Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon

Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon Xinfang Xu, Kemiao Hong, Mengting Liu, Lixin Qian, Ming Bao, Gang Chen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3892850/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Jun, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Cycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, substantial hurdles remain for extending the C4 synthon, which is mainly limited to dienes and 1,4-dipoles so far, to construct diverse heterocycles via programmable [4 + n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a novel and versatile C4 synthon. In contrast to the well-documented intramolecular cycloaddition of benzocyclobutenones (BCBs), this is a complementary version using a heteroarene-fused reagent as a C4 building block. It involves a catalytic C-C bond activation and stepwise annulation sequence, including a Rh-catalyzed highly enantioselective [4 + 2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4 + 4]-cycloaddition with anthranils. The furan-fused polycyclic lactam products and their synthetic derivatives, which are pivotal motifs that present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods with multi-steps. Preliminary antitumor activity study of these compounds indicates that 6e and 6f exhibit high anticancer potency against colon cancer cells (HCT-116 cells, IC 50 = 0.50 ± 0.05 µM) and esophageal squamous cell carcinoma cells (KYSE-520 cells, IC 50 = 0.89 ± 0.13 µM), respectively. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Medicinal chemistry/Chemical libraries Physical sciences/Chemistry/Catalysis/Asymmetric catalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Furan-based heterocycles are ubiquitous in natural products, bioactive compounds, and functional materials 1–4 , and they are also valuable synthetic building blocks that can be transformed into many other functional groups 5–7 . In particular, the furan-fused derivatives are widely used in the field of drug discovery 8–10 . Hence, the synthesis of these scaffolds with structural diversity is always an important topic in organic synthesis and has drawn much attention the past decades 11–13 . Beyond the methods for the straightforward construction of furan-ring frameworks 14–19 , a practical strategy through selective interception of in situ furan-based intermediates has been emerged as an effective and powerful method for the expeditious assembly of furan derivatives with fused architectures 20–23 . This cascade reaction protocol, in which multiple bonds form successively in a one-pot process and structural complexity is rapidly assembly, dramatically boosts the efficiency of synthetic endeavors. For example, the all carbon metal 1,3-dipole species Int-1 , which is generated via transition-metal-mediated cyclization of yne-enones 30 , has been well-documented as a versatile C3 synthon in the synthesis of 3,4-furan-fused molecules through a variety of [3 + n]-cycloadditions (Fig. 1 a, left) 25–30 . Furthermore, furan-based o -quinodimethanes ( o -QDMs) 31,32 or azadienes 33 ( Int-2 ) derived from cycloisomerization of enynones or enynamides, respectively, could be used for the efficient preparation of 2,3-furan-fused structures via [4 + n]-cycloaddition reactions (Fig. 1 a, middle). Despite these advances, the previously mentioned products are limited to only a few types of N - or O -heterocycles due to the structural uniqueness of these two furan-based species, Int-1 and Int-2 , for which their derivatization of which to synthesize lactams is very rare. The elegant discovery by Chi, involving a gold complex and NHC-carbene relay catalytic formal [4 + 2]-cycloaddition of ynamides and enals, represents the only example for the synthesis of furan-fused six-membered lactams 34 . In this context, the identification of novel furan-based intermediates in cycloaddition reactions is highly desired for the construction of structurally diverse heterocycles as potential candidates for medicinal chemistry and drug discovery. For example, although only a few [4 + 4]-cycloadditions have been disclosed with prepared bench stable azadienes 35–42 , an analogous version for the direct construction of furan-fused eight-membered lactams through interception of in situ formed C4 species remains elusive. Recently, the transition metal (TM) catalyzed carbon-carbon (C-C) bond activation of benzocyclobutenones (BCBs), followed by intramolecular insertion of an unsaturated unit, has emerged as an attractive and atom-economical approach for the direct construction of fused-, spirocyclic-, and bridged-frameworks through [4 + n]-cycloaddition (Fig. 1 b) 43–47 . However, challenges remain in this area, including: ( 1 ) derivatization of BCBs to those that are heteroarene-fused remains elusive; ( 2 ) these transformations are mainly limited to the intramolecular versions due to the high reactivity of in situ formed metallacycle species; ( 3 ) the unsaturated units for [4 + 2]-cycloaddition have been primarily restricted to alkenes 48–51 , alkynes 52–55 , carbonyls 56 , oximes 57 , allenes/1,3-dienes 58 , and heteroarenes 59 , but imines and other readily available nucleophilic reagents are still unexploited; ( 4 ) only few catalytic asymmetric methods have been reported, and the asymmetric synthesis of chiral (hetero)arene fused heterocycles represents a significant challenge 60–65 . To address these limitations, development of a platform molecule as a versatile C4 synthon is a pivotal aspect. Accordingly, with the development of corresponding catalytic C-C bond activation strategies, the in situ formed novel intermediate should exhibit distinctive chemical reactivities which facilitate unique types of bond formation that are difficult to construct with the use of conventional intermediates. In our recent work, we have disclosed a dirhodium-catalyzed 4-exo-dig carbocyclization/[3 + 2] annulation cascade reactions of alkyne-tethered diazo compounds that provides a straightforward access to previously unknown furan-fused cyclobutanone (FCBs) scaffolds 66 . Thus, we envisioned that these unique products might serve as a C4 synthon for the catalytic [4 + n] annulations via C-C bond activation through metallacycle species Int-3 (Fig. 1 a, right). Herein, we report our recent results in this direction, a modular intermolecular [4 + n]-cycloaddition using FCBs as a novel and versatile C4 synthon, including a Rh-catalyzed highly enantioselective [4 + 2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4 + 4]-cycloaddition with anthranils 67–69 (Fig. 1 c). Notably, the former is the first example of intermolecular asymmetric carboacylation of imines, and the latter is the first example of [4 + 4]-cycloaddition through interception of an in situ formed C4 intermediate for the direct construction of eight-membered lactams. Moreover, these furan-fused six/eight-membered polycyclic lactams, which are pivotal motifs present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods, even with multi-step precedures 70–72 . Furthermore, the derivatization of these resultant poly-functionalized fused molecules can be readily transformed into various heterocycles with structural diversity by routine manipulations, which demonstrates the significant synthetic potential of this protocol. Results and Discussion To test our hypothesis, we started our investigation by employing furan-fused cyclobutanone 1a and cyclic imine 2a as the model substrates. The desired furan-fused six-membered lactam 3a could be obtained in 