Asymmetric δ-Lactam Synthesis with a Monomeric Streptavidin Artificial Metalloenzyme

• DOI: 10.1021/jacs.9b01596
• Publication Date: 2019-03-13T18:02:37Z
• Authors: Isra S. Hassan; Angeline N. Ta; Michael W. Danneman; Natthawat Semakul; Matthew Burns; Corey H. Basch; Vanessa N. Dippon; Brian R. McNaughton; Tomislav Rovis
• Keywords: Streptavidin; Reactivity; Cyclopentadienyl complex; Annulation; Lactam; Enantiomeric excess

Reliable design of artificial metalloenzymes (ArMs) to access transformations not observed in nature remains a long-standing and important challenge. We report that monomeric streptavidin (mSav) Rh(III) ArM permits asymmetric synthesis α,β-unsaturated-δ-lactams via tandem C-H activation [4+2] annulation reaction. These products are readily derivatized enantioenriched piperidines, the most common N-heterocycle found FDA approved pharmaceuticals. Desired δ-lactams achieved yields as high 99% enantiomeric excess 97% under aqueous conditions at room temperature. Embedding Rh cyclopentadienyl (Cp*) catalyst active site mSav results improved stereocontrol 7-fold enhancement reactivity relative isolated biotinylated cofactor. In addition, mSav-Rh outperforms its well-established tetrameric forms, displaying 11-33 times more reactivity.