.9, 123.4, 122.9, 120.9, 109.2, 56.5, 51.1, 43.8,39.6, 34.3, 30.3. HRMS计算值为M+(C38H39ClNO4) m/z 608.2568, 实际值608.2574. Theenantiomeric ratio was determineδto be 96:4 by HPLC. [IC column, 254 nm, n-hexane:IPA = 96:4, 0.8 mL/min]: 13.1 min (minor), 15.1 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2c (0.05 mmol, 17.2 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a yellow-white solid 3ac (67%). 1 H NMR (CDCl 3 , 500 MHz): δ(ppm) 7.60 (s, 1H), 7.49-7.47 (m, 1H), 7.34-7.31 (m, 1H), 7.25-7.21 (m, 3H), 7.18 -7.16 (d, J = 10.0 Hz, 1H), 7.06-7.03 (m, 4H), 6.96(s, 2H), 6.42-6.41 (m, 1H), 5.23 (d, J = 20.0 Hz, 1H), 5.12 (s, 1H), 4.68 (s,1H), 4.18 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.38 (d, J = 15.0Hz, 1H), 1.32 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.7, 168.1, 153.2, 149.5, 141.2, 135.5, 135.0, 131.4, 131.3, 130.4, 130.3, 128.8, 128.6, 12 127.7, 127.2, 127.1, 123.9, 123.4, 122.9, 120.9, 109.2, 56.5, 51.1, 43.8,39.6, 34.3, 30.3. HRMS calculated for M + (C 38 H 39 ClNO 4 ) 25. Actual 408.2768, . The enantiomeric ratio was determineδto be 96:4 by HPLC. [IC column, 254 nm, n -hexane:IPA = 96:4, 0.8 mL/min]: 13.1 min (minor), 15.1 min (major).

实施例4Example 4

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2δ(0.05 mmol, 19.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.01 mmol, 6.59 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3aδ(74%)。1H NMR (CDCl3,500 MHz): δ(ppm) 7.77-7.76 (m, 1H), 7.49-7.47 (m, 2H), 7.25-7.21 (m, 3H),7.12-7.11 (d, J = 5.0 Hz, 1H), 7.06-7.03 (m, 4H), 6.96 (s, 2H), 6.42-6.40 (m,1H), 5.22 (d, J = 15.0 Hz, 1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.19 (d, J = 15.0Hz, 1H), 3.46 (d, J = 15.0 Hz, 1H), 2.38 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H).13C NMR (CDCl3, 125 MHz): δ(ppm) 175.7, 168.0, 153.2, 150.1, 141.2, 135.5,135.0, 133.3, 131.7, 131.6, 130.4, 128.8, 128.6, 127.7, 127.2, 127.1, 123.9,123.4, 122.8, 121.3, 119.2, 109.2, 56.5, 51.1, 43.8, 39.6, 34.3, 30.3. HRMS计算值为M+(C38H39BrNO4) m/z 652.2062, 实际值652.2068. The enantiomeric ratio wasdetermineδto be 95:5 by HPLC. [IC column, 254 nm, n-hexane:IPA = 96:4, 0.8mL/min]: 13.7 min (minor), 16.3 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2δ (0.05 mmol, 19.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.01 mmol, 6.59 mg) were weighed into the reaction tube in sequence, and the nitrogen was replaced by pumping , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain white solid 3aδ (74%). 1 H NMR (CDCl 3 , 500 MHz): δ(ppm) 7.77-7.76 (m, 1H), 7.49-7.47 (m, 2H), 7.25-7.21 (m, 3H), 7.12-7.11 (d, J = 5.0 Hz, 1H), 7.06-7.03 (m, 4H), 6.96 (s, 2H), 6.42-6.40 (m,1H), 5.22 (d, J = 15.0 Hz, 1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.19 (d, J = 15.0Hz, 1H), 3.46 (d, J = 15.0 Hz, 1H), 2.38 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13 C NMR (CDCL 3 , 125 MHz): Δ (PPM) 175.7, 168.0, 153.2, 150.1, 141.2, 135.5,135.0, 131.7, 131.6, 130.4, 128.6, 127.2, 123.9,123.4 , 122.8, 121.3, 119.2, 109.2, 56.5, 51.1, 43.8, 39.6, 34.3, 30.3. HRMS calculated M + (C 38 H 39 BrNO 4 ) m/z 652.2062, actual 652.2068. The enantiomeric de 9 terme to δas :5 by HPLC. [IC column, 254 nm, n -hexane:IPA = 96:4, 0.8mL/min]: 13.7 min (minor), 16.3 min (major).

