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

Autor: Panth N; Department of Chemistry, University of Kentucky, Lexington, Kentucky, 40546-0312, USA., Wenger ES; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA., Krebs C; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA.; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA., Bollinger JM Jr; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA.; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA., Grossman RB; Department of Chemistry, University of Kentucky, Lexington, Kentucky, 40546-0312, USA.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2022 Jul 05; Vol. 23 (13), pp. e202200081. Date of Electronic Publication: 2022 May 17.
DOI: 10.1002/cbic.202200081
Abstrakt: 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.
(© 2022 Wiley-VCH GmbH.)
Databáze: MEDLINE
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