Photochemical Cycloaddition as a Gateway to Bicyclic Lactones: Toward Tricyclic Iridoid-Inspired Scaffolds

Photochemical Cycloaddition as a Gateway to Bicyclic Lactones: Toward Tricyclic Iridoid-Inspired Scaffolds | 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 Short Report Photochemical Cycloaddition as a Gateway to Bicyclic Lactones: Toward Tricyclic Iridoid-Inspired Scaffolds Bello Makama, Laurence M Harwood This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6515640/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 photochemical [2 + 2] cycloaddition between cyclopentene-1-one and 1,1-dimethoxyethylene was effectively utilized to synthesize a key bicyclic intermediate in the preparation of tricyclic iridoid-inspired scaffolds. The regioselective outcome of the cycloadduct was confirmed through ¹H NMR and subsequent chemical reactivity studies, indicating that the methoxy groups do not occupy positions β to the carbonyl. Following this, hydrolysis of the cycloadduct yielded a diketone in an excellent yield of 85%, which was subsequently subjected to Baeyer–Villiger oxidation, resulting in a fused γ-lactone with a yield of 64%. Structural elucidation of the intermediates and the final product was conducted using NMR, IR, and mass spectrometry techniques. This photochemical synthetic pathway offers a concise approach to bioinspired tricyclic architectures that may hold significance in natural product chemistry and the design of neuroactive compounds. Photochemical cycloaddition Bicyclic lactones Tricyclic iridoid scaffold Baeyer–Villiger oxidation Regiochemistry 1 1-Dimethoxyethylene Cyclopentenone Natural product synthesis Spectroscopic characterization Figures Figure 1 Figure 2 Figure 3 Introduction This study is part of an ongoing effort to develop synthetic access to bicyclic lactones (AB-ring system) and later tricyclic iridoid lactones, structures that are inherently present in many bioactive secondary metabolites. Among the most notable sources of such compounds is Verbena littoralis , a medicinal plant traditionally used across South America to treat diarrhea, typhoid, and tonsillitis. More recently, extracts of V. littoralis have been reported to potentiate nerve growth factor (NGF)-induced neurite outgrowth in PC12D cells, suggesting that its iridoid lactone constituents may serve as promising lead structures for neurodegenerative disease research¹,². The key bioactive component littoralisone, a highly oxygenated iridoid lactone, embodies a complex tricyclic lactone scaffold. Such motifs are frequently found in natural products with neurotrophic, anti-inflammatory, and cytoprotective properties³. Motivated by their pharmacological potential, our group has previously reported multiple routes for the stereoselective synthesis of bicyclic lactones, including an annelation protocol involving 2-chlorocyclopentanone and diesters⁴, and a Lewis acid-mediated ene-reaction strategy utilizing silver triflate as a promoter⁵. In this work, we expand our synthetic toolbox by applying a photochemical [2 + 2] cycloaddition strategy, specifically the reaction of cyclopentene-1-one with ketene, to access highly functionalized bicyclic lactone cores. This approach offers several synthetic advantages, including mild reaction conditions, minimal byproducts, and high stereocontrol. Photochemical [2 + 2] cycloadditions of enones and ketenes are well-established for generating strained and reactive bicyclic intermediates, suitable for further derivatization into natural product-inspired scaffolds⁶,⁷. As shown in Scheme 1, this method provides an efficient entry into the target lactone framework while simultaneously enabling ketone functionalization. This feature is particularly important for elaboration toward tricyclic iridoid analogs, positioning this approach as a versatile and practical alternative for accessing neuroactive lactone architectures. 1.2 Photochemical reaction of cyclopentene-1-one with ketene A quick retrosynthetic analysis reveals that replacement of cyclopentadiene with cyclopentene-1-one ( 1 ) should lead us to AB-ring system ( 4 ) lacking a side chain. It was hoped the ketone could provide easier funtionalization and further elaboration of the bicyclic framework. This strategy in the end finally rewarded us with some success. Results and Discussion The protocol is depicted in Scheme 1.1 . 1,1-Dimethoxyethene ( 2 ) was redistilled twice prior to its photochemical reaction; the ensuing photochemical [2 + 2] cycloaddition proceeded without any problem and the reaction was quantitative with two products being formed. The cycloadduct ( 3 ), thus formed, had a 1 H NMR spectrum that displayed methylene protons (dd, J 8.8 Hz, centred at 2.49 ppm), two resonances for the methoxy groups (s, 3.18 ppm and 3.16 ppm), and bridgehead protons at 2.68–2.49 ppm. The molecular ion peak (MH + 171) together with the presence of nine carbons as shown in the 13 C NMR bears testimony to a successful [2 + 2] cycloaddition. The carbonyl stretches at 1735 cm − 1 together with 13 C NMR chemical shifts 221.9 (C = O), 101.3 (C(OMe) 2 ), also provide additional evidence for the formation of ( 3 ). However, a side product was also isolated. This product ( 5 ) was characterized by the appearance of a band at 1748 cm − 1 in the IR spectrum. The 1 H NMR spectrum showed a two proton multiplet at 3.82–3.65 ppm and a two proton multiplet at 3.39–3.15 ppm corresponding to the four methine protons. The molecular ion peak at (MH + 164) further showed the undesired adduct to be ( 5 ) Scheme 2.1. 