Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应

引用本文: 武力左, 张峰源, 章振涛, 尚垒, 刘宇. Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应[J]. 有机化学, 2020, 40(8): 2460-2467. doi: 10.6023/cjoc202004038 shu

Citation: Wu Lizuo, Zhang Fengyuan, Zhang Zhentao, Shang Lei, Liu Yu. Ming-Phos/Copper(I)-Catalyzed Asymmetric Intermolecular[3+2] Cycloaddition of Azomethine Ylides with Trifluoromethyl Enones[J]. Chinese Journal of Organic Chemistry, 2020, 40(8): 2460-2467. doi: 10.6023/cjoc202004038 shu

Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应

长春工业大学化学与生命科学学院材料科学高等研究院吉林长春 130012

通讯作者: 尚垒, shanglei@ccut.edu.cn; 刘宇, yuliu@ccut.edu.cn

基金项目:
吉林省科技发展计划（No.20170520137JH）和国家自然科学基金青年基金（No.21602015）资助项目

摘要: 含有三氟甲基的手性吡咯烷骨架是许多天然产物和药物的重要中间体，其高效的不对称合成方法是有机化学研究热点之一.通过Ming-Phos手性配体实现了铜催化的甲亚胺叶立德与β-三氟甲基-α，β-不饱和酮的不对称[3+2]环加成反应，以较高的产率和对映选择性合成了一系列含三氟甲基的手性吡咯烷化合物（ee值高达98%，产率高达99%）.该方法条件温和，操作简单，配体简单易得，且具有良好的底物普适性和官能团兼容性.

关键词:

English

Ming-Phos/Copper(I)-Catalyzed Asymmetric Intermolecular[3+2] Cycloaddition of Azomethine Ylides with Trifluoromethyl Enones

College of Chemistry and Life Science, Advanced Institute of Materials Science, Changchun University of Technology, Changchun, Jilin 130012

Corresponding author: Shang, Lei. E-mail: shanglei@ccut.edu.cn; Liu, Yu. E-mail: yuliu@ccut.edu.cn

Received Date: 25 April 2020
Revised Date: 29 April 2020
Available Online: 01 August 2020
Fund Project:
Project supported by the Science and Technology Development Project of Jilin Province (No. 20170520137JH) and the National Natural Science Foundation of China for Youth (No. 21602015)

Abstract: Chiral pyrrolidine skeletons containing trifluoromethyl group are core structural motifs in many natural products and medicines. As a consequence, extensive studies have been conducted on the exploitation of efficient methods for the asymmetric synthesis of such compounds. In this paper, Ming-Phos/Cu(I)-catalyzed asymmetric intermolecular[3+2] cycloaddition reaction of azomethine ylides and β-trifluoromethyl-α, β-unsaturated ketone was reported. A broad substrate scope was observed with high yield and enantioselectivity (up to 99% yield and 98% ee). The method is featured by its mild conditions, simple operation, easily available ligands and good functional group compatibility.

Key words:

近年来, 有机氟化学领域一直在快速发展.随着氟原子的引入, 使得许多有机化合物表现出独特的理化性质、药理及生物活性^[1], 因此有机氟化合物在材料化学、生物医学和药物化学等领域被广泛应用^[2].随着含氟有机化合物需求的日益增加, 发展新的含氟有机化合物合成方法也显得更为迫切^[3].在一系列有机氟分子中, 手性三氟甲基作为常见的官能团, 广泛出现于农业和药物化学领域^[4].

过渡金属催化甲亚胺叶立德与缺电子烯烃的不对称1, 3-偶极环加成反应, 是构建吡咯烷环高效的合成方法之一^{[5, 6]}.由于手性三氟甲基吡咯烷类化合物表现出的独特生物活性, 其不对称合成也备受化学家们的关注^[7](图 1).

图 1

图 1. 带有CF₃立体中心的农业和药物化学杂环化合物

Figure 1. Asymmetric [3+2] cycloaddition of azomethine ylides with electron-deficient alkenes

