Synthesis And Chiral Discrimination Ability Of Chiral Ionic Liquids Derived From Dehydroabietic Acid And Dehydroabietylamine

Chiral drugs refer to the drugs with chiral components in their molecular structures,which exist in the specific enantiomeric form.As the primary material of life,protein is composed of more than 20 kinds of chiral amino acids,so,chirality is the fundamental attribute of the organism.The different drug enantiomers with differing spatial structures lead to different action sites between drug enantiomers and proteins,resulting in significant differences in the pharmacological activities of enantiomers.It is therefore imperative that enantiomers of chiral drugs be separated and used only in the effective single isomer to ensure the safety and effectiveness of chiral drugs.However,owing to the same physical and chemical properties of enantiomers of chiral drugs,the resolution of chiral drugs has always been a challenge in the pharmaceutical industry.Cationic or anionic structures of chiral ionic liquids（CILs）contain chiral centers in them,making them capable of chiral selectivity.Low vapor pressure,and high thermal and chemical stability are some of its notable features.The present article describes the synthesis of several DA/DAA-CILs employing dehydroabietic acid（DA）and dehydroabietylamine（DAA）,both of which are abundant natural resources,as the chiral source.The chiral recognition performance and mechanism of DA/DAA-CILs for chiral compounds with different structures were investigated by NMR and quantitative calculation.DA/DAA-CILs with good chiral recognition were chosen as the resolution agent to explore the chiral separation effect on the selected chiral compounds.As a consequence of our investigation,we found the following contents and results:（1）Using DA/DAA as a chiral source,seven kinds of cationic dehydroabietic acid imidazole chloride/bromine salts（DA⁺-CILs）,four kinds of anionic dehydroabietic acid ionic liquids（DA^--CILs）and eight kinds of cationic dehydroabietylamine quaternary ammonium chloride/bromine salts（DAA-CILs）were synthesized.HPLC,¹H NMR,and ¹³C NMR were used to investigate and characterize the intermediate and target products,respectively.A series of DA/DAA-CILs were synthesized by replacing the halogen anions of DA⁺-CILs and DAA-CILs with PF₆^-,BF₄^-,NO₃^-,and NTf₂^-anions by ion exchange.67DA/DAA-CILs were obtained and 52 DA/DAA-CILs were reported for the first time.（2）The enantiomeric recognition ability of DA/DAA-CILs for 45 chiral compounds was studied by NMR.The results indicated that DAA-NH-CILs had a good chiral recognition impact on mandelic acid and its derivatives,the chemical shift difference（ΔΔδ）of chiral protons of R,S-α-methoxyphenylacetic acid reaches 25.5 Hz;Additionally,other DA/DAA-CILs lack enantiomeric recognition ability for nonsalifying chiral compounds,whereas DA⁺-CILs,DA^--CILs and DAA-NR₃-CILs exhibit favorable chiral recognition performance for tetrabutylammonium salt of mandelic acid and its derivatives,propranolol salt and tetrabutylammonium salt of valsartan and ofloxacin,respectively.The chiral recognition ability of DA/DAA-CILs is dependent on their concentration,the structure of cation or anion,the structure of chiral compounds,and so on.（3）The spatial architectures of 6 DA/DAA-CILs which have chiral recognition ability,6 enantiomers of chiral compounds,and their corresponding complexes were optimized using quantum chemical calculation.The thermodynamic parameters of the complexes generated by DA/DAA-CILs and enantiomers were calculated.The interaction types and sites between DA/DAA-CILs and enantiomers in the complexes were analyzed by the independent gradient model（IGM）,and the chiral recognition mechanism of DA/DAA-CILs was hypothesized.Among them,the ionic bonds fashioned via electrostatic interaction between the chiral cations（or chiral anions）of DA⁺-CILs,DA^--CILs,DAA-NR₃-CILs,and the chiral anions（or chiral cations）of chiral compounds,and between the secondary amine groups of DAA-NH-CILs and the carboxyl groups of mandelic acid and its derivatives are necessary sites for chiral recognition of DA/DAA-CILs;The distinction ofπ-πstacking between the benzene ring of DA/DAA framework and the benzene ring of chiral compounds is another important factor for chiral recognition of DA/DAA-CILs.（4）The method for chiral resolution of mandelic acid and its derivative racemates by utilizing[DAAPrTMA]PF₆ as a chiral resolution agent was explored.A visual chiral recognition method of[DAAPrTMA]PF₆ for mandelic acid and its derivatives in toluene was established.The[DAAPrTMA]PF₆ is capable of forming gels with S-enantiomer of mandelic acid,α-methoxyphenylacetic acid,O-acetyl mandelic acid,and 2-phenylpropionic acid,but forms dispersion colloid with there R-enantiomers.The method of chiral resolution ofα-methoxymandelic acid racemate by diastereomer crystallization with[DAAPrTMA]PF₆ as resolution agent and n-butanol as solvent was investigated.The chiral resolution procedure ofα-methoxyphenylacetic acid racemate was optimized by the Box-Behnken response surface experiment.The ee value of R-α-methoxyphenylacetic acid was 55.4%,and the yield was 60.3%.