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Click Chemistry : A ‘Click’ away from discovery. David Marcoux Charette’s Laboratories February 6 th. Table of Contents. Introduction Concept of ‘Click Chemistry’ ‘Click Reaction’ ‘Click Application’ ‘Click Conclusion’. Table of Contents. Introduction Concept of ‘Click Chemistry’ - PowerPoint PPT Presentation
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Click Chemistry : A ‘Click’ Click Chemistry : A ‘Click’ away from discovery.away from discovery.
David MarcouxCharette’s Laboratories
February 6th
Table of ContentsTable of Contents
1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’
Table of ContentsTable of Contents
1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’
Chemistry of LifeChemistry of Life
????????
Jean-Nicolas
Amino acids
Nucleotides
Sugars
Polynucleotides
Polysaccaharides
Polypeptides
Primary metabolites
ATP ADP
Complexe molecules
Secondary metabolites
Nature’s ChemistryNature’s Chemistry
Polypetides : Enzymes - Catalyze carbonyl chemistry - Make C-C bond - Efficiently - Regiospecifically - Stereospecifically
Lots of complexes enzymes to make spefic reactions.And it took a few billions years to get there !!
For a chemist ...
Chemist’s ChemistryChemist’s ChemistryO
2H+ O OH
H = - 3 kcal mol-1
O LDA OLiO
O OHi.
ii. H+Play on H
Play on S
G = H - TS
O
O O
O
OMeOMe OMe+ MeOH
Chemist’s ChemistryChemist’s ChemistryChemists developped many transformations to access polyfunctionalized molecules.
With theses transformations, they synthesize complexe secondary metabolites with interesting structure.
They try to repeat what enzymes do so well !!
Pharmaceutical industries :
Interesting natural product
Lead compound
SAR studies
Manipulation offunctional groups
Therapeutic agent
Finally !!
Process Chemistry
Have fun !!N
OHH
O
H
OHO
S
NH2
6 years
N
OHH
O
H
OHO
S
NH
N
O
Drug DiscoveryDrug DiscoveryThe way organic synthesis is done has pervasive ef fects on the entire process of drug dicovery, development, and manuf acture.
Thus, the way that drugs discovery is performed todayrequires time and money wich lead to expensive drugs.
Let's go back with our best friend : nature !
Amino acids
Nucleotides
Sugars
Polynucleotides
Polysaccaharides
Polypeptides
Primary metabolites
ATP ADP
Complexe molecules
Secondary metabolites
Reversible simpleC-X bonds are made
Sophisticated C-Cbonds are made
Nature’s ChemistryNature’s Chemistry
Primary metabolites - less than 6 continuous C - Contain many C-X
CH C
CH3
OH
O
H2N CH C
CH
HN
O
CH3
CH3
Nature is thus a combinatorial chemist :
From approximately 35-40 building blocks, it makes a diversity of biopolymer with simple C-X bond formation.
Primary metabolites
Sharpless Point of ViewSharpless Point of View
So, why do we spend time and money to synthetize secondary metabolites by difficult C-C bond formation ?
If such 'new' C-C bonds are required, it is best to make them intramolecularly, but it is better still to leave the really tough C-C bond synthesis to nature.
How to think about drug discovery then ? Think about it as a 'Process Chemistry' point of view ! all searches must be restrited to molecules that are easy to make !! Make easy molecule and look for potential properties.
