Catalyst-Controlled Regiodivergence in Enantioselective Synthesis of Spirocyclic γ-versus δ-Lactams

Catalyst-Controlled Regiodivergence in Enantioselective Synthesis of Spirocyclic γ-versus δ-Lactams | 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 Catalyst-Controlled Regiodivergence in Enantioselective Synthesis of Spirocyclic γ-versus δ-Lactams Qing-Hai Deng, Shao-Hua Wu, Fan Gong, Yang-Bo Bi, Yi-Ze Bai, Cheng Zhong, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8979415/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 We report an unprecedented regiodivergent strategy for the catalytic asymmetric synthesis of enantioenriched spirocyclic γ - and δ -lactams from a single alkyne-tethered β -ketoamide precursor. Critically, simply switching the catalyst system between Cu(I)/Pyrabox and Ni(II)/Box enables precise toggling of the cyclization between 5- exo -dig and 6- endo -dig modes, allowing direct and highly stereoselective access to either γ -lactam or δ -lactam spirocycles, each bearing a challenging quaternary spiro-stereocenter. The method exhibits broad functional group compatibility and allows for gram-scale synthesis. Mechanistic experiments and DFT calculations reveal that regioselectivity arises from the mode of metal coordination or the joint regulation by metal and ligand, whereas stereocontrol is governed by steric hindrance between the ligand and the substrate. This practical and atom-economical approach provides a powerful platform for the divergent synthesis of privileged spirocyclic pharmacophores. 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 Figure 7 Introduction Spirocyclic γ - and δ -lactams are privileged structural motifs widely found in medicinal chemistry and natural products 1–7 . Their rigid spiro-chiral architectures enable precise three-dimensional arrangement of pharmaco-phores, often translating to enhanced target selectivity and metabolic stability 8 . As a result, the strategic integration of spirocyclic architectures has emerged as a cornerstone strategy in contemporary drug discovery paradigms 9–15 . Typical examples include Chaetochalasin A 9,10 , which exhibits antibacterial activity; Fusarisetin A 11 , a pentacyclic fungal metabolite that potently inhibits acinar morphogenesis; antitumor MDM2 inhibitor 12–14 ; and the marine toxin Surugatoxin found in living organisms 15 (Fig. 1 a). Despite the sustained interest in these structural motifs, the asymmetric synthesis of spirocycles remains highly challenging, primarily due to the difficulty in constructing a stereogenic quaternary spiro carbon center 16 . Over the past decade, a series of innovative asymmetric catalysis methods have provided robust platforms for constructing chiral spirocyclic scaffolds 17–19 . In particular, catalytic asymmetric intramolecular nucleophilic addition to alkynes has emerged as a highly important and atom-economical approach for building enantiopure chiral frameworks in modern synthesis 20–23 . However, selectively switching between 5- exo -dig and 6- endo -dig cyclization modes while concurrently achieving high asymmetric induction remains an unsolved challenge. For example, via 5- exo -dig spirocyclization 24–29 , Zhang/You 24 and Jacobsen 25 achieved asymmetric ortho - and para -spirocyclization of alkynyl naphthols with gold catalysis, respectively (Fig. 1 b, method 1 and method 2). Meanwhile, Ye 26 employed chiral phosphoric acids to activate ynamides for a catalytic asymmetric dearomatization (CADA) spirocyclization (Fig. 1 b, method 3). Ye and co-workers 27 also reported silver-catalyzed Conia-ene-type 5- exo -dig spiroannulations to generate enantiopure spirocyclic enones (Fig. 1 b, method 4). In stark contrast, only a few non-asymmetric 6- endo -dig examples have been reported 30–33 , with representative cases including Xiao/Luo’s electrochemical spirocyclization 30 (Fig. 1 c, method 1) and Jia/Liang’s Pd-catalyzed dearomative cycloisomerization 31 (Fig. 1 c, method 2). To the best of our knowledge, a catalytic asymmetric 6- endo -dig spirocyclization has not yet been realized, let alone achieving simultaneous and switchable control over 5- exo - versus 6- endo -dig regioselectivity. According to the revised Baldwin's rules, the 5- exo -dig cyclization is favored over the 6- endo -dig pathway in ionic reactions 34–36 , primarily because nucleophilic attack at the internal alkyne carbon is stabilized by the substituent. In contrast, the 6- endo -dig transition state often experiences unfavorable transannular interactions and a higher entropic barrier 37 . Thus, developing a general catalytic strategy that can switch the cyclization mode of a single alkyne-tethered precursor by simply changing the metal salt and the chiral ligand, while achieving high regioselectivity and exceptional enantioselectivity in both pathways, remains a major unmet synthetic challenge and a key bottleneck for accessing diverse spiro-lactam pharmacophores. Herein, we address this challenge by demonstrating that intentional modulation of the metal catalyst and chiral ligand environment can precisely dictate the cyclization pathway. This strategy enables unprecedented regiodivergence and excellent enantioselectivity for both spirocyclic γ - and δ -lactams from a common alkyne-tethered β -ketoamide precursor. Employing a Cu(I)/Pyrabox catalytic system selectively promotes the kinetically favored 5- exo -dig cyclization to deliver the spiro γ -lactams in high yield with excellent regio- and enantio-selectivities. Strikingly, simply switching to a Ni(II)/bis(oxazoline) catalyst completely redirects the reaction toward the thermodynamically favored but typically difficult 6- endo -dig pathway, affording the isomeric spiro δ -lactams with equally high selectivity and efficiency (Fig. 1 d). Results We employed N -propargyl- β -ketoamide 1a as model substrate to evaluate the regioselectivity and stereoselectivity of the reaction under the conditions of 10 mol % copper salt, 12 mol % ligand in CH 2 Cl 2 at 40°C. Under copper-catalyzed conditions, the reaction proceeded with high regioselectivity to give only the spirocyclic γ -lactam 2 , with no detectable formation of 3 . Initial ligand screening was performed using Cu(MeCN) 4 PF 6 as the metal source and DIPEA as the base (Table 1, entry 1). A range of Box and Pybox ligands afforded 2 with only modest enantioselectivity (Table 1, entries 1–7). Notably, a marked improvement was observed with Pyrabox ligands, which were designed in our laboratory and are applied here in asymmetric catalysis for the first time (Table 1, entries 8–10). Ligand L9 proved optimal, delivering 2 with 76% ee albeit in a moderate 57% yield (Table 1, entry 9). Subsequent optimization of the base identified DABCO as superior to Et₃N or DIPEA, enhancing both the yield and enantioselectivity (Table 1, entries 11–12). Evaluation of copper salts then revealed Cu(MeCN) 4 BF 4 to be the most effective source (Table 1, entries 13–15). A slight increase in the loadings of both the catalyst and the ligand further boosted the isolated yield to 92% while maintaining high enantioselectivity (94% ee) (Table 1, entry 16; see the Supplementary Information for details). With the optimized reaction conditions established, we explored the substrate scope for the copper-catalyzed synthesis of spirocyclic γ -lactams, as illustrated in Fig. 2. A wide array of substituents on the aromatic ring (R¹) were well-tolerated, including electron-withdrawing groups (e.g., -F, -Cl, -Br, -CN, -CF₃), electron-donating groups (e.g., -Me, - t Bu -OMe), phenyl, cyclopropyl and electron-neutral group (H), affording the corresponding products 2 – 21 in high yields (35–97%) and with excellent enantioselectivities (80–96% ee). The process was also compatiblewith