A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem pummerer/mannich cyclization sequence.
A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem pummerer/mannich cyclization sequence.
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DOI：
10.1021/jo026471g
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发表时间：
2003-06
期刊：
影响因子：
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通讯作者：
A. Padwa;M. Danca;K. Hardcastle;M. Mcclure
中科院分区：
文献类型：
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作者：
A. Padwa;M. Danca;K. Hardcastle;M. Mcclure
2-苯基六-5-烯醛与苯甲胺反应，然后与乙基硫代乙酰氯和高碘酸钠氧化反应，得到E/Z混合α-亚磺酰胺。正如从4PI-旋转机理所预期的那样，每个烯烃的环化得到了稠合的异喹啉内酰胺，在乙硫基位置作为单一的非对映异构体，没有任何交叉污染。对利用3，4-二甲氧基芳基合成介膜进行了一些初步研究。在这种情况下，Z-烯胺更倾向于进行亲电芳香族取代，以87%的产率得到取代氮杂酮作为首选产品。相反，E-烯胺异构体提供了所需的氢化吲哚酮。与串联Pummerer/Mannich环化相关的聚集性和立体化学控制使其特别适合组装JAMTINE，一种四氢异喹啉生物碱，以其治疗特性而闻名。合成中的关键步骤包括多米诺硫正离子/N-酰亚胺离子环合，以提供作为主要非对映异构体的三环骨架27A。用NaH对27A进行去质子化，得到28A，其中包含完全组装的JAMTINE骨架。合成的完成需要双键的安装和内酰胺的还原。用MCPBA氧化JAMTINE的合成样品得到相应的N-氧化物，这与文献中报道的这种生物碱的光谱数据不匹配。我们的综合努力增加了修改先前作业的可能性。
Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.