Development of a New Synthetic Strategy Utilizing 6π-Azaelectrocyclization and its Synthetic Application

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During the course of our recent studies on the syntheses of the enzyme inhibitors and the elucidation of their inhibitory mechanism, we have found that (E)-3-carbonyl-2, 4, 6-trienal compounds inhibit the hydrolytic ability of phospholipase A_2(PLA_2) by the formation of the dihydropyridine derivatives resulting from the reaction with the particular lysine residues of PLA_2 via the 6π-electrocyclization of the intermediary Schiff bases. The thermal cyclization of 1-azatrienes to 1, 2-dihydropyridines, which is the so-called 6π-azaelectrocyclization, is one of the well-known concerted pericyclic reactions. Although a number of examples of the 6π-azaelectrocyclization have been reported, the process required a high temperature and a long reaction time, therefore, the application of this reaction toward natural products synthesis is very limited in the literature. We succeeded in significant acceleration of the aza-electrocyclization, based on the remarkable orbital interaction between the HOMO and LUMO of the 1-aza-trienes by the combination of substituent effects. We also developed the novel one-pot substituted pyridine synthesis, and achieved the synthesis of the ocular age pigment. Furthermore, we established the novel highly stereoselective asymmetric 6π-azaelectrocyclization based on the reactions between the (E)-3-carbonyl-2, 4, 6-trienal compounds and the new chiral cis-1-amino-2-indanol derivatives using a remarkably simple operation under quite mild conditions. In addition, the developed method was applied toward the formal synthesis of an indole alkaloid, 20-epiuleine.