Selective P450BM3 hydroxylation of cyclobutylamine and bicyclo[1.1.1]pentylamine derivatives: underpinning synthetic chemistry for drug discovery

Journal article

Achieving single-step syntheses of a set of related compounds divergently and selectively from a common starting material affords substantial efficiency gains when compared with preparing those same compounds by multiple individual syntheses. In order for this approach to be realized, complementary reagent systems must be available; here, a panel of engineered P450BM3 enzymes is shown to fulfill this remit in the selective C–H hydroxylation of cyclobutylamine derivatives at chemically unactivated sites. The oxidations can proceed with high regioselectivity and stereoselectivity, producing valuable bifunctional intermediates for synthesis and applications in fragment-based drug discovery. The process also applies to bicyclo[1.1.1]pentyl (BCP) amine derivatives to achieve the first direct enantioselective functionalization of the bridging methylenes and open a short and efficient route to chiral BCP bioisosteres for medicinal chemistry. The combination of substrate, enzyme, and reaction engineering provides a powerful general platform for small-molecule elaboration and diversification.

Authors: Harwood, L; Xiong, Z; Christensen, K; Wang, R; Wong, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of the American Chemical Society
• Volume: 145
• Issue: 50
• Pages: 27767-27773
• Publication date: 2023-12-05
• Acceptance date: 2023-11-15
• DOI: 10.1021/jacs.3c10542
• EISSN: 1520-5126
• ISSN: 0002-7863
• Language: English
• Keywords: P450BM3; cyclobutane; Bicyclo[1.1.1]pentane; stereoselective hydroxylation; fragment molecules