32% yield in the presence of Rh(COD) 2 BF 4 (5.0 mol%) in DCE at 40 ℃ (entry 1, Table 1 ). This result prompted us to systematically optimize the reaction conditions to improve the yield of desired product 3a , and the outcomes are summarized in Table 1 . Other transition metals could also be used to catalyze this [4 + 2]-cycloaddition reaction (entries 2–10), with IPrAuNTf 2 giving the higher yields (entry 8, 62% yield). Then, different solvents were screened with IPrAuNTf 2 as the metal catalyst (entries 11–16), showing that the isolated yields could be increased to 88% by conducting the reaction in MeCN (entry 15). Further increasing the reaction temperature to 60°C did not provide better results (entry 17). With the optimal reaction conditions in hand (Table 1 , entry 15), the substrate scope with respect to imines 2 was investigated (Table 2 , top). Remarkably, a variety of substituents at different positions of dibenzazepines were all well tolerated, delivering the [4 + 2]-cycloaddition products 3a-3n in 78–95% yields. Moreover, the corresponding reactions proceeded smoothly when replacing the oxygen atom with a sulfur linkage, leading to the 3o in 56% yield. Notably, phenanthridine displayed remarkable reactivity, giving 3p in high yield. To our delight, quinoxalinone afforded the 3q in a synthetically useful yield. Finally, the other two cyclic ketimines, 2r and 2s , were also suitable substrates, providing the desired products 3r and 3s in 80% and 40% yields, respectively. Subsequently, we investigated the scope of furan-fused cyclobutanones under standard conditions (Table 2 , bottom). FCBs 1 bearing different functionalities, including chloro, bromo, fluoro, trifluoromethyl, cyanide, ethoxy, methyl, phenyl, and methoxy groups at different positions on the 5-aryl ring participated in this reaction to form the expected six-membered lactams 4a - 4m in 39–89% yields. Likewise, the 1-naphthyl substituted reactant underwent the reaction smoothly, delivering 4n in 80% yield. Notably, alkyl halide is also a compatible substituent under these conditions, exemplified by the formation of the chlorine-containing product 4o in 83% yield. Subsequently, the substitution pattern on the styryl moiety was examined, resulting in six-membered N -heterocycle 4p in 78%. Notably, the variation of the ether part had a negligible influence on the reactivity, giving the bromoethyl derivative 4q in 70% yield. In addition, the structure of product 4k was confirmed by single-crystal X -ray diffraction analysis, and the stereochemistry of the others were assigned analogously. Encouraged by the above results, we envisioned that higher order cycloaddition using FCB as the C4-synthon might be feasible with appreciate dienophiles under compatible catalytic conditions. Thus, we further explored of the gold-catalyzed [4 + 4]-cycloaddition by using commercially available anthranil 5a and FCB 1a as model substrates. After optimization, the best conditions were identified using JohnPhos(MeCN)AuSbF 6 (5.0 mol%) as the catalyst, DCE as the solvent at 40°C for 18 h, affording the desired product 6a in 93% yield (see Table S1 in the Supporting Information for details). With these optimal reaction conditions in hand, the scope with respect to FCBs 1 was investigated (Table 3 , top). A range of FCBs with aryl groups bearing different substitutions, such as chloride ( 6b ), bromide ( 6c ), fluoride ( 6d , 6e , 6i ), methyl ( 6f ), ethoxy ( 6g ), and trifluoromethyl ( 6h ) were all tolerated, providing the desired cycloadducts 6b-6h in good to superior yields (79–92%). For FCBs 1 bearing 1-naphthyl, 1-thienyl, the corresponding annulation products 6j and 6k were obtained in 89% and 61% yields, respectively. To our delight, the corresponding reactions proceeded smoothly when the aryl ring was replaced with an alkyl halide, leading to 6l in 60% yield. The substituents on the styrene motif (e.g., 2-methoxy, 4-bromide, and 4-trifluoromethyl) have little effect on the reaction outcomes, and the [4 + 4] annulation products 6m-6o were obtained in 74–89% yields. Switching the ethyl group on the ether unit (R 1 ) with tert -butyl or benzyl was highly compatible, and the reactions occurred with high efficiency, leading to 6p-6q with excellent results (85–93%). The D -menthol and estrone derived furan-fused cyclobutanones also worked very well under the optimal conditions, delivering 6r and 6s in 87% and 88% yields, respectively. In addition, this reaction could be conducted on a 1.5 mmol scale, providing 581 mg 6a in 89% yield (note b). The structure of 6f was established by X -ray crystallographic analysis, and the stereochemistry of the others were assigned analogously. Next, the scope of anthranils 5 was examined with FCB 1a (Table 3 , bottom). Various functional groups, such as halides (F, Cl, Br), methoxy, methyl, methyl ester, and pivalate were compatible, affording the [4 + 4] cycloaddition products 7a-7j in good to excellent yields. Among them, the sterically hindered C4-substituted and C7-substituted anthranils ( 5a and 5j ) also reacted well, yielding 7a and 7j in 76% and 91% yields, respectively. The electronic-rich substrate 5k with the 5,6-dimethoxyl substitute, reacted smoothly to give 7k in 83% yield. Furthermore, anthranils with methyl, ethyl, and phenyl groups at the C3-position afforded furan-fused eight-membered lactams 7l-7n in excellent yields. Notably, the naproxen derived anthranil also worked very smoothly under the optimal conditions, generating the product 7o in 86% yield as two diastereomers. Furthermore, the asymmetric [4 + 2]- and [4 + 4]-cycloaddition reactions were investigated with a variety of chiral gold complexes. Unfortunately, only moderate stereoselectivity was observed after extensive survey of the chiral ligand and counterions, although high yields were obtained in some cases (see Table S2 , S5, and S6 in the Supporting Information for details), suggesting a significant background reaction. However, when we used chiral rhodium complexes, the [4 + 2]-cycloaddition was achieved with high enantioselective control under the optimized conditions (10 mol% of Rh(COD) 2 BF 4 , 12 mol% of L32 , in MeCN at 100 ℃) (see Table S3 and S4 in SI for details), highlighting the ligand’s boosting effect on the reactivity against the background reaction in the Rh-catalysis system. However, these conditions were not effective for the [4 + 4]-cycloaddition, which might be due to the inhibition effect of anthranil to the rhodium complexes. Under the optimal conditions, all the tested FCBs 1 and imines 2 underwent the [4 + 2]-cycloaddition reaction very well, yielding the chiral furan-fused six-membered lactams products 3a-4u in good yields and excellent enantioselectivity (Table 4 , up to 81%, 90–99% ee ). Regardless of the electron-donating or electron-withdrawing nature of the substituents on different positions, including halide, trifluoromethyl, nitro, methoxy, methyl, and tert- butyl groups, these substituted imines all resulted in excellent outcomes in this reaction ( 3a - 3m ). Beyond the aryl substituted FCBs 1 , which provided the lactams 4a - 4m in high yields with 90–99% ee . These with alkyl chloride imbedded and a variety of alcohols derived ones were also well tolerated under the current conditions, leading to the chiral products 4o - 4u with comparable high reactivity and above 90% ee . In addition, the reaction could be performed on a 2.0 mmol scale with negligible effect on the yield and enantioselectivity ( 4n , 0.95 g, 85% yield, and 95% ee . Table 4 , note b). The significant advantage