波谱学杂志, 2025, 42(3): 221-230   doi: 10.11938/cjmr20243141   cstr: 32225.14.cjmr20243141

研究论文

含氨基酸单元手性脲的对映体识别性能研究

寇新慧,*, 张玉冰

青岛科技大学分析测试中心，山东 青岛 266042

Study on the Enantiomeric Recognition of Chiral Ureas Containing Amino Acid Units

KOU Xinhui,*, ZHANG Yubing

Analytical and Testing Center, Qingdao University of Science and Technology, Qingdao 266042, China

通讯作者: * Tel: 15726259486, E-mail:kouxinhui@qust.edu.cn.

收稿日期: 2024-12-23   网络出版日期: 2025-01-22

基金资助: 国家自然科学基金资助项目(21901134)

Corresponding authors: * Tel: 15726259486, E-mail:kouxinhui@qust.edu.cn.

Received: 2024-12-23   Online: 2025-01-22

摘要

手性分子识别对于化学及制药行业至关重要，我们合成了三种含氨基酸结构单元的手性脲（L-Phe-U、L-Ala-U以及L-Val-U）作为手性溶剂化试剂，利用NMR技术对含有不同取代基的手性有机羧酸分子进行对映体识别. 在4-二甲氨基吡啶的辅助作用下，L-Phe-U对不同的有机羧酸都具有一定的手性识别能力，R型和S型CαH基团1H的化学位移差（ΔΔδ）范围可达2.4 ~ 16 Hz，同时能够准确测定RS-扁桃酸的对映体过量值. 通过比较发现手性溶剂化试剂含有的苯基及底物手性碳中心连接的基团都会影响手性脲的识别能力. 我们利用DOSY实验测定了扁桃酸在不同体系下的扩散系数，对R型和S型对映体进行区分，揭示了其手性识别的动力学变化.

关键词： 核磁共振（NMR）; 手性溶剂化试剂; 手性羧酸; 对映体识别; 化学位移差; 对映体过量

Abstract

Recognition of chiral molecules is critical for the chemical and pharmaceutical industries. Three kinds of urea containing chiral centers (L-Phe-U, L-Ala-U and L-Val-U) were synthesized as chiral solvating agents (CSAs) to identify chiral organic carboxylic acids with different substituents, whose chiral anion recognition properties were further examined by NMR spectroscopy. In the presence of 4-dimethylaminopyridine (DMAP), enantiomeric signals of the benzylic C-H protons of mandelic acid were observed when mixed with L-Phe-U. The ΔΔδ values of the CαH signals ranged from 2.4 to 16.0 Hz, and the enantiomer excess (ee) value of RS-rac-mandelic acid (rac-MA) can be determined accurately. It was found that the phenyl group contained in chiral solvating agents and the groups connected to the chiral carbon center of substrates would affect the separation of enantiomeric signals. Moreover, DOSY spectra reveal that the diffusion coefficients of rac-MA enantiomers differ in the chiral solvating agents, providing insights into the dynamics of chiral recognition.

Keywords： nuclear magnetic resonance (NMR); chiral solvating agents; chiral carboxylic acid; enantiomeric recognition; chemical shift difference; enantiomeric excess

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本文引用格式

寇新慧, 张玉冰. 含氨基酸单元手性脲的对映体识别性能研究[J]. 波谱学杂志, 2025, 42(3): 221-230 doi:10.11938/cjmr20243141

KOU Xinhui, ZHANG Yubing. Study on the Enantiomeric Recognition of Chiral Ureas Containing Amino Acid Units[J]. Chinese Journal of Magnetic Resonance, 2025, 42(3): 221-230 doi:10.11938/cjmr20243141

