Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer

Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer | 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 Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer Yu Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8609924/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Chiral spirocycles exhibit tremendous potential in drug discovery and asymmetric synthesis, owing to their unique three-dimensional rigid framework and superior stability. However, stereoselective construction of polycyclic spiro compounds through a single catalytic transformation remains significant and enduring challenge, owing to steric hindrance and electronic effects. Here we report a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade Heck/Tsuji–Trost dearomative spiroannulation of racemic phenolic biaryls with 1,3-cyclohexadienes via transient axial-to-point chirality induction and transfer. A variety of valuable polycyclic spiro enones bearing three contiguous tertiary/quaternary stereocenters were afforded with excellent regio-, diastereo- and enantioselectivity. Moreover, in vitro experiments suggested that these multifunctional spiro enones have the potential to be lead compounds for anti-inflammatory drugs. Earth and environmental sciences/Environmental sciences/Environmental chemistry/Geochemistry Biological sciences/Biochemistry/Biogeochemistry/Carbon cycle Introduction Chiral spiro scaffolds are important privileged structures in natural products, bioactive molecules, and chiral catalysts. 1-7 They offer the advantage of unique (C)sp 3 -rich three-dimensional rigid scaffolds and excellent chemical stability. Over the past two decades, owing to their profound importance, significant efforts have been devoted to developing catalytic asymmetric synthesis strategies. 8-14 However, one-step catalytic asymmetric construction of chiral polycyclic spiro compounds remains so far largely underdeveloped despite their high value ( Scheme 1A ). Probably due to the interactions between substituents at adjacent chiral centers through steric hindrance and electronic effects 15-17 , it is challenging to simultaneously control multiple stereocenters and achieve polycyclic assembly in a single catalytic system. Consequently, the development of general and efficient strategies for the stereoselective synthesis of polycyclic spiro scaffolds bearing multiple contiguous stereocenters from readily available starting materials is highly attractive and challenging. 18-21 Asymmetric transient axial chirality transfer strategy 22- 23 offers an efficient and streamlined approach for accessing spiro quaternary carbon stereocenters. 16 In this catalytic process, racemic or prochiral arenes undergo a well-defined dynamic sequence of axial chirality formation, loss, and transfer ( Scheme 1B ). Since Luan 24 and You 25 independently reported back-to-back pivotal milestones in 2015, the asymmetric formal spiroannulation has emerged as an indispensable tool for stereoselective construction of chiral spirocycles via transient axial-to-point chirality transfer. 26-33 Specifically, Xu and colleagues demonstrated the first successful example of a catalytic chirality transfer strategy featuring transient axially chiral styrene intermediates. 34 Zhou and co-workers systematically established a palladium/chiral norbornene cooperative catalytic system, relying on transient axial-to-central chirality transfer through an intramolecular termination pathway. 35-37 We envision synergizing the dual capabilities of stereoinduction and chirality transfer from transient chiral intermediates to sequentially assemble multiple chiral centers in a single catalytic cycle. If successful, this strategy may open a new avenue for the asymmetric synthesis of multi-chiral-center spirocyclic compounds. As part of our long-standing expertise in Sadphos-enabled asymmetric domino annulation reactions, 38-45 we herein disclose the dynamic kinetic asymmetric cascade dearomative Heck/Tsuji−Trost reaction of racemic biaryls 1 with cyclic dienes 2 , which stereospecifically furnishes enantioenriched polycyclic spiro enones 46,4 7 via transient axial-to-point chirality induction and transfer ( Scheme 1C ). Several key challenges need to be addressed for this transformation: (1) precise control over enantio- and diastereoselectivity via traisient stereoinduction and chirality transfer; (2) suppression of unwanted 1,4-palladium migration in arylpalladium intermediates Pd-1 , which can form from o -iodobiaryls via a Heck-type reaction; 48 (3) inhibition of unwanted β -hydride elimination to avoid the Heck byproduct. 