2.2 Regiochemistry of the photoaddition product ( 4 ) Corey 8 raised possible problems pertaining to the regiochemistry of cycloadditions involving 1,1-dimethoxyethylene with cycloalkanones. As much as we hoped that the cycloaddition of the cyclopentene-1-one would afford the desired cycloadduct ( 3 ) there was some uncertainty about the regiochemical outcome of the reaction. However, when the cycloaddition was accomplished 1 H NMR studies of the desired product ( 3 ) revealed that cycloaddition had indeed occurred. Evidence that confirmed the orientation to be of structure ( 3 ) came from the fact that when the photoadduct was treated with sodium ethoxide in ethanol, we noted a lack of replacement of methoxy by ethoxy, which suggests that the methoxy groups are not β to the carbonyl. The conversion of the cycloadduct ( 3 ) into the diketone ( 6 ) was readily achieved by treatment with concentrated hydrochloric acid. The diketone was obtained in high yield (85%). The data obtained for ( 6 ) were consistent with those published in the literature Scheme 3.19. 108 2.3 Ring expansion of diketone ( 6 ) The lactone ( 4 ) was derived from the diketone ( 6 ) in essentially quantitative yield via Baeyer-Villager oxidation, (acetic acid and H 2 O 2 ) to afford a potentially useful product ( 4 ). The 1 H NMR spectrum of the lactone was diagnostic, with a single methine proton appearing as a broad triplet at 5.24 ppm ( J 5.0 Hz), a methine proton as double double doublet at 2.96 ppm ( J 5.0 and 2.5 Hz), the diastereotopic CH 2 protons adjacent to the ester appeared as a doublet, centred at 2.85 ppm ( J 10 and 2.5 Hz) and a doublet at 2.78 ppm. The carbonyl stretchings at 1751 cm − 1 and 1737 cm − 1 are those expected for the γ-lactone ( 4 ) Scheme 2.3 Experimental Techniques Commercial reagents were obtained from Aldrich and Lancaster chemical suppliers and were used directly as supplied or purified prior to use following the guidelines of Perrin and Amarego. 9 Dichloromethane and acetonitrile were refluxed over and distilled from CaH 2 prior to use. Diethyl ether and ethanol were obtained dry from Aldrich. THF was dried by distillation from the sodium benzophenone ketyl radical under nitrogen. Light petroleum is the fraction of petroleum ether boiling in the range 30-40 o C, and it was fractionally distilled through a 36 cm Vigreux column before use. Non-aqueous reagents were transferred under argon via syringe. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator using a water bath. Thin-layer chromatography (TLC) was performed on Merck aluminium-backed plates coated with 0.2 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by UV fluorescence quenching at 254nm, or by staining with a KMnO 4 solution. 1 H and 13 C NMR spectra were recorded on a Bruker DPX250 (250 MHz for protons) and a Brüker AMX400 (400 MHz for protons). Data for 1 H NMR are reported as follows: chemical shift (δ-ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant in (Hz). Data for 13 C NMR spectra are reported in terms of chemical shift (ppm) down field from TMS. IR spectra were recorded on a Perkin Elmer Paragon 1000 or a Perkin Elmer 881 spectrometer as a thin film between sodium chloride plates or as a KBr disk. All absorptions are reported in terms of frequency of absorption (cm -1 ). Mass spectrometric data were recorded on VG Autospec, under conditions of chemical ionisation (C.I) using ammonia as the ionising source. Peaks are quoted in the form ( m /z) (relative intensity). 6,6-dimethoxybicyclo[3.2.0]heptan-2-one (6) 10 anti -tricyclo[5.3.0 2,6 ]decan-3,8-dione (5) solution of redistilled cyclopentanone (4.00 g, 48.8 mmol, 1.00 equiv) in pentane (70 mL) was added 1,1-dimethoxy-ethylene (4.30 g, 48.8 mmol, 1.00 equiv) under nitrogen was cooled in a dry ice bath and irradiated using high pressure mercury arc, quartz well, and corex filter in a Rayonet ® photoreactor (366 nm) for 3 h. TLC analysis indicated no starting material was present. The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica, eluting with hex : ethyl acetate (2:1) to afford (273) as a colourless oil (6.1 g, 75%); υ max (thin film/cm -1 ), 2928, 1718, 1636, 1158; δ H (250 MHz, CDCl 3 ) 3.82-3.65 (2H, m, O=CC H= C H C=O), 3.39-3.15 (2H, m, O=CC H= C H C=O), 2-86-2.70 (4H, m, C H 2 C=O, C H 2 C=O), 2.52-1.99 (4H, m, C H 2 C=O, C H 2 C=O); δ C (62.5 MHz, CDCl 3 ) 220.1, 49.9, 37.7, 36.5, 28.5; m / z (C.I) 164 (M + , 100%), 162, (56%), 161, (8%) C 10 H 13 O 2 , requires 164.0837, found, 164.0834; further elution gave (272) (1.9 g, 23%), m.p. 29-30 o C; υ max (thin film/cm -1 ), 2970, 2836, 1735, 1142, 1043; δ H (250 MHz, CDCl 3 ) 3.18 (1H, s, COC H 3 ), 3.16 (1H, s, COCH 3 ), 2.68-2.49 (2H, m, C H= C H bridgehead), 2.49 (1H, dd, J 8.8 Hz, J 3.0 Hz, C H 2 COMe 2 ), 2.33-2.15 (3H, m, C H 2 COMe 2, C H 2 CH 2 , CH 2 C H 2 ), 2.02-1.93 (2H, m, C H 2 CH 2 , CH 2 C H 2 ); δ C (62.5 MHz, CDCl 3 ) 221.9, 101.3, 48.8, 48.7, 45.5, 37.9, 37.1, 35.8, 20.9; m / z (C.I) 171 (MH + , 79%), 169 (48%), 167 (9%), 163 (5%), 161 (11%), C 9 H 16 O 3 , requires 171.1022 found, 171.1016. Bicyclo[3.2.0]heptane-2,6-dione (6) 10 To a stirred solution of 6,6-dimethoxybicyclo[3.2.0]heptan-2-one (272) (70 mg, 0.41 