0910 Sf Master Bloque1

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Drug synthesis, Part 1

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0910 Sf Master Bloque1

  1. 1. ASSIGNATURA 564520: Medicaments i nutrició / Drugs & nutrition Medicinal Chemistry (20h) Synthetic drugs (10h)-Part 1 MASTER ON DRUGS, COSMETICS AND FOOD QUALITY Dr. Antonio Delgado Universitat de Barcelona October 2009
  2. 2. <ul><li>Introduction to drug synthesis: design and strategies </li></ul><ul><li>Combinatorial synthesis: a high throughput “hit-finding” strategy </li></ul><ul><li>Synthesis of single enantiomers </li></ul>Synthetic drugs
  3. 3. Introduction to drug synthesis: Design and strategies
  4. 4. Drugs “ Chemical compounds of known structure used for therapeutic or diagnostic purposes” Also commonly used for abused substances. Synonymous with medicine, pharmaceutical Obtained by application of the principles and tactics of Organic Synthesis Most of the drugs are synthetic organic compounds (carbon skeleton)
  5. 5. <ul><li>Common sources of drugs </li></ul><ul><li>  </li></ul><ul><ul><li>Total synthesis (around 70%) </li></ul></ul><ul><li>  </li></ul><ul><ul><li>Isolation from natural sources (natural products) </li></ul></ul><ul><ul><ul><li>Plants (alkaloids, enzymes, sugars….) </li></ul></ul></ul><ul><ul><ul><li>Animals (hormones, vaccines, enzymes,……… </li></ul></ul></ul><ul><ul><ul><li>Algae, sponges, etc. </li></ul></ul></ul><ul><li>  </li></ul><ul><ul><li>Fermentation (antibiotics, amino acids, antibodies, peptide hormones, etc.) </li></ul></ul><ul><ul><li>  </li></ul></ul><ul><ul><li>Chemical modification of natural products (semisynthesis): steroids, β-lactam antibiotics, etc. </li></ul></ul>
  6. 6. Semisynthesis biotechnology
  7. 7. <ul><li>Construction of the carbon skeleton </li></ul><ul><li>Functional group transformations </li></ul><ul><li>Functional group protection </li></ul><ul><li>Stereochemical control (stereogenic centers) </li></ul>About synthetic sequences Basic steps
  8. 8. About synthetic sequences Linear vs convergent synthesis Linear synthesis Convergent synthesis
  9. 9. Construction of the carbon skeleton Retrosynthetic analysis
  10. 10. Construction of the carbon skeleton Retrosynthetic analysis: Strategic disconnections and synthon generation Reagent Real species Synthon ( “virtual”) Ionic or radical fragment arising from a disconnection
  11. 11. Equivalence between synthons and reagents
  12. 12. Reagents Different disconnection approaches are possible for a single synthetic operation Synthons
  13. 13. Guidelines for choosing a disconnection
  14. 14. Guidelines for choosing a disconnection
  15. 15. Guidelines for choosing a disconnection
  16. 16. Transformación de grupos funcionales Quimioselectividad Una reacción quimioselectiva diferencia entre grupos funcionales identicos o de reactividad muy parecida 3
  17. 17. Reacción no quimioselectiva
  18. 18. Guidelines for choosing a disconnection Two functional groups are involved in the same disconnection Example of a 1,2-disconnection 4
  19. 19. Guidelines for choosing a disconnection Example of a 1,3-disconnection
  20. 20. Guidelines for choosing a disconnection Other 1,3-disconnections
  21. 21. Guidelines for choosing a disconnection 1,4-disconnections
  22. 22. Construcción del esqueleto carbonado Control de la regioselectividad Eligiendo los reactivos adecuados se puede preparar el regioisómero que interesa REGIOISÓMEROS Compuestos que difieren en la disposición de los sustituyentes
  23. 23. Chirons contain chiral information of the target compound Construction of the carbon skeleton Retrosynthetic analysis: Chiron: the chiral version of a synthon
  24. 24. Algo del chiral pool: concepto y ejemplos El “chiral pool”
  25. 25. El “chiral pool”
  26. 26. El “chiral pool”
  27. 27. <ul><li>Construction of the carbon skeleton </li></ul><ul><li>Functional group transformations </li></ul><ul><li>Functional group protection </li></ul><ul><li>Stereochemical control (stereogenic centers) </li></ul>About synthetic sequences Basic steps
  28. 29. Reduction of carbonyl derivatives
  29. 30. The versatility of acyl chlorides
  30. 31. <ul><li>Construction of the carbon skeleton </li></ul><ul><li>Functional group transformations </li></ul><ul><li>Functional group protection </li></ul><ul><li>Stereochemical control (stereogenic centers) </li></ul>About synthetic sequences Basic steps
  31. 32. Protecting groups
  32. 33. Protecting groups in peptide synthesis Directionality in peptide bond formation
  33. 34. Protecting groups in peptide synthesis Reactivity control
  34. 35. Carbamates: amine protecting groups in peptide synthesis
  35. 36. Other amine protecting groups
  36. 37. Carboxylic acid protecting groups
  37. 38. Hydroxyl protecting groups
  38. 39. Protecting groups
  39. 40. <ul><li>Construction of the carbon skeleton </li></ul><ul><li>Functional group transformations </li></ul><ul><li>Functional group protection </li></ul><ul><li>Stereochemical control (stereogenic centers) </li></ul>About synthetic sequences Basic steps
  40. 41. Control de los centro s estereogénico s Reacción estereoselectiva : Se forma mayoritariamente un estereoisómero. Según la naturaleza del diastereómero que se forme, la reacción será diastereoselectiva o enantioselectiva diastereoselectiva enantioselectiva
  41. 42. Stereospecificity and Stereoselectivity
  42. 43. Examples of stereospecific reactions S N 2 and E 2 reactions
  43. 44. Examples of stereospecific reactions Alkene halogenation Alkene epoxidation
  44. 45. Stereoselective reactions can be diastereoselective or enantioselective Diastereoselective: one diastereoisomer predominates Enantioselective: one enantiomer predominates diastereoselective enantioselective
  45. 46. A model to predict the diastereoselectivity in carbonyl additions: The Felkin-Ahn model
  46. 47. Diastereoselective synthesis
  47. 48. Diastereoselective synthesis Preferred hydride attack
  48. 49. Diastereoselective synthesis Microorganisms as chiral reagents: double diastereoselection

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