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Radical Tropolone Biosynthesis

preprint
submitted on 07.08.2020 and posted on 10.08.2020 by Tyler J. Doyon, Kevin Skinner, Di Yang, Leena Mallik, Troy Wymore, Markos Koutmos, Paul M. Zimmerman, Alison Narayan

Non-heme iron (NHI) enzymes perform a variety of oxidative rearrangements to advance simple building blocks toward complex molecular scaffolds within secondary metabolite pathways. Many of these transformations occur with selectivity that is unprecedented in small molecule catalysis, spurring an interest in the enzymatic processes which lead to a particular rearrangement. In-depth investigations of NHI mechanisms examine the source of this selectivity and can offer inspiration for the development of novel synthetic transformations. However, the mechanistic details of many NHI-catalyzed rearrangements remain underexplored, hindering full characterization of the chemistry accessible to this functionally diverse class of enzymes. For NHI-catalyzed rearrangements which have been investigated, mechanistic proposals often describe one-electron processes, followed by single electron oxidation from the substrate to the iron(III)-hydroxyl active site species. Here, we examine the ring expansion mechanism employed in fungal tropolone biosynthesis. TropC, an α-ketoglutarate- dependent NHI dioxygenase, catalyzes a ring expansion in the biosynthesis of tropolone natural product stipitatic acid through an under-studied mechanism. Investigation of both polar and radical mechanistic proposals suggests tropolones are constructed through a radical ring expansion. This biosynthetic route to tropolones is supported by X-ray crystal structure data combined with molecular dynamics simulations, alanine-scanning of active site residues, assessed reactivity of putative biosynthetic intermediates, and quantum mechanical (QM) calculations. These studies support a radical ring expansion in fungal tropolone biosynthesis.

History

Email Address of Submitting Author

arhardin@umich.edu

Institution

University of Michigan

Country

Unites States

ORCID For Submitting Author

0000-0001-8290-0077

Declaration of Conflict of Interest

No conflict of interest.

Version Notes

Version 1 TropC

Exports