{"paper_id":"1a4e7e3e-5a27-45d2-8f37-73a78ca7fd95","body_text":"Enantioselective One Pot Construction of Bridged Tricyclic Lactones | 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 Enantioselective One Pot Construction of Bridged Tricyclic Lactones Hyeung-geun Park, So Hyun Jung, Ju Ha Baek, So Young Jang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7888018/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A bridged tricyclic scaffold with an sp3-rich framework offers a versatile core structure for the design of bioactive molecules that resemble those found in numerous natural products with notable biological activities. This scaffold faces key challenges in medium-sized ring synthesis, such as poor site selectivity and stereoselectivity and competing reaction pathways, which are prevalent in current synthetic methods. Here, we describe a highly efficient and one pot method for constructing a bridged tricyclic scaffold using a bifunctional cinchona alkaloid-derived squaramide catalyst. The reaction between 3-hydroxy-2-pyridones and α,β-unsaturated aldehydes results in the formation of a [4+2] cycloaddition adduct as an intermediate. The catalyst directs both enantioselectivity and diastereoselectivity in the initial cycloaddition step and subsequently functions as a Lewis base in the rearrangement process, thus driving the formation of the tricyclic compound in a one-pot reaction. This methodology provides a versatile approach for accessing various bridged tricyclic scaffolds that exhibit excellent enantio- and diastereoselectivities (up to 99% ee and dr > 20:1). The protocol is scalable to gram quantities and was successfully applied for the first total synthesis of the enantiomer of the alkaloid (-)-peduncularine and the preparation of analogous derivatives, which highlights the method’s utility in the synthesis of complex, enantioenriched natural product derivatives. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Catalysis/Asymmetric catalysis Figures Figure 1 Figure 2 Introduction Conformationally defined, sp³-rich polycyclic frameworks are important architectures in the design of bioactive molecules and offer increased structural diversity, good pharmacological performance, and three-dimensional complementarity to biological targets 1 -3 (Figure 1a). Among these, nitrogen-bridged polycycles are frequently encountered in natural products and therapeutic agents, where their spatially constrained geometry enables precise functional group orientation and contributes to both metabolic stability and target selectivity. However, despite their prominence, efficient and stereocontrolled access to these scaffolds remains a formidable challenge. Although strategies including transition-metal-catalyzed annulations 4 -10 , dearomative cyclizations 4,11 , photochemical closures, and radical or cascade-based sequences have been developed 12 -16 , these approaches often suffer from multistep protocols, limited generality, and a reliance on specialized building blocks. Consequently, broadly applicable and operationally simple strategies that can assemble such frameworks with high stereocontrol from readily available materials remain an unmet need. Cycloaddition is among the most powerful strategies for the rapid generation of molecular complexity and offers the possibility to construct multiple bonds and stereocenters in a single operation with exceptional atom economy 17,18 . However, the application of this transformation to the synthesis of polycyclic frameworks still faces several restrictions (Figure 1b). First, most reported systems rely on intramolecular substrates, which ensure favorable orbital alignment but severely limit substrate scope and functional group tolerance 13,19 . In contrast, intermolecular cycloadditions, although conceptually more versatile, have proven difficult to render efficient and stereoselective 8,10,20,21 . Second, stereocontrol remains a major obstacle: although the pericyclic nature of these reactions should enable precise stereochemical transfer, in practice, stereoselective variants, particularly intermolecular stereoselective variants, are rare, and the majority of products are obtained in racemic or otherwise poorly defined form. Third, the field remains dominated by transition-metal catalysts, which often demand elaborate ligand scaffolds and preactivated substrates, thus leaving organocatalytic approaches comparatively underdeveloped. Finally, the vast majority of accessible products are fused polycycles, which, although structurally dense, do not have the rigidity or three-dimensional complementarity characteristic of sp³-bridged frameworks. Together, these factors highlight the continuing absence of a general strategy that combines intermolecular scope, stereocontrol capability, organocatalytic conditions, and rigid bridged frameworks—a challenge that is addressed herein through the development of a new organocatalytic platform. Within this context, 3-hydroxy-2-pyridones stand out as highly effective cycloaddition partners for the stereocontrolled construction of nitrogen-containing polycycles, which are widely valued in chemical biology and medicinal chemistry 22 -28 (Figure 1c). The C3-hydroxyl moiety enables base-catalyzed activation, thus promoting cycloadditions that assemble multiple bonds and stereocenters in a single step. Despite this potential, the substrate scope has remained narrow, with maleimides predominating and only a limited number of α,β-unsaturated ketones and esters, primarily terminal alkenes, reported. To expand the electrophile scope in a manner that is compatible with intermolecular reactivity and mild conditions, we selected α,β-unsaturated aldehydes (enals) as a practical yet underutilized class to evaluate their generality and functional-group tolerance (Figure 1d). The incorporation of enals into 3-hydroxy-2-pyridone cycloadditions represents a powerful approach for obtaining richly functionalized, stereochemically defined nitrogen polycycles. Moreover, a distinct post-cycloaddition pathway that reorganizes the initial adduct was unexpectedly identified. Building on our enantioenriched tricyclic platform, a concise derivatization sequence furnished the normorphan core 29 -40 , which in turn enabled the first asymmetric total synthesis of (+)-peduncularine—the enantiomer of the natural product—with high enantiopurity 41 -50 . Moreover, our strategy provided access to the migrated olefin isomer 53 , thereby overcoming a key obstacle that hindered earlier efforts. Herein, we introduce an organocatalytic platform that forges rigid sp³-bridged nitrogen frameworks with high stereocontrol, culminating in the first total synthesis of (+)-peduncularine. Results Reaction development We initiated our study by coupling 3-hydroxy-2-pyridone ( 1a ) and crotonaldehyde ( 2a ) at room temperature (Table 1). Neither triethylamine nor quinine affected conversion (entry1 and entry 2). Introduction of a urea H-bond donor B triggered the formation of 3a / 3a ′(entry 3). These products were unexpected: in a single operation, the transformation formed three new σ-bonds and installed five stereocenters—among them an OH-bearing quaternary carbon—embedded in a rigid sp 3 -bridged nitrogen tricycle, as confirmed by single-crystal X-ray analysis (Table 2) 51 . In view of the limited access to chiral, functionalizable N-bridged tricycles, we explored the reaction in depth. We further optimized the catalysts. Replacement of the urea donor with monomeric squaramide C enhanced