of this protocol is that the resultant poly-functionalized fused molecules can be readily transformed into various heterocycles with structural diversity by routine manipulations (Fig. 2 ). Treatment of 4n with aryne precursor, 2-(trimethylsilyl)phenyl triflate, in the presence of CsF in MeCN led to the Diels-Alder reaction product 8 as a single diastereomer in 82% yield and 95% ee . The absolute configuration of 8 was confirmed by single-crystal X-ray diffraction analysis. Hydrolysis of 4n occurred smoothly to produce the chiral butenolide product 9 in 91% yield with 92% ee and > 20:1 dr . The absolute stereochemistry of 9 was determined as ( S ) using X -ray crystallographic analysis, and the stereochemistry of the chiral lactams 3 and 4 were assigned analogously. Reduction of the styryl motif with LiAlH 4 produced the hydroxy product 10 as a single diastereomer in 80% yield with 92% ee . The oxidative ring-opening reaction of 4n occurred smoothly in the presence of meta -chloroperoxybenzoic acid ( m -CPBA), giving 11 in 86% yield with 95% ee . In addition, the furan-fused eight-membered lactam 6a can also be converted into diverse O -bridged eight-membered lactams ( 12 – 15 ) in good yields under similar conditions. Anticancer activity evaluation Moreover, a few of synthesized compounds have been selected ( 6b − 6o , 6s , 7b − 7c , 7e , 7g − 7i , and 7l − 7m ) for the anticancer activity evaluation on cell viability via the CCK8 assay for MCF-7 (breast cancer), HCT-116 (colon cancer), A549 (lung adenocarcinoma), and KYSE-520 (esophageal squamous cell carcinoma) human cancer cell lines (see Supplementary Tables S7 and S8 in the Supplementary Information for details). The results show that compounds 6e and 6f exhibited significant anticancer potency on HCT-116 (IC 50 = 0.50 ± 0.05 µM) and KYSE-520 (IC 50 = 0.89 ± 0.13 µM) human cancer cell lines, respectively (Fig. 3 ). Further structure-activity relationship study is ongoing in the laboratory. Mechanistic studies To shed light on the mechanism of the developed cycloadditions using FCBs as the C4 synthon, control experiments of metal complexes with FCB 1b were conducted in deuterated solvent to investigate C-C bond activation process (Fig. 4 ). The reaction of 1b in the presence of Rh(COD) 2 BF 4 (1.0 equiv.) was carried out in CD 3 CN at 100 o C, which was intended to reveal the C-C bond insertion intermediate. Complete conversion of 1b to the metallacycle species A takes place in 1.0 hour, as is apparent from its 13 C NMR spectrum (Fig. 4 a) 73 . Moreover, an analogous phenomenon was observed when 1b was treated with gold-complex in CDCl 3 , leading to the 13 C NMR signal of the carbonyl group shift from 174.7 ppm to 194.3 ppm (Fig. 4 b). These results clearly suggested the initial C-C bond activation process in this cycloaddition reaction. On the basis of above results and previous studies 43–59 , a plausible reaction pathway has been proposed in Fig. 5 . Initially, metallacycle A is generated from furan-fused cyclobutanone 1 through oxidative addition 73 . Then, imine 2 or anthranil 5 67 can coordinate with metal to form complexes B-1 or B-2 , followed by migratory insertion that leads to the corresponding seven-membered or nine-membered metallacycle species C-1 or C-2 . Finally, reductive elimination gives the desired lactams products 3/4 or 6/7 , respectively. Conclusion In summary, we have developed a modular and atom-economic carboacylation reaction using furan-fused cyclobutanones as a versatile C4 building block via C-C bond activation. Using this method, the unprecedented intermolecular highly enantioselective Rh(I)-catalyzed [4 + 2]-cycloaddition and Au(I)-catalyzed diastereoselective [4 + 4]-cycloaddition of the in situ formed metallacycle species has been established with imines and anthranils as corresponding dienophiles. This process produces unique poly-substituted furan-fused lactams in good yields and excellent stereoselectivity under mild conditions. Further synthetic derivatization of these structures led to densely functionalized six/eight-membered lactams with structural diversity in high yields. Meanwhile, a preliminary antitumor activity study of these generated products indicates that the eight-membered lactams 6 have high anticancer potency against human colon cancer cells (HCT-116) and esophageal squamous cell carcinoma cells (KYSE-520). Overcoming the catalytic protocol for the selective C-C bond activation of fused cyclobutanones should unlock the potential of these unique FCB scaffolds in heterocycle synthesis and other applications by enabling the design of analogous [4 + n] annulation products. Further studies of this kind by expansion of the reaction scope to other dienophiles are ongoing in our laboratories, especially the asymmetric catalytic methods, and will be reported in due course. Methods Representative procedure for the [4 + 2] cycloaddition reaction Condition A. To a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone 1 (0.12 mmol, 1.2 equiv.), imine 2 (0.1 mmol, 1.0 equiv.), IPrAuNTf 2 (4.3 mg, 5.0 mol%), and MeCN (2.0 mL) were added sequentially under argon atmosphere. After addition, the reaction mixture was stirred overnight at 40 ºC until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then, the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc = 50:1 to 10:1) to give the pure products 3 or 4 in good to high yields. Condition B. To a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone 1 (0.12 mmol, 1.2 equiv.), imine 2 (0.1 mmol, 1.0 equiv.), Rh(COD) 2 BF 4 (4.0 mg, 10 mol%), 4Å MS (50 mg), chiral ligand L32 (4.6 mg, 12 mol%), and MeCN (2.0 mL) were added sequentially under argon atmosphere at 100 ºC. After addition, the reaction mixture was stirred overnight under these conditions until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc = 50:1 to 10:1) to give the pure products 3 or 4 in good to high yields with generally excellent enantioselectivity. Representative procedure for the [4 + 4] cycloaddition reaction To a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone 1 (0.1 mmol, 1.0 equiv.), and anthranil 5 (0.11 mmol, 1.1 equiv.) in DCE (1.0 mL), was added a solution of JohnPhosAu(MeCN)SbF 6 (3.9 mg, 5.0 mol%) in DCE (1.0 mL) via syringe under argon atmosphere at 40 ºC. After addition, the reaction mixture was stirred 12 h under these conditions until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then, the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc = 30:1 to 10:1) to give the pure products 6 or 7 in good to high yields. Declarations Data availability The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2225032 ( 4k ), 2218249 ( 6f ), 2297136 ( 8 ), and 2309002 ( 9 ). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Acknowledgements Support for this research from the National Natural Science Foundation of China (22371309) and Guangdong Provincial Key R&D Programme (21202107201900002) is greatly acknowledged. We also thank Prof. Michael P. Doyle from UTSA for discussion and suggestions during the preparation of the manuscript. 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Angew. Chem. Int. Ed. 54 , 5236–5240 (2015). Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files 4kcifreport.pdf 4k.cif 6f.cif 6fcifreport.pdf 8.cif 9.cif 9.cif 8cifreport.pdf 9.cif 9cifreport.pdf supportinginformation.pdf supporting information Tables1to4.docx Cite Share Download PDF Status: Published Journal Publication published 26 Jun, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-3892850","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":270515995,"identity":"72f64e18-2849-4558-b72a-c8a4ea509b2c","order_by":0,"name":"Xinfang 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[4+2]- \u0026amp; [4+4]-Cycloadditions \u003cem\u003evia\u003c/em\u003e C-C bond activation of furan-fused cyclobutenones (FCBs).