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Pitt CHEM 2320 - Synthetic Studies on Heterocyclic

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Synthetic Studies on Heterocyclic Natural ProductsTohru FukuyamaGraduate School of Pharmaceutical SciencesUniversity of TokyoNNHMeHO2CHOHNONNHMeCO2MeOMeOMeOMeOONHONHNMeOOHNONHOHOMeOSMeNHCO2MeNHNHNMeO2CMeO NNMeOHOAcCO2MeHOHHNNOHHOHDevelopment of First-Generation Indole SynthesisIt all started with this idea at Rice in 1993 …JACS, 116, 3127 (1994)RNCRN CSnBu3NRNRSnBu3SnBu3NHRSnBu3Bu3SnHAIBNHHHNHRINHRArArX, Pd(0)Stille couplingNIS or I2Bu3SnHVersatility of 2-IodoindolesNHCO2Men-BuNHCOOMeINHCO2MeOn-BuPdCl2(PPh3)2CuI, Et2NH89% PdCl2(dppf)CO (1atm), DMF78%n-BuBu3Snn-BuCO2MeSnBu3NHCO2MeCO2MeBnPdCl(PPh3)2Ph3As, CuIHMPA-DMF68%Application to Total Synthesis of Indole AlkaloidsNHCO2MeNHNHN(CHO)CO2MeOHHPProposed byWenkert andScottVincadifformineNHNHCHOCO2MeNHNCO2MeWhat is P ???NCO2MeOHP'N(CHO)HPNN(CHO)CO2MeP'PNHNCHOCO2MePNHNCHOCO2MeHTL, 36, 6373 (1995), TL, 38, 5831 (1997)JSOC,Jp, 59, 779 (2001), CC, 353 (2004)A Novel Activating Group for Primary Amines MeisenheimercomplexSO2NRNO2HSO2NRNO2HSO2NRR'NO2NO2SO2NRR'NO2NO2RSSRNO2NO2N SOO–+RHN R'RR'RS–SO2+H+SO2NRNO2NO2HR'XbaseR'OHPh3PDEADMitsunobu reaction works particularly well.The by-productcan be removedeasily bypartitioning.NO2NO2S CO2HCO2EtHNSO2NO2NO2Me CO2EtOHHH+DEAD, Ph3Pbenzene97%CO2EtNHNO2O2SO2N MeCO2EtHHSCH2CO2H (1.3 eq)Et3N (2 eq)CH2Cl223 °C, 5 min91%CO2EtHNHMeCO2EtH+Total Synthesis of (±)-VincadifformineTL, 40, 1519 (1999)VincadifformineNOHBoc CO2MeNHS OONO2NO2OMeOMe+Ph3PDEADbenzenert91%TFACH2Cl2NNCO2MeSO2ArOMeOMeBocNHNCHOCO2MeO2SO2N NO2OKCH3CNrt, 4.5 h67%(2 steps)NHCO2MeNHNHNCO2MeVindoline and CatharanthineNHNMeO2CMeO NNMeOHOAcCO2MeHOHHVinblastineVindolineCatharanthinePotier & Langlois sp3NHNCO2MeNNCO2MeMeOOHHOAcHMeAttempts to introduce an sp3 carbonto the 2-position failed!NHNCO2MeCatharanthineNBocINMeO Oh! or FeCl2NaNH2liq NH3NBocNMeCO2tBuXAn entirely new indolesynthesis needs to bedeveloped for catharanthine!SRN1 rxnRNS R'RNHBu3SnHAIBNH– Bu3SnSHNRR'NHRR'HR'SSnBu3NHRR'HSSnBu3NHRR'HSSnBu3HBu3SnHSecond-Generation Indole SynthesisJACS, 121, 3791 (1999)Conversion of Quinolines to Indoles !!Hull, J. Chem. Soc., Perkin I, 922 (1975)85%(3 steps)70-95% RNCSCl2BaCO3CH2Cl2, H2ONCSOHCNCSTHPO1) NaBH42) DHP, CSANTHPOHS RNHROTHPEt3B (0.1-0.2 eq)n-Bu3SnH (1.2-3 eq)toluene, rt, 5-60 min60-95%JACS, 121, 3791 (1999)Examples of the Indoles PreparedNHOTHPOOEtNHOTHPNO TBSNHOTHPCO2MeCO2MeNHOTHPNHOTHPNHOTHP83%94%78%85%93%82%66%NHOAcNHOAcOMeNHOAcNHCO2MeMeH36%87%Total Synthesis of Indole Alkaloids(–)-VindolineNNCO2MeMeOOHHOAcHMeNNHCO2Me(±)- CatharanthineNHCO2MeNHNHCO2MeNH(±)-Vincadifformine(–)-TabersonineNHNMeO2CMeO NNMeOHOAcCO2MeHOHH(+)-VinblastineNNOHHOH(–)-StrychnineNMeNMeOOMeOOH(–)-AspidophytineNHMeOCO2MeNOHONHNCO2MeMeOHOO(–)-ConophyllineDevelopment of Sulfonamide Chemistry- Selective Sulfonylation of Diamines -NHHNNHNHONHNH2HO 416bH2NnNH2H2NHNSO2NO2SO2ClNO2EtOH, –20 °C;NaOEt (1 eq)n = 1: 83%n = 2: 77%n = 3: 87%(3 eq)nPreparation of a Novel Trityl Chloride ResinTL, 40, 4711 (1999)2-Chlorotrityl Chloride ResinMerrifield ResinK2CO3DMF, 60 °CClOOHOClOHHOSOCl2CH2Cl2ClClPSPSPSPSPPPPTotal Synthesis of Spider Toxin HO-416bBr NNHHO NHBr BrHNNH2HO N NNHNsBocNsNs NsBocNsI N NNH1) Boc2O, Et3N CH2Cl2, rt 2) K2CO3, DMF, 60 °CCs2CO3, n-Bu4NICH3CN, 60 °C86%Ns NsBocPivCl, Et3N, CH2Cl2, rt;NHHNNHONHOHOH2NNHNsNs98%1) MsCl, Et3N, CH2Cl2, rt2) NaI, 2-butanone, 60 °C97% (2 steps)Et3N, DMAP97%Cs2CO3CH3CN60 °C94%HO-416bi-Pr2NEt, CH2Cl2, rtOClNHHNNNsNNsONNsNHBoc1) HCl, MeOH2)NHHNNNsNNsONNsNH1) HSCH2CH2OH DBU, DMF2) TFA, CH2Cl2NHHNNHNHONHNH265%(4 steps)TL, 40, 4711 (1999)PPFurther Application of Nosyl ChemistryNNsCO2HNsNC8H17BrNNsHNNHNsNsNC8H17OBrPivCl, Et3N, CH2Cl2;Et3N90%NNsHNNNsNsNC8H17OCs2CO3, n-Bu4NIMeCN, 60 °C0.10 M86%NHNsH2NNNNHHNC8H17OOOLipogrammistin-ALipogrammistin-ASynlett, 1667 (2000)ONHHHNNHHONHOOHTotal Synthesis of (–)-Ephedradine A(–)-Ephedradine AONOHHTBDPSOAcOCO2MeNsHNArHO OTBSPPh3DEADtoluene60 °C95%Ar =OBnONOHHTBDPSOAcOCO2MeNsNArOTBS1) PhSH, KOH CH3CN, 60 °C2) CbzCl NaHCO3 CH2Cl2-H2O85%(2 steps)ONOHHTBDPSOAcOCO2MeCbzNArOTBSONOHHOHAcOCO2MeCbzNArNHNsOOBnNHHNNsHOCO2MeAcOCbzN1) CSA, MeOH2) NsNH2, DEAD PPh3, toluene-THF3) aq. HF, CH3CN79%(3 steps)PPh3DEADtoluene0.05 M77%JACS, 125, 8112 (2003)Total Synthesis of (+)-VinblastineK2CO3DMF90 °Covernight85%NBocMeO2COTBDPSHOOEtNBocMeO2COTBDPSNOEtNsHNsNH2 (2 eq)DEAD, Ph3Ptoluenert, 