实施例5Example 5

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2e (0.05 mmol, 16.2 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ae (73%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.51-7.49 (m, 1H), 7.42 (s, 1H), 7.25-7.20 (m, 3H),7.16-7.11 (m, 2H), 7.05-7.04 (m, 4H), 6.99 (s, 2H), 6.41-6.39 (m, 1H), 5.23(d, J = 15.0 Hz, 1H), 5.09 (s, 1H), 4.70 (s, 1H), 4.16 (d, J = 15.0 Hz, 1H),3.46 (d, J = 10.0 Hz, 1H), 2.33 (m, 4H), 1.32 (s, 18H). 13C NMR (CDCl3, 125MHz): δ(ppm) 175.9, 169.1, 152.9, 149.0, 141.2, 135.3, 135.2, 135.1, 130.8,130.5, 129.1, 128.9, 128.8, 128.4, 127.6, 127.4, 127.1, 124.6, 123.4, 122.8,119.3, 109.1, 56.7, 51.2, 43.8, 39.6, 34.3, 30.3, 21.4. HRMS计算值为M+(C39H42NO4) m/z 588.3114, 实际值588.3119. The enantiomeric ratio was determineδto be 98:2 by HPLC. [IC column, 254 nm, n-hexane:IPA = 96:4, 0.8 mL/min]:16.3 min (minor), 18.5 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2e (0.05 mmol, 16.2 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and the nitrogen was replaced by evacuation , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, silica gel was added directly, followed by spin-drying column chromatography to obtain 3ae (73%) as a white solid. 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.51-7.49 (m, 1H), 7.42 (s, 1H), 7.25-7.20 (m, 3H),7.16-7.11 (m, 2H), 7.05 -7.04 (m, 4H), 6.99 (s, 2H), 6.41-6.39 (m, 1H), 5.23(d, J = 15.0 Hz, 1H), 5.09 (s, 1H), 4.70 (s, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.46 (d, J = 10.0 Hz, 1H), 2.33 (m, 4H), 1.32 (s, 18H). 13 C NMR (CDCl 3 , 125MHz): δ( ppm) 175.9, 169.1, 152.9, 149.0, 141.2, 135.3, 135.2, 135.1, 130.8,130.5, 129.1, 128.9, 128.8, 128.4, 127.6, 127.4, 127.1, 124.6, 123.4, 122.8,119.3, 109.1, 56.7, 51.2, 43.8, 39.6, 34.3, 30.3, 21.4. HRMS calculated M + (C 39 H 42 NO 4 ) m/z 588.3114, actual value 588.3119. The enantiomeric ratio was determineδto be 98:2 by HPLC. [IC column, 254 nm, n -hexane:IPA = 96:4, 0.8 mL/min]: 16.3 min (minor), 18.5 min (major).

实施例6Example 6

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2f (0.05 mmol, 19.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状液体3af (77%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.46-7.38 (m, 4H), 7.24-7.21 (m, 3H), 7.08-7.04 (m,4H), 6.95 (s, 2H), 6.46-6.44 (m, 1H), 5.29 (d, J = 15.0 Hz, 1H), 5.10 (s,1H), 4.69 (s, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.42 (d, J = 15.0 Hz, 1H), 2.37(d, J = 10.0 Hz, 4H), 1.31 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.9,167.9, 153.1, 151.3, 141.1, 135.5, 135.1, 131.3, 130.4, 129.0, 128.9, 128.8,128.6, 127.8, 127.2, 126.9, 124.3, 123.3, 122.9, 122.8, 121.5, 109.2, 56.3,50.9, 43.9, 39.9, 34.3, 30.3. HRMS计算值为M+(C38H39NO4) m/z 652.2062, 实际值652.2067. The enantiomeric ratio was determineδto be 95:5 by HPLC. [ICcolumn, 254 nm, n-hexane:IPA = 96:4, 0.8 mL/min]: 13.7 min (major), 19.2 min(minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2f (0.05 mmol, 19.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain yellow oily liquid 3af (77%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.46-7.38 (m, 4H), 7.24-7.21 (m, 3H), 7.08-7.04 (m,4H), 6.95 (s, 2H), 6.46 -6.44 (m, 1H), 5.29 (d, J = 15.0 Hz, 1H), 5.10 (s,1H), 4.69 (s, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.42 (d, J = 15.0 Hz, 1H), 2.37(d, J = 10.0 Hz, 4H), 1.31 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.9,167.9, 153.1, 151.3, 141.1, 135.5, 135.1, 131.3, 130.4, 129.0, 128.9, 128.8,128.6, 127.8, 126.9, 124.3, 123.3, 122.8, 121.5, 109.2, 56.3,50.9, 39.9, 34.3, 30.3. HRMSS calculation The value was M + (C 38 H 39 NO 4 ) m/z 652.2062, the actual value was 652.2067. The enantiomeric ratio was determineδto be 95:5 by HPLC. [ICcolumn, 254 nm, n -hexane:IPA = 96:4, 0.8 mL/min]: 13.7 min (major), 19.2 min (minor).

实施例7Example 7

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2g (0.05 mmol, 17.0 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ag (79%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.49-7.45 (m, 2H), 7.25-7.20 (m, 3H), 7.07-7.03 (m,4H), 6.96 (s, 2H), 6.81-6.79 (m, 2H), 6.42-6.41 (m, 1H), 5.28 (d, J = 15.0Hz, 1H), 5.07 (s, 1H), 4.68 (s, 1H), 4.15 (d, J = 15.0 Hz, 1H), 3.83 (s, 3H),3.45 (d, J = 10.0 Hz, 1H), 2.35 (d, J = 10.0 Hz, 1H), 1.31 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 176.0, 168.8, 159.7, 152.9, 151.6, 141.1, 135.2,130.8, 130.4, 128.8, 128.3, 127.7, 127.2, 127.1, 124.9, 123.4, 122.8, 121.5,111.2, 109.0, 105.7, 56.8, 55.6, 50.9, 43.8, 39.9, 34.2, 30.3. HRMS计算值为M+(C39H42NO5) m/z 604.3063, 实际值604.3068. The enantiomeric ratio was determineδto be 99.5:0.5 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 95:5, 0.8 mL/min]: 13.7 min (major), 17.6 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2g (0.05 mmol, 17.0 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ag (79%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.49-7.45 (m, 2H), 7.25-7.20 (m, 3H), 7.07-7.03 (m,4H), 6.96 (s, 2H), 6.81 -6.79 (m, 2H), 6.42-6.41 (m, 1H), 5.28 (d, J = 15.0Hz, 1H), 5.07 (s, 1H), 4.68 (s, 1H), 4.15 (d, J = 15.0 Hz, 1H), 3.83 (s, 3H), 3.45 (d, J = 10.0 Hz, 1H), 2.35 (d, J = 10.0 Hz, 1H), 1.31 (s, 18H). 13 C NMR(CDCl 3 , 125 MHz): δ(ppm) 176.0, 168.8, 159.7, 152.9, 151.6, 141.1, 135.2,130.8, 130.4, 128.8, 128.3, 127.7, 127.2, 127.1, 124.9, 123.4, 122.8, 121.5,111.2, 109.0, 105.7, 56.8, 55.6, 50.9, 43.8, 39.9, 34.2, 30.3. HRMS calculated M + (C 39 H 42 NO 5 ) m/z 604.3063, actual 604.3068. The enantiomeric ratio was determineδto be 99.5:0.5 by HPLC. [ IΔcolumn, 254 nm, n -hexane:EtOH = 95:5, 0.8 mL/min]: 13.7 min (major), 17.6 min (minor).

