Protecting Groups in Organic Synthesis: Types, Removal, and Stability, Lecture notes of Organic Chemistry

Download Protecting Groups in Organic Synthesis: Types, Removal, and Stability and more Lecture notes Organic Chemistry in PDF only on Docsity! 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  functionalities Review: Albericio et al., Chem. Rev., 2009, 109, 2455 2 For α‐carboxylic acids, Aspartic and Glutamic Acid Carboxylic acid PGs Introduction Isobutene Trt‐Cl Dmb‐OH, Dmb‐Cl Fm‐OH Bn‐Cl, Bn2O Removal 90% TFA  1% TFA in  CH2Cl2 1% TFA in  CH2Cl2 20% Piperidine TFMSA, HF, H2,  NaOH Stable Basic  conditions,  Hydrogenation Basic  conditions,  Hydrogenation Basic  conditions,  Hydrogenation Acidic  Conditions,  Hydrogenation Basic and  Acidic Conditions Orthogonal Fmoc, Z, Trt,  Alloc Fmoc, Alloc Fmoc, Alloc Boc, Trt, Alloc Boc, Fmoc, Trt,  Alloc 5 Amino Acids: Arginine Protect one or two nitrogen atoms  Other protecting group: Boc Side reactions: deguanidilation, lactamization Guanidinium PGs Introduction Pbf‐Cl Removal 90% TFA Stable Basic conditions, Hydrogenation Orthogonal Fmoc, Trt, Alloc 6 Amino Acids: Asparagine and Glutamine • Other protecting group: Trt • Often used without protection • Prone to dehydrogenation under basic conditions Amide PGs Introduction Xan‐OH Removal 90% TFA, scavengers Stable Basic conditions,  Hydrogenation Orthogonal Fmoc, Trt, Alloc 7 Amino Acids: Serine, Threonine, Hydroxyproline, Tyrosine Other protecting groups: Bn and tBu Hydroxyl PGs Introduction TBDMS‐Cl Allyl ONB‐Br Removal TBAF, 35%  TFA Pd(PPh3)4,  scavengers Photolytic cleavage (320  nm) Stable Basic  conditions Basic and Acidic  Conditions Acidic and mild  basic conditions Orthogonal Fmoc Boc, Fmoc, Z Fmoc, Boc 10 Amino Acids: Cysteine Other protecting group: Trt Protected thiols can still undergo several side reaction Ex: β‐Elimination, reaction with carbocations, …. Scavengers are necessary during deprotection (TIPS, p‐anisole, … ) Thiol PGs Introduction Meb‐Br Acm‐OH Removal HF, MeSiCl3 I2, DTNP, Tl(III), Hg(II),  Stable Basic conditions Basic and Acidic conditions Orthogonal Boc, Fmoc, Trt, Alloc Boc, Fmoc, Alloc 11 Amino Acids: Methionine In Fmoc‐strategy SPPS Used unprotected but thioanisole or ethylmethylsulfide added  during cleavage and general deprotection to avoid oxidation In Boc‐strategy SPPS Met is directly coupled as Met sulfoxide and reduced at the end  of the synthesis Reduction: HF + scavengers, N‐Methylmercaptoacetamide Side reaction: S‐alkylation, oxidation, lactonization Thioether PG OH N O S H N O O HF Cleavage O OH N OH S O R O Homoserine lactone 12