stereocontrol (entry 4, dr up to 15:1; 76% ee, DCM). The use of an achiral analog D yielded racemic material at elevated temperature, thus confirming that chiral induction arises from the catalyst (entry 5). Dimeric squaramide E proved superior by delivering the highest enantioselectivity (entry 6, 83% ee). On the basis of systematic variations in the solvent, temperature, reaction concentration, and stoichiometry (for detailed optimization results, see Tables S1–S4 in the Supporting Information), 1,4-dioxane, which provided 3a in 85% yield (entry 8, dr 14.4:1, 89% ee), was identified as optimal. We next examined the influence of the N-protecting groups of 3-hydroxy-2-pyridone (Table 2). The o-nosyl derivative delivered a high yield with 98% ee. Changing the nosyl unit to p -nosyl or employing 1,3-dinitrobenzenesulfonyl reduced diastereoselectivity to 5.5:1 and 2.8:1, with 96% ee and 94% ee, respectively. The configuration of 6a’ was unambiguously assigned by single-crystal X-ray analysis (see the Supporting Information for more details) 52 . Replacing the strongly electron-withdrawing nosyl with electron-donating arylsulfonyl groups increased the dr to >20:1 but lowered the ee to 81–89%. Non-sulfonyl protection resulted in no reaction. Owing to its superior enantioselectivity and robust reactivity, we adopted o-nosyl for subsequent studies. Substrate scope We next evaluated the reaction scope with α,β-unsaturated aldehydes in combination with tosyl- and o-nosyl-protected pyridines (Table 3). In the case of acrolein ( 3b ) and β-benzyl enals ( 3c – 3i ) being substituted directly adjacent to the double bond, reactions with the tosyl derivatives displayed higher reactivity than reactions with o-nosyl, although even after prolonged reaction times (7 days), full conversion was not achieved. Despite this kinetic limitation, the products were obtained with uniformly excellent stereocontrol, typically with dr >14:1 and ee values up to 98%, independent of whether the aryl substituents were electron-donating ( 3g ), electron-withdrawing ( 3h ), or halogenated ( 3d–3f ). However, cinnamyl-type aldehydes did not react because of their low reactivity. Nitrogen-containing enals, including phthalimide derivatives ( 3j ), also proved to be competent partners, which underscored the robustness of the transformation. For simple aliphatic enals ( 4a , 4k – 4n ) and β-phenethyl enals ( 4o – 4v ), the o-nosyl-protected pyridones yielded the best results by affording products with high efficiency and excellent stereocontrol across a range of electronic environments. Furthermore, heteroaryl aldehydes such as thiophenes ( 4w ) and furans ( 4x ) were well tolerated, and oxygen-protected aldehydes (OTBS and OTBDPS) ( 4y – 4z ) also furnished products with excellent selectivity. Collectively, these findings demonstrate that the reaction displays broad functional-group tolerance while maintaining high levels of stereocontrol across challenging aldehyde partners. Mechanism studies After mapping the substrate scope, we investigated the mechanistic basis of this unusual transformation. To elucidate how the substrates interact with the catalyst, we monitored the results of 1 H nuclear magnetic resonance (NMR) titrations (400 MHz, CDCl₃, 750 μL, rt; Figure 2a). Because the optimal dimeric squaramide catalyst E showed poor solubility, we employed the monomeric analog C , which provides comparable enantioselectivity. The addition of 1a (0.10–2.0 equiv.) to catalyst C immediately perturbed both squaramide NH resonances, and in the complementary experiment, 1a (1.0 equiv.) with increasing catalyst C (0.10–0.40 equiv.) resulted in a pronounced downfield shift of the 1a –OH signal, which is consistent with acid–base engagement by the quinuclidine site (see Supporting Information Fig. S2). In contrast, the titration of 2a at low loadings (0.10–0.40 equiv.) caused no significant change in the NH region of catalyst C , but at higher 2a concentrations (1, 2, 5, 10, and 20 equiv.), both NH signals progressively shifted downfield. This pattern indicates that 2a interacts more weakly with the squaramide donors than 1a does with the tertiary amine and requires higher equivalents to reveal the effect. Taken together, these observations support a cooperative activation model: the quinuclidine nitrogen of catalyst C engages the OH group of 1a to organize the complex in advance, and the squaramide NH donor hydrogen bond to the aldehyde carbonyl of 2a provides the electrophilic activation that is necessary for catalysis. Under the standard catalytic conditions, we were able to capture a transient intermediate int - 4z (Figure 2b). This species was highly unstable and could be characterized only by 1 H NMR prior to its decomposition into the starting materials. To test whether it is genuinely involved in the productive cycle, we subjected the intermediate to two contrasting environments. In the presence of triethylamine, it underwent complete decomposition with no trace amount of product. In contrast, exposing the isolated intermediate ( int - 4z ) to the bifunctional squaramide catalyst E regenerated not only the desired product 4z but also the original substrates ( 1b and 2a ), thus indicating that the intermediate can both revert to the starting materials and advance to the product within the catalytic manifold. Consistent with this view, TLC monitoring over 24 h revealed the immediate reappearance of 1b / 2a upon the addition of catalyst E , whereas 4z accumulated gradually; at early reaction times, the reverse pathway predominated, with the forward rearrangement proceeding more slowly. Together, these observations support two competing pathways: a rapid reversible reaction to the starting materials and a slower catalyst-mediated rearrangement into the tricyclic products. Long-term 1 H NMR monitoring of the standard reaction (aliquots from day 1 to day 10) further revealed the temporal evolution of this species: it appeared early, gradually diminished, and was ultimately replaced by the product. These observations confirm that the transformation proceeds via an observable intermediate that undergoes a catalyst-promoted rearrangement to furnish the product. Additional support was provided by HRMS analysis of the reaction mixture (Figure 4c). Under catalytic conditions, a molecular ion peak that was consistent with a catalyst–intermediate adduct was observed, thus providing direct evidence that the quinuclidine nitrogen of catalyst E forms a covalent bond with int - 3a . To probe the turnover-limiting event, we measured secondary KIEs with deuterated enals (Figure 4d). Deuteration at the aldehydic position ( 2n – d1 ) yielded a normal KIE of k H /k D = 1.25, which is consistent with substantial rehybridization at the carbonyl carbon during nucleophilic capture; this finding suggests that the rearrangement phase is involved in one of rate limiting steps. Taken together, these mechanistic studies establish that the transformation operates through a cascaded cycloaddition/rearrangement sequence, with the rearrangement step as the rate-determining event, and that the stereochemical outcome is controlled entirely by the catalyst. On the basis of these observations, we propose the following reaction mechanism, which is illustrated in Figure 4e. First, enals ( 2a ) form hydrogen bonds with the squaramide moiety of catalyst E ( I ). The subsequent deprotonation of 1a by the quinuclidine of catalyst E organizes the complex so that 1a can approach in only one productive