Skip to main content
NCBI home page
Nature Communications logoLink to Nature Communications
. 2026 Jan 9;17:821. doi: 10.1038/s41467-025-67526-6

Efficient synthesis of chiral vicinal diamines with four contiguous stereocenters via sequential dynamic kinetic resolution of 2,3-diamino-1,4-diketones

Jinming Ma 1, Jiaxin Yuan 2,✉, Hui Lv 1,2,3,4,✉
PMCID: PMC12824288  PMID: 41507181

Abstract

The stereoselective construction of chiral vicinal diamines bearing multiple contiguous stereocenters remains a formidable challenge in modern organic synthesis. Herein, we report an Ir-catalyzed sequential dynamic kinetic resolution of 2,3-diamino-1,4-diketones that furnishes acyclic vicinal diamines containing four contiguous stereocenters in high yields with excellent diastereo- and enantioselectivity. The protocol exhibits broad substrate generality and high catalytic efficiency, enabling streamlined access to structurally diverse, functionally enriched chiral vicinal diamines. A gram-scale reaction proceeds smoothly with only 0.1 mol% catalyst loading, and versatile downstream derivatizations further highlights the synthetic utility of the method. Mechanistic investigations support a stepwise dynamic kinetic resolution pathway operative in this transformation.

Subject terms: Asymmetric synthesis, Synthetic chemistry methodology

The stereoselective construction of acyclic molecules bearing three or more contiguous stereocenters remains a long-standing challenge in modern organic synthesis. Here, the authors describe an iridium-catalyzed dynamic kinetic resolution of 2,3-diamino-1,4-diketones to enable the efficient synthesis of acyclic vicinal diamines containing four contiguous stereocenters.

Introduction

The simultaneous construction of multiple contiguous stereocenters in an acyclic molecule is an important goal of modern organic synthesis1. Considerable efforts have been devoted to this pursuit, leading to the development of numerous approaches for synthesizing acyclic molecules with two consecutive chiral centers2–6. However, methods for synthesizing chiral acyclic molecules that bear three or more contiguous stereogenic centers have been rarely reported due to the free rotation of the acyclic chain and the formidable challenges in controlling stereoselectivity7–10. Thus, the development of new methods to efficiently prepare acyclic molecules with multiple continuous stereocenters at once is highly desirable and of great significance for improving synthesis efficiency.

Chiral α-hydroxy substituted vicinal diamines are a family of unique molecules that contain both vicinal diamine and vicinal aminoalcohol subunits, widely occurring in many natural products, pharmaceuticals, and exhibited important bioactivities11–19. In particular, chiral 2,3-diamino-1,4-diols and its analogues are known to be medicinally important motifs with a wide range of biological activities (Fig. 1a)20–23. For example, Oseltamivir phosphate and Zanamivir are common drugs for the treatment of influenza20,21, 1,2-diaminocyclitols are glucoceresidase activators and potential therapeutics for Gaucher disease22, DACH-PtCl2 has antitumor activity against P388 leukemia23.

Fig. 1. Current status of the synthesis of chiral 2,3-diamino-1,4-diols and our strategy.

Fig. 1

Open in a new tab

a Represent bioactive molecules containing α-hydroxyl substituted chiral vicinal diamines. b The state of art for asymmetric synthesis of chiral vicinal amines. c The synthesis of chiral acyclic 2,3-diamino-1,4-diols from chiral starting materials. d Our strategy for asymmetric synthesis of chiral acyclic 2,3-diamino-1,4-diols.

As a result, the synthesis of chiral 2,3-diamino-1,4-diols has received considerable attention. Nonetheless, efficient catalytic methods for constructing functionalized vicinal diamines remain scarce (Fig. 1b). Consequently, current syntheses of chiral 2,3-diamino-1,4-diols typically rely on multistep sequences that employ valuable chiral starting materials (Fig. 1c), resulting in low overall efficiency and limited substrate scope24,25. To the best of our knowledge, no catalytic method has yet been developed for the asymmetric synthesis of 2,3-diamino-1,4-diols containing four contiguous stereocenters. Accordingly, the development of new catalytic strategies to address this challenge is highly desirable.

