- Lipase catalyzed regio- and stereospecific hydrolysis: Chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid
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Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)- butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α- thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both(S)- and (R)-enantiomers of α-lipoic acid and their analogues.
- Fadnavis,Babu, Ravi Luke,Vadivel, S. Kumara,Deshpande, Ashlesha A.,Bhalerao
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- Asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of R-(+)-α-lipoic acid
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The asymmetric synthesis of methyl (S)-6,8-dihydroxyoctanoate (5) and (S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (13), key precursors to R-(+)-α-lipoic acid (6) is described using OsO4-catalyzed asymmetric dihydroxylation and Ru-catalyzed asymmetric hydrogenation, respectively, as the key steps in the reaction sequence. These methods lead to an efficient formal synthesis of R-(+)-α-lipoic acid in 90% ee.
- Upadhya,Nikalje,Sudalai
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- Interaction of α-Lipoic acid Enantiomers and Homologues with the Enzyme Components of the Mammalian Pyruvate Dehydrogenase Complex
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Lipoic acid (α-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mM for R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoic acid enantiomers and homologues exist between free and complex-bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18 mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.
- Loeffelhardt, Sabine,Bonaventura, Christoph,Locher, Mathias,Borbe, Harald O.,Bisswanger, Hans
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- Preparation method of R-(+)-lipoic acid
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The invention discloses a preparation method of R-(+)-lipoic acid. The method comprises the following steps: performing salt formation on a raw material of racemic lipoic acid and a resolving agent ofR-phenylethylamine, so as to obtain diastereoisomeric R-phenylethylamine racemic lipoic acid salt; performing recrystallization separation on a raw material of the salt, so as to obtain a single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt; finally, acidizing the single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt, so as to obtain the target compound R-(+)-lipoic acid in a structure of the formula (I) at a yield of 40%. The method is simple in operation, lower in requirements on equipment, mild in conditions and higher in yield, so that the method is suitable for industrial production.
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Paragraph 0038; 0043; 0044; 0046; 0050; 0052; 0054
(2018/06/23)
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- Chirality induction and chiron approaches to enantioselective total synthesis of α-lipoic acid
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Abstract An efficient, short and convenient asymmetric synthesis of (R)-(+)-lipoic acid in seven steps from chiral hydroxy aldehyde with 32.5% overall yield is described. Synthesis of S and R enantiomers of α-lipoic acid from cis-1,4-butene diol derived chiral lactone is reported with 34 % overall yield. The present synthesis involves use of simple reaction conditions making it a convenient synthesis.
- Chavan, Subhash P.,Pawar, Kailash P.,Praveen, Ch.,Patil, Niteen B.
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p. 4213 - 4218
(2015/06/02)
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- Enantioselective synthesis of R-(+)-α and S-(-)-α-lipoic acid
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An efficient synthesis of α-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.
- Chavan, Subhash P.,Praveen, Cherukupally,Ramakrishna,Kalkote
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p. 6027 - 6028
(2007/10/03)
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- The synthesis of R (+) α-lipoamino acid
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Process for the synthesis of R(+)alpha-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(-)alpha-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)alpha-lipoic acid.
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- Production and use of salts of 6, 8-bis (amidiniumthio) -octanoic acid
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The invention relates to the production and purification of salts of 6,8-bis(amidiniumthio) octanoic acid, its enantiomers (+)-6,8-bis(amidiniumthio)octanoic acid and (-)-6,8-bis (amidiniumthio)octanoic acid and of the esters of these compounds as well as to their use to produce dihydrolipoic acid and α-lipoic acid.
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- Application of Enzymic Baeyer-Villiger Oxidations of 2-Substituted Cycloalkanones to the Total Synthesis of (R)-(+)-Lipoic Acid
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Oxidation of ketones 1a-h using a monooxygenase from Pseudomonas putida NCIMB 10007 gave the lactones 2a-h in optically active form: lactone 2h was converted into (R)-(+)-lipoic acid 9.
- Adger, Brian,Bes, M. Teresa,Grogan, Gideon,McCague, Ray,Pedragosa-Moreau, Sandrine,et al.
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p. 1563 - 1564
(2007/10/02)
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- Preparation of R/S-γ-lipoic acid or R/S-α-lipoic acid
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A process for preparing R/S-γ-lipoic acid of the formula I or R/S-α-lipoic acid of the formula II STR1 is disclosed.
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- One-electron Redox Potentials of RSSR(1+.)-RSSR Couples from Dimethyl Disulphide and Lipoic Acid
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One-electron redox potentials have been measured for three (RSSR)(1+.)/RSSR couples by reference to (SCN)2(1-.)/2 SCN(1-) and/or I2(1-.)/2 I(1-) in pulse radiolysis experiments: E0 (CH3SSCH3(1+.)/CH3SSCH) +(1.391 +/- 0.003) V; E0 COOH(1+.)/lip(SS)COOH> +(1.13 +/- 0.01) V; and E0 COO(1-)(1+.)/lip(SS)COO(1-)> +(1.10 +/- 0.01) V .The paper also includes equilibrium constants for the underlying RSSR + X2(1-.) RSSR(1+.) + 2 X(1-) equilibria (X=SCN or I), and rate constants for the respective back and/or forward reactions.The results are discussed in the light of structural considerations and in relation to other redox couples involving sulphur-centred radial species.
- Bonifacic, Marija,Asmus, Klaus-Dieter
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p. 1805 - 1810
(2007/10/02)
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- Proof that the Absolute Configuration of Natural α-Lipoic Acid is R by the Synthesis of its Enantiomer from (S)-Malic Acid
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The absolute configuration of natural (+)-α-lipoic acid is confirmed to be R by the synthesis of its enantiomer from (S)-malic acid.
- Brookes, Michael H.,Golding, Bernard T.,Howes, David A.,Hudson, Alan T.
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p. 1051 - 1053
(2007/10/02)
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