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Stereodivergent transformation of a natural polyester to enantiopure PHAs

Nature volume 643, pages 967–974 (2025)Cite this article

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Abstract

Natural chiral polymers, such as DNA, proteins, cellulose and poly[(R)-3-hydroxybutyrate] ((R)-P3HB), are prevalent in their enantiopure forms1,2. Existing methods to synthesize enantiopure polymers focus on enantiospecific polymerization, in which only one specific enantiomer is obtained from the corresponding chiral monomer3,4,5,6. Here we introduce a catalytic stereodivergent synthetic strategy to access all enantiopure di-isotactic poly(3-hydroxyalkanoate) (PHA) diastereomers from bacterial (R)-P3HB as the single chiral source. A series of enantiopure (R,R)-α-alkylated-β-butyrolactones are obtained from (R)-P3HB and then subjected to the catalyst-controlled diastereodivergent ring-opening polymerization (ROP) to enantiopure di-isotactic α-alkylated PHAs. Metal-catalysed coordination–insertion ROP results in threo-(R,R)-di-isotactic PHAs with chiral retention, whereas anionic ROP catalysed by an organic superbase produces erythro-(R,S)-di-isotactic PHAs with chiral inversion, achieving precision di-isotactic PHAs with exclusive regio- and stereoregularity. This strategy has also enabled the stereodivergent synthesis of all four [(R,R), (S,S), (R,S) and (S,R)] stereoisomers of α,α-dialkylated PHAs from (R)-P3HB, which can be depolymerized to chiral α,α-dialkylated-β-butyrolactones with high stereoselectivity. Overall, this catalyst-controlled regio- and stereoselective, stereodivergent synthetic methodology provides access to 16 enantiopure stereoisomers of α(α)-(di)substituted PHAs and enables the stereochemistry-defined structure–property relationship study of the di-isotactic PHAs, providing insights into the effects of main-chain stereoconfigurations and alkyl side chains on their thermal properties, melt processability, mechanical performance and supramolecular stereocomplexation.

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Fig. 1: Catalytic stereodivergent polymerization for enantiopure di-isotactic PHAs.
Fig. 2: Determining stereoregularity and stereoconfiguration of di-isotactic PHAs.
Fig. 3: Thermal, mechanical and rheological properties of enantiopure di-isotactic PHAs.
Fig. 4: Stereocomplexation behaviour and chiroptical activities of enantiomeric di-isotactic PHAs.

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All data that support the findings of this study are available in the Article and its Supplementary Information.

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Acknowledgements

The work by J.-J.T., R.L., J.N. and E.Y.-X.C. was supported in part by RePLACE (Redesigning Polymers to Leverage a Circular Economy), funded by the Office of Science of the US Department of Energy (award no. DE-SC0022290). The work by E.C.Q., E.R.C., Z.Z., L.Z., R.R.G. and E.Y.-X.C. was supported in part by the US Department of Energy, Office of Energy Efficiency and Renewable Energy, Advanced Materials and Manufacturing Technologies Office (AMMTO) and Bioenergy Technologies Office (BETO), performed as part of the BOTTLE Consortium, which includes members from Colorado State University and funded under contract no. DE-AC36-08GO28308 with the National Renewable Energy Laboratory, operated by Alliance for Sustainable Energy. We thank J. Boes of the Kennan group for assistance in CD measurements.

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Author notes

  1. These authors contributed equally: Jun-Jie Tian, Ruirui Li

Authors and Affiliations

  1. Department of Chemistry, Colorado State University, Fort Collins, CO, USA

    Jun-Jie Tian, Ruirui Li, Ethan C. Quinn, Jiyun Nam, Eswara Rao Chokkapu, Zhen Zhang, Li Zhou, Ravikumar R. Gowda & Eugene Y.-X. Chen

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  1. Jun-Jie Tian
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Contributions

E.Y.-X.C. conceived the project, acquired the funding and directed the research. J.-J.T. and R.L. led the experimental design and study. J.-J.T., R.L., E.C.Q., J.N., E.R.C., Z.Z., L.Z. and R.R.G. designed and conducted experiments as well as acquired, analysed and interpreted data or results. J.-J.T. and R.L. wrote the original draft and revised the subsequent manuscript versions. E.Y.-X.C. edited the initial and subsequent versions of the paper. All authors have reviewed and approved the paper.

Corresponding author

Correspondence to Eugene Y.-X. Chen.

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Extended data figures and tables

Extended Data Fig. 1 The structures of 22 enantiopure diisotactic PHAs synthesized and investigated in this study.

Sixteen enantiopure diisotactic PHAs were derived from (R)-P3HB and six enantiopure diisotactic PHAs were derived from ethyl-(S)-3-hydroxybutanoate.

Extended Data Fig. 2 Synthesis and absolute stereoconfiguration determination of (R)- and (S)-[P3H(Me)2B].

a, Catalytic stereodivergent polymerization of (R)-[(Me)2BL] leads to enantiopure (R)- and (S)-[P3H(Me)2B], and their hydrolysis gives the corresponding enantiopure (R)- and (S)-hydroxyacids. b, Comparative 13C NMR spectra (CDCl3) of atactic P3H(Me)2B and enantiopure (R)- and (S)-[P3H(Me)2B].

Extended Data Fig. 3 Chemical recycling of enantiopure P3H(Me)2B to chiral lactones.

a, Catalytic stereodivergent polymerization of virgin (R)-(Me)2BL and NaOH-catalyzed depolymerization of enantiopure P3H(Me)2B. b, Comparative crude 1H NMR spectra (CDCl3) of virgin (R)-(Me)2BL, recycled (S)-(Me)2BL, and recycled (R)-(Me)2BL.

Extended Data Fig. 4 Chemical recycling of diastereomeric P(M5) to chiral lactones.

a, Catalytic stereodivergent polymerization of virgin (R,R)-M5 and chemical recycling of (R,R)-P(M5) and (R,S)-P(M5). b, Catalytic stereodivergent polymerization of virgin (S,R)-M5 and chemical recycling of (S,R)-P(M5) and (S,S)-P(M5). c, Comparative crude 1H NMR spectra (CDCl3) of virgin (R,R)-M5, recycled (R,S)-M5 and recycled (R,R)-M5. d, Comparative crude 1H NMR spectra (CDCl3) of virgin (S,R)-M5, recycled (S,S)-M5 and recycled (S,R)-M5.

Extended Data Fig. 5 Stereocomplexation behavior of enantiomeric P(M2).

a, DSC second heating scans (10 °C/min) for (R,R)-P(M2), (S,S)-P(M2), and their 1:1 physical blend. b, DSC second heating scans (10 °C/min) for (R,S)-P(M2), (S,R)-P(M2), and stereocomplex, sc-PHEBRS/SR. c, DSC first cooling scans (10 °C/min) for (R,S)-P(M2), (S,R)-P(M2), and sc-PHEBRS/SR. d, Stacked WAXS profiles of (R,S)-P(M2), (S,R)-P(M2), and sc-PHEBRS/SR.

Extended Data Fig. 6 Stacked DSC crystallization thermograms of P(M3) enantiomers and their stereocomplexes.

a, DSC first cooling scans (10 °C/min) for (R,R)-P(M3), (S,S)-P(M3), and sc-PHPBRR/SS. b, DSC first cooling scans (10 °C/min) for (R,S)-P(M3), (S,R)-P(M3), and sc-PHPBRS/SR.

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Tian, JJ., Li, R., Quinn, E.C. et al. Stereodivergent transformation of a natural polyester to enantiopure PHAs. Nature 643, 967–974 (2025). https://doi.org/10.1038/s41586-025-09220-7

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