Department of Chemistry , University of California, Berkeley , 826 Latimer Hall , Berkeley , California 94720 , United States.
J Am Chem Soc. 2019 Sep 18;141(37):14904-14915. doi: 10.1021/jacs.9b08001. Epub 2019 Sep 6.
With hundreds of unique members isolated to date, guaianolide lactones represent a particularly prolific class of terpene natural products. Given their extensive documented therapeutic properties and fascinating chemical structures, these metabolites have captivated the synthetic chemistry community for many decades. As a result of divergent biosynthetic pathways, which produce a wide array of stereochemical and oxidative permutations, a unifying synthetic pathway to this broad family of natural products is challenging. Herein we document the evolution of a chiral-pool-based synthetic program aimed at accessing an assortment of guaianolides, particularly those from the plant family Apiaceae as well as Asteraceae, members of which possess distinct chemical substructures and necessitate deviating synthetic platforms. An initial route employing the linear monoterpene linalool generated a lower oxidation state guaianolide but was not compatible with the majority of family members. A double-allylation disconnection using a carvone-derived fragment was then developed to access first an Asteraceae-type guaianolide and then various Apiaceae congeners. Finally, using these findings in conjunction with a tandem polyoxygenation cascade, we developed a pathway to highly oxygenated nortrilobolide. A variety of interesting observations in metal-mediated aldehyde allylation and alkene polyoxygenation are reported and discussed.
迄今为止，已分离出数百种独特的成员，此类愈创木烷内酯代表了萜类天然产物中一个特别丰富的类别。鉴于它们广泛记载的治疗特性和引人入胜的化学结构，这些代谢产物吸引了合成化学界数十年的关注。由于产生广泛的立体化学和氧化变化的分歧生物合成途径，因此建立一个统一的合成途径来制备这一广泛的天然产物家族具有挑战性。本文记录了一个基于手性池的合成计划的发展，该计划旨在获得各种愈创木烷内酯，特别是来自伞形科和菊科的那些，其中的成员具有独特的化学亚结构，需要不同的合成平台。最初采用线性单萜芳樟醇的路线生成较低氧化态的愈创木烷内酯，但与大多数家族成员不兼容。然后，使用来源于香芹酮的片段进行双烯丙基化断裂，从而首先获得菊科型愈创木烷内酯，然后获得各种伞形科同系物。最后，使用这些发现并结合串联多氧化级联反应，我们开发了一种合成高度氧化的北美黄连内酯的途径。报告并讨论了在金属介导的醛烯丙基化和烯烃多氧化中观察到的各种有趣现象。
