Cycloaddition reactions have consumed the rising field of bioorthogonal chemistry, where highly selective reactions are utilized to study biological systems. In this arena, researchers aim to carry out reactions in vivo without experiencing side reactions that might interfere with natural processes. It is in this context where cycloadditions shine, avoiding the formation of charged intermediates and often providing stable linkages in the form of aromatic products. A variety of reactions are currently utilized in biological settings. Still, the right balance of speed, selectivity, and stability remains elusive. While the strain-promoted azide–alkyne cycloaddition (SPAAC) has overshadowed much of the landscape, the diazo group has overlooked potential in biological applications. 1,3-Dipolar cycloadditions of diazo compounds can be more rapid than those of azides and are more prone to electronic tuning. Ultimately, however, the high reactivity of diazo compounds has shied researchers away from exploring their potential. Recent advances in our laboratory provide both the means to access stabilized diazo compounds—namely, diazoacetamides—and applications that illustrate their potential as a tool for chemical biology. The ability to survive cellular metabolism and provide unique reactivity makes the diazo group a practical alternative to the azido moiety. Still, shared reactivity with choice strained alkynes (DIBAC, BCN, etc.) illustrates the need to understand cycloaddition reactivity to engender selectivity. By removing strain and exploring electronic factors controlling reactivity, we have demonstrated diazo-selective reactions with naturally occurring amino acids in the presence of azides at rates comparable to early-generation SPAACs. When pushed to its limits, the strategy of electronic tuning provides cycloadditions with unstrained alkenes and alkynes displaying reaction rates rivaling those of optimized SPAACs. Current efforts are in the pursuit of an optimal balance of strain and electronic effects to provide robust diazo-selective 1,3-dipolar cycloadditions to be carried out in physiological conditions.

Optimizing 1,3-dipolar cycloadditions of diazoacetamides for chemical ligation

256th National Meeting (2018)

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