下载: 全尺寸图片幻灯片

将三氟甲基烯烃引入到该反应体系, 可以高效地实现三氟甲基吡咯烷的合成. 1985年, Bonnet-Delpon课题组^[8]使用化学计量的AgOAc, 成功地实现了反式二取代三氟甲基烯酯与甲亚胺叶立德的1, 3-偶极环加成反应, 得到了系列endo-选择性的消旋三氟甲基化吡咯烷类化合物.直到二十多年以后, 王春江课题组^[9]才首次报道了铜催化的反/顺式二取代三氟甲基烯酯和甲亚胺叶立德的1, 3-偶极的不对称[3+2]环加成反应, 该催化体系表现出高反应活性, 优异的非对映选择性和良好的对映选择性(图 2a). 2016年, 周志明课题组^[10]也以非常优秀的产率、对映和非对映选择性完成了β-三氟甲基-β, β-二取代硝基烯烃与甲亚胺叶立德的不对称[3+2]环加成反应(图 2b).近期, 张俊良课题组^[11]通过使用自主开发的Ming-Phos等配体, 成功实现了铜催化的甲亚胺叶立德和三取代三氟甲基烯酯/酮(β-三氟甲基-β, β-二取代烯酮、α-三氟甲基-α, β-不饱和酯)不对称环加成反应, 以非常高的产率、出色的对映和非对映选择性, 获得了含三氟甲基季碳全碳手性中心的吡咯烷化合物(图 2c)^{[11c, 12]}.我们与张俊良课题组^[13]合作, 将Ming-Phos配体应用于甲亚胺叶立德与环内烯烃的不对称环加成反应, 也表现出色的催化活性.鉴于上述反应体系中未考查β-单取代三氟甲基烯酮的反应性, 本工作对该体系进行了扩展, 探索了甲亚胺叶立德与反式三氟甲基烯酮的1, 3-偶极不对称环加成反应(图 2d).

图 2

图 2. 甲亚胺叶立德与三氟甲基烯烃的[3+2]不对称环加成反应

Figure 2. Asymmetric [3+2] cycloaddition of azomethine ylides with trifluoromethyl alkenes

下载: 全尺寸图片幻灯片

2. 结果与讨论

2.1 Ming-Phos配体筛选

首先以反式三氟甲基烯酮(1a)和甲亚胺叶立德2a为模板底物, Cu(CH₃CN)₄BF₄为催化剂, 甲基叔丁基醚为溶剂, 碳酸铯为碱, 反应温度为－30℃, 对Ming- Phos配体进行了筛选, 结果如表 1所示:当使用M1作为配体时, 反应能以3:1的dr值, 70%的产率和92% ee得到endo构型的产物(Entry 1);随后, 使用位阻较小的M2作为配体时, 反应结果较差, dr值为1:1, ee值也降至86% (Entry 2);当使用含有叔丁基的M3时, 反应的选择性有了明显的提升(Entry 3);当使用苯基取代的配体M4时, 反应的dr值为2:1, ee值为98% (Entry 4);当使用萘基配体M5时, 反应的选择性有了明显降低, ee值降到了12% (Entry 5);最后使用构型相反的M6配体时, 反应的产率和选择性都明显降低(Entry 6).

表 1

表 1 Ming-phos配体筛选^a

Table 1. Screening of Ming-phos ligands

下载: 导出CSV


Entry	Ligand	dr^b	Yield^c/%	ee^d/%
1	M1	3:1	70	92
2	M2	1:1	43	86
3	M3	4:1	78	98
4	M4	2:1	63	98
5	M5	1:1	70	12
6	M6	1:1	40	34
^a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a, 5 mol% catalyst ([Cu] to ligand＝1:1.1) in 2.0 mL of MTBE at －30 ℃ for 6 h. ^b The diastereomeric ratios were determined by ¹H NMR analysis of the crude products. ^c The yield of 3aa was determined by ¹H NMR analysis using CH₂Br₂ as the internal reference. ^d The ee values were determined by chiral HPLC.

2.2 反应条件优化

接下来考察了其他条件对反应的影响(表 2).首先对催化剂铜盐进行了考察, 结果显示:当使用Cu(CH₃- CN)₄ClO₄、Cu(CH₃CN)₄PF₆、[Cu(OTf)₂]•Tol、Cu(CF₃- SO₃)₂、Cu(CH₃CN)₄NTF₂时, 并未得到更好的结果(Entries 1~6).接着考察了其他的无机碱和有机碱, 当使用叔丁醇钾时, 对映选择性大幅度降低; 而使用1, 5-二氮杂二环[5.4.0]十一烯-5 (DBU)作为碱时, 完全失去了选择性(Entry 7~10).最后考察了溶剂对反应的影响, 与叔丁基甲基醚相比, 以四氢呋喃为溶剂时, 非对映选择性略有提升, 而对映选择性保持不变(Entry 11).然而, 换作其他醚类溶剂或甲苯作为溶剂时, 均没有得到更好的结果(Entries 12~14).通过对反应条件的系统优化, 最终确定了反应的最优条件: M3 (5.5 mol%)作为配体, Cu(CH₃CN)₄BF₄ (5 mol%)作为催化剂, 碳酸铯作为碱, 四氢呋喃作为溶剂, 反应温度为－30 ℃.

