Synthetic methodology towards allylic<i>trans</i>-cyclooctene-ethers enables modification of carbohydrates: bioorthogonal manipulation of the<i>lac</i>repressor

Abstract

The inverse electron-demand Diels-Alder (IEDDA) pyridazine elimination is one of the key bioorthogonal bond-breaking reactions. In this reaction <i>trans</i>-cyclooctene (TCO) serves as a tetrazine responsive caging moiety for amines, carboxylic acids and alcohols. One issue to date has been the lack of synthetic methods towards TCO ethers from functionalized (aliphatic) alcohols, thereby restricting bioorthogonal utilization. Two novel reagents were developed to enable controlled formation of <i>cis</i>-cyclooctene (CCO) ethers, followed by optimized photochemical isomerization to obtain TCO ethers. The method was exemplified by the controlled bioorthogonal activation of the <i>lac</i> operon system in <i>E. coli</i> using a TCO-ether-modified carbohydrate inducer.