Investigation of chiral silicon compounds for the determination of enantiomeric purity

Collicott, Roland (2002). Investigation of chiral silicon compounds for the determination of enantiomeric purity. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e33b

Abstract

Over the past two decades, chiral synthesis and separation have grown in importance, particularly in pharmaceuticals, where gross differences in pharmacological behaviour can occur between the enantiomers of a compound. The most tragic example is that of the racemic sedative, thalidomide. Widely used by pregnant women in the 1960's, it was the cause of deformity in many of their children. Under certain circumstances, only the S-(-)-enantiomer produces the teratogenic effect.

The search for specific information on the effects of different enantiomers and increasing attempts to prepare enantiomerically enriched compounds has led to a large demand for enantioselective analytical methods. The two most widely employed techniques are NMR spectroscopy and chromatography.

My research at the Open University focused on reagents based on silicon which could be used for derivatisation with the facility of the ubiquitous trimethylsilyl (TMS) reagents. I have investigated chiral chiorosilanes, in racemic form, to derivatise nucleophilic analytes. Because of the symmetry properties of some of the chiral silicon reagents prepared, the stereochemistry of the products is not dependent on the mechanism of reaction between an analyte and the reagent.

The reagents were assessed by derivatising three chiral alcohols, which were used as model analytes: (1R, 2S, 5R)-menthol, 2-octanol and 1-phenylethanol. Chloromethylphenylsilane produced derivatives that were well resolved by GC, but was considered a poor choice of reagent on the grounds of its instability to racemisation and the instability of the diastereoisomeric products. 1 -Phenylethylchlorodimethylsilane gave derivatives that were well distinguished by NMR, while only partial separation by HPLC was obtained from the 2-octanol and 1-phenylethanol derivatives. No GC separations were achieved from this reagent. Two reagents possessing pseudo-C 2 symmetry, bis(1-phenylethyl)chloromethylsilane and 1 -chloro-1-methyl-2,5-diphenylsilacyclopentane were also unsuccessful in GC analysis, but the latter provided some promise for NMR analysis, with the derivatives of menthol being particularly well resolved.

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