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Biocatalytic radical C-N bond forming reactions. a, Enzymatic C-N bond formation reactions predominantly rely on polar nucleophilic mechanisms and very few on organometallic mechanisms. Biocatalytic radical C-N bond forming reactions would be of great value but are unknown in nature. b, A general photoenzymatic platform enabling biocatalytic radical C-N bond formation is realized by the combination of enzymatic catalysis and photoredox catalysis. X, oxygen or carbon atom; L, ligand; LG, leaving group; Me, methyl; Ph, phenyl.
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The construction of C–N bonds is essential for the preparation of numerous molecules critical to modern society1,2. Nature has evolved enzymes to facilitate these transformations using nucleophilic and nitrene transfer mechanisms3,4. However, neither natural nor engineered enzymes are known to generate and control nitrogen-centered radicals, which...
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Context 1
... the flavin semiquinone (FMNsq). Importantly, these results demonstrate the compatibility of EREDs with radical intermediates and the ability of this enzyme family to control the stereochemical outcome of radical reactions 27 . Here, we report our development of an EREDbased photoenzymatic platform capable of harnessing NCRs for C-N bond formation (Fig. ...
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... within protein active sites, we tested a series of photocatalysts for this reaction [32][33][34] . Gratifyingly, we found that exposure of 1 to a solution of YqjM in the presence of 1 mol% Ru(bpy)3Cl2 (bpy = 2,2′-bipyridyl) 35 and subsequent irradiation under blue light (lem = 456 nm) produced the desired product (R)-2 in 52% yield with 81:19 er (Fig. 2a, entry 1). Control experiments revealed that the photocatalyst, the cofactor regeneration mix, and light are all crucial to the transformation (Fig. 2a, entries 3-5). Additionally, when 1 mol% of FMNox is used in place of YqjM, 2 is formed in only 22% yield as a racemic mixture (Fig. 2a, entry 6). Note that, based on reported binding affinities ...
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The formation of C–N bonds—of great importance to the pharmaceutical industry—can be facilitated enzymatically using nucleophilic and nitrene transfer mechanisms. However, neither natural nor engineered enzymes are known to generate and control nitrogen-centred radicals, which serve as valuable species for C–N bond formation. Here we use flavin-dep...
Citations
... [62] This approach has been further expanded to an ERED-based photoenzymatic platform capable of harnessing nitrogencentered radicals for CÀ N bond formation (Figure 2b). [63] Although the concept of using light and photocatalysts to harness new-to-nature chemistry from an existing and often engineered enzyme scaffold is a rather recent development in photobiocatalysis, we believe that it will open up a new era in sustainable organic synthesis. [1,16,61,64] Next to using light for catalysis, various strategies have been developed to efficiently light-regulate enzyme activity using natural photoreceptors or optochemical tools, that are promising for the application in biocatalysis. ...
... (a) EREDs catalyzing the deacetoxylation of α-acetoxyketones by using photoexcited RB [53] and (b) photoenzymatic platform enabling radical CÀ N bond formations. [63] RB: rose bengal; LG: leaving group. ...
The recent increase of interest in photocatalysis spread to biocatalysis and triggered a rush for the development of light‐dependent enzyme‐mediated or enzyme‐coupled processes. After several years of intense research on photobiocatalysis, it is time to evaluate the state of the field in a structured manner. In this Perspective, we suggest to group photobiocatalysis into distinct disciplines and provide principal guidelines and standards for the reporting of photobiocatalytic research results as well as advice on performing photobiocatalytic reactions. Overall, we assess that the field contributes to the diversity of biocatalytic reactions while offering the selectivity of enzymes to photocatalysis. We foresee that the ongoing excitement for light‐dependent enzymatic processes will lead to the discovery of novel photobiocatalytic mechanisms to complement biocatalysis with new bond‐forming reactions and will provide additional innovative strategies to utilize light as a possible benign energy source.
Synthetic chemists have long focused on selective C(sp3)–N bond-forming approaches in response to the high value of this motif in natural products, pharmaceutical agents and functional materials. In recent years, visible light-induced protocols have become an important synthetic platform to promote this transformation under mild reaction conditions. These photo-driven methods rely on converting visible light into chemical energy to generate reactive but controllable radical species. This Review highlights recent advances in this area, mostly after 2014, with an emphasis placed on C(sp3)–H bond activations, including amination of olefins and carbonyl compounds, and cross-coupling reactions. The construction of the highly valuable C(sp3)–N bond motif in a generalizable, selective, robust manner has been in demand for decades. This Review highlights the new and rising avenues towards this goal in the context of visible light-induced chemistry.
