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Enantioselective synthesis of ammonium cations


Control of molecular chirality is a fundamental challenge in organic synthesis. Whereas methods to construct carbon stereocentres enantioselectively are well established, routes to synthesize enriched heteroatomic stereocentres have garnered less attention1,2,3,4,5. Of those atoms commonly present in organic molecules, nitrogen is the most difficult to control stereochemically. Although a limited number of resolution processes have been demonstrated6,7,8, no general methodology exists to enantioselectively prepare a nitrogen stereocentre. Here we show that control of the chirality of ammonium cations is easily achieved through a supramolecular recognition process. By combining enantioselective ammonium recognition mediated by 1,1′-bi-2-naphthol scaffolds with conditions that allow the nitrogen stereocentre to racemize, chiral ammonium cations can be produced in excellent yields and selectivities. Mechanistic investigations demonstrate that, through a combination of solution and solid-phase recognition, a thermodynamically driven adductive crystallization process is responsible for the observed selectivity. Distinct from processes based on dynamic and kinetic resolution, which are under kinetic control, this allows for increased selectivity over time by a self-corrective process. The importance of nitrogen stereocentres can be revealed through a stereoselective supramolecular recognition, which is not possible with naturally occurring pseudoenantiomeric Cinchona alkaloids. With practical access to the enantiomeric forms of ammonium cations, this previously ignored stereocentre is now available to be explored.

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Fig. 1: Nitrogen stereocentres.
Fig. 2: General enantioselective ammonium recognition.
Fig. 3: Dynamic behaviour of ammonium cations.
Fig. 4: Enantioselective synthesis of ammonium cations.

Data Availability

Full crystallographic details in CIF format have been deposited in the Cambridge Crystallographic Data Centre database (deposition numbers: CCDC-1987042–1987058; 1987061–1987068; 1987165–1987180; 2047299–2047303). All other data are available from the corresponding author upon request.


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We acknowledge funding from The Royal Society to M.O.K in the form of a University Research Fellowship (UF150536) and equipment grant (RGS\R2\180467) award. Durham University is acknowledged for providing a doctoral studentship (M.P.W.). J.M.P acknowledges support from the Laidlaw Undergraduate Research and Leadership programme in the form of a scholarship. The Royal Society is also acknowledged for providing M.E.L. with funding for a summer studentship. We thank our colleagues at Durham University and beyond, as well as members of the Kitching group, for input and advice during the preparation of this manuscript.

Author information




The project was conceived by M.O.K. and M.P.W. Experiments were devised by M.O.K. and M.P.W. M.P.W., J.M.P. and M.E.L. carried out starting material synthesis for the project. M.P.W. carried out experimental work to develop the enantioselective recognition, dynamic studies and enantioselective syntheses. X-ray crystallography was conducted by M.P.W. and D.S.Y. The manuscript was prepared by M.O.K. and M.P.W. with input from all authors.

Corresponding author

Correspondence to Matthew O. Kitching.

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The authors have filed a patent on this work (GB2017799.4).

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Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Recognition screening.

Addition of recognition species (0.5 equiv) to 60 mM solution (CDCl3) of (rac)-1b. Recognition was monitored by observing changes in chemical shift and increased multiplicities of 1H resonances of salt (rac)-1b.

Extended Data Fig. 2 Crystal structure of ternary complex 2b.

a, The asymmetric unit (P43). b, Viewed along the b axis. c, Viewed along the c axis.

Extended Data Fig. 3 BINOL–halide network.

The (R)-BINOL and bromide counterions of complex 2d are shown as a van der Waals surface (teal), displaying the chiral hydrogen-bond network that encapsulates the ammonium cation (S)-1d.

Extended Data Fig. 4 Control reactions.

a, Table of control reactions, demonstrating the requirement for correct balance of temperature, alkylating agent and concentration for optimal results. b, Analysis of both the solid and solution phases of the reaction mixture. Both phases show bias towards the (S) enantiomer of the quaternary ammonium cation.

Extended Data Fig. 5 Ammonium hexafluorophosphate salts.

a, X-ray crystal structures of enantioenriched hexafluorophosphate salts (S)-1t and (R)-1t. b, Evaluation of the stereochemical stability of (S)-1t and (R)-1t by exposing both enantiomers to conditions previously used to racemize ammonium halide salts, while also observing minimal changes to their optical activity after 24 h.

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Walsh, M.P., Phelps, J.M., Lennon, M.E. et al. Enantioselective synthesis of ammonium cations. Nature 597, 70–76 (2021).

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