Click Reactions in Organic Synthesis E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Endlich ein Buch zu Click-Reaktionen mit Schwerpunkt auf der organischen Synthese. Beschrieben werden das Click-Konzept, die zugrunde liegenden Mechanismen und Hauptanwendungsgebiete. NÜTZLICH: Die Click-Chemie ist ein wirkungsvoller Ansatz, um auf einfache Weise komplexe organische Moleküle aus verfügbaren Ausgangsmaterialien zu erzeugen ? der Traum jedes Organikers. EINZIGARTIGER SCHWERPUNKT: Aufgrund des besonderen Schwerpunkts auf der organischen Synthese ist dieses Buch für jeden Synthesechemiker von hohem Interesse. HILFREICH: Click-Reaktionen sind stereospezifisch, einfach durchzuführen, hoch ergiebig und lassen sich in einfach zu entfernenden oder nicht schädlichen Lösungsmitteln durchführen. INTERDISZIPLINÄR: Das Click-Konzept ist bei der Herstellung natürlicher Produkte, bioaktiver Verbindungen, von Kohlenhydraten, Arzneimitteln, Polymeren, supramolekularer Strukturen und Materialien weit verbreitet.
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Seitenzahl: 501
Veröffentlichungsjahr: 2016
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Table of Contents
Cover
Title Page
Copyright
List of Contributors
Preface
Chapter 1: Click Chemistry: Mechanistic and Synthetic Perspectives
1.1 Cycloaddition Click Reactions
1.2 Thiol-Based Click Reactions
1.3 Miscellaneous Click Reactions
References
Chapter 2: Applications of Click Chemistry in Drug Discovery and Development
2.1 Introduction
2.2 Part A: Application of Click Chemistry to Drug Discovery and Development
2.3 Part B: Synthesis of Triazole-Based Drugs Currently in use
References
Chapter 3: Green Chemical Synthesis and Click Reactions
3.1 Introduction
3.2 Huisgen 1,3-Dipolar Cycloaddition
3.3 Other 1,3-Dipolar Cycloadditions
3.4 Atom Economy and Simplicity of Procedures in Multicomponent Reactions
3.5 Summary and Conclusions
References
Chapter 4: Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis
4.1 Introduction
4.2 Preformed-Enolate-Based Synthesis of Substituted 1,2,3-Triazoles
4.3 Preformed-Enamine-Based Synthesis of Substituted 1,2,3-Triazoles
4.4 Synthesis of Substituted 1,2,3-Triazoles via Catalytic Enolate Intermediates
4.5 General Mechanistic Aspects of Enolate Route
4.6 Synthesis of Substituted 1,2,3-Triazoles via Enamine Intermediates
4.7 General Mechanistic Aspects of Enamine Route
4.8 Synthesis of Substituted 1,2,3-Triazoles via Iminium Intermediate
4.9 Miscellaneous Routes for the Synthesis of 1,2,3-Triazoles
4.10 Conclusions
Acknowledgments
References
Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides
5.1 Introduction
5.2 CuAAC-Mediated Peptide Conjugation Strategies
5.3 CuAAC-Mediated Peptide Backbone Modification Strategies
5.4 Conclusions
References
Chapter 6: Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry
6.1 Introduction
6.2 Cu-Catalyzed Click Chemistry in the Synthesis of Diverse Glycoconjugates
6.3 Synthesis of Carbohydrate-Based Simple to Complex Macrocycles
6.4 Click-Inspired Synthesis of Diverse Neoglycoconjugates
6.5 Conclusion and Future Perspective
Acknowledgment
References
Chapter 7: Azide–Alkyne Click Reaction in Polymer Science
7.1 Introduction
7.2 Linear, Dendritic, and Hyperbranched Polymers
7.3 Telechelic and Block Copolymers
7.4 Star and Star-Block Polymers
7.5 Cyclic Polymers
7.6 Side-Chain Clickable Polymers
7.7 Cross-linked Polymeric Systems
7.8 Porous Organic Polymers
7.9 Surface Modification using CuAAC Reaction
7.10 Strain-Promoted Click Reaction
7.11 Topochemical Azide–Alkyne Cycloaddition (TAAC) Reactions
7.12 Summary and Outlook
References
Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design
8.1 Introduction
8.2 Thiol Chemistry for Macromolecular Architecture Design
8.3 Conclusion
Acknowledgments
References
Chapter 9: Synthesis of Macrocycles and Click Chemistry
9.1 Introduction
9.2 Summary and Conclusions
References
Chapter 10: Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen's [3+2] Azide–Alkyne Cycloaddition: Opening Pandora's Box
10.1 Introduction
10.2 Nucleotide and Nucleic Acid Modifications
10.3 Conclusion
Acknowledgments
References
Index
End User License Agreement
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Guide
Table of Contents
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 1: Click Chemistry: Mechanistic and Synthetic Perspectives
Scheme 1.1 Huisgen 1,3-dipolar cycloaddition between alkynes and azides.
Scheme 1.2 CuAAC click reaction.
Figure 1.1 Sialic-acid-based neuraminidase inhibitors; a disaccharide mimic
A
and a dendrimer
B
.
Figure 1.2 Triazole-containing macrocycles used for the detection of anions.
Scheme 1.3 Mechanism of the CuAAC reaction as proposed by Jan H. van Maarseveen [15].
Figure 1.3 Ligands used in CuAAC click reactions.
Scheme 1.4 Formation of 1,5-disubstituted or 1,4,5-trisubstituted triazoles via Ru-catalyzed 1,3-dipolar cycloaddition reaction between azides and alkynes.
Scheme 1.5 Proposed mechanism of RuAAC click reactions.
Scheme 1.6 An example for SPAAC click reaction.
Scheme 1.7 Proline-catalyzed synthesis of fused triazole from Hagemann's ester and tosyl azide.
Scheme 1.8 Mechanism for amine-catalyzed 1,3-dipolar cycloaddition between aldehydes and azides.
Scheme 1.9 The hydrothiolation of a CC bond in the presence of hν or a radical initiator.
Scheme 1.10 The mechanism for the hydrothiolation of a CC bond in the presence of a photoinitiator and light.
Scheme 1.11 The reaction mechanism of thiol–yne addition reaction.
Scheme 1.12 Multistep thiol–yne mediated synthesis of a highly functional dendrimer.
Scheme 1.13 Base catalyzed thiol–epoxy ring-opening click reaction.
Scheme 1.14 Tertiary-amine-catalyzed thiol–isocyanate click reaction.
Scheme 1.15 The base-catalyzed mechanism for the hydrothiolation of an activated CC bond.
Scheme 1.16 Nucleophilic catalysis of thiol–Michael addition reactions.
Scheme 1.17 Staudinger and traceless Staudinger ligation click reactions.
Chapter 2: Applications of Click Chemistry in Drug Discovery and Development
Scheme 2.1
Scheme 2.2
Figure 2.1 Triazole bioisostere of Resveratrol.
Figure 2.2 Triazole as a non-classical bioisostere of labile esters.
Figure 2.3 Role of triazole in improving intrinsic potency and bioavailability.
Figure 2.4 Application of
in situ
click chemistry in the discovery of new ligands.
Figure 2.5 Enzyme- directed fragment- based lead discovery of Huprin-based inhibitors.
Figure 2.6 Huprin moiety as a catalytic site binder for
in situ
click chemistry.
Scheme 2.3
Scheme 2.4
Figure 2.7 Conjugation strategy for combating bacterial resistance.
Figure 2.8 Triazole variant of podophyllotoxin as antimicrotubule agents.
Figure 2.9 Triazolylmethyl analogue of podophyllotoxin for improved anticancer activity.
Figure 2.10 Traizole NSC746457 as a novel HDAC-1 inhibitor.
Figure 2.11 Optimisation of NSC746457 as potent HDAC inhibitors.
Figure 2.12 Triazole moiety as selective HDAC-8 inhibitor.
Figure 2.13 Triazole linked Ematinib analog as potent Src Kinase inhibitor.
Figure 2.14 Substituted triazoles as novel microtubule agents.
Figure 2.15 Functionalised triazoles as HSP-90 inhibitors.
Scheme 2.5
Figure 2.16 Galactoside-derived triazoles as novel anticancer agents.
Figure 2.17 Oleanolic acid-coupled triazoles as novel anticancer agents.