Dynamic kinetic resolution (DKR), which enables the simultaneous establishment of multiple stereogenic centers from racemic starting materials, has emerged as a powerful strategy for synthesizing chiral molecules26–43. In this context, the DKR of α-amino substituted ketones has been extensively explored44–48, offering an efficient pathway for the synthesis of vicinal aminoalcohols49–58. However, the sequential DKR of 2,3-diamino-1,4-diketones, which could provide an ideal route to acyclic vicinal diamines bearing four stereogenic centers remains unachieved. The possible reasons are as follows: (1) Racemization of stereocenters is greatly influenced by the equilibrium of multiple isomers, making the DKR process very complicated; (2) Selective production of a single double-reduction product from the 32 possible reduction products is extremely difficult due to the complex stereoselectivity inherent in the double DKR system, which includes 16 mono-reduction stereoisomers and 16 double-reduction stereoisomers. (3) Presence of multiple contiguous polar functional groups in the target product may attenuate the catalyst’s activity to some extent, further complicating the reaction. As a result, achieving the double DKR of 2,3-diamino-1,4-diketones is exceedingly challenging.

As our ongoing interest in synthesis of valuable chiral amines59–65, we aim to develop a new catalytic system to achieve the double DKR of 2,3-diamino-1,4-diols, thereby providing efficient access to functionalized vicinal diamines. Encouraged by our recent work on ferrocene-based multidentate ligands-mediated double reduction of enones66, we believe that the double DKR process can also be accomplished through rational substrate design and the selection of an appropriate catalytic system, thereby enabling the formation of vicinal diamines with four contiguous stereocenters in a single transformation. Herein, we report the sequential DKR of 2,3-diamino-1,4-diketones to stereospecifically afford chiral 2,3-diamino-1,4-diols in high yields (Fig. 1d).

Results and Discussion

Reaction optimization

Our initial studies commenced with the optimization of reaction conditions by choosing the Ir-catalyzed asymmetric hydrogenation of the mixture isomers of N-Boc protected 2,3-diamino-1,4-diphenylbutane-1,4-dione 1a as a model reaction. The tridentate chiral ligands f-Ampha L1 and f-Amphol L2 which have excellent performance in the AH of ketones were evaluated67,68, to our depression, both of them gave a very complicated mixture of mono-reduction product, double-reduction product and their isomers (Table 1, entries 1-2). Then the f-PNNO type tetradentate ligands which were developed by our group69 and Prof. Zhang group were employed70,71, and the results revealed that the f-PNNO type ligands are very efficient for this transformation, afford the target product with high yields and excellent stereoselectivities (90-99% yield and 93-99% ee, Table 1, entries 1-7). Among them, L6 had the best performance in this transformation, affording 2a with 99% yield and more than 99% ee (Table 1, entry 6), thus it was chosen as the best ligand for further optimization. Subsequently, the solvent effect was investigated, and the results disclosed that solvents have only a slight effect on the enantioselectivity of this reaction but a significant impact on the yield. When EtOAc, n-hexane, and i-PrOH were used as solvents, only moderate yields were obtained albeit the enantioselectivity remained very high (Table 1, entries 8-10). The reaction was inhibited when the reaction was conducted in MeOH or 1,4-dioxane (Table 1, entries 11-12). Next, a series of bases were evaluated to examine their effect on the DKR process. The results revealed that the base exerted a significant influence on this transformation, with Cs₂CO₃ emerging as the most efficient (Table 1, entries 13–18). Its superior performance is likely due to the synergistic effects of its optimal basicity and the favorable contribution of the cesium cation.

Table 1.

Conditions Optimization for Asymmetric Hydrogenation of the Mixture Isomers of 1aaInline graphic

Entry Ligand Solvent Base Yield (%)b ee (%)c
1 L1 THF Cs2CO3 -d -
2 L2 THF Cs2CO3 -d -
3 L3 THF Cs2CO3 92 95
4 L4 THF Cs2CO3 90 93
5 L5 THF Cs2CO3 97 99
6 L6 THF Cs2CO3 99 >99
7 L7 THF Cs2CO3 92 >99
8 L6 EtOAc Cs2CO3 79 98
9 L6 n-hexane Cs2CO3 79 97
10 L6 i-PrOH Cs2CO3 35 98
11 L6 MeOH Cs2CO3 trace -
12 L6 1,4-dioxane Cs2CO3 trace -
13 L6 THF LiOt-Bu 50 95
14 L6 THF LiOH 58 94
15 L6 THF NaOMe 96 98
16 L6 THF Na2CO3 trace -
17 L6 THF K2CO3 trace -
18 L6 THF KOH 94 96
Open in a new tab

aUnless otherwise mentioned, all reactions were performed on a 0.2 mmol scale at room temperature in 1 mL THF with 0.5 mol% [Ir(COD)Cl]2, 1.1 mol% ligand, 50 bar H2, and a reaction time of 24 h. bDetermined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. c Enantiomeric excess (ee) was determined by chiral HPLC, and diastereomeric ratios (dr) were determined by ¹H NMR analysis. All reported diastereomeric ratios exceeded 20:1 unless otherwise noted. d1a was partly consumed, but the mixture is too complicated to afford pure 2a.

