Recent advances in the total synthesis of vinigrol 高难度二萜分子vinigrol的全合成进展

(-)-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 C8a-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 co-workers 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.