Iron-Catalyzed Stereospecific Heterocycle N-Glycosylation with Glycal Epoxides

Iron-Catalyzed Stereospecific Heterocycle N-Glycosylation with Glycal Epoxides | 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 Research Article Iron-Catalyzed Stereospecific Heterocycle N -Glycosylation with Glycal Epoxides Xiao-Wen Zhang, Dakang Zhang, Zixiang Jiang, Hao Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8650471/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 Stereospecific N -glycosylation of heterocycles with glycal epoxides could readily provide valuable building blocks for drug discovery, but heterocycle N -glycosylation with a pyranose-based glycal epoxide is still difficult using existing methods. We report herein an iron-catalyzed, stereospecific heterocycle N -glycosylation method for these glycal epoxides in high yields and with low catalyst loadings. This method is functional-group tolerant and effective for a wide variety of functionalized, complex glycal epoxides and heterocycles. Organic Chemistry Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Heterocycle N -glycosylation plays an important role in the discovery of nucleoside-based therapeutics for infectious diseases (Figure 1A). The pioneering Vorbrüggen reaction 1 (reaction of a silylated pyrimidine with a glycosyl acetate in the presence of a Lewis acid) is still practiced today and can be scaled up to the multi-kilogram scale for the synthesis of a complex nucleoside analogue. 2 However, development of effective and functional group-tolerant catalytic methods for heterocycle N -glycosylation remains a challenge. 3 The Lewis-basic heterocyclic nitrogen atoms often deactivate Lewis acid catalysts and promoters so that the glycosylation reaction requires forcing conditions. Additionally, the basic reaction medium that facilitates most C–N bond forming reactions is less compatible with functional groups presented in commonly used glycosyl donors. These challenges inspired the development of an array of valuable heterocycle N -glycosylation methods, 4-26 but a mechanistically distinct approach could capitalize on the stereospecific N -glycosylation with glycal epoxides (Figure 1B). It is known that a furanose-based glycal epoxide can readily glycosylate a silylated or a deprotonated heterocycle in the absence of a catalyst or a promoter, 27-32 but stereospecific N -glycosylation with a pyranose-based glycal epoxide is still difficult. The existing methods require electron-rich, persilylated and perbenzylated glycosyl donors and even these have limitations (Figure 1B). 32-33 A stoichiometric ZnCl 2 -mediated method afforded an N -glycosylated thymine in modest yield. 32 An N -glycosylation promoted by a sub-stoichiometric amount of TMSOTf had to be operated at elevated temperatures leading to decreased dr (Figure 1B). 33 Thus, a generally applicable and functional group-tolerant, heterocycle N -glycosylation method with glycal epoxides has yet to be developed. We have recently discovered the iron-catalyzed highly stereospecific glycosylation of hindered secondary sugar acceptors with glycal epoxides. 34 Building upon this discovery, we report here an iron-catalyzed stereospecific heterocycle N -glycosylation method that is functional group-tolerant and effective for a wide variety of complex glycal epoxides (Figure 1C). Electron deficient glucuronic acid-based glycosyl donors are less reactive and therefore difficult to activate. 35-38 Only limited catalytic methods are effective in promoting stereospecific glycosylation with glucuronic ester epoxides. 34-35 Therefore, we selected glucuronal 2 as a model substrate for reaction discovery (Figure 2). Epoxidation of glucuronal 2 in a biphasic reaction medium with Oxone ® 39 quantitatively afforded the corresponding glucuronic ester a-epoxide (Figure S1, dr >20:1, 3 J H1-H2 = 2.6 Hz), 40 which was azeotropically dried and used directly. Bis-silylation of uracil ( 3 ) with N , O -bis(trimethylsilyl)trifluoroacetamide (BSTFA) 41 followed by solvent exchange (MeCN®CH 2 Cl 2 ) quantitatively generated the activated glycosyl acceptor. Extensive exploration of catalysts and other reaction parameters revealed that the readily available, hemin-derived iron catalyst 1a (5 mol %) used