向有机分子中引入氟原子及其含氟基团对药物发现与功能材料开发具有重要意义[1]. 其中, CF2H作为一类重要的氟烷基基团, 它能够有效地提高分子的代谢稳定性、亲脂性与生物利用度[2]. 此外, CF2H作为羟基和巯基的生物电子等排体, 兼具相似极性和亲脂性氢键供体能力, 在药物研发中常被用于替代先导化合物中的羟基、氨基及巯基等官能团[3]. 尽管目前已报道了多种非手性含二氟甲基化合物的合成方法[4], 然而基于过渡金属等催化策略构建二氟甲基手性化合物的合成方法较为有限[5]. 因此, 发展高效、对映选择性地构建含CF2H碳手性中心的方法具有重要研究价值.
催化不对称去芳构化反应为从平面芳香化合物直接构建复杂的三维多环分子提供了高效策略[6]. 其中, 吲哚衍生物的不对称去芳构化反应发展极为迅速. 近年来, 通过发展[2＋2]、[2＋3]和[2＋4]等多种环化模式的不对称催化体系, 结构多样的吲哚啉及二氢吲哚类分子得以高效合成[7]. 3-乙烯基吲哚及其衍生物因其高反应活性, 已成为该领域广泛使用的重要合成砌块. 在与苯醌、马来酰亚胺、亚甲基吲哚酮及硝基烯烃的Diels- Alder反应中, 其可以作为富电子双烯参与反应, 来构建咔唑衍生物(Scheme 1a)[8]. 此外, 利用偶氮二甲酸酯作为亲双烯体与3-乙烯基吲哚衍生物反应, 同样可高效构建氮杂二氢吲哚衍生物[9]. 2024年, 我们课题组[9b]通过银催化偶氮二甲酸酯与偕二氟乙烯吲哚的不对称去芳构化环加成反应, 成功地实现了该类转化(Scheme 1b). 尽管无取代基或给电子基团修饰的3-乙烯基吲哚与各类亲双烯体的不对称去芳构化反应已取得显著进展, 然而对于含氟吸电子基团取代的3-乙烯基吲哚与偶氮二甲酸酯的去芳构化反应仍未见报道. 本文报道了一种通过银催化3-二氟甲基取代乙烯吲哚与偶氮二甲酸酯的不对称去芳构化环加成反应, 以优异的分离收率和良好的对映选择性得到了一系列含有二氟甲基手性中心的氮杂多环化合物(Scheme 1c).
1 结果与讨论
1.1 反应条件优化
首先制备了三种带有不同保护基[乙酰基(Ac)、叔丁氧羰基(Boc)、对甲苯磺酰基(Ts)]的底物, 进行反应条件优化. 考察了偶氮二甲酸酯与银盐的种类以及手性膦配体对反应的影响, 观察到反应的对映选择性随保护基吸电子能力的增强而显著提高. 接下来使用Ts保护的底物1a和偶氮二甲酸二苄酯(DBAD, 2a)在AgSbF6催化下形成的反应体系作为模板, 围绕该体系对反应参数进行了系统研究. 对若干双齿膦和单齿膦配体(L1~L2)进行了筛选(表1, Entry 1~2). 结果表明: 单齿膦配体在提升反应对映选择性方面表现出更显著的优势. 参考课题组前期的相关研究[10], 本研究选用单齿膦类手性配体开展后续筛选. 按照文献报道的方法[11]合成了一系列单齿膦配体后, 对其催化性能进行了系统筛选. 结果表明, 使用L3替代L2作为反应配体时, 反应的对映选择性显著提高(表1, Entry 3). 相比之下, 其它类型的单齿膦配体(L4~L6)的催化效果均未能超过L3(表1, Entries 4~6). 接下来, 为探究单齿膦配体中烷氧基结构对不对称选择性的潜在影响, 将配体L7~L12应用于后续反应中. 筛选结果表明, 在L7~L12系列中, 随着烷氧基位阻增大, 产物的ee值相应提升(表1, Entries 7~12). 尽管如此, 其最高值仍未能超过此前表现最优的配体L3. 通过在L3上增大二芳基膦的位阻(L13, L14), 发现了与此前规律相反的趋势: ee值随位阻增大而下降(表1, Entries 13~14). 综合以上结果, 异丙基烷氧基的单齿膦配体L3展现了最优的催化性能, 被确定为最佳配体.
表1 反应条件优化aTable 1 Optimization of the reaction conditions |
| Entry | Ligand | Cat. loading/mol% | Yieldb/% | eec/% |
|---|---|---|---|---|
| 1d | L1 | 10 | NR | ND |
| 2 | L2 | 10 | 85 | 68 |
| 3 | L3 | 10 | 87 | 85 |
| 4 | L4 | 10 | 85 | 21 |
| 5 | L5 | 10 | 84 | 31 |
| 6 | L6 | 10 | 78 | 85 |
| 7 | L7 | 10 | 84 | 43 |
| 8 | L8 | 10 | 85 | 71 |
| 9 | L9 | 10 | 85 | 71 |
| 10 | L10 | 10 | 81 | 83 |
| 11 | L11 | 10 | 82 | 84 |
| 12 | L12 | 10 | 84 | 49 |
| 13 | L13 | 10 | 79 | 80 |
| 14 | L14 | 10 | 80 | 73 |
| 15 | L3 | 5 | 84 | 85 |
| 16 | L3 | 2 | 87 | 87 |
| 17e | L3 | 2 | 75 | 70 |
a Unless otherwise specified, the reaction was carried out with 1a (0.10 mmol), 2a (0.12 mmol), ligand (10 mol%) and AgSbF6 (10 mol%) in distilled CH2Cl2 (1.0 mL), NR=no reaction, ND=not detected. b Yield of isolated and purified product. c Determined by chiral HPLC analysis. d The reaction was carried out at room temperature. e The reaction was carried out in toluene. |
1.2 底物拓展
在获得最优条件后, 考察了该反应的底物适用范围(表2). 底物吲哚母核苯环上取代基的种类与位置对反应产率均无显著影响. 无论带有给电子基团还是吸电子基团的底物均可顺利参与反应, 并以良好的分离收率获得目标产物. 然而, 取代基的位置对反应的对映选择性具有调控作用. 在C4或C5位带有取代基的底物能顺利参与反应, 并以中等至良好的对映选择性获得目标产物3b~3k. 产物3h的绝对构型通过X射线单晶衍射分析确定. 当C7或C8位带有给电子取代基时, 产物的对映选择性会有所降低(3i, 3n~3p, 3r); 而当这些位点被氟原子、酯基等吸电子基团取代时, 则能实现较高的对映选择性(3m, 3q). 带有CO2Me基团的底物1q反应活性较低, 但通过延长反应时间至24 h, 仍能在－78 ℃下以83%的分离收率和93%的对映选择性获得产物3q. 值得注意的是, 在CF2H邻近位引入甲基时, 反应仍可顺利进行(3s). 然而, 当甲基被引入底物吲哚C2位时, 反应则无法发生. 拓展其他杂环底物, 即使用3-二氟甲基乙烯苯并呋喃或苯并噻吩作为底物的反应中, 催化剂用量可降至0.5 mol%, 并顺利得到相应的环加成产物(3v, 3w).
