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• 非天然手性氨基酸是多肽和蛋白质的重要合成砌块^[1].将非天然氨基酸引入多肽中, 可调节多肽的二级或三级结构^[2].脯氨酸及其衍生物是许多天然产物的重要合成片段, 如生物碱类天然产物、考琳类天然产物以及卟啉类天然产物^[3].此外, 脯氨酸及其衍生物也是许多天然产物的关键中间体, 如薄荷素(lamellarins)^[4]、hanishin和longamide B^[5].同时, 脯氨酸及其衍生物还作为手性催化剂、手性配体用于不对称合成^[6].因此, 开发高效的脯氨酸及其衍生物的不对称合成方法具有重要的研究意义^[7].研究人员开发了多种3, 5-二取代脯氨酸及其衍生物的不对称合成方法^[8]. Opatz等^[8b]以甘氨酸乙酯盐酸盐为起始原料, 采用醋酸铜或氯化铜作为催化剂, 不对称合成3, 5-二取代脯氨酸及其衍生物(Scheme 1, a). Xu等^[8c]在醋酸银与手性催化剂(Xing-phos)共催化作用的条件下, 不对称合成了3, 5-二取代脯氨酸及其衍生物(Scheme 1, b). Vicario等^[8d]以金鸡纳生物碱为手性催化剂, 进行催化不对称Miceael加成反应制备手性的3, 5-二取代脯氨酸及其衍生物(Scheme 1, c).以上方法均能有效地不对称合成3.5-二取代脯氨酸及其衍生物, 但上述报道的合成方法大多需要复杂的起始原料、昂贵的催化剂或苛刻的反应条件, 很难将其进行放大量合成.

  图式 1

  

  图式 1.  3, 5-二取代脯氨酸及其衍生物的不对称合成方法

  Scheme 1.  Asymmetric synthetic approaches of 3, 5-disubstituted prolines

  下载: 全尺寸图片 幻灯片

  镍螯合物诱导不对称合成和拆分非天然氨基酸是手性非天然氨基酸的重要制备方法, 目前, 已经实现了多种α-氨基酸和β-氨基酸的不对称合成及拆分工作^[9], 包括aldol缩合反应^[10]、Michael加成反应^[11]、烷基化反应^[12]等.与传统的有机合成方法相比, 甘氨酸等当体镍螯合物相对较稳定, 且可用于大规模的生产. Belokon等^[11a]利用甘氨酸等当体镍螯合物与α, β-不饱和醛、甲基乙烯基酮设计合成了一些3, 5-二取代脯氨酸及其衍生物(Scheme 1, d).基于此工作, 我们运用甘氨酸等当体镍螯合物与α, β-不饱和酮进行不对称Michael加成反应, 实现了3, 5-二取代脯氨酸及其衍生物的不对称合成(Scheme 1, e).

  1.   结果与讨论

  1.1   反应条件的优化

  首先, 对反应条件进行筛选, 以甘氨酸等当体镍螯合物(S)-1与查尔酮2a作为模板反应优化反应条件(表 1).甘氨酸等当体镍螯合物(S)-1 (1.0 equiv.), 查尔酮2a (1.2 equiv.), 以1, 8-二氮杂二环十一碳-7-烯(DBU, 1.5 equiv.)为碱, N, N-二甲基甲酰胺(DMF)为溶剂, 室温条件反应10 h.发现该条件中, 不对称Michael加成反应具有较高的转化率(99%)和良好的非对映选择性(dr＝89/11/0/0).根据该反应得到的粗产物在液相色谱法-质谱联用(LC-MS)中保留时间的不同, 将4个产物(非对映异构体)分别定义为A、B、C和D (LC-MS中出现时间的先后顺序, 第一个为A, 依次为B、C和D).柱层析分离后以87%的产率获得了产物A, 该反应证实了镍螯合物与不饱和酮的Michael加成反应的可行性.为了进一步提高单一构型的产率和非对映选择性, 我们考察了不同碱对该不对称Michael加成反应的影响, 分别选用氢氧化钾(KOH)、氢化钠(NaH)、氢氧化钠(NaOH)、叔丁醇钠(t-BuONa)、甲醇钠(CH₃ONa)以及叔丁醇钾(t-BuOK) (Entries 2~7, 表 1).研究结果表明:该反应在不同碱的参与下都能顺利的进行, 且DBU为碱时, 单一构型收率(87%)和立体选择性(dr＝89/11/0/0)最佳.随后, 我们锁定DBU为该反应的碱, 考察溶剂对该反应体系的影响, 分别选用二氯甲烷(CH₂Cl₂)、丙酮(Acetone)、乙腈(MeCN)、甲醇(MeOH)和四氢呋喃(THF)进行溶剂效应的考察(Entries 8~12, 表 1).溶剂对该反应体系的影响较大, 各种条件中都能获得目标产物, 当选用DBU为碱, 甲醇为溶剂时能获得较优的产率与立体选择性(Entry 11, 表 1).最后, 我们对反应温度进行优化考察(Entries 13~15, 表 1), 结果表明:反应温度的改变对反应的收率和立体选择性影响不大.综上所述, 我们确定了反应的最优条件:甘氨酸等当体镍螯合物(S)-1 (1.0 equiv.), DBU (1.5 equiv.)为碱, 甲醇为溶剂, 室温条件搅拌10 h.我们将获得的产物3a-(A)进行单晶培养, 通过X单晶衍射确定了其绝对构型为(S)(2S, 3R).

  表 1

  

  表 1  优化Michael加成反应条件^a

  Table 1.  Optimization of the Michael addition reaction conditions^a

  下载: 导出CSV

  Entry	Base	Solvent	Temp./℃	Conv./%	Yieldb/%	dr (A/B/C/D)c
  1	DBU	DMF	r.t.	99	87	89/11/0/0
  2	KOH	DMF	r.t.	80	65	85/3/12/0
  3	NaH	DMF	r.t.	83	41	45/54/1/0
  4	NaOH	DMF	r.t.	82	68	82/15/3/0
  5	t-BuONa	DMF	r.t.	81	55	80/12/8/0
  6	CH3ONa	DMF	r.t.	89	54	62/20/18/0
  7	t-BuOK	DMF	r.t.	89	67	78/13/9/0
  8	DBU	CH2Cl2	r.t.	98	67	69/11/20/0
  9	DBU	Acetone	r.t.	87	70	82/0/18/0
  10	DBU	MeCN	r.t.	70	60	91/6/3/0
  11	DBU	MeOH	r.t.	99	89	90/4/4/2
  12	DBU	THF	r.t.	98	63	65/11/23/1
  13	DBU	MeOH	-40	88	46	53/12/35/0
  14	DBU	MeOH	0	85	64	77/4/19/0
  15	DBU	MeOH	40	95	81	86/10/4/0
  a Reactions were run with 0.20 mmol of (S)-1, 0.24 mmol of 2a in 5 mL of solvent with 0.30 mmol of base for 10 h at r.t. b Isolated yield of (S)(2S, 3R)-3a. c Determined by LC/MS analysis of the crude products.

