click chemistry
DESCRIPTION
Click chemistryTRANSCRIPT
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M2 recherche
Click Chemistry
2014-2015
Prof. Paul-Alain Jaffrs
Laboratoire de Chimie, UMR CNRS 6521
Web.: http://www-tmp.univ-brest.fr/phosvec/
Bureau : C123
E-mail : [email protected] 1
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2
Summary
1- Introduction
2- CuAAC
4- Staudinger
9- Novel developments
3- Copper Free AAC
5- Isocyanate / isothiocyante
7- Thiol-ene
8- Thiol-ynes
2
6- Epoxide
10- Conclusion
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Kolb, H.C.; Finn, M.G.; Sharpless, B.K. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.
1- Introduction
Historique
The notion of Click reaction : introduced by Sharpless, Finn, Fokin in 2001
Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew Chem Int Ed Engl. 2002, 41, 2596-9.
B. Sharpless
Scripps Research Institute
Nobel Price 2001
(Chemistry)
V.V Fokin
Scripps Research Institute
M.G. Finn
Georgia Institute
of Technology
C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057.
M. Meldal
Coppenhagen
3
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A click reaction must be modular,
wide in scope, high yielding, create
only inoffensive by-products (that
can be removed without
chromatography), are stereospecific,
simple to perform and that require
benign or easily removed solvent.
- Barry Sharpless
1- Introduction
Historique
Kolb, H.C.; Finn, M.G.; Sharpless, B.K. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.
Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew Chem Int Ed Engl. 2002, 41, 2596-9. 4
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1- Introduction
Criteria for click reaction
be modular
be wide in scope
give very high chemical yields
generate only inoffensive byproducts
be stereospecific
have high atom economy.
The process would preferably:
have simple reaction conditions
use readily available starting materials and reagents
use no solvent or use a solvent that is benign or easily removed
(preferably water)
provide simple product isolation by non-chromatographic methods
(crystallisation or distillation)Wikipedia, 17-10-2013 (selection)
5
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2-1- Cycloaddition de Huisgen
L. Pauling. Proc. Natl. Acad. Sci. USA 1933, 19, 860-867; Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 633-696
R'' R'N3 N NN
R'
R''
1
5
+80oC N N
NR'
R''
1
4
+
1933 Dipolar nature of azide first recognized by Linus Pauling
Mechanism of 1,3-dipolar cycloaddition of azides and alkynes pioneered by Rolf Huisgen
1960
Azide R N3 R NNN R NNNR NNN
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
H+N
Cl-
HNN3
N+
NH2
Neat, 80oC, 6 days
N+
NH2
N+
NH2
HNNH
N N NH
NH
44
HNNH
N N
1,5 1,4
6Kolb. J. Am. Chem. Soc. 2004, 126, 12809
6
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2-1- Cycloaddition de Huisgen
Sharpless, K.B. et al. Angew. Chem. Int. Ed 2002, 41, 2596-2599; Meldal,M.J. et al. J. Org. Chem. 2002, 67, 3057-3064
2001/2002 Copper catalyzed 1,3-Dipolar cycloaddition by Sharpless/Meldal
R'' R'N3N N
NR'
R''
1
4
+ Cu(I)
rtRegioselectivity
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
7
-
2-2- CuAAC Possible mechanism
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
HR'
H+
CuLxR'
N N N
R2
CuLxR'
N N N
R2
CuLx
N N N
R1
R2
N NN
R CuLx
H+
N NN
R H
R2
R2
[CuLx]
RDS
CuLxR'
N N N
R2
CuLx
18 kcal/molHimo, F. et al. J. Am. Chem. Soc, 2005, 127, 210-216.
Ahlquist, M., Fokin, V.V. Organometallics 2007, 26, 4389-4391.
Direct
8
+
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2-3- CuAAC Experimental conditions
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
OPh
Ph N3
CuSO4 5H2O 1mol%
Sodium Ascorbate 5mol%
H2O : tBuOH 4:1, RT, 8h
NN
N
O
Ph
Ph
91%
O
O
N
NNPh
92%
N
NN
NN
N NH
HN
NH2
NH
88%
N
N NHO
O
O Ph
88%
OH
H
H H
N
NN OH
OH
94%
Sharpless. Angew. Chem. Int. Ed. 2002, 41(14), 2596 9
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2-3- CuAAC Experimental conditions
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
OPh
Ph N3
CuSO4 5H2O 1mol%
Sodium Ascorbate 5mol%
H2O : tBuOH 4:1, RT, 8h
NN
N
O
Ph
Ph
91%
Sodium ascorbate is a reducing agent
Cu(II) Cu(I)
(ox) (red)
(red)
10
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11
-H+
+H+
pK = 4.1
2-3- CuAAC Experimental conditions
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
Rq: Addition of a slight excess of sodium ascorbate prevents the
formation of oxidative homocoupling products.