表 2

表 2 反应条件优化^a

Table 2. Optimization of the reaction conditions

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Entry	[Cu]	Base	Solvent	dr ^b	Yield ^c (ee) ^d/%
1	Cu(CH₃CN)₄ClO₄	Cs₂CO₃	MTBE	5:1	74 (98)
2	Cu(CH₃CN)₄PF₆	Cs₂CO₃	MTBE	5:1	80 (98)
3	[Cu(OTf)]₂"Tol	Cs₂CO₃	MTBE	5:1	77 (96)
4	Cu(CF₃SO₃)₂	Cs₂CO₃	MTBE	5:1	76 (96)
5	Cu(CH₃CN)₄NTf₂	Cs₂CO₃	MTBE	4:1	78 (93)
6	Cu(CH₃CN)₄BF₄	Cs₂CO₃	MTBE	5:1	79 (98)
7	Cu(CH₃CN)₄BF₄	^tBuOK	MTBE	3:1	56 (11)
8	Cu(CH₃CN)₄BF₄	DBU	MTBE	1:1	35 (0)
9	Cu(CH₃CN)₄BF₄	Et₃N	MTBE	4:1	66 (96)
10	Cu(CH₃CN)₄BF₄	K₂CO₃	MTBE	5:1	78 (98)
11	Cu(CH₃CN)₄BF₄	Cs₂CO₃	THF	6:1	85 (96)
12	Cu(CH₃CN)₄BF₄	Cs₂CO₃	ⁱPr₂O	5:1	78 (98)
13	Cu(CH₃CN)₄BF₄	Cs₂CO₃	Et₂O	4:1	74 (97)
14	Cu(CH₃CN)₄BF₄	Cs₂CO₃	Toluene	6:1	77 (96)
^a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a 5 mol% of catalyst ([Cu] to ligand＝1:1.1) in 2.0 mL solvent at －30 ℃ for 6 h. ^b The diastereomeric ratios were determined by ¹H NMR analysis of the crude products. ^c The yields were determined by ¹H NMR analysis using CH₂Br₂ as the internal reference. ^d The ee values were determined by chiral HPLC.

2.3 底物普适性研究

在此条件下, 对底物的范围进行了考察(表 3).结果表明, 当三氟甲基烯酮底物的苯环上4-位是氟、氯、溴、三氟甲基、硝基等吸电子基团时, 反应能以较好的产率和优秀的选择性得到产物(3aa~3ea).当苯环上不含取代基或带有给电子的甲氧基时, 反应同样以优异的产率和对映选择性得到目标产物, 但非对映选择性大幅度降低(3fa, 3ga).以邻位和间位取代的三氟甲基烯酮作为底物时, 反应均可顺利进行并都给出了较好的产率和优秀的选择性(3ha, 3ia).另外, 还考察了苯环上含多个取代基的底物, 当2, 4-位或3, 4-位为氯原子取代时, 能以良好的产率和优异的选择性得到产物(3ja, 3ka).最后考察了甲亚胺叶立德上苯环取代基的影响, 当没有取代基时, 能以84%的产率和97%的ee值得到产物(3eb).当取代基为甲基和甲氧基的时候, 反应顺利进行, 并以良好到优秀的产率和优异的选择性得到目标产物(3ec, 3ed).

表 3

表 3 底物范围^a^{, b}

Table 3. Substrate scope

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^a All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2, 5 mol% of catalyst ([Cu] to ligand＝1:1.1) in 6.0 mL THF at －30 ℃ for 2~8 h. ^b Isolated yield. The ee values were determined by chiral HPLC. The diastereomeric ratios were determined by ¹H NMR analysis of the crude products.

3. 结论

研究了铜催化的甲亚胺叶立德与β-三氟甲基-α, β-不饱和酮的不对称[3+2]环加成反应, 通过使用张俊良课题组发展的Ming-Phos手性配体, 以中等到优秀的产率、优异的对映选择性得到目标产物.该方法条件温和, 操作简单, 配体合成简单, 底物普适性较好.因此为含三氟甲基的吡咯烷类化合物的合成提供了一种较为有效的方法.课题组将继续从事进一步的体系扩展和优化.

