骨化三醇合成方法比较[精选].ppt

从Vitamin D2 合成片段3 1， of vitamin D2 6 经KMnO4 氧化的7：2， 7经Mitsunobu反应得到8；3， 8用SeO2氧化，得到9；4， 9用TMS保护的105， 10经水解得到11，6， 11用TMS保护得到127， 12氧化裂解后在氢化还原为13，8， 13经过一步氧化得到3 A new enantioselective synthesis of the building block 2 was developed based upon the asymmetric Mukaiyama–Michael reaction.19 Optically active thioester? 14 (96% ee, Scheme 3), was treated with LDA and then with TMSCl to give ketene acetals 15. The latter were allowed to react with enone 5 in the presenceof 5 mol% of TrSbCl6. When the majority of the reagents were consumed, the second Michael acceptor 16 was added.20 Thereaction product consisted of three diasteromers in a ratio of 85:11:4 (by HPLC). All our attempts to separate the major component, to which structure 17 was later assigned, failed. The mixture was subjected to cyclization to give 18 along with minordiastereomers. After NaBH4–CeCl3 reduction21 of these a,b-unsaturated ketones a crystalline material was obtained, which was recrystallized to afford allylic alcohol 19 in a 53% yield from 17. The structure of 19 was determined by X-ray analysis.11 骨化三醇成品合成 In contrast to Kocienski’s23 procedure for executing the Julia alkylation, the coupling of sulfone 2 and aldehyde 3 was accomplished using an excess of the sulfone. Treatment of 2, in THF, with BuLi (1.2 mol equivalent), at ?20°C, followed with a mixture of 3 and 3a (0.66 mol equivalents), at?78°C, afforded the adduct which was quenched with AcCl. The crude product 23was then reduced with 6% sodium amalgam in methanol in the presence24 of Na2HPO4. A mixture of silyloxy and acetoxy trienes 24 was obtained in a 25% overall yield from 3. This mixture was allowed to react with TBAF·3H2O in THF and then with methanolic KOH to give the respective trihydroxy trienes as a mixture of geometric isomers25 in a ratio of 94:5:1. Themajor isomer, ent-1, was separated by preparative HPLC. Its retention time on an analytical HPLCcolumn was the same as that of natural 1a,25-dihydroxyvitaminD3 and the