Myers Protective Groups – Silicon-Based Protection …

1 RO Sii-Pri-Pri-PrRO SiEtEti-PrRO SiCH3CH3CH3 ROHROHOSiOSiOi-Pri-Pri-Pri-PrRRRO SiCH3CH3t-BuRO SiEtEtEtRO SiCH3CH3i-PrRO SiPhPht-BuORORSit-But-BuChem 115 Protective Groups Silicon-Based Protection of the Hydroxyl GroupMyersGeneral Reference:Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed. John Wiley & Sons: New York, Silyl Ether Protective Groups :Trimethylsilyl (TMS)Triethylsilyl (TES)Triisopropylsilyl (TIPS)Dimethylisopropylsilyl (IPDMS)Diethylisopropylsilyl (DEIPS)t-Butyldimethylsilyl (TBS)t-Butyldiphenylsilyl (TBDPS)Di-t-butyldimethylsilylene (DTBS)Tetraisopropyldisilylene (TIPDS)General methods for the formation of silyl ethers:R'3 SiCl imidazole, DMFROSiR'3 ROSiR'3R'3 SiOTf 2,6 lutidine, CH2Cl2 Corey, E.

2 J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, , E. J.; Cho, H.; R cker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, (CH3)2n-C6H13 OTBSn-C6H13 OSiCH3Ph2n-C6H13 OTIPSn-C6H13 OTBDPS 1 minStable for 24 h 1 minStable for 24 hStable for 24 h 1 min 1 min 1 min14 min55 min225 minSilyl EtherHalf Life(5% NaOH 95% MeOH)Half Life(1% HCl MeOH, 25 C)Davies, J. S.; Higginbotham, L. C. L.; Tremeer, E. J.; Brown, C.; Treadgold, J. Chem. Soc., Perkin Trans . 1 1992, (Oi-Pr)n-C12H25 OSiPh2(Ot-Bu)n-C12H25 OPh(t-Bu)(OCH3) 140 h 375 h< h22 h> 200 h200hSilyl EtherHalf Life Bu4N+F ( M, 6 equiv)Half Life HClO4 ( M)Gillard, ; Fortin, R.

3 ; Morton, H. E.; Yoakim, C.; Quesnell, C. A.; Daignault, S.; Guindon, Y. J. Org. Chem. 1988, 53, 2602. In general, the stability of silyl ethers towards acidic media increases as indicated:TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000) In general, stability towards basic media increases in the following order:TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000) A study comparing alkoxysilyl vs. trialkylsilyl Groups has also been done:P. Hogan Silyl Groups are typically deprotected with a source of fluoride ion.

4 The Si F bond stength is about 30 kcal/mol stronger than the Si O sources:Tetrabutylammonium fluoride, Bu4N+F (TBAF)Pyridine (HF)x Triethylamine trihydrofluoride, Et3N 3 HFHydrofluoric acidTris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)Ammonium fluoride, H4N+F Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed. John Wiley & Sons: New York, Jersey, (IPDMS)Di-t-butylsilylene (DTBS)Tetraisopropyldisiloxanylidene (TIPDS)2,6-lutidine,n-C12H25 OSiPh(t-Bu)(OCH3)1 OHHOOHHOnnOOCH2 OHOHOTIPSHHONCH3OH3 CHHOHCH3 HONOOHOTESHOCH3 OOCH2 HOHHHONCH3OH3 CHHOCH3 HONOOHHOCH3 OOHCH3 OCH3 BrHOOHOHTBSOHOOTBSOHTBDPSOOOOHOHOTIPSONC H3OH3 CHHOHCH3 HONOOTESOTESHOCH3CH2 HHOCH3 OBOMTESOCH3CH3H3 CTBSOOOOHAcOOOCH3 OAcOAcAcOHOOTBSHTBSOAcOCH3CH3H3 COHOBzOONHOOHPhOCH3 OAcOHOHOOHO2 CCH3 OAcOHOOCH3HO2 CHOCO2 HOCH3 OBOMHOCH3CH3H3 CTBSOOOOHAcOOOCH3 OAcOAcAcOHOOHHTBSOTESCl, 2,6-lutidineCH2Cl2, 78 C97%Phorboxazole BEvans, D.

5 A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, , R. A., et al. J. Am. Chem. Soc., 1994, 116, HF, CH3CN0 C, 11 h, Monosilylation of symmetrical diols is possible, and , TBSCl, THF75-97%n = 2-6,10nTBDPSCl, i-Pr2 NEt, DMF, 23 C75-86%n = 2,3,5,7,9nHu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, , ; Rico, ; Oh, Y.; Condon, B. D. J. Org. Chem. 1986, 51, 3388. Selective Protection of alcohols is of great importance in synthesis. Conditions often must be determined empirically. Selective deprotection of silyl ethers is also important, and is also subject to empirical determination.

