1、The Diels-Alder ReactionOOOMeMeOPMBXXOTBSLecture NotesKey Reviews:Total SynthesisK.C.Nicolaou,S.A.Snyder,T.Montagnon,G.Vasillikogiannakis,Angew.Chem.Int.Ed.2002,41,1668.AsymmetricE.J.Corey,Angew.Chem.Int.Ed.2002,41,1650.HeteroD.L.Boger,Comprehensive Organic Synthesis,Vol.5.,1991,p.451-512.Biomimetic
2、E.M.Stocking,R.M.Williams,Angew.Chem.Int.Ed.2003,42,3078.TransannularP.Deslongchamps,Tetrahedron 2001,57,4243.The Diels-Alder Reaction:Original DiscoveryOOOMeMeOPMBXXOTBSO.Diels,K.Alder,Justis Leibigs Ann.Chem.1928,460,98.OOHHOOOOHHOOHHHHDiels-AlderreactionDiels-AlderreactionOO+endo endoQuickTime an
3、d aPhoto-JPEG decompressorare needed to see this picture.Otto Diels(1876-1952)Kurt Alder(1902-1958)The Diels-Alder Reaction:Almost a Reaction of Another NameOOOMeMeOPMBXXOTBSFor commentary,see:J.Berson,Tetrahedron 1992,48,3.OOHHHHOO+Correct ProductThiele(1906):Albrecht(1906):OOC5H5C5H5The Diels-Alde
4、r Reaction:Almost a Reaction of Another NameOOOMeMeOPMBXXOTBSFor commentary,see:J.Berson,Tetrahedron 1992,48,3.OOHHHHOO+Correct ProductThiele(1906):Albrecht(1906):OOC5H5C5H5Staudinger(1912):OOThe Diels-Alder Reaction:Almost a Reaction of Another NameOOOMeMeOPMBXXOTBSFor commentary,see:J.Berson,Tetra
5、hedron 1992,48,3.OOHHHHOO+Correct ProductThiele(1906):Albrecht(1906):OOC5H5C5H5Staudinger(1912):OOvon Euler(1920):OO+OOOOandThe Diels-Alder Reaction:Original DiscoveryOOOMeMeOPMBXXOTBSO.Diels,K.Alder,Justis Leibigs Ann.Chem.1928,460,98.OOHHOOOOHHOOHHHHDiels-AlderreactionDiels-AlderreactionOO+endo en
6、doQuickTime and aPhoto-JPEG decompressorare needed to see this picture.Otto Diels(1876-1952)Kurt Alder(1902-1958)The Diels-Alder Reaction:Original DiscoveryOOOMeMeOPMBXXOTBSO.Diels,K.Alder,Justis Leibigs Ann.Chem.1928,460,98.OOHHOOOOHHOOHHHHDiels-AlderreactionDiels-AlderreactionOO+endo endoQuickTime
7、 and aPhoto-JPEG decompressorare needed to see this picture.Otto Diels(1876-1952)Kurt Alder(1902-1958)“Thus i t appears to us that the possi bi l i ty of synthesi s of com pl ex com pounds rel ated to or i denti cal w i th natural products such as terpenes,sesqui terpenes,perhaps even al kal oi ds,h
8、as been m oved to the near prospect.”The Diels-Alder Reaction:Original DiscoveryOOOMeMeOPMBXXOTBSO.Diels,K.Alder,Justis Leibigs Ann.Chem.1928,460,98.OOHHOOOOHHOOHHHHDiels-AlderreactionDiels-AlderreactionOO+endo endoQuickTime and aPhoto-JPEG decompressorare needed to see this picture.Otto Diels(1876-
