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Development and Application of Novel Hydrogenase-Inspired Mn Complexes

Periodic Reporting for period 1 - DANHIMC (Development and Application of Novel Hydrogenase-Inspired Mn Complexes)

Reporting period: 2018-03-01 to 2020-02-29

Hydrogenation reactions are one of the most important chemical transformations in both academic study and chemical industry. Tons of fuels, chemicals and pharmaceuticals are produced through this type of reactions every year. Over the past decades, many hydrogenation catalysts have been developed. However, they are mostly based on precious late transition metals such as Ru, Ir and Rh. From the viewpoint of sustainability and green chemistry, catalysts developed from cheap and less toxic earth-abundant base metals are more favored. In recent years, more and more research efforts are put on Fe, Co and Mn catalysis.

Nature has its own way to do similar hydrogenation reactions. Hydrogenases are biological catalysts for the production and activation of H2. There are three types of hydrogenases: [NiFe]-hydrogenase, [FeFe]-hydrogenase, and [Fe]-hydrogenase. The [Fe]-hydrogenase is found in some methanogenic archaea growing on H2 and CO2. The enzyme catalyzes the reaction of methenyltetrahydromethanopterin (methenyl-H4MPT+) with H2 to form methylenetetrahydromethanopterin (methylene-H4MPT) and H+. The reaction is rapid under 1 atmosphere of H2 at room temperature, with turnover frequencies of 100-200 per second. Thus, [Fe]-hydrogenase might be considered as an excellent hydrogenation catalyst for unsaturated organic substrates.

Impressed by the high activity of [Fe]-hydrogenase and considering its base metal nature, we plan to learn from this natural hydrogenase for new base metal dependent hydrogenation catalysts development. On the other hand, the limited activities from reported Fe based mimic models force us to reconsider the choice of metal center. Inspired by the vast development of Mn hydrogenation catalysts in recent years and given that Mn(I) and Fe(II) are isoelectronic, we decided to combine [Fe]-hydrogenase and Mn(I) together. Moreover, we expect our new biomimetic synthetic models will provide insights on this enzyme’s working mechanism and result in even better catalytic performance.

As a result, we managed to synthesize some novel Mn(I) based complexes mimicking natural [Fe]-hydrogenase. These complexes not only showed the highest catalytic activities among all the known analogous mimic models, but also delivered useful hydrogenation systems for various substrates. At the same time, semi-synthetic artificial [Mn]-hydrogenases were constructed with enhanced activity and gave insights for mechanism study.
Various structurally diverse Mn(I) based mimic complexes were synthesized and studied in this project. Complex 1 faithfully resembles the core structure of the active site of [Fe]-hydrogenase with an acylpyridinol bidentate ligand and several CO ligands. Unlike the previously reported Fe based mimic models, this new model was able to heterolytically cleave H2 as well as catalyze hydrogenation reactions. Further efforts towards better catalytic performance led to the design of complex 2. In the past several years, although many Fe complexes have been made to model the active site of [Fe]-hydrogenase, only few of them could activate H2. However, these pioneering works provided valuable insights for this project. Complex 2 incorporates a carbamoyl donor instead of the original acyl one, which makes it easier to access and more robust. A basic 2-NMe2 moiety is used to replace the native 2-OH group to render complex 2 more stable. As a result, complex 2 turned out to be the best hydrogenation catalyst derived from the modeling of [Fe]-hydrogenase. It was able to efficiently hydrogenate various unsaturated compounds including aldehydes, ketones and imines. Due to the biomimetic nature of this catalyst, it worked very well with biomimetic substrates related to methylene-H4MPT (the native substrate of [Fe]-hydrogenase). More importantly, this catalyst successfully realized asymmetric relay hydrogenation of benzoxazinones and benzoxazines. This transformation coupled a complex 2 catalyzed hydrogenation of a chiral hydride transfer agent with a Lewis acid-catalyzed hydride transfer from this agent to the substrates. Various substrates with different substitutes were efficiently reduced in good yields and enantioselectivities. Such transformation mainly relies on precious metal catalysis before the report of our system.

Except for hydrogenation catalyst development, these new Mn(I) based mimic models were also subjected to semi-synthetic hydrogenases constructions. Complex 1 was successfully transferred into the apo-enzyme of [Fe]-hydrogenase to deliver the first hydrogenase incorporating a Mn metal center. Encouragingly, this new [Mn]-hydrogenase not only retained the original catalytic functionality of [Fe]-hydrogenase, but also showed 25% activity higher than that of analogous semi-synthetic Fe based hydrogenase. These findings demonstrated that hydrogenases based on a Mn active site are viable and there are great potentials in creating better-than-nature artificial hydrogenases through our biomimetic synthesis/reconstitution strategy. The higher activity of this Mn mimic model over Fe models also proved our strategy of using non-natural metal center feasible.
This project represents a successful example of biomimetic catalyst development and artificial enzyme development. It will encourage researchers to pay more attention to the field of Biomimetic Chemistry and attract new players. The new Mn catalytic system developed in this project can be a useful tool for laboratory synthesis. The results of this project have already caught attention from both academic area and the wider public. They were accepted to publish on top journals such as Nature Chemistry and Angewandte Chemie International Edition. There were also news reports on our results and highly positive comments were given.
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