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Lythranidine is an alkaloid that was first isolated from the plant Lythrum anceps. The compound requires eight steps to synthesize in vitro which requires the formation of a 17 membered ring with a trans-2,6-disubstituted piperidine ring. Lythranidine was first synthesized by Fuji Kaoru, Kohei Ichikawa and Eiichi Fujita in 1971. They were the first paper published on the synthesis of lythranidine. In 1991, a paper was published about the synthesis of lythranidine by William Carruthers , Peter Coggins and John B. Weston who had synthesized the compound in 11 steps using nitrone cycloaddition.
Synthesis
Lythranidine is classified as an alkaloid and it contains a piperidine group that defines the synthesis of the structure via nitrone cycloaddition. The synthesis of this compound can take 11 steps instead or 8 depending on if the reaction undergone is a nitrone cycloaddition.
The synthesis described below was taken from the Fujita et. al, 1980, 1651-1653
2,6-Bis(chloromethyl)pyridine is treated with three equivalents of triphenylphosphine and refluxed with dimethylformamide and is afforded the bisphosphonium salt. The salt is subsequently treated with sodium hydride in dichloromethane to form a ylide .Wittig reaction of the dialdehyde given in the paper with another alkaloid in the lythracae family under high dilution conditions yielded the cyclophane. On dehydrogenation over palladium-charcoal, the reactant forms the 17 membered ring. The 17 membered ring with n-chloroperbenzoic acid was hydrogenolysed over palladium-charcoal ; subsequent acetylation with acetic anhydride-triethylamine yielded lythranidine in the stereoisomer shown. In the nitrone cycoladdition synthesis, when the pyridine is reduced, it forms a cis product and the product wanted is trans. The cis product was treated with formic acid and formalin to create the trans product.