Novel Mannich-Type Multicomponent Reactions: Discovery, Mechanism, and Application

ConspectusThe development of efficient multicomponent reactions (MCRs) represents a vital frontier for the rapid construction of structurally sophisticated molecules from simple precursors in an atom- and step-economic manner. In particular, the Mannich reaction is a prototypical three-component reaction that rapidly assembles a resonance-stabilized carbon nucleophile, an aldehyde (or ketone), and an amine to afford alkylamines and serves as a particularly valuable tool for diversity-oriented synthesis in drug discovery and development. Typically, the nucleophilic components of the Mannich reaction rely on Brønsted-acidic carbonyl C(sp3)-H and electron-rich aromatic C(sp2)-H. However, the development of Mannich reactions involving unactivated C(sp3)-H remains a formidable challenge, which would be largely attributed to their difficult deprotonation and therefore non-nucleophilic properties.In this Account, we detail the journey from a serendipitous discovery to mechanistic elucidation, wherein an unprecedented double Mannich alkylamination occurred in both C(sp2)-H and unactivated benzylic C(sp3)-H bonds to eventually enable alkylaminative cyclization. Mechanistic studies revealed a distinctive pathway in which a multiple Mannich and retro-Mannich process and the dehydrogenation of benzylic C(sp3)-H bonds were key steps to constitute the alkylamination. Enlightened by the mechanistic investigations, our group successfully developed a series of Mannich-type MCRs in which benzofurans/indoles, formaldehyde, and alkylamine hydrochlorides assemble efficiently to furnish piperidine-fused benzofurans/indoles, demonstrating broad compatibility with medicinally relevant functionalities. Inspired by the dual C(sp2)-H/C(sp3)-H alkylaminative cyclization paradigm, we developed a unique Mannich-type MCR of indoles wherein the MCR process occurred in both N-H and the adjacent 2-position C(sp2)-H bonds to access indole-fused seven-membered heterocycles.More importantly, these MCRs serve as a powerful synthetic toolbox in the scaffold evolution of natural products as well as in drug discovery and development. Notably, the modification of natural products (NPs) presents significant challenges due to their inherent structural complexity, and thus efficient synthetic methods could enable more accessible modification of NPs, thereby unlocking their full therapeutic potential. We employed our established MCRs to successfully achieve an innovative scaffold evolution of natural product tanshinones, in which the highly lipophilic tanshinones could be easily transformed to N-heterocyclic scaffolds with improved functionality, drug-likeness, and biological specificity. As a result, we have pioneered the chemical evolution of Tan I for the discovery of a new class of potent NLRP3 inflammasome inhibitors and the chemical evolution of Tan IIA for the effective treatment of ALI. Furthermore, leveraging these MCRs to access a privileged scaffold, we have successfully developed a number of promising candidates, including the novel HDAC inhibitors, intestine specific P-gp inhibitors, and STAT3 inhibitors, each showing significant potential for further advancement. Finally, it is anticipated that these MCRs will become essential tools in modern medicinal chemistry and expedite the discovery of new therapeutic agents.