Substrate scope

With the optimal conditions in hand, the substrate scope of this transformation was investigated and the results were summarized in Fig. 2. Gratifyingly, the reaction has a broad substrate scope and exhibits good tolerance to a variety of functional groups, such as alkyl (Me, Et, 2 d, 2e), alkoxyl (MeO, 2k), aryl (Ph, 2 f), halides (F, Cl, Br, 2g-2i), trifluoromethyl (2j), and amino group (2ab). Moreover, the reaction was not affected by the electronic properties and the position of substituents on the benzene ring (para, meta and ortho), furnishing target products with almost quantitative yields and excellent enantioselectivities (98-99% yield and 96-99% ee). Installing multiple substituents on the benzene ring of the substrate didn’t cause any change in reactivity and enantioselectivity (2 s, 2t). Substrates containing other aromatic fragments, such as 2-naphthyl, and 2-thienyl, were also successfully compatible in this transformation (2 u, 2 v). To our delight, the sequential DKR of unsymmetrical 2,3-diamino-1,4-diketones, which possess four isomers as the starting material, also performed very well, delivering acyclic vicinal diamines with four contiguous stereocenters in high yields with excellent enantioselectivities (2w-2ah). Alkyl substituted substrate was also compatible in this reaction, affording target product 2ai in high yields with excellent enantioselectivities, which demonstrates the good compatibility of this catalytic system(See Supplementary Table 2 for unsuitable substrates). Notably, the diastereoselectivity of this reaction was excellent, and only a single isomer was detected in this transformation, indicating that the discrimination of chiral ketones was stereospecific and only the matched ketones could be hydrogenated during the second DKR process. The absolute configuration of 2 h was unambiguously determined as (1 R, 2S, 3S, 4 R) by X-ray crystallography.

Fig. 2. Substrate Scope of 2,3-Diamino-1,4-diketones.

Fig. 2

Open in a new tab

Unless otherwise mentioned, all reactions were performed on a 0.2 mmol scale at room temperature in 1 mL THF with 0.5 mol% [Ir(COD)Cl]2, 1.1 mol% ligand, 50 bar H2, and a reaction time of 24 h. All yields are reported as isolated yields unless otherwise noted. The ee and dr were determined by chiral HPLC and ¹H NMR analysis, respectively. All products were obtained with > 20:1 dr.

To demonstrate the utility of the current methodology, the gram-scale reaction was conducted with 0.1 mol% catalyst loading, and the reaction proceeded very smoothly to afford the desired product 2a without any loss in yield and enantioselectivity (98% yield, 99% ee, Fig. 3a), which indicated that this methodology has potential practical uses. Subsequently, the applications of 2a in organic synthesis were investigated. The Boc protecting group of 2a can be easily removed in the presence of TFA, affording free α-hydroxy vicinal diamines 3 in quantitative yield (Fig. 3b-1). The Dess-Martin regent enabled oxidation of 2a proceeded smoothly at room temperature, delivering valuable chiral (S)-1a in quantitative yield without any erosion in enantioselectivity (Fig. 3b–2). In the presence of sodium hydride, 2a can be easily transformed into a novel dioxazolidinone 4 in 90% yield (Fig. 3b–3). Treatment of substrate 2a with LiAlH4 leads to the formation of product 5 through reduction (Fig. 3b–4). In addition, compound 7, a bisoxazoline ligand with a novel structure, can be efficiently prepared by treating 2c with DAST at -78 °C (Fig. 3b–5).

Fig. 3. Gram-Scale Reaction and the Application of Chiral 2,3-Diamino-1,4-diols in Organic Synthesis.

Fig. 3

Open in a new tab

a Gram scale DKR of 2,3-diamino-1,4-diketones 1a with 0.1 mol% catalyst loading. b The transformation of chiral 2,3-diamino-1,4-diols.

Mechanistic investigations

To shed light on the reaction mechanism, a series of control experiments were conducted. Initially, the effect of the base on the distribution of the stereoisomers of starting material was investigated (See Supplementary Table 3 and Fig. 1 for details). It was observed that the ratio of meso-1a to dl-1a was gradually increased in the presence of 5 mol% Cs2CO3 at room temperature, reaching an equilibrium when the ratio of meso-1a to dl-1a was 17:83. Subsequently, the change of product distribution with reaction time was investigated. As shown in Fig. 4, the ratio of meso-1a increased slightly in the first three hours before gradually decreasing. Concurrently, (S,S)-1a was gradually decreased along with the reaction time, while there was almost no consumption for (R,R)-1a in the first three hours, which indicates that (S,S)-1a, as the matched substrate, was preferentially hydrogenated in this transformation. The mono-reduction products 6 increased gradually until their consumption exceeded their production. Interestingly, the kinetic resolution of dl-1a was detected in the mono-reduction process, and the ee value of 1a gradually increased with reaction time, and the highest ee value of 1a was obtained after 7 h of reaction. It’s worth noting that the double DKR of 1a is a stepwise process, and the the second DKR process was completed after 12 h, affording the single chiral product 2a.