mmol, 1.00 equiv) in water (5 mL) and THF (1 mL) was added two drops of concentrated hydrochloric acid. The reaction was stirred at room temperature for 10 h until TLC analysis showed no presence of starting material. The product was concentrated in vacuo to remove the THF and most of the water. The residue was extracted with ethyl acetate (4 x 10 mL), washed with brine (4 x 5 mL), dried over MgSO 4 and concentrated in vacuo to give a near colourless oil. The oil was further purified by column chromatography on silica using hexane : ethyl acetate (1:1) to afford the title compound (268) as a colourless oil (43 mg, 85%); υ max (thin film/cm -1 ), 3164, 2360, 1783, 1738, 1145; δ H (250 MHz, CDCl 3 ) 3.95-3.51 (2H, m, C H C=O, C H 2 C=O), 3.06-2.98 (2H, m, C H CH 2 C=O, C H 2 C=O), 2.58-2.15 (4H, m, C H 2 CH 2, CH 2 CH 2 C=O); δ C (62.5 MHz, CDCl 3 ) 224.4, 221.6, 61.9, 52.4, 36.2, 36.1, 22.3; m / z (C.I) 124 (M + , 21%), 123, (67%), 100, (99%), 86 (54%), 84 (82%), C 7 H 9 O 2 , requires 124.0524, found, 124.0519. Tetrahydro-cyclopenta[ b ]furan-2,4-dione (4) To a stirred solution of bicyclo [3.2.0] hept-2-ene-6-one (268) (50.0 mg, 0.40 mmol, 1.00 equiv) in 90% aqueous acetic acid (5 mL) cooled to 0 o C was added 27.5% H 2 O 2 (110 mg, 3.23 mmol, 8.00 equiv) in 90% aqueous acetic acid (5 mL). The reaction was allowed to warm-up to room temperature for 24 hr, by which time TLC analysis revealed a new product been formed. The product was extracted with ether (4 x 10 mL), washed with 10% aqueous sodium sulfite (2 x 5 mL) and saturated sodium carbonate (4 x 5mL). The ether layer was dried over MgSO 4 and the solvents were removed in vacuo . Column chromatography on silica, eluting with hexane : ethyl acetate gave the product as a colourless oil (36 mg, 64%); υ max (thin film/cm -1 ), 2929, 2851, 1751, 1737, 1644, 1088; δ H (250 MHz, CDCl 3 ) 5.24 (1H, t, J 5.0 Hz, CH O), 2.96 (1H, dddd, J 5.0 Hz, J 2.5 Hz, C H =CH 2 C=O), 2.85 (1H, d, J 10 Hz, J 2.5 Hz, C H 2 C=O), 2.78 (1H, d, J 15.0 Hz, C H 2 C=O), 2.57-2.43 (3H, m, C H 2 CHO, C H 2 C=O), 2.32-2.22 (1H, m, C H 2 CHO); δ C (62.5 MHz, CDCl 3 ) 209, 176.6, 82.6, 77.6, 48.0, 35.0, 32.8, 27.3; m / z (C.I) 141 (MH + , 90%), 130 ( 61%), 132 (100%), 112 (21%), 99 (11%) C 7 H 10 O 3 requires 141.0809, found, 141.0549. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and material Not applicable, as the manuscript does not rely on external datasets; all data and observations are included in the manuscript discussion and analysis. Competing interests The authors declare that there are no competing interests. Funding This study did not receive any external funding. Authors' contributions Dr. Bello Makama conducted all experimental work, analyzed the results, and drafted the manuscript. Prof. Laurence M. Harwood supervised the project and contributed to the characterization of all compounds via NMR, IR, and mass spectrometry, as well as providing critical revisions to the manuscript. Acknowledgements The authors gratefully acknowledge the University of Reading, United Kingdom, for providing laboratory space, instrumentation, and technical support essential to the successful completion of this research. Clinical Trial Number Not applicable. References Li YS, Matsunaga K, Ishibashi M, Ohizumi Y. Littoralisone, a novel neuritogenic iridolactone having an unprecedented heptacyclic skeleton from Verbena littoralis . J Org Chem. 2001;66(6):2165–2167. https://doi.org/10.1021/jo001522l Zhao Y, Wang J, Wang Y. Recent advances in iridoid chemistry: biosynthesis and chemical synthesis. Chem Asian J. 2020;15(24):4073–4085. https://doi.org/10.1002/asia.202001034 Zhou J, Wang H. Iridoids: research advances in their phytochemistry, biological activities, and pharmacokinetics. Front Pharmacol. 2020;11:879. https://doi.org/10.3389/fphar.2020.00879 Makama BY. Stereoselective synthesis of bicyclic lactones via annelation protocol. Am J Org Chem. 2012;2(6):127–131. https://doi.org/10.5923/j.ajoc.20120206.01 Makama BY. Preparation of bicyclic lactones using Lewis acids catalyzed ene-reaction. Sci World J. 2010;5(1):15–16. https://www.ajol.info/index.php/swj/article/view/61508 Zimmerman HE, Mariano PS. Photochemical [2 + 2] cycloaddition reactions of ketenes and enones: mechanisms and synthetic applications. Chem Rev. 1996;96(1):123–140. https://doi.org/10.1021/cr950053p Ischay MA, Anzovino ME, Du J, Yoon TP. Efficient visible light photocatalysis of [2 + 2] enone cycloadditions. J Am Chem Soc. 2008;130(39):12886–12887. https://doi.org/10.1021/ja805387f Corey, E.J., Bass, J.D., LeMahieu, R., Mitra, R. A new stereospecific synthesis of bicyclic lactones. J. Am. Chem. Soc. 86, 5570 (1964). Perrin, D.D., Armarego, W.L.F. Purification of Laboratory Chemicals , 4th edn. Pergamon Press, Oxford (1998). Termont, D., De Keukeleire, D.D., Vandewalle, M. Photochemical reaction of cyclopentenone derivatives. J. Chem. Soc., Perkin Trans. 1 1977, 2349. Schemes Schemes 1.1 to 2.3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Schemes.