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Catalysis of an SN2 pathway by geometric preorganization

Nature volume 632, pages 1052–1059 (2024)Cite this article

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Abstract

Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the SN2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes. Mechanistic and computational investigations show that the hydrogen-bond donor diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.

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Fig. 1: Applying enzymatic strategies to the catalysis of ionic SN2 mechanisms.
Fig. 2: Reaction discovery and isolation of catalyst components.
Fig. 3: Mechanistic studies.
Fig. 4: Origins of catalytic rate acceleration.
Fig. 5: Enantioselective phosphonium dealkylation of phosphonites and stereospecific elaborations of H-phosphinate products.

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Data availability

The data that support the findings in this work are available in the paper and in the Supplementary Information.

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Acknowledgements

This work was supported by the National Institutes of Health through grant nos. GM043214 and GM 149244, and F32 postdoctoral fellowship (GM136042) to G.J.L. We thank D. Cui and A. Lowe (Harvard University) for assistance with the NMR experiments, and J. Gair, M. Isomura and S. Nistanaki for their helpful discussions.

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Author notes

  1. These authors contributed equally: Gabriel J. Lovinger, Marcus H. Sak

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Gabriel J. Lovinger, Marcus H. Sak & Eric N. Jacobsen

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  1. Gabriel J. Lovinger
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  2. Marcus H. Sak
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Contributions

G.J.L. and E.N.J. conceived the work; G.J.L. and M.H.S. designed and conducted the experiments; E.N.J. supervised and directed the research; and all authors wrote the paper.

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Correspondence to Eric N. Jacobsen.

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Extended data figures and tables

Extended Data Fig. 1 Origins of enantioselectivity.

All calculations were performed at the B3LYP-D3/6-311 + + G (d,p)/PCM(toluene)//B3LYP-D3/def2-SVP/PCM(toluene) level of theory at 195.15 K and 1 atm. Most hydrogens are hidden for clarity. (A) Analysis of non-covalent interactions (B) Density-functional-theory-modeled diastereomeric transition states for dealkylation with highlighted differential stabilizing interactions hypothesized to be the origin of enantioinduction.

Supplementary information

Supplementary Information

This file includes Materials and Methods, Supplementary Text, Supplementary Figs. 1–13, Supplementary Tables 1–6 and References.

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Lovinger, G.J., Sak, M.H. & Jacobsen, E.N. Catalysis of an SN2 pathway by geometric preorganization. Nature 632, 1052–1059 (2024). https://doi.org/10.1038/s41586-024-07811-4

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