Fig. 4. The Distribution of Products with Reaction Time and the Change of Enantioselectivity of 1a with Reaction Time.

Fig. 4

Open in a new tab

a The possible reduction products. b Yield as a function of time for the hydrogenation of 1a. c ee  as a function of time for the hydrogenation of 1a.

In conclusion, we have developed Ir/f-PNNO complex enabled asymmetric hydrogenation of the mixture of racemic 2,3-diamino-1,4-diketones, affording chiral 2,3-diamino-1,4-diols in high yields and excellent stereoselectivities. The mechanism studies revealed that a stepwise dynamic kinetic resolution was involved in this transformation. We anticipate that this facile, effective, and practical synthetic method will not only significantly facilitate the synthesis of functionalized vicinal diamines, but also provides a general strategy for the construction of challenging acyclic chiral molecules with four adjacent stereocenters. The application of the double DKR strategy in synthesis of complicated molecules with multiple stereocenters is undergoing in our lab.

Methods

General procedure of asymmetric hydrogenation of 2,3-diamino-1,4-diketones

To a 4.0 mL vial was added the catalyst precursor [Ir(COD)Cl]2 (3.3 mg, 5 × 10-3 mmol, 1.0 eq.), (SC, SC, RFC)-L6 (6.3 mg, 1.1 × 10-2mmol, 2.2 eq.) and anhydrous i-PrOH (1.0 mL) in the argon-filled glovebox. The mixture was stirred for 1.0 h at 25 °C. The resulting orange solution (50 μL) was transferred by syringe into a vial (5.0 mL) charged with substrate (0.05 mmol), Cs2CO3 (0.8 mg, 0.0025 mmol) and anhydrous THF (1.0 mL). The vial was transferred to an autoclave, which was then charged with of H2 (50 bar) and stirred at room temperature for 24 h. The hydrogen gas was released slowly in a well-ventilated hood and the solution was concentrated and purified by flash chromatography on silica gel (CH2Cl2/MeOH, 10:1) to afford the product.

Supplementary information

Supplementary Information (11.5MB, pdf)
Transparent Peer Review file (271.8KB, pdf)

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (Grant Nos. 22371217, 22071188), Hubei Provincial Natural Science Foundation of China (2023AFA011).

Author contributions

H.L. directed the project. H.L. contributed to the concept and design of the experiments. J.Y. gave valuable advice for this project. J.M. performed the experiments and data analysis. J.M. wrote the manuscript with feedback and guidance from H.L. and J.Y. All authors discussed the experimental results and commented on the manuscript.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

Data availability

The data supporting the findings of this study are available in the paper and its Supplementary Information, further data are available from the corresponding author on request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers CCDC 2034549 (2 h). These data can be obtained free of charge from the Cambridge Crystallographic Data Center via (www.ccdc.cam.ac.uk/data_request/cif).

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Jiaxin Yuan, Email: yjx98571@163.com.

Hui Lv, Email: huilv@whu.edu.cn.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-025-67526-6.