  1.2   底物的适用范围

  在确定最优反应条件后, 我们对底物的适用范围进行系统的考察.该反应将镍螯合物(S)-1与不同取代α, β-不饱和酮2进行不对称Michael加成反应, 结果如表 2所示.该方法考察了苯环上不同取代基、芳杂环以及烷基取代对不对称反应体系的影响.首先, 我们对羰基端苯环上取代进行考察(Entries 1~3, 表 2), 结果表明: 3-位与4-位甲基取代使其产率与dr值有略微下降, 无取代时反应产率与非对映选择性较高.考察卤素与吸电子基团取代时(Entries 4~7, 表 2), 该体系以67%~90%的产率和75/2/1/22~98/1/1/0的dr值得到目标产物.但当取代基为给电子甲氧基取代时, 产率仅为54% (Entry 8, 表 2).当羰基端苯环为4-溴取代时, 收率和立体选择性较优, 其单一构型产率为90%, dr值为96/4/0/0.对苯环上不同取代基的考察表明:苯环上为吸电子取代反应优于推电子取代.随后, 我们考察了杂芳基对该反应体系的适用性(Entries 9~11, 表 2), 研究结果表明:当苯环替换为杂芳基取代时, 产率略下降, 其中羰基端的苯环由噻吩取代基替换时产率较低, 仅为44%.随后我们尝试将该α, β-不饱和酮的两个苯环均改为杂环(反应12和13, 表 2), 羰基端为推电子杂环噻吩时, 产率较低(41%).最后考察了脂肪取代对反应体系的影响(Entries 14和15, 表 2), 尽管其产率仅为31%~34%, 但也获得了目标产物.其中产物3l、3m和3o的绝对构型与其他目标产物相同, 但是, 按照Cahn-Ingold-Prelog (CIP)命名原则, 化合物3l、3m和3o的命名分别为镍(Ⅱ)-(S)-N- (2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3S)-2-氨基-5-羰基-5-(2-吡啶基)-3-(2-噻吩基)戊酸席夫碱复合物(3l)、镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3S)-2-氨基-5-羰基-3, 5-双-(2-吡啶基)戊酸席夫碱复合物(3m)和镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基己酸席夫碱复合物(3n).

  表 2

  

  表 2  镍螯合物和α, β-不饱和酮类化合物的不对称Michael加成反应^a

  Table 2.  Asymmetric Michael addition reaction of Ni(Ⅱ)-complex with α, β-unsaturated ketones

  下载: 导出CSV

  Entry	3	R1	R2	Conv./%	Yieldb/%	dr c
  1	(S)(2S, 3R)-3a	Ph	Ph	99	89	90/4/4/2
  2	(S)(2S, 3R)-3b	3-MeC6H4	Ph	94	65	70/4/2/24
  3	(S)(2S, 3R)-3c	4-MeC6H4	Ph	86	76	90/6/4/0
  4	(S)(2S, 3R)-3d	4-FC6H4	Ph	95	72	77/4/17/2
  5	(S)(2S, 3R)-3e	4-ClC6H4	Ph	80	73	92/3/5/0
  6	(S)(2S, 3R)-3f	4-BrC6H4	Ph	95	90	96/4/0/0
  7	(S)(2S, 3R)-3g	4-CF3C6H4	Ph	78	75	98/1/1/0
  8	(S)(2S, 3R)-3h	4-MeOC6H4	Ph	80	54	71/6/23/0
  9	(S)(2S, 3R)-3i	2-Naphthyl	Ph	78	69	91/9/0/0
  10	(S)(2S, 3R)-3j	2-Thiophenyl	Ph	65	44	69/5/26/0
  11	(S)(2S, 3R)-3k	2-Pyridyl	Ph	75	72	97/3/0/0
  12	(S)(2S, 3S)-3l	2-Pyridyl	2-Thienyl	77	73	97/2/1/0
  13	(S)(2S, 3S)-3m	2-Pyridyl	2-Pyridyl	50	41	85/8/4/3
  14	(S)(2S, 3R)-3n	Me	Ph	50	34	68/6/26/0
  15	(S)(2S, 3S)-3o	Et	Me	35	31	91/9/0/0
  a Reactions were run with 0.20 mmol of (S)-1, 0.24 mmol of 2 in 5 mL of MeOH with 0.30 mmol of DBU for 10 h at r.t. b Isolated yield of (S)(2S, 3R)-3. c Determined by LC/MS analysis of the crude products.

  1.3   水解获得目标氨基酸

  将获得的Michael加成产物(S)(2S, 3R)-3c和(S)(2S, 3R)-3f在酸性条件下, 以乙醇为溶剂水解(Eq. 1), 得到手性化合物(2S, 3R)-4c和(2S, 3R)-4f, 同时回收手性配体(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺[(S)-BPB], 将该手性配体(S)-BPB通过一步反应即可重制起始原料甘氨酸等当体镍螯合物(S)-1, 实现了手性配体的循环使用^[13].

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  最后, 为了进一步证明该合成方法的实用性, 我们选用二氧化铂为催化剂, 将化合物(2S, 3R)-4c进行氢化还原(Eq. 2), 以较高的产率(91%)获得了含三个手性中心的3, 5-二取代的脯氨酸衍生物(2S, 3R, 5S)-5c, 其de值高达99%.由于2位具有酯基立体位阻的影响, 因此, 获得的产物绝对构型为(2S, 3R, 5S).

  2.   结论

  本文开发了一种不对称Michael加成的方法制备手性3, 5-二取代脯氨酸及其衍生物.选用廉价易得的甘氨酸等当体镍螯合物(S)-1与取代的α, β-不饱和酮2为起始原料.该反应底物适用范围广, 适用于芳基、杂芳基, 且此方法无需任何催化剂、反应简单高效、反应条件温和、操作方法简单, 能够以较高产率与高立体选择性获得目标产物.

