The SYNTHESIS OF Α-Monofluoroalkanoic ACIDS

Pattison, F. L. M.; Buchanan, R. L.; Dean, F. H.

doi:10.1139/v65-224

Cited by 46 publications

(9 citation statements)

References 23 publications

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“…FMA was prepared by two different synthetic routes (Figure 1) (Pattison et al, 1965). The first route (i) involved the fluorobromination of 1-tetradecene to yield l-bromo-2fluorotetradecane (5).…”

Section: Resultsmentioning

confidence: 99%

Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase

Paige¹,

Zheng²,

DeFrees³

et al. 1990

Biochemistry

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The importance of myristoylation for the proper biological functioning of many acylated proteins has generated interest in the enzymes of the myristoylation pathway and their interactions with substrates and inhibitors. Previous observations that S-(2-oxopentadecyl)-CoA, a nonhydrolyzable methylene-bridged analogue of myristoyl-CoA, was a potent inhibitor of myristoyl-CoA:protein N-myristoyltransferase (NMT) [Paige, L. A., Zheng, G.-q., DeFrees, S. A., Cassady, J. M., & Geahlen, R. L. (1989) J. Med. Chem. 32, 1665] prompted a closer examination of the effect of substituents at the 2-position on the interactions of myristic acid and myristoyl-CoA analogues with NMT. As an initial approach, three myristic acid derivatives bearing different substituents at the 2-position, 2-fluoromyristic acid, 2-bromomyristic acid, and 2-hydroxymyristic acid, were selected for study. Both 2-bromomyristic acid and 2-hydroxymyristic acid were available commercially; 2-fluoromyristic acid was prepared synthetically. All three compounds were found to be only weak inhibitors of NMT in vitro. Of the three, 2-bromomyristic acid was the most potent (Ki = 100 microM). In cultured cells, however, 2-hydroxymyristic acid was by far the more effective inhibitor of protein myristoylation. Neither 2-hydroxymyristic acid nor 2-bromomyristic acid significantly inhibited protein palmitoylation in cultured cells, indicating that inhibition was not occurring at the level of acyl-CoA synthetase. Activation of the 2-substituted myristic acid derivatives to their corresponding acyl-CoA thioesters by acyl-CoA synthetase resulted in inhibitors of greatly increased potency. The 2-substituted acyl-CoA analogues, 2-hydroxymyristoyl-CoA, 2-bromomyristoyl-CoA, and 2-fluoromyristoyl-CoA, were synthesized and shown to be competitive inhibitors of NMT in vitro (Ki's = 45, 450, and 200 nM, respectively). These data suggested that the enhanced inhibitory potency of 2-hydroxymyristic acid seen in cells was most probably a result of its metabolic activation to the CoA thioester. The presence of substituents at the 2-position also affected the ability of the acyl group to be transferred by NMT to a peptide substrate. Of the three acyl-CoA analogues, only 2-fluoromyristoyl-CoA served as a substrate for NMT.

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Section: Resultsmentioning

confidence: 99%

Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase

Paige¹,

Zheng²,

DeFrees³

et al. 1990

Biochemistry

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“…The consequences of these factors, among others, lead to variable fluorine effects that have been described . For example, while the fluoromalonate anion was believed to be a weaker nucleophile than malonate in the reaction with alkyl bromides, the conjugate addition of α‐fluorodinitromethide anion to methyl acrylate in water is about 2000 times faster than that of α‐chlorodinitromethide or α‐alkyldinitromethide . Seminal work by Hu and co‐workers showed that α‐fluorodi(benzenesulfonyl)methane, (PhSO 2 ) 2 CFH, reacts with enones faster than di(benzenesulfonyl)methane, (PhSO 2 ) 2 CH 2 .…”

Section: Figurementioning

confidence: 99%

The Nucleophilicity of Persistent α‐Monofluoromethide Anions

et al. 2016

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a-Fluorocarbanions are key intermediates in nucleophilic fluoroalkylation reactions.A lthough frequently discussed, the origin of the fluorine effect on the reactivity of afluorinated CH acids has remained largely unexplored. We have nowinvestigated the kinetics of aseries of reactions of asubstituted carbanions with reference electrophiles to elucidate the effects of a-F, a-Cl, and a-OMe substituents on the nucleophilic reactivities of carbanions.