引言

手性是自然界中普遍存在的现象，从分子氨基酸和纳米级DNA螺旋到肉眼可见的人手都具有手性. 手性分子的结构镜像对称但是无法重合，它们具有相同的组成元素和官能团，表现出许多相同的物理性质，但是在生物和药理活性上可能具有不同甚至相反的性能，因此快速鉴别手性分子对于加速药物发现、手性催化剂的筛选具有重要意义[1,2].目前手性分析的方法有很多，包括圆二色谱[3,4]、荧光法[5,6]、高效液相色谱法[7-9]、质谱法[10,11]、生物化学方法等[12]，其中高效液相色谱方法是目前使用最广泛的方法之一，可以采用不同的手性固定相实现样品分离或者通过衍生化试剂对样品进行前处理获得非对映异构体，从而利用两个对映异构体的差别吸附准确地将其分离[13].这种方法有时需要对样品进行处理，且色谱优化和分离通常很耗时、成本高，阻碍了它们在原位或高通量分析对映异构体方面的应用. 相比之下，核磁共振(NMR)是揭示化学结构和手性识别的有力工具，可以实现不同对映体的原位或者高通量分析[14-20]. NMR观测核在非手性介质中是等价的，不被区分，但在手性环境中，这些核是各向异性的，由此产生的NMR谱图将显示两个具有不同化学位移的信号，每个对映体被识别[21].

在过去的十多年中，用于分析手性分子的探针、介质和实验方法迅速发展[22]. 新型手性衍生化试剂(CDAs)、手性溶剂化试剂(CSAs)，以及利用1H、13C、19F、31P和77Se NMR谱立体识别和确定有机化合物绝对构型的检测方法逐步成熟，NMR可以借助耦合常数、化学位移、核Overhauser效应（Nuclear Overhauser Effect，NOE）、扩散系数、弛豫时间等参数来研究分子的手性特点[22-26]. 手性衍生化试剂通过衍生化反应，与底物的活性基团形成共价键，使其对映异构体转化为非对映异构体的衍生物，手性溶剂化试剂则提供一个手性环境，通过与底物对映体之间的范德华力、氢键等作用力，使对映体的NMR信号分开[27,28]. 目前手性化合物大多局限于羧酸、羟基酸、氨基酸、仲醇、胺等，对其他结构报道很少[26,29]，不同的手性化合物对CDAs或者CSAs具有不同的响应. 在手性识别过程中，通常使用对映体过量（enantiomeric excess，ee）值来衡量手性化合物的纯度. 然而由于绝大多数市售的CDAs不完全是光学纯化合物，因此CDAs用于ee值分析时，容易产生系统误差，相比之下CSAs更适合快速筛选分析手性样品.

近几年，手性硫脲因其在各种不对称反应中的催化作用备受关注[30-33]，其催化活性高、选择性强，也被逐渐用作CSAs，用于识别不同的手性分子[26,34-39]. 2016年Song课题组合成了双硫脲，能够对多种手性底物如醇、亚砜、内酯、环氧化物、氨基醇、酰胺、手性羧酸等进行识别[22,23]. Dogan课题组研究了6种硫脲作为CSAs对羧酸的识别能力，对扁桃酸的手性识别ΔΔδ可达0.13 ppm[26]. 自然界中的氨基酸具有L构型，目前已有利用其为原料合成手性主体的报道[40]，受到硫脲结构的启发，我们利用不同的氨基酸（丙氨酸、苯丙氨酸以及缬氨酸）甲酯盐酸盐，分别与4-三氟甲基苯异氰酸酯、三乙胺按照一定比例反应，合成出三种含氨基酸手性单元的脲（L-ALa-U、L-Phe-U以及L-Val-U），并利用它们成功催化聚乳酸的合成，获得具有高立构规整度的聚合物，证明了其手性催化作用[41]. 本文中，我们将这三种手性脲作为CSAs，利用NMR技术探究该类物质对不同手性羧酸底物的对映体识别能力.

