The Nonmerculic Oxidation Of Desmosterol And Its Application In Synthesis Of Vitamin D₃ Derivatives

The oxysterol is the precursor of Vitamin D3 derivates and other steroidal drugs.As an important class of steroid,it is increasingly gaining recognition due to their significant biological activity and medicinal value.Based on the systematic review of previous literatures,this dissertation mainly contains several parts as follows:the synthesis route of 25-hydroxycholest-5,7-diene via 25-hydroxycholesterol was developed;Several oxysterols,including 24R,25-dihydroxycholesterol,24S,25-dihydroxycholesterol,24R-hydroxycholesterol,245-hydroxycholesterol and 24-ketocholesterol were synthesized.A new procedure from desmosterol to 25-hydroxycholesterol via bromohydrin reaction and easy reduction of C-Br was designed.The bromohydrin reaction was performed using readily available NBS as the brominating agent in THF-water(4:1,v/v)at-10? to give bromohydrin product in 85.0%.Then the bromohydrin product was transformed into 25-hydroxycholesterol by directly subjecting to the reduction with lithium aluminum hydride in THE.Excellent yields(82%)and regioselectivity have been obtained in the absence of heavy metal reagent.A new and opti1ized procedure for the allylic oxidation of ?5-Steroids with Pbutyl hydroperoxide(4.0 eq.)in the presence of N-hydroxyphthalimide(0.1 eq.)and cobalt acetate(0.01 eq.)under mild conditions was developed,showing excellent regioselectivity and chemoselevtivity(functional group compatibility).The reaction mechanism and the scope of the reaction with a variety of ?5-Steroidal substrates were also investigated.The method to synthesize 25-hydroxycholest-5,7-diene was developed.In the first step,the ?5-7-keto compound was reacted with tosylhydrazide in methanol at room temperature to afford the corresponding tosylhydrazone in 95.0%after easy fitration.The course of this reaction was preceded much faster in the presence of concentrated hydrochloric acid as catalyst.Meanwhile,the reaction mechanism was also investigated.Reductive elimation of the 7-hydrazone function with sodium hydride in toluene at reflux yield the 3?-acetoxy-25-hydroxycholest-5,7-diene in 83.9%,which was hydrolyzed in KOH/methanol to give final product.A new highly stereoselective construction of the side chain of the C-24 and C-25 oxysterols has been achieved by using desmosterol as the starting material with an improved Sharpless catalytic asymmetric dihydroxylation and selectively dehydration as the key step.By means of using desmosterol acetate and addition of suitable auxiliary solvent to increase the solubility of the substrate in the solvent system,the disadvantages such as long reaction time and low yield were solved smoothly.Meanwhile,we found that the Sharpless catalytic asymmetric dihydroxylation proceeded more efficiently when K2OsO2(OH)4 was added to the reaction mixture in portions.The yield was improved from initial 82.5%to 95.0%in 6 h.In the next step,24,25-dihydroxycholesterol was selectively acetylated.Thionyl chloride and pyridine system was used firstly to dehydration of the 25-tert-hydroxy group.Finally,the double bond between C-25 and C-26 was selectively hydrogenated over 10%Pd/C.Cleaner,cheaper and efficient selective oxidation system of the 24-hydroxycholesterol was developed.The oxidation of 24-hydroxycholesterol acetate was proceeded in the presence of NaBr and Oxone under mild conditions to yield the 24-keto product in 95%.TBN(0.04 eq.)/TEMPO(0.05 eq.)/FeCl3(0.05 eq.)catalyst system was also developed to activate molecular oxygen for the aerobic oxidation of 24-hydroxycholesterol and the 24-keto product was obtained in 86.2%.The oxidation system has never been reported before.