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Palladium-catalyzed reactions in medicinal chemistry
- 1. “Palladium-catalyzed reactions: a revolutionary impact in Medicinal Chemistry” Scuola di dottorato in scienze e tecnologie della chimica e dei materiali Corso di Scienze Farmaceutiche, alimentari e cosmetologiche Andrea Desogus, PhD
- 2. PALLADIUM (Pd) From “Pallas” (asteroid / goddess)
- 3. PALLADIUM Isolation in 1803, by dissolution of Platinum in HNO3 and H2SO4 1805 - Recognition of the discovery by the English Royal Society of Chemistry WILLIAM HYDE WOLLASTON 1766 - 1828
- 4. PALLADIUM PROPERTIES atomic number 46 atomic weight 106.42 phisical state at r.t. solid melting point 1554.9 °C Boiling point 2963 °C density 12.023 Electronic configuration [Kr]4d10 Oxidation states 0, +1,+2,+3,+4,+5,+6 Common isotopes: Pd-102, Pd-104, Pd-105, Pd-106, Pd-108, Pd-110
- 5. COMMON USES Catalytic converter for cars Jewelry Electronics Hydrogen storage Dentistry Organic synthesis PALLADIUM
- 6. Pd-catalyzed Hydrogenation of alkenes •Two hydrogen atoms added across the double bond •Thermodynamically favorable reaction •Pd catalyst cleaves H2 into 2H, attaching them on its surface together with the alkene syn addiction
- 7. Hydrogenator
- 9. Pt group Very reactive and very useful in catalysis “18 rule” 3d10 4s2 4p6 e.c. of Kr and Xe They strongly want to reach 18 external e- Pd: 10 e-
- 10. Pd in coupling reactions Wide interest in C-C,C-N, C-O bonds formation Palladium complexes are catalysts: they can switch oxydation state and lower the activation energy Pd complexes are coupled with a ligand, usually a phosphine
- 11. Pd(0) •Good nucleophilic •Good Base •Reductant Pd(II) •Good electrophilic •Good reactivity with electron-rich olefines •Good reactivity with Lewis bases •Oxydant Palladium complex species
- 12. Types of Pd catalysts •Pd precursors Used with a suitable ligand •1° generation catalysts PPh3 as ligand Palladium Acetate Pd2(dba)3
- 13. • 2 nd generation catalysts Bidentate phosphine palladium complexes Types of Pd catalysts Pd(dppf)Cl2 Pd(dppb)Cl2 • 3 rd generation catalysts Pd(I) dimer Triaryl phosphite based palladacycle
- 14. New catalysts Types of Pd catalysts Buchwald 2012 Enantioselective asymmetric SMR Synthesis of tri-ortho-substituted biaryls RT synthesis of tetra-ortho-substuted biaryls Zwitterion, RT SMR for sterically hindred substrates
- 15. Evolution of Phosphine ligands dppf
- 16. Nobel Prize in chemistry 2010 “Palladium-catalyzed cross couplings in organic synthesis” Akira Suzuki Richard Heck Ei-ichi Negishi
- 17. Palladium-catalyzed cross-couplings Mild reaction conditions Thermally stable reagents Inert to water and oxygen Chemoselective Low toxicity of reagents, ligands and catalysts ADVANTAGES
- 18. Important reactions in Palladium-catalyzed cross-couplings • Oxydative addition / Reductive elimination • β–hydride elimination • Transmetalation β α
- 20. HECK CROSS-COUPLING Arylation or alkylation of olefines •Not cataylitic arylation of olefines (1968) •Organopalladium generation through RHgX and Pd(II) salt. •Cataylitic with CuCl2 as reoxidant of Pd(0) to the Pd salt.
