Triazoles in click chemistry: Ligands, copper(I)-catalysis, and organocatalysis.

摘要

Click chemistry is a process-based approach for streamlining the molecular discovery process. It relies upon an exclusive set of reactions, known as click reactions, that are nearly perfect reactions with respect to their reliability, modularity, experimental simplicity, and selectivity. This entire work has been guided by the click chemistry philosophy.; The copper(I)-catalyzed ligation of azides and terminal alkynes is a uniquely powerful reaction for forming 1,4-disubstituted-1,2,3-triazoles with clean conversions, high yields, exclusive regioselectivity, and excellent functional group tolerance. Unfortunately, the main weakness of this reaction is the relative instability of copper(I) with respect to oxidation and disproportionation. To solve these problems, a C3-symmetrical N-tripodal ligand containing three triazoles, tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA), was developed and shown to be an effective ligand for supporting the copper(I)-ligation. TBTA has enabled the copper(I)-ligation to be successfully applied to a wide variety of challenging bioconjugation conditions.; A solid-supported copper(I)-catalyst was developed by immobilizing TBTA onto a Tentagel resin and loading with copper(I)-salts. The catalyst achieves high catalyst turnovers in numerous solvents with a wide variety of substrates. The exceptionally clean conversions and high yields of the copper(I)-catalyzed ligation ensures that the only workup that is required is a simple filtration of the immobilized catalyst and evaporation of the solvent. The automated parallel synthesis of 1,4-disubstituted-1,2,3-triazoles was successfully demonstrated utilizing the copper(I)-resin.; Another click reaction was successfully developed, the pyrrolidine catalyzed synthesis of 1,4,5-trisubstituted-1,2,3-triazoles. This reaction is catalyzed by 10--20 mol% of pyrrolidine and reacts aryl and heteroaryl azides with ketones containing an electron withdrawing group at the alpha-position (e.g. beta-keto esters, alpha-cyano ketones, etc). The cycloaddition is perfectly regioselective and commonly achieves high yields (80--99%). In general, electron-poor azides react faster than electron-rich azides. Functional groups such as carboxylic acids, sulfonamides, esters and amines are tolerated under these mild conditions. Terminal alkynes and alkyl azides may also be carried through for the rapid generation of building blocks in copper-driven click chemistry.