Click Chemistry, a New Approach to Familiar Reactions. Andrea Molengraft January 26, 2005
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1 Click Chemistry, a ew Approach to Familiar eactions Andrea Molengraft January 26, 2005
2 Click Chemistry? As defined by K. B. Sharpless Click chemistry a set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds via heteroatom links (C-X-C) Click chemistry is integral now to all research within the Sharpless Lab. Borman, S. C & En. 2002, 80(6), 29.
3 Click Chemistry? Strategy for the rapid and efficient assembly of molecules with diverse functionality enabled by a few nearly perfect reactions, it guarantees reliable synthesis of the desired products in high yield and purity Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. lson, A.; Fokin, V.; Sharpless, B.; Wong,. Chem. Bio. Chem. 2003, 4, Designing powerful and selective reactions for an efficient synthesis of interesting compounds and combinatorial libraries through heteroatom links The uisgen 1,3-dipolar cycloaddition of azides and alkynes is regarded as the cream of the crop of concerted reactions Lober, S.; odriguez-loaiza, P.; Gmeiner, P. rg. Lett. 2003, 5, Synthetic appeal high yields, simple reaction conditions, tolerance of oxygen and water, and simple product isolation... elms, B.; Mynar, J; awker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126,
4 Classes of Click eactions ucleophilic opening of highly strained rings S 2 ring opening reactions Epoxides, aziridines, cyclic sulfates, cyclic sulfamidates, aziridinium ions Protecting Group eactions eversible carbonyl chemistry Acetals, ketals and their aza-analogs Cycloaddition eactions etero Diels-Alder, 1,3 dipolar cycloadditions involving heteroatoms ' 3 + ' ' + Kolb,.; Finn, M.; Sharpless, B. Angew. Chem. Int. Ed. 2001, 40, ,4 triazole 1,5 triazole
5 Applications of Triazoles Agricultural Fungicides erbicides Antimicrobial Medicinal Cytostatic Virostatic Antiinflamatory Industrial Photostabilizers Fluorescent whiteners ptical brightening agents Corrosion retardants Macromolecules Drug delivery anoscale electronics ligonucleotides Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
6 uisgen s [1,3] Dipolar Cycloaddition Cycloaddition between azides and acetylenes to form triazoles ' ' ' ,4 triazole 1,5 triazole 1: ' or ' 4 uisgen, ,3-dipolar cycloaddition- Introduction, survey, mechanism. In: Padwa, A.; ed. 1,3-dipolar Cycloaddition Chemistry (Vol. 1). Wiley. P
7 egioselectivity of Click Chemistry Addition of Cu(I)-catalyst the champion click process ' ' [Cu] Alkyne activation 1,4 triazole ostovtsev, V., Green, L., Fokin, V. Sharpless. B. Angew. Chem Int. Ed. 2002, 41, Li, Z.; Seo, T.; Ju, J. Tetrahedron. Lett. 2004, 45, 3143.
8 Proposed catalytic cycle for Cu(I)- catalyzed ligation 1 CuLn 2 1 IV CuLn 2 1 V 2 1,4 triazole Stepwise III Direct [CuLn] + 1 CuLn CuLn II I 2 ostovtsev, V.; Green, L.;Fokin, V;Sharpless. B. Angew. Chem Int. Ed. 2002, 41, Sonogashira, K.; Tohda, Y.; agihara,. Tetrahedron Lett. 1975, 16, Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
9 ostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, egioselectivity using Cu(I) CuS 4 2 (1mol%) a ascorbate (5mol%) 2 : t Bu (2:1), r.t., 8 hr 91 % ,4 substituted triazole Cu catalyzed: neat, 92 o C, 18 h (1,4) (1,5) 1.6 : 1 + Thermal:
10 Functional Group Tolerance Ph 92 % Ph 88 % ' 4 5 CuS 4 (1mol%) a ascorbate (10 mol%) 2 : t Bu hr. Ph Ph Ph Ph 93% 82% 84 % Ph Ph 84 % 88 % [ ] M 91 % Ph Et 2 90 % 2 S 2 2 ostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, % 94 %
11 egioselectivity of Click Chemistry Addition of Cu(I)-catalyst the champion click process ' ' [Cu] Alkyne activation 1,4 triazole ostovtsev, V.; Green, L.; Fokin, V.; Sharpless, B. Angew. Chem Int. Ed. 2002, 41, Li, Z.; Seo, T.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.
