Efficient Synthesis of Chiral Vicinal Diamines with Four Contiguous Stereocenters via Sequential Dynamic Kinetic Resolution of 2,3-Diamino-1,4-diones

Efficient Synthesis of Chiral Vicinal Diamines with Four Contiguous Stereocenters via Sequential Dynamic Kinetic Resolution of 2,3-Diamino-1,4-diones | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Efficient Synthesis of Chiral Vicinal Diamines with Four Contiguous Stereocenters via Sequential Dynamic Kinetic Resolution of 2,3-Diamino-1,4-diones Hui Lv, Jinming Ma, Jiaxin Yuan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7047584/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The Ir/ f -PNNO complex catalyzed sequential dynamic kinetic resolution (DKR) of 2,3-diamino-1,4-diones has been successfully achieved, yielding acyclic vicinal diamines with four contiguous stereocenters in high yields and excellent diastereo- and enantioselectivity (> 20:1 dr and > 99% ee). This method exhibits a wide substrate scope and high efficiency, rendering it valuable for synthesizing functionalized chiral vicinal diamines. A gram-scale reaction performed with high efficiency at just 0.1 mol% catalyst loading, along with successful product derivatization, demonstrated the synthetic utility of this methodology. Mechanistic studies revealed that a stepwise DKR process was involved in this transformation. Physical sciences/Chemistry/Chemical synthesis/Asymmetric synthesis Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The simultaneous construction of multiple contiguous stereocenters in an acyclic molecule is an important goal of modern organic synthesis. 1 Considerable efforts have been devoted to this pursuit, leading to the development of numerous approaches for synthesizing acyclic molecules with two consecutive chiral centers. 2–6 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 stereoselectivity ( Fig. 2a ). 7–10 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 bioactivities. 11–14 In particular, chiral 2,3-diamine-1,4-diols and its analogues are known to be medicinally important motifs with a wide range of biological activities ( Fig. 1 ). 15–18 For example, Oseltamivir phosphate and Zanamivir are common drugs for the treatment of influenza, 15,16 1,2-diaminocyclitols are glucoceresidase activators and potential therapeutics for Gaucher disease, 17 DACH-PtCl 2 has antitumor activity against P388 leukemia. 18 As a result, the synthesis of chiral 2,3-diamino-1,4-diols has received considerable attention, and some approaches have been developed. However, current methods for synthesizing chiral 2,3-diamino-1,4-diols heavily rely on multi-step synthesis using valuable chiral molecules as starting materials ( Fig. 2b ), which limits their applications due to relatively low efficiency and a narrow substrate scope. 19,20 To the best our knowledge, catalytic methods for the asymmetric synthesis of 2,3-diamino-1,4-diols containing four contiguous stereocenters have not yet been established. Thus, it is imperative to develop new methods to address this challenging issue. 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 molecules. 21–36 In this context, the DKR of α -amino substituted ketones has been extensively explored, 37–41 offering an efficient pathway for the synthesis of vicinal aminoalcohols. 42–51 However, the sequential DKR of 2,3-diamino-1,4-diones, 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 24 possible reduction products is extremely difficult due to the complex stereoselectivity inherent in the double DKR system, which includes 8 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-diones is exceedingly challenging. As our ongoing interest in synthesis of valuable chiral amines, 52–58 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 enones, 59 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 first sequential DKR of 2,3-diamino-1,4-diones to stereospecifically afford chiral 2,3-diamine-1,4-diols in high yields ( Fig. 2c ). Results and Discussion 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 evaluated, 60 , 61 to our depressed, 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 developed by our group 62 and Prof. Zhang group were employed, 63 , 64 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, the bases were screened to evaluate their impact on the DKR process, and the results showed that the bases played an important role in this transformation, and Cs 2 CO 3 