Aldolase-catalysed stereoselective synthesis of fluorinated small molecules

Abstract

The introduction of fluorine has been widely exploited to tune the biological functions of small molecules. Indeed, around 20% of leading drugs contain at least one fluorine atom. Yet, despite profound effects of fluorination on conformation, there is only a limited toolkit of reactions that enable stereoselective synthesis of fluorinated compounds. Aldolases are useful catalysts for the stereoselective synthesis of bioactive small molecules; however, despite fluoropyruvate being a viable nucleophile for some aldolases, the potential of aldolases to control the formation of fluorine-bearing stereocentres has largely been untapped. Very recently, it has been shown that aldolase-catalysed stereoselective carboncarbon bond formation with fluoropyruvate as nucleophile enable the synthesis of many -fluoro -hydroxy carboxyl derivatives. Furthermore, an understanding of the structural basis for the stereocontrol observed in these reactions is beginning to emerge.Here, we review the application of aldolase catalysis in the stereocontrolled synthesis of chiral fluorinated small molecules, and highlight likely areas for future developments.

Chemoenzymatic Platform for Synthesis of Chiral Organofluorines Based on Type II Aldolases

“…For example, KDPG aldolases are powerful biocatalysts with wide acceptor scope for pyruvate addition, but the ability to utilize fluoropyruvate is either limited to the native acceptor or non‐existent . DHDPS family aldolases have successfully been used for fluoropyruvate addition with resulting 3 R configuration at the carbon atom bearing fluorine, but have specialized acceptor requirements such as long‐chain aldose or heteroaromatic aldehydes –. Furthermore, type I aldolases are sensitive to high aldehyde concentrations that may cause inhibition of the catalytic lysine .…”

Recent trends in the stereoselective synthesis of (poly)-substituted 2-oxo acids by biocatalyzed aldol reaction

“…Fluorine substituents provide unique options to new organofluorine core structures, offering great pharmacological potential [ 25 , 26 ]. The groundbreaking work of Berry and co-workers with fluoropyruvic acid as nucleophile utilizes class I aldolases, thus, not the scope of this review and is reviewed here in detail [ 26 – 28 ].…”

“…Fluorine substituents provide unique options to new organofluorine core structures, offering great pharmacological potential [ 25 , 26 ]. The groundbreaking work of Berry and co-workers with fluoropyruvic acid as nucleophile utilizes class I aldolases, thus, not the scope of this review and is reviewed here in detail [ 26 – 28 ]. With class II aldolase HpcH E.coli a change of the nucleophile to fluoropyruvic acid over pyruvic acid resulted in a 500-fold decrease in the turnover number and was accompanied by substrate inhibition.…”

Recent Advances in the Substrate Selectivity of Aldolases

“…NAL Ecoli Catalyzed Synthesis of Fluoro Ketoacids from Fluoropyruvate and Aldehydes. A: α-S Configured Aldehydes (1, 2, and 3), B: α-R Configured Aldehyde (9)89,90…”