The meticulous orchestration of atoms within molecules, known as stereocontrol, is a cornerstone in the realm of synthetic chemistry1. It carves the pathway to creating molecules with defined three-dimensional structures, a requisite in fields such as pharmaceuticals and agrochemicals where the 3D configuration of atoms holds the key to efficacy2. Our recently unveiled study at the University of Illinois at Urbana-Champaign illuminates a novel technique to attain remote stereocontrol in azaarenes via an enzymatic hydrogen atom transfer mechanism, marking a significant stride towards more efficient and sustainable synthetic methodologies3.
Historically, the journey towards achieving asymmetric catalysis with azaarenes—a class of nitrogen-containing aromatic compounds—has been riddled with challenges, predominantly due to their inherent ring rigidity. Our quest was to broaden the accessibility to distinct azaarenes with remote chiral centers. The major roadblock was the elusive superior enantioselectivity for remote stereocontrol stemming from the azaarene ring structure's rigidity. However, the introduction of an ene-reductase system capable of modulating the enantioselectivity of remote carbon-centered radicals on azaarenes through a mechanism of chiral hydrogen atom transfer has been a game-changer4.
Central to our method is a photoenzymatic process, guiding prochiral radical centers located more than six chemical bonds, or over 6Å, from the azaarene's nitrogen atom. This innovation enables the production of a myriad of azaarenes possessing a remote γ-stereocenter. The breakthrough was catalyzed by the advent of photoenzymes, propelling enzymatic catalysis into uncharted reaction domains. Our approach leveraged a flavin mononucleotide (FMN)-dependent ene-reductase for enantioselective radical hydroalkylation reactions, showcasing the successful utilization of this enzyme for achieving remote stereocontrol with azaarenes.
One of the compelling facets of our study was the exploration of the role of specific amino acid residues in determining enantioselectivity. Through a combined experimental and computational approach, we investigated the mechanisms of the reaction. For instance, mutagenesis studies were conducted to understand the pivotal roles played by residues H191 and N194. Our experiments showed that mutations at N194 had a noticeable effect on reactivity, shedding light on the discernible role it plays in substrate interaction. Furthermore, our investigation spanned across a broad range of azaarenes for hydroalkylation with α-methyl styrene under optimal reaction conditions. The results demonstrated high enantioselectivities across different substituted 2-bromomethyl pyridines. Also, the exploration of α-methyl vinyl arenes in the hydroalkylation of 4-bromomethyl pyridines revealed good to high yields with excellent enantioselectivities.
Our expedition was financially supported by the U.S. Department of Energy Center for Advanced Bioenergy and Bioproducts Innovation. The collaborative venture, woven together by a team of dedicated researchers, witnessed a fusion of experimental and computational studies. The project was led by Professor Huimin Zhao, with significant contributions from Maolin Li, who spearheaded the experiments and computational studies, alongside others who were pivotal in synthesizing substrates and constructing mutants. The insights garnered from our study, we believe, will significantly expand the current boundaries of asymmetric catalysis, steering us closer to more efficient and sustainable synthetic methodologies.
For more information, please see our recent publication in Nature Chemistry:
1. Carreira, E. M. & Kvaerno, L. Classics in Stereoselective Synthesis. (Wiley-VCH, Weinheim, 2008).
2. Devine, P. N. et al. Extending the application of biocatalysis to meet the challenges of drug development. Nat. Rev. Chem. 2, 409–421 (2018).
3. Harrison, W., Huang, X. & Zhao, H. Photobiocatalysis for abiological transformations. Acc. Chem. Res. 55, 1087-1096 (2022).
4. Emmanuel, M. A. et al. Photobiocatalytic strategies for organic synthesis. Chem. Rev. 123, 5459–5520 (2023).