orientation, which explains the high enantioselectivity ( II ). A stepwise cycloaddition that consists of a vinylogous Michael addition followed by ring closure produces a bicyclic adduct that bears a pendant aldehyde ( int -3a ). Importantly, the subsequent rearrangement is feasible only from the exo cycloadduct; although endo adducts may form, the cycloaddition is reversible, and only the exo geometry properly orients the aldehyde for rearrangement. In this conformation, the squaramide forms hydrogen bonds with the aldehyde, which itself is stabilized by intramolecular hydrogen bonding to the vicinal hydroxyl group, thus positioning the quinuclidine near the N-tosyl lactam carbonyl. Nucleophilic attack of the quinuclidine at this amide carbonyl generates a transient acylammonium species, which, through concerted proton transfer, releases sulfonamidate ( TsN⁻ ) ( III ). The hydrogen-bond-activated aldehyde is subsequently captured by TsN⁻ , and a hemiaminal is formed within the preorganized complex ( IV ). The resulting alkoxide then promotes intramolecular acyl transfer onto the acylammonium, which regenerates the catalyst and closes the lactone ring to afford the rigid tricyclic product ( 3a ). Overall, these data support a cascade mechanism in which stereocontrolled cycloaddition is followed by amine-promoted acyl transfer and sulfonamide capture of the aldehyde, which accounts for catalyst turnover and the formation of 3a . Recognizing the importance of catalyst economy for scaling and complex molecule synthesis, we evaluated the recyclability of catalyst E. The catalyst was reused in five consecutive runs, and in each case, the yield and enantioselectivity remained virtually unchanged. These results confirm that the catalyst can be efficiently recycled without loss of activity or stereocontrol, thus demonstrating the robustness of the protocol and its suitability for large-scale applications, including total synthesis and industrial applications (see Figure S9 in the Supporting Information for additional details). Application Total synthesis of (+)- peduncularine Given that bridged tricyclic lactones have an internal normorphan core skeleton, we applied our methodology to the total synthesis of (+) peduncularine 41 -50 . The alkaloid (–)-peduncularine, which was first isolated in 1971 from Aristotelia species, has attracted sustained interest owing to its rigid normorphan-derived framework and reported anticancer properties. Several synthetic approaches have been described, including racemic routes and asymmetric variants, although these typically require lengthy sequences or deliver only modest stereocontrol. The most recent asymmetric attempt advanced toward the target but ultimately stalled owing to alkene migration, which left the natural product inaccessible 53 . The gram-scale preparation of enantioenriched tricycle 4z (1.6 g, 86% yield, and 97% ee) provided a reliable starting point for total synthesis. First, we needed to convert 4z to a normorphan core skeleton. Attempts to open the lactone directly under reducing conditions were unsuccessful; Luche reduction produced only hemiacetal 11 . However, oxidative cleavage of 11 with NaIO₄ successfully furnished the normorphan framework 12 while fully retaining enantiopurity (97% ee). Following Roberson and Woerpel’s precedent, the C7 substituent was stereoselectively introduced under Hosomi–Sakurai conditions to yield 13 48,54 . To prevent alkene migration from hindering earlier syntheses, a masking–unmasking strategy was adopted. Thiophenol-mediated Ns-deprotection/Michael addition afforded 25 , which was transformed into 26 by reduction and Teoc protection. Barton–McCombie deoxygenation furnished 28 in excellent yield. Subsequent oxidation under H₂O₂/HFIP was performed, followed by heat-induced sulfoxide elimination. Owing to the rigid geometry of the scaffold, only one sulfoxide conformer underwent elimination, whereas the other remained intact. Recycling the unreacted conformer back to 28 enabled efficient conversion to 29 , which restored the olefin in high yield. Hydroboration/oxidation followed by Swern oxidation afforded the aldehyde, which was converted to its acetal 33 to improve stability and facilitate the subsequent Fischer step. Global deprotection/reductive amination yielded 34 . Fischer indolization, which was performed from the acetal-protected precursor, produced 35 in high yield, and finally, Grieco elimination completed the synthesis of the natural product enantiomer (+)-peduncularine. The overall sequence was completed in 7.9% yield from 1b . Thus, this route is among the most efficient asymmetric routes to this alkaloid that have been reported to date. Total synthesis of Δ 2,3 (+)-peduncularine We also performed total synthesis of Δ 2,3 (+)-peduncularine, which is an olefin-migrated analog. Starting from compound 13 , reduction followed by nosyl deprotection and Teoc protection provided entry to the deoxygenation stage, where the installation of the Δ 2,3 olefin proved highly sensitive to the reaction conditions. Several methods were examined (Table 4). Mesylation of the intermediate alcohol followed by hydride substitution revealed striking differences: LiAlH₄ delivered a near-statistical mixture of direct substitution (P) and migrated olefin (P′), whereas LiBEt₃H favored the SN2′ pathway, which produced P′ at a ratio of 1:17. Alternative approaches, including the use of Tsuji–Trost and Barton–McCombie conditions, resulted in either low yield or poor selectivity. On this basis, the LiBEt₃H substitution strategy was selected as the most effective route to the desired migrated olefin. From intermediate 17 , hydroboration–oxidation followed by Swern oxidation and acetal protection furnished 20 . Global deprotection and reductive amination then yielded 21 , which was advanced by Fischer indolization to 22 . Finally, Grieco elimination completed the synthesis of Δ 2,3 -(+)-peduncularine ( 23 ). This sequence not only delivers Δ 2,3 -(+)-peduncularine with high enantiopurity but, together with the synthesis of (+)-peduncularine, demonstrates that both natural and migrated olefin isomers can now be accessed from a single enantioenriched tricyclic platform. Conclusions We developed an organocatalytic one pot strategy that transforms simple 3-hydroxy-2-pyridones and α,β-unsaturated aldehydes into rigid, sp³-bridged nitrogen tricycles through a cascade of cycloaddition and rearrangement. This platform enables high levels of diastereo- and enantiocontrol under ambient and metal-free conditions while tolerating a wide range of functionalized enals. Mechanistic experiments, including direct observation of a short-lived intermediate, KIE measurements, HRMS analysis, and NMR binding studies, established that the transformation proceeded through a reversible cycloaddition followed by a catalyst-triggered rearrangement, with the stereochemical outcome fully dictated by the catalyst scaffold. In addition to methodological significance of this platform, the use of this platform was demonstrated through the first asymmetric total synthesis of (+)-peduncularine and its Δ 2,3 -migrated isomer, thereby providing enantioenriched access to both natural and nonnatural members of the peduncularine family. 