30 min88%NHNMeO2CMeO NNMeOHOAcCO2MeHOHH(+)-VinblastineJACS, 124, 2137 (2002)NBocNMeO2COTBDPSNsEtOHNBocNHOMOMCO2MeNsNH2PPh3, DEADtoluene95%NBocHOMOMOHCO2MeHONsTotal Synthesis of (–)-StrychnineNNOHHOH(–)-StrychnineJACS, 126, 10246 (2004)Total Synthesis of (+)-Lysergic AcidBrBrNHBocNCO2MeHOTBDPSPd(OAc)2, PPh3Et3N, Cs2CO3EtCNreflux, 1 h70%NCO2MeNBocHHTBDPSOHNMeNHHHO2C(+)-Lysergic acidTo be published.n-BuLitoluene–78 °C15 minLiBrMe BrBrMe BrEtNO2EtNO2quant.IBrBrMeTotal Synthesis of (+)-Duocarmycin AOHNONNHMeCO2MeOMeOMeOMeO(+)-Duocarmycin ABnOBrBrBnONBrBnORNHBnOR?Problematic Pd-Catalyzed Aryl AminationMeOBrBrMeONBrBnMeONHBnOBnNHBncat. Pd(0)OBnOBn+Pd2(dba)3, P(o-tol)3, CsOAc, CuIDMFDMFtoluenereagentssolvent timetempyieldrtdebrominatednonePd2(dba)3, P(o-tol)3, CsOAc 4 h120 °C34% trace3 h5 min100 °C 28% 7%66%Pd(PPh3)4, t-BuONa, K2CO3Functionalities on NitrogenSynlett, 231 (2002)BrHNRNRCuI (2 eq) CsOAcDMSOCbzAcAllocHBnRtemp (°C)time (h) yield (%)90902424827790 24 75aCatalytic amount of CuI (20 mol%) was used.CsOAc (eq)101010rtrt15478755Ns 901925Bna9024835Boc 90 24 8210Novel Cu-Mediated Aryl Amination!BnOBrNBnOTBSTBSClImidDMFquant.BnOBrBrBnONBrBnOHNHBnHOHCuI (10 mol%)CsOAcDMSOrt, 24 h70%Addition to Optically Active AzlactoneMeO OMeO OMe NHCbzMeO OHO OMe NHCbzNOOOBnMeO2CMePLEacetone-H2OpH 7.5 - 8.0rt, 3 dquant.(94% ee)triphosgeneEt3NEtOAcrt, 5 minquant.BnOBrNBnOTBSBnOOCbzHNCO2MeMeNBnOTBSn-BuLiTHF, –78 °C;toluene75%NOOBnOMeO2CMeZn1M KH2PO4THF-H2Ort69%BnONCbzOCO2MeMeNHOTBSBnONCbzOCO2MeMeNOTBSTrocClNaHCO3MeCN 70 °C70%TrocConstruction of the Tricyclic SkeletonBnOOCbzHNCO2MeMeNBnOTBSBnOOCbzHNCO2MeMeNBnOTBSBrNBSDMFrt72%BnONCbzOCO2MeMeNOTBSBn CuICsOAcDMSOrt, 3 hquant.Preparation of the Indolecarboxylic AcidCuI (1.5 eq)CsOAc (7 eq)DMSOrt, 24 h98%NMeOMeOOMeCbzCO2MeNHMeOMeOOMeCO2MeH2, Pd/CEtOH-EtOAcrt, 3 h99%NHMeOMeOOMeCO2Haq. KOHMeOH85%NHMeOMeOOMeCOClSOCl2toluene60 °CCHOMeOOMeMeOCHOMeOOMeMeOBrBr2AcOH-CH2Cl275%MeOOMeMeOBrCO2MeCbzHNCbzHN CO2MePO(OMe)2TMGCH2Cl2, rt92%1) TBAF, THF rt2) MsCl, Py rt 3) H2, Pd/C EtOH-EtOAc rt 58% (3 steps)Completion of the Total


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Pitt CHEM 2320 - Synthetic Studies on Heterocyclic

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