Highly Electron-Deficient Pyridinium-Nitrones for Rapid and Tunable Inverse-Electron-Demand Strain-Promoted Alkyne-Nitrone Cycloaddition

Abstract

Highly accelerated inverse-electron-demand strain-promoted alkyne-nitrone cycloaddition (IED SPANC) between a stable cyclooctyne (bicyclo[6.1.0]nonyne (BCN)) and nitrones delocalized into a C α -pyridinium functionality is reported, with the most electron-deficient "pyridiniumnitrone" displaying among the most rapid cycloadditions to BCN that is currently reported. Density functional theory (DFT) and X-ray crystallography are explored to rationalize the effects of N-and C α -substituent modifications at the nitrone on IED SPANC reaction kinetics and the overall rapid reactivity of pyridinium-delocalized nitrones.

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

“…Although the kinetics with BCN are slower than those with BARAC or DIBO, BCN is more easily synthesized and less lipophilic than dibenzannulated alkynes which may bind nonspecifically to proteins, so its use in biological settings is more favorable . To overcome the lesser reactivity of nitrones with BCN, the Workentin group designed highly electron-deficient pyridinium-nitrones which react significantly faster than their diphenyl counterparts . The significantly lower LUMO of the pyridinium-nitrones decreases the HOMO–LUMO gap, resulting in second-order rate constants up to 8.3 M –1 s –1 , more than 100-fold larger than the diphenyl counterparts (Table ).…”

“…68 To overcome the lesser reactivity of nitrones with BCN, the Workentin group designed highly electrondeficient pyridinium-nitrones which react significantly faster than their diphenyl counterparts. 37 The significantly lower LUMO of the pyridinium-nitrones decreases the HOMO− LUMO gap, resulting in second-order rate constants up to 8.3 M −1 s −1 , more than 100-fold larger than the diphenyl counterparts (Table 1). Now, with these improved rates, pyridinium and diphenyl acyclic nitrones can be used with BCN and BARAC to achieve fast duplex labeling.…”

Synthesis of 2,3-Disubstituted 4-Ethoxycarbonyl-β-carbolin-1-ones: Application to the Synthesis of SL651498 and Its Analogue

“…In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3a (686 mg, 3.48 mmol), CuI (66.3 mg, 0.348 mmol), 1,2-bis­(diphenylphosphino)­ethane (DPPE, 139 mg, 0.348 mmol), and K 2 CO 3 (529 mg, 3.83 mmol), and to it were added H 2 O (0.13 mL, 6.96 mmol) and 1-bromo-2-ethynylbenzene S2a (629 mg, 3.48 mmol) in DMF (14 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. H 2 O (25 mL) was added to quench the reaction.…”

Highly Strained Unsaturated Carbocycles

“…The same group have also reported the reaction of 115 with nitrone 118 in a strain-promoted alkyne-nitrone cycloaddition (SPANC) to give the isooxazoline product 119 (Scheme 41). [122] Scheme 41. Reaction of (Z)-cycloocten-5-yne with nitrones.…”