Rapid Optical Methods for Enantiomeric Excess Analysis: From Enantioselective Indicator Displacement Assays to Exciton-Coupled Circular Dichroism
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- 作者：Hyun Hwa Jo ; Chung-Yon Lin ; Eric V. Anslyn
- 刊名：Accounts of Chemical Research
- 出版年：2014
- 出版时间：July 15, 2014
- 年：2014
- 卷：47
- 期：7
- 页码：2212-2221
- 全文大小：657K
- ISSN：1520-4898
文摘
Conspectus
The advent of high-throughput screening (HTS) for chiral catalysts has encouraged the development of fast methods for determining enantiomeric excess (ee). Traditionally, chromatographic methods such as chiral HPLC have been used for ee determination in HTS. These methods, however, are not optimal because of high duty cycle. Their long analysis time results in a bottleneck in the HTS process. A more ideal method for HTS that requires less analysis time such as chiroptical methods are thus of interest.
In this Account, we summarize our efforts to develop host鈥揼uest systems for ee determination. The first part includes our enantioselective indicator displacement assays (eIDAs), and the second part focuses on our circular dichroism based host鈥揼uest systems. Our first eIDA utilizes chiral boronic acid receptors, along with prescreened indicators, to determine ee for chiral 伪-hydroxyacids and vicinal diols with 卤7% average error (AE). To further the practicality for this system, a HTS protocol was developed. Our second eIDA uses diamino chiral ligands and CuII as the receptor for the ee determination of 伪-amino acids. The system reported 卤12% AE, and a HTS protocol was developed for this system.
Our first CD based host鈥揼uest system uses metal complexes composed of CuI or PdII with enantiopure 2,2鈥?diphenylphosphino-1,1鈥?binaphthyl (BINAP) as host to determine the ee of chiral vicinal diamines (卤4% AE), primary amines (卤17% AE), and cyclohexanones (卤7% AE). Primary amines and cyclohexanones were derivatized to form chiral imines or chiral hydrazones to allow coordination with the metal complex. Upon coordination of chiral analytes, the metal-to-ligand (BINAP) charge transfer band was modulated, thus allowing the discrimination of chiral analytes. As an effort to improve the accuracy for chiral primary amine ee determination, a system with a host composed of o-formylphenyl boronic acid (FPBA) and enantiopure 1,1鈥?bi-2-naphthol (BINOL) was used to reduce the AE to 卤5.8%. In the presence of amines, the FPBA鈥揃INOL host forms an imine-coordinated boronic ester, thus affecting the CD signal of the boron complex. Another chiral primary amine ee determination system was developed with FeII and 3-hydroxy-2-pyridinecarbaldehyde. The chiral imines, formed by the pyridinecarbaldehyde and chiral amines, would coordinate to the FeII ion yielding exciton-coupled circular dichroism (ECCD) active metal complexes. This system was able to determine the ee of chiral amines with 卤5% AE. Furthermore, this imine鈥揊eII complex system also successfully determined the ee of 伪-chiral aldehydes with 卤5% AE. Other ECCD based hosts were subsequently developed; one with bisquinolylpyridylamine and CuII for chiral carboxylates and amino acids and another multicomponent system with pyridine chromophores for chiral secondary alcohol ee determination. Both of the systems were able to determine ee of the chiral analytes with 卤3% AE.
Overall, our group has developed ee determining host鈥揼uest systems that target various functionalities. To date, we are able to determine the ee of vicinal diols, 伪-hydroxyacids, vicinal diamines, cyclohexanones, amines, 伪-chiral aldehydes, carboxylates, amino acids, and secondary alcohols with 卤7% or lower average error. Future development will involve improving the average error and employing the current systems to analyze real-life samples resulting from parallel syntheses.
The advent of high-throughput screening (HTS) for chiral catalysts has encouraged the development of fast methods for determining enantiomeric excess (ee). Traditionally, chromatographic methods such as chiral HPLC have been used for ee determination in HTS. These methods, however, are not optimal because of high duty cycle. Their long analysis time results in a bottleneck in the HTS process. A more ideal method for HTS that requires less analysis time such as chiroptical methods are thus of interest.
In this Account, we summarize our efforts to develop host鈥揼uest systems for ee determination. The first part includes our enantioselective indicator displacement assays (eIDAs), and the second part focuses on our circular dichroism based host鈥揼uest systems. Our first eIDA utilizes chiral boronic acid receptors, along with prescreened indicators, to determine ee for chiral 伪-hydroxyacids and vicinal diols with 卤7% average error (AE). To further the practicality for this system, a HTS protocol was developed. Our second eIDA uses diamino chiral ligands and CuII as the receptor for the ee determination of 伪-amino acids. The system reported 卤12% AE, and a HTS protocol was developed for this system.
Our first CD based host鈥揼uest system uses metal complexes composed of CuI or PdII with enantiopure 2,2鈥?diphenylphosphino-1,1鈥?binaphthyl (BINAP) as host to determine the ee of chiral vicinal diamines (卤4% AE), primary amines (卤17% AE), and cyclohexanones (卤7% AE). Primary amines and cyclohexanones were derivatized to form chiral imines or chiral hydrazones to allow coordination with the metal complex. Upon coordination of chiral analytes, the metal-to-ligand (BINAP) charge transfer band was modulated, thus allowing the discrimination of chiral analytes. As an effort to improve the accuracy for chiral primary amine ee determination, a system with a host composed of o-formylphenyl boronic acid (FPBA) and enantiopure 1,1鈥?bi-2-naphthol (BINOL) was used to reduce the AE to 卤5.8%. In the presence of amines, the FPBA鈥揃INOL host forms an imine-coordinated boronic ester, thus affecting the CD signal of the boron complex. Another chiral primary amine ee determination system was developed with FeII and 3-hydroxy-2-pyridinecarbaldehyde. The chiral imines, formed by the pyridinecarbaldehyde and chiral amines, would coordinate to the FeII ion yielding exciton-coupled circular dichroism (ECCD) active metal complexes. This system was able to determine the ee of chiral amines with 卤5% AE. Furthermore, this imine鈥揊eII complex system also successfully determined the ee of 伪-chiral aldehydes with 卤5% AE. Other ECCD based hosts were subsequently developed; one with bisquinolylpyridylamine and CuII for chiral carboxylates and amino acids and another multicomponent system with pyridine chromophores for chiral secondary alcohol ee determination. Both of the systems were able to determine ee of the chiral analytes with 卤3% AE.
Overall, our group has developed ee determining host鈥揼uest systems that target various functionalities. To date, we are able to determine the ee of vicinal diols, 伪-hydroxyacids, vicinal diamines, cyclohexanones, amines, 伪-chiral aldehydes, carboxylates, amino acids, and secondary alcohols with 卤7% or lower average error. Future development will involve improving the average error and employing the current systems to analyze real-life samples resulting from parallel syntheses.