Synthesis Of Cationic ?-cyclodextrins And Their Application For Chiral Separations

With the development of modern separation techniques,cyclodextrins(CDs)are playing an ever-increasing role in the field of chiral separations.Compared with native or neutral CDs,cationic CDs exhibit relatively good water solubility,and improved chiral recognition ability due to the electrostatic interactions formed with acidic drugs and amino acids.CD derivatives with well-defined structures can be developed by selectively chemical modification and adjusting the type and position of substituents.The work of this dissertation is mainly focused on the synthesis of a series of single-isomer cationic ?-CD(mono-,bis-or persubstituted.Following the concept of constructing electrostatic and hydrogen-bonding interactions as additional driving forces to enhance the chiral recognition,one or two positively charged centers are introduced to the C6 position of CD.The enantioseparations of the as-designed cationic cyclodextrins towards acidic,amino acids,neutral even alkaline racemates are evaluated by means of capillary electrophoresis(CE)or high performance liquid chromatography(HPLC).A combination of optimizing the enantioseparation results and molecular modeling helps to reveal the chiral recognition mechanism with multiple driving forces.Firstly,we have designed and developed eight mono-substituted alkylammonium-?-CD chlorides.With 6A-(2-hydroxyethyl-l-ammonium)-?-CD chloride(HEtAMCD)as chiral selector,we have achieved the baseline enantioseparations for over 20 acidic drugs and dansyl-amino acids in CE.The background electrolyte containing 10 mM HEtAMCD at pH 6.0 was found to be the optimal separation condition for most analytes.The interaction behaviour of the complexes formed between HEtAMCD and mandelic acid enantiomers was further investigated via one-dimensional and two-dimensional(ROESY)nuclear magnetic resonance(NMR)techniques;In the concentration range of chiral selectors(1-20 mM)as studied,HEtAMCD,6A-(3-hydroxypropyl-l-ammonium)-?-CD chloride(HPrAMCD),6A-(4-hydroxybutyl-1-ammonium)-?-CD chloride(HBuAMCD)and 6A-(3-methoxypropyl-l-ammonium)-?-CD chloride(MPrAMCD)showed excellent enantioseparation ability towards six representative racemic enantiomers.The complexation constant(K)of each inclusion complex,theoretical selectivity(?cplx)and optimum concentration of these CD(Copt)was obtained through theoretical calculations.Due to the poor water solubility of other four CDs,the chiral separation performance was also limited.Comparison study demonstrated that CD with three carbon chain and single substituent were the best choices,and methoxy and hydroxy terminal group provided differnt recognition advantages with different alkyl chains.Secondly,we successfully prepared monosubstituted CD at C6 position containing both imidazolium and ammonium cationic moieties via Gabriel reaction.The nucleophilic reagents precursor used in synthetic route was(imidazolylalkyl)phalimides.By adjusting the deprotection strategies of phthalimide to afford different nucleophilic reagents,two series of positively charged CDs were thus obtained,namely,6A-[3-(ammoniumalkyl)-1-imidazolium]-?-CD chlorides and 6A-imidazolylalkylammonium-?-CD chlorides,respectively.Taking 6A-[3-(4-ammoniumbutyl)-1-imidazolium]-?-CD chloride as a model chiral selector,the enantioseparations of eight dansyl amino acids and seven acidic drugs with different concentrations of chiral selector were evaluated in CE.All racemic enantiomers were found to be well separated at 2.5 mM,with higher chiral resolutions in comparison to those with a single positively charged imidazolium or alkylammonium CDs.Thirdly,we creatively prepared C6-disubstituted cationic CDs as chiral selectors in mobile phase for CE via click chemistry.Different from the traditional "capping" method to synthesize di substituted CDs,a better position-directing nucleophilic reagent,2-mesitylenesulfonyl chloride,was utilized to attack 6A-azido-?-CD to afford AC disubstutited CD precursor as principal product due to steric hindrance.Followed by nucleophilic replacement of 2-mesitylenesulfonyl and click reaction of azido group,di substituted cationic CDs were obtained.With two conjugated moieties in presence,6A-[4-(2-hydroxyethyl)-1,2,3-triazolyl]-6C-[3-(3-methoxypropyl)-1-imidazolium]-?-CD has exhibited good chiral resolution towards dansyl amino acids at 5.0 mM.Meanwhile,6A-[4-(2-hydroxyethyl)-1,2,3-triazolyl]-6c-(3-methoxypropyl-l-ammonium)-?-CD chloride can achieve the enantioseparations for both acidic drugs and amino acids.Compared with MPrAMCD,the introduction of triazole group can,to some extent,improve the chiral recognition ability of dansyl amino acidsFinally,AC disubstituted cationic CD was further persubstituted with 3-chloro-4-methyl-phenylisocyanate,followed by the covalent immobilization onto the alkynylated silica through click chemistry to prepare CD-clicked chiral stationary phase(CSP)for HPLC.With pure methanol as mobile phase,seven flavonoids except hesperetin and naringenin can be well separated,meanwhile,the chiral resolution of 7-methoxyflavanone exceeded 8.0.Furthermore,the performance of this CSP can be greatly tuned by changing the proportion of methanol and water in mobile phase.With the addition of different pH buffers,theCSP exhibited certain resolution ability towards other neutral,acidic and basic drugs.Especially for acidic drugs,the enantioseparations can be promoted by constructing electrostatic interactions between the positively charged CD and negatively charged drug molecules.In the binary or ternary mobile phase systems,the enantioseparations could be tuned by the polarity of mobile phases through varying the percentage of organic modifiers.The results revealed that the enantioseparations ability of phenylcarbamoylated CD-based CSP can be adjusted by inclusion complexation and other interactions(such as hydrogen bonding,?-? conjugation,electrostatic and dipole-dipole interactions,etc.).Therefore,strengthening the recognition driving force of chiral selectors is demonstrated as an effective approach to improve the chiral separation of chiral selectors.