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Formal synthesis of (±)-peduncularine: Use of the [3+ 2] annulation of allylic silanes and chlorosulfonyl isocyanate. Org. Lett. 2 , 621–623 (2000). Roberson, C. W. & Woerpel, K. Development of the [3+ 2] annulations of cyclohexenylsilanes and chlorosulfonyl isocyanate: Application to the total synthesis of (±)-peduncularine. J. Am. Chem. Soc. 124 , 11342–11348 (2002). Shelton, R. E., Sezer, S. & Hodgson, D. M. Enantioselective desymmetrisation of an epoxytropinone for peduncularine synthesis. Tetrahedron 76 (2020). Washburn, D. G., Heidebrecht, R. W. & Martin, S. F. Concise formal synthesis of (−)-peduncularine via ring-closing metathesis. Org. Lett. 5 , 3523–3525 (2003). CCDC2495584 ( 3a ). The ORTEP structures of 3a showed thermal ellipsoids at the 50% probability level. CCDC2495586 ( 6a’ ). The ORTEP structures of 6a’ showed thermal ellipsoids at the 50% probability level. Liang, G., Christensen, K. E. & Anderson, E. A. An Asymmetric Approach toward the Aristotelia Alkaloid (-)-Penduncularine. Org Lett 27 , 7798–7803 (2025). Lee, J. H. Use of the Hosomi-Sakurai allylation in natural product total synthesis. Tetrahedron 76 , 131351 (2020). Tables Tables 1 to 4 are available in the Supplementary Files section. Schemes Schemes1 to 2 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files NatureChemSI.pdf Enantioselective One Pot Construction of Bridged Tricyclic Lactones Schemes.docx Tables.docx Cite Share Download PDF Status: Posted 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. 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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-7888018\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":532326401,\"identity\":\"af9e504e-8fd5-4398-b19d-ce7f742b0cfc\",\"order_by\":0,\"name\":\"Hyeung-geun Park\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArklEQVRIiWNgGAWjYBACAwYGZoYPUA5jA7FaGGeQrIWZhyQt5vxrDxvb/LmT2MB++AHjzD1EaLGc8S45ObftWWIDT5oB44ZnxDjsxhnjw7kNhxMbGHIYGB8cIFaLxR+gFv43xGo532OczMAG1CIBtGUDcbbwJRv2th02bpN4ZnBwBnG2nD0s8ePPYdl+/uSHD3uI0cIAdA8YsAExURoYGPjPEKduFIyCUTAKRjAAAGcBO6DviW4EAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Seoul National University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Hyeung-geun\",\"middleName\":\"\",\"lastName\":\"Park\",\"suffix\":\"\"},{\"id\":532326402,\"identity\":\"cf80984f-8b59-4cdc-bfe5-79681c82c505\",\"order_by\":1,\"name\":\"So Hyun Jung\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"College of Pharmacy, Seoul National University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"So\",\"middleName\":\"Hyun\",\"lastName\":\"Jung\",\"suffix\":\"\"},{\"id\":532326403,\"identity\":\"d7a9e293-84c2-4498-931a-1323957c3a00\",\"order_by\":2,\"name\":\"Ju Ha Baek\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"College of Pharmacy, Seoul National University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ju\",\"middleName\":\"Ha\",\"lastName\":\"Baek\",\"suffix\":\"\"},{\"id\":532326404,\"identity\":\"d73fa35f-9b9a-44a4-9cbe-32671a7eba14\",\"order_by\":3,\"name\":\"So Young Jang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"College of Pharmacy, Seoul National University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"So\",\"middleName\":\"Young\",\"lastName\":\"Jang\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-10-17 15:15:40\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7888018/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7888018/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":94248983,\"identity\":\"cf89afec-ec6a-4367-bc97-96511c6a551a\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:13:12\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":147284,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBackground and our strategy for accessing sp\\u003csup\\u003e3\\u003c/sup\\u003e-rich N-bridged tricyclic lactones. a) Selected N-bridged polycyclic scaffolds in natural and therapeutic systems, b) Status and limitations of [4+2] cycloaddition, c) Previous works on cycloadditions that involve 3-hydroxy-2-pyridones, d) This work: cinchona alkaloid-derived bifunctional squaramide catalyst-mediated enantioselective cycloaddition followed by rearrangement to construct sp\\u003csup\\u003e3\\u003c/sup\\u003e-rich N-bridged tricyclic lactones.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/300a41d3912562e3cab4f319.png\"},{\"id\":94248982,\"identity\":\"6675718e-cbad-442d-8ae8-07707b414295\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:13:12\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":302253,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eMechanism studies: a) NMR titrations of catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e with substrates \\u003cstrong\\u003e1a\\u003c/strong\\u003e and \\u003cstrong\\u003e2a\\u003c/strong\\u003e, b) reaction pattern that was obtained by \\u003csup\\u003e1\\u003c/sup\\u003eH-NMR analysis, c) [4+2] cycloaddition intermediate (\\u003cem\\u003eint\\u003c/em\\u003e-\\u003cstrong\\u003e4a\\u003c/strong\\u003e) trapping, d) secondary isotope effect on the rearrangement process, and e) the proposed mechanism. GC–MS, gas chromatography–mass spectrometry; cal., calculated\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/609584c92d81b800a88246a8.png\"},{\"id\":94728536,\"identity\":\"95f04605-5575-4106-8302-9e47d2b290b7\",\"added_by\":\"auto\",\"created_at\":\"2025-10-30 07:04:00\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1026661,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/a397b56f-d3b9-4147-8c70-19f158a04806.pdf\"},{\"id\":94248986,\"identity\":\"943e247f-0ab7-42b5-8b17-ab85bf3546ee\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:13:12\",\"extension\":\"pdf\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":9377138,\"visible\":true,\"origin\":\"\",\"legend\":\"Enantioselective One Pot Construction of Bridged Tricyclic Lactones\",\"description\":\"\",\"filename\":\"NatureChemSI.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/d732dfabc0032317e37611cf.pdf\"},{\"id\":94248985,\"identity\":\"4c04084b-df8f-448d-9cb6-2363ca69ab84\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:13:12\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":143130,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Schemes.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/75cea48436a3caa2b8566c97.docx\"},{\"id\":94248984,\"identity\":\"16d6a727-3793-4d5b-b398-513d364d0e26\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:13:12\",\"extension\":\"docx\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":432435,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Tables.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7888018/v1/bbf2927db8ac7ac2327ca8ec.docx\"}],\"financialInterests\":\"There is \\u003cb\\u003eNO\\u003c/b\\u003e Competing Interest.\",\"formattedTitle\":\"Enantioselective One Pot Construction of Bridged Tricyclic Lactones\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eConformationally defined, sp\\u0026sup3;-rich polycyclic frameworks are important architectures in the design of bioactive molecules and offer increased structural diversity, good pharmacological performance, and three-dimensional complementarity to biological targets\\u003csup\\u003e1\\u003c/sup\\u003e\\u003csup\\u003e-3\\u003c/sup\\u003e\\u003csup\\u003e\\u0026nbsp;\\u003c/sup\\u003e(Figure 1a). Among these, nitrogen-bridged polycycles are frequently encountered in natural products and therapeutic agents, where their spatially constrained geometry enables precise functional group orientation and contributes to both metabolic stability and target selectivity. However, despite their prominence, efficient and stereocontrolled\\u0026nbsp;access to these scaffolds remains a formidable challenge. Although strategies including transition-metal-catalyzed annulations\\u003csup\\u003e4\\u003c/sup\\u003e\\u003csup\\u003e-10\\u003c/sup\\u003e, dearomative cyclizations\\u003csup\\u003e4,11\\u003c/sup\\u003e, photochemical closures, and radical or cascade-based sequences have been developed\\u003csup\\u003e12\\u003c/sup\\u003e\\u003csup\\u003e-16\\u003c/sup\\u003e, these approaches often suffer from multistep protocols, limited generality, and a reliance on specialized building blocks. Consequently, broadly applicable and operationally simple strategies that can assemble such frameworks with high stereocontrol from readily available materials remain an unmet need.