Rearrangements and addition reactions of biarylazacyclooctynones and the implications to copper-free click chemistry

Abstract

Highly strained biarylazacyclooctynone (BARAC) and analogous bioconjugation reagents were shown to undergo novel rearrangement and addition reactions leading to tetracyclic products. This may limit their practical applicability as bioorthogonal reporters for imaging biomolecules within living systems.

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

“…The reactivity of the cyclooctyne can be modulated (Figure 5B) by appending electron withdrawing groups at the propargylic position (MOFO, DIFO) (Agard et al, 2006; Baskin et al, 2007), or by augmentation of strain energy through aryl ring (DIBO, DIBAC and BARAC) (Debets et al, 2010a; Jewett et al, 2010; Ning et al, 2008) or cyclopropyl (BCN) (Dommerholt et al, 2010) ring fusion (Sletten et al, 2014). The superior reaction rate of BARAC is counterbalanced by its instability toward hydrolysis in phosphate buffered saline (t 1/2 = 24 h), and tendency for intramolecular rearrangement under acidic conditions (Chigrinova et al, 2013). Additionally, cyclooctynes have been reported to undergo nucleophilic addition with cellular nucleophiles such as glutathione (Beatty et al, 2010; Chang et al, 2010), homotrimerization (Sletten et al, 2010), and reaction with cysteine sulfenic acids (with trapping rates that are an order of magnitude faster than SPAAC and exceed the rates of previously sulfenic acid capture reactions by more than 100-fold) (Figure 5C,D) (Poole et al, 2014).…”

Small gold nanoparticles for interfacial Staudinger–Bertozzi ligation

“…10,11 While the [3 + 2] Huisgen cycloaddition and its catalyzed version are not completely compatible with AuNPs chemistry because the high temperature or the Cu(I) required to push the reaction to completion cause severe nanoparticle aggregation, 12 the SPAAC reaction presents limited chemoselectivity due to the possibility of nucleophilic attacks (especially from thiols and amines largely present in biomolecules) to the highly reactive strained triple bond. [13][14][15] A recent work of ours highlighted this issue showing how post assembly deprotection of peptides once "clicked" on the AuNP surface was necessary to efficiently synthesize a nanoparticle bioconjugate through the SPAAC reaction. 16 The Bertozzi-Staudinger ligation is a reaction that was specifically developed for investigating the metabolic engineering of cell surfaces 17 and takes place between the azide and a substituted triphenylphosphine.…”

[18F]FPyZIDE: A versatile prosthetic reagent for the fluorine‐18 radiolabeling of biologics via copper‐catalyzed or strain‐promoted alkyne‐azide cycloadditions

“…Only the dibenzyl cyclooctyne BARAC displayed a higher rate constant (k = 0.96 M −1 s −1 ) than BCN or DBCO but with lower commercial availability and with stability issues due to rearrangements depending on the functionalization of the cyclooctyne ring. 50 Nonradioactive BCN-based reference 17 was prepared by reaction of FPyZIDE with 16 and was obtained in 99% yield. Nonradioactive DBCO-based reference 20 was synthesized in two steps starting from DBCO 18.…”