Synthesis of l-4,4-Difluoroglutamic Acid via Nucleophilic Addition to a Chiral Aldehyde

Abstract

Fluorine-containing derivatives of amino acids are assuming increasing importance as probes of biological function and enzyme mechanism. We now report a new, flexible route to enantiomerically pure L-4,4-difluoroglutamic acid that exploits the addition of difluorinated nucleophiles to configurationally stable alpha-aminoaldehydes. Conversion of the difluorinated adducts to L-4,4-difluoroglutamic acid can be accomplished in three steps by Barton-McCombie dehydroxylation and acid hydrolysis.

Syntheses of new difluoromethylene benzoxazole and 1,2,4-oxadiazole derivatives, as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

“…The Dess-Martin periodiane [15] was found to be the reagent of choice for the preparation of ketone derivatives (22)(23)(24) in quantitative yields. This oxidant has been used previously for oxidation of trifluoromethylated alcohols or gem-difluorinated substrates [16].…”

“…The corresponding ketones (22)(23)(24) were then subjected to fiuorination using two equivalent of DAST in anhydrous dichloromethane. The reactions were run at low temperature (À78 8C) and were slowly warmed to ambient temperature.…”

“…Dehydroxylation of the alcohols was achieved via the modified Barton-McCombie reaction using PhO(C=S)Cl [21,22]. 4-Dimethylaminopyridine (DMAP) was used as a catalyst in pyridine and anhydrous acetonitrile, and the product O-phenoxythiocarbonyl derivatives (not isolated and obtained in good yields as determined by 1 H and 19 F NMR), were treated with n-Bu 3 SnH/AIBN in refluxing anhydrous toluene.…”

γ‐Fluorinated Analogues of Glutamic Acid and Glutamine

“…Acid hydrolysis of the deoxygenated product 66 followed by anion exchange chromatography gave optically pure L-4,4difluoroglutamic acid L-48 in 44% overall yield based on 64 (Scheme 17). Optical purity was determined by comparison with the reported specific rotation values (Ding et al, 2001).…”

A series of 23,24-dihydrodiscodermolide analogues with simplified lactone regions

“…10 The excellent activity of the 3-acetate justified the further investigation of this position and the 3-methoxy-and 3-deoxy-23,24-dihydrodiscodermolide derivatives, 8 and 9, were targeted. Both of these compounds are accessed through the common precursor 2 by O-methylation using the Meerwein reagent and Barton-McCombie deoxygenation via the pentafluorophenylthiocarbonate, 11 respectively, followed by conversion to the corresponding methyl ketones 10 and 11 (Scheme 3) using standard procedures. 4 Both of these substrates underwent aldol reaction in good yield with excellent selectivity and were taken through to obtain the desired discodermolide analogues.…”