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

Abstract

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.

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

“…Many (>10) "minor" compounds, including isoanatabine, have been isolated from A. angulatus by high-pressure liquid chromatography and identified by nuclear magnetic resonance and mass spectrometric methods (Kem et al, in preparation). The presence of 3methyl-2,3′-bipyridyl and isoanatabine has already been reported [29][30][31].…”

“…Isoanatabine synthesis was achieved via a procedure using simple and inexpensive starting materials [31]. The key step of our synthesis was introduction of the pyridyl group via a Bruylants reaction, reacting 1-methyl-2-cyano-3-piperideine [54] with 3-pyridyl magnesium chloride.…”

New Pyridyl and Dihydroisoquinoline Alkaloids Isolated from the Chevron Nemertean Amphiporus angulatus

“…The GC peak 2 molecular ion was m/z 160, the same as for anabaseine (peak 5). However, its EIMS fragmentation spectrum (Table 1) was distinctly different from those of anabaseine and the tobacco alkaloid anatabine, but nearly identical to the EIMS data for the anatabine isomer 1,2,5,6-tetrahydro-2,3 ′ -bipyridyl [22,23]. The elemental composition of the peak 2 compound (See bottom of Figure 4) was the same as that of anatabine, 1,2,5,6-tetrahydro-2,3 ′ -bipyridyl and anabaseine.…”

Racemic synthesis of 2′‐substituted nicotine analogs

“…Its condensation with 5 equiv of 3-pyridylmagnesium bromide was attempted in THF at 0 C, followed by rt and in some cases by heating to reflux. However, the Bruylants reaction did not take place and 2 0 -methylnicotine was never obtained [22][23][24]. It only resulted in recovered starting material.…”

“…Replacement of this cyano group with an alkyl substituent was accomplished by a Bruylants reaction with an organomagnesium compound [22][23][24]. Displacement of the cyano group leads to an intermediate, stabilized iminium carbocation, which reacts further with the nucleophile alkyl organomagnesium (Scheme 4).…”