实施例8Example 8

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2h (0.05 mmol, 17.0 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ah (78%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.51-7.49 (m, 1H), 7.23-7.18 (m, 4H), 7.14 (d, J =5.0 Hz, 1H), 7.08 (d, J = 5.0 Hz, 2H), 7.04-7.02 (m, 2H), 6.98-6.97 (m, 3H),6.43-6.42 (m, 1H), 5.30 (d, J = 15.0 Hz, 1H), 5.06 (s, 1H), 4.75 (s, 1H),4.14 (d, J = 20.0 Hz, 1H), 3.92 (s, 3H), 3.46 (d, J = 10.0 Hz, 1H), 2.34 (d,J = 10.0 Hz, 1H), 1.31 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 176.0,168.5, 152.9, 149.7, 141.1, 139.9, 135.3, 135.2, 130.9, 130.7, 128.8, 128.4,127.7, 127.2, 127.1, 125.8, 124.9, 123.5, 122.8, 121.3, 111.6, 108.9, 56.5,56.1, 51.2, 43.8, 39.9, 34.2, 30.3. HRMS计算值为M+(C39H42NO5) m/z 604.3063,实际值604.3068. The enantiomeric ratio was determineδto be 99:1 by HPLC. [ICcolumn, 254 nm, n-hexane:IPA = 9:1, 0.8 mL/min]: 27.6 min (major), 33.7 min(minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2h (0.05 mmol, 17.0 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ah (78%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.51-7.49 (m, 1H), 7.23-7.18 (m, 4H), 7.14 (d, J =5.0 Hz, 1H), 7.08 (d, J = 5.0 Hz, 2H), 7.04-7.02 (m, 2H), 6.98-6.97 (m, 3H),6.43-6.42 (m, 1H), 5.30 (d, J = 15.0 Hz, 1H), 5.06 (s, 1H), 4.75 (s, 1H), 4.14 (d, J = 20.0 Hz, 1H), 3.92 (s, 3H), 3.46 (d, J = 10.0 Hz, 1H), 2.34 (d, J = 10.0 Hz, 1H), 1.31 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 176.0,168.5, 152.9, 149.7, 141.1, 139.9, 135.3, 135.2, 130.9, 130.7, 128.8, 127.8 , 127.2, 127.1, 125.8, 124.9, 123.5, 122.8, 121.3, 111.6, 108.9, 56.5,56.1, 51.2, 43.8, 39.9, 34.2, 30.3. HRMS calculated as M + (C 39 H 42 m z NO 5 604.3063, actual value 604.3068. The enantiomeric ratio was determineδto be 99:1 by HPLC. [ICcolumn, 254 nm, n -hexane:IPA = 9:1, 0.8 mL/min]: 27.6 min (major), 33.7 min(minor ).

实施例9Example 9

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 15.8 mg)，底物2i (0.05 mmol, 14.1 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ai (63%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.53-7.48 (m, 2H), 7.37-7.34 (m, 1H), 7.25-7.22 (m,5H), 7.04-7.03 (m, 4H), 6.89 (s, 2H), 6.48-6.46 (m, 1H), 5.25 (d, J = 15.0Hz, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.29 (d, J = 15.0 Hz, 1H), 3.44 (d, J =10.0 Hz, 1H), 3.03-2.97 (m, 2H), 2.34 (d, J = 10.0 Hz, 1H), 1.12 (m, 12H). 13CNMR (CDCl3, 125 MHz): δ(ppm) 176.1, 168.7, 150.9, 149.1, 141.2, 135.2, 133.3,130.6, 129.9, 129.6, 128.7, 128.6, 128.5, 127.6, 127.1, 126.2, 125.9, 125.6,123.3, 122.9, 119.5, 109.2, 56.4, 50.9, 43.7, 40.3, 26.9, 22.9, 22.5. HRMS计算值为M+(C36H36NO4) m/z 546.2644,实际值546.2649. The enantiomeric ratio wasdetermineδto be 99:1 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8mL/min]: 10.4 min (major), 13.0 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 15.8 mg), substrate 2i (0.05 mmol, 14.1 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ai (63%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.53-7.48 (m, 2H), 7.37-7.34 (m, 1H), 7.25-7.22 (m,5H), 7.04-7.03 (m, 4H) , 6.89 (s, 2H), 6.48-6.46 (m, 1H), 5.25 (d, J = 15.0Hz, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.29 (d, J = 15.0 Hz, 1H), 3.44 (d, J =10.0 Hz, 1H), 3.03-2.97 (m, 2H), 2.34 (d, J = 10.0 Hz, 1H), 1.12 (m, 12H). 13 CNMR (CDCl 3 , 125 mHz): Δ (PP) 176.1, 168.7, 150.9, 149.1, 141.2, 135.2, 133.3 ,130.6, 129.9, 129.6, 128.6, 127.6, 126.2, 125.6,123.9, 119.5, 119.5 , 109.2, 56.4, 50.9, 43.7, 40.3, 26.9, 22.9, 22.5. The HRMS calculated value was M + (C 36 H 36 NO 4 ) m/z 546.2644, the actual value was 546.2649. The enantiomeric ratio was determinedδto be 99:1 by HPLC . [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8mL/min]: 10.4 min (major), 13.0 min (minor).