Figure 2.18 1,2,3-Triazole variants of TSAO nucleosides.
Figure 2.19 1,2,3-Triazole carbanucleoside analogue of Neplanocin A.
Figure 2.20 Cidofovir as a reference standard for antiviral agent.
Scheme 2.6
Figure 2.21 1,2,3-Triazole linked carbazole analogues as anti tubercular agents.
Scheme 2.7
Figure 2.22 Diaryltriazole carbinols as antitubercular agents.
Figure 2.23 Diaryltriazoles as follow up antitubercular agents.
Figure 2.24 Evaluation of aminoaryl and its acyl derivatives as antitubercular agents.
Figure 2.25 1,2,3-Triazole-admantyl acetamide hybrids as antitubercular agents.
Figure 2.26 Improved variants of L-708906 as non-nucleoside HIV integrase inhibitors.
Scheme 2.8
Figure 2.27 1,2,3-Triazole as a bioisotere of amide leading to Dopamine 3 receptor selective ligands.
Figure 2.28 1,2,3-Triazole- based drugs currently in use.
Figure 2.29 1,2,3-Triazole-based pharmaceuticals in clinical trials.
Scheme 2.9
Scheme 2.10
Figure 2.30 Impurities formed during the synthesis of tazobactam [131a].
Scheme 2.11
Scheme 2.12
Scheme 2.13
Scheme 2.14
Scheme 2.15
Scheme 2.16
Scheme 2.17
Scheme 2.18
Scheme 2.19
Scheme 2.20
Scheme 2.21
Scheme 2.22
Chapter 3: Green Chemical Synthesis and Click Reactions
Scheme 3.1 General 1,3-dipolar cycloaddition of azides and alkynes.
Figure 3.1 Phosphinite and phosphonite copper complexes.
Scheme 3.2 Reaction of N,N′-bis[2,6-diisopropylphenyl]imidazolin-2-ylidene with propargyl alcohol.
Scheme 3.3 Synthesis of 5-substituted-1,2,3-triazoles.
Scheme 3.4 Regioselective 1,3-dipolar cycloaddition on a terminal alkyne.
Scheme 3.5 Sinthesis of a fluerescent chemosensor by a CuAAc.
Scheme 3.6 1,3-Dipolar cycloaddition of an azomethine imine with a terminal alkyne.
Chapter 4: Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis
Scheme 4.1 Thermal-, metal-, and strain-promoted 1,2,3-triazole synthesis.
Scheme 4.2 Synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.3 Potassium
tert
-butoxide mediated synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.4 Synthesis of 1-vinyl-1,2,3-triazoles.
Scheme 4.5 Synthesis of 5-methyl-1,4-diphenyl-1,2,3-triazole.
Scheme 4.6 Base-promoted 1,3-dipolar cycloaddition of cyanoacetamide and 2,3,5-tri-
O
-benzoyl-β-
D
-ribofuranosyl azide.
Scheme 4.7 Synthesis of 5-amino-1-benzyl-1
H
-1,2,3-triazoles.
Scheme 4.8 1
H
-1,2,3-Triazole synthesis from heterocyclic CH-active compounds.
Figure 4.9 1
H
-1,2,3-Triazole synthesis from 2-benzothiazolylacetone.
Scheme 4.10 Synthesis of aryl-1
H
-1,2,3-triazol-4-yl sulfones.
Scheme 4.11 Synthesis of aryl 1,2,3-triazoles in a continuous-flow reactor.
Scheme 4.12 One-pot, three-component synthesis of 1,4,5-trisubstituted 1,2,3-triazoles starting from primary alcohols.
Scheme 4.13 Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF
3
-directed cyclization.
Scheme 4.14 Reaction of dienamines with aryl azides.
Scheme 4.15 Reaction of cyclic dienamine with aryl azides.
Scheme 4.16 Reaction of enamines with aryl azides.
Scheme 4.17 Synthesis of 1-aryl-4,5-dihydro-5-morpholinotriazoles.
Scheme 4.18 1,3-Dipolar cycloaddition reactions of 2-alkylidenedihydroquinolines and phenyl azide.
Scheme 4.19 1,3-Dipolar cycloaddition reactions of organic azides with morpholinobuta-1,3-dienes.
Scheme 4.20 Reactions of β-azolylenamines with sulfonyl azides for the synthesis of N-unsubstituted 1,2,3-triazoles.
Scheme 4.21 TMG (1,1,3,3-tetramethylguanidine)-catalyzed synthesis of 1,2,3-triazoles.
Scheme 4.22 Recyclable DBU-H
2
O catalytic system for synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.23 Organocatalytic azide–aldehyde [3+2]-cycloaddition for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.24 Organocatalytic azide–ketone [3+2]-cycloaddition for regioselective synthesis of fully decorated 1,2,3-triazoles.
Scheme 4.25 Carbonate-catalyzed synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.26 General mechanism for base-catalyzed 1,2,3-triazole synthesis.
Scheme 4.27 Synthesis of
NH
-1,2,3-triazoles via push–pull dienamine intermediate.
Scheme 4.28 Organocatalytic enamide–azide cycloaddition for regiospecific synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.29 Organocatalytic synthesis of 1,2,3-triazoles from unactivated ketones and aryl azides.
Scheme 4.30 Pyrrolidine-catalyzed synthesis of highly substituted 1,2,3-triazoles.
Scheme 4.31 Synthesis of arylselanyl-1
H
-1,2,3-triazole-4-carboxylates by organocatalytic cycloaddition.
Scheme 4.32 Diethylamine-catalyzed cycloaddition of azides to unsaturated aldehydes for the synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.33 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via dienamine intermediate.
Scheme 4.34 Organocatalytic 1,3-dipolar cycloaddition reactions of ketones and azides with water as a solvent.
Scheme 4.35 Organocatalytic synthesis of (arylselanyl)phenyl-1
H
-1,2,3-triazole-4-carboxamides by cycloaddition of azidophenyl arylselenides and β-oxo-amides.
Scheme 4.36 Organocatalytic 1,3-dipolar cycloaddition reaction of allyl ketones with azides for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.37 One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.38 General mechanism for enamine-mediated 1,2,3-triazole synthesis.
Scheme 4.39 Organocatalytic 1,3-dipolar cycloaddition of α,β-unsaturated ketones with azides for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.40 Mechanism of 1,2,3-triazole formation via iminium intermediate.
Scheme 4.41 Tetramethylammonium-hydroxide-catalyzed synthesis of 1,5-disubstituted 1,2,3-triazole.
Scheme 4.42 Synthesis of 1,5-disubstituted 4-(trimethylsilyl)-1
H
-1,2,3-triazoles.
Scheme 4.43 One-pot, two-step synthesis of 1,5-fused-1,2,3-triazoles.
Scheme 4.44 Multicomponent cascade reaction for regiospecific synthesis of 1,5-disubstituted 1,2,3-triazoles.
Scheme 4.45 Synthesis of 1,5-disubstituted 1,2,3-triazolylated carbohydrates.
Scheme 4.46 Propargyl-cation-mediated rapid synthesis of fully substituted 1,2,3-triazoles.
Scheme 4.47 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via three-component reaction.
Scheme 4.48 Lewis-base-catalyzed synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via azide–zwitterion cycloaddition.
Scheme 4.49 Mechanism for 1,2,3-triazole synthesis via azide–zwitterion cycloaddition.
Scheme 4.50 One-pot strategy for synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.51 Synthesis of 1,4-disubstituted 1,2,3-triazoles in one pot from ketones,
N
-tosylhydrazines, and amines.
Scheme 4.52 Mechanism for I
2
mediated 1,2,3-triazole synthesis from ketones,
N
-tosylhydrazines, and amines.
Scheme 4.53 I
2
/TBPB-mediated synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.54
p
-TsOH-mediated synthesis of 4-aryl-
NH
-1,2,3-triazoles.
Scheme 4.55 Synthesis of 4-trifluoromethanesulfonyl-1,2,3-triazoles.
Scheme 4.56 Silver-catalyzed access to synthesis of 1,5-fused-1,2,3-triazoles.
Scheme 4.57 Synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles via cycloaddition of α-chlorotosylhydrazones with arylamines.
Scheme 4.58 Mechanism for the synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles from α-chlorotosylhydrazones.
Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides
Figure 5.1 The CuAAC or click reaction.
Figure 5.2 Examples of clickable amino acids and tags.
