手性单Schiff碱大环对青霉胺对映体识别研究

doi:10.6023/A22090400

摘要/Abstract

大量手性药物分子均具有D-和L-对映异构体, 呈镜像结构的对映体通常表现出截然不同的生理学反应. 青霉胺(Pen)是从青霉素中获取的一种常见的手性药物, 研究者为了实现这两种对映异构体严格区辨和分析一直在不断付出努力. 基于含有NH功能基的手性席夫碱大环化合物具有合成条件温和、结构收敛的优点, 本工作报道了含NH功能基的手性单Schiff碱大环对映异构体的合成(C_R和C_S)及其对小分子青霉胺对映体(D-Pen和L-Pen)的键合作用及对映体识别选择性. 通过X射线单晶衍射技术解析了单Schiff碱大环对映异构体的晶体结构, 结果表明这两个大环对映体均具有扭曲的非平面构型, 环状骨架中与环己基手性碳相连的亚胺(NH)质子均指向环腔内侧. 采用紫外可见光吸收光谱(UV-Vis)和核磁共振氢谱(¹H NMR)滴定技术对手性大环与青霉胺对映体之间相互作用行为进行考察, 表明手性大环与青霉胺不同对映体键合比均为1∶1, 键合常数接近10⁷ L•mol^-1, 电喷雾电离质谱法(ESI-MS)表征观察到大环与青霉胺按1∶1键合的缔合物[C-Pen+H]⁺的分子离子峰. ¹H NMR滴定表明手性大环与青霉胺对映体之间的缔合源于大环结构中不对称NH功能基与青霉胺对映体之间形成分子间氢键作用. 通过手性大环与青霉胺对映异构体之间的键合常数比较, 表明大环C_R对L-Pen具有更高的选择性键合能力, 而C_S则对D-Pen表现出更高的选择性键合能力, 选择性键合常数比均接近2倍. 进一步通过圆二色光谱(CD)滴定考察, 阐释了手性大环与青霉胺对映体选择性键合作用能力与两者之间对映体结构的手性匹配性质密切相关, 主体大环对与其手性相匹配青霉胺对映体表现出较高的键合作用能力, 而与手性不相匹配的青霉胺对映体键合作用则相对较弱.

关键词: 手性单Schiff碱大环, 青霉胺, 对映体, 氢键, 圆二色光谱(CD), 对映选择性

A large number of chiral drug molecules have a chiral structure containing both D- and L-enantiomers, leading to the mirror image arrangements of the two forms eliciting quite different physiological responses. Penicillamine (Pen) is a common chiral drug that is obtained from penicillin, and researchers have been making continuous efforts to achieve rigorous analysis and discrimination of the two enantiomers. Based on chiral Schiff base macrocycles containing NH functionalities have the advantages of mild synthesis conditions and convergence of structural arrangement. Here we report two enantiomers of the mono-Schiff base macrocycle containing chiral NH moiety in the cyclic structure (C_R and C_S), and the binding affinity and enantioselectivity of the cyclic enantiomers toward small molecules penicillamine (D-Pen and L-Pen). The crystal structures of the mono-Schiff base cyclic enantiomers were determined by X-ray diffraction analysis, and the results show that the two cyclic enantiomers exhibit twisted non-planar conformation, in which the chiral NH proton points to the inside of the ring cavity. The interactions between different enantiomers of the chiral macrocycle and penicillamine were investigated by ultraviolet visible (UV-Vis) and hydrogen nuclear magnetic resonance (¹H NMR) titration, and the results show that the chiral macrocycle binds with the enantiomers of penicillamine with a bonding ratio of 1∶1, binding constants around 10⁷ L•mol^-1, and the complexes of [C-Pen+H]⁺ can be easily formed and detected by electrospray ionization-mass spectrometry (ESI-MS). The interactions between different enantiomers of the chiral macrocycle and penicillamine are attributed to the intermolecular hydrogen bonding of enantiomers by the asymmetrical chiral NH moiety in the mono-Schiff base macrocycle. Comparison of bonding constants based on the chiral macrocycle binds with the enantiomers of penicillamine, the results show that the chiral C_R exhibits higher enantioselectivity for L-Pen, while C_S exhibits the higher enantioselectivity for D-Pen, with a binding constant ratio around 2, respectively. Further, investigation of circular dichroism (CD) spectroscopic titration indicate that the penicillamine with the same chirality as the host macrocycle binds stronger with the host than its enantiomer with the host.

Key words: chiral mono-Schiff base macrocycle, penicillamine, enantiomer, hydrogen bonding, circular dichroism spectra, enantioselectivity

引用此文

田小茂, 林悦群, 朱菡, 黄超, 朱必学. 手性单Schiff碱大环对青霉胺对映体识别研究[J]. 化学学报, 2023, 81(1): 20-28.