表2 底物范围Table 2 Scope of substrates |
 |
a Unless otherwise specified, the reaction was carried out with 1 (0.2 mmol), 2 (0.24 mmol), L3 (2 mol%), and AgSbF6 (2 mol%) in CH2Cl2 (2.0 mL). Yields are for isolated and purified products. The ee value was determined by chiral HPLC analysis. b L3 (0.5 mol%), AgSbF6 (0.5 mol%). |
为进一步拓展该方法的适用性, 对其它吲哚乙烯类化合物的反应活性进行了系统研究. 尝试了Z式3-二氟甲基乙烯吲哚[(Z)-1a]与DBAD在室温下的去芳构化反应, 受二氟甲基较大空间位阻影响, 该反应无法进行(Scheme 2a). 当使用2-二氟甲基乙烯吲哚(1u)与DBAD在－78 ℃反应, 成功地以84%的分离收率和74%的对映选择性获得目标产物3u (Scheme 2b). 基于课题组[9b]前期对(E/Z)-3-丙烯基吲哚与偶氮二甲酸异丙酯(DIAD)的不对称去芳构化环加成研究, 进一步拓展了底物范围, 尝试采用(E/Z)-3-苯乙烯基吲哚(1aa, 1ab)与DBAD分别进行去芳构化反应, 最终以中等偏低的对映选择性得到了目标产物(3aa, 3ab) (Scheme 2c). 此外, 在二氟甲基乙烯吲哚反应体系的基础上, 进一步将研究拓展至3-三氟甲基乙烯吲哚与偶氮二甲酸酯的去芳构化反应. 在标准反应条件下, 开展了Ts保护的底物1ac和DBAD在室温下的去芳构化反应. 实验结果表明, 可能是由于三氟甲基有着更强的吸电子性, 底物的反应活性较低, 导致所得产物几乎无对映选择性. 接下来, 通过对底物保护基、配体和反应温度等关键参数的筛选, 确定了最佳的反应条件: 以10 mol% AgSbF6/(S)-BINAP作为催化剂, Ac保护的底物1ad和偶氮二甲酸乙酯(DEAD)在室温下反应24 h. 在该条件下, 以85%的分离收率获得产物3ad, 并实现68%的对映选择性(Scheme 2d).
基于吲哚去芳构化环加成的反应体系, 将研究拓展至苯环取代的二氟甲基烯烃与偶氮二甲酸酯的反应. 由于苯环去芳构化反应能垒高, 使用对位甲氧基苯环取代 的二氟甲基烯烃(1ae)与DBAD进行反应, 以中等分离收率获得了产物3ae, 其结构经X射线单晶衍射分析确认(Scheme 3).
2 结论
在课题组开发的单齿膦配体和金属银盐的催化体系基础上, 利用3-二氟甲基乙烯吲哚和偶氮二甲酸酯的不对称去芳构化环加成反应, 得到了一系列含有二氟甲基的手性氮杂多环化合物. 该合成策略不仅能高效地构建手性含二氟甲基的二氢吲哚多环骨架, 同时表现出高催化效率与选择性, 实现了高产物收率、低催化剂用量以及良好的对映选择性控制. 在后续拓展研究中, 还考察了三氟甲基、苯乙烯基等取代的3-乙烯基吲哚衍生物与偶氮二甲酸酯的反应, 成功地得到了一系列结构新颖的吲哚去芳构化的产物. 此外, 通过该催化体系, 以苯环取代的二氟甲基烯烃作为原料, 同样可以构建出结构新颖的二氟甲基化合物.
3 实验部分
3.1 仪器与试剂
核磁共振谱图由Bruker AMX-400或者Agilent 400型核磁共振仪测定. 1H NMR的内标为四甲基硅烷(TMS) (δ 0.00)或CDCl3 (δ 7.26), 13C NMR内标为CDCl3 (δ 77.0)或DMSO-d6 (δ 39.5). 红外(IR)由Thermo Scientific Nicolet iS5 FT-IR测定. EI-HRMS在Finnigan MAT- 8430型高分辨质谱仪上测定. 熔点由未经校正的SGW- 4显微熔点仪测定. 手性化合物的比旋光度由Anton Paar Mcp 5500分光光度计测定. 产物的对映体过量百分数利用Chiralpak AD-H、OD-H和IF-3等手性柱, 在HPLC(赛默飞世尔或岛津)上测定. 实验中的无水二氯甲烷、四氢呋喃购自百灵威公司, 甲苯购自Adamas公司. 配体L1~L3购自Adamas公司, 其余配体通过已知文献报道的方法合成[11]. 底物二氟甲基乙烯吲哚(1a~1w)、苯乙烯基吲哚(1aa~1ab)、三氟甲基乙烯吲哚(1ac~1ad)以及苯基取代的二氟甲基烯烃(1ae)参考已知文献合成[12-14].
3.2 实验方法
在手套箱中称取L3 (2.0 mg, 0.004 mmol, 2 mol%), AgSbF6 (1.4 mg, 0.004 mmol, 2 mol%), 加入到干燥的反应瓶中后, 加入干燥CH2Cl2 (2.0 mL), 室温搅拌15 min后, 在氩气保护下降温至－78 ℃, 依次加入1 (0.2 mmol, 1.0 equiv.), 2 (0.24 mmol, 1.2 equiv.). 加料完成后, 保温搅拌, 薄层色谱(TLC)监控反应. 反应结束后, 温度恢复至室温, 加入粗硅胶, 减压蒸干, 粗产物经柱层析纯化[V(石油醚)∶V(乙酸乙酯)=4∶1]得到目标产物3.
(3R,9aR)-3-(二氟甲基)-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3a): 白色固体, 产率87% (112.3 mg), m.p. 141.9~142.8 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋163.20 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.75~7.45 (m, 5H), 7.45~7.16 (m, 8H), 7.15~6.88 (m, 5H), 6.11~5.61 (m, 2H), 5.51~5.35 (m, 2H), 5.26 (d, J=12.2 Hz, 1H), 5.05 (d, J=12.2 Hz, 1H), 4.96 (d, J=18.4 Hz, 1H), 4.80 (d, J=12.2 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.56, 154.82, 144.54, 144.04, 139.27, 135.61, 135.03, 133.98, 131.33, 129.67, 128.65, 128.48, 128.43, 128.29, 128.04, 127.86, 127.59, 125.11, 124.15, 121.33, 115.41, 113.97 (t, J=248.3 Hz), 107.66 (t, J=3.6 Hz), 75.62, 68.92, 68.23, 55.75 (t, J=23.9 Hz), 21.53; 19F NMR (376 MHz, CDCl3) δ: －122.40 (dd, J=286.1, 54.3 Hz), －126.41 (d, J=285.0 Hz); IR (film) ν: 3033, 2957, 1725, 1600, 1462, 1171, 1117, 664, 575 cm－1. HRMS (ESI) calcd for C34H30- F2N3O6S [M＋H]＋ 646.1818, found 646.1824. 对映体过量值: 86%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=270 nm, 流速1.0 mL/min; tmajor=16.42 min; tminor=13.77 min].
