An improved synthesis of a cyclopropene-based molecule for the fabrication of bioengineered tissues via copper-free click chemistry

Abstract

Background: Since its introduction in the field of biological imaging, the use of copper-free click chemistry has been extended to produce improved materials for vascular surgery, ophthalmology, environmental, and automotive applications. This wide applicability suggests that larger quantities of the chemical reagents for copper-free click chemistry will be required in the future. However, the large-scale synthesis of such chemicals has been barely investigated. A possible reason is the shortage of reliable synthetic protocols to obtain large quantities of these building blocks. We therefore present in this paper an improved synthetic protocol to obtain a cyclopropene-based carbonate, a key building block for the well-known copper-free click chemistry. Method: Our protocol builds upon an already available method to obtain a cyclopropene-based carbonate. When scaled up, several parameters of this method were changed in order to obtain an improved yield. First, the use of lower temperatures and slower addition rates of the chemicals avoided the formation of detrimental hotspots in the reaction system. Second, the use of less hygroscopic solvents minimized the decomposition of the cyclopropene carbonate. Finally, chromatographic purifications were minimized and improved by using deactivated silica. Results: We obtained the compound (2-methylcycloprop-2-en-1-yl)methyl (4-nitrophenyl) carbonate, a key building block for copper-free click chemistry, in an unprecedented 60% overall yield on a six-gram scale. Conclusions: Our improved synthetic protocol demonstrates the potential of large-scale production of improved materials using click chemistry, with potential future applications in the fields of molecular imaging, vascular surgery, ophthalmology, and theranostics.

Isolable Copper(I) η2-Cyclopropene Complexes

“…Cyclopropenes are highly strained, small carbocyclic alkenes with a long history . They have been investigated extensively during past decades and found to be impactful in multiple fields ranging from organic synthesis, − materials chemistry, ,, horticulture, , biochemistry, and natural product chemistry to the bioorthogonal labeling reactions. , For example, cyclopropenes are energy packed organic synthones (with strain energy of over 200 kJ mol –1 ) that undergo reactions such as addition, substitution, isomerization, and metatheses often not seen in the related nonstrained olefins. − 1-Methyl cyclopropene is an economically important ethylene antagonist utilized widely to prolong the shelf life of fruits, vegetables, and cut flowers. , Cyclopropenes are popular mini-tags in chemical biology to label biomolecules in live cells. ,, …”