CN109535059B - Method for efficiently synthesizing optically active 2-pyrroline compound by asymmetric organic phosphine catalysis - Google Patents

Method for efficiently synthesizing optically active 2-pyrroline compound by asymmetric organic phosphine catalysis Download PDF

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CN109535059B
CN109535059B CN201811539457.4A CN201811539457A CN109535059B CN 109535059 B CN109535059 B CN 109535059B CN 201811539457 A CN201811539457 A CN 201811539457A CN 109535059 B CN109535059 B CN 109535059B
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李鹏飞
钱辰骁
张庞淼淼
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Abstract

本发明属于有机合成方法领域，公开了一种不对称有机膦催化高效合成光学活性2‑吡咯啉类化合物的方法，以手性膦化合物为催化剂，式A化合物和式B化合物反应，得到式C化合物：

Figure DDA0001907647880000011
其中，Ar1选自苯基或取代苯基，Ar2选自苯基或取代苯基，R1选自磺酰系保护基，R2选自烷基或苄基。本发明的方法催化效果好，膦介导的MBH碳酸酯和α，β‑不饱和亚胺的对映选择性[1+4]环化，得到一系列光学活性多取代的2‑吡咯啉，产率高，立体选择性好，催化效率高，底物适用范围广，操作简单，成本低廉，具有非常良好的工业化应用前景。The invention belongs to the field of organic synthesis methods, and discloses a method for efficiently synthesizing optically active 2-pyrroline compounds catalyzed by asymmetric organic phosphines. A chiral phosphine compound is used as a catalyst, and a compound of formula A is reacted with a compound of formula B to obtain formula C Compound:
Figure DDA0001907647880000011
Wherein, Ar 1 is selected from phenyl or substituted phenyl, Ar 2 is selected from phenyl or substituted phenyl, R 1 is selected from sulfonyl protecting group, and R 2 is selected from alkyl or benzyl. The method of the invention has good catalytic effect, and the enantioselective [1+4] cyclization of phosphine-mediated MBH carbonate and α,β-unsaturated imine can obtain a series of optically active polysubstituted 2-pyrrolines, The invention has the advantages of high yield, good stereoselectivity, high catalytic efficiency, wide application range of substrates, simple operation and low cost, and has very good industrial application prospects.

Description

一种不对称有机膦催化高效合成光学活性2-吡咯啉类化合物 的方法Efficient synthesis of optically active 2-pyrrolines catalyzed by an asymmetric organophosphine Methods

技术领域technical field

本发明属于有机合成方法领域，具体是一种不对称有机膦催化高效合成光学活性2-吡咯啉类化合物的方法。The invention belongs to the field of organic synthesis methods, in particular to a method for efficiently synthesizing optically active 2-pyrroline compounds catalyzed by an asymmetric organic phosphine.

背景技术Background technique

手性吡咯啉及其衍生物在天然产物、药物和对映选择性催化中有着重要意义，科研工作者致力于开发吡咯啉类化合物的不对称合成方法。Chiral pyrrolines and their derivatives are of great significance in natural products, drugs, and enantioselective catalysis. Researchers are devoted to developing asymmetric synthesis methods for pyrroline compounds.

有机膦催化的对映选择性环化是一种有效的合成策略，例如，有机膦介导的亚胺或炔酸盐与亚胺的不对称[3+2]环化可以获得光学活性的3-吡咯啉类化合物，然而，不对称催化[1+4]环化合成手性吡咯啉还未见报道。Organophosphine-catalyzed enantioselective cyclization is an efficient synthetic strategy, for example, organophosphine-mediated asymmetric [3+2] cyclization of imines or alkynoates with imines can yield optically active 3 -pyrroline compounds, however, asymmetric catalyzed [1+4] cyclization to synthesize chiral pyrroline has not been reported yet.

2015年，Gregory C.Fu等人用手性螺环膦催化环磺酰胺与γ-取代丙二烯类化合物对映选择性[1+4]环化合成3-吡咯啉，同年，陈应春等人报道了手性胺介导的3-溴羟吲哚和缺电子1-氮杂二烯不对称[1+4]环化合成合成2-吡咯啉，值得注意的是，增加碱性添加剂的用量无助于提供上述环化反应的对映选择性和产率。In 2015, Gregory C.Fu et al. catalyzed the enantioselective [1+4] cyclization of cyclic sulfonamide and γ-substituted allenes to synthesize 3-pyrroline with a chiral spirocyclic phosphine. In the same year, Chen Yingchun et al. reported chiral amine-mediated asymmetric [1+4] cyclization of 3-bromooxindole and electron-deficient 1-azadiene to synthesize 2-pyrroline, notably, increasing the amount of basic additives does not contribute to the enantioselectivity and yield of the cyclization reaction described above.

鉴于Morita-Baylis-Hillman(MBH)衍生物的多样性和反应活性，施敏等用构建了膦催化的2-(叔丁氧基羰基)烯丙基叔丁基碳酸酯与羟吲哚衍生的α，β-不饱和亚胺[1+4]环化反应，以78％产率、61％ee、7：1dr得到2-吡咯啉。贺峥杰等借助于新的手性膦催化剂，开发了MBH碳酸盐和α，β-不饱和亚胺高对映选择性和非对映选择性[1+4]的环化反应，α，β-不饱和亚胺的氮原子上的取代基对膦介导的环化的立体选择性有很大影响，用其他基团(甲苯磺酰基，苯磺酰基)代替4-硝基苯磺酰基会导致对映选择性很差。In view of the diversity and reactivity of Morita-Baylis-Hillman (MBH) derivatives, Shi Min et al. constructed a phosphine-catalyzed 2-(tert-butoxycarbonyl)allyl tert-butyl carbonate and oxindole-derived α,β-Unsaturated imine [1+4] cyclization gave 2-pyrroline in 78% yield, 61% ee, 7:1 dr. With the help of a new chiral phosphine catalyst, He Zhengjie et al. developed a highly enantioselective and diastereoselective [1+4] cyclization reaction between MBH carbonate and α,β-unsaturated imine, α , Substituents on the nitrogen atom of β-unsaturated imines have a large effect on the stereoselectivity of phosphine-mediated cyclization, replacing 4-nitrobenzenesulfonyl with other groups (toluenesulfonyl, benzenesulfonyl) Acyl groups result in poor enantioselectivity.

因此，对映选择性合成多取代2-吡咯啉类化合物的合成方法仍有待发展。Therefore, synthetic methods for enantioselective synthesis of polysubstituted 2-pyrrolines still need to be developed.

发明内容SUMMARY OF THE INVENTION

本发明的目的是提供一种高收率、高选择性合成光学活性多取代2-吡咯啉类化合物的方法。The object of the present invention is to provide a method for synthesizing optically active multi-substituted 2-pyrroline compounds with high yield and high selectivity.

为达到上述目的，本发明采用以下技术方案：To achieve the above object, the present invention adopts the following technical solutions:

一种不对称合成2-吡咯啉类化合物的方法，以手性膦化合物为催化剂，式A化合物和式B化合物反应，得到式C化合物：A method for asymmetrically synthesizing 2-pyrroline compounds, using a chiral phosphine compound as a catalyst, reacting a compound of formula A with a compound of formula B to obtain a compound of formula C:

Figure BDA0001907647870000021
Figure BDA0001907647870000021

其中，Ar1选自苯基或取代苯基，Ar2选自苯基或取代苯基，R1选自磺酰系保护基，R2选自烷基或苄基。Wherein, Ar 1 is selected from phenyl or substituted phenyl, Ar 2 is selected from phenyl or substituted phenyl, R 1 is selected from sulfonyl protecting group, and R 2 is selected from alkyl or benzyl.

进一步地，所述Ar1选自苯基、卤代苯基，所述Ar2选自苯基、卤代苯基、烷基苯基，R1选自甲磺酰基、三氟甲磺酰基、对甲苯磺酰基、对硝基苯磺酰基、苯磺酰基。Further, the Ar 1 is selected from phenyl, halophenyl, the Ar 2 is selected from phenyl, halophenyl, and alkylphenyl, and R 1 is selected from methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl.

进一步地，所述Ar1选自苯基、氟苯基、溴苯基、氯苯基，所述Ar2选自苯基、氟苯基、溴苯基、氯苯基、甲苯基，R1选自对甲苯磺酰基、对硝基苯磺酰基、苯磺酰基。Further, the Ar 1 is selected from phenyl, fluorophenyl, bromophenyl, and chlorophenyl, and the Ar 2 is selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, and tolyl, and R 1 Selected from p-toluenesulfonyl, p-nitrobenzenesulfonyl, and benzenesulfonyl.

进一步地，R2选自甲基、乙基、异丁基、苄基。Further, R 2 is selected from methyl, ethyl, isobutyl, benzyl.

进一步地，所述手性膦化合物选自以下结构之一：Further, the chiral phosphine compound is selected from one of the following structures:

Figure BDA0001907647870000022
Figure BDA0001907647870000022

进一步地，所述手性膦化合物的用量至少是10mol％。Further, the amount of the chiral phosphine compound used is at least 10 mol%.

进一步地，所述反应以乙腈、二氯甲烷、氯仿、甲苯、四氢呋喃、乙酸乙酯中的一种或多种为溶剂。Further, the reaction uses one or more of acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, and ethyl acetate as a solvent.

进一步地所述式A化合物和式B化合物的摩尔比为1：1～14。Further, the molar ratio of the compound of formula A and the compound of formula B is 1:1-14.

进一步地，所述反应的温度为25℃以上。Further, the temperature of the reaction is above 25°C.

进一步地，所述反应的时间至少是48h。Further, the reaction time is at least 48h.