Figure 5.3 Clickable fluorescent coumarins.
Figure 5.4 A PEGylated peptide.
Figure 5.5 A polymer–peptide hybrid.
Figure 5.6 Triazole-linked glycopeptide structures.
Figure 5.7 Triazole-linked glycopeptides derived from C34.
Figure 5.8 Glycoamino acids and cyclic peptides synthesized by Kuijpers
et al
. [18].
Figure 5.9 Late-stage fluorination through the click reaction.
Figure 5.10 Late-stage fluorination click reaction of an RGD derivative.
Figure 5.11 Azide-functionalized
18
F-label for conjugation with alkyne-containing peptides.
Figure 5.12 Backbone-modified analog of a cyclic RGD peptide.
Figure 5.13 Triazole-containing backbone-modified analogs of PSmac-21 (
23
).
Figure 5.14 Triazole-containing peptides self-assembling to nanotubes.
Figure 5.15 Cyclopeptides and triazole-backbone modifications.
Figure 5.16 Leu-enkephalin (
33
) and a triazole-modified mimic.
Figure 5.17 A radiolabeled triazole-containing bombesin peptidomimetic.
Figure 5.18 Examples of triazolamers.
Figure 5.19 (a) Native dipeptide and the triazole derivative. (b) Sequences of pLI-GCN4 (
43
) and modified peptides
44–46
.
Figure 5.20 Triazole-based β-turn mimetics.
Figure 5.21 β-Turn mimetics containing a 1,4-triazole.
Figure 5.22 Triazole-mimetics to study β-turn
cis
/
trans
-isomerization.
Figure 5.23 Triazole-containing locked conformations of SFTI-1.
Chapter 6: Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry
Scheme 6.1 Regioselectivity in azide–alkyne [3+2] cycloaddition reaction.
Scheme 6.2 Synthesis of triazole-linked disaccharide analog 7.
Scheme 6.3 Click-inspired synthesis of morpholine-fused triazolyl glycoconjugates.
Scheme 6.4 Synthesis of ethisterone glycoconjugates via Cu-catalyzed click chemistry.
Scheme 6.5 Click-inspired synthesis of noscapine glycoconjugates.
Scheme 6.6 Synthesis of triazolyl glycoconjugates.
Scheme 6.7 Synthesis of ferrocene-containing triazolyl glycoconjugates.
Scheme 6.8 Synthesis of glycosyl triazoles as potential insecticidal activity.
Scheme 6.9 Synthesis of antileishmanial triazolyl
O
-benzylquercetin glycoconjugates.
Scheme 6.10 Click-inspired synthesis of dual HIV-1 PR/HIV-1 RT inhibitor.
Scheme 6.11 Synthesis of glycopeptide hybrid lactam mimetics using CuAAC.
Scheme 6.12 Click-inspired synthesis of α- and β-
D
-glucopyranosyl triazoles.
Scheme 6.13 Synthesis of galactose-derived TcTs inhibitors using CuAAC reaction.
Figure 6.1 Structure of triazolyl glycoconjugates as TcTS inhibitory activity.
Scheme 6.14 Synthetic multivalent iminosugars prepared by click reaction.
Scheme 6.15 Triazolyl glycoconjugates as selective PTP1B inhibitors.
Figure 6.2 Diverse triazolyl glycoconjugates as glycogen phosphorylase inhibitors.
Scheme 6.16 Synthesis of triazolyl glycoconjugate as antiproliferative activity.
Scheme 6.17 Synthesis of glycosyl triazoles as anticancer agents.
Figure 6.3 Chemical structures of anticancer agent created via triazole linkage.
Scheme 6.18 Synthesis of triazole-linked divalent glycoamino acid mimics.
Scheme 6.19 Multicomponent synthesis of Triazolyl
N
-carboxamides.
Figure 6.4 Chemical structures of carbonic anhydrase inhibitors explored via click chemistry.
Scheme 6.20 Synthesis of zanamivir-based anti-AIV agent.
Figure 6.5 Neuraminidase inhibition activity of developed glycosyl triazoles.
Scheme 6.21 Triazole-linked sialic-acid-based neuraminidase inhibitors.
Figure 6.6 Triazolyl glycoconjugates as antifungal and antibacterial agents.
Scheme 6.22 Triazole-linked glycoconjugate against ManT activity.
Scheme 6.23 Synthesis of α-tocopherol-based triazolyl glycoconjugate.
Scheme 6.24 Click-inspired synthesis of rapamycin triazolyl glycoconjugate.
Scheme 6.25
18
F-glycosylation of sugar azide and subsequent clicking with peptide moieties.
Scheme 6.26 Synthesis of diarylpyrazole glycoconjugate.
Scheme 6.27 Synthesis of
18
F-fluoroglycosylation of alkyne-bearing RGD peptides.
Scheme 6.28 Click-to-chelate procedure for a regular click ligand.
Scheme 6.29 Synthesis of pyridine–tetraacetic acid glycoconjugates.
Scheme 6.30 Synthesis of triazolyl glycoconjugate 1
19
as suitable ligand.
Scheme 6.31 Synthesis of Michael addition catalyst
121
via click reaction.
Scheme 6.32 Preparation of glucose-linked 1,2,3-triazolium ionic liquids.
Scheme 6.33 Click-inspired synthesis of
D
-glucose-derived chemosensor for Cu
2+
ions.
Scheme 6.34 Synthesis of sugar-based fluorescent-labeled biomolecules.
Scheme 6.35 Click-inspired synthesis of triazole-containing glycolipids.
Scheme 6.36 Synthesis of 1,2,3-triazole-linked α-GalCer analogs.
Scheme 6.37 Functionalization of alkyne-grafted analog of monophosphoryl lipid A.
Scheme 6.38 Click-inspired synthesis of
C
-2 and
C
-3 symmetric glyco-macrocyles.
Scheme 6.39 Cu(I)-catalyzed cyclooligomerization of azidoalkyne-functionalized furanosides.
Scheme 6.40 Synthesis of macrocyclic carbohydrate/amino acid hybrids via CuAAC reaction.
Scheme 6.41 Synthesis of
C
n
-symmetric triazole-linked cycloglucopyranosides.
Scheme 6.42 Amino-acid-templated macrocyclization to access sucrose-derived macrocycles.
Scheme 6.43 Synthesis of monomeric triazolophane from furanoside-tethered azido–alkyne.
Scheme 6.44 Synthesis of carbohydrate-based macrocycle.
Scheme 6.45 Chemoenzymatic synthesis of sialic-acid-containing macrocycle.
Scheme 6.46 Intramolecular glycosidation through click-generated triazole as rigid spacer.
Scheme 6.47 Click-inspired synthesis of cyclic arginine–glycine–aspartate-containing macrocycle.
Scheme 6.48 Click-inspired synthesis of cyclopeptide-based fucosylated glycodendrimers
180
.
Scheme 6.49 Click-inspired synthesis of neoglycopeptides.
Scheme 6.50 Synthesis of glycopolymer by combining click reaction with CCCTP technique.
Scheme 6.51 4-Vinyl-traizole monomer by combining CuAAC and RAFT technique.
Scheme 6.52 Click-inspired synthesis of porphyrin core glycodendrimer.
Scheme 6.53 Multivalent
C
-sialoside monomers via Click reaction.
Scheme 6.54 Synthesis of biologically active mannose-centered tetragalactose clusters.
Scheme 6.55 Click-inspired synthesis of virus glycoconjugates.
Scheme 6.56 Crown-like tetra-fucosylated glycocluster-based on a mannose core.
Scheme 6.57 Synthesis of calix[4]arene glycocluster.
Scheme 6.58 Click-inspired synthesis of calix[4]arene glycocluster using calix[4]arene platform.
Scheme 6.59 Synthesis of glycosylated calixarene using CuAAC.
Figure 6.7 A link-spacer-controlled supramolecular chirality based on self-assembly of the perylene bisimide glycoconjugates.
Chapter 7: Azide–Alkyne Click Reaction in Polymer Science
Scheme 7.1 The azide–alkyne click reaction.
Scheme 7.2 Schematic representation of the various types of polymers.
Scheme 7.3 Types of step-growth polymerization processes.
Scheme 7.4 CuAAC-reaction-mediated synthesis of linear polymers; examples of trialkynes and triazides used for the preparation of cross-linked polymers.
