The Synthesis Of Alfacalcidol And Palladium/Sulfur-ligand Catalyzed Allylic Oxyacylation Of Olefins

Alfacalcidol?1?-hydroxyvitamin D₃?is known as a preferred drug for the treatment of osteoporosis which has good market demand and application prospects.Besides,its high-selective synthesis has always been regarded as a research hotspot and challenge.Employing vitamin D₃ as a starting material,alfacalcidol was obtained by a five-step reaction sequence of esterification,cyclization,oxidation,solvolysis ring-opening,and subsequent Diels-Alder separation.However,this process was still suffering from the use of the highly toxic reagent selenium dioxide and the product of cis-trans isomers,which markedly reduced the yield of pure product.Besides,the synthesis process was neither in line with the green chemical principle nor atomic economy.In order to solve these problems:1)We used the photochemical transformation to convert the 5,6-trans isomer into the targeted 5,6-cis isomer;New synthetic strategies of allylic oxidation were designed for the replacement of original method and the feasibility of the route were verified by experimental.2)Novel sulfur-ligands were designed and synthesized,which were applied to the allylic C-H esterification of olefins and the synthesis of 1?-hydroxyvitamin D_3.Specific contents are as follows:The first part comprehensively presented the origin,structure,pharmacological activity and related drugs of vitamin D_3.Besides,specific introduced the semi-chemical synthesis of vitamin D₃ derivatives.The cis-isotachysterol was found to be a new substrate in preparing alfacalcidol.Using blue light catalyzed photochemical transformation,the difficulties of separating cis-trans isomers in the current process were avoided.The overall yield has been greatly improved from 17%to 34%and the final product purity was up to 99%.The second part firstly reviewed the range,yield and selectivity of three main allylic oxidation systems and made a specific introduction for the design,application and mechanism of different ligands in the palladium-ligand catalytic system.Then,the first bis-thiadiazole ligand was designed and used in the palladium?II?/thiadiazole-ligand system to catalyze mono-substituted terminal olefins into linear allylic acetates.Employing this strategy,a range of allylic esters were synthesized in43%to 80%yields with excellent regio-and stereoselectivities.Two differentiated potential mechanisms?1??-allyl and?2?acetoxypalladation were discussed.Furthermore,we modified the thiadiazole-ligand into less hindered ligands for the acetoxylation of unreactive 1,1-disubtituted olefins.Compared with bis-thiadiazole ligand,mono-thiadiazole ligand has higher catalytic efficiency and a wider range of substrates.The monoterpenes and cycle olefins were also tolerated for this system and the allylic acetates were obtained in moderate to good yields?33%-86%?.Attempts have been made to apply this catalytic system to the allylic esterification of vitamin D₃derivatives,but no desired product has been obtained.In summary,a preferred route for preparation of 1?-OH vitamin D₃ from vitamin D₃ introduced photochemical transformation was proposed.The bis-thiadiazole ligand was designed to catalyze mono-substituted olefins into high regioselective allylic acetates.The mono-thiadiazole ligand was found to have a broad scope and significantly increase the reaction yields of 1,1-disubstituted olefins.