术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.

术语“取代苯基”指至少有一个取代基的苯基，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "substituted phenyl" refers to a phenyl group having at least one substituent, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.

术语“卤代苯基”指至少有一个卤素(氟、氯、溴、碘)作为取代基的苯基。The term "halophenyl" refers to a phenyl group having at least one halogen (fluorine, chlorine, bromine, iodine) as a substituent.

术语“烷基苯基”指至少有一个烷基作为取代基的苯基。The term "alkylphenyl" refers to a phenyl group having at least one alkyl group as a substituent.

本发明具有以下有益效果：The present invention has the following beneficial effects:

1、催化效果好，膦介导的MBH碳酸酯和α，β-不饱和亚胺的对映选择性[1+4]环化，得到一系列光学活性多取代的2-吡咯啉，产率高，ee值大多在90％以上，dr值>20：1。1. Good catalytic effect, phosphine-mediated enantioselective [1+4] cyclization of MBH carbonate and α,β-unsaturated imine to obtain a series of optically active polysubstituted 2-pyrrolines in yields High, the ee value is mostly above 90%, and the dr value is >20:1.

2、底物适用范围广，α，β-不饱和亚胺的N保护基可以是多种磺酰系保护基，取代基的电子性质和位阻大小对产率、对映选择性没有显著影响。2. The substrate is suitable for a wide range of applications. The N protecting group of α,β-unsaturated imine can be a variety of sulfonyl protecting groups. The electronic properties and steric hindrance of the substituents have no significant effect on the yield and enantioselectivity. .

3、催化效率高，催化剂用量小，可以在短时间内得到产物。3. The catalytic efficiency is high, the amount of catalyst is small, and the product can be obtained in a short time.

4、本发明操作简单，成本低廉，具有原子经济性高、环境友好等优点，具有非常良好的工业化应用前景。4. The present invention has the advantages of simple operation, low cost, high atom economy, environmental friendliness and the like, and has very good industrial application prospects.

具体实施方式Detailed ways

下面结合具体实施例对本发明做进一步的说明。The present invention will be further described below with reference to specific embodiments.

以下实施例，所有反应均在无水条件下用干燥的新蒸馏溶剂进行，从钠中蒸馏出甲苯和THF，从CaH2中蒸馏出二氯甲烷，并立即使用。除非另有说明，所有化学品都可以在市场上买到，无需进一步纯化。所有反应均在干燥氮气氛下进行。薄层色谱分析(TLC)使用60F254硅胶板、254和365nm紫外光。硅胶柱层析使用粒径300～400目硅胶。NMR(400MHz 1HNMR，100MHz 13C NMR)的溶剂为氯仿或丙酮，以四甲基硅烷(TMS)为内标。化学位移的单位是ppm，耦合常数的单位是Hz。在1H NMR中，δ表示化学位移，s表示单峰，d表示双峰，t表示三重峰，q表示四重峰，m表示多重峰。在13C NMR中，δ表示化学位移。高分辨质谱(HRMS)使用ESI电离。In the following examples, all reactions were performed under anhydrous conditions with dry freshly distilled solvent, toluene and THF were distilled from sodium, and dichloromethane was distilled from CaH, and used immediately. All chemicals were commercially available without further purification unless otherwise stated. All reactions were carried out under dry nitrogen atmosphere. Thin layer chromatography (TLC) was performed using 60F254 silica gel plates, 254 and 365 nm UV light. Silica gel column chromatography uses silica gel with a particle size of 300-400 mesh. The solvent for NMR (400 MHz 1 H NMR, 100 MHz 13 C NMR) was chloroform or acetone, and tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are in ppm and coupling constants are in Hz. In 1 H NMR, δ represents a chemical shift, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, and m represents a multiplet. In 13 C NMR, δ represents a chemical shift. High resolution mass spectrometry (HRMS) uses ESI ionization.

实施例1Example 1

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在CH2Cl2(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst I (10 mol%) in CH2Cl2 ( 2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

Figure BDA0001907647870000041
Figure BDA0001907647870000041

收率46％，dr>20：1，88％ee。Yield 46%, dr > 20:1, 88% ee.

白色固体，mp 102.4-105.1℃.1H NMR(500Hz,CDCl3):δ(ppm)7.71-7.68(m,2H),7.44-7.42(m,3H),7.31(d,J＝8.0Hz,2H),7.12-6.99(m,5H),6.71(d,J＝7.2Hz,2H),6.51(s,1H),6.28(s,1H),5.28(d,J＝3.6Hz,1H),5.01(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.62(t,J＝3.4Hz,1H),2.40(s,3H),2.02-1.92(m,1H),0.95(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.9,143.9,142.2,141.1,133.6,132.7,129.6,129.1,128.5,128.2,128.0,127.9,127.4,126.3,125.3,116.1,71.1,69.7,53.5,27.8,21.6,19.2,19.1.HRMS:精确质量计算[M+H]+(C30H32NO4S)为m/z 502.20466,实测值为m/z 502.20441.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝75/25,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝15.167min,tR(minor)＝17.977min.[α]30 D＝-176(c＝0.5,CH2Cl2)。White solid, mp 102.4-105.1 °C. 1 H NMR (500 Hz, CDCl 3 ): δ (ppm) 7.71-7.68 (m, 2H), 7.44-7.42 (m, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.12-6.99(m, 5H), 6.71(d, J=7.2Hz, 2H), 6.51(s, 1H), 6.28(s, 1H), 5.28(d, J=3.6Hz, 1H), 5.01(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.62(t,J＝3.4Hz,1H),2.40(s,3H),2.02-1.92(m,1H),0.95 (d, J=6.8Hz, 3H), 0.94 (d, J=6.8Hz, 3H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 144.9, 143.9, 142.2, 141.1, 133.6, 132.7 ,129.6,129.1,128.5,128.2,128.0,127.9,127.4,126.3,125.3,116.1,71.1,69.7,53.5,27.8,21.6,19.2,19.1.HRMS:Accurate mass calculation [M+H] + (C 30 H 32 NO 4 S) is m/z 502.20466, the measured value is m/z 502.20441. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=75/25, flow rate=1.0mL/min, λ=254nm , retention time: t R (major)=15.167min, t R (minor)=17.977min. [α] 30 D =-176 (c=0.5, CH 2 Cl 2 ).

实施例2Example 2

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂II(10mol％)在CH2Cl2(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst II (10 mol%) in CH2Cl2 ( 2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

Figure BDA0001907647870000051
Figure BDA0001907647870000051

收率6％，dr>20：1，86％ee。Yield 6%, dr > 20:1, 86% ee.

实施例3Example 3

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂III(10mol％)在CH2Cl2(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst III (10 mol%) in CH2Cl2 ( 2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

Figure BDA0001907647870000052
Figure BDA0001907647870000052

收率5％，dr>20：1，67％ee。Yield 5%, dr > 20:1, 67% ee.

实施例4Example 4

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在CHCl3(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst 1 (10 mol%) in CHCl3 (2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率11％，dr>20：1，80％ee。Yield 11%, dr > 20:1, 80% ee.

实施例5Example 5

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在甲苯(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst 1 (10 mol%) in toluene (2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率49％，dr>20：1，82％ee。Yield 49%, dr > 20:1, 82% ee.

实施例6Example 6

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在THF(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst 1 (10 mol%) in THF (2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率28％，dr>20：1，84％ee。Yield 28%, dr > 20:1, 84% ee.

实施例7Example 7

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在EtOAc(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst I (10 mol%) in EtOAc (2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率38％，dr>20：1，87％ee。Yield 38%, dr > 20:1, 87% ee.

实施例8Example 8

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在MeCN(2.0mL)中的混合物于25℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst I (10 mol%) in MeCN (2.0 mL) was stirred at 25 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率37％，dr>20：1，94％ee。Yield 37%, dr > 20:1, 94% ee.

实施例9Example 9

在氮气气氛下密封管中，将化合物1a(0.25mmol)、化合物2a(0.30mmol)、催化剂I(10mol％)在MeCN(2.0mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25 mmol), compound 2a (0.30 mmol), catalyst I (10 mol%) in MeCN (2.0 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率42％，dr>20：1，93％ee。Yield 42%, dr > 20:1, 93% ee.

实施例10Example 10

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2a(0.18mmol)、催化剂I(10mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2a (0.18 mmol), catalyst 1 (10 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率67％，dr>20：1，91％ee。Yield 67%, dr > 20:1, 91% ee.

实施例11Example 11

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率75％，dr>20：1，91％ee。Yield 75%, dr > 20:1, 91% ee.

实施例12Example 12

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌56h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3aa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 56 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3aa.

收率65％，dr>20：1，90％ee。Yield 65%, dr>20:1, 90% ee.

实施例13Example 13

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2b(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ab。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2b (0.18 mmol), catalyst 1 (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ab.

Figure BDA0001907647870000081
Figure BDA0001907647870000081

收率70％，dr>20：1，88％ee。Yield 70%, dr>20:1, 88%ee.

