A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene (+)-connatusin B from toluene

This study details the first total synthesis of (+)-connatusin B, a hirsutene-type sesquiterpenoid originally isolated from the fungus Lentinus connatus. The researchers aimed to confirm the structure and absolute configuration of the natural product through a de novo chemical synthesis. Their approach utilizes a chemoenzymatic strategy, starting from cis-1,2-dihydrocatechol, which is produced in enantiomerically pure form via the microbial dihydroxylation of toluene. This starting material provides a chiral scaffold that is then elaborated through a series of key transformations, including a Diels-Alder cycloaddition and an oxa-di-pi-methane rearrangement, to construct the required linear triquinane framework.

The synthesis successfully reached the target molecule, (+)-connatusin B. The reaction sequence effectively installed the necessary functional groups, including the vicinal diol and the cyclopentenone moiety. The synthetic material was characterized using spectroscopic techniques (NMR, IR, MS) and single-crystal X-ray analysis, which matched the data reported for the natural product. The authors also addressed minor discrepancies in the reported NMR data of the natural product, concluding that certain signals were likely misassigned or artifacts, and attributed differences in melting points to varying degrees of hydration between the synthetic and natural samples.

This work demonstrates the utility of toluene-derived cis-1,2-dihydrocatechols as versatile building blocks in the synthesis of complex natural products. By confirming the structure and absolute configuration of (+)-connatusin B, the study provides a definitive chemical reference for this sesquiterpenoid family. Furthermore, the successful application of the Diels-Alder and oxa-di-pi-methane rearrangement sequence highlights a robust strategy for accessing functionalized linear triquinanes, which are common structural motifs in various bioactive terpenes.