Sulfone-mediated total synthesis of (±)-lepadiformine
Sulfone-mediated total synthesis of (±)-lepadiformine
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DOI：
10.1002/anie.200604670
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Craig, Donald
中科院分区：
文献类型：
--
作者：
Caldwell, John J.;Craig, Donald
（N）-Lepadiformine（1）是Biard埃塔尔在1994年分离的十氢-1H-吡咯并[1，2-j]喹啉。来自被囊类的小棒藻[1]Lepadiformine对各种肿瘤细胞系（包括非小细胞肺癌（NSCLCN 6））具有中度体外细胞毒活性，也是一种心脏K+通道阻滞剂。[2]Lepadiformin在生物学和结构上与海洋生物碱（À）-fasicularin（2）[3]和柱花草碱3相关。[4]在20世纪90年代后期，Weinreb [5]和Pearson [6]的研究小组通过明确的全合成独立地表明，1必须具有7aR，11 aS相对构型，对应于碳环到八氢中氮茚亚结构的融合。结构1中所有立构中心的相对构型由Kibayashi及其同事在1999年底完成的外消旋天然产物的第一次全合成证明。[7a]同一研究小组在2002年建立了1的绝对构型。[7b]迄今为止，已经完成了另外四个外消旋或对映体纯的1的总合成[8-11]，以及2 [7a，c，d，e，8d，12]和3的值得注意的部分和全合成。[5b 7 d，10，13]我们对lepadiformine的全合成的兴趣在很大程度上源于三环核心中嵌入的高度取代的吡咯烷环的存在。本实验室先前的研究导致了含吡咯烷的生物碱（+）-monomorine I [14]和（+）-preussin的全合成。[15]吡咯烷环是由碱介导的5-内-外环化反应形成的，其中酰胺与原位生成的乙烯基砜进行分子内反应。我们想到，1中的己基侧链可以通过取代缩醛胺引入，缩醛胺又可以从通过适当取代的乙烯基砜的5-内-内环化形成的吡咯烷获得（方案1）。我们计划从螺环氮丙啶通过用锂化甲基苯基砜进行亲核开环，然后与醛缩合来制备不饱和环化底物，
(À)-Lepadiformine (1) is a decahydro-1H-pyrrolo [1, 2-j] quinoline isolated in 1994 by Biard etal. from the tunicate Clavelina lepadiformis.[1] Lepadiformine has moderate in vitro cytotoxic activity towards various tumor cell lines, including nonsmall-cell lung carcinoma (NSCLCN6), and is also a cardiac-K+-channel blocker.[2] Lepadiformine is related both biologically and structurally to the marine alkaloid (À)-fasicularin (2)[3] and the cylindricines 3.[4] In the late 1990s, the research groups of Weinreb [5] and Pearson [6] showed independently through unambiguous total syntheses that 1 must have the 7aR, 11aS relative configuration corresponding to trans fusion of the carbocycle to the octahydroindolizine substructure. The relative configuration of all stereocenters in structure 1 was proved by the first total synthesis of the racemic natural product, which was completed by Kibayashi and co-workers in late 1999.[7a] The same research group established the absolute configuration of 1 in 2002.[7b] To date, a further four total syntheses of racemic or enantiomerically pure 1 have been completed,[8–11] together with notable partial and total syntheses of 2 [7a, c, d, e, 8d, 12] and 3.[5b, 7d, 10, 13]Our interest in the total synthesis of lepadiformine stemmed in large part from the presence of a highly substituted pyrrolidine ring embedded in the tricyclic core. Previous studies in this laboratory resulted in total syntheses of the pyrrolidine-containing alkaloids (+)-monomorine I [14] and (+)-preussin.[15] The pyrrolidine rings were formed by base-mediated 5-endo-trig cyclization reactions, in which amides undergo an intramolecular reaction with vinylic sulfones generated in situ. It occurred to us that the hexyl side chain in 1 could be introduced by substitution of an aminal, which could in turn be accessed from a pyrrolidine formed through a 5-endo-trig cyclization of a suitably substituted vinylic sulfone (Scheme 1). We planned to make the unsaturated cyclization substrate from a spirocyclic aziridine by nucleophilic ring opening with lithiated methyl phenyl sulfone followed by condensation with an aldehyde,