白色固体,mp 131.4-132.6℃,56.9mg.1H NMR(400Hz,CDCl3):δ(ppm)7.67-7.65(m,2H),7.41-7.31(m,8H),7.27(d,J＝8.0Hz,2H),7.10-6.94(m,5H),6.66(d,J＝7.2Hz,2H),6.54(s,1H),6.28(s,1H),5.30-5.21(m,3H),5.03(d,J＝2.8Hz,1H),3.60(t,J＝3.4Hz,1H),2.36(s,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.6,144.9,143.9,142.2,140.9,135.6,133.6,132.7,129.6,129.2,128.6,128.5,128.3,128.2,128.0,127.9,127.4,126.3,126.1,116.0,69.8,66.9,53.5,21.6.HRMS:精确质量计算[M+H]+(C33H30NO4S)为m/z536.18901,实测值为m/z536.18842.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝19.861min,tR(minor)＝30.665min.[α]30 D＝-142(c＝0.5,CH2Cl2)。White solid, mp 131.4-132.6°C, 56.9 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.67-7.65 (m, 2H), 7.41-7.31 (m, 8H), 7.27 (d, J= 8.0Hz, 2H), 7.10-6.94(m, 5H), 6.66(d, J=7.2Hz, 2H), 6.54(s, 1H), 6.28(s, 1H), 5.30-5.21(m, 3H), 5.03 (d, J=2.8Hz, 1H), 3.60 (t, J=3.4Hz, 1H), 2.36 (s, 3H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.6, 144.9, 143.9 ,142.2,140.9,135.6,133.6,132.7,129.6,129.2,128.6,128.5,128.3,128.2,128.0,127.9,127.4,126.3,126.1,116.0,69.8,66.9,53.5,21.6.HRMS: Exact mass calculation +H] + (C 33 H 30 NO 4 S) is m/z536.18901, the found value is m/z536.18842. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, Flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 19.861 min, t R (minor) = 30.665 min. [α] 30 D = -142 (c = 0.5, CH 2 Cl 2 ) .

实施例14Example 14

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2c(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ac。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2c (0.18 mmol), catalyst 1 (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ac.

Figure BDA0001907647870000082
Figure BDA0001907647870000082

收率76％，dr>20：1，89％ee。Yield 76%, dr > 20:1, 89% ee.

白色固体,mp 115.8-117.0℃,51.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.67(m,2H),7.43-7.42(m,3H),7.30(d,J＝8.4Hz,2H),7.13-7.00(m,5H),6.72(d,J＝7.2Hz,2H),6.50(s,1H),6.26(s,1H),5.27(d,J＝3.6Hz,1H),5.01(d,J＝2.8Hz,1H),4.32-4.25(m,2H),3.62(t,J＝3.2Hz,1H),2.40(s,3H),1.30(t,J＝7.0Hz,3H).13C NMR(126Hz,CDCl3):δ(ppm)165.9,145.0,143.9,142.4,141.1,133.7,132.7,129.7,129.2,128.6,128.3,128.1,128.0,127.5,126.4,125.6,116.2,69.9,61.2,53.5,21.7,14.3.HRMS:精确质量计算[M+H]+(C28H28NO4S)为m/z474.17336,实测值为m/z 474.17212.HPLC条件:DaicelChiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝15.219min,tR(minor)＝19.67min.[α]30 D＝-122(c＝0.5,CH2Cl2)。White solid, mp 115.8-117.0°C, 51.7 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.70-7.67 (m, 2H), 7.43-7.42 (m, 3H), 7.30 (d, J= 8.4Hz, 2H), 7.13-7.00(m, 5H), 6.72(d, J=7.2Hz, 2H), 6.50(s, 1H), 6.26(s, 1H), 5.27(d, J=3.6Hz, 1H), 5.01(d, J=2.8Hz, 1H), 4.32-4.25(m, 2H), 3.62(t, J=3.2Hz, 1H), 2.40(s, 3H), 1.30(t, J=7.0 Hz, 3H). 13 C NMR (126 Hz, CDCl 3 ): δ(ppm) 165.9, 145.0, 143.9, 142.4, 141.1, 133.7, 132.7, 129.7, 129.2, 128.6, 128.3, 128.1, 128.0, 127.5, 126.4, 125.6 , 116.2, 69.9, 61.2, 53.5, 21.7, 14.3. HRMS: Accurate mass calculation [M+H] + (C 28 H 28 NO 4 S) is m/z 474.17336, found m/z 474.17212. HPLC conditions : DaicelChiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0mL/min, λ=254nm, retention time: t R (major)=15.219min, t R (minor)=19.67min. [α] 30 D = -122 (c=0.5, CH 2 Cl 2 ).

实施例15Example 15

在氮气气氛下密封管中，将化合物1a(0.15mmol)、化合物2d(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ad。In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.15 mmol), compound 2d (0.18 mmol), catalyst 1 (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ad.

Figure BDA0001907647870000091
Figure BDA0001907647870000091

收率86％，dr>20：1，88％ee。Yield 86%, dr>20:1, 88% ee.

白色固体,mp 135.7-137.4℃,58.9mg.1H NMR(500Hz,CDCl3):δ(ppm)7.69-7.68(m,2H),7.43-7.42(m,3H),7.30(d,J＝8.0Hz,2H),7.13-7.10(m,1H),7.07-7.01(m,4H),6.70(d,J＝7.5Hz,2H),6.51(s,1H),6.29(s,1H),5.27(d,J＝3.5Hz,1H),5.00(d,J＝2.5Hz,1H),3.83(s,3H),3.60(t,J＝3.3Hz,1H),2.40(s,3H).13C NMR(100Hz,CDCl3):δ(ppm)166.3,145.0,143.9,142.3,140.7,133.8,132.7,129.7,129.3,128.6,128.3,128.1,128.0,127.5,126.4,125.9,116.1,69.9,53.5,52.1,21.7.HRMS:精确质量计算[M+H]+(C27H26NO4S)为m/z 460.15771,实测值为m/z 460.15695.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝15.185min,tR(minor)＝20.817min.[α]30 D＝-186(c＝0.5,CH2Cl2)。White solid, mp 135.7-137.4°C, 58.9 mg. 1 H NMR (500 Hz, CDCl 3 ): δ (ppm) 7.69-7.68 (m, 2H), 7.43-7.42 (m, 3H), 7.30 (d, J= 8.0Hz, 2H), 7.13-7.10(m, 1H), 7.07-7.01(m, 4H), 6.70(d, J=7.5Hz, 2H), 6.51(s, 1H), 6.29(s, 1H), 5.27(d,J＝3.5Hz,1H),5.00(d,J＝2.5Hz,1H),3.83(s,3H),3.60(t,J＝3.3Hz,1H),2.40(s,3H). 13 C NMR (100 Hz, CDCl 3 ): δ(ppm) 166.3, 145.0, 143.9, 142.3, 140.7, 133.8, 132.7, 129.7, 129.3, 128.6, 128.3, 128.1, 128.0, 127.5, 126.4, 125.9, 116.1, 9 53.5, 52.1, 21.7. HRMS: Accurate mass calculated [M+H] + (C 27 H 26 NO 4 S) as m/z 460.15771, found m/z 460.15695. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0mL/min, λ=254nm, retention time: t R (major)=15.185min, t R (minor)=20.817min. [α] 30 D =- 186 (c=0.5, CH2Cl2 ) .

实施例16Example 16

在氮气气氛下密封管中，将化合物1b(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ba。In a sealed tube under nitrogen atmosphere, a mixture of compound 1b (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ba.

Figure BDA0001907647870000101
Figure BDA0001907647870000101

收率51％，dr>20：1，88％ee。Yield 51%, dr > 20:1, 88% ee.

白色固体,mp 144.0-145.5℃,42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.92(d,J＝8.4Hz,2H),7.73-7.71(m,2H),7.49-7.47(m,5H),7.10-6.94(m,5H),6.53(s,1H),6.31(s,1H),5.51(d,J＝3.6Hz,1H),5.19(s,1H),4.06(d,J＝6.8Hz,2H),3.66(s,1H),2.09-1.99(m,1H),1.00(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,150.4,144.6,142.4,142.1,140.2,132.0,129.8,128.9,128.5,128.4,127.1,126.8,125.5,124.0,116.9,71.5,70.4,52.2,27.9,19.3.HRMS:精确质量计算[M+H]+(C29H29N2O6S)为m/z 533.17408,实测值为m/z 533.17334.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝70/30,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝21.99min,tR(minor)＝28.041min.[α]30 D＝-122(c＝0.5,CH2Cl2)。White solid, mp 144.0-145.5°C, 42.4 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.92 (d, J=8.4 Hz, 2H), 7.73-7.71 (m, 2H), 7.49-7.47 (m,5H),7.10-6.94(m,5H),6.53(s,1H),6.31(s,1H),5.51(d,J＝3.6Hz,1H),5.19(s,1H),4.06( d, J=6.8Hz, 2H), 3.66(s, 1H), 2.09-1.99(m, 1H), 1.00(d, J=6.8Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ( ppm) 165.9, 150.4, 144.6, 142.4, 142.1, 140.2, 132.0, 129.8, 128.9, 128.5, 128.4, 127.1, 126.8, 125.5, 124.0, 116.9, 71.5, 70.4, 52.2, 27.9, 19.3.HRMS: Exact mass calculation [ M+H] + (C 29 H 29 N 2 O 6 S) is m/z 533.17408, found m/z 533.17334. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=70/30 , flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 21.99 min, t R (minor) = 28.041 min. [α] 30 D = -122 (c = 0.5, CH 2 Cl 2 ).

实施例17Example 17

在氮气气氛下密封管中，将化合物1b(0.15mmol)、化合物2c(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3bc。In a sealed tube under nitrogen atmosphere, a mixture of compound 1b (0.15 mmol), compound 2c (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3bc.

Figure BDA0001907647870000111
Figure BDA0001907647870000111

收率42％，dr>20：1，87％ee。Yield 42%, dr > 20:1, 87% ee.

