Access to Electron‐Rich Arene‐Fused Hexahydroquinolizinones through a Gold‐Catalysis‐Initiated Cascade Process

Abstract

We have recently developed a two-step, one-pot synthesis of piperidine-4-ols. [1] In this reaction, the protonated cyclic imidate intermediate A, which is prepared by a gold-catalyzed [2] amide cyclization, is reduced by an external hydride (e.g., catecholborane), which initiates a key Ferrier rearrangement [3] (Scheme 1 a). We envisioned that a carbon nucleophile could replace the hydride in this chemistry; moreover, if such a nucleophile is attached to the amide nitrogen atom, addition of reagent in the course of the reaction is not needed. The reaction would constitute a goldcatalysis-initiated cascade process and might provide an efficient access to bicyclic piperidin-4-ones (e.g., 1, Scheme 1 b). Herein, we disclose our implementation of this strategy, which leads to an expedient synthesis of electronrich arene-fused hexahydroquinolizinones; its synthetic utility is illustrated by a succinct and stereoselective synthesis of dihydrocorynantheol without the use of any protecting group, and a formal synthesis of yohimbine and b-yohimbine.We chose tertiary formamide 1 a as substrate, as the formyl group would minimize steric hindrance for nucleophilic attack and the indole ring can act as a good neutral carbon nucleophile. Importantly, the anticipated product 2 a, a tetracyclic piperidine-4-one, shares a common hexahydro-indolo[2,3-a]quinolizine skeleton with various indole alkaloids, including dihydrocorynantheol, [4] yohimbine, [5] and vincamine [6] (Scheme 2). Notably, the latter two are marketed drugs for peripheral vasodilation. [7] The formamide 1 a was readily prepared from tryptamine through a straightforward two-step sequence: alkylation with but-3-yn-1-yl tosylate and formylation with ethyl formate. When 1 a was treated with IPrAuNTf 2 (5 mol %) at ambient temperature, desired product 2 a could not be detected (Table 1, entry 1). Instead, tricyclic formamide 3, which was formed by a gold-catalyzed 8-exo-dig cyclization, [8] was Scheme 1. A gold-catalysis-initiated cascade process toward bicyclic piperidine-4-ones.Scheme 2. Selected alkaloids containing the indolo[2,3-a]quinolizine skeleton. Table 1: Initial discovery and condition optimization. [a] EntryCatalyst Acid additive (equiv) Yield [%] [b]