Biocatalytic Carbene Transfer Using Diazirines



Biocatalytic carbene transfer from diazo compounds is a versatile strategy in asymmetric synthesis. However, the limited pool of stable diazo compounds constrains the variety of accessible products. To overcome this restriction, we have engineered variants of Aeropyrum pernix protoglobin (ApePgb) that use diazirines as carbene precursors. While the enhanced stability of diazir- ines relative to their diazo isomers enables access to a diverse array of carbenes, they have previously resisted catalytic activation. Our engineered ApePgb variants represent the first example of catalysts for selective carbene transfer from these species at room temperature. The structure of an ApePgb variant, determined by microcrystal electron diffraction (MicroED), reveals that evolution has enhanced access to the heme active site to facilitate this new-to-nature catalysis. Using readily prepared aryl diazirines as model substrates, we demonstrate the application of these highly-stable carbene precursors in biocatalytic cyclopropanation, N–H insertion, and Si–H insertion reactions.


Thumbnail image of Diazirines_Final.pdf

Supplementary material

Thumbnail image of Diazirines_SI_Final.pdf
Supplementary Information for Biocatalytic Carbene Transfer Using Diazirines
Supplementary figures, materials, experimental methods, compound synthesis and characterization, HPLC and GC-FID calibration curves, structural determination and analysis, HPLC and SFC traces.