白色固体,mp 128.6-129.6℃,32.5mg.1H NMR(500Hz,CDCl3):δ(ppm)7.93(d,J＝9.0Hz,2H),7.73-7.71(m,2H),7.49-7.47(m,5H),7.10-7.07(m,1H),7.02-6.94(m,4H),6.54(s,1H),6.30(s,1H),5.51(d,J＝4.0Hz,1H),5.18(s,1H),4.39-4.29(m,2H),3.66(t,J＝2.5Hz,1H),1.37(t,J＝7.3Hz,3H).13C NMR(126Hz,CDCl3):δ(ppm)165.8,150.3,144.5,142.3,142.0,140.0,131.9,129.7,128.8,128.4,128.3,127.0,126.7,125.6,123.9,116.8,70.3,61.4,52.0,14.3.HRMS:精确质量计算[M+H]+(C27H25N2O6S)为m/z 505.14278,实测值为m/z 505.14230.HPLC条件:Daicel Chiralpak AD-H柱,正己烷/异丙醇＝95/5,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝12.7min,tR(minor)＝15.555min.[α]30 D＝-152(c＝0.5,CH2Cl2)。White solid, mp 128.6-129.6°C, 32.5 mg. 1 H NMR (500 Hz, CDCl 3 ): δ (ppm) 7.93 (d, J=9.0 Hz, 2H), 7.73-7.71 (m, 2H), 7.49-7.47 (m, 5H), 7.10-7.07(m, 1H), 7.02-6.94(m, 4H), 6.54(s, 1H), 6.30(s, 1H), 5.51(d, J＝4.0Hz, 1H), 5.18 (s, 1H), 4.39-4.29 (m, 2H), 3.66 (t, J=2.5Hz, 1H), 1.37 (t, J=7.3Hz, 3H). 13 C NMR (126 Hz, CDCl 3 ): δ(ppm) 165.8, 150.3, 144.5, 142.3, 142.0, 140.0, 131.9, 129.7, 128.8, 128.4, 128.3, 127.0, 126.7, 125.6, 123.9, 116.8, 70.3, 61.4, 52.0, 14.3.HRMS: Accurate Mass Calculation M+H] + (C 27 H 25 N 2 O 6 S) is m/z 505.14278, found m/z 505.14230. HPLC conditions: Daicel Chiralpak AD-H column, n-hexane/isopropanol=95/5 , flow rate = 1.0mL/min, λ = 254nm, retention time: t R (major) = 12.7min, t R (minor) = 15.555min. [α] 30 D = -152 (c = 0.5, CH 2 Cl 2 ).

实施例18Example 18

在氮气气氛下密封管中，将化合物1c(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ca。In a sealed tube under nitrogen atmosphere, a mixture of compound 1c (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ca.

Figure BDA0001907647870000112
Figure BDA0001907647870000112

收率69％，dr>20：1，90％ee。Yield 69%, dr>20:1, 90% ee.

无色油状,53.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.68-7.66(m,2H),7.52-7.41(m,6H),7.32-7.28(m,2H),7.11-7.00(m,3H),6.68(d,J＝7.6Hz,2H),6.50(s,1H),6.26(s,1H),5.25(d,J＝3.6Hz,1H),5.04(d,J＝3.2Hz,1H),4.07-3.95(m,2H),3.63(t,J＝3.2Hz,1H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝8.4Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.8,142.3,141.2,136.9,133.2,132.6,129.3,129.0,128.6,128.5,128.2,128.0,127.5,126.7,125.4,116.3,71.5,70.0,53.8,27.9,19.3,19.2.HRMS:精确质量计算[M+H]+(C29H30NO4S)为m/z 488.18901,实测值为m/z 488.18842.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝70/30,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝13.928min,tR(minor)＝15.937min.[α]30 D＝-162(c＝0.5,CH2Cl2)。Colorless oil, 53.7 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.68-7.66 (m, 2H), 7.52-7.41 (m, 6H), 7.32-7.28 (m, 2H), 7.11- 7.00(m, 3H), 6.68(d, J=7.6Hz, 2H), 6.50(s, 1H), 6.26(s, 1H), 5.25(d, J=3.6Hz, 1H), 5.04(d, J =3.2Hz,1H),4.07-3.95(m,2H),3.63(t,J=3.2Hz,1H),2.01-1.91(m,1H),0.94(d,J=6.8Hz,3H),0.93 (d, J=8.4 Hz, 3H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 144.8, 142.3, 141.2, 136.9, 133.2, 132.6, 129.3, 129.0, 128.6, 128.5, 128.2, 128.0 , 127.5, 126.7, 125.4, 116.3, 71.5, 70.0, 53.8, 27.9, 19.3, 19.2. HRMS: Accurate mass calculation [M+H] + (C 29 H 30 NO 4 S) as m/z 488.18901, measured value m/z 488.18842.HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=13.928 min, t R (minor) = 15.937 min. [α] 30 D = -162 (c = 0.5, CH 2 Cl 2 ).

实施例19Example 19

在氮气气氛下密封管中，将化合物1d(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3da。In a sealed tube under nitrogen atmosphere, a mixture of compound 1d (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3da.

Figure BDA0001907647870000121
Figure BDA0001907647870000121

收率72％，dr>20：1，92％ee。Yield 72%, dr > 20:1, 92% ee.

无色油状,54.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.68(m,2H),7.44-7.42(m,3H),7.28(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.78-6.67(m,4H),6.51(s,1H),6.31(s,1H),5.27(d,J＝3.6Hz,1H),5.00(t,J＝1.2Hz,1H),4.06-3.97(m,2H),3.58(t,J＝3.0Hz,1H),2.41(s,3H),2.05-1.95(m,1H),0.97(d,J＝6.4Hz,3H),0.96(d,J＝6.4Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)166.0,161.5(J＝243.6Hz),145.2,141.1,140.7,138.3,133.8,132.6,129.6,129.4,129.1(J＝7.8Hz),128.5,128.0,125.4,115.7,114.9(J＝21.0Hz),71.2,69.8,52.4,27.9,21.6,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SF)为m/z520.19523,实测值为m/z 520.19421.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.562min,tR(minor)＝12.394min.[α]30 D＝-180(c＝0.5,CH2Cl2)。Colorless oil, 54.7 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.70-7.68 (m, 2H), 7.44-7.42 (m, 3H), 7.28 (d, J=8.0 Hz, 2H) ,7.05(d,J＝8.0Hz,2H),6.78-6.67(m,4H),6.51(s,1H),6.31(s,1H),5.27(d,J＝3.6Hz,1H),5.00( t, J=1.2Hz, 1H), 4.06-3.97(m, 2H), 3.58(t, J=3.0Hz, 1H), 2.41(s, 3H), 2.05-1.95(m, 1H), 0.97(d , J=6.4Hz, 3H), 0.96 (d, J=6.4Hz, 3H). 13 C NMR (100Hz, CDCl 3 ): δ (ppm) 166.0, 161.5 (J=243.6Hz), 145.2, 141.1, 140.7 HRMS : Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SF) is m/z 520.19523, the measured value is m/z 520.19421. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 9.562 min, t R (minor) = 12.394 min. [α] 30 D = -180 (c = 0.5, CH 2 Cl 2 ).

实施例20Example 20

在氮气气氛下密封管中，将化合物1e(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ea。In a sealed tube under nitrogen atmosphere, a mixture of compound 1e (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ea.

Figure BDA0001907647870000131
Figure BDA0001907647870000131

收率63％，dr>20：1，93％ee。Yield 63%, dr > 20:1, 93% ee.

白色固体,mp 132.7-134.0℃,49.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.69(m,2H),7.44-7.43(m,3H),7.26-7.24(m,2H),7.03-6.96(m,4H),6.79(d,J＝8.4Hz,2H),6.51(s,1H),6.32(s,1H),5.29(d,J＝3.2Hz,1H),5.03(t,J＝1.0Hz,1H),4.06-3.98(m,2H),3.57(t,J＝3.0Hz,1H),2.41(s,3H),2.06-1.96(m,1H),0.97(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)166.0,145.5,144.3,141.1,140.5,133.7,132.5,132.2,129.5,129.4,128.8,128.5,128.3,128.1,127.9,125.5,115.4,71.3,69.7,52.2,27.9,21.6,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SCl)为m/z 536.16568,实测值为m/z536.16455.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.993min,tR(minor)＝13.444min.[α]30 D＝-148(c＝0.5,CH2Cl2)。White solid, mp 132.7-134.0°C, 49.3 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.71-7.69 (m, 2H), 7.44-7.43 (m, 3H), 7.26-7.24 (m, 2H), 7.03-6.96(m, 4H), 6.79(d, J=8.4Hz, 2H), 6.51(s, 1H), 6.32(s, 1H), 5.29(d, J=3.2Hz, 1H), 5.03(t,J＝1.0Hz,1H),4.06-3.98(m,2H),3.57(t,J＝3.0Hz,1H),2.41(s,3H),2.06-1.96(m,1H),0.97 (d, J=6.8Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 166.0, 145.5, 144.3, 141.1, 140.5, 133.7, 132.5, 132.2, 129.5, 129.4, 128.8, 128.5, 128.3 , 128.1, 127.9, 125.5, 115.4, 71.3, 69.7, 52.2, 27.9, 21.6, 19.3, 19.2. HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SCl) as m/z 536.16568, measured The value is m/z 536.16455. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=9.993 min,t R (minor) = 13.444 min. [α] 30 D = -148 (c = 0.5, CH 2 Cl 2 ).

实施例21Example 21

在氮气气氛下密封管中，将化合物1f(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3fa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1f (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3fa.

Figure BDA0001907647870000141
Figure BDA0001907647870000141

收率53％，dr>20：1，93％ee。Yield 53%, dr>20:1, 93% ee.

