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Amide bond formation and peptide coupling

Amide bond formation and peptide coupling. Mgr. Juraj Dobia š 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

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Amide bond formation and peptide coupling

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  1. Amide bond formation and peptide coupling Mgr. Juraj Dobiaš KOCH PRIF UK Ch. A. G. N.,Montalbetti; V.,FalqueTetrahedron2005, 61,10827–10852.

  2. Comparison to esterification

  3. Activation methods non-classicalconditions: - microwaveiradiation - enzymaticcatalysis - solidphasesynthesis

  4. Acidchlorides Preparation: Coupling:

  5. Acidfluorides Preparation: • Advantages over acidchlorides in coupling: • no base needed • lesswatersensitive • more electrophilic • lesssterichindrance

  6. Acidazides Preparation: Coupling: Sidereaction: Curtiusrearangement

  7. Acylimidazoles Preparation: Coupling: • compatiblealsowithaminesalts – no additional base needed • one-potsynthesis

  8. Symetricalacidanhydrides Preparation: Coupling: • no base required • fewcommerialyacidanhydridesavailable • oneequivalentofacidiswasted

  9. Mixedacidanhydrides - cheapsecondcarboxylicmoiety – reducedwastebutselectivityproblem, solutions: Stericeffect: Electroniceffect: Othersyntheticapproach:

  10. Broadened concept of mixed anhydrides ethoxyacetylene: carbodiimines: - HOBtovercomesproblemswithN-acylureas

  11. Activeesters examples: • someavailableactivatedaminoacids • oftennotstable = in situ formationfromotherhigh-energyacidderivatives

  12. Activeesters – one-potsolutions phosphoniumsalts: uroniumsalts:

  13. Summary commonmechanismofactivation: • suppressing acidic properties • first step is nucleophilic attack of carboxylate • oxygen is taken to form low energy side product desiredreactionrealization: • one-pot synthesis • easy separable, non-toxic and non-corrosive side products • watertolerant • no additional base needed • roomtemperature, highyields

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