49-51 We hypothesize that the chiral ligand is the key to overcoming these challenges. Results To validate this hypothesis, we initiated our investigation into the dynamic kinetic asymmetric dearomative Heck/Tsuji−Trost reaction of racemic phenolic biaryls 1a with cyclic 1,3-diene 2a by using Pd 2 (dba) 3 as a precatalyst and K 2 HPO 4 as the base in mesitylene at 60 o C. Full optimization of the reaction conditions is provided in the Supplementary information (SI), with key findings presented in Table 1 . A series of commercially available privileged ligands (representative chiral C 2 -symmetric bisphosphine ligand L1 , DACH-Ph Trost ligand L2 , N,N-bidentate bisoxazoline ligand L3 , and monodentate chiral phosphoramidite ligands L4 − L5 ), which have also shown good performance in π -allylpalladium chemistry, were first investigated. Unfortunately, none of them delivered 3aa in satisfactory yields, and only very poor enantiocontrol was achieved in each case ( Table 1 and SI, Fig. S1 for details). Furthermore, this domino Si -face-selective spiroannulation occurs chemo-, regio-, and enantioselectively at the less-hindered olefin of dienes 2 , and no other possible regioisomers were detected by 1 H NMR analysis. Additionally, unconsumed 1a was consistently recovered as a racemic mixture when the reaction of 1a and 2a was conducted. To our delight, chiral sulfinamide phosphine ligands Sadphos family ( PC-Phos, PC1 - PC5 ), developed by our group and characterized by non- C2 symmetry, tunable structure, easy availability, and adaptive coordination, turned out to be superior in terms of both efficiency and selectivity for this transformation. Inspired by previous findings that tuning the electronic nature of the backbone could affect the catalytic activity and enantioselectivity, 40 we synthesized a new ligand PC4 bearing an electron-donating group on the xanthene backbone and subjected it to the reaction, the enantioselectivity increased from 92% to 96% ee. Subsequently, the best- performing ligand PC4 was further optimized with respect to other reaction parameters, including catalyst precursor, solvent, catalyst loading, and control experiments. Nevertheless, this optimization did not yield performance superior to that under the standard conditions. (see Table 1B, entries 1−14 and SI, Fig. S2 ). With the optimal reaction conditions in hand, we investigated the substrate scope using various racemic phenolic biaryls 1 and conjugated dienes 2 ( Table 2 ). A variety of phenol-based biaryl substrates 1 reacted smoothly under the spiroannulation conditions, affording spirocyclic molecules 3 and 4 in moderate to high yields with excellent enantioselectivities. Notably, the electron-donating (methoxyl, trifluoromethoxy, methyl), electron-withdrawing (trifluoromethyl, methoxycarbonyl), and halide (fluoro, chloro) groups substituted at various positions of the phenyl ring were compatible, delivering products 3aa − 3an in good to high yields with 81–98% ee . Moreover, cyclic 1,3-diene 2 can be easily synthesized through the 1,4-dehydration of allylic alcohols. The applicability of this protocol to a wide range of substituents and functional groups on dienes 2 was explored, providing the corresponding products 3ba − 3by in comparable efficiency and selectivity. For example, substituents including fluoro, chloro, methyl, phenyl, methoxyl, methylthio, trimethylsilyl, trifluoromethoxy, and trifluoromethyl on the aryl moiety of 1-aryl-cyclohexadienes 2 are well-tolerated, affording the desired spirocyclic products 3ba – 3bo in 60–85% yields with 84–99% ee. The configuration of product 3bh has been established as ( R,R,S ) by X-ray crystallographic analysis (CCDC 2422360). It's supposed that the Pd/Sadphos catalyst system can preferentially undergo oxidative addition with ( Sa )- 1 , following a domino Si -face-selective spiroannulation. 24 Moreover, 2-naphthyl, dioxaphthyl, 6-benzofuryl, 6-benzothienyl, 3-thienyl, benzyl, n -butyl, and cyclohexyl derived cyclohexadienes 2 and cyclohexadiene could also produce 3bp – 3bx in good yields with 91−97% ee as single regioisomer and diastereomer. Additionally, acyclic 1,3-dienes with a phenyl substituent at the terminal position, which exhibit relatively lower reactivity compared to cyclic dienes, can also undergo the dynamic kinetic cascade reaction. This reaction yields compound 3by in 52% yield with 32% ee , suggesting that new ligands should be screened. With the pharmaceutical derivatives ( L -Menthol, L -Borneol, and L -Perillyl alcohol) as dienes, the desired products 4a − 4c could be obtained in moderate yields with excellent diastereoselectivity. To demonstrate the practical utility of our protocol, a gram-scale reaction was carried out under standard reaction conditions, furnishing 1.2 g of 3aa in 63% yield with 96% ee ( Table 3A ). The presence of unsaturations in the spirocyclic scaffold provides a handle for further divergent manipulations ( Table 3B ). For instance, the selective Luche reduction of 3aa in the presence of NaBH 4 afforded the alcohol 5 in 52% yield with 96% ee and was followed by treatment with p -toluenesulfonic acid (TsOH), delivering the rearranged product 6 in 47% yield with 93% ee. The selective epoxidation of the two olefin moieties of 3aa with m -CPBA delivered the target epoxide 7 in 55% yield with 96% ee. In light of the structures of the chiral Pd/Sadphos catalyst 5 2 and the ( R,R,S )-spiro enones 3 , a possible catalytic chirality induction model was proposed for the reaction ( Table 3C ). The atroposelective O.A. of rapidly racemizing biaryls 1 with the Pd/Sadphos catalytic complex proceeds. 