白色固体,mp 141.9-143.5℃,45.9mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.69(m,2H),7.44-7.43(m,3H),7.25-7.23(m,2H),7.12(d,J＝8.4Hz,2H),7.02(d,J＝8.0Hz,2H),6.74(d,J＝8.4Hz,2H),6.51(s,1H),6.32(s,1H),5.29(d,J＝3.6Hz,1H),5.04(d,J＝0.8Hz,1H),4.06-3.98(m,2H),3.55(t,J＝2.8Hz,1H),2.42(s,3H),2.06-1.96(m,1H),0.98(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)166.0,145.6,144.4,141.6,140.5,133.7,132.5,131.2,129.5,129.2,128.5,128.1,127.9,125.5,120.3,115.3,71.3,69.7,52.2,27.9,21.7,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SBr)为m/z 580.11517,实测值为m/z580.11359.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝10.412min,tR(minor)＝14.071min.[α]30 D＝-172(c＝0.5,CH2Cl2)。White solid, mp 141.9-143.5°C, 45.9 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.71-7.69 (m, 2H), 7.44-7.43 (m, 3H), 7.25-7.23 (m, 2H), 7.12(d, J＝8.4Hz, 2H), 7.02(d, J＝8.0Hz, 2H), 6.74(d, J＝8.4Hz, 2H), 6.51(s, 1H), 6.32(s, 1H), 5.29(d, J＝3.6Hz, 1H), 5.04(d, J＝0.8Hz, 1H), 4.06-3.98(m, 2H), 3.55(t, J＝2.8Hz, 1H), 2.42( s, 3H), 2.06-1.96 (m, 1H), 0.98 (d, J=6.8Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 166.0, 145.6, 144.4, 141.6, 140.5, 133.7, 132.5, 131.2, 129.5, 129.2, 128.5, 128.1, 127.9, 125.5, 120.3, 115.3, 71.3, 69.7, 52.2, 27.9, 21.7, 19.3, 19.2. HRMS: Accurate Mass Calculation [M+H] + (C 30 H 31 NO 4 SBr) is m/z 580.11517, the observed value is m/z 580.11359. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ = 254 nm, retention time: t R (major) = 10.412 min, t R (minor) = 14.071 min. [α] 30 D = -172 (c=0.5, CH 2 Cl 2 ).

实施例22Example 22

在氮气气氛下密封管中，将化合物1g(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ga。In a sealed tube under nitrogen atmosphere, a mixture of compound 1 g (0.15 mmol), compound 2a (0.18 mmol), catalyst 1 (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ga.

Figure BDA0001907647870000151
Figure BDA0001907647870000151

收率54％，dr>20：1，91％ee。Yield 54%, dr > 20:1, 91% ee.

无色油状,42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.72-7.70(m,2H),7.45-7.43(m,3H),7.28(d,J＝8.0Hz,2H),7.08-7.03(m,3H),6.85-6.77(m,2H),6.52(s,1H),6.31(s,1H),6.18(d,J＝10.0Hz,1H),5.26(d,J＝3.6Hz,1H),5.01(d,J＝2.4Hz,1H),4.07-3.97(m,2H),3.61(t,J＝3.0Hz,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,162.6(J＝244.2Hz),145.7,145.1,144.5,140.8,133.3,132.6,129.7(J＝8.5Hz),129.4,128.5,128.1,127.9,125.6,123.6,115.2,114.1(J＝21.9Hz),113.4,113.2,71.3,69.6,52.8,27.9,21.6,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SF)为m/z 520.19523,实测值为m/z 520.19507.HPLC条件:Daicel ChiralpakIC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.266min,tR(minor)＝13.564min,.[α]30 D＝-196(c＝0.5,CH2Cl2)。Colorless oil, 42.4 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.72-7.70 (m, 2H), 7.45-7.43 (m, 3H), 7.28 (d, J=8.0 Hz, 2H) ,7.08-7.03(m,3H),6.85-6.77(m,2H),6.52(s,1H),6.31(s,1H),6.18(d,J＝10.0Hz,1H),5.26(d,J =3.6Hz,1H),5.01(d,J=2.4Hz,1H),4.07-3.97(m,2H),3.61(t,J=3.0Hz,1H),2.38(s,3H),2.04-1.94 (m, 1H), 0.96 (d, J=6.8 Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.9, 162.6 (J=244.2 Hz), 145.7, 145.1, 144.5, 140.8, 133.3, 132.6, 129.7 (J=8.5Hz), 129.4, 128.5, 128.1, 127.9, 125.6, 123.6, 115.2, 114.1 (J=21.9Hz), 113.4, 113.2, 71.3, 69.6, 52.8, 27.9, 21.6, 19.3, 19.2.HRMS: Accurate mass calculated [M+H] + (C 30 H 31 NO 4 SF) as m/z 520.19523, found m/z 520.19507. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropyl Alcohol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 9.266 min, t R (minor) = 13.564 min, .[α] 30 D = -196 (c = 0.5, CH 2 Cl 2 ).

实施例23Example 23

在氮气气氛下密封管中，将化合物1h(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ha。In a sealed tube under nitrogen atmosphere, a mixture of compound 1h (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ha.

Figure BDA0001907647870000152
Figure BDA0001907647870000152

收率48％，dr>20：1，92％ee。Yield 48%, dr > 20:1, 92% ee.

无色油状,38.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.70(m,2H),7.44-7.43(m,3H),7.28-7.25(m,2H),7.08-6.93(m,5H),6.66(s,1H),6.52(s,1H),6.31(s,1H),5.28(d,J＝3.6Hz,1H),5.06(s,1H),4.07-3.98(m,2H),3.59(s,1H),2.36(s,3H),2.03-1.96(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,145.7,144.6,144.3,140.7,134.0,133.4,132.5,129.6,129.4,128.5,128.1,127.8,127.5,126.6,126.0,125.7,115.0,71.3,69.5,52.6,27.9,21.8,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SCl)为m/z 536.16568,实测值为m/z 536.16516.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.976min,tR(minor)＝14.539min.[α]30 D＝-148(c＝0.5,CH2Cl2)。Colorless oil, 38.7 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.71-7.70 (m, 2H), 7.44-7.43 (m, 3H), 7.28-7.25 (m, 2H), 7.08- 6.93(m, 5H), 6.66(s, 1H), 6.52(s, 1H), 6.31(s, 1H), 5.28(d, J＝3.6Hz, 1H), 5.06(s, 1H), 4.07-3.98 (m, 2H), 3.59 (s, 1H), 2.36 (s, 3H), 2.03-1.96 (m, 1H), 0.96 (d, J=6.4Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ) :δ(ppm)165.9,145.7,144.6,144.3,140.7,134.0,133.4,132.5,129.6,129.4,128.5,128.1,127.8,127.5,126.6,126.0,125.7,115.0,71.3,69.8.52 , 19.3, 19.2.HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SCl) is m/z 536.16568, the observed value is m/z 536.16516. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane Alkane/isopropanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 9.976 min, t R (minor) = 14.539 min. [α] 30 D = -148 (c=0.5, CH2Cl2 ) .

实施例24Example 24

在氮气气氛下密封管中，将化合物1i(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ia。In a sealed tube under nitrogen atmosphere, a mixture of compound 1i (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ia.

Figure BDA0001907647870000161
Figure BDA0001907647870000161

收率55％，dr>20：1，93％ee。Yield 55%, dr>20:1, 93% ee.

无色油状,48.8mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.69(m,2H),7.44-7.43(m,3H),7.28-7.22(m,3H),7.04(d,J＝8.0Hz,2H),6.95-6.90(m,3H),6.52(s,1H),6.31(s,1H),5.29(d,J＝3.2Hz,1H),5.07(s,1H),4.07-3.98(m,2H),3.59(s,1H),2.37(s,3H),2.03-1.95(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,145.7,144.9,144.2,140.6,133.4,132.5,130.5,129.9,129.6,129.5,129.4,128.5,128.1,127.8,126.4,125.8,122.5,115.0,71.3,69.5,52.6,27.9,21.9,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SBr)为m/z 580.11517,实测值为m/z 580.11491.HPLC条件:DaicelChiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝10.681min,tR(minor)＝15.472min.[α]30 D＝-146(c＝0.5,CH2Cl2)。Colorless oil, 48.8 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.70-7.69 (m, 2H), 7.44-7.43 (m, 3H), 7.28-7.22 (m, 3H), 7.04 ( d, J＝8.0Hz, 2H), 6.95-6.90(m, 3H), 6.52(s, 1H), 6.31(s, 1H), 5.29(d, J＝3.2Hz, 1H), 5.07(s, 1H) ), 4.07-3.98(m, 2H), 3.59(s, 1H), 2.37(s, 3H), 2.03-1.95(m, 1H), 0.96(d, J=6.4Hz, 6H). 13 C NMR( 100Hz, CDCl 3 ): δ(ppm) 165.9, 145.7, 144.9, 144.2, 140.6, 133.4, 132.5, 130.5, 129.9, 129.6, 129.5, 129.4, 128.5, 128.1, 127.8, 126.4, 125.8, 71.5, 1 69.5, 52.6, 27.9, 21.9, 19.3, 19.2. HRMS: Accurate mass calculated [M+H] + (C 30 H 31 NO 4 SBr) as m/z 580.11517, found m/z 580.11491. HPLC conditions: DaicelChiralpak IC-3 column, n-hexane/isopropanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 10.681 min, t R (minor) = 15.472 min. [α ] 30 D = -146 (c = 0.5, CH 2 Cl 2 ).

实施例25Example 25

在氮气气氛下密封管中，将化合物1j(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ja。In a sealed tube under nitrogen atmosphere, a mixture of compound 1j (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ja.