Xiaomao Tian, Yuequn Lin, Han Zhu, Chao Huang, Bixue Zhu. Enantiomers Identification of Penicillamine by Chiral Mono-Schiff Base Macrocycles[J]. Acta Chimica Sinica, 2023, 81(1): 20-28.

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图/表 10

图式1. 手性单Schiff碱大环合成及青霉胺结构

Scheme 1. Synthesis of chiral mono-Schiff base macrocycles and structures of penicillamine

图1. 大环对映体CR和CS分子结构及其相应的UV-Vis光谱(a)和圆二色光谱(b) (c=2.00×10-5 mol/L)

Figure 1. Crystal structures of the cyclic enantiomers and their UV-Vis spectra (a) as well as CD spectra (b) (c=2.00×10-5 mol/L)

图2. 随着(a) D-Pen和(b) L-Pen (c=2.00×10-4 mol/L)滴加量的增加(0~3 equiv.)分别导致CR (c=2.00×10-5 mol/L)的UV-Vis吸收光谱变化曲线

Figure 2. The UV-Vis absorption spectra of CR (c=2.00×10-5 mol/L) varied with the addition of D-Pen (a) and L-Pen (b) (c=2.00×10-4 mol/L, 0~3 equiv.)

图3. (a) D-Pen和(b) L-Pen (c=2.00×10-4 mol/L)分别与CR (c=2.00×10-5 mol/L)作用的等物质的量连续变化图(0~3 equiv., λ=295 nm)

Figure 3. Equimolar continuous variation plots of (a) D-Pen and (b) L-Pen (c=2.00×10-4 mol/L) interacting with CR (c=2.00×10-5 mol/L), respectively (0~3 equiv., λ=295 nm)

图4. (a) D-Pen和(b) L-Pen (c=1.00×10-4 mol/L)分别与CR (c=1.00×10-4 mol/L)作用的Job图(λ=295 nm)

Figure 4. Job diagrams of (a) D-Pen and (b) L-Pen (c=1.00×10-4 mol/L) interacting with CR (c=1.00×10-4 mol/L) respectively (λ=295 nm)

图5. CR (c=2.00×10-5 mol/L)分别与D-Pen (a)、L-Pen (b) (c=2.00×10-4 mol/L)作用体系的拟合曲线(0~3 equiv., λ=295 nm)

Figure 5. The fitting curves of CR (c=2.00×10-5 mol/L) with D-Pen (a) and L-Pen (b) (c=2.00×10-4 mol/L) interaction systems respectively (0~3 equiv., λ=295 nm)

Host-guest	K_D (D-Pen)	K_L (L-Pen)	K_L/K_D	K_D/K_L
C_R-pen	2.12×10⁷	3.44×10⁷	1.62	0.61
C_S-pen	3.20×10⁷	1.77×10⁷	0.55	1.81

表1. 主体大环与客体青霉胺对映体的缔合常数K (L?mol-1)

Table 1. Bonding constants K of the cyclic host with penicillamine enantiomers (L?mol-1)

图6. 在DMSO-d6/D2O (V/V=9∶1)溶液中分别随着(a) D-Pen和(b) L-Pen (c=0.05 mol/L)的滴加导致CR (c=5.00×10-3 mol/L)的质子化学位移变化(0~2 equiv.)

Figure 6. 1H NMR spectra of CR (c=5.00×10-3 mol/L) upon titration with (a) D-Pen and (b) L-Pen (c=0.05 mol/L) in DMSO-d6/D2O (V/V=9∶1) (0~2 equiv.)

图7. 甲醇溶液中分别滴加(a) D-Pen和(b) L-Pen (c=2.00×10-4 mol/L)导致CR (c=2.00×10-5 mol/L)的CD光谱变化以及滴加(c) D-Pen和(d) L-Pen (c=2.00×10-4 mol/L)导致CS (c=2.00×10-5 mol/L)的CD光谱变化曲线(0~3 equiv.) 甲醇溶液中分别滴加(a) D-Pen和(b) L-Pen (c=2.00×10-4 mol/L)导致CR (c=2.00×10-5 mol/L)的CD光谱变化以及滴加(c) D-Pen和(d) L-Pen (c=2.00×10-4 mol/L)导致CS (c=2.00×10-5 mol/L)的CD光谱变化曲线(0~3 equiv.)

Figure 7. The CD spectra of CR (c=2.00×10-5 mol/L) varied with the addition of (a) D-Pen or (b) L-Pen (c=2.00×10-4 mol/L) and the CD spectra of CS (c=2.00×10-5 mol/L) varied with the addition of (c) D-Pen or (d) L-Pen (c=2.00×10-4 mol/L) in methanol solution (0~3 equiv.)