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“…The fluoroacids were synthesized according to the method of Pattison et al (10,11) but yields on large scale preparations were poor especially for the branched-chain acid. Microanalyses were obtained from Schwarzkopf Microanalytical Laboratory, Woodside, New York.…”

Section: Ch3(ch2)4-ch-ch-(ch2)4ch3mentioning

confidence: 99%

Electrolysis of α-Chloro- and α-Fluorocarboxylic Acids

Arora¹,

Woolford²

1971

Can. J. Chem.

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The electrolysis of a-chlorovaleric, a-chlorocaproic, and a-chloroisobutyric acids in methanol gave none of the Kolbe dimer; the main products were chloroester and hydrogen ester with aldehydes and acetals formed in lesser amounts. In water, straight chain a-chloroacids gave dimeric esters as the major product. However, Kolbe dimer was formed in fairly good yields together with small amounts of fluoroester and acetal, when a-fluorocaproic and a-fluoroheptanoic acids were electrolyzed in methanol. N o Kolbe dimer was produced from 2-fluoro-2-ethylbutanoic and a-fluorophenylacetic acids; the corresponding ketone or aldehyde was the major product.Les Blectrolyses dans le methanol des acides a-chloroval6rique, a-chlorocaprdique, et a-chloroisobutyrique ne conduisent pas aux dimeres de Kolbe; les produits principaux sont les chloro-esters et les hydrogenoesters; en plus petite quantitk se forment des aldehydes et des acbtals. Dans l'eau, les a-chloroacides en chaine droite conduisent aux esters dimkriques en tant que produits majoritaires. Cependant, dans 1'8lectrolyse dans le methanol des acides a-fluorocapro.ique et a-fluoroheptano'ique, des dirnkres de Kolbe se forment avec un assez bon rendement avec toutefois de petites quantites de fluoro-esters et d'acetals. Canadian Journal of Chemistry, 49,2681 (1971)In a previous paper (1) from this laboratory, the electrolysis of a-bromocarboxylic acids in methanol produced hydrogen ester and bromoester as major products. The results were regarded as the result of attack of an initial carboxy radical on the solvent. Reduction of C-Br to C-H in both the ester and acid occurred at the cathode with migration of Brto the anode and oxidation there to Br,. Electrolysis experiments with branched chain cibromoacids in water indicated production of carbonium ions. In all the acids studied, no Kolbe dimer was detected, nor were other possible products such as alcohols, ethers, and paraffins obtained. Hoping to understand better the electrochemical processes involved with a-halo substituents, the behavior of a-chloroand a-fluorocarboxylic acids during Kolbe electrolysis was examined. It was anticipated especially that the smaller, more stable fluorosubstituent might allow dimer formation to occur. Conway and Dzieciuch (2) previously found that normal Kolbe coupling took place with trifluoroacetic acid; this reaction was the only previous example of successful coupling with an a-fluoro substituent present.The electrolyses of a-chlorocarboxylic acids were carried out in methanol and water. The results of various electrolysis reactions of cichlorovaleric, a-chlorocaproic, and a-chloroisobutyric acids in methanol (Scheme 1) are summarized in Table 1 and show that chloroester is the major organic product. Hydrogen ester is formed in low yields with the ratio of hydrogen ester to chloro ester increasing as the time of electrolysis is increased. The straight-chain a-chloroacids also produced acetals in low yield but this behavior was not observed with the branched-chain acid. It is probable...

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The SYNTHESIS OF Α-Monofluoroalkanoic ACIDS

Cited by 46 publications

References 23 publications

Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase

Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase

The Nucleophilicity of Persistent α‐Monofluoromethide Anions

Electrolysis of α-Chloro- and α-Fluorocarboxylic Acids

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