for stereospecific glycosylation with hindered sugar acceptors 34 is optimal in promoting this N -glycosylation at 0 °C in 2 h to afford 4 (91% yield, dr >20:1). Further experiments suggested that both the iron catalyst 1a and bis-silylation of the glycosyl acceptor 3 are crucial for the effective glycosylation (Figure 2. entries 1–2). Replacement of catalyst 1a with either AgOTf, TMSOTf, Fe(OTf) 2 , or iron catalyst 1b 42-43 resulted in significantly lower reactivity (<5% conversion in 2 h in Table S1). The glycosylation in prolonged time (24 h) afforded 4 in 13–21% yields with a variety of byproducts (entries 3–6 of Figure 2). We observed that this glycosylation can be carried out in acetonitrile used for pyrimidine bis-silylation without solvent exchange, albeit with a slower rate (entry 7) and that the N -glycosylation product 4 can still be obtained in 90% yield with a low catalyst loading (2 mol %) by increasing the reaction time to 6 h (entry 8). With the optimal catalyst 1a confirmed, we explored a variety of glycals and heterocycles to determine the generality of this method (Figures 3 and 4). An N -glycosylated uronic ester is a valuable building block for the synthesis of Ningnanmycin-type antibiotics and Gougerotin. 44 Therefore, we are particularly interested in heterocycle N -glycosylation with glycal epoxides derived from highly electron-deficient glucuronal S2 and galactoronal S4 (Figure 2). The epoxides obtained from these two glycals can be smoothly converted to the N -glycosylated uracils in good yields (products 4 – 6 , dr >20:1). Next, we examined an array of electronically differentiated glucals and galactals, as well as a 6-deoxy glucal and a xylal: all of them are excellent substrates and the corresponding glycal epoxides can readily N -glycosylate a bis-silylated uracil in excellent yield (products 7 – 13 , dr >20:1). To probe for the functional-group compatibility and synthetic utility of this method, we subsequently evaluated a range of readily available, disaccharide-based glycosyl donors, 34 including the epoxides derived from glucosamine (GlcN)-a-1,6-glucose (Glu), GlcN-a-1,4-glucuronic acid (GlcA), GlcN-a-1,3-Glu, GlcN-b-1,3-Glu, as well as those from maltose and lactose. Using iron catalyst 1a , the N -glycosylation with all of these donors afforded single diastereomeric products in high yield (products 14 – 19 , dr >20:1). It is also worth mentioning the bis-silylated thymine and N -benzoyl cytosine are both compatible with this method affording N -glycosylated thymines and cytosines in good yields (products 20 – 26 , dr >20:1). Interestingly, heterocycles with multiple Lewis-basic nitrogen atoms can directly participate in this iron-catalyzed stereospecific N -glycosylation without BSTFA activation (Figure 4). 1,4-Dioxane is a necessary co-solvent for heterocycles that have low solubility in CH 2 Cl 2 , and longer reaction time is often needed for full conversion. Ribosylated benzimidazoles are promising inhibitors of human cytomegalovirus (HCMV), 45 so we first evaluated benzimidazole N -glycosylation with an array of functionalized, pyranose-based glycal epoxides. All of these glycosylations afford the desired products in good yield (products 27 – 33 , dr >20:1). 1,2,4-Triazoles are synthetically valuable because of their relevance to antiviral medicine Ribavirin. 46 We observed that the catalytic N -glycosylation occurs regioselectively at the triazole N1 position in decent yields (corresponding products 34 – 36 , dr >20:1, see Supporting Information for details). Furthermore, we explored the N -glycosylation of an indazole and a tetrazole: both of the regioselectively N -glycosylated heterocycles were isolated in excellent yields (corresponding products 37 – 42 , dr >20:1, see Supporting Information for details). Most known purine N -glycosylation methods predominantly afford the N 9-glycosylated adenines. The initially formed N 3-glycosylated adenine undergoes an irreversible N 3 to N 9 transglycosylation, presumably by formation of the 3,9- N , N '-diglycosylated adenine and cleavage of the N 3 glycoside. 