was superior to others in this reaction (Table 1 , entries 13–18). With the optimal conditions in hand, the substrate scope of this transformation was investigated and the results were summarized in Fig. 4 . Gratifyingly, the reaction has a broad substrate scope and exhibits good tolerance to a variety of functional groups, such as alkyl (Me, Et, 2d, 2e ), alkoxyl (MeO, 2k ), aryl (Ph, 2d ), 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 ( 2s , 2t ). Substrates containing other aromatic fragments, such as 2-naphthyl, and 2-thienyl, were also successfully compatible in this transformation ( 2u , 2v ). To our delight, the sequential DKR of unsymmetrical 2,3-diamino-1,4-diones, 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 Supporting Information for more details). 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 2h was unambiguously determined as (1 R , 2 S , 3 S , 4 R ) by X-ray crystallography. 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. 5 − 1 ), 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. 5 - 2 a). 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. 5 - 2 b). In the presence of sodium hydride, 2a can be easily transformed into a novel dioxazolidinone 4 in 90% yield (Fig. 5 - 2 c). Treatment of substrate 2a with LiAlH₄ leads to the formation of product 5 through reduction. In addition, compound 6 , a bisoxazoline ligand with a novel structure, can be efficiently prepared by treating 2c with DAST at -78 ℃ (Fig. 5 - 2 e). 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. It was observed that the ratio of meso - 1a to dl - 1a was gradually increased in the presence of 5 mol% Cs 2 CO 3 at room temperature, reaching an equilibrium when the ratio of meso - 1a to dl -1a was 17: 83 (see supporting information). Subsequently, the change of product distribution with reaction time was investigated. As shown in Fig. 6 , 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 hours 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 hours, affording the single chiral product 2a . In conclusion, we have developed Ir/ f -PNNO complex enabled asymmetric hydrogenation of the mixture of racemic 2,3-diamine-1,4-diones, affording chiral 2,3-diamine-1,4-diols in high yields and excellent stereoselectivities. The mechanism studies revealed that a stepwise dynamic kinetic resolution were 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 are undergoing in our lab. Methods 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.), ( S C , S C , R FC )- L6 (6.3 mg, 1.1 ×10 − 2 mmol, 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 ℃. The resulting orange solution (50 µL) was transferred by syringe into a vial (5.0 mL) charged with substrate (0.05 mmol), Cs 2 CO 3 (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 H 2 (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 (CH 2 Cl 2 /MeOH, 10:1) to afford the product. Declarations 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 Centre (CCDC), under deposition numbers CCDC 2034549 ( 2h ). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Author contributions H. Lv directed the project. H. Lv contributed to the concept and design of the experiments. J. Yan gave valuable advice for this project. J. Ma performed the experiments and data analysis. J. Ma wrote the manuscript with feedback and guidance from H. Lv. All authors discussed the experimental results and commented on the manuscript. Acknowledgment 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). Competing financial interests The authors declare no competing financial or non-financial interests. References Eppe, G., Didier, D. & Marek, I. Stereocontrolled Formation of Several Carbon–Carbon Bonds in Acyclic Systems. Chem. Rev. 115 , 9175–9206 (2015). Kraft, S., Ryan, K. & Kargbo, R. B. 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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). 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). 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). Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files Supportinginformation.pdf Supporting Information Table1.docx Cite Share Download PDF Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7047584","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":484965574,"identity":"0bfeaa66-5bc9-4a2d-a72d-3702b76609d2","order_by":0,"name":"Hui Lv","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYBACAwbGxgMMFQwJII4EsVoaDjCcIU0LA8MBxjZStJhLJDcc5p13OM/gAPPB2zwMdnkEtVjOSARq2Xa42OAAW7I1D0NyMWGH3UhsODhz2+3EDQd4zKR5GA4kNhCnZQ5IC/834rUc+NgAtoWNSC1nHjYc+HDsf+LMw2zGlnMMkonQcjz94YOEmrTEvuPND2+8qbAjrAUBmMEmEK9+FIyCUTAKRgEeAACYw0TEK7CosgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1378-1945","institution":"Wuhan University","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Lv","suffix":""},{"id":484965575,"identity":"d6c7c5ff-1618-484e-94dc-32783801efbd","order_by":1,"name":"Jinming Ma","email":"","orcid":"","institution":"Wuhan University","correspondingAuthor":false,"prefix":"","firstName":"Jinming","middleName":"","lastName":"Ma","suffix":""},{"id":484965576,"identity":"00376a2e-1549-425c-8f9b-2108d9ecfe2c","order_by":2,"name":"Jiaxin Yuan","email":"","orcid":"","institution":"Wuhan University","correspondingAuthor":false,"prefix":"","firstName":"Jiaxin","middleName":"","lastName":"Yuan","suffix":""}],"badges":[],"createdAt":"2025-07-04 14:15:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7047584/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7047584/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-67526-6","type":"published","date":"2026-01-09T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88395514,"identity":"1246889f-4cc8-4299-916a-11d13ef91e32","added_by":"auto","created_at":"2025-08-06 05:56:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58791,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBioactive molecues containing α-hydroxyl substituted chiral vicinal diamines.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/4e69fea5d8a72876a9595914.png"},{"id":88396557,"identity":"29eae74f-ff49-4283-9c50-58017b67757d","added_by":"auto","created_at":"2025-08-06 06:12:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265300,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMethods for synthesis of chiral 2,3-diamine-1,4-diols.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/795094fb8a26591283d95a98.png"},{"id":88395519,"identity":"3c5fd929-063d-4468-a5b5-cf2f6c6c2fe6","added_by":"auto","created_at":"2025-08-06 05:56:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":101722,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStructures of the phosphine ligands for asymmetric hydrogenation of 1a.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/dbab644f35826eb3ef3b9feb.png"},{"id":88395528,"identity":"a1444168-74c3-4073-860f-608e3e02cb00","added_by":"auto","created_at":"2025-08-06 05:56:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":708310,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate Scope of 2,3-Diamines-1,4-Dion. \u003c/strong\u003eUnless otherwise mentioned, all reactions were performed on a 0.2 mmol scale at room temperature in 1 mL THF with 0.5 mmol% [Ir(COD)Cl]\u003csub\u003e2\u003c/sub\u003e, 1.1 mmol% ligand, 50 bar H\u003csub\u003e2\u003c/sub\u003e, and a reaction time of 24 hours. The dr was determined by \u003csup\u003e1\u003c/sup\u003eH NMR. The yield was an isolated yield. The ee was determined by HPLC analysis using a chiral stationary phase.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/a5f1f77a97d7425961e728e6.png"},{"id":88395765,"identity":"c205bc3f-1f42-4bd6-9f21-b3aec7246125","added_by":"auto","created_at":"2025-08-06 06:04:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":251728,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGram-Scale Reaction and the Application of Chiral 2,3-Diamines-1,4-Diols in Organic Synthesis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/c1e9dd298fdaee167772f366.png"},{"id":88395532,"identity":"2191088c-56ac-4022-88f6-9fcd4e98b542","added_by":"auto","created_at":"2025-08-06 05:56:57","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":253644,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Distribution of Products with Reaction Time and the Change of Enantioselectivity of 1a with Reaction Time.