Mitsunobu反應(yīng)詳述.PPT

1、1The Mitsunobu reactions2ContentsA Whirlwind Tour of Current Mitsunobu Chemistry 1. Alcohol Inversions 2. Other Nucleophiles 3. Carbon-Carbon Bond Formation 4. Alternative Reagents-Azodicabonyl Portion 5. Alternative Reagents-Trisubstituted Phosphine Portion 6. Some Alternatives to Mitsunbu Chemistr

2、yReferencesAcknowledgements3Alcohol InversionScheme 1ROH+HOArOPh3PDEADROArOScheme 2CO2EtEtO2CNN(DEAD)Ph3PCO2EtEtO2CNN-Ph3+PbetaineArOHOCO2EtEtO2CNNHPh3+PArO-OROHROP+Ph3ArO-OROArOCO2EtEtO2CHNNHPh3PO+SN2mechanism4Alcohol Inversion When a secondary alcohol substrate was used, the esterification reactio

3、n was shown to proceed with a net inversion of stereochemi- stry at the alcohol carbon.Scheme 4C8H17HORCO2HPh3PDEADTHFC8H17ORO97%, R = H90%, R = Ph99%, R = CH2Ph5Alcohol InversionScheme 3ROHPh3PDEADRNCO2EtHNCO2EtIn cases where no nucleophile was added to the reaction mixture, or when the betaine was

4、 not able to abstract the proton of the nucleophilic precursor (pKa13),the hydrazine portion of the reagent was shown to react with the alcohol substrate(Scheme 3)6Alcohol Inversion-Intermolecular The alcohol inversion and hydrolysis procedure may be easily carried out in the presence of sensitive f

5、unctionality(scheme 5)OOOHOHHHOEtPhCO2H, Ph3PDEAD, THFOOOOHHHOEtOOOOHHHOEtOHK2CO3MeOH78% OverTwo StepsScheme 57Alcohol Inversions Smith and coworkersnBu3SnCO2HOTBSITBSOTBSOOH+DEADPh3P, PhH74%nBu3SnOTBSITBSOTBSOOOOTBSTBSOTBSOOOScheme 68Alcohol Inversions 1991, Eli Lilly chemists Martin and DodgeOOOTB

6、SOHOMe1. PNBA, Ph3PDEAD, PhCH3/Et2OOOOTBSOOMeONO2Scheme7OOOTBSOHOMe2. K2CO3MeOH92% OverTwo StepsHO2COMPMOTBSOH9Alcohol Inversions PNBA was also useful in preventing the elimination side reaction. CbzHNOHCO2MePhCO2HPh3P, DEADPh3P, DEADPNBACbzHNCO2MeCbzHNO2CC6H4pNO2CO2Me53%86%Scheme 810Alcohol Inversi

7、ons Tsunoda and coworkers found that the use of TMAD and Bu3P was more tolerant of sterically congested alcohols, resulting in consistently better yields than the PPh3/DEADScheme 9OHMeOCO2HnBu3P, PhH, 60 CNNNNOO(TMAD)99%OOMeO11Alcohol Inversions The Mitsunobu reaction has also entered the area of so

8、lid-phase synthesis.POHNHAcCO2HPh3P, DEAD, THF98%POONHAc1. nBu3SnH, t-BuI RX, AIBN, PhH2. 20% TFA/DCM49-60%HOONHAcRScheme 1012Alcohol Inversion-Intramolecular Synthesis of lactones, a valuable precursor to amino acidsHOCO2HHNBocPh3P, DEADTHF, -78 C40%OOHNBocTsOHTFA, 0 COONH3+-OTsRCO2HNH2Scheme 1113A

9、lcohol Inversions Synthesis of bis-lactonesOSSCO2HOH(S)OSSOOSSO(R,R)Ph3P, DEADPhCH384%OO14Alcohol InversionsOther Oxygen NucleophilesOOHOMeOOBnOHBnOBnOOBn+1. nBu3P, ADDP, THF2. cat Pd(OH)2, H255%OOOMeOOHOHOHOHScheme 1315Alcohol Inversions cyclizationsO2NOHOHDEAD, Ph3PTHF61%O2NOScheme 1416Alcohol Inv