disubstituted aryl ring and naphthalene-derived substrates, providing products 22 – 25 , respectively. Interestingly, heteroatom-substituted indanone substrate also yielded the corresponding spirocyclic compound 26 with 84% ee and in high yield (91%). The amide substituents (R) were further investigated. Methyl, ethyl, n -propyl, i -propyl, phenyl, 1-naphthalenemethyl, and t -butyl all participated effectively, yielding the desired spiro-lactams ( 27 – 33 ) with high yields (67–97%) and enantioselectivities (91–96% ee). The absolute configuration of the quaternary spiro-stereocenter in 2 was unambiguously determined to be R by single-crystal X-ray diffraction analysis, and the stereochemistry of all other products was assigned by analogy. Notably, although compound 4 suffered a slight reduction in ee value, optically pure product could be obtained through a single recrystallization. Having established an efficient protocol for synthesizing spirocyclic γ -lactams, we next aimed to achieve catalyst-controlled switching of the reaction pathway toward the complementary 6- endo -dig cyclization. Under the Cu/ L9 catalytic system for γ -lactam formation, only trace amounts of the δ -lactam were detected, suggesting that an alternative catalytic system would be required. We hypothesized that altering the metal center could change the coordination geometry and electronic properties of the catalyst in a way that favors 6- endo -dig pathway. Screening of nickel salts in combination with Box-type ligands successfully enabled the desired reactivity profile (Table 2). Using Ni(ClO 4 ) 2 ●6H 2 O and ligand L4 in toluene with Et₃N as the base at 80°C, the δ -lactam 34 was obtained in 80% yield and 74% ee, while other bases such as DIPEA and LiHMDS showed lower enantioselectivity (Table 2, entries 1–3). Subsequent ligand evaluation identified that L14 was uniquely effective, significantly improving both the yield (87%) and enantioselectivity (86% ee, Table 2, entries 4–8). Examination of various nickel salts confirmed Ni(BF 4 ) 2 ●6H 2 O as optimal with 88% ee (Table 2, entries 9–10). Because product formation involves protonation of a carbanion intermediate, we attempted to add water to facilitate this step, which led to a modest increase in yield (Table 2, entry 11). Further optimization revealed that using ethyl acetate as the solvent afforded the target product in 88% yield and 90% ee (Table 2, entry 12; see the Supplementary Information for details). The scope of this nickel-catalyzed 6- endo -dig cyclization was subsequently investigated under conditions B (Fig. 3). When the amide nitrogen protecting group was methyl, the reaction demonstrated broad functional group tolerance, accommodating a variety of aromatic substituents (R¹), including electron-withdrawing groups (5-Br, 4-Br, 6-Br, 5-Cl, 6-Cl, 5-F, 6-F, 6-CN, 6-CF 3 , 5,6-dichloro), as well as electron-donating groups (5-Me, 4-Me, 6-Me, 5- t Bu, 5-OMe, 6-OMe, 5-allyloxy), phenyl, and cyclopropyl, affording the corresponding spirocyclic δ -lactam products 34 – 52 in good to excellent yields (24–92%) with high enantioselectivities (78–93% ee). Moreover, the protocol was successfully applied to substrates bearing electron-neutral group (H), two electron-donating groups and naphthalene-derived substrates, delivering the corresponding spirocyclic products in good yields with excellent enantiocontrol ( 53 – 57 ). Variation of the amide nitrogen protecting groups were also tolerated, such as ethyl, n -propyl, i -propyl, benzyl ( 3 , 58 – 61 ). The structure and absolute configuration of spirocyclic δ -lactam 34 were unambiguously confirmed by X-ray crystallographic analysis, which established an R configuration at the spiro-carbon center. Notably, optically pure compound 61 could be obtained via a single recrystallization. Moreover, this methodology proved amenable to gram-scale synthesis. Under the optimized conditions, two representative reactions were conducted, affording 2 (0.89 g, 89% yield, 92% ee) and 34 (0.60 g, 60% yield, 90% ee), respectively, without loss of enantioselectivity (Fig. 4a). Furthermore, the synthetic versatility of the obtained γ - and δ -lactams was explored through diverse downstream transformations, which highlighting the potential for late-stage functionalization. Compounds 2 and 34 can be further transformed into the corresponding methylenes derivatives ( 62 , 63 ) under silane reduction, to chiral alcohols ( 64 , 65 ) by sodium borohydride reduction, and to thioamides ( 66 , 67 ) using Lawesson's reagent. The absolute configurations of 64 and 65 were unequivocally assigned by X-ray crystallography. Critically, the excellent enantioselectivity was fully retained throughout these derivatizations (Fig. 4b). Mechanistic investigations To investigate the reaction mechanism, we performed a series of control experiments. The reaction proceeded, even in the presence of radical scavengers such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 1,1-diphenylethylene (DPE), or 2,6-di- tert -butyl-4-methylphenol (BHT), indicating that a radical pathway is unlikely. The observed decrease in the yield of 34 in the presence of TEMPO is likely attributable to catalyst poisoning by TEMPO (Fig. 5a). The ee values of L9 and L14 correlated linearly with the enantioenrichment of the corresponding products, suggesting that in both cyclization modes, the enantiodetermining transition states may involve only a single catalyst (Fig. 5b). Exchanging the respective metals or ligands between standard conditions A and B substantially reduced both the yield and enantioselectivity. These results indicate that for the 5- exo -dig cyclization, regioselectivity is primarily controlled by the metal identity. In contrast, regioselectivity in the 6- endo -dig pathway is co-regulated by both the metal and the ligand. Consequently, the cooperative action of a suitable metal and ligand is essential for the efficient progress of the reaction (Fig. 5c). Under the standard conditions, the carbonyl-free substrate 1ax did not afford any product, underscoring that coordination of the carbonyl group to the metal is crucial for enabling the reaction pathway (Fig. 5d). To gain deeper insight into the reaction mechanism and elucidate the origins of regioselectivity and enantioselectivity, DFT calculations were performed to delineate the critical roles of the metal and ligand. The copper center adopts a tetrahedral coordination geometry, facilitating simultaneous interaction with the substrate’s triple bond and carbanion. Bond formation proceeds via a reductive elimination-like pathway ( IM-I-R ). Enantioselectivity originates from steric interactions between the ethyl group on the ligand and the carbonyl moiety in the substrate ( IM-I-S ). This stereoselectivity mechanism is directly revealed through analysis of the TS-I-R and TS-I-S structures. The transition state TS-I-R is energetically favored by 3.06 kcal/mol over its enantiomer TS-I-S , which accounts for the excellent enantioselectivity observed experimentally (Fig. 6a). Nickel exhibits a strong preference for square planar coordination, in which both the oxygen atom and the triple bond of the substrate simultaneously bind to the nickel center ( IM-II-R ). Due to steric constraints, the N-Ni-N plane of the ligand and the O-Ni-C plane of the substrate adopt a dihedral angle of approximately 50°. As the terminal atom of the triple bond approaches the five-membered ring, geometric reorganization of the substrate reduces steric congestion, leading to a decrease in the dihedral angle to about 30° at the transition state. This more coplanar arrangement stabilizes the square planar geometry of nickel, thereby facilitating the formation of the transition state. Enantiocontrol is governed