Studies of Synthetic Methodologies for Introduction of Hydroxy Groups onto Sterol Ring C and Ring D

Abstract

In the last few decades, research became more and more interested in this area. However the chemistry aspect has somehow held up the research of oxysterols. Despite continuing advances in studies in the chemistry of oxysterols, most researchers rely on commercial materials that are unfortunately very limited with regard to structure types, available quantities, and unreasonable costs. Many naturally occurring potent oxysterols have not been well studied simply because they are not chemically synthesized and therefore not commercially available. In this project, we developed a synthetic route to prepare C-, D-ring oxygenated cholesterol in an acceptable yield. Two useful intermediates, Cholest-7, 14-dien-6-one 22 and cholest-7-en-6-one 20 were also synthesized by a new method, from which introduction of hydroxy groups into ring C and D could be achieved in one or two steps. It was suggested in our experiments that hydroxy groups on sterol ring A and B could more or less decrease the yield of an important intermediate, cholest-7-en-6-one, which however is of great importance to introduce hydroxy groups onto ring C and D. To prepare this cholest-7-en-6-one in good yield, several synthetic routes were tried in this project. Synthesis of cholest-7-en-6-one with 3-OH and 5-OH on sterol ring was not successful. Despite all the effort, only 20% yield of 5α-cholestan-3β, 5α-diol-7-en-6-one-3-acetate 5 was given in the experiment. In the preparation of cholest-7-en-6-one with 3-OH and 4-OH on sterol rings, an important reaction, 7-bromination, however ended up in multiple products and hence the following step could not be carried out. A compound 15 with no hydroxy groups on sterol rings was synthesized by treating 3-chloro-cholesterol 14 with Na/ethanol at -50 °C. From this compound, the cholest-7-en-6-one 20 was finally achieved in 76% yield and a 14-OH sterol 21 was synthesized by allylic oxidation in over 90% yield.