Protecting Groups (PG) - ETH Zürich

1 Protecting Groups (PG)General Considerations Avoid undesired side reaction PGs have to be Easily introduced and safely removed Stable in reaction conditions Orthogonal Which Groups need protection?If R contains NH2, OH, SH, COOH or other reactive functionalitiesReview: Albericio et al., Chem. Rev., 2009, 109, 24552 Amine PGsMost commonIntroductionFmoc ClBoc2 ORemovalPiperidineTFAS tableAcidic conditions, HydrogenationBasic conditions, HydrogenationOrthogonalBoc, Z, Trt, AllocFmoc, Z, Trt, Alloc3 amino Acids: LysineOther Protecting group : BocAmine PGsIntroduction Cbz2O, Cbz ClAlloc2O, Alloc ClivDde OHRemovalH2Pd(PPh3), PhSiH32% N2H4 StableBasic and Acidic conditionsBasic and Acidic conditionsBasic and Acidic conditions, HydrogenationOrthogonal Boc, Fmoc, TrtBoc, Fmoc, TrtBoc, Fmoc, Z, Trt, Alloc4 For carboxylic acids, Aspartic and Glutamic AcidCarboxylic acid PGsIntroductionIsobuteneTrt ClDmb OH,Dmb ClFm OHBn Cl, Bn2 ORemoval90% TFA 1% TFA in CH2Cl21% TFA in CH2Cl220% Piperidine TFMSA, HF, H2, NaOHStableBasic conditions, HydrogenationBasic conditions, HydrogenationBasic conditions, HydrogenationAcidic Conditions, HydrogenationBasic and AcidicConditionsOrthogonalFmoc, Z, Trt, AllocFmoc, AllocFmoc, AllocBoc, Trt, AllocBoc, Fmoc, Trt.

2 Alloc5 amino Acids: ArginineProtect one or two nitrogen atoms Other Protecting group : BocSide reactions: deguanidilation, lactamizationGuanidinium PGsIntroductionPbf ClRemoval90% TFAS tableBasic conditions,HydrogenationOrthogonalFmoc, Trt, Alloc6 amino Acids: Asparagine and Glutamine Other Protecting group : Trt Often used without protection Prone to dehydrogenation under basic conditionsAmide PGsIntroductionXan OHRemoval90% TFA, scavengersStableBasic conditions, HydrogenationOrthogonalFmoc, Trt, Alloc7 amino Acids: HistidineOther Protecting group : Trt, BocProtection of N decreases basicity of N Prone to racemization: N abstracts H Imidazole PGsIntroductionTs OHBom ClRemovalHFHF, TFMSA TFAS tableAcidic conditions Basic conditionsOrthogonalBoc, TrtBoc, Fmoc, Trt8 amino Acids: TryptophanOther Protecting group : BocSide reaction: DimerizationIndole PGsIntroduction ParaformaldehydeRemovalHF, PiperidineStableAcidic conditionsOrthogonalBoc9 amino Acids: Serine, Threonine, Hydroxyproline, TyrosineOther Protecting Groups .

3 Bnand tBuHydroxyl PGsIntroduction TBDMS Cl AllylONB BrRemovalTBAF, 35% TFAPd(PPh3)4, scavengersPhotolyticcleavage (320 nm)StableBasic conditionsBasic and Acidic ConditionsAcidic and mild basic conditionsOrthogonal FmocBoc, Fmoc, ZFmoc, Boc10 amino Acids: CysteineOther Protecting group : TrtProtected thiols can still undergo several side reactionEx: Elimination, reaction with carbocations, ..Scavengers are necessary during deprotection (TIPS, p anisole, .. )Thiol PGsIntroductionMeb BrAcm OHRemovalHF, MeSiCl3I2, DTNP,Tl(III), Hg(II), StableBasic conditionsBasic and Acidic conditionsOrthogonalBoc, Fmoc, Trt, Alloc Boc, Fmoc, Alloc11 amino Acids: MethionineIn Fmoc strategy SPPSUsed unprotected but thioanisole or ethylmethylsulfide added during cleavage and general deprotection to avoid oxidationIn Boc strategy SPPSMet is directly coupled as Met sulfoxide and reduced at the end of the synthesisReduction: HF + scavengers, N MethylmercaptoacetamideSide reaction.

4 S alkylation, oxidation, lactonizationThioether PGOHNOSHNOOHF CleavageOOHNOHSOROH omoserine lactone12 Fmoc Strategy SPPSFmoc: NHBoc: Lysine, Tryptophan, HistidinePbf: Arginine Trt: Cysteine, Aspartic acid , Glutamic acidAcm: CysteinetBu: Serine, Threonine, Hydroxyproline, Tyrosine, Aspartic acid , Glutamic acid13