Table of ContentsTable of Contents
1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’
K. Barry SharplessK. Barry Sharpless
BA, Dartmouth College (T. A. Spencer), 1963PhD, Stanford University (E. E. van Tamelen), 1968postdoctoral, Stanford University (J. P. Collman), 1968postdoctoral, Harvard University (K. Bloch), 1969
Massachusetts Institute of Technology, 1970–7, 1980–90 Arthur C. Cope Professor, 1987–90Stanford University, 1977–80The Scripps Research Institute, W. M. Keck Prof, 1990–Skaggs Institute for Chemical Biology of TSRI, 1996–Kitasato University, Visiting Professor, 2002–
1976 : Catalytic amino and dihydroxylation1979 : Asymetric dihyroxylation1980 : Catalytic asymetric epoxydation1987 : Catalytic asymetric dihydroxylation1996 : Catalytic asymetric aminodihydroxylation2001 : Click Chemistry2001 : Nobel laureate (with Knowles and Noyori)
K. Barry SharplessK. Barry SharplessAward for Creative Work in Organic Synthesis, 1983Arthur C. Cope Scholar, 1986Harrison Howe Award, Rochester Section, 1987Remsen Award, Maryland Section, 1989Arthur C. Cope Award, 1992San Diego Scientist of the Year, San Diego Section, 1992Roger Adams Award in Organic Chemistry, 1997Top 75 Contributors to the Chemical Enterprise, 1998Richards Medal, Northeastern Section, 1998Carothers Award, Delaware Section, 1999Allan Day Award, Philadelphia Organic Chemists Club, 1985Dr. Paul Janssen Prize, Belgium, 1986 (1st recipient)Prelog Medal, ETH, Switzerland, 1988Sammet Award, Göthe University, Frankfurt-am-Main, 1988Chemical Pioneer Award, American Institute of Chemists, 1988Scheele Medal, Swedish Academy of Pharma Sciences, 1991Tetrahedron Prize (with Noyori), 1993Centenary Lectureship Medal, Royal Society of Chemistry, 1993Cliff Hamilton Award, University of Nebraska, Lincoln, 1995King Faisal Prize for Science, Saudi Arabia, 1995Microbial Chemistry Medal, Kitasato Institute, Tokyo, 1997Harvey Science & Technology Prize, Israel Inst of Tech, 1998Rylander Award, Organic Reactions Catalysis Society, 2000Chemical Sciences Award, National Academy of Sciences, 2000Chiralty Medal, Italian Chemical Society, 2000Rhone Poulenc Medal, Royal Society of Chemistry, 2000Benjamin Franklin Medal, Franklin Institute, Philadelphia, 2001Wolf Prize (with Kagan & Noyori), Weizmann Institute, 2001John Scott Medal Award, City of Philadelphia, 2001ISI Highly Cited Researchers Database, original member, 2001Nobel Prize in Chemistry (with Knowles & Noyori), 2001Distinguished Professor (Hon), Hong Kong Polytechnic University, Hong Kong, 2002
Click ChemistryClick Chemistry
Top 10 of most requested chemistry journal article :
2004 - Top 2 : The growing impact of click chemistry on drug discovery Sharpless in Drug Discovery Today (2003) - Top 7 : Click Chemistry : diverse chemical function from a few good reaction Sharpless in Angew. Chm., Int. Ed. (2001)
2005 - Top 8 : Towards organo-click chemistry : Development of organocatalytic multicomponent reaction through combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder, and Huisgen cycloaddition reactions. Barbas in Chem. Eur. J. - Top 9 : Click Chemistry : diverse chemical function from a few good reaction Sharpless in Angew. Chm., Int. Ed. (2001)
2006 - Top 8 : Click Chemistry : diverse chemical function from a few good reaction Sharpless in Angew. Chm., Int. Ed. (2001)
Click Chemistry : over 700 publications on the subject since 1999
Click ChemistryClick Chemistry
Such reaction would make a diversity of product from different 'blocks' in both small- and large-scale application ... CLICK CHEMISTRY !
Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
Do what nature do so easily and what is easier to do in the lab : C-X bond !
