PROTECTING GROUPS 57 Smith: Chapter 7

1 PROTECTING GROUPS 57 Carey & Sundberg Chapter # 1; 2; 3a, b, c ;Smith: Chapter 7 PROTECTING Greene & Wuts, Protective GROUPS in Organic Synthesis (2nd edition) J. Wiley & Sons, J. Kocienski, PROTECTING GROUPS , Georg Thieme Verlag, groups2 Ketones and Acids- Protect functional GROUPS which may be incompatible with a set of reactionconditions- 2 step process- must be efficient- Selectivity a. selective protectionb. selective deprotectionHydroxyl PROTECTING GroupsEthersMethyl ethersR-OH R-OMedifficult to remove except for on phenolsFormation:- CH2N2, silica or HBF4- NaH, MeI, THFC leavage:- AlBr3, EtSH- PhSe -- Ph2P -- Me3 SiIOOOBzOMeOOOBzOHAlBr3, EtSHTL 1987, 28 , 3659 Methoxymethyl ether MOMR-OH R-OCH2 OMestable to base and mild acidFormation:- MeOCH2Cl, NaH, THF- MeOCH2Cl, CH2Cl2, iPr2 EtNCleavage- Me2 BBr2TL 1983, 24 , 3969 PROTECTING GROUPS 58 Methoxyethoxymethyl ethers (MEM)R-OH R-OCH2 OCH2CH2 OMestable to base and mild acidFormation.

2 - MeOCH2CH2 OCH2Cl, NaH, THF- MeOCH2CH2 OCH2Cl, CH2Cl2, iPr2 EtNTL 1976, 809 Cleavage- Lewis acids such as ZnBr2, TiCl4, Me2 BBr2OC5H11 MEM-OO-Si(Ph)2tBuBSSClOC5H11 HOO-Si(Ph)2tBuTL 1983, 24 , 3965, 3969- can also be cleaved in the presence of THP ethersMethyl Thiomethyl Ethers(MTM)R-OH R-OCH2 SMeStable to base and mild acidFormation:- MeSCH2Cl, NaH, THFC leavage:- HgCl2, CH3CN/H2O- AgNO3, THF, H2O, baseBenzyloxymethyl Ethers(BOM)R-OH R-OCH2 OCH2 PhStable to acid and baseFormation:- PhOCH2CH2Cl, CH2Cl2, iPr2 EtNCleavage:- H2/ PtO2- Na/ NH3, EtOHTetrahydropyranyl Ether(THP)OOORH + , PhHR-OHStable to base, acid labileFormation- DHP (dihydropyran), pTSA, PhHCleavage:- AcOH, THF, H2O- Amberlyst H-15, MeOHEthoxyethyl ethers (EE)JACS 1979, 101 , 7104; JACS 1974, 96 , + (R-OEE)base stable, acid labileBenzyl Ethers(R-OBn)R-OH R-OCH2 Phstable to acid and baseFormation: - KH, THF, PhCH2Cl- PhCH2OC(=NH)CCl3, F3 CSO3 HJCS P1 1985, 2247 Cleavage:- H2 / PtO2- Li / NH3 PROTECTING GROUPS 592-Napthylmethyl Ethers (NAP)JOC 1998, 63, 4172formation: 2-chloromethylnapthalene, KHcleavage: hydrogenolysisBnOOHOONAPH2, Pd/C(86%)BnOOHOOHp- Methoxybenzyl Ethers(PMB)Formation: - KH, THF, p-MeOPhCH2Cl- p-MeOPhCH2OC(=NH)CCl3, F3 CSO3 HTL 1988, 29 , 4139 Cleavage:- H2 / PtO2- Li / NH3- DDQ- Ce(NH4)2(NO3)6(CAN)- e-o-Nitrobenzyl ethersReview: Synthesis 1980, 1.

3 Organic Photochemistry, 1987, 9 , 225NO2 ClROO2 NNaH, THFR-OHCleavage:- photolysis at 320 nmHOOONO2 HOHOOHHOOOHHOHOOHh , 320 nm, pyrex, H2 OJOC 1972, 37 , 2281, EtherTL 1990, 31 , 389-selective removal with DDQ, hydrogenolysis or elctrochemically9-Phenylxanthyl- (pixyl, px)TL 1998, 39, 1653 ROH +OPhClpyridineOPhORFormation:Removal:OPh ORh (300 nm)CH3CN,H2 OROH +OPhOHTrityl Ethers-CPh3 = TrR-OH R-OCPh3- selective for 1 alcohols- removed with mild acid ; base stableformation:- Ph3C-Cl, pyridine, DMAP- Ph3C+ BF4-Cleavage: - mild acidPROTECTING GROUPS 60 Methoxytrityl EthersJACS 1962, 84 , 430- methoxy group (s) make it easier to removeCORR2R1R3(p-Methoxyphenyl)diphenyl methyl ether4'-methoxytrityl MMTr-ORDi-(p-methoxyphenyl)phenylmethyl ether 4',4'-dimethoxytrityl DMTr-ORTri-(p-methoxyphenyl)methyl ether 4',4',4'-trimethoxytrityl TMTr-ORTr-OR < MMTr-OR < DMTr-OR << TMTr-OROOHNHOOHNOOROOHNHOHOHNOOR = Tr 48 MMTr 2 DMTr 15 TMTr 1 min.

