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精选文档.ppt》由会员分享，可在线阅读，更多相关《骨化三醇合成方法比较精选文档.ppt（11页珍藏版）》请在淘文阁 - 分享文档赚钱的网站上搜索。

1、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 sy

2、nthesis 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

3、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 cycl

4、ization 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

5、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,afforde

6、d 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 me

7、thanolic 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

8、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

9、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