click chemistry presentation - for department of chemistry, university of missouri - circa 2010
TRANSCRIPT
Outline Introduction- Definition
Classes of click reactions
- Nucleophilic ring opening reactions
-Protecting groups
- Cycloaddtion chemistry
-Huisgen 1,3 dipolar addition.
-Benzyne addition
-Multicomponent reaction
Clickphines
Summary
Acknowledgement
IntroductionChemical Philosophy introduced by K. Barry Sharpless in 2001.
Basis
o Nature (Quintessential Chemist) prefers Carbon heteroatom bond (C-X-C) than C-C-C bond. examples : Nucleic acid, Proteins,polysaccharides.
Philosophy
“All Searches must be restricted to molecules that are easy to make”.
Prerequisite
o Reactions that are modular, high yielding, wide in scope,stereospecific, use benign solvent.
Kolb, C. H.; Finn, G. M.; Sharpless, B. K. Angew.Chem.Int.Ed., 2001, 40, 2004-2021.
Click Impact
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Number of "Click chemistry" papers
Source : www.chem.wisc.edu/areas/organic/studsemin/mangold/mangold-sem.ppt
Areas of Impact
• Bioconjugation.
• Materials science.
• Drug discovery.
Classes of Click Reactions
C=C additions
Nucleophilic opening ofhighly strained rings
Protecting groups
Cycloaddition Reactions
C=C addition
Olefins are primary organic starting materials.
Creation of modules by oxidative addition of heteroatom to olefins.
Primary oxidation of olefins gives epoxides, aziridines, diols and hydroxyl amines.
Nucleophilic Opening of Spring Loaded Rings
A distinct exothermic reaction –release of strain energy by ring opening ,makes the reactants “spring loaded”.
SN2 ring opening of epoxides, aziridines, cyclic sulfates , episulfoniumions, cyclic sulfamidates, aziridinium ions are
-Reliable
-Stereospecific
-Mostly regioselective
-Quantitative.
Reactions are frequently performed in alcohol/water mixtures.
Click Synthesis from Epoxides
1,3 selectivity is due to
1. Trans diaxial epoxideopening
2. Intramolecular epoxideactivationby the hydroxyl group from the first step.
Polar solvent diminishes latter effect.
Kolb, C. H.; Finn, G. M.; Sharpless, B. K. Angew.Chem.Int.Ed., 2001, 40, 2004-2021.
Click synthesis from aziridines Regioselective ring
opening of aziridinesare primarly substrate controlled.
In first set of example, Benzyl substitution is more reactive than 1o
,
2o .
Substituent on the nitrogen also influences the regioselectivity of aziridine ring opening as in the second set .
Lin, P. Y.; Bellos, K.; Stamm, H.; Onistschenko, A. Tetrahedron, 1992, 48, 2359-2372
Protecting Groups Acetals, ketals, and their aza
analogues, have been considered for long as only protecting groups.
They can also be considered as heterocycles with tremendous potential in medicinal chemistry applications.
The formation of acetals, ketals and their aza analogues are part of click chemistry.
Huisgen 1,3-dipolar cycloaddition Cycloaddtion of azide and acetylene was first reported by
Dimroth in early 1900s.
1933- Dipolar nature of azide first recognized by LinusPauling
1960- Mechanism of 1,3-dipolar cycloaddition of azides and alkynes pioneered by Rolf Huisgen
L. Pauling. Proc. Natl. Acad. Sci. USA 1933, 19, 860-867Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 633-696
Copper Catalyzed Alkyne Azidecycloaddition (CuAAC)
• Using copper catalyst and at room temperature.
• Discovered concurrently by K.Barry Sharpless and Morten Meldal.
Regiospecific
Chemoselective
Concerted reaction: no intermediate
Cream of the crop
Perfect click reaction.
Sharpless, K.B. et al. Angew. Chem. Int. Ed 2002, 41, 2596-2599Meldal,M.J. et al. J. Org. Chem. 2002, 67, 3057-3064
CuAAC 105-106 times rate enhancement.
Thermodynamic and kinetically favorable (50 and 26 kcal/mol, respectively)
Terminal alkyne required.
Triazole stable to oxidation and acid hydrolysis
CuAAC Catalytic Cycle
Himo, F. et al. J. Am. Chem. Soc, 2005, 127, 210-216.Ahlquist, M., Fokin, V.V. Organometallics 2007, 26, 4389-4391
Benzyne Click Chemistry A variety of substituted benzotriazoles prepared using
[3+2] cyclo addition.
Fluoride promoted ortho elimination of o-(trimethylsilyl)aryl triflates results in arynes.
Such arynes are highly reactive towards nulceophilicadditions and annulations.
Shi, F.; Waldo, P. J.; Chen, Y.; Larock, C. R. Org. Lett. 2008, 10, 2409-2412
Bioconjugation• Detection of enzyme activities
- Modification of enzyme active site
- Tag may influence properties, e.g. cell permeability.
Speers , Cravatt, Chem. Biol. 2004, 11, 535-46.
Imaging using copper free
azide reaction Detection by click chemistry
Copper is toxic to cells
click chemistry not applicable for imaging in vivo
Introduction of azido-carbohydrates on cell surface
Use of copper free 1,3 azide alkyne reaction.
Baskin et al, PNAS 2007, 104, 16793-97
Multi Component Reaction High degree of atom economy .
Barbas, demonstrated domino Aldol/Knoevenagel/Michael reactions using proline/pyrolidine as organo catalysts.
Incorporation of Diels-Alder and Huisgen cycloaddtionreaction sequences enable construction of complex polycycles and thus called Organo-Click Chemistry.
The reaction sequence and mechanism are shown below.
Ramachary, B. D.; Barbas , F. C. Chem. Eur. J. 2004, 10, 5323-5331.
Clickphines Novel P, N-type ligand is synthesized using click chemistry.
First use of triazoles as nitrogen donors in P, N ligands.
Phosphine is protected to avoid unwanted iminophosphoraneformation.
These ligands showed excellent regioselectivity in palladium catalyzed allylic alkylation reaction.
Detz, J. R.; Heras, A. S.; Gelder, D. R.; van Leeuwan, M. N. W. P.; Hiemstra, H.; Reek, H. N. J.; van Maarseveen, H. J. Org. Lett., 2006, 8, 3227-3230.
Advantages
• Functional group tolerance
• Aqueous conditions
• Shorter reaction time
• High yield
• High purity
• Regiospecificity
Summary Click chemistry concept received with bipolar degrees of acceptance.
Many click type reactions can/must be identified and improved.
Detractors say that it is just a restatement of common sense concerns of synthetic chemists who always seek to employ the most efficient reaction for the task.
Although considerable number of reactions can be called as “click” type reactions, Click chemistry lacks broad spectrum of reactions that can be widely used.
Process chemists and pharmaceuticals have utilised click chemistry , but synthetic chemists are yet to embrace click chemistry.
Acknowledgements
Thanks to Dr. Harmata and group members
Thanks to Dr. Glaser.
Thanks to audience for the patient attention and attendance.
Drug Discovery Target guided synthesis
Lead compound:
– Chemical with desired biological activity
– Starting point for modifications
Synthesis of Lead discovery libraries:
High diversity of compounds
Low amount of synthetic steps