Figure BDA0001907647870000171
Figure BDA0001907647870000171

收率87％，dr>20：1，91％ee。Yield 87%, dr>20:1, 91% ee.

无色油状,65.6mg.1H NMR(400Hz,CDCl3):δ(ppm)7.66(s,2H),7.29-7.25(m,2H),7.13-6.99(m,7H),6.69(d,J＝6.8Hz,2H),6.49(s,1H),6.22(s,1H),5.24(s,1H),4.99(s,1H),4.07-3.95(m,2H),3.62(s,1H),2.39(s,3H),1.99-1.93(m,1H),0.94(d,J＝6.0Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.7,163.2(J＝246.9Hz),144.0,143.9,142.2,141.0,133.5,130.2(J＝8.2Hz),129.7,128.7(J＝2.9Hz),128.2,128.0,127.4,126.4,125.4,116.0,115.0(J＝21.7Hz),71.1,69.9,53.4,27.8,21.6,19.2,19.1.HRMS:精确质量计算[M+H]+(C30H31NO4SF)为m/z 520.19523,实测值为m/z 520.19470.HPLC条件:DaicelChiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝12.982min,tR(minor)＝19.376min.[α]30 D＝-168(c＝0.5,CH2Cl2)。Colorless oil, 65.6 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.66 (s, 2H), 7.29-7.25 (m, 2H), 7.13-6.99 (m, 7H), 6.69 (d, J=6.8Hz, 2H), 6.49(s, 1H), 6.22(s, 1H), 5.24(s, 1H), 4.99(s, 1H), 4.07-3.95(m, 2H), 3.62(s, 1H) ), 2.39(s, 3H), 1.99-1.93(m, 1H), 0.94(d, J=6.0Hz, 6H). 13 C NMR(100Hz, CDCl 3 ): δ(ppm) 165.7, 163.2(J= 246.9Hz), 144.0, 143.9, 142.2, 141.0, 133.5, 130.2(J=8.2Hz), 129.7, 128.7(J=2.9Hz), 128.2, 128.0, 127.4, 126.4, 125.4, 116.0, 115.0(J=21.7Hz) ), 71.1, 69.9, 53.4, 27.8, 21.6, 19.2, 19.1. HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SF) is m/z 520.19523, measured m/z 520.19470. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=12.982 min, t R (minor)=19.376 min. [α] 30 D = -168 (c=0.5, CH 2 Cl 2 ).

实施例26Example 26

在氮气气氛下密封管中，将化合物1k(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ka。In a sealed tube under nitrogen atmosphere, a mixture of compound 1k (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ka.

Figure BDA0001907647870000181
Figure BDA0001907647870000181

收率72％，dr>20：1，92％ee。Yield 72%, dr>20:1, 92% ee.

无色油状,58.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.62(d,J＝8.0Hz,2H),7.39(d,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.12-6.98(m,5H),6.67(d,J＝7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.27(d,J＝2.8Hz,1H),4.98(s,1H),4.06-3.95(m,2H),3.62(s,1H),2.40(s,3H),1.99-1.93(m,1H),0.94(d,J＝6.0Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.1,142.1,141.0,135.0,133.4,131.2,129.7,128.3,128.1,127.4,126.5,125.5,116.7,71.2,69.9,53.6,27.8,21.7,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SCl)为m/z 536.16568,实测值为m/z 536.16541.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝11.789min,tR(minor)＝17.445min.[α]30 D＝-134(c＝0.5,CH2Cl2)。Colorless oil, 58.3 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.62 (d, J=8.0 Hz, 2H), 7.39 (d, J=7.6 Hz, 2H), 7.29 (d, J =7.6Hz,2H),7.12-6.98(m,5H),6.67(d,J=7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.27(d,J=2.8Hz ,1H),4.98(s,1H),4.06-3.95(m,2H),3.62(s,1H),2.40(s,3H),1.99-1.93(m,1H),0.94(d,J=6.0 Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ(ppm) 165.8, 144.1, 142.1, 141.0, 135.0, 133.4, 131.2, 129.7, 128.3, 128.1, 127.4, 126.5, 125.5, 116.7, 71.2, 69.9 , 53.6, 27.8, 21.7, 19.3, 19.2. HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SCl) is m/z 536.16568, found m/z 536.16541. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 11.789 min, t R (minor) = 17.445 min. [α ] 30 D = -134 (c = 0.5, CH 2 Cl 2 ).

实施例27Example 27

在氮气气氛下密封管中，将化合物1l(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3la。In a sealed tube under nitrogen atmosphere, a mixture of compound 11 (0.15 mmol), compound 2a (0.18 mmol), catalyst 1 (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 31a.

Figure BDA0001907647870000182
Figure BDA0001907647870000182

收率58％，dr>20：1，92％ee。Yield 58%, dr>20:1, 92%ee.

无色油状,52.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.55(s,4H),7.29(d,J＝8.0Hz,2H),7.12-6.98(m,5H),6.67(d,J＝7.2Hz,2H),6.49(s,1H),6.20(s,1H),5.28(d,J＝3.6Hz,1H),4.98(d,J＝2.4Hz,1H),4.06-3.94(m,2H),3.62(s,1H),2.40(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.1,143.9,142.1,141.0,133.4,131.7,131.2,130.0,129.8,128.3,128.1,127.4,126.5,125.5,123.3,116.8,71.2,69.9,53.6,27.8,21.7,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SBr)为m/z 580.11517,实测值为m/z 580.11493.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝12.814min,tR(minor)＝18.369min.[α]30 D＝-108(c＝0.5,CH2Cl2)。Colorless oil, 52.3 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.55 (s, 4H), 7.29 (d, J=8.0 Hz, 2H), 7.12-6.98 (m, 5H), 6.67 (d,J＝7.2Hz,2H),6.49(s,1H),6.20(s,1H),5.28(d,J＝3.6Hz,1H),4.98(d,J＝2.4Hz,1H),4.06 -3.94(m, 2H), 3.62(s, 1H), 2.40(s, 3H), 2.01-1.91(m, 1H), 0.94(d, J=6.4Hz, 6H). 13 C NMR(100Hz, CDCl) 3 ): δ(ppm) 165.8, 144.1, 143.9, 142.1, 141.0, 133.4, 131.7, 131.2, 130.0, 129.8, 128.3, 128.1, 127.4, 126.5, 125.5, 123.3, 116.8, 71.2, 621.9, 53.6 , 19.3, 19.2.HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SBr) is m/z 580.11517, found m/z 580.11493. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane Alkane/isopropanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 12.814 min, t R (minor) = 18.369 min. [α] 30 D = -108 (c=0.5, CH2Cl2 ) .

实施例28Example 28

在氮气气氛下密封管中，将化合物1m(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ma。In a sealed tube under nitrogen atmosphere, a mixture of compound 1m (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ma.

Figure BDA0001907647870000191
Figure BDA0001907647870000191

收率77％，dr>20：1，90％ee。Yield 77%, dr > 20:1, 90% ee.

白色固体,mp 148.4-149.8℃,61.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.59(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.10-6.97(m,5H),6.70(d,J＝7.6Hz,2H),6.50(s,1H),6.28(s,1H),5.22(d,J＝3.6Hz,1H),5.01(s,1H),4.06-3.95(m,2H),3.59(t,J＝2.8Hz,1H),2.41(s,3H),2.38(s,3H),2.03-1.91(m,1H),0.94(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,144.9,143.8,142.4,141.1,139.2,133.7,129.8,129.6,128.7,128.4,128.2,128.1,127.5,126.3,125.4,115.3,71.1,69.7,53.5,27.8,21.6,21.5,19.3,19.2.HRMS:精确质量计算[M+H]+(C31H34NO4S)为m/z516.22031,实测值为m/z516.22009.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝10.503min,tR(minor)＝15.169min.[α]30 D＝-180(c＝0.5,CH2Cl2)。White solid, mp 148.4-149.8°C, 61.4 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.59 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.23(d, J=8.0Hz, 2H), 7.10-6.97(m, 5H), 6.70(d, J=7.6Hz, 2H), 6.50(s, 1H), 6.28(s, 1H), 5.22(d , J＝3.6Hz, 1H), 5.01(s, 1H), 4.06-3.95(m, 2H), 3.59(t, J＝2.8Hz, 1H), 2.41(s, 3H), 2.38(s, 3H) , 2.03-1.91 (m, 1H), 0.94 (d, J=6.8Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.9, 144.9, 143.8, 142.4, 141.1, 139.2, 133.7, 129.8, 129.6, 128.7, 128.4, 128.2, 128.1, 127.5, 126.3, 125.4, 115.3, 71.1, 69.7, 53.5, 27.8, 21.6, 21.5, 19.3, 19.2. HRMS: Exact Mass Calculation [M+H] + (C 31 H 34 NO 4 S) is m/z 516.22031, the measured value is m/z 516.22009. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=10.503 min, t R (minor)=15.169 min. [α] 30 D = -180 (c=0.5, CH 2 Cl 2 ).

实施例29Example 29

在氮气气氛下密封管中，将化合物1n(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3na。In a sealed tube under nitrogen atmosphere, a mixture of compound 1n (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3na.

Figure BDA0001907647870000201
Figure BDA0001907647870000201

收率52％，dr>20：1，91％ee。Yield 52%, dr>20:1, 91% ee.

