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1、Protective Groups in SyntheticOrganic ChemistryOOOMeMeOPMBXXOTBSLecture NotesKey TextsP. J. Kocienski, Protecting Groups (2nd Edition), 1994,Georg Thieme Verlag: Stuttgart, p. 260.P. J. Kocienski, Protecting Groups (3rd Edition), 2004,Georg Thieme: Stuttgart, p. 679.T. W. Greene, P. G. M. Wutz, Prot
2、ective Groups in Organic Synthesis (3rd Edition), 1999,John Wiley and Sons: New York, p. 779.Key ReviewsSelective Deprotections: T. D. Nelson, R. D. Crouch, Synthesis 1996, 1065.Protective Groups:Background and General ConsiderationsProtection is a principle, not an expedient Benjamin Disraeli, Brit
3、ish Prime Minister, 1845Like death and taxes, protecting groups have becomea consecrated obstruction which we cannot elude Peter Kocienski, Organic ChemistEvery protecting group adds at least one, if not two steps to a synthesisThey only detract from the overall efficiency and beauty of a route, but
4、, without them,there are certainly transformations which we would not be able to do at all.Remember:Protective Groups:Temporary ProtectionTemporary protection involves the ideal for protecting groups when they are required:the protection step, desired reaction, and deprotection all occur in the same
5、 pot.MeOOOOTHF, -40 CMeOOOOLiNPhMeLiNPhMeMeOOOHOLiLiaqueouswork-upProtective Groups:Background and General ConsiderationsTactical considerations to consider for each protecting group selected in a synthesis:It should be easily and efficiently introduced.It should be cheap and readily available.It sh
6、ould be easy to characterize and avoid the introduction of new stereogenic centers.It should not afford so many spectroscopic signals that it hides key resonances for the substrate.It should be stable to chromatography.It should be stable to a wide range of reaction conditions.It should be removed s
7、electively and efficiently under highly specific conditions.The by-products of deprotection shoud be easily separated from the substrate.Protective Groups:Something to be Very Carefully ConsideredOHNNHOOHNONHOMeOMeMeOOTBSONHMeO2COClClOMeOTBSOMeMeNMeHONHDdmHNOBocOHNNHOOHNONHOHOHHOOHONHHO2COClClOHOHOM
8、eMeHNMeHONH2HNOvancomycin aglycon(62% overall)Global deprotections1. HFpy/py, THF, 025 C, 12 h2. AlBr3, EtSH/CH2Cl2 (1:1), 25 C, 4 hK. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2708.Protective Groups:Orthogonal Sets of Protecting GroupsOrthogonal Set = a groups of protecting groups
9、 whose removal is accomplished in any order with reagents and conditions that do not affect protecting groups in any other orthogonal set.OOBzOAcHPvOTESOMeMeMeTBDPSOTBSOMeOrthogonalSet #1OrthogonalSet #2In practice this concept is incredibly difficult to reduce to practice, but it is a useful framew
10、ork and organizing principle to think about protecting group regimes for a complex molecule synthesis.Protective Groups:Orthogonal Sets of Protecting Groups1. Cleavage by basic solvolysisROOMeROHOHROOMeROOROOROOClClClClClCl176016,000100,000krelProtective Groups:Orthogonal Sets of Protecting Groups1.
