天然有機合成方法(研究生用)

史炳鋒浙江大學化學系有機合成方法Email:bfshi@Cellffice：西溪校區(qū)西七437參考文獻UsefulWebsite:/areas/reich/syntheses/syntheses.htm/Highlights/totalsynthesis.shtmBooks:K.C.Nicolaou:ClassicsinTotalSynthesis(I,II,III)E.J.Corey:TheLogicofChemicalSynthesis吳毓林，姚祝軍“現(xiàn)代有機合成化學”Andliteratures…“如果有人編寫一部權(quán)威性的20世紀科學史，那么關(guān)于復雜分子的化學合成，特別是天然產(chǎn)物的全合成很可能成為其中的精華之一?！? E.J.CoreyNobelPrize@1990IntroductiontoTotalSynthesisOrganicsynthesisdelivers‘moleculesinthebottle’andisanimportantdrivingforcefordiscoveryandinventioninchemistry,materialsscience,biologyandmedicine.TheImportanceofOrganicSynthesis1990:逆合成分析1975:有機分子和反應(yīng)的立體

化學研究1965:有機小分子的合成1955:多肽和激素的合成1947:生物堿等植物產(chǎn)物的合成1939:性激素和高級萜烯的研究1938

:類胡蘿卜素、維生素的

研究1937

:碳水化合物和維生素等

的研究1930:血紅素的合成1902:糖類和嘌呤衍生物的合成2010:鈀催化偶聯(lián)反應(yīng)2005:烯烴復分解反應(yīng)2001:不對稱氫化

和氧化1994:碳正離子化學1984:多肽固相合成法1979:硼和磷化合物在有機

合成中的應(yīng)用1973:有機金屬化合物1950:Diels-Alder反應(yīng)1912:格氏試劑和催化加氫有機小分子的高效創(chuàng)制有機全合成合成方法學諾貝爾化學獎TheImportanceofOrganicSynthesis與天然產(chǎn)物全合成相關(guān)的諾貝爾獎獲得者1981-2006期間上市的983個小分子藥物的來源分布(J.Med.Chem.2008,51,2589)天然產(chǎn)物49.65.727.617.1一般的合成化合物天然產(chǎn)物類似物天然產(chǎn)物衍生物有機合成仍然是有機小分子藥物的來源的主要手段TheImportanceofOrganicSynthesisTotalSynthesisinMedicine300mgHalichondrinB

toncollectionofspongeOver$500000抗腫瘤抗腫瘤細胞毒素抗腫瘤PhaseII抗腫瘤SupplyProblemWhyTotalSynthesis?Discodermolide–spongeDiscodermiadissoluta–antitumor,phaseI–Source-totalsynthesis?39stepsgave60g(0.65%yield）YondelisET-743–tunicateEcteinascidiaturbinata–antitumor,phaseIII–Source-semi-synthesisWhyTotalSynthesis?SynthesisandStructureModificationWhyTotalSynthesis?SARstudiesandLeadEvaluationE7389FDA2010.11.15乳腺癌TheDevelopmentofOrganicSynthesisTheRoleofTotalSynthesis

促進發(fā)展新的合成方法學和策略Eschenmosersulfidecontraction

促進了解更加復雜的化學結(jié)構(gòu)及理論Woodward–HoffmannrulesTemplatesynthesis

創(chuàng)造新的物質(zhì)

培養(yǎng)人才LinearSynthesis（線性合成）

Severalstepsareperformedoneafteranotheruntilthemoleculeiscomplete.----Timeconsuming----Lowefficiency

For4LinearSteps

OverallYield90%perstep67%60%perstep13%ConvergentSynthesis（匯聚式合成）Individuallypreparedintermediatesareconvergentlycoupledtogethertomakethetarget.----shorterroute----simplertooperate----higheroverallyields----highefficiencyFor4LinearSteps

OverallYield90%perstep81%60%perstep36%TargetConvergentSynthesisofBiyouyanaginAK.C.Nicolaou,Angew.Chem.Int.Ed.2007,46,4708-47113steps8steps[2+2]cycloadditionDiversitySynthesis（多樣性合成）Generatealibraryofstructurallyrelatedchemicalcompounds.----goodforstructure-activitystudies----highefficiencyingeneratestructuraldiversityS.L.Schreiber,Angew.Chem.Int.Ed.2004,43,46-58StuartL.SchreiberDiversitySynthesis（多樣性合成）D.R.Spring,NatureCommun.2010,43,1-13Multi-componentreactionsCycloadditionreactionsRing-closingmetathesisTandemreactionsClickchemistryDiversitySynthesis（多樣性合成）Generatealibraryofstructurallyrelatedchemicalcompounds.S.L.Schreiber,Angew.Chem.Int.Ed.2006,45,2635-2638StuartL.SchreiberTotalSynthesis（全合成）

Thecompletechemicalsynthesisofcomplextargetmoleculesfromsimple,commercialavailablematerials.

P.G.Harran,Angew.Chem.Int.Ed.2003,42,4961Semi-Synthesis（半合成）Startwithanaturallyoccurringcompoundoranadvancedintermediateandindependentlyconvertthattothetargetmolecule.

青霉素頭孢菌素Semi-SynthesisofTaxol(Holton@Florida)半合成是許多天然產(chǎn)物藥物的主要來源Semi-SynthesisofTaxol(Holton@Florida)半合成也促進了許多新藥的發(fā)現(xiàn)FormalSynthesis（形式合成）Thesynthesisofacompoundthatisalreadyknownfromtheliteraturetobeaprecursortothatdesiredendproduct..P.S.Baran,J.Am.Chem.Soc.2009,131,17066L.Barriault,Angew.Chem.Int.Ed.2012,51,2111-2114SelectedLandmarkfrom1824-1944TheWoodwardEra(1950-1970)R.B.WoodwardNobelPrize@1965WithA.EschenmoserA.EschenmoserTheWoodwardEra(1950-1970)TheWoodwardEra(1950-1970)TotalSynthesisofStrychnine(1954)TotalSynthesisofStrychnine(1954)TotalSynthesisofStrychnine(1954)TotalSynthesisofProgesterone(1971)TheCoreyEra(1970-1990)E.J.CoreyNobelPrize@1990TheCoreyEra(1970-1990)TheCoreyEra(1970-1990)ModernEra(1990~):Nicolaou/nicolaou/K.C.Nicolaou@TSRIModernEra(1990~)ThomasJ.Maimone@BerkeleyRyanA.Shenvi@TSRIP.S.Baran@TSRI/baran/html/home.html/shenvi/Ryan_Shenvi.html/tjm/Lab_website/Home.html天然產(chǎn)物全合成的全盛時期RepresentativeNaturalProductsRepresentativeNaturalProductsTotalSynthesisofTaxolPalytoxin(?？舅兀℡.Kishi@Harvard其他代表性海洋毒素Maitotoxin（刺尾魚毒素）Maitotoxin97