9、1952)Kurt Alder(1902-1958)“W e expl i ci tl y reserve for oursel ves the appl i cati on of the reacti on devel oped by us to the sol uti on of such probl em s.”The Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSStereospecificCO2MeMeO2CCO2MeCO2MeCO2MeCO2MeCO2MeCO2MeHHHH+Regioselective Diels-
10、Alder Reactions:Early ExamplesOOOMeMeOPMBXXOTBSR.B,Woodward and co-workers,J.Am.Chem.Soc.1956,78,2023.R.B,Woodward and co-workers,Tetrahedron 1958,2,1.OOOO+CO2MeCO2MeNHNHHHMeO2COMeOOOMeOMeOMeABCDMeOHH reserpineOOMeO2CbenzeneDiels-AlderreactionDE E(27%)endo TSRegioselective Diels-Alder Reactions:Earl
11、y ExamplesOOOMeMeOPMBXXOTBSR.B.Woodward and co-workers,J.Am.Chem.Soc.1952,74,4223.butadiene,benzene,100 C,96 hDiels-Alderreactionaq.NaOH,dioxane;then 1 N aq.HClOOMeOMeHOOMeOMeHCDCD(86%)OOMeOMeOOMeOMeendo TSepimerizationMeHMeOHHOOHOOHcortisoneMeHMeHOHHcholesterolHMeMeMeD+Note the regioselectivity in
12、this reactionThe Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSStereospecificCO2MeMeO2CCO2MeCO2MeCO2MeCO2MeCO2MeCO2MeHHHHDiastereoselectiveOO+endoOHHHHHHOendokineticexothermodynamic+not formedThe Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSStereospecificCO2MeMeO2CCO2MeCO2MeCO2M
13、eCO2MeCO2MeCO2MeHHHHDiastereoselectiveOO+endoOHHHHHHOendokineticexothermodynamicEWGABBAEWGBEWGHHHAHendo product+not formed+Scotts EasyProduct IdentificationMnemonicThe Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSRegioselective651234123456123465+A question of regio-,or orientational,selec
14、tivity arises when both the diene anddienophile are unsymmetrically substituted.In these instances,a mixture of two regioisomeric products could result in a proportion that depends upon on theindividual nature of,and interplay between,substituent effects.andThe Diels-Alder Reaction:General Principle
15、sOOOMeMeOPMBXXOTBSEDGEWGEDGEWGortho cycloadductEWGEWGEDGEDGpara cycloadduct+The Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSEDGEWGEDGEWGortho cycloadductEWGEWGEDGEDGpara cycloadductEWGEWGEDG2EDG2EDG1EDG1synergisticdiene+The Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSEDGEWGED
16、GEWGortho cycloadductEWGEWGEDGEDGpara cycloadductEWGEWGEDG2EDG2EDG1EDG1OMeOMeMeOOMeMeOMeOOOOsynergisticdiene+orRegioselective Diels-Alder Reactions:Danishefskys DieneOOOMeMeOPMBXXOTBSS.J.Danishefsky,T.Kitahara,J.Am.Chem.Soc.1974,96,7808.S.J.Danishefsky,Acc.Chem.Res.1981,14,400.OMeTMSODanishefskysdie
17、ne+R1EWGDiels-AlderreactionOMeEWGR1TMSOOEWGR1HR2R3Synergistic diene:the methoxy and silyloxy substituents reinforce each other in termsof regioselectivity and provide sufficient electron density on the diene subunit that mostDiels-Alder reactions proceed with good dienophiles at low temperature(with