by steric interactions between the fused ring system of the substrate and the phenyl group-oriented perpendicular to the ligand plane ( IM-II-S ). This mechanism is supported by the relative energies of the key transition states; TS-II-R is more stable than TS-II-S by 1.68 kcal/mol, consistent with the observed enantioselectivity (Fig. 6b). Based on mechanistic investigations and DFT calculations, two plausible reaction pathways are proposed in Fig. 7. The catalytic cycle begins with coordination of a copper ion to a Box ligand, forming the chiral catalyst A . Under basic conditions, A reacts with substrate 1a to afford the Cu L9 -acetylide complex B . This complex then undergoes a 5- exo -dig cyclization to generate the chiral intermediate C . Finally, product 2 is then formed through the protodemetalation of intermediate C , a step that is concomitant with the regeneration of the chiral copper catalyst (Fig. 7a). Similarly, the activation of nickel by ligand L14 generates catalyst D , which is converted to complex E upon sequential deprotonation under basic conditions. E then undergoes a 6- endo -dig cyclization to give chiral intermediate F . Finally, intermediate F undergoes protodemetalation (likely assisted by trace water) to furnish product 3 , with concomitant regeneration of catalyst D (Fig. 7b). Discussion In summary, we have developed an efficient and catalyst-controlled regiodivergent asymmetric cyclization. This method enables the unified synthesis of both spirocyclic γ -lactams and δ -lactams from a single alkyne-tethered β -ketoamide precursor. By rational modulation of the metal-ligand environment, the intrinsic preference for 5- exo -dig cyclization can be overridden to selectively promote the otherwise challenging 6- endo -dig pathway (regioselectivity > 20:1), while maintaining excellent enantioselective control in both manifolds (up to 96% ee for 5- exo -dig and 93% ee for 6- endo -dig). This strategy of switching metals and ligands provides an efficient solution to the long-standing difficulty of simultaneously controlling regio- and stereoselectivity in alkyne-based spirocyclizations. Mechanistic studies, corroborated by DFT calculations, highlight the decisive role of metal coordination geometry in governing regioselectivity and clarify how chiral ligand sterics dictate asymmetric cyclization. The broad functional group tolerance highlights its utility for the rapid diversification of valuable spirocyclic scaffolds from simple precursors. Methods General Procedure for the Synthesis of Racemic Products 2, 4–33. A mixture of CuBH 4 (PPh 3 ) 2 (0.01 mmol, 10 mol %), substrate 1 (0.10 mmol, 1.0 equiv.), K 2 CO 3 (0.15 mmol, 1.5 equiv.) and dry DCM (2 mL) was stirred at 40°C under a nitrogen atmosphere for 18 h. After complete consumption of substrate 1 (as monitored by TLC), the crude product was purified by flash chromatography on silica gel to afford the desired products rac - 2 , rac - 4 - 33 . General Procedure for the Synthesis of Racemic Products 3, 34–61. A mixture of Ni(ClO 4 ) 2 •6H 2 O (0.01 mmol, 10 mol %), ligand (0.012 mmol, 12 mol %) in dry toluene (1 mL) was stirred at 25 o C under a nitrogen atmosphere for 1.5 h. Subsequently, substrate 1 (0.10 mmol, 1.0 equiv.) and Et 3 N (0.15 mmol, 1.5 equiv.) and H 2 O (5 µL) and additional toluene (1 mL) were added. The reaction mixture was then stirred at 80 o C under a nitrogen atmosphere. After three days, substrate 1 had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products rac - 3 , rac - 34 - 61 . General Procedure for the Synthesis of Chiral Products 2, 4–33. A mixture of Cu(MeCN) 4 BF 4 (0.015 mmol, 15 mol %), ligand (0.018 mmol, 18 mol %) in dry DCM (1 mL) was stirred at 25 o C under a nitrogen atmosphere for 1.5 h. Subsequently, substrate 1 (0.10 mmol, 1.0 equiv.) and DABCO (0.15 mmol, 1.5 equiv.) and additional dry DCM (1 mL) were added. The reaction mixture was then stirred at 40 o C under nitrogen. After 18 h, substrate 1 had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products 2 , 4 – 33 . General Procedure for the Synthesis of Chiral Products 3, 34–61. A mixture of Ni(BF 4 ) 2 •6H 2 O (0.01 mmol, 10 mol %), ligand (0.012 mmol, 12 mol %) in dry EtOAc (1 mL) was stirred at 25 o C under a nitrogen atmosphere for 1.5 h. Subsequently, substrate 1 (0.10 mmol, 1.0 equiv.) and Et 3 N (0.15 mmol, 1.0 equiv.) and H 2 O (5 µL) and dry EtOAc (1 mL) were added. The reaction mixture was then stirred at 80 o C under nitrogen. After three days, substrate 1 had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products 3 , 34 – 61 . Declarations Data availability All data for the replication of this work are given in the supplementary information or can be obtained by the lead contact upon reasonable request. Acknowledgements We are grateful for the financial support from the Shuguang program (20SG44) from Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the National Natural Science Foundation of China (22371187, 22501184), the Natural Science Foundation of Shanghai (22ZR1445200, 25ZR1402406), the Chinese Education Ministry Key Laboratory and International Joint Laboratory on Resource Chemistry, the “111” Innovation and Talent Recruitment Base on Photochemical and Energy Materials (D18020), the Shanghai Engineering Research Center of Green Energy Chemical Engineering (18DZ2254200), and the State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials (2026PT0022). Author Contributions Z.C. and Q.-H.D. conceived and directed the project. S.-H.W. conducted most of the experiments including the synthesis of the ligands and substrates. F.G., Y.-B.B. and Y.-Z.B. synthesized some substrates. S.-H.W. drafted the Supplementary Information. 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J Am Chem Soc 133:12608–12623 Alabugin IV, Gilmore K (2013) Finding the right path: Baldwin ‘‘rules for ring closure’’ and stereoelectronic control of cyclizations. Chem Commun 49:11246–11250 Hack D, Blümel M, Chauhan P, Philipps AR, Enders D (2015) Catalytic Conia-ene and related reactions. Chem Soc Rev 44:6059–6093 Tables Tables are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files WSHSpirolactamsSl.pdf Supplementary Information 2.cif CIF of compound 2 34.cif CIF of compound 34 64.cif CIF of compound 64 65.cif CIF of compound 65 Tables.docx 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. 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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-8979415","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":599106146,"identity":"373affcd-ad53-40e6-b6c9-eaa16959a9cf","order_by":0,"name":"Qing-Hai 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University","correspondingAuthor":false,"prefix":"","firstName":"Shao-Hua","middleName":"","lastName":"Wu","suffix":""},{"id":599106148,"identity":"9f2ca6fc-ce3b-4682-8331-0abb16109203","order_by":2,"name":"Fan Gong","email":"","orcid":"","institution":"Shanghai Normal University","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Gong","suffix":""},{"id":599106149,"identity":"7cf432e5-73ac-4d7d-a2a9-f22dc0f63d21","order_by":3,"name":"Yang-Bo Bi","email":"","orcid":"","institution":"Shanghai Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yang-Bo","middleName":"","lastName":"Bi","suffix":""},{"id":599106150,"identity":"9baeb7e1-c853-47fc-b5b5-6b5a330665dc","order_by":4,"name":"Yi-Ze Bai","email":"","orcid":"","institution":"Shanghai Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yi-Ze","middleName":"","lastName":"Bai","suffix":""},{"id":599106151,"identity":"f68164f6-f3a5-4658-9d89-afb3729d6a3e","order_by":5,"name":"Cheng Zhong","email":"","orcid":"","institution":"Wuhan university","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Zhong","suffix":""},{"id":599106152,"identity":"2fb5e446-fe23-4e57-b85c-3d4f7870cc87","order_by":6,"name":"Zhu Cao","email":"","orcid":"","institution":"Shanghai Normal University","correspondingAuthor":false,"prefix":"","firstName":"Zhu","middleName":"","lastName":"Cao","suffix":""}],"badges":[],"createdAt":"2026-02-26 15:21:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8979415/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8979415/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103826727,"identity":"118b240d-7f4a-47b1-8908-19ae43bdf1d2","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":570898,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStrategies for synthesizing \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eγ\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-lactams and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eδ\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-lactams by switching different metal complexes.