Department of Chemistry, University of California, Irvine, California 92697-2025, United States.
Institute for Integrative Genome Biology, Center for Infectious Disease and Vector Research, 900 University Avenue, Department of Molecular, Cell, and Systems Biology, University of California, Riverside, California 92521, United States.
J Am Chem Soc. 2023 Feb 15;145(6):3716-3726. doi: 10.1021/jacs.2c13137. Epub 2023 Feb 2.
We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product─along with a hypothesis about a biosynthetic relationship to related family members─inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging -to- decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.
我们描述了一种罕见的异氰酸酯萜烯天然产物异新茴芹烷及其两种非天然对映异构体的全合成。报道的天然产物具有显著的刚性环体系，以及与相关家族成员生物合成关系的假设，这激发了我们考虑结构相对构型的潜在错误分配。因此，我们最初将目标锁定在报道的天然产物的两种应变较小、更容易获得的立体异构体上。当这些化合物未能表现出与异新茴芹烷相匹配的光谱数据时，我们开始通过一种依赖于具有挑战性的-降蒈烯差向异构化的方法合成最初提出的应变结构。最终，我们实施了一种新颖的环状亚硫酸酯频哪醇型重排来生成刚性环系统。这项工作的其他特点包括应用非环硅基酮缩醛的立体控制 Mukaiyama-Michael 加成、不寻常的分子内烷氧基介导的区域选择性消除以及 HAT 介导的烯烃氢氮加成来形成叔异腈的 C-N 键。在整个工作过程中，我们的合成计划受到了大量计算分析的指导，以了解立体化学控制的关键问题。
