Research Projects

Enamine and iminium ion intermediates are central to biosynthetic and synthetic chemistry, playing key roles in constructing C–C and C–N bonds. These nitrogen-based species have enabled access to structurally complex molecules, including natural products and medicinal scaffolds for over a century. Their relevance was highlighted by the 2021 Nobel Prize awarded to MacMillan and List for advancing asymmetric organocatalysis via in situ generated enamine and iminium species. Among primary iminium ions, N-aryliminium and N-acyliminium ions have been widely studied. N-Aryliminium ions are stabilized by resonance and typically formed via α-elimination or oxidation of N, N-dialkylanilines. N-Acyliminium ions, bearing electron-withdrawing substituents on nitrogen, exhibit high electrophilicity and broad reactivity, featuring prominently in named reactions like Mannich and Pictet–Spengler. Despite these advancements, the development of the secondary enamine-iminium ion intermediate remains underexplored. Moreover, the design of new nitrogen-containing secondary enamine–iminium ion intermediates that can be generated in situ, decorated with other suitably reactive functionality that could participate in cascade/domino processes, is challenging in controlling the reactivity and selectivity. In our proposal plan, we took this challenge to introduce a new type of secondary N-aryl(o-acyl)iminium ion that will have reactivity between these two existing primary N-aryl- and N-acyl iminium ions. Thus, the controlled reactivity pattern in the presence of other reactive sites will enable them to be a promising intermediate for exploring tandem/sequential cascade reactions. In this context, asymmetric cascade/tandem processes with at least two consecutive reactions, by virtue of the chemical functionality formed in the previous step, provide an exciting platform to access chiral complex molecular scaffolds. The focal theme of the proposal involves the utilization of glutaraldehyde as linear dialdehyde, as “folding-up” substrates under amine catalysis with well-designed cyclic imines to access corresponding chiral N-aryl(o-acyl)hemiaminals in one step, which will be trapped with a series of nucleophiles under mild conditions for subsequent tandem process in the same pot to access diverse alkaloid-like structures asymmetrically. Herein, we introduce N-aryl(o-acyl)hemiaminals as suitable precursors to a novel class of in situ generated secondary N-aryl(o-acyl)iminium ions involved in the sequential cascade process. Interestingly, the presence of an ortho-carbonyl group on the N-aryl ring is key to achieving selective and stereocontrolled transformations, a feature not previously leveraged. Based on the potential advantages expected from in situ generated N-aryl(o-acyl)iminium ion in access polycyclic bridged N-heterocycles, we designed to develop this proposal with two differently designed cyclic imines. Accordingly, the proposal is divided into two work plans: 1. Using indol-3-one-based imines to access pseudoindoxyl alkaloids-inspired units. 2. Employing underexplored dibenzoazepin-11-ones to construct complex seven-membered polycyclic units under mild, metal-free conditions. Thus, the ultimate objective of the proposed work is to design two new types of secondary enamine-iminium ions precursors and their utilization in accessing complex bridged N-heterocycles through multiple bond formation in a one-pot tandem process. If successful, this strategy will open new avenues for easy access to diverse alkaloid-inspired scaffolds without any purification at the intermediate stage, providing an edge over the multistep synthesis of complex molecules. Moreover, this outcome will significantly contribute to understanding the reactivity and selectivity pattern of secondary enamine-iminium ion precursors with multiple reactive sites.