\\u003c/p\\u003e\\n\\u003cp\\u003eCycloaddition is among the most powerful strategies for the rapid generation of molecular complexity and offers the possibility to construct multiple bonds and stereocenters in a single operation with exceptional atom economy\\u003csup\\u003e17,18\\u003c/sup\\u003e. However, the application of this transformation to the synthesis of polycyclic frameworks still faces several restrictions (Figure 1b). First, most reported systems rely on intramolecular substrates, which ensure favorable orbital alignment but severely limit substrate scope and functional group tolerance\\u003csup\\u003e13,19\\u003c/sup\\u003e. In contrast, intermolecular cycloadditions, although conceptually more versatile, have proven difficult to render efficient and stereoselective\\u003csup\\u003e8,10,20,21\\u003c/sup\\u003e. Second, stereocontrol remains a major obstacle: although the pericyclic nature of these reactions should enable precise stereochemical transfer, in practice, stereoselective variants, particularly intermolecular stereoselective variants, are rare, and the majority of products are obtained in racemic or otherwise poorly defined form. Third, the field remains dominated by transition-metal catalysts, which often demand elaborate ligand scaffolds and preactivated substrates, thus leaving organocatalytic approaches comparatively underdeveloped. Finally, the vast majority of accessible products are fused polycycles, which, although structurally dense, do not have the rigidity or three-dimensional complementarity characteristic of sp\\u0026sup3;-bridged frameworks. Together, these factors highlight the continuing absence of a general strategy that combines intermolecular scope, stereocontrol capability, organocatalytic conditions, and rigid bridged frameworks\\u0026mdash;a challenge that is addressed herein through the development of a new organocatalytic platform.\\u003c/p\\u003e\\n\\u003cp\\u003eWithin this context, 3-hydroxy-2-pyridones\\u0026nbsp;stand out as highly effective cycloaddition partners for the stereocontrolled\\u0026nbsp;construction of nitrogen-containing polycycles, which are widely valued in chemical biology and medicinal chemistry\\u003csup\\u003e22\\u003c/sup\\u003e\\u003csup\\u003e-28\\u003c/sup\\u003e\\u003csup\\u003e\\u0026nbsp;\\u003c/sup\\u003e(Figure 1c). The C3-hydroxyl moiety enables base-catalyzed activation, thus promoting cycloadditions that assemble multiple bonds and stereocenters in a single step. Despite this potential, the substrate scope has remained narrow, with maleimides predominating and only a limited number of \\u0026alpha;,\\u0026beta;-unsaturated ketones and esters, primarily terminal alkenes, reported. To expand the electrophile scope in a manner that is compatible with intermolecular reactivity and mild conditions, we selected \\u0026alpha;,\\u0026beta;-unsaturated aldehydes (enals) as a practical yet underutilized class to evaluate their generality and functional-group tolerance (Figure 1d). The incorporation of enals\\u0026nbsp;into 3-hydroxy-2-pyridone\\u0026nbsp;cycloadditions represents a powerful approach for obtaining richly functionalized, stereochemically\\u0026nbsp;defined nitrogen polycycles. Moreover, a distinct post-cycloaddition pathway that reorganizes the initial adduct was unexpectedly identified.\\u003c/p\\u003e\\n\\u003cp\\u003eBuilding on our enantioenriched tricyclic platform, a concise derivatization sequence furnished the normorphan core\\u003csup\\u003e29\\u003c/sup\\u003e\\u003csup\\u003e-40\\u003c/sup\\u003e, which in turn enabled the first asymmetric total synthesis of (+)-peduncularine\\u0026mdash;the enantiomer of the natural product\\u0026mdash;with high enantiopurity\\u003csup\\u003e41\\u003c/sup\\u003e\\u003csup\\u003e-50\\u003c/sup\\u003e. Moreover, our strategy provided access to the migrated olefin isomer\\u003csup\\u003e53\\u003c/sup\\u003e, thereby overcoming a key obstacle that hindered earlier efforts. Herein, we introduce an organocatalytic platform that forges rigid sp\\u0026sup3;-bridged nitrogen frameworks with high stereocontrol, culminating in the first total synthesis of (+)-peduncularine.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eReaction development\\u003c/p\\u003e\\n\\u003cp\\u003eWe initiated our study by coupling 3-hydroxy-2-pyridone\\u0026nbsp;(\\u003cstrong\\u003e1a\\u003c/strong\\u003e) and crotonaldehyde (\\u003cstrong\\u003e2a\\u003c/strong\\u003e) at room temperature (Table 1). Neither triethylamine nor quinine affected conversion (entry1 and entry 2). Introduction of a urea H-bond donor B triggered the formation of \\u003cstrong\\u003e3a\\u003c/strong\\u003e/\\u003cstrong\\u003e3a\\u003c/strong\\u003e\\u0026prime;(entry 3). These products were unexpected: in a single operation, the transformation formed three new \\u0026sigma;-bonds and installed five stereocenters\\u0026mdash;among them an OH-bearing quaternary carbon\\u0026mdash;embedded in a rigid sp\\u003csup\\u003e3\\u003c/sup\\u003e-bridged nitrogen tricycle, as confirmed by single-crystal X-ray analysis (Table 2)\\u003csup\\u003e51\\u003c/sup\\u003e. In view of the limited access to chiral, functionalizable N-bridged tricycles, we explored the reaction in depth. We further optimized the catalysts. Replacement of the urea donor with monomeric squaramide C enhanced stereocontrol (entry 4, dr up to 15:1; 76% ee, DCM). The use of an achiral analog D yielded racemic material at elevated temperature, thus confirming that chiral induction arises from the catalyst (entry 5). Dimeric squaramide \\u003cstrong\\u003eE\\u003c/strong\\u003e proved superior by delivering the highest enantioselectivity (entry 6, 83% ee). On the basis of systematic variations in the solvent, temperature, reaction concentration, and stoichiometry (for detailed optimization results, see Tables S1\\u0026ndash;S4 in the Supporting Information), 1,4-dioxane, which provided \\u003cstrong\\u003e3a\\u003c/strong\\u003e in 85% yield (entry 8, dr 14.4:1, 89% ee), was identified as optimal.\\u003c/p\\u003e\\n\\u003cp\\u003eWe next examined the influence of the N-protecting groups of 3-hydroxy-2-pyridone (Table 2). The o-nosyl derivative delivered a high yield with 98% ee. Changing the nosyl unit to \\u003cem\\u003ep\\u003c/em\\u003e-nosyl or employing 1,3-dinitrobenzenesulfonyl reduced diastereoselectivity to 5.5:1 and 2.8:1, with 96% ee and 94% ee, respectively. The configuration of \\u003cstrong\\u003e6a\\u0026rsquo;\\u003c/strong\\u003e was unambiguously assigned by single-crystal X-ray analysis (see the Supporting Information for more details)\\u003csup\\u003e52\\u003c/sup\\u003e. Replacing the strongly electron-withdrawing nosyl with electron-donating arylsulfonyl groups increased the dr to \\u0026gt;20:1 but lowered the ee to 81\\u0026ndash;89%. Non-sulfonyl protection resulted in no reaction. Owing to its superior enantioselectivity and robust reactivity, we adopted o-nosyl for subsequent studies.