Synthetic Studies of Kobusine-type Aconite Alkaloids

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Aconitum, which has a beautiful blue-purple flower, is well-known as a poisonous herb, which occasionally results in fatalities following accidental ingestion. The aconite alkaloids, mainly contained in the tuberous root, have long been of interest to researchers, because of both their pharmacological activities and their structural complexity.Our palladium-catalyzed intramolecular α-arylation of formyl group was successfully applied to a total synthesis of (±)-nominine, a hetisine-type aconite alkaloid isolated from Aconitum sanyoense Nakai in 1956. The synthesis consists of forty-steps from 2-bromo-5-methoxyphenethyl iodide in 0.15% overall yield, and constitutes the first total synthesis of an aconite alkaloid having the hetisan framework, the sole aconite skeleton whose total synthesis has long remained unsuccessful among five representative aconite skeletons [atidane, veatchane, cycloveatchane, aconitane, and hetisan (the name of which is derived from hetisine)].Key steps other than the above α-arylation are (i)acetal ene-reaction to form the C14-C20 bond, (ii)stereoselective hydrocyanation to introduce C19 and nitrogen functions, (iii)LiAlH_4 reduction of cyano-enol silyl ether to form the N-C6 bond, (iv)radical cyclization from enyne precursor to construct the methylenebicyclo[2.2.2]octane framework, and (v)allylic oxidation with SeO_2-tert-BuOOH to introduce 15β-OH. Completion of the synthesis was verified unequivocally by single crystal X-ray analysis of (±)-Nominine.