click chemistry : a ‘click’ away from discovery

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Click Chemistry : A Click Chemistry : A ‘Click’ away from ‘Click’ away from discovery. discovery. David Marcoux Charette’s Laboratories February 6 th

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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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Page 1: Click Chemistry : A ‘Click’ away from discovery

Click Chemistry : A ‘Click’ Click Chemistry : A ‘Click’ away from discovery.away from discovery.

David MarcouxCharette’s Laboratories

February 6th

Page 2: Click Chemistry : A ‘Click’ away from discovery

Table of ContentsTable of Contents

1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’

Page 3: Click Chemistry : A ‘Click’ away from discovery

Table of ContentsTable of Contents

1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’

Page 4: Click Chemistry : A ‘Click’ away from discovery

Chemistry of LifeChemistry of Life

????????

Jean-Nicolas

Amino acids

Nucleotides

Sugars

Polynucleotides

Polysaccaharides

Polypeptides

Primary metabolites

ATP ADP

Complexe molecules

Secondary metabolites

Page 5: Click Chemistry : A ‘Click’ away from discovery

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 ...

Page 6: Click Chemistry : A ‘Click’ away from discovery

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

Page 7: Click Chemistry : A ‘Click’ away from discovery

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

Page 8: Click Chemistry : A ‘Click’ away from discovery

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

Page 9: Click Chemistry : A ‘Click’ away from discovery

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

Page 10: Click Chemistry : A ‘Click’ away from discovery

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.

Page 11: Click Chemistry : A ‘Click’ away from discovery

Table of ContentsTable of Contents

1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’

Page 12: Click Chemistry : A ‘Click’ away from discovery

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)

Page 13: Click Chemistry : A ‘Click’ away from discovery

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

Page 14: Click Chemistry : A ‘Click’ away from discovery

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

Page 15: Click Chemistry : A ‘Click’ away from discovery

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)

Page 16: Click Chemistry : A ‘Click’ away from discovery

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

Page 17: Click Chemistry : A ‘Click’ away from discovery

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

Page 18: Click Chemistry : A ‘Click’ away from discovery

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

Page 19: Click Chemistry : A ‘Click’ away from discovery

‘‘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 ...

Page 20: Click Chemistry : A ‘Click’ away from discovery

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

Page 21: Click Chemistry : A ‘Click’ away from discovery

Table of ContentsTable of Contents

1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’

Page 22: Click Chemistry : A ‘Click’ away from discovery

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.

Page 23: Click Chemistry : A ‘Click’ away from discovery

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

Page 24: Click Chemistry : A ‘Click’ away from discovery

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

Page 25: Click Chemistry : A ‘Click’ away from discovery

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.

Page 26: Click Chemistry : A ‘Click’ away from discovery

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

Page 27: Click Chemistry : A ‘Click’ away from discovery

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

Page 29: Click Chemistry : A ‘Click’ away from discovery

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 %

Page 30: Click Chemistry : A ‘Click’ away from discovery

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.

Page 31: Click Chemistry : A ‘Click’ away from discovery

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 %

Page 32: Click Chemistry : A ‘Click’ away from discovery

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

Page 33: Click Chemistry : A ‘Click’ away from discovery

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'.

Page 34: Click Chemistry : A ‘Click’ away from discovery

TetrazoleTetrazole

Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2110.

N

NN

N

Ph

Ts

PhSHN

NN

N

Ph

SPh95 %

Page 35: Click Chemistry : A ‘Click’ away from discovery

TetrazoleTetrazole

Demko, Z. P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2113.

SO O

NN

O

R

Page 36: Click Chemistry : A ‘Click’ away from discovery
Page 37: Click Chemistry : A ‘Click’ away from discovery
Page 38: Click Chemistry : A ‘Click’ away from discovery

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

Page 39: Click Chemistry : A ‘Click’ away from discovery

« 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

Page 40: Click Chemistry : A ‘Click’ away from discovery

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

Page 41: Click Chemistry : A ‘Click’ away from discovery

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

Page 42: Click Chemistry : A ‘Click’ away from discovery
Page 43: Click Chemistry : A ‘Click’ away from discovery

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.

Page 44: Click Chemistry : A ‘Click’ away from discovery

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.

Page 45: Click Chemistry : A ‘Click’ away from discovery

1,5 Triazole1,5 Triazole

Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.

Page 46: Click Chemistry : A ‘Click’ away from discovery

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

Page 47: Click Chemistry : A ‘Click’ away from discovery

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

Page 48: Click Chemistry : A ‘Click’ away from discovery
Page 49: Click Chemistry : A ‘Click’ away from discovery

Table of ContentsTable of Contents

1. Introduction2. Concept of ‘Click Chemistry’3. ‘Click Reaction’4. ‘Click Application’5. ‘Click Conclusion’

Page 50: Click Chemistry : A ‘Click’ away from discovery

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

Page 51: Click Chemistry : A ‘Click’ away from discovery

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

Page 52: Click Chemistry : A ‘Click’ away from discovery

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.

Page 53: Click Chemistry : A ‘Click’ away from discovery

In SituIn Situ Click Chemistry Click Chemistry

Page 54: Click Chemistry : A ‘Click’ away from discovery

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

Page 55: Click Chemistry : A ‘Click’ away from discovery

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

Page 56: Click Chemistry : A ‘Click’ away from discovery

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.

Page 57: Click Chemistry : A ‘Click’ away from discovery

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

Page 58: Click Chemistry : A ‘Click’ away from discovery

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

Page 59: Click Chemistry : A ‘Click’ away from discovery

BiologyBiology

Prescher, J. A.; Dube, D. H.; Bertozzi, C. R. Nature 2004, 430, 873.

Page 60: Click Chemistry : A ‘Click’ away from discovery

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.

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BiologyBiology

Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046.

Page 62: Click Chemistry : A ‘Click’ away from discovery

ColumnColumn

Wang resin Immobilised initiator

“clickable” polymer

Multivalent ligand Lectin conjugate

“click”

Page 63: Click Chemistry : A ‘Click’ away from discovery

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

Page 64: Click Chemistry : A ‘Click’ away from discovery

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."

Page 65: Click Chemistry : A ‘Click’ away from discovery

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

Page 66: Click Chemistry : A ‘Click’ away from discovery

Click ConclusionClick Conclusion• Nice concept to facilitate drug discovery

• Revisited Chemistry

• Lots of applications

• We will continue to hear about it

Page 67: Click Chemistry : A ‘Click’ away from discovery

Click ConclusionClick Conclusion• Click can now be used as

– A noun : click– Verb : clicking– Adverb : clickable– Click-Click