实施例10Example 10

在25mL的试管反应器中，用氮气交换空气3次。将底物1b (0.06 mmol, 16.9 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状液体3ba (84%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.56 (d, J = 5.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.27-7.26 (m, 1H), 7.25-7.20 (m, 5H), 7.06-7.05 (m, 2H), 7.00 (s, 2H), 6.76-6.72(m, 1H), 6.35-6.33 (m, 1H), 5.32 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.70 (s,1H), 4.12 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.37 (d, J = 10.0Hz, 1H), 1.33 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.7, 168.5, 159.3(d, J = 960.0 Hz), 153.1, 150.9, 137.1 (d, J = 10.0 Hz), 135.5, 134.8, 132.4(d, J = 30.0 Hz), 129.9, 129.2, 128.9, 128.8, 127.8, 127.1, 127.0, 126.0,124.4, 119.6, 114.7 (d, J = 95.0 Hz), 111.7 (d, J = 100.0 Hz), 109.7 (d, J =35.0 Hz), 56.8, 51.3, 43.9, 39.8, 34.3, 30.3. HRMS计算值为M+(C38H39FNO4)m/z592.2863,实际值592.2866. The enantiomeric ratio was determineδto be 97:3 byHPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8 mL/min]: 7.8 min (major),9.8 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1b (0.06 mmol, 16.9 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain yellow oily liquid 3ba (84%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.56 (d, J = 5.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.27-7.26 (m, 1H), 7.25-7.20 (m , 5H), 7.06-7.05 (m, 2H), 7.00 (s, 2H), 6.76-6.72(m, 1H), 6.35-6.33 (m, 1H), 5.32 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.70 (s,1H), 4.12 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.37 (d, J = 10.0Hz, 1H), 1.33 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.7, 168.5, 159.3(d, J = 960.0 Hz), 153.1, 150.9, 137.1 (d, J = 10.0 Hz), 135.5, 134.8, 132.4(d, J = 30.0 Hz), 129.9, 129.2, 128.9, 128.8, 127.8, 127.1, 127.0, 126.0, 124.4, 119.6, 114.7 ( d , J = 75.0 Hz), 11 100.0 Hz), 109.7 (d, J =35.0 Hz), 56.8, 51.3, 43.9, 39.8, 34.3, 30.3. HRMS calculated M + (C 38 H 39 FNO 4 )m/z 592.2863, actual value 592.2866. The enantiomeric ratio was determineδto be 97:3 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8 mL/min]: 7.8 min (major),9.8 min (minor).

实施例11Example 11

在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.06 mmol, 17.8 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状液体3ca (87%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.59 (d, J = 10.0 Hz, 1H), 7.49 (s, 1H), 7.39-7.36(m, 1H), 7.28-7.26 (m, 1H), 7.25-7.22 (m, 4H), 7.05-7.04 (m, 2H), 7.02-6.99(m, 3H), 6.33 (d, J = 10.0 Hz, 1H), 5.32 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H),4.70 (s, 1H), 4.08 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.39 (d,J = 15.0 Hz, 1H), 1.34 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.5,168.4, 153.1, 150.9, 139.7, 135.5, 134.7, 132.4, 129.8, 129.0, 128.9, 128.8,128.5, 128.4, 127.9, 127.1, 127.0, 126.0, 124.3, 124.1, 119.6, 109.9, 56.8,51.4, 43.9, 39.6, 34.3, 30.3. HRMS计算值为M+(C38H39ClNO4) m/z 608.2568,实际值608.2574. The enantiomeric ratio was determineδto be 98:2 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8 mL/min]: 7.8 min (major), 9.5 min(minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1a (0.06 mmol, 17.8 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, silica gel was directly added, and column chromatography was spin-dried to obtain yellow oily liquid 3ca (87%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.59 (d, J = 10.0 Hz, 1H), 7.49 (s, 1H), 7.39-7.36(m, 1H), 7.28-7.26 (m, 1H ), 7.25-7.22 (m, 4H), 7.05-7.04 (m, 2H), 7.02-6.99(m, 3H), 6.33 (d, J = 10.0 Hz, 1H), 5.32 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.08 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.39 (d, J = 15.0 Hz, 1H), 1.34 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.5,168.4, 153.1, 150.9, 139.7, 135.5, 134.7, 132.4, 129.8, 129.5, 128.9, 128. , 128.4, 127.9, 127.1, 127.0, 126.0, 124.3, 124.1, 119.6, 109.9, 56.8,51.4, 43.9, 39.6, 34.3, 30.3. HRMS calculated for M + (C 38 H 89 ClNO 608 , 608 ) m/z 5 Actual value 608.2574. The enantiomeric ratio was determineδto be 98:2 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8 mL/min]: 7.8 min (major), 9.5 min(minor).

