Click Chemistry as a Tool for Medicinal Chemistry

Click Chemistry and Reaction of Azides and Alkynes

In medicinal chemistry, it is important to find the hits and lead compounds as fast as possible. Simple synthetic methods are a necessity for such purposes. In 2001 K. Barry Sharpless with co-workers postulated the concept of “Click-chemistry”. For a reaction to be called a click-reaction, it is supposed to be: high yielding, wide in scope, stereospecific, easily purifiable, used with easily removable and benign solvents and with simple synthetic procedures. All of these ideas works great for medicinal chemistry. One of the most popular prime examples of a “Click-reaction” is Huisgen 1,3-dipolar cycloaddition. Thermally guided reaction between azide and alkyne yields only 1,2,3-triazoles – a privileged scaffold in medicinal chemistry as compounds, that contains this structure possess wide spectrum of biological activity.

Introduction of Copper(I) Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

The only problem with the Huisgen conditions is that the reaction is not stereospecific. But, by the remarkable efforts of Sharpless and Valery V. Fokin (doi: 10.1039/B904091A), method for selective 1,4-disubstituted 1,2,3-triazoles has been developed. By the introduction of catalytic amounts of copper(I), reaction proceeds smoothly to yield 1,4-substituted products. Although, reaction can be facilitated by the use of commercially available copper(I) sources (Cu2O, CuBr, CuI, etc), it can just as well be done with in situ generated Cu(I) from Cu(II) (typically used system is CuSO4 and sodium ascorbate as reducting agent, but other systems works as well). As this reaction yields triazoles from terminal alkynes and azides, formally, it is not Huisgen 1,3-dipolar cycloaddition. Much more appropriate term would be copper(I) catalyzed azide-alkyne cycloaddition (CuAAC).

Although, usually Cu(I) is enough to run this reaction, to enhance this reaction, for example in ambient conditions, ligands can be used. Most typical ligands are highly donating polydentate nitrogen ligands – Tris(triazolyl)methylamine ligands have been reported by several groups. Also, phosphine and carboxylate ligands can be used.

Typically there are low restrictions on azide and acetylene substituents, however, electron deficient and less hindered azides show higher reaction rates. Also alpha-carboxylic acetylenes show higher reactivity then alkylacetylenes. Regarding solvent, this reaction can be run on wide variety of them. Solvents like toluene, dichloromethane and chloroform, tetrahydrofuran, dioxane and pyridine, dimethylformamide, dimethylsulfoxide and alcohols and even water. Solvent choice rather depends on solubility of your starting materials and catalysts. (For more information: doi: 10.1039/C5OB01457C)

Less atraction but just as interesting chemistry has been developed using ruthenium catalysis. Ruthenium catalyzed azide-alkyne cycloaddition (RuAAC) has showed selectivity for both selective 1,4 and 1,5 substituted product formation. Also, several other transition metal catalyzed versions have been developed for such pursposes.

For Medicinal Chemistry Purposes

In terms of medicinal chemistry, CuAAC allows to easily combine two different structures that contains either azido- or alkynyl- functions. In short period of time chemists are able to fast and cleanly combine two different structural motifs – either combining properties of two complex molecules for synergistic effect or to screen large scope of substituents for quantitative structure-activity relationship (QSAR) studies.

Several screenings of betulin derivatives using click chemistry have shown potential for medicinal chemistry purposes. To help you access faster screening, we can provide you with several “click-ready” compounds like Betulinic Amido-TOTA-Azide, Betulinic Amido-DOOA-Poc and other azido and alkynyl- derived betulin compounds. For all “click-ready” compounds click here.