47-48 However, the iron-catalyzed glycosylation of bis-( N 6-Boc)-protected adenine S24 affords both the N 9- ( 43a – 45a ) and the N 3-glycosylated adenines ( 43b – 45b ) in excellent combined yield. Notably, 43a and 43b do not interconvert under the reaction conditions (Figure S7) and they are readily separable by column chromatography, providing an expedient way for the synthesis of 3-isoadenosine analogs. Interestingly, the iron-catalyzed N -glycosylation of a protected guanine S27 exclusively generated the N 9-glycosylated guanines ( 46 and 47 ). In conclusion, we have developed an iron-catalyzed highly stereospecific heterocycle N -glycosylation method with pyranose-based glycal epoxides. This method is effective for a wide variety of glycals and heterocycles and it is compatible with an array of functional groups often used in complex-glycan synthesis. Our current effort focuses on applications of this method in rapid synthesis of small-molecule therapeutics. Declarations ASSOCIATED CONTENT Supporting Information Experimental procedure, characterization data for all new compounds and selected NMR spectra. The Supporting Information is available free of charge on the ACS Publications website. AUTHOR INFORMATION Corresponding Author * [email protected] ORCID: 0000-0001-5029-8392 Notes The subject matter described in this article is included in patent applications filed by Brandeis University. ACKNOWLEDGMENT This research was supported by the National Institutes of Health (GM134926). We thank NIH Shared Instrumentation grant S10OD034395 (NMR) for the instrument support. References Niedballa U, Vorbrüggen H (1970) A General Synthesis of Pyrimidine Nucleosides. 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Biochemistry 4:354–365 Framski G, Gdaniec Z, Gdaniec M, Boryski J (2006) A Reinvestigated Mechanism of Ribosylation of Adenine under Silylating Conditions. Tetrahedron 62:10123–10129 Additional Declarations The authors declare potential competing interests as follows: The subject matter described in this article is included in patent applications filed by Brandeis University. Supplementary Files XuIronCatalyzedHeterocycleNGlycosylationSIDecember29.pdf Xu Iron-Catalyzed Heterocycle N-Glycosylation SI Screenshot20260121205303.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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15:28:50","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106511,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/04bfef74400e1dc6fd183b3e.html"},{"id":100810428,"identity":"1d9984c3-64e0-410b-bebe-c6d4004b22eb","added_by":"auto","created_at":"2026-01-21 15:28:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77437,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Biologically active \u003cem\u003eN\u003c/em\u003e-glycosylated heterocycles: Ribavirin and Ningnanmycin. (B) Existing heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation methods with glycal epoxides. (C) This research: iron-catalyzed stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/9595da681ff3dfd3f33c8b48.png"},{"id":100810429,"identity":"3dae2734-602e-4ded-a086-42c404683c0c","added_by":"auto","created_at":"2026-01-21 15:28:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75608,"visible":true,"origin":"","legend":"\u003cp\u003eCatalyst discovery for the iron-catalyzed stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eEpoxidation was carried out in a biphasic reaction medium with Oxone\u003csup\u003e®\u003c/sup\u003e and acetone. The glycal epoxide was dried azeotropically with toluene, assayed by \u003csup\u003e1\u003c/sup\u003eH NMR, and then directly used. The glycosylation was carried out at 0 °C in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e. The reaction was quenched by methanol and imidazole for conversion measurement. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003eIsolated\u003csup\u003e \u003c/sup\u003eyield; \u003cem\u003edr\u003c/em\u003e was determined by \u003csup\u003e1\u003c/sup\u003eH NMR analysis. Iron(III) porphyrin catalyst \u003cstrong\u003e1a\u003c/strong\u003e was formed in situ from the corresponding iron porphyrin chloride (6 mol %) and AgOTf (5 mol %).