Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis Nucleophilic aromatic substitution (SNAr) is one of the most broadly utilized reactions in pharmaceutical and medicinal chemistry, allowing access to aromatic and heterocyclic molecules. Despite its enormous importance, the scope of this reaction class remains constrained by its intrinsic mechanistic features. As a result, the diversity of structures that can be explored in medicinal chemistry research using SNAr is relatively limited. Existing methods suffer from several limitations: 1) reliance on harsh reaction conditions and powerful stoichiometric reagents, which limits functional group compatibility, 2) required use of aryl substrates with strongly electron withdrawing groups, which inherently restricts the scope of accessible products, 3) reliance on aryl electrophiles with halide leaving groups, precluding the use of inexpensive phenol, anisole, and aniline feedstock chemicals and producing large quantities of halogenated waste. Alternative cross coupling approaches often rely on expensive transition metal catalysts that must be removed assiduously before biological testing. The use of SNAr to generate medicinally valuable enantioenriched structures is largely unexplored. An attractive new approach would be to use an organocatalyst to promote an asymmetric SNAr reaction in which tertiary or even quaternary enantioenriched stereocenters might be generated by coupling unactivated aryl electrophiles and prochiral nucleophiles such as enolates. This approach would address each of the previously mentioned key limitations. Hydrogen-bond donor (HBD) organocatalysts are known to activate neutral organic molecules via leaving group binding while also controlling the stereochemical outcome of nucleophilic trapping of these species. By leveraging the powerful transition state stabilization and synergistic dual nucleophilic and electrophilic activation capabilities unique to HBD catalysts, this approach should enable previously unfeasible SNAr reactions to be accomplished with exquisite site- and enantioselectivity. The goal of this proposal is to design a leaving group binding organocatalyst that will catalyze the first general and synthetically useful asymmetric SNAr reaction capable of merging unactivated aryl electrophiles and prochiral nucleophiles. The research plan outlines a strategy to develop such a catalyst system guided by hypothesis-driven experimentation, computational modeling, and structure-activity studies. To add to the information gained in the reaction development, a detailed mechanistic study of HBD organocatalyst activation of simple aryl electrophiles such as anisole, analine, and phenol derivatives, as well as more traditional aryl halides will be undertaken using data-intensive multi-dimensional correlation. This study will enable simple and inexpensive bench-stable feedstock aryl electrophiles to be utilized to produce medicinally relevant enantioenriched compounds in a novel manner and will have enormous importance to medicinal research and catalyst development, substantially contributing to scientific knowledge.
The proposed research is aimed toward the development of a new enzyme-inspired organocatalytic reaction that leverages networks of synergistic attractive interactions to rapidly and mildly transform inexpensive starting materials into valuable stereochemically defined products. The proposed strategy will allow preparation and biological study of new structures that were previously inaccessible or prohibitively difficult to synthesize. Ultimately, the proposed research will facilitate the exploration of new chemical structures in pharmaceutical research, and contribute to a greater understanding of new activation modes in small molecules catalysis.