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  3.   实验部分

  3.1   仪器和试剂

  熔点用上海精密科学仪器有限公司生产的X-4型熔点仪, 温度未经校正; 核磁共振(¹H NMR、¹³C NMR)由Bruker AMX-300、Bruker AMX-400、Bruker AMX-500和Bruker AMX-600型核磁共振测定, TMS为内标.质谱(LRMS和HRMS)由Finnigan MAT-711型、MAT-95型和LCQ-DECA型质谱仪以及IonSpec 4.7 Tesla质谱仪测定.柱层析用硅胶为200~300目或300~400目(青岛海洋化工厂生产); 薄层色谱(TLC)硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板; 采用紫外灯.所使用的化学试剂主要来源于以下厂商:国药集团上海试剂公司、Alfa Aesar、Sigma Aldrich、TCI、韶远、百灵威、安耐吉、阿达玛斯、阿拉丁等, 石油醚沸程为60~90 ℃.

  3.2   实验方法

  3.2.1   化合物3a~3o的合成

  将甘氨酸等当体镍螯合物(S)-1a (100 mg, 0.20 mmol)和2a (50.00 mg, 0.24 mmol)溶于5 mL的甲醇中, 加入DBU (45.6 mg, 0.3 mmol), 室温搅拌10 h. TLC检测反应完全后加入10 mL水淬灭, 旋蒸除去甲醇.二氯甲烷萃取(15 mL×3), 合并有机相, 饱和氯化钠溶液水洗两次, 无水硫酸钠干燥, 浓缩, 残留物用柱层析方法[V(石油醚):V(乙酸乙酯)＝1:1]得到红色固体3a, 收率89%, dr＝90/4/4/2.化合物3b~3o制备方法类似.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3, 5-二苯基戊酸物席夫碱复合物(3a): 125 mg, 产率89%, dr＝90/4/4/2.红色固体, m.p. 222~225 ℃; [α]_D²⁵+769 (c 0.055, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.31~8.26 (m, 1H), 8.00~7.95 (m, 2H), 7.81~7.76 (m, 2H), 7.55~7.45 (m, 6H), 7.43 (t, J＝5.8 Hz, 3H), 7.36 (t, J＝7.7 Hz, 2H), 7.30~7.26 (m, 3H), 7.25~7.22 (m, 1H), 7.18~7.12 (m, 2H), 6.74~6.65 (m, 2H), 4.24 (dd, J＝8.0, 4.5 Hz, 2H), 3.89 (dd, J＝17.6, 9.9 Hz, 1H), 3.56~3.47 (m, 1H), 3.41 (d, J＝12.6 Hz, 1H), 3.23 (t, J＝8.7 Hz, 1H), 2.88~2.81 (m, 1H), 2.75 (dd, J＝17.6, 4.4 Hz, 1H), 2.24~2.08 (m, 2H), 2.00~1.92 (m, 1H), 1.83~1.74 (m, 1H), 1.46~1.38 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.9, 180.4, 177.8, 171.9, 143.2, 139.1, 136.7, 134.3, 133.8, 133.3, 133.0, 132.6, 131.6, 129.9, 129.8, 129.2, 129.1, 129.1, 128.8, 128.7, 128.5, 128.3, 128.2, 127.9, 126.9, 126.0, 123.2, 120.6, 74.5, 70.5, 63.7, 57.4, 45.0, 40.8, 30.8, 23.2; LRMS (ESI) m/z: 706 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₂H₃₈N₃NiO₄ [M+H]⁺ 706.2210, found 706.2207. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min (λ＝254 nm, 1.0 mL/min). t_R(major)＝14.210 min, dr＝90/4/4/2.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基-5-间甲基苯基戊酸席夫碱复合物(3b): 94 mg, 产率65%, dr＝70/4/2/24.红色固体, m.p. 144~147 ℃; [α]_D²⁵+706 (c 0.08 CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.32 (d, J＝8.5 Hz, 1H), 8.00 (d, J＝7.3 Hz, 2H), 7.60 (d, J＝8.5 Hz, 2H), 7.56~7.51 (m, 2H), 7.51~7.47 (m, 3H), 7.46~7.42 (m, 3H), 7.32~7.27 (m, 5H), 7.21~7.15 (m, 2H), 6.74 (dd, J＝8.2, 1.6 Hz, 1H), 6.69 (t, J＝7.4 Hz, 1H), 4.28~4.24 (m, 2H), 3.90 (dd, J＝17.6, 10.0 Hz, 1H), 3.59~3.49 (m, 1H), 3.44 (d, J＝12.6 Hz, 1H), 3.25 (t, J＝8.7 Hz, 1H), 2.90~2.84 (m, 1H), 2.73 (dd, J＝17.7, 4.2 Hz, 1H), 2.35 (s, 3H), 2.23~2.14 (m, 2H), 1.99~1.96 (m, 1H), 1.86~1.76 (m, 1H), 1.48~1.40 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 197.0, 180.5, 177.9, 171.9, 143.2, 139.2, 138.3, 136.8, 134.4, 133.8, 133.3, 132.6, 131.7, 129.9, 129.8, 129.3, 129.2, 129.1, 128.9, 128.8, 128.8, 128.4, 127.9, 126.9, 126.0, 125.5, 123.3, 120.6, 74.7, 70.5, 63.7, 57.4, 45.1, 40.9, 30.8, 23.2, 21.4; LRMS (ESI) m/z: 720 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₃H₄₀N₃NiO₄ [M+H]⁺ 720.2367, found 720.2355. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝22.039 min, dr＝70/4/2/24.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基-5-对甲基苯基戊酸席夫碱复合物(3c): 109 mg, 产率76%, dr＝90/6/4/0.红色固体, m.p. 248~251 ℃; [α]_D²⁵+283 (c 0.075, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d, J＝8.7 Hz, 1H), 7.94 (d, J＝7.1 Hz, 2H), 7.65 (d, J＝8.2 Hz, 2H), 7.50~7.36 (m, 8H), 7.22 (t, J＝9.5 Hz, 4H), 7.21~7.14 (m, 4H), 6.71~6.61 (m, 2H), 4.23~4.14 (m, 2H), 3.83 (dd, J＝17.4, 10.2 Hz, 1H), 3.50~3.44 (m, 1H), 3.37 (d, J＝12.6 Hz, 1H), 3.20 (t, J＝8.7 Hz, 1H), 2.85~2.76 (m, 1H), 2.65 (dd, J＝17.5, 4.3 Hz, 1H), 2.32 (s, 3H), 2.17~2.08 (m, 2H), 2.01~1.93 (m, 1H), 1.81~1.69 (m, 1H), 1.44~1.34 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.5, 180.5, 177.9, 171.9, 143.9, 143.3, 139.2, 134.4, 133.9, 133.4, 132.6, 131.7, 129.9, 129.9, 129.3, 129.2, 129.2, 129.1, 128.9, 128.8, 128.4, 127.9, 126.9, 126.0, 123.3, 120.6, 74.7, 70.5, 63.7, 57.4, 45.2, 40.7, 30.9, 23.2, 21.7; LRMS (ESI) m/z: 720 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₃H₄₀N₃NiO₄ [M+H]⁺ 720.2367, found 720.2379. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝20.599 min, dr＝90/6/4/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-(4-氟苯基)-5-羰基-3-苯基戊酸席夫碱复合物(3d): 104 mg, 产率72%, dr＝77/4/17/2.红色固体, m.p. 156~160 ℃; [α]_D²⁵+891 (c 0.075, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (d, J＝8.5 Hz, 1H), 7.98 (d, J＝7.1 Hz, 2H), 7.82 (dd, J＝8.9, 5.5 Hz, 2H), 7.57~7.38 (m, 7H), 7.29 (d, J＝7.6 Hz, 2H), 7.24 (d, J＝7.5 Hz, 1H), 7.18~7.11 (m, 2H), 7.03 (t, J＝8.7 Hz, 2H), 6.74~6.65 (m, 2H), 4.23 (dd, J＝8.2, 4.6 Hz, 2H), 3.78 (dd, J＝17.4, 9.6 Hz, 1H), 3.53~3.46 (m, 1H), 3.41 (d, J＝12.6 Hz, 1H), 3.23 (t, J＝8.7 Hz, 1H), 2.88~2.77 (m, 2H), 2.23~2.08 (m, 2H), 2.01~1.92 (m, 1H), 1.85~1.74 (m, 1H), 1.48~1.38 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 195.5, 180.5, 177.9, 172.0, 143.3, 139.1, 134.4, 133.9, 133.3, 132.7, 131.7, 131.0, 130.0, 129.8, 129.3, 129.2, 128.9, 128.8, 128.4, 128.1, 127.0, 126.0, 123.3, 120.7, 115.7, 115.5, 74.4, 70.5, 63.8, 57.4, 45.1, 40.7, 30.9, 23.2; LRMS (ESI) m/z: 724 ([M+H]⁺). HRMS (ESI-TOF) calcd for C₄₂H₃₇FN₃NiO₄ [M+H]⁺ 724.2116, found 724.2105. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝17.183 min, dr＝77/4/17/2.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-(4-氯苯基)-5-羰基- 3-苯基戊酸席夫碱复合物(3e): 99 mg, 产率73%, dr＝75/2/1/22.