Allenamide‐Initiated Cascade [2+2+2] Annulation Enabling the Divergent Total Synthesis of (−)‐Deoxoapodine, (−)‐Kopsifoline D and (±)‐Melotenine A

Abstract

A facile method for the construction of the aspidosperma core from indoles functionalized with a nonterminal N-allenamide and dimethyl methylenemalonate is described. Various polysubstituted tetracyclic spiroindolines (27 examples) were afforded in good yields (61-90 %) with > 99/1 dr and > 99/1 Z/E selectivity under mild conditions. The annulation reaction provides straightforward access to the tetracyclic spiroindoline skeleton with substituents at the C5 position occurring in many natural products. As an application of this reaction, the total synthesis of three important natural products, (À )-deoxoapodine, (À )kopsifoline D and (�)-melotenine A, was possible in short routes from tryptamine.

Aza-Achmatowicz rearrangement coupled with intermolecular aza-Friedel–Crafts enables total syntheses of uleine and aspidosperma alkaloids

“…1–7 They continue to influence the research fields of natural products, drug discovery, biochemistry, and especially organic chemistry (total synthesis and methodology development). 8,9 Structurally, the direct covalent C3–C2′ linkage of indole (in blue) with piperidine (in red) characterizes this subclass of alkaloids and thus has sparked great interest from generations of organic chemists in developing novel and efficient synthetic strategies 10–40 (Scheme 1c). For example, many innovative synthetic strategies for aspidosperma alkaloids have been developed, most of which can be classified into three categories: (i) intermolecular or intramolecular indolization of anilines with piperidine derivatives, 41–50 (ii) late-stage piperidine formation from 1,2,3,4-tetrahydrocarbazoles, 51–62 and (iii) intramolecular (or transannular) Mannich reaction of indoles with tethered piperidinium.…”

Insights into Stereoselectivity Switch in Michael Addition-Initiated Tandem Mannich Cyclizations and Their Extension from Enamines to Vinyl Ethers

“…In 2022, we developed an allenamide involved distereoselective tandem cyclization reaction on the construction of tetracyclic indolines bearing an alkenyl group. 38 By increasing the ring tension in the polycyclic system, cis-fused tetracyclic spiroindolines could be made, which enabled the efficient construction of the aspidosperma core. However, both with the multistep protocol and in the allenamide-substitution manner, the methods are limited to specific substrates and are not universally applicable.…”

“…However, this multistep protocol was not so practical and suffered from low efficiency such that the key [4+2] reaction only gave 50% yield and failed to scale up, which limits the further application of this useful skeleton. In 2022, we developed an allenamide involved distereoselective tandem cyclization reaction on the construction of tetracyclic indolines bearing an alkenyl group . By increasing the ring tension in the polycyclic system, cis -fused tetracyclic spiroindolines could be made, which enabled the efficient construction of the aspidosperma core.…”