11、 Cleavage by basic solvolysis2. Cleavage by acidic hydrolysisROOMeROHOHROOMeROOROOROOClClClClClCl176016,000100,000krelOOOHHOHOOROOMeRROther groups easily cleaved by acidProtective Groups:Orthogonal Sets of Protecting Groups3. Cleavage by heavy metalsSSHgCl2OProtective Groups:Orthogonal Sets of Prote
12、cting Groups3. Cleavage by heavy metals4. Cleavage by fluorideSSHgCl2OSiMeMeMeROMeMeSiMeMeMeROMeMen-Bu4NFFH2OROH-t-BuMe2SiFStrength of Si-F bond is 810 kJ/mol while Si-O bond is 530 kJ/molRO n-Bu4Nn-Bu4NProtective Groups:Orthogonal Sets of Protecting Groups5. Reductive EliminationOROOTroc = trichlor
13、oethoxycarbonylZn, AcOHROHClClClOROOZnClClClHClCl-CO2Protective Groups:Orthogonal Sets of Protecting Groups5. Reductive Elimination6. -eliminationOROOTroc = trichloroethoxycarbonylZn, AcOHROHClClClOROOZnClClClHClCl-OR2NOOR2NOR2NH2-CO2Fmoc = 9-fluorenylmethylcarbamate+-CO2MildbaseProtective Groups:Or
14、thogonal Sets of Protecting Groups7. HydrogenolysisORH2, Pd/C+ROHOORRPhOther examples of cleavable groupsbenzyl etherProtective Groups:Orthogonal Sets of Protecting Groups7. Hydrogenolysis8. OxidationORH2, Pd/C+ROHOORRPhORDDQ or CAN,THF/H2O+ROHMeOOOCNCNClClOxidation viaSingle-electrontransferOMeOOth
15、er examples of cleavable groupsDDQbenzyl etherp-methoxybenzyletherProtective Groups:Orthogonal Sets of Protecting Groups9. Dissolving Metal ReductionORLi/NH3,t-BuOH+ROHOOROnly other protecting group applicable to these conditionsProtective Groups:Orthogonal Sets of Protecting Groups9. Dissolving Met
16、al Reduction10. Transition Metal Catalysis (i.e. Allyl-based protecting groups)ORLi/NH3,t-BuOH+ROHOORROPd,morpholineor dimedoneCan also use (Ph3P)3RhCl and acidROHROPdL2Only other protecting group applicable to these conditionsProtective Groups:Orthogonal Sets of Protecting Groups11. LightNO2ORh NOO
17、ROHNO2OOORNO2OORalcohol PGacid PG+Protective Groups:Orthogonal Sets of Protecting Groups11. Light12. EnzymesNO2ORh NOOROHNO2OOORNO2OORalcohol PGacid PGOONHFmocOOOMeAcHNOAcAcOAcOOONHFmocOHAcHNOAcAcOAcOOONHFmocOOOMeAcHNOHHOHOwheat germ lipasepapaincysteinebuffer+Protective Groups:Relay DeprotectionOSO
18、2PhMeMeMeOMeOMeOClMeOSO2PhMeMeMeOMeOMeOSO2PhMe1. NaSPh2. mCPBANaBH4OHSO2PhMeMeMeOMeOMeOHMeRelay deprotection: when a protecting group that is stable under most conditions is transformed chemically into a new, and more labile, protecting group.Protective Groups:Mutual ProtectionUne pierre, deux oisea
19、uxZwei Fleigen mit einer Klappe schlagenTo kill two birds with one stoneMeNCHOTBSOHMeMeNCOTBSOHMepyHBr3pyridineBrOHMeBrOOHOHOCO2MeOHHOHMeOOHOHOCO2MeOHZn,AcOH(96%)(96%)B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131.Protective Groups:Sometimes Not-So-Innocent BystandersOOOTsOTsNaCN,DMSO
20、80 COOOTsCNOONCProtective Groups:Sometimes Not-So-Innocent BystandersOOOTsOTsNaCN,DMSO80 COOOTsCNOONCOOMeMeOOOMeMeOBr3BOOMeBrOMeOBBr3BrHydroxyl Protecting Groups:Silyl EthersRO SiMeMeMeRO SiEtEtEtRO SiMeMet-BuRO Sii-Pri-Pri-PrRO SiPhPht-Butrimethylsilyl(TMS)triethylsilyl(TES)t-butyldimethylsilyl(TBS