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/6253c8c79562f1e4fdbabb49.png"},{"id":103826728,"identity":"faa2106f-cca7-41f6-8a21-41fffb5fcceb","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":433206,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope for the synthesis of spirocyclic \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eγ\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-lactams. \u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003cstrong\u003e1\u003c/strong\u003e (0.20 mmol), Cu(MeCN)\u003csub\u003e4\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e (15 mol %), \u003cstrong\u003eL9\u003c/strong\u003e (18 mol %), DABCO (1.5 equiv.) in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (2 mL) at 40 \u003csup\u003eo\u003c/sup\u003eC for 18 h. \u003csup\u003eb\u003c/sup\u003eAfter a single recrystallization from CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e and petroleum ether. \u003csup\u003ec\u003c/sup\u003eDIPEA instead of DABCO.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/cc5aaba0e913a93982029fab.png"},{"id":103826740,"identity":"df604fcf-ac48-4298-822a-53e44c8f7e32","added_by":"auto","created_at":"2026-03-03 11:44:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":393721,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope for the synthesis of spirocyclic \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eδ\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-lactams.\u003c/strong\u003e \u003csup\u003ea\u003c/sup\u003e\u003cstrong\u003e1\u003c/strong\u003e (0.20 mmol), Ni(BF\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e–6H\u003csub\u003e2\u003c/sub\u003eO (10 mol %), \u003cstrong\u003eL14\u003c/strong\u003e (12 mol %), H\u003csub\u003e2\u003c/sub\u003eO (5 µL), Et\u003csub\u003e3\u003c/sub\u003eN (1.0 equiv.) in EtOAc (2 mL) at 80 \u003csup\u003eo\u003c/sup\u003eC for 3-5 d. \u003csup\u003eb\u003c/sup\u003ePhCF\u003csub\u003e3\u003c/sub\u003e instead of EtOAc. \u003csup\u003ec\u003c/sup\u003eAfter a single recrystallization from CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e and petroleum ether.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/53f1db00d0d1d8c10f207499.png"},{"id":103826729,"identity":"959e48fc-8431-492f-af29-f9be260d363e","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":396396,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGram-scale preparation and synthetic applications.\u003c/strong\u003e \u003csup\u003ea\u003c/sup\u003eReaction conditions: \u003cem\u003eCondition a\u003c/em\u003e: Et\u003csub\u003e3\u003c/sub\u003eSiH, BF\u003csub\u003e3\u003c/sub\u003e–Et\u003csub\u003e2\u003c/sub\u003eO, DCM, 40 \u003csup\u003eo\u003c/sup\u003eC. \u003cem\u003eCondition b\u003c/em\u003e: NaBH\u003csub\u003e4\u003c/sub\u003e, CeCl\u003csub\u003e3\u003c/sub\u003e–7H\u003csub\u003e2\u003c/sub\u003eO, MeOH, 0 \u003csup\u003eo\u003c/sup\u003eC. \u003cem\u003eCondition c\u003c/em\u003e: NaBH\u003csub\u003e4\u003c/sub\u003e, MeOH, 0 \u003csup\u003eo\u003c/sup\u003eC. \u003cem\u003eCondition d\u003c/em\u003e: Lawesson's reagent, toluene, 70 \u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/237f172af2d0a4490bb7e370.png"},{"id":104401100,"identity":"e13bc4d2-8a31-4016-9d00-005f34cac247","added_by":"auto","created_at":"2026-03-11 12:11:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":478234,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic experiments.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/b4ef72ffa492b5a37a7ce6b1.png"},{"id":104400775,"identity":"ca6d6b11-109a-4253-91de-a8a3bad4507e","added_by":"auto","created_at":"2026-03-11 12:10:59","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":489166,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDFT calculations.\u003c/strong\u003eTo gain clearer insight into the structures of \u003cstrong\u003eTS-II-R\u003c/strong\u003e and \u003cstrong\u003eTS-II-S\u003c/strong\u003e, the 4-\u003cem\u003etert\u003c/em\u003e-butylbenzyl groups in Ligand (\u003cstrong\u003eL14\u003c/strong\u003e) were truncated to methyl groups.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/38dadd3a12b55d8a798b394e.png"},{"id":104401229,"identity":"3b74a2c0-ae15-4958-884b-5973281ce7a4","added_by":"auto","created_at":"2026-03-11 12:12:10","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":162274,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed mechanism.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/2734ae9e184b5aaa3742b252.png"},{"id":104408090,"identity":"3fbb65bf-f35d-4484-83c9-bb29dc81444d","added_by":"auto","created_at":"2026-03-11 12:41:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3132197,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/d8c5bc62-548e-4798-acd4-9daa9b964c5b.pdf"},{"id":103826731,"identity":"d906ef20-e75b-4dbd-b3a0-5f7d6fd67a3c","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8846324,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"WSHSpirolactamsSl.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/c3bbae577e9d6ce9325e3406.pdf"},{"id":103826734,"identity":"74d75e76-bc4f-457c-bacb-b8e67d47450d","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"cif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":537264,"visible":true,"origin":"","legend":"CIF of compound 2","description":"","filename":"2.cif","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/16e8c0942ac3e5823c07a695.cif"},{"id":104400882,"identity":"38223dcd-c108-4553-86c7-7f340738a493","added_by":"auto","created_at":"2026-03-11 12:11:20","extension":"cif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":368584,"visible":true,"origin":"","legend":"CIF of compound 34","description":"","filename":"34.cif","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/d9fa7a9a0b67a18593da16a4.cif"},{"id":103826736,"identity":"55375acb-be19-4ce1-ae9f-9182a3a8d682","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"cif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":647825,"visible":true,"origin":"","legend":"CIF of compound 64","description":"","filename":"64.cif","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/ca71544fd6e085d1be96d3ba.cif"},{"id":103826737,"identity":"708562d2-0596-41f1-850b-a50b41e7e7e0","added_by":"auto","created_at":"2026-03-03 11:44:37","extension":"cif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":647097,"visible":true,"origin":"","legend":"CIF of compound 65","description":"","filename":"65.cif","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/e2601d8de3cbbb5fe9f2b031.cif"},{"id":103826735,"identity":"a5fe58fc-8b3d-45b7-b91c-e7d08fcd9cdf","added_by":"auto","created_at":"2026-03-03 11:44:36","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":171966,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8979415/v1/7d009abb8d3290c9c8015c1a.