红色固体, m.p. 243~245 ℃; [α]_D²⁵+931 (c 0.08, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (d, J＝8.3 Hz, 1H), 7.98 (d, J＝7.1 Hz, 2H), 7.73 (d, J＝8.6 Hz, 2H), 7.55~7.43 (m, 6H), 7.43~7.38 (m, 2H), 7.33 (d, J＝8.6 Hz, 2H), 7.30~7.26 (m, 3H), 7.23 (d, J＝6.7 Hz, 1H), 7.18~7.12 (m, 2H), 6.73~6.65 (m, 2H), 4.23 (dd, J＝8.1, 4.4 Hz, 2H), 3.76 (dd, J＝17.5, 9.5 Hz, 1H), 3.52~3.44 (m, 1H), 3.41 (d, J＝12.6 Hz, 1H), 3.23 (t, J＝8.8 Hz, 1H), 2.91~2.79 (m, 2H), 2.23~2.09 (m, 2H), 2.01~1.90 (m, 1H), 1.84~1.75 (m, 1H), 1.47~1.39 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 195.9, 180.5, 177.8, 172.0, 143.2, 139.6, 139.0, 135.1, 134.3, 133.8, 133.3, 132.7, 131.7, 130.0, 129.8, 129.7, 129.3, 129.2, 129.2, 128.9, 128.8, 128.4, 128.1, 127.0, 126.0, 123.3, 120.6, 74.3, 70.5, 63.7, 57.4, 45.0, 40.7, 30.8, 23.2; LRMS (ESI) m/z: 740 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₂H₃₇ClN₃NiO₄ [M+H]⁺ 740.1821, found 740.1837. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (250 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝75/25) for 50 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝21.238 min, dr＝92/3/5/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-(4-溴苯基)-5-羰基- 3-苯基戊酸席夫碱复合物(3f): 141 mg, 产率90%, dr＝96/4/0/0.红色固体, m.p. 245~247 ℃; [α]_D²⁵+512 (c 0.065, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (d, J＝8.6 Hz, 1H), 7.98 (d, J＝7.2 Hz, 2H), 7.65 (d, J＝8.6 Hz, 2H), 7.56~7.43 (m, 8H), 7.40 (d, J＝6.6 Hz, 2H), 7.29 (d, J＝7.4 Hz, 3H), 7.23 (d, J＝6.6 Hz, 1H), 7.19~7.11 (m, 2H), 6.75~6.63 (m, 2H), 4.27~4.19 (m, 2H), 3.76 (dd, J＝17.4, 9.5 Hz, 1H), 3.53~3.45 (m, 1H), 3.41 (d, J＝12.7 Hz, 1H), 3.23 (t, J＝8.8 Hz, 1H), 2.89~2.77 (m, 2H), 2.23~2.10 (m, 2H), 2.01~1.91 (m, 1H), 1.84~1.75 (m, 1H), 1.50~1.39 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.2, 180.5, 177.8, 172.0, 143.3, 139.0, 135.5, 134.3, 133.9, 133.3, 132.7, 131.8, 131.7, 130.0, 129.9, 129.8, 129.3, 129.2, 129.2, 128.9, 128.8, 128.4, 128.34, 128.1, 127.0, 126.0, 123.3, 120.7, 74.3, 70.5, 63.8, 57.4, 45.0, 40.7, 30.8, 23.2; LRMS (ESI) m/z: 784 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₂H₃₇BrN₃NiO₄ [M+H]⁺ 784.1315, found 784.1306. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝29.567 min, dr＝96/4/0/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基-5-(4-(三氟甲基)苯基)戊酸席夫碱(3g): 116 mg, 产率75%, dr＝98/1/1/0.红色固体, m.p. 226~230 ℃; [α]_D²⁵+665 (c 0.085, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (d, J＝8.7 Hz, 1H), 7.98 (d, J＝7.5 Hz, 2H), 7.89 (d, J＝8.0 Hz, 2H), 7.63 (d, J＝8.1 Hz, 2H), 7.55~7.39 (m, 8H), 7.31~7.26 (m, 3H), 7.26~7.22 (m, 1H), 7.19~7.11 (m, 2H), 6.73~6.64 (m, 2H), 4.27~4.19 (m, 2H), 3.80 (dd, J＝17.6, 9.4 Hz, 1H), 3.52~3.45 (m, 1H), 3.41 (d, J＝12.6 Hz, 1H), 3.23 (t, J＝8.7 Hz, 1H), 2.95~2.81 (m, 2H), 2.22~2.07 (m, 2H), 2.00~1.92 (m, 1H), 1.84~1.74 (m, 1H), 1.48~1.38 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.3, 180.4, 177.8, 143.2, 139.4, 138.9, 134.3, 133.8, 133.3, 132.7, 131.7, 130.0, 129.8, 129.3, 129.2, 128.9, 128.8, 128.6, 128.4, 128.1, 127.0, 126.0, 125.6, 123.3, 120.6, 74.2, 70.5, 63.8, 57.4, 44.8, 41.1, 30.8, 23.2; LRMS (ESI) m/z: 774 ([M+H]⁺). HRMS (ESI-TOF) calcd for C₄₃H₃₇F₃N₃NiO₄ [M+H]⁺ 774.2084, found 774.2071. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝29.886 min, dr＝98/1/1/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-(4-甲氧基苯基)-5-羰基-3-苯基戊酸席夫碱复合物(3h): 79 mg, 产率54%, dr＝71/6/23/0.红色固体, m.p. 96~99 ℃; [α]_D²⁵+522 (c 0.12, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d, J＝8.7 Hz, 1H), 8.01 (d, J＝7.2 Hz, 2H), 7.81 (d, J＝8.9 Hz, 2H), 7.58~7.53 (m, 1H), 7.51~7.48 (m, 4H), 7.47~7.42 (m, 3H), 7.30 (dd, J＝13.8, 7.5 Hz, 3H), 7.21~7.15 (m, 2H), 6.86 (d, J＝8.9 Hz, 2H), 6.75 (dd, J＝8.2, 1.7 Hz, 1H), 6.73~6.64 (m, 1H), 4.25 (dd, J＝7.8, 6.7 Hz, 2H), 3.85 (s, 3H), 3.82 (dd, J＝13.5, 6.1 Hz, 1H), 3.57~3.51 (m, 1H), 3.43 (d, J＝12.6 Hz, 1H), 3.26 (t, J＝8.7 Hz, 1H), 2.92~2.85 (m, 1H), 2.75 (dd, J＝17.2, 4.5 Hz, 1H), 2.26~2.14 (m, 2H), 2.01~1.95 (m, 1H), 1.81~1.78 (m, 1H), 1.51~1.41 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 195.5, 180.5, 177.9, 171.9, 163.5, 143.2, 139.3, 134.3, 133.8, 133.4, 132.6, 131.7, 130.6, 130.0, 129.9, 129.8, 129.3, 129.1, 129.1, 128.9, 128.8, 128.4, 127.9, 126.9, 126.0, 123.3, 120.6, 113.6, 74.7, 70.5, 63.7, 57.4, 55.5, 45.4, 40.3, 30.8, 23.2; LRMS (ESI) m/z: 736 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₃H₄₀N₃NiO₅ [M+H]⁺ 736.2316, found 736.2311. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝13.812 min, dr＝71/6/23/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-(1-奈基)-5-羰基-3-苯基戊酸席夫碱复合物(3i): 104 mg, 产率69%, dr＝91/9/0/0.红色固体, m.p. 200~208 ℃; [α]_D²⁵+529 (c 0.085, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (s, 1H), 8.31 (d, J＝8.7 Hz, 1H), 7.99 (d, J＝7.3 Hz, 2H), 7.93 (d, J＝8.0 Hz, 1H), 7.84~7.77 (m, 3H), 7.59~7.41 (m, 10H), 7.31~7.25 (m, 4H), 7.18~7.12 (m, 2H), 6.73 (dd, J＝8.2, 1.5 Hz, 1H), 6.68 (t, J＝7.4 Hz, 1H), 4.29 (d, J＝3.5 Hz, 1H), 4.25 (d, J＝12.6 Hz, 1H), 3.98 (dd, J＝17.3, 9.7 Hz, 1H), 3.61~3.55 (m, 1H), 3.42 (d, J＝12.6 Hz, 1H), 3.24 (t, J＝8.7 Hz, 1H), 2.94 (dd, J＝17.3, 4.6 Hz, 1H), 2.90~2.84 (m, 1H), 2.25~2.12 (m, 2H), 2.00~1.93 (m, 1H), 1.84~1.75 (m, 1H), 1.48~1.38 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.9, 180.5, 177.9, 172.0, 143.3, 139.2, 135.6, 134.3, 134.1, 133.8, 133.3, 132.6, 132.5, 131.7, 130.2, 129.9, 129.9, 129.8, 129.3, 129.1, 128.9, 128.8, 128.5, 128.4, 128.2, 128.0, 127.7, 126.9, 126.8, 126.0, 123.9, 123.3, 120.6, 74.6, 70.5, 63.7, 57.4, 45.3, 40.8, 30.8, 23.2; LRMS (ESI) m/z: 756 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₆H₄₀N₃NiO₄ [M+H]⁺ 756.2367, found 756.2359. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝29.957 min, dr＝91/9/0/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基-5-(2-噻吩基)戊酸席夫碱复合物(3j): 63 mg, 产率44%, dr＝69/5/26/0.