Synthesis of 6,6- and 7,7-Difluoro-1-acetamidopyrrolizidines and Their Oxidation Catalyzed by the Nonheme Fe Oxygenase LolO

Nabin Panth, Eliott S. Wenger, Carsten Krebs, J. Martin Bollinger, Robert B. Grossman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

LolO, a 2-oxoglutarate-dependent nonheme Fe oxygenase, catalyzes both the hydroxylation of 1-exo-acetamidopyrrolizidine (AcAP), a pathway intermediate in the biosynthesis of the loline alkaloids, and the cycloetherification of the resulting alcohol. We have prepared fluorinated AcAP analogues to aid in continued mechanistic investigation of the remarkable LolO-catalyzed cycloetherification step. LolO was able to hydroxylate 6,6-difluoro-AcAP (prepared from N,O-protected 4-oxoproline) and then cycloetherify the resulting alcohol, forming a difluorinated analogue of N-acetylnorloline and providing evidence for a cycloetherification mechanism involving a C(7) radical as opposed to a C(7) carbocation. By contrast, LolO was able to hydroxylate 7,7-difluoro-AcAP (prepared from 3-oxoproline) but failed to cycloetherify it, forming (1R,2R,8S)-7,7-difluoro-2-hydroxy-AcAP as the sole product. The divergent LolO-catalyzed reactions of the difluorinated AcAP analogues provide insight into the LolO cycloetherification mechanism and indicate that the 7,7-difluorinated compound, in particular, may be a useful tool to accumulate and characterize the iron intermediate that initiates the cycloetherification reaction.

Original languageEnglish
Article numbere202200081
JournalChemBioChem
Volume23
Issue number13
DOIs
StatePublished - Jul 5 2022

Bibliographical note

Funding Information:
This work was supported by the US National Institutes of Health (GM113106, and MIRA award GM127079 to C.K.). We thank Dr. Sean Parkin for the X‐ray crystallographic studies.

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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