4. 实验部分

4.1 仪器与试剂

仪器: SHZ-D(III)型循环水式真空泵, X-5型显微熔点测定仪, N-1100型旋转蒸发仪, OSB-2100型油浴锅, DL-400型循环冷却器, 2XZ-2型旋片式真空泵, ZF-20D型暗箱式紫外分析仪, DZTW型调温电热套, RCT B S025型磁力搅拌器, AV-400型核磁共振谱仪Q-TRA- PLC/MS/MS system型质谱仪, LC-2030C 3D高效液相色谱仪.

试剂:苯甲醛, 4-氯苯甲醛, 4-溴苯甲醛, 4-氰基苯甲醛, 4-氟苯甲醛, 4-硝基苯甲醛, 4-甲氧基苯甲醛, 4-甲基苯甲醛, 3-硝基苯甲醛, 2-硝基苯甲醛, 2, 4-二氯苯甲醛, 3, 4-二氯苯甲醛, 二异丙胺, 2-溴-3, 3, 3-三氟丙烯, 正丁基锂, 三乙胺, 甘氨酸甲酯盐酸盐, 无水硫酸镁, 四氢呋喃，碳酸铯.

4.2 实验方法

在室温下将M3 (5.5 mol%)和Cu(CH₃CN)₄BF₄ (5 mol%)在四氢呋喃(THF, 6 mL)中搅拌2 h.将反应温度降至－30 ℃后, 依次加入甲亚胺叶立德2 (0.6 mmol), Cs₂CO₃ (0.15 mmol)和三氟甲基烯酮1 (0.3 mmol).薄层色谱(TLC)监测三氟甲基烯酮1完全反应后, 减压除去溶剂.粗产物用¹H NMR分析以确定非对映体选择性, 然后将粗产物通过硅胶快速柱色谱纯化(石油醚/乙酸乙酯, V:V＝8:1)得到产物3.使用手性柱进行HPLC检测, 测定产物的对映选择性.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3aa): 125.1 mg白色固体, 85%产率, 6:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/min, 210 nm]; major enantiomer t_R＝33.6 min, minor enantiomer t_R＝14.2 min]. m.p. 142~143 ℃; [α]_D²⁰－0.22 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.44 (d, J＝8.6 Hz, 2H), 7.25~7.18 (m, 4H), 6.99 (d, J＝8.4 Hz, 2H), 4.70 (d, J＝7.5 Hz, 1H), 4.37~4.35 (m, 1H), 4.13 (d, J＝6.2 Hz, 1H), 3.91 (s, 3H), 3.77~3.69 (m, 1H), 2.98 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.3, 171.2, 139.9, 135.2, 134.9, 131.4, 129.4, 128.7, 128.7, 126.6 (q, J_C-F＝278.3 Hz), 122.1, 66.4, 60.4, 53.0, 51.3, 50.7 (q, J＝27.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: 68.87; ESI-MS calcd for C₂₀H₁₆BrClF₃NNaO₃ [M+Na⁺] 511.9852, found 511.9856.