4 (too labile to be useful)20 C80% AcOH (aq)Oligonucleotide Synthesis (phosphoramidite method - Lessinger)Review: Tetrahedron 1992, 48 , 2223 OHOHOHOOOSi(CH2)3NH2 OOOSi(CH2)3 NHC(CH2)2 OCOOHOOOSi(CH2)3 NHC(CH2)2 OCOOPBODMTrOON (iPr)2 BOHOOOB'ODMTrOCNOBOPOOOB'ODMTrOCNOBOPO -OOB'ODMTrOOBOPO -OOB'ODMTrOO -OBOPO -OOB'OHOO -SSSR epeat CycleI2, H2 OCl3 CCOOHBaseScouplingCl3 CCOOHSSILICASILICASILICASILICAPROTECTING GROUPS 61 Silyl EthersSynthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031R-OH R-O-SiR3formation:- R3Si-Cl, pyridine, DMAP- R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP- R3Si-OTf, iPr2 EtN, CH2Cl2 Trimethylsilyl ethersMe3Si-ORTMS-OR- very acid and water labile- useful for transiant protectionTriethylsilyl ethersEt3Si-OR TES-OR- considerably more stable that TMS- can be selectively removed in the presence of more robust silyl ethers with with F- ormild acidOTBSTESOOH2O/ACOH/THF(3:5:11), 15 hrOOTBSOH(97%)Liebigs Ann.

5 Chem. 1986, 1281 Triisopropylsilyl ethersiPr3Si-ORTIPS-OR- more stabile to hydrolysis than TMSP henyldimethylsilyl ethersJ. Org. Chem. 1987, 52 , 165t-Butyldimethylsilyl EthertBuMe2Si-ORTBS-ORTBDMS-ORJACS 1972, 94 , 6190- Stable to base and mild acid - under controlled condition is selective for 1 alcoholst-butyldimethylsilyl triflatetBuMe2Si-OTfTL 1981, 22 , 3455- very reactive silylating reagent, will silylate 2 alcoholscleavage:- acid - F- (HF, nBu4NF, CsF, KF)OTBSOCO2 MeOTBSHF, CH3 CNOHOCO2 MeHO(70%)JCS Perkin Trans. 1 1981, 2055t-Butyldiphenylsilyl EthertBuPh2Si-ORTBDPS-OR -OR- stable to acid and base- selective for 1 alcohols- Me3Si- and iPr3Si GROUPS can be selectively removed in the presence of TBS or TBS can be selectively removed in the presence of TBDPS by acid 1989, 30 , 19 PROTECTING GROUPS 62cleavage- F-- Fluoride sources:- nBu4NF (basic reagent)- HF / H2O /CH3 CNTL 1979, HF pyridineSynthesis 1986, 453- SiF4.

6 CH2Cl2TL 1992, 33 , 2289 SiPhPhtBuOOSitBuMeMeSiPhPhtBuOHOOTHPOtBu MeMeSiOHOtBuMeMeSiJACS 1984, 106 , 3748 PPTS / EtOHJOC 1981, 46 ,1506TL 1989, 30 , / THF/ H2 OEstersR-OH R-O2CR'Formation:- "activated acid ", base, solvent, (DMAP)Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, "activated acid " carboxylic acid derivative (ester, amide, etc.) acid ChloridesRClOROHONNRNONRNON+acyl pyridinium ion (more reactive)+1. SOCl22. PCl53. (COCl)2 AnhydridesROOROROHO2P2O5 Activating Agents:Carbonyl DiimidazoleROHONNONNRNONNNH + CO +Acyl Imidazole+ PROTECTING GROUPS 63 DicyclohexylcarbodiimideNCNROHOROOCNC6H1 1C6H11 RNHNuOC6H11 NHNHC6H11O+Nu:+Ketene formation is a common side reaction- scambling of chiral centersOOCNC6H11C6H11 NHRHRCO"ketene"Hydroxybenzotriazole (HOBT) - reduces ketene formationROOCNC6H11C6H11 NHNNNOHROONNN+N-Hydroxysuccinimide (NHS)ROOCNC6H11C6H11 NHNOOHOROONOO+2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent)Aldrichimica Acta 1971, 4 , 33 ROHONSSNRSONNSHPh3P=O++Ph3P:+Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1-methyl pyridinium p-toulenesulfonate)Aldrichimica Acta 1987, 20 , 54 Chem.