6 TESCl/imidazole and TESOTf, 2,6-lutidine both gave the bis-silylated Hogan Selective deprotections in organic synthesis have been reviewed: Nelson, T. D.; Crouch, R. D. Synthesis 1996, acidCarreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, , THF; TBSCl88%Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 1983, 49, and TESOTf, 2,6-lutidine both gave the bis-silylated product. OONOCH3 OHCH3 HHH3 CONOOTESOCH3 HOTESOHHOOHHOTIPSHCH2 Phorboxazole BOONOCH3 OCH3 HHH3 CONOOHOCH3 HOHHHOHHCH2 OCH3 OHOCH3 BrTaxolH3 COHOCH3CH3 OBzOHAcOAcOOCH3 OHONHPhOHOH3 CTBSOOCH3CH3 OOHAcOTESOCH3 OBOMOH3 CTBSOOCH3CH3 OOHAcOHOCH3 OBOMOS elective deprotection of silyl ethers is also important, and is also subject to empirical 115 Protective Groups Protection of Hydroxyl Groups , Esters, and CarbonatesMyersEsters and CarbonatesGeneral methods used to form esters and carbonates:P.

7 Hogan/Seth B. HerzonClOROCH3 OROClOROClClOROClClAcetate (Ac)ChloroacetateDichloroacetateTrichlor oacetateCH3 OROOROOROOROT rifluoroacetate (TFA)Pivaloate (Piv)Benzoate (Bz)p-MethoxybenzoateFFFH3 CCH3 OCH3p-BromobenzoateMethyl Carbonate9-(Fluorenylmethyl) Carbonate(Fmoc)Allyl Carbonate(Alloc)OROBrOCH3 OROROROOOOOROROROROROOClClClOOOOCH3CH3CH 3 OOOSi(CH3)3 SNH3 CCH32,2,2-Trichloroethyl Carbonate(Troc)2-(Trimethylsilyl)ethyl Carbonate(Teoc)Benzyl Carbonate (Cbz)t-Butyl Carbonate(Boc)Dimethylthiocarbamate (DMTC)ClR'OROR'OROHpyr, DMAPOR'OROR'OROHpyr, DMAPR'OClOR'OROOR'OROHpyrNNCH3H3 CNNCH3H3 CORX DMAP = 4-Dimethylaminopyridine: Proposed intermediateDMAP is used to accelerate reactions between nucleophiles and activated esters.

8 Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522. In general, the susceptibility of esters to base-catalyzed hydrolysis increases with the acidity of the product <<<<<<3 OAcOAcHOOBnHOOOOClOAcCH3CH3 OHOAcOBnOSnOBuBuPCCOOOClOHCH3CH3 OOAcAcOOBnHOOOOOHOOOH3CH3 CClOOOHCH3CH3 OOOOOOOOOHHOCH3 NHCH3 OOHOCH3CH3n-PrNH2 OOOHOHOOOH3CH3 COCH3 OOHCH3 Acetate Esters: Several methods for forming and cleaving acetate esters have been developed. Lipases can often be used for the enantioselective hydrolysis of acetate esters.

9 The enantioselective hydrolysis of meso diesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases. A potentially general method for selectively acylating the primary hydroxyl group of a 1,2-diol makes use of stannylene acetals as intermediates: Bu2 SnO, toluene, 100 CReview: Hannessian, S.; David, S. Tetrahedron, 1985, 41, Chromophore71% Good selectivity can often be achieved in the selective deprotection of different esters. Lipases can also be effective for deprotection under very mild conditions, as in the case shown below, where conventional methods were M pH buffer28 C, 4 daysSakaki, J.

10 ; Sakoda, H.; Sugita, Y.; Sato, M.; Kaneto, C. Tetrahedron: Asymmetry, 1991, 2, cholinesterase94%, 99% eeDeardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986,27, , A. G.; Liang, J.; Hammond, M.; Wu, Y.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, HoganAcCl,CH2Cl2, 0 CHanessian, S.; David, S. Tetrahedron 1985, 41, potentially general method for selectively acylating the primary hydroxyl group of a 1,2-diol makes use of stannylene acetals as intermediates:4 Summary of methods for deprotecting carbonates: When one Protective group is stable to conditions that cleave another and the converse is also true, these Groups are often said to bear an orthogonal relationship.