53 This stereocontrol is achieved by PC4 , which bears a 4-(trifluoromethyl)phenyl group and effectively discriminates the enantiotopic faces of 1 's phenolic ring, thus differentiating the formation rates of axially chiral intermediates ( Sa )- Pd-1 and ( Ra )- Pd-1 . Consequently, syn -migratory insertion of dienes 2 into the C−Pd bond and subsequent intramolecular nucleophilic attack occur exclusively at the Si -face of the alkene moiety, driven by the transient axial-to-point chirality induction and transfer, thus affording the cis -configured spiroannulated product 3 with high diastereo- and enantioselectivity. On the other hand, natural products and small molecules containing conjugated cycloenone skeletons have demonstrated broad anti-inflammatory activity, 54,55 yet the anti-inflammatory effects of these newly synthesized spiro enones derivatives 3 ( Scheme 2 ) remain underexplored. Notably, the increased pro-inflammatory cytokine production in RAW 264.7 cells has been implicated as the key mediators in the inflammation response. 56 To evaluate the anti-inflammatory effects of the spiro enones 3 in vitro, enzyme-linked immunosorbent assay (ELISA) kits were employed to investigate their effects on the lipopolysaccharide (LPS)–induced pro-inflammatory cytokine production in RAW 264.7 cells. Following treatment of RAW 264.7 cells with spiro enones 3 (20 and 50 µM) and stimulated by LPS, the levels of two main pro-inflammation cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were reduced. Collectively, these results indicate that the five derivatives ( 3ac , 3ah , 3am, 3ao , and 3bb ) of spiro enones 3 may serve as promising novel inflammatory inhibitors. Discussion In summary, we have developed a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade dearomative Heck/Tsuji−Trost reaction of racemic phenolic biaryls with 1,3-cyclohexadienes via the transient axial-to-point chirality induction and transfer, which provides a promising tool for the modular synthesis of enantioenriched spiro enones with three contiguous tertiary/quaternary stereocenters and intrinsic anti-inflammatory activity. The chiral sulfinamide phosphine (Sadphos) ligand plays a pivotal role in regulating the selectivity and catalytic activity of this domino Si -face-selective spiroannulation. Further studies include expanding the application of Sadphos in asymmetric metal catalysis, especially in more challenging asymmetric cascade reactions, via the synergistic effect of stereoinduction and chirality transfer. Methods General procedure for the synthesis of 3 and 4 Under argon atmosphere, to an oven-dried 10 mL Schlenk tube equipped with a magnetic stir bar were added Pd 2 (dba) 3 (5 mol%, Energy Chemical ), Sadphos (20 mol%, PC4 ), K 2 HPO 4 (2.0 equiv), and mesitylene (1.5 mL). The catalyst, ligand and base in solution were stirred for 1 h at room temperature. After 1 h, racemic biaryl 1 (0.3 mmol, 1.0 equiv) and 1,3-dienes 2 (3.0 equiv) were added sequentially. The resulting mixture was then stirred vigorously (550 rpm) at 60 o C in oil bath for about 96–108 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to afford the desired product 3 and 4 . Declarations Data availability All data supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2422360 ( 3bh ). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. Data relating to the characterization data of materials and products, general methods, optimization studies, experimental procedures,mechanistic studies, and NMR spectra are available in the Supplementary information. All data are also available from the corresponding author upon request. Acknowledgements We gratefully acknowledge the funding support of National Key R&D Program of China (Grant 2021YFF0701600) to J.Z., the National Natural Science Foundation of China (Grants 22401293, 22371019, 22031004 and 21921003) to P.-C.Z., Y.L. and J.Z., the Shanghai Municipal Education Commission (Grant 20212308) to J.Z., and the School Youth Initiation Foundation (Grant 2023QN024) to P.-C.Z.. We greatly appreciate Yanfei Niu and Prof. Xiaoli Zhao at East China Normal University for their kind help with X-ray single-crystal structural analysis. Author contributions P.-C.Z., J.Z., and Y.L. conceived the project, analyzed the data, and wrote the paper. Q.W. and P.-C.Z., performed most of experiments. M.-H.H. and W.-W.Z. helped with the synthesis of substrates. All authors discussed the results and commented on the paper. Competing interests The authors declare no competing interests. Corresponding Author P.-C. Zhang: [email protected] Y. Liu: [email protected] J. 