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

在近年来对酶抑制剂的合成和抑制机理的研究中，我们发现(E)-3-羰基- 2,4,6 -三烯醛化合物通过与PLA_2的特定赖氨酸残基通过中间席夫碱的6π电环反应生成二氢吡啶衍生物，从而抑制磷脂酶A_2（PLA_2）的水解能力。1-氮杂杂烯到1,2 -二氢吡啶的热环化，即所谓的6π-氮杂电环化，是众所周知的协同周环反应之一。虽然已经报道了一些6π-氮杂电环化的例子，但该过程需要较高的温度和较长的反应时间，因此，该反应在天然产物合成中的应用在文献中非常有限。我们成功地通过取代基的组合效应，在1-氮杂三烯的HOMO和LUMO之间显著的轨道相互作用的基础上，显著地加速了氮杂电环化。我们还开发了新的一锅取代吡啶合成方法，并实现了眼老化色素的合成。此外，我们利用(E)-3-羰基- 2,4,6 -三烯基化合物与新的手性顺-1-氨基-2-吲哚酚衍生物之间的反应，在相当温和的条件下，用非常简单的操作建立了新的具有高度立体选择性的6π-氮杂电环化反应。并将该方法应用于吲哚类生物碱20-肾上腺碱的正式合成。

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.