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/120302d5eb3dadfdd3a56ad7.jpg"},{"id":50716342,"identity":"f36f2f2c-c6fd-4de5-849e-5053796c55ae","added_by":"auto","created_at":"2024-02-06 08:56:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":373329,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthetic applications.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, Diels-Alder reaction of\u003cstrong\u003e 4n\u003c/strong\u003e. \u003cstrong\u003eb\u003c/strong\u003e, Hydrolysis reaction of\u003cstrong\u003e 4n\u003c/strong\u003e. \u003cstrong\u003ec\u003c/strong\u003e, Reduction reaction of\u003cstrong\u003e 4n\u003c/strong\u003e. \u003cstrong\u003ed\u003c/strong\u003e, Oxidation reaction of\u003cstrong\u003e 4n\u003c/strong\u003e. \u003cstrong\u003ee\u003c/strong\u003e, Diels-Alder reaction of\u003cstrong\u003e 6a\u003c/strong\u003e. \u003cstrong\u003ef\u003c/strong\u003e, Hydrolysis reaction of\u003cstrong\u003e 6a\u003c/strong\u003e. \u003cstrong\u003eg\u003c/strong\u003e, Reduction reaction of\u003cstrong\u003e 6a\u003c/strong\u003e. \u003cstrong\u003eh\u003c/strong\u003e, Oxidation reaction of\u003cstrong\u003e 6a\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/1b1a436a82ab005215bc8798.jpg"},{"id":50716343,"identity":"e737338e-8de0-4614-8b59-20d7d8d69443","added_by":"auto","created_at":"2024-02-06 08:56:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":114291,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe cytotoxicity of the synthetic compounds on HCT-116 and KYSE-520 human cell lines. a\u003c/strong\u003e, The IC\u003csub\u003e50\u003c/sub\u003e curves of compound \u003cstrong\u003e6e\u003c/strong\u003e.\u003cstrong\u003e b\u003c/strong\u003e, The IC\u003csub\u003e50\u003c/sub\u003e curves of compound \u003cstrong\u003e6f\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/84654b6eb2804d4b6141f91a.jpg"},{"id":50716345,"identity":"0534471c-ff98-4394-8475-ab91fc5ab9ea","added_by":"auto","created_at":"2024-02-06 08:56:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":190545,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eControl experiments. a\u003c/strong\u003e, \u003csup\u003e13\u003c/sup\u003eC NMR spectra of \u003cstrong\u003e1b\u003c/strong\u003e and \u003cstrong\u003e1b\u003c/strong\u003e with Rh-complex in CD\u003csub\u003e3\u003c/sub\u003eCN. \u003cstrong\u003eb\u003c/strong\u003e, \u003csup\u003e13\u003c/sup\u003eC NMR spectra of \u003cstrong\u003e1b\u003c/strong\u003e and \u003cstrong\u003e1b\u003c/strong\u003e with Au-complex in CDCl\u003csub\u003e3\u003c/sub\u003e.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/51c431c8ec98bf2493bfb0fe.jpg"},{"id":50717217,"identity":"0245a5a3-e786-4b1c-a500-643c3a44db99","added_by":"auto","created_at":"2024-02-06 09:04:46","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":186259,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed reaction mechanism\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/e6d7251ccd1536b77d78c531.jpg"},{"id":59165906,"identity":"53cd0bf3-1899-4452-9392-cbb46759c8ec","added_by":"auto","created_at":"2024-06-27 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information\u003c/p\u003e","description":"","filename":"supportinginformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/c41bae29daba8a1b23ed325a.pdf"},{"id":50717219,"identity":"3f1d045c-2204-4324-858c-d6eb320757a0","added_by":"auto","created_at":"2024-02-06 09:04:47","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":1108735,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Tables1to4.docx","url":"https://assets-eu.researchsquare.com/files/rs-3892850/v1/860236a49a4e3c5ba8b719e2.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFuran-based heterocycles are ubiquitous in natural products, bioactive compounds, and functional materials\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e, and they are also valuable synthetic building blocks that can be transformed into many other functional groups\u003csup\u003e5\u0026ndash;7\u003c/sup\u003e. In particular, the furan-fused derivatives are widely used in the field of drug discovery\u003csup\u003e8\u0026ndash;10\u003c/sup\u003e. Hence, the synthesis of these scaffolds with structural diversity is always an important topic in organic synthesis and has drawn much attention the past decades\u003csup\u003e11\u0026ndash;13\u003c/sup\u003e. Beyond the methods for the straightforward construction of furan-ring frameworks\u003csup\u003e14\u0026ndash;19\u003c/sup\u003e, a practical strategy through selective interception of in situ furan-based intermediates has been emerged as an effective and powerful method for the expeditious assembly of furan derivatives with fused architectures\u003csup\u003e20\u0026ndash;23\u003c/sup\u003e. This cascade reaction protocol, in which multiple bonds form successively in a one-pot process and structural complexity is rapidly assembly, dramatically boosts the efficiency of synthetic endeavors. For example, the all carbon metal 1,3-dipole species \u003cb\u003eInt-1\u003c/b\u003e, which is generated \u003cem\u003evia\u003c/em\u003e transition-metal-mediated cyclization of yne-enones\u003csup\u003e30\u003c/sup\u003e, has been well-documented as a versatile C3 synthon in the synthesis of 3,4-furan-fused molecules through a variety of [3\u0026thinsp;+\u0026thinsp;n]-cycloadditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, left)\u003csup\u003e25\u0026ndash;30\u003c/sup\u003e. Furthermore, furan-based \u003cem\u003eo\u003c/em\u003e-quinodimethanes (\u003cem\u003eo\u003c/em\u003e-QDMs)\u003csup\u003e31,32\u003c/sup\u003e or azadienes\u003csup\u003e33\u003c/sup\u003e (\u003cb\u003eInt-2\u003c/b\u003e) derived from cycloisomerization of enynones or enynamides, respectively, could be used for the efficient preparation of 2,3-furan-fused structures \u003cem\u003evia\u003c/em\u003e [4\u0026thinsp;+\u0026thinsp;n]-cycloaddition reactions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, middle). Despite these advances, the previously mentioned products are limited to only a few types of \u003cem\u003eN\u003c/em\u003e- or \u003cem\u003eO\u003c/em\u003e-heterocycles due to the structural uniqueness of these two furan-based species, \u003cb\u003eInt-1\u003c/b\u003e and \u003cb\u003eInt-2\u003c/b\u003e, for which their derivatization of which to synthesize lactams is very rare. The elegant discovery by Chi, involving a gold complex and NHC-carbene relay catalytic formal [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition of ynamides and enals, represents the only example for the synthesis of furan-fused six-membered lactams\u003csup\u003e34\u003c/sup\u003e. In this context, the identification of novel furan-based intermediates in cycloaddition reactions is highly desired for the construction of structurally diverse heterocycles as potential candidates for medicinal chemistry and drug discovery. For example, although only a few [4\u0026thinsp;+\u0026thinsp;4]-cycloadditions have been disclosed with prepared bench stable azadienes\u003csup\u003e35\u0026ndash;42\u003c/sup\u003e, an analogous version for the direct construction of furan-fused eight-membered lactams through interception of in situ formed C4 species remains elusive.