\u003c/strong\u003e (a) yield variation for the hydrogenation of \u003cstrong\u003e1a\u003c/strong\u003e. (b) ee variation for the hydrogenation of \u003cstrong\u003e1a\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/a66f12dfcf76d44b63ca66a7.png"},{"id":101202499,"identity":"5b17e8b9-0c86-4701-9108-3f11db1f3928","added_by":"auto","created_at":"2026-01-27 09:35:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2098749,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/18e04cd2-85e1-4fc6-be81-2934d8c872ca.pdf"},{"id":88395761,"identity":"a34dc4b1-d088-4cac-9206-b9a82a4d5c86","added_by":"auto","created_at":"2025-08-06 06:04:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13265186,"visible":true,"origin":"","legend":"Supporting Information","description":"","filename":"Supportinginformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/0d73b04af72f1ee052211c4c.pdf"},{"id":88395515,"identity":"c762294b-2954-408a-8924-917dff25890a","added_by":"auto","created_at":"2025-08-06 05:56:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36998,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7047584/v1/622939fb7ff0c6d5c4aae1f4.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Efficient Synthesis of Chiral Vicinal Diamines with Four Contiguous Stereocenters via Sequential Dynamic Kinetic Resolution of 2,3-Diamino-1,4-diones","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe simultaneous construction of multiple contiguous stereocenters in an acyclic molecule is an important goal of modern organic synthesis.\u003csup\u003e\u0026nbsp;1\u003c/sup\u003e Considerable efforts have been devoted to this pursuit, leading to the development of numerous approaches for synthesizing acyclic molecules with two consecutive chiral centers.\u003csup\u003e2–6\u003c/sup\u003e 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 stereoselectivity (\u003cstrong\u003eFig. 2a\u003c/strong\u003e).\u003csup\u003e7–10\u003c/sup\u003e 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.\u003c/p\u003e\n\u003cp\u003eChiral 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 bioactivities.\u003csup\u003e11–14\u003c/sup\u003e In particular, chiral 2,3-diamine-1,4-diols and its analogues are known to be medicinally important motifs with a wide range of biological activities (\u003cstrong\u003eFig. 1\u003c/strong\u003e). \u003csup\u003e15–18\u003c/sup\u003e For example, Oseltamivir phosphate and Zanamivir are common drugs for the treatment of influenza,\u003csup\u003e15,16\u003c/sup\u003e 1,2-diaminocyclitols are glucoceresidase activators and potential therapeutics for Gaucher disease,\u003csup\u003e17\u003c/sup\u003e DACH-PtCl\u003csub\u003e2\u003c/sub\u003e has antitumor activity against P388 leukemia.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAs a result, the synthesis of chiral 2,3-diamino-1,4-diols has received considerable attention, and some approaches have been developed. However, current methods for synthesizing chiral 2,3-diamino-1,4-diols heavily rely on multi-step synthesis using valuable chiral molecules as starting materials (\u003cstrong\u003eFig. 2b\u003c/strong\u003e), which limits their applications due to relatively low efficiency and a narrow substrate scope.\u003csup\u003e19,20\u003c/sup\u003e To the best our knowledge, catalytic methods for the asymmetric synthesis of 2,3-diamino-1,4-diols containing four contiguous stereocenters have not yet been established. Thus, it is imperative to develop new methods to address this challenging issue.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDynamic 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 molecules.\u003csup\u003e21–36\u003c/sup\u003e In this context, the DKR of \u003cem\u003eα\u003c/em\u003e-amino substituted ketones has been extensively explored,\u003csup\u003e37–41\u003c/sup\u003e offering an efficient pathway for the synthesis of vicinal aminoalcohols.\u003csup\u003e42–51\u003c/sup\u003e However, the sequential DKR of 2,3-diamino-1,4-diones, 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 24 possible reduction products is extremely difficult due to the complex stereoselectivity inherent in the double DKR system, which includes 8 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-diones is exceedingly challenging.\u003c/p\u003e\n\u003cp\u003eAs our ongoing interest in synthesis of valuable chiral amines,\u003csup\u003e52–58\u003c/sup\u003e 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 enones,\u003csup\u003e59\u003c/sup\u003e 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 first sequential DKR of 2,3-diamino-1,4-diones to stereospecifically afford chiral 2,3-diamine-1,4-diols in high yields (\u003cstrong\u003eFig. 2c\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eOur initial studies commenced with the optimization of reaction conditions by choosing the Ir-catalyzed asymmetric hydrogenation of the mixture isomers of \u003cem\u003eN\u003c/em\u003e-Boc protected 2,3-diamino-1,4-diphenylbutane-1,4-dione \u003cstrong\u003e1a\u003c/strong\u003e as a model reaction. The tridentate chiral ligands \u003cem\u003ef\u003c/em\u003e-Ampha \u003cstrong\u003eL1\u003c/strong\u003e and \u003cem\u003ef\u003c/em\u003e-Amphol \u003cstrong\u003eL2\u003c/strong\u003e which have excellent performance in the AH of ketones were evaluated,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e to our depressed, both of them gave a very complicated mixture of mono-reduction product, double-reduction product and their isomers (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 1–2). Then the \u003cem\u003ef\u003c/em\u003e-PNNO type tetradentate ligands which developed by our group\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e and Prof. Zhang group were employed,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e and the results revealed that the \u003cem\u003ef\u003c/em\u003e-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 \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 1–7). Among them, \u003cstrong\u003eL6\u003c/strong\u003e had the best performance in this transformation, affording \u003cstrong\u003e2a\u003c/strong\u003e with 99% yield and more than 99% ee (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, 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, \u003cem\u003en\u003c/em\u003e-hexane, and \u003cem\u003ei\u003c/em\u003e-PrOH were used as solvents, only moderate yields were obtained albeit the enantioselectivity remained very high (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 8–10). The reaction was inhibited when the reaction was conducted in MeOH or 1,4-dioxane (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 11–12). Next, the bases were screened to evaluate their impact on the DKR process, and the results showed that the bases played an important role in this transformation, and Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e was superior to others in this reaction (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entries 13–18).\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003eWith the optimal conditions in hand, the substrate scope of this transformation was investigated and the results were summarized in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Gratifyingly, the reaction has a broad substrate scope and exhibits good tolerance to a variety of functional groups, such as alkyl (Me, Et, \u003cstrong\u003e2d, 2e\u003c/strong\u003e), alkoxyl (MeO, \u003cstrong\u003e2k\u003c/strong\u003e), aryl (Ph, \u003cstrong\u003e2d\u003c/strong\u003e), halides (F, Cl, Br, \u003cstrong\u003e2g\u003c/strong\u003e-\u003cstrong\u003e2i\u003c/strong\u003e), trifluoromethyl (\u003cstrong\u003e2j\u003c/strong\u003e), and amino group (\u003cstrong\u003e2ab\u003c/strong\u003e). Moreover, the reaction was not affected by the electronic properties and the position of substituents on the benzene ring (\u003cem\u003epara\u003c/em\u003e, \u003cem\u003emeta\u003c/em\u003e and \u003cem\u003eortho\u003c/em\u003e), 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 (\u003cstrong\u003e2s\u003c/strong\u003e, \u003cstrong\u003e2t\u003c/strong\u003e). Substrates containing other aromatic fragments, such as 2-naphthyl, and 2-thienyl, were also successfully compatible in this transformation (\u003cstrong\u003e2u\u003c/strong\u003e, \u003cstrong\u003e2v\u003c/strong\u003e). To our delight, the sequential DKR of unsymmetrical 2,3-diamino-1,4-diones, 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 (\u003cstrong\u003e2w\u003c/strong\u003e-\u003cstrong\u003e2ah\u003c/strong\u003e). Alkyl substituted substrate was also compatible in this reaction, affording target product \u003cstrong\u003e2ai\u003c/strong\u003e in high yields with excellent enantioselectivities, which demonstrates the good compatibility of this catalytic system(see Supporting Information for more details). 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 \u003cstrong\u003e2h\u003c/strong\u003e was unambiguously determined as (1\u003cem\u003eR\u003c/em\u003e, 2\u003cem\u003eS\u003c/em\u003e, 3\u003cem\u003eS\u003c/em\u003e, 4\u003cem\u003eR\u003c/em\u003e) by X-ray crystallography.