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PreprintCC BYChemRxiv

A Library of Iron and α-Ketoglutarate Dependent Dioxygenases Enables the Synthesis of Six Fungal Natural Products

  • Gonzalo J Villegas Rodríguez1,2,3
  • Evan O Romero1,2,3
  • Jonathan C Perkins1,2,3
  • Diego N Rojas1,2,3
  • Maximilian S Hrigora1,2,3
  • Alison R H Narayan1,2,3,4
4 affiliations
  1. 1Department of Chemistry
  2. 2University of Michigan
  3. 3Life Sciences Institute
  4. 4Program in Chemical Biology
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Abstract

Achieving selective oxygenation chemistry offers a powerful strategy for streamlining routes to complex target molecules, yet the development of site-selective C-H functionalization reactions remain a significant challenge. Several enzyme families are capable of catalyzing C-H hydroxylation reactions and, in principle, provide an attractive solution for achieving selective oxidative transformations. In practice, however, the difficulty of identifying a biocatalyst suited to a specific synthetic target often renders chemoenzymatic strategies impractical. For example, biosynthetic enzymes such as CitB and ClaD can mediate site-selective benzylic hydroxylation, enabling access to select natural products that share structural features with their native substrates. Nonetheless, such approaches typically lack generality and do not readily extend to broader collections of natural products. Here, we explore the previously unstudied natural sequence space of the hydroxylases CitB and ClaD to generate a bespoke panel of uncharacterized enzymes that collectively expand the scope of this chemoenzymatic strategy. Development of this curated biocatalyst panel enabled the synthesis of six natural products, demonstrating that assembling this enzyme collection effectively derisks the use of biocatalysis in synthetic campaigns.

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Cite

BibTeXRIS
BibTeX
@misc{rodriguez2026library,
  title = {{A Library of Iron and α-Ketoglutarate Dependent Dioxygenases Enables the Synthesis of Six Fungal Natural Products}},
  author = {Gonzalo J Villegas Rodríguez and Evan O Romero and Jonathan C Perkins and Diego N Rojas and Maximilian S Hrigora and Alison R H Narayan},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.10001506/v2},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.10001506/v2},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - A Library of Iron and α-Ketoglutarate Dependent Dioxygenases Enables the Synthesis of Six Fungal Natural Products
AU  - Gonzalo J Villegas Rodríguez
AU  - Evan O Romero
AU  - Jonathan C Perkins
AU  - Diego N Rojas
AU  - Maximilian S Hrigora
AU  - Alison R H Narayan
PY  - 2026
DA  - 2026/09/17
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.10001506/v2
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.10001506/v2
AB  - Achieving selective oxygenation chemistry offers a powerful strategy for streamlining routes to complex target molecules, yet the development of site-selective C-H functionalization reactions remain a significant challenge. Several enzyme families are capable of catalyzing C-H hydroxylation reactions and, in principle, provide an attractive solution for achieving selective oxidative transformations. In practice, however, the difficulty of identifying a biocatalyst suited to a specific synthetic target often renders chemoenzymatic strategies impractical. For example, biosynthetic enzymes such as CitB and ClaD can mediate site-selective benzylic hydroxylation, enabling access to select natural products that share structural features with their native substrates. Nonetheless, such approaches typically lack generality and do not readily extend to broader collections of natural products. Here, we explore the previously unstudied natural sequence space of the hydroxylases CitB and ClaD to generate a bespoke panel of uncharacterized enzymes that collectively expand the scope of this chemoenzymatic strategy. Development of this curated biocatalyst panel enabled the synthesis of six natural products, demonstrating that assembling this enzyme collection effectively derisks the use of biocatalysis in synthetic campaigns.
ER  -