A 'CLICK REACTION' would : - be modular - be wide in scope - give very high yields - generate only inoffensive byproducts (easily removed) - be stereospecific (not necessarily enantioselective) - required simple reaction conditions - required readily available reagents and starting material - required no or benign solvent or easily removable solvent - required simple product isolation and purification (no Flash) - gives product that are stable in physiological conditions - be atom economic - have a high thermodynamic driving force (more than 20 kcal mol-1)
A 'CLICK REACTION' would : - be modular - be wide in scope - give very high yields - generate only inoffensive byproducts (easily removed) - be stereospecific (not necessarily enantioselective) - required simple reaction conditions - required readily available reagents and starting material - required no or benign solvent or easily removable solvent - required simple product isolation and purification (no Flash) - gives product that are stable in physiological conditions - be atom economic - have a high thermodynamic driving force (more than 20 kcal mol-1)
Click ChemistryClick Chemistry
Starting MaterialsRemember : let C-C bond formation to nature ! - Fatty acids - Terpenes - Etc.
Petroleum : metabolites made from ancien organisms contains many C-C bonds mainly saturated
Petrochemistry :
n
SteamCraking
n + CH4H +S + G = H - TS
Many other efficient process that give readily and useful material :
- Alkenes- Alkynes- Aromatic compounds
Wittcoff, H. A.; Reuben, B. G. Industr ial Organic Chemicals, Wiley, New York, 1996
Benign SolventBenign Solvent
Water is the solvent of choice :
- Free energies of oganic molecules are substantially greater when poorly solvated by water, and often impart increase reactivity.- Perfect milieu of hydrogene bonding which helps reaction such as ring opening of small ring.- Afforded the greatest leverage for differentiating the reactivities of competing hard and soft species.- High heat capacity and high boiling point- Low cost- Low environmental impact
‘‘CLICK REACTIONS’CLICK REACTIONS’
Cycloaddition : 1,3-dipolar cycloaddition Diels-Alder
Nucleophilic substitution : Ring-opening of strained heterocycle electrophile Epoxide, aziridine, aziridinium, episulfonium
Carbonyl chemistry (non aldol) : Formation of ureas, thioureas, aromatic heterocycles, Oxime ether, hydrazones, amides
Addition to C-C multiple bond : epoxidation, dihydroxylation, aziridination, Michael addition
Protection reaction : Ms, Ts ...
Solid-Phase SynthesisSolid-Phase Synthesis
Why is it that popular ?
Because it has a 'click' status ! - high yield - easy purification
BUT ! : - large excess of reactants is needed - very expensive - highly wasteful - not efficient for large scale - difficult to analyze intermediates - installation and cleavage of a linkage
Table of ContentsTable of Contents
1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’
Hantzsch Ester SynthesisHantzsch Ester Synthesis
R1
O
R2 O
O
R3
NH3
R1
O
R2O
neat (or alcohol)heat
2-20 h
NH
R2 R2
O
R1
O
R1
R3
Bergstom, F. W. Chem. Rev. 1944, 35, 77.
EpoxidationEpoxidation
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; Wiley-VCH: Weinheim, 2000; Chapter 6A
R OH
Ti(OR)4tartrate
tBuOOHDCM
R OH
O
- Readily available starting materials- Allylic alcohol must be present - Low loading due to ligand acceleration effect of tartrate- MS enhances reactivity- Good chemical yields and good enantiocontrol
EtO
O
OH
OH
O
OEt
(+)-DET
EtO
O
OH
OH
O
OEt
(-)-DET
DihydroxylationDihydroxylation
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetr ic Synthesis; Ojima, I. Ed.; Wiley-VCH: Weinheim, 2000; Chapter 6D
R'R
R'R
OH
OH
Os (cat)cinchona (cat)
reoxidant
N
MeO
OR
N
H
DHQ
- No directing group needed- Low level of Os required- Cinchona alcaloides are readily available- Tolerate water and air- Applicable on large scale
Small Rings OpeningSmall Rings OpeningOO
MeOH:BnNH21:1
reflux, 90 %
OH
NHBn
BnHNHO
OBnHN
OH
BnNH2
150 oC94 %
OH NHBnHO
BnHN
OOH
NHBn
NTs
PhSNa
MeOH
NHTs
SPh
SPh
NHTs
NAc
PhSNa
MeOH
NHAc
SPh
SPh
NHAc
16 1
1 30Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
Small Rings OpeningSmall Rings Opening
Chuang, T.-H.; Sharpless, K. B. Org. Lett. 1999, 1, 1435.