12 egioselectivity by Alkyne Activation no [Cu] CuCl (0.1eq.), 1 h Et Et Et 81% /A Et + 3 2, rt, 6-12 h Et 94% Et /A ' '' Et Me 82% 90% Et S 67% 85% Li, Z.; Seo, T.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.
13 Click Applications in Macromolecules Dendrimer Synthesis Solid Support Chemistry SPS SPPS DA functionalization
14 Dendrimer Synthesis Divergent-Growth Convergent-Growth Tomalia, I. Polymer J. 1985, 17, 117. Frechet, J.; awker, C. J. Amer. Chem. Soc. 1990, 112, 7638.
15 Dendrimer Synthesis + 1. CuS 4 (5 mol %) X Cl a ascorbate (10 mol %) 2 / t Bu (1:1) X Cl equiv a 3, acetone/ 2 (4:1) 60 o C, 1-3 h X 3 1 st Generation [G-1] > 95% [G-1] 2 equiv. + X Cl 1. CuS 4 (5 mol %) a ascorbate (10 mol %) 2 / t Bu (1:1) equiv a 3, acetone/ 2 (4:1) 60 o C, 1-3 h X X 3 X 2 nd Generation [G-2] X X X X X X X > 90% 3 3 rd Generation [G-3] Wu, P.; Feldman, A.; ugent, A.; awker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, 3928.
16 Dendrimer Synthesis Azides: 3 3 Bu t Alkynes: branching "cores" S Cl Cl Cl Central "cores"
17 Dendrimer Synthesis 4 th generation dendrimer synthesis X X X X 3 + Cl X X Cu(I) r.t., 30 h X 3 3 rd Generation [G-3] Wu, P.; Feldman, A.; ugent, A.; awker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, 3928.
18 Wu, P.; Feldman, A.; ugent, A.; awker, C.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.; Sharpless, B.; Fokin, V. Angew. Chem. Int. Ed. 2004, 43, % yield
19 Dendronized linear polymers Three main pathways I grafting-to + II grafting-from III incorporate dendrons into the monomer elms, B.; Mynar,J; awker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126,
20 Dendronized linear polymers Br + TMS Pd/Cl 2 (PPh 3 ) 2 CuI, Et 3 AIB 60 o C, 24 h n K, 2 TF, Me n TMS TMS poly vinylacetylene (PV acet) n + CuS (5 mol %) a ascorbate (10 mol %) 1:1 TF/ 2 n 3 PV acet 1st generation dendrimer Quantitative yield chiai, B.; Tomalia, I.; Endo, T. Macromol. Chem. Phys. 2001, 202, elms, B.; Mynar, J.; awker, C.; Frechet, J. J. Am. Chem. Soc. 2004, 126,
21 Click Applications in Macromolecules Dendrimer Synthesis Solid Support Chemistry SPS SPPS DA functionalization
22 Click Chemistry Using a Solid Support Solid Phase rganic Synthesis (SPS) Solid Phase Peptide Synthesis (SPPS) 3
23 SPS: Solid Phase rganic Synthesis BAL esin: C Ar C Ar C "Click" esin 3 + Ar C Ar C Lober, S.; odriguez-loaiza, P.; Gmeiner, P. rg. Lett. 2003, 5, 1753.
24 SPS: Library of Tertiary Amines Ar "click" C Ar C BAL Library of amides (Backbone Amide Linker) 3 "click" EM Library of tertiary amines (egenerative Michael Acceptor) = polystyrene Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
25 SPS: Library of Tertiary Amines Triazolylmethyl acrylate (TMA) esin Cl a 3 3, DMS, 70 o C, 48 h CuI,DMF, TF,DIPEA 35 o C, 10 h TMA esin benzylmethylamine DMF rt, 16 h Cl TMA esin + Cl Cl Br 1. Cl DMS, rt, 16h 2. TEA, DMF, rt, 16 h Bn 68% 66% Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
26 Parallel synthesis: TMA & EM esins -' ' 1. ''Br 2. cleavage ''' TMA esin a-e TMA yield (purity) EM yield (purity) tetrahydro-isochinoline a b Tetrahydro-isochinoline Tetrahydro-isochinoline Allyl p-itrobenzyl 82 (95) 77 (92) 88 (>90) 63 (>90) c d Tetrahydro-isochinoline -Phenyl-piperazine C 2 C 2 Me Allyl 75 (92) 79 (93) 73 (>90) 75 (>90) -phenyl piperazine e -Phenyl-piperazine p-itrobenzyl 53 (91) 47 (>90) Lober, S.; Gmeiner, P. Tetrahedron, 2004, 60, 8699.