1 实验部分

1.1 仪器与试剂

RS-扁桃酸（RG，99%）、R-扁桃酸（RG，99%）、S-扁桃酸（RG，99%）、α-溴苯乙酸（RG，99%）、RS-α-甲氧基苯基乙酸（RG，98%）、4-三氟甲基扁桃酸（RG，98%）、2-氯丙酸（RG，98%）、2-羟基-3-甲基丁酸（RG，98%）、2-苯基丙酸（RG，98%）、2-羟基-3-甲基丁酸（RG，98%）、苯甘氨醇（RG，98%）、氧化苯乙烯（RG，98%）、L-苯丙氨酸甲酯盐酸盐（H-Phe-OMe•HCl，RG，99%）、1,8-二氮杂双环[5.4.0]十一碳-7-烯（DBU，RG，98%）、4-二甲氨基吡啶（DMAP，RG，98%）购自阿达玛斯（Adamas）公司. L-丙氨酸甲酯盐酸盐（H-Ala-OMe•HCl，RG，99%）、L-缬氨酸甲酯盐酸盐（H-Val-OMe•HCl，RG，99%）购自吉尔吉化（上海）有限公司，4-三氟甲基苯异氰酸酯（RG，99%）购自TCI公司，二氯甲烷、乙酸乙酯、环己烷购自天津市北联精细化学品开发有限公司，甲醇钾购自北京伊诺凯科技有限公司，三乙胺购自天津市富宇精细化工有限公司.

NMR实验在AVANCE NEO 400 MHz NMR谱仪（瑞士Bruker公司）上进行.

1.2 实验过程

1.2.1 手性脲的合成

L-Phe-U、L-Val-U和L-ALa-U的合成过程参见文献[41].

1.2.2 手性识别的1H NMR实验

在1H NMR手性识别测定实验中，将手性羧酸底物溶解于CDCl3（以TMS为内标，δH 0 ppm）中，配制成溶液，加入CSAs形成一定比例的主客体系，随后在液体NMR波谱仪测定不同体系的1H NMR谱. 1H NMR的工作频率为400.12 MHz，实验温度为25℃，弛豫时间为2 s，累加次数16，采样点数为2 048. 实验步骤如下：

（1）先称取RS-扁桃酸（rac-MA）1.4 mg溶于500 μL CDCl3，置于NMR样品管中，采集1H NMR谱；随后按照摩尔比rac-MA : L-Phe-U = 1: 1加入L-Phe-U，再次采集1H NMR谱；在此基础上，按照摩尔比rac-MA : L-Phe-U : DMAP =1 : 1 : 1，加入DMAP，采集1H NMR谱. 3次1H NMR谱做对比，观察CSAs对R型和S型扁桃酸的识别能力.

（2）rac-MA和DMAP量不变，改变L-Phe-U的浓度（0.25，0.5，0.75，2.0，3.0，4.0 equiv.）重复步骤（1）中的实验.

（3）将手性底物分子换成α-溴苯乙酸、4-三氟甲基扁桃酸、2-苯基丙酸、2-氯丙酸、苯甘氨醇等，重复步骤（1）中的实验，观察手性化学位移试剂对不同手性底物的识别能力.

（4）在rac-MA : L-Phe-U : DMAP = 1: 3: 1的基础上，将L-Phe-U换成L-Ala-U以及L-Val-U，相同条件下采集1H NMR谱，比较不同CSAs的对映体识别能力.

（5）称取2 mg rac-MA溶于500 μL CDCl3中，设置DOSY实验参数；采集完之后，加入L-Phe-U使得rac-MA : L-Phe-U的摩尔比为1 : 3，再次采集DOSY实验；实验结束后，加入DMAP使得rac-MA : L-Phe-U : DMAP的摩尔比为1: 3: 1，采集DOSY实验. 将三次DOSY实验数据进行拟合，获得rac-MA的CαH信号在不同体系里的扩散系数并进行分析.

1.2.3 NMR扩散排序谱（DOSY）实验

DOSY实验使用Bruker公司的标准实验脉冲序列：ledbpgp2s，谱宽是3 601.08 Hz，激发中心为1 600.48 Hz，1H通道射频脉冲脉宽为10 μs，功率为20.07 W，弛豫延迟时间为（D1）为2 s，累加次数为64，脉冲序列中的扩散时间为10 ms，梯度脉冲宽度分别为2 320 μs、3 000 μs、3 450 μs，每个DOSY实验梯度脉冲的强度变化范围为2%~95%，采用线性模式在该范围内选取24个变化值，采样数据点为2 048.

