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Double-click enables synthesis of chemical libraries for drug discovery

Operationally simple chemical reactions, termed click reactions, are widely used in many scientific fields. A streamlined synthesis of compounds called azides looks set to expand the role of click chemistry still further.
Joseph J. Topczewski is in the Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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En-Chih Liu is in the Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.

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Generating molecules and materials that have desirable functional properties is arguably the central goal of synthetic chemistry. For example, drugs are developed to have a set of physical and pharmacological properties that can treat a specific disease safely. Writing in Nature, Meng et al.1 report a reagent that greatly simplifies the synthesis of compounds known as azides, and thereby opens up a remarkably straightforward route to making libraries of compounds that might have useful biological functions.

Altering the structures of molecules to tune their properties is much more complicated than modifying objects in the everyday world. In carpentry, for instance, the same starting materials (timber, nails and screws) and tools (saws, hammers and screwdrivers) can be used to construct objects that have diverse shapes and functions, such as chairs, doors and crates. By contrast, building structural analogues of molecules often requires very different starting materials (reagents) and tools (reactions). The need to develop a range of synthetic routes to such analogues can be a bottleneck when optimizing functional molecular properties2, given that optimization can involve the laborious, resource-intensive synthesis of hundreds, or even thousands, of structural analogues.

A way of streamlining the optimization of desired functional properties was formalized in 2001, in a concept known as click chemistry3. A reaction is defined as click chemistry if it is operationally simple, is ‘spring-loaded’ (thermodynamically driven to produce a single product quickly), and generates new chemical bonds between two molecules. Ideally, the reactants should be used in a one-to-one ratio, rather than with an excess of one or more components (which is a common requirement for many reactions). Click reactions must be high-yielding, applicable to a broad range of compounds, and yet exceptionally selective, meaning that the chemical groups that undergo the reaction must react only with each other, and not with any other groups in the reactants. The product should also be easy to isolate or use without extensive purification. Although many synthetic reactions meet some of these criteria, surprisingly few meet all of them.

In 2002, two research groups independently reported4,5 that copper(i) salts are effective catalysts for reactions known as alkyne–azide cycloadditions (the copper-catalysed reaction is abbreviated as CuAAC). These reactions link an azide group (N3) with the carbon–carbon triple bond in an alkyne compound to form a triazole ring (Fig. 1). Because the CuAAC reaction fulfils all of the click criteria, it has become the poster child for click chemistry. It was the first click reaction to be widely adopted, and is now used in applications spanning many disciplines, from materials science to chemical biology6,7.

Figure 1 | A two-step click-chemistry sequence. a, Meng et al.1 report that a reagent called fluorosulfuryl azide rapidly converts almost any primary amine into an azide at room temperature — a type of reaction known as diazotransfer. The reactions are fast and high yielding, and the reagent does not react with chemical groups other than amines; they therefore fulfil the criteria to be categorized as ‘click’ reactions. b, The authors show that the resulting azide solution can be used without purification in a copper(i)-catalysed click reaction with alkynes (compounds that contain carbon–carbon triple bonds) to produce products called triazoles, which are potentially useful in drug discovery. R, Rʹ and Rʹʹ represent any chemical group or molecular fragment.

Several other click reactions have emerged over the past few years. Of particular note is one known as sulfur(vi)–fluoride exchange (SuFEx), which links an oxygen or nitrogen atom to an SO2F group. SuFEx is generally recognized as a second category of click reaction8,9 (unlike other click reactions, it is not a cycloaddition process), and has been used in a diverse range of chemical transformations9,10.

Despite the power of CuAAC reactions, their applications would be even broader if structurally complex, azide-containing compounds were more widely available. Conventionally, organic azides are synthesized by replacing a molecular fragment called a leaving group with an azide group; the leaving group can be a variety of chemical groups or just a single atom. However, the azide anions used in these substitution reactions are highly nucleophilic (electron-rich) and therefore very reactive. Substitutions with azide anions are thus often incompatible with having other chemical groups in the molecule. Furthermore, the leaving group often needs to be made in advance from an alcohol group (OH), which can be difficult or impossible to achieve selectively on molecules that contain many chemical groups.

Alternatively, azides can be prepared from primary amines (compounds that contain NH2 groups) by a ‘diazotransfer’ reaction. Until now, the state-of-the-art reagent used to carry out diazotransfer had been trifluoromethanesulfonyl azide11 (CF3SO2N3). However, the reactions often require an excess of this reagent, are slow, and do not always proceed to completion, with 60–70% as the typical yield.

Meng et al. have addressed these limitations by developing a more efficient diazotransfer reagent, fluorosulfuryl azide (FSO2N3). They report that it reacts with almost any primary amine in a one-to-one ratio, achieving a nearly 100% yield of the corresponding azide. The authors demonstrated the reagent’s substrate scope and practicality by using it to make a library of 1,224 azides in 96-well plates. It is notable that 49% of these azides had not been synthesized before, according to the authors’ literature search.

The number of azides synthesized is impressive (see Supplementary Information Section 6 of the paper1 for a full list), but the most striking aspect of this study is the substrate scope: the reaction works for different amine subclasses, on complex molecules, and in the presence of various chemical groups. Moreover, Meng and colleagues’ diazotransfer reaction meets the speed, breadth and efficiency criteria for click chemistry.

In addition, the authors demonstrated that the prepared azide solutions can be used directly in CuAAC reactions. This opens the door to a highly efficient and general two-step method for converting primary amines — a common chemical group in organic molecules — into triazoles. Notably, this method does not require the amines to be modified in advance to prevent unwanted side reactions at other chemical groups; nor does it require the intermediate azides to be purified.

Triazoles are functional mimics of the amide bond12, which is found in many pharmaceutical agents and in all proteins. Triazoles can also function as surrogates for sugars in polysaccharides13. Meng and co-workers’ chemistry could therefore be used to synthesize well-characterized libraries of complex small molecules and biomacromolecules from readily available precursors. More broadly, the work brings us a step closer to the vision laid out by the pioneers of click chemistry3,5: the development of a few operationally simple reactions that use common precursors to rapidly generate diverse libraries of (bio)molecules that have desirable functional properties.

Nature 574, 42-43 (2019)

doi: 10.1038/d41586-019-02905-w

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