钯(0)/铜(I)协同催化脱羧不对称4+2环加成反应合成四环香豆素

doi:10.1016/S1872-2067(21)64051-2

摘要/Abstract

摘要：

香豆素衍生物是天然产物中广泛存在的一类化合物, 具有丰富的生理活性, 因而受到广泛关注. 其中四环香豆素结构包含多个连续的手性中心和复杂的四环结构, 其手性合成是化学领域的挑战之一. 利用简单易得的香豆素衍生物例如3-氰基香豆素作为原料设计手性催化反应, 是构建这些复杂香豆素衍生物的有效方法. 迄今为止, 关于3-氰基香豆素的不对称转化依然很少, 因为氰基和酯基间较长的距离限制了它们与金属离子形成刚性的环状过渡态. 如果仅以氰基作为活化位点, 较弱的配位能力、与反应位点较远的距离对手性诱导构成挑战. 协同催化可以有效提升反应选择性和活性, 近年来逐渐成为研究重点. 特别是钯/铜协同催化取得较大的进展, 然而仍存在一些局限性, 例如每次催化循环形成一个碳碳键, 只能合成简单的化合物, 铜的活化模式也仅局限于和酰胺或醛亚胺酯形成刚性结构, 相应亲核试剂范围有待扩展. 因此, 本文发展了一种新的钯/铜协同催化策略, 通过金属钯形成烯丙基钯物种活化烯基苯并噁嗪酮, 铜作为路易斯酸活化3-氰基香豆素, 实现了两者的脱羧不对称[4+2]环化反应, 不仅解决了单一催化剂立体选择性控制不足的问题, 而且合成了具有三个连续手性中心的香豆素衍生的稠环. 该方法反应条件温和, 立体选择性控制优秀. 控制实验证明, 手性铜-恶唑啉复合物能够活化3-氰基香豆素且产生手性诱导. 钯/铜催化剂负载量会极大影响反应收率和产物立体选择性, 当钯/铜<1时能够得到几乎光学纯的产物.

本文选用烯基苯并噁嗪酮和3-氰基香豆素作为模板底物, 通过对钯络合物上配体、溶剂、烯基苯并噁嗪酮上的保护基以及铜路易斯酸进行考察, 筛选出了最佳钯铜络合物组合和溶剂. 在优化的反应条件下, 考察该方法对不同底物的适应情况. 改用不同取代基的3-氰基香豆素, 5-位取代基会遮挡烯烃, 抑制氨基的进攻导致反应无法进行. 此外, 其它无论吸电子或给电子底物, 催化反应均可顺利进行, 并且以中等到优秀的收率, 优秀的非对映选择性和对映选择性得到成环产物. 考察了取代的烯基苯并噁嗪酮在该反应中的表现, 通过改变保护基、混合溶剂、手性配体和铜源以中等的收率和令人满意的立体选择性得到相应的四环香豆素. 另外培养了手性四环香豆素的单晶, 通过X射线衍射分析确定产物的绝对构型是(R,R,R).

为更深入认识反应机理, 进行了系列的控制实验. 使用消旋的钯络合物和手性的铜络合物, 可以顺利得到相应的产物. 尽管收率和立体选择性均较低, 但说明手性铜复合物可以与氰基结合, 并且能够成功诱导出手性. 另外, 回收的原料烯基苯并噁嗪酮是消旋的, 说明钯催化的脱羧过程与手性铜复合物无关, 两种催化剂的循环过程是完全相互独立的. 考察了催化剂的负载量对反应的影响. 固定钯催化剂用量, 手性铜复合物越多, 产率越低, 立体选择性越高; 固定铜催化剂用量, 降低钯催化剂则会抑制原料烯基苯并噁嗪酮的转化. 另外, 当铜/钯催化剂负载比大于1.0时, 能够得到接近光学纯的产物, 可以理解为铜活化的3-氰基香豆素完全参与转化, 抑制了背景反应. 据此提出了相应的催化模型来解释立体选择性的成因. 手性铜复合物与3-氰基香豆素结合, 使得潜手性面两边位阻不等价, 氨基负离子更容易从Si面进攻并关环, 最后得到(R,R,R)构型的产物. 综上, 本文不仅为手性四环香豆素的合成提供了一种新方法, 所发展的铜钯双活化模式也为发展手性催化反应提供新的策略.

