Stereoselective Synthesis of Bicyclo[6.1.0]nonene Precursors of the Bioorthogonal Reagents s-TCO and BCN

摘要

The cyclooctyne BCN and the trans-cyclooctene s-TCO are widely used in bioorthogonal chemistry. A bottleneck for their synthesis had been a poorly selective cyclopropanation with ethyl diazoacetate. Here, we describe that low catalyst loadings (0.27 mol %) of Rh-2(S-BHTL)(4) provide the BCN precursor with 79:21 syn/anti selectivity. The synthesis of the s-TCO precursor was best achieved through a sequence of Rh-2(OAc)(4) (0.33 mol %)-catalyzed cyclopropanac tion, followed by ester hydrolysis under epimerizing conditions. Both sequences could be carried out on multigram scale.