骨化三醇合成方法比較

從VitaminD2合成片段3第1頁/共10頁1，ofvitaminD26

經KMnO4氧化的7：

2，7經Mitsunobu反應得到8；

3，8用SeO2氧化，得到9；

4，9用TMS保護的10

5，

10經水解得到11，

6，

11用TMS保護得到12

7，

12氧化裂解后在氫化還原為13，

8，

13經過一步氧化得到3第2頁/共10頁片段2的合成第3頁/共10頁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頁/共10頁骨化三醇成品合成第5頁/共10頁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頁/共10頁方法二：第7頁/共10頁片段2a的合成第8頁/共10頁片段3的合成第9頁/共10頁謝謝大家的關注

以上方法并不適合實際生產應用，方法一合成步驟太