无色油状,41.2mg.1H NMR(400Hz,CDCl3):δ(ppm)7.48(d,J＝7.6Hz,1H),7.41-7.30(m,4H),7.12-6.99(m,6H),6.69(d,J＝7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.32(d,J＝3.6Hz,1H),4.99(d,J＝2.4Hz,1H),4.07-3.95(m,2H),3.63(t,J＝3.2Hz,1H),2.40(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,162.4(J＝244.3Hz),144.1,143.8,142.0,141.0,134.9(J＝8.0Hz),133.4,129.7,129.6,129.5,128.3,128.1,127.4,126.5,125.5,124.2(J＝2.6Hz),117.3,116.0(J＝21.0Hz),115.4(J＝22.8Hz),71.2,69.9,53.6,27.8,21.7,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SF)为m/z520.19523,实测值为m/z 520.19495.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.997min,tR(minor)＝12.845min.[α]30 D＝-152(c＝0.5,CH2Cl2)。Colorless oil, 41.2 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.48 (d, J=7.6 Hz, 1H), 7.41-7.30 (m, 4H), 7.12-6.99 (m, 6H) ,6.69(d,J＝7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.32(d,J＝3.6Hz,1H),4.99(d,J＝2.4Hz,1H) ,4.07-3.95(m,2H),3.63(t,J=3.2Hz,1H),2.40(s,3H),2.01-1.91(m,1H),0.94(d,J=6.8Hz,6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 162.4 (J=244.3 Hz), 144.1, 143.8, 142.0, 141.0, 134.9 (J=8.0 Hz), 133.4, 129.7, 129.6, 129.5, 128.3, 128.1, 127.4, 126.5, 125.5, 124.2 (J=2.6Hz), 117.3, 116.0 (J=21.0Hz), 115.4 (J=22.8Hz), 71.2, 69.9, 53.6, 27.8, 21.7, 19.2.HRMS: Exact Mass Calculated [M+H] + (C 30 H 31 NO 4 SF) is m/z 520.19523, found m/z 520.19495. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/ 20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: t R (major) = 9.997 min, t R (minor) = 12.845 min. [α] 30 D = -152 (c = 0.5, CH 2 Cl 2 ).

实施例30Example 30

在氮气气氛下密封管中，将化合物1o(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3oa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1o (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3oa.

Figure BDA0001907647870000202
Figure BDA0001907647870000202

收率63％，dr>20：1，91％ee。Yield 63%, dr > 20:1, 91% ee.

无色油状,49.8mg.1H NMR(400Hz,CDCl3):δ(ppm)7.59-7.58(m,2H),7.39-7.30(m,4H),7.13-7.01(m,5H),6.70(d,J＝7.2Hz,2H),6.49(s,1H),6.20(s,1H),5.32(d,J＝3.2Hz,1H),5.00(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.64(s,1H),2.41(s,3H),2.01-1.91(m,1H),0.95(d,J＝6.4Hz,3H),0.94(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.2,143.7,142.0,141.0,134.6,133.9,133.5,129.8,129.3,129.2,128.4,128.3,128.1,127.5,126.8,126.5,125.6,117.4,71.2,69.9,53.7,27.9,21.7,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SCl)为m/z 536.16568,实测值为m/z536.16541.HPLC条件:Daicel Chiralpak IC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.751min,tR(minor)＝12.132min.[α]30 D＝-140(c＝0.5,CH2Cl2)。Colorless oil, 49.8 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.59-7.58 (m, 2H), 7.39-7.30 (m, 4H), 7.13-7.01 (m, 5H), 6.70 ( d, J＝7.2Hz, 2H), 6.49(s, 1H), 6.20(s, 1H), 5.32(d, J＝3.2Hz, 1H), 5.00(d, J＝2.8Hz, 1H), 4.07- 3.95(m, 2H), 3.64(s, 1H), 2.41(s, 3H), 2.01-1.91(m, 1H), 0.95(d, J=6.4Hz, 3H), 0.94(d, J=6.8Hz , 3H). 13 C NMR (100Hz, CDCl 3 ): δ (ppm) 165.8, 144.2, 143.7, 142.0, 141.0, 134.6, 133.9, 133.5, 129.8, 129.3, 129.2, 128.4, 128.3, 128.1, 127.5, 126.8, 126.5, 125.6, 117.4, 71.2, 69.9, 53.7, 27.9, 21.7, 19.3, 19.2. HRMS: Accurate mass calculation [M+H] + (C 30 H 31 NO 4 SCl) as m/z 536.16568, found m /z536.16541.HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=9.751 min, t R (minor) = 12.132 min. [α] 30 D = -140 (c = 0.5, CH 2 Cl 2 ).

实施例31Example 31

在氮气气氛下密封管中，将化合物1p(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3pa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1p (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3pa.

Figure BDA0001907647870000211
Figure BDA0001907647870000211

收率59％，dr>20：1，92％ee。Yield 59%, dr > 20:1, 92% ee.

无色油状,54.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.73(s,1H),7.63(d,J＝7.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.32-7.25(m,3H),7.13-7.01(m,5H),6.70(d,J＝7.6Hz,2H),6.49(s,1H),6.20(s,1H),5.31(d,J＝3.2Hz,1H),5.00(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.64(t,J＝3.4Hz,1H),2.41(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.2,143.5,142.0,140.9,134.8,133.5,132.1,131.1,129.8,129.6,128.3,128.1,127.4,127.3,126.5,125.6,122.0,117.4,71.2,69.8,53.7,27.8,21.7,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H31NO4SBr)为m/z 580.11517,实测值为m/z 580.11462.HPLC条件:Daicel ChiralpakIC-3柱,正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝10.271min,tR(minor)＝12.423min.[α]30 D＝-140(c＝0.5,CH2Cl2)。Colorless oil, 54.3 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.73 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H) ), 7.32-7.25(m, 3H), 7.13-7.01(m, 5H), 6.70(d, J=7.6Hz, 2H), 6.49(s, 1H), 6.20(s, 1H), 5.31(d, J=3.2Hz, 1H), 5.00(d, J=2.8Hz, 1H), 4.07-3.95(m, 2H), 3.64(t, J=3.4Hz, 1H), 2.41(s, 3H), 2.01- 1.91 (m, 1H), 0.94 (d, J=6.8Hz, 3H), 0.93 (d, J=6.8Hz, 3H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 144.2, 143.5 HRMS: Exact Mass calculation [M+H] + (C 30 H 31 NO 4 SBr) is m/z 580.11517, and the measured value is m/z 580.11462. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20 , flow rate = 1.0mL/min, λ = 254nm, retention time: t R (major) = 10.271min, t R (minor) = 12.423min. [α] 30 D = -140 (c = 0.5, CH 2 Cl 2 ).

实施例32Example 32

在氮气气氛下密封管中，将化合物1q(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3qa。In a sealed tube under nitrogen atmosphere, a mixture of compound 1q (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3qa.

Figure BDA0001907647870000221
Figure BDA0001907647870000221

收率60％，dr>20：1，93％ee。Yield 60%, dr>20:1, 93%ee.

无色油状,48.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.49-7.46(m,2H),7.32-7.29(m,3H),7.24-7.21(m,1H),7.12-6.99(m,5H),6.73(d,J＝7.6Hz,2H),6.50(s,1H),6.27(s,1H),5.25(d,J＝3.6Hz,1H),5.03(d,J＝2.8Hz,1H),4.06-3.95(m,2H),3.60(t,J＝3.2Hz,1H),2.41(s,3H),2.39(s,3H),2.03-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,145.0,143.8,142.4,141.2,137.5,133.8,132.6,130.0,129.6,129.1,128.2,128.1,127.9,127.5,126.3,125.7,125.4,115.9,71.2,69.7,53.6,27.8,21.6,19.3,19.2.HRMS:精确质量计算[M+H]+(C31H34NO4S)为m/z 516.22031,实测值为m/z 516.21985.HPLC条件:Daicel Chiralpak IC-3柱，正己烷/异丙醇＝80/20,流速＝1.0mL/min,λ＝254nm，保留时间:tR(major)＝9.645min,tR(minor)＝12.465min.[α]30 D＝-178(c＝0.5,CH2Cl2)。Colorless oil, 48.7 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.49-7.46 (m, 2H), 7.32-7.29 (m, 3H), 7.24-7.21 (m, 1H), 7.12- 6.99(m, 5H), 6.73(d, J=7.6Hz, 2H), 6.50(s, 1H), 6.27(s, 1H), 5.25(d, J=3.6Hz, 1H), 5.03(d, J =2.8Hz,1H),4.06-3.95(m,2H),3.60(t,J=3.2Hz,1H),2.41(s,3H),2.39(s,3H),2.03-1.91(m,1H) , 0.94 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.9, 145.0, 143.8, 142.4, 141.2, 137.5 ,133.8,132.6,130.0,129.6,129.1,128.2,128.1,127.9,127.5,126.3,125.7,125.4,115.9,71.2,69.7,53.6,27.8,21.6,19.3,19.2.HRMS: Exact Mass Calculation [M+H ] + (C 31 H 34 NO 4 S) is m/z 516.22031, the measured value is m/z 516.21985. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL /min, λ=254 nm, retention time: t R (major)=9.645 min, t R (minor)=12.465 min. [α] 30 D =-178 (c=0.5, CH 2 Cl 2 ).

实施例33Example 33

在氮气气氛下密封管中，将化合物1r(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ra。In a sealed tube under nitrogen atmosphere, a mixture of compound 1r (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ra.

Figure BDA0001907647870000231
Figure BDA0001907647870000231

收率51％，dr>20：1，92％ee。Yield 51%, dr > 20:1, 92% ee.