(3R,9aR)-3-(二氟甲基)-5-甲基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3b): 白色固体, 产率84% (110.5 mg), m.p. 65.5~66.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋128.69 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.62~7.48 (m, 5H), 7.37 (q, J=6.4 Hz, 3H), 7.25~7.12 (m, 4H), 7.02 (dd, J=14.3, 7.4 Hz, 4H), 6.81 (d, J=7.6 Hz, 1H), 6.09~5.62 (m, 2H), 5.48~5.37 (m, 2H), 5.25 (d, J=12.1 Hz, 1H), 5.06 (d, J=12.3 Hz, 1H), 4.99 (d, J=20.5 Hz, 1H), 4.76 (d, J=12.3 Hz, 1H), 2.28 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 155.63, 155.07, 144.52, 144.28, 139.79, 135.68, 135.29, 135.09, 134.08, 130.70, 129.68, 128.67, 128.54, 128.45, 128.28, 128.06, 127.90, 127.63, 126.10, 123.42, 114.07 (t, J=248.5 Hz), 112.67, 109.49, 75.78, 68.92, 68.19, 55.97 (t, J=28.9 Hz), 21.54, 20.25; 19F NMR (376 MHz, CDCl3) δ: －122.41 (dd, J=285.3, 55.0 Hz), －126.48 (dd, J=284.8, 43.2 Hz); IR (film) ν: 3064, 2955, 1725, 1589, 1371, 1171, 668, 576 cm－1. HRMS (ESI) calcd for C35H32- F2N3O6S [M＋H]＋ 660.1974, found 660.1980. 对映体过量值: 83%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=16.70 min; tminor=12.16 min].
(3R,9aR)-3-(二氟甲基)-5-氟-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3c): 白色固体, 产率85% (112.3 mg), m.p. 59.1~60.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋129.87 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.67~6.92 (m, 16H), 6.71 (t, J=8.7 Hz, 1H), 6.07 (s, 1H), 5.87 (t, J=55.2 Hz, 1H), 5.49~5.35 (m, 2H), 5.26 (d, J=12.2 Hz, 1H), 5.12~4.90 (m, 2H), 4.75 (d, J=12.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 158.33 (d, J=253.7 Hz), 155.51, 154.85, 145.55 (d, J=7.2 Hz), 144.83, 135.63, 135.57, 134.94, 134.00, 132.40 (d, J=8.6 Hz), 129.77, 128.68, 128.49, 128.34, 128.17, 127.91, 127.61, 113.84 (t, J=248.4 Hz), 113.46 (d, J=19.4 Hz), 111.39, 111.10, 110.97 (d, J=3.6 Hz), 110.91, 75.66, 69.00, 68.28, 55.82 (t, J=28.8 Hz), 21.53; 19F NMR (376 MHz, CDCl3) δ: －115.24~－115.45 (m),－122.45 (dd, J=286.8, 54.6 Hz), －126.40 (dd, J=285.1, 39.8 Hz); IR (film) ν: 3065, 2956, 1725,1622, 1404, 1174, 1041, 669, 577 cm－1. HRMS (ESI) calcd for C34H29- F3N3O6S [M＋H]＋ 664.1724, found 664.1717. 对映体过量值: 90%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=12.57 min; tminor=9.33 min].
(3R,9aR)-3-(二氟甲基)-5-氯-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3d): 白色固体, 产率89% (121.0 mg), m.p. 67.5~68.4 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋128.79 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.65~7.47 (m, 5H), 7.44~7.30 (m, 3H), 7.30~7.12 (m, 4H), 7.10~6.91 (m, 5H), 6.50 (s, 1H), 5.88 (t, J=55.4 Hz, 1H), 5.48~5.38 (m, 2H), 5.27 (d, J=12.2 Hz, 1H), 5.09~4.94 (m, 2H), 4.72 (d, J=12.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.44, 154.92, 145.48, 144.85, 137.31, 135.57, 134.93, 134.03, 131.40, 130.20, 129.78, 128.68, 128.54, 128.49, 128.35, 128.18, 127.90, 127.61, 125.08, 122.59, 113.86 (t, J=248.6 Hz), 113.23, 112.05, 75.59, 69.01, 68.27, 55.99 (t, J=26.9 Hz), 21.55; 19F NMR (376 MHz, CDCl3) δ: －122.45 (dd, J=287.1, 54.7 Hz), －126.36 (d, J=286.1 Hz); IR (film) ν: 3033, 2956, 1725, 1595, 1307, 1171, 667, 576 cm－1. HRMS (ESI) calcd for C34H29ClFN3O6S2Na [M＋Na]＋ 702.1248, found 702.1236. 对映体过量值: 89%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=270 nm, flow rate1.0 mL/min; tmajor=13.88 min; tminor=10.21 min].
(3R,9aR)-3-(二氟甲基)-5-溴-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3e): 白色固体, 产率97% (140.3 mg), m.p. 67.7~68.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$ ＋107.64 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.67~7.44 (m, 5H), 7.42~7.18 (m, 6H), 7.17~6.95 (m, 6H), 6.67 (s, 1H), 5.88 (t, J=56.1 Hz, 1H), 5.49~5.38 (m, 2H), 5.26 (d, J=12.2 Hz, 1H), 5.07~4.94 (m, 2H), 4.72 (d, J=12.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.46, 154.93, 145.70, 144.88, 138.07, 135.57, 134.92, 134.00, 133.95, 131.49, 129.80, 128.69, 128.56, 128.50, 128.37, 128.19, 127.91, 127.61, 124.03, 118.23, 113.86 (t, J=248.6 Hz), 113.73, 111.77, 75.57, 69.02, 68.28, 55.87 (t, J=26.6 Hz), 21.57; 19F NMR (376 MHz, CDCl3) δ: －122.48 (dd, J=285.5, 54.8 Hz), －126.34 (d, J=286.7 Hz); IR (film) ν: 3033, 2955, 1725, 1593, 1404, 1307, 1171, 666, 576 cm－1. HRMS (ESI) calcd for C34H28BrF2N3O6SNa [M＋Na]＋ 746.0742, found 746.0753. 对映体过量值: 85%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=270 nm, 流速1.0 mL/min; tmajor=14.81 min; tminor=11.02 min].
