A biomimetic enantioselective approach to the decahydroquinoline class of dendrobatid alkaloids
A biomimetic enantioselective approach to the decahydroquinoline class of dendrobatid alkaloids
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DOI：
10.1002/anie.200705888
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Bosch, Joan
中科院分区：
文献类型：
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作者：
Amat, Mercedes;Griera, Rosa;Bosch, Joan
新热带树蛙科的蛙类产生一系列非常多样化的生物活性生物碱。这些两栖生物碱的主要类别之一[1]是十氢喹啉类化合物，它们不仅是从树突蛙和曼陀罗的皮肤提取物中分离出来的，[2]，也是从蟾蜍、[3]被毛虫、[4]海洋扁虫、[4b]和桃金娘中分离出来的。[5]它们具有顺式或反式十氢喹啉环融合，在C2和C5位都有侧链取代基，在Lepadin系列中，[4]在C3位有酰化羟基。最具代表性的十氢喹啉生物碱是cis-195A(以前称为Pomiliooxin C)，它于1969年首次从巴拿马的树枝石竹种群中分离出来。[6]两栖生物碱的来源仍然是一个悬而未决的具有挑战性的问题，[1]特别是在发现其中一些生物碱也存在于蚂蚁体内之后，从而加强了关于它们起源于青蛙的饮食假说。[5]尽管关于这些毒素的生物合成还没有确凿的研究，因此，人们对生物合成途径知之甚少，但有猜测认为，可能是聚酮路线通过多碳基中间体(A)的环化而产生，导致2，2，2，2，2，2，2，4，2，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，2，4，4，2，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，2，3，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，3，4，3，4，4，4，3，4，3，4，4，4，4，4，4，4，4，5-二取代十氢喹啉(C)或螺哌啶(组氨酸毒素)。[1a，b，7]根据这一假设，在方案1中描述了通往十氢喹啉类树突生物碱的一条看似合理的生物合成途径。[8]与这类生物碱相关的结构多样性和药理活性，以及来自自然来源的有限的量，在这一领域激发了相当大的合成努力，[9]包括一些仿生方法。[10]在此，我们提出了一种仿生立体选择性的方法来合成十氢喹啉类树枝状生物碱，[11]我们的合成方法包括使用适当的1，5-聚酮基衍生物作为假想的生物生成聚酮中间体A的合成等价物，以及(R)-苯甘氨酚作为氨的手性潜伏形式，以诱导
Frogs of the neotropical family Dendrobatidae produce a remarkably diverse array of biologically active alkaloids. One of the major classes of these amphibian alkaloids [1] are the decahydroquinolines, which have been isolated not only from skin extracts of dendrobatid and mantelline frogs,[2] but also from bufonid toads,[3] tunicates,[4] marine flatworms,[4b] and myrmicine ants.[5] They possess either a cis or trans decahydroquinoline ring fusion, with a side-chain substituent at both the C2 and C5 positions and, in the lepadin series,[4] an acylated hydroxy group at the C3 position. The most representative decahydroquinoline alkaloid is cis-195A (formerly called pumiliotoxin C), first isolated in 1969 from a Panamanian population of Dendrobates pumilio.[6] The source of amphibian alkaloids remains an unresolved and challenging question,[1] in particular after the discovery that some of these alkaloids also occur in ants, thus strengthening a dietary hypothesis for their origin in frogs.[5] Although there are no conclusive studies concerning the biosynthesis of these toxins and, consequently, little is known about the biosynthetic pathways, there has been speculation as to possible derivation from the polyketide route by aminocyclization of polycarbonyl intermediates (A), leading to either 2, 5-disubstituted decahydroquinolines (C) or spiropiperidines (histrionicotoxins).[1a, b, 7] In accordance with this hypothesis, a plausible biosynthetic pathway to the decahydroquinoline class of dendrobatid alkaloids is depicted in Scheme 1.[8]The structural diversity and pharmacological activity associated with this class of alkaloids, as well as the limited amounts available from natural sources, have stimulated considerable synthetic effort in this area,[9] including some biomimetic approaches.[10] In this context, we present herein a biomimetic enantioselective approach to the decahydroquinoline class of dendrobatid alkaloids, which has culminated in the biomimetic synthesis of (À)-pumiliotoxin C.[11] Our synthetic approach involves the use of an appropriate 1, 5-polycarbonyl derivative as a synthetic equivalent of the hypothetical biogenetic polyketide intermediate A, and (R)-phenylglycinol as a chiral latent form of ammonia, to induce