红色固体, m.p. 207~208 ℃; [α]_D²⁵+860 (c 0.105, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d, J＝8.7 Hz, 1H), 7.95 (d, J＝7.5 Hz, 2H), 7.70 (d, J＝3.6 Hz, 1H), 7.55~7.36 (m, 9H), 7.26~7.15 (m, 4H), 7.11 (t, J＝7.2 Hz, 2H), 7.01 (t, J＝4.1 Hz, 1H), 6.72~6.64 (m, 2H), 4.26~4.14 (m, 2H), 3.60 (dd, J＝16.2, 9.2 Hz, 1H), 3.48~3.41 (m, 1H), 3.37 (d, J＝12.6 Hz, 1H), 3.20 (t, J＝8.6 Hz, 1H), 2.89~2.77 (m, 2H), 2.20~2.07 (m, 2H), 1.98~1.89 (m, 1H), 1.79~1.70 (m, 1H), 1.45~1.34 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 190.1, 180.5, 177.8, 172.0, 144.4, 143.1, 138.9, 134.1, 133.9, 133.8, 133.3, 132.8, 132.6, 131.6, 130.0, 129.8, 129.4, 129.1, 128.8, 128.8, 128.3, 128.2, 128.0, 126.8, 126.0, 123.2, 120.6, 74.2, 70.5, 63.7, 57.4, 45.4, 41.3, 30.8, 23.2; LRMS (ESI) m/z: 712 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₀H₃₆N₃NiO₄S [M+ H]⁺ 712.1775, found 712.1770. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝9.514 min, dr＝69/5/26/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基-5-(2-吡啶基)戊酸席夫碱复合物(3k): 102 mg, 产率72%, dr＝97/3/0/0.红色固体, m.p. 203~207 ℃; [α]_D²⁵+909 (c 0.075, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.43 (d, J＝4.4 Hz, 1H), 8.12 (d, J＝8.6 Hz, 1H), 7.82 (d, J＝7.2 Hz, 2H), 7.56~7.48 (m, 2H), 7.40~7.35 (m, 1H), 7.32~7.27 (m, 3H), 7.26~7.18 (m, 4H), 7.15~7.09 (m, 4H), 7.04~6.95 (m, 3H), 6.57~6.47 (m, 2H), 8.84~1.20 (m, 50H), 4.20 (dd, J＝18.0, 10.2 Hz, 1H), 4.14 (d, J＝3.7 Hz, 1H), 4.09 (d, J＝12.7 Hz, 1H), 3.43~3.37 (m, 1H), 3.23 (d, J＝12.6 Hz, 1H), 3.08 (t, J＝8.7 Hz, 1H), 2.79~2.68 (m, 2H), 2.04 (dd, J＝15.8, 7.4 Hz, 2H), 1.83~1.76 (m, 1H), 1.75~1.67 (m, 1H), 1.34~1.25 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 198.9, 180.5, 177.6, 171.8, 153.1, 148.9, 143.2, 139.3, 136.6, 134.5, 133.8, 133.4, 132.6, 131.7, 130.0, 129.8, 129.2, 129.1, 129.0, 128.8, 128.4, 127.8, 127.1, 127.0, 126.1, 123.2, 121.7, 120.6, 74.7, 70.6, 63.7, 57.5, 45.3, 40.2, 30.9, 23.2; LRMS (ESI) m/z: 707 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₁H₃₇N₄NiO₄ [M+H]⁺707.2163, found 707.2164. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝20.250 min, dr＝97/3/0/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3S)-2-氨基-5-羰基-5-(2-吡啶基)-3-(2-噻吩基)戊酸席夫碱复合物(3l): 104 mg, 产率73%, dr＝97/2/1/0.红色固体, m.p. 213~215 ℃; [α]_D²⁵+634 (c 0.08, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ: 8.60 (d, J＝4.5 Hz, 1H), 8.32 (d, J＝8.7 Hz, 1H), 7.98 (d, J＝7.3 Hz, 2H), 7.76 (d, J＝7.8 Hz, 1H), 7.70 (t, J＝7.7 Hz, 1H), 7.59~7.53 (m, 1H), 7.51~7.45 (m, 2H), 7.40~7.34 (m, 2H), 7.34~7.26 (m, 3H), 7.21~7.13 (m, 4H), 6.74~6.64 (m, 2H), 4.30 (dd, J＝8.3, 3.4 Hz, 2H), 3.85~3.78 (m, 1H), 3.48 (d, J＝12.7 Hz, 1H), 3.28 (t, J＝8.6 Hz, 1H), 3.11~3.04 (m, 2H), 2.44~2.15 (m, 3H), 2.04~1.95 (m, 2H), 1.63~1.53 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ: 198.3, 180.4, 177.5, 172.1, 153.0, 149.0, 143.2, 141.8, 136.7, 134.4, 133.8, 133.3, 132.6, 131.7, 129.9, 129.3, 129.1, 128.8, 128.3, 127.7, 127.1, 127.0, 126.6, 126.1, 124.9, 123.3, 121.8, 120.6, 73.9, 70.6, 63.6, 57.3, 41.3, 39.7, 30.8, 23.1. LRMS (ESI) m/z: 713 ([M+H]⁺). HRMS (ESI-TOF) calcd for C₃₉H₃₅N₄NiO₄S [M+H]⁺713.1727, found 713.1707. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝7.982 min, dr＝97/2/1/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3S)-2-氨基-5-羰基-3, 5-双-(2-吡啶基)戊酸席夫碱复合物(3m): 58 mg, 产率41%, dr＝85/8/4/3.红色固体, m.p. 82~87 ℃; [α]_D²⁵+547 (c 0.055, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.61 (dd, J＝19.4, 4.3 Hz, 2H), 8.29 (d, J＝8.7 Hz, 1H), 7.96 (d, J＝7.4 Hz, 2H), 7.76~7.63 (m, 3H), 7.54 (t, J＝7.2 Hz, 1H), 7.48~7.40 (m, 2H), 7.38~7.26 (m, 5H), 7.28~7.22 (m, 1H), 7.19 (d, J＝7.1 Hz, 1H), 7.11 (t, J＝7.3 Hz, 2H), 6.72~6.61 (m, 2H), 4.42 (dd, J＝18.6, 10.2 Hz, 1H), 4.33 (dd, J＝19.9, 8.7 Hz, 2H), 3.92~3.83 (m, 1H), 3.47 (d, J＝12.6 Hz, 1H), 3.33~3.19 (m, 2H), 3.11~3.03 (m, 1H), 2.40~2.21 (m, 4H), 2.03~1.92 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 199.1, 180.2, 177.4, 172.1, 159.4, 153.1, 149.7, 149.0, 143.0, 136.6, 136.4, 134.4, 133.9, 133.2, 132.5, 131.6, 129.8, 129.1, 129.0, 128.8, 128.6, 127.1, 127.0, 126.2, 124.6, 123.0, 122.4, 121.6, 120.5, 73.6, 70.4, 63.5, 57.0, 46.5, 39.6, 30.7, 23.2; LRMS (ESI) m/z: 708 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₄₀H₃₆N₅NiO₄ [M+H]⁺ 708.2215, found 708.2096. The de value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝5.112 min, dr＝85/8/4/3.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3R)-2-氨基-5-羰基-3-苯基己酸席夫碱复合物(3n): 44 mg, 产率34%, dr＝68/6/26/0.红色固体, m.p. 244~245 ℃; [α]_D²⁵+593 (c 0.085, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.32~8.27 (m, 1H), 7.98 (d, J＝7.1 Hz, 2H), 7.61~7.55 (m, 3H), 7.52~7.44 (m, 3H), 7.38~7.34 (m, 2H), 7.32~7.27 (m, 3H), 7.24~7.20 (m, 1H), 7.17~7.10 (m, 2H), 6.71 (dd, J＝8.2, 1.8 Hz, 1H), 6.69~6.65 (m, 1H), 4.22 (d, J＝12.6 Hz, 1H), 4.15 (d, J＝3.8 Hz, 1H), 3.40 (d, J＝12.6 Hz, 1H), 3.32~3.26 (m, 1H), 3.25~3.13 (m, 1H), 3.20~3.15 (m, 1H), 2.92~2.85 (m, 1H), 2.41 (dd, J＝17.4, 5.0 Hz, 1H), 2.23~2.08 (m, 2H), 2.01~1.93 (m, 1H), 1.86 (s, 3H), 1.85~1.78 (m, 1H), 1.49~1.40 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 205.6, 180.4, 177.7, 171.8, 143.2, 138.9, 134.4, 133.8, 133.4, 132.6, 131.65, 129.9, 129.8, 129.3, 129.2, 129.1, 128.9, 128.8, 128.4, 128.1, 127.1, 126.0, 123.2, 120.6, 74.1, 70.5, 63.7, 57.4, 45.8, 44.4, 30.8, 30.6, 23.2; LRMS (ESI) m/z: 644 ([M+H]⁺). HRMS (ESI-TOF) calcd for C₃₇H₃₆N₃NiO₄ [M+H]⁺ 644.2054, found 644.2058. The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝6.050 min, dr＝68/6/26/0.