(2S, 3S, 4S, 5R)-甲基-4-(4-溴苯甲酰基)-5-(4-溴苯基)-3- (三氟甲基)吡咯烷-2-羧酸酯(3ba): 136.4 mg白色固体, 85%产率, 8:1 dr, 97% ee [Chiralpak AD-H column [V(he-xanes):V(2-propanol)＝90:10, 0.8 mL/min, 210 nm]; minor enantiomer t_R＝36.5 min, major enantiomer t_R＝14.6 min]. m.p. 137~138 ℃; [α]_D²⁰－0.26 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.42~7.35 (m, 4H), 7.19 (d, J＝8.5 Hz, 2H), 6.99 (d, J＝8.4 Hz, 2H), 4.70 (d, J＝7.5 Hz, 1H), 4.37~4.35 (m, 1H), 4.13 (d, J＝6.2 Hz, 1H), 3.92 (s, 3H), 3.77~3.68 (m, 1H), 2.99 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.5, 171.2, 135.3, 135.2, 131.6, 131.3, 129.4, 128.7, 128.6, 128.0 (t, J_C-F＝278.4 Hz), 122.1, 66.3, 60.3, 52.9, 51.2, 50.5 (q, J＝27.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.86; ESI-MS calcd for C₂₀H₁₆Br₂F₃NNaO₃ [M+Na⁺] 555.9347, found 555.9345.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氟苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ca): 101.0 mg白色固体, 71%产率, 3:1 dr, 94% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/min, 210 nm]; major enantiomer t_R＝29.3 min, minor enantiomer t_R＝14.1 min]. m.p. 165~166 ℃; [α]_D²⁰－0.08 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.56~7.52 (m, 2H), 7.19 (d, J＝8.5 Hz, 2H), 7.01~6.91 (m, 4H), 4.70 (d, J＝7.3 Hz, 1H), 4.39~4.36 (m, 1H), 4.14 (d, J＝6.0 Hz, 1H), 3.92 (s, 3H), 3.78~3.68 (m, 1H), 3.00 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 196.9, 171.2, 165.7 (d, J＝256.5 Hz), 135.2, 133.1, 131.3, 130.8 (d, J＝9.5 Hz), 128.7, 126.7 (q, J_C-F＝278.3 Hz), 122.0, 115.5 (d, J＝21.9 Hz), 66.5, 60.4, 53.0, 51.2, 50.7 (q, J＝26.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.88, －103.90; ESI-MS calcd for C₂₀H₁₆BrF₄NNaO₃ [M+Na⁺] 496.0147, found 496.0151.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氰基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3da): 131.4 mg白色固体, 91%产率, 12:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/ min, 233 nm]; minor enantiomer t_R＝57.7 min, major enantiomer t_R＝31.4 min]. m.p. 135~136 ℃; [α]_D²⁰－0.24 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.55 (s, 4H), 7.16 (d, J＝8.4 Hz, 2H), 6.98 (d, J＝8.4 Hz, 2H), 4.74 (d, J＝7.6 Hz, 1H), 4.42~4.39 (m, 1H), 4.14 (d, J＝6.3 Hz, 1H), 3.92 (s, 3H), 3.85~3.75 (m, 1H), 2.94 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 198.1, 171.4, 144.4, 135.4, 134.1, 131.3 (2 C), 129.1, 128.8, 128.3, 126.7 (q, J_C-F＝278.4 Hz), 121.9, 66.6, 60.6, 53.0, 51.1, 51.0 (q, J＝27.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.84; ESI-MS calcd for C₂₁H₁₆BrF₃N₂NaO₃ [M+Na⁺] 503.0194, found 503.0190.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ea): 120.3 mg白色固体, 80%产率, 10:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝80:20, 0.8 mL/min, 233 nm]; major enantiomer t_R＝26.8 min, minor enantiomer t_R＝16.0 min]. m.p. 149~150 ℃; [α]_D²⁰－0.47 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 8.09 (d, J＝8.9 Hz, 2H), 7.62 (d, J＝8.9 Hz, 2H), 7.17 (d, J＝8.5 Hz, 2H), 7.00 (d, J＝8.5 Hz, 2H), 4.76 (d, J＝7.6 Hz, 1H), 4.42~4.41 (m, 1H), 4.15 (d, J＝6.3 Hz, 1H), 3.93 (s, 3H), 3.84~3.78 (m, 1H), 2.94 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.2, 171.1, 150.0, 141.0, 135.0, 131.6, 129.0, 128.8, 126.5 (q, J_C-F＝278.3 Hz), 123.5, 122.4, 66.2, 60.2, 53.1, 52.0, 50.2 (q, J＝27.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.87; ESI-MS calcd for C₂₀H₁₆Br- F₃N₂NaO₅ [M+Na⁺] 523.0092, found 523.0096.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(苯甲酰基)- 3-(三氟甲基)吡咯烷-2-羧酸酯(3fa): 117.6 mg白色固体, 86%产率, 1:1 dr, 91% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.5 mL/min, 210 nm]; minor enantiomer t_R＝32.2 min, major enantiomer t_R＝20.6 min]. m.p. 164~165 ℃; [α]_D²⁰－0.10 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.50 (d, J＝8.2 Hz, 2H), 7.43 (t, J＝7.4 Hz, 1H), 7.26~7.24 (m, 2H), 7.15 (d, J＝8.4 Hz, 2H), 6.99 (d, J＝8.4 Hz, 2H), 4.70 (d, J＝7.5 Hz, 1H), 4.45~4.43 (m, 1H), 4.14 (d, J＝6.2 Hz, 1H), 3.92 (s, 3H), 3.76~3.73 (m, 1H), 3.01 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 198.6, 171.3, 136.6, 135.3, 133.3, 131.2, 128.8, 128.3, 128.1, 126.5 (q, J＝278.4 Hz), 121.9, 66.5, 53.0, 51.3, 50.7 (q, J＝27.