21、 or TBDMS)t-butyldiphenylsilyl(TBDPS)triisopropylsilyl(TIPS)Hydroxyl Protecting Groups:Silyl EthersRO SiMeMeMeRO SiEtEtEtRO SiMeMet-BuRO Sii-Pri-Pri-PrRO SiPhPht-Butrimethylsilyl(TMS)triethylsilyl(TES)t-butyldimethylsilyl(TBS or TBDMS)t-butyldiphenylsilyl(TBDPS)triisopropylsilyl(TIPS)Relative Acid S
22、tability16420,000700,0005,000,000Relative Base Stability110 - 10020,00020,000100,000(t1/2 in 5% NaOH/MeOH)( 24 h)( 24 h)( 24 h)(t1/2 in 1% HCl/MeOH)(1 min)(1 min)(1 min)(255 min)(55 min)Hydroxyl Protecting Groups:Silyl EthersFormation:RROHR3SiCl,imidazole, DMFRROSiR3or R3SiOTf,2,6-lutidine,CH2Cl2Cle
23、avage:RROHFluoride sourceRROSiR3Common Fluoride SourcesHF3HFNEt3HFpyrn-Bu4NF (TBAF)/AcOHHFpyr/pyrn-Bu4NF (TBAF)Hydroxyl Protecting Groups:Silyl EthersSelective Monosilylation of Diols is Possible:NaH (1 eq),THF; TBSCl,or n-BuLi (1 eq),THF; TBSCl,HOOHHOOTBSONOOHTESOMeOMeOHONOOOMeMeOOHOTIPSONOOTESTESO
24、MeOMeOHONOOOMeMeOOHOTIPSTESCl,2,6-lutidine,CH2Cl2,-78 C(97%)TESCl/imid and TESOTf/2,6-lutidine gave bis-silylated productD. A. Evans, D. M. Fitch, Angew. Chem. Int. Ed. 2000, 39, 2536.Hydroxyl Protecting Groups:Silyl EthersSelective Deprotection of Silyl Ethers is Also Possible:R. A. Holton and co-w
25、orkers, J. Am. Chem. Soc. 1994, 116, 1599.OOHOOAcHBzOAcOMeMeMeHOONHPhOOHPhOMeTaxolOOBOMOAcHOHOMeMeMeOTBSOMeOOOBOMOAcHOTESOMeMeMeOTBSOMeOHFpyr, CH3CN,0 C, 11 h(100%)Hydroxyl Protecting Groups:Silyl EthersSelective Deprotection of Silyl Ethers is Also Possible:E. M. Carreira, J. DuBois, J. Am. Chem. S
26、oc. 1995, 117, 8106.OOCO2HOHHO2CHO2COHOOOAcMezaragozic acidMeOOOHOAcAcOOAcMeOTBSTBSOOOOHOAcAcOOAcMeOHTBSOCl2CHCO2HHydroxyl Protecting Groups:Esters and CarbonatesROOMeROOROOROOROOROOROOROOacetate (Ac)ClClClClClClchloroacetatedichloroacetatetrichloroacetateFFFtrifluoroacetateMeMeMepivaloate (Pv)OMebe
27、nzoate (Bz)p-methoxybenzoateHydroxyl Protecting Groups:Esters and CarbonatesROOMeROOROOROOROOROOROOacetate (Ac)ClClClClCldichloroacetatetrichloroacetateFFFtrifluoroacetateMeMeMepivaloate (Pv)OMebenzoate (Bz)p-methoxybenzoateIn general, the ease with which esters hydrolyze under basic conditions incr
28、eases withthe acidity of the product acid. Sterics also can play a role (i.e. pivaloate group)ROCarbonyl Protecting GroupsRates of formation:HOOHMe MeHOOHHOOHOORROORRRates of cleavage:OORRMeMeOORRMeOORRkrel50,0005,0001M. Ohno and co-workers, Tetrahedron Lett. 1982, 23, 1087.Carbonyl Protecting Group
29、sMeOOHOOHp-TsOHMeOOO(95%)Carbonyl Protecting GroupsMeOOHOOHp-TsOHMeOOO(95%)MeOMeOOMeOOHOOHacidfumaric acid (pKa = 3.03)phthalic acid (pKa = 2.89)oxalic acid (pKa = 1.23)p-TsOH (pKa 1.0)1007080003020100+Carbonyl Protecting GroupsRRSMeMeSRRSSRRSSdimethyl thioacetal1,3-dithiane1,2-dithiolaneRRNC ORcyan
