Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis

Project Summary/Abstract Stereogenic-at-phosphorus (P-chiral) P(V) compounds are an increasingly important motif in the design of life- saving pharmaceuticals such as broad spectrum anti-viral medications (Remdesivir, Sofosbuvir, Tenofovir Alafenamide) to treat hepatitis B and C as well as Ebola and COVID-19. Despite the enormous importance of being able to introduce P-chiral centers into compounds to develop new medications to combat existing and emergent diseases, access to this chemical motif remains constrained by a lack of efficient chemical methods. As a result, the diversity of structures that can be efficiently explored and produced in medicinal chemistry research is relatively limited. Existing methods suffer from several limitations: 1) reliance on non-selective synthesis routes, which require additional resolution steps, thus limiting the efficiency of these approaches and 2) the predominant use of electrophilic P(V) substrates that required pre-activation steps to install an appropriately reactive leaving group. Catalytic cross coupling approaches to access P-chiral compounds currently have relatively narrow product scopes and often rely on expensive transition metal catalysts that must be removed assiduously before biological testing. An attractive new approach would be an organocatalytic asymmetric phosphonium dealkylation reaction that generates P-chiral stereogenic centers by coupling P(III) nucleophiles and electrophilic activating agents. This approach would address the previously mentioned key limitations while enabling chemists to catalytically and selectively control the wide range of powerful reactions know to proceed through phosphonium species. Hydrogen-bond donor (HBD) organocatalysts are known to catalyze the formation of ionic species by anion 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 phosphonium desymmetrization to be accomplished with exquisite enantioselectivity. The goal of this proposal is to design an anion pair binding organocatalyst to promote the first catalytic enantioselective phosphonium dealkylation reaction capable of producing P-chiral products. 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 phosphorus (III) substrates such as phosphonites and phosphites will be undertaken using data-intensive multi-dimensional correlation. This study will enable simple reagents to be utilized to produce medicinally relevant enantioenriched compounds in a novel manner, contributing enormously to medicinal research, catalyst development, and substantially contributing to scientific knowledge.