Catalyzed Reformatsky Reactions with Ethyl Bromofluoroacetate for the Synthesis of α-Fluoro-β-hydroxy Acids

Abstract

The presence of catalytic amounts of CeCl(3) improves yields and simplifies procedure in the Reformatsky reactions of ethyl bromofluoroacetate with aldehydes and ketones to generate diastereomeric mixtures of alpha-fluoro-beta-hydroxy esters, some of which can be separated by crystallization or column flash chromatography. Diastereomerically pure alpha-fluoro-beta-hydroxy acids are obtained by mild alkaline hydrolysis of the resolved alpha-fluoro-beta-hydroxy esters. Detailed NMR data of new alpha-fluoro-beta-hydroxy esters and alpha-fluoro-beta-hydroxy acids are also presented.

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

“…[16] Typically, 25, 50, 100 or 200 μmol of substrate was reacted in water/methanol with either isopropyl alcohol or glucose/glucose dehydrogenase for co-factor recycling. [28,31] The anti and syn configuration exhibit characteristic three-bond 19 F-1 H couplings of 17.8 and 22.1 Hz, respectively, which aids in identification. Crude products were analyzed by quantitative 19 F NMR spectroscopy to assess diastereomeric ratio (anti:syn ratio) and percent conversion, which were typically 86-97 % isolated yields.…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…No traces of rearranged or diastereomeric fluorinated products have been detected in the crude product mixture by 19 F NMR spectroscopy. This shows that this ring opening is an S N 2-process favoring the formation of the fluorohydrin with fluorine in the less hindered primary position (Scheme 52) [144].…”

“…Ten years ago Shen and Qi reported that the Reformatsky reaction of ethyl chlorofluoro acetate with aldehydes in the presence of catalytic amounts of lanthanide salts in dimethylacetamide (DMA) as the solvent provided high yields of the desired fluorohydrins, while the reactions with ketones gave only moderate yields [18]. Very recently, Journal of Fluorine Chemistry 125 (2004) Dolbier and co-workers reported several high yielding CeCl 3 catalyzed Reformatsky reactions of ethyl bromofluoro acetate with aldehydes and ketones [19].…”

Aldolase-catalysed stereoselective synthesis of fluorinated small molecules

“…In sharp contrast, reactions between metal enolates of fluoroacetate derivatives general exhibit poor stereoselectivity. [18,19] Although aldolases had previously been shown to accept substrates with remote fluorine atoms, [20,21] …”