Asymmetric δ-Lactam Synthesis with a Monomeric Streptavidin Artificial Metalloenzyme
J. Am. Chem. Soc. 2019, 141, 4815-4819, 10.1021/jacs.9b01596
Reliable design of artificial metalloenzymes (ArMs) to access transformations not observed in nature remains a long-standing and important challenge. We report that a monomeric streptavidin (mSav) Rh(III) ArM permits asymmetric synthesis of α,β-unsaturated-δ-lactams via a tandem C–H activation and [4+2] annulation reaction. These products are readily derivatized to enantioenriched piperidines, the most common N-heterocycle found in FDA approved pharmaceuticals. Desired δ-lactams are achieved in yields as high as 99% and enantiomeric excess of 97% under aqueous conditions at room temperature. Embedding a Rh cyclopentadienyl (Cp*) catalyst in the active site of mSav results in improved stereocontrol and a 7-fold enhancement in reactivity relative to the isolated biotinylated Rh(III) cofactor. In addition, mSav-Rh outperforms its well-established tetrameric forms, displaying 11–33 times more reactivity.
Metal: RhHost protein: Streptavidin (monmeric)Anchoring strategy: SupramolecularOptimization: Chemical & geneticReaction: Lactam synthesisMax TON: 33ee: 97PDB: ---Notes: ---