全合成resolvin

TOTALSYNTHESISOFRESOLVINE1MelissaAllard,KeithBarnes,XuemeiChen,Yiu-YinCheung,BryanDuffy,CharlesHeap,JohnInthavongsay,MatthewJohnson,RaviKrishnamoorthy,ChrisManleyStephanSteffke,DeepuVarughese,RuifangWang,YiWang,andC.E.SchwartzAMRI,21CorporateCircle,Albany,NY12212,USAResolvyxPharmaceuticals,222ThirdStreet,Cambridge,MA02142,USACurrently:AvilaTherapeutics,Waltham,MA02453,USA;[e-mail]作者单位Foundedin1991asAlbanyMolecularResearch,Inc.,AMRI(NASDAQ:AMRI)providesscientificservices,productsandtechnologiesfocusedonimprovingthequalityoflife.Thecompanyhassteadilyevolved,withglobalfacilitiesnowintheUnitedStates,EuropeandAsia.Its1,200+employeeshavetheexperienceandcommitmentnecessarytoprovidecustomerswithawiderangeofservices,technologiesandcostmodels.AMRIperformsservicesincludingdrugdiscovery,pharmaceuticaldevelopment,andmanufacturingofactiveingredientsandpharmaceuticalintermediatesformanyoftheworld'sleadinghealthcarecompanies.Aseparate,standaloneR&Ddivisionofthecompanyisalsodevelopingtechnologythatitintendstopartnerandoutlicense,anareaoftenviewedasahighervalueaddedservicetothemanycompanieswithwhichAMRIisworking.作者单位ResolvyxPharmaceuticalsisdevelopinganentirelynewclassofmedicinescalledResolvins.Resolvinsarenaturally-occurring,smallmoleculelipidmediatorswiththepotentialtotreatawiderangeofinflammatorydiseases.Unlikemostanti-inflammatorydrugswhichsuppressthebody'sinflammatoryresponse,Resolvinsworkbyactivatingthebody'sownmechanismsforshuttingoff,orresolving,inflammation.Initiallyfundedin2005,ResolvyxisthefirstandonlycompanydedicatedtothedevelopmentofnewmedicinesfromitsResolvinplatform.Pre-clinicalresearchdemonstratesthatResolvinshavesignificantpotentialtotreatauto-immunediseases(likecrohn‘sdisease回肠病,rheumatoid类风湿arthritis关节炎andpsorisasis),allergicdiseases(likeasthma哮喘)andchronicinflammatorydiseases(likeatherosclerosis动脉硬化,degenerativeretinal视网膜退化diseasesandchronicdryeye干眼病).文章摘要TheenantioselectivetotalsynthesisofResolvinE1(RvE1),anaturallyoccurringsmallmoleculemediatorofinflammationresolution,isreported.Tworoutesarepresented,bothmodularandconvergentinnature,withexcellentcontrolofallstereocenters.TheC12-andC18-hydroxygroupsarederivedfrom(S)-glycidolwhiletheC5-hydroxygroupisinstalledviaenantioselectivereductionofaketoneprecursor.Bothcis-alkenesareintroducedwithexcellentcontrolbyreductionofalate-stagebis-alkyneintermediate.Thesyntheticdisconnectionsareveryamenabletoanalogpreparation,andfurthermodificationstothechemistryhaveallowedforthescale-upandFirstinMantestingofthisnovelpro-resolutionmolecule.ONaO15OH810CH3OH181612OHRvE1分子作用鱼油是近年来颇受宠爱的保健品，研究显示它对缓解从哮喘到心脏病的多种疾病有好处，但它有益健康的具体原理一直不为人知。