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003eCatalyst-Controlled Regiodivergence in Enantioselective Synthesis of Spirocyclic γ-versus δ-Lactams\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpirocyclic \u003cem\u003eγ\u003c/em\u003e- and \u003cem\u003eδ\u003c/em\u003e-lactams are privileged structural motifs widely found in medicinal chemistry and natural products\u003csup\u003e1\u0026ndash;7\u003c/sup\u003e. Their rigid spiro-chiral architectures enable precise three-dimensional arrangement of pharmaco-phores, often translating to enhanced target selectivity and metabolic stability\u003csup\u003e8\u003c/sup\u003e. As a result, the strategic integration of spirocyclic architectures has emerged as a cornerstone strategy in contemporary drug discovery paradigms\u003csup\u003e9\u0026ndash;15\u003c/sup\u003e. Typical examples include Chaetochalasin A\u003csup\u003e9,10\u003c/sup\u003e, which exhibits antibacterial activity; Fusarisetin A\u003csup\u003e11\u003c/sup\u003e, a pentacyclic fungal metabolite that potently inhibits acinar morphogenesis; antitumor MDM2 inhibitor\u003csup\u003e12\u0026ndash;14\u003c/sup\u003e; and the marine toxin Surugatoxin found in living organisms\u003csup\u003e15\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Despite the sustained interest in these structural motifs, the asymmetric synthesis of spirocycles remains highly challenging, primarily due to the difficulty in constructing a stereogenic quaternary spiro carbon center\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOver the past decade, a series of innovative asymmetric catalysis methods have provided robust platforms for constructing chiral spirocyclic scaffolds\u003csup\u003e17\u0026ndash;19\u003c/sup\u003e. In particular, catalytic asymmetric intramolecular nucleophilic addition to alkynes has emerged as a highly important and atom-economical approach for building enantiopure chiral frameworks in modern synthesis\u003csup\u003e20\u0026ndash;23\u003c/sup\u003e. However, selectively switching between 5-\u003cem\u003eexo\u003c/em\u003e-dig and 6-\u003cem\u003eendo\u003c/em\u003e-dig cyclization modes while concurrently achieving high asymmetric induction remains an unsolved challenge. For example, via 5-\u003cem\u003eexo\u003c/em\u003e-dig spirocyclization\u003csup\u003e24\u0026ndash;29\u003c/sup\u003e, Zhang/You\u003csup\u003e24\u003c/sup\u003e and Jacobsen\u003csup\u003e25\u003c/sup\u003e achieved asymmetric \u003cem\u003eortho\u003c/em\u003e- and \u003cem\u003epara\u003c/em\u003e-spirocyclization of alkynyl naphthols with gold catalysis, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, method 1 and method 2). Meanwhile, Ye\u003csup\u003e26\u003c/sup\u003e employed chiral phosphoric acids to activate ynamides for a catalytic asymmetric dearomatization (CADA) spirocyclization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, method 3). Ye and co-workers\u003csup\u003e27\u003c/sup\u003e also reported silver-catalyzed Conia-ene-type 5-\u003cem\u003eexo\u003c/em\u003e-dig spiroannulations to generate enantiopure spirocyclic enones (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, method 4). In stark contrast, only a few non-asymmetric 6-\u003cem\u003eendo\u003c/em\u003e-dig examples have been reported\u003csup\u003e30\u0026ndash;33\u003c/sup\u003e, with representative cases including Xiao/Luo\u0026rsquo;s electrochemical spirocyclization\u003csup\u003e30\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, method 1) and Jia/Liang\u0026rsquo;s Pd-catalyzed dearomative cycloisomerization\u003csup\u003e31\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, method 2). To the best of our knowledge, a catalytic asymmetric 6-\u003cem\u003eendo\u003c/em\u003e-dig spirocyclization has not yet been realized, let alone achieving simultaneous and switchable control over 5-\u003cem\u003eexo\u003c/em\u003e- versus 6-\u003cem\u003eendo\u003c/em\u003e-dig regioselectivity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAccording to the revised Baldwin's rules, the 5-\u003cem\u003eexo\u003c/em\u003e-dig cyclization is favored over the 6-\u003cem\u003eendo\u003c/em\u003e-dig pathway in ionic reactions\u003csup\u003e34\u0026ndash;36\u003c/sup\u003e, primarily because nucleophilic attack at the internal alkyne carbon is stabilized by the substituent. In contrast, the 6-\u003cem\u003eendo\u003c/em\u003e-dig transition state often experiences unfavorable transannular interactions and a higher entropic barrier\u003csup\u003e37\u003c/sup\u003e. Thus, developing a general catalytic strategy that can switch the cyclization mode of a single alkyne-tethered precursor by simply changing the metal salt and the chiral ligand, while achieving high regioselectivity and exceptional enantioselectivity in both pathways, remains a major unmet synthetic challenge and a key bottleneck for accessing diverse spiro-lactam pharmacophores.\u003c/p\u003e \u003cp\u003eHerein, we address this challenge by demonstrating that intentional modulation of the metal catalyst and chiral ligand environment can precisely dictate the cyclization pathway. This strategy enables unprecedented regiodivergence and excellent enantioselectivity for both spirocyclic \u003cem\u003eγ\u003c/em\u003e- and \u003cem\u003eδ\u003c/em\u003e-lactams from a common alkyne-tethered \u003cem\u003eβ\u003c/em\u003e-ketoamide precursor. Employing a Cu(I)/Pyrabox catalytic system selectively promotes the kinetically favored 5-\u003cem\u003eexo\u003c/em\u003e-dig cyclization to deliver the spiro \u003cem\u003eγ\u003c/em\u003e-lactams in high yield with excellent regio- and enantio-selectivities. Strikingly, simply switching to a Ni(II)/bis(oxazoline) catalyst completely redirects the reaction toward the thermodynamically favored but typically difficult 6-\u003cem\u003eendo\u003c/em\u003e-dig pathway, affording the isomeric spiro \u003cem\u003eδ\u003c/em\u003e-lactams with equally high selectivity and efficiency (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe employed \u003cem\u003eN\u003c/em\u003e-propargyl-\u003cem\u003e\u0026beta;\u003c/em\u003e-ketoamide \u003cstrong\u003e1a\u003c/strong\u003e as model substrate to evaluate the regioselectivity and stereoselectivity of the reaction under the conditions of 10 mol % copper salt, 12 mol % ligand in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e at 40\u0026deg;C. Under copper-catalyzed conditions, the reaction proceeded with high regioselectivity to give only the spirocyclic \u003cem\u003e\u0026gamma;\u003c/em\u003e-lactam \u003cstrong\u003e2\u003c/strong\u003e, with no detectable formation of \u003cstrong\u003e3\u003c/strong\u003e. Initial ligand screening was performed using Cu(MeCN)\u003csub\u003e4\u003c/sub\u003ePF\u003csub\u003e6\u003c/sub\u003e as the metal source and DIPEA as the base (Table 1, entry 1). A range of Box and Pybox ligands afforded \u003cstrong\u003e2\u003c/strong\u003e with only modest enantioselectivity (Table 1, entries 1\u0026ndash;7). Notably, a marked improvement was observed with Pyrabox ligands, which were designed in our laboratory and are applied here in asymmetric catalysis for the first time (Table 1, entries 8\u0026ndash;10). Ligand \u003cstrong\u003eL9\u003c/strong\u003e proved optimal, delivering \u003cstrong\u003e2\u003c/strong\u003e with 76% ee albeit in a moderate 57% yield (Table 1, entry 9). Subsequent optimization of the base identified DABCO as superior to Et₃N or DIPEA, enhancing both the yield and enantioselectivity (Table 1, entries 11\u0026ndash;12).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003eEvaluation of copper salts then revealed Cu(MeCN)\u003csub\u003e4\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e to be the most effective source (Table 1, entries 13\u0026ndash;15). A slight increase in the loadings of both the catalyst and the ligand further boosted the isolated yield to 92% while maintaining high enantioselectivity (94% ee) (Table 1, entry 16; see the Supplementary Information for details).