Ring–Chain Isomeric Conversions of Aldehydo-carboxylic and Keto-carboxylic Acids and Their Derivatives

Valter, R. E.

doi:10.1070/rc1973v042n06abeh002641

Cited by 20 publications

(8 citation statements)

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“…However, when Levi (or its R-equivalent) is added to the solution, it is suspected to selectively stabilize one enantiomer of the lactol form or promote its formation through hydrogen bonding (Figure , panels a and b respectively), which thus influences the corresponding equilibrium. This was already suggested by Valter concerning the solvation effect on γ-aldehydo- and γ-keto-carboxylic acids: “intermolecular hydrogen bonds may play an important part in stabilizing a particular form, the cyclic isomer showing a greater tendency to form such bonds involving both carbonyl and hydroxyl groups” . The exact mechanism is nonetheless rather difficult to ascertain as cocrystallization from solution is complex and involves different equilibria , and was thus not investigated here.…”

Section: Discussionmentioning

confidence: 91%

“…A way to rationalize AKGA cyclization in the enantiopure cocrystals consists of paying attention to its mechanism. In particular, one has to consider the two types of factors that influence the intramolecular addition of the carboxyl to the carbonyl, leading to the cyclization . The first type is electronic and refers to the presence of groups adjacent to the ketone and/or the γ-carboxy group that may affect their electro-/nucleophilic character respectively and/or induce/prevent resonance stabilization.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for the absence of a crystal structure of pure AKGA as lactol may be due to its conformational flexibility. Indeed, there exists several cyclic γ-keto-carboxylic acids crystallized in the ring-form due to their geometrical restrictions. , …”

Section: Discussionmentioning

confidence: 99%

“…In particular, one has to consider the two types of factors that influence the intramolecular addition of the carboxyl to the carbonyl, leading to the cyclization. 51 The first type is electronic and refers to the presence of groups adjacent to the ketone and/or the γ-carboxy group that may affect their electro-/nucleophilic character respectively and/or induce/prevent resonance stabilization. The second type is geometric and concerns the proximity in space of these two functional groups.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Indeed, there exists several cyclic γ-keto-carboxylic acids crystallized in the ringform due to their geometrical restrictions. 15,51 However, when Levi (or its R-equivalent) is added to the solution, it is suspected to selectively stabilize one enantiomer of the lactol form or promote its formation through hydrogen bonding (Figure 8, panels a and b respectively), which thus influences the corresponding equilibrium. This was already suggested by Valter concerning the solvation effect on γaldehydo-and γ-keto-carboxylic acids: "intermolecular hydrogen bonds may play an important part in stabilizing a particular form, the cyclic isomer showing a greater tendency to form such bonds involving both carbonyl and hydroxyl groups".…”

Section: ■ Discussionmentioning

confidence: 99%

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Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

George

Norberg

Robeyns

et al. 2016

Crystal Growth & Design

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In this contribution, we demonstrate that it is possible to obtain the lactol tautomer of alpha-ketoglutaric acid (AKGA) in the solid state by cocrystallizing it with Leviteracetam, a chiral nootropic drug used to treat epilepsy. In addition, we show that a cocrystal can be isolated with the racemic equivalent of Levetiracetam, Etiracetam (Eti), in which AKGA stays in the keto-form. We also report the existence of a cocrystal conglomerate in the Etiracetam−AKGA system, which is more stable than the racemic cocrystal at room temperature. The existence of a stable conglomerate is put in relation to the enantiospecificity of the Levetiracetam cocrystals, which is likely related to the ability of the Etiracetam enantiomers to stabilize one lactol tautomer at a time in solution or to promote its formation by hydrogen bonding. By comparing the peculiarities of the system in hand to the general behavior of cocrystallizing chiral systems with and without zwitterionic coformers, we suggest that for a pseudoquaternary cocrystal (made up of two racemate compounds) to exist the pseudoternary combinations (made up of one racemate and an enantiomer of the second compound) should exist and the enantiomers of the two compounds should form a diastereomeric pair at the binary level, rather than behave enantiospecifically.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

George

Norberg

Robeyns

et al. 2016

Crystal Growth & Design

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Ring‐Ketten‐Isomerie bei N ‐(2‐Hydroxyalkyl)nitronen, I Substituierte Benzaldehyd‐nitrone

Kliegel

Becker

1977

Chem. Ber.