27 SPS: Selective eceptor Ligands 3 = polystyrene Ar "click" C C Ar SPS by BAL Library of lead amides C ' C FAMT: Formyl Aryloxy Methyl Triazole FIMT: Formyl Indole Methyl Triazole FAMT FIMT Lober, S.; odriguez-loaiza, P.; Gmeiner, P. rg. Lett. 2003, 5, 1753.
28 SPS: Selective eceptor Ligands ' C Br DMF, K 2 C 3, 70 o C, 24 h + ' C TF, DIPEA,CuI 35 o C, 16 h FAMT ' C 3 C 1. Br + C TF, DIPEA,CuI 35 o C, 16 h TF, rt to 60 o C, 1 h 2. a, 2 rt, 0.5 h FIMT Lober, S.; odriguez-loaiza, P.; Gmeiner, P. rg. Lett. 2003, 5, 1753.
29 SPS: Selective eceptor Ligands C a-e C ' 1. 4-amino-1-benzylpiperdine, a(ac) 3 B 2. benzothiophene-2-carboxylic acid DIC, At, DIPEA, DMF, rt, 16 h Ar S Bn TFA (2% in C 2 Cl 2 ) rt, 2 h S g Bn f C C C C C C a b c d e f Yield (purity) of g 6 (>95) 9 (>95) 94 (>95) 9 (>95) 67 (>95) 94 (>95) Lober, S.; odriguez-loaiza, P.; Gmeiner, P. rg. Lett. 2003, 5, 1753.
30 Preparation of Amide Library using FIMT esins ' C f 1. A(1-5)- 2, a(ac) 2 B, C 2 Cl 2, rt, 16 h 2. B(1-4)-C 2, TFF, DIPEA, DMF, rt, 24 h TFA (2% in C 2 Cl 2 ) rt, 16 h ' % yield % purity = B1 B2 B3 B4 ' = Et C A1 A2 A3 A4 A5 Me Me S B1 B2 B3 B4 A1 A2 A3 A4 A5 55% (85%) 50% (77%) 58% (90%) 53% (90%) 60% (97%) 92% (94%) 91% (98%) 93% (93%) 90% (96%) 90% (99%) 90% (94%) 88% (97%) 93% (93%) 53% (96%) 60% (99%) 73% (85%) 74% (91%) 78% (95%) 72% (95%) 74% (99%)
31 Click Applications in Macromolecules Dendrimer Synthesis Solid Support Chemistry SPS SPPS DA functionalization
32 SPPS: Cu(I) catalysis on Solid Support Fmoc FGFG FGFG FGFG=Phe-Gly-Phe-Gly = MBA-PEGA 800 Solvents: CC C 2 Cl 2 TF toluene,-dimethylformamide -ethyldiisopropylamine Quantitative conversions & purities: 75-95% Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
33 SPPS: Cu(I) catalysis on Solid Support Fmoc FGFG FGFG=Phe-Gly-Phe-Gly = MBA-PEGA , DIPEA,Cu(I) 20% piperidine/dmf M a (aq) Fmoc a-e FGFG All conversions > 95% * 2 3 Si 3 S 3 Fmoc 3 GAL a b c d e 90% 79% 78% 75% Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
34 SPPS:Cu(I) catalysis on Solid Support 1. 3 FGFG DIPEA,Cu(I) M a (aq.) > 95% conversion > % purity % Si S 2 84 % % 93 % 90 % Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
35 SPPS: Cu(I) catalysis on Solid Support Peptide Protecting Group Compatibility Xxx FG 1. 3 DIPEA,Cu(I) M a (aq.) Xxx FG > 95% conversion Xxx % purity Xxx % purity Ala > 95 is(trt) 80 Pro > 95 Cys(Trt) 81 Triphenylmethyl (Trt) t-butyloxycarbonyl (Boc) Thr( t Bu) > 95 Met 85 S Tyr ( t Bu) Asp ( t Bu) > 95 > 95 Lys(Boc) Trp(Boc) > 95 > 95 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl (Pmc) Asn(Trt) 90 Arg(Pmc) 88 Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
36 SPPS: Cu(I) catalysis on Solid Support Scale Up 2 Ph 3 DIPEA,CuI 0.1M a (aq) 3 DIPEA,CuI 0.1M a (aq) Ph 79% 87% Ph Tornoe, C.; Christensen, C.; Meldal, M. J. rg. Chem. 2002, 67, 3057.