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2-3- CuAAC Experimental conditions
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
Other conditions
12
CuI
CuBr(PPh3)3
An abnormal NHC complex of copper with 1,4-diphenyl-1,2,3-triazol-5-ylidene [CuCl(TPh)] efficiently catalyzed click reactions
of azides with alkynes to give 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature with short reaction
times. CuCl(TPh) was particularly effective for the reaction between sterically hindered azides and alkynes.
T. Nakamura, T. Terashima, K. Ogata, S.-i. Fukuzawa, Org. Lett., 2011, 13, 620-623.
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1,5-regioisomer
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2-4- RuAAC
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
Suggested mechanism
B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia, V. V. Fokin,
J. Am. Chem. Soc., 2008, 130, 8923-8930.
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2-4- RuAAC
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
Rq : possibility to use di-substituted alkyne
Not possible with CuAAC
Different regioisomer
with CuAAC
Rq : Active catalysts : RuCp*L2Cl
RuAAC is not as robust as the CuAAC with respect to functional group
tolerance and reaction conditions compatibility.
The catalyst should not be mixed with the azide in the absence of alkyne
(side reaction below dimerization of RN3 to produce a characteristic
green product).
R-N3
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Exemples
Synthesis of polymers
N3 N3
Cu(I)
Synthesis of gel
D. J. V. C. van Steenis, O. R. P. David, G. P. F. van Strijdonck, J. H. van Maarseveen, J. N. H. Reek, Chem. Commun.
2005, 4333.
D. D. Diaz, K. Rajagopal, E. Strable, J. Schneider, M. G. Finn, J. Am. Chem. Soc. 2006, 128, 6056;
2-5- Exemples
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
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Exemple
Cu(I)
Synthesis of dendrimers : divergent syntesis
V. V. Fokin et al., Macromolecules 2005, 38, 3663.
2-5- Exemples
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
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Exemple
Cu(I)
Synthesis of dendrimers : convergente syntesis
J. W. Lee, B.-K. Kim, J. H. Kim, W. S. Shin, S.-H. Jin, J. Org. Chem. 2006, 71, 4998.
2-5- Exemples
2- CuAAC : copper catalyse Alkyne-Azide Cycloaddition
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3-1- Introduction
3- Copper free Alkyne-Azide Cycloaddition
Toxicity of copper
The nature of ligand (L) influence the toxicity.
Reactive
Oxygen
Species
(ROS)
Rq
The nature of ligand (L) modify the reduction potential Cu(II/I)
The nature of ligand (L) modify cell uptake
Toxicity
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Kennedy et al., J Am Chem Soc. 2011, 133, 17993-8001.
Low toxicity
High
toxicity
L-Histidine
3-2- Bio-compatible copper complexes
3- Copper free Alkyne-Azide Cycloaddition
Cu(histidine)2
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3-2- Bio-compatible copper complexes
3- Copper free Alkyne-Azide Cycloaddition
Cu(histidine)2
Kennedy et al., J Am Chem Soc. 2011, 133, 17993-8001.
Huh7.5 cells
Viable cells only with Cu(Hist)2
Biotine
Steptavidin
Mannosamine
(Incorporation into
glycan glycoprotein)
O
S
HN NH
H H
O
Wikipedia 21-10-2013
Tetrameric structure
of streptavidin with
2 bound biotins
Streptavidine/biotine :
dissociation constant (Kd) on
the order of 1014 mol/L
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3-2- Bio-compatible copper complexes
3- Copper free Alkyne-Azide Cycloaddition
Cu(histidine)2
Kennedy et al., J Am Chem Soc. 2011, 133, 17993-8001.