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Background and reaction development. A) Chiral polycyclic spiro enones as a privileged motif in functional molecules B) Transient axial-to-point chirality transfer strategy of racemic or prochiral arenes. C) Transition-metal-catalyzed cascade Heck/Tsuji–Trost reaction D) Dynamic kinetic asymmetric cascade dearomative Heck/Tsuji–Trost reaction. scheme2.jpg Scheme 2. The Effect of 3 on Pro-inflammatory Cytokine Secretion in Vitro. Cite Share Download PDF Status: Under Review 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. 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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-8609924","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":582377376,"identity":"f2b178f0-7a4b-4110-a16f-2c53b5141101","order_by":0,"name":"Yu Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtUlEQVRIiWNgGAWjYFAC5oYDDBVQNg9xWhiBWs4AaTZStDAwtpGixeBGYuNh3nl28gb3GxgfvG1jkDcnQkvDYd5tyYYbjjEwG85tYzDc2UCclgMJBscY2KR52xgSDA4QpWUOWAv7bxK0NEBsYSZKi+SZhw0H5xxLNpx5LLFZcs45CcMNhLTwHU8+/OFNjZ083+HDBz+8KbORJ2iLAkIBMIIYGCQIqAcC+QbCakbBKBgFo2CkAwDNRkNzKNpRQwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1304-9498","institution":"Changchun University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Yu","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2026-01-15 11:25:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8609924/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8609924/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101751576,"identity":"9e988c79-1119-421f-9d85-66f9078587a1","added_by":"auto","created_at":"2026-02-03 10:21:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":532354,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8609924/v1/87d1d03f-fd80-4272-8e7f-aa6cfa05614f.pdf"},{"id":101480472,"identity":"c17c3b17-a33c-4cfa-9694-6f90844ad1c2","added_by":"auto","created_at":"2026-01-30 07:58:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32974897,"visible":true,"origin":"","legend":"Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8609924/v1/060e5f3724339d1017b9554f.docx"},{"id":101480471,"identity":"aca1e2bf-e5d6-4b8c-a9b3-50bd470fd825","added_by":"auto","created_at":"2026-01-30 07:58:52","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2757435,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8609924/v1/bca6de7bfcbc8c68d3f0c02d.docx"},{"id":101480468,"identity":"1f4df241-0782-4666-8809-5a05a0f46d3e","added_by":"auto","created_at":"2026-01-30 07:58:52","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":226742,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003e. Background and reaction development. \u003cstrong\u003eA\u003c/strong\u003e) Chiral polycyclic spiro enones as a privileged motif in functional molecules \u003cstrong\u003eB\u003c/strong\u003e) Transient axial-to-point chirality transfer strategy of racemic or prochiral arenes. \u003cstrong\u003eC\u003c/strong\u003e) Transition-metal-catalyzed cascade Heck/Tsuji–Trost reaction \u003cstrong\u003eD\u003c/strong\u003e) Dynamic kinetic asymmetric cascade dearomative Heck/Tsuji–Trost reaction.\u003c/p\u003e","description":"","filename":"scheme1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8609924/v1/31f9e0bae0b290794b2c8895.jpg"},{"id":101480469,"identity":"9c3f0bf5-ee42-4cf7-913d-075a56213cb5","added_by":"auto","created_at":"2026-01-30 07:58:52","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":122005,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2\u003c/strong\u003e. The Effect of \u003cstrong\u003e3\u003c/strong\u003e on Pro-inflammatory Cytokine Secretion in Vitro.\u003c/p\u003e","description":"","filename":"scheme2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8609924/v1/746d7d8f889339ab486eff10.jpg"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChiral spiro scaffolds are important privileged structures in natural products, bioactive molecules, and chiral catalysts.\u003csup\u003e1-7\u003c/sup\u003e They offer the advantage of unique (C)sp\u003csup\u003e3\u003c/sup\u003e-rich three-dimensional rigid scaffolds and excellent chemical stability. Over the past two decades, owing to their profound importance, significant efforts have been devoted to developing catalytic asymmetric synthesis strategies.\u003csup\u003e8-14\u003c/sup\u003e However, one-step catalytic asymmetric construction of chiral polycyclic spiro compounds remains so far largely underdeveloped despite their high value (\u003cstrong\u003eScheme 1A\u003c/strong\u003e). Probably due to the interactions between substituents at adjacent chiral centers through steric hindrance and electronic effects\u003csup\u003e15-17\u003c/sup\u003e, it is challenging to simultaneously control multiple stereocenters and achieve polycyclic assembly in a single catalytic system. Consequently, the development of general and efficient strategies for the stereoselective synthesis of polycyclic spiro scaffolds bearing multiple contiguous stereocenters from readily available starting materials is highly attractive and challenging.\u003csup\u003e18-21\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAsymmetric transient axial chirality transfer strategy\u003csup\u003e22-\u003c/sup\u003e\u003csup\u003e23\u003c/sup\u003e offers an efficient and streamlined approach for accessing spiro quaternary carbon stereocenters.