Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.
J Org Chem. 2010 Apr 16;75(8):2429-44. doi: 10.1021/jo100201f.
A highly stereoselective joint total synthesis of the potent polyketide macrolide antibiotics etnangien and etnangien methyl ester was accomplished by a convergent strategy and proceeds in 23 steps (longest linear sequence). Notable synthetic features include a sequence of highly stereoselective substrate-controlled aldol reactions to set the characteristic assembly of methyl- and hydroxyl-bearing stereogenic centers of the propionate portions, an efficient diastereoselective Heck macrocyclization of a deliberately conformationally biased precursor, and a late-stage introduction of the labile side chain by means of a high-yielding Stille coupling of protective-group-free precursors. Along the way, an improved, reliable protocol for a Z-selective Stork-Zhao-Wittig olefination of aldehydes was developed, and an effective protocol for a 1,3-syn reduction of sterically particularly hindered beta-hydroxy ketones was devised. Within the synthetic campaign, a more detailed understanding of the intrinsic isomerization pathways of these labile natural products was elaborated. The expedient and flexible strategy of the etnangiens should be amenable to designed analogues of these RNA-polymerase inhibitors, thus enabling further exploration of the promising biological potential of these macrolide antibiotics.
通过汇聚策略，以 23 步（最长线性序列）完成了强力聚酮大环内酯抗生素恩坦格恩和恩坦格恩甲酯的高度对映选择性联合全合成。显著的合成特征包括一系列高度对映选择性的底物控制的羟醛反应，以确定丙酸盐部分中带有甲基和羟基的手性中心的特征组装，通过故意构象偏置前体的高效非对映选择性 Heck 大环化反应，以及通过无保护基的前体高产 Stille 偶联反应在后期引入不稳定侧链。在此过程中，开发了改进的、可靠的 Z-选择性 Stork-Zhao-Wittig 醛烯丙基化反应的方案，并且设计了一种有效方案用于立体位阻特别大的β-羟基酮的 1,3-顺式还原。在合成过程中，对这些不稳定天然产物的固有异构化途径有了更详细的了解。这些恩坦吉恩的便捷灵活的策略应该适用于这些 RNA 聚合酶抑制剂的设计类似物，从而能够进一步探索这些大环内酯抗生素的有前途的生物学潜力。
