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

Abstract

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 chemoenzymatic approach using the recombinant monooxygease SorbC. In the present work, we systematically screened the effects of structural changes to the natural substrate sorbicillin by HPLCbased 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.

Current Progress in the Chemoenzymatic Synthesis of Natural Products

“…The synthesis of sorbicillins requires a dearomatization to afford a sensitive, cyclohexadienone diol. This challenging transformation has been implemented by Gulder and coworkers, using a SorbC monooxygenase enzyme, in order to afford sorbicillinoids which could then be elaborated to natural products including Saturnispol C ( 54 ), D, and Trichosorbicillin A ( Scheme 16 ) [ 71 ]. Interestingly enough, the only requisite reaction to afford these three natural products was a Diels-Alder reaction, which was facile using the electron rich cyclic diene afforded by the dearomative hydroxylation of the enzyme under atmospheric conditions.…”

Chemoenzymatic total synthesis of sorbicillactone A

“…Starting from 2-methylresorcinol, 1 can readily be synthesized in three steps and enantioselectively converted to 2 using the recombinantly produced enzyme SorbC 16 . This approach offers access to various sorbicillinoids, including 3, 4 , and 5 17 – 20 . Due to its unusual structure, a potential synthesis of 7 must overcome challenges not typical for other sorbicillinoids, particularly the stereoselective installation of three contiguous stereogenic centers at C5, C6, and C9.…”