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSubstrate scope\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe next evaluated the reaction scope with \\u0026alpha;,\\u0026beta;-unsaturated aldehydes in combination with tosyl- and o-nosyl-protected pyridines (Table 3). In the case of acrolein (\\u003cstrong\\u003e3b\\u003c/strong\\u003e) and \\u0026beta;-benzyl enals (\\u003cstrong\\u003e3c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e3i\\u003c/strong\\u003e) being substituted directly adjacent to the double bond, reactions with the tosyl derivatives displayed higher reactivity than reactions with o-nosyl, although even after prolonged reaction times (7 days), full conversion was not achieved. Despite this kinetic limitation, the products were obtained with uniformly excellent stereocontrol, typically with dr \\u0026gt;14:1 and ee values up to 98%, independent of whether the aryl substituents were electron-donating (\\u003cstrong\\u003e3g\\u003c/strong\\u003e), electron-withdrawing (\\u003cstrong\\u003e3h\\u003c/strong\\u003e), or halogenated (\\u003cstrong\\u003e3d\\u0026ndash;3f\\u003c/strong\\u003e). However, cinnamyl-type aldehydes\\u0026nbsp;did not react because of their\\u0026nbsp;low reactivity. Nitrogen-containing enals, including phthalimide derivatives (\\u003cstrong\\u003e3j\\u003c/strong\\u003e), also proved to be competent partners, which underscored the robustness of the transformation. For simple aliphatic enals (\\u003cstrong\\u003e4a\\u003c/strong\\u003e, \\u003cstrong\\u003e4k\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e4n\\u003c/strong\\u003e) and \\u0026beta;-phenethyl enals (\\u003cstrong\\u003e4o\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e4v\\u003c/strong\\u003e), the o-nosyl-protected pyridones yielded the best results by affording products with high efficiency and excellent stereocontrol across a range of electronic environments. Furthermore, heteroaryl aldehydes such as thiophenes (\\u003cstrong\\u003e4w\\u003c/strong\\u003e) and furans (\\u003cstrong\\u003e4x\\u003c/strong\\u003e) were well tolerated, and oxygen-protected aldehydes (OTBS and OTBDPS) (\\u003cstrong\\u003e4y\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e4z\\u003c/strong\\u003e) also furnished products with excellent selectivity. Collectively, these findings demonstrate that the reaction displays broad functional-group tolerance while maintaining high levels of stereocontrol across challenging aldehyde partners.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMechanism studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAfter mapping the substrate scope, we investigated the mechanistic basis of this unusual transformation. To elucidate how the substrates interact with the catalyst, we monitored the results of \\u003csup\\u003e1\\u003c/sup\\u003eH nuclear magnetic resonance (NMR) titrations (400 MHz, CDCl₃, 750 \\u0026mu;L, rt; Figure 2a). Because the optimal dimeric squaramide catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e showed poor solubility, we employed the monomeric analog \\u003cstrong\\u003eC\\u003c/strong\\u003e, which provides comparable enantioselectivity. The addition of \\u003cstrong\\u003e1a\\u003c/strong\\u003e (0.10\\u0026ndash;2.0 equiv.) to catalyst \\u003cstrong\\u003eC\\u003c/strong\\u003e immediately perturbed both squaramide NH resonances, and in the complementary experiment, \\u003cstrong\\u003e1a\\u003c/strong\\u003e (1.0 equiv.) with increasing catalyst \\u003cstrong\\u003eC\\u003c/strong\\u003e (0.10\\u0026ndash;0.40 equiv.) resulted in a pronounced downfield shift of the \\u003cstrong\\u003e1a\\u003c/strong\\u003e\\u0026ndash;OH signal, which is consistent with acid\\u0026ndash;base engagement by the quinuclidine site (see Supporting Information Fig. S2). In contrast, the titration of \\u003cstrong\\u003e2a\\u003c/strong\\u003e at low loadings (0.10\\u0026ndash;0.40 equiv.) caused no significant change in the NH region of catalyst \\u003cstrong\\u003eC\\u003c/strong\\u003e, but at higher \\u003cstrong\\u003e2a\\u003c/strong\\u003e concentrations (1, 2, 5, 10, and 20 equiv.), both NH signals progressively shifted downfield.\\u003c/p\\u003e\\n\\u003cp\\u003eThis pattern indicates that \\u003cstrong\\u003e2a\\u003c/strong\\u003e interacts more weakly with the squaramide donors than \\u003cstrong\\u003e1a\\u003c/strong\\u003e does with the tertiary amine and requires higher equivalents to reveal the effect. Taken together, these observations support a cooperative activation model: the quinuclidine nitrogen of catalyst \\u003cstrong\\u003eC\\u003c/strong\\u003e engages the OH group of \\u003cstrong\\u003e1a\\u003c/strong\\u003e to organize the complex in advance, and the squaramide NH donor hydrogen bond to the aldehyde carbonyl of \\u003cstrong\\u003e2a\\u003c/strong\\u003e provides the electrophilic activation that is necessary for catalysis. Under the standard catalytic conditions, we were able to capture a transient intermediate \\u003cem\\u003eint\\u003c/em\\u003e-\\u003cstrong\\u003e4z\\u003c/strong\\u003e (Figure 2b). This species was highly unstable and could be characterized only by \\u003csup\\u003e1\\u003c/sup\\u003eH NMR prior to its decomposition into the starting materials. To test whether it is genuinely involved in the productive cycle, we subjected the intermediate to two contrasting environments. In the presence of triethylamine, it underwent complete decomposition with no trace amount of product. In contrast, exposing the isolated intermediate (\\u003cem\\u003eint\\u003c/em\\u003e-\\u003cstrong\\u003e4z\\u003c/strong\\u003e) to the bifunctional squaramide catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e regenerated not only the desired product \\u003cstrong\\u003e4z\\u003c/strong\\u003e but also the original substrates (\\u003cstrong\\u003e1b\\u003c/strong\\u003e and \\u003cstrong\\u003e2a\\u003c/strong\\u003e), thus indicating that the intermediate can both revert to the starting materials and advance to the product within the catalytic manifold. Consistent with this view, TLC monitoring over 24 h revealed the immediate reappearance of \\u003cstrong\\u003e1b\\u003c/strong\\u003e/\\u003cstrong\\u003e2a\\u003c/strong\\u003e upon the addition of catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e, whereas \\u003cstrong\\u003e4z\\u003c/strong\\u003e accumulated gradually; at early reaction times, the reverse pathway predominated, with the forward rearrangement proceeding more slowly. Together, these observations support two competing pathways: a rapid reversible reaction to the starting materials and a slower catalyst-mediated rearrangement into the tricyclic products. Long-term \\u003csup\\u003e1\\u003c/sup\\u003eH NMR monitoring of the standard reaction (aliquots from day 1 to day 10) further revealed the temporal evolution of this species: it appeared early, gradually diminished, and was ultimately replaced by the product. These observations confirm that the transformation proceeds via an observable intermediate that undergoes a catalyst-promoted rearrangement to furnish the product. Additional support was provided by HRMS analysis of the reaction mixture (Figure 4c). Under catalytic conditions, a molecular ion peak that was consistent with a catalyst\\u0026ndash;intermediate adduct was observed, thus providing direct evidence that the quinuclidine nitrogen of catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e forms a covalent bond with \\u003cem\\u003eint\\u003c/em\\u003e-\\u003cstrong\\u003e3a\\u003c/strong\\u003e. To probe the turnover-limiting event, we measured secondary KIEs\\u0026nbsp;with deuterated enals\\u0026nbsp;(Figure 4d). Deuteration at the aldehydic position (\\u003cstrong\\u003e2n\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003ed1\\u003c/strong\\u003e) yielded a normal KIE of k\\u003csub\\u003eH\\u003c/sub\\u003e/k\\u003csub\\u003eD\\u003c/sub\\u003e = 1.25, which is consistent with substantial rehybridization at the carbonyl carbon during nucleophilic capture; this finding suggests that the rearrangement phase is involved in one of rate limiting steps. Taken together, these mechanistic studies establish that the transformation operates through a cascaded cycloaddition/rearrangement sequence, with the rearrangement step as the rate-determining event, and that the stereochemical outcome is controlled entirely by the catalyst.