  镍(Ⅱ)-(S)-N-(2-苯甲酰基苯基)-1-苄基吡咯烷-2-甲酰胺/(2S, 3S)-2-氨基-3-甲基5-羰基己酸席夫碱复合物(3o): 37 mg, 产率31%, dr＝91/9/0/0.红色固体, m.p. 167~169 ℃; [α]_D²⁵+777 (c 0.12, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d, J＝8.6 Hz, 1H), 8.01 (d, J＝7.2 Hz, 2H), 7.53~7.45 (m, 3H), 7.32 (t, J＝7.7 Hz, 2H), 7.24~7.21 (m, 1H), 7.19~7.12 (m, 2H), 6.99 (d, J＝7.1 Hz, 1H), 6.67~6.62 (m, 2H), 4.45 (d, J＝12.8 Hz, 1H), 3.84 (d, J＝3.8 Hz, 1H), 3.62 (d, J＝12.8 Hz, 1H), 3.50~3.43 (m, 2H), 3.38~3.24 (m, 1H), 2.83~2.77 (m, 1H), 2.55~2.47 (m, 1H), 2.41 (dd, J＝17.3, 9.3 Hz, 1H), 2.26~2.15 (m, 3H), 2.11~2.00 (m, 3H), 1.97 (d, J＝6.7 Hz, 3H), 0.91 (t, J＝7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 209.4, 180.4, 178.0, 171.6, 142.6, 134.0, 133.7, 133.2, 132.5, 131.7, 129.8, 129.1, 129.0, 129.0, 128.1, 126.9, 126.4, 123.5, 120.8, 73.9, 70.4, 63.4, 56.7, 45.9, 36.7, 33.4, 30.8, 23.1, 15.9, 7.8; LRMS (ESI) m/z: 596 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₃₃H₃₆N₃NiO₄ [M+H]⁺ 596.2054, found 596.2053; The dr value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) for 25 min, rise to 80/20 (V/V) in 1 min, then 80/20 (V/V) sustained 15 min, λ＝254 nm, 1.0 mL/min. t_R(major)＝6.995 min, dr＝91/9/0/0.