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/9c332c9c73a40efc9db279e8.png"},{"id":100858111,"identity":"09b866fe-b5d1-4ae4-82e8-e7a6d6d754ec","added_by":"auto","created_at":"2026-01-22 07:23:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95281,"visible":true,"origin":"","legend":"\u003cp\u003eSubstrate scope for the iron-catalyzed stereospecific pyrimidine \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides. All yields are isolated yields. See Supporting Information for experimental details.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/b8b1beddd453c6cdca0be132.png"},{"id":100858120,"identity":"60757de5-da41-43fb-8009-98eac73e6eb6","added_by":"auto","created_at":"2026-01-22 07:23:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":107902,"visible":true,"origin":"","legend":"\u003cp\u003eSubstrate scope for the iron-catalyzed stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides. All yields are isolated yields. See Supporting Information for experimental details.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/3c45fcdd94f8ced5ad456ad7.png"},{"id":100952566,"identity":"6a9cc76b-0b9e-4200-b220-b373c62967c0","added_by":"auto","created_at":"2026-01-23 07:17:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":620614,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/6db03efd-adc1-4ef9-8781-be4df1927d50.pdf"},{"id":100858379,"identity":"bbfcdf35-89ad-46b0-9ab9-35b8c29b41ee","added_by":"auto","created_at":"2026-01-22 07:24:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12748617,"visible":true,"origin":"","legend":"\u003cp\u003eXu Iron-Catalyzed Heterocycle N-Glycosylation SI\u003c/p\u003e","description":"","filename":"XuIronCatalyzedHeterocycleNGlycosylationSIDecember29.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/77b14b0e0f96acb45566a60d.pdf"},{"id":100810430,"identity":"c2816f69-1f72-4bcf-b235-38f4dea4dca9","added_by":"auto","created_at":"2026-01-21 15:28:49","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24821,"visible":true,"origin":"","legend":"","description":"","filename":"Screenshot20260121205303.png","url":"https://assets-eu.researchsquare.com/files/rs-8650471/v1/aad4745dd5c068a9d394eea3.png"}],"financialInterests":"The authors declare potential competing interests as follows: The subject matter described in this article is included in patent applications filed by Brandeis University.","formattedTitle":"\u003cp\u003eIron-Catalyzed Stereospecific Heterocycle \u003cem\u003eN\u003c/em\u003e-Glycosylation with Glycal Epoxides\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eHeterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation plays an important role in the discovery of nucleoside-based therapeutics for infectious diseases (Figure 1A). The pioneering Vorbr\u0026uuml;ggen reaction\u003csup\u003e1\u003c/sup\u003e (reaction of a silylated pyrimidine with a glycosyl acetate in the presence of a Lewis acid) is still practiced today and can be scaled up to the multi-kilogram scale for the synthesis of a complex nucleoside analogue.\u003csup\u003e2\u003c/sup\u003e However, development of effective and functional group-tolerant catalytic methods for heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation remains a challenge.\u003csup\u003e3\u003c/sup\u003e The Lewis-basic heterocyclic nitrogen atoms often deactivate Lewis acid catalysts and promoters so that the glycosylation reaction requires forcing conditions. Additionally, the basic reaction medium that facilitates most C\u0026ndash;N bond forming reactions is less compatible with functional groups presented in commonly used glycosyl donors.\u003c/p\u003e\n\u003cp\u003eThese challenges inspired the development of an array of valuable heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation methods,\u003csup\u003e4-26\u003c/sup\u003e but a mechanistically distinct approach could capitalize on the stereospecific \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides (Figure 1B). It is known that a furanose-based glycal epoxide can readily glycosylate a silylated or a deprotonated heterocycle in the absence of a catalyst or a promoter,\u003csup\u003e27-32\u003c/sup\u003e but stereospecific \u003cem\u003eN\u003c/em\u003e-glycosylation with a pyranose-based glycal epoxide is still difficult. The existing methods require electron-rich, persilylated and perbenzylated glycosyl donors and even these have limitations (Figure 1B).