(3R,9aR)-3-(二氟甲基)-5-甲氧基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3f): 白色固体, 产率85% (140.87 mg), m.p. 168.6~169.0 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$ ＋140.87 (c 1.00, CHCl3); 1H NMR (400 MHz, CD2Cl2) δ: 7.74~7.27 (m, 13H), 7.25~7.12 (m, 4H), 6.66 (dd, J=7.8, 1.4 Hz, 1H), 6.21 (s, 1H), 5.90 (t, J=55.7 Hz, 1H), 5.57~5.42 (m, 2H), 5.36 (d, J=12.3 Hz, 2H), 5.15 (d, J=12.3 Hz, 1H), 5.06 (d, J=17.3 Hz, 1H), 4.90 (d, J=12.3 Hz, 1H), 3.90 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 158.48, 157.33, 156.96, 146.92, 146.86, 138.91, 137.86, 137.24, 135.66, 134.09, 131.65, 130.50, 130.26, 130.20, 130.16, 129.92, 129.71, 129.50, 116.26 (t, J=247.9 Hz), 115.55, 111.15, 109.51, 108.30, 77.65, 70.65, 70.04, 57.84, 57.46, 23.18; 19F NMR (376 MHz, CDCl3) δ: －120.98 (dd, J=284.0, 54.8 Hz), －124.77 (dd, J=283.5, 40.6 Hz); IR (film) ν: 2943, 2895, 1724, 1597, 1494, 1272, 1170, 668, 590 cm－1. HRMS (ESI) calcd for C35H31F2N3O7SNa [M＋Na]＋ 698.1743, found 698.1747. 对映体过量值: 86%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=15.15 min; tminor=10.58 min].
(3R,9aR)-3-(二氟甲基)-6-甲基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3g): 白色固体, 产率81% (106.4 mg), m.p. 67.5~68.3 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋103.55 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.74~7.45 (m, 5H), 7.46~7.31 (m, 3H), 7.29~7.17 (m, 3H), 7.13~6.95 (m, 6H), 6.04~5.68 (m, 2H), 5.44 (d, J=12.2 Hz, 1H), 5.35 (t, J=3.2 Hz, 1H), 5.24 (d, J=12.3 Hz, 1H), 5.07 (d, J=12.3 Hz, 1H), 4.95 (d, J=18.0 Hz, 1H), 4.82 (d, J=12.3 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.55, 154.89, 144.48, 141.93, 139.37, 135.68, 135.13, 134.01, 133.89, 132.17, 129.68, 128.65, 128.45, 128.41, 128.26, 128.00, 127.87, 127.63, 125.20, 121.68, 115.30, 114.06 (t, J=248.3 Hz), 107.32, 75.84, 68.87, 68.20, 55.82 (t, J=27.0 Hz), 21.51, 20.81; 19F NMR (376 MHz, CDCl3) δ: －122.30 (dd, J=286.3, 54.8 Hz), －126.33 (dd, J=283.4, 40.8 Hz); IR (film) ν: 3032, 2956, 1724, 1597, 1404, 1170, 666, 593 cm－1. HRMS (DART-TOF) calcd for C35H32F2N3O6S[M＋H]＋ 660.1974, found 660.1968. 对映体过量值: 82%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=270 nm, 流速1.0 mL/min; tmajor=22.06 min; tminor=12.94 min].
(3R,9aR)-3-(二氟甲基)-6-氟-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3h): 白色固体, 产率91% (121.2 mg), m.p. 63.6~64.7 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋154.89 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.67~7.44 (m, 5H), 7.44~7.33 (m, 3H), 7.31~7.16 (m, 3H), 7.15~6.94 (m, 6H), 6.07~5.65 (m, 2H), 5.44 (d, J=12.1 Hz, 1H), 5.38 (t, J=3.2 Hz, 1H), 5.26 (d, J=12.1 Hz, 1H), 5.07 (d, J=12.2 Hz, 1H), 4.96 (d, J=18.7 Hz, 1H), 4.80 (d, J=12.2 Hz, 1H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 159.65 (d, J=244.0 Hz), 155.45, 154.79, 144.77, 140.15, 138.62, 135.58, 134.97, 133.75, 129.78, 128.68, 128.49, 128.34, 128.17, 127.96, 127.60, 126.72 (d, J=8.9 Hz), 118.04 (d, J=24.0 Hz), 116.61 (d, J=8.4 Hz), 113.90 (t, J=248.4 Hz), 109.25, 108.17 (d, J=24.6 Hz), 76.00, 68.98, 68.31, 55.80, 29.69, 21.53; 19F NMR (376 MHz, CDCl3) δ: －118.22 (dd, J=7.1, 6.4 Hz), －122.31 (dd, J=286.6, 54.6 Hz), －126.29 (dd, J=285.6, 46.3 Hz); IR (film) ν: 3034, 2825, 1725, 1476, 1283, 1169, 666, 595 cm－1. HRMS (ESI) calcd for C34H28F3N3O6SNa [M＋Na]＋ 686.1543, found 686.1533. 对映体过量值: 87%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=17.00 min; tminor=11.66 min].
(3R,9aR)-3-(二氟甲基)-6-氯-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3i): 白色固体, 产率91% (123.4 mg), m.p. 69.2~70.0 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋85.05 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.63~7.43 (m, 5H), 7.43~7.31 (m, 3H), 7.31~7.14 (m, 5H), 7.11~6.96 (m, 4H), 6.08~5.67 (m, 2H), 5.47~5.36 (m, 2H), 5.25 (d, J=12.2 Hz, 1H), 5.04 (d, J=12.1 Hz, 1H), 4.96 (d, J=19.0 Hz, 1H), 4.73 (d, J=12.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.45, 154.82, 144.83, 142.62, 138.31, 135.55, 134.90, 133.93, 133.91, 131.06, 129.80, 129.65, 128.68, 128.49, 128.34, 128.19, 127.97, 127.58, 126.71, 121.35, 116.34, 112.64 (t, J=248.9 Hz), 109.26, 75.84, 69.01, 68.32, 55.84 (t, J=25.6 Hz), 21.53; 19F NMR (376 MHz, CDCl3) δ: －122.34 (dd, J=285.4, 54.4 Hz), －126.27 (d, J=287.0 Hz); IR (film) ν: 3034, 2957, 1725, 1597, 1462, 1308, 1168, 666, 588 cm－1. HRMS (ESI) calcd for C34H29Cl F2N3O6S[M＋H]＋ 680.1428, found 680.1427. 对映体过量值: 72%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=18.38 min; tminor=11.51 min].
(3R,9aR)-3-(二氟甲基)-6-溴-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3j): 白色固体, 产率85% (123.4 mg), m.p. 72.4~73.2 ℃. ${[\alpha ]}_{\text{D}}^{\text{25}}$＋57.22 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.61~7.44 (m, 5H), 7.44~7.31 (m, 5H), 7.29~7.17 (m, 3H), 7.12~6.91 (m, 4H), 6.06~5.63 (m, 2H), 5.48~5.38 (m, 2H), 5.32~5.21 (m, 2H), 5.04 (d, J=12.2 Hz, 1H), 4.96 (d, J=19.6 Hz, 1H), 4.72 (d, J=12.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.42, 154.81, 144.82, 143.09, 138.19, 135.52, 134.86, 133.91, 129.79, 128.67, 128.50, 128.35, 128.25, 128.20, 127.99, 127.57,126.94, 127.08, 124.28, 117.01, 116.72, 113.85 (t, J=248.4 Hz), 109.25, 75.74, 69.02, 68.33, 55.83 (t, J=27.7 Hz), 21.54; 19F NMR (376 MHz, CDCl3) δ: －122.37 (dd, J=286.0, 54.3 Hz), －126.33 (dd, J=287.5, 42.2 Hz). IR (film) ν: 3033, 2955, 1724, 1596, 1308, 1168, 666, 585 cm－1. HRMS (ESI) calcd for C34H28Br- F2N3O6SNa [M＋Na]＋ 746.0742, found 746.0750. 对映体过量值: 75%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=19.49 min; tminor=11.79 min].
