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Electrophilic Reactions of Purines: Mechanisms, Selectivity, and Applications in Drug Development

This chapter explores the various electrophilic reactions that occur at the nitrogen and carbon atoms of purines, highlighting the influence of substituents and reaction conditions on alkylation and acylation selectivity. It discusses the stability of reaction products, the role of sterics in N7/N9 positioning, and the dynamics of reversible reactions. The chapter also examines the synthesis of bioactive purines, key strategies such as carbonyl condensation, and the potential for anticancer and antiviral applications. Additionally, it addresses natural products related to diterpenes and plant growth hormones.

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Electrophilic Reactions of Purines: Mechanisms, Selectivity, and Applications in Drug Development

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  1. PURINES - kap 24 Reaction with electrophiles at N - Protonation

  2. Reaction with electrophiles at N - Alkylation Selectivity depends on substituents and conditions

  3. N7/N9: - Sterical factors (Large 6-subst) Termodyn. control (reversible react.) Electrophiles - cancer

  4. Reaction with electrophiles at N - Acylation / Sulfonation Acylation products generally unstable Sulfonation - Stable prod., selective N9 Reaction with electrophiles at N - oxidation

  5. Reaction with electrophiles at C

  6. Reaction with electrophiles at C E-fil Ar subst, generally not working Reaction with nucleophiles

  7. Nu.Ar.Subst: Reactivity F>Cl>Br>I Other leaving groups

  8. Deprotonation at N

  9. Deprotonation at C / C-metallation

  10. Org. Lett, 2003, 4289

  11. JOC 1997, 6833

  12. Oxy purines -Oxo forms Alkylation, acylation etc

  13. Replacement of O with other hetero atoms Amino purines Amino form

  14. Alkylation, acylation etc Diazotation etc.

  15. Synthesis of Purines Carbonyl condensations Strategy A - Traube synth. etc

  16. Carbonyl condensations Strategy B Cycloadditions

  17. Bioactive Purines DNA / RNA bases Anticancer / antiviral drugs

  18. Adenosin og adenosinreseptorligander Sel. A2A antag. Parkinston /Alsheimer? AKB PhD-lecture, august 05 Cytokinins - Plant growth hormones

  19. Natural products • Heteromines • Isolated from Heterostemma brownii • Treatment of tumors in Taiwanese folk medicine Agelasines from marine sponges (Agelas spp) Asmarines for marine sponges Agelasine D

  20. Reversine http://www.scripps.edu/news/press/122203.html

  21. Heterocycles cont. more than 2 heteroatoms in one ring kap 26 5-membered rings Triazoles and tetrazoles 6-membered rings Triazines and tetrazines

  22. 5-membered rings Triazoles and tetrazoles (pentazoles highly unstable) More acidic - less basic comp to diazoles Bioisostere - CO2H

  23. 1,2,3-Triazole React. at N

  24. React. at C 1,2,3-Triazole

  25. Benzo-1,2,3-Triazole

  26. React. at N 1,2,4-Triazole React. at C

  27. Small diff. stab. taut. Tetrazole Bioisostere - CO2H React. at N

  28. React. at C

  29. Oxadiazoles and thiadiazoles (thiatriazole) - No acidic NH -Generally low basicity (cf triazoles) -Some examles N-quart. -Few ex. Introd of E-fils on C -Prone to Nu attack Aromaticity (NMR shifts, bond lenghts)

  30. Ring opening (esp. O-cont. rings) C-lithiation easy, but often low stab of lithiated prod

  31. 6-membered rings Triazines and tetrazines Highly activated for Nu attack No simple react with electrophiles

  32. Diels Alder react. Leading to azines with fewer N (see synth of pyridines, diazines)

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