Mannosamine
(Incorporation into
glycan glycoprotein)
O
NH2 HClHO
HOHO
OH
1) NaOMe/MeOH
2) (ClCH2CO)2O
O
HNHO
HOHO
OH
O
Cl NaN3, DMF
reflux
O
HNHO
HOHO
OH
O
N3
59% 2 Steps
Ac2O, DMAP,
Pyridine
95% YieldO
HNAcO
AcOAcO
OAc
O
N3
Syntheis of non-natural saccharides
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P. Wu et al.,
J. Am. Chem. Soc., 2010, 132, 16893-16899.
3- Copper free Alkyne-Azide Cycloaddition
Cu-BTTES
3-2- Bio-compatible copper complexes
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P. Wu et al.,
J. Am. Chem. Soc., 2010, 132, 16893-16899.
3- Copper free Alkyne-Azide Cycloaddition
Cu-BTTES
Cell growth curve after click chemistry treatment.
Low toxicity
With ligand
High toxicity
Without ligand
Toxicity : importance of the ligand
3-2- Bio-compatible copper complexes
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P. Wu et al.,
J. Am. Chem. Soc., 2010, 132, 16893-16899.
3- Copper free Alkyne-Azide Cycloaddition
Cu-BTTES
Fucosylation of glycan : use GDP-fucose as substrate
Two biosynthetic ways to produce GDP-fucose
(GuanosineDiPhosphate - GDP)
90 %
10 %
% of bioproductionof GDP-fucose
Alkyne-basedsynthetic equivalent
3-2- Bio-compatible copper complexes
GDP-fucose
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P. Wu et al.,
J. Am. Chem. Soc., 2010, 132, 16893-16899.
3- Copper free Alkyne-Azide Cycloaddition
Cu-BTTES
Micro-injection in
zebrafish embryo
Alexa Fluor 488-azide
Goal : track the fucosilated glycan after embryo developement
3-2- Bio-compatible copper complexes
Rq : GDP-Fuc-N3 : toxic
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3-3- Reactive substrates Real copper free
3- Copper free Alkyne-Azide Cycloaddition
Context
Classical Huisgen cycloaddition : require thermal activation
R'' R'N3 N NN
R'
R''
1
5
+80oC N N
NR'
R''
1
4
+
Alternative : activated substrates to enhance chemical reactivity
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27
Carolyn Bertozzi
Z. Li, T. Seo, J. Ju.
Tetrahedron Lett. 2004, 45, 3143-3146.
G. Wittig, A. Krebs.
Chem. Ber. 1961, 94, 3260-3275.
J. M. Nolte
ChemBioChem 2007, 8, 1504-1508.
3- Copper free Alkyne-Azide Cycloaddition
Proc Natl Acad Sci U S A. 2007 ,104, 16793
activated substrates to enhance chemical reactivity
3-3- Reactive substrates Real copper free
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sp hybridized C
; but 160angles
Due to the cyclic structure
C. R. Bertozzi. J. Am. Chem. Soc. 2004, 126, 15046-15047.
3-4- Strained Alkyne
3- Copper free Alkyne-Azide Cycloaddition
Enhance the reactivity
Concept
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3-4- Strained Alkyne
3- Copper free Alkyne-Azide Cycloaddition
Kinetic of cycloaddition (relative rate)
Krel = 1 Krel = 3 Krel = 60Krel = 1.5 Krel = 450
C. R. Bertozzi.
ACS Chem. Biol.
2006, 1, 644-648.
C. R. Bertozzi.
Proc. Natl. Acad. Sci. U.S.A.
2007, 104, 16793-16797.
C. R. Bertozzi.
Org. Lett.
2008, 10, 3097-3099.
R. Bertozzi.
J. Am. Chem. Soc.
2004, 126, 15046
Rq : limited
solubilityRq : More water
soluble
Synthesis of fluorine derivative : difficult, expensive
Adjacent aryl groups also increase the reactivity of alkyne.
Adjacent aryl
groups
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3-4- Strained Alkyne
3- Copper free Alkyne-Azide Cycloaddition
Adjacent aryl group s: synthesis
L. S. Campbell-Verduyn, PhD-thesis
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3-4- Strained Alkyne
3- Copper free Alkyne-Azide Cycloaddition
Commercial compounds
1 mg : 21
10 mg : 55
5 mg : 47
Dibenzocyclooctyne-fluor 488
1 mg : 68
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4-1- Introduction
4- Staudinger ligation
Staudinger (Nobel Laureate -1953) and Meyer first reported in 1919 that azides react
smoothly with triaryl phosphines to form iminophosphoranes after elimination of
nitrogen
iminophosphoranes
Reactivity of iminophosphoranes
aza-ylide
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Saxon, E. and Bertozzi, C. Cell surface engineering by a modified Staudinger reaction. Science, 2000, 287:2007-10 33
4-2- Application in biology
4- Staudinger ligation
Used for the production of bioconjugate : Saxon and Bertozzi, 2000
Azides are ideal for bioorthogonal chemical reporter strategies.