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRecently, the transition metal (TM) catalyzed carbon-carbon (C-C) bond activation of benzocyclobutenones (BCBs), followed by intramolecular insertion of an unsaturated unit, has emerged as an attractive and atom-economical approach for the direct construction of fused-, spirocyclic-, and bridged-frameworks through [4\u0026thinsp;+\u0026thinsp;n]-cycloaddition (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb)\u003csup\u003e43\u0026ndash;47\u003c/sup\u003e. However, challenges remain in this area, including: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) derivatization of BCBs to those that are heteroarene-fused remains elusive; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) these transformations are mainly limited to the intramolecular versions due to the high reactivity of in situ formed metallacycle species; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) the unsaturated units for [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition have been primarily restricted to alkenes\u003csup\u003e48\u0026ndash;51\u003c/sup\u003e, alkynes\u003csup\u003e52\u0026ndash;55\u003c/sup\u003e, carbonyls\u003csup\u003e56\u003c/sup\u003e, oximes\u003csup\u003e57\u003c/sup\u003e, allenes/1,3-dienes\u003csup\u003e58\u003c/sup\u003e, and heteroarenes\u003csup\u003e59\u003c/sup\u003e, but imines and other readily available nucleophilic reagents are still unexploited; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) only few catalytic asymmetric methods have been reported, and the asymmetric synthesis of chiral (hetero)arene fused heterocycles represents a significant challenge\u003csup\u003e60\u0026ndash;65\u003c/sup\u003e. To address these limitations, development of a platform molecule as a versatile C4 synthon is a pivotal aspect. Accordingly, with the development of corresponding catalytic C-C bond activation strategies, the in situ formed novel intermediate should exhibit distinctive chemical reactivities which facilitate unique types of bond formation that are difficult to construct with the use of conventional intermediates.\u003c/p\u003e \u003cp\u003eIn our recent work, we have disclosed a dirhodium-catalyzed \u003cem\u003e4-exo-dig\u003c/em\u003e carbocyclization/[3\u0026thinsp;+\u0026thinsp;2] annulation cascade reactions of alkyne-tethered diazo compounds that provides a straightforward access to previously unknown furan-fused cyclobutanone (FCBs) scaffolds\u003csup\u003e66\u003c/sup\u003e. Thus, we envisioned that these unique products might serve as a C4 synthon for the catalytic [4\u0026thinsp;+\u0026thinsp;n] annulations \u003cem\u003evia\u003c/em\u003e C-C bond activation through metallacycle species \u003cb\u003eInt-3\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, right). Herein, we report our recent results in this direction, a modular intermolecular [4\u0026thinsp;+\u0026thinsp;n]-cycloaddition using FCBs as a novel and versatile C4 synthon, including a Rh-catalyzed highly enantioselective [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition with anthranils\u003csup\u003e67\u0026ndash;69\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Notably, the former is the first example of intermolecular asymmetric carboacylation of imines, and the latter is the first example of [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition through interception of an in situ formed C4 intermediate for the direct construction of eight-membered lactams. Moreover, these furan-fused six/eight-membered polycyclic lactams, which are pivotal motifs present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods, even with multi-step precedures\u003csup\u003e70\u0026ndash;72\u003c/sup\u003e. Furthermore, the derivatization of these resultant poly-functionalized fused molecules can be readily transformed into various heterocycles with structural diversity by routine manipulations, which demonstrates the significant synthetic potential of this protocol.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eTo test our hypothesis, we started our investigation by employing furan-fused cyclobutanone \u003cstrong\u003e1a\u003c/strong\u003e and cyclic imine \u003cstrong\u003e2a\u003c/strong\u003e as the model substrates. The desired furan-fused six-membered lactam \u003cstrong\u003e3a\u003c/strong\u003e could be obtained in 32% yield in the presence of Rh(COD)\u003csub\u003e2\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e (5.0 mol%) in DCE at 40 ℃ (entry 1, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). This result prompted us to systematically optimize the reaction conditions to improve the yield of desired product \u003cstrong\u003e3a\u003c/strong\u003e, and the outcomes are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Other transition metals could also be used to catalyze this [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition reaction (entries 2\u0026ndash;10), with IPrAuNTf\u003csub\u003e2\u003c/sub\u003e giving the higher yields (entry 8, 62% yield). Then, different solvents were screened with IPrAuNTf\u003csub\u003e2\u003c/sub\u003e as the metal catalyst (entries 11\u0026ndash;16), showing that the isolated yields could be increased to 88% by conducting the reaction in MeCN (entry 15). Further increasing the reaction temperature to 60\u0026deg;C did not provide better results (entry 17).\u003c/p\u003e\n\u003cp\u003eWith the optimal reaction conditions in hand (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 15), the substrate scope with respect to imines \u003cstrong\u003e2\u003c/strong\u003e was investigated (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, top). Remarkably, a variety of substituents at different positions of dibenzazepines were all well tolerated, delivering the [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition products \u003cstrong\u003e3a-3n\u003c/strong\u003e in 78\u0026ndash;95% yields. Moreover, the corresponding reactions proceeded smoothly when replacing the oxygen atom with a sulfur linkage, leading to the \u003cstrong\u003e3o\u003c/strong\u003e in 56% yield. Notably, phenanthridine displayed remarkable reactivity, giving \u003cstrong\u003e3p\u003c/strong\u003e in high yield. To our delight, quinoxalinone afforded the \u003cstrong\u003e3q\u003c/strong\u003e in a synthetically useful yield. Finally, the other two cyclic ketimines, \u003cstrong\u003e2r\u003c/strong\u003e and \u003cstrong\u003e2s\u003c/strong\u003e, were also suitable substrates, providing the desired products \u003cstrong\u003e3r\u003c/strong\u003e and \u003cstrong\u003e3s\u003c/strong\u003e in 80% and 40% yields, respectively.\u003c/p\u003e\n\u003cp\u003eSubsequently, we investigated the scope of furan-fused cyclobutanones under standard conditions (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, bottom). FCBs \u003cstrong\u003e1\u003c/strong\u003e bearing different functionalities, including chloro, bromo, fluoro, trifluoromethyl, cyanide, ethoxy, methyl, phenyl, and methoxy groups at different positions on the 5-aryl ring participated in this reaction to form the expected six-membered lactams \u003cstrong\u003e4a\u003c/strong\u003e-\u003cstrong\u003e4m\u003c/strong\u003e in 39\u0026ndash;89% yields. Likewise, the 1-naphthyl substituted reactant underwent the reaction smoothly, delivering \u003cstrong\u003e4n\u003c/strong\u003e in 80% yield. Notably, alkyl halide is also a compatible substituent under these conditions, exemplified by the formation of the chlorine-containing product \u003cstrong\u003e4o\u003c/strong\u003e in 83% yield. Subsequently, the substitution pattern on the styryl moiety was examined, resulting in six-membered \u003cem\u003eN\u003c/em\u003e-heterocycle \u003cstrong\u003e4p\u003c/strong\u003e in 78%. Notably, the variation of the ether part had a negligible influence on the reactivity, giving the bromoethyl derivative \u003cstrong\u003e4q\u003c/strong\u003e in 70% yield. In addition, the structure of product \u003cstrong\u003e4k\u003c/strong\u003e was confirmed by single-crystal \u003cem\u003eX\u003c/em\u003e-ray diffraction analysis, and the stereochemistry of the others were assigned analogously.