Acceleration of 1,3-Dipolar Cycloadditions by Integration of Strain and Electronic Tuning

Abstract

The 1,3-dipolar cycloaddition between azides and alkynes provides new means to probe and control biological processes. A major challenge is to achieve high reaction rates with stable reagents. The optimization of alkynyl reagents has relied on two strategies: increasing strain and tuning electronics. We report on the integration of these strategies. A computational analysis suggested that a CH → N aryl substitution in dibenzocyclooctyne (DIBO) could be beneficial. In transition states, the nitrogen of 2-azabenzo-benzocyclooctyne (ABC) engages in an n→π* interaction with the C=O of α-azidoacetamides and forms a hydrogen bond with the N–H of α-diazoacetamides. These dipole-specific interactions act cooperatively with electronic activation of the strained π-bond to increase reactivity. We found that ABC does indeed react more quickly with α-azidoacetamides and α-diazoacetamides than its constitutional isomer, dibenzoazacyclooctyne (DIBAC). ABC and DIBAC have comparable chemical stability in a biomimetic solution. Both ABC and DIBO are accessible in three steps by the alkylidene carbene-mediated ring expansion of commercial cycloheptanones. Our findings enhance the accessibility and utility of 1,3-dipolar cycloadditions and encourage further innovation.

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

“…This kind of analysis separates the activation energy into distortion energy and the energy of interactions, which helps to analyze the impact of geometrical similarity between reactants and TSs as opposed to TS stabilization approaches. 86 Distortion−interaction analysis has been used for studying cyclooctynes with endocyclic and exocyclic sigma acceptors 27 as well as for dibenzocyclooctynes, 85,87 aza-modified dibenzocyclooctyne, 34 and nonmodi- ‡ are given in kcal/mol; b Bending was calculated as 180°− (∠1 + ∠2)/2; bending is given for the conformations with the lowest value of ΔG 298 ‡ for 8-membered cycles; c all rate constants were calculated using the transition state theory: k = k B T/h × exp(−ΔG 298 ‡ /RT); calculated k values are given as a sum of (k 1,4-Triazole + k 1,5-Triazole ) as follows: k × (10 −3 ) M −1 s −1 ; d the value is given with 0.6 kcal/mol (for IC9C_st) and 0.5 kcal/mol (for BT9C_st) correction for the conformation with the minimal free energy IC9C_ecl and BT9C_ecl, respectively; e the value is given with 0.1 kcal/mol correction for the conformation with the minimal free energy C9C_1 (see Table S23 for C9C and C9C_1 conformers). fied 7-, 8-and 9-membered homologues.…”

“…The synthesized IC9N-BDP-FL was stable enough under purification and storage in a solid state and dissolved in aprotic solvents (acetone, DMSO). We also tested the stability of IC9N-BDP-FL under conditions close to physiological ones: the solution of IC9N-BDP-FL in phosphate-buffered saline containing reduced and oxidized forms of glutathione (Table S5, Figure S12) was incubated at 37 °C for 6 h. 34 The rate of degradation for IC9N-BDP-FL (t 1/2 = 16.2 h) lays between the degradation rates values of cyclononynes (IC9O: t 1/2 = 25.6 h and BT9NTs: t 1/2 = 5.0 h). Moreover all tested cyclononynes were more stable, than reactive cyclooctynes DIBO (t 1/2 = 3.8 h) and ABC (t 1/2 = 1.9 h).…”

“…49 It should be noted that among all structures mentioned, only a few have both attached rings and σ-acceptors bound to propargylic carbon atoms: unstable 8-membered DIFBO, 37 9membered ABSACN, 47 10-membered rac-BINOC, 48 and 8membered ABC, the synthesis of which was recently reported. 34 Both structural features can be considered as a combination providing additional strain for the destabilization of cycloalkyne core and stereoelectonic effects to stabilize TSs of the cycloaddition. However, no conclusions were drawn on strain/stereoelectronic influence in the case of ABSACN, while the H-bond formation was proposed as a key activator of SPAAC.…”

“…34 The authors reported a very elegant synthetic route toward cyclooctyne ABCa modified DIBO molecule in which one of fused benzene ring is replaced by a pyridine heterocycle. 34 In ABC, the nitrogen atom of a fused pyridine ring acts as a stereolectronic player with a synperiplanar arrangement of σ* CN orbital relative to forming bonds in TS, while both fused rings control the strain. This combination provided significantly increased ABC reactivity over DIBO for specific dipolesα-azidoacetamide and diazoacetamide as a result of n → π* interaction with the CO and hydrogen bond with the N−H, respectively.…”

“…Although several examples of the combination of strain and electronic parameters have been employed to create new SPAAC reagents, the integration of the increase in strain arising from the annulated heterocyclic ring, along with the stabilization of TS through the stereoelectric effect emerging from the endocyclic σ-acceptor remains unexplored. In this work, we aimed to apply both an increase in strain by a heterocycle fusion and stabilization of TS by an endocyclic σacceptor with an anti-periplanar arrangement of σ* CX orbital and the orbital of the forming C−N bond of triazole in TS (in contrast to the exocyclic σ-acceptor and the sin-periplanar orbitals arrangement in ABC), 34 to develop a new type of SPAAC reagents−heterocycloalkynes fused to heterocycles (Figure 1). Both structural motifsa heterocycle and a heteroatomcould serve to modulate the stability/reactivity balance of strained cycloalkyne molecules.…”