Syntheses of Bioactive Steroid Derivatives Through the Development of Regioselective Oxidations with Copper, Chromium and Rhodium

In 2020, 11 out of the top 200 small molecule pharmaceutical drugs in retail sale were steroids. Therefore, the functionalization of the steroid system, which is comprised of a tetracyclic backbone (i.e. ABCD ring system with three 6-membered rings and a 5-membered ring, numbered from C1-C19), is an important research area of study to yield bioactive small molecules. In order to develop new methods to access specific steroid target molecules, various reactions were explored. Specifically, the steroid core was functionalized at the C1, C3, C5, C6, C7, C12, C17, and C19 positions to obtain a variety of oxygenated steroids using the Schönecker reaction with copper and the allylic oxidation with rhodium and chromium transition metals. In addition, the chemical synthesis of new C12α-hydroxylated and C7 oxygenated steroids of dehydroepiandrosterone (DHEA, 19C) and pregnenolone (21C) were accomplished by using the Schönecker oxidation to install the C12-hydroxy group and the allylic oxidation on the Δ5 alkene of the B-ring steroid to install the C7 oxygenated groups. Also, the semi-synthesis of menarandroside A, the pregnane glycoside natural product, which has potential anti-diabetic activity, is reported. Furthermore, the synthesis of 7α-hydroxycholest-4-en-3-one, the biomarker for irritable bowel syndrome, was completed in 10 linear steps. The key step in the transformation involved the allylic oxidation to install the C3 ketone from the C3 desoxy Δ4 precursor. Finally, exploring the Schönecker oxidation with the C19 imine resulted in the discovery of the C1-hydroxylation and C19 hydroperoxidation on the C5α-reduced A-B ring system. The olefin difunctionalization at the C5 and C6 positions was observed when the Schönecker oxidation was carried out on the Δ5 steroid. This research inspires new synthetic approaches to yield biologically relevant small molecules.