18、outthe need for Lewis acid catalysis)with incredibly regioselectivity.R3R3R2R2Regioselective Diels-Alder Reactions:Danishefskys DieneOOOMeMeOPMBXXOTBSS.J.Danishefsky and co-workers,J.Am.Chem.Soc.1979,101,7013.OMeTMSOSOPhTMSOMeOSOPh1.9-BBN2.NaOHHOOCO2NaCO2Na+100 CDiels-AlderreactionAcOH,EtOAcneat,26
19、hOCO2MeOMeOOOCO2MeOMeOOOOMeCO2Medisodium prephenateRegioselective Diels-Alder Reactions:Danishefskys DieneOOOMeMeOPMBXXOTBSS.J.Danishefsky and co-workers,J.Am.Chem.Soc.1992,114,8883.S.J.Danishefsky and co-workers,J.Am.Chem.Soc.1994,116,11213.MeTBSOOO+THF,25 C,5 daysDiels-AlderreactionOOHHTBSOMeHOHMe
20、CHOHHOOMeHOHOOMeHbenzene OO(94%)(100%endo)CHOMe(90%,100%endo)IntramolecularDiels-Alderreaction80 C,13 hMeHOOMeOHOHOmyrocin CThe Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSEDG1However.EDG2EDG1EGD2EDG2EDG1Predictions are hard since these groups are battling each other for controlThe Diels
21、-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSEDG1However.EDG2EDG1EGD2EDG2EDG1Predictions are hard since these groups are battling each other for controlNHCO2RSRORalkylWhat Determines Who Wins?Both position and electronics matterMeMeOMeMeCHOThe C-1 methyl group dominates the reactionMeOOMeMeMeO
22、COMeMePhSPhS+The Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBSEDG1However.EDG2EDG1EGD2EDG2EDG1Predictions are hard since these groups are battling each other for controlNHCO2RSRORalkylWhat Determines Who Wins?Both position and electronics matterMeMeOMeMeCHOThe C-1 methyl group dominates t
23、he reactionMeOOMeMeMeOCOMeMePhSPhSMeEtOOMeEtOCHOWhen a group is at C-1,it tends to win even if the C-2 group is a better donor+The Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBS+MeOMeCO2MeO2NMeOMeNO2CO2MeMeCO2MeMeCO2Me+MeOMereverse polaritydienophileCO2MeMeOMeCO2MeacidacidThese contrasting
24、 outcomes are quite strikingReactivity Principles for Dienes/DienophilesOOOMeMeOPMBXXOTBSnot a viable dieneDienes must be able to adopt an s-cis orientationReactivity Principles for Dienes/DienophilesOOOMeMeOPMBXXOTBS1.Stronger electron-withdrawing groups=greater reactivityXX+XXHHX COClPhSO2PhCOCOCH
25、3CNCO2Me67001551841.11.0krel2.Ring strain always increases reactivitynot a viable dieneDienes must be able to adopt an s-cis orientationThe Diels-Alder Reaction:General PrinciplesOOOMeMeOPMBXXOTBS+200 C+OMe+OOSiMe3O80 C0 COOMe3SiOHHOSynthetic Equivalence:Alternate Forms of Impossible Dienes/Dienophi