OEt
OO morpholine
EtOHreflux
12h, 76 %OEt
ON
OH
O
MsClEt3N
DCM94 %
N
OEtO
Cl
OEt
OCl
N
O
NuH (1.2 equiv)K2CO3MeCN
60 oC, 12 h79-93 %
ratio 92:8 to 100:0
OEt
ONu
N
O
OEt
ON
Nu
O
+
NuH : Alkyl- and aryl-amine 1o, 2o amine NH3
Small Rings OpeningSmall Rings Opening
Chuang, T.-H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555.
OEt
OO morpholine
EtOHreflux
12h, 96 %OEt
ON
OH
O
OEt
OOH
N
O87:13
+MsCl, Et3N
DCM, 0 oC96 %
OEt
OCl
N
O
OEt
ONHR
N
O
RNH2
68-99 %MeMgBr
THF
0 oC88-99 %
NO
N
O
R
Beta-LactamBeta-Lactam
Clavulanic acid
Small Rings OpeningSmall Rings Opening
Chuang, T.-H.; Sharpless, K. B. HeIv. Chim. Acta 2000, 83, 1734.
OEt
OCl
N
O
N2H4K2CO3MeCN
60 oC, 12h
HN NH
Ph
NR2
O
N N
Ph
NR2
O
ArN N
Ph
NR2
O
E
EPh
N N
Ph
NR2
O
E
EPh
N N
Ph
NR2
O
E
MePh
N N
Ph
NR2
O
NHPh N N
Ph
NR2
O
Ph
NO
O
Ph
ArCHO, TFAEtOH, 61-88 %
TetrazoleTetrazoleR
NNaN3
Lewis acid or acid
DMF
N
NNH
N
R
R
NNaN3ZnBr2
H2O, 100-170 oC2-48 h
N
NNH
N
R
57-96 %
R
N MN3
N
NM
NN N
NN
N
R
M
R
N MN3
R
N
M
NN
N N
NN
N
RM
Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
TetrazoleTetrazole
Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091.
YN N N
N
n
140 oCDMF
N
Y
NN
N
n
TsON3
NaSCN
DMF, 130 oC N
S
NN
N
96 %
N3
OH BrCNEt3N
DCMrt N
O
N N
N
N3
NH2 BrCN
DCMrt N
HN
N N
N
71 %
92 %
TetrazoleTetrazole
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2110.
RZ
N
Z = O, S, N, C
+ N
N
NX
N
NN
N
R X
X = M, H, C
Most nitriles are not enough dipolarophile to engage organic azide and expand the scope of the reaction.
Solution :S
O O
N
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2110.
As the reactions are run neat and only one equivalent of each reagent is needed, there are no side products, and no work up is needed, other than chipping the stir bar away f rom the solid product.
... the yields are virtually quantitative, and as the processis run neat, no purif ication is needed; truly a 'Click Reaction'.
TetrazoleTetrazole
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2110.
N
NN
N
Ph
Ts
PhSHN
NN
N
Ph
SPh95 %
TetrazoleTetrazole
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2113.
SO O
NN
O
R
Polyfunctionalized TetrazolePolyfunctionalized Tetrazole
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2113.
Nu + TsCN +N
N
NN N
NNNu
Nu + +N
N
NN N
NN
Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2110.
O
O2N
N
ONu
O
« Cream of the Crop »« Cream of the Crop »Huisgen Cycloaddition
1,3-Dipolar Cycloaddition
Huisgen, R. in 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed., Wiley: New York, 1984, Chapter 1, pp 1-176.