  3.2.2   化合物4c和4f合成方法

  将(S)(2S, 3R)-3c (100 mg, 0.139 mmol)溶解于3 mL乙醇中, 加入3 mol/L盐酸(1 mL), 60 ℃条件反应1 h, 溶液从红色变为淡绿色, TLC检测反应物完全转化后.将反应液冷却至室温, 旋去反应液中的乙醇, 加入水, 乙酸乙酯(10 mL)萃取三遍, 合并有机层, 再分别用饱和碳酸氢钠溶液, 饱和氯化钠溶液水洗一遍, 提取有机层, 无水硫酸钠干燥, 浓缩; 残留物用柱层析方法[V(石油醚):V(乙酸乙酯)＝20:1]得到透明浅黄色液体(2S, 3R)-4c, 收率71%, ee＞99%. 4f制备方法类似.

  (2S, 3R)-5-(4-溴苯基)-3-苯基-3, 4-二氢吡咯-2-羧酸(4c): 30 mg, 产率71%, ee＞99%.浅黄色液体, [α]_D²⁵+31.8 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (d, J＝6.4 Hz, 2H), 7.32 (t, J＝7.3 Hz, 2H), 7.26~7.20 (m, 5H), 4.92 (d, J＝5.8 Hz, 1H), 4.29~4.20 (m, 2H), 3.89~3.82 (m, 1H), 3.70~3.60 (m, 1H), 3.16 (dd, J＝17.4, 6.4 Hz, 1H), 2.40 (s, 3H), 1.29 (t, J＝7.1 Hz, 3H); ¹³C NMR (125MHz, CDCl₃) δ: 175.0, 172.4, 143.5, 141.7, 131.1, 129.4, 129.0, 128.3, 127.1, 127.0, 82.7, 61.4, 46.6, 44.8, 21.7, 14.3; LRMS (ESI) m/z: 308 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₂₀H₂₂NO₂ [M+H]⁺ 308.1645, found 308.1637. The ee value was determined by chiral HPLC with a Chiralpak OD-H column [V(n-hexane)/ V(i-PrOH)＝96/4, λ＝254 nm, 1.0 mL/min]. t_R(major enantiomer)＝22.455 min, t_R(minor enantiomer)＝13.867 min, ee＞99%.

  (2S, 3R)-5-(4-甲基苯基)-3-苯基-3, 4-二氢吡咯-2-羧酸(4f): 31 mg, 产率66%, ee＞99%.白色固体, m.p. 99~104 ℃; [α]_D²⁵+37.5 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ: 7.75~7.70 (m, 2H), 7.54~7.49 (m, 2H), 7.30~7.24 (m, 2H), 7.21~7.18 (m, 1H), 7.18~7.14 (m, 2H), 4.86 (dt, J＝6.1, 1.9 Hz, 1H), 4.23~4.14 (m, 2H), 3.82 (dt, J＝9.6, 6.3 Hz, 1H), 3.61~3.51 (m, 1H), 3.11~3.04 (m, 1H), 1.24 (t, J＝7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 174.1, 172.2, 143.2, 132.6, 131.9, 129.8, 129.1, 127.2, 127.1, 126.0, 82.8, 61.6, 46.6, 44.7, 14.4; LRMS (ESI) m/z: 372 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₁₉H₁₉BrNO₂ [M+H]⁺ 372.0594, found 372.0582. The ee value was determined by chiral HPLC with a Chiralpak OD-H column [V(n-hexane)/V(i-PrOH)＝85/15, λ＝254 nm, 1.0 mL/min]. t_R (major enantiomer)＝8.808 min, t_R (minor enantiomer)＝11.561 min, ee＝94%.