\u003c/p\u003e\n\u003cp\u003eEncouraged by the above results, we envisioned that higher order cycloaddition using FCB as the C4-synthon might be feasible with appreciate dienophiles under compatible catalytic conditions. Thus, we further explored of the gold-catalyzed [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition by using commercially available anthranil \u003cstrong\u003e5a\u003c/strong\u003e and FCB \u003cstrong\u003e1a\u003c/strong\u003e as model substrates. After optimization, the best conditions were identified using JohnPhos(MeCN)AuSbF\u003csub\u003e6\u003c/sub\u003e (5.0 mol%) as the catalyst, DCE as the solvent at 40\u0026deg;C for 18 h, affording the desired product \u003cstrong\u003e6a\u003c/strong\u003e in 93% yield (see Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e in the Supporting Information for details). With these optimal reaction conditions in hand, the scope with respect to FCBs \u003cstrong\u003e1\u003c/strong\u003e was investigated (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, top). A range of FCBs with aryl groups bearing different substitutions, such as chloride (\u003cstrong\u003e6b\u003c/strong\u003e), bromide (\u003cstrong\u003e6c\u003c/strong\u003e), fluoride (\u003cstrong\u003e6d\u003c/strong\u003e, \u003cstrong\u003e6e\u003c/strong\u003e, \u003cstrong\u003e6i\u003c/strong\u003e), methyl (\u003cstrong\u003e6f\u003c/strong\u003e), ethoxy (\u003cstrong\u003e6g\u003c/strong\u003e), and trifluoromethyl (\u003cstrong\u003e6h\u003c/strong\u003e) were all tolerated, providing the desired cycloadducts \u003cstrong\u003e6b-6h\u003c/strong\u003e in good to superior yields (79\u0026ndash;92%). For FCBs \u003cstrong\u003e1\u003c/strong\u003e bearing 1-naphthyl, 1-thienyl, the corresponding annulation products \u003cstrong\u003e6j\u003c/strong\u003e and \u003cstrong\u003e6k\u003c/strong\u003e were obtained in 89% and 61% yields, respectively. To our delight, the corresponding reactions proceeded smoothly when the aryl ring was replaced with an alkyl halide, leading to \u003cstrong\u003e6l\u003c/strong\u003e in 60% yield. The substituents on the styrene motif (e.g., 2-methoxy, 4-bromide, and 4-trifluoromethyl) have little effect on the reaction outcomes, and the [4\u0026thinsp;+\u0026thinsp;4] annulation products \u003cstrong\u003e6m-6o\u003c/strong\u003e were obtained in 74\u0026ndash;89% yields. Switching the ethyl group on the ether unit (R\u003csup\u003e1\u003c/sup\u003e) with \u003cem\u003etert\u003c/em\u003e-butyl or benzyl was highly compatible, and the reactions occurred with high efficiency, leading to \u003cstrong\u003e6p-6q\u003c/strong\u003e with excellent results (85\u0026ndash;93%). The \u003cem\u003eD\u003c/em\u003e-menthol and estrone derived furan-fused cyclobutanones also worked very well under the optimal conditions, delivering \u003cstrong\u003e6r\u003c/strong\u003e and \u003cstrong\u003e6s\u003c/strong\u003e in 87% and 88% yields, respectively. In addition, this reaction could be conducted on a 1.5 mmol scale, providing 581 mg \u003cstrong\u003e6a\u003c/strong\u003e in 89% yield (note b). The structure of \u003cstrong\u003e6f\u003c/strong\u003e was established by \u003cem\u003eX\u003c/em\u003e-ray crystallographic analysis, and the stereochemistry of the others were assigned analogously.\u003c/p\u003e\n\u003cp\u003eNext, the scope of anthranils \u003cstrong\u003e5\u003c/strong\u003e was examined with FCB \u003cstrong\u003e1a\u003c/strong\u003e (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, bottom). Various functional groups, such as halides (F, Cl, Br), methoxy, methyl, methyl ester, and pivalate were compatible, affording the [4\u0026thinsp;+\u0026thinsp;4] cycloaddition products \u003cstrong\u003e7a-7j\u003c/strong\u003e in good to excellent yields. Among them, the sterically hindered C4-substituted and C7-substituted anthranils (\u003cstrong\u003e5a\u003c/strong\u003e and \u003cstrong\u003e5j\u003c/strong\u003e) also reacted well, yielding \u003cstrong\u003e7a\u003c/strong\u003e and \u003cstrong\u003e7j\u003c/strong\u003e in 76% and 91% yields, respectively. The electronic-rich substrate \u003cstrong\u003e5k\u003c/strong\u003e with the 5,6-dimethoxyl substitute, reacted smoothly to give \u003cstrong\u003e7k\u003c/strong\u003e in 83% yield. Furthermore, anthranils with methyl, ethyl, and phenyl groups at the C3-position afforded furan-fused eight-membered lactams \u003cstrong\u003e7l-7n\u003c/strong\u003e in excellent yields. Notably, the naproxen derived anthranil also worked very smoothly under the optimal conditions, generating the product \u003cstrong\u003e7o\u003c/strong\u003e in 86% yield as two diastereomers.\u003c/p\u003e\n\u003cp\u003eFurthermore, the asymmetric [4\u0026thinsp;+\u0026thinsp;2]- and [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition reactions were investigated with a variety of chiral gold complexes. Unfortunately, only moderate stereoselectivity was observed after extensive survey of the chiral ligand and counterions, although high yields were obtained in some cases (see Table \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003e, S5, and S6 in the Supporting Information for details), suggesting a significant background reaction. However, when we used chiral rhodium complexes, the [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition was achieved with high enantioselective control under the optimized conditions (10 mol% of Rh(COD)\u003csub\u003e2\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e, 12 mol% of \u003cstrong\u003eL32\u003c/strong\u003e, in MeCN at 100 ℃) (see Table \u003cspan class=\"InternalRef\"\u003eS3\u003c/span\u003e and S4 in SI for details), highlighting the ligand\u0026rsquo;s boosting effect on the reactivity against the background reaction in the Rh-catalysis system. However, these conditions were not effective for the [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition, which might be due to the inhibition effect of anthranil to the rhodium complexes. Under the optimal conditions, all the tested FCBs \u003cstrong\u003e1\u003c/strong\u003e and imines \u003cstrong\u003e2\u003c/strong\u003e underwent the [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition reaction very well, yielding the chiral furan-fused six-membered lactams products \u003cstrong\u003e3a-4u\u003c/strong\u003e in good yields and excellent enantioselectivity (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, up to 81%, 90\u0026ndash;99% \u003cem\u003eee\u003c/em\u003e). Regardless of the electron-donating or electron-withdrawing nature of the substituents on different positions, including halide, trifluoromethyl, nitro, methoxy, methyl, and \u003cem\u003etert-\u003c/em\u003ebutyl groups, these substituted imines all resulted in excellent outcomes in this reaction (\u003cstrong\u003e3a\u003c/strong\u003e-\u003cstrong\u003e3m\u003c/strong\u003e). Beyond the aryl substituted FCBs \u003cstrong\u003e1\u003c/strong\u003e, which provided the lactams \u003cstrong\u003e4a\u003c/strong\u003e-\u003cstrong\u003e4m\u003c/strong\u003e in high yields with 90\u0026ndash;99% \u003cem\u003eee\u003c/em\u003e. These with alkyl chloride imbedded and a variety of alcohols derived ones were also well tolerated under the current conditions, leading to the chiral products \u003cstrong\u003e4o\u003c/strong\u003e-\u003cstrong\u003e4u\u003c/strong\u003e with comparable high reactivity and above 90% \u003cem\u003eee\u003c/em\u003e. In addition, the reaction could be performed on a 2.0 mmol scale with negligible effect on the yield and enantioselectivity (\u003cstrong\u003e4n\u003c/strong\u003e, 0.95 g, 85% yield, and 95% \u003cem\u003eee\u003c/em\u003e. