高难度二萜分子vinigrol的全合成进展

Recent advances in the total synthesis of vinigrol

二萜分子vinigrol(权霉醇)是近几十年来最难合成的复杂天然产物之一,其独特的十氢-1,5-丁基萘结构首次在天然产物中出现.Vingrol新颖和独特的结构吸引了众多有机合成化学家的兴趣.截至目前,共报道了4例全合成工作.2009年,美国化学家Baran课题组首次实现了vinigrol的消旋体全合成;2013年,美国化学家Njardarson课题组完成了第2例vinigrol的消旋体全合成;2019年,北京大学罗佗平课题组完成了vinigrol的首例不对称全合成;同年,本课题组完成了vinigrol的第2例不对称全合成.本文对这4例全合成进行了总结和回顾,探讨了每个合成工作的设计思想和策略,并对关键反应进行了深入讨论,期望能够管中窥豹式地介绍天然产物全合成领域的最新进展.

(-)-Vinigrol,a unique,novel,and biologically significant diterpenoid,was isolated from fungal strain Virgaria nigra F-5408 in 1987 by Ando and co-workers.Initial biological studies found that vinigrol possesses both antihypertensive and platelet aggregation-inhibitory properties.More recent studies have identified vinigrol as a tumor necrosis factor(TNF)antagonist.In addition,vinigrol has also been shown to be effective in the treatment of human immunodeficiency virus(HIV)and inflammation.Structurally,the 1,5-butanodecahydronaphthalene core with eight contiguous stereocenters located in vinigrol represents the unprecedented and unique motif found in natural product small molecules.This promising biological activities of vinigrol combined with its unique terpene framework have attracted significant attention from the synthetic community.However,the total synthesis of vinigrol has been regarded as one of the most challenging tasks in the synthesis community for more than two decades.Numerous research efforts have been oriented toward the total synthesis of vinigrol,including Paquette,Corey,Hanna and other groups before 2008.Until now,four elegant total syntheses have been reported.In 2009,Baran and co-workers completed the first total synthesis of(±)-vinigrol,and the challenging 1,5-butanodecahydronaphthalene core was constructed by a way of intermolecular Diels-Alder and intramolecular Diels-Alder reactions followed by Grob fragmentation.Key salient features including an unusual dipolar cycloaddition for establishing the cis-orientation of the C8-methyl and C8 a-hydroxy groups,and a later stage of Shapiro reaction via the tri-anionic species to deliver the final target.The synthesis was completed in a 23-step route with 3%overall yield from commercially available materials.This work represented a landmark achievement in the vinigrol synthesis.In 2013,Njardarson and coworkers completed another remarkable total synthesis of(±)-vinigrol,and the challenging 1,5-butanodecahydronaphthalene core was established with an elegant oxidative dearomatization/intramolecular Diels-Alder reaction followed by a Wharton fragmentation.In 2019,Luo and co-workers reported the first asymmetric total synthesis of(-)-vinigrol,with an impressive transannular Diels-Alder reaction as the key step.This scalable synthesis of(-)-vinigrol was completed in a 20-step route with 1.4%overall yield from commercially available materials,and provided over 600 mg of natural product in one operation.It should be noted that the Diels-Alder reaction was a crucial element in the synthetic strategy toward vinigrol in all these noteworthy achievements.Later,our group reported another asymmetric total synthesis of(-)-vinigrol using a unique Type II[5+2]cycloaddition and a novel ring contraction cascade as the key reactions.This synthetic work represents the first example of an intramolecular[5+2]cycloaddition to construct eight-membered ring system in natural product synthesis.Furthermore,the linear sequence of our concise asymmetric total synthesis of(-)-vinigrol was only 14 steps from commercially available material and without the need for protecting groups during the whole synthesis.The goal of this review is to provide a survey of advances in the total synthesis of vinigrol and discuss the synthetic strategies and tactics in each synthesis.The authors also hope that this review will serve a useful guidance for organic chemists who involved in total synthesis of natural products and provide a stimulus for inventions and further advances in this exciting area.