Total synthesis of the xyloketal natural products and alboatrin
Total synthesis of the xyloketal natural products and alboatrin
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木缩酮天然产物和阿博特林的全合成
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发表时间：
2006
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通讯作者：
J. Pettigrew
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作者：
J. Pettigrew
最近，Lin及其同事报道了从一种红树林木耳中分离出的7种密切相关的天然产物木酮的结构特征。在这些天然产物中，所有这些产物都含有相同的手性非外消旋5,6-双环缩醛部分，木酮A具有独特的、美观的c3对称分子结构，这是通过详细的光谱研究和x射线晶体学来阐明的。木酮A、B、C和D也被证明是乙酰胆碱酯酶的有效抑制剂，因此代表了治疗神经系统疾病的重要先导化合物。此外，木酮A、B和F已被证明具有l -钙通道阻断活性。因此，这些天然产物及其结构类似物的全合成具有重要意义。为此，开发了一系列新的合成路线来制备这些化合物。在初始路线中，关键的合成转化涉及适当取代的邻醌和二氢呋喃之间的逆电子需求异Diels-Alder反应，得到（±）-,(+)-和(-)-木酮D。此外，还制备了木酮A和D的去甲基类似物。然而，应用该合成路线制备结构更复杂的木酮化合物是不成功的。第二种途径是利用苯硼酸介导的缩合反应作为关键的合成转化，得到了一系列新的三- 2h -铬，它们代表了天然产物木酮A的结构类似物。然而，由于关键反应中间体的不稳定性，该途径不能完全合成木酮A。我们还研究了以三氟化硼二乙醚促进亲电芳取代反应为关键步骤的第三条路线。利用该合成路线完成了木酮A、B、D、E、F和G的全合成，并制备了木酮A、B、C、D、E和G的脱甲基类似物。研究了亲电芳香族取代反应在结构相关且具有生物活性的天然产物醛虫苷的全合成中的应用。这导致了这种天然产物以及一种去甲基类似物的第一次不对称全合成。
The isolation and structural characterization of seven closely related natural products, the xyloketals, from a mangrove fungus of the Xylaria species have been reported recently by Lin and co-workers. Of these natural products, all of which incorporate identical chiral nonracemic 5,6-bicyclic acetal moieties, xyloketal A has a unique and aesthetically pleasing C3-symmetric molecular structure that was elucidated by detailed spectroscopic studies and by X-ray crystallography. Xyloketal A, B, C and D have also been shown to be potent inhibitors of acetylcholine esterase and so represent important lead compounds for the treatment of neurological diseases. In addition, xyloketal A, B and F have been shown to have L-calcium channel blocking activity. Thus, the total synthesis of these natural products, and structural analogues thereof, is of notable significance. Towards these ends, a series of novel synthetic routes to prepare these compounds were developed. The initial route, in which the key synthetic transformation involved an inverse electron demand hetero Diels-Alder reaction between appropriately substituted ortho-quinone methides and dihydrofurans, afforded (±)-, (+)- and (–)-xyloketal D. In addition, demethyl analogues of xyloketal A and D were prepared. However, the application of this synthetic route to prepare the more structurally complex xyloketals was unsuccessful. A second route, utilizing a phenylboronic acid-mediated condensation reaction as the key synthetic transformation, afforded a series of novel tris-2H-chromenes that represent structural analogues of the natural product xyloketal A. However, due to the instability of a key reaction intermediate, the total synthesis of xyloketal A was not completed by this route. A third route was also investigated that featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction as a key step. This synthetic route was used to complete total syntheses of xyloketal A, B, D, E, F and G. Moreover, demethyl analogues of xyloketal A, B, C, D, E and G were also prepared. The application of the electrophilic aromatic substitution reaction towards the total synthesis of the structurally related and biologically active natural product alboatrin was also investigated. This led to the first asymmetric total synthesis of this natural product as well as a demethyl analogue.