26、lesOOOMeMeOPMBXXOTBSEtOSO2PhSO2PhEtOSO2PhEtO OOONO2NO2n-Bu3SnH,AIBN2,3,allylic,benzylic nitro only+1.LDA,alkyl halide2.Na/Hgacid1.Na/Hg2.acid+NO2Synthetic Equivalence:Alternate Forms of Impossible Dienes/DienophilesOOOMeMeOPMBXXOTBSPPh3Br+CH3CN,150 CLDA,HCHO(80%)PPh3BrPPh3BrDiels-AlderreactionWittig
27、 ReactionSynthetic Equivalence:Alternate Forms of Impossible Dienes/DienophilesOOOMeMeOPMBXXOTBSFor a review,see:O.De Lucchi,G.Modena,Tetrahedron 1984,40,2585.+SO2PhSO2PhNa/HgSO2PhMe3SiMe3SiSO2PhSO2PhPhO2SSO2PhSO2PhSO2PhSO2PhMe3SiSO2PhPhO2S+toluene115 Ctoluene115 Ctoluene160 CTBAFNa/HgSynthetic Equi
28、valence:Alternate Forms of Impossible Dienes/DienophilesOOOMeMeOPMBXXOTBSFor a review,see:O.De Lucchi,G.Modena,Tetrahedron 1984,40,2585.+SO2PhSO2PhNa/HgSO2PhMe3SiMe3SiSO2PhFSO2PhPhO2SSO2PhSO2PhSO2PhSO2PhMe3SiSO2PhPhO2S+toluene115 Ctoluene115 Ctoluene160 CTBAFNa/HgSynthetic Equivalence:Alternate Form
29、s of Impossible Dienes/DienophilesOOOMeMeOPMBXXOTBSE.J.Corey and co-workers,J.Am.Chem.Soc.1969,91,5675.CNCl+Cu(BF4)2,0 CLewis acid-catalyzedDiels-Alder KOH,H2OHOHOCO2HMeHOPGF2(90%)(80%)HMeOHCNClMeOHOOMeOCNClAcOCNClOCClO2NImproving Diels-Alder Reactivity:Intramolecular Reactions Via Temporary Tethers
30、OOOMeMeOPMBXXOTBSK.C.Nicolaou and co-workers,Nature 1994,367,630.OHMeOEtOOOOH+PhB(OH)2OOEtO2CMeOBOPhbenzene,80 C,48 h-H2OOOOHHOHOOHMe MeBoronate cleavageMeEtO2COOEtO2CMeOBOPh25 C,1 hOOHHOHMeOEtO2COOHOOAcHBzOAcOMeMeMeHOONHPhOOHPhOMe TaxolCImproving Diels-Alder Reactivity:Intramolecular Reactions Via
31、Temporary TethersOOOMeMeOPMBXXOTBSA.D.Brosius,L.E.Overman,L.Schwink,J.Am.Chem.Soc.1999,121,700.IntramolecularDiels-AlderNBocNTsNNTsSiMeMeCO2MeTMSI,2,6-lutidine,CH2Cl2,25 C;MeOH,NaOH;TfOMe2SiCO2MeEt3N,ANTsNSiMeMeHHHHCO2Me(5:1 ds)025 C,3.5 h1.HF pyr,25 C2.mesitylene,LactamizationNNTsHHSiMe2FO(+)-alope
32、rineNNHHHAImproving Diels-Alder Reactivity:Intramolecular Reactions Via Temporary TethersOOOMeMeOPMBXXOTBSA.D.Brosius,L.E.Overman,L.Schwink,J.Am.Chem.Soc.1999,121,700.IntramolecularDiels-AlderNBocNTsNNTsSiMeMeCO2MeTMSI,2,6-lutidine,CH2Cl2,25 C;MeOH,NaOH;TfOMe2SiCO2MeEt3N,ANTsNSiMeMeHHHHCO2Me(5:1 ds)
33、025 C,3.5 hF1.HF pyr,25 C2.mesitylene,LactamizationNNTsHHSiMe2FO(+)-aloperineNNHHHALewis Acid Complexation:A Way to Improve Reaction Conditions and Endo SelectivityOOOMeMeOPMBXXOTBSEDGEWGLUMOHOMONormal demandDiels-Alderreaction(HOMOdiene-LUMOdienophile)E E1EDGEWGLUMOHOMOLewis acid-catalyzedDiels-Ald