10、ersions The use of TMAD was shown to enhance the reactivity of these nucleophiles of larger pKa,leading to higher overall yieldsOHOHOOHOHODEAD, Ph3PPhH57%TMAD, nBu3PPhH73%Scheme 1517Alcohol Inversions N-hydroxyphthalimide was also an excellent nucleo- phile for the inthemolecular Mitsunobu reactionN

11、OOBocNOHNOOOHPh3P, DEADNOOBocNONOOH2NNH298%NOH2NNH2BocScheme 1618Alcohol Inversions Oximes serve as oxygen nucleophilesOHPhSeArNOEtOOOHPh3P, DMADPhCH3, 0 C64%NOEtOOOPhSeArNSNHONOSONH2NPhHHCO2NaScheme 1719Alcohol Inversions Preparation of sulfonatesNHOCO2MeBz1. RSO3H, Et3N Ph3P, DIAD, PhH2. NaOH, HCl

12、NOCO2MeBzSROO82%, R = p-Tol84%, R = MeScheme 1820Preparation of sulfonatesScheme 19HOMsOH, THFPh3PDEADOHOHCO2MeOOHOHCO2MeSMeOOOHOHCO2MeN3NaN3DMPU, 45 C75% OverTwo Steps21Other nucleophiles Nitrogen NucleophilesSulfonamides as NucleophilesOHTsNHBocPh3P, DEAD, THF86%NBocTsNa/naphthalaeneDME82%DMSO, 18

13、0 CorTFA, DCM69%HNBocNHTsScheme 2022Other nucleophiles Application 1 - the synthesis of natural product Sarain AOHOTHPMeOOH1.DIAD, Ph3P2. TsOH, MeOH77%OPMPOHTsNHBoc1.DIAD, Ph3P, THF2. DMSO, 180 C86%OPMPHNTsNNOHHOPMPBnTsNNBnTsScheme 2123Other nucleophiles Application 2 - the synthesis of Boc-protecte

14、d amines or amine hydrochloride.SETNHBocROHPh3P, DEADNBocRSSiMe3OOnBu4NFNHBocRNH2RHCl6 N HClScheme 2224Other nucleophiles Application 3- Nitroarylsulfonamides as good leaving moiety.PhOHArO2SNHPMBNPMBSOOPhXYPhNHPMBPh3P, DEADDCM91%PhSH, K2CO3DMF, rt, 1 hX, Y = H or NO2Scheme 2325Other nucleophiles Ot

15、her applications Fmoc protected sulfonamides Amides and Imides as nucleophilesOPhOTMSOHTsNHFmocPh3P, DEAD, THFOPhOTMSNHTsNPhTsOHOHOOHNR2XOR1ONR2XOR1NH2NHOO1.Ph3P, DEAD, PhH2. H2NNH2, EtOHScheme 2626Other nucleophiles Hydroxylamines as nucleophilesOOOHFOHPh3P, DIAD, THF67%OOOFOOFOHONHCO2PhPhO2CPh3P,

16、DIAD, THFOOFNOOOOONH4OH62% OverTwo StepsOOFNHNH2OScheme 27CMI-97727Other nucleophiles Provide a propargyl hydrazineNOHHNOBnOBocPh3P, DEADTHF86%NBocNOBnONCORNOSO3HOOHSNO2NHNH2OOPh3P, DEADTHF, -15 CSNO2NNH2OOwarm to rt- N2HH85%Scheme 2928Other nucleophiles The preparation of guanidines.NNHNBocBocNBocH

17、NOHPhPh3P, DEAD, THF92%NNNBocBocNHNBocPhNNNBocBocBocPhScheme 30NHNH2NBocBocEtOHPh3P, DEAD, THF95%NNH2NBocBocEtTFADCM88%HNNH2NHEt-TFAScheme 3129Other nucleophiles Two method of the formation of azideNOMsOHClHN3, THFPh3P, DEAD82%NOMsClN3NClHNScheme 32nC12H25HOPOPhOPhON3Ph3P, DEAD, THF83%nC12H25N3nC12H

18、25HNScheme 3330Other nucleophiles Synthesis of lysine and arginine analogsOHNHHNBocCbzNSHNCO2EtBocPh3P, DEAD, THF84%NSNCO2EtHNHNBocCbzBocScheme 3431Other nucleophiles Secondary and tertiary benzylamines with activated aryl substratesCO2EtEtO2CNN-HR3NH2ONO2P+Ph3CO2EtEtO2CNNHHNHNO2R3+R1NHR2Ph3P, DEAD,