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.76; ESI-MS calcd for C₂₀H₁₇Br- F₃NNaO₃ [M+Na⁺] 478.0242, found 478.0239.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-甲氧基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ga): 128.3 mg白色固体, 88%产率, 2:1 dr, 94% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/ min, 210 nm]; minor enantiomer t_R＝37.4 min, major enantiomer t_R＝18.7 min]. m.p. 124~125 ℃; [α]_D²⁰－0.28 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (d, J＝8.9 Hz, 2H), 7.18 (d, J＝8.5 Hz, 2H), 7.01 (d, J＝8.4 Hz, 2H), 6.73 (d, J＝8.9 Hz, 2H), 4.67 (d, J＝7.3 Hz, 1H), 4.39~4.36 (m, 1H), 4.13 (d, J＝6.1 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.74~3.65 (m, 1H), 3.06 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 196.8, 171.3, 163.7, 135.5, 131.2, 130.5, 129.6, 128.7, 126.75 (q, J＝278.6 Hz), 121.7, 113.5, 60.6, 55.4, 52.9, 50.9 (q, J＝26.8 Hz), 50.75; ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.89; ESI-MS calcd for C₂₁H₁₉BrF₃NNaO₄ [M+ Na⁺] 508.0347, found 508.0345.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(2-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ha): 108.3 mg白色固体, 72%产率, 10:1 dr, 93% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝80:20, 0.8 mL/min, 210 nm]; minor enantiomer t_R＝24.1 min, major enantiomer t_R＝14.2 min]. m.p. 123~124 ℃; [α]_D²⁰－0.20 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J＝9.1 Hz, 1H), 7.50~7.45 (m, 1H), 7.32 (d, J＝8.5 Hz, 3H), 7.04 (d, J＝8.2 Hz, 2H), 5.95 (d, J＝9.0 Hz, 1H), 4.64 (d, J＝5.9 Hz, 1H), 4.17 (d, J＝4.5 Hz, 1H), 3.95 (s, 3H), 3.83~3.77 (m, 2H), 3.16 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 196.2, 171.1, 147.7, 137.5, 135.0, 133.4, 131.5, 129.5, 128.7, 127.2, 126.5 (q, J_C-F＝278.3 Hz), 123.0, 122.3, 66.2, 60.0, 53.0, 51.8, 49.9 (q, J＝27.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －69.03; ESI-MS calcd for C₂₀H₁₆BrF₃N₂NaO₅ [M+Na⁺] 523.0092, found 523.0095.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(3-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ia): 133.8 mg白色固体, 89%产率, 9:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝80:20, 0.8 mL/min, 233 nm]; minor enantiomer t_R＝13.4 min, major enantiomer t_R＝14.2 min]. m.p. 125~126 ℃; [α]_D²⁰－0.18 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 8.27~8.24 (m, 2H), 7.81 (d, J＝7.8 Hz, 1H), 7.46 (t, J＝7.9 Hz, 1H), 7.14 (d, J＝8.4 Hz, 2H), 7.02 (d, J＝8.4 Hz, 2H), 4.80~4.79 (m, 1H), 4.41~4.40 (m, 1H), 4.16 (d, J＝6.1 Hz, 1H), 3.93 (s, 3H), 3.87~3.81 (m, 1H), 2.91 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 196.1, 171.0, 147.7, 137.5, 135.0, 133.4, 131.4, 129.5, 128.7, 127.2, 126.5 (q, J＝278.4 Hz), 123.0, 122.2, 66.2, 60.0, 53.0, 51.8, 49.8 (q, J＝27.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.93; ESI-MS calcd for C₂₀H₁₆BrF₃N₂NaO₅ [M+Na⁺] 523.0092, found 523.0090.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(2, 4-二氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ja): 132.3 mg浅黄色固体, 84%产率, 8:1 dr, 97% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.5 mL/min, 210 nm]; minor enantiomer t_R＝21.4 min, major enantiomer t_R＝17.2 min]. m.p. 98~99 ℃; [α]_D²⁰－0.11 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.27 (s, 3H), 6.99 (t, J＝8.8 Hz, 3H), 6.40 (d, J＝8.4 Hz, 1H), 4.69~4.61 (m, 2H), 4.14 (d, J＝5.6 Hz, 1H), 3.91 (s, 3H), 3.77~3.69 (m, 1H), 2.97 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 200.1, 171.1, 137.9, 136.8, 134.9, 131.87, 131.6, 130.5, 130.0, 128.3, 127.1, 126.6 (d, J_C-F＝278.4 Hz), 122.1, 66.0, 60.5, 55.5, 53.1, 50.6 (q, J＝27.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.71; ESI-MS calcd for C₂₀H₁₅BrCl₂- F₃NNaO₃ [M+Na⁺] 545.9462, found 545.9466.

