Aliphatic Halogenase Enables Late-Stage C-H Functionalization: Selective Synthesis of a Brominated Fischerindole
Qin Zhu1, Matthew L Hillwig1, Yohei Doi2
1Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260, USA.
Abstract:
The anion promiscuity of a newly discovered standalone aliphatic halogenase WelO5 was probed and enabled the selective synthesis of 13R-bromo-12-epi-fischerindole U via late-stage enzymatic functionalization of an unactivated sp(3) C-H bond. Pre-saturating the WelO5 active site with a non-native bromide anion was found to be critical to the highly selective in vitro transfer of bromine, instead of chlorine, to the target carbon center and also allowed the relative binding affinity of bromide and chloride towards the WelO5 enzyme to be assessed. This study further revealed the critical importance of halogen substitution on modulating the antibiotic activity of fischerindole alkaloids and highlights the promise of WelO5-type aliphatic halogenases as enzymatic tools to fine-tune the bioactivity of complex natural products.
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