First synthesis of 22-oxa-Chenodeoxycholic Acid analogue in worldwide

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Chenodeoxycholic acid (CDCA) is a major component in bile acids. It activates farnesoid X receptor (FXR), which regulates redox homeostasis and elicits a cytoprotective effect. Moreover, chenodeoxycholic acid also plays a major role in inhibiting tumor growth, protecting the liver, promoting the secretion of bile, dissolving gallstones of the cholesterol type, reducing lipid, spasmolysis, antiphlogosis and anti-microbial activity. As a result, pursuing potential drug candidates through the derivatives of CDCA have been the approach of many drug discovery attempts. Our group has been working on steroid drugs for many years, such as the synthesis of Ulipristal acetate and its stereoisomers. And to the best of our knowledge, the synthesis of 22-oxa-chenodeoxycholic acid (22-oxa-CDCA) analogue has not been reported in the literature until now. In this article, we describe the first synthesis of 22-oxa-CDCA from androstenedione and progesterone, respectively. We hope 22-oxa-CDCA can become as effective a drug as chenodeoxycholic acid.
22-Oxa-chenodeoxycholic acid (22-oxa-CDCA). Compound 11 (0.10 g, 0.18 mmol) was dissolved in a 2:3:2 solution of CH3CN/H2O/CCl4 (7 mL). RuCl3.H2O (4 mg, 0.018 mmol) and NaIO4 (0.15 g, 0.72 mmol) were added to the mixture and the solution was stirred at room temperature for 3 h. The precipitate was filtered off and washed with ethyl acetate (10 mL *3). The combined filtrate was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a mixture of THF (10 mL) and 4 mol/L hydrochloric acid (5 mL), and then stirred at room temperature for 10 h. The mixture adjusted to pH 12 with aqueous solution of NaOH, then extracted with ethyl acetate.
The 22-oxa-Chenodeoxycholic acid analogue was synthesized. The structure of the new analogue was characterized by MS and NMR. However, the starting material androstenedione 1 underwent 11 steps to give the analogue, which resulted the low6.4% overall yield. Hence, we designed another route to obtain the 22-oxa analogue starting from progesterone 13. The progesterone underwent the similar process, dehydrogenation, epoxidation, hydrogenation, reduction and protection, to give the same intermediate. Then, after the same process, the designed product steroids 22-oxa-CDCA was obtained from 9. The synthetic route in Scheme 3 increased the yield of the desired compound 22-oxa-CDCA to 12.7%. The first synthesis of the 22-oxa-CDCA analogue from readily available starting materials, androstenedione and progesterone, in 11 and 8 steps with overall yields of 6.4% and 12.7% was reported, respectively.