(2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(3, 4-二氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ka): 137.1 mg浅黄色固体, 87%产率, 7:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.5 mL/ min, 210 nm]; major enantiomer t_R＝32.5 min, minor enantiomer t_R＝17.2 min]. m.p. 143~144 ℃; [α]_D²⁰－0.23 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J＝15.3 Hz, 1H), 7.33 (s, 2H), 7.22 (d, J＝7.2 Hz, 2H), 7.00 (d, J＝7.1 Hz, 2H), 4.73~4.72 (m, 1H), 4.29 (s, 1H), 4.13 (s, 1H), 3.92 (s, 3H), 3.75 (s, 1H), 2.95 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 196.3, 171.2, 138.0, 136.1, 135.1, 133.1, 131.5, 130.4, 130.1, 128.7, 127.0, 126.6 (q, J_C-F＝278.3 Hz), 122.4, 66.4, 60.3, 53.1, 51.6, 50.3 (q, J＝27.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.85; ESI-MS calcd for C₂₀H₁₅BrCl₂F₃NNaO₃ [M+Na⁺] 545.9462, found 545.9464.

(2S, 3S, 4S, 5R)-甲基-4-(4-硝基苯甲酰基)-5-苯基- 3-(三氟甲基)吡咯烷-2-羧酸酯(3eb): 106.4 mg浅黄色固体, 84%产率, 10:1 dr, 97% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/min, 233 nm]; minor enantiomer t_R＝31.9 min, major enantiomer t_R＝24.8 min]. m.p. 135~136 ℃; [α]_D²⁰－0.12 (c 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, J＝8.9 Hz, 2H), 7.58 (d, J＝8.9 Hz, 2H), 7.10 (d, J＝7.4 Hz, 2H), 7.03 (q, J＝7.2, 5.9 Hz, 3H), 4.80 (d, J＝7.5 Hz, 1H), 4.43~4.40 (m, 1H), 4.16 (d, J＝6.1 Hz, 1H), 3.94 (s, 3H), 3.82~3.77 (m, 1H), 3.09 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.5, 171.2, 149.8, 141.1, 135.5, 129.0, 128.5 (2C), 127.1, 126.6 (q, J_C-F＝278.3 Hz), 123.3, 67.2, 60.4, 53.1, 52.4, 50.5 (q, J＝27.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.83; ESI-MS calcd for C₂₀H₁₇F₃N₂NaO₅ [M+Na⁺] 445.0987, found 445.0982.

(2S, 3S, 4S, 5R)-甲基4-(4-硝基苯甲酰基)-5-(对甲苯基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ec): 121.8 mg浅黄色固体, 93%产率, 15:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/ min, 233 nm]; minor enantiomer t_R＝33.4 min, major enantiomer t_R＝23.6 min]. m.p. 113~114 ℃; [α]_D²⁰－0.18 (c 0.3, CHCl₃); ¹ H NMR (400 MHz, CDCl₃) δ: 8.02 (d, J＝8.9 Hz, 2H), 7.58 (d, J＝8.9 Hz, 2H), 7.10 (d, J＝7.4 Hz, 2H), 7.03 (q, J＝7.2, 5.9 Hz, 2H), 4.80 (d, J＝7.5 Hz, 1H), 4.41~4.39 (m, 1H), 4.16 (d, J＝6.1 Hz, 1H), 3.94 (s, 3H), 3.80~3.75 (m, 1H), 3.03 (s, 1H), 2.11 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.7, 171.3, 149.8, 141.1, 138.3, 132.4, 129.1, 129.1, 127.0, 126.6 (q, J_C-F＝278.2 Hz), 123.2, 67.0, 60.4, 53.0, 52.6, 50.6 (q, J＝27.2 Hz), 20.88; ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.81; ESI-MS calcd for C₂₁H₁₉F₃N₂NaO₅ [M+Na⁺] 459.1144, found 459.1147.

