Biocatalytic Asymmetric Construction of Secondary and Tertiary Fluorides from β-Fluoro-α-Ketoacids

Fluorine is a critical element for the design of bioactive compounds, driving advances in selective and sustainable fluorination. However, stereogenic tertiary fluorides pose a synthetic challenge and are thus present in only a few approved drugs (fluticasone, solithromycin, and sofosbuvir). The aldol reaction of fluorinated donors provides an atom-economical approach to asymmetric C-F motifs via C-C bond formation. We report that the type II pyruvate aldolase HpcH and engineered variants perform addition of beta-fluoro-alpha-ketoacids (including fluoropyruvate, beta-fluoro-alpha-ketobutyrate, and beta-fluoro-alpha-ketovalerate) to diverse aldehydes. The reactivity of HpcH towards these fluoro-donors grants access to enantiopure secondary or tertiary fluorides. In addition to representing the first synthesis of tertiary fluorides via biocatalytic carboligation, the afforded products could improve the diversity of fluorinated building blocks and enable the synthesis of fluorinated drug analogs.

Automated summary

Fluorine is a critical element in designing bioactive compounds, but the synthesis of stereogenic tertiary fluorides is challenging and limited to a few approved drugs. In this study, the aldol reaction of fluorinated donors catalyzed by HpcH and engineered variants was found to generate enantiopure secondary and tertiary fluorides. This method not only represents the first synthesis of tertiary fluorides via biocatalysis but also increases the diversity of fluorinated building blocks and enables the synthesis of fluorinated drug analogs.