Synthesis of Imidazolidin-4-ones via a Cytochrome P450-Catalyzed Intramolecular C−H Amination

Journal article

Expanding Nature’s catalytic repertoire to include reactions important in synthetic chemistry opens new opportunities for biocatalysis. An intramolecular C–H amination route to imidazolidin-4-ones via α-functionalization of 2-aminoacetamides catalyzed by evolved variants of cytochrome P450BM3 (CYP102A1) from Bacillus megaterium has been developed. Screening of a library of ca. 100 variants based on four template mutants with enhanced activity for the oxidation of unnatural substrates and preparative scale reactions in vitro and in vivo show that the enzymes give up to 98% isolated yield of cyclization products for diverse substrates. 2-Aminoacetamides with one- and two-ring cyclic amines bearing substituents and aliphatic, alicyclic, and substituted aromatic amides are cyclized. Regiodivergent C–H amination was achieved at benzylic and nonbenzylic positions in a tetrahydroisoquinolinyl substrate by the use of different mutants. This C–H amination reaction offers a scalable route to imidazolidin-4-ones with varied functionalized substituents that may have desirable biological activity.

Authors: Ren, X; O'Hanlon, J; Morris, M; Robertson, J; Wong, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Catalysis
• Volume: 6
• Issue: 10
• Pages: 6833–6837
• Publication date: 2016-09-01
• Acceptance date: 2016-09-01
• DOI: 10.1021/acscatal.6b02189
• ISSN: 2155-5435
• Keywords: C−H activation; protein engineering; heme monooxygenases; C−H amination; P450