\u003c/div\u003e\n\u003cp\u003eWith the optimized reaction conditions established, we explored the substrate scope for the copper-catalyzed synthesis of spirocyclic \u003cem\u003e\u0026gamma;\u003c/em\u003e-lactams, as illustrated in Fig. 2. A wide array of substituents on the aromatic ring (R\u0026sup1;) were well-tolerated, including electron-withdrawing groups (e.g., -F, -Cl, -Br, -CN, -CF₃), electron-donating groups (e.g., -Me, -\u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBu -OMe), phenyl, cyclopropyl and electron-neutral group (H), affording the corresponding products \u003cstrong\u003e2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e21\u003c/strong\u003e in high yields (35\u0026ndash;97%) and with excellent enantioselectivities (80\u0026ndash;96% ee). The process was also compatiblewith disubstituted aryl ring and naphthalene-derived substrates, providing products \u003cstrong\u003e22\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e25\u003c/strong\u003e, respectively. Interestingly, heteroatom-substituted indanone substrate also yielded the corresponding spirocyclic compound \u003cstrong\u003e26\u003c/strong\u003e with 84% ee and in high yield (91%). The amide substituents (R) were further investigated. Methyl, ethyl, \u003cem\u003en\u003c/em\u003e-propyl, \u003cem\u003ei\u003c/em\u003e-propyl, phenyl, 1-naphthalenemethyl, and \u003cem\u003et\u003c/em\u003e-butyl all participated effectively, yielding the desired spiro-lactams (\u003cstrong\u003e27\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e33\u003c/strong\u003e) with high yields (67\u0026ndash;97%) and enantioselectivities (91\u0026ndash;96% ee). The absolute configuration of the quaternary spiro-stereocenter in \u003cstrong\u003e2\u003c/strong\u003e was unambiguously determined to be \u003cem\u003eR\u003c/em\u003e by single-crystal X-ray diffraction analysis, and the stereochemistry of all other products was assigned by analogy. Notably, although compound \u003cstrong\u003e4\u003c/strong\u003e suffered a slight reduction in ee value, optically pure product could be obtained through a single recrystallization.\u003c/p\u003e\n\u003cp\u003eHaving established an efficient protocol for synthesizing spirocyclic \u003cem\u003e\u0026gamma;\u003c/em\u003e-lactams, we next aimed to achieve catalyst-controlled switching of the reaction pathway toward the complementary 6-\u003cem\u003eendo\u003c/em\u003e-dig cyclization. Under the Cu/\u003cstrong\u003eL9\u003c/strong\u003e catalytic system for \u003cem\u003e\u0026gamma;\u003c/em\u003e-lactam formation, only trace amounts of the \u003cem\u003e\u0026delta;\u003c/em\u003e-lactam were detected, suggesting that an alternative catalytic system would be required. We hypothesized that altering the metal center could change the coordination geometry and electronic properties of the catalyst in a way that favors 6-\u003cem\u003eendo\u003c/em\u003e-dig pathway.\u003c/p\u003e\n\u003cp\u003eScreening of nickel salts in combination with Box-type ligands successfully enabled the desired reactivity profile (Table 2). Using Ni(ClO\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e●6H\u003csub\u003e2\u003c/sub\u003eO and ligand \u003cstrong\u003eL4\u003c/strong\u003e in toluene with Et₃N as the base at 80\u0026deg;C, the \u003cem\u003e\u0026delta;\u003c/em\u003e-lactam \u003cstrong\u003e34\u003c/strong\u003e was obtained in 80% yield and 74% ee, while other bases such as DIPEA and LiHMDS showed lower enantioselectivity (Table 2, entries 1\u0026ndash;3). Subsequent ligand evaluation identified that \u003cstrong\u003eL14\u003c/strong\u003e was uniquely effective, significantly improving both the yield (87%) and enantioselectivity (86% ee, Table 2, entries 4\u0026ndash;8). Examination of various nickel salts confirmed Ni(BF\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e●6H\u003csub\u003e2\u003c/sub\u003eO as optimal with 88% ee (Table 2, entries 9\u0026ndash;10). Because product formation involves protonation of a carbanion intermediate, we attempted to add water to facilitate this step, which led to a modest increase in yield (Table 2, entry 11). Further optimization revealed that using ethyl acetate as the solvent afforded the target product in 88% yield and 90% ee (Table 2, entry 12; see the Supplementary Information for details).\u003c/p\u003e\n\u003cdiv\u003eThe scope of this nickel-catalyzed 6-\u003cem\u003eendo\u003c/em\u003e-dig cyclization was subsequently investigated under conditions B (Fig. 3). When the amide nitrogen protecting group was methyl, the reaction demonstrated broad functional group tolerance, accommodating a variety of aromatic substituents (R\u0026sup1;), including electron-withdrawing groups (5-Br, 4-Br, 6-Br, 5-Cl, 6-Cl, 5-F, 6-F, 6-CN, 6-CF\u003csub\u003e3\u003c/sub\u003e, 5,6-dichloro), as well as electron-donating groups (5-Me, 4-Me, 6-Me, 5-\u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBu, 5-OMe, 6-OMe, 5-allyloxy), phenyl, and cyclopropyl, affording the corresponding spirocyclic \u003cem\u003e\u0026delta;\u003c/em\u003e-lactam products \u003cstrong\u003e34\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e52\u003c/strong\u003e in good to excellent yields (24\u0026ndash;92%) with high enantioselectivities (78\u0026ndash;93% ee). Moreover, the protocol was successfully applied to substrates bearing electron-neutral group (H), two electron-donating groups and naphthalene-derived substrates, delivering the corresponding spirocyclic products in good yields with excellent enantiocontrol (\u003cstrong\u003e53\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e57\u003c/strong\u003e). Variation of the amide nitrogen protecting groups were also tolerated, such as ethyl, \u003cem\u003en\u003c/em\u003e-propyl, \u003cem\u003ei\u003c/em\u003e-propyl, benzyl (\u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e58\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e61\u003c/strong\u003e). The structure and absolute configuration of spirocyclic \u003cem\u003e\u0026delta;\u003c/em\u003e-lactam \u003cstrong\u003e34\u003c/strong\u003e were unambiguously confirmed by X-ray crystallographic analysis, which established an \u003cem\u003eR\u003c/em\u003e configuration at the spiro-carbon center. Notably, optically pure compound \u003cstrong\u003e61\u003c/strong\u003e could be obtained via a single recrystallization.\u003c/div\u003e\n\u003cp\u003eMoreover, this methodology proved amenable to gram-scale synthesis. Under the optimized conditions, two representative reactions were conducted, affording \u003cstrong\u003e2\u003c/strong\u003e (0.89 g, 89% yield, 92% ee) and \u003cstrong\u003e34\u003c/strong\u003e (0.60 g, 60% yield, 90% ee), respectively, without loss of enantioselectivity (Fig. 4a). Furthermore, the synthetic versatility of the obtained \u003cem\u003e\u0026gamma;\u003c/em\u003e- and \u003cem\u003e\u0026delta;\u003c/em\u003e-lactams was explored through diverse downstream transformations, which highlighting the potential for late-stage functionalization. Compounds \u003cstrong\u003e2\u003c/strong\u003e and \u003cstrong\u003e34\u003c/strong\u003e can be further transformed into the corresponding methylenes derivatives (\u003cstrong\u003e62\u003c/strong\u003e, \u003cstrong\u003e63\u003c/strong\u003e) under silane reduction, to chiral alcohols (\u003cstrong\u003e64\u003c/strong\u003e, \u003cstrong\u003e65\u003c/strong\u003e) by sodium borohydride reduction, and to thioamides (\u003cstrong\u003e66\u003c/strong\u003e, \u003cstrong\u003e67\u003c/strong\u003e) using Lawesson\u0026apos;s reagent. The absolute configurations of \u003cstrong\u003e64\u003c/strong\u003e and \u003cstrong\u003e65\u003c/strong\u003e were unequivocally assigned by X-ray crystallography. Critically, the excellent enantioselectivity was fully retained throughout these derivatizations (Fig. 4b).