关键词: 协同催化, 钯-铜双金属催化, 不对称催化, [4+2]环加成, 四环香豆素, 手性催化

Abstract:

Tetracyclic coumarins are a class of important compounds with diverse and superior pharmacological activities. However, a direct stereoselective method from simple and readily-made coumarins derivatives remains challenging due to the inertness of coumarins as dienophiles. Herein, we develop a decarboxylative asymmetric [4+2] cycloaddition of 3-cyanocoumarins with vinyl benzoxazinones, affording the coumarin-derived condensed rings bearing three continuous stereocenters in high yields with excellent diastereoselectivities (>20/1 d.r.) and enantioselectivities (up to 99% ee). This direct enantioselective reaction was achieved by a Pd(0)/Cu(I) bimetallic catalytic system. The mechanism studies indicated that the synergistic activation effect, in which chiral Cu(I) as an available Lewis acid catalyst activates 3-cyanocoumarin and chiral Pd(0) complex activates benzoxazinone by the formation of π-allyl-palladium intermediate, plays an important role on the stereoselective control. The current work provides a new activation modes of Cu catalyst in the Pd/Cu bimetallic catalytic system.

Key words: Synergistic catalysis, Pd(0)/Cu(I) catalysis, Asymmetric catalysis, [4+2] Cycloaddition, Tetracyclic coumarins, Chiral catalysis

王凯, 林祥丰, 李倩, 刘䶮, 李灿. 钯(0)/铜(I)协同催化脱羧不对称4+2环加成反应合成四环香豆素[J]. 催化学报, 2022, 43(7): 1812-1817.

Kai Wang, Xiangfeng Lin, Qian Li, Yan Liu, Can Li. The synthesis of tetracyclic coumarins via decarboxylative asymmetric [4+2] cycloadditions enabled by Pd(0)/Cu(I) synergistic catalysis[J]. Chinese Journal of Catalysis, 2022, 43(7): 1812-1817.

×
扫码分享

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(21)64051-2

https://www.cjcatal.com/CN/Y2022/V43/I7/1812

图/表 6

Scheme 1. Asymmetric synthesis of tetracyclic coumarins and our strategy.

Table 1 Optimization of reaction conditions a.


Entry	Change from standard condition	Yield (%) ^b	d.r. ^c	ee (%) ^d
1	none	74	>20:1	95
2	without Pd catalyst	0	—	—
3	without Cu catalyst	64	>20:1	67
4	A1 instead of A2	66	>20:1	65
5	A3 instead of A2	10	>20:1	76
6	A4 instead of A2	50	>20:1	97
7	A5 instead of A2	53	>20:1	80
8	A11 instead of A2	51	>20:1	43
9	A12 instead of A2	46	>20:1	67
10	B1 instead of B5	65	>20:1	93
11	B2 instead of B5	61	>20:1	85
12	B3 instead of B5	54	>20:1	69
13	B4 instead of B5	56	>20:1	95
14	ent-B5 instead of B5	41	>20:1	78

Scheme 2. Scope of 3-cyanocoumarins. Reaction conditions: 1a (0.10 mmol), 2 (3.0 equiv), Pd2(dba)3·CHCl3 (5 mol%), A2 (12 mol%), Cu(OTf) (5 mol%), B5 (6 mol%), rt, MeCN/DMF = 1:1 (1 mL), 6 h. Yields were for the isolated products after column chromatography. The ee values were determined by chiral HPLC.

Scheme 3. Scope of vinyl benzoxazinones. Reaction conditions: 1 (0.10 mmol), 2a (1.5 equiv), Pd2(dba)3·CHCl3 (5 mol%), A1 (12 mol%), CuTc (10 mol%), B4 (12 mol%), rt, MeCN/o-xylene = 1:1 (1 mL), 6 h. Yields were for the isolated products after column chromatography. The ee values were determined by chiral HPLC.