所有实验数据处理软件为Bruker公司提供的Topspin 4.20，通过其中的dynamics模块程序对数据进行处理，选择扁桃酸CαH为目标，对该峰进行积分，拟合.

2 结果与讨论

2.1 含氨基酸单元手性脲对rac-MA的手性识别

本文中我们选择了手性识别研究中常用的不同结构的手性羧酸作为底物，以此来探究含不同氨基酸结构单元手性脲（图1）的对映体识别能力. 首先，选用L-Phe-U作为CSAs，以rac-MA为手性客体底物，展开实验. 在NMR实验过程中，以rac-MA的甲基质子（CαH）信号变化为依据，通过观察R型与S型化学位移差（ΔΔδ = |ΔδS-ΔδR|），来判断L-Phe-U的对映体识别能力. 我们将10 μmol/L rac-MA溶于500 μL氘代氯仿（CDCl3）中，按照摩尔浓度比1 : 1加入L-Phe-U，在1H NMR谱图上并没有观察到rac-MA CαH的化学位移变化[图2(a)]. 宋玲课题组在2013年发现DMAP与手性羧酸通过NH…O键形成carboxylate-DMAPH+ 离子对，加强了CSAs和手性客体底物之间的氢键相互作用，可以帮助区分羧酸的对映体[42]. 我们按照一定比例加入DMAP（L-Phe-U : DMAP : rac-MA = 1 : 1 : 1），发现rac-MA的CαH出现两个信号，ΔΔδ = 8.8 Hz[图2(b)]，说明DMAP在手性识别过程中发挥积极作用，与L-Phe-U和rac-MA之间有相互作用.

图1

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图1   手性化学位移试剂（L-Phe-U、L-Ala-U和L-Val-U）以及4-二甲氨基吡啶（DMAP）结构

Fig. 1   Structure of chiral chemical shift reagent (L-Phe-U, L-Ala-U, L-Val-U) and DMAP


图2

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图2   rac-MA（10 μmol/L，CDCl3）苯基CαH在不同条件下的1H NMR图. (a)加入10 μmol/L L-Phe-U；(b)加入10 μmol/L L-Phe-U和10 μmol/L DMAP

Fig. 2   Partial 1H NMR spectra showing the benzylic C-H protons of rac-MA (10 μmol/L, CDCl3) in the presence of (a) L-Phe-U (10 μmol/L) and (b) L-Phe-U (10 μmol/L) and DMAP (10 μmol/L)


随后我们进行了CSAs浓度滴定实验，随着L-Phe-U量的不断增加，rac-MA CαH质子对映体信号化学位移差逐渐增大. 当L-Phe-U : DMAP : rac-MA = 3 : 1 : 1时，ΔΔδ = 15.2 Hz，继续滴加时，化学位移差仍略有增加（ΔΔδ = 16.0 Hz）（图3），但是变化幅度减小，这说明当L-Phe-U的浓度高于30 μmol/L时，其对rac-MA的手性识别能力不再随浓度的增大而显著增强.

图3

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图3   在DMAP作用下rac-MA（10 μmol/L，CDCl3）CαH随着L-Phe-U浓度变化（0~4.0当量）的1H NMR谱图

Fig. 3   1H NMR spectra of the benzylic C-H protons of rac-MA (10 μmol/L) with 0~4.0 equivalents of L-Phe-U in the presence of DMAP (in CDCl3)


在同样的条件下（L-Phe-U : DMAP : rac-MA = 3 : 1 : 1），逐渐增加rac-MA的含量（图4），发现随着rac-MA含量的增加，ΔΔδ逐渐减小（10 μmol/L：ΔΔδ = 15.2 Hz；40 μmol/L：ΔΔδ = 10.8 Hz）.这些结果显示，在L-Phe-U与MA以及DMAP三者之间存在着动力学平衡，当三者之间的浓度（比例）发生变化时，这种平衡受到干扰，从而影响对映体的识别.

