Login / Signup

An NmrA-like enzyme-catalysed redox-mediated Diels-Alder cycloaddition with anti-selectivity.

Zhiwen LiuSebastian RiveraSean A NewmisterJacob N SandersQiuyue NieShuai LiuFanglong ZhaoJoseph D FerraraHao-Wei ShihSiddhant PatilWeijun XuMitchell D MillerGeorge N PhilipsKendall N HoukDavid H ShermanXue Gao
Published in: Nature chemistry (2023)
The Diels-Alder cycloaddition is one of the most powerful approaches in organic synthesis and is often used in the synthesis of important pharmaceuticals. Yet, strictly controlling the stereoselectivity of the Diels-Alder reactions is challenging, and great efforts are needed to construct complex molecules with desired chirality via organocatalysis or transition-metal strategies. Nature has evolved different types of enzymes to exquisitely control cyclization stereochemistry; however, most of the reported Diels-Alderases have been shown to only facilitate the energetically favourable diastereoselective cycloadditions. Here we report the discovery and characterization of CtdP, a member of a new class of bifunctional oxidoreductase/Diels-Alderase, which was previously annotated as an NmrA-like transcriptional regulator. We demonstrate that CtdP catalyses the inherently disfavoured cycloaddition to form the bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity. Guided by computational studies, we reveal a NADP + /NADPH-dependent redox mechanism for the CtdP-catalysed inverse electron demand Diels-Alder cycloaddition, which serves as the first example of a bifunctional Diels-Alderase that utilizes this mechanism.
Keyphrases
  • transition metal
  • transcription factor
  • small molecule
  • high throughput
  • highly efficient
  • single cell
  • dna methylation
  • oxidative stress
  • quality improvement
  • reactive oxygen species