(3R,9aR)-3-(二氟甲基)-6-甲氧基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3k): 白色固体, 产率95% (128.6 mg), m.p. 61.4~62.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋60.82 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J=9.0 Hz, 1H), 7.58~7.42 (m, 4H), 7.42~7.28 (m, 3H), 7.27~7.18 (m, 3H), 7.17~7.08 (m, 2H), 7.02 (d, J=7.9 Hz, 2H), 6.86 (dd, J=8.9, 2.6 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 6.09~5.67 (m, 2H), 5.45 (d, J=12.3 Hz, 1H), 5.31 (t, J=3.2 Hz, 1H), 5.23 (d, J=12.3 Hz, 1H), 5.09 (d, J=12.3 Hz, 1H), 4.96 (d, J=20.6 Hz, 1H), 4.86 (d, J=12.3 Hz, 1H), 3.74 (s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 156.92, 155.63, 154.87, 144.55, 139.32, 137.79, 135.69, 135.13, 133.51, 129.72, 128.67, 128.46, 128.43, 128.30, 128.05, 127.89, 127.65, 126.27, 118.02, 116.70, 114.06 (t, J=248.4 Hz), 107.89, 105.56, 75.99, 68.86, 68.26, 55.80, 55.70, 21.52; 19F NMR (376 MHz, CDCl3) δ: －122.23 (dd, J=285.4, 54.7 Hz), －126.19 (dd, J=281.6, 45.7 Hz). HRMS (ESI) calcd for C35H32F2N3O7S[M＋H]＋ 676.1924; Found 676.1921. IR (film) ν: 3033, 2956, 1725, 1484, 1287, 1169, 666, 545 cm－1. 对映体过量值: 71%, d高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(正己烷)∶V(异丙醇)=70∶30, λ=254 nm, 流速1.0 mL/min; tmajor=19.22 min; tminor=12.20 min].
(3R,9aR)-3-(二氟甲基)-7-甲基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3l): 白色固体, 产率92% (121.5 mg), m.p. 62.4~63.3 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋91.34 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.62~7.46 (m, 5H), 7.43~7.31 (m, 3H), 7.29~7.14 (m, 4H), 7.13~6.94 (m, 4H), 6.84 (dd, J=7.9, 1.4 Hz, 1H), 6.03~5.59 (m, 2H), 5.51~5.34 (m, 2H), 5.26 (d, J=12.1 Hz, 1H), 5.03 (d, J=12.2 Hz, 1H), 4.94 (d, J=19.0 Hz, 1H), 4.76 (d, J=12.2 Hz, 1H), 2.37 (s, 3H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.54, 154.92, 144.44, 144.28, 142.16, 139.20, 135.64, 135.04, 134.23, 129.64, 128.64, 128.47, 128.41, 128.23, 128.00, 127.90, 127.56, 125.12, 122.62, 121.01, 115.90, 114.03 (t, J=248.2 Hz), 106.27, 75.94, 68.90, 68.19, 56.10 (t, J=25.7 Hz), 22.18, 21.51; 19F NMR (376 MHz, CDCl3) δ: －122.49 (dd, J=284.5, 54.4 Hz), －126.51 (d, J=284.3 Hz); IR (film) ν: 3033, 2955, 1728, 1610, 1296, 1120, 666, 584 cm－1. HRMS (ESI) calcd for C35H32F2N3O6S [M＋H]＋ 660.1974, found 660.1967. 对映体过量值: 86%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=16.77 min; tminor=11.60 min].
(3R,9aR)-3-(二氟甲基)-7-氟-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯 (3m): 白色固体, 产率96% (127.7 mg), m.p. 63.1~63.6 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋122.22 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.62~7.46 (m, 4H), 7.48~7.30 (m, 4H), 7.31~7.10 (m, 4H), 7.11~6.91 (m, 4H), 6.70 (td, J=8.6, 2.3 Hz, 1H), 6.06~5.69 (m, 2H), 5.51~5.35 (m, 2H), 5.26 (d, J=12.2 Hz, 1H), 5.01 (d, J=12.1 Hz, 1H), 4.94 (d, J=21.7 Hz, 1H), 4.71 (d, J=12.1 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 164.64 (d, J=249.7 Hz), 155.47, 154.91, 145.52 (d, J=12.4 Hz), 144.88, 138.27, 135.55, 134.84, 134.02, 133.99, 129.81, 128.69, 128.50, 128.33, 128.22, 127.96, 127.60, 122.50 (d, J=10.3 Hz), 121.23 (d, J=2.8 Hz), 115.20 (t, J=248.9 Hz), 111.35 (d, J=23.3 Hz), 107.00, 103.50 (d, J=29.3 Hz), 76.11, 69.00, 68.32, 55.79 (t, J=26.6 Hz), 21.54; 19F NMR (376 MHz, CDCl3) δ: －106.47 (dd, J=13.9, 9.1 Hz), －122.50 (dd, J=285.5, 54.8 Hz), －126.46 (d, J=286.3 Hz); IR (film) ν: 3034, 2956, 1728, 1610, 1597, 1300, 1168, 667, 584 cm－1. HRMS (ESI) calcd for C34H29F3N3O6S [M＋H]＋ 664.1724, found 664.1726. 对映体过量值: 88%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=13.18 min; tminor=10.71 min].
(3R,9aR)-3-(二氟甲基)-7-氯-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3n): 白色固体, 产率86% (116.4 mg), m.p. 64.7~65.5 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋70.52 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.57 (d, J=1053.8 Hz, 5H), 7.46~7.30 (m, 3H), 7.31~7.13 (m, 4H), 7.12~6.86 (m, 5H), 6.11~5.68 (m, 2H), 5.49~5.37 (m, 2H), 5.26 (d, J=12.1 Hz, 1H), 5.04~4.87 (m, 2H), 4.68 (d, J=11.9 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.44, 154.92, 144.91, 144.84, 138.35, 137.07, 135.50, 134.73, 134.12, 134.10, 129.80, 128.69, 128.52, 128.33, 128.26, 127.97, 127.57, 124.29, 123.67, 122.00, 115.63, 113.91 (t, J=248.2 Hz), 108.11, 75.93, 69.05, 68.37, 55.85 (t, J=26.0 Hz), 21.55; 19F NMR (376 MHz, CDCl3) δ: －122.45 (dd, J=286.2, 54.6 Hz), －126.38 (d, J=285.4 Hz); IR (film) ν: 3033, 2954, 1727, 1600, 1926.6, 1172, 1123, 666, 582 cm－1. HRMS (ESI) calcd for C34H29ClF2N3O6S [M＋H]＋ 680.1428, found 680.1420. 对映体过量值: 65%, 高效液相色谱测定[V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=16.77 min; tminor=11.60 min].