Scheme 7.5 Examples of linear conjugated polymers and conjugated foldamers via CuAAC.
Scheme 7.6 Tetraphenyl ethylene containing polymer via CuAAC; the polymer exhibits AIE.
Scheme 7.7 Biocompatible trehalose–oligoethyleneimine containing polymers for potential use as DNA delivery vehicles.
Scheme 7.8 CuAAC reaction of preassembled organogelators – a case of pseudo-topotactic polymerization.
Scheme 7.9 Convergent synthesis of dendron via CuAAC reaction.
Scheme 7.10 Synthesis of unsymmetrical dendrimer via CuAAC reaction of azide and alkyne containing dendrons.
Scheme 7.11 Synthesis of diblock dendrimer via CuAAC reaction (a) and a dendrinized linear polymer via CuAAC reaction of azido dendron with poly(vinylacetylene) (b).
Scheme 7.12 Convergent synthesis of hydrophilic dendrimer via iterative CuAAC reaction.
Scheme 7.13 Direct synthesis of a hyperbranched polymer via CuAAC reaction of an AB
2
monomer.
Scheme 7.14 Synthesis of hyperbranched polymer via CuAAC reaction of trialkyne and diazide.
Scheme 7.15 Unusual synthesis of a HBP with low PDI and high DB via pseudo-chain-growth CuAAC polymerization of an AB
2
monomer carrying two azides and one alkyne group.
Scheme 7.16 Synthesis of clickable hyperbranched polyesters and their postpolymerization modification to generate core–shell-type and Janus-type structures.
Scheme 7.17 Anionic polymerization (a), ATRP process (b).
Scheme 7.18 Synthesis of PS-PMMA diblock copolymer via CuAAC reaction.
Scheme 7.19 Synthesis of polystyrene-block-polyvinyl acetate copolymer via using RAFT polymerization in conjunction with CuAAC reaction.
Scheme 7.20 Synthesis of ABC triblock copolymer using a combination of CuAAC and Diels–Alder reaction.
Scheme 7.21 Synthesis of rod–coil block copolymers by a combination of ROP, ATRP, and CuAAC reaction.
Scheme 7.22 Synthesis of ABA triblock copolymer containing P3HT central block via CuAAC reaction of a dialkyne derivative of P3HT and azide-terminated polystyrene.
Scheme 7.23 CuAAC-reaction-mediated synthesis of alternating multiblock copolymer poly(Ph2TPh-OEG).
Scheme 7.24 Synthesis of four-arm PS-star polymer via CuAAC reaction of PS-azide with a core bearing multiple propargyl groups.
Scheme 7.25 Synthesis of three-arm PS-PEO star-block copolymer grown from a trifunctional ATRP initiator by combination of ATRP and CuAAC reaction.
Scheme 7.26 Single-step
in situ
formation of star-block copolymer using a combination of CuAAC and Diels–Alder reaction; three components, namely a heterotelechelic polystyrene bearing anthracene and azide end groups, maleimide-terminated PMMA, and a tris(propargyl ether) core, were used.
Scheme 7.27 Synthesis of star-like diblock copolymer via CuAAC reaction using solvent-assisted collocation of the azide and an alkyne groups placed at the same end of the polymer chain; the bottom panel depicts the aggregation of PDMA-block-PNIPAM in water at 50 °C, which is above the LCST of PNIPAM.
Scheme 7.28 Synthesis of cyclic-PS from a heterotelechelic propargyl-PS-azide via CuAAC reaction.
Scheme 7.29 Synthesis of cyclic diblock copolymer of PMA and PS by a combination of ATRP and CuAAC reaction.
Scheme 7.30 Synthesis of cyclic diblock copolymer of PS and PEO by intermolecular CuAAC reaction between a PS-diazide and dipropargylated PEO.
Scheme 7.31 Preparation of heterotelechelic PNIPAM via CuAAC reaction.
Scheme 7.32 Preparation of different cyclic polymer topologies using a combination of time-regulated dosing of an alkyne-bearing comonomer during CRP and CuAAC reaction for generation of the ring.
Scheme 7.33 Iterative flow synthesis of precise oligomers from a TIPS-protected ω-bromoalkyne.
Scheme 7.34 Synthesis of glycopolymers by a combination of ATRP and CuAAC reaction.
Scheme 7.35 Synthesis of azide-containing clickable polymer by ATRP and subsequent postpolymerization modification with various alkynes via CuAAC reaction.
Scheme 7.36 Synthesis of a series of periodically clickable polyesters and their postpolymerization modification with MPEG-350 azide via CuAAC reaction.
Scheme 7.37 Synthesis of cross-linked hydrogels using the CuAAC reaction between a dialkyne and a tetraazide.
Scheme 7.38 Synthesis of PVA-based hydrogels via CuAAC reaction between azide- and alkyne-functionalized PVA.
Scheme 7.39 Synthesis of hydrogels via CuAAC reaction between a PEG-diazide and a dendronized triblock copolymer carrying propargyl ester terminal groups and a central PEG segment.
Scheme 7.40 Synthesis of liquid-crystalline elastomers via CuAAC reaction between a diazide liquid crystalline block and tripropargyl amine.
Scheme 7.41 Synthesis of porous organic polymers by CuAAC reaction between tetrakis(4-azidophenyl)methane and tetrakis(4-ethynylphenyl)methane.
Scheme 7.42 Porous organic polymers bearing BTP ligands for efficient anchoring of Pd nanoparticles.
Scheme 7.43 Surface modification via a combination of SAM, ATRP and CuAAC reaction.
Scheme 7.44 Modification of CVD-coated surface via CuAAC reaction.
Scheme 7.45 Formation of a cross-linked polymer coating on an alkyne-functionalized substrate using strain-promoted click reaction.
Scheme 7.46 Synthesis of PEGylated polyamido dendrimers via SPAAC.
Scheme 7.47 Topochemical azide–alkyne click reaction for the synthesis of a polynucleoside from its monomer in the crystalline solid state.
Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design
Figure 8.1 Example of reactions carried out in thiol-based “click” for the fabrication of polymeric materials.
Figure 8.2 Synthesis of linear polymers by polymerizing dithiol and molecules with two thiol-reactive functionalities.
Figure 8.3 Synthesis of linear polymers by thiol–epoxy “click” polymerization.
Figure 8.4 Synthesis of linear polymers by polyhydrothiolation of diynes with dithiols.
Figure 8.5 Synthesis of linear polymers by polymerization of monoalkyne and a dithiol compound.
Figure 8.6 Synthesis of the graft or comb polymers by thiol-based click reactions.
Figure 8.7 Synthetic strategies for the preparation of glucose-functionalized polymers [20].
Figure 8.8 Synthesis of graft polymers by the photo-triggered deprotection of the 2-nitrobenzyl thioether moiety on a polymer backbone, followed by the highly efficient thiol–maleimide chemistry.
Figure 8.9 Visible light photocatalytic thiol–ene reaction [25].
Figure 8.10 The “arm-first” technique used to fabricate star polymers via thiol-based “click” reaction.
Figure 8.11 Synthesis of three-arm star polymers via a thiol–vinyl Michael “click” reaction.
Figure 8.12 Synthesis of cyclodextrin-centered star polymers via thiol-based “click” reaction.
Figure 8.13 Cyclization of linear polymers by thiol-based click reaction to form cyclic polymer.
Figure 8.14 Synthesis of cyclic poly(lactide) by thiol-based click reaction.
Figure 8.15 Synthesis of cyclic PNIPAM via thiol–ene in combination with CuAAc chemistry [32].
Figure 8.16 Schematic illustration of the syntheses of cyclic polymer template, functionalized cationic and thermoresponsive cyclic polymers.
Figure 8.17 Synthesis of dendrimers by thiol–ene.
Figure 8.18 Synthesis of dendrimers via thiol–yne chemistry and esterification reactions.
Figure 8.19 Synthesis of hyperbranched polymer by polymerization of a molecule bearing an alkyne and a thiol.
Figure 8.20 Synthesis of hyperbranched polymer by sequential thiol–ene and thiol–ene click chemistry.
Figure 8.21 Synthesis of hyperbranched polymer by sequential thiol–halogen and thiol–yne chemistry.
Figure 8.22 One-pot preparation of multiblock and hyperbranched polymers.
Figure 8.23 Synthesis of protein–polymer conjugate via thiol–ene chemistry.