R + R1A
AA A
AA
R1
R
+A
AA
R
R1heat
R + R1A
AA A
AA
R1
R
+A
AA
R
R1heatR
R R
1,4 and 1,5 Triazole1,4 and 1,5 Triazole
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
R + R1N
NN
Cu (I) 1 mol %
H2O/tBuOHrt, 8h
NN
NR1
R
+N
NN
R
R1
1 : 1
Ph ON
N N Ph NN
N
heat
Ph
OPh
91 % only one regio.
Without copper : neat, 92 oC, 18h gives 1.6:1 ratio, no yield reported
Sources of Cu(I)Sources of Cu(I)
Cu (I)
A 'click reaction' has to be user friendly, do not require Ar atmosphere ....
+
O
O OH
ONaHHO
HO2
sodium ascorbate
CuSO4 Cu2(SO4) + Na2SO4 +
O
O O
OHHO
HO
CuSO4 + Cu(s) Cu2SO4
Typically : CuSO4 5 H2O (1 mol %), sodium ascorbate (5 mol %), H2O/tBuOH, rt, 8h
MechanismMechanism
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodlemann, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
1,5 Triazole1,5 TriazoleN
NNR
R
NN
NR
R
1,4 1,5
R
i. EtMgBrii. R'N3
iii. H+
NN
NR'
R
R
EtMgBr
- EtH R
MgBr NN N
R'
R
NN
NR'
MgBr
NN
N R'
RBrMg
ENN
N R'
RE
Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
1,5 Triazole1,5 Triazole
Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
1,5 Triazole1,5 Triazole
Zhang, L.; Chen, X.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
NN
N
+ NN
N NN
N
+
Cu (I) 0 100
Ru(OAc)2(PPh3)2 0 100CpRuCl(PPh3)2 85 15Cp*RuCl(PPh3)2 100 0
M
MechanismMechanism
Zhang, L.; Chen, X.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
Ru ClN
NNR
R
Ru Cl
N NN
R
R
R
R NN
N
NN
NR
R
Table of ContentsTable of Contents
1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’
Multi-Step Click ChemistryMulti-Step Click Chemistry
OO
OO
NaN3, NH4Cl
H2O, reflux
NaN3, NH4Cl
H2O, reflux
HO
N3N3
OH
N3
N3HO
OH
5 g
5 g
97 %8.5 g
97 %8.5 g
EE
H2O, 70 oC
EE
H2O, 70 oC
N
OH OHN
N N
NN
E
E
NN
OH
OHN
N
N N
E
E
E
E
E
E
97 %22.4 g
97 %22.4 g
Multi-Step Click ChemistryMulti-Step Click Chemistry
N
OH OHN
N N
NN
H3COOC
E
NN
OH
OHN
N
N N
H3COOC
E
E
E
E
E
97 %22.4 g
97 %22.4 g
iPr2EtN, Tol.
reflux
iPr2EtN, Tol.
reflux
N
OH
NN
E
E ON
O
NN
E
85 %17.4 g
N
OH
NN
E
E
ON
O
NN
E
81 %16.7 g
In SituIn Situ Click Chemistry Click Chemistry
Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc. 2005, 127, 6686.Bourne, Y.; Kolb, H. C.; Ridic, Z.; Sharpless, K. B.; Taylor, P.; Marchot, P. Proc. Natl. Acad. Sci. U.S.A 2004, 101, 1449.Manetsch, R.; Krasinski, A.; Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc. 2004, 126, 665.Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 1053.
