Research On High-value Products Of 5α-Chenodeoxycholic Acid And Their Biological Activity

5α-Chenodeoxycholic acid(CDCA),the C5 hydrogen isomer of chenodeoxycholic acid(CDCA),is discarded as an impurity in the extraction of animal biles because of low medical value.By studying the catalytic hydrogenation of unsaturated steroids,synthesis of high-value chenodeoxycholic acid and bile acid derivatives from 5α-chenodeoxycholic acid had been designed which had the advantages of high-efficient use of wasted material,environmental friendliness.Besides,the control of C5 hydrogen configuration of bile acids has general rule,which is of great significance to the research and development of steroid hormones and bile acids derivates.Meanwhile,trihydroxyl bile acid derivatives were synthesised from 5α-chenodeoxycholic acid and their biological activities were been evaluated.The paper mainly includes the following aspects:1、The structure,property,physiological function,medical value of bile acids,advances of the pre-synthesis of chenodeoxycholic acid and the interaction between Farnesoid X Receptor(FXR)with bile acids were briefly introduced.2、The influence of different substrates on the C5 hydrogen configuration via Pd/C catalytic hydrogenation was explored: 1)It were confirmed that Ag2CO3 and Mn O2 could be used to selectively oxidaze C3-hydroxyl of ursodeoxycholic acid which was used to synthesize substrates;it were confirmed that PBB and Cu Br2 could be used to introduce bromine when using 5α-chenodeoxycholic acid as raw material to synthesize substrates.2)5-ene-7-one bile acid substrate mainly feature 5α configuration.While compared with the 4-en-3-one substrates,the 1,4-dien-3-one substrates feature higher 5β stereoselectivity,for both 1,4-dien-3-one substrates and 4-en-3-one substrates,the larger side chain in C17,the higher 5β stereoselectivity.3)Possible reaction mechanism was got through the crystal structure of raw materials,products and the NMR analysis of the incomplete reaction intermediates.3、A synthetic route for synthesis of chenodeoxycholic acid from 5α-chenodeoxycholic acid was explored based on the rule of catalytic hydrogenation.Using 5α-chenodeoxycholic acid as raw material,the target was synthesized via esterification,selective oxidation,oxidative dehydrogenation,asymmetric hydrogenation,carbonyl reduction and hydrolysis reactions.The overall yield of this route is 31%.This route has the advantages of high-efficient use of wasted material,easy operation and simple seperation.Three key reactions in this route were studied: 1)It was confirmed that Ag2CO3,Mn O2 and Ph I(OAc)2 could be used to selectively oxidaze C3-hydroxyl.2)Optimised the reaction condition of constructing 1,4-dien-3-one moiety 1m through oxidative dehydrogenation by IBX.3)Asymmetric hydrogenation to produce nearly pure 5β intermediate 2m by using Pd/C,which was determined by single crystal structure.4、Based on the synthesis route of 5α-chenodeoxycholic acid,two new compounds were designed and synthesized for biological evaluation in order to develop highly active bile acid derivatives.Trihydroxyl derivatives were obtained by double bond oxidation,the introduction of epoxy and epoxide ring-opening from 5α-chenodeoxycholic acid,in which the absolute configuration of D1 was determined by single crystal structure.The two bile acid analogs D1 and D2,along with CDCA and 5α-CDCA were subjected to agonistic activity assay on Farnesoid X Receptor(FXR).The results showed that both D1 and D2 had no agonistic activity on the FXR receptor.All the structures of the above synthesized compounds were confirmed by NMR and HRMS,the structure of some of the key intermidiates,substrates and final products were further confirmed by X-ray single crystal diffraction.