图4

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图4   在L-Phe-U和DMAP（3 : 1）作用下，不同浓度的rac-MA CαH的1H NMR谱图（CDCl3）

Fig. 4   1H NMR spectra of the benzylic C-H protons of rac-MA mixtures with varying concentrations in the presence of 3.0 equivalents of L-Phe-U and 1.0 equivalent of DMAP in CDCl3


2.2 不同CSAs与手性羧酸的相互作用

挑选不同的手性羧酸客体底物（溴苯乙酸、2-苯基丙酸、4-三氟甲基扁桃酸、2-甲氧基苯基乙酸、2-氯丙酸、苯甘氨醇和氧化苯乙烯），检验L-Phe-U作为CSAs的对映体识别能力. 按照L-Phe-U : 客体底物 : DMAP = 3 : 1 : 1的条件进行实验，发现L-Phe-U对不同手性客体底物的识别能力不同. 如表1所示，L-Phe-U对rac-MA有很好的识别作用（ΔΔδ = 15.2 Hz）（表1，序号1），当扁桃酸苯基对位氢被三氟甲基取代时，ΔΔδ可以达到9.6 Hz（表1，序号2），其CαH化学位移差较扁桃酸CαH有所降低，但是仍能很好的区分R, S构型. 对于2-苯基丙酸而言ΔΔδ只能达到2.4 Hz（表1，序号3），但是当2-苯基丙酸的甲基被吸电子基团Br取代时，CαH R型和S型的化学位移差增大（ΔΔδ = 11.2 Hz，表1，序号4）.当扁桃酸羟基氢被甲基取代时，CαH对映体的化学位移差仅有0.64 Hz，L-Phe-U结构上的甲基氢与其信号重叠，影响判断（表1，序号5）.Dogan课题组指出，手性底物的苯环结构以及DMAP吡啶环结构之间的π-π堆积相互作用影响对映体之间的手性识别[26]. 为了进一步验证这一推论，我们选择了没有苯基结构的2-氯丙酸，发现L-Phe-U也有一定的识别能力，ΔΔδ可达2.4 Hz（表1，序号6），但是当客体底物为苯甘氨醇和氧化苯乙烯时，L-Phe-U没有任何的手性识别能力.

表1   不同的手性脲存在条件下，外消旋羧酸CαH的化学位移差值（ΔΔδ）（CDCl3）

Table 1  The chemical shift differences (ΔΔδ) of CαH of racemic carboxylic acids in the presence of chiral ureas by 1H NMR in CDCl3

序号手性羧酸手性化学位移试剂谱图ΔΔδ/Hz
1L-Phe-U15.2
2L-Phe-U9.6
3L-Phe-U2.4
4L-Phe-U11.2
5L-Phe-U0.64
6L-Phe-U2.4
7L-ALa-U3.2
8L-ALa-U4.0
9L-ALa-U3.6

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为了对比不同的CSAs对手性客体底物的识别能力，我们选择了另外两种含氨基酸结构的手性脲（L-ALa-U和L-Val-U）进行实验，结果发现这两种CSAs的对映体识别能力比L-Phe-U弱.在DMAP作用条件下，当CSAs为L-ALa-U时，rac-MA的化学位移差ΔΔδ仅有3.2 Hz（表1，序号7），当扁桃酸上的羟基被极性基团Br取代时，ΔΔδ有所增加，R型和S型扁桃酸被区分开（ΔΔδ = 4.0 Hz，表1，序号8）；2-甲氧基苯基乙酸的对映体也能够被识别，其ΔΔδ = 3.6 Hz（表1，序号9）. 同样条件下用L-Val-U作为CSAs进行实验，发现其对rac-MA无手性识别能力. 通过比较实验结果我们推测CSAs的苯基结构以及客体底物手性碳上连接的基团会影响两者之间的手性识别，此类脲对手性羧酸对映体的选择效果比较明显. 手性识别是一个相对比较复杂的过程，手性化学位移试剂、底物以及加入体系中其他辅助识别的物质结构都会对这一过程造成影响. L-Phe-U手性识别效果优于其它两个取代的氨基酸硫脲的原因是由于苯环的环电流屏蔽效果较好，因此选择具有更大环电流屏蔽作用的氨基酸如色氨酸合成手性化学位移试剂，可能有助于手性羧酸的识别.目前带有色氨酸及其衍生物结构的化合物已被用于扁桃酸的手性识别[43]，非天然氨基酸取代基的双硫脲手性识别体系已有报道[44]，我们后续研究将在此基础上继续探究带有不同氨基酸结构的手性化学位移试剂对手性识别的影响.