(3R,9aR)-3-(二氟甲基)-7-溴-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3o): 白色固体, 产率88% (128.2 mg), m.p. 62.5~63.1 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋53.96 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.77 (s, 1H), 7.63~7.42 (m, 4H), 7.43~7.15 (m, 6H), 7.16~6.92 (m, 6H), 6.10~5.62 (m, 2H), 5.47~5.37 (m, 2H), 5.26 (d, J=12.2 Hz, 1H), 5.03~4.88 (m, 2H), 4.67 (d, J=11.8 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.46, 154.92, 144.96, 144.85, 138.44, 135.50, 134.72, 134.11, 129.80, 128.69, 128.59, 128.52, 128.34, 128.29, 127.97, 127.57, 127.18, 125.15, 124.11, 122.25, 118.45, 113.88 (t, J=248.4 Hz), 108.29, 75.83, 69.05, 68.38, 55.88 (t, J=25.1 Hz), 21.56; 19F NMR (376 MHz, CDCl3) δ: －122.45 (dd, J=285.5, 54.5 Hz), －126.35 (d, J=285.6 Hz); IR (film) ν: 3033, 2955, 1727, 1597, 1292, 1172, 666, 581 cm－1. HRMS (ESI) calcd for C34H28N3O6SF2ClNa [M＋Na]＋ 702.1248, found 702.1245. 对映体过量值: 70%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80∶20, λ=254 nm, 流速1.0 mL/min; tmajor=14.78 min; tminor=11.50 min].
(3R,9aR)-3-(二氟甲基)-7-甲氧基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3p): 白色固体, 产率77% (103.8 mg), m.p. 66.6~67.4 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋89.20 (c 1.00, CHCl3); 1H NMR (400 MHz, CD2Cl2) δ: 7.72~7.36 (m, 7H), 7.37~7.01 (m, 9H), 6.66 (dd, J=8.5, 2.3 Hz, 1H), 6.10~5.65 (m, 2H), 5.52~5.39 (m, 2H), 5.37~5.33 (m, 1H), 5.11 (d, J=12.2 Hz, 1H), 4.98 (d, J=17.2 Hz, 1H), 4.86 (d, J=12.3 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CD2Cl2) δ: 162.67, 155.42, 155.00, 145.52, 145.02, 138.57, 135.89, 135.22, 133.78, 133.74, 129.78, 128.58, 128.36, 128.26, 128.04, 127.88, 127.58, 122.22, 118.00, 114.31 (t, J=247.9 Hz), 110.81, 104.72, 100.93, 76.20, 68.76, 68.20, 56.00, 55.69, 21.27; 19F NMR (376 MHz, CD2Cl2) δ: －123.01 (dd, J=283.6, 55.2 Hz), －126.82 (d, J=284.8 Hz); IR (film) ν: 2959, 1716, 1611, 1376, 1306, 1115, 1028, 586, 544 cm－1. HRMS (DART-TOF) calcd for C35H32F2N3O7S [M＋H]＋ 676.1924, found 676.1920. 对映体过量值: 69%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=80 : 20, λ=270 nm, 流速1.0 mL/min; tmajor=20.69 min; tminor=16.05 min].
1,2-二苄基-7-甲基 (3R,9aR)-3-(二氟甲基)-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2,7(3H)-三甲酸酯(3q): 白色固体, 产率83% (116.2 mg), m.p. 65.4~66.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋77.41 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J=1.2 Hz, 1H), 7.72 (dd, J=8.0, 1.4 Hz, 1H), 7.64~7.46 (m, 4H), 7.44~6.94 (m, 11H), 6.13~5.71 (m, 2H), 5.49 (t, J=3.2 Hz, 1H), 5.43 (d, J=12.1 Hz, 1H), 5.27 (d, J=12.2 Hz, 1H), 4.99 (t, J=10.4 Hz, 2H), 4.70 (d, J=12.1 Hz, 1H), 3.94 (s, 3H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 166.05, 155.47, 154.82, 144.73, 144.11, 138.70, 135.48, 134.76, 134.11, 132.78, 129.74, 129.05, 128.67, 128.51, 128.50, 128.30, 128.13, 127.95, 127.60, 125.62, 120.98, 116.10, 113.81 (t, J=248.5 Hz), 110.47, 75.82, 69.06, 68.35, 55.93 (t, J=27.0 Hz), 52.43, 21.53; 19F NMR (376 MHz, CDCl3) δ: －122.39 (dd, J=286.3, 54.8 Hz), －126.29 (d, J=284.2 Hz); IR (film) ν: 2955, 1717, 1421, 1378, 1351, 1289, 1030, 670, 584 cm－1. HRMS (ESI) calcd for C34H32F2- N3O8S [M＋H]＋ 704.1873, found 704.1865. 对映体过量值: 93%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=70∶30, λ=270 nm, 流速1.0 mL/min; tmajor=16.74 min; tminor=13.61 min].
(3R,9aR)-3-(二氟甲基)-8-甲基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3r): 白色固体, 产率84% (110.7 mg), m.p. 59.6~60.4 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋21.76 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.68~7.37 (m, 4H), 7.34~7.17 (m, 5H), 7.16~6.89 (m, 6H), 6.84 (d, J=7.5 Hz, 2H), 6.19~5.52 (m, 3H), 5.33 (d, J=12.2 Hz, 1H), 5.28 (d, J=12.2 Hz, 1H), 5.01 (d, J=19.3 Hz, 1H), 4.94 (d, J=12.0 Hz, 1H), 4.69 (d, J=12.0 Hz, 1H), 2.32 (s, 3H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.62, 155.54, 143.93, 143.89, 139.93, 135.98, 135.92, 135.48, 134.85, 134.31, 129.35, 128.58, 128.45, 128.41, 128.34, 128.31, 128.17, 128.05, 127.34, 125.45, 118.51, 114.04 (t, J=248.3 Hz), 107.38, 76.43, 69.11, 68.27, 56.29 (t, J=28.9 Hz), 21.51, 20.90; 19F NMR (376 MHz, CDCl3) δ: －122.72 (dd, J=285.3, 54.6 Hz), －126.66 (d, J=285.5 Hz); IR (film) ν: 3033, 2957, 1728, 1596, 1291, 1165, 670, 576 cm－1. HRMS (ESI) calcd for C35H32F2N3O6S [M＋H]＋ 660.1974, found 660.1973. 对映体过量值: 70%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=70∶30, λ=254 nm, 流速1.0 mL/min; tmajor=20.02 min; tminor=8.36 min].
