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

在我们近年来对酶抑制剂的合成及其抑制机理的研究过程中，我们发现（E）-3-羰基-2，4，6-三烯醛类化合物通过与磷脂酶A_2（PLA_2）的特定赖氨酸残基经6π-还原反应生成二氢吡啶衍生物，从而抑制PLA_2的水解能力中间体席夫碱的电环化。1-氮杂三烯热环化生成1，2-二氢吡啶，即所谓的6π-氮杂电环化反应，是一种著名的协同周环反应。虽然已经报道了一些6π-氮杂电环化反应的实例，但是该过程需要高温和长的反应时间，因此，该反应在天然产物合成中的应用在文献中非常有限。我们成功地在显着加速氮杂-电环化，基于显着的轨道之间的相互作用的HOMO和LUMO的1-氮杂三烯的取代基效应的组合。我们还开发了新的取代吡啶一锅法合成方法，实现了眼用抗衰老色素的合成。在此基础上，我们建立了一种新的基于（E）-3-羰基-2，4，6-三烯醛化合物与新的手性顺式-1-氨基-2-茚满醇衍生物之间的反应的高立体选择性的6π-氮杂电环化反应。此外，开发的方法被应用于正式合成的吲哚生物碱，20-epiuleine。

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.