实施例12Example 12

在25mL的试管反应器中，用氮气交换空气3次。将底物1δ(0.06 mmol, 20.5 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3da (85%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.62-7.59 (m, 2H), 7.39-7.36 (m, 1H), 7.28-7.26 (m,1H), 7.25-7.23 (m, 4H), 7.16-7.14 (m, 1H), 7.05-7.04 (m, 2H), 6.99 (s, 2H),6.28 (d, J = 5.0 Hz, 1H), 5.31 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.69 (s,1H), 4.07 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 15.0 Hz, 1H), 2.39 (d, J = 15.0Hz, 1H), 1.34 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.4, 168.4, 153.1,150.9, 140.2, 135.5, 134.7, 132.8, 131.3, 129.8, 129.0, 128.9, 128.8, 127.9,127.1, 126.8, 126.0, 124.2, 119.7, 115.7, 110.4, 56.8, 51.4, 43.9, 39.6,34.3, 30.3. HRMS计算值为M+(C38H39NO4) m/z 652.2062,实际值652.2065. Theenantiomeric ratio was determineδto be 99:1 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8 mL/min]: 8.1 min (major), 9.7 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1δ (0.06 mmol, 20.5 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and the nitrogen was replaced by pumping , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3da (85%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.62-7.59 (m, 2H), 7.39-7.36 (m, 1H), 7.28-7.26 (m,1H), 7.25-7.23 (m, 4H) , 7.16-7.14 (m, 1H), 7.05-7.04 (m, 2H), 6.99 (s, 2H),6.28 (d, J = 5.0 Hz, 1H), 5.31 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.69 (s,1H), 4.07 (d, J = 15.0 Hz, 1H), 3.45 (d, J = 15.0 Hz, 1H), 2.39 (d, J = 15.0Hz, 1H), 1.34 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.4, 168.4, 153.1, 150.9, 140.2, 135.5, 134.7, 132.8, 131.3, 129.8, 129.0, 128.9, 12 127.1, 126.8, 126.0, 124.2, 119.7, 115.7, 110.4, 56.8, 51.4, 43.9, 39.6, 34.3, 30.3. HRMS calculated M + (C 38 H 39 NO 4 ) m/z 652.2062, actual 652.2 ratio was determineδto be 99:1 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8 mL/min]: 8.1 min (major), 9.7 min (minor).

实施例13Example 13

在25mL的试管反应器中，用氮气交换空气3次。将底物1e (0.06 mmol, 16.6 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在0 oC下反应72小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ea (66%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.59 (d, J = 10.0 Hz, 1H), 7.37-7.34 (m, 1H), 7.31(s, 1H), 7.25-7.21 (m, 5H), 7.07-7.05 (m, 2H), 6.98 (s, 2H), 6.83 (d, J = 5.0Hz, 1H), 6.30 (d, J = 10.0 Hz, 1H), 5.27 (d, J = 20.0 Hz, 1H), 5.07 (s, 1H),4.73 (s, 1H), 4.10 (d, J = 15.0 Hz, 1H), 3.44 (d, J = 15.0 Hz, 1H), 2.36 (d,J = 15.0 Hz, 1H), 2.32 (s, 3H), 1.32 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.9, 168.9, 152.9, 151.0, 138.8, 135.3, 135.2, 132.4, 130.7, 129.8,129.6, 128.7, 128.6, 128.5, 127.6, 127.2, 127.1, 125.9, 124.8, 124.2, 119.6,108.8, 56.6, 51.2, 43.8, 39.9, 34.2, 30.3, 21.1. HRMS计算值为M+(C39H42NO4) m/z588.3114,实际值588.3118. The enantiomeric ratio was determineδto be 99:1 byHPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8 mL/min]: 7.7 min (major),10.3min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1e (0.06 mmol, 16.6 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at 0 o C for 72 hours. After the reaction was detected by TCL, silica gel was directly added, and column chromatography was spin-dried to obtain a white solid 3ea (66%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.59 (d, J = 10.0 Hz, 1H), 7.37-7.34 (m, 1H), 7.31(s, 1H), 7.25-7.21 (m, 5H ), 7.07-7.05 (m, 2H), 6.98 (s, 2H), 6.83 (d, J = 5.0Hz, 1H), 6.30 (d, J = 10.0 Hz, 1H), 5.27 (d, J = 20.0 Hz , 1H), 5.07 (s, 1H), 4.73 (s, 1H), 4.10 (d, J = 15.0 Hz, 1H), 3.44 (d, J = 15.0 Hz, 1H), 2.36 (d, J = 15.0 Hz , 1H), 2.32 (s, 3H), 1.32 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.9, 168.9, 152.9, 151.0, 138.8, 135.3, 135.2, 132.4, 130.7 , 129.8, 129.6, 128.7, 128.6, 128.5, 127.6, 127.2, 127.1, 125.9, 124.8, 124.2, 119.6, 108.8, 56.6, 51.2, 43.8, 39.9, 34.2, 210.3 calculated for M + MS 3.9 H 42 NO 4 ) m/z 588.3114, actual value 588.3118. The enantiomeric ratio was determineδto be 99:1 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8 mL/min]: 7.7 min (major),10.3min (minor).

实施例14Example 14

在25mL的试管反应器中，用氮气交换空气3次。将底物1f (0.06 mmol, 17.8 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3an (74%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.56 (d, J = 10.0 Hz, 1H), 7.41 (d, J = 10.0 Hz,1H), 7.38-7.35 (m, 1H), 7.28-7.27 (m, 1H), 7.25-7.23 (m, 4H), 7.08-7.07 (m,2H), 7.04-7.02 (m, 1H), 6.97 (s, 2H), 6.43 (s, 1H), 5.29 (d, J = 15.0 Hz,1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.44 (d, J = 15.0Hz, 1H), 2.33 (d, J = 10.0 Hz, 1H), 1.34 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.9, 168.5, 153.1, 150.9, 142.4, 135.5,134.6, 134.3, 129.9, 129.2,129.1, 128.9, 128.8, 127.9, 127.1, 127.0, 126.0, 124.4, 124.3, 122.7, 119.6,109.6, 56.3, 51.3, 43.9, 39.8, 34.3, 30.3. HRMS计算值为M+ (C38H39NO4) m/z608.2568, 实际值608.2572. The enantiomeric ratio was determineδto be 97:3 byHPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 96:4, 0.8 mL/min]: 7.9 min (major),9.8 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1f (0.06 mmol, 17.8 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3an (74%). 1 H NMR (CDCl 3 , 500 MHz): δ(ppm) 7.56 (d, J = 10.0 Hz, 1H), 7.41 (d, J = 10.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.28- 7.27 (m, 1H), 7.25-7.23 (m, 4H), 7.08-7.07 (m,2H), 7.04-7.02 (m, 1H), 6.97 (s, 2H), 6.43 (s, 1H), 5.29 ( d, J = 15.0 Hz,1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.44 (d, J = 15.0Hz, 1H), 2.33 ( d, J = 10.0 Hz, 1H), 1.34 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.9, 168.5, 153.1, 150.9, 142.4, 135.5, 134.6, 134.3, 129.9, 129.2, 129.1, 128.9, 128.8, 127.9, 127.1, 127.0, 126.0, 124.4, 124.3, 122.7, 119.6, 109.6, 56.3, 51.3, 43.9, 127.1 , 127.0 , 126.0, 124.4, 124.3, 122.7, 119.6, 109.6, 56.3, 51.3, 43.9, 39.8 . 4 ) m/z608.2568, actual value 608.2572. The enantiomeric ratio was determineδto be 97:3 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 96:4, 0.8 mL/min]: 7.9 min (major) ,9.8 min (minor).

