Protecting Groups in Organic Synthesis-1 Ready

1 Protecting Groups in Organic Synthesis-1 ReadyProtecting Groups are a sad fact of synthetic chemistryThey are usually needed, but rarely desiredMany syntheses have stalled because of trouble putting on or removing Protecting groups4 basic questions to address when choosing a :1. Can I put it on where and only where I want?2. Can I take it and only it off?3. Will it survive all future reaction conditions?4. Will it affect the reactivity of my substrate?Your guide to these questions should be: Protective Groups in Organic synthesis by Theodora Greene and Peter WutsAn even better strategy is to plan your syntheses to avoid Protecting groupsProtecting Groups for Alcohols4 major classes: silyl ethers, ethers, esters, acetalsSilyl EthersSiOTMSSiOTESSiOTBS or TBDMSTBS: Corey, JACS, 1972, 6190 (23rd most cited JACS paper)SiOSiOTIPSTBDPSON:OHR3 SiCl, ImidazoleDMFWe will discuss general features of Protecting Groups ,for specific examples and exotic methods for attachment or removal, see GreeneOSiR3 NNHR3Si+viaOHR3 SiOTf2,6-lutidine, CH2Cl2 OSiR3 These transformations are very water Groups in Organic synthesis -2 ReadyBrook RearrangementbondBDE (kcal/mol)CSiOSiFSi69103141question: using approx.

2 PKa values and the BDE above, estimate Keq for different R's in the equation , 1998, 5243 OOSiMe2tBuLiOSiMe2tBuLiOOTBSOLi1/2 , JACS, 2002, 11290 Other potential methods:Hydrosilylation of ketones: always some stupid silyl groupTamao oxidation of alkyl silanes: Silyl group rarely survivesLess Common methods for Silyl introduction: Protecting Groups in Organic synthesis - 3 Readysilyl migrations -smaller is faster -1,2 and 1,3 most common -good if planned; usually not plannedOHOTBSOOHOHDBU83%OTBSOHOOHOHNote: 2 primary alcohols would make selective protection difficultMolander, JOC1994, 7148 OHTBDPSOOBn>95%eeNaHC15H31 BrOC16H33 TBDPSOOBn0% eeWelzel, Tet, 1987, 3803 Migrations likely via associative displacement:-OOSiR3 OOSi-pentavalent intermediateO-R3 SiOhow does this happen?RemovalUsually F- or H+Usually, bigger is more stableROSiR3 ROHOH- or H+Silyl groupkrel H+krel -OHTMS5,000,000500,000 TES100,00050,000-5,000 TBDMS2505 TIPS105 TBDPS11 Recall BDE: O-Si (~100 kcal/mol) vs F-Si (~140 kcal/mol)Common F- sources:TBAF (nBu4NF)HF-Pyridine3HF-Et9 NHFTASF [tris(dimethylamino)sulfonium difluorotrimethylsilicate]FSiCH3H3 CFCH3 NMe2 SNMe2Me2 NProtecting Groups in Organic synthesis -3 ReadySelective cleavage (review: synthesis , 1996, 1065)OPivTESOOTBDMS2% HF, CH3 CNOPivOHOTBDMSM asamune, TL, 1985, 5239 Commercial TBAF is wet (to varying degrees).

3 Dry TBAF is very basic; may need buffer:OOROROORR = TBSR = HTBAFAcOH,7d, 37%relative rates of Fluoride-induced cleavage:Silyl group1/2 lifeTBSTIPStHexDMSTBDPSTPS20 min15 min15 min50 often need to be determined empiricallyCarreira, Du Bois JACS, 1995, 8106 OOOHCO2tBuTBSOAcOOAcPhOAcCH3HF-PyridineC H3 CNOOOHCO2tBuHOAcOOAcPhOAcCH31 HFCl3CO2 HHF-Et3 NTBAFOOOHCO2tBuAcOHOOAcPhOAcCH3+190%Prot ecting Groups in Organic synthesis -5 ReadyEthersusually very robust, with orthogonal modes of removalusually:ROHR' LG+ROR'common ethers:Methyl ether: easy on, hard off. Usually only good for phenolsOn: MeI, Me2SO4, Me3O BF4 Off: BBr3, TMSI,Benzyl ether (Bn)On: usually BnCl + base; somtimes with cat. I- (do you know what I- does?)Off: H2, Pd/C - competitive (usually slower) than olefin reductionLewis Acid: SN1 mechanismNa/NH3 OROR_HOR2e-, H+CrO3: via benzoateORORHORCrO3-OHOallyl etheron: usually allyl Br/Cl + base.

