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

Chemical Science
Simone GiovaniRudi Fasan

Abstract

The oxidation of primary azides to aldehydes constitutes a convenient but underdeveloped transformation for which no efficient methods are available. Here, we demonstrate that engineered variants of the hemoprotein myoglobin can catalyze this transformation with high efficiency (up to 8,500 turnovers) and selectivity across a range of structurally diverse aryl-substituted primary azides. Mutagenesis of the 'distal' histidine residue was particularly effective in enhancing the azide oxidation reactivity of myoglobin, enabling these reactions to proceed in good to excellent yields (37-89%) and to be carried out at a synthetically useful scale. Kinetic isotope effect, isotope labeling, and substrate binding experiments support a mechanism involving heme-catalyzed decomposition of the organic azide followed by alpha hydrogen deprotonation to generate an aldimine which, upon hydrolysis, releases the aldehyde product. This work provides the first example of a biocatalytic azide-to-aldehyde conversion and expands the range of non-native chemical transformations accessible through hemoprotein-mediated catalysis.

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Citations

Jan 15, 2016·Angewandte Chemie·Vikas Tyagi, Rudi Fasan
Aug 11, 2017·Dalton Transactions : an International Journal of Inorganic Chemistry·Le-Le LiYing-Wu Lin
Mar 12, 2019·Chemical Communications : Chem Comm·Nan ChenChu Wang
Mar 20, 2020·Chembiochem : a European Journal of Chemical Biology·Maria Agustina VilaRudi Fasan
Apr 25, 2020·Angewandte Chemie·Frank HollmannCaroline E Paul
Jan 13, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Koji Oohora, Takashi Hayashi
Jul 18, 2017·Current Opinion in Biotechnology·Oliver F BrandenbergFrances H Arnold
May 15, 2020·Journal of the American Chemical Society·Viktoria SteckRudi Fasan
Aug 11, 2021·Chemical Communications : Chem Comm·Bayu ArdiansahKiyomi Kakiuchi
Mar 3, 2018·Organic Letters·Angela S CarlsonJoseph J Topczewski
Aug 17, 2021·Current Opinion in Green and Sustainable Chemistry·Xinkun Ren, Rudi Fasan

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