Mechanism Of Separation Of Enantiomers Of DOPA And Phenylalanine By α-cyclodextrin

Chirality is closely related to our life.At present,a large part of the drugs used to treat diseases in humans have chiral centers,and the two enantiomers of chiral drugs often show different or even opposite pharmacological properties in the human body,so the chiral separation is one of the most widely studied topics.Each unit of cyclodextrin(CD)has 5 chiral carbon atoms,which can identify and separate enantiomers through host-guest interaction,and has the advantages of high efficiency,recyclability and environmental friendly,and is an ideal chiral resolving reagents.At present,the mechanism regarding its chiral separation at the electron-atom-molecular level remains unclear.Therefore,in this paper,α-cyclodextrin(α-CD)was used as the host,DOPA and phenylalanine enantiomers were used as guests,and the ratio of host and guest was 1:1 and 2:1.Tried to find out the difference of the interaction mode and interaction intensity of the complexes,and then studied the interaction mechanism and separation rule of the enantiomers,and provided a theoretical basis for the chiral separation in the pharmaceutical and chemical industries.The main contents of this paper are as follows:In the first chapter,the existing chiral separation technologies and chiral separation reagents are reviewed,and α-CD is selected as the research object,and the characteristics of CD and its development status as chiral separation reagents are discussed in detail.In the second chapter,the basic knowledge of quantum chemistry and the quantum chemistry methods used in this paper are introduced,including self-consistent charge density functional tight-binding method(SCC-DFTB),natural bond orbital theory(NBO),atoms in molecules(AIM),independent gradient model(IGM)and other theoretical methods.In the third chapter,we calculated and simulated the interaction mode and strength of αCD and D,L-DOPA(D,L-DOPA)by combining molecular dynamics simulation and quantum mechanical ab initio calculation.The main driving force leading to the separation of D,L-DOPA.We first performed a conformational search using SCC-DFTB molecular dynamics simulations,and randomly sampled the structures of the complexes with lower energy when α-CD and D,L-DOPA were combined with each other.The results showed that the complex structures formed by the combination of D-DOPA and L-DOPA with α-CD were quite different,and DDOPA behaved as "insertion",that was,the benzene ring of D-DOPA was vertically inserted into the α-CD cavity to form inclusion complexes;L-DOPA was "recumbent",that was,the LDOPA was placed horizontally above the large mouth of α-CD.Subsequently,higher-precision quantum chemical calculations were performed on the stable structure of the complex obtained by SCC-DFTB,and a comprehensive and detailed computational simulation of the mode and strength of the complex was carried out.We found that the binding energy of the D-DOPA/αCD system was higher than that of the L-DOPA/α-CD system,and the D-system was still intercalated,and the L-sy stem was still horizontal.Through further analysis of AIM,IGM,NBO and other methods,it was concluded that although the role of hydrogen bonds in the process ofα-CD separating D,L-DOPA cannot be ignored,the difference between hydrophobic interaction and van der Waals interaction was the main factor causing D,L-DOPA separation.The 2:1 inclusion ratio results were consistent with the 1:1 results,both of which were stronger binding of D-DOPA with α-CD.In the fourth chapter,the mode and intensity of action of D,L-phenylalanine(D,L-PHE)and α-CD were studied.The results showed that the interaction modes of PHE and DOPA withα-CD were very different:the complexes formed by D,L-PHE and α-CD were all benzene ring insertion.From the analysis of the strength of action,the binding energy of α-CD and D-PHE is stronger.Through the analysis methods such as IGM and AIM,it was finally found that the van der Waals interaction between D,L-PHE and α-CD was similar,and the difference in hydrogen bonding was the main factor leading to the separation of D,L-PHE.The 2:1 inclusion ratio results were consistent with the 1:1 results,both of which were stronger binding of D-PHE with α-CD.DOPA and PHE have similar structures,both are aromatic amino acids,the former has two more phenolic hydroxyl groups than the latter.In this paper,by observing the interaction mode of the two molecules with α-CD,it wsa concluded that the addition of phenolic hydroxyl groups on the benzene ring affects the interaction mode of DOPA and PHE with α-CD.When the benzene ring part of the amino acid attacked α-CD,the interaction between the two molecules and α-CD was benzene ring insertion,and the hydroxyl group on DOPA formed a hydrogen bond with the hydroxyl group in the small mouth of α-CD;During the attack,the benzene ring part of DOPA molecule did not enter the α-CD cavity,while PHE was still inserted into the benzene ring.Moreover,the introduction of phenolic hydroxyl groups maked the binding energy of DOPA and α-CD higher than that of PHE and α-CD,and increased the binding energy difference between D,L-enantiomers,and promoted chiral separation.