实施例15Example 15

在25mL的试管反应器中，用氮气交换空气3次。将底物1g (0.06 mmol, 20.5 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ga (81%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.56 (d, J = 10.0 Hz, 1H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 1H), 7.25-7.19 (m, 5H), 7.08-7.07 (m, 2H), 6.97 (s, 2H), 6.58 (s,1H), 5.28 (d, J = 20.0 Hz, 1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.06 (d, J = 15.0Hz, 1H), 3.43 (d, J = 10.0 Hz, 1H), 2.33 (d, J = 10.0 Hz, 1H), 1.34 (s, 18H).13C NMR (CDCl3, 125 MHz): δ(ppm) 175.8. 168.5, 153.2, 150.9, 142.6, 135.5,134.6, 129.9, 129.8, 129.2, 128.9, 128.8, 127.9, 127.1, 127.0, 126.0, 125.7,124.8, 124.3, 122.1, 119.6, 112.3, 56.3, 51.2, 43.9, 39.7, 34.3, 30.3. HRMS计算值为M+(C38H39BrNO4) m/z 652.2062, 实际值652.2065. The enantiomeric ratio wasdetermineδto be 98:2 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 96:4, 0.8mL/min]: 8.2 min (major), 10.0 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1g (0.06 mmol, 20.5 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, silica gel was directly added, and column chromatography was spin-dried to obtain a white solid 3ga (81%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.56 (d, J = 10.0 Hz, 1H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 1H), 7.25-7.19 (m , 5H), 7.08-7.07 (m, 2H), 6.97 (s, 2H), 6.58 (s,1H), 5.28 (d, J = 20.0 Hz, 1H), 5.13 (s, 1H), 4.69 (s, 1H), 4.06 (d, J = 15.0Hz, 1H), 3.43 (d, J = 10.0 Hz, 1H), 2.33 (d, J = 10.0 Hz, 1H), 1.34 (s, 18H). 13 C NMR ( CDCL 3 , 125 MHz): Δ (PPM) 175.8. 168.5, 153.2, 150.9, 142.6, 135.5,134.6, 129.8, 129.2, 128.9, 127.9, 127.0, 126.0, 125.7, 124.3, 122.1.1.1 , 119.6, 112.3, 56.3, 51.2, 43.9, 39.7, 34.3, 30.3. HRMS calculated value M + (C 38 H 39 BrNO 4 ) m/z 652.2062, actual value 652.2065. The enantiomeric ratio was determinedδto be PLC98:2 by H . [IΔcolumn, 254 nm, n -hexane:EtOH = 96:4, 0.8mL/min]: 8.2 min (major), 10.0 min (minor).

实施例16Example 16

在25mL的试管反应器中，用氮气交换空气3次。将底物1h (0.06 mmol, 16.9 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在0 oC下反应72小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ha (86%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.55 (d, J = 5.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.29-7.27 (m, 2H), 7.24-7.21 (m, 4H), 7.18-7.16 (m, 2H), 7.02-6.97 (m, 3H), 6.85-6.81 (m, 1H), 5.34 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.72 (s, 1H), 4.45 (d,J = 15.0 Hz, 1H), 3.41 (d, J = 10.0 Hz, 1H), 2.33 (d, J = 10.0 Hz, 1H), 1.34(s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 175.8, 168.5, 153.1, 150.9, 147.2(d, J = 975.0 Hz), 136.5, 135.5, 133.8 (d, J = 10.0 Hz), 129.9, 129.2, 128.8,128.6, 127.9 (d, J = 35.0 Hz), 127.7, 127.4, 126.9, 125.9, 124.4, 123.6 (d, J= 10.0 Hz), 119.6, 119.4 (d, J = 15.0 Hz), 116.5 (d, J = 80.0 Hz), 56.8,51.4, 45.4, 40.0, 34.3, 30.3. HRMS计算值为M+(C38H39FNO4) m/z 592.2863,实际值592.2867. The enantiomeric ratio was determineδto be 98:2 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 9:1, 0.8 mL/min]: 6.6 min (major), 7.7 min(minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1h (0.06 mmol, 16.9 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in sequence, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at 0 o C for 72 hours. After the reaction was detected by TCL, silica gel was directly added, and column chromatography was spin-dried to obtain a white solid 3ha (86%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.55 (d, J = 5.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.29-7.27 (m, 2H), 7.24-7.21 (m , 4H), 7.18-7.16 (m, 2H), 7.02-6.97 (m, 3H), 6.85-6.81 (m, 1H), 5.34 (d, J = 15.0 Hz, 1H), 5.12 (s, 1H), 4.72 (s, 1H), 4.45 (d, J = 15.0 Hz, 1H), 3.41 (d, J = 10.0 Hz, 1H), 2.33 (d, J = 10.0 Hz, 1H), 1.34(s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 175.8, 168.5, 153.1, 150.9, 147.2(d, J = 975.0 Hz), 136.5, 135.5, 133.8 (d, J = 10.0 Hz), 129.9, 129.2 , 128.8, 128.6, 127.9 (d, J = 35.0 Hz), 127.7, 127.4, 126.9, 125.9, 124.4, 123.6 (d, J = 10.0 Hz), 119.6, 119.4 (d, J = 15.0 Hz), 116.5 (d , J = 80.0 Hz), 56.8,51.4, 45.4, 40.0, 34.3, 30.3. The calculated HRMS value was M + (C 38 H 39 FNO 4 ) m/z 592.2863, and the actual value was 592.2867. The enantiomeric ratio was determineδto be 98: 2 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH = 9:1, 0.8 mL/min]: 6.6 min (major), 7.7 min(minor).

