Stereoselective Synthesis of Bicyclo6.1.0nonene Precursors of the Bioorthogonal Reagents s-TCO and BCN

摘要

The cyclooctyne BCN and the trans-cyclooctene s-TCO are broadly used reagents for bioorthogonal chemistry. A bottleneck for the synthesis of these reagents had been a poorly selective cyclopropanation reaction with ethyl diazoacetate and catalytic Rh2(OAc)4. Here, we describe that low catalyst loadings (0.27 mol%) of Rh2(S−BHTL)4 provides the BCN precursor with 79:21 syn:anti selectivity. The synthesis of the s-TCO precursor was best achieved through a sequence of Rh2(OAc)4 (0.33 mol%) catalyzed cyclopropanation, followed by ester hydrolysis under epimerizing conditions. Both sequences could be carried out on multigram scale.