\u003csup\u003e16\u003c/sup\u003e In this catalytic process, racemic or prochiral arenes undergo a well-defined dynamic sequence of axial chirality formation, loss, and transfer (\u003cstrong\u003eScheme 1B\u003c/strong\u003e). Since Luan\u003csup\u003e24\u003c/sup\u003e and You\u003csup\u003e25\u003c/sup\u003e independently reported back-to-back pivotal milestones in 2015, the asymmetric formal spiroannulation has emerged as an indispensable tool for stereoselective construction of chiral spirocycles via transient axial-to-point chirality transfer.\u003csup\u003e26-33\u003c/sup\u003e Specifically, Xu and colleagues demonstrated the first successful example of a catalytic chirality transfer strategy featuring transient axially chiral styrene intermediates.\u003csup\u003e34\u003c/sup\u003e Zhou and co-workers systematically established a palladium/chiral norbornene cooperative catalytic system, relying on transient axial-to-central chirality transfer through an intramolecular termination pathway.\u003csup\u003e35-37\u003c/sup\u003e We envision synergizing the dual capabilities of stereoinduction and chirality transfer from transient chiral intermediates to sequentially assemble multiple chiral centers in a single catalytic cycle. If successful, this strategy may open a new avenue for the asymmetric synthesis of multi-chiral-center spirocyclic compounds. As part of our long-standing expertise in Sadphos-enabled asymmetric domino annulation reactions,\u003csup\u003e38-45\u003c/sup\u003e we herein disclose the dynamic kinetic asymmetric cascade dearomative Heck/Tsuji\u0026minus;Trost reaction of racemic biaryls \u003cstrong\u003e1\u003c/strong\u003e with cyclic dienes \u003cstrong\u003e2\u003c/strong\u003e, which stereospecifically furnishes enantioenriched polycyclic spiro enones\u003csup\u003e46,4\u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e via transient axial-to-point chirality induction and transfer (\u003cstrong\u003eScheme 1C\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eSeveral key challenges need to be addressed for this transformation: (1) precise control over enantio- and diastereoselectivity via traisient stereoinduction and chirality transfer; (2) suppression of unwanted 1,4-palladium migration in arylpalladium intermediates \u003cstrong\u003ePd-1\u003c/strong\u003e, which can form from \u003cem\u003eo\u003c/em\u003e-iodobiaryls via a Heck-type reaction;\u003csup\u003e48\u003c/sup\u003e (3) inhibition of unwanted \u003cem\u003e\u0026beta;\u003c/em\u003e-hydride elimination to avoid the Heck byproduct.\u003csup\u003e49-51\u003c/sup\u003e We hypothesize that the chiral ligand is the key to overcoming these challenges.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTo validate this hypothesis, we initiated our investigation into the dynamic kinetic asymmetric dearomative Heck/Tsuji\u0026minus;Trost reaction of racemic phenolic biaryls \u003cstrong\u003e1a\u003c/strong\u003e with cyclic 1,3-diene \u003cstrong\u003e2a\u003c/strong\u003e by using Pd\u003csub\u003e2\u003c/sub\u003e(dba)\u003csub\u003e3\u003c/sub\u003e as a precatalyst and K\u003csub\u003e2\u003c/sub\u003eHPO\u003csub\u003e4\u003c/sub\u003e as the base in mesitylene at 60 \u003csup\u003eo\u003c/sup\u003eC. Full optimization of the reaction conditions is provided in the Supplementary information (SI), with key findings presented in \u003cstrong\u003eTable 1\u003c/strong\u003e. A series of commercially available privileged ligands (representative chiral \u003cem\u003eC\u003csub\u003e2\u003c/sub\u003e\u003c/em\u003e-symmetric bisphosphine ligand \u003cstrong\u003eL1\u003c/strong\u003e, DACH-Ph Trost ligand \u003cstrong\u003eL2\u003c/strong\u003e, N,N-bidentate bisoxazoline ligand \u003cstrong\u003eL3\u003c/strong\u003e, and monodentate chiral phosphoramidite ligands \u003cstrong\u003eL4\u003c/strong\u003e\u0026minus;\u003cstrong\u003eL5\u003c/strong\u003e), which have also shown good performance in \u003cem\u003e\u0026pi;\u003c/em\u003e-allylpalladium chemistry, were first investigated. Unfortunately, none of them delivered \u003cstrong\u003e3aa\u003c/strong\u003e in satisfactory yields, and only very poor enantiocontrol was achieved in each case (\u003cstrong\u003eTable 1\u003c/strong\u003e and SI,\u003cstrong\u003e\u0026nbsp;Fig. S1\u003c/strong\u003e for details). Furthermore, this domino \u003cem\u003eSi\u003c/em\u003e-face-selective spiroannulation occurs chemo-, regio-, and enantioselectively at the less-hindered olefin of dienes \u003cstrong\u003e2\u003c/strong\u003e, and no other possible regioisomers were detected by \u003csup\u003e1\u003c/sup\u003eH NMR analysis. Additionally, unconsumed \u003cstrong\u003e1a\u003c/strong\u003e was consistently recovered as a racemic mixture when the reaction of \u003cstrong\u003e1a\u003c/strong\u003e and \u003cstrong\u003e2a\u003c/strong\u003e was conducted. To our delight, chiral sulfinamide phosphine ligands Sadphos family (\u003cstrong\u003ePC-Phos, PC1\u003c/strong\u003e-\u003cstrong\u003ePC5\u003c/strong\u003e), developed by