Enantioselective Synthesis and Application of N-stereogenic Ammonium Cations

Abstract

Enantioselective synthesis is vital in the construction of many biologically and commercially relevant molecules. Despite having potentially wide-ranging applications, routes to synthesise enriched heteroatomic stereocentres have received less consideration than carbon-based analogues. The use of nitrogen as a stereocentre is commonly neglected due to its ability to readily pyramidally invert at room temperature, enabled by quantum tunnelling. In 1899, Pope and Peachy achieved the first successful resolution of a quaternary ammonium salt, establishing a conformationally and configurationally stable nitrogen stereocentre. However despite this, a general enantioselective methodology to access these stereogenic elements remained elusive until
recently.

Novel work by our group pioneered the enantioselective synthesis of N-stereocentres as the sole stereogenic element in a molecule. This methodology was made possible through the integration of a supramolecular recognition event and in situ racemisation within a crystallisation-induced asymmetric transformation (CIAT). The supramolecular
recognition was facilitated by 1,1′-bi-2-naphthol (BINOL), which played a crucial role in orchestrating the molecular interactions and directing the desired stereochemical
outcome.

To better explore the utility of the CIAT and increase both the scope and application of this methodology, initially the the supramolecular recognition phenomenon is investigated on a diverse library of achiral ammonium salts. The salts form ternary complexes with BINOL, which serve as supramolecular recognition units in solution. These recognition units assemble into a dynamic and flexible hydrogen-bonded network
of (R)-BINOLs and counterions. Subsequently, this network is abstracted into the solid phase, manifesting as a crystalline helical host that encapsulates ammonium cations. These hosts create discrete isostructures, adapting to offer a suitable multipoint recognition environment for the cation to which they are presented. Remarkably, quaternary ammonium cation complexes access a lower energy solid-state compared to their less substituted counterparts, resulting in their selective abstraction from solution, even under aqueous conditions. This discovery challenges selectivity based on hydrogen bonding ability and cation-p interaction strength, marking a potential paradigm shift in the field through use of the solid state.

Due to the significance of the crystalline state to a CIAT-like methodology any manipulation of its morphology has pronounced effects on the products synthesised. As such, it was established that consideration of both solvent selection and the enantiopurity of the chiral resolving agent is imperative to precisely control the solid-state end-point of the recognition process.

Leveraging an improved understanding of solid-state recognition phenomenon, this study integrates knowledge into the enantioselective methodology, shedding light on the influence of isostructure selection on enantiopurity. Furthermore, empirical observations on ammonium salt·BINOL complexes reveal that positioning steric bulk in close proximity to the stereocentre and minimising functionality on substituent groups are important factors in enhancing enantioselectivity. Analysis of the thermodynamic parameters dictating enantiomer selection in microcrystalline solids illuminates how the stereoselectivity is dictated through multiple mechanisms based on diastereomeric interactions in the solid-state. The study also reports a chiral High Performance Liquid Chromatography (HPLC) methodology to determine the enrichment levels of the newly synthesised ammonium salts. Finally, a newly synthesised ammonium salt (Nallyl, N-methyl, N-phenylacetyl anilinium bromide) was successfully applied to direct the stereochemistry of a substituted atropoisomeric scaffold, showcasing its potential as valuable tool for precise control over molecular chirality in complex chemical structures.