Metal-Free Sequential [3 + 2]-Dipolar Cycloadditions using Cyclooctynes and 1,3-Dipoles of Different Reactivity

Abstract

Although metal free cycloadditions of cyclooctynes and azides to give stable 1,2,3-triazoles have found wide utility in chemical biology and material sciences, there is an urgent need for faster and more versatile bioorthogonal reactions. We have found that nitrile oxides and diazocarbonyl derivatives undergo facile 1,3-dipolar cycloadditions with cyclooctynes. Cycloadditions with diazocarbonyl derivatives exhibited similar kinetics compared to azides whereas the reaction rates of cycloadditions with nitrile oxides were much faster. Nitrile oxides could conveniently be prepared by direct oxidation of the corresponding oximes with BAIB and these conditions made it possible to perform oxime formation, oxidation and cycloaddition as a one-pot procedure. The methodology was employed to functionalize the anomeric center of carbohydrates with various tags. Furthermore, oximes and azides provide an orthogonal pair of functional groups for sequential metal free click reactions and this feature makes it possible to multi-functionalize biomolecules and materials by a simple synthetic procedure that does not require toxic metal catalysts.

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

“…For example, we were to apply [41] strain-promoted alkyne-nitrone cycloaddition (SPANC), a reaction also reported by McKay et al in the same year [37], for the N-terminal labeling of proteins. Similarly, both our laboratory [27] and Sanders et al [47] reported the reaction of cyclooctynes with nitrile oxides (SPANOC) leading to isoxazoles, which is a factor *10 faster than SPAAC and SPANC. Finally, strain-promoted cycloaddition with diazo-compounds is also known [47] as well as reaction of BCN with sydnone [42,61].…”

“…Similarly, both our laboratory [27] and Sanders et al [47] reported the reaction of cyclooctynes with nitrile oxides (SPANOC) leading to isoxazoles, which is a factor *10 faster than SPAAC and SPANC. Finally, strain-promoted cycloaddition with diazo-compounds is also known [47] as well as reaction of BCN with sydnone [42,61]. Interestingly, in the field of (4 ?…”

Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents

“…Therefore, there is a clear necessity for metal-free protocols. This green approach has been conducted by different oxidative reagents such as oxone, [43][44] iodine, [45][46][47] iodobenzene trifluoroacetate, 48 iodobenzene diacetate, [49][50][51] tert-butyl hypoiodite 52 or chloramine-T. 53 However, these new protocols have several inconveniencies such as stability, price and manipulation of reagents. The importance of the used solvent has been recently addressed by the use of aqueous biphasic protocols, [54][55] ionic liquid, 56 and aqueous polyethylene glycol.…”

Protected Maleimide Building Blocks for the Decoration of Peptides, Peptoids, and Peptide Nucleic Acids

“…Other experiments also involving Cu(I)-catalyzed Huisgen cycloadditions [15][16][17] have made use of a scaffold with two different appending groups, an azide and either a group that can be transformed into azide or a latent 1,3-dipole. The alkyne-azide reaction was 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 followed by functional group conversion (that is, transformation of the azide precursors into azides or of the latent 1,3-dipole into dipole), and this by the second cycloaddition.…”