On the origin of the haouamine alkaloids
On the origin of the haouamine alkaloids
复制标题
DOI：
10.1002/anie.200704576
复制
发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Baran, Phil S.
中科院分区：
文献类型：
--
作者：
Burns, Noah Z.;Baran, Phil S.
Haouamines（1和2，图1）是最近被分离出来的一些最迷人的天然产物。[1]它们的拓扑结构独特的碳骨架，异国情调的氧化模式，和神秘的生物合成，使他们从合成和生物化学的Vantage位置有趣的目标。[2，3]本通讯通过详细的化学调查揭示了这些生物碱的后一个方面，结果是：1）有力的证据反对看似合乎逻辑的四聚化途径1和2，[2，4] 2）改进涉及经典Chichibabin吡啶合成的错误文献报道，[4，5] 3）“异常”Chichibabin吡啶合成的温和变体的发现和机理探索，以及4）1的简单的对映选择性合成，其阐明了其绝对构型并指向基于苯丙氨酸的生物合成。在2006年，我们报道了从外消旋酮3全合成Haouamine A（图1）。[2]虽然采用“非生物”策略来完成合成，但提出了一种理论来解释由于四当量的间羟基化苯乙醛（5）和一当量的氨合并而产生的卤胺骨架的起源（图1）。Poupon和他的同事后来发表了一个类似的关于伪对称生物组装的观点。[4]卤代胺可以在自然界中由2，3，5-三取代的吡啶物质（例如吡啶鎓 4）产生的想法是合乎逻辑的，因为Chichibabin吡啶合成[6]是众所周知的，可以在单一操作中产生这种适当官能化的杂环。虽然文献中几乎所有的反应都是用脂肪醛进行的，但Wang和同事[5]的一个有希望的例子引起了我们的注意。其中，苯乙醛与苄基氯化铵在三氟甲磺酸镱存在下在水中反应，生成所需的2-苄基-3，5-二苯基吡啶鎓盐6（方案1A）。然而，令人惊讶的是，试图重现这个相同的反应得到了一个与公布的光谱相匹配的化合物，但似乎与提出的结构不一致。尽管缺乏明确的机理解释，3，5-二苯基吡啶鎓盐7与所获得的数据一致地匹配。通过3，5-二苯基吡啶（8）的简单苄基化反应和与三氟甲磺酸银交换反离子的反应合成了该化合物。将其它取代的苯乙醛置于相同的反应条件下产生相同的结果，而不管醛组分的电子性质如何（方案1B）。如通过X射线晶体学所证实的，在反应条件下容许间甲氧基（9）、对溴（10）、间三氟甲基（11）和邻甲基（12）取代。该反应的产物对应于“异常”Chichibabin吡啶合成的产物--一种直到现在还没有合成用途的变体。[7]这种方法代表了第一个温和的一锅法路线，这种3，5-二芳基吡啶系统（已知的生物活性剂[8]），不需要预官能化的杂环。
The haouamines (1 and 2, Figure 1) are some of the most fascinating natural products to be isolated as of late.[1] Their topologically unique carbon skeleton, exotic oxygenation pattern, and mysterious biosynthesis render them interesting targets from both synthetic and biochemical vantage points.[2, 3] This Communication sheds light on the latter aspect of these alkaloids through a detailed chemical inquiry resulting in: 1) compelling evidence against a seemingly logical tetramerization pathway to 1 and 2,[2, 4] 2) amelioration of erroneous literature reports dealing with the classicChichibabin pyridine synthesis,[4, 5] 3) discovery and mechanistic exploration of a mild variant of the “abnormal” Chichibabin pyridine synthesis, and 4) a simple, enantioselective synthesis of 1 that illuminates its absolute configuration and points towards a phenylalanine-based biosynthesis. In 2006, we reported a total synthesis of haouamine A from racemic ketone 3 (Figure 1).[2] Although an “abiotic” strategy was employed to complete the synthesis, a theory was presented to explain the origin of the haouamine skeleton as arising from the merger of four equivalents of a metahydroxylated phenylacetaldehyde (5) and one equivalent of ammonia (Figure1). A similar view of pseudosymmetric biological assembly was later published by Poupon and coworkers.[4] The idea that the haouamines could arise in nature from a 2, 3, 5-trisubstituted pyridine species (such as pyridinium 4) is logical, for the Chichibabin pyridine synthesis [6] is well known to produce such appropriately functionalized heterocycles in a single operation. Although nearly all examples of this reaction in the literature are performed with aliphatic aldehydes, a promising example by Wang and co-workers [5] came to our attention. Therein, phenylacetaldehyde reacted with benzylammonium chloride in the presence of ytterbium triflate in water to produce the requisite 2-benzyl-3, 5-diphenylpyridinium salt 6 (Scheme 1A). Surprisingly, however, attempts to reproduce this identical reaction gave a compound that matched the published spectrum but seemed inconsistent with the proposed structure. Despite the lack of a clear mechanistic explanation, the 3, 5-diphenylpyridinium salt 7 uniformly matched the acquired data. The structure was confirmed synthetically by simple benzylation of 3, 5-diphenylpyridine (8) and reaction with silver triflate to exchange counterions. Submitting other substituted phenylacetaldehydes to the identical reaction conditions produced the same results, regardless of the electronic nature of the aldehyde component (Scheme 1B). As confirmed by X-ray crystallography, meta-methoxy (9), para-bromo (10), metatrifluoromethyl (11), and ortho-methyl (12) substitution is tolerated under the reaction conditions. The products of this reaction correspond to those of the “abnormal” Chichibabin pyridine synthesis—a variant that, until now, was not synthetically useful.[7] This approach represents the first mild one-pot route to such 3, 5-diarylpyridine systems (known bioactive agents [8]) that does not require prefunctionalized heterocycles.