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Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Nature Synthesis volume 3, pages 1275–1282 (2024)Cite this article

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Abstract

Macrolactones are privileged motifs in materials science, aromachemicals and pharmaceuticals. The pivotal ester linkage is often formed from chiral secondary alcohols, with macrolactonization using stoichiometric reagents to ensure retention or inversion of stereochemistry without compromising enantiopurity. An ideal strategy for macrolactonization is via dynamic kinetic resolution (DKR), which involves the simultaneous formation of the ester bond and introduction of a chiral centre with high stereocontrol. Surprisingly, a DKR method within the context of macrocyclization is yet to be reported. Here, using a chemoenzymatic approach, the macrocyclic DKR of seco esters affords enantioenriched macrolactones. An optimized protocol (using Candida antarctica lipase B (~0.04 mol%) and Shvo’s catalyst) forms 14–19-membered macrocycles with excellent enantioselectivities (85–99% e.e.). A variety of macrolactones were synthesized including aliphatic macrocycles, meta- and paracyclophanes as well as a macrodiolide via a dimerization protocol that was converted to the natural product macrolide (−)-pyrenophorin.

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Fig. 1: Comparing inter- and intramolecular DKR processes.
Fig. 2: Optimization of chemoenzymatic DKR.
Fig. 3: Plausible mechanism for the chemoenzymatic DKR method.
Fig. 4: Scope of the DKR protocol towards macrolactones.

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Data availability

All data relating to the materials and methods, experimental procedures, mechanistic studies and NMR spectra are available in the Supplementary Information.

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Acknowledgements

We acknowledge the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery 1043344 and RGPIN-2020-05006), Université de Montréal and the Fonds de Recherche Nature et Technologies via the Centre in Green Chemistry and Catalysis (FRQNT-2020-RS4-265155-CCVC) for generous funding. We thank E. Godin for preliminary results. N. Moitessier, B. Weiser and S. Ma are thanked for computational help with the FORECASTER program.

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Authors and Affiliations

  1. Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, Montreal, Québec, Canada

    Javier Guerrero-Morales, Marie Scaglia, Edouard Fauran, Guillaume Lepage & Shawn K. Collins

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  1. Javier Guerrero-Morales
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  2. Marie Scaglia
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  3. Edouard Fauran
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Contributions

S.K.C. and J.G.-M. were involved in the discovery of the macrocyclization process. J.G.-M., M.S., E.F., G.L. and S.K.C. participated in the development of the methods and investigations. S.K.C. designed and directed the investigations. S.K.C. and J.G.-M. wrote the manuscript.

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Correspondence to Shawn K. Collins.

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Nature Synthesis thanks Jan-Erling Bäckvall, Jose M. Palomo, Xiang Sheng and William Unsworth for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Figs. 1 and 2, experimental details and characterization data.

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Guerrero-Morales, J., Scaglia, M., Fauran, E. et al. Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols. Nat. Synth 3, 1275–1282 (2024). https://doi.org/10.1038/s44160-024-00591-9

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