Stereodirected synthesis of alkaloid-like quinolizidine systems

New stereoselective methods for the chemical modification of cytisine based on T-reactions are reported. A reaction of cytisine with 2-chloro-5-nitrobenzaldehyde and followed condensation with 1,3-dimethylbarbituric acid affords N-(5-nitro-2-{1,3-dimethylperhydropyrimidine-2,4,6-trione-5-methynyl})cytisine, which undergoes a cyclization with the tetrahydropyridine ring closure. The cyclization proceeds via two competing routes yielding 5,5-spirobarbituric acid derivatives with 11,19-diaza-pentacyclo[,11.05,10.014,19]henicosane and 11,15-diazapentacyclo-[,11.05,10.015,20]henicosane skeletons. The cyclization reaction in solutions afford either 24.25-trans and 15,16-trans isomers or trans and cis isomer mixtures, depending on the specific solvent. Meanwhile, 24,25-cis and 15,16-cis isomers are formed stereoselectively under heterogeneous conditions in water suspensions. Trans-5,5-spirobarbiturates under similar conditions undergo isomerization into more stable cis-analogs by the configuration inversion at the C7 atom. The synthesized 5,5-spirobarbituric acid derivatives were successfully converted into alkaloid-like quinolizidine systems (1R,2R,3R,13S)-7-nitro-18-oxo-11,19-diazapentacyclo[,11.05,10.014,19]henicosa-5(10),6,8,14,16-pentaene-3-carboxylic acid and (1R,2S,3S,13S)-nitro-16-oxo-11,15-diazapentacyclo[11,7,1.02,11,05,10,015,20]henicosa-5,7,9,17,19-pentaene-3-carboxylic acid and their derivatives via the spiropyrimidine moiety removal by the stereoselective hydrolysis. The molecular and crystal structures of the target substances were elucidated by X-ray crystallography and NMR. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

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  • 1 Institute of Toxicology, Saint Petersburg, Russian Federation
  • 2 InterBioScreen Ltd, Chernogolovka, Russian Federation
  • 3 Kurchatov Complex for Synchrotron and Neutron Investigations, National Research Center ‘Kurchatov Institute’, Moscow, Russian Federation
  • 4 Inorganic Chemistry Department, Peoples’ Friendship University of Russia (RUDN University), Moscow, Russian Federation
5,5-spirobarbituric acid derivatives; Cytisine; diastereomers; hydrolysis; quinolizidine alkaloids; synchrotron X-ray diffraction; T-reactions
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