实施例17Example 17

在25 mL的试管反应器中，用氮气交换空气3次。将底物1i (0.06 mmol, 17.8 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ia (71%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.52 (d, J = 5.0 Hz, 1H), 7.42-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.19 (m, 5H), 7.07-7.03 (m, 2H), 7.02-6.98 (m, 2H), 6.94(s, 2H), 5.38 (d, J = 20.0 Hz, 1H), 5.11 (s, 1H), 5.06 (d, J = 20.0 Hz, 1H),4.71 (s, 1H), 3.43 (d, J = 15.0 Hz, 1H), 2.38 (d, J = 10.0 Hz, 1H), 1.34 (s,18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 176.8, 168.6, 153.2, 150.9, 137.4,136.9, 135.5, 133.9, 130.9, 129.9, 129.2, 128.8, 128.6, 127.4, 126.7, 126.5,126.0, 124.3, 123.8, 122.0, 119.5, 115.4, 56.2, 51.7, 44.9, 40.2, 34.3, 30.3.HRMS计算值为M+(C38H39ClNO4) m/z 608.2568, 实际值608.2572. The enantiomericratio was determineδto be 99:1 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH =9:1, 0.8 mL/min]: 6.7 min (major), 7.9 min (minor).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1i (0.06 mmol, 17.8 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, silica gel was added directly, and column chromatography was spin-dried to obtain a white solid 3ia (71%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.52 (d, J = 5.0 Hz, 1H), 7.42-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.19 (m , 5H), 7.07-7.03 (m, 2H), 7.02-6.98 (m, 2H), 6.94(s, 2H), 5.38 (d, J = 20.0 Hz, 1H), 5.11 (s, 1H), 5.06 ( d, J = 20.0 Hz, 1H), 4.71 (s, 1H), 3.43 (d, J = 15.0 Hz, 1H), 2.38 (d, J = 10.0 Hz, 1H), 1.34 (s, 18H). 13 C NMR (CDCL 3 , 125 MHz): Δ (PPM) 176.8, 168.6, 153.2, 150.9, 137.4,136.9, 135.5, 133.9, 130.9, 129.2, 128.6, 127.7, 126.5,126.0, 123.8, 123.8, 123.8 , 122.0, 119.5, 115.4, 56.2, 51.7, 44.9, 40.2, 34.3, 30.3. HRMS calculated M + (C 38 H 39 ClNO 4 ) m/z 608.2568, actual value 608.2572. The enantiomericratio was determine9δ1to be 9 by HPLC. [IΔcolumn, 254 nm, n -hexane:EtOH =9:1, 0.8 mL/min]: 6.7 min (major), 7.9 min (minor).

实施例18Example 18

在25 mL的试管反应器中，用氮气交换空气3次。将底物1j (0.06 mmol, 14.9 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ja (84%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.61-7.58 (m, 2H), 7.46-7.42 (m, 2H), 7.37-7.33 (m,2H), 7.24-7.19 (m, 2H), 7.17-7.10 (m, 4H), 7.00 (s, 2H), 6.65 (d, J = 10.0Hz, 1H), 5.09 (s, 1H), 4.79 (s, 1H), 3.48 (d, J = 15.0 Hz, 1H), 2.48 (d, J =10.0 Hz, 1H), 1.25 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 174.9, 168.7,153.1, 151.0, 141.9, 135.3, 133.9, 130.7, 129.9, 129.4, 129.3, 128.6, 128.4,127.8, 127.4, 125.9, 125.8, 124.6, 123.7, 123.3, 119.6, 109.4, 56.6, 51.5,40.1, 34.2, 30.2. HRMS计算值为M+(C37H38NO4) m/z 560.2801, 实际值560.2805. Theenantiomeric ratio was determineδto be 96:4 by HPLC. [IΔcolumn, 254 nm, n-hexane:IPA = 95:5, 0.8 mL/min]: 11.9 min (minor), 13.2 min (major).In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1j (0.06 mmol, 14.9 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ja (84%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.61-7.58 (m, 2H), 7.46-7.42 (m, 2H), 7.37-7.33 (m,2H), 7.24-7.19 (m, 2H) , 7.17-7.10 (m, 4H), 7.00 (s, 2H), 6.65 (d, J = 10.0Hz, 1H), 5.09 (s, 1H), 4.79 (s, 1H), 3.48 (d, J = 15.0 Hz, 1H), 2.48 (d, J =10.0 Hz, 1H), 1.25 (s, 18H). 13 C NMR (CDCl 3 , 125 MHz): δ(ppm) 174.9, 168.7, 153.1, 151.0, 141.9, 135.3 , 133.9, 130.7, 129.9, 129.4, 129.3, 128.6, 128.4, 127.8, 125.9, 125.8, 123.7, 123.3, 119.6, 56.6, 51.5, 40.1, 34.2. HRMS calculation value is m + (HRMS calculation value M + ((HRMS is m + (m + (HRMS (HRMS is m + (m + (HRMS. C 37 H 38 NO 4 ) m/z 560.2801, actual value 560.2805. Theenantiomeric ratio was determineδto be 96:4 by HPLC. [IΔcolumn, 254 nm, n -hexane:IPA = 95:5, 0.8 mL/min]: 11.9 min (minor), 13.2 min (major).

