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

Abstract

Aldolases are C À Cbond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons.H owever,e nzymatic methods of fluorine incorporation into such compounds are lacking due to the rarity of fluorine in nature.Recently,the use of fluoropyruvate as anonnative aldolase substrate has arisen as as olution. Here,w e report that the type II HpcH aldolases efficiently catalyze fluoropyruvate addition to diverse aldehydes,w ith exclusive (3S)-selectivity at fluorine that is rationalized by DFT calculations on am echanistic model. We also measure the kinetic parameters of aldol addition and demonstrate engineering of the hydroxylgroup stereoselectivity.Our aldolase collection is then employed in the chemoenzymatic synthesis of novel fluoroacids and ester derivatives in high stereopurity (d.r.8 0-98 %). The compounds made available by this method serve as precursors to fluorinated analogs of sugars,a mino acids,a nd other valuable chiral building blocks.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

One Step Forward in Exploration of Class II Pyruvate Aldolases Nucleophile and Electrophile Substrate Specificity

“…In contrast, a strict 3 S configuration was formed, also confirming the stereoselectivity observed in the above‐mentioned isotopic exchanges. This strict stereochemistry has already been reported for this family of enzymes, especially when fluoropyruvate was used as nucleophile [21] . Indeed, a ( Z )‐fluoroenolate geometry found through density‐functional theory calculations explained this 3 S configuration.…”

“…This strict stereochemistry has already been reported for this family of enzymes, especially when fluoropyruvate was used as nucleophile. [21] Indeed, a (Z)-fluoroenolate geometry found through densityfunctional theory calculations explained this 3S configuration. Concerning the configuration in C4, 4 could either present its re or si face within the active site.…”

Recent Advances in the Substrate Selectivity of Aldolases

“…In 2019, Chang’s group studied several class II pyruvate aldolases belonging to the PF03328 family (Uniprot KB Id. : P23522, B1IS70, P76469, A5VH82; respectively GarL, HpcH, and RhmA from E. coli , putative HpcH from Sphingomonas wittichii ).…”

Progress in Stereoselective Construction of C–C Bonds Enabled by Aldolases and Hydroxynitrile Lyases

“…Highly enantioselective aromatic products were obtained via this chemo-enzymatic method ( Table 1 , entries 1–12). Fang et al used five different enzymes from the type II HpcH aldolase family (EcGarL, EcRhmA, and EcHpcH from Escherichia coli , and SwHpcH1 and SwHpcH2 from Sphingomonas wittichi ) to expand the condensation reaction between fatty aldehydes and 3-fluoropropionic acid ( Fang et al, 2019 ). Among the reactive receptor substrates ( Table 1 , entries 13–18), EcGarL catalyzed the production of 2-fluoro-3-hydroxysuccinate with high reactivity (99%) and enantioselectivity (99%) ( Table 1 , entry 14).…”

“… Fang et al (2019) used five different pyruvate aldolases to catalyze the introduction of fluorine atoms to form monoalcohol products. The same method was used to form valuable fluorine-containing polyhydroxylated products ( Supplementary Table 1 , entries 68–72) ( Fang et al, 2019 ).…”