Figure 8.24 Polymer synthesis and protein conjugation [42].
Figure 8.25 Synthesis of bioactive Janus particles by SEP and thiol–halogen chemistry.
Figure 8.26 Modified inorganic nanoparticles via thiol–ene chemistry.
Figure 8.27 Preparation of multimodal latex particles by composite miniemulsion polymerization, followed by attachment of PEG chains to the surface of composite particles using thiol–ene chemistry.
Figure 8.28 Overall synthetic approach for the surface modification of TiO
2
nanoparticles with POEGMA.
Figure 8.29 Synthesis of glycopolymer-coated iron oxide nanoparticles.
Chapter 9: Synthesis of Macrocycles and Click Chemistry
Scheme 9.1 Prototypical conditions for: the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, (a) 1,3-dipolar cycloaddition and (b) the thiol–ene click reaction.
Figure 9.1 Strategy for the modular synthesis of macrocyclic organopeptide hybrids
4
. The starting linear polypeptides comprise an N-terminal tail (light gray),
O
-propargyl tyrosine, a target sequence (AA
1
…AA
n
), and a GyrA intein segment. Macrocyclization occurs upon coupling of this protein to a synthetic precursor (SP) by concomitant CuAAC and thioester–hydrazide coupling [33].
Figure 9.2 Synthetic route to on-resin peptide macrocyclization using thiol–ene photochemistry [38].
Figure 9.3 Cyclic peptides obtained by CuAAC or RuAAC click chemistries incorporating 1,4- or 1,5-disubtituted triazole linkages as trypsin inhibitors analog of
9
[39].
Figure 9.4 Regioisomeric triazole-containing cyclic peptides composed of
cis
-β-furanoids and β-alanines [51].
Figure 9.5 Synthesis of click macrocycles through the cyclization of oligosaccharide linear monomers of varying lengths [61].
Figure 9.6 Structures of BODIPY-based sugar-containing macrocycles [62].
Figure 9.7 Triazole- and triazolium-containing macrocycles for the binding of anions. In gray: triazole or triazolium amide surrogates as the key functionalities responsible for binding [65–68].
Figure 9.8 Structures of macrocycle
23
and control compound
24
, and (bottom) operating principles of the macrocyclic chiroptical sensor
23
in which the variation of the CD response of the Binol unit is the key sensing output.
Figure 9.9 High-yielding synthesis of “Sauvage-type” symmetrical catenane
26
[89].
Figure 9.10 Synthesis of trefoil knot
29
by Leigh and coworkers [92].
Figure 9.11 Terminal insertion of azide and “Click” cyclization of polystyrene prepared via ATRP [105].
Figure 9.12 The synthetic routes of the linear and cyclic polymers [108].
Chapter 10: Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen's [3+2] Azide–Alkyne Cycloaddition: Opening Pandora's Box
Figure 10.1 Base-modified nucleosides
1–4
.
Figure 10.2 Base-modified nucleoside analogs.
Figure 10.3 Structures of sugar-modified nucleosides
15–23
.
Figure 10.4 Nucleoside bioconjugates bearing carboranes and
closo-
dodecarborane.
Figure 10.5 Structures of nucleoside bioconjugates
27–30
.
Figure 10.6 Structure of bioconjugates nucleosides
31–33
.
Figure 10.7 Fucosyltransferase inhibitor
34
.
Figure 10.8 Structures of bioconjugate nucleosides
35
.
Figure 10.9 Structures of nucleoside bioconjugates
36–41
.
Figure 10.10 Structure of nucleoside bioconjugates
42
.
Figure 10.11 Structure of radiolabeled bioconjugate
43
and cavitand
44
.
Figure 10.12 Examples of “artificial” DNAs.
Figure 10.13 Pyrene-containing nucleosides
50
and
51
.
Figure 10.14 Structures of boronic-acid-modified thymidine-5′-triphosphate
52
and lipid–oligonucleotide conjugates
53
.
Figure 10.15 Synthesis of fluorophore gamma-labeled nucleoside 5′-triphosphates.
Figure 10.16 Preparation of the nile-red-modified DNA1.
Figure 10.17 Internal DNA labeling between 8-aza-7-deaza-2′-deoxyadenosine, 5′-modified dU alkyne precursors and azide-labeled fluorogenic dyes.
Figure 10.18 Labeling of the 5-position of uridine analog with 3-azido-7-hydroxycoumarins.
Figure 10.19 Sequential modification of DNA by three consecutive CuAAC reactions.
Figure 10.20 Preparation of DNA–peptide hybrids via CuAAC.
Figure 10.21 Selective functionality transfer and click reaction on
O
6
-Me-dG with FAM-N
3
.
Figure 10.22 Dye labeling at the 2-position of ribose in ODNs using CuAAC.
Figure 10.23 Xanthene- and cyanine-labeled probe prepared by postsynthetic CuAAC reactions.
Figure 10.24 (a) bs-TO and bs-TR as two base surrogates allow excitionic interactions that interfere with energy transfer (ET). (b) U-TO clicked at 2′-position of uridine, U-A base pairing block undesired excitonic interactions.
Figure 10.25 Synthesis of the polymer-escorted siRNA.
Figure 10.26 Click reaction between DNA-bounded picazoplatin and a dansyl fluorophore.
Figure 10.27 Synthesis of catenated DNA by click chemistry.
Figure 10.28 Construction of branched DNA structures using CuAAC.
Figure 10.29 Stepwise click reactions on DNA using a chelating and a nonchelating azido group containing linker.
Figure 10.30 Site-specific click reaction.
Figure 10.31 Postsynthetic CuAAC click reactions with a 5′-bisalkyne ODN.
Figure 10.32 Immobilization of azide-modified gold nanoparticles to alkyne-modified DNA.
Figure 10.33 SPAAC click between DIBO and Texas red tag for terminal labeling of DNA.
Figure 10.34 DNA cross-linking using copper-free SPAAC click reactions with DIBO and BCN (R = DNA).
Figure 10.35 SPAAC click product obtained by reaction between 5-azidomethyl dU and BCN-labeled fluorophore.
Figure 10.36 Selective SPAAC-mediated biotin labeling of mismatched 5hmU.
List of Tables
Chapter 2: Applications of Click Chemistry in Drug Discovery and Development
Table 2.1 m-AChE-directed synthesis of huprine-based heterodimers
Table 2.2 IC
50
of OvCHT1 inhibition
Table 2.3 IC
50
values (μM)
Table 2.4 Cytotoxicity data
Table 2.5 IC
50
values (nM)
Table 2.6 IC
50
values (μM)
Table 2.7 IC
50
values (μM)
Table 2.8 IC
50
values (nM)
Table 2.9
In vitro
anticancer activity (IC
50
μM) of compound
52
Table 2.10 IC
50
value of compound
54
against human cancer cell lines
Table 2.11 EC
50
values (μM)
Table 2.12 EC
50
values (μM)
Table 2.13
K
i
(μM) value of compound
46
and reference compounds
67
and
68
Table 2.14
K
i
values ±SEM
Table 2.15 Effect of solvents on yield
Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides
Table 5.1 Stability tests for
13a
and
13b
, respectively
Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design
Table 8.1 Example of polymers synthesized via thiol-based click chemistry
Edited by Srinivasan Chandrasekaran
Click Reactions in Organic Synthesis
Editor
Prof. Srinivasan Chandrasekaran
Indian Institute of Science
Department of Organic Chemistry
C. V. Raman Avenue
560 012 Bangalore
India
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List of Contributors
Franck Amblard
Emory University School of Medicine
Center for AIDS Research
and Department of Pediatrics
Atlanta, GA 30322
USA
Kengadarane Anebouselvy
University of Hyderabad, Central University (P.O.)
