Enantioselective reformatsky reaction of methyl bromodifluoroacetate

Abstract

The Reformatsky reagent 2 generated from methyl bromodifluoroacetate is added to benzaldehyde in the presence of carbinols 3a, b, amino alcohols 3c-g, or amino alkoxide 3h. N-Methylephedrine 3c provides the highest enantioselectivity in the formation of the adduct S-4a (84 YO ee; >96 % after recrystallization) whose absolute configuration is determined by an X-ray structural analysis of the amide 6.Many fluorinated organic compounds display substantial and unexpected biological activity. Since the fluorine atom is the second smallest substituent after hydrogen (van der Waals radii: 1.35 and 1.20 A, resp.) enzymes often accept fluorinated analogs as readily as their hydrogen-substituted parent compounds. Due to the high carbon-fluorine bond energy, enzyme inhibition results in as far as metabolic transformations of the fluorinated compounds are widely suppressed [']. Since a-unsubstituted p-hydroxy carbonyl compounds are frequently found amongst both natural products and synthetic drugs, we felt that a method for the enantioselective formation of the a,a-difluoro-0-hydroxy carbonyl moiety would be useful in the light of the postulate that bioactive agents should be available in enantiomerically pure formL21. Whereas Reformatsky reactions of ahalo-a,a-difluoroacetates are w e l l -k n o~n [~~~] , no attempts have been made to bring about enantioselective additions of difluoro Reformatsky reagents to aldehydes. Surprisingly, this lack contrasts with the plethora of methods for enantioselective reactions of dialkylzinc compounds with aldehyde~ [~].In this communication, we report on the first enantioselective Reformatsky reaction of an a,a-difluoroacetate. Thereby, carbinols 3a and 3b, amino alcohols 3c-g, and alkoxide 3h were used as chiral additives. Thus, the organozinc reagent 2 was generated in THF by treatment of activatedr61 zinc powder with methyl bromodifluoroacetate (1). Subsequently, the chiral ligands 3 and benzaldehyde were added. The enantiomeric excess of the P-hydroxy ester 4a obtained was determined by 'H-NMR spectroscopy in the presence of E~( h f c )~[~] and by GC detection (after protection of the hydroxy group as trifluoroacetate) on a y-CD (FS-Lipodex E) column.As shown in Table 1, best chemical yields combined with highest enantiomeric excesses are obtained with (1 R,2S)-Nmethylephedrine (3c). An excess of the Reformatsky reagent 2 over the chiral additive 3c turned out to be favorable because of deprotonation of the hydroxy group (entries 5 and 6). On the other hand, the amino alcohol 3c is also effective in substoichiometric amounts (entries 3 and 4). Remarkably, the enantioselectivity does not vanish when the mandelic acid-derived[*] ligands 3a and 3b are used which do not contain a nitrogen donor. O n the other hand, the lithiated amino alcohol 3h displays only marginal enantioselectivity (entry 11). In order to elucidate the absolute configuration of the ester 4a formed in the N-methylephedrine-mediated reac-

Catalytic Asymmetric Synthesis of Fluoroorganic Compounds: Mukaiyama-Aldol and Henry Reactions

“…Braun et al and Andrés et αϊ. have independently reported that the Reformatsky reagents generated from bromodifluoroacetates react with aromatic aldehydes in the presence of stoichiometric amounts of chirai amino alcohols such as iV-methylephedrine to afford the corresponding desired aldols in good optical yields (22,23). However, these methods are not catalytic, and the decrease in quantity of the chirai ligands dramatically suppresses the enantioselectivity.…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…In the presence of stoichiometric amounts of chiral amino alcohols, such as methylephedrine, this reaction affords the corresponding products with moderate enantioselectivity [27].…”

Asymmetric processes

“…Two recent examples use ephedrine derivatives; in one case for the addition of a lithium acetylide to a trifluoromethyl aryl ketone in 96-98% ee, 84 and in the second for an enantioselective Reformatsky reaction (Scheme 24). 85 Two equivalents of N-methylephedrine 57 are required to give the product in 84% ee, with three equivalents of organozinc reagent, since deprotonation of 57 occurs. Sub-stoichiometric amounts of 57 give reduced selectivities (54% ee with 0.1 equiv.…”