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

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 Rh2(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 Rh2(OAc)4 (0.33 mol %)-catalyzed
cyclopropanation, followed by ester hydrolysis under epimerizing conditions.
Both sequences could be carried out on multigram scale.