4.8 Article

Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions**

Journal

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 44, Pages 23672-23677

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202107982

Keywords

artificial metalloenzymes; cascade catalysis; directed evolution; dirhodium catalysis; molecular dynamics simulations

Funding

  1. U.S. Army Research Laboratory
  2. U.S. Army Research Office [W911NF-18-1-0034, W911NF-15-1-0334, W911NF-18-1-0200]
  3. NSF under the CCI Center for Selective C-H Functionalization (CCHF) [CHE-1700982]

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Artificial metalloenzymes (ArMs) were engineered to catalyze diazo cross-coupling resulting in high enantioselectivity alkene reduction to alkane in a one-pot cascade reaction. Directed evolution improved reaction yields and selectivities for various substrates. Molecular dynamics simulations of ArM variants were used to understand the structural role of the cofactor on ArM conformational dynamics, highlighting the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity in complex media.
Artificial metalloenzymes (ArMs) are commonly used to control the stereoselectivity of catalytic reactions, but controlling chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross-coupling to form an alkene that, in a one-pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99 % ee) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis. Directed evolution of the ArM led to improved yields and E/Z selectivities for a variety of substrates, which translated to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on ArM conformational dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.

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