Synthesis And Applications Of Carbohydrate-Based Chiral Derivatizing Reagents And Chiral Stationary Phases

Chiral separation and recognition have played an important role in many fields ofresearch, including organic chemistry, medicinal chemistry, and life science.Chromatographic techniques, especially the high performance liquid chromatography(HPLC), are indispensable tools for separation of optical isomers. Depending on theway in which the chiral recognition occurs, the HPLC methods for separation ofisomers can be classified into the following catagories: chiral derivtizing reagent(CDR), chiral mobile phase additions (CMPA), chiral stationary phase (CSP).Currently, chiral dirivating reagents and chiral stationary phases used inpharmaceutical research, development, and manufacturing in China are all importedfrom abroad, their high prices limit the widespread use of chiral technology andconsequently the deveopment of chiral drugs. The major objective of this study is todevelope methods for synthesis of chiral derivatizing reagents and chiral stationaryphases using glucose and its oligomers and polymers as starting materials, paving theway for the domestic manufacture of chiral separation products which are moreaffordable and readily available.First, a chiral derivatizing reagent, 2,3,4,6-tetrad-O-acetyl-(β-D-glycosyl)-isothiocyanate(GITC), was synthesized through acylation, bromination andthiocyanation starting from α-D-glucose. And the key step of the synthesis,thiocyanation, was investigated and optimized. As such, the GITC thus preparedcontains much less isomer impurites, making the post-synthesis purification mucheasier. In present experiments, with the GITC pre-column derivative technique, anumber of β-amino acids and β-adrenergic receptor blockers were easily separated onnon-chiral C18 column by reversed phase HPLC. The effects of the derivative time, theamount of GITC, the pH and flow rate of the mobile phase on the enantiomericseparation were discussed. It is also used for determining the enantiomeric excess of(R,R)1,2-diaminocyclohexane. The results suggest that the method is feasible andreliable.Cellulose tri(3,5-dimethylphenylcarbamate) was synthesized from microcrystalli-ne cellulose. The cellulose derivatives were then coated onto undodified silica gel toprepare CSP. Enantiomers of warfarin, propranolol, metoprolol were separated by thisCSP in normal chromatographic conditions. This method for preparation of CSP wasmore convenient and cheaper than the traditional one since silanization reaction onsilica was avoided. A CSP was prepared by chemically bonding 3,5-dimethylphenyl–carbamates of cellulose to silica gel. Enantiomers of warfarin were separated bythis bonded CSP. The factors influencing chiral separation were studied.Some derivatived β-cyclodextrins were synthesized. A CSP was prepared bychemically bonding derivatived β-cyclodextrin onto silica gel. The given racemiccompounds can not be separated on the resulting bonded CSP. The factors influencingchiral separation were discussed.