图8. 手性大环与其同手性的青霉胺对映体1∶1键合时的缔合物的CD光谱曲线

Figure 8. The CD spectra of the association of chiral macrocycle with the same chiral penicillamine enantiomer at 1∶1 bonding interaction

参考文献 40

[1]	Xiao, T.; Li, S.; Zhang, X.; Lin, C.; Wang, L. Y. Chin. J. Chem. 2013, 31, 627. doi: 10.1002/cjoc.201300246
[2]	Geer, M. F.; Walla, M.; Solntsev, K.; Strassert, C.; Shimizu, L. S. J. Org. Chem. 2013, 78, 5568. doi: 10.1021/jo400685u
[3]	Radujević, A.; Penavic, A.; Pavlović, R. Z.; Badjić, J. D.; Anzenbacher, P. Chem 2022, 8, 2228. doi: 10.1016/j.chempr.2022.05.010
[4]	Wang, D.; You, L.; Wang, J.; Wang, H.; Zhang, D.; Li, Z. T. Tetrahedron Lett. 2013, 54, 6967. doi: 10.1016/j.tetlet.2013.10.064
[5]	María, D.; Claramunt, R.; Torralba, M.; Torres, M.; Elguero, J. Tetrahedron Lett. 2019, 60, 1206. doi: 10.1016/j.tetlet.2019.03.066
[6]	Wei, X. K.; Gu, J. C.; Liu, X. L.; Huang, C.; Zhu, B. X. Chin. J. Org. Chem. 2018, 38, 3386. (in Chinese) doi: 10.6023/cjoc201805012
	( 魏小康, 谷静池, 刘兴丽, 黄超, 朱必学, 有机化学, 2018, 38, 3386.) doi: 10.6023/cjoc201805012
[7]	Xiong, Y.; Huang, C.; Liu, H. J.; Yi, R.; Zhu, B. X.; Ni, X. L. Chin. Chem. Lett. 2021, 32, 3522. doi: 10.1016/j.cclet.2021.04.060
[8]	Li, D. H.; Smith, B. D. Beilstein J. Org. Chem. 2019, 15, 1086. doi: 10.3762/bjoc.15.105
[9]	Barisic, D.; Lesic, F.; Vlasic, M. T.; Uzarevic, K.; Bregovic, N.; Tomisi, V. Tetrahedron 2022, 120, 132875. doi: 10.1016/j.tet.2022.132875
[10]	Tromans, R. A.; Carter, T. S.; Chabanne, L.; Crump, M. P.; Li, H. Y.; Matlock, J. V.; Orchard, M. G.; Davis, A. P. Nat. Chem. 2019, 11, 52. doi: 10.1038/s41557-018-0155-z pmid: 30420776
[11]	Roth, J. Chem. Rev. 2002, 102, 285. doi: 10.1021/cr000423j
[12]	Glavin, D. P.; Burton, A. S.; Elsila, J. E.; Aponte, J. C.; Dworkin, J. P. Chem. Rev. 2019, 120, 4660. doi: 10.1021/acs.chemrev.9b00474
[13]	Lu, H. J.; Yu, C. T.; Guo, Y. L. Acta Chim. Sinica 2002, 60, 882. (in Chinese)
	( 陆豪杰, 余翀天, 郭寅龙, 化学学报, 2002, 60, 882.)
[14]	Li, D.; Gao, B. J.; Xu, W. M. Acta Chim. Sinica 2011, 69, 3019 (in Chinese)
	( 李丁, 高保娇, 许文梅, 化学学报, 2011, 69, 3019.) doi: 10.6023/A1106192
[15]	Liu, Z.; Zhang, S.; Cheng, M.; Yang, L.; Li, G.; Xu, W. W.; Qu, H. N.; Liang, F.; Cheng, J.; Li, H. B. Analyst 2022, 147, 1803. doi: 10.1039/D2AN00310D
[16]	Zhu, B. X.; Ruan, W. J.; Gao, F.; Hu, G. H.; Zhu, Z. A. Acta Chim. Sinica 2004, 62, 58. (in Chinese)
	( 朱必学, 阮文娟, 高峰, 胡国航, 朱志昂, 化学学报, 2004, 62, 58.)
[17]	Liu, T.; Ruan, W. J.; Nan, J.; Zhu, Z. A. Chin. J. Chem. 2003, 21, 751. doi: 10.1002/cjoc.20030210709
[18]	Forte, G.; Sfrazzetto, G. T.; Pappalardo, A. Comput. Theor. Chem. 2015, 1068, 8. doi: 10.1016/j.comptc.2015.06.007
[19]	Ikbal, S. A.; Sakata, Y.; Akine, S. Dalton Trans. 2021, 50, 4119. doi: 10.1039/d1dt00218j pmid: 33662079