Catalysis Laboratory
School of Chemistry
Prof. CR Rao Road
Gachibowli
500 046 Hyderabad
India
Maria José Arévalo
Universidad de Extremadura
Escuela Politécnica
Departamento de Química Orgánica e Inorgánica
Avenida de la Universidad
s/n, 10004 Cáceres
Spain
Kalpattu Kuppusamy Balasubramanian
INSA Senior Scientist
Department of Biotechnology
Indian Institute of Technology
Madras
Chennai 600036
India
Sebastien Boucle
Emory University School of Medicine
Center for AIDS Research
and Department of Pediatrics
Atlanta, GA 30322
USA
Poonam Chauhan
Indian Institute of Technology
Department of Chemistry
208016 Kanpur
India
Gaojian Chen
Soochow University
Center for Soft Condensed Matter Physics and Interdisciplinary Research
1 ShiZi Street
Jiangsu Province
Suzhou 215006
P. R. China
Kui Chen
Soochow University
Center for Soft Condensed Matter Physics and Interdisciplinary Research
1 ShiZi Street
Jiangsu Province
Suzhou 215006
P. R. China
Maria Victoria Gil
Universidad de Extremadura
Departamento de Química Orgánica e Inorgánica
Facultad de Ciencias
Avda. de Elvas
s/n, 06071 Badajoz
Spain
Balasubramanian Gopalan
Orchid Chemicals and Pharmaceuticals Limited
Drug Discovery Research
Plot #476/14
Old Mahabalipuram Road
Sholinganallur
600119 Chennai
India
Freek A. B. M. Hoogstede
Radboud University
Institute for Molecules and Materials
Department of Synthetic Organic Chemistry
Heyendaalseweg 135
6525 AJ Nijmegen
The Netherlands
Ahmed Khalil
Emory University School of Medicine
Center for AIDS Research
and Department of Pediatrics
Atlanta, GA 30322
USA
Óscar López
Universidad de Sevilla
Departamento de Química Orgánica
Facultad de Químicas
c/Profesor García González
s/n, 41012 Seville
Spain
Joydeb Mandal
Indian Institute of Science
Department of Inorganic and Physical Chemistry
560012 Bangalore
India
Amrita Mishra
Banaras Hindu University
Department of Chemistry
Faculty of Science
221005 Varanasi, UP
India
Kunj B. Mishra
Banaras Hindu University
Department of Chemistry
Faculty of Science
221005 Varanasi, UP
India
Dario Pasini
University of Pavia
Department of Chemistry and INSTM Research Unit
Viale Taramelli
10-27100 Pavia
Italy
Dhevalapally B. Ramachary
University of Hyderabad
Central University (P.O.)
Catalysis Laboratory
School of Chemistry
Prof. CR Rao Road
Gachibowli
500 046 Hyderabad
India
S. Ramakrishnan
Indian Institute of Science
Department of Inorganic and Physical Chemistry
560012 Bangalore
India
Ramesh Ramapanicker
Indian Institute of Technology
Department of Chemistry
208016 Kanpur
India
Floris P. J. T. Rutjes
Radboud University
Institute for Molecules and Materials
Department of Synthetic Organic Chemistry
Heyendaalseweg 135
6525 AJ Nijmegen
The Netherlands
Ozkan Sari
Emory University School
of Medicine
Center for AIDS Research
and Department of Pediatrics
Atlanta, GA 30322
USA
Raymond F. Schinazi
Emory University School
of Medicine
Center for AIDS Research
and Department of Pediatrics
Veterans Affairs Medical Center
Atlanta, GA 30322
USA
Anoop S. Singh
Banaras Hindu University
Department of Chemistry
Faculty of Science
221005 Varanasi, UP
India
Vinod K. Tiwari
Banaras Hindu University
Institute of Science
Department of Chemistry
Centre of Advanced Study
221005 Varanasi, UP
India
Weidong Zhang
Soochow University
Center for Soft Condensed Matter Physics and Interdisciplinary Research
1 ShiZi Street
Jiangsu Province
Suzhou 215006
P. R. China
Preface
Organic chemists are generally familiar with “Name Reactions” and many of these have had profound influence over the way we practice organic chemistry. However, there are a few reactions without a name that changed the course of history (science) and are unparalleled in terms of their impact over a wide range of scientific disciplines. “Olefin metathesis” is one such reaction that led to the award of Nobel Prize to the pioneers who contributed to the development of this reaction. In a similar vein, we have a group of reactions without a proper name that have taken the scientific community by storm in less than fifteen years, that is, “Click Reactions.”
Click chemistry is a chemical concept enunciated by Barry Sharpless, Scripps Research Institute, USA, in 2001, which highlights the importance of using a set of powerful, highly reliable, selective reactions under simple reaction conditions to join small molecular units together quickly for the rapid synthesis of new compounds via heteroatom links and create molecular diversity. Several types of reactions have been identified that fulfill the criteria- thermodynamically favored reactions that lead specifically to one product such as nucleophilic ring opening reactions of epoxides and aziridines, nonaldol type carbonyl reactions, additions to carbon–carbon multiple bonds, Michael additions, and cycloaddition reactions. The best-known click reactions are the copper-catalyzed reaction of azides and alkynes or the so-called CuAAC reaction and the thiol-ene reaction.
After the advent of click chemistry, the synthesis of molecules with outstanding, multifaceted properties has become very popular and easier simply by conjugating two or more molecules that possess remarkable individual properties. Over the past fifteen years, developments in the area of click chemistry have been extraordinary, and these reactions have been explored to their limits in various fields.
Who would have imagined that this simple set of reactions referred to as “click reactions” would revolutionize the approach to science cutting across disciplines such as drug discovery, polymer synthesis, materials science, chemical biology, supramolecular chemistry, and cosmetic chemistry in a short span of time. The tenth anniversary of the discovery of this concept of click reactions was celebrated with a lot of fanfare in the scientific community in 2011.
A number of review articles appeared in leading scientific journals covering the impact of this simple but elegant set of reactions in the design and synthesis of novel molecular architectures. While there are a couple of books that have been published dealing with click chemistry and its application to biology and material science, no book has been published so far that highlights the “click concept” and its far-reaching implications in various facets of organic synthesis. Hopefully, this book would fulfill this need and would also serve as a ready reckoner for accessing all information in pursuit of newer vistas in scientific research.
This book Click Reactions in Organic Synthesis covers ten different topics that would illustrate the scope of click reactions in various facets of organic synthesis. Leading experts who are active in this field have contributed to this venture. In the introductory chapter, Ramapanicker and Chauhan provide the mechanistic and synthetic perspectives of click reactions. Gopalan and Balasubramanian discuss the applications of click reactions in the synthesis of pharmaceuticals and drug discovery/development in Chapter 2. In Chapter 3, Gil and coworkers present the perspectives of green chemical synthesis. Ramachary and Anebouselvy have focused the attention on metal-free click reactions in organic synthesis in Chapter 4. Rutjes and Hoogstede have provided details on the use of click chemistry to peptide synthesis in Chapter 5. In Chapter 6, work related to the application of click chemistry to the synthesis of carbohydrate derivatives is discussed by Tiwari and coworkers. Synthesis of polymers and modifications using CuAAC click reactions are enunciated by Ramakrishnan and Mandal in Chapter 7. Chemistry related to thiol-ene (click) reactions in polymer synthesis and modifications are presented by Chen and coworkers in Chapter 8. Pasini highlights the importance of click chemistry in the synthesis of macrocycles in Chapter 9. In the last chapter, Schinazi and coworkers discuss the importance of click chemistry in DNA synthesis and modifications. I feel honored by the excellent contributions that the authors have delivered, and I owe my special thanks to all these scientists. I would also like to thank publishing editors /staff of Wiley-VCH for their fruitful collaboration.
Finally, I would like to place on record my sincere thanks to the pioneer of this area of work, Professor Barry Sharpless on the occasion of the 15th anniversary of “Click Reactions.”
Srinivasan Chandrasekaran
BangaloreApril 2, 2016
Chapter 1Click Chemistry: Mechanistic and Synthetic Perspectives
Ramesh Ramapanicker and Poonam Chauhan
Search for reactions that can be used to link two or more diversely functionalized molecules with minimum effort and without the formation of side products has become increasingly important in the past 15 years. As organic molecules started to find their place as easily tunable and functional materials, the requirement of new conjugation reactions that can be used effectively by nonsynthetic organic chemists became unavoidable. Such a reaction should be easier to carry out, yield high selectivity, should be compatible with water and other protic solvents, and should lead to quantitative conversions. Click chemistry is a collection of such reactions that has evolved as an efficient tool for ligation, which gained quick acceptance in biotechnology, material and polymer science, medicinal chemistry, and so on. Among all the click reactions, copper-catalyzed 1,3-dipolar Huisgen cycloaddition (HDC) between a terminal alkyne and an azide is the jewel in the crown. Owing to its remarkable functional group tolerance, researchers can fearlessly introduce easily functionalizable groups such as hydroxyl, carboxyl, and amino groups into conjugate molecules using this reaction.