our group and characterized by non-\u003cem\u003eC2\u003c/em\u003e symmetry, tunable structure, easy availability, and adaptive coordination, turned out to be superior in terms of both efficiency and selectivity for this transformation. Inspired by previous findings that tuning the electronic nature of the backbone could affect the catalytic activity and enantioselectivity,\u003csup\u003e40\u003c/sup\u003e we synthesized a new ligand \u003cstrong\u003ePC4\u0026nbsp;\u003c/strong\u003ebearing an electron-donating group on the xanthene backbone and subjected it to the reaction, the enantioselectivity increased from 92% to 96% ee. Subsequently, the best- performing ligand \u003cstrong\u003ePC4\u003c/strong\u003e was further optimized with respect to other reaction parameters, including catalyst precursor, solvent, catalyst loading, and control experiments. Nevertheless, this optimization did not yield performance superior to that under the standard conditions. (see \u003cstrong\u003eTable 1B,\u0026nbsp;\u003c/strong\u003eentries 1\u0026minus;14 and \u003cstrong\u003eSI, Fig. S2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWith the optimal reaction conditions in hand, we investigated the substrate scope using various racemic phenolic biaryls \u003cstrong\u003e1\u003c/strong\u003e and conjugated dienes \u003cstrong\u003e2\u003c/strong\u003e (\u003cstrong\u003eTable 2\u003c/strong\u003e). A variety of phenol-based biaryl substrates \u003cstrong\u003e1\u0026nbsp;\u003c/strong\u003ereacted smoothly under the spiroannulation conditions, affording spirocyclic molecules \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e in moderate to high yields with excellent enantioselectivities. Notably, the electron-donating (methoxyl, trifluoromethoxy, methyl), electron-withdrawing (trifluoromethyl, methoxycarbonyl), and halide (fluoro, chloro) groups substituted at various positions of the phenyl ring were compatible, delivering products \u003cstrong\u003e3aa\u003c/strong\u003e\u0026minus;\u003cstrong\u003e3an\u003c/strong\u003e in good to high yields with 81\u0026ndash;98% \u003cem\u003eee\u003c/em\u003e. Moreover, cyclic 1,3-diene \u003cstrong\u003e2\u003c/strong\u003e can be easily synthesized through the 1,4-dehydration of allylic alcohols. The applicability of this protocol to a wide range of substituents and functional groups on dienes \u003cstrong\u003e2\u003c/strong\u003e was explored, providing the corresponding products \u003cstrong\u003e3ba\u003c/strong\u003e\u0026minus;\u003cstrong\u003e3by\u003c/strong\u003e in comparable efficiency and selectivity. For example, substituents including fluoro, chloro, methyl, phenyl, methoxyl, methylthio, trimethylsilyl, trifluoromethoxy, and trifluoromethyl on the aryl moiety of 1-aryl-cyclohexadienes \u003cstrong\u003e2\u003c/strong\u003e are well-tolerated, affording the desired spirocyclic products \u003cstrong\u003e3ba\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e3bo\u003c/strong\u003e in 60\u0026ndash;85% yields with 84\u0026ndash;99% ee. The configuration of product \u003cstrong\u003e3bh\u003c/strong\u003e has been established as (\u003cem\u003eR,R,S\u003c/em\u003e) by X-ray crystallographic analysis (CCDC 2422360). It\u0026apos;s supposed that the Pd/Sadphos catalyst system can preferentially undergo oxidative addition with (\u003cem\u003eSa\u003c/em\u003e)-\u003cstrong\u003e1\u003c/strong\u003e, following a domino \u003cem\u003eSi\u003c/em\u003e-face-selective spiroannulation.\u003csup\u003e24\u003c/sup\u003e Moreover, 2-naphthyl, dioxaphthyl, 6-benzofuryl, 6-benzothienyl, 3-thienyl, benzyl, \u003cem\u003en\u003c/em\u003e-butyl, and cyclohexyl derived cyclohexadienes \u003cstrong\u003e2\u003c/strong\u003e and cyclohexadiene could also produce \u003cstrong\u003e3bp\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e3bx\u003c/strong\u003e in good yields with 91\u0026minus;97% \u003cem\u003eee\u0026nbsp;\u003c/em\u003eas single regioisomer and diastereomer. Additionally, acyclic 1,3-dienes with a phenyl substituent at the terminal position, which exhibit relatively lower reactivity compared to cyclic dienes, can also undergo the dynamic kinetic cascade reaction. This reaction yields compound \u003cstrong\u003e3by\u003c/strong\u003e in 52% yield with 32% \u003cem\u003eee\u003c/em\u003e, suggesting that new ligands should be screened. With the pharmaceutical derivatives (\u003cem\u003eL\u003c/em\u003e-Menthol, \u003cem\u003eL\u003c/em\u003e-Borneol, and \u003cem\u003eL\u003c/em\u003e-Perillyl alcohol) as dienes, the desired products \u003cstrong\u003e4a\u003c/strong\u003e\u0026minus;\u003cstrong\u003e4c\u003c/strong\u003e could be obtained in moderate yields with excellent diastereoselectivity.