实施例19Example 19

在25 mL的试管反应器中，用氮气交换空气3次。将底物1k (0.06 mmol, 11.2 mg)，底物2a (0.05 mmol, 15.5 mg)，醋酸钠 (0.05 mmol, 4.1 mg)，催化剂 (0.005 mmol, 3.3mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入DCE (0.3 mL)，在室温下反应48小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到白色固体3ka (89%)。1H NMR(CDCl3, 500 MHz): δ(ppm) 7.55 (d, J = 5.0 Hz, 1H), 7.50 (d, J = 5.0 Hz, 1H),7.37-7.34 (m, 1H), 7.25-7.22 (m, 2H), 7.16-7.13 (m, 1H), 7.09-7.06 (m, 1H),6.91 (s, 2H), 6.52 (d, J = 10.0 Hz, 1H), 5.02 (s, 1H), 4.68 (s, 1H), 3.37 (d,J = 15.0 Hz, 1H), 3.03 (s, 3H), 2.34 (d, J = 15.0 Hz, 1H), 1.29 (s, 18H). 13CNMR (CDCl3, 125 MHz): δ(ppm) 175.6, 169.0, 152.9, 150.9, 142.1, 135.2, 130.9,129.8, 129.4, 128.6, 128.5, 126.9, 125.9, 124.5, 123.3, 122.8, 119.5, 107.7,56.6, 51.6, 39.4, 34.2, 30.3, 26.3. HRMS计算值为M+ (C32H36NO4) m/z 498.2644,实际值498.2648. The enantiomeric ratio was determineδto be 92:8 by HPLC. [IΔcolumn, 254 nm, n-hexane:EtOH = 95:5, 0.8 mL/min]: 13.5 min (minor), 14.4 min(major)。In a 25 mL test tube reactor, exchange the air with nitrogen 3 times. Substrate 1k (0.06 mmol, 11.2 mg), substrate 2a (0.05 mmol, 15.5 mg), sodium acetate (0.05 mmol, 4.1 mg), catalyst (0.005 mmol, 3.3 mg) were weighed into the reaction tube in turn, and evacuated for nitrogen , and DCE (0.3 mL) was added under nitrogen atmosphere, and reacted at room temperature for 48 hours. After the reaction was detected by TCL, directly add silica gel, spin dry column chromatography, and obtain a white solid 3ka (89%). 1 H NMR(CDCl 3 , 500 MHz): δ(ppm) 7.55 (d, J = 5.0 Hz, 1H), 7.50 (d, J = 5.0 Hz, 1H),7.37-7.34 (m, 1H), 7.25- 7.22 (m, 2H), 7.16-7.13 (m, 1H), 7.09-7.06 (m, 1H),6.91 (s, 2H), 6.52 (d, J = 10.0 Hz, 1H), 5.02 (s, 1H) , 4.68 (s, 1H), 3.37 (d, J = 15.0 Hz, 1H), 3.03 (s, 3H), 2.34 (d, J = 15.0 Hz, 1H), 1.29 (s, 18H). 13 CNMR (CDCl 3 , 125 MHz): δ(ppm) 175.6, 169.0, 152.9, 150.9, 142.1, 135.2, 130.9,129.8, 129.4, 128.6, 128.5, 126.9, 125.9, 124.5, 123.3, 122.8, 119.5, 107.7,56.6, 51.6, 39.4, 34.2, 30.3, 26.3. HRMS calculated M + (C 32 H 36 NO 4 ) m/z 498.2644, actual value 498.2648. The enantiomeric ratio was determineδto be 92:8 by HPLC. [IΔcolumn, 254 nm, n -Hexane:EtOH = 95:5, 0.8 mL/min]: 13.5 min (minor), 14.4 min (major).

Claims (5)

  1. A kind of 1. synthetic method of chiral seven yuan of spiro indole ketone compounds, it is characterised in that with compound 1 and 2 for reaction Raw material, using Cabbeen as catalyst, chiral seven yuan of spiro indole ketone compounds are reacted to obtain under certain temperature in reaction dissolvent；Its In, the temperature is 20-80 DEG C；Shown in course of reaction such as formula (I)：
    Wherein R1, R2, R3And R4It is alkyl, aromatic radical or substituted aromatic ring.
  2. 2. the synthetic method of seven yuan of spiro indole ketone compounds of chirality as claimed in claim 1, it is characterised in that described to urge Agent is Cabbeen；The dosage of the catalyst is 1-100%.
  3. 3. the synthetic method of seven yuan of spiro indole ketone compounds of chirality as claimed in claim 1, it is characterised in that described anti- It is dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, methyl phenyl ethers anisole, xylene compound or acetonitrile to answer solvent.
  4. 4. the synthetic method of seven yuan of spiro indole ketone compounds of chirality as claimed in claim 1, it is characterised in that describedization The ratio of compound 1 and compound 2 is 1:1-1:5.
  5. 5. a kind of synthetic method of chiral seven yuan of spiro indole ketone compounds, course of reaction is as shown in formulas below：
    In 25 mL test tube reactor, with nitrogen exchange of air 3 times；By 0.06 mmol substrates 1a, 0.05 mmol substrates 2a Reaction tube is weighed into successively with 0.005 mmol Cabbeens, and nitrogen is changed in evacuation, and adds 0.3 mL DCE under nitrogen atmosphere；Will be anti- System is answered to react at room temperature 48 hours；After TCL detection reactions terminate, directly add silica gel, be spin-dried for column chromatography, obtain 3aa.
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CN116768895A (en) * 2022-03-11 2023-09-19 南开大学 A kind of synthesis method of chiral polycyclic indole compounds

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