Efficient conversion of primary azides to aldehydes catalyzed by active site variants of myoglobin

Giovani, Simone; Singh, Ritesh; Fasan, Rudi

doi:10.1039/c5sc02857d

Cited by 42 publications

(43 citation statements)

References 64 publications

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“…To this end, we characterized and compared the catalytic activity and selectivity of a set of single and double reversion mutants in the reaction with phenyl allyl sulfide ( 1 ) and EDA (SI Table S2). In line with our previous observations, [3d, 9a, 16] mutation of the distal His residue (H64V) increases both the TTN (2,230 vs. 1,615 for Mb) and product formation rate (121 vs. 79 min −1 ), possibly through facilitating access of the substrate to the heme cavity (SI Figure S1). The L29S mutation further enhances the catalytic competency of the hemoprotein, as suggested by the increased total turnovers (3,085 TTN) supported by Mb(L29S,H64V).…”

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confidence: 92%

“…Previously, we found that mutations at these positions can dramatically alter the activity and selectivity of Mb variants as carbene [3d, 7, 9, 16] and nitrene [17] transfer catalysts. Upon testing in the reaction with 1 and EDA, a number of Mb variants with significantly improved catalytic activity compared to the wild-type protein were identified (Figure S3).…”

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confidence: 99%

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Biocatalytic Synthesis of Allylic and Allenyl Sulfides through a Myoglobin‐Catalyzed Doyle–Kirmse Reaction

et al. 2016

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The first example of a biocatalytic [2,3]-sigmatropic rearrangement reaction involving allylic sulfides and diazo reagents (Doyle-Kirmse reaction) is reported. Engineered variants of sperm whale myoglobin catalyze this synthetically valuable C–C bond forming transformation with high efficiency and product conversions across a variety of sulfide substrates (i.e., aryl-, benzyl-, and alkyl-substituted allylic sulfides) and α-diazo esters. Moreover, the scope of this myoglobin-mediated transformation could be extended to the conversion of propargylic sulfides to give substituted allenes. Active site mutations proved effective toward enhancing the catalytic efficiency of the hemoprotein in these reactions as well as modulating its enantioselectivity, resulting in the identification of a myoglobin variant, Mb(L29S, H64V, V68F), capable of mediating asymmetric Doyle-Kirmse reactions with an enantiomeric excess up to 71%. This work extends the toolbox of currently available biocatalytic strategies for realizing the asymmetric formation of carbon–carbon bonds.

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confidence: 92%

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Biocatalytic Synthesis of Allylic and Allenyl Sulfides through a Myoglobin‐Catalyzed Doyle–Kirmse Reaction

et al. 2016

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“…Giovani et al have shown that engineered myoglobins can catalyze the oxidative deamination of benzylic azides to yield aldehydes [37•], providing a biocatalytic alternative for aldehyde synthesis by alcohol oxidation with chromium- or manganese-based reagents. Myoglobin variant Mb(H64V,V68A) converted a broad range of primary azides to the corresponding aldehydes with up to 89% yield, exhibiting between 100- and 1000-fold higher catalytic activity than previously reported synthetic catalysts.…”

Section: Nitrene Transfer Reactions Catalyzed By Engineered Hemoproteinsmentioning

confidence: 99%

“…While not involving a heme enzyme, this reaction was proposed to involve catalytic intermediates that are reminiscent of those implicated in hemoprotein-catalyzed nitrene C–H insertion [11] and azide oxidation [37•]. …”

Section: Nitrene Transfer Reactions Catalyzed By Engineered Hemoproteinsmentioning

confidence: 99%

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

Brandenberg

Fasan

Arnold

2017

Current Opinion in Biotechnology

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The surge in reports of heme-dependent proteins as catalysts for abiotic, synthetically valuable carbene and nitrene transfer reactions dramatically illustrates the evolvability of the protein world and our nascent ability to exploit that for new enzyme chemistry. We highlight the latest additions to the hemoprotein-catalyzed reaction repertoire (including carbene Si–H and C–H insertions, Doyle-Kirmse reactions, aldehyde olefinations, azide-to-aldehyde conversions, and intermolecular nitrene C–H insertion) and show how different hemoprotein scaffolds offer varied reactivity and selectivity. Preparative-scale syntheses of pharmaceutically relevant compounds accomplished with these new catalysts are beginning to demonstrate their biotechnological relevance. Insights into the determinants of enzyme lifetime and product yield are providing generalizable cues for engineering heme-dependent proteins to further broaden the scope and utility of these non-natural activities.

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“…They have developed several target chemical transformations that are synthetically valuable to organic synthesis methodology. In the last two years, their group has shown significantly enhanced reactivity towards olefin cyclopropanation [55], provided the first biocatalytic example of the conversion of primary azides to aldehydes [56], carbene N-H and S-H insertion [57,58], and olefination of aldehydes by fine-tuning the active site with larger and smaller apolar residues within the protein scaffold of myoglobin [59].…”

Section: Some Recent Examples Of the Versatility Of Myoglobin Mutantsmentioning

confidence: 99%

Advances in Engineered Hemoproteins that Promote Biocatalysis

Stone

Ahmed

2016

Inorganics

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Some hemoproteins have the structural robustness to withstand extraction of the heme cofactor and replacement with a heme analog. Recent reports have reignited interest and exploration in this field by demonstrating the versatility of these systems. Heme binding proteins can be utilized as protein scaffolds to support heme analogs that can facilitate new reactivity by noncovalent bonding at the heme-binding site utilizing the proximal ligand for support. These substituted hemoproteins have the capability to enhance catalytic reactivity and functionality comparatively to their native forms. This review will focus on progress and recent advances of artificially engineered hemoproteins utilized as a new target for the development of biocatalysts.

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Efficient conversion of primary azides to aldehydes catalyzed by active site variants of myoglobin

Abstract: Engineered variants of myoglobin can efficiently catalyze the conversion of primary azides to aldehydes in water and at room temperature

Cited by 42 publications

References 64 publications

Biocatalytic Synthesis of Allylic and Allenyl Sulfides through a Myoglobin‐Catalyzed Doyle–Kirmse Reaction

Biocatalytic Synthesis of Allylic and Allenyl Sulfides through a Myoglobin‐Catalyzed Doyle–Kirmse Reaction

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

Advances in Engineered Hemoproteins that Promote Biocatalysis

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