2,2-Difluoro-3-hydroxyesters by reformatskii reaction

Hallinan, E. Ann; Fried, Josef

doi:10.1016/s0040-4039(01)80239-2

Cited by 135 publications

(30 citation statements)

References 5 publications

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“…The Reformatsky reaction starting from ethyl bromodifluoroacetate, introduced by Fried et al, 8 is a well-established method to introduce a CF 2 -containing moiety. 9 Despite the low diastereoselectivity, many groups have used Hertel's Reformatsky procedure for the synthesis of 2-deoxy-2,2-difluororibose.…”

Section: Reformatsky Reactionmentioning

confidence: 99%

The synthesis of gemcitabine

Brown¹,

Dixey²,

Weymouth‐Wilson³

et al. 2014

Carbohydrate Research

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Section: Reformatsky Reactionmentioning

confidence: 99%

The synthesis of gemcitabine

Brown¹,

Dixey²,

Weymouth‐Wilson³

et al. 2014

Carbohydrate Research

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“…The Reformatsky reaction has also been used for syntheses of a,a-difluoro-b-hydroxy-carboxylates from difluorohalocarboxylates and aldehydes (or ketones) [17,[20][21][22][23][24][25][26]. In the presence of stoichiometric amounts of chiral amino alcohols, such as methylephedrine, this reaction affords the corresponding products with moderate enantioselectivity [27].…”

Section: Synthesis By C-c Bond Formation Of Partially Fluorinated Buimentioning

confidence: 99%

Regio- and stereoselective synthesis of vicinal fluorohydrins

Haufe

2004

Journal of Fluorine Chemistry

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“…Diethyl 2,2-difluorooxaloacetate was prepared following the method of Hallinan and Fried (1984). A mixture of ethyl difluoroacetate (5.0 g, 24.6 mmol) and diethyloxalate (2.76 g, 19 mmol) in dry tetrahydrofuran (20 ml) was added dropwise to a refluxing suspension of zinc dust (1.96 g, 30 mmol) and trimethylsilyl chloride (0.4 g, 3 mmol) in dry tetrahydrofuran (20 ml) (Picotin and Migniac, 1987) under argon.…”

Section: Synthesisofdisodium(+)and (-)-22-difluorocitratementioning

confidence: 99%

Synthesis and evaluation of (+) and (−)‐2,2‐difluorocitrate as inhibitors of rat‐liver ATP‐citrate lyase and porcine‐heart aconitase

Saxty¹,

Novelli²,

Dolle³

et al. 1991

European Journal of Biochemistry

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The enantiomers (+) and (-)-2,2-difluorocitrate have been synthesized. Both are good inhibitors of ATP-citrate lyase, showing competitive inhibition against citrate, with Kis = 0.7 pM for (+)-2,2-difluorocitrate and 3.2 pM for (-)-2,2-difluorocitrate. The inhibition patterns with either ATP or CoA as the varied substrate were uncompetitive and mixed, respectively, but with much weaker inhibition constants. Neither isomer undergoes carbon-carbon bond cleavage as a substrate and there is no evidence of irreversible time-dependent inactivation. When ATP-citrate lyase is incubated with CoA and difluorocitrate, the maximal intrinsic ATPase rate is 10% of the citrate-induced rate for the (+)-enantiomer and 2% for the (-)-enantiomer. 19F-NMR studies confirm that only the (+)-enantiomer is chemically processed.The effects of the difluorocitrate enantiomers on the reaction catalysed by aconitase were examined. (-)-2,2-Difluorocitrate is a competitive inhibitor against citrate (Ki, = 1.5 pM), whereas the (+)-enantiomer is a relatively poor mixed inhibitor (Ki > 300 pM). The (-)-enantiomer irreversibly inactivates aconitase at 1.1 min-' . mM-' at 25°C and pH 7.4, whereas no irreversible inhibition is seen with the (+)-enantiomer. Therefore, it would be expected that the (+)-enantiomer would slow the rate of acetyl-CoA synthesis in vivo, without inhibiting the citric acid cycle.ATP-citrate lyase catalyses the production of cytosolic acetyl-CoA and oxaloacetate from citrate, with the concomitant hydrolysis of ATP to ADP and inorganic phosphate. The acetyl-CoA produced, plays a central role in mammalian fatty acid and cholesterol biosynthesis. In vivo dosing of hydroxycitrate, a potent inhibitor of ATP-citrate lyase reduces de m v o synthesis of fatty acids and cholesterol in the liver and adipose tissues (Sullivan et al., 1973). Inhibition of this enzyme would therefore be a useful strategy for treating hyperlipidaemia or hypercholes terolaemia.A mechanism has been proposed for the enzyme (Walsh, 1979; Wells, 1991) which involves enzyme phosphorylation, transfer of the phosphate to activate citrate, formation of a citryl-CoA intermediate and fragmentation of citryl-CoA to produce acetyl-CoA and oxaloacetate. The final step is a basecatalysed retro-Claisen reaction and will generate an incipient anion on the acetyl fragment. This allows several possibilities for the design of mechanism-based inhibitors of ATP-citrate lyase (Dolle et al., 1991). If the hydrogens on the nascent acetyl-CoA were replaced by fluorine, the incipient anion could have novel decay modes. For example, fluoride loss would generate a carbene within the active site. This could then attack groups within the active site, irreversibly inCurrespondenre to T. N.

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2,2-Difluoro-3-hydroxyesters by reformatskii reaction

Cited by 135 publications

References 5 publications

The synthesis of gemcitabine

The synthesis of gemcitabine

Regio- and stereoselective synthesis of vicinal fluorohydrins

Synthesis and evaluation of (+) and (−)‐2,2‐difluorocitrate as inhibitors of rat‐liver ATP‐citrate lyase and porcine‐heart aconitase

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