[20]	Peluso, P.; Chankvetadze, B. Chem. Rev. 2022, 122, 13235. doi: 10.1021/acs.chemrev.1c00846 pmid: 35917234
[21]	Rajasekar, P.; Jose, C.; Sarkar, M.; Boomishankar, R. Angew. Chem. Int. Ed. 2021, 60, 4023. doi: 10.1002/anie.202012392
[22]	Wang, S. Y.; Li, L.; Xiao, Y.; Wang, Y. Trends Anal. Chem. 2019, 121, 115691. doi: 10.1016/j.trac.2019.115691
[23]	Padovani, D.; Galardon, E. Chem. Res. Toxicol. 2022, 35, 412. doi: 10.1021/acs.chemrestox.1c00313
[24]	Durán, G. M.; Abellán, C.; Contento, A. M.; Ríos, Á. Microchim. Acta 2017, 184, 815. doi: 10.1007/s00604-017-2074-x
[25]	Mendes, J.; Almeida, K. J.; Neto, J. L.; Ramalho, T. C.; Duarte, H. A. J. Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 2017, 184, 308. doi: 10.1016/j.saa.2017.05.025
[26]	Yang, N.; Zhang, K.; Guan, Q. W.; Wang, Z. J.; Chen, K. N.; Mao, X. Y. Antioxidants 2022, 11, 1602. doi: 10.3390/antiox11081602
[27]	Zhang, Y.; Wang, H. Y.; He, X. W.; Li, W. Y.; Zhang, Y. K. J. Hazard. Mater. 2021, 412, 125249. doi: 10.1016/j.jhazmat.2021.125249
[28]	Sun, L.; Huang, F.; Liu, W. W.; Lin, L.; Hong, Y.; Kong, X. L. Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 2020, 241, 118653. doi: 10.1016/j.saa.2020.118653
[29]	Li, Z. B.; Lin, J.; Pu, L. Angew. Chem. Int. Ed. 2005, 44, 1690. doi: 10.1002/anie.200462471
[30]	Zhu, Y. Y.; Wu, X. D.; Gu, S. H.; Pu, L. J. Am. Chem. Soc. 2019, 141, 175. doi: 10.1021/jacs.8b07803
[31]	Pu, L. Chem. Commun. 2022, 58, 8038. doi: 10.1039/D2CC02363F
[32]	Dong, J. Q.; Tan, C. X.; Zhang, K.; Liu, Y.; Low, P. J.; Jiang, J. W.; Cui, Y. J. Am. Chem. Soc. 2017, 139, 1554. doi: 10.1021/jacs.6b11422
[33]	Gangemi, C. M. A.; Rimkaite, U.; Cipria, F.; Sfrazzetto, G. T.; Pappalardo, A. Front. Chem. 2019, 7, 836. doi: 10.3389/fchem.2019.00836 pmid: 31850322
[34]	Yang, S. T.; Wu, F. L.; Yu, F. Z.; Gu, L. C.; Wang, H. H.; Liu, Y. Y.; Chu, Y. Q.; Wang, F. Y.; Fang, X.; Ding, C. F. Anal. Chim. Acta 2021, 1184, 339017. doi: 10.1016/j.aca.2021.339017
[35]	Ema, T.; Yamasaki, T.; Watanabe, S.; Hiyoshi, M.; Takaishi, K. J. Org. Chem. 2018, 83, 10762. doi: 10.1021/acs.joc.8b01327
[36]	Wen, J.; Feng, L.; Zhao, H. M.; Zheng, L.; Stavropoulos, P.; Ai, L.; Zhang, J. X. J. Org. Chem. 2022, 87, 7934. doi: 10.1021/acs.joc.2c00587
[37]	Ohishi, Y.; Chiba, J.; Inouye, M. J. Org. Chem. 2022, 87, 10825. doi: 10.1021/acs.joc.2c01095 pmid: 35938888
[38]	Thordarson, P. Chem. Soc. Rev. 2011, 40, 1305. doi: 10.1039/c0cs00062k pmid: 21125111
[39]	Shi, M.; Qian, H. X. Tetrahedron 2005, 61, 4949. doi: 10.1016/j.tet.2005.03.043
[40]	Chen, Z. H.; Wu, C. T. Chin. J. Org. Chem. 2002, 22, 582. (in Chinese)
	( 陈展虹, 吴成泰, 有机化学, 2002, 22, 582.)