Total synthesis of celogentin C.
Total synthesis of celogentin C.
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DOI：
10.1002/anie.200902425
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Castle SL
中科院分区：
文献类型：
--
作者：
Ma B;Litvinov DN;He L;Banerjee B;Castle SL
小林及其同事从青冠草种子中分离出双环八肽celogentin C（1，图1）。[1]其他结构相似的天然产物包括双环肽moroidin，[2] celogentin A-H，[3]和celogentin J，[3]以及单环肽celogentin K [4]和stephanotic acid。[5]这些化合物中的一些抑制微管蛋白聚合，[6]其中1被列为该天然产物家族中最有效的抗有丝分裂剂。1的不寻常结构来自氨基酸侧链之间的两个交联。亮氨酸β-碳原子和色氨酸的吲哚C6之间的键形成1的左手环，而右手大环在吲哚C2和咪唑N1之间含有C-N键。所得的杂联芳基轴引入阻转异构体立体化学的潜力。有用的生物活性和有趣的结构的组合促使了许多针对1和相关化合物的合成努力。[7-10]然而，尚未报道celogentin家族的双环成员之一的全合成。[11]在本文中，我们描述了我们的努力，其最终合成了celogentin C。我们的合成计划概述于图1中。我们先前通过使用分子间吲哚-咪唑氧化偶联和随后在Pro-Arg位点的大环内酰胺化构建了1的右手环。[7a]我们设想利用我们的自由基缀合物加成方法[12，13]制备由Leu和Trp侧链结合产生的β-取代的α-氨基酸部分。自由基受体将通过Knoevenagel缩合形成。在自由基缀合物加成后，通过在Val-Trp位点的大环内酰胺化来完成1的左手环的形成。该方法的设计在环闭合顺序方面是灵活的;然而，将左手环附加到右手环上的尝试没有成功。[14]因此，我们开始了从左到右的顺序。
The bicyclic octapeptide celogentin C (1, Figure 1) was isolated by Kobayashi and coworkers from the seeds of Celosia argentea.[1] Other structurally similar natural products include the bicyclic peptides moroidin,[2] celogentins A–H,[3] and celogentin J,[3] as well as the monocyclic peptides celogentin K [4] and stephanotic acid.[5] Some of these compounds inhibit tubulin polymerization,[6] with 1 ranking as the most potent antimitotic agent of this natural product family. The unusual structure of 1 is derived from two cross-links between amino acid side chains. A bond between the leucine β-carbon atom and the indole C6 of tryptophan forms the left-hand ring of 1, whereas the right-hand macrocycle contains a C–N linkage between the indole C2 and the imidazole N1. The resultant heterobiaryl axis introduces the potential of atropisomer stereochemistry. The combination of useful biological activity and intriguing architecture has prompted numerous synthetic efforts targeting 1 and related compounds.[7–10] However, a total synthesis of one of the bicyclic members of the celogentin family has not yet been reported.[11] Herein, we describe our efforts which have culminated in the synthesis of celogentin C.Our synthetic plan is outlined in Figure 1. We previously constructed the right-hand ring of 1 by using an intermolecular indole–imidazole oxidative coupling and subsequent macrolactamization at the Pro–Arg site.[7a] We envisioned utilizing our radical conjugate addition methodology [12, 13] to prepare the β-substituted α-amino acid moiety resulting from union of the Leu and Trp side chains. The radical acceptor would be fashioned by means of a Knoevenagel condensation. After the radical conjugate addition, formation of the left-hand ring of 1 was to be accomplished by macrolactamization at the Val–Trp site. The approach was designed to be flexible in terms of the order of ring closures; however, attempts to append the left-hand ring onto the right-hand ring were unsuccessful.[14] Consequently, we embarked upon a left-to-right-sequence.