一项新研究解开了这个谜，并提出阿斯匹林可以增强鱼油的效果。ResolvinE1(RvE1;5S,12R,18R-trihydroxyeicosapentaenoicacid)isanantiinflammatorylipidmediatorderivedfromomega-3fattyacideicosapentaenoicacid(EPA).Atthelocalsiteofinflammation,aspirintreatmentenhancesEPAconversionto18R-oxygenatedproducts,includingRvE1,whichcarrypotentanti-inflammatorysignals.OHOeicosapentaenoicacid分子作用Omega-3脂肪酸可促进骨密度增加。Omega-3脂肪酸对肌肉组织的蛋白质代谢有积极的促进作用。DHA可改善高甘油三酯患者的血脂水平。Omega-6降血清胆固醇Omega-3脂肪酸可在易患人群中明显减少精神分裂症的罹患风险。DHA对早产儿视觉系统发育有显著促进作用。Omega-3脂肪酸可降低心血管疾病发生率。大多数人可以从膳食中获得足够的omega-6PUFA，但可能缺乏最适量的Omega-3PUFA（多不饱和脂肪酸）炎症反应ONaO15OH810CH3OH181612OHRvE1SelectivealkynereductionOMeOOTBSOTBSCH3TBSOHWEolefinationSonogashiracouplingSonogashiracoupling以前的方法OMeOOTBS158P(O)(OEt)210CHOTMSOTBSICH3TBSORingopeningOHOAlpineBoranereduction121618HOBrROMe51OOTMSR=-ClR=以前的方法原来路径的不足之处1.做烯丙位叶立德路线太长2.C-5的ee值比较低91%3.C-8~C-10的片段不好做4.HWE反应产率不稳定，E/Z率低。加成路径与形成α-硅氧醛是竞争关系OMeOOTBS158P(O)(OEt)210CHOTMSOTBS12HOBr810OOOHOTBDPSCH3HOI-PrWittigolefinationTakai/SonogashiracouplingsSonogashiracouplingICH3HOOHOITMSOTBDPSOOHi-PrOHOOO41BCA作者的方法模块A的合成OOHi-PrOHOOOOOTMSi-PrOHa,b123c,d70%86%模块B的合成OHOa,b77%OTBSTMSOHc,d456TMSOTBDPSe77%85%7CHOTMSOTBDPSOH模块C的合成H3CIORH3CCHOOTBDPSe69%c,d79%H3COTBDPSOTBSOTBSa,b86%O8910R=TBDPS11R=Hf72%汇聚式合成TMSCHOOTBDPSa80%7TMSOTBDPSCHO12b,c50%TMSOTBDPSOOHOi-Pr13汇聚式合成TMSOTBDPSOOHOi-Pr13d,e68%OHOOHOi-PrCH3HO14f,g45%OHONaOHORvE1CH3OHF）Zn(Cu/Ag),I-PrOH,H2O,40℃,15h本文所用到的缩写TBS叔丁基二甲基硅基TBDPS叔丁基二苯基硅基TMS三甲基硅基TBAF四丁基氟化铵三水合物DMAP4-二甲氨基吡啶CSA樟脑磺酸Pyr-SO3吡啶与三氧化硫的配合物SONOGASHIRA反应Thiscouplingofterminalalkyneswitharylorvinylhalidesisperformedwithapalladiumcatalyst,acopper(I)cocatalyst,andanaminebase.Typically,thereactionrequiresanhydrousandanaerobicconditions,butnewerprocedureshavebeendevelopedwheretheserestrictionsarenotimportant.SONOGASHIRA反应KenkichiSonogashira(薗頭健吉,SonogashiraKenkichi),bornOctober1931)isaJapanesechemistandwasaProfessorofChemistryatOsakaUniversityinJapan.HediscoveredtheSonogashiracouplingin1975.SonogashirawaslateraprofessoratOsakaCityUniversityandretiredin2004.TAKAI反应Takai反应（高井反应），又称Takai烯化反应（Takaiolefination）、Takai烯烃合成，由TakaiKazuhiko（高井和彦）首先报道。醛与偕二卤代烃在二价铬催化下形成碳-碳双键，在醛基碳上延长碳原子。此反应一般有很高的E/Z选择性，很适合反式双键的制备。其最早形式(1986)为苯甲醛与碘仿或溴仿在过量氯化亚铬作用下偶联为苯乙烯卤。TAKAI反应InthereactionmechanismproposedbyTakai,chromium(II)isoxidizedtochromium(III)whenreplacingbothhalogenatoms.Thegeminalcarbodianioncomplexthusformedreact