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Click chemistry

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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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

    +

  • 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

  • 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

  • 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.

  • 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.

  • 1,5-regioisomer

    13

    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.

  • 14

    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

  • 15

    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

  • 16

    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

  • 17

    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

  • 18

    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

  • 19

    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

  • 20

    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

  • 21

    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

  • 22

    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

  • 23

    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

  • 24

    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

  • 25

    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

  • 26

    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

  • 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

  • 28

    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

  • 29

    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

  • 30

    3-4- Strained Alkyne

    3- Copper free Alkyne-Azide Cycloaddition

    Adjacent aryl group s: synthesis

    L. S. Campbell-Verduyn, PhD-thesis

  • 31

    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

  • 32

    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

  • 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

  • 35

    4-2- Application in biology

    4- Staudinger ligation

    Zhang et al., Molecules, 2013, 18, 7145

    Concept

  • 36

    4-3- Application in biology - Example

    4- Staudinger ligation

    Bertozzi. Nature. 2004, 430, 873

  • 37

    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

  • 38

    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

  • 39

    4-4- Traceless Staudinger Ligation

    4- Staudinger ligation

    Mercaptomethylenediphenylphosphine

    Nilsson, B.L.; Kiessling, L.L.; Raines, R.T. Org. Lett. 2000, 2, 1939.

  • 40

    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

  • 41

    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

  • 42

    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

  • 43

    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

  • 44

    5- Isocyanate / isothiocyante

    Curtius rearrangement

    Diphenylphosphoryl azide

    5-1- Synthesis of isocyanate and isothiocyanante

  • 45

    5- Isocyanate / isothiocyante

    Synthesis of isothiocyanante

    5-1- Synthesis of isocyanate and isothiocyanante

    With CS2

    With thiophosgene

  • 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

  • 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

  • 48

    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

  • 49

    6-1- Synthesis of epoxide

    6- Epoxide

    If a ketone is present, Baeyer-

    Villiger reaction may occur.

  • 50

    6-2- Reactivity of epoxide

    6- Epoxide

    With thiol

    Hoyle et al., Chem. Soc. Rev., 2010, 39, 1355-1387

  • 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

  • 52

    6-2- Reactivity of epoxide

    6- Epoxide

    With thiol

    Hoyle et al., Chem. Soc. Rev., 2010, 39, 1355-1387

  • 53

    6-2- Examples

    6- Epoxide

    L. D. S. Yadav et al., Synthesis, 2012, 2353-2358.

    90 %

    With amine

  • 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

  • 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

  • 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

  • 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

  • 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

  • 63

    9- Novel developments

    Tyrosine-Click reaction

    C.F. Barbas, Bioconjugate Chem., 2013, 24, 520-532

  • 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

  • 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

  • 68

    10- Conclusion

    Many reactions available

    Many application in material sciences, biology etc..

    New reaction are welcome

    A good strategy to produce complex molecules