Total synthesis of brevetoxin A
Total synthesis of brevetoxin A
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DOI：
10.1038/32623
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发表时间：
1998-03-19
期刊：
影响因子：
64.8
通讯作者：
Gärtner, P
中科院分区：
文献类型：
--
作者：
Nicolaou, KC;Yang, Z;Gärtner, P
Brevetoxin A 是由 Gymnodinium breve Davis 分泌的最有效的神经毒素，这是一种海洋生物，通常与称为“赤潮”的有害藻华相关(1-3)。该化合物的作用机制涉及结合并打开钠通道 (4-7)，其毒性足以在每英里纳伽浓度下杀死鱼类（参考文献 3、4），并且在滤食性贝类中积累后，可毒害人类消费者。目前尚不清楚自然界构建短尾毒素 A 的精确途径(8,9)，但其全合成策略已经被考虑了一段时间。短尾毒素 A 带来的合成挑战反映了其分子结构的高度复杂性：10 个氧原子和 44 个碳原子链编织成一个多环大分子，该大分子包括 10 个环（包含 5 至 9 个原子）和 22 个立体中心。特别具有挑战性的是 7、8 和 9 元环，它们允许分子经历缓慢的构象变化并迫使其中一个环 (1-6) 扭转 90 度。在这里，我们描述了专门为构建这些环（10,11）而开发的方法成功地将其纳入天然存在形式的短尾毒素 A 全合成的总体策略中。这里报道的聚合合成使得这种稀有的神经毒素可以合成，更重要的是，允许设计和合成类似物以用于进一步的生化研究。
Brevetoxin A is the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as 'red tides'(1-3). The compound, whose mechanism of action involves binding to and opening of sodium channels(4-7), is sufficiently toxic to kill fish at concentrations of nanogams per mi (refs 3, 4) and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown(8,9), but strategies for its total synthesis have been contemplated for some time. The synthetic challenge posed by brevetoxin A reflects the high complexity of its molecular structure: 10 oxygen atoms and a chain of 44 carbon atoms are woven into a polycyclic macromolecule that includes 10 rings (containing between 5 and 9 atoms) and 22 stereogenic centres. Particularly challenging are the 7-, 8- and 9-membered rings which allow the molecule to undergo slow conformational changes and force a 90 degrees twist at one of its rings(1-6). Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings(10,11) into an overall strategy for the total synthesis of brevetoxin A in its naturally occurring form. The convergent synthesis reported here renders this scarce neurotoxin synthetically available and, more importantly, allows the design and synthesis of analogues for further biochemical studies.