骨化三醇合成方法比较精选文档.ppt
骨化三醇合成方法比较本讲稿第一页，共十一页从Vitamin D2 合成片段3本讲稿第二页，共十一页1，of vitamin D2 6 经经KMnO4 氧化的氧化的7：2，7经经Mitsunobu反应得到反应得到8；3，8用用SeO2氧化，得到氧化，得到9；4，9用用TMS保护的保护的105，10经水解得到经水解得到11，6，11用用TMS保护得到保护得到127，12氧化裂解后在氢化还原为氧化裂解后在氢化还原为13，8，13经过一步氧化得到经过一步氧化得到3本讲稿第三页，共十一页片段片段片段片段2 2的合成的合成的合成的合成本讲稿第四页，共十一页A new enantioselective synthesis of the building block 2 was developed based upon the asymmetric MukaiyamaMichael 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 NaBH4CeCl3 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本讲稿第五页，共十一页骨化三醇成品合成本讲稿第六页，共十一页In contrast to Kocienskis23 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 20C,followed with a mixture of 3 and 3a(0.66 mol equivalents),at78C,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 TBAF3H2O 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 1H NMR spectrum was identical tothat of the natural compound.本讲稿第七页，共十一页方法二：本讲稿第八页，共十一页片段2a的合成本讲稿第九页，共十一页片段3的合成本讲稿第十页，共十一页谢谢大家的关注 以上方法并不适合实际生产应用，方法一合成步骤太多，并且原料也不便宜；方法以上方法并不适合实际生产应用，方法一合成步骤太多，并且原料也不便宜；方法以上方法并不适合实际生产应用，方法一合成步骤太多，并且原料也不便宜；方法以上方法并不适合实际生产应用，方法一合成步骤太多，并且原料也不便宜；方法二相对方法一来说能经济一些，同时也存在很大问题，合成步骤太多且收率不高，不适二相对方法一来说能经济一些，同时也存在很大问题，合成步骤太多且收率不高，不适二相对方法一来说能经济一些，同时也存在很大问题，合成步骤太多且收率不高，不适二相对方法一来说能经济一些，同时也存在很大问题，合成步骤太多且收率不高，不适于大生产。如果将两种方法糅合，取其精华去其糟粕，将会使生产成本下降。本人有现于大生产。如果将两种方法糅合，取其精华去其糟粕，将会使生产成本下降。本人有现于大生产。如果将两种方法糅合，取其精华去其糟粕，将会使生产成本下降。本人有现于大生产。如果将两种方法糅合，取其精华去其糟粕，将会使生产成本下降。本人有现成的工艺方法，有需要的可以和本人交流成的工艺方法，有需要的可以和本人交流成的工艺方法，有需要的可以和本人交流成的工艺方法，有需要的可以和本人交流本讲稿第十一页，共十一页