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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6515640","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":453878647,"identity":"8fe8ca37-6736-482e-9bf8-ecb12c190975","order_by":0,"name":"Bello Makama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYBACAwbmxgMghgSI+ACkYCKMDTi1MDbAtTDOAGuBiBCnhZkHSQSnFnP2xoYDHxi2yUu2n078bLvDQh4kcvAHg43shgPYtVj2HGw4OIPhtuFsntzN0rlnJAx3AkUO8zCkGePSYnAjEaTgNuM8htwN0rltEglgEQaGw4k4tdx/CNZiP4//7ebfllAtQIf9x63lBiNYS+Jsidxt0oxQLQd4GA7g1GLZAzRzhsHt5Jkz3m6z7G2TMNxwBuQXg2TjmTi0mLMfPvjgQ8Vt2xnnczff+NlWJ29wvPngwx8VdrJ9OLRAnUeEyCgYBaNgFIwCEgAAkxds2eLWtngAAAAASUVORK5CYII=","orcid":"","institution":"Nicholls State University","correspondingAuthor":true,"prefix":"","firstName":"Bello","middleName":"","lastName":"Makama","suffix":""},{"id":453878648,"identity":"a8e664ce-e2e2-4920-b548-45c953809e46","order_by":1,"name":"Laurence M Harwood","email":"","orcid":"","institution":"Nicholls State University","correspondingAuthor":false,"prefix":"","firstName":"Laurence","middleName":"M","lastName":"Harwood","suffix":""}],"badges":[],"createdAt":"2025-04-23 22:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6515640/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6515640/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82381163,"identity":"5da2cd3f-5331-4356-91e0-cac3533ab1db","added_by":"auto","created_at":"2025-05-09 15:29:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12428,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Experimental Techniques section.\u003c/p\u003e","description":"","filename":"UF1.png","url":"https://assets-eu.researchsquare.com/files/rs-6515640/v1/f1cb95f3aa0c55b83436d917.png"},{"id":82381619,"identity":"3a144602-042b-43f1-9051-3a6f37152102","added_by":"auto","created_at":"2025-05-09 15:37:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2890,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Experimental Techniques section.\u003c/p\u003e","description":"","filename":"UF2.png","url":"https://assets-eu.researchsquare.com/files/rs-6515640/v1/183ce2d8a831f657c144e6ff.png"},{"id":82381620,"identity":"7aea9f31-db2f-4cf8-83ec-91f7fac7a57c","added_by":"auto","created_at":"2025-05-09 15:37:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3220,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Experimental Techniques section.\u003c/p\u003e","description":"","filename":"UF3.png","url":"https://assets-eu.researchsquare.com/files/rs-6515640/v1/732e6cbb25d6971737d6fe5c.png"},{"id":85237357,"identity":"6907f8ab-1531-4b72-a676-118a9ff4b23f","added_by":"auto","created_at":"2025-06-23 17:16:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":558487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6515640/v1/848b5299-fa0b-4d3a-81fa-f53604377301.pdf"},{"id":82381165,"identity":"e507396d-1709-4a81-b741-a12f09a29a0e","added_by":"auto","created_at":"2025-05-09 15:29:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":63469,"visible":true,"origin":"","legend":"","description":"","filename":"Schemes.docx","url":"https://assets-eu.researchsquare.com/files/rs-6515640/v1/769576896606e6473d94d92c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Photochemical Cycloaddition as a Gateway to Bicyclic Lactones: Toward Tricyclic Iridoid-Inspired Scaffolds","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThis study is part of an ongoing effort to develop synthetic access to bicyclic lactones (AB-ring system) and later tricyclic iridoid lactones, structures that are inherently present in many bioactive secondary metabolites. Among the most notable sources of such compounds is \u003cem\u003eVerbena littoralis\u003c/em\u003e, a medicinal plant traditionally used across South America to treat diarrhea, typhoid, and tonsillitis. More recently, extracts of \u003cem\u003eV. littoralis\u003c/em\u003e have been reported to potentiate nerve growth factor (NGF)-induced neurite outgrowth in PC12D cells, suggesting that its iridoid lactone constituents may serve as promising lead structures for neurodegenerative disease research\u0026sup1;,\u0026sup2;.\u003c/p\u003e \u003cp\u003eThe key bioactive component littoralisone, a highly oxygenated iridoid lactone, embodies a complex tricyclic lactone scaffold. Such motifs are frequently found in natural products with neurotrophic, anti-inflammatory, and cytoprotective properties\u0026sup3;. Motivated by their pharmacological potential, our group has previously reported multiple routes for the stereoselective synthesis of bicyclic lactones, including an annelation protocol involving 2-chlorocyclopentanone and diesters⁴, and a Lewis acid-mediated ene-reaction strategy utilizing silver triflate as a promoter⁵.\u003c/p\u003e \u003cp\u003eIn this work, we expand our synthetic toolbox by applying a photochemical [2\u0026thinsp;+\u0026thinsp;2] cycloaddition strategy, specifically the reaction of cyclopentene-1-one with ketene, to access highly functionalized bicyclic lactone cores. This approach offers several synthetic advantages, including mild reaction conditions, minimal byproducts, and high stereocontrol. Photochemical [2\u0026thinsp;+\u0026thinsp;2] cycloadditions of enones and ketenes are well-established for generating strained and reactive bicyclic intermediates, suitable for further derivatization into natural product-inspired scaffolds⁶,⁷.\u003c/p\u003e \u003cp\u003eAs shown in Scheme 1, this method provides an efficient entry into the target lactone framework while simultaneously enabling ketone functionalization. This feature is particularly important for elaboration toward tricyclic iridoid analogs, positioning this approach as a versatile and practical alternative for accessing neuroactive lactone architectures.