34、erreaction E2LALewis acid complexationlowers the energy of the LUMO of the diene.Consequently,reactionsoccur at lower temperatureand are more endo selectivesince they are better underkinetic control.Regioselective Diels-Alder Reactions:Using Lewis Acid CatalysisOOOMeMeOPMBXXOTBSOMeOMe+OOOMeHOMeMeMeO
35、OOMeHMeMeheat(100 C)BF3OEt2(-16 C)SnCl4(-16 C)1411120most Lewisbasic carbonyl+Regioselective Diels-Alder Reactions:Using Lewis Acid CatalysisOOOMeMeOPMBXXOTBSOMeOMe+OOOMeHOMeMeMeOOOMeHMeMeOOMeOMeheat(100 C)BF3OEt2(-16 C)SnCl4(-16 C)1411120most Lewisbasic carbonylvs.+BF3OOMeOMeSnClClRegioselective Di
36、els-Alder Reactions:Using Lewis Acid CatalysisOOOMeMeOPMBXXOTBSY.Kishi and co-workers,J.Am.Chem.Soc.1972,94,9217.Y.Kishi and co-workers,J.Am.Chem.Soc.1972,94,9219.OHOHO(83%)MeMeN+OOMeHMeNtetrodotoxinOLewis acid-catalyzed intermolecular Diels-Alder reactionOOMeHNNHOH2NHOHOOHNMeOHSnCl4,MeCNSnClClHOIn
37、the absence of this Lewis acid,1,3-butadiene engages the other olefinof the quinone exclusively!For first LA catalyzed D-A reaction,see:P.Yates,P.Eaton,J.Am.Chem.Soc.1960,82,4436.Asymmetric Diels-Alder Reactions:DiastereoselectiveOOOMeMeOPMBXXOTBSK.C.Nicolaou and co-workers,J.Org.Chem.1985,50,1440.C
38、O2MeTBDPSOHHMeTBDPSOMeMeO2Ctoluene,130 C,48 hOMeMeCO2MeMeHHHHMeONHIntramolecularDiels-Alderantibiotic X-14547A(70%)Asymmetric Diels-Alder Reactions:DiastereoselectiveOOOMeMeOPMBXXOTBSE.J.Corey and co-workers,J.Am.Chem.Soc.1975,97,6908.HOHOCO2HMeHOPGF2 HMeOMeMeOMeOHOOR(89%)(97:3 diastereoselectivity)
39、Cl3AlChiral auxiliary-mediated Diels-AlderOBnR=MeMeMePhAlCl3,CH2Cl2,-55 CDiastereoselective Diels-Alder Reactions:Using Implanted AuxiliariesOOOMeMeOPMBXXOTBSD.A.Evans,W.C.Black,J.Am.Chem.Soc.1993,115,4497.OOOXHHHHOMeOOMeNMe2HMe(+)-lepicidin AOOOTBSHMeOTIPSHMeHHONOOBnOTESOOMeOTIPSHMeOTESNOOOAlMeMeRT
40、BSOOTBSONOOBn endo transition stateStillecouplingMe2AlCl,CH2Cl2025 C(71%)(10:1 ds)Lewis acid-catalyzedDiels-Alder reactionHR=macrocycleOOMeOMeOMeMeX=Note:Withoutauxiliary,the alternateendo product resultspreferentiallyAsymmetric Diels-Alder Reactions:EnantioselectiveOOOMeMeOPMBXXOTBSE.J.Corey and co
41、-workers,J.Am.Chem.Soc.1989,111,5493.HOHOCO2HMeHOPGF2 H+ONOONAlNPhPhMeNNAlRMeONOORHBnOBnOHONOO R=SO2CF3CH2Cl2,-78 C,18 hAsymmetricDiels-AlderOBn(93%)(95%ee)endo adductRRAsymmetric Diels-Alder Reactions:EnantioselectiveOOOMeMeOPMBXXOTBSE.J.Corey and co-workers,J.Am.Chem.Soc.1992,114,8290.HOHOCO2HMeHO
42、PGF2 H+exo adductBnOHBrCH2Cl2,-78 C,8 hAsymmetricDiels-AlderOBn(82%)(19:1 exo/endo)NBOOHNHHOBnOBrHOBNOHNHHTsTsCHOBrCHOH(92%ee)Enantioselective Diels-Alder ReactionsUsing Chiral Oxaborolidinium CationsOOOMeMeOPMBXXOTBSONBHMeHONBORXXHHNTf2E.J.Corey,T.Shibata,T.W.Lee,J.Am.Chem.Soc.2002,124,3808.D.H.Ryu