In SituIn Situ Click Chemistry Click Chemistry
In SituIn Situ Click Chemistry Click Chemistry
NH
Ph
MeO
MeO
OO
OO
O
COOH
RecristallisationiPrOH
NH
Ph
MeO
MeO
NH
Ph
MeO
MeO
Crystals
Liquor mother
K2CO3
Iodoalkyne
K2CO3
Iodoalkyne
N
Ph
MeO
MeO n
N
Ph
MeO
MeO n
n = 5 and 6
N
Ph
MeO
MeO n
n = 5 and 6
N
NH
N3
CuI, MeCNN
Ph
MeO
MeOn
n = 5 and 6
N NN
N
NH
In SituIn Situ Click Chemistry Click Chemistry
N
Ph
MeO
MeO n
n = 5 and 6
N
NH
N3N
Ph
MeO
MeO n
n = 5 and 6
EtMgBr
N NN
N
NH
In SituIn Situ Click Chemistry Click Chemistry
Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588.
Polymer ChemistryPolymer Chemistry
O
Cl mCPBAO
OCl
O
O
O
Cl
O
O
O4 5
xn m
NaN3DMF
O
N3
O
O
O4 5
xn m
R
CuI/Base
O
N
O
O
O4 5
xn m
NN
R
Riva, R.; Schmeits, S.; Jérome, C.; Jérome, R.; Lecomte, P. Macromelecules ASAP
Polymer ChemistryPolymer Chemistry
Laurent, B. A.; Grayson, S. M. J. Am. Chem. Soc. 2006, 128, 4238.
O O
Brn
NaN3O O
N3n
O O
n
Cu(I)N
NN
BiologyBiology
Prescher, J. A.; Dube, D. H.; Bertozzi, C. R. Nature 2004, 430, 873.
BiologyBiology
Link, A. J.; Vink, M. K.; Tirell, D. A. J. Am. Chem. Soc. 2004, 126, 10598.
Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686.
Review : Prescher, J. A.; Bertozzi, C. R. Nature Chem. Biol. 2005, 1, 13.
BiologyBiology
Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046.
ColumnColumn
Wang resin Immobilised initiator
“clickable” polymer
Multivalent ligand Lectin conjugate
“click”
ColumnColumn
Reagent and conditionsReagent and conditions: a) 2-bromo-2-methyl-propionyl bromide, triethylamine, DMAP, CH2Cl2, b) methacrylic acid 3-trimethylsilanyl-prop-2-ynyl ester, Cu(I)Br/ N-(n-propyl)-2 pyridylmethanimine, toluene, 60 ºC, c) TBAF·3H2O, acetic acid, THF, -20 to 25 ºC d) (PPh3)3Cu(I)Br, -(3-azido-1-propyl)-D-mannose, DIPEA, 60 ºC.
O
OBr
OH O
O
Br
OO
Si
n
O
O
Br
OOn
O
O
Br
OOn
NN
N
OHO
HO
OH
O
OH
a b c
d
wang resin
Click ColumnsClick Columns
OSi
O OEtN3 +
OH Cu(I)
OSi
O OEtN
NN
OH
"The team prepared several 'Click Column' using packings functionalised throughthe click process."
Click-Click ChemistryClick-Click Chemistry
OTMS
PheGlyGlyO O
i. CuSO4 (10 mol %) Naascorbate (20 mol %) tBuOH/H2O 35 oC 18h
N3
O
aa1
OTMS
PheGlyGlyO O
N NN
i. CuSO4 (10 mol %) Naascorbate (20 mol %) AgPF6 (20 mol %) tBuOH/H2O 35 oC 18h
N3
O
aa2
O
PheGlyGlyO O
N NN
NN
N
88-93 %
Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
A methodology for the successive regiospecif ic "Clicking" together...
Chemoselective Formation of Successive Triazole Linkage in One Pot :"Click-Click" Chemistry
1aaO
O aa2
1aaO
Click ConclusionClick Conclusion• Nice concept to facilitate drug discovery
• Revisited Chemistry
• Lots of applications
• We will continue to hear about it
Click ConclusionClick Conclusion• Click can now be used as
– A noun : click– Verb : clicking– Adverb : clickable– Click-Click