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Photochemical reaction of cyclopentene-1-one with ketene\u003c/h2\u003e \u003cp\u003eA quick retrosynthetic analysis reveals that replacement of cyclopentadiene with cyclopentene-1-one (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) should lead us to AB-ring system (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) lacking a side chain. It was hoped the ketone could provide easier funtionalization and further elaboration of the bicyclic framework. This strategy in the end finally rewarded us with some success.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003cp\u003eThe protocol is depicted in Scheme \u003cspan class=\"InternalRef\"\u003e1.1\u003c/span\u003e. 1,1-Dimethoxyethene (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) was redistilled twice prior to its photochemical reaction; the ensuing photochemical [2\u0026thinsp;+\u0026thinsp;2] cycloaddition proceeded without any problem and the reaction was quantitative with two products being formed. The cycloadduct (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e), thus formed, had a \u003csup\u003e1\u003c/sup\u003eH NMR spectrum that displayed methylene protons (dd, \u003cem\u003eJ\u003c/em\u003e 8.8 Hz, centred at 2.49 ppm), two resonances for the methoxy groups (s, 3.18 ppm and 3.16 ppm), and bridgehead protons at 2.68\u0026ndash;2.49 ppm. The molecular ion peak (MH\u003csup\u003e+\u003c/sup\u003e 171) together with the presence of nine carbons as shown in the \u003csup\u003e13\u003c/sup\u003eC NMR bears testimony to a successful [2\u0026thinsp;+\u0026thinsp;2] cycloaddition. The carbonyl stretches at 1735 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e together with \u003csup\u003e13\u003c/sup\u003eC NMR chemical shifts 221.9 (C\u0026thinsp;=\u0026thinsp;O), 101.3 (C(OMe)\u003csub\u003e2\u003c/sub\u003e), also provide additional evidence for the formation of (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). However, a side product was also isolated. This product (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e) was characterized by the appearance of a band at 1748 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in the IR spectrum. The \u003csup\u003e1\u003c/sup\u003eH NMR spectrum showed a two proton multiplet at 3.82\u0026ndash;3.65 ppm and a two proton multiplet at 3.39\u0026ndash;3.15 ppm corresponding to the four methine protons. The molecular ion peak at (MH\u003csup\u003e+\u003c/sup\u003e 164) further showed the undesired adduct to be (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e) Scheme 2.1.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Regiochemistry of the photoaddition product (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/h2\u003e\n \u003cp\u003eCorey\u003csup\u003e8\u003c/sup\u003e raised possible problems pertaining to the regiochemistry of cycloadditions involving 1,1-dimethoxyethylene with cycloalkanones. As much as we hoped that the cycloaddition of the cyclopentene-1-one would afford the desired cycloadduct (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) there was some uncertainty about the regiochemical outcome of the reaction. However, when the cycloaddition was accomplished \u003csup\u003e1\u003c/sup\u003eH NMR studies of the desired product (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) revealed that cycloaddition had indeed occurred. Evidence that confirmed the orientation to be of structure (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) came from the fact that when the photoadduct was treated with sodium ethoxide in ethanol, we noted a lack of replacement of methoxy by ethoxy, which suggests that the methoxy groups are not \u0026beta; to the carbonyl. The conversion of the cycloadduct (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e) into the diketone (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e) was readily achieved by treatment with concentrated hydrochloric acid. The diketone was obtained in high yield (85%). The data obtained for (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e) were consistent with those published in the literature Scheme 3.19.\u003csup\u003e108\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Ring expansion of diketone (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/h2\u003e\n \u003cp\u003eThe lactone (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) was derived from the diketone (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e) in essentially quantitative yield via Baeyer-Villager oxidation, (acetic acid and H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) to afford a potentially useful product (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). The \u003csup\u003e1\u003c/sup\u003eH NMR spectrum of the lactone was diagnostic, with a single methine proton appearing as a broad triplet at 5.24 ppm (\u003cem\u003eJ\u003c/em\u003e 5.0 Hz), a methine proton as double double doublet at 2.96 ppm (\u003cem\u003eJ\u003c/em\u003e 5.0 and 2.5 Hz), the diastereotopic CH\u003csub\u003e2\u003c/sub\u003e protons adjacent to the ester appeared as a doublet, centred at 2.85 ppm (\u003cem\u003eJ\u003c/em\u003e 10 and 2.5 Hz) and a doublet at 2.78 ppm. The carbonyl stretchings at 1751 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 1737 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are those expected for the \u0026gamma;-lactone (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) Scheme 2.3\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Experimental Techniques","content":"\u003cp\u003eCommercial reagents were obtained from Aldrich and Lancaster chemical suppliers and were used directly as supplied or purified prior to use following the guidelines of Perrin and Amarego.