Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Abstract

Bioorthogonal chemical reactions have emerged as convenient and rapid methods for incorporating unnatural functionality into living systems. Different prototype reactions have been optimized for use in biological settings. Optimization of 3 + 2 dipolar cycloadditions involving nitrones has resulted in highly efficient reaction conditions for bioorthogonal chemistry. Through substitution at the nitrone carbon or nitrogen atom, stereoelectronic tuning of the reactivity of the dipole has assisted in optimizing reactivity. Nitrones have been shown to react rapidly with cyclooctynes with bimolecular rate constants approaching k 2 = 102 M–1 s–1, which are among the fastest bioorthogonal reactions reported (McKay et al. Org. Biomol. Chem. 2012, 10, 3066–3070). Nitrones have also been shown to react with trans-cyclooctenes (TCO) in strain-promoted TCO-nitrone cycloadditions reactions. Copper catalyzed reactions involving alkynes and nitrones have also been optimized for applications in biology. This review provides a comprehensive accounting of the different bioorthogonal reactions that have been developed using nitrones as versatile reactants, and provides some recent examples of applications for probing biological systems.

Synthesis of Dihydroquinolinone Derivatives via the Cascade Reaction of o-Silylaryl Triflates with Pyrazolidinones

“…Third, the formation of 3a should involve an unprecedented cascade procedure consisting of the in situ formation of aryne and its coupling with pyrazolidinone followed by N–N bond cleavage and intramolecular C–N bond formation/annulation. Notably, this is different from previous findings on the reactions of arynes leading to the formation of the fused heterocyclic product. ,, Therefore, this serendipitously found reaction deserves a systematic and thorough investigation.…”

Diazophosphonates: Effective Surrogates for Diazoalkanes in Pyrazole Synthesis

“…Recently, such efficient cycloadditions have come to the fore in bioorthogonal chemistry, [6,7] a term first introduced by Bertozzi in 2003 to cover chemical reactions that can be conducted in living systems without disrupting natural processes [8,9] . Although bioorthogonal cycloadditions are mainly exemplified by the well known azide‐alkyne click chemistry, [10–13] other 1,3‐dipoles including diazo compounds also function, sometimes at higher rates [14–20] . In continuation of our interest in the generation and reaction of diazo compounds, [21–27] we now report that diazophosphonates are particularly suitable 1,3‐dipoles in both intermolecular, and for the first time, intramolecular cycloaddition reactions with alkynes to give N ‐unsubstituted pyrazoles.…”

An N-Allyl Glyoxylamide Based Bioorthogonal Nitrone Trap

“…Nitrones are reactive 1,3-dipoles in bioorthogonal reactions when combined with strained alkynes and strained alkenes (SPANC reactions). [12] Some SPANC reactions have impressive rate constants (>50 M -1 s -1 ), significantly greater than that of an azide with the same strained alkyne. [13] This difference in rates can afford reaction orthogonality to SPAAC chemistry, and SPANC reactions have proven to be useful in the context of many biological and materials applications.…”