A new method for one-step construction of the tetracyclic core structure of the indole alkaloid (+)-minfiensine was developed utilizing a palladium-catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)-minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.Monoterpeneindolealkaloidsconstitutealargecategoryof natural products.[1] Among them, an array of strychnos and akuammiline alkaloids are quite attractive because of their unique cagelike structure and promising biological activity (Figure 1). [1, 2] These natural products share a common core structure, the 4a,9a-heterocycle-fused tetrahydrocarbazole skeleton, which bears two adjacent quaternary stereocenters.To address the synthetic challenges posed by these complex alkaloids, the development of strategies for efficient asymmetric assembly of the core structure is in demand. During the past decade, these monoterpene indole alkaloids attracted much research interest from the synthetic community. As a result, a large number of total syntheses have been reported. [3][4][5] However, the strategies that rendered efficient asymmetric syntheses are still limited. [3a,b,d, 4d, 5b,c] For instance, for a representative member in these alkaloids, (+)-minfiensine, only two catalytic asymmetric methods have been reported to date for achieving its total synthesis (Scheme 1). [3a,b,d] Given the effort devoted to the syntheses of these important alkaloids, the discovery of efficient and flexible new strategies for asymmetric assembly of the core framework would promote advances in this field.We sought to develop a new and straightforward approach to (+)-minfiensine based on the catalytic asymmetric dearomatization of indole (Scheme 1). It is envisioned that intramolecular asymmetric allylic substitution of the indole substrate A gives the intermediate C, which upon in situ trapping of the generated iminium ion [3a-d,g, 6, 8f] affords the tetracycle D, having the desired core structure. The advantage of this design is that the exocyclic C = C bond formed by allylic alkylation largely facilitates creation of the hydroxymethyl functionality in (+)-minfiensine. To our surprise, although palladium- [7] and iridium-catalyzed [8] asymmetric allylic alkylations of indole have been well established, [9] very little effort was made to utilize the synthetic power of those protocols in Figure 1. Representative strychnos and akuammiline alkaloids and their common core structure. Scheme 1. Previous asymmetric syntheses of (+)-minfiensine and the designed asymmetric cascade cyclization strategy. Boc = tert-butoxycarbonyl, PMB = para-methoxybenzyl.