30、ohydrindeprotected with Hg, NBS, IBXCarbonyl Protecting GroupsRRSMeMeSRRSSRRSSdimethyl thioacetal1,3-dithiane1,2-dithiolaneRRNC ORcyanohydrindeprotected with Hg, NBS, IBXRSSRNC ORbaseRSSRNC OR RXRSSRNC ORRROUmpolung = formal reversal of thepolarity of a functional groupThese groups turnaldehydes int
31、o nucleophilesSpecial uses for these protecting groups:orororCarboxylic Acid Protecting GroupsROMeROOmethyl estert-butyl esterallyl esterOMep-methoxybenzyl esterMeRObenzyl esterRsilyl estermust be TBS, TBDPS,or TIPS if you wantto purify by chromatographyOOMeMeOOOROOROSiR3RORORORortho esterAmine Prot
32、ecting GroupsR2NOOMemethyl carbamate9-(fluorenylmethyl)carbamate (Fmoc)allyl carbamate (Alloc)2,2,2-trichloroacetylcarbamate (Troc)2-(trimethylsilyl)ethyl carbamate (Teoc)benzyl carbamate (Cbz)R2NOOR2NOOR2NOOClClClR2NOOR2NOOMeR2NOOSiMe3MeMet-butylcarbamate (Boc)resistant tonucleophilic attackcleaved
33、 by mild basecleaved with Zn/HOAccleaved with fluoridecleaved byhydrogenolysiscleaved with PdR2NR2NProtecting Groups:Putting it all TogetherOTBDPSOTESOTMSMeNHTHPOMeO2COTBDPSMeNBocHOMeO2CO1. Boc2O, Et3N, 4-DMAP, CH2Cl2, 25 C2. AcOH/H2O (19:1), 80 CNaHCO3, DMF, 80 C(83%)(62% overall)OTBDPSHOOHMeNBocHO
34、MeO2Cp-TsCl, n-Bu2SnO,Et3N, CH2Cl2, 25 COTBDPSTsOOHMeNBocHOMeO2C(84%)T. Fukuyama and co-workers, J. Am. Chem. Soc. 2002, 124, 2137.Protective Groups:Sometimes They Really Are Not Needed . . .OMeOHOTBSOMeOMeOMeOMeMeHOMeOMeOPMPOOOMeMeOMeOMeMeOTBSMeOMeOPMPMeOHOOTBSOOOMeOOOMeOHHOMeOMeHO HOMeMeOMeOHOHMeO
35、MeOMeMeMeOHOMeMeHOMeOMeswinholide A1.OClClClClEt3N, toluene,25 C, 2.5 h;4-DMAP,80 C, 15 h2. HF, MeCN, 0 C, 105 min(42% overall)Yamaguchimacrolactonizationand globaldeprotectionWith protecting group present on the other alcohol,dramatically lower yields observedI. Paterson and co-workers, J. Am. Chem
36、. Soc. 1994, 116, 9391.Retrosynthetic Analysis:General Principles and BackgroundMeMeRetrosynthetic Analysis:General Principles and BackgroundMeMeMeMeHydrogenationRetrosynthetic Analysis:General Principles and BackgroundMeMeMeMe+Diels-AlderreactionHydrogenationMeMeRetrosynthetic Analysis:General Prin
37、ciples and BackgroundMeMeMeMeMeMeMeMeOOMeMePOOEtOEtO+Diels-AlderreactionHydrogenationMcMurryCouplingOlefinmetathesisTandemWittigreactionHWEolefinationMeMeRetrosynthetic Analysis:Case Study #1: Epothilone AOOOHHOONSOepothilone ARetrosynthetic Analysis:Case Study #1: Epothilone AOOOHHOONSOepothilone A
38、OOOHHOONSepothilone CEpoxidationRetrosynthetic Analysis:Case Study #1: Epothilone AOOOHHOONSOepothilone AOOOTBSHOONSOOOHHOONSepothilone CEpoxidationOlefin metathesisRetrosynthetic Analysis:Case Study #1: Epothilone AOOOHHOONSOepothilone AOOOTBSHOONSOOOHHOONSepothilone CCO2HHOOEpoxidationEsterificati
39、onOlefin metathesisOTBSOHNSRetrosynthetic Analysis:Case Study #1: Epothilone ACO2HHOOAldolreactionOTBSOHNSCO2HOOH+OTBSOR1CO2HOR2OHR3Retrosynthetic Analysis:Case Study #2: Colombiasin AOOHMeOMeMeHMeHOOHMeOMeHMeHHMeMe12colombiasin Aelisabethin ARetrosynthetic Analysis:Case Study #2: Colombiasin AOOHMe
