Efficient low-cost preparation of trans-cyclooctenes using a simplified flow setup for photoisomerization

Abstract

Bioorthogonal ligations have emerged as highly versatile chemical tools for biomedical research. The exceptionally fast reaction between 1,2,4,5-tetrazines and trans-cyclooctenes (TCOs), also known as tetrazine ligation, is frequently used in this regard. Growing numbers of applications for the tetrazine ligation led to an increased demand for TCO compounds, whose commercial availability is still very limited. Reported photochemical procedures for the preparation of TCOs using flow chemistry are straightforward and high yielding but require expensive equipment. Within this contribution, we present the construction and characterization of a low-cost flow photoreactor assembled from readily accessible components. Syntheses of all commonly used trans-cyclooctene derivatives were successfully carried out using the described system. We are convinced that the presented system for photoisomerization will promote access to bioorthogonally reactive TCO derivatives.Graphical abstractElectronic supplementary materialThe online version of this article (doi:10.1007/s00706-016-1668-z) contains supplementary material, which is available to authorized users.

Micro-flow photosynthesis of new dienophiles for inverse-electron-demand Diels–Alder reactions. Potential applications for pretargeted in vivo PET imaging

“…With this optimized method using microreactors, 85% conversion can be achieved for trans -for- cis isomerization of cyclooctenol in 3 h (ESI†), compared to a reported 73% in 8 h or 70% in 3 h for non-microfluidic productions. 13,16 For the new functionalized cyclooctene derivatives, photoisomerization yields reached 76% for a 6 h experiment, with fluoro-compound 3 . For sulfonate precursors, only mesylate 11b and 20 could be isolated after isomerization, but 11b was quite unstable (data not shown).…”

Inverse electron demand Diels–Alder reactions in chemical biology

“…Recently, in order to improve the trans/cis ratios and reduce the photo degradation of the active transcyclooctene, a new synthetic route was proposed in a closed-loop flow apparatus. 108,109 In this synthesis, the reaction mixture is continuously photo irradiated at 254 nm and pumped through AgNO 3 impregnated silica, which binds strongly with the desired trans-isomer, eluting the cis-isomer to be isomerised again until completely consumed. This direct method was further applied in the synthesis of most TCO derivatives published so far since then.…”

A computational model to predict the Diels–Alder reactivity of aryl/alkyl-substituted tetrazines

“…Trans -cyclooctene ( 11 ) and tetrazines 9 and 10 were prepared following known procedures [ 31 , 32 ]. The synthesis of compounds 1 – 8 will be published elsewhere (manuscript in preparation).…”