Versatile Synthetic Route for the Hetisan-type Aconite Alkaloids

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Aconitum, one of the Japanese three major poisonous plants, has long been used as a useful Chinese medicine. We commenced, several years ago, synthetic studies of the hetisine-type aconite alkaloid, the sole aconite representative framework whose total synthesis has remained unsuccessful, in the wake of the finding of the palladium catalyzed α-arylation reaction of ketone, aldehyde, and nitro groups. Our synthetic studies culminated in the first total synthesis of (±)-Nominine. This synthesis, however, is constituted of forty steps, and consequently requires tremendous energies and expert synthetic skills. So, we reviewed the synthetic route, and contrived to improve it and get a clue for the preparation of the optical active alkaloid.Attempted improvement of the synthetic route : Although transformation of 2-methoxybenzoic acid into 2-alkylenone derivative, applying the Taber's method, was investigated in detail in order to foreshorten the route toward the 2-phenethylcyclohexenone intermediate, only the undesired styrene derivative was obtained through dehydroiodination from the starting phenethyliodide derivative. On the other hand, a novel quantity synthetic method of the starting 2-bromo-5-methoxyphenethyliodide was efficiently devised.Attempted optical resolution of intermediates: Asymmetric addition of nitromethane to the cyclohexenone intermediate did not proceed at all under the all literature methods tried. The obtained product in a small amount under drastic conditions was found to be racemic. The acetal derived from ell-nitromethane adducts and dimethyl tartrate, meanwhile, became clear to be separable to four diastereoisomers by the HPLC analysis. But attempted separation by an open column chromatography failed under the same eluting solvent. It was concluded from the above results that the most practical method for the preparation of optical-active nominine would be chiral-HPLC separation of a benzoate derived from (±)-Nominine.