Synthesis of 6-aza-bicyclo[3,2,1]octan-3-ones via vinylogous imide photochemistry: An approach to the synthesis of the hetisine alkaloids
Synthesis of 6-aza-bicyclo[3,2,1]octan-3-ones via vinylogous imide photochemistry: An approach to the synthesis of the hetisine alkaloids
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DOI：
10.1021/ja010542w
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发表时间：
2001-08-01
影响因子：
15
通讯作者：
Winkler, JD
中科院分区：
文献类型：
--
作者：
Kwak, YS;Winkler, JD
我们已经证明，在2的逆曼尼希断裂和衍生的酮亚胺鎓 3的异构曼尼希闭合后，乙烯基双酰胺（1，6-二烯）1的分子内光环加成导致全氢吲哚4的合成，如方案1所述。[1]这种方法在合成含氮环体系中的应用，通过成功地应用于合成mesembrine，[2] vindorosine，[3]和manzamine A，得到了进一步的证实。[4]我们最近研究了相应的1，5-二烯，即5的光环化加成，并且我们在此报道了这些底物通过“交叉”光加合物，6导致氮杂双环[3，2，1]辛酮，8的一般合成。氮杂双环[3，2，1]辛酮环系在自然界分子中广泛分布，即sarain A、9，5一叶秋碱、10，6和hetisine、11，7和该环系统在药物化学中对于开发镇痛剂8和毒蕈碱拮抗剂9的重要性表明，5的光化学应具有与1相当的实用性。5，并且其转化为8的过程概述于方案2中。烯丙胺与3-丁酮的Michael加成得到乙烯基乙酰胺12，其在DMAP存在下与碳酸二叔丁酯反应，两步得到光底物5，产率为85%。有趣的是，12的直接照射没有产生所需的光加合物，6的胺类似物，这一结果与Swindell的工作一致。光反应性的这种差异可归因于氮的sp2特征在光环化加成中的重要性，这是乙烯基乙酰胺光化学反应中微妙平衡的指示。
We have demonstrated that the intramolecular photocycloaddition of vinylogous amides (1, 6-dienes) 1 leads, upon retro-Mannich fragmentation of 2 and isomeric Mannich closure of the derived ketoiminium 3, to the synthesis of perhydroindoles 4, as outlined in Scheme 1. 1 The utility of this methodology for the synthesis of nitrogen-containing ring systems is underscored by the successful application of this methodology to the syntheses of mesembrine, 2 vindorosine, 3 and manzamine A. 4 We have recently examined the photocycloaddition of the corresponding 1, 5-dienes, that is, 5, and we report herein that these substrates lead to a general synthesis of azabicyclo [3, 2, 1] octanones, 8, via the “crossed” photoadduct, 6. The widespread distribution of the azabicyclo [3, 2, 1] octanone ring system in molecules of nature, that is, sarain A, 9, 5 securinine, 10, 6 and hetisine, 11, 7 and the importance of this ring system in medicinal chemistry for the development of analgesics8 and muscarinic antagonists9 suggests that the photochemistry of 5 should be of comparable utility to that of 1.The synthesis of 5 and its conversion to 8 is outlined in Scheme 2. Michael addition of allylamine to 3-butynone gave vinylogous amide 12, which on reaction with di-tert-butyl-carbonate in the presence of DMAP gave the photosubstrate 5 in 85% yield over two steps. It is interesting to note that direct irradiation of 12 did not produce the desired photoadduct, the amine analogue of 6, a result that is consistent with the work of Swindell. 10 This difference in photoreactivity can be attributed to the importance of sp2 character of the nitrogen in the photocycloaddition, an indication of the subtle balance in vinylogous amide photochem-