\u003c/p\u003e\n\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eMechanistic investigations\u003c/h2\u003e\n \u003cp\u003eTo investigate the reaction mechanism, we performed a series of control experiments. The reaction proceeded, even in the presence of radical scavengers such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 1,1-diphenylethylene (DPE), or 2,6-di-\u003cem\u003etert\u003c/em\u003e-butyl-4-methylphenol (BHT), indicating that a radical pathway is unlikely. The observed decrease in the yield of \u003cstrong\u003e34\u003c/strong\u003e in the presence of TEMPO is likely attributable to catalyst poisoning by TEMPO (Fig. 5a). The ee values of \u003cstrong\u003eL9\u003c/strong\u003e and \u003cstrong\u003eL14\u003c/strong\u003e correlated linearly with the enantioenrichment of the corresponding products, suggesting that in both cyclization modes, the enantiodetermining transition states may involve only a single catalyst (Fig. 5b). Exchanging the respective metals or ligands between standard conditions A and B substantially reduced both the yield and enantioselectivity. These results indicate that for the 5-\u003cem\u003eexo\u003c/em\u003e-dig cyclization, regioselectivity is primarily controlled by the metal identity. In contrast, regioselectivity in the 6-\u003cem\u003eendo\u003c/em\u003e-dig pathway is co-regulated by both the metal and the ligand. Consequently, the cooperative action of a suitable metal and ligand is essential for the efficient progress of the reaction (Fig. 5c). Under the standard conditions, the carbonyl-free substrate \u003cstrong\u003e1ax\u003c/strong\u003e did not afford any product, underscoring that coordination of the carbonyl group to the metal is crucial for enabling the reaction pathway (Fig. 5d).\u003c/p\u003e\n \u003cp\u003eTo gain deeper insight into the reaction mechanism and elucidate the origins of regioselectivity and enantioselectivity, DFT calculations were performed to delineate the critical roles of the metal and ligand. The copper center adopts a tetrahedral coordination geometry, facilitating simultaneous interaction with the substrate\u0026rsquo;s triple bond and carbanion. Bond formation proceeds via a reductive elimination-like pathway (\u003cstrong\u003eIM-I-R\u003c/strong\u003e). Enantioselectivity originates from steric interactions between the ethyl group on the ligand and the carbonyl moiety in the substrate (\u003cstrong\u003eIM-I-S\u003c/strong\u003e). This stereoselectivity mechanism is directly revealed through analysis of the \u003cstrong\u003eTS-I-R\u003c/strong\u003e and \u003cstrong\u003eTS-I-S\u003c/strong\u003e structures. The transition state \u003cstrong\u003eTS-I-R\u003c/strong\u003e is energetically favored by 3.06 kcal/mol over its enantiomer \u003cstrong\u003eTS-I-S\u003c/strong\u003e, which accounts for the excellent enantioselectivity observed experimentally (Fig. 6a).\u003c/p\u003e\n \u003cp\u003eNickel exhibits a strong preference for square planar coordination, in which both the oxygen atom and the triple bond of the substrate simultaneously bind to the nickel center (\u003cstrong\u003eIM-II-R\u003c/strong\u003e). Due to steric constraints, the N-Ni-N plane of the ligand and the O-Ni-C plane of the substrate adopt a dihedral angle of approximately 50\u0026deg;. As the terminal atom of the triple bond approaches the five-membered ring, geometric reorganization of the substrate reduces steric congestion, leading to a decrease in the dihedral angle to about 30\u0026deg; at the transition state. This more coplanar arrangement stabilizes the square planar geometry of nickel, thereby facilitating the formation of the transition state. Enantiocontrol is governed by steric interactions between the fused ring system of the substrate and the phenyl group-oriented perpendicular to the ligand plane (\u003cstrong\u003eIM-II-S\u003c/strong\u003e). This mechanism is supported by the relative energies of the key transition states; \u003cstrong\u003eTS-II-R\u003c/strong\u003e is more stable than \u003cstrong\u003eTS-II-S\u003c/strong\u003e by 1.68 kcal/mol, consistent with the observed enantioselectivity (Fig. 6b).\u003c/p\u003e\n \u003cp\u003eBased on mechanistic investigations and DFT calculations, two plausible reaction pathways are proposed in Fig. 7. The catalytic cycle begins with coordination of a copper ion to a Box ligand, forming the chiral catalyst \u003cstrong\u003eA\u003c/strong\u003e. Under basic conditions, \u003cstrong\u003eA\u003c/strong\u003e reacts with substrate \u003cstrong\u003e1a\u003c/strong\u003e to afford the Cu\u003cstrong\u003eL9\u003c/strong\u003e-acetylide complex \u003cstrong\u003eB\u003c/strong\u003e. This complex then undergoes a 5-\u003cem\u003eexo\u003c/em\u003e-dig cyclization to generate the chiral intermediate \u003cstrong\u003eC\u003c/strong\u003e. Finally, product \u003cstrong\u003e2\u003c/strong\u003e is then formed through the protodemetalation of intermediate \u003cstrong\u003eC\u003c/strong\u003e, a step that is concomitant with the regeneration of the chiral copper catalyst (Fig. 7a). Similarly, the activation of nickel by ligand \u003cstrong\u003eL14\u003c/strong\u003e generates catalyst \u003cstrong\u003eD\u003c/strong\u003e, which is converted to complex \u003cstrong\u003eE\u003c/strong\u003e upon sequential deprotonation under basic conditions. \u003cstrong\u003eE\u003c/strong\u003e then undergoes a 6-\u003cem\u003eendo\u003c/em\u003e-dig cyclization to give chiral intermediate \u003cstrong\u003eF\u003c/strong\u003e. Finally, intermediate \u003cstrong\u003eF\u003c/strong\u003e undergoes protodemetalation (likely assisted by trace water) to furnish product \u003cstrong\u003e3\u003c/strong\u003e, with concomitant regeneration of catalyst \u003cstrong\u003eD\u003c/strong\u003e (Fig. 7b).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn summary, we have developed an efficient and catalyst-controlled regiodivergent asymmetric cyclization. This method enables the unified synthesis of both spirocyclic \u003cem\u003eγ\u003c/em\u003e-lactams and \u003cem\u003eδ\u003c/em\u003e-lactams from a single alkyne-tethered \u003cem\u003eβ\u003c/em\u003e-ketoamide precursor. By rational modulation of the metal-ligand environment, the intrinsic preference for 5-\u003cem\u003eexo\u003c/em\u003e-dig cyclization can be overridden to selectively promote the otherwise challenging 6-\u003cem\u003eendo\u003c/em\u003e-dig pathway (regioselectivity\u0026thinsp;\u0026gt;\u0026thinsp;20:1), while maintaining excellent enantioselective control in both manifolds (up to 96% ee for 5-\u003cem\u003eexo\u003c/em\u003e-dig and 93% ee for 6-\u003cem\u003eendo\u003c/em\u003e-dig). This strategy of switching metals and ligands provides an efficient solution to the long-standing difficulty of simultaneously controlling regio- and stereoselectivity in alkyne-based spirocyclizations. Mechanistic studies, corroborated by DFT calculations, highlight the decisive role of metal coordination geometry in governing regioselectivity and clarify how chiral ligand sterics dictate asymmetric cyclization. The broad functional group tolerance highlights its utility for the rapid diversification of valuable spirocyclic scaffolds from simple precursors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cb\u003eGeneral Procedure for the Synthesis of Racemic Products 2, 4\u0026ndash;33.