Synthetic Studies towards New 22(S)-Hydroxycholesterol Analogues

Abstract

Liver X receptor is a transcription factor that is important for the metabolism of fat and cholesterol in the body. Known liver X receptor activators are endogenous oxysterols (cholesterol metabolites). 22S-hydroxycholesterol is a synthetic oxysterol which acts as an antagonist reducing production of fat but also increasing glucose uptake in skeletal muscle cells. A variety of chiral and achiral compounds have been prepared in an effort to be utilized towards synthesis of new 22S-hydroxycholesterol analogues. The different syntheses have been optimized with yields ranging from 9- 91%.

Two stereogenic compounds generated are new which have not heretofore been described in the literature. The developed process described in this master thesis has given the desired stereochemistry, which has been confirmed by X-ray crystallography. In this context, it has been established a method of providing high-quality crystals of the syn aldol adduct.

Several attempts to synthesize two modulators of LXR have been investigated, but proven difficult and unsuccessful. Alkylation of the stereogenic diol with two naphatyl derivatives to obtain a new analogue has been studied at various temperatures and reaction conditions. Second, the synthesis of another analogue produced multiple products indicating a high reactivity of the stereogenic diol.