The concept of click chemistry was first introduced by Sharpless and coworkers in 2001 at the Scripps Research Institute [1]. Click chemistry is not limited to a set of organic reactions, but is a synthetic philosophy inspired by nature in terms of their efficiency, selectivity, and simplicity. Any reaction that can produce conjugate molecules efficiently from smaller units under simpler reaction conditions can be considered as a click reaction. The catchy term click refers to reactions that are modular in approach, efficient, selective, versatile in nature, give single product (high yielding), and can be performed in benign and easily removable solvents without the need for chromatographic purification. There are various reactions with different mechanisms that can be considered as click reactions, provided they follow a simple common reaction trajectory [1].
Sharpless first introduced the concept of click chemistry to provide an effective conjugation technique in drug discovery [2], but the concept and methodology were widely accepted, and click chemistry found its applications in almost all facets of research and technology, which employ organic molecules, such as polymer science [3], nanoscience [4], bioconjugation [5], and development of sensors [6] .
In this chapter, we have provided a detailed account of various click reactions with emphasis on their mechanisms and synthetic details. The discussions are based on the following classification of click reactions.
1.1 Cycloaddition Click Reactions
1.1.1 Azide–Alkyne Huisgen 1,3-Dipolar Cycloaddition
The classical HDC reaction between an alkyne and an azide is the most discussed among click reactions. Both alkynes and azides are unreactive under physiological conditions and undergo a cycloaddition reaction only at elevated temperatures (Scheme 1.1) [7, 8]. Although both alkynes and azide functions can easily be introduced on to the substrates, the cycloaddition reaction is highly exothermic (ΔH0 is between −50 and −65 kcal/mol) and has a high activation barrier of 25–26 kcal/mol (for methyl azide and propyne). Hence, the uncatalyzed reaction is generally slow and is not regioselective [9]. The difference between HOMO-LUMO energy levels of both azide and alkyne are comparable, thus both dipole HOMO and dipole LUMO pathways can operate in this reaction leading to a mixture of 1,4 and 1,5-triazole regioisomers. It is, however, observed that the use of electron-deficient terminal alkynes can impart 1,4-regioselectivity to a reasonable extent. These factors limit the use of uncatalyzed Huisgen cycloaddition as an effective conjugation technique.
Scheme 1.1 Huisgen 1,3-dipolar cycloaddition between alkynes and azides.
1.1.2 Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Click Reaction
Sharpless [9] and Meldal [10] independently reported a Cu(I)-catalyzed version of the cycloaddition reaction between azides and terminal alkynes, which is 107 times faster than the uncatalyzed reaction. The interaction between Cu(I) and terminal alkynes makes the latter a better 1,3-dipolarophile, enhancing its reaction with azides. The Cu(I)-catalyzed reaction is highly regioselective and only the 1,4-adducts are formed. The Cu(I)-catalyzed reactions can be carried out at room temperature and at a much faster rate.
Sharpless reported the possibility of using in situ generated copper(I), obtained through the reduction of copper sulfate pentahydrate (CuSO4·5H2O) with ascorbic acid, as an efficient catalyst for carrying out azide–alkyne conjugation reactions in solutions [9]. The reactions worked well when a mixture of water and an alcohol is used as the solvent. The solvent mixture allowed effective dissolution of the metal salt and the organic components needed to be conjugated. Meldal and coworkers reported a very practical application of azide–alkyne cycloaddition catalyzed with cuprous iodide in conjugating peptides through side chains or the backbone in solid phase [10]. Both reactions were selective for the formation of 1,4-disubstituted 1,2,3-triazoles and together revolutionized the concept of click reactions (Scheme 1.2).
Scheme 1.2 CuAAC click reaction.
In addition to being a stable linker, the triazole group has certain other advantages. On comparison with an amide bond, which was otherwise the most common linkage used, a triazole group exhibits certain interesting and unique properties. Unlike an amide bond, triazoles are not susceptible to hydrolytic cleavage. They cannot be reduced or oxidized under normal conditions. A triazole linkage, with an extra atom in its backbone, places the carbon atoms linked to 1- and 4-positions at a distance of 5.0 Å, while an amide linkage places the carbon atoms only at 3.8 Å apart from each other. The nitrogen atoms at 2- and 3-positions of the triazole have weak hydrogen-bond-accepting properties. The inherent dipole moment in a triazole ring leads to polarization of the C5–H bonds, making them hydrogen bond donors and enabling C–H⋯X hydrogen bonds, similarly to an amide bond [11]. These properties also enabled Cu(I)-catalyzed triazole formation to gain attention as an effective conjugation method.
Conjugation of functional molecules through triazoles received immediate attention especially in drug discovery. Linhardt et al. synthesized some sialic acid conjugates using copper catalyzed azide–alkyne cycloaddition (CuAAC), which are potential neuraminidase inhibitors with good IC50 values (Figure 1.1) [12]. There are a large number of such examples of CuAAC being used effectively for assembling small molecular units to obtain more functional and useful molecules. An interesting example is the synthesis of the rigid macrocycle C (Figure 1.2) by Flood et al., in which triazole units function as rigid structural units and provide acidic hydrogens to interact and detect chloride ions in organic solvents [13]. In a similar attempt, Beer et al. have reported a ferrocene-containing bis(triazole) macrocycle D (Figure 1.2), in which they have increased the anion binding tendency of the C–H of triazole by converting triazole units to cationic triazolium moieties. Alkylation of a triazole increases its binding capability with anions such as chloride and benzoate ions even in polar organic solvents [14].
Figure 1.1 Sialic-acid-based neuraminidase inhibitors; a disaccharide mimic A and a dendrimer B.
Figure 1.2 Triazole-containing macrocycles used for the detection of anions.
1.1.2.1 Mechanism of CuAAC Click Reactions
A detailed mechanistic analysis of CuAAC was reported by Jan H. van Maarseveen and coworkers in 2006 [15]. The report was based on comprehensive kinetic studies and DFT calculations. Studies showed that the Cu-catalyzed cycloaddition reaction proceeds through a stepwise mechanism and the activation energy is 11 kcal/mol less than that of the uncatalyzed reaction, which has an activation energy of 26 kcal/mol. However, a concerted mechanism involving Cu–acetylene π-complex and the azide was calculated to have a higher activation energy of 27.8 kcal/mol. The reaction begins with the formation of a Cu–alkyne π complex, which then forms a copper acetylide after deprotonation of the alkyne proton. Coordination of copper with the alkyne makes the acetylenic proton more acidic, increasing its acidity by up to 9.7 pH units, which allows the deprotonation to occur in aqueous media even in the absence of a base. The copper acetylide exists in equilibrium between a monomer and a dimer. One of the Cu ions in the dimer coordinates with the azide nitrogen and activates it. This complex then cyclizes to give a metallacycle via a nucleophilic attack of the terminal nitrogen of the azide group on the internal carbon of the alkyne. The metallacycle then undergoes a ring contraction through a transannular interaction between the lone pair of electrons on the substituted nitrogen of the azide and the CCu bond. This relatively faster step yields a Cu triazolide, which undergoes protonation to liberate the 1,4-disubstituted triazole and regenerates the Cu(I) catalyst (Scheme 1.3) [16].
Scheme 1.3 Mechanism of the CuAAC reaction as proposed by Jan H. van Maarseveen [15].
1.1.2.2 Catalysts used for CuAAC Click Reactions
The success achieved in CuAAC click reactions prompted researchers to look for better and more stable catalysts to carry out the azide–alkyne cycloaddition to triazoles. However, despite several efforts, Cu+1 is found to be the best catalyst. The unique activity of Cu+1 over other metal ions is due to its ability to involve the terminal alkynes in both σ and π interactions and the possibility of immediate replacement of the ligands in its coordination sphere (generally in aqueous medium). However, Cu+1 is thermodynamically unstable and oxidizes to Cu+2 or disproportionates to a mixture of Cu+2 and Cu under aerobic conditions. Cu+2 is catalytically inactive, and its generation halts the reaction.