白色固体,mp 54.8-55.1℃,42.0mg.1H NMR(400Hz,CDCl3):δ(ppm)7.63(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.27-7.22(m,3H),7.05(d,J＝8.0Hz,2H),6.95-6.85(m,3H),6.51(s,1H),6.24(s,1H),5.30(d,J＝3.2Hz,1H),5.03(s,1H),4.07-3.97(m,2H),3.60(s,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.6,144.4,140.5,135.2,133.1,131.0,130.4,129.9,129.7,129.6,128.4,127.8,126.4,125.8,122.5,115.2,71.3,69.6,52.6,27.8,21.9,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H30NO4SClF)为m/z 554.15626,实测值为m/z554.15588.HPLC条件:Daicel Chiralpak IC-3柱，正己烷/异丙醇＝80/20，流速＝1.0mL/min,λ＝254nm，保留时间:tR(major)＝10.918min,tR(minor)＝15.753min.[α]30 D＝-98(c＝0.5,CH2Cl2)。White solid, mp 54.8-55.1°C, 42.0 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.63 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.27-7.22(m, 3H), 7.05(d, J=8.0Hz, 2H), 6.95-6.85(m, 3H), 6.51(s, 1H), 6.24(s, 1H), 5.30(d, J= 3.2Hz, 1H), 5.03(s, 1H), 4.07-3.97(m, 2H), 3.60(s, 1H), 2.38(s, 3H), 2.04-1.94(m, 1H), 0.96(d, J =6.4Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 144.6, 144.4, 140.5, 135.2, 133.1, 131.0, 130.4, 129.9, 129.7, 129.6, 128.4, 127.8, 126.4, 125.8 , 122.5, 115.2, 71.3, 69.6, 52.6, 27.8, 21.9, 19.3, 19.2. HRMS: Accurate mass calculation [M+H] + (C 30 H 30 NO 4 SClF) is m/z 554.15626, the measured value is m/ z554.15588.HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, λ=254 nm, retention time: t R (major)=10.918 min, t R (minor)= 15.753 min. [α] 30D =-98 (c=0.5, CH2Cl2 ) .

实施例34Example 34

在氮气气氛下密封管中，将化合物1s(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3sa。In a sealed tube under nitrogen atmosphere, a mixture of compound Is (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3sa.

Figure BDA0001907647870000241
Figure BDA0001907647870000241

收率40％，dr>20：1，91％ee。Yield 40%, dr > 20:1, 91% ee.

白色固体,mp 76.4-78.4℃,33.5mg.1H NMR(400Hz,CDCl3):δ(ppm)7.64(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),7.09-6.99(m,4H),6.90(d,J＝7.6Hz,1H),6.61(s,1H),6.51(s,1H),6.24(s,1H),5.30(d,J＝3.6Hz,1H),5.02(d,J＝2.4Hz,1H),4.07-3.97(m,2H),3.60(t,J＝3.2Hz,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.8,144.7,144.5,144.4,140.6,135.3,134.1,133.1,131.0,129.7,128.4,127.8,127.4,126.7,126.0,125.8,115.6,71.3,69.6,52.7,27.9,21.8,19.3,19.2.HRMS:精确质量计算[M+H]+(C30H30NO4SCl2)为m/z570.12671，实测值为m/z 570.12628.HPLC条件:Daicel Chiralpak IC-3柱，正己烷/异丙醇＝80/20，流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝10.169min,tR(minor)＝14.851min.[α]30 D＝-134(c＝0.5,CH2Cl2)。White solid, mp 76.4-78.4°C, 33.5 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.64 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.27(d,J＝8.0Hz,2H),7.09-6.99(m,4H),6.90(d,J＝7.6Hz,1H),6.61(s,1H),6.51(s,1H),6.24(s ,1H),5.30(d,J＝3.6Hz,1H),5.02(d,J＝2.4Hz,1H),4.07-3.97(m,2H),3.60(t,J＝3.2Hz,1H),2.38 (s, 3H), 2.04-1.94 (m, 1H), 0.96 (d, J=6.4Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.8, 144.7, 144.5, 144.4, 140.6 ,135.3,134.1,133.1,131.0,129.7,128.4,127.8,127.4,126.7,126.0,125.8,115.6,71.3,69.6,52.7,27.9,21.8,19.3,19.2.HRMS: Exact Mass Calculation [M+H] + (C 30 H 30 NO 4 SCl 2 ) was m/z 570.12671, found m/z 570.12628. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL /min, λ=254 nm, retention time: t R (major)=10.169 min, t R (minor)=14.851 min. [α] 30 D =-134 (c=0.5, CH 2 Cl 2 ).

实施例35Example 35

在氮气气氛下密封管中，将化合物1t(0.15mmol)、化合物2a(0.18mmol)、催化剂I(15mol％)在MeCN(0.8mL)中的混合物于30℃下搅拌48h。除去溶剂后，粗残余物通过硅胶柱色谱(石油醚/乙酸乙酯)纯化，得到相应的产物3ta。In a sealed tube under nitrogen atmosphere, a mixture of compound 1t (0.15 mmol), compound 2a (0.18 mmol), catalyst I (15 mol%) in MeCN (0.8 mL) was stirred at 30 °C for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3ta.

Figure BDA0001907647870000242
Figure BDA0001907647870000242

收率48％，dr>20：1，92％ee。Yield 48%, dr > 20:1, 92% ee.

白色固体,mp 53.0-54.3℃,42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.62(d,J＝8.0Hz,2H),7.39(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,2H),6.74-6.66(m,4H),6.50(s,1H),6.24(s,1H),5.28(d,J＝3.2Hz,1H),4.97(s,1H),4.06-3.97(m,2H),3.59(s,1H),2.40(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,161.5(J＝243.7Hz),144.3,144.1,140.6,138.1,138.0,135.1,133.5,131.0,129.7,129.0(J＝8.0Hz),128.3,127.9,125.5,116.3,114.9(J＝21.1Hz),71.2,69.9,52.4,27.8,21.6,19.2.HRMS:精确质量计算[M+H]+(C30H30NO4SClF)为m/z554.15626,实测值为m/z554.15601.HPLC条件:Daicel Chiralpak IC-3柱，正己烷/异丙醇＝80/20，流速＝1.0mL/min,λ＝254nm,保留时间:tR(major)＝9.897min,tR(minor)＝13.743min.[α]30 D＝-148(c＝0.5,CH2Cl2)。White solid, mp 53.0-54.3°C, 42.4 mg. 1 H NMR (400 Hz, CDCl 3 ): δ (ppm) 7.62 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.27(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,2H),6.74-6.66(m,4H),6.50(s,1H),6.24(s,1H),5.28(d , J=3.2Hz, 1H), 4.97(s, 1H), 4.06-3.97(m, 2H), 3.59(s, 1H), 2.40(s, 3H), 2.04-1.94(m, 1H), 0.96( d, J=6.4 Hz, 6H). 13 C NMR (100 Hz, CDCl 3 ): δ (ppm) 165.9, 161.5 (J=243.7 Hz), 144.3, 144.1, 140.6, 138.1, 138.0, 135.1, 133.5, 131.0, 129.7, 129.0 (J=8.0Hz), 128.3, 127.9, 125.5, 116.3, 114.9 (J=21.1Hz), 71.2, 69.9, 52.4, 27.8, 21.6, 19.2. HRMS: Accurate mass calculation [M+H] + ( C 30 H 30 NO 4 SClF) was m/z 554.15626, and the found value was m/z 554.15601. HPLC conditions: Daicel Chiralpak IC-3 column, n-hexane/isopropanol=80/20, flow rate=1.0 mL/ min, λ=254 nm, retention time: t R (major)=9.897 min, t R (minor)=13.743 min. [α] 30 D = -148 (c=0.5, CH 2 Cl 2 ).

以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, All should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.

Claims (7)

1. A method for asymmetrically synthesizing 2-pyrroline compounds is characterized in that chiral phosphine compounds are used as catalysts, and a compound of a formula A reacts with a compound of a formula B to obtain a compound of a formula C:
Figure FDA0002382122570000011
wherein, Ar is1Selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, said Ar2Selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, tolyl, R1Selected from p-toluenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, R2Selected from alkyl or benzyl;
the chiral phosphine compound is selected from
Figure FDA0002382122570000012
2. The method of claim 1, wherein R is2Selected from methyl, ethyl, isobutyl, benzyl.
3. The process according to claim 1 or 2, wherein the chiral phosphine compound is used in an amount of at least 10 mol%.
4. The method according to claim 1 or 2, wherein the reaction is carried out with one or more of acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, and ethyl acetate as a solvent.
5. The method according to claim 1 or 2, wherein the molar ratio of the compound of formula a to the compound of formula B is 1: 1 to 1.4.
6. The process according to claim 1 or 2, wherein the temperature of the reaction is 25 ℃ or higher.
7. The process according to claim 1 or 2, wherein the reaction time is at least 48 h.
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Publication number Priority date Publication date Assignee Title
CN107400105A (en) * 2017-07-11 2017-11-28 南方科技大学 Method for efficiently synthesizing optically active polysubstituted 2, 3-dihydrofuran compound by asymmetric organic catalysis

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Publication number Priority date Publication date Assignee Title
CN107400105A (en) * 2017-07-11 2017-11-28 南方科技大学 Method for efficiently synthesizing optically active polysubstituted 2, 3-dihydrofuran compound by asymmetric organic catalysis

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Title
Enantioselective [4 + 1]-Annulation of α,β-Unsaturated Imines with Allylic Carbonates Catalyzed by a Hybrid P‑Chiral Phosphine Oxide−Phosphine;Hanyuan Li，等;《Org. Lett.》;20171003;第19卷;第5637-5640页 *
Hanyuan Li，等.Enantioselective [4 + 1]-Annulation of α,β-Unsaturated Imines with Allylic Carbonates Catalyzed by a Hybrid P‑Chiral Phosphine Oxide−Phosphine.《Org. Lett.》.2017,第19卷第5637-5640页. *

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