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.

 

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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.

 

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Publication History

Article published online:
14 February 2024