骨化三醇合成方法比较

从VitaminD2合成片段3第1页/共10页1，ofvitaminD26

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10

5，

10经水解得到11，

6，

11用TMS保护得到12

7，

12氧化裂解后在氢化还原为13，

8，

13经过一步氧化得到3第2页/共10页片段2的合成第3页/共10页Anewenantioselectivesynthesisofthebuildingblock2wasdevelopedbasedupontheasymmetricMukaiyama–Michaelreaction.19Opticallyactivethioester‡14(96%ee,Scheme3),wastreatedwithLDAandthenwithTMSCltogiveketeneacetals15.Thelatterwereallowedtoreactwithenone5inthepresence

of5mol%ofTrSbCl6.Whenthemajorityofthereagentswereconsumed,thesecondMichaelacceptor16wasadded.20The

reactionproductconsistedofthreediasteromersinaratioof85:11:4(byHPLC).Allourattemptstoseparatethemajorcomponent,towhichstructure17waslaterassigned,failed.Themixturewassubjectedtocyclizationtogive18alongwithminor

diastereomers.AfterNaBH4–CeCl3reduction21ofthesea,b-unsaturatedketonesacrystallinematerialwasobtained,whichwasrecrystallizedtoaffordallylicalcohol19ina53%yieldfrom17.Thestructureof19wasdeterminedbyX-rayanalysis.11第4页/共10页骨化三醇成品合成第5页/共10页IncontrasttoKocienski’s23procedureforexecutingtheJuliaalkylation,thecouplingofsulfone2andaldehyde3wasaccomplishedusinganexcessofthesulfone.Treatmentof2,inTHF,withBuLi(1.2molequivalent),at−20°C,followedwithamixtureof3and3a(0.66molequivalents),at−78°C,affordedtheadductwhichwasquenchedwithAcCl.Thecrudeproduct23

wasthenreducedwith6%sodiumamalgaminmethanolinthepresence24ofNa2HPO4.Amixtureofsilyloxyandacetoxytrienes24wasobtainedina25%overallyieldfrom3.ThismixturewasallowedtoreactwithTBAF·3H2OinTHFandthenwithmethanolicKOHtogivetherespectivetrihydroxytrienesasamixtureofgeometricisomers25inaratioof94:5:1.Themajorisomer,ent-1,wasseparatedbypreparativeHPLC.ItsretentiontimeonananalyticalHPLCcolumnwasthesameasthatofnatural1a,25-dihydroxyvitaminD3andthe1HNMRspectrumwasidenticaltothatofthenaturalcompound.第6页/共10页方法二：第7页/共10页片段2a的合成第8页/共10页片段3的合成第9页/共10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