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, note b).\u003c/p\u003e\n\u003cp\u003eThe significant advantage of this protocol is that the resultant poly-functionalized fused molecules can be readily transformed into various heterocycles with structural diversity by routine manipulations (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Treatment of \u003cstrong\u003e4n\u003c/strong\u003e with aryne precursor, 2-(trimethylsilyl)phenyl triflate, in the presence of CsF in MeCN led to the Diels-Alder reaction product \u003cstrong\u003e8\u003c/strong\u003e as a single diastereomer in 82% yield and 95% \u003cem\u003eee\u003c/em\u003e. The absolute configuration of \u003cstrong\u003e8\u003c/strong\u003e was confirmed by single-crystal X-ray diffraction analysis. Hydrolysis of \u003cstrong\u003e4n\u003c/strong\u003e occurred smoothly to produce the chiral butenolide product \u003cstrong\u003e9\u003c/strong\u003e in 91% yield with 92% \u003cem\u003eee\u003c/em\u003e and \u0026gt;\u0026thinsp;20:1 \u003cem\u003edr\u003c/em\u003e. The absolute stereochemistry of \u003cstrong\u003e9\u003c/strong\u003e was determined as (\u003cem\u003eS\u003c/em\u003e) using \u003cem\u003eX\u003c/em\u003e-ray crystallographic analysis, and the stereochemistry of the chiral lactams \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e were assigned analogously. Reduction of the styryl motif with LiAlH\u003csub\u003e4\u003c/sub\u003e produced the hydroxy product \u003cstrong\u003e10\u003c/strong\u003e as a single diastereomer in 80% yield with 92% \u003cem\u003eee\u003c/em\u003e. The oxidative ring-opening reaction of \u003cstrong\u003e4n\u003c/strong\u003e occurred smoothly in the presence of \u003cem\u003emeta\u003c/em\u003e-chloroperoxybenzoic acid (\u003cem\u003em\u003c/em\u003e-CPBA), giving \u003cstrong\u003e11\u003c/strong\u003e in 86% yield with 95% \u003cem\u003eee\u003c/em\u003e. In addition, the furan-fused eight-membered lactam \u003cstrong\u003e6a\u003c/strong\u003e can also be converted into diverse \u003cem\u003eO\u003c/em\u003e-bridged eight-membered lactams (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e) in good yields under similar conditions.\u003c/p\u003e\n\u003ch3\u003eAnticancer activity evaluation\u003c/h3\u003e\n\u003cp\u003eMoreover, a few of synthesized compounds have been selected (\u003cstrong\u003e6b \u0026minus;\u0026thinsp;6o\u003c/strong\u003e, \u003cstrong\u003e6s\u003c/strong\u003e, \u003cstrong\u003e7b \u0026minus;\u0026thinsp;7c\u003c/strong\u003e, \u003cstrong\u003e7e\u003c/strong\u003e, \u003cstrong\u003e7g \u0026minus;\u0026thinsp;7i\u003c/strong\u003e, and \u003cstrong\u003e7l \u0026minus;\u0026thinsp;7m\u003c/strong\u003e) for the anticancer activity evaluation on cell viability \u003cem\u003evia\u003c/em\u003e the CCK8 assay for MCF-7 (breast cancer), HCT-116 (colon cancer), A549 (lung adenocarcinoma), and KYSE-520 (esophageal squamous cell carcinoma) human cancer cell lines (see Supplementary Tables S7 and S8 in the Supplementary Information for details). The results show that compounds \u003cstrong\u003e6e\u003c/strong\u003e and \u003cstrong\u003e6f\u003c/strong\u003e exhibited significant anticancer potency on HCT-116 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 \u0026micro;M) and KYSE-520 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 \u0026micro;M) human cancer cell lines, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Further structure-activity relationship study is ongoing in the laboratory.\u003c/p\u003e\n\u003ch3\u003eMechanistic studies\u003c/h3\u003e\n\u003cp\u003eTo shed light on the mechanism of the developed cycloadditions using FCBs as the C4 synthon, control experiments of metal complexes with FCB \u003cstrong\u003e1b\u003c/strong\u003e were conducted in deuterated solvent to investigate C-C bond activation process (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The reaction of \u003cstrong\u003e1b\u003c/strong\u003e in the presence of Rh(COD)\u003csub\u003e2\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e (1.0 equiv.) was carried out in CD\u003csub\u003e3\u003c/sub\u003eCN at 100 \u003csup\u003eo\u003c/sup\u003eC, which was intended to reveal the C-C bond insertion intermediate. Complete conversion of \u003cstrong\u003e1b\u003c/strong\u003e to the metallacycle species \u003cstrong\u003eA\u003c/strong\u003e takes place in 1.0 hour, as is apparent from its \u003csup\u003e13\u003c/sup\u003eC NMR spectrum (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea)\u003csup\u003e73\u003c/sup\u003e. Moreover, an analogous phenomenon was observed when \u003cstrong\u003e1b\u003c/strong\u003e was treated with gold-complex in CDCl\u003csub\u003e3\u003c/sub\u003e, leading to the \u003csup\u003e13\u003c/sup\u003eC NMR signal of the carbonyl group shift from 174.7 ppm to 194.3 ppm (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb). These results clearly suggested the initial C-C bond activation process in this cycloaddition reaction.\u003c/p\u003e\n\u003cp\u003eOn the basis of above results and previous studies\u003csup\u003e43\u0026ndash;59\u003c/sup\u003e, a plausible reaction pathway has been proposed in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. Initially, metallacycle \u003cstrong\u003eA\u003c/strong\u003e is generated from furan-fused cyclobutanone \u003cstrong\u003e1\u003c/strong\u003e through oxidative addition\u003csup\u003e73\u003c/sup\u003e. Then, imine \u003cstrong\u003e2\u003c/strong\u003e or anthranil \u003cstrong\u003e5\u003c/strong\u003e\u003csup\u003e67\u003c/sup\u003e can coordinate with metal to form complexes \u003cstrong\u003eB-1\u003c/strong\u003e or \u003cstrong\u003eB-2\u003c/strong\u003e, followed by migratory insertion that leads to the corresponding seven-membered or nine-membered metallacycle species \u003cstrong\u003eC-1\u003c/strong\u003e or \u003cstrong\u003eC-2\u003c/strong\u003e. Finally, reductive elimination gives the desired lactams products \u003cstrong\u003e3/4\u003c/strong\u003e or \u003cstrong\u003e6/7\u003c/strong\u003e, respectively.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we have developed a modular and atom-economic carboacylation reaction using furan-fused cyclobutanones as a versatile C4 building block \u003cem\u003evia\u003c/em\u003e C-C bond activation. Using this method, the unprecedented intermolecular highly enantioselective Rh(I)-catalyzed [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition and Au(I)-catalyzed diastereoselective [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition of the in situ formed metallacycle species has been established with imines and anthranils as corresponding dienophiles. This process produces unique poly-substituted furan-fused lactams in good yields and excellent stereoselectivity under mild conditions. Further synthetic derivatization of these structures led to densely functionalized six/eight-membered lactams with structural diversity in high yields. Meanwhile, a preliminary antitumor activity study of these generated products indicates that the eight-membered lactams \u003cb\u003e6\u003c/b\u003e have high anticancer potency against human colon cancer cells (HCT-116) and esophageal squamous cell carcinoma cells (KYSE-520). Overcoming the catalytic protocol for the selective C-C bond activation of fused cyclobutanones should unlock the potential of these unique FCB scaffolds in heterocycle synthesis and other applications by enabling the design of analogous [4\u0026thinsp;+\u0026thinsp;n] annulation products. Further studies of this kind by expansion of the reaction scope to other dienophiles are ongoing in our laboratories, especially the asymmetric catalytic methods, and will be reported in due course.