2.3 手性识别测定以及动力学研究

为了验证L-Phe-U对手性识别的准确性，我们按照不同的ee值将R型和S型扁桃酸混合，分别采集1H NMR谱进行分析. 根据扁桃酸CαH对映体信号积分计算得到ee值，并与实验设定的ee值进行对比[图5(a)]，发现扁桃酸设定的ee值与实验值之间存在很好的线性关系，相关系数为R2 = 0.991 3[图5(b)]，可以进行对映体的定量分析.

图5

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图5   (a)在L-Phe-U和DMAP作用下，不同ee值的R-扁桃酸、S-扁桃酸的1H NMR谱；(b)实验设计ee值与实验检测ee值的线性相关图

Fig. 5   (a) Selected region of the 1H NMR spectra of mandelic acid of various enantiomeric impurities in the presence of L-Phe-U and DMAP; (b) Correlation between prepared and observed ee values obtained by 400 MHz 1H NMR titrations of enantiomerically enriched mixtures of mandelic acid using L-Phe-U and DMAP in CDCl3


除此之外，我们分别测试了rac-MA体系、rac-MA/L-Phe-U二元体系以及rac-MA/L-Phe-U/DMAP三元体系的NMR扩散排序谱（DOSY），比较了CαH的扩散系数. 单一的rac-MA的CαH（12 μmol/L）扩散系数（diffusion coefficient）为1.154×10-9 m2/s[图6(a)]，当加入3 equiv. L-Phe-U时，其扩散系数为 7.406×10-10 m2/s，CαH的扩散系数明显减小，但是R型和S型并没有被区分开[图6(b)]，继续加入1 equiv. DMAP，此时CαH手性被识别. 分别对R型和S型信号进行拟合，发现R型的CαH扩散系数为 5.797×10-10 m2/s，S型的CαH扩散系数为5.812×10-10 m2/s，两者的扩散运动存在差异[图6(c)]. 通过DOSY实验我们发现CSAs会减慢手性分子的运动，这种状态更有利于对映体被识别.

图6

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图6   在相同扩散时间和不同扩散梯度强度（2%~95%）的情况下，(a) rac-MA体系；(b) rac-MA/L-Phe-U二元体系；(c) rac-MA/L-Phe-U/DMAP三元体系CαH扩散系数拟合曲线（Diff. Con.指扩散系数，SD指拟合的标准偏差）

Fig. 6   Simulated diffusion decay curves of CαH (black circle) in (a) rac-MA, (b) rac-MA and L-Phe-U, (c) rac-MA, L-Phe-U and DMAP by varying the gradient strength from 2% to 95% with the same diffusion time and different diffusion gradient strength (Diff. Con. is for diffusion coefficient, and SD is for standard deviation)


3 结论

我们利用NMR技术研究了三种含氨基酸结构单元CSAs的对映体识别能力，其中L-Phe-U对所选的手性羧酸底物识别性能比较好. 羧酸底物手性中心上所连接的基团以及CSAs结构都会影响对映体R型和S型信号的区分. CSAs会影响对映体的运动，通过DOSY实验发现，扁桃酸R型和S型对映体的扩散系数变小，尽管两者存在的差异性比较小，但其手性依然能够被区分. 含氨基酸结构单元的手性脲合成过程简单、稳定性强，能够准确地用于对映体的定量分析，我们将继续研究这类物质，期待能够用于更多手性底物对映体的识别.

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