\\u003c/p\\u003e\\n\\u003cp\\u003eOn the basis of these observations, we propose the following reaction mechanism, which is illustrated in Figure 4e. First, enals\\u0026nbsp;(\\u003cstrong\\u003e2a\\u003c/strong\\u003e) form hydrogen bonds with the squaramide moiety of catalyst \\u003cstrong\\u003eE\\u0026nbsp;\\u003c/strong\\u003e(\\u003cstrong\\u003eI\\u003c/strong\\u003e). The subsequent deprotonation of \\u003cstrong\\u003e1a\\u003c/strong\\u003e by the quinuclidine of catalyst \\u003cstrong\\u003eE\\u003c/strong\\u003e organizes the complex so that \\u003cstrong\\u003e1a\\u003c/strong\\u003e can approach in only one productive orientation, which explains the high enantioselectivity\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003e(\\u003cstrong\\u003eII\\u003c/strong\\u003e). A stepwise cycloaddition that consists of a vinylogous Michael addition followed by ring closure produces a bicyclic adduct that bears a pendant aldehyde (\\u003cstrong\\u003e\\u003cem\\u003eint\\u003c/em\\u003e-3a\\u003c/strong\\u003e). Importantly, the subsequent rearrangement is feasible only from the \\u003cstrong\\u003eexo\\u003c/strong\\u003e cycloadduct; although \\u003cstrong\\u003eendo\\u003c/strong\\u003e adducts may form, the cycloaddition is reversible, and only the \\u003cstrong\\u003eexo\\u003c/strong\\u003e geometry properly orients the aldehyde for rearrangement. In this conformation, the squaramide forms hydrogen bonds with the aldehyde, which itself is stabilized by intramolecular hydrogen bonding to the vicinal hydroxyl group, thus positioning the quinuclidine near the N-tosyl\\u0026nbsp;lactam carbonyl. Nucleophilic attack of the quinuclidine at this amide carbonyl generates a transient acylammonium\\u0026nbsp;species, which, through concerted proton transfer, releases sulfonamidate\\u0026nbsp;(\\u003cstrong\\u003eTsN⁻\\u003c/strong\\u003e) (\\u003cstrong\\u003eIII\\u003c/strong\\u003e). The hydrogen-bond-activated aldehyde is subsequently captured by \\u003cstrong\\u003eTsN⁻\\u003c/strong\\u003e, and a hemiaminal is formed within the preorganized complex (\\u003cstrong\\u003eIV\\u003c/strong\\u003e). The resulting alkoxide then promotes intramolecular acyl transfer onto the acylammonium, which regenerates the catalyst and closes the lactone ring to afford the rigid tricyclic product (\\u003cstrong\\u003e3a\\u003c/strong\\u003e). Overall, these data support a cascade mechanism in which stereocontrolled\\u0026nbsp;cycloaddition is followed by amine-promoted acyl transfer and sulfonamide capture of the aldehyde, which accounts for catalyst turnover and the formation of \\u003cstrong\\u003e3a\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eRecognizing the importance of catalyst economy for scaling and complex molecule synthesis, we evaluated the recyclability of catalyst E. The catalyst was reused in five consecutive runs, and in each case, the yield and enantioselectivity remained virtually unchanged. These results confirm that the catalyst can be efficiently recycled without loss of activity or stereocontrol, thus demonstrating the robustness of the protocol and its suitability for large-scale applications, including total synthesis and industrial applications (see Figure S9 in the Supporting Information for additional details).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eApplication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal synthesis of (+)-\\u003c/strong\\u003e\\u003cstrong\\u003epeduncularine\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eGiven that bridged tricyclic lactones have an internal normorphan\\u0026nbsp;core skeleton, we applied our methodology to the total synthesis of (+) peduncularine\\u003csup\\u003e41\\u003c/sup\\u003e\\u003csup\\u003e-50\\u003c/sup\\u003e. The alkaloid (\\u0026ndash;)-peduncularine, which was first isolated in 1971 from \\u003cem\\u003eAristotelia\\u003c/em\\u003e species, has attracted sustained interest owing to its rigid normorphan-derived framework and reported anticancer properties. Several synthetic approaches have been described, including racemic routes and asymmetric variants, although these typically require lengthy sequences or deliver only modest stereocontrol. The most recent asymmetric attempt advanced toward the target but ultimately stalled owing to alkene migration, which left the natural product inaccessible\\u003csup\\u003e53\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003eThe gram-scale preparation of enantioenriched tricycle \\u003cstrong\\u003e4z\\u003c/strong\\u003e (1.6 g, 86% yield, and 97% ee) provided a reliable starting point for total synthesis. First, we needed to convert \\u003cstrong\\u003e4z\\u003c/strong\\u003e to a normorphan core skeleton. Attempts to open the lactone directly under reducing conditions were unsuccessful; Luche reduction produced only hemiacetal \\u003cstrong\\u003e11\\u003c/strong\\u003e. However, oxidative cleavage of \\u003cstrong\\u003e11\\u003c/strong\\u003ewith NaIO₄ successfully furnished the normorphan framework \\u003cstrong\\u003e12\\u003c/strong\\u003e while fully retaining enantiopurity (97% ee). Following Roberson and Woerpel\\u0026rsquo;s precedent, the C7 substituent was stereoselectively introduced under Hosomi\\u0026ndash;Sakurai conditions to yield \\u003cstrong\\u003e13\\u003c/strong\\u003e\\u003csup\\u003e48,54\\u003c/sup\\u003e. To prevent alkene migration from hindering earlier syntheses, a masking\\u0026ndash;unmasking strategy was adopted. Thiophenol-mediated Ns-deprotection/Michael addition afforded \\u003cstrong\\u003e25\\u003c/strong\\u003e, which was transformed into \\u003cstrong\\u003e26\\u003c/strong\\u003e by reduction and Teoc protection. Barton\\u0026ndash;McCombie deoxygenation furnished \\u003cstrong\\u003e28\\u003c/strong\\u003e in excellent yield. Subsequent oxidation under H₂O₂/HFIP was performed, followed by heat-induced sulfoxide elimination. Owing to the rigid geometry of the scaffold, only one sulfoxide conformer underwent elimination, whereas the other remained intact. Recycling the unreacted conformer back to \\u003cstrong\\u003e28\\u003c/strong\\u003e enabled efficient conversion to \\u003cstrong\\u003e29\\u003c/strong\\u003e, which restored the olefin in high yield. Hydroboration/oxidation followed by Swern oxidation afforded the aldehyde, which was converted to its acetal \\u003cstrong\\u003e33\\u003c/strong\\u003e to improve stability and facilitate the subsequent Fischer step. Global deprotection/reductive amination yielded \\u003cstrong\\u003e34\\u003c/strong\\u003e. Fischer indolization, which was performed from the acetal-protected precursor, produced \\u003cstrong\\u003e35\\u003c/strong\\u003e in high yield, and finally, Grieco elimination completed the synthesis of the natural product enantiomer (+)-peduncularine. The overall sequence was completed in 7.9% yield from \\u003cstrong\\u003e1b\\u003c/strong\\u003e. Thus, this route is among the most efficient asymmetric routes to this alkaloid that have been reported to date.