Novel asymmetric microenvironments for the separation of enantiomers of chiral drugs and natural products

Rimmer, Duncan Adam (1990). Novel asymmetric microenvironments for the separation of enantiomers of chiral drugs and natural products. PhD thesis The Open University.



The determination of enantiomeric composition is of great importance in the pharmaceutical and natural product industries where two enantiomeric forms of a chiral molecule can have very different biological activities.

Homochiral derivatization of enantiomeric compounds followed by chromatographic separation of the resultant diastereoisomers on conventional achiral columns has proved to be a cheap and useful method for enantioquantification.

Reactions of simple alkyl halides with alcohols, acids, thiols and amines are known. Novel homochiral derivatization procedures based on two such reactions have been investigated. In these reactions, homochiral alkyl halide reagents, some of which are prepared here for the first time, have been based on proline and lactone ring systems and chiral esters.

Another derivatization approach utilising highly reactive and novel homochiral chloromethyl ether reagents has proved successful. For example, racemic secondary alcohols when derivatized with (S)-(+)- tetrahydro-5-oxo-2-furanmethyl chloromethyl ether, have been separated to baseline. Quantification of 1% of one enantiomer in the presence of 99% of its antipode has been achieved. The presence of 5 bonds between the chiral centres of such diastereisomeric derivatives makes their separation an interesting result. Indeed, further work on the effects of spacing between chiral centres indicated that the separation efficiency of these systems were in the order 3>4<5 (bonds). An order of 3>4>5 is expected.

The chloromethyl ether reagents, unlike the alkyl halides, do not have a proton on the atom P to the halide and thus cannot undergo dehydrohalogénation as a side reaction. The mild reaction conditions, employing diisopropylethylamine as a hindered non nucleophilic base make such derivatizations amenable to compounds containing acid and base sensitive functions.

Assessment of the performances of both the alkyl halide and chloromethyl ether reagents are made by comparison with enantioseparations achieved when using N-acetyl-(S)-(-)-prolyl chloride and (+)-(trans)- chrysanthemoyl chloride reagents. Synthetic procedures for the preparation of all the homochiral reagents are reported.

NMR techniques were investigated by employing modified cyclodextrins in an attempt to form diastereoisomeric inclusion complexes with chiral analytes. It was hoped that differences in their spectra would enable enantioquantification.

Initial attempts at preparing novel homochiral polyesters by the condensation polymerisation of polyethylene glycol (400) with homochiral diacids were made. Such polymers may have use as homochiral chromatographic stationary phases.

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