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<p>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.
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Concise synthesis of 3-alkylthieno[3,2-b]thiophenes; building blocks for organic electronic and optoelectronic materials