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal synthesis of \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e(+)-peduncularine\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe also performed total synthesis of \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e(+)-peduncularine, which is an olefin-migrated analog. Starting from compound \\u003cstrong\\u003e13\\u003c/strong\\u003e, reduction followed by nosyl\\u0026nbsp;deprotection and Teoc\\u0026nbsp;protection provided entry to the deoxygenation stage, where the installation of the \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e olefin proved highly sensitive to the reaction conditions. Several methods were examined (Table 4). Mesylation\\u0026nbsp;of the intermediate alcohol followed by hydride substitution revealed striking differences: LiAlH₄ delivered a near-statistical mixture of direct substitution (P) and migrated olefin (P\\u0026prime;), whereas LiBEt₃H\\u0026nbsp;favored the SN2\\u0026prime; pathway, which produced P\\u0026prime; at a ratio of 1:17. Alternative approaches, including the use of Tsuji\\u0026ndash;Trost and Barton\\u0026ndash;McCombie conditions, resulted in either low yield or poor selectivity. On this basis, the LiBEt₃H\\u0026nbsp;substitution strategy was selected as the most effective route to the desired migrated olefin. From intermediate \\u003cstrong\\u003e17\\u003c/strong\\u003e, hydroboration\\u0026ndash;oxidation followed by Swern\\u0026nbsp;oxidation and acetal protection furnished \\u003cstrong\\u003e20\\u003c/strong\\u003e. Global deprotection and reductive amination then yielded \\u003cstrong\\u003e21\\u003c/strong\\u003e, which was advanced by Fischer indolization\\u0026nbsp;to \\u003cstrong\\u003e22\\u003c/strong\\u003e. Finally, Grieco elimination completed the synthesis of \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e-(+)-peduncularine (\\u003cstrong\\u003e23\\u003c/strong\\u003e). This sequence not only delivers \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e-(+)-peduncularine with high enantiopurity but, together with the synthesis of (+)-peduncularine, demonstrates that both natural and migrated olefin isomers can now be accessed from a single enantioenriched tricyclic platform.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eWe developed an organocatalytic one pot strategy that transforms simple 3-hydroxy-2-pyridones\\u0026nbsp;and \\u0026alpha;,\\u0026beta;-unsaturated aldehydes into rigid, sp\\u0026sup3;-bridged nitrogen tricycles through a cascade of cycloaddition and rearrangement. This platform enables high levels of diastereo- and enantiocontrol under ambient and metal-free conditions while tolerating a wide range of functionalized enals. Mechanistic experiments, including direct observation of a short-lived intermediate, KIE measurements, HRMS analysis, and NMR binding studies, established that the transformation proceeded through a reversible cycloaddition followed by a catalyst-triggered rearrangement, with the stereochemical outcome fully dictated by the catalyst scaffold. In addition to methodological significance of this platform, the use of this platform was demonstrated through the first asymmetric total synthesis of (+)-peduncularine and its \\u0026Delta;\\u003csup\\u003e2,3\\u003c/sup\\u003e-migrated isomer, thereby providing enantioenriched access to both natural and nonnatural members of the peduncularine family. 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The ORTEP structures of \\u003cstrong\\u003e3a\\u003c/strong\\u003e showed thermal ellipsoids at the 50% probability level.\\u003c/li\\u003e\\n\\u003cli\\u003eCCDC2495586 (\\u003cstrong\\u003e6a\\u0026rsquo;\\u003c/strong\\u003e). The ORTEP structures of \\u003cstrong\\u003e6a\\u0026rsquo;\\u003c/strong\\u003e showed thermal ellipsoids at the 50% probability level.\\u003c/li\\u003e\\n\\u003cli\\u003eLiang, G., Christensen, K. E. \\u0026amp; Anderson, E. A. An Asymmetric Approach toward the Aristotelia Alkaloid (-)-Penduncularine. \\u003cem\\u003eOrg Lett\\u003c/em\\u003e \\u003cstrong\\u003e27\\u003c/strong\\u003e, 7798\\u0026ndash;7803 (2025).\\u003c/li\\u003e\\n\\u003cli\\u003eLee, J. H. Use of the Hosomi-Sakurai allylation in natural product total synthesis. \\u003cem\\u003eTetrahedron\\u003c/em\\u003e \\u003cstrong\\u003e76\\u003c/strong\\u003e, 131351 (2020).\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables 1 to 4 are available in the Supplementary Files section.\\u003c/p\\u003e\"},{\"header\":\"Schemes\",\"content\":\"\\u003cp\\u003eSchemes1 to 2 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7888018/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7888018/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"A bridged tricyclic scaffold with an sp3-rich framework offers a versatile core structure for the design of bioactive molecules that resemble those found in numerous natural products with notable biological activities. This scaffold faces key challenges in medium-sized ring synthesis, such as poor site selectivity and stereoselectivity and competing reaction pathways, which are prevalent in current synthetic methods. Here, we describe a highly efficient and one pot method for constructing a bridged tricyclic scaffold using a bifunctional cinchona alkaloid-derived squaramide catalyst. The reaction between 3-hydroxy-2-pyridones and α,β-unsaturated aldehydes results in the formation of a [4+2] cycloaddition adduct as an intermediate. The catalyst directs both enantioselectivity and diastereoselectivity in the initial cycloaddition step and subsequently functions as a Lewis base in the rearrangement process, thus driving the formation of the tricyclic compound in a one-pot reaction. This methodology provides a versatile approach for accessing various bridged tricyclic scaffolds that exhibit excellent enantio- and diastereoselectivities (up to 99% ee and dr \\u003e 20:1). The protocol is scalable to gram quantities and was successfully applied for the first total synthesis of the enantiomer of the alkaloid (-)-peduncularine and the preparation of analogous derivatives, which highlights the method’s utility in the synthesis of complex, enantioenriched natural product derivatives.\",\"manuscriptTitle\":\"Enantioselective One Pot Construction of Bridged Tricyclic Lactones\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-10-24 06:13:07\",\"doi\":\"10.21203/rs.3.rs-7888018/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"3c13ae1e-a40c-4008-bb55-5cb612762f0b\",\"owner\":[],\"postedDate\":\"October 24th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":56583732,\"name\":\"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology\"},{\"id\":56583733,\"name\":\"Physical sciences/Chemistry/Catalysis/Asymmetric catalysis\"}],\"tags\":[],\"updatedAt\":\"2025-10-29T16:10:23+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-10-24 06:13:07\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7888018\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7888018\",\"identity\":\"rs-7888018\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}