Formylation of bile acid oxo derivatives - synthesis of new glucocorticoid precursors

Glucocorticoids (GCs) are essential drugs for treating inflammatory diseases and immune system pathological conditions. Dexamethasone, a potent synthetic GC was the first successful treatment for severe COVID-19 patients. However, serious side effects, e.g., osteoporosis, Cushing’s syndrome, high blood pressure, etc., limit the long-term and systematic use of these drugs. There is no alternative for GCs, and the search for GCs with better pharmacological properties is an urgent need. It is known that the carbonyl group at the C-3 steroid position is needed for recognition of some steroid hormones by an appropriate enzyme. This is also the case for GC; GCs have 4-en-3-one or 1,4-dien-3-one systems and by binding to GC receptor they mediate their physiological effect. Recent studies have shown that the ligand-binding domain of the GC receptor can accommodate N-phenyl pyrazole moieties attached to A steroid ring. A common way to fuse heterocycle on the steroid skeleton is the condensation of formyl, dicarbonyl steroid derivative with substituted hydrazines. Easily accessible and appropriately functionalized, bile acids are promising starting compounds for the development of potently new GC. Here, we want to report the synthesis of 2-methylidene derivate of 3-oxo- Δ4,6-diene-bile acid ethyl ester, and regiospecific synthesis of 3-methylidene derivate of 3-oxo-bile acid as well as the stereochemical aspect of this reaction.