37 Click Applications in Macromolecules Dendrimer Synthesis Solid Support Chemistry SPS SPPS DA functionalization
38 Click Chemistry in Biology Construction of fluorescent oligonucleotides for DA sequencing Biological Inhibitors In-situ Click approach
39 DA Sequencing Modified ligonucleotides Introducing additional functional groups in DA Staudinger reaction 3 P: 3 ' 3 P ' 2 + P ' Limitations: aqueous conditions required hydrolyze intermediate aza-ylide Seo, T.; Li, Z.; uparel.; Ju J. J. rg Chem. 2003, 68, 609. Saxon, E.; Bertozzi C. Science, 2002, 287, 2007.
40 DA Sequencing Fluorescent ss DA sequencing Br Et 1. a 3, DMS 2. a, Me, 2 3. Cl 3 EDC, C 2 Cl GTT TTC CCA GTC ACG ACG-3' Azide labeled DA 3 96% GTT TTC CCA GTC ACG ACG-3' Seo, T.; Li, Z.; uparel.; J. rg Chem. 2003, 68, 609.
41 DA Sequencing 2 C + 2 DMF ac 3 2 C 3 GTT TTC CCA GTC ACG ACG-3' DMS/ 2 80'C, 72 h 2 C GTT TTC CCA GTC ACG ACG-3' 2 C + 91% GTT TTC CCA GTC ACG ACG-3' Seo, T.; Li, Z.; uparel.; J. rg Chem. 2003, 68, 609.
42 Biological Inhibitors IV-1 protease (IV-1 P) a 3, Et/ 2 60 o C, 2 h Cl/dioxane 2. (S)-3-tetrahydrofuranyl -oxysuccinimidyl carbonate, Et 3 83% 3 1. i-bu 2, Me 2. p-methoxybenenesulfonyl chloride, K 2 C 3, C 3 C, 3 h. S 1. 4 Cl/dioxane 2. Tf 3, 2 /C 2 Cl 2 /Me, rt. 3 S 76% Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. lson, A.; Fokin, V.; Sharpless, B.; Wong,. Chem. Bio. Chem. 2003, 4, 1246.
43 Biological Inhibitors , t Bu (1:1) Cu +/ Cu ++ 3 S 1. 2, t Bu (1:1) Cu +/ Cu ++ S = Boc 1 2 Enzyme IV P IC 50 [nm] / / V82F G48V 19 +/ / / / V82A 46 +/ /- 2 Brik, A.; Muldoon, J.; Lin, Y.; Elder, J. Goodsell, D. lson, A.; Fokin, V.; Sharpless, B.; Wong,. Chem. Bio. Chem. 2003, 4, 1246.
44 In Situ Click Chemistry PEFECT FIT Model of acetylcholinesterase inhibitor. Lewis, W.; Green, L.; Grynszpan, F.; adic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.
45 In-Situ Click Chemistry Enzyme Templating Inhibitor for acetylcholinesterase Cl n m 80 o C 6 days 1 (n=2-6) 2 (m=2-6) Cl 2 2 n 3 (n=1-3) 4 (m=6-8) m 3 (1,5) (1,4) Lewis, W.; Green, L.; Grynszpan, F.; adic, Z.; Carlier, P.; Taylor, P.; Finn, M.; Sharpless, B. Angew chemie. Int. Ed, 2002, 41, 1054.
46 Why Click Chemistry? Functional group tolerance Aqueous conditions Shorter reaction time igh yield igh purity egiospecificity
47 Acknowledgments Dr. Jackson Dr. Borhan Dr. dom Jackson & Miller esearch Group
48
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