Tertiary Amine Oxide Rearrangements. III. The Mechanism of the Demethylation of Nicotine

Craig, J. Cymerman; Mary, Nouri Y.; Goldman, Norman L.; Wolf, Lynn

doi:10.1021/ja01072a054

Cited by 43 publications

(10 citation statements)

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“…Possible reactions with ROS are shown (25). Their probability is corroborated by various chemical studies on nicotine (Hucker et al, 1959;Taylor and Boyer, 1959;Wada et al, 1959;Craig et al, 1964;Mohrle and Berlitz, 2008;Mohrle and Berlitz, 2009).…”

Section: Hormesis and Plant Secondary Metabolitesmentioning

confidence: 74%

Hormesis and a Chemical Raison D'ětre for Secondary Plant Metabolites

Hadaček¹,

Bachmann²,

Engelmeier³

et al. 2010

Dose-Response

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ᮀ In plants, accumulation in specific compartments and huge structural diversity of secondary metabolites is one trait that is not understood yet. By exploring the diverse abiotic and biotic interactions of plants above-and belowground, we provide examples that are characterized by nonlinear effects of the secondary metabolites. We propose that redox chemistry, specifically the reduction of reactive oxygen species (ROS) and, in their absence, reduction of molecular oxygen by the identical secondary metabolite, is an important component of the hormetic effects caused by these compounds. This is illustrated for selected phenols, terpenoids, and alkaloids. The redox reactions are modulated by the variable availability of transition metals that serve as donors of electrons in a Fenton reaction mode. Low levels of ROS stimulate growth, cell differentiation, and stress resistance; high levels induce programmed cell death. We propose that provision of molecules that can participate in this redox chemistry is the raison d'être for secondary metabolites. In this context, the presence or absence of functional groups in the molecule is more essential than the whole structure. Accordingly, there exist no constraints that limit structural diversity. Redox chemistry is ubiquitous, from the atmosphere to the soil.

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Section: Hormesis and Plant Secondary Metabolitesmentioning

confidence: 74%

Hormesis and a Chemical Raison D'ětre for Secondary Plant Metabolites

Hadaček¹,

Bachmann²,

Engelmeier³

et al. 2010

Dose-Response

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“…Nicotine‐ N ‐oxide also suffers the competition of the benzyl effect during its N ‐demethylation by the nonclassical Polonovski reaction. A mixture in water at pH 6 of nicotine‐ N ‐oxide, Fe(NO 3 ) 3 , L ‐(+)‐tartaric acid and sodium carbonate was heated [32]. Nornicotine was obtained with a yield of 56%, besides several other alkaloids arising from the transformation of nicotine: myosmine (6.9%), N ‐methyl‐myosmine (2.1%), and nicotine (3.0%).…”

Section: Resultsmentioning

confidence: 99%

“…N ‐demethylation of (±)‐ N ‐methyl‐isoanatabine 3a by decomposition of its N ‐oxide 10 was attempted under the conditions used by Craig et al . for the N ‐demethylation of nicotine [32]. The pH of a mixture in water of 10 , 3 equiv of Fe(NO 3 ) 3 , and 30 equiv of L ‐(+)‐tartaric acid was adjusted to 6.3 by adding a solution of sodium carbonate.…”

Section: Resultsmentioning

confidence: 99%

“…They could make some association with the N ‐oxide and the iron porphyrin, orienting in this way the decomposition of the N ‐oxide toward the N ‐demethylation, and overcoming the benzyl effect. In the N ‐demethylation of the N ‐oxides of the N , N ‐dimethyl‐benzylamine [24b,c] noscapine [31] and nicotine [32] cited earlier, the chelation of the iron ions by the tartaric and citric acids and their salts present in large excess, would explain the orientation by steric effects of the rearrangement of the N ‐oxide toward the N ‐demethylation. The increase of the yield of the N ‐demethylation of the N ‐dimethyl benzazepine N ‐oxide by the use of the additives imidazole or tetrazole corroborated that hypothesis.…”

Section: Resultsmentioning

confidence: 99%

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A convenient racemic synthesis of two isomeric tetrahydropyridyl alkaloids: Isoanatabine and anatabine

Rouchaud

Kem

2010

Journal of Heterocyclic Chem

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Anatabine is a major alkaloid in Nicotiana tabacum and its isomer, isoanatabine, was recently found in a marine worm. Reduction of 1-methylpyridinium iodide with sodium borohydride gave 1-methyl-3-piperideine, which was transformed with hydrogen peroxide into the N-oxide. Reaction of the N-oxide successively with trifluoroacetic anhydride and potassium cyanide gave 2-cyano-1-methyl-3-piperideine. Its reaction with 3-pyridylmagnesium chloride gave (6)-N-methyl-isoanatabine. This was transformed with m-chloroperbenzoic acid into the N-oxide which was N-demethylated with iron(II) sulfate, giving (6)-isoanatabine. The successive applications of literature procedures for the N-demethylation by decomposition of N-oxide contributed to the knowledge of the mechanism of this oxidative rearrangement. On the other hand, the reduction of 1-methylpyridinium iodide with sodium borohydride and with potassium cyanide present since the start of the reaction in a two layer ether-water system, gave 2-cyano-1-methyl-4-piperideine. This was transformed into (6)-anatabine by the same sequence of reactions used for the synthesis of (6)-isoanatabine.

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“…Chemicals. 3-Pyridylacetic acid (6), 3-pyridylmethanol (9), nicotinic acid (10), isopropylamine, 3-amino-1-propene, n-propylamine (11), myosmine (1), iodomethane, and 3,5-dinitrobenzoyl chloride were obtained from Sigma-Aldrich (Deisenhofen, Germany). All solvents and chemicals were analytical grade and purchased from VWR (Darmstadt, Germany).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Isolation of Nicotinic Acid (Vitamin B3) and N-Propylamine after Myosmine Peroxidation

Zwickenpflug¹,

Högg²,

Feierfeil³

et al. 2015

J. Agric. Food Chem.

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The alkaloid myosmine (3-(1-pyrroline-2-yl)pyridine) is widespread in biological matrixes including foodstuffs and tobacco products. Some in vitro tests in cellular systems showed mutagenic activity for myosmine. Myosmine activation including peroxidation mechanism employs unstable oxazirane intermediates. The formation of minor metabolite 3-hydroxymethyl-pyridine in rat metabolism experiments as well as in in vitro peroxidation assays suggests its further oxidation to nicotinic acid and possible concomitant formation of n-propylamine. A sensitive high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed for the direct analysis of n-propylamine in the peroxidation assay solution of myosmine employing derivatization with 3,5-dinitrobenzoyl chloride. Additionally, during peroxidation procedures, formation of 3-pyridylmethanol to nicotinic acid, the essential vitamin B3, was observed and characterized using HPLC-UV and gas chromatography/mass spectrometry. This new reaction pathway may present further contribution to our knowledge of myosmine's significance in human food including its activation in human organism, foodstuffs, and biological systems.

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Tertiary Amine Oxide Rearrangements. III. The Mechanism of the Demethylation of Nicotine

Cited by 43 publications

References 0 publications

Hormesis and a Chemical Raison D'ětre for Secondary Plant Metabolites

Hormesis and a Chemical Raison D'ětre for Secondary Plant Metabolites

A convenient racemic synthesis of two isomeric tetrahydropyridyl alkaloids: Isoanatabine and anatabine

Isolation of Nicotinic Acid (Vitamin B3) and N-Propylamine after Myosmine Peroxidation

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