Multi-functionalization of macromolecules by sequential 1,3-dipolar cycloadditions
Ledin, Petr Andreyevich
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Macromolecules with two or more types of reactive groups for modification provide versatile multi-functional scaffolds, which allow precise tuning of molecular properties, tailored to a particular function. Dendrimers and polymers with multiple sites for attachment of various biologically active moieties such as carbohydrates, peptides, nucleotides and drugs have an immense potential in biomedical applications and material science. Functionalization of macromolecules with biomolecules having rich functionality requires chemoselective and efficient reactions to avoid a need for protecting groups and hence post-modification deprotection steps. A novel synthetic methodology for efficient dendrimer assembly and hetero-bi-functionalization based on three sequential azide-alkyne cycloadditions is described in chapters 2 and 3. The methodology is compatible with biologically important compounds rich in chemical functionalities such as peptides, carbohydrates and fluorescent tags. A strain-promoted azide-alkyne cycloaddition (SPAAC) between polyester dendrons modified at the focal point with an azido and 4 dibenzocyclooctynol moiety provided dendrimers bearing terminal and TMS-protected alkynes at the periphery. The terminal alkynes were outfitted with azido-modified polyethylene glycol chains or galactosyl residues using Cu(I) catalyzed azide-alkyne cycloadditions (CuAAC). Next, a one-pot TMS-deprotection and second CuAAC reaction of the resulting terminal alkyne with azido-containing compounds gave multi-functional dendrimers bearing complex biologically active moieties at the periphery. Nitrile oxides and azides undergo facile 1,3-dipolar cycloadditions with cyclooctynes and provide an orthogonal pair of functional groups for sequential metal-free click reactions. Such selectivity makes it possible to multi-functionalize biomolecules and materials by simple synthetic procedures that do not require toxic metal catalysts. In chapter 4 we demonstrate the utility of this methodology by developing a unique synthetic route to oxime and azide bearing block copolymers via reversible addition-fragmentation chain transfer copolymerization of 4-vinylbenzaldehyde and 1-(chloromethyl)-4-vinylbenzene with styrene. These block copolymers served as scaffolds for attachment of hydrophobic and hydrophilic moieties by sequential strain-promoted alkyne-azide cycloaddition and strain-promoted alkyne-nitrile oxide cycloaddition reactions.