40、OMeMeHMeHOOHMeOMeHMeHHMeMe12OOHMeOMeHMeHHMe2HOBasecolombiasin Aelisabethin AC-12OxidationC2-C12Alkylation12Retrosynthetic Analysis:Case Study #2: Colombiasin AOOHMeOMeMeHMeHOOHMeOMeMeMeHOOHMeOMeMeHMeMeHOOOHMeOMeHMeHHMeMe12OOHMeOMeHMeHHMe2HOBasecolombiasin Aelisabethin AC1-C9CyclizationC-12OxidationC
41、2-C12AlkylationDehydrationDiels-Alderreaction191212Retrosynthetic Analysis:Case Study #2: Colombiasin Acolombiasin AOOHMeOMeMeHMeHDiels-Alder reaction5DemethylationDeoxygenationOOMeMeOMeMeMeHHO16Retrosynthetic Analysis:Case Study #2: Colombiasin Acolombiasin AOOHMeOMeMeHMeHDiels-Alder reaction5Witti
42、golefinationOMeOMeMeOMeMeMeTBSOH5DemethylationDeoxygenationOOMeMeOMeMeMeHHOOMeOMeMeOMeMeMeTBSOHOMePPh3BrQuinoneformation166HydroborationOxidation67Retrosynthetic Analysis:Case Study #2: Colombiasin AOMeOMeMeOMeMeMeTBSOH56Retrosynthetic Analysis:Case Study #2: Colombiasin AOMeOMeMeOMeMeMeTBSOH5Pd-Cat
43、alyzedallylic alkylationOMeOMeMeOMeMeOOO6MeRetrosynthetic Analysis:Case Study #2: Colombiasin AOMeOMeMeOMeMeMeTBSOH5Pd-Catalyzedallylic alkylationOMeOMeMeOMeMeOOOO-AcylationOMeOMeMeOMeMeOOClO6MeMeRetrosynthetic Analysis:Case Study #2: Colombiasin AOMeOMeMeOMeMeMeTBSOH5Pd-Catalyzedallylic alkylationO
44、MeOMeMeOMeMeOOOO-AcylationOMeOMeMeOMeMeOOClO6MeMeAromatizationandmethylationOOMeMeOMeOHHRetrosynthetic Analysis:Case Study #2: Colombiasin AOMeOMeMeOMeMeMeTBSOH5Pd-Catalyzedallylic alkylationOMeOMeMeOMeMeOOOO-AcylationOMeOMeMeOMeMeOOClO6MeMeAromatizationandmethylationOOMeMeOMeOAsymmetricDiels-Alderr
45、eactionHHOOOMeMeMeTBSO+Retrosynthetic Analysis:General Principles and BackgroundMeOMeONNMeHOOi-PrHMeOMeONNMeOOHOxidativelactonizationMeOMeONMeNH2Oi-PrOOOTMSHH+Never be afraid to add groups to yourmolecule; often, the most impressivesynthetic schemes seek to do thenon-obvious.aspidophytineOne-pot cas
46、cadeG. Stork and co-workers, J. Am. Chem. Soc. 2001, 123, 3239.( )-quinineNOMeNOHHdeoxyquinineNOMeNNOMeNHORRabedisconnectionAlkylationHoffmann-LaRocheoxygenation88Retrosynthetic Analysis:General Principles and BackgroundG. Stork and co-workers, J. Am. Chem. Soc. 2001, 123, 3239.( )-quinineNOMeNOHHde
47、oxyquinineNOMeNNOMeNHORRabedisconnectionAlkylationHoffmann-LaRocheoxygenation88Words of wisdom from Robert Ireland:All too often the most convenient way to a molecule onpaper belies the most efficient synthetic approachRetrosynthetic Analysis:General Principles and BackgroundG. Stork and co-workers,
48、 J. Am. Chem. Soc. 2001, 123, 3239.( )-quinineNOMeNOHHdeoxyquinineNOMeNNOMeNHORRabedisconnectionAlkylationHoffmann-LaRocheoxygenation88NOMeNORSelectivehydridedeliveryHH8NOMeNNOMeNORORWords of wisdom from Robert Ireland:All too often the most convenient way to a molecule onpaper belies the most efficient synthetic approachRetrosynthetic Analysis:General Principles and Background