\u003csup\u003e9\u003c/sup\u003e Dichloromethane and acetonitrile were refluxed over and distilled from CaH\u003csub\u003e2\u003c/sub\u003e prior to use. Diethyl ether and ethanol were obtained dry from Aldrich. THF was dried by distillation from the sodium benzophenone ketyl radical under nitrogen. Light petroleum is the fraction of petroleum ether boiling in the range 30-40 \u003csup\u003eo\u003c/sup\u003eC, and it was fractionally distilled through a 36 cm Vigreux column before use.\u003c/p\u003e\n\u003cp\u003eNon-aqueous reagents were transferred under argon \u003cem\u003evia\u003c/em\u003e syringe. Organic solutions were concentrated under reduced pressure on a B\u0026uuml;chi rotary evaporator using a water bath. Thin-layer chromatography (TLC) was performed on Merck aluminium-backed plates coated with 0.2 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by UV fluorescence quenching at 254nm, or by staining with a KMnO\u003csub\u003e4\u0026nbsp;\u003c/sub\u003e solution.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on a Bruker DPX250 (250 MHz for protons) and a Br\u0026uuml;ker AMX400 (400 MHz for protons). Data for \u003csup\u003e1\u003c/sup\u003eH NMR are reported as follows: chemical shift (\u0026delta;-ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant in (Hz). Data for \u003csup\u003e13\u003c/sup\u003eC NMR spectra are reported in terms of chemical shift (ppm) down field from TMS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIR spectra were recorded on a Perkin Elmer Paragon 1000 or a Perkin Elmer 881 spectrometer as a thin film between sodium chloride plates or as a KBr disk. All absorptions are reported in terms of frequency of absorption (cm\u003csup\u003e-1\u003c/sup\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMass spectrometric data were recorded on VG Autospec, under conditions of chemical ionisation (C.I) using ammonia as the ionising source. Peaks are quoted in the form \u003cem\u003e(\u003csup\u003em\u003c/sup\u003e/z)\u003c/em\u003e (relative intensity).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6,6-dimethoxybicyclo[3.2.0]heptan-2-one (6)\u003c/strong\u003e\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eanti\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-tricyclo[5.3.0 \u003csup\u003e2,6\u003c/sup\u003e]decan-3,8-dione (5)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003esolution of redistilled cyclopentanone (4.00 g, 48.8 mmol, 1.00 equiv) in pentane (70 mL) was added 1,1-dimethoxy-ethylene \u0026nbsp;(4.30 g, 48.8 mmol, 1.00 equiv) under nitrogen was cooled in a dry ice bath and irradiated using high pressure mercury arc, quartz well, and corex filter in a Rayonet\u003csup\u003e\u0026reg;\u003c/sup\u003e photoreactor (366 nm) for 3 h. TLC analysis indicated no starting material was present. The solvent was removed \u003cem\u003ein vacuo,\u0026nbsp;\u003c/em\u003eand the residue was subjected to column chromatography on silica, eluting with hex : ethyl acetate (2:1) to afford \u0026nbsp;\u003cstrong\u003e(273)\u0026nbsp;\u003c/strong\u003eas a colourless oil (6.1 g, 75%); \u0026upsilon;\u003csub\u003emax\u003c/sub\u003e (thin film/cm\u003csup\u003e-1\u003c/sup\u003e), 2928, 1718, 1636, 1158; \u0026delta;\u003csub\u003eH\u003c/sub\u003e (250 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 3.82-3.65 (2H, m, O=CC\u003cstrong\u003eH=\u003c/strong\u003eC\u003cstrong\u003eH\u003c/strong\u003eC=O), 3.39-3.15 (2H, m, O=CC\u003cstrong\u003eH=\u003c/strong\u003eC\u003cstrong\u003eH\u003c/strong\u003eC=O), 2-86-2.70 (4H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 2.52-1.99 (4H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O); \u0026delta;\u003csub\u003eC\u0026nbsp;\u003c/sub\u003e(62.5 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 220.1, 49.9, 37.7, 36.5, 28.5; \u003csup\u003em\u003c/sup\u003e/\u003csub\u003ez\u003c/sub\u003e (C.I) 164 (M\u003csup\u003e+\u003c/sup\u003e, 100%), 162, (56%), 161, (8%) C\u003csub\u003e10\u003c/sub\u003eH\u003csub\u003e13\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, requires 164.0837, found, 164.0834; further elution gave \u003cstrong\u003e(272)\u003c/strong\u003e (1.9 g, 23%), m.p. 29-30 \u003csup\u003eo\u003c/sup\u003eC; \u0026nbsp;\u0026upsilon;\u003csub\u003emax\u003c/sub\u003e (thin film/cm\u003csup\u003e-1\u003c/sup\u003e), 2970, 2836, 1735, 1142, 1043; \u0026delta;\u003csub\u003eH\u003c/sub\u003e (250 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 3.18 (1H, s, COC\u003cstrong\u003eH\u003csub\u003e3\u003c/sub\u003e\u003c/strong\u003e), 3.16 (1H, s, COCH\u003csub\u003e3\u003c/sub\u003e ), 2.68-2.49 (2H, m, C\u003cstrong\u003eH=\u003c/strong\u003eC\u003cstrong\u003eH\u003c/strong\u003e bridgehead), 2.49 (1H, dd, \u003cem\u003eJ\u0026nbsp;\u003c/em\u003e8.8 Hz, \u003cem\u003eJ\u003c/em\u003e 3.0 Hz, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCOMe\u003csub\u003e2\u003c/sub\u003e), 2.33-2.15 (3H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCOMe\u003csub\u003e2,\u0026nbsp;\u003c/sub\u003eC\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCH\u003csub\u003e2\u003c/sub\u003e, CH\u003csub\u003e2\u003c/sub\u003eC\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003e), 2.02-1.93 (2H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCH\u003csub\u003e2\u003c/sub\u003e, CH\u003csub\u003e2\u003c/sub\u003eC\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003e); \u0026delta;\u003csub\u003eC\u0026nbsp;\u003c/sub\u003e(62.5 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 221.9, 101.3, 48.8, 48.7, 45.5, 37.9, 37.1, 35.8, 20.9; \u003csup\u003em\u003c/sup\u003e/\u003csub\u003ez\u003c/sub\u003e (C.I) 171 (MH\u003csup\u003e+\u003c/sup\u003e, 79%), 169 (48%), 167 (9%), 163 (5%), 161 (11%), C\u003csub\u003e9\u003c/sub\u003eH\u003csub\u003e16\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e, requires 171.1022 found, 171.1016. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBicyclo[3.2.0]heptane-2,6-dione (6)\u003c/strong\u003e\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTo a stirred solution of 6,6-dimethoxybicyclo[3.2.0]heptan-2-one\u003cstrong\u003e\u0026nbsp;(272)\u003c/strong\u003e (70 mg, 0.41 mmol, 1.00 equiv) in water (5 mL) and THF (1 mL) was added two drops of concentrated hydrochloric acid. The reaction was stirred at room temperature for 10 h until TLC analysis showed no presence of starting material. The product was concentrated \u003cem\u003ein\u003c/em\u003e \u003cem\u003evacuo\u003c/em\u003e to remove the THF and most of the water. The residue was extracted with ethyl acetate (4 x 10 mL), washed with brine (4 x 5 mL), dried over MgSO\u003csub\u003e4\u003c/sub\u003e and concentrated \u003cem\u003ein\u003c/em\u003e \u003cem\u003evacuo\u003c/em\u003e to give a near colourless oil. The oil was further purified by column chromatography on silica using hexane : ethyl acetate (1:1) to afford the title compound \u003cstrong\u003e(268)\u003c/strong\u003e as a colourless oil (43 mg, 85%); \u0026upsilon;\u003csub\u003emax\u003c/sub\u003e (thin film/cm\u003csup\u003e-1\u003c/sup\u003e), 3164, 2360, 1783, 1738, 1145; \u0026delta;\u003csub\u003eH\u003c/sub\u003e (250 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 3.95-3.51 (2H, m, C\u003cstrong\u003eH\u003c/strong\u003eC=O, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 3.06-2.98 (2H, m, C\u003cstrong\u003eH\u003c/strong\u003eCH\u003csub\u003e2\u003c/sub\u003eC=O, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 2.58-2.15 (4H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCH\u003csub\u003e2,\u003c/sub\u003e CH\u003csub\u003e2\u003c/sub\u003e\u003cstrong\u003eCH\u003c/strong\u003e\u003csub\u003e2\u003c/sub\u003eC=O); \u0026delta;\u003csub\u003eC\u0026nbsp;\u003c/sub\u003e(62.5 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026nbsp;224.4, 221.6, 61.9, 52.4, 36.2, 36.1, 22.3; \u003csup\u003e\u0026nbsp;m\u003c/sup\u003e/\u003csub\u003ez\u003c/sub\u003e (C.I) 124 (M\u003csup\u003e+\u003c/sup\u003e, 21%), 123, (67%), 100, (99%), 86 (54%), 84 (82%), \u0026nbsp;C\u003csub\u003e7\u003c/sub\u003eH\u003csub\u003e9\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, requires 124.0524, found, 124.0519.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTetrahydro-cyclopenta[\u003cem\u003eb\u003c/em\u003e]furan-2,4-dione (4)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo a stirred \u0026nbsp;solution of bicyclo [3.2.0] hept-2-ene-6-one \u003cstrong\u003e(268)\u003c/strong\u003e (50.0 mg, 0.40 mmol, 1.00 equiv) in \u0026nbsp;90% aqueous acetic acid (5 mL) \u0026nbsp;cooled to 0 \u003csup\u003eo\u003c/sup\u003eC was added 27.5% H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e\u0026nbsp; \u0026nbsp;(110 mg, 3.23 mmol, 8.00 equiv) in \u0026nbsp; 90% aqueous acetic acid (5 mL). The reaction was allowed to warm-up to room temperature for 24 hr, by which time TLC analysis revealed a new product been formed. \u0026nbsp;The product was extracted with ether (4 x 10 mL), washed with 10% aqueous sodium sulfite (2 x 5 mL) and saturated sodium carbonate (4 x 5mL). The ether layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and the solvents were removed \u003cem\u003ein vacuo\u003c/em\u003e. Column chromatography on silica, eluting with hexane : ethyl acetate gave the product as a colourless oil (36 mg, 64%); \u0026upsilon;\u003csub\u003emax\u003c/sub\u003e (thin film/cm\u003csup\u003e-1\u003c/sup\u003e), 2929, 2851, 1751, 1737, 1644, 1088; \u0026delta;\u003csub\u003eH\u003c/sub\u003e (250 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 5.24 \u0026nbsp;(1H, t, \u003cem\u003eJ\u0026nbsp;\u003c/em\u003e5.0 Hz, \u003cstrong\u003eCH\u003c/strong\u003eO), 2.96 (1H, dddd, \u003cem\u003eJ\u003c/em\u003e 5.0 Hz, \u003cem\u003eJ\u003c/em\u003e 2.5 Hz, C\u003cstrong\u003eH\u003c/strong\u003e=CH\u003csub\u003e2\u003c/sub\u003eC=O), 2.85 (1H, d, \u003cem\u003eJ\u003c/em\u003e 10 Hz, \u003cem\u003eJ\u003c/em\u003e 2.5 Hz, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 2.78 (1H, d, \u003cem\u003eJ\u003c/em\u003e 15.0 Hz, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 2.57-2.43 (3H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCHO, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eC=O), 2.32-2.22 (1H, m, C\u003cstrong\u003eH\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003eCHO); \u0026delta;\u003csub\u003eC\u0026nbsp;\u003c/sub\u003e(62.5 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) 209, 176.6, 82.6, 77.6, 48.0, 35.0, 32.8, 27.3; \u003csup\u003e\u0026nbsp;m\u003c/sup\u003e/\u003csub\u003ez\u003c/sub\u003e (C.I) 141 (MH\u003csup\u003e+\u003c/sup\u003e, 90%), 130 ( 61%), 132 (100%), 112 (21%), 99 (11%) C\u003csub\u003e7\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e requires 141.0809, found, 141.0549.