- 21. HECK CROSS-COUPLING Important modification (1972) •Fitton’s discovery: aryl halides react with Pd(0) to give arylpalladium halides •The organopalladium complex RPdX is generated from an organohalide, RX, and Pd(0) Oxidative addition Standard protocol
- 22. HECK CROSS-COUPLING Arylation or alkylation of olefines •Organohalide RX •Alkene •Pd catalyst •Ligand (usually with PPh3)
- 23. HECK CROSS-COUPLING Oxidative addition Migratory insertion β-hydride elimination Olefine decomplexation Reductive elimination
- 25. NEGISHI CROSS- COUPLING C-C coupling with organometallic species •First studies: organozirconium and organoalluminium compounds as coupling partners good results •Attempt with even less reactive species: organozinc compounds Superior yields Very mild Highly selective
- 26. NEGISHI CROSS- COUPLING Coupling of aryl or alkyl compounds •Organozinc •Organohalide •Pd catalyst •Ligand (usually PPh3)
- 29. SUZUKI CROSS-COUPLING Coupling of aryl and alkyl compounds with organoboronates •Organoboron compounds in the presence of a base can be used as coupling partners in palladium-catalyzed cross coupling with vinyl and aryl halides •Organoboron compounds: stable, weak nucleophils, chemoselective (wide range of functional groups), not toxic, not reactive •Study with Miyaura: also named Suzuki-Miyaura reaction (SMR)
- 30. SUZUKI CROSS-COUPLING Boronic acids or esters Base NaOH, NaHCO3, K2CO3, Et3N, Cs2CO3, NaOEt, CsF Base activation of organoboron reagents as boronate intermediates facilitated the transfer of the organic group from boron to palladium transmetalation
- 31. SUZUKI CROSS-COUPLING Coupling of aryl and alkyl compounds •Organohalide •Boronic acid or ester •Base •Pd catalyst •Ligand (usually PPh3)
- 32. SUZUKI CROSS-COUPLING Oxidative addition Transmetalation (rate limit step) Reductive elimination
- 33. Other Pd Cross-couplings Sonogashira Reaction •Ethinylation •Double cycle: oPalladium cycle oCopper cycle with base Transmetalation Inert atmosphere!
- 34. Other Pd Cross-couplings Stille Reaction •Base not needed •Use of Stannanes, compounds with Sn 4+ and 3 alkyl groups •Difficult to couple an alkyl no selectivity •Not Green: organo-tin compounds are TOXIC Tributyltin chloride Hexamethylditin
- 35. Other Pd Cross-couplings Buchwald-Hartwig amination •C-N bond between aromatic carbon and amine •Very difficult with traditional methods: stressed conditions
- 36. Cross-Coupling Applications in Medicinal Chemistry Drug synthesis Natural products synthesis Industrial applications Chemical transformation in living organisms
- 37. Heck coupling in Taxol® synthesis Paclitaxel (Taxol®) BMS
- 38. Heck coupling in morphine synthesis Morphine
- 39. Negishi coupling in Pumiliotoxin A synthesis Pumiliotoxin A (toxic alkaloid)
- 40. Other applications of Negishi coupling Hennoxazole A antiviral Negishi coupling 5-HT1A agonist (Eli Lilly,1997) Negishi coupling
- 41. Suzuki coupling in (+)-dynemicin A synthesis (+)-dynemicin A (antitumor agent)
- 42. Other applications of Suzuki coupling Boscalid (fungicide) Dragamacidin F antiviral Suzuki coupling Suzuki coupling
- 43. Suzuki nano-coupling in cells •Pd-catalyzed reactions in living organisms: biocompatibility •Palladium-meditated cell-surface labeling •SMR with cell penetrating Pd[0]-nanocatalyst Pd(OAc)2(ADHP)2 •Coupling between a modified pore protein with a fluorescent boronic acid on a surface of E. coli Pore protein Spicer et al. J. Am. Chem. Soc. 2012, 134, 800
- 44. …Some personal experience… Attempt of a Heck coupling Possible reasons: •Chlorine si the worst leaving atom (I>Br>Cl) •Not a real alkene (N and X whitdraw e-)
- 45. …Some personal experience… General procedure of a Suzuki coupling R= H, CH3, F, Cl, acetyl, indolyl Tintori et al. J. Med. Chem. 2015, 58, 347
- 46. CONCLUSIONS Palladium is the most versatile and ubiquitous metal in modern organic synthesis. Its use as catalyst has allowed the discovery of new reaction, most of them worthy the Nobel Prize. Heck, Negishi and Suzuki cross-couplings, together with other Pd catalyzed reactions, are frequently used in drug synthesis. Thanks to them, new useful active compounds have been discovered. The study of Pd complexes is still in progress, so new reaction, impossible to perform so far, could appear in the future.
Editor's Notes
- You can modofy P as parameter to reach reduction quickly
- Catalizzatori sviluppati per differenti scopi