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

11/19/2021 - 11:00am to 12:00pm
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Speaker(s) / Presenter(s): 
Nabin Panth

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

Abstact: One of the remarkable steps in loline alkaloid biosynthesis is the installation of an ether bridge between two unactivated C atoms in 1-exo-acetamidopyrrolizidine (AcAP). LolO, a 2-oxoglutarate-dependent nonheme Fe oxygenase, catalyzes both the hydroxylation of AcAP and the resulting alcohol's cycloetherification to give N-acetylnornoline (NANL). The mechanism of hydroxylation is well understood, but the mechanism of the oxacyclization is not. We synthesized difluorinated analogs of AcAP in an attempt to further understand the mechanism of the unusual cycloetherification step.

We prepared 6,6-F2-AcAP in eight steps from N,O-protected 4-oxoproline. The key step was a Dieckmann condensation that annulated the A ring onto the B ring. When we subjected 6,6-F2-AcAP to LolO, the enzyme was able to catalyze both the hydroxylation and the cycloetherification to make 6,6-F2-NANL, suggesting that the LolO has a flexible active site, as it did not differentiate between the natural substrate (AcAP) and this difluorinated analog of AcAP. Also, it suggested that cycloetherification mechanism most likely involves a C(7) radical as opposed to a C(7) carbocation. Then, we prepared 7,7-F2-AcAP from 3-oxoproline in 17 steps where the key step was radical cyclization to make the pyrrolizidine ring in 5-exo-dig fashion. By contrast, when we subjected the difluorinated analog 7,7-F2-AcAP to LolO, the cycloetherification step was shut down completely, giving 2-OH-7,7-F2-AcAP as the sole product. Because 7,7-F2-AcAP completely blocks the cycloetherification step, it may be used in the future to further understand the cycloetherification of 2-hydroxy-AcAP by accumulating and characterizing the LolO intermediates responsible for cycloetherification.

Zoom Link: (Password: 235734)

Faculty Advisor: Dr. Robert Grossman

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