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material\u003c/p\u003e\n\u003cp\u003eNot applicable, as the manuscript does not rely on external datasets; all data and observations are included in the manuscript discussion and analysis.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study did not receive any external funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eDr. Bello Makama conducted all experimental work, analyzed the results, and drafted the manuscript. Prof. Laurence M. Harwood supervised the project and contributed to the characterization of all compounds via NMR, IR, and mass spectrometry, as well as providing critical revisions to the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge the University of Reading, United Kingdom, for providing laboratory space, instrumentation, and technical support essential to the successful completion of this research.\u003c/p\u003e\n\u003cp\u003eClinical Trial Number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi YS, Matsunaga K, Ishibashi M, Ohizumi Y. Littoralisone, a novel neuritogenic iridolactone having an unprecedented heptacyclic skeleton from \u003cem\u003eVerbena littoralis\u003c/em\u003e. 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Sci World J. 2010;5(1):15\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ajol.info/index.php/swj/article/view/61508\u003c/span\u003e\u003cspan address=\"https://www.ajol.info/index.php/swj/article/view/61508\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZimmerman HE, Mariano PS. Photochemical [2\u0026thinsp;+\u0026thinsp;2] cycloaddition reactions of ketenes and enones: mechanisms and synthetic applications. Chem Rev. 1996;96(1):123\u0026ndash;140. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1021/cr950053p\u003c/span\u003e\u003cspan address=\"10.1021/cr950053p\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIschay MA, Anzovino ME, Du J, Yoon TP. Efficient visible light photocatalysis of [2\u0026thinsp;+\u0026thinsp;2] enone cycloadditions. J Am Chem Soc. 2008;130(39):12886\u0026ndash;12887. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1021/ja805387f\u003c/span\u003e\u003cspan address=\"10.1021/ja805387f\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorey, E.J., Bass, J.D., LeMahieu, R., Mitra, R. A new stereospecific synthesis of bicyclic lactones. J. Am. Chem. Soc. 86, 5570 (1964).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerrin, D.D., Armarego, W.L.F. \u003cem\u003ePurification of Laboratory Chemicals\u003c/em\u003e, 4th edn. Pergamon Press, Oxford (1998).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTermont, D., De Keukeleire, D.D., Vandewalle, M. Photochemical reaction of cyclopentenone derivatives. J. Chem. Soc., Perkin Trans. \u003cem\u003e1\u003c/em\u003e 1977, 2349.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1.1 to 2.3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"[email protected]","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":"Photochemical cycloaddition, Bicyclic lactones, Tricyclic iridoid scaffold, Baeyer–Villiger oxidation, Regiochemistry, 1,1-Dimethoxyethylene, Cyclopentenone, Natural product synthesis, Spectroscopic characterization","lastPublishedDoi":"10.21203/rs.3.rs-6515640/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6515640/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA photochemical [2\u0026thinsp;+\u0026thinsp;2] cycloaddition between cyclopentene-1-one and 1,1-dimethoxyethylene was effectively utilized to synthesize a key bicyclic intermediate in the preparation of tricyclic iridoid-inspired scaffolds. The regioselective outcome of the cycloadduct was confirmed through \u0026sup1;H NMR and subsequent chemical reactivity studies, indicating that the methoxy groups do not occupy positions β to the carbonyl. Following this, hydrolysis of the cycloadduct yielded a diketone in an excellent yield of 85%, which was subsequently subjected to Baeyer\u0026ndash;Villiger oxidation, resulting in a fused γ-lactone with a yield of 64%. Structural elucidation of the intermediates and the final product was conducted using NMR, IR, and mass spectrometry techniques. This photochemical synthetic pathway offers a concise approach to bioinspired tricyclic architectures that may hold significance in natural product chemistry and the design of neuroactive compounds.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Photochemical Cycloaddition as a Gateway to Bicyclic Lactones: Toward Tricyclic Iridoid-Inspired Scaffolds","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 15:29:34","doi":"10.21203/rs.3.rs-6515640/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"e72d1e20-68d2-4e33-ab82-568884b87f7e","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-23T17:08:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 15:29:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6515640","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6515640","identity":"rs-6515640","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}