Enzymatic synthesis of fluorinated compounds

Abstract

Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research. Key points • Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science . • Enzyme catalysis is essential for the synthesis of fluorinated compounds . • The loop structure of fluorinase is the key to forming the C-F bond . Supplementary Information The online version contains supplementary material available at 10.1007/s00253-021-11608-0.

Oligomerization engineering of the fluorinase enzyme leads to an active trimer that supports synthesis of fluorometabolites in vitro

“…Organic chemistry methods exist for the synthesis of organofluorines and, more often than not, these require hazardous and noxious reagents. It follows that there are attractive prospects for the development of a biotechnology in this area (Cheng and Ma, 2021 ), but this goal is presently challenged by very limited access to appropriate enzymatic routes towards organofluorine biosynthesis. As such, developing a biotechnology for the site‐selective introduction of F into structurally diverse molecules would circumvent the harsh chemistry associated with chemical fluorination, and remains one of the great goals in metabolic engineering (Wu et al ., 2020 ).…”

“…This observation on the structural features of FlA, together with the fact that a homologous chlorinase enzyme (SalL) forms a functional trimer while displaying a k cat / K M specificity constant 100‐fold higher than that of the fluorinase (Eustáquio et al ., 2008 ), led us to investigate the role of FlA hexamerization on catalysis. The few other fluorinase enzymes described in the literature have not been characterized in detail thus far (e.g., by crystallographic analysis), and the oligomerization status of these halogenases remain to be explored (Cheng and Ma, 2021 ). On this background, in this article we report our efforts towards rational deconstruction of the hexameric form of the FlA fluorinase.…”

Biocatalytic synthesis of 2-fluoro-3-hydroxypropionic acid

“…Organic fluorides are important compounds that are widely used in the fields of pharmaceuticals, molecular imaging, and materials ( Klopries et al, 2014 ; Wu et al, 2020a ; Cheng and Ma, 2021 ). Fluorinated natural products are extremely rare in nature ( Cheng and Ma, 2021 ).…”

“…Organic fluorides are important compounds that are widely used in the fields of pharmaceuticals, molecular imaging, and materials ( Klopries et al, 2014 ; Wu et al, 2020a ; Cheng and Ma, 2021 ). Fluorinated natural products are extremely rare in nature ( Cheng and Ma, 2021 ). However, the introduction of fluorine atoms into organic compound molecules can often give these compounds new functions and make them have better performance ( Klopries et al, 2014 ; Ningning et al, 2020 ; Tu et al, 2020 ).…”

“…Despite the many advantages provided by fluorine for tuning key molecular properties, it is rarely found in natural metabolism, which limits the application of fluorine-containing compounds ( Thuronyi and Chang, 2015 ; Cheng and Ma, 2021 ). Accordingly, the artificial synthesis of fluorinated compounds has become an important alternative in modern society.…”