Note: When clicking on a Digital Object Identifier (DOI) number, you will be taken to an external site maintained by the publisher.
Some full text articles may not yet be available without a charge during the embargo (administrative interval).
What is a DOI Number?
Some links on this page may take you to non-federal websites. Their policies may differ from this site.
-
Abstract Trifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of
trans ‐CF3‐CPAs, stereoselective production of correspondingcis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis ‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix (Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery. -
Abstract Trifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of
trans ‐CF3‐CPAs, stereoselective production of correspondingcis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis ‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix (Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery. -
Previous work has demonstrated that variants of a heme protein, Rhodothermus marinus cytochrome c (Rma cyt c), catalyze abiological carbene boron–hydrogen (B–H) bond insertion with high efficiency and selectivity. Here we investigated this carbon–boron bond-forming chemistry with cyclic, lactone-based carbenes. Using directed evolution, we obtained a Rma cyt c variant BORLAC that shows high selectivity and efficiency for B–H insertion of 5- and 6-membered lactone carbenes (up to 24,500 total turnovers and 97.1:2.9 enantiomeric ratio). The enzyme shows low activity with a 7-membered lactone carbene. Computational studies revealed a highly twisted geometry of the 7-membered lactone carbene intermediate relative to 5- and 6-membered ones. Directed evolution of cytochrome c together with computational characterization of key iron-carbene intermediates has allowed us to expand the scope of enzymatic carbene B–H insertion to produce new lactone-based organoborons.more » « less