(3R,9aR)-3-(二氟甲基)-4-甲基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3s): 白色固体, 产率88% (120.1 mg), m.p. 60.5~61.1 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋176.36 (c 0.50, CHCl3); 1H NMR (400 MHz, CD2Cl2) δ: 7.85 (d, J=8.3 Hz, 1H), 7.69~7.51 (m, 4H), 7.51~7.32 (m, 9H), 7.28 (dd, J=6.6, 3.0 Hz, 2H), 7.20~7.13 (m, 2H), 6.10 (t, J=54.6 Hz, 1H), 5.56~5.45 (m, 2H), 5.37 (d, J=12.4 Hz, 1H), 5.22 (d, J=12.4 Hz, 1H), 5.01 (dd, J=27.8, 11.5 Hz, 2H), 2.38 (s, 3H), 2.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.31, 154.48, 144.51, 143.87, 135.68, 135.21, 133.46, 131.29, 129.95, 129.62, 128.65, 128.39, 128.36, 128.29, 127.99, 127.88, 127.77, 126.32, 124.36, 124.05, 120.83, 115.91 (t, J=252.4 Hz), 115.29, 75.50, 68.76, 68.22, 58.36 (t, J=26.1 Hz), 21.50, 15.51 (dd, J=4.6, 2.6 Hz); 19F NMR (376 MHz, CDCl3) δ: －111.10 (dd, J=281.4, 54.5 Hz), －124.39 (d, J=282.0 Hz); IR (film) ν: 3371, 3032, 1720, 1597, 1458, 1407, 1295, 1172, 751, 668 cm－1. HRMS (ESI) calcd for [M＋Na]＋ C35H32O6N3SF2Na 682.1794, found 682.1791. 对映体过量值: 82%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=90∶10, λ=254 nm, 流速1.0 mL/min; tmajor=30.23 min; tminor=27.27 min].
(3S,9bS)-3-(二氟甲基)-5-对甲苯磺酰基-5,9b-二氢-1H-吡啶并[4,3-b]吲哚-1,2(3H)-二甲酸二苄酯(3u): 白色固体, 产率84% (108.1 mg), m.p. 112.2~113.0 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$ －59.07 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.9 Hz, 2H), 7.51~7.27 (m, 10H), 7.23 (d, J=7.9 Hz, 2H), 7.11 (t, J=7.5 Hz, 1H), 7.02 (d, J=7.1 Hz, 2H), 6.15 (s, 1H), 5.87 (t, J=55.9 Hz, 1H), 5.35~5.20 (m, 2H), 5.19~4.95 (m, 2H), 4.85 (d, J=12.3 Hz, 1H), 4.79 (d, J=12.3 Hz, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 155.31, 155.06, 145.80, 142.25, 140.41, 136.42, 135.57, 133.56, 130.37, 129.74, 128.83, 128.66, 128.37, 128.34, 127.79, 127.55, 127.42, 127.00, 126.30, 125.21, 114.89, 114.85 (t, J=246.9 Hz), 97.98, 68.16, 67.92, 60.60, 54.65, 21.44; 19F NMR (376 MHz, DMSO-d6) δ: －123.95 (d, J=281.3 Hz), －126.16 (d, J=281.8 Hz); IR (film) ν: 32751, 3043, 1715, 1625, 1454, 1398, 1256, 1135, 741, 662 cm－1. HRMS (DART-TOF) calcd for C34H30F2N3O6S [M＋H]＋ 646.1818, found 646.1811. 对映体过量值: 74%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=90∶10], λ=254 nm, 流速1.0 mL/min; tmajor=20.24 min; tminor=22.84 min].
(3R,9aR)-3-(二氟甲基)-3,9a-二氢苯并[4,5]呋喃并[2,3-c]哒嗪-1,2-二甲酸二苄酯(3v): 无色油状液体, 产率88% (86.4 mg); ${[\alpha ]}_{\text{D}}^{\text{25}}$－21.30 (c 0.50, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ: 7.64 (t, J=7.0 Hz, 1H), 7.48~6.73 (m, 15H), 6.30~5.95 (m, 1H), 5.45~4.93 (m, 5H); 19F NMR (376 MHz, DMSO-d6) δ: －121.40 (dd, J=283.8, 57.7 Hz), －127.11 (dd, J=285.6, 53.1 Hz); 13C NMR (101 MHz, DMSO-d6) δ: 160.98, 159.96, 135.64, 131.70, 128.59, 128.55, 128.45, 128.38, 128.31, 128.09, 127.96, 127.72, 126.88, 122.36, 121.96, 121.70, 111.46, 111.04, 68.73, 68.03. HRMS (ESI) calcd for C27H23F2N2 O5[M＋H]＋ 493.1570, found 493.1562. 对映体过量值: 60%, 高效液相色谱测定[Chiralpak OD-H手性色谱柱, V(正己烷)∶V(异丙醇)=90∶10, λ=254 nm, 流速1.0 mL/min; tmajor=30.69 min; tminor=23.70 min].
(3R,9aR)-3-(二氟甲基)-3,9a-二氢苯并[4,5]噻吩并[2,3-c]哒嗪-1,2-二甲酸二苄酯(3w): 白色固体, 产率90% (91.6 mg), m.p. 105.4~106.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋0.52 (c 0.50, CHCl3); 1H NMR (600 MHz, DMSO-d6, 343 K) δ: 7.60~7.56 (m, 1H), 7.37~7.28 (m, 12H), 7.17 (ddd, J=7.7, 6.7, 1.7 Hz, 1H), 6.26~6.22 (m, 1H), 6.18 (td, J=54.9, 4.5 Hz, 1H), 5.91 (t, J=2.9 Hz, 1H), 5.26~5.02 (m, 5H); 19F NMR (565 MHz, DMSO-d6, 343 K) δ: －121.76 (ddd, J=282.8, 55.4, 12.4 Hz), －125.95 (dd, J=283.0, 54.9 Hz); 13C NMR (151 MHz, DMSO-d6, 343 K) δ: 155.18, 155.08, 144.14, 141.78, 136.12, 135.79, 134.03, 130.98, 128.90, 128.77, 128.70, 128.42, 128.13, 127.78, 125.84, 122.90, 122.75, 114.78 (t, J=249.6 Hz), 114.34, 69.24, 68.24, 62.34; IR (film) ν: 3033, 2959, 1721, 1498, 1401, 1266, 1071, 1039, 749, 696 cm－1. HRMS (ESI) calcd for C27H23F2N2O4S [M＋H]＋ 509.1341, found 509.1335. 对映体过量值: 93%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=90∶10, λ=254 nm, 流速1.0 mL/min; tmajor=22.92 min; tminor=17.34 min].
(3R,9aR)-3-苯基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二羧酸二苄酯(3aa): 白色固体, 产率87% (116.5mg), m.p. 68.5~69.4 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$ －112.75 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, J=8.4 Hz, 1H), 7.62~7.45 (m, 4H), 7.37~7.26 (m, 7H), 7.25~6.94 (m, 9H), 6.78 (d, J=6.9 Hz, 2H), 5.93 (t, J=2.7 Hz, 1H), 5.82 (s, 1H), 5.53 (t, J=3.0 Hz, 1H), 5.38 (d, J=12.3 Hz, 1H), 5.17 (d, J=12.3 Hz, 1H), 4.91 (d, J=12.4 Hz, 1H), 4.38 (d, J=12.4 Hz, 1H), 2.28 (s, 3H); 13C NMR (101 MHz, cdcl3) δ: 155.53, 154.38, 144.45, 144.13, 139.33, 136.60, 136.09, 135.29, 134.12, 134.06, 130.87, 129.66, 128.58, 128.50, 128.42, 128.23, 128.18, 128.12, 127.75, 127.59, 126.94, 125.63, 124.12, 121.11, 116.30, 115.49, 75.50, 68.29, 67.37, 57.70, 21.54. HRMS (ESI) calcd for C39H33N3O6NaS [M＋Na]＋ 694.1982, found 694.1985; IR (film) ν: 3031, 2949, 1713, 1496, 1461, 1290, 1170, 751, 665, 576 cm－1. 对映体过量值: 55%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=60∶40, λ=254 nm, 流速1.0 mL/min; tmajor=17.06 min; tminor=12.68 min].