19、 THF43-86%R3NH2OHNO2R3NH2NNO2R1R2-Ph3POScheme 3532Other nucleophiles Sulfur nucleophilesthioesterScheme 37HOPh3P, DIADSHOTHF, 0 CAcSHSLiALH4Et2O94%81%33Other nucleophiles Aryl thiols as nucleophilesNSHSBocNHOHPh3P, EDAD74%NSSNHBocOHOOHHONNNNHNClSSNNBocOHPhSSPhnBu3P, DEAD, THF57%NBocSOHOOHClNNNNHNClN

20、SScheme 3834Other nucleophiles HalogenationsSynthesis of the alkyl halogensOH66LiXPh3P, DEAD, THFX6650%, X = F97%, X = Cl97%, X = Br91%, X = IScheme 3935Other nucleophilesSynthesis of the intermediate of the marine natural products astins A,B and CNCO2MeBocHOMeI, THFPh3P, DEAD94%NCO2MeBocMe+OPPh3I-N

21、CO2MeBocIScheme 4036Other nucleophiles ZnCl2 as catalystONH2OHFFZnCl2, Ph3P, DEADMeCN, reflux75%ONH2FFClONHFFScheme 4137Carbon-Carbon Bond Formations Lithium cyanide as nucleophiles Limitation: primary alcohols and sterically unencumbered secondary substratesROHLiCN orOHCNPh3P, DEADTHF or Et2ORCNSch

22、eme 4238Carbon-Carbon Bond Formations Methanetricarboxylate as nucleophileCO2EtOHH(CO2Et)Ph3P, DEAD, THF56%CO2EtCO2EtEtO2CCO2Et1. 6 N HCl2.CO2HCO2HScheme 4339Carbon-Carbon Bond Formations C-alkylation of monosubstituted Meldrums acidsOOOOOHPh3P, DEAD, THF96%OOOOScheme 4440Carbon-Carbon Bond Formatio

23、ns Preparation of -nitrocyclopropanesOHNO2Ph3P, DEADPhHHNO2HH92%Scheme 4541Carbon-Carbon Bond Formations DHAD and Bu3P were effective for the deprotonation of activated methylene substrates with large pKaNNNNOO(DHTD)R1R2OHnBu3P, PhHPhO2SCNpKa 12.0R1R2SO2PhCNR1R2CO2EtCo2EtR1R2SO2TolSMeEtO2CCO2EtpKa 1

24、3.3TolO2SSMepKa 23.4Scheme 4642Alternative Reagents- Azodicarbonyl PortionDEAD and ADDPThe reactivity : DEAD=DIAD ADDP TMAD DHADH2NNH2H2O1, 2 equiv. ClCO2Et Na2CO32. HNO2, 0 C70%NNEtO2CCO2Et(DEAD)NNNNXXOOADDP, X = CH2Also, X = O, NMeScheme 48NNPhO2CCO2PhNHHNEt3N, DCM, reflux36%HNHNNNOOBr2, DCMpyridi

25、ne89%NNNNOODHTDScheme 4943Alternative Reagents- Trisubstituted PortionPPDPPEPNMe2DAP-DPScheme 50PNPh2P-PyPNNMe2NMe2Me2NTris-DAP44Alternative Reagents- Trisubstituted Portion DPPE: great polarty of the resulting bis-phosphine oxide byproduct.- insoluble, removed by filtration. Bu3PO : water soluble P

26、h2Py: water soluble45Alternative Reagents- Trisubstituted PortionO2NOHNNOOOO+OH1.THF2. HCl workup68%O2NOHNNHOOOO+ CO2 + N2H4(extracts into aqueous)+PN(extracts into aqueous)PN(extracts into aqueous)O+PN(extracts into aqueous)PN(extracts into aqueous)O46Appendix of Abbreviations & Acronyms PNBA - p-Nitrobenzoic Acid DPPA - diphenylphosphoryl azide DEAD - Diethyl Azodicarboxylate DIAD - Diisopropyl Azodicarboxylate DMAD - Dimethyl Azodicarboxylate ADDP - 1,1-(Azodicarbonyl)dipiperidine TMAD - N,N,N,N,-Tetramethylazocarboxamide DHTD - 4,7-Dimethyl-3,5,7-henxahydro-1,2,