References

  • 1.Eppe, G., Didier, D. & Marek, I. Stereocontrolled formation of several carbon–carbon bonds in acyclic systems. Chem. Rev.115, 9175–9206 (2015). [DOI] [PubMed] [Google Scholar]
  • 2.Kraft, S., Ryan, K. & Kargbo, R. B. Recent advances in asymmetric hydrogenation of tetrasubstituted olefins. J. Am. Chem. Soc.139, 11630–11641 (2017). [DOI] [PubMed] [Google Scholar]
  • 3.Holmes, M., Schwartz, L. A. & Krische, M. J. Intermolecular metal-catalyzed reductive coupling of dienes, allenes, and enynes with carbonyl compounds and Imines. Chem. Rev.118, 6026–6052 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hamada, Y. et al. Diastereo- and enantioselective anti-selective hydrogenation of α-amino-β-keto ester hydrochlorides and related compounds using transition-metal-chiral-bisphosphine catalysts. Chem. Rec.14, 235–250 (2014). [DOI] [PubMed] [Google Scholar]
  • 5.Beletskaya, I. P., Nájera, C. & Yus, M. Stereodivergent catalysis. Chem. Rev.118, 5080–5200 (2018). [DOI] [PubMed] [Google Scholar]
  • 6.Wei, L., Fu, C., Wang, Z.-F., Tao, H.-Y. & Wang, C.-J. Synergistic dual catalysis in stereodivergent synthesis. ACS Catal.14, 3812–3844 (2024). [Google Scholar]
  • 7.Watson, C. G. et al. Construction of multiple, contiguous quaternary stereocenters in acyclic molecules by lithiation-borylation. J. Am. Chem. Soc.136, 17370–17373 (2014). [DOI] [PubMed] [Google Scholar]
  • 8.Anderson, J. C. et al. Enantioselective conjugate addition nitro-mannich reactions: solvent controlled synthesis of acyclic anti- and syn-β-nitroamines with three contiguous stereocenters. J. Org. Chem.76, 1961–1971 (2011). [DOI] [PubMed] [Google Scholar]
  • 9.Wang, J. et al. Facile synthesis of enantiopure sugar alcohols: asymmetric hydrogenation and dynamic kinetic resolution combined. Angew. Chem. Int. Ed.59, 18166–18171 (2020). [DOI] [PubMed] [Google Scholar]
  • 10.Chen, T. et al. Dynamic kinetic resolution of β-substituted α-diketones via asymmetric transfer hydrogenation. J. Am. Chem. Soc.145, 585–599 (2023). [DOI] [PubMed] [Google Scholar]
  • 11.Paul, B. J. et al. Synthesis, structure, and biological evaluation of novel N- and O-Linked Diinositols. J. Am. Chem. Soc.124, 10416–10426 (2002). [DOI] [PubMed] [Google Scholar]
  • 12.Coverdale, J. P. C. et al. Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells. Nat. Chem.10, 347–354 (2018). [DOI] [PubMed] [Google Scholar]
  • 13.Vu, B. et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett.4, 466–469 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Bakhonsky, V. V. et al. Synthesis and antiproliferative activity of hindered, chiral 1,2-diaminodiamantane platinum(II) complexes. Dalton Trans.49, 14009–14016 (2020). [DOI] [PubMed] [Google Scholar]
  • 15.Foubelo, F., Nájera, C., Retamosa, M. G., Sansano, J. M. & Yus, M. Catalytic asymmetric synthesis of 1,2-diamines. Chem. Soc. Rev.53, 7983–8085 (2024). [DOI] [PubMed] [Google Scholar]
  • 16.Gan, X.-C., Zhang, C.-Y., Zhong, F., Tian, P. & Yin, L. Synthesis of chiral anti-1,2-diamine derivatives through copper(I)-catalyzed asymmetric α-addition of ketimines to aldimines. Nat. Commun.11, 4473 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Zhou, M. et al. Enantioselective reductive coupling of imines templated by chiral diboron. J. Am. Chem. Soc.142, 10337–10342 (2020). [DOI] [PubMed] [Google Scholar]
  • 18.Tao, Z., Gilbert, B. B. & Denmark, S. E. Catalytic, enantioselective syn-diamination of alkenes. J. Am. Chem. Soc.141, 19161–19170 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Chen, Y., Pan, Y., He, Y.-M. & Fan, Q.-H. Consecutive intermolecular reductive amination/asymmetric hydrogenation: facile access to sterically tunable chiral vicinal diamines and N-heterocyclic carbenes. Angew. Chem. Int. Ed.58, 16831–16834 (2019). [DOI] [PubMed] [Google Scholar]
  • 20.von Itzstein, M. et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature363, 418–423 (1993). [DOI] [PubMed] [Google Scholar]
  • 21.Magano, J. Recent synthetic approaches to oseltamivir phosphate (TamifluTM) for the treatment of influenza. Tetrahedron67, 7875–7899 (2011). [Google Scholar]