(2S, 3S, 4S, 5R)-甲基-5-(4-甲氧基苯基)-4-(4-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ed): 112.6 mg黄色固体, 83%产率, 11:1 dr, 91% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)＝90:10, 0.8 mL/ min, 254 nm]; minor enantiomer t_R＝61.6 min, major enantiomer t_R＝43.2 min]. m.p. 134~135 ℃; [α]_D²⁰－0.16 (c 0.3, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J＝8.7 Hz, 2H), 7.61 (d, J＝8.7 Hz, 2H), 7.01 (d, J＝8.6 Hz, 2H), 6.55 (d, J＝8.6 Hz, 2H), 4.76 (d, J＝7.7 Hz, 1H), 4.40~4.38 (m, 1H), 4.13 (d, J＝6.2 Hz, 1H), 3.93 (s, 3H), 3.80 (d, J＝15.9 Hz, 1H), 3.61 (s, 3H), 2.94 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 197.6, 171.2, 159.5, 149.7, 141.0, 129.0, 128.2, 127.5, 126.6 (q, J_C-F＝278.3 Hz), 123.2, 113.7, 66.6, 55.1, 53.0, 52.4, 50.4, 50.3 (q, J＝27.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －68.78; ESI-MS calcd for C₂₁H₁₉F₃N₂NaO₆ [M+Na⁺] 475.1093, found 475.1089.

辅助材料(Supporting Information) 化合物3的¹H NMR, ¹⁹F NMR, ¹³C NMR和HPLC谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图 1 带有CF₃立体中心的农业和药物化学杂环化合物

Figure 1 Asymmetric [3+2] cycloaddition of azomethine ylides with electron-deficient alkenes

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图 2 甲亚胺叶立德与三氟甲基烯烃的[3+2]不对称环加成反应

Figure 2 Asymmetric [3+2] cycloaddition of azomethine ylides with trifluoromethyl alkenes

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表 1 Ming-phos配体筛选^a

Table 1. Screening of Ming-phos ligands


Entry	Ligand	dr^b	Yield^c/%	ee^d/%
1	M1	3:1	70	92
2	M2	1:1	43	86
3	M3	4:1	78	98
4	M4	2:1	63	98
5	M5	1:1	70	12
6	M6	1:1	40	34
^a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a, 5 mol% catalyst ([Cu] to ligand＝1:1.1) in 2.0 mL of MTBE at －30 ℃ for 6 h. ^b The diastereomeric ratios were determined by ¹H NMR analysis of the crude products. ^c The yield of 3aa was determined by ¹H NMR analysis using CH₂Br₂ as the internal reference. ^d The ee values were determined by chiral HPLC.

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表 2 反应条件优化^a

Table 2. Optimization of the reaction conditions


Entry	[Cu]	Base	Solvent	dr ^b	Yield ^c (ee) ^d/%
1	Cu(CH₃CN)₄ClO₄	Cs₂CO₃	MTBE	5:1	74 (98)
2	Cu(CH₃CN)₄PF₆	Cs₂CO₃	MTBE	5:1	80 (98)
3	[Cu(OTf)]₂"Tol	Cs₂CO₃	MTBE	5:1	77 (96)
4	Cu(CF₃SO₃)₂	Cs₂CO₃	MTBE	5:1	76 (96)
5	Cu(CH₃CN)₄NTf₂	Cs₂CO₃	MTBE	4:1	78 (93)
6	Cu(CH₃CN)₄BF₄	Cs₂CO₃	MTBE	5:1	79 (98)
7	Cu(CH₃CN)₄BF₄	^tBuOK	MTBE	3:1	56 (11)
8	Cu(CH₃CN)₄BF₄	DBU	MTBE	1:1	35 (0)
9	Cu(CH₃CN)₄BF₄	Et₃N	MTBE	4:1	66 (96)
10	Cu(CH₃CN)₄BF₄	K₂CO₃	MTBE	5:1	78 (98)
11	Cu(CH₃CN)₄BF₄	Cs₂CO₃	THF	6:1	85 (96)
12	Cu(CH₃CN)₄BF₄	Cs₂CO₃	ⁱPr₂O	5:1	78 (98)
13	Cu(CH₃CN)₄BF₄	Cs₂CO₃	Et₂O	4:1	74 (97)
14	Cu(CH₃CN)₄BF₄	Cs₂CO₃	Toluene	6:1	77 (96)
^a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a 5 mol% of catalyst ([Cu] to ligand＝1:1.1) in 2.0 mL solvent at －30 ℃ for 6 h. ^b The diastereomeric ratios were determined by ¹H NMR analysis of the crude products. ^c The yields were determined by ¹H NMR analysis using CH₂Br₂ as the internal reference. ^d The ee values were determined by chiral HPLC.

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表 3 底物范围^a^{, b}

Table 3. Substrate scope



^a All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2, 5 mol% of catalyst ([Cu] to ligand＝1:1.1) in 6.0 mL THF at －30 ℃ for 2~8 h. ^b Isolated yield. The ee values were determined by chiral HPLC. The diastereomeric ratios were determined by ¹H NMR analysis of the crude products.

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