\u003c/b\u003e A mixture of CuBH\u003csub\u003e4\u003c/sub\u003e(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e (0.01 mmol, 10 mol %), substrate \u003cb\u003e1\u003c/b\u003e (0.10 mmol, 1.0 equiv.), K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (0.15 mmol, 1.5 equiv.) and dry DCM (2 mL) was stirred at 40\u0026deg;C under a nitrogen atmosphere for 18 h. After complete consumption of substrate \u003cb\u003e1\u003c/b\u003e (as monitored by TLC), the crude product was purified by flash chromatography on silica gel to afford the desired products \u003cem\u003erac\u003c/em\u003e-\u003cb\u003e2\u003c/b\u003e, \u003cem\u003erac\u003c/em\u003e-\u003cb\u003e4\u003c/b\u003e-\u003cb\u003e33\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for the Synthesis of Racemic Products 3, 34\u0026ndash;61.\u003c/b\u003e A mixture of Ni(ClO\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e\u0026bull;6H\u003csub\u003e2\u003c/sub\u003eO (0.01 mmol, 10 mol %), ligand (0.012 mmol, 12 mol %) in dry toluene (1 mL) was stirred at 25 \u003csup\u003eo\u003c/sup\u003eC under a nitrogen atmosphere for 1.5 h. Subsequently, substrate \u003cb\u003e1\u003c/b\u003e (0.10 mmol, 1.0 equiv.) and Et\u003csub\u003e3\u003c/sub\u003eN (0.15 mmol, 1.5 equiv.) and H\u003csub\u003e2\u003c/sub\u003eO (5 \u0026micro;L) and additional toluene (1 mL) were added. The reaction mixture was then stirred at 80 \u003csup\u003eo\u003c/sup\u003eC under a nitrogen atmosphere. After three days, substrate \u003cb\u003e1\u003c/b\u003e had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products \u003cem\u003erac\u003c/em\u003e-\u003cb\u003e3\u003c/b\u003e, \u003cem\u003erac\u003c/em\u003e-\u003cb\u003e34\u003c/b\u003e-\u003cb\u003e61\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for the Synthesis of Chiral Products 2, 4\u0026ndash;33.\u003c/b\u003e A mixture of Cu(MeCN)\u003csub\u003e4\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e (0.015 mmol, 15 mol %), ligand (0.018 mmol, 18 mol %) in dry DCM (1 mL) was stirred at 25 \u003csup\u003eo\u003c/sup\u003eC under a nitrogen atmosphere for 1.5 h. Subsequently, substrate \u003cb\u003e1\u003c/b\u003e (0.10 mmol, 1.0 equiv.) and DABCO (0.15 mmol, 1.5 equiv.) and additional dry DCM (1 mL) were added. The reaction mixture was then stirred at 40 \u003csup\u003eo\u003c/sup\u003eC under nitrogen. After 18 h, substrate \u003cb\u003e1\u003c/b\u003e had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products \u003cb\u003e2\u003c/b\u003e, \u003cb\u003e4\u003c/b\u003e\u0026ndash;\u003cb\u003e33\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral Procedure for the Synthesis of Chiral Products 3, 34\u0026ndash;61.\u003c/b\u003e A mixture of Ni(BF\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e\u0026bull;6H\u003csub\u003e2\u003c/sub\u003eO (0.01 mmol, 10 mol %), ligand (0.012 mmol, 12 mol %) in dry EtOAc (1 mL) was stirred at 25 \u003csup\u003eo\u003c/sup\u003eC under a nitrogen atmosphere for 1.5 h. Subsequently, substrate \u003cb\u003e1\u003c/b\u003e (0.10 mmol, 1.0 equiv.) and Et\u003csub\u003e3\u003c/sub\u003eN (0.15 mmol, 1.0 equiv.) and H\u003csub\u003e2\u003c/sub\u003eO (5 \u0026micro;L) and dry EtOAc (1 mL) were added. The reaction mixture was then stirred at 80 \u003csup\u003eo\u003c/sup\u003eC under nitrogen. After three days, substrate \u003cb\u003e1\u003c/b\u003e had completely disappeared (as monitored by TLC). Finally, the crude product was purified by flash chromatography on silica gel to afford the desired products \u003cb\u003e3\u003c/b\u003e, \u003cb\u003e34\u003c/b\u003e\u0026ndash;\u003cb\u003e61\u003c/b\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData availability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data for the replication of this work are given in the supplementary information or can be obtained by the lead contact upon reasonable request.\u003c/p\u003e\u003cp\u003eAcknowledgements\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe are grateful for the financial support from the Shuguang program (20SG44) from Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the National Natural Science Foundation of China (22371187, 22501184), the Natural Science Foundation of Shanghai (22ZR1445200, 25ZR1402406), the Chinese Education Ministry Key Laboratory and International Joint Laboratory on Resource Chemistry, the \u0026ldquo;111\u0026rdquo; Innovation and Talent Recruitment Base on Photochemical and Energy Materials (D18020), the Shanghai Engineering Research Center of Green Energy Chemical Engineering (18DZ2254200), and the State Key\u0026nbsp;Laboratory of Fluorine and Nitrogen Chemistry and\u0026nbsp;Advanced Materials (2026PT0022).\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eZ.C. and Q.-H.D. conceived and directed the project. S.-H.W. conducted most of the experiments including the synthesis of the ligands and substrates. F.G., Y.-B.B. and Y.-Z.B. synthesized some substrates. S.-H.W. drafted the Supplementary Information.\u0026nbsp;C.Z. performed the computations. Z.C. and Q.-H.D. prepared the manuscript and revised the Supplementary Information.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHayashi E, Isogai M, Kagawa Y, Takayanagi N, Yamada S (1984) Neosurugatoxin, a specific antagonist of nicotinic acetylcholine receptors. J Neurochem Vol 42:1491\u0026ndash;1494\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng Y, Tice CM, Singh SB (2014) The use of spirocyclic scaffolds in drug discovery. 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Chem Soc Rev 44:6059\u0026ndash;6093\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 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-8979415/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8979415/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report an unprecedented regiodivergent strategy for the catalytic asymmetric synthesis of enantioenriched spirocyclic \u003cem\u003eγ\u003c/em\u003e- and \u003cem\u003eδ\u003c/em\u003e-lactams from a single alkyne-tethered \u003cem\u003eβ\u003c/em\u003e-ketoamide precursor. Critically, simply switching the catalyst system between Cu(I)/Pyrabox and Ni(II)/Box enables precise toggling of the cyclization between 5-\u003cem\u003eexo\u003c/em\u003e-dig and 6-\u003cem\u003eendo\u003c/em\u003e-dig modes, allowing direct and highly stereoselective access to either \u003cem\u003eγ\u003c/em\u003e-lactam or \u003cem\u003eδ\u003c/em\u003e-lactam spirocycles, each bearing a challenging quaternary spiro-stereocenter. The method exhibits broad functional group compatibility and allows for gram-scale synthesis. Mechanistic experiments and DFT calculations reveal that regioselectivity arises from the mode of metal coordination or the joint regulation by metal and ligand, whereas stereocontrol is governed by steric hindrance between the ligand and the substrate. This practical and atom-economical approach provides a powerful platform for the divergent synthesis of privileged spirocyclic pharmacophores.\u003c/p\u003e","manuscriptTitle":"Catalyst-Controlled Regiodivergence in Enantioselective Synthesis of Spirocyclic γ-versus δ-Lactams","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-03 11:44:31","doi":"10.21203/rs.3.rs-8979415/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":"200268d4-4f7f-4b98-970c-25c529fb7d98","owner":[],"postedDate":"March 3rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"revise","date":"2026-05-11T14:45:27+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":63842639,"name":"Physical sciences/Chemistry/Chemical synthesis/Asymmetric synthesis"},{"id":63842640,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-05-11T14:50:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-03 11:44:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8979415","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8979415","identity":"rs-8979415","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}