Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,11/7/2009,#,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,骨化(hu)三醇合成方法比较,第一页，共11页。,从Vitamin D2 合成(hchng)片段3,第二页，共11页。,1，of vitamin D2 6 经KMnO4 氧化的7：2，7经Mitsunobu反应得到(d do)8；3，8用SeO2氧化，得到(d do)9；4，9用TMS保护的105，10经水解得到(d do)11，6，11用TMS保护得到(d do)127，12氧化裂解后在氢化还原为13，8，13经过一步氧化得到(d do)3,第三页，共11页。,片段(pin dun)2的合成,第四页，共11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,第五页，共11页。,骨化三醇成品(chngpn)合成,第六页，共11页。,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，不适于大生产。,片段(pin dun)2的合成,19 Optically active thioester 14(96%ee,Scheme 3),was treated with LDA and then with TMSCl to give ketene acetals 15.,谢谢大家(dji)的关注,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，不适于大生产。,19 Optically active thioester 14(96%ee,Scheme 3),was treated with LDA and then with TMSCl to give ketene acetals 15.,片段(pin dun)2a的合成,Themajor isomer,ent-1,was separated by preparative HPLC.,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.,谢谢大家(dji)的关注,When the majority of the reagents were consumed,the second Michael acceptor 16 was added.,片段(pin dun)2a的合成,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，不适于大生产。,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.,19 Optically active thioester 14(96%ee,Scheme 3),was treated with LDA and then with TMSCl to give ketene acetals 15.,骨化(hu)三醇合成方法比较,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,23,was 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.,第七页，共11页。,方法(fngf)二：,第八页，共11页。,片段(pin dun)2a的合成,第九页，共11页。,片段(pin dun)3的合成,第十页，共11页。,谢谢大家(dji)的关注,以上(yshng)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,第十一页，共11页。,