Chemoenzymatic Platform for Synthesis of Chiral Organofluorines Based on Type II Aldolases. (19th July 2019)

• Record Type: Journal Article
• Authors: Fang, Jason; Hait, Diptarka; Head‐Gordon, Martin; Chang, Michelle C. Y.
• Is Part Of: Angewandte Chemie. Volume 131:Number 34(2019)
• Page Start: 11967
• Page End: 11971
• Publication Date: 2019-07-19
• Subjects: Aldolreaktion -- Biokatalyse -- Fluor -- Lyasen; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201906805
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Aldolases are C−C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons. However, enzymatic methods of fluorine incorporation into such compounds are lacking due to the rarity of fluorine in nature. Recently, the use of fluoropyruvate as a non‐native aldolase substrate has arisen as a solution. Here, we report that the type II HpcH aldolases efficiently catalyze fluoropyruvate addition to diverse aldehydes, with exclusive (3 S )‐selectivity at fluorine that is rationalized by DFT calculations on a mechanistic model. We also measure the kinetic parameters of aldol addition and demonstrate engineering of the hydroxyl group stereoselectivity. Our aldolase collection is then employed in the chemoenzymatic synthesis of novel fluoroacids and ester derivatives in high stereopurity (d.r. 80–98 %). The compounds made available by this method serve as precursors to fluorinated analogs of sugars, amino acids, and other valuable chiral building blocks. Abstract : Pyruvat‐Aldolasen der Typ‐II‐HpcH‐Familie sind ausgezeichnete Katalysatoren für die Fluoropyruvat‐Addition an Aldehyde. Die Stereoselektivität und das kinetische Verhalten werden untersucht, und die gezielte Abstimmung der Hydroxyl‐Stereoselektivität wird aufgezeigt. Nachgeschaltete Reaktionen ermöglichen die Synthese zahlreicher fluorierter Analoga von Zuckern, Aminosäuren und anderen wertvollen chiralen Organofluorverbindungen.