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eRepresentative procedure for the [4\u0026thinsp;+\u0026thinsp;2] cycloaddition reaction\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eCondition A.\u003c/strong\u003e To a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone \u003cstrong\u003e1\u003c/strong\u003e (0.12 mmol, 1.2 equiv.), imine \u003cstrong\u003e2\u003c/strong\u003e (0.1 mmol, 1.0 equiv.), IPrAuNTf\u003csub\u003e2\u003c/sub\u003e (4.3 mg, 5.0 mol%), and MeCN (2.0 mL) were added sequentially under argon atmosphere. After addition, the reaction mixture was stirred overnight at 40 \u0026ordm;C until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then, the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc\u0026thinsp;=\u0026thinsp;50:1 to 10:1) to give the pure products \u003cstrong\u003e3\u003c/strong\u003e or \u003cstrong\u003e4\u003c/strong\u003e in good to high yields.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCondition B.\u003c/strong\u003e To a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone \u003cstrong\u003e1\u003c/strong\u003e (0.12 mmol, 1.2 equiv.), imine \u003cstrong\u003e2\u003c/strong\u003e (0.1 mmol, 1.0 equiv.), Rh(COD)\u003csub\u003e2\u003c/sub\u003eBF\u003csub\u003e4\u003c/sub\u003e (4.0 mg, 10 mol%), 4\u0026Aring; MS (50 mg), chiral ligand \u003cstrong\u003eL32\u003c/strong\u003e (4.6 mg, 12 mol%), and MeCN (2.0 mL) were added sequentially under argon atmosphere at 100 \u0026ordm;C. After addition, the reaction mixture was stirred overnight under these conditions until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc\u0026thinsp;=\u0026thinsp;50:1 to 10:1) to give the pure products \u003cstrong\u003e3\u003c/strong\u003e or \u003cstrong\u003e4\u003c/strong\u003e in good to high yields with generally excellent enantioselectivity.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eRepresentative procedure for the [4\u0026thinsp;+\u0026thinsp;4] cycloaddition reaction\u003c/h2\u003e\n\u003cp\u003eTo a 10-mL oven-dried vial containing a magnetic stirring bar, cyclobutanone \u003cstrong\u003e1\u003c/strong\u003e (0.1 mmol, 1.0 equiv.), and anthranil \u003cstrong\u003e5\u003c/strong\u003e (0.11 mmol, 1.1 equiv.) in DCE (1.0 mL), was added a solution of JohnPhosAu(MeCN)SbF\u003csub\u003e6\u003c/sub\u003e (3.9 mg, 5.0 mol%) in DCE (1.0 mL) via syringe under argon atmosphere at 40 \u0026ordm;C. After addition, the reaction mixture was stirred 12 h under these conditions until consumption of the material (monitored by TLC). The solvent was evaporated in vacuo. Then, the residues was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc\u0026thinsp;=\u0026thinsp;30:1 to 10:1) to give the pure products \u003cstrong\u003e6\u003c/strong\u003e or \u003cstrong\u003e7\u003c/strong\u003e in good to high yields.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2225032 (\u003cstrong\u003e4k\u003c/strong\u003e), 2218249 (\u003cstrong\u003e6f\u003c/strong\u003e), 2297136 (\u003cstrong\u003e8\u003c/strong\u003e), and 2309002 (\u003cstrong\u003e9\u003c/strong\u003e). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupport for this research from the National Natural Science Foundation of China (22371309) and Guangdong Provincial Key R\u0026amp;D Programme (21202107201900002) is greatly acknowledged. We also thank Prof. Michael P. Doyle from UTSA for discussion and suggestions during the preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.X. supervised the project and wrote the manuscript. K.H. and M.L. designed the experiments. K.H., M.L., L.Q. and G.C. performed the experiments and analyzed the data. X.J. and J.H. carried out the anticancer activity evaluation. All authors discussed the results and commented on the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCraig, R. A. \u0026amp; Stoltz, B. M. Polycyclic furanobutenolide-derived cembranoid and norcembranoid natural products: biosynthetic connections and synthetic efforts. \u003cem\u003eChem. 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Ed.\u003c/em\u003e \u003cstrong\u003e54\u003c/strong\u003e, 5236\u0026ndash;5240 (2015).\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 "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3892850/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3892850/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, substantial hurdles remain for extending the C4 synthon, which is mainly limited to dienes and 1,4-dipoles so far, to construct diverse heterocycles \u003cem\u003evia\u003c/em\u003e programmable [4\u0026thinsp;+\u0026thinsp;n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a novel and versatile C4 synthon. In contrast to the well-documented intramolecular cycloaddition of benzocyclobutenones (BCBs), this is a complementary version using a heteroarene-fused reagent as a C4 building block. It involves a catalytic C-C bond activation and stepwise annulation sequence, including a Rh-catalyzed highly enantioselective [4\u0026thinsp;+\u0026thinsp;2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4\u0026thinsp;+\u0026thinsp;4]-cycloaddition with anthranils. The furan-fused polycyclic lactam products and their synthetic derivatives, which are pivotal motifs that present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods with multi-steps. Preliminary antitumor activity study of these compounds indicates that \u003cb\u003e6e\u003c/b\u003e and \u003cb\u003e6f\u003c/b\u003e exhibit high anticancer potency against colon cancer cells (HCT-116 cells, IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 \u0026micro;M) and esophageal squamous cell carcinoma cells (KYSE-520 cells, IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 \u0026micro;M), respectively.\u003c/p\u003e","manuscriptTitle":"Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-06 08:56:41","doi":"10.21203/rs.3.rs-3892850/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bb1efc72-c91b-45c1-9b54-ea0e76ee0b91","owner":[],"postedDate":"February 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28517904,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":28517905,"name":"Physical sciences/Chemistry/Medicinal chemistry/Chemical libraries"},{"id":28517906,"name":"Physical sciences/Chemistry/Catalysis/Asymmetric catalysis"}],"tags":[],"updatedAt":"2024-06-27T07:07:54+00:00","versionOfRecord":{"articleIdentity":"rs-3892850","link":"https://doi.org/10.1038/s41467-024-49664-5","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2024-06-26 04:00:00","publishedOnDateReadable":"June 26th, 2024"},"versionCreatedAt":"2024-02-06 08:56:41","video":"","vorDoi":"10.1038/s41467-024-49664-5","vorDoiUrl":"https://doi.org/10.1038/s41467-024-49664-5","workflowStages":[]},"version":"v1","identity":"rs-3892850","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3892850","identity":"rs-3892850","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}