Amide bond formation and peptide coupling Mgr. Juraj Dobiaš KOCH PRIF UK Ch. A. G. N., Montalbetti; V., Falque Tetrahedron 2005, 61, 10827–10852.

Comparison to esterification

Activation methods non-classical conditions: - microwave iradiation - enzymatic catalysis - solid phase synthesis

Acid chlorides Preparation: Coupling:

Acid fluorides Preparation: Advantages over acid chlorides in coupling: - no base needed - less water sensitive - more electrophilic - less steric hindrance

Acid azides Preparation: Coupling: Side reaction: Curtius rearangement

Acylimidazoles Preparation: Coupling: - compatible also with amine salts – no additional base needed - one-pot synthesis

Symetrical acid anhydrides Preparation: Coupling: - no base required - few commerialy acid anhydrides available - one equivalent of acid is wasted

Mixed acid anhydrides - cheap second carboxylic moiety – reduced waste but selectivity problem, solutions: Steric effect: Electronic effect: Other synthetic approach:

Broadened concept of mixed anhydrides ethoxyacetylene: carbodiimines: - HOBt overcomes problems with N-acylureas

Active esters examples: - some available activated aminoacids - often not stable = in situ formation from other high-energy acid derivatives

Active esters – one-pot solutions phosphonium salts: uronium salts:

Summary common mechanism of activation: -suppressing acidic properties -first step is nucleophilic attack of carboxylate -oxygen is taken to form low energy side product desired reaction realization: -one-pot synthesis -easy separable, non-toxic and non-corrosive side products -water tolerant -no additional base needed -room temperature, high yields