Azide-functionnlized natural substrates can be incorporated in bio-synthesis of
peptide, polysaccharides etc
Small
Stable in physiological conditions
Have metabolic precursors compatible with existing cellular machinery
Not found in many natural species
Reacts only with soft nucleophiles (highly selective)
-
Saxon, E. and Bertozzi, C. Cell surface engineering by a modified Staudinger reaction. Science, 2000, 287:2007-10 34
4-2- Application in biology
4- Staudinger ligation
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4-2- Application in biology
4- Staudinger ligation
Zhang et al., Molecules, 2013, 18, 7145
Concept
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4-3- Application in biology - Example
4- Staudinger ligation
Bertozzi. Nature. 2004, 430, 873
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4-4- Traceless Staudinger Ligation
4- Staudinger ligation
Incorporation of triphenylphosphine oxide
moiety
Traceless Staudinger Ligation = Without the incorporation of triphenylphosphine oxide
in the final conjugate
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4-4- Traceless Staudinger Ligation
4- Staudinger ligation
Goal : amide bond formation but without the incorporation of the unnatural
phosphine oxide moiety in the final product.
Developed by Bertozzi and Raines simultaneously
Saxon, E.; Armstrong, C.R.; Bertozzi, C.R. Org. Lett. 2000, 2, 2141.
Nilsson, B.L.; Kiessling, L.L.; Raines, R.T. Org. Lett. 2000, 2, 1939.
The auxiliary phosphine reagent can be cleaved from the final product after the ligation
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4-4- Traceless Staudinger Ligation
4- Staudinger ligation
Mercaptomethylenediphenylphosphine
Nilsson, B.L.; Kiessling, L.L.; Raines, R.T. Org. Lett. 2000, 2, 1939.
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4-4- Traceless Staudinger Ligation
4- Staudinger ligation
Phenol-phosphine
Saxon, E.; Armstrong, C.R.; Bertozzi, C.R. Org. Lett. 2000, 2, 2141.
PPh2
O
O
R2
-N N+
N
RP+
O
R2
O
PhPh
-NR
P+
O-Ph
Ph
N
R
R2
OH2OPPh2
OH OHN
RR2
O
P+
O
PhPh
NR
-O R2
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4-5- Examples
4- Staudinger ligation
Context: Dynamic alterations in cell surface glycosylation occur in numerous biological processes that involve cellcell communication and cell migration. We report here imaging of cell surface glycosylation in live mice using double click chemistry.
Brindle et al., Bioconjugate Chem., 2013, 24, 924-941
Copper free Huisgen Staudinger ligation
1st Click
2ndClick
Diels Alder
Mice were injected i.p. daily for 3 days
with peracetylated azido-labeled N-
acetylgalactosamine
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4-5- Examples
4- Staudinger ligation
Context: Dynamic alterations in cell surface glycosylation occur in numerous biological processes that involve cellcell communication and cell migration. We report here imaging of cell surface glycosylation in live mice using double click chemistry.
Brindle et al., Bioconjugate Chem., 2013, 24, 924-941
1st Click
2ndClick
Imagerie des tumeurs
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5-1- Synthesis of isocyanate and isothiocyanante
5- Isocyanate / isothiocyante
Phosgene route
DiphosgeneAliphatic
or
Aromatic
amine
hydrochloride
Non
Nucleophilic
amine
Eckstein et al., J. Org. Chem., 1996, 61, 3883
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44
5- Isocyanate / isothiocyante
Curtius rearrangement
Diphenylphosphoryl azide
5-1- Synthesis of isocyanate and isothiocyanante
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45
5- Isocyanate / isothiocyante
Synthesis of isothiocyanante
5-1- Synthesis of isocyanate and isothiocyanante
With CS2
With thiophosgene
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46
5- Isocyanate / isothiocyante
Isocyanate
More reactive
Use to produce polymers
Tolune diisocyanate(2,6 TDI)
Polyaddition
Polyurethanes
(carbamates)
With diol : polyurethanes
With diamine: polyurea
C NHHN
H
H
O
NH
HN
O
HN C
H
H
NH
NH
O
HN
O
Polyurea
5-2- Reactivity of isocyanate and isothiocyanante
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47
5- Isocyanate / isothiocyante
isothiocyanante
5-2- Reactivity of isocyanate and isothiocyanante
Less reactive than isocyanate
Compatible with biologic materials and environment
Acharya et al., Bioconjugate Chem., 2008, 19, 1352-13620
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5- Isocyanate / isothiocyante
isothiocyanante
5-2- Reactivity of isocyanate and isothiocyanante
Less reactive than isocyanate
Compatible with biologic materials and environment
Acharya et al., Bioconjugate Chem., 2008, 19, 1352-13620
pH 8.5
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49
6-1- Synthesis of epoxide
6- Epoxide
If a ketone is present, Baeyer-
Villiger reaction may occur.