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Die Ring-Ketten-Umlagerung von N-(2-Hydroxyalkyl)nitronen 9, die man aus substituierten Benzaldehyden erhalt, wird mit Hilfe von Reaktionen untersucht, bei denen die B,N-BetainBorchelate 16 aus dex offenkettigen Nitron-Form, die Acylderivate 21 und 23 von beiden Isomeren und die Oxidationsprodulcte der cyclischen N-Hydroxyoxazolidin-Form 10 gebildet werden. Ring-Chain Isomerism of N-(2HydroxyaIkyl)nitrones, INitrones of Substituted EenzaldehydesThe ring-chain transformation of N-(2-hydroxyalkyl)nitrones 9, obtained from substituted benzaldehydes, is studied by reactions forming the B,N-betaine type boron chelates 16 from the openchain nitrone form, the acyl derivatives 21 and 23 from both isomers, and the oxidation products from the cyclic N-hydroxyoxazolidine form 10.Es ist bekannt daO die Kondensationsprodukte aus 2-Aminoalkoholen und CarbonylVerbindungen sowohl als offene (,,Ketten"-)Isomere 1 als auch in cyclischer (,,Ring"-)Form 2 existieren und in Losung oder Gasphase 4, einem dynamischen Gleichgewicht unterliegen, das in erweitertem Verstandnis reversibler Umlagerungen 5, auch als "Ring-Ketten-Tautomerie" bezeichnet wird -g! \

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Synthesis of certain metabolites and analogs of vitamin B₆ and their ring‐chain tautomerism

Paul

Korytnyk

1976

Journal of Heterocyclic Chem

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Pyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3‐O‐benzylpyridoxol (IV) and 3‐O‐benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide‐pyridine‐acetic acid complex gave 3‐O‐benzyl‐4‐pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4‐pyridoxic acid. Treatment of VI with dimethylamine gave 2‐methyl‐3‐benzyloxy‐5‐hydroxymethylpyridine‐4‐N,N‐dimethylcarbox‐amide (X) which oxidized to form the 5‐formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2‐methyl‐3‐hydroxy‐5‐formylpyridine‐4‐carboxylic acid (I). When reacted with liquid ammonia, VI gave 3‐O‐benzyl‐4‐pyridoxamide (VII) which was then oxidized to give 2‐methyl‐3‐benzyloxypyridine‐4,5‐dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2‐methyl‐3‐hydroxypyridine‐4,5‐dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2‐methyl‐3‐benzyloxy‐5‐carboxypyridine‐4‐N,N‐dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2‐methyl‐3‐hydroxy‐4‐formylpyridine‐5‐carboxylic acid (XVII) was synthesized starting from 3‐O‐benzyl‐5‐pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring‐chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2‐carboxy‐4,5‐dimethoxy)‐phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine‐d5 the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine‐d5), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate‐d2, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0‐d6 both cyclic and open‐chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C6‐H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open‐chain form as observed by ir spectroscopy.

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Ring–Chain Isomeric Conversions of Aldehydo-carboxylic and Keto-carboxylic Acids and Their Derivatives

Cited by 20 publications

References 6 publications

Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

Ring‐Ketten‐Isomerie bei N ‐(2‐Hydroxyalkyl)nitronen, I Substituierte Benzaldehyd‐nitrone

Synthesis of certain metabolites and analogs of vitamin B₆ and their ring‐chain tautomerism

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Ring–Chain Isomeric Conversions of Aldehydo-carboxylic and Keto-carboxylic Acids and Their Derivatives

Cited by 20 publications

References 6 publications

Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam

Ring‐Ketten‐Isomerie bei N ‐(2‐Hydroxyalkyl)nitronen, I Substituierte Benzaldehyd‐nitrone

Synthesis of certain metabolites and analogs of vitamin B6 and their ring‐chain tautomerism

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Synthesis of certain metabolites and analogs of vitamin B₆ and their ring‐chain tautomerism