7 Lett. 1975, 1045; 1159; 1976, 49; 1977, 575 ROHONMeFROONMeI -+TsO -++AcetatesR-OH R-O2 CCH3- stable to acid and mild base- not compatable with strong base or strong nucleophiles such as organometallicreagentsFormation:- acetic anhydride, pyridine- acetyl chloride, pyridinePROTECTING GROUPS 64 Cleavage:- K2CO3, MeOH, reflux- KCN, EtOH, reflux- NH3, MeOH- LiOH, THF, H2O- enzymatic hydrolysis (Lipase)Org. Rxns. 1989, 37, 1988, 30 , 6189(96% ee)Porcine Pancreatic LipaseChloroacetates- can be selectively cleaved with Zn dust or CC 1987, 1026H2 NNHCOSHT rifluoroacetatesFormation: - with trifluoroacetic anhydride or trifluoroacetyl chlorideCleavage:- K2CO3, MeOHPivaloate (t-butyl ester)- Fairly selective for primary alcoholsFormation:- tbutylacetyl chloride or t-butylacetic anhydrideCleavage:- removed with mild baseBenzoate(Bz)- more stable to hydrolysis than :- benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) ,benzoyl tetrazole (TL 1997, 38, 8811)Cleavage:- mild base- KCN, MeOH, reflux1,2 and 1,3- DiolsSynthesis 1981, 501 Chem.

8 Rev. 1974, 74, 581RR1 OHOHR2 OOR3OR2R3RR1H+, -H2 OIsopropylidenes(acetonides)RR1 OHOHOMeOOMeMeRR1 OMeOMeoracetone orH+- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored- cleaved with mild aqueous acidPROTECTING GROUPS 65 Cycloalkylidene Ketals- Cyclopentylidene are slightly easier to cleave than acetonides- Cyclohexylidenes are slightly harder to cleave than acetonidesRR1 OHOHOOO(CH2)nRR1(CH2)nMeO(CH2)nOMe-or-H+ , -H2 OBenzylidene AcetalsRR1 OHOHPhOORR1 PhCHO -or- PhCH(OMe)2H+, -H2O- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usuallyfavored- benzylidenes can be removed by acid hydrolysis or hydrogenolysis- benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or hydrolyzed about 10X faster than regular benzylidenes- Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN)OBnOMeOOOOBnOMeOBnOMeOOHOHOBn(95%)C e(NH4)2(NO3)6CH3CN, H2 OOther Reactions of Benzylidenes- Reaction with NBS(Hanessian Reaction)OOOHOOMeHOPhHBrOOHOOMeHOPhOOrg.

9 Syn. 1987, 65, 243 NBS, CCl4- if benzylidene of a 1 alcohol, then 1 bromide- Reductive CleavageOOMeO2 CPhMeO2 CCO2 MeCO2 MeOHOBnNa(CN)BH3, TiCl4,CH3 CNSynthesis 1988, 1985, 41, 3867 TMS-CNBF3 OEt2 PROTECTING GROUPS 66 OOPhOOMeBnOOHOOMeTL 1988, 29 , 4085 DIBAL-HCarbonatesRR1 OHOHOOORR1(Im)2CO- stable to acid ; removed with base- more difficult to hydrolyze than estersDi-t-Butylsilylene(DTBS)TL 1981, 22 , 4999- used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed- cleaved with fluoride (HF, CH3CN -or- Bu4NF -or- HF pyridine)- will not fuctionalize a 3 -alcoholOHOHOOSitButBu(t-Bu)2 SiCl2, Et3 NCH3CN, HOBT1,3-(1,1,3,3)-tetraisopropyldisiloxa nylidene(TIPDS)TL 1988, 29 , 1561- specific for 1,3- and 1,4-diols- cleaved with fluoride or TMS-IOOHNHOHOHNOOOOHNOOHNOOSiOSi iPr2Si(Cl)-O-Si(Cl)iPr2 pyridineKetones and Aldehydes- ketones and aldehydes are protected as cyclic and acyclic ketals and acetals- Stable to base.

10 Removed with H3O+RORR1 OMeR1 OMeROR1 OROR1O1,3-dioxanesCH2(CH2OH)2, H+, PhH, -H2O1,3-dioxolanesTL 1980, 21 , 1357 -or- (CH2 OSiMe3)2,TMS-OTf, CH2Cl2(CH2OH)2, H+ PhH, -H2 OMeOH, H+ PROTECTING GROUPS 67 Cleavage rate of substituted 1,3-dioxanes:Chem. Rev. 1967, 67 , >>>- Ketal formation of , -unsaturated carbonyls are usually slower than for thesaturated (CH2OH)2, H+, PhH, -H2 OFluoride cleavable ketal:LiBF4TL 1997, 38, 1873 OOOOMe3 SiOOO(88%)Base cleavable ketal:R1R2 OHOOHSO2 PhpTSA, C6H6 OOSO2 PhR1R2 DBU, CH2Cl2R1R2 OTL 1998, 39, 2401 Carboxylic AcidsTetrahedron 1980, 36, 1993, 49, 3691 Nucelophilic Ester Cleavage:Organic Reactions 1976, 24, Estersformation:- Fisher esterification (RCOOH +R'OH + H+)- acid Chloride + R-OH, pyridine- t-butyl esters: isobutylene and acid - methyl esters: diazomethaneCleavage:- LiOH, THF, H2O- enzymatic hydrolysisOrg.