Biocatalytic synthesis of allylic and allenyl sulfides via a myoglobin-catalyzed Doyle-Kirmse reaction

• Published in: Angewandte Chemie International Edition
• Main Authors: Tyagi, Vikas, Sreenilayam, Gopeekrishnan, Bajaj, Priyanka, Tinoco, Antonio, Fasan, Rudi
• Format: Text
• Language: English
• Published: 2016
• Subjects: Article; Doyle; Sperm whale
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189672/; http://www.ncbi.nlm.nih.gov/pubmed/27647732; https://doi.org/10.1002/anie.201607278

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.