(3S,9aR)-3-苯基-9-对甲苯磺酰基-9,9a-二氢-1H-吡啶并[3,4-b]吲哚-1,2(3H)-二羧酸二苄酯(3ab): 白色固体, 产率90% (120.9 mg), m.p. 151.6~152.9 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$ －5.55 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J=7.9 Hz, 2H), 7.78 (d, J=8.3 Hz, 1H), 7.55~7.12 (m, 17H), 7.11~6.86 (m, 3H), 6.49 (dd, J=7.0, 3.2 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 6.16 (d, J=7.0 Hz, 1H), 5.23 (s, 2H), 4.98 (d, J=12.4 Hz, 1H), 4.12 (d, J=12.5 Hz, 1H), 2.32 (s, 3H); 13C NMR (101 MHz, cdcl3) δ: 156.92, 155.74, 144.38, 141.49, 136.09, 135.21, 134.63, 133.50, 130.24, 129.61, 129.20, 129.02, 128.72, 128.61, 128.52, 128.31, 128.28, 127.82, 127.74, 127.69, 127.29, 125.71, 124.11, 122.44, 120.65, 115.68, 73.11, 68.28, 68.10, 55.46, 21.58. HRMS (ESI) calcd for C39H33N3O6NaS [M＋Na]＋ 694.1982, found 694.1986; IR (film) ν: 3029, 2941, 1709, 1459, 1322, 1171, 662, 569 cm－1. 对映体过量值: 40%, 高效液相色谱测定[ChiralPak IF-3手性色谱柱, V(石油醚)∶V(异丙醇)=60∶40, λ=254 nm, 流速1.0 mL/min; tmajor=8.94 min; tminor=28.15 min].
(3R,9aR)-9-甲苯磺酰基-3-(三氟甲基)-9,9a-二氢-1H-哒嗪并[3,4-b]吲哚-1,2(3H)-二甲酸二苄酯(3ac): 白色固体, 产率83% (110.4 mg), m.p. 55.8~56.5 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.77~7.67 (m, 1H), 7.62~7.41 (m, 3H), 7.40~7.11 (m, 12H), 7.03 (ddd, J=12.6, 6.7, 3.0 Hz, 2H), 5.79 (t, J=2.7 Hz, 1H), 5.43 (d, J=12.2 Hz, 1H), 5.37 (t, J=3.1 Hz, 1H), 5.27 (d, J=12.2 Hz, 1H), 5.15 (d, J=5.1 Hz, 1H), 5.11 (d, J=12.4 Hz, 1H), 4.84 (d, J=12.3 Hz, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 155.53, 153.51, 144.54, 144.25, 140.07, 135.38, 135.23, 133.86, 133.84, 131.70, 129.64, 128.63, 128.53, 128.46, 128.23, 127.93, 127.88, 127.67, 124.76, 124.64 (q, J=284.3 Hz), 124.22, 121.46, 115.60, 106.02, 74.67, 69.31, 68.00, 54.37 (q, J=32.0 Hz); 19F NMR (376 MHz, CDCl3) δ: －73.27. HRMS (ESI) calcd for C34H28F3- N3O6NaS [M＋Na]＋ 686.1534, found 686.1530; IR (film) ν: 3033, 2952, 1731, 1560, 1373, 1266, 1172, 1124, 752, 571 cm－1. 对映体过量值: 9%, 高效液相色谱测定[Chiralpak OD-H手性色谱柱, V(正己烷)∶V(异丙醇)=90∶10, λ=254 nm, 流速1.0 mL/min; tmajor=17.14 min; tminor=12.68 min].
(3R,9aS)-9-乙酰基-3-(三氟甲基)-9,9a-二氢-1H-哒嗪并[3,4-b]吲哚-1,2(3H)-二甲酸二乙酯(3ad): 白色固体, 产率85% (72.6 mg), m.p. 97.5~98.2 ℃; ${[\alpha ]}_{\text{D}}^{\text{25}}$＋72.22 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.33 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.41~7.31 (m, 1H), 7.11 (td, J=7.7, 1.0 Hz, 1H), 6.11~5.75 (m, 1H), 5.60 (s, 1H), 5.30 (s, 1H), 4.66~4.26 (m, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.45 (s, 3H), 1.51~1.32 (m, 3H), 1.16 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 169.76, 155.32, 153.57, 145.11, 140.77, 131.81, 124.23, 124.13, 123.49 (q, J=283.6 Hz), 120.76, 117.51, 105.58, 73.80, 63.97, 62.80, 54.70, 23.13, 14.31, 13.81; 19F NMR (376 MHz, CDCl3) δ: －73.10 (d, J=7.1 Hz); IR (film) ν: 2984, 2944, 1720, 1682, 1408, 1299, 1264, 1120, 755 cm－1. HRMS (ESI) calcd for C19H21F3N3O5 [M＋H]＋ 428.1428, found 428.1434. 对映体过量值: 68%, 高效液相色谱测定[Chiralpak AD-H柱, V(正己烷)∶V(异丙 醇)=90∶10, λ=254 nm, 流速1.0 mL/min; tmajor=29.00 min; tminor=25.22 min].
(Z)-1-(3,3-二氟-1-(4-甲氧基苯基)丙-1-烯-2-基)肼-1,2-二甲酸二苄酯(3ae): 白色固体, 产率51% (46.8 mg), m.p. 70.5~71.3 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 10.27 (d, J=61.3 Hz, 1H), 7.66 (dd, J=15.1, 8.1 Hz, 2H), 7.51~7.05 (m, 10H), 6.99~6.76 (m, 4H), 6.49 (td, J=54.3, 6.4 Hz, 1H), 5.15 (d, J=27.8 Hz, 3H), 4.90 (s, 1H), 3.79 (d, J=8.9 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ: 160.64, 156.80, 154.38, 153.60, 136.76, 135.83, 131.96, 130.24, 129.99, 128.89, 128.58, 128.52, 128.25, 127.96, 125.42, 114.39, 113.87 (t, J=238.6 Hz), 68.30, 66.90, 55.66; 19F NMR (565 MHz, DMSO-d6) δ: －112.32. HRMS (ESI) calcd forC26H25F2N2O5 [M＋H]＋ 483.1726, found 483.1734.
辅助材料(Supporting Information) 底物1a~1y, 1aa~1ae和产物3a~3w, 3aa~3ae的1H NMR、13C NMR和19F NMR 图谱、对映体过量值测定的HPLC图谱及单晶衍射数据. 这些材料可以免费从本刊网站(http://sioc- journal.cn/)上下载.
(Lu, Y.)