Synthetic Studies on Nitrogen-containing Spiro Compounds by Means of Aromatic Oxidation in Medicinal Chemistry

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Nitrogen-containing natural products were recognized to be important candidates for searching new drugs in medicinal chemistry. Among them, a number of nitrogen-containing spiro-compounds exhibit interesting biological activities. For example, TAN1251A, B, C and D, having unique structural features with a 1,4-diazabicyclo[3.2.1]octane ring system and a spirocyclic cyclohexanone, isolated from a Penicillium thomii RA-89 by Takeda Industries, exhibit cholinergic activity and inhibit the acetylcholine-induced contraction of Guinea-pig ileum with ED_<50> values of 8.0 and 10.0 nM, respectively. TAN1251A is also known as a selective muscarinic M_1 subtype receptor antagonist. Due to the attractive biological activities and also their unique structural features, we investigated to develop a novel strategy for the synthesis of TAN1251 compounds, in which we thought that the carbon-nitrogen bond formation to generate a spirocyclic ring could be achieved by intramolecular aromatic oxidation of … More secondary amine using hypervalent iodine reagent. By applying the above synthetic strategy, we have succeeded in a facile synthesis of optically pure (-)-TAN 1251 A, C, and D.Securinine, isolated from Securinega suffruticasa, was another biologically active nitrogen-containing spiro-compound. This alkaloid has been clinically used in Russia as a CNS stimulating drug, and has been shown to act as a stereospecific antagonist at the GABA biding site of the GABAA-receptor complex. Viroallosecurinine, a diastereoisomeric alkaloid of securinine, was also isolated from the leaves of Securinega virosa as a cytotoxic alkaloid exhibiting a MIC of 0.48 μg/ml for Ps. aeruginosa and Staph. aureus. This alkaloid is recognized to be bactericidal since the yields of MIC/MBC were less than 1. After careful investigation of reaction conditions, we could establish the first diastereoselective chiral synthesis of securinine and viroallosecurinine by employing ring-closing metathesis (RCM) as the key reaction. Less