4 Usually easyOOOHHOHOOHHOOOPhBu2 SnOOOOHHOOOHOOOPhSnBuBu"stanylene acetal"BrOOOHHOOOHHOOOPh95%Ogawa, TL, 1988, 4097 This is a general method for monprotection of a 1,2 diol (not limited to allyl). In this case, note selective formation with equitorial OH' : Isomerization with base or transition metal, then hydrolysis:ROB- or MROROHH3O+ Protecting Groups in Organic synthesis -6 Readyp-methoxybenzyl (PMB or MPM)OOROn: PMB-Cl, baseOONHCF3 ROH+H+ or Lewis AcidOOR+ONH2F3 COff: OxidationOOROOR+H2 OOOROH+[O] = DDQ, CAN, Ph3C BF4, Br2, NBS[O]intermediate can be intercepted:HOPMBOOHDDQHOOOHOMeHOOOOMeHo ffman, ACIEE, 1993, 101+o-nitrobenzylOff: h ORNOOORNOOh H1,5 H abstractionORNOOHH2 OHORT riphenyl Methyl (trityl)On: Ph3 CCl, via SN1 Off: AcidORexample:Wen-Hong Li, JACS, 2004, 4653 OOClOHNONCO2-CO2-NO2O-OClOHNONCO2-CO2-pK a ArOH = nm h non-fluorescentfluorescentProtecting Groups in Organic synthesis -7 Readyacetalsacetals of mono-ols:many eg's of the formOROR'advantages.

5 ClOR'very active electrophilelikely formsOR'+Methoxy Methyl (MOM)On:ClO'MOM-Cl' thought to be very toxic even more toxicOff: AcidClOClBenzyloxy methyl (BOM)On:ClOPhOff: all the methods for removing Bn Groups :OOPhOTESLi/NH3 OOHOTESOHOTESM asamune, TL, 1985, 5239 OTetrahydropyranyl (THP)ROH+H+OOREasy on, easy off, get diastereomers with chiral molecues:HNPhHOOOHcan complicate NMR spectra (and sometimes chromatography) Protecting Groups in Organic synthesis -8 Readyacetal protection of diolsCyclic acetal are wonderful Protecting Groups for 1,2 and 1,3 of the most common:OOOOOOOO'acetonide'most stableleast stableUsually, 1,2 >1,3>1,4 HOOHOHOHHOOOOO5:1On:OMeMeOCat. H+OMecat. H+orwhy not acetone + H+? Hint: Consider pKa's of protonated ketones vs ethersOHOHOOHOHHOOM ecat. TsOHOHOHOOOOHH75% , 1978, 4620reactions often under thermodynamic control:OHOOTsOHOOHHO1:10 OHOOTsOHOOHHO>100:1oxonium intermediates can be interceptedCH2 OBnCH2 OBnHHOOMe3 AlCH2 OBnCH2 OBnHHOtBuOHTL 1988, 1823 Protecting Groups in Organic synthesis -9 Readybenzylidene acetalsOOPhOn: PhCHO/H+ or Lewis acidOff: H3O+ or H2 Pd/CCan be converted to benzyl:OOOPPhiBu2 AlH>20:1 OOHOPBnCO2 MeMeO2 Cdo you know how?

6 X-rayOOPhHHMeOPHHAlR2 OOPhHHMeOPHAlR2 HHHHOOHOPBnSchreiber, TL, 1988, 4085. Usually see protection of less hindered OHFor protection of more hindered OH by a similar reaction, see Yamamoto, TL, 1988, 1947-1950 Protecting Groups in Organic synthesis -10 Readydiols can be protected as diacetals:OOOOOHHOOHOHOHOOCSA, CH(OMe)3 MeOHOHOMeOMeOHOMeLey, Perkin 1, 1997, 2023 Esters as Protecting groupsIn general, ease of introduction and removal isfu ncti on of sterics and electr onicsusually:ROH+OLGR'ROOR'egsOClR'OOR'R 'OOOR'OClClCl'Yamaguchi conditions'more often for macr olactonizationsinsitugeneratedactiveeste rOOHR+R'OHROOR'NNR""Rca rbodiimides:OORNNHR"R''+ONHR""RHNviarxn is 'self-drying'removal of urea can be troublemost common egs:NNNNNNDIC - li quid at rt,easy to use on small scaleDCC - mp=34oCre ported sensitizerincreased solubilityNEDCI - canextract ureawith acidBOP-Cl:OOHR+R'OHROOR'ONPONOOClOEt3 Nsynthesis, 1980, 547 Include CH2N2 Include CH2N2 Protecting Groups in Organic synthesis - 11 ReadyCleavage: base hydrolysis rates depend on sterics and electronicsstability to baseOOROORMeOOOROOROORClOORF3 CPivBzAcTFAmore stableless stableLipases: ester (usually Ac) on or off under mild conditions; often enantioselectivelyOOOOOHOHAc2 OLipaseOOOOOAcOHOOOOOHOH44%, 100%ee54%, 88%eekinetic resolution(rac)-TL, 1992, 1911desymmetrizationOAcOAclipaseOHOAc96% eefor references, see Greene, 3rd Groups in Organic synthesis -12 ReadyCarbonatessimilar deal as with esters, but more stable to base.