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50
6-2- Reactivity of epoxide
6- Epoxide
With thiol
Hoyle et al., Chem. Soc. Rev., 2010, 39, 1355-1387
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51
6-2- Reactivity of epoxide
6- Epoxide
With primary amine
With secondary amine
M. R. Saidi, Org. Lett., 2005, 7, 3649-3651
Love et al., PNAS, 2010, 107, 1864-1869
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6-2- Reactivity of epoxide
6- Epoxide
With thiol
Hoyle et al., Chem. Soc. Rev., 2010, 39, 1355-1387
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53
6-2- Examples
6- Epoxide
L. D. S. Yadav et al., Synthesis, 2012, 2353-2358.
90 %
With amine
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54
7- Thiol-ene
7-1- Thiol-Michael addition
With a base
With a nucleophile
Nu : Phosphine (better than amine as catalyst)
In water : use of TCEP : Tris(2-carboxyethyl)phosphine)
TCEP
-
55
7- Thiol-ene
7-1- Thiol-Michael addition
M.G. Finn et al., J. Am. Chem. Soc., 2009, 131, 9986-94
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56
7- Thiol-ene
7-2- Thiol-radical click
Initiation : Photochemical, Thermal, Redox
Photochemical : DMPA (2,2-Dimethoxy-2-phenylacetophenone)
DMPA
Thermal: AIBN
Decomposition above 65C
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57
7- Thiol-ene
7-2- Thiol-radical click
Propagation and chain transfer
-
58
7- Thiol-ene
7-2- Thiol-radical click
Example
h, 60 min
DMPA
General procedure for thiol-ene reaction.The thiol-ene reaction between Gn(OHx)-Enez and cysteaminehydrochloride (3.0 eq to each ene moiety) was carried out using2,2-dimethoxy-2-phenylacetophenone (0.05 eq. to each enemoiety) as photo-initiator in methanol. The reaction mixture wassparged with dry nitrogen for about 20 mins and then exposed tothe hand-held UV-lamp (exc = 365nm) for 60 minutes. Triethylamine andwater were then added to the reaction mixture until the pH of thesolution became 10 (to neutralize the hydrochloride salt andobtain free amines). Methanol and excess triethylamine werethen removed under reduced pressure.
C.J. Hawker et al., ChemComm, 2010, 46, 1556-1558
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59
8- Thiol-yne
8-1- Mechanism
-
60
8- Thiol-yne
8-2- Experimental conditions
Xu et al.,
ChemComm., 2011, 47, 3930-3932
Xu et al.,
ChemComm., 2011, 47, 7509-7511
Shiu et al.,
ChemEur J., 2009, 15, 3839-3850
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61
8- Thiol-yne
8-2- Examples
Lowe et al., J. Am. Chem. Soc., 2009, 131, 5751-5753
-
62Wendeln et al., Langmuir, 2010, 26, 15966-15971
8- Thiol-yne
8-2- Examples
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63
9- Novel developments
Tyrosine-Click reaction
C.F. Barbas, Bioconjugate Chem., 2013, 24, 520-532
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64
9- Novel developments
Diels Alder reaction
furane maleimide
84%
-
65
9- Novel developments
Dienophile (maleimide)
Diene (furane)
NHS, DCC, 1,4-dioxane, RT
puis amine + NaHCO3, H2O, 50C
Reactions for the synthesis of PEG-amine
Diels Alder reaction
-
66
9- Novel developments
Reactions for the synthesis of maleimide-PEG (A)
furane maleimide
84%
Mitsunobu
Retro-DA
Diels Alder reaction
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67
9- Novel developments
Reactions for the synthesis of maleimide-PEG (A)
furane maleimide
84%
Direct Mitsunobu reaction
with maleimide : low yield
Mitsunobu
Retro-DA
Diels Alder reaction
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68
10- Conclusion
Many reactions available
Many application in material sciences, biology etc..
New reaction are welcome
A good strategy to produce complex molecules