Ⅰ.Synthesis, Isolation And Elucidation Of Impurities And Biological Activities Research On Steroids Ⅱ.Stereoselective Synthesis Of Five-membered Ring Carbasugars

This doctoral dissertation is divided into two parts. Part I is Synthesis, Impurities Isolation and elucidation, Biological Activities Research on Steroids. Part II is Stereoselective Synthesis of Five-Membered Ring Carbasugars.1. The first part of this dissertation consists of three subparts(1) The synthesis of brassinosteroid derivatives and research on biological activities. Brassinosteroid, as a powerful steroidal plant growth regulator, has received much attention. In this subpart, we described the new biological activity and the synthesis of derivatives of brassinosteroid. In the aspect of new biological activity, the anti-prostatic hyperplasia activity was firstly reported. A series of brassinosteroids were tested in vitro, and 24-epibrassinolide (25) exhibited fairly good activity. Furthermore, through the test of the mixture of 24-epibrassinolide (BR-3) and its main components,24-epibrassinolide (25) and (22S, 23S)-24-epibrassinolide (59) in vivo, we found 24-epibrassinolide (25) could specifically inhibit the hyperplasia of prostate, while the isomer 59 was almost ineffective. In the aspect of the synthesis of derivatives, we started from the cheap and commercially available material, hyodeoxycholic acid to synthesize a series of derivatives with modificationon ring A and B. This structurally diverse modification will help us to investigate structure-activity relationship of brassinosteroids on new bioactivities.(2) The epoxidation is the key step in the synthesis of antiprogestin drug, mifepristone. People always focus on the enantioselective to improve the desired alpha epoxide. In this subpart, a modified phase-transfer catalysed enantioselective epoxidation of estra-△5(10)9(11)-diene has been determined and investigated. Eight chiral ammonium salts (PTC A-H), used as phase-transfer catalysts, have been synthesized from cinchona alkaloids. Among them, PTC G and PTC H have exhibited satisfying catalytic activity to improve the ratio ofα/βepoxide up to 7:1. We presume that the chiral ammonium salts assembling the oxidant and the estra-△A5(10),9(11)-diene in a specific three-dimensional arrangement may channel epoxidation through an energetically and entropically favored transition state, which exerted an great influence on the ratio ofα/βepoxide. Meanwhile, this modified method significantly expanded the scope of phase-transfer catalysed epoxidation reaction.(3) In this subpart, We have clarified the existence of the impurities in canrenone produced by the process starting from androsta-4-ene-3,17-dione (4-AD for short), and four new and seven known impurities have been confirmed. The structures and configurations of these compounds were elucidated by means of ID and 2D (HMQC, HMBC and ROESY) NMR. The discovery of the new and known compounds which have similar chemical structure may be useful in the quality control of the production of canrenone.2. The second part is stereoselective synthesis of five member ring carbasugars.Carbasugars are a series of derivatives in which the ring oxygen of a monosaccharide are replaced by a methylene group. The synthesis of carbasugars has undergone extensive development during the 20th century. Here, we wish to establish a simple way to construct the cyclopentene intermediate 112, which could be easily converted to entecavir 93, a powerful anti-HBV drug.Starting from commercially available (R)-(+)-2,2-Dimethyl-1,3-dioxolane-4-carboxaldehyde 134, we have used ring-closing metathesis as the key step to prepare five-membered ring carbasugars mimics 148 and 160, in which the unsaturated double bonds provide potent reaction site for introducing other functional groups. For example, compound 160 could be recognized as the critical intermediate in the preparation of antiviral agent N-MCT. However, the whole synthetic route of entecavir hasn't completely finished yet. Further research is still in progress.