  • 22.Trapero, A. & Llebaria, A. The myo-1,2-Diaminocyclitol Scaffold Defines Potent Glucocerebrosidase Activators and Promising Pharmacological Chaperones for Gaucher Disease. ACS Med. Chem. Lett.2, 614–619 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hanessian, S. & Wang, J. Hydrophilic analogs of (R, R)-diaminocyclohexane dichloroplatinum (DACH) and the influence of relative stereochemistry on antitumor activity. Can. J. Chem.71, 2102–2108 (1993). [Google Scholar]
  • 24.Hanessian, S., Gauthier, J.-Y., Okamoto, K., Beauchamp, A. L. & Theophanides, T. Synthesis of diaminodideoxyalditol analogs of cisplatin as antitumor agents. Can. J. Chem.71, 880–885 (1993). [Google Scholar]
  • 25.Fiorelli, C., Maini, L., Martelli, G., Savoia, D. & Zazzetta, C. Study of the regioselectivity and diastereoselectivity in the addition of 3-substituted-2-propenylmetal reagents to N, N′-di[1(S)-phenylethyl]ethanediimine. Tetrahedron58, 8679–8688 (2002). [Google Scholar]
  • 26.Xie, Q.-X., Liu, L.-X., Zhu, Z.-H., Yu, C.-B. & Zhou, Y.-G. Asymmetric transfer hydrogenation of 2,3-disubstituted flavanones through dynamic kinetic resolution enabled by retro-oxa-Michael addition: construction of three contiguous stereogenic centers. J. Org. Chem.87, 7521–7530 (2022). [DOI] [PubMed] [Google Scholar]
  • 27.Li, J. et al. RuPHOX–Ru catalyzed asymmetric hydrogenation of α-substituted tetralones via a dynamic kinetic resolution. Chem. Commun.58, 4905–4908 (2022). [DOI] [PubMed] [Google Scholar]
  • 28.Vyas, V. K., Clarkson, G. J. & Wills, M. Sulfone group as a versatile and removable directing group for asymmetric transfer hydrogenation of ketones. Angew. Chem. Int Ed.59, 14265–14269 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Zhang, L., Wang, Z., Han, Z. & Ding, K. Manganese-catalyzed anti-selective asymmetric hydrogenation of α-substituted β-ketoamides. Angew. Chem. Int. Ed.59, 15565–15569 (2020). [DOI] [PubMed] [Google Scholar]
  • 30.Touge, T. et al. Multiple absolute stereocontrol in cascade lactone formation via dynamic kinetic resolution driven by the asymmetric transfer hydrogenation of keto acids with oxo-tethered ruthenium catalysts. J. Am. Chem. Soc.141, 16354–16361 (2019). [DOI] [PubMed] [Google Scholar]
  • 31.Zhou, A., Amer, M. M. K. & Yin, Q. Recent advances on asymmetric reduction via dynamic kinetic resolution. Chin. Chem. Lett.10.1016/j.cclet.2025.111929 (2025).
  • 32.Liu, J., Krajangsri, S., Yang, J., Li, J.-Q. & Andersson, P. G. Iridium-catalysed asymmetric hydrogenation of allylic alcohols via dynamic kinetic resolution. Nat. Catal.1, 438–443 (2018). [Google Scholar]
  • 33.Cotman, A. E., Cahard, D. & Mohar, B. Stereoarrayed CF3-substituted 1,3-diols by dynamic kinetic resolution: ruthenium(ii)-catalyzed asymmetric transfer hydrogenation. Angew. Chem. Int. Ed.55, 5294–5298 (2016). [DOI] [PubMed] [Google Scholar]
  • 34.Chen, M.-W., Cai, X.-F., Chen, Z.-P., Shi, L. & Zhou, Y.-G. Facile construction of three contiguous stereogenic centers via dynamic kinetic resolution in asymmetric transfer hydrogenation of quinolines. Chem. Commun.50, 12526–12529 (2014). [DOI] [PubMed] [Google Scholar]
  • 35.Corbett, M. T. & Johnson, J. S. Diametric stereocontrol in dynamic catalytic reduction of racemic acyl phosphonates: divergence from α-keto ester congeners. J. Am. Chem. Soc.135, 594–597 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Steward, K. M., Gentry, E. C. & Johnson, J. S. Dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation. J. Am. Chem. Soc.134, 7329–7332 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Xie, J.-H. et al. Highly enantioselective and diastereoselective synthesis of chiral amino alcohols by ruthenium-catalyzed asymmetric hydrogenation of α-amino aliphatic ketones. J. Am. Chem. Soc.131, 4222–4223 (2009). [DOI] [PubMed] [Google Scholar]
  • 38.Xie, J.-H., Zhou, Z.-T., Kong, W.-L. & Zhou, Q.-L. Ru-catalyzed asymmetric hydrogenation of racemic aldehydes via dynamic kinetic resolution:  efficient synthesis of optically active primary alcohols. J. Am. Chem. Soc.129, 1868–1869 (2007). [DOI] [PubMed] [Google Scholar]
