Readily Accessible Strained Difunctionalized trans-Cyclooctenes with Fast Click and Release Capabilities

Abstract

The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective steps starting from commercially available compounds. The click kinetics and payload release were assessed with various functionalized derivatives and local drug release was shown in a cellular toxicity study.

A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

“…We hypothesized that this stereoselective and efficient method could also be used to prepare cleavable sTCO linkers using a syn-positioned carboxylic acid substituent on the fused cyclopropane of a bicyclo[6.1.0]non-2-ene, forming a 5-and 10-, and a 7-and 8-membered bicyclic lactone ring starting from 1,3-cyclooctadiene and 1,5-cyclooctadiene respectively (Scheme 2 and 4). During the completion of this manuscript, Mikula 15 and Rutjes 16 recently published elegant alternative approaches to stereoselective preparation of cleavable d-TCO and sTCO linkers. Starting from 1,3-cyclooctadiene, following the method of Fox and co-workers, 12 we used a Rh-catalyzed reaction of ethyl diazoacetate to form bicyclo[6.1.0]non-2-ene-9-carboxylate 1 as a mixture of anti-and syn-isomers.…”

A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

“…We hypothesized that this stereoselective and efficient method could also be used to prepare cleavable sTCO linkers using a syn-positioned carboxylic acid substituent on the fused cyclopropane of a bicyclo[6.1.0]non-2-ene, forming a 5-and 10-, and a 7-and 8-membered bicyclic lactone ring starting from 1,3-cyclooctadiene and 1,5-cyclooctadiene respectively (Scheme 2 and 4). During the completion of this manuscript, Mikula 15 and Rutjes 16 recently published elegant alternative approaches to stereoselective preparation of cleavable d-TCO and sTCO linkers. Starting from 1,3-cyclooctadiene, following the method of Fox and co-workers, 12 we used a Rh-catalyzed reaction of ethyl diazoacetate to form bicyclo[6.1.0]non-2-ene-9-carboxylate 1 as a mixture of anti-and syn-isomers.…”