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Peptide Coupling

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  1. Peptide Coupling Rob Brown Special Topic – 25/01/112

  2. Peptide Coupling The Amide Bond – Biological Importance • Key chemical bond in proteins: • Enzymes (biological catalysis) • Structural and mechanical function • Cell signalling • Immune response • Cell adhesion - Amide-containing pharmaceuticals:

  3. Peptide Coupling The Peptide Bond – Biological Synthesis - Ribosomal Protein Translation - DNA → RNA → Peptides/Proteins -Chemical Synthesis? - Solid Phase - Solution Phase

  4. Peptide Coupling The Peptide Bond – Chemical Synthesis Problem: Solution:

  5. Peptide Coupling The Peptide Bond – Chemical Synthesis

  6. Peptide Coupling Chemical Synthesis – Racemization

  7. Peptide Coupling Chemical Synthesis – Racemization

  8. Peptide Coupling Chemical Synthesis – Racemization

  9. Peptide Coupling Chemical Synthesis – Racemization

  10. Peptide Coupling Chemical Synthesis – Common Side Reactions

  11. Peptide Coupling Coupling reagent comparison Published epimerisation tests:

  12. Peptide Coupling Carbodiimide coupling

  13. Peptide Coupling Carbodiimide coupling

  14. Peptide Coupling Carbodiimide coupling

  15. Peptide Coupling Carbodiimide coupling

  16. Peptide Coupling Carbodiimide coupling

  17. Peptide Coupling Carbodiimide coupling

  18. Peptide Coupling Carbodiimide reagents: Additives:

  19. Peptide Coupling HOXt-based coupling reagents

  20. Peptide Coupling HOXt-based coupling reagents

  21. Peptide Coupling HOXt-based coupling reagents

  22. Peptide Coupling HOXt-uronium/aminium salts

  23. Peptide Coupling HOXt-uronium/aminium salts

  24. Peptide Coupling HOXt-phosphonium salts

  25. Peptide Coupling HOXt-immonium salts

  26. Peptide Coupling Other HOXt-derived reagents

  27. Peptide Coupling Acid Halide-generating reagents • Harsh activation method • Lack of functional group compatibility • Works well with hindered amino acids • Racemization a major problem e.g.

  28. Peptide Coupling Acid Halide-generating reagents: Triazines

  29. Peptide Coupling Acid Halide-generating reagents: Halo-uronium & phosphonium salts

  30. Peptide Coupling Pentafluorophenol-based reagents

  31. Peptide Coupling HODhbt-reagents

  32. Peptide Coupling HOSu-reagents

  33. Peptide Coupling Phosphorus-reagents

  34. Peptide Coupling Mixed carbonic anhydrides

  35. Peptide Coupling Polymer-supported reagents

  36. Peptide Coupling Newer approaches to amide bond fomation

  37. Peptide Coupling Conclusions • Most reagents are not broadly applicable, relatively narrow uses. • Specialized, expensive reagents work well for SPPS • -High yields required, by products can be washed out • -Simpler, cheaper all-purpose reagents better for solution phase: • - HATU & HBTU – general and excellent reactivity. • - HATU favoured for quick coupling times • - DIC/HOBt still among the best combinations • - Substitute EDC when inseparable by-products become problematic • - For hindered couplings: PyBrop for N-Me amino acids • PyBop for hindered tertiary amino acid couplings • Triazines for hindered quaternary amino acids • - PS-IIDQ and PS-Mukaiyama reagents best for library synthesis • -Finally, keep it simple, don’t be mislead by needlessly expensive reagents • Main refs: E.Valeur, M. Bradley; Chem. Soc. Rev., 2009, 38, 606-631 • A. El-Faham, F. Albericio; Chem. Rev., 2011, 111, 6557-6602