Drug synthesis, Part 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

3. Introduction to drug synthesis: Design and strategies

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)

6. Semisynthesis biotechnology

8. About synthetic sequences Linear vs convergent synthesis Linear synthesis Convergent synthesis

9. Construction of the carbon skeleton Retrosynthetic analysis

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. Equivalence between synthons and reagents

12. Reagents Different disconnection approaches are possible for a single synthetic operation Synthons

13. Guidelines for choosing a disconnection

14. Guidelines for choosing a disconnection

15. Guidelines for choosing a disconnection

16. Transformación de grupos funcionales Quimioselectividad Una reacción quimioselectiva diferencia entre grupos funcionales identicos o de reactividad muy parecida 3

17. Reacción no quimioselectiva

18. Guidelines for choosing a disconnection Two functional groups are involved in the same disconnection Example of a 1,2-disconnection 4

19. Guidelines for choosing a disconnection Example of a 1,3-disconnection

20. Guidelines for choosing a disconnection Other 1,3-disconnections

21. Guidelines for choosing a disconnection 1,4-disconnections

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. Chirons contain chiral information of the target compound Construction of the carbon skeleton Retrosynthetic analysis: Chiron: the chiral version of a synthon

24. Algo del chiral pool: concepto y ejemplos El “chiral pool”

25. El “chiral pool”

26. El “chiral pool”

29. Reduction of carbonyl derivatives

30. The versatility of acyl chlorides

32. Protecting groups

33. Protecting groups in peptide synthesis Directionality in peptide bond formation

34. Protecting groups in peptide synthesis Reactivity control

35. Carbamates: amine protecting groups in peptide synthesis

36. Other amine protecting groups

37. Carboxylic acid protecting groups

38. Hydroxyl protecting groups

39. Protecting groups

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

42. Stereospecificity and Stereoselectivity

43. Examples of stereospecific reactions S N 2 and E 2 reactions

44. Examples of stereospecific reactions Alkene halogenation Alkene epoxidation

45. Stereoselective reactions can be diastereoselective or enantioselective Diastereoselective: one diastereoisomer predominates Enantioselective: one enantiomer predominates diastereoselective enantioselective

46. A model to predict the diastereoselectivity in carbonyl additions: The Felkin-Ahn model

47. Diastereoselective synthesis

48. Diastereoselective synthesis Preferred hydride attack

49. Diastereoselective synthesis Microorganisms as chiral reagents: double diastereoselection