  3.2.3   化合物(2S, 3R, 5S)-5c合成方法

  将化合物(2S, 3R)-4c (30 mg, 0.097 mmol)溶入10 mL乙醇中, 加入氧化铂(3.0 mg, 0.013 mmol)通入氢气, 室温搅拌8 h, 硅藻土抽滤, 有机相浓缩, 残留物用柱层析方法[V(石油醚):V(乙酸乙酯)＝20:1]得到(2S, 3R, 5S)-3-苯基-5-(对甲苯基吡咯烷)-2-羧酸(5c) 28 mg, 产率91%, de＞99%.浅黄色液体, [α]_D²⁵-38.4 (c 0.04, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.39~7.30 (m, 6H), 7.26~7.23 (m, 1H), 7.19~7.14 (m, 2H), 4.50 (t, J＝7.6 Hz, 1H), 4.25~4.11 (m, 3H), 3.97 (d, J＝6.8 Hz, 1H), 3.59~3.54 (m, 1H), 2.35 (s, 3H), 2.27~2.23 (m, 1H), 1.21 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 174.2, 143.0, 140.7, 137.0, 129.4, 128.7, 127.6, 126.8, 68.2, 62.4, 61.2, 49.7, 43.4, 21.2, 14.3; LRMS (ESI) m/z: 310 ([M+H]⁺); HRMS (ESI-TOF) calcd for C₂₀H₂₄NO₂ [M+H]⁺ 310.1793, found 310.1802. The de value was determined by LC-MS with an Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) MeOH/H₂O (V/V＝70/30) (λ＝214 nm, 1.0 mL/min). t_R(major enantiomer)＝30.170 min, de＞99%.

  辅助材料(Supporting Information)  化合物3~5的分析谱图, 化合物(S)(2S, 3R)-3a的X单晶衍射图, 化合物3~5的¹H NMR和¹³C NMR谱图.这些材料可以从本刊网站(http://sioc-journal.cn/)上下载.

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• 

  图式 1  3, 5-二取代脯氨酸及其衍生物的不对称合成方法

  Scheme 1  Asymmetric synthetic approaches of 3, 5-disubstituted prolines

  下载: 全尺寸图片 幻灯片

  表 1  优化Michael加成反应条件^a

  Table 1.  Optimization of the Michael addition reaction conditions^a

  Entry	Base	Solvent	Temp./℃	Conv./%	Yieldb/%	dr (A/B/C/D)c
  1	DBU	DMF	r.t.	99	87	89/11/0/0
  2	KOH	DMF	r.t.	80	65	85/3/12/0
  3	NaH	DMF	r.t.	83	41	45/54/1/0
  4	NaOH	DMF	r.t.	82	68	82/15/3/0
  5	t-BuONa	DMF	r.t.	81	55	80/12/8/0
  6	CH3ONa	DMF	r.t.	89	54	62/20/18/0
  7	t-BuOK	DMF	r.t.	89	67	78/13/9/0
  8	DBU	CH2Cl2	r.t.	98	67	69/11/20/0
  9	DBU	Acetone	r.t.	87	70	82/0/18/0
  10	DBU	MeCN	r.t.	70	60	91/6/3/0
  11	DBU	MeOH	r.t.	99	89	90/4/4/2
  12	DBU	THF	r.t.	98	63	65/11/23/1
  13	DBU	MeOH	-40	88	46	53/12/35/0
  14	DBU	MeOH	0	85	64	77/4/19/0
  15	DBU	MeOH	40	95	81	86/10/4/0
  a Reactions were run with 0.20 mmol of (S)-1, 0.24 mmol of 2a in 5 mL of solvent with 0.30 mmol of base for 10 h at r.t. b Isolated yield of (S)(2S, 3R)-3a. c Determined by LC/MS analysis of the crude products.

  下载: 导出CSV

  表 2  镍螯合物和α, β-不饱和酮类化合物的不对称Michael加成反应^a

  Table 2.  Asymmetric Michael addition reaction of Ni(Ⅱ)-complex with α, β-unsaturated ketones

  Entry	3	R1	R2	Conv./%	Yieldb/%	dr c
  1	(S)(2S, 3R)-3a	Ph	Ph	99	89	90/4/4/2
  2	(S)(2S, 3R)-3b	3-MeC6H4	Ph	94	65	70/4/2/24
  3	(S)(2S, 3R)-3c	4-MeC6H4	Ph	86	76	90/6/4/0
  4	(S)(2S, 3R)-3d	4-FC6H4	Ph	95	72	77/4/17/2
  5	(S)(2S, 3R)-3e	4-ClC6H4	Ph	80	73	92/3/5/0
  6	(S)(2S, 3R)-3f	4-BrC6H4	Ph	95	90	96/4/0/0
  7	(S)(2S, 3R)-3g	4-CF3C6H4	Ph	78	75	98/1/1/0
  8	(S)(2S, 3R)-3h	4-MeOC6H4	Ph	80	54	71/6/23/0
  9	(S)(2S, 3R)-3i	2-Naphthyl	Ph	78	69	91/9/0/0
  10	(S)(2S, 3R)-3j	2-Thiophenyl	Ph	65	44	69/5/26/0
  11	(S)(2S, 3R)-3k	2-Pyridyl	Ph	75	72	97/3/0/0
  12	(S)(2S, 3S)-3l	2-Pyridyl	2-Thienyl	77	73	97/2/1/0
  13	(S)(2S, 3S)-3m	2-Pyridyl	2-Pyridyl	50	41	85/8/4/3
  14	(S)(2S, 3R)-3n	Me	Ph	50	34	68/6/26/0
  15	(S)(2S, 3S)-3o	Et	Me	35	31	91/9/0/0
  a Reactions were run with 0.20 mmol of (S)-1, 0.24 mmol of 2 in 5 mL of MeOH with 0.30 mmol of DBU for 10 h at r.t. b Isolated yield of (S)(2S, 3R)-3. c Determined by LC/MS analysis of the crude products.

  下载: 导出CSV
•