7 Also, some alternative cleavage methods Et3N, T1/2=20minBOOROClClClTrocZn(0)OOROZnClCl ClOOROTeocSiMe3 OOROSiMe3 OOROSiMe3orLALA=lewis acidF-OOROA lloccat Pd(0)PdIINuHNuHNu+ ROH + CO2 Dimethyl Thiocarbamateon:OHRNaH;SMe2 NClorNNSNN; Me2 NHSRONMe2 SRONMe2stable to:Cr(VI); EtMgBr; DIBAL; LiAlH4; BH3; nBuLi; Wittig; TBAF; DDQ; TiCl4 SRONMe2 OFF:NaIO4 SRONMe2OH+H2 OROHor NaOH/H2O2 Falck, Org. Lett., 2003,4755pKa ~ 10 Protecting Groups in Organic synthesis -13 ReadyProtection for carboxylateMostly, same deal as ester and carbonatecommon Eg'sOOMeROOR protected substratedeprotectionCF3K2CO3/MeOHOORH+ (TFA, HCl, TsOH)OORPd(0), NuHOORPhH2 Pd/C or Li/NH3as before, enzymes can workOMeOOMeOPLE96%eeOHOOMeOPLE = pig liver esteraseWhen enzymes work, they're nearly to get ent-PLEortho esters: not electophilic, no acidic protonsHOOHOH+OOEtEtOKOH, OHOROHO various waysROOOOOROBF3 Et2 Ostep 1step 2egOOOBr1.

8 BF3 Et2O2. PPh33. KN(TMS)3 OOOPh3 PCHOHHCO2 MeHHCO2 MeOOO1. LiAlH42. o-NO2C6H4 SeCNBu3P3. mCPBAHOOOHOOOHHOcat NaOHHHCO2 HCorey, TL 1983, 5571 Corey, JACS, 1985, 4339 Protecting Groups in Organic synthesis -14 ReadyProtection for aminesMostly carbamates; same deal as ester and carbonateGroupRemovalOOMeR2 NOn:R2 NHOOROOROClOROOORONOO-OSu+OORONNNOBtOORO FFFFFNaOH; PrSLiOOR2 Namine base (piperidine most common)FmocOOR2 NCCl3 TrocZn(0)GroupRemovalOOR2 NBocacid (TFA most common)OOR2 NSiMe3 TeocF- (TBAF most common)OOR2 NallocPd(0), NuHOOOOM eldrum's acid; common NuHOOR2 NPhCbzH2, Pd/C; Na/NH3 OCF3R2 NTFANaOHProtecting Groups in Organic synthesis - 15 ReadyBenzyl Groups for amine protectionOn:RNH2+ BnClRNHBnRNBn2 RNBn3Cl-++simple alkylation can be difficultRNH2 RNHPhORNHPhLiAlH4 BzCl2 step methodreductive aminationRNH2+OPhAcOH, NaCNBH3 RNHPhSchiff's bases: Many examples, benzhydryl one of most commonRNH2 OPhPh+H+ -H2OH+ +H2 ORNPhPhSulfonatesTosyl: Easy on (TsCl); can be difficult to removeNosyl (Ns) nice alternative:C8H17 HNCO2 MeSOONOONsNHOBrNs35 DEAD, aromatic substitutionC8H17 NHHNHNONH-3 SO2-3 RSArReview: FukuyamaChem Comm.

9 2004, 353 Protecting Groups in Organic synthesis -16 ReadyProtection of carbonyl groupmostly of the form:XYX and Y = OR, SR, NR, CNMost common:RRMeOOMedimethyl acetalRRMeSSMedimethyl thioacetalRROO1,3 dioxaneRRSS1,3 dithianeRROO1,3 dioxolaneRRSS1,3 dithiolaneacetals:Formation:(CH2)nHOOH+k etoneTsOH or HClrelative rates: for the ketone, relative rates same as normal addition to carbonyls: aldehyde>acylic ketone~cyclohexanone>cyclpentanone>enone >>aromatic ketoneOHOH>HOOH>OHOHC leavage: usually hydrolysis or rate usually follows cation (oxonium) stabilityMany variations on this theme; in practice, consult GreeneOOOOHOOHPPTS, acetoneH2O, O100%OOOO1M HCl71%OOOD ithioacetalsCNOOMeMeOHSSHBF3-Et2 Omost common conditionsother lewis acids work, tooCNMeOSS90%MeOOther Offs: Sulfur-loving metals (HgII), [O] (IBX, NBS, I2)MeOSSMeOCO2 EtCH3 IMeOH, H2 OMeOMeOCO2 EtOWeinreb, JOC, 1978, 4172