Abstract
Dynamic kinetic resolution (DKR) is an efficient chiral induction strategy that transforms both enantiomers of the substrate racemates into the same optically enriched product. Typically, the absolute configurations of the products should be determined by the chiral catalyst. Here we report an adaptive DKR strategy that forges diverse azapolycycles with high stereochemical selectivities by taking full advantage of the dynamic interconversion of diastereomeric aminoalkyl cyclopalladated complexes. Notably, this innovative adaptive DKR model achieves alterations of absolute configurations at the contiguous stereocentres with the same chiral diphosphine-ligated palladium catalyst by changing the ring sizes of the annulation products. Moreover, a concise and efficient total synthesis of martinellic acid was carried out by using the adaptive DKR process as the key chirality forging and scaffold establishment step, which further demonstrated the efficacy of this strategy.
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Data availability
All data supporting the findings of this study are available within the article and its Supplementary Information. The supplementary crystallographic data for this article are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under accession numbers CCDC 2350635 (compound 4a), CCDC 2350636 (compound 3a), CCDC 2350637 (compound 5a), CCDC 2417704 (compound 5h), CCDC 2350638 (compound ent-6h), CCDC 2417682 (compound 7u), CCDC 2350639 (compound 7v) and CCDC 2350640 ([Pd(R)-MeOBIPHEP(OAc)2]).
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Acknowledgements
Financial support for this project was provided by the National Natural Science Foundation of China (grant nos. 21925111, 92356302 and 22350008 to H.H. and 22301290 to B.Y.), the Strategic Priority Research Program of Chinese Academy of Sciences (grant no. XDB0450301 to H.H.), the National Key R&D Program of China (grant no. 2023YFA1507500 to H.H.) and Anhui Provincial Natural Science Foundation (grant no. 2308085QB45 to B.Y.).
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H.H. conceived the concept and supervised the project. B.Y. and Y.H. developed the reaction and conducted the main experimental work. H.Z., B.Y. and H.H. prepared the paper, which was approved by all authors.
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Supplementary information
Supplementary Information
Supplementary Figs. 1–21 and Tables 1–19.
Supplementary Data 1
X-ray structure of 3a.
Supplementary Data 2
X-ray structure of 4a.
Supplementary Data 3
X-ray structure of 5a.
Supplementary Data 4
X-ray structure of 5h.
Supplementary Data 5
X-ray structure of 7u.
Supplementary Data 6
X-ray structure of 7v.
Supplementary Data 7
X-ray structure of chiral Pd catalyst.
Supplementary Data 8
X-ray structure of ent-6h.
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Yu, B., Huang, Y., Zhang, H. et al. Adaptive dynamic kinetic resolution enables alteration of chiral induction with ring sizes. Nat. Chem. 17, 1256–1264 (2025). https://doi.org/10.1038/s41557-025-01850-8
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DOI: https://doi.org/10.1038/s41557-025-01850-8