Scheme 4. Mechanistic investigations.

Scheme 5. Synthetic transformations.

参考文献

[1]	G. Nonaka, I. Nishioka, Chem. Pharm. Bull., 1982, 30, 4268-4276.
[2]	S. Nishmura, M. Taki, S. Takashi, Y. Iijima, T. Akiyama, Chem. Pharm. Bull., 2000, 48, 505-508.
[3]	X. Zhang, H. Wang, Y. Song, L. Nie, L. Wang, B. Liu, P. Shen, Y. Liu, Bioorg. Med. Chem. Lett., 2006, 16, 949-953.
[4]	N. Hamdi, M. C. Puerta, P. Valerga, Eur. J. Med. Chem., 2008, 43, 2541-2548.
[5]	S. Stanchev, G. Momekov, F. Jensen, I. Manolov, Eur. J. Med. Chem., 2008, 43, 694-706.
[6]	J. Mateos, N. Meneghini, M. Bonchio, N. Marino, T. Carofiglio, X. Companyó, L. Dell’Amico, Beilstein J. Org. Chem., 2018, 14, 2418-2424.
[7]	P. M. Wright, I. B. Seiple, A. G. Myers, Angew. Chem. Int. Ed., 2014, 53, 8840-8869.
[8]	L. Zhi, C. M. Tegley, B. Pio, J. P. Edward, M. Motamedi, T. D. Jones, K. B. Marschke, D. E. Mais, B. Risek, W. T. Schrader, J. Med. Chem., 2003, 46, 4104-4112.
[9]	K. Nagaiah, A. Venkatesham, R. Srinivasa Rao, V. Saddanapu, J. S. Yadav, S. J. Basha, A. V. S. Sarma, B. Sridhar, A. Addlagatta, Bioorg. Med. Chem. Lett., 2010, 20, 3259-3264.
[10]	N. V. Kumar, S. P. Rajendran, Asian J. Chem., 2003, 15, 111-116.
[11]	L. Jarrige, F. Blanchard, G. Masson, Angew. Chem. Int. Ed., 2017, 56, 10573-10577.
[12]	C. Wang, J. A. Tunge, J. Am. Chem. Soc., 2008, 130, 8118-8119.
[13]	Y. Wei, L. Q. Lu, T. R. Li, B. Feng, Q. Wang, W. J. Xiao, H. Alper, Angew. Chem. Int. Ed., 2016, 55, 2200-2204.
[14]	L. A. Leth, F. Glaus, M. Meazza, L. Fu, M. K. Thogersen, E. A. Bitsch, K. A. Jorgensen, Angew. Chem. Int. Ed., 2016, 55, 15272-15276.
[15]	G. J. Mei, D. Li, G. X. Zhou, Q. Shi, Z. Cao, F. Shi, Chem. Commun., 2017, 53, 10030-10033.
[16]	C. Wang, Y. Li, Y. Wu, Q. Wang, W. Shi, C. Yuan, L. Zhou, Y. Xiao, H. Guo, Org. Lett., 2018, 20, 2880-2883.
[17]	Y. N. Lu, J. P. Lan, Y. J. Mao, Y. X. Wang, G. J. Mei, F. Shi, Chem. Commun., 2018, 54, 13527-13530.
[18]	C. Guo, M. Fleige, D. Janssen-Muller, C. G. Daniliuc, F. Glorius, J. Am. Chem. Soc., 2016, 138, 7840-7843.
[19]	T. R. Li, Y. N. Wang, W. J. Xiao, L. Q. Lu, Tetrahedron Lett., 2018, 59, 1521-1530.
[20]	T. R. Li, F. Tan, L. Q. Lu, Y. Wei, Y. N. Wang, Y. Y. Liu, Q. Q. Yang, J. R. Chen, D. Q. Shi, W. J. Xiao, Nat. Commun., 2014, 5, 5500.
[21]	J. Fu, X. Huo, B. Li, W. Zhang, Org. Biomol. Chem., 2017, 15, 9747-9759.