The thermodynamic instability of Cu+1 places importance on its introduction to a reaction mixture. It is observed that Cu+1 species are relatively stable in organic solvents and in the absence of water and oxygen. Cu(I) salts such as CuI, CuBr, and CuOTf·C6H6 have been found to be efficient catalysts in organic solvents. The use of Cu(I) salts in organic solvents is generally carried out with the addition of a tertiary amine base such as diisopropylethylamine (DIPEA) or 2,6-lutidine [17]. This is attributed largely to the requirement of a base to deprotonate the Cu–alkyne π complex, so as to generate the copper acetylide. It is also observed that amines and certain solvents such as acetonitrile [18] stabilize the Cu(I) species through coordination, preventing its degradation through oxidation or disproportionation.
When the reactions are carried out in aqueous media or in a mixture of water and an alcohol (most commonly tert-butanol), the degradation of Cu(I) salts is inevitable. It is found that the use of a Cu(II) salt such as CuSO4·5H2O along with reducing agents such as sodium ascorbate, hydrazine, or tris(2-carboxyethyl)phosphine (TCEP) generates Cu+1in situ. This method, where the active catalyst is generated in the reaction mixture via reduction of Cu(II) salts, works well in aqueous solutions and even in the presence of oxygen [19]. Additionally, the ability of water to act as a base allows these reactions to be carried out in the absence of an external base such as DIPEA. The continuous presence of a reducing agent such as sodium ascorbate ensures the regeneration of Cu(I) even if the active catalysts is quenched by air [19b]. It is also advantageous that carrying out reactions in aqueous media with in situ generation of Cu(I) species allows the use of substrates with unprotected amino and hydroxyl functions.
A third but less explored method for introduction of Cu+1 into the reaction mixture is by vigorously shaking or by microwave irradiation of a solution containing metallic copper. While the amount of Cu+1 ions produced in solution by vigorous shaking is quite less leading to extended reaction times (12–48 h) [20], microwave irradiation completes the reaction in 10–15 min at elevated temperatures [21]. An advantage of this method is the isolation of products with negligible copper contamination. Various other forms of copper such as Cu(I)-modified zeolites, copper oxide nanoparticles [22], or copper nanoparticles adsorbed on charcoal [23] have all been utilized successfully for CuAAC reactions.
1.1.2.3 Ligands used for CuAAC Click Reactions
Although CuAAC can be performed with Cu+1 generated in situ or provided as a Cu(I) salt in the absence of any ligands, certain ligands such as those that can form heterocyclic chelates with Cu+1 ions are shown to increase the rate of the reaction (Figure 1.3) [24]. The role of these ligands is assumed to be based on restraining Cu+1 from interactions, which lead to its degradation. Tris-(benzyltriazolylmethyl)amine (TBTA, E), a tetradentate ligand, is shown to be very efficient in increasing the rate of CuAAC click reactions [25]. Owing to its tetradentate-binding ability, it completely surrounds the Cu(I) center and does not provide any free binding sites for destabilizing interactions. The tertiary amino group in TBTA can also act as the required base, when reactions are carried out in organic solvents. Certain ligands are known to reduce the minimum catalyst loading by almost 10 times with no increase in reaction time [26]. Some common nitrogen-based ligands used in facilitating CuAAC are shown in Figure 1.3. Other than those based on nitrogen, ligands containing oxygen, phosphorous [27], carbon [28], and sulfur [29] as donor atoms are also reported.
Figure 1.3 Ligands used in CuAAC click reactions.
1.1.3 Ruthenium-Catalyzed Azide–Alkyne Cycloaddition (RuAAC) Click Reactions
Among various other metal ions studied for catalyzing HDC between azides and alkynes, Ru(II) catalysts were found to be the most notable. The catalytic activity and regioselectivity of the reaction were found to be dependent on the ligand environment of the Ru center. Unlike the Cu(I)-catalyzed reactions, azide–alkyne cycloaddition reactions catalyzed by ruthenium complexes showed a preference for the formation of 1,5-disubstituted triazoles to the formation of 1,4-disubstituted triazoles (Scheme 1.4). Out of the various ruthenium complexes studied for catalysis of this cycloaddition reaction, the most successful catalysts are Cp*RuCl, Cp*RuCl(PPh3)2, Cp*RuCl(COD), and Cp*RuCl(NBD). The reactions are performed with 1–2 mol% of the catalyst in THF/dioxane or in any nonprotic solvent at temperatures ranging from ambient to 80 °C. Another salient feature of Ru-catalyzed reactions is the possibility to use internal alkynes for the reaction to obtain 1,4,5-trisubstituted triazoles as the products in good yields (Scheme 1.4) [30]. Other than Cu and Ru, attempts have been made to use other metals such as Ni, Fe, Sm, Ce, and Zn also as catalysts for HDC reactions, but none of them gave satisfying results to be used widely [31].
Scheme 1.4 Formation of 1,5-disubstituted or 1,4,5-trisubstituted triazoles via Ru-catalyzed 1,3-dipolar cycloaddition reaction between azides and alkynes.
Unlike CuAAC reactions, the Ru-catalyzed version of HDC reactions was more dependent on the steric details of the azides than those of the alkyne components. Primary and secondary azides in the presence of catalytic amount of Ru complexes react with a wide range of terminal alkynes, but tertiary azides seem to be less reactive [24]. Electronic and steric properties of the alkynes too play a crucial role in these reactions, but not as much as those of the azides. Alkynes having H-bond donor groups such as propargyl alcohols and propargyl amines show high regioselectivity even for unsymmetrical alkynes. Strong H-bond between OH or NH2 of the alkyne and Cl on the Ru complex is the driving force for the reaction. The new bond is always formed between β carbon of alkyne and terminal nitrogen of the azides.
1.1.3.1 Mechanism of RuAAC Click Reactions
Mechanistic insights into ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC) reactions were provided by Fokin and coworkers in 2008, based on DFT calculations [32]. The mechanism is proposed to have two important steps. After the initial coordination of the alkyne and azide onto ruthenium, an irreversible oxidative coupling takes place, which also involves the formation of a C–N bond by the nucleophilic attack of the electronegative carbon of the activated alkyne on the terminal electrophilic nitrogen of the coordinated azide, forming a six-membered ruthenacycle intermediate. This cyclic intermediate then undergoes a rate-determining reductive elimination to give a triazolyl complex, which liberates a 1,5-disubstituted triazole product through ligand exchange (Scheme 1.5).
Scheme 1.5 Proposed mechanism of RuAAC click reactions.
1.1.4 Strain-Promoted Azide–Alkyne Cycloaddition (SPAAC) Reactions
Apart from the applications in synthesizing drug molecules with a triazole linkage, azide–alkyne cycloaddition reactions have also been used for various biological applications such as site-specific protein/viruses modifications and functionalization of cell surfaces. Use of transition-metal-catalyzed reactions for such applications is not advisable as metal salts could be detrimental to living cells. Copper salts are known to degrade oligonucleotide strands, and copper is cytotoxic at higher concentrations. This has placed an importance on the search for click reactions that can be carried out without the use of metal catalysts.
Use of electron-deficient alkynes is a possible option for increasing the rate of an uncatalyzed azide–alkyne cycloaddition reaction. However, this requirement places a serious restriction on the nature of functionalities that can be incorporated on the alkyne. A rapid cycloaddition reaction between neat cyclooctyne, the smallest stable cycloalkyne, and phenyl azide to give a triazole product in high yields was reported as early as in 1961. The release of substantial ring strain of nearly 18 kcal/mol in the cyclooctyne was the driving force for this reaction. Bertozzi and coworkers explored the possibility of using this strain-promoted azide–alkyne cycloaddition (SPAAC) reaction as a click reaction for bioconjugation [33]. They introduced electron-withdrawing groups (EWGs) on to the cyclooctyne system to increase its reactivity toward cycloaddition reactions further. Mono- and difluorinated cyclooctyne derivatives were prepared, which have lower energy LUMO providing an increased second-order rate constants for cycloaddition reactions (Scheme 1.6) [34].
Scheme 1.6 An example for SPAAC click reaction.
Boons and coworkers employed a different strategy and introduced benzyl groups adjacent to the alkyne function, thereby increasing the ring strain in the cyclooctyne molecule [35]. They succeeded in using these benzyl derivatives for reaction with azides and employed this strategy in visualizing labeled glycoconjugates metabolically in living cells.
Various other cycloaddition reactions including Diels–Alder reaction and hetero-Diels–Alder reactions have been employed as click reactions. However, all such reactions have found no or limited applications as conjugation methods.