\u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003eTo 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 \u003cstrong\u003e2a\u003c/strong\u003e without any loss in yield and enantioselectivity (98% yield, 99% ee, Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e \u003cstrong\u003e− 1\u003c/strong\u003e), which indicated that this methodology has potential practical uses. Subsequently, the applications of \u003cstrong\u003e2a\u003c/strong\u003e in organic synthesis were investigated. The Boc protecting group of \u003cstrong\u003e2a\u003c/strong\u003e can be easily removed in the presence of TFA, affording free \u003cem\u003eα\u003c/em\u003e-hydroxy vicinal diamines \u003cstrong\u003e3\u003c/strong\u003e in quantitative yield (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e-\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). The Dess-Martin regent enabled oxidation of \u003cstrong\u003e2a\u003c/strong\u003e proceeded smoothly at room temperature, delivering valuable chiral (\u003cem\u003eS\u003c/em\u003e)-\u003cstrong\u003e1a\u003c/strong\u003e in quantitative yield without any erosion in enantioselectivity (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e-\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). In the presence of sodium hydride, \u003cstrong\u003e2a\u003c/strong\u003e can be easily transformed into a novel dioxazolidinone \u003cstrong\u003e4\u003c/strong\u003e in 90% yield (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e-\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec). Treatment of substrate \u003cstrong\u003e2a\u003c/strong\u003e with LiAlH₄ leads to the formation of product \u003cstrong\u003e5\u003c/strong\u003e through reduction. In addition, compound \u003cstrong\u003e6\u003c/strong\u003e, a bisoxazoline ligand with a novel structure, can be efficiently prepared by treating \u003cstrong\u003e2c\u003c/strong\u003e with DAST at -78 ℃ (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e-\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ee).\u003c/p\u003e\n\u003cp\u003eTo 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. It was observed that the ratio of \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003e1a\u003c/strong\u003e to \u003cem\u003edl\u003c/em\u003e-\u003cstrong\u003e1a\u003c/strong\u003e was gradually increased in the presence of 5 mol% Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e at room temperature, reaching an equilibrium when the ratio of \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003e1a\u003c/strong\u003e to \u003cem\u003edl\u003c/em\u003e\u003cstrong\u003e-1a\u003c/strong\u003e was 17: 83 (see supporting information). Subsequently, the change of product distribution with reaction time was investigated. As shown in Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e, the ratio of \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003e1a\u003c/strong\u003e increased slightly in the first three hours before gradually decreasing. Concurrently, (\u003cem\u003eS,S\u003c/em\u003e)-\u003cstrong\u003e1a\u003c/strong\u003e was gradually decreased along with the reaction time, while there was almost no consumption for (\u003cem\u003eR\u003c/em\u003e,\u003cem\u003eR\u003c/em\u003e)-\u003cstrong\u003e1a\u003c/strong\u003e in the first three hours, which indicates that (\u003cem\u003eS,S\u003c/em\u003e)-\u003cstrong\u003e1a\u003c/strong\u003e, as the matched substrate, was preferentially hydrogenated in this transformation. The mono-reduction products \u003cstrong\u003e6\u003c/strong\u003e increased gradually until their consumption exceeded their production. Interestingly, the kinetic resolution of \u003cem\u003edl\u003c/em\u003e-\u003cstrong\u003e1a\u003c/strong\u003e was detected in the mono-reduction process, and the ee value of \u003cstrong\u003e1a\u003c/strong\u003e gradually increased with reaction time, and the highest ee value of \u003cstrong\u003e1a\u003c/strong\u003e was obtained after 7 hours of reaction. It’s worth noting that the double DKR of \u003cstrong\u003e1a\u003c/strong\u003e is a stepwise process, and the the second DKR process was completed after 12 hours, affording the single chiral product \u003cstrong\u003e2a\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eIn conclusion, we have developed Ir/\u003cem\u003ef\u003c/em\u003e-PNNO complex enabled asymmetric hydrogenation of the mixture of racemic 2,3-diamine-1,4-diones, affording chiral 2,3-diamine-1,4-diols in high yields and excellent stereoselectivities. The mechanism studies revealed that a stepwise dynamic kinetic resolution were 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 are undergoing in our lab.