[22]	M. Sawamura, M. Sudoh, Y. Ito, J. Am. Chem. Soc., 1996, 118, 3309-3310.
[23]	X. Zhao, D. Liu, H. Guo, Y. Liu, W. Zhang, J. Am. Chem. Soc., 2011, 133, 19354-19357.
[24]	X. Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang, Angew. Chem. Int. Ed., 2014, 53, 6776-6780.
[25]	K. J. Schwarz, J. A. Amos, J. C. Klein, D. Do, T. N. Snaddon, J. Am. Chem. Soc., 2016, 138, 5214-5217.
[26]	J. Meng, L.-F. Fan, Z.-Y. Han, L.-Z. Gong, Chem, 2018, 4, 1047-1058.
[27]	X. Huo, R. He, X. Zhang, W. Zhang, J. Am. Chem. Soc., 2016, 138, 11093-11096.
[28]	X. Huo, J. Zhang, J. Fu, R. He, W. Zhang, J. Am. Chem. Soc., 2018, 140, 2080-2084.
[29]	X. Jiang, P. Boehm, J. F. Hartwig, J. Am. Chem. Soc., 2018, 140, 1239-1242.
[30]	L. Wei, Q. Zhu, S.-M. Xu, X. Chang, C.-J. Wang, J. Am. Chem. Soc., 2018, 140, 1508-1513.
[31]	S.-M. Xu, L. Wei, C. Shen, L. Xiao, H.-Y. Tao, C.-J. Wang, Nat. Commun., 2019, 10, 5553.
[32]	Z.-T. He, X. Jiang, J. F. Hartwig, J. Am. Chem. Soc., 2019, 141, 13066-13073.
[33]	T. Jia, P. Cao, B. Wang, Y. Lou, X. Yin, M. Wang, J. Liao, J. Am. Chem. Soc., 2015, 137, 13760-13763.
[34]	F. Nahra, Y. Macé, D. Lambin, O. Riant, Angew. Chem. Int. Ed., 2013, 52, 3208-3212.
[35]	K. Yabushita, A. Yuasa, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2019, 141, 113-117.
[36]	X. Huo, R. He, J. Fu, J. Zhang, G. Yang, W. Zhang, J. Am. Chem. Soc., 2017, 139, 9819-9822.
[37]	L. Wei, S.-M. Xu, Q. Zhu, C. Che, C.-J. Wang, Angew. Chem. Int. Ed., 2017, 56, 12312-12316.
[38]	X. Huo, J. Fu, X. He, J. Chen, F. Xie, W. Zhang, Chem. Commun., 2018, 54, 599-602.
[39]	P. Liu, X. Huo, B. Li, R. He, J. Zhang, T. Wang, F. Xie, W. Zhang, Org. Lett., 2018, 20, 6564-6568.
[40]	H.-C. Liu, Y.-Z. Hu, Z.-F. Wang, H.-Y. Tao, C.-J. Wang, Chem.-Eur. J., 2019, 25, 8681-8685.
[41]	R. He, X. Huo, L. Zhao, F. Wang, L. Jiang, J. Liao, W. Zhang, J. Am. Chem. Soc., 2020, 142, 8097-8103.
[42]	Y. Peng, X. Huo, Y. Luo, L. Wu, W. Zhang, Angew. Chem. Int. Ed., 2021, 60, 24941-24949.
[43]	J. Zhang, X. Huo, J. Xiao, L. Zhao, S. Ma, W. Zhang, J. Am. Chem. Soc., 2021, 143, 12622-12632.
[44]	X. Huo, L. Zhao, Y. Luo, Y. Wu, Y. Sun, G. Li, T. Gridneva, J. Zhang, Y. Ye, W. Zhang, CCS Chem., 2021, 3, 1933-1944.
[45]	L. Zhao, G. Li, R. He, P. Liu, F. Wang, X. Huo, M. Zhao, W. Zhang, Org. Biomol. Chem., 2021, 19, 1955-1959.