\u003c/p\u003e\n\u003cp\u003eTo demonstrate the practical utility of our protocol, a gram-scale reaction was carried out under standard reaction conditions, furnishing 1.2 g of \u003cstrong\u003e3aa\u003c/strong\u003e in 63% yield with 96% ee (\u003cstrong\u003eTable 3A\u003c/strong\u003e). The presence of unsaturations in the spirocyclic scaffold provides a handle for further divergent manipulations (\u003cstrong\u003eTable 3B\u003c/strong\u003e). For instance, the selective Luche reduction of \u003cstrong\u003e3aa\u003c/strong\u003e in the presence of NaBH\u003csub\u003e4\u003c/sub\u003e afforded the alcohol \u003cstrong\u003e5\u003c/strong\u003e in 52% yield with 96% ee and was followed by treatment with \u003cem\u003ep\u003c/em\u003e-toluenesulfonic acid (TsOH), delivering the rearranged product \u003cstrong\u003e6\u003c/strong\u003e in 47% yield with 93% ee. The selective epoxidation of the two olefin moieties of \u003cstrong\u003e3aa\u003c/strong\u003e with \u003cem\u003em\u003c/em\u003e-CPBA delivered the target epoxide \u003cstrong\u003e7\u003c/strong\u003e in 55% yield with 96% ee. In light of the structures of the chiral Pd/Sadphos catalyst\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e and the (\u003cem\u003eR,R,S\u003c/em\u003e)-spiro enones \u003cstrong\u003e3\u003c/strong\u003e, a possible catalytic chirality induction model was proposed for the reaction (\u003cstrong\u003eTable 3C\u003c/strong\u003e). The atroposelective O.A. of rapidly racemizing biaryls \u003cstrong\u003e1\u003c/strong\u003e with the Pd/Sadphos catalytic complex proceeds.\u003csup\u003e53\u003c/sup\u003e This stereocontrol is achieved by \u003cstrong\u003ePC4\u003c/strong\u003e, which bears a 4-(trifluoromethyl)phenyl group and effectively discriminates the enantiotopic faces of \u003cstrong\u003e1\u003c/strong\u003e\u0026apos;s phenolic ring, thus differentiating the formation rates of axially chiral intermediates (\u003cem\u003eSa\u003c/em\u003e)-\u003cstrong\u003ePd-1\u003c/strong\u003e and (\u003cem\u003eRa\u003c/em\u003e)-\u003cstrong\u003ePd-1\u003c/strong\u003e. Consequently, \u003cem\u003esyn\u003c/em\u003e-migratory insertion of dienes \u003cstrong\u003e2\u003c/strong\u003e into the C\u0026minus;Pd bond and subsequent intramolecular nucleophilic attack occur exclusively at the \u003cem\u003eSi\u003c/em\u003e-face of the alkene moiety, driven by the transient axial-to-point chirality induction and transfer, thus affording the \u003cem\u003ecis\u003c/em\u003e-configured spiroannulated product \u003cstrong\u003e3\u0026nbsp;\u003c/strong\u003ewith high diastereo- and enantioselectivity. On the other hand, natural products and small molecules containing conjugated cycloenone skeletons have demonstrated broad anti-inflammatory activity,\u003csup\u003e54,55\u003c/sup\u003e yet the anti-inflammatory effects of these newly synthesized spiro enones derivatives \u003cstrong\u003e3\u0026nbsp;\u003c/strong\u003e(\u003cstrong\u003eScheme 2\u003c/strong\u003e) remain underexplored. Notably, the increased pro-inflammatory cytokine production in RAW 264.7 cells has been implicated as the key mediators in the inflammation response.\u003csup\u003e56\u003c/sup\u003e To evaluate the anti-inflammatory effects of the spiro enones \u003cstrong\u003e3\u003c/strong\u003e in vitro, enzyme-linked immunosorbent assay (ELISA) kits were employed to investigate their effects on the lipopolysaccharide (LPS)\u0026ndash;induced pro-inflammatory cytokine production in RAW 264.7 cells. Following treatment of RAW 264.7 cells with spiro enones \u003cstrong\u003e3\u003c/strong\u003e (20 and 50 \u0026micro;M) and stimulated by LPS, the levels of two main pro-inflammation cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-\u0026alpha;), were reduced. Collectively, these results indicate that the five derivatives (\u003cstrong\u003e3ac\u003c/strong\u003e, \u003cstrong\u003e3ah\u003c/strong\u003e, \u003cstrong\u003e3am, 3ao\u003c/strong\u003e, and \u003cstrong\u003e3bb\u003c/strong\u003e) of spiro enones \u003cstrong\u003e3\u003c/strong\u003e may serve as promising novel inflammatory inhibitors.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn summary, we have developed a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade dearomative Heck/Tsuji\u0026minus;Trost reaction of racemic phenolic biaryls with 1,3-cyclohexadienes via the transient axial-to-point chirality induction and transfer, which provides a promising tool for the modular synthesis of enantioenriched spiro enones with three contiguous tertiary/quaternary stereocenters and intrinsic anti-inflammatory activity. The chiral sulfinamide phosphine (Sadphos) ligand plays a pivotal role in regulating the selectivity and catalytic activity of this domino \u003cem\u003eSi\u003c/em\u003e-face-selective spiroannulation. Further studies include expanding the application of Sadphos in asymmetric metal catalysis, especially in more challenging asymmetric cascade reactions, via the synergistic effect of stereoinduction and chirality transfer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eGeneral procedure for the synthesis of 3 and 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnder argon atmosphere, to an oven-dried 10 mL Schlenk tube equipped with a magnetic stir bar were added Pd\u003csub\u003e2\u003c/sub\u003e(dba)\u003csub\u003e3\u003c/sub\u003e (5 mol%, \u003cem\u003eEnergy Chemical\u003c/em\u003e), Sadphos (20 mol%, \u003cstrong\u003ePC4\u003c/strong\u003e), K\u003csub\u003e2\u003c/sub\u003eHPO\u003csub\u003e4\u003c/sub\u003e (2.0 equiv), and mesitylene (1.5 mL). The catalyst, ligand and base in solution were stirred for 1 h at room temperature. After 1 h, racemic\u003cem\u003e\u0026nbsp;\u003c/em\u003ebiaryl \u003cstrong\u003e1\u003c/strong\u003e (0.3 mmol, 1.0 equiv) and 1,3-dienes \u003cstrong\u003e2\u003c/strong\u003e (3.0 equiv) were added sequentially. The resulting mixture was then stirred vigorously (550 rpm) at 60 \u003csup\u003eo\u003c/sup\u003eC in oil bath for about 96\u0026ndash;108 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to afford the desired product \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2422360 (\u003cstrong\u003e3bh\u003c/strong\u003e). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. Data relating to the characterization data of materials and products, general methods, optimization studies, experimental procedures,mechanistic studies, and NMR spectra are available in the Supplementary information. All data are also available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge the funding support of National Key R\u0026amp;D Program of China (Grant 2021YFF0701600) to J.Z., the National Natural Science Foundation of China (Grants 22401293, 22371019, 22031004 and 21921003) to P.-C.Z., Y.L. and J.Z., the Shanghai Municipal Education Commission (Grant 20212308) to J.Z., and the School Youth Initiation Foundation (Grant 2023QN024) to P.-C.Z.. We greatly appreciate Yanfei Niu and Prof. Xiaoli Zhao at East China Normal University for their kind help with X-ray single-crystal structural analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP.-C.Z., J.Z., and Y.L. conceived the project, analyzed the data, and wrote the paper. Q.W. and P.-C.Z., performed most of experiments. M.-H.H. and W.-W.Z. helped with the synthesis of substrates. All authors discussed the results and commented on the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP.-C. Zhang: [email protected]\u003c/p\u003e\n\u003cp\u003eY. Liu: [email protected]\u003c/p\u003e\n\u003cp\u003eJ. Zhang: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChupakhin E, Babich O, Prosekov A, Asyakina L, Krasavin M (2019) Spirocyclic motifs in natural products. Molecules 24:4165\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith LK, Baxendale IR (2015) Total syntheses of natural products containing spirocarbocycles. Org Biomol Chem 13:9907\u0026ndash;9933\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarela MT et al (2025) Spirocyclic compounds as innovative tools in drug discovery for medicinal chemists. Eur J Med Chem 287:117368\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiesinger K, Dar\u0026rsquo;in D, Proschak E, Krasavin M (2021) Spirocyclic Scaffolds in Medicinal Chemistry. J Med Chem 64:150\u0026ndash;183\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe Y-M et al (2023) Recent Progress of Asymmetric Catalysis from a Chinese Perspective. 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Mol Immunol 83:46\u0026ndash;51\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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-8609924/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8609924/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChiral spirocycles exhibit tremendous potential in drug discovery and asymmetric synthesis, owing to their unique three-dimensional rigid framework and superior stability. However, stereoselective construction of polycyclic spiro compounds through a single catalytic transformation remains significant and enduring challenge, owing to steric hindrance and electronic effects. Here we report a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade Heck/Tsuji\u0026ndash;Trost dearomative spiroannulation of racemic phenolic biaryls with 1,3-cyclohexadienes via transient axial-to-point chirality induction and transfer. A variety of valuable polycyclic spiro enones bearing three contiguous tertiary/quaternary stereocenters were afforded with excellent regio-, diastereo- and enantioselectivity. Moreover, in vitro experiments suggested that these multifunctional spiro enones have the potential to be lead compounds for anti-inflammatory drugs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-30 07:58:47","doi":"10.21203/rs.3.rs-8609924/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":"c8ff6328-67dd-4da9-b0ec-de832658aa4b","owner":[],"postedDate":"January 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61958777,"name":"Earth and environmental sciences/Environmental sciences/Environmental chemistry/Geochemistry"},{"id":61958778,"name":"Biological sciences/Biochemistry/Biogeochemistry/Carbon cycle"}],"tags":[],"updatedAt":"2026-03-05T09:15:22+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-30 07:58:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8609924","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8609924","identity":"rs-8609924","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}