全合成resolvin.pptx

单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2011-03-30,#,单击此处编辑母版标题样式,Total synthesis of resolvin e1,Melissa Allard,Keith Barnes,Xuemei Chen,Yiu-Yin Cheung,Bryan Duffy,Charles Heap,John,Inthavongsay,Matthew Johnson,Ravi Krishnamoorthy,Chris Manley Stephan Steffke,Deepu,Varughese,Ruifang Wang,Yi Wang,and C.E.Schwartz,AMRI,21 Corporate Circle,Albany,NY 12212,USA,Resolvyx Pharmaceuticals,222 Third Street,Cambridge,MA 02142,USA,Currently:Avila Therapeutics,Waltham,MA 02453,USA;eschwartz,作者单位,Founded in 1991 as,Albany Molecular Research,Inc,.,AMRI(,NASDAQ:AMRI,)provides scientific services,products and technologies focused on,improving the quality of life,.The company has steadily evolved,with global facilities now in the United States,Europe and Asia.Its 1,200+employees have the experience and commitment necessary to provide customers with a wide range of services,technologies and cost models.,AMRI performs services including drug discovery,pharmaceutical development,and manufacturing of active ingredients and,pharmaceutical intermediates,for many of the worlds leading healthcare companies.,A separate,stand alone,R&D,division of the company is also developing technology that it intends to partner and outlicense,an area often viewed as a higher value added service to the many companies with which AMRI is working.,作者单位,Resolvyx Pharmaceuticals,is developing an entirely new class of medicines called Resolvins.Resolvins are naturally-occurring,small molecule lipid mediators with the potential to treat a wide range of,inflammatory diseases,.Unlike most anti-inflammatory drugs which,suppress,the bodys inflammatory response,Resolvins work,by activating the bodys own mechanisms,for shutting off,or resolving,inflammation.,Initially funded in 2005,Resolvyx is the first and only company dedicated to the development of new medicines from its Resolvin platform.Pre-clinical research demonstrates that Resolvins have significant potential to treat,auto-immune,diseases(like crohns disease,回肠病,rheumatoid,类风湿,arthritis,关节炎,and psorisasis),allergic,diseases(like asthma,哮喘,)and,chronic inflammatory,diseases(like atherosclerosis,动脉硬化,degenerative retinal,视网膜退化,diseases and chronic dry eye,干眼病,).,文章摘要,The enantioselective total synthesis of Resolvin E1(RvE1),a naturally occurring small molecule mediator of,inflammation resolution,is reported.Two routes are presented,both modular and convergent in nature,with excellent control of all stereocenters.The,C12-and C18-hydroxy,groups are derived from,(S)-glycidol,while the,C5-hydroxy,group is installed via enantioselective,reduction,of a ketone precursor.Both,cis-alkenes,are introduced with excellent,control by reduction of a late-stage,bis-alkyne,intermediate.The synthetic disconnections are,very amenable to analog preparation,and further modifications to the chemistry have allowed for the scale-up and First in Man testing of this novel pro-resolution molecule.,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。,Resolvin E1(RvE1;5,S,12R,18R-trihydroxyeicosapentaenoic acid)is,an antiinflammatory lipid mediator derived from omega-3 fatty acid eicosapentaenoic acid(EPA).At the local site of inflammation,aspirin,treatment enhances EPA conversion to 18,R-oxygenated,products,including RvE1,which carry potent anti-inflammatory signals.,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-6 PUFA,，但可能缺乏最适量的,Omega-3 PUFA,（多不饱和脂肪酸）,炎症反应,以前的方法,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-8C-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,-,硅氧醛是竞争关系,作者的方法,模块,a,的合成,模块,B,的合成,模块,C,的合成,汇聚式合成,汇聚式合成,F,）,Zn(Cu/Ag),I-PrOH,H,2,O,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,DMAP 4-,二甲氨基吡啶,CSA,樟脑磺酸,Pyr-SO,3,吡啶与三氧化硫的配合物,Sonogashira,反应,This coupling of,terminal alkynes,with aryl or vinyl halides is performed with a palladium catalyst,a copper(I)cocatalyst,and an amine base.Typically,the reaction requires,anhydrous,and,anaerobic,conditions,but newer procedures have been developed where these restrictions are not important.,Sonogashira,反应,Kenkichi Sonogashira(,薗頭 健吉,Sonogashira Kenkichi),born October 1931)is a Japanese chemist and was a Professor of Chemistry at Osaka University in Japan.He discovered the Sonogashira coupling in 1975.Sonogashira was later a professor at Osaka City University and retired in 2004.,Takai,反应,Takai,反应（高井反应），又称,Takai,烯化反应（,Takai olefination,）、,Takai,烯烃合成，由,Takai Kazuhiko,（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,In the reaction mechanism proposed by Takai,chromium(II)is oxidized to chromium(III)when,replacing,both halogen atoms.The geminal carbodianion complex thus formed reacts with the aldehyde in a,1,2-addition,along one of the carbon to chromium bonds and in the next step both chromium bearing groups engage in an elimination reaction.In,newman projection,it can be seen how the steric bulks of chromium groups and the,steric bulks,of the alkyl and halogen groups drive this reaction towards,anti elimination,.,Noyori,催化,Noyori,催化,本文亮点,1.,作者单位,2.,分子的新颖,3.,工作量的保证,4.,试剂及方法的特殊,5.,手性及顺反控制,Thank you for your attention!,Its my pleasure to discuss with you and thus broaden my horizon!,王寅,2011,年,3,月,