palladium-catalyzed reactions in medicinal chemistry
TRANSCRIPT
“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
PALLADIUM (Pd)
From “Pallas” (asteroid / goddess)
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
PALLADIUMPROPERTIES
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
COMMON USES
Catalytic converter for cars
Jewelry
Electronics
Hydrogen storage
Dentistry
Organic synthesis
PALLADIUM
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
Hydrogenator
The Pt group
PALLADIUM
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-
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
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
Types of Pd catalysts
•Pd precursors
Used with a suitable ligand
•1° generation catalysts
PPh3 as ligand
Palladium Acetate
Pd2(dba)3
• 2 nd generation catalysts
Bidentate phosphine
palladium complexes
Types of Pd catalysts
Pd(dppf)Cl2 Pd(dppb)Cl2
• 3 rd generation catalysts
Pd(I) dimerTriaryl phosphite based palladacycle
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
Evolution of Phosphine ligands
dppf
Nobel Prize in chemistry 2010
“Palladium-catalyzed cross couplings in organic synthesis”
Akira Suzuki Richard Heck Ei-ichi Negishi
Palladium-catalyzed cross-couplings
Mild reaction conditions
Thermally stable reagents
Inert to water and oxygen
Chemoselective
Low toxicity of reagents, ligands and catalysts
ADVANTAGES
Important reactions in Palladium-catalyzed cross-couplings• Oxydative addition / Reductive elimination
• β–hydride elimination
• Transmetalation
β
α
HECK CROSS-COUPLING
1972
HECK CROSS-COUPLINGArylation 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.
HECK CROSS-COUPLINGImportant 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
HECK CROSS-COUPLINGArylation or alkylation of olefines
•Organohalide RX
•Alkene
•Pd catalyst
•Ligand (usually with PPh3)
HECK CROSS-COUPLINGOxidative addition
Migratory insertion
β-hydride eliminationOlefine decomplexation
Reductive elimination
NEGISHI CROSS-COUPLING1977
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
NEGISHI CROSS-COUPLING
Coupling of aryl or alkyl compounds
•Organozinc
•Organohalide
•Pd catalyst
•Ligand (usually PPh3)
NEGISHI CROSS-COUPLING
Oxidative addition
Transmetalation
Reductive elimination
SUZUKI CROSS-COUPLING1979
SUZUKI CROSS-COUPLINGCoupling 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)
SUZUKI CROSS-COUPLINGBoronic 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
SUZUKI CROSS-COUPLINGCoupling of aryl and alkyl compounds
•Organohalide
•Boronic acid or ester
•Base
•Pd catalyst
•Ligand (usually PPh3)
SUZUKI CROSS-COUPLING
Oxidative addition
Transmetalation(rate limit step)
Reductive elimination
Other Pd Cross-couplings
Sonogashira Reaction
•Ethinylation
•Double cycle:
oPalladium cycle oCopper cycle with base Transmetalation
Inert atmosphere!
Other Pd Cross-couplingsStille 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
Other Pd Cross-couplingsBuchwald-Hartwig amination
•C-N bond between aromatic carbon and amine
•Very difficult with traditional methods: stressed conditions
Cross-Coupling Applicationsin Medicinal Chemistry
Drug synthesis
Natural products synthesis
Industrial applications
Chemical transformation in living organisms
Heck coupling in Taxol® synthesis
Paclitaxel (Taxol®) BMS
Heck coupling in morphine synthesis
Morphine
Negishi coupling in Pumiliotoxin A synthesis
Pumiliotoxin A(toxic alkaloid)
Other applications of Negishi coupling
Hennoxazole Aantiviral
Negishi coupling
5-HT1A agonist(Eli Lilly,1997)
Negishi coupling
Suzuki coupling in (+)-dynemicin A synthesis
(+)-dynemicin A(antitumor agent)
Other applications of Suzuki coupling
Boscalid(fungicide)
Dragamacidin F antiviral
Suzuki coupling
Suzuki coupling
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 proteinSpicer et al. J. Am. Chem. Soc. 2012, 134, 800
…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-)
…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
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.
THANKS FOR YOUR ATTENTION