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

6π-氮杂电环化新合成策略的开发及其合成应用

• 批准号: 13680679
• 负责人: KATSUMURA Shigeo
• 金额: $ 2.24万
• 依托单位: Kwansei Gakuin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680679/
• 关键词: 6π-azacyclization; phospholipase A_2 inhibitor; activation of azacyclization; molecular orbital calculation; one-pot pyridine synthesis; asymmetric 6π-azaelectrocyclization; indole alkaloid; chiral auxiliary; 酵素機能阻害機構; フロンティア軌道相互作用; アミノインダノール誘導体

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.

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。

项目成果

Tanaka, K., Mori, H., Yamamoto, M., Katsumura, S.: "Significant Acceleration of 6π-Azaelectrocyclization Resulting from a Remarkable Substituent Effect and Formal Synthesis of the Ocular Age Pigment A2-E by a New Method for Substituted Pyridine Synthesis"

Tanaka, K.、Mori, H.、Yamamoto, M.、Katsumura, S.：“显着的取代效应导致 6π-Aza 电环化显着加速，并通过一种新的取代基方法正式合成了眼龄色素 A2-E” 《吡啶的合成》

Tanaka, K., Mori, H., Yamamoto, M., Katsumura, S.: "Significant Acceleration of 6π-Azaelecirocyclization Resulting from a Remarkable Substituent Effect and Formal Synthesis of the Ocular Age Pigment A2-E by a New Method for Substituted Pyridine Synthesis"

Tanaka, K.、Mori, H.、Yamamoto, M.、Katsumura, S.：“显着的取代基效应导致 6π-Azaelecirocyclization 显着加速，并通过一种新的取代基方法正式合成了眼龄色素 A2-E” 《吡啶的合成》

Tanaka, K., Kobayashi, T., Mori, H., Katsumura, S.: "Highly Stereoselective Asymmetric 6π-Azaelectrocyclization Utilizing the Novel 7-Alkyl Substituted cis-1-Amino-2-indanols : Fomal Synthesis of 20-Epiuleine"(submitted).

Tanaka, K.、Kobayashi, T.、Mori, H.、Katsumura, S.：“利用新型 7-烷基取代的 cis-1-Amino-2-indanols 进行高度立体选择性不对称 6π-Aza 电环化：20-Epiuleine 的正式合成“（已提交）。

Furuichi, N., Katsumura, S.* et al.: "Highly Efficient Stereocontrolled Total Synthesis of the Polyfunctional Carotenoid Peridinin"Angewandte Chemie, International Edition. 41. 1023-1026 (2002)

Furuichi, N.、Katsumura, S.* 等人：“多官能类胡萝卜素围甲素的高效立体控制全合成”Angewandte Chemie，国际版。

Kobayashi, T., Tanaka, K., Miwa, J., Katsumura, S.: "Synthesis of New Chiral Auxiliary for 6π-Azaelectrocyclization ; 4-and 7-Alkyl Substituted cis-1-Amino-2-indanols"(submitted). (2003)

Kobayashi, T.、Tanaka, K.、Miwa, J.、Katsumura, S.：“用于 6π-Aza 电环化的新型手性助剂的合成；4-和 7-烷基取代的 cis-1-Amino-2-indanols”（已提交）（2003）。