\u003c/p\u003e\n\n"},{"header":"Methods","content":"\u003cp\u003eTo a 4.0 mL vial was added the catalyst precursor [Ir(COD)Cl]\u003csub\u003e2\u003c/sub\u003e (3.3 mg, 5 ×10\u003csup\u003e− 3\u003c/sup\u003e mmol, 1.0 eq.), (\u003cem\u003eS\u003c/em\u003e\u003csub\u003e\u003cem\u003eC\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003eS\u003c/em\u003e\u003csub\u003e\u003cem\u003eC\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003eR\u003c/em\u003e\u003csub\u003e\u003cem\u003eFC\u003c/em\u003e\u003c/sub\u003e)-\u003cstrong\u003eL6\u003c/strong\u003e (6.3 mg, 1.1 ×10\u003csup\u003e− 2\u003c/sup\u003emmol, 2.2 eq.) and anhydrous \u003cem\u003ei-\u003c/em\u003ePrOH (1.0 mL) in the argon-filled glovebox. The mixture was stirred for 1.0 h at 25 ℃. The resulting orange solution (50 µL) was transferred by syringe into a vial (5.0 mL) charged with substrate (0.05 mmol), Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (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 H\u003csub\u003e2\u003c/sub\u003e (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 (CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e/MeOH, 10:1) to afford the product.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability.\u003c/strong\u003e 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 Centre (CCDC), under deposition numbers CCDC 2034549 (\u003cstrong\u003e2h\u003c/strong\u003e). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH. Lv directed the project. H. Lv contributed to the concept and design of the experiments. J. Yan gave valuable advice for this project. J. Ma performed the experiments and data analysis. J. Ma wrote the manuscript with feedback and guidance from H. Lv. All authors discussed the experimental results and commented on the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe 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).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting financial interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial or non-financial interests.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEppe, G., Didier, D. \u0026amp; Marek, I. Stereocontrolled Formation of Several Carbon\u0026ndash;Carbon Bonds in Acyclic Systems. \u003cem\u003eChem. 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Catal. \u003c/em\u003e\u003cstrong\u003e3\u003c/strong\u003e, 175\u0026ndash;178 (2022).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7047584/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7047584/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Ir/\u003cem\u003ef\u003c/em\u003e-PNNO complex catalyzed sequential dynamic kinetic resolution (DKR) of 2,3-diamino-1,4-diones has been successfully achieved, yielding acyclic vicinal diamines with four contiguous stereocenters in high yields and excellent diastereo- and enantioselectivity (\u0026gt; 20:1 dr and \u0026gt; 99% ee). This method exhibits a wide substrate scope and high efficiency, rendering it valuable for synthesizing functionalized chiral vicinal diamines. A gram-scale reaction performed with high efficiency at just 0.1 mol% catalyst loading, along with successful product derivatization, demonstrated the synthetic utility of this methodology. Mechanistic studies revealed that a stepwise DKR process was involved in this transformation.\u003c/p\u003e","manuscriptTitle":"Efficient Synthesis of Chiral Vicinal Diamines with Four Contiguous Stereocenters via Sequential Dynamic Kinetic Resolution of 2,3-Diamino-1,4-diones","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 05:56:52","doi":"10.21203/rs.3.rs-7047584/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"31161ed2-6c32-4850-a25e-bcc87bb76db1","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51477529,"name":"Physical sciences/Chemistry/Chemical synthesis/Asymmetric synthesis"},{"id":51477530,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-01-22T08:10:33+00:00","versionOfRecord":{"articleIdentity":"rs-7047584","link":"https://doi.org/10.1038/s41467-025-67526-6","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2026-01-09 05:00:00","publishedOnDateReadable":"January 9th, 2026"},"versionCreatedAt":"2025-08-06 05:56:52","video":"","vorDoi":"10.1038/s41467-025-67526-6","vorDoiUrl":"https://doi.org/10.1038/s41467-025-67526-6","workflowStages":[]},"version":"v1","identity":"rs-7047584","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7047584","identity":"rs-7047584","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}