  • 39.Noyori, R., Tokunaga, M. & Kitamura, M. Stereoselective organic synthesis via dynamic kinetic resolution. Bull. Chem. Soc. Jpn.68, 36–55 (1995). [Google Scholar]
  • 40.Noyori, R. et al. Stereoselective hydrogenation via dynamic kinetic resolution. J. Am. Chem. Soc.111, 9134–9135 (1989). [Google Scholar]
  • 41.Liu, W. et al. Regio- and stereoselective transfer hydrogenation of aryloxy group-substituted unsymmetrical 1,2-diketones: synthetic applications and mechanistic studies. J. Am. Chem. Soc.146, 20092–20106 (2024). [DOI] [PubMed] [Google Scholar]
  • 42.Liang, M.-R. et al. Dynamic kinetic resolution-based asymmetric transfer hydrogenation of racemic 2-substituted quinolines. J. Am. Chem. Soc.147, 4239–4248 (2025). [DOI] [PubMed] [Google Scholar]
  • 43.Rong, N., Zhou, A., Liang, M., Wang, S.-G. & Yin, Q. Asymmetric hydrogenation of racemic 2-substituted indoles via dynamic kinetic resolution: an easy access to chiral indolines bearing vicinal stereogenic centers. J. Am. Chem. Soc.146, 5081–5087 (2024). [DOI] [PubMed] [Google Scholar]
  • 44.Huerta, F. F., Minidis, A. B. E. & Bäckvall, J.-E. Racemisation in asymmetric synthesis. Dynamic kinetic resolution and related processes in enzyme and metal catalysis. Chem. Soc. Rev.30, 321–331 (2001). [Google Scholar]
  • 45.Pellissier, H. et al. Chirality from Dynamic Kinetic Resolution. The Royal Society of Chemistry, 49–143 (2011).
  • 46.Echeverria, P.-G., Ayad, T., Phansavath, P. & Ratovelomanana-Vidal, V. Recent developments in asymmetric hydrogenation and transfer hydrogenation of ketones and imines through dynamic kinetic resolution. Synthesis48, 2523–2539 (2016). [Google Scholar]
  • 47.Bhat, V., Welin, E. R., Guo, X. & Stoltz, B. M. Advances in stereoconvergent catalysis from 2005 to 2015: transition-metal-mediated stereoablative reactions, dynamic kinetic resolutions, and dynamic kinetic asymmetric transformations. Chem. Rev.117, 4528–4561 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Betancourt, R. M., Echeverria, P.-G., Ayad, T., Phansavath, P. & Ratovelomanana-Vidal, V. Recent progress and applications of transition-metal-catalyzed asymmetric hydrogenation and transfer hydrogenation of ketones and imines through dynamic kinetic resolution. Synthesis53, 30–50 (2021). [Google Scholar]
  • 49.Ohkuma, T., Ishii, D., Takeno, H. & Noyori, R. Asymmetric hydrogenation of amino ketones using chiral RuCl2(diphophine)(1,2-diamine) complexes. J. Am. Chem. Soc.122, 6510–6511 (2000). [Google Scholar]
  • 50.Liu, S., Xie, J.-H., Wang, L.-X. & Zhou, Q.-L. Dynamic kinetic resolution allows a highly enantioselective synthesis of cis-α-aminocycloalkanols by ruthenium-catalyzed asymmetric hydrogenation. Angew. Chem. Int. Ed.46, 7506–7508 (2007). [DOI] [PubMed] [Google Scholar]
  • 51.Seashore-Ludlow, B., Saint-Dizier, F. & Somfai, P. Asymmetric transfer hydrogenation coupled with dynamic kinetic resolution in water: synthesis of anti-β-hydroxy-α-amino acid derivatives. Org. Lett.14, 6334–6337 (2012). [DOI] [PubMed] [Google Scholar]
  • 52.Rasu, L. et al. Highly enantioselective hydrogenation of amides via dynamic kinetic resolution under low pressure and room temperature. J. Am. Chem. Soc.139, 3065–3071 (2017). [DOI] [PubMed] [Google Scholar]
  • 53.Lu, B. et al. Highly diastereo- and enantioselective access to syn-α-amido β-hydroxy esters via ruthenium-catalyzed dynamic kinetic resolution-asymmetric hydrogenation. J. Org. Chem.84, 3201–3213 (2019). [DOI] [PubMed] [Google Scholar]
  • 54.Cao, J. & Hyster, T. K. Pyridoxal-catalyzed racemization of α-aminoketones enables the stereodivergent synthesis of 1,2-amino alcohols using ketoreductases. ACS Catal.10, 6171–6175 (2020). [Google Scholar]
  • 55.Gediya, S. K., Clarkson, G. J. & Wills, M. Asymmetric transfer hydrogenation: dynamic kinetic resolution of α-amino ketones. J. Org. Chem.85, 11309–11330 (2020). [DOI] [PubMed] [Google Scholar]