43、,T.W.Lee,E.J.Corey,J.Am.Chem.Soc.2002,124,9992.or OTfNBORXXHNH OHXXHOBOBOBRRR+toluene,12 htolueneor CH2Cl2,-30 C,15 minHNTf2or TfOHMeMeCHO+MeMeCHONBOo-tolPhPhHHNTf2toluene,-78 C,13 h(96%)(97%e.e.)MeFor a review on enantioselective Diels-Alder reactions,see:E.J.Corey,Angew.Chem.Int.Ed.2002,41,1650.En
44、antioselective Diels-Alder ReactionsUsing Chiral Oxaborolidinium CationsOOOMeMeOPMBXXOTBSONBHMeOOOMeMeMeHMeTf2NOOOMeMeMeMeOOOMeMeMe+MeHOOMeOMeMeMeHNHHHOOMeMeMe()-dendrobineNBOo-tolPhPhHHNTf2MeOOMeOMeMeMeHOHtoluene,-50 C,48 h(99%,99%e.e.)Q.-Y.Hu,G.Zhou,E.J.Corey,J.Am.Chem.Soc.2004,126,13708.Original
45、dendrobine synthesis:A.S.Kende,T.J.Bentley,J.Am.Chem.Soc.1974,96,4332.Asymmetric Diels-Alder Reactions:EnantioselectiveOOOMeMeOPMBXXOTBSK.C.Nicolaou and co-workers,Chem.Eur.J.2001,7,5359.MeTBSOOOOMeMe Lewis acid-catalyzedasymmetricDiels-AlderMeTBSOOOOMeMe(S)-BINOL-TiCl2,toluene,-60-10 C,7 hOOMeOMeMe
46、OTBSHH(90%)(94%ee)OOTiOOMeMeOHMeMeHH()-colombiasin AThis system is known as Mikamis catalystHetero Diels-Alder Reactions:Aldehydes as Dienophile ComponentsOOOMeMeOPMBXXOTBSTMSOOMeMeMeOPhOOMeMePhOOMeMePhendoexo+Lewisacid+BF3OEt2,CH2Cl2ZnCl2,THF2391682Hetero Diels-Alder Reactions:Aldehydes as Dienophi
47、le ComponentsOOOMeMeOPMBXXOTBSTMSOOMeMeMeOPhOOMeMePhOOMeMePhendoexo+Lewisacid+BF3OEt2,CH2Cl2ZnCl2,THF2391682OMeMeOMeTMSOPhLAsolventsolventsolventIn polar solvents(i.e.THF),the LA-solvent array is bulky and orients itself away from dieneTMSOOMeMeMeOPhLAOTMSOLAPhOMeMeMeIn non-polar solvent(i.e.CH2Cl2)
48、,the union occurs in an ionic,Mukaiyama-type aldol pathwayHetero Diels-Alder Reactions:Aldehydes as Dienophile ComponentsP.Liu,E.N.Jacobsen,J.Am.Chem.Soc.2001,123,10772.NOMeCrClOTBSONOMeCrOOHTBDPSOOHTBDPSO+neat,25 COBnTBSOOBnOTBSOOBnOTBDPSAsymmetrichetero Diels-Alder(64%)(97%ee)(+)-ambruticinOOHOHCO
49、2HMeMeMeOMeMeHetero Diels-Alder Reactions:Furans as Diene ComponentsFor a review,see:D.L.Boger,Comprehensive Organic Synthesis,Vol.5.,1991,p.451-512.NMeHHHOOMeMeMedendrobineNHMetBuO2CMeMeHONMeMeMetBuO2CNHMetBuO2CMeMeHONHMetBuO2CMeMeHOIntramolecularDiels-Alder(74%)toluene,165 C,15 hexo adductRingopen
50、ingOHHydrideshiftFurans are normally poor dienes;retro Diels-Alder reactions occur withequal facility as Diels-Alder reactionsNote:Thiopheneand pyrrole arenot viable dienesHetero Diels-Alder Reactions:Oxazoles as Diene ComponentsOOOMeMeOPMBXXOTBSP.A.Jacobi and co-workers,Tetrahedron Lett.1989,30,717
