Evaluation of the Substrate Promiscuity of SorbC for the Chemo-Enzymatic Total Synthesis of Structurally Diverse Sorbicillinoids

Sorbicillinoids are a fungal natural product class with diverse and strong biomedical activities, ranging from antibiotic and antiviral properties to cytotoxicity. Synthetically, these natural products can efficiently be assembled by a chemo-enzymatic approach using the recombinant monooxygease SorbC. In the present work, we systematically screened the effects of structural changes to the natural substrate sorbicillin by HPLC-based analysis and comparative determination of key kinetic parameters. This not only provides important insights into substrate promiscuity of SorbC but also facilitates the efficient chemo-enzymatic preparation of unnatural dimeric sorbicillinoids possessing modified backbones or hydroxylated sorbyl side chains. In addition, the total syntheses of the natural saturnispol C, saturnispol D, and trichosorbicillin A, as well as of demethyltrichosorbicillin A and dihydroxybisorbicillinol, both not yet known in nature, are reported.

Automated summary

This study systematically investigated the effects of structural changes to the natural substrate sorbicillin on its activity, providing important insights into its promiscuity and facilitating the efficient preparation of unnatural sorbicillinoids. Additionally, the total syntheses of several natural and unnatural sorbicillinoids were reported.