  • 56.Bin, H.-Y. et al. Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution. Chem. Sci.12, 7793–7799 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Xu, Y. et al. Rh-catalyzed sequential asymmetric hydrogenations of 3-amino-4-chromones via an unusual dynamic kinetic resolution process. J. Am. Chem. Soc.144, 20078–20089 (2022). [DOI] [PubMed] [Google Scholar]
  • 58.Ishikawa, H. et al. Asymmetric hydrogenation of α-amino esters into optically active β-amino alcohols through dynamic kinetic resolution catalyzed by ruthenabicyclic complexes. Org. Lett.25, 2355–2360 (2023). [DOI] [PubMed] [Google Scholar]
  • 59.Wang, Q. et al. Rhodium-catalyzed enantioselective hydrogenation of tetrasubstituted α-acetoxy β-enamido esters: a new approach to chiral α-hydroxyl-β-amino acid derivatives. J. Am. Chem. Soc.136, 16120–16123 (2014). [DOI] [PubMed] [Google Scholar]
  • 60.Gao, M., Meng, J., Lv, H. & Zhang, X. Highly regio- and enantioselective synthesis of γ,δ-unsaturated amido esters by catalytic hydrogenation of conjugated enamides. Angew. Chem. Int. Ed.54, 1885–1887 (2015). [DOI] [PubMed] [Google Scholar]
  • 61.Gao, W. et al. Nickel-catalyzed asymmetric hydrogenation of β-acylamino nitroolefins: an efficient approach to chiral amines. Chem. Sci.8, 6419–6422 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Guan, Y.-Q. et al. A cheap metal for a challenging task: nickel-catalyzed highly diastereo- and enantioselective hydrogenation of tetrasubstituted fluorinated enamides. Chem. Sci.10, 252–256 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Zhao, X., Zhang, F., Liu, K., Zhang, X. & Lv, H. Nickel-catalyzed chemoselective asymmetric hydrogenation of α,β-unsaturated ketoimines: an efficient approach to chiral allylic amines. Org. Lett.21, 8966–8969 (2019). [DOI] [PubMed] [Google Scholar]
  • 64.Ma, Y., Liu, K., He, L. & Lv, H. Divergent synthesis of chiral amines via Ni-catalyzed chemo- and enantioselective hydrogenation of alkynone imines. Sci. China Chem.66, 3186–3192 (2023). [Google Scholar]
  • 65.Jiao, B., Wang, F. & Lv, H. Rhodium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated amides: efficient access to chiral β-amino amides. Chin. J. Chem.42, 2641–2646 (2024). [Google Scholar]
  • 66.Li, W. et al. Ir/f-Ampha complex catalyzed asymmetric sequential hydrogenation of enones: a general access to chiral alcohols with two contiguous chiral centers. Chem. Sci.13, 1808–1814 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Yu, J. et al. Iridium-catalyzed asymmetric hydrogenation of ketones with accessible and modular ferrocene-based amino-phosphine acid (f-Ampha) ligands. Org. Lett.19, 690–693 (2017). [DOI] [PubMed] [Google Scholar]
  • 68.Yu, J. et al. Readily accessible and highly efficient ferrocene-based amino-phosphine-alcohol (f-Amphol) ligands for iridium-catalyzed asymmetric hydrogenation of simple ketones. Chem. Eur. J.23, 970–975 (2017). [DOI] [PubMed] [Google Scholar]
  • 69.Ma, J., Li, W., He, L. & Lv, H. Iridium-catalyzed chemoselective asymmetric hydrogenation of conjugated enones with ferrocene-based multidentate phosphine ligands. Chem. Commun.58, 5841–5844 (2022). [DOI] [PubMed] [Google Scholar]
  • 70.Yin, C. et al. A 13-million turnover-number anionic Ir-catalyst for a selective industrial route to chiral nicotine. Nat. Commun.14, 3718 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Yu, J. et al. Discovery and development of ferrocene-based tetradentate ligands for Ir-catalysed asymmetric hydrogenation of ketone. Green. Synth. Catal.3, 175–178 (2022). [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information (11.5MB, pdf)
Transparent Peer Review file (271.8KB, pdf)

Data Availability Statement

The data supporting the findings of this study are available in the paper and its Supplementary Information, further data are available from the corresponding author on request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers CCDC 2034549 (2 h). These data can be obtained free of charge from the Cambridge Crystallographic Data Center via (www.ccdc.cam.ac.uk/data_request/cif).

Articles from Nature Communications are provided here courtesy of Nature Publishing Group

RESOURCES