Enzymatic C–H Amidation toward Stereoselective Construction of β-, γ- and δ-Lactams

Key words

C–H amidation - myoglobin - dioxazolones - enantiodivergence - nitrene transfer

Significance

Houk, Fasan, and co-workers disclose the haemoprotein-catalysed intramolecular C–H amidation of dioxazolone reagents toward the asymmetric synthesis of β-, γ- and δ-lactams with good to excellent enantioselectivity. Mechanistic studies suggest that the protein-mediated enantioinduction in the C–N bond-forming process occurs in the radical rebound step. Furthermore, an alkaloid natural product and a drug molecule were synthesized in a reduced number of steps (7–8 versus 11–12) compared to previous reports.

Comment

Enantiodivergent biocatalysts are highly desirable for medicinal chemistry and other synthetic applications, yet their development is often challenging. Notably, examination of the primary myoglobin (Mb) active-site mutant library uncovered a variant, Mb(L29T,H64V,V68L), which induces the cyclization with opposite enantioselectivity to that of Mb*, resulting in the production of the R-configured γ-lactam product.

Publication History

Article published online:
14 February 2024