Enantioselective Resolution of Racemic Amino Acids by Liquid-Liquid Extraction Using Chiral Extractors with tert-Butyl Ketone Group

Abstract

In chapter 1, General introduction the background of chirality. It is proposed to understand this study. I introduced several methods for acquiring enantiomer of amino acids especially the ELLE system commonly used in our laboratory. In chapter 2, Enantioselective extraction coupled with racemization (EECR) has been developed for underivatized amino acids, where one enantiomer in a basic aqueous solution containing a racemization catalyst is selectively extracted to an organic layer. Upon back-extraction of the organic layer to an acidic aqueous solution, a complete deracemization of the amino acid is achieved. The process could be automated in a continuously recycling flow reactor through a modification of the well-known U-tube design. The success of EECR relied on the discovery of the bulky pivaloylated extractant 5, which formed hydrophobic extractable imines with amino acids rapidly, reversibly and enantioselectively. Paradoxically and unexpectedly, the extractant 5 outclassed less hindered analogues in EECR experiments, even in the absence of a stabilizing resonance-assisted hydrogen bond. The nonplanar molecular geometry of the imine derived from 5 also prevented the co-extraction of the Cu2+ racemization catalyst, enabling the continuous operation of EECR. The merits of the EECR process may enable it to compete with enzymatic dynamic kinetic resolution in the production of unnatural amino acids. In chapter 3, A class of chiral extractants containing a central chiral center has been developed and their chiral resolution ability for enantiomeric amino acids in ELLE (enantioselective liquid-liquid extraction) system was studied. The introduction of the tert-butyl ketone structure in chiral extractant (R)-5 effectively improved the enantioselectivity due to special hydrogen bondings formed with amino acids. On the other hand, replacing the benzene ring on the central chiral carbon with a larger naphthalene ring also plays an auxiliary role in the improvement of selectivity. The stereoselectivities of (R)-5 is higher than others, that is, D/L ratio of seven amino acid extracted, ranged from 5.41-9.36. The research provides a new idea for the development of new chiral extractants. In chapter 4, Axially chiral binaphthoic acid (BNA) was studied as a resolving agent for a stereoselective crystallization of 1-(4-chlorophenyl)ethylamine (CPEA). The diastereo-meric pair of (R)-BNA/(S)-CPEA crystallizes in methylene chloride, on the other hand, the pair of (S)-BNA/(S)-CPEA crystallizes in acetone. The switch of the solubility of the diastereomeric pair is due to the imine formation with acetone. The very low solubility of the BNA/imine pair appears to be responsible for the fast and complete imine formation. The crystal structure of the BNA part in both crystals of the diastereomers maintains a same feature. Asymmetric chiral channels and pockets composed by intermolecular packing of BNA molecules appear in the crystal structures, and the robustness of them seem to contribute to the recognition of the chirality of CPEA with high selectivity.;1장에서는 이 연구를 이해하는데 도움이 되는 배경지식인 키랄성을 소개한다. 저는 아미노산의 거울상 이성질체를 얻기 위한 몇 가지 방법 중 특히 ELLE 시스템에 대해 제시하였다. 2 장에서는ELLE에서 더 우수한 성능 및 높은 거울상 선택성을 나타내는 t-butyl ketone extractant (R )-5를 개발하였다. 7개의 대표적인 아미노산의 선택성 비율(L/D)은 98 % 이상이다. EECR 의 성공은 highly sterically hindered pivaloylated extractant 5에 결정이 되고, 아미노산의 racemization 를 위한 compatible catalyst 에 의존한다. 다른 프로세스와 비교하여 EECR 의 가장 큰 장점은 자동 된 연속 프로세스의 개발 가능성이다. 이 작업은 이 규모 이상으로 실용적이고 고효율적인 비용을 예상한다. 3장에서는 3개 central chirality extractants을 개발했다. Carbonyl group 과 chiral center의 구조를 변화시킴으로써, extractant의 선택성이 효과적으로 개선되었다. Extractant (R )-3은 보편적인 관점의resonance-assisted hydrogen bond (RAHB) 을 깨고, 안정된 imine 구조를 형성해서, bulkiest carbonyl extractant 은 선택성을 갖는 imine을 신속하게 형성하는 것으로 밝혀졌다. Extractant (R )-3의 입체 선택성은 다른 extractants보다 높으며, 추출 된 7 개의 아미노산의 선택성 비율(L/D)은 5.41-9.36의 범위였다. 이 연구는 새로운 chiral extractant 개발에 대한 새로운 아이디어를 제공한다. 4장에서는 (R)-BNA / (S)-CPEA의 diastereomeric pair가 CH2Cl2에서 결정화되고, (S) -BNA / (S) -CPEA 쌍이 5% 아세톤이 존재하는 CH2Cl2에서 결정화됨을 보여줬다. Diastereomeric pair의 용해도의 전환은 아세톤에서 imine형성에 기인 한 것으로 밝혀졌다. BNA-imine pair의 특히 낮은 용해도는 빠르고 완전한 imine 형성에 도움이 된다. BNA로 구성된 chiral channels 와 pockets 의 robustness이 키랄성 인식에 기여할 수 있다. Resolution 과정의 deliberate controls는 BNA를 산업적으로 중요한 화합물의 광학적으로 순수한 CPEA 를 해결하는 실용적인 물질로 만들 것이다.