\u003csup\u003e32-33\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA stoichiometric ZnCl\u003csub\u003e2\u003c/sub\u003e-mediated method afforded an \u003cem\u003eN\u003c/em\u003e-glycosylated thymine in modest yield.\u003csup\u003e32\u003c/sup\u003e An \u003cem\u003eN\u003c/em\u003e-glycosylation promoted by a sub-stoichiometric amount of TMSOTf had to be operated at elevated temperatures leading to decreased \u003cem\u003edr\u003c/em\u003e (Figure 1B).\u003csup\u003e33\u003c/sup\u003e Thus, a generally applicable and functional group-tolerant, heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation method with glycal epoxides has yet to be developed. We have recently discovered the iron-catalyzed highly stereospecific glycosylation of hindered secondary sugar acceptors with glycal epoxides.\u003csup\u003e34\u003c/sup\u003e Building upon this discovery, we report here an iron-catalyzed stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation method that is functional group-tolerant and effective for a wide variety of complex glycal epoxides (Figure 1C).\u003c/p\u003e\n\u003cp\u003eElectron deficient glucuronic acid-based glycosyl donors are less reactive and therefore difficult to activate.\u003csup\u003e35-38\u003c/sup\u003e Only limited catalytic methods are effective in promoting stereospecific glycosylation with glucuronic ester epoxides.\u003csup\u003e34-35\u003c/sup\u003e Therefore, we selected glucuronal \u003cstrong\u003e2\u003c/strong\u003e as a model substrate for reaction discovery (Figure 2). Epoxidation of glucuronal\u003cstrong\u003e\u0026nbsp;2\u003c/strong\u003e in a biphasic reaction medium with Oxone\u003csup\u003e\u0026reg;\u003c/sup\u003e\u003csup\u003e39\u003c/sup\u003e quantitatively afforded the corresponding glucuronic ester a-epoxide (Figure S1, \u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1,\u003csup\u003e\u0026nbsp;3\u003c/sup\u003e\u003cem\u003eJ\u003c/em\u003e\u003csub\u003eH1-H2\u003c/sub\u003e = 2.6 Hz),\u003csup\u003e40\u003c/sup\u003e which was azeotropically dried and used directly. Bis-silylation of uracil (\u003cstrong\u003e3\u003c/strong\u003e) with \u003cem\u003eN\u003c/em\u003e,\u003cem\u003eO\u003c/em\u003e-bis(trimethylsilyl)trifluoroacetamide (BSTFA)\u003csup\u003e41\u003c/sup\u003e followed by solvent exchange (MeCN\u0026reg;CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e) quantitatively generated the activated glycosyl acceptor. Extensive exploration of catalysts and other reaction parameters revealed that the readily available, hemin-derived iron catalyst \u003cstrong\u003e1a\u0026nbsp;\u003c/strong\u003e(5 mol %) used for stereospecific glycosylation with hindered sugar acceptors\u003csup\u003e34\u003c/sup\u003e is optimal in promoting this \u003cem\u003eN\u003c/em\u003e-glycosylation at 0 \u0026deg;C in 2 h to afford \u003cstrong\u003e4\u0026nbsp;\u003c/strong\u003e(91% yield, \u003cem\u003edr\u003c/em\u003e \u0026gt;20:1). Further experiments suggested that both the iron catalyst \u003cstrong\u003e1a\u003c/strong\u003e and bis-silylation of the glycosyl acceptor \u003cstrong\u003e3\u003c/strong\u003e are crucial for the effective glycosylation (Figure 2. entries 1\u0026ndash;2). Replacement of catalyst \u003cstrong\u003e1a\u003c/strong\u003e with either AgOTf, TMSOTf, Fe(OTf)\u003csub\u003e2\u003c/sub\u003e, or iron catalyst \u003cstrong\u003e1b\u003c/strong\u003e\u003csup\u003e42-43\u003c/sup\u003e resulted in significantly lower reactivity (\u0026lt;5% conversion in 2 h in Table S1). The glycosylation in prolonged time (24 h) afforded \u003cstrong\u003e4\u003c/strong\u003e in 13\u0026ndash;21% yields with a variety of byproducts (entries 3\u0026ndash;6 of Figure 2). We observed that this glycosylation can be carried out in acetonitrile used for pyrimidine bis-silylation without solvent exchange, albeit with a slower rate (entry 7) and that the \u003cem\u003eN\u003c/em\u003e-glycosylation product \u003cstrong\u003e4\u003c/strong\u003e can still be obtained in 90% yield with a low catalyst loading (2 mol %) by increasing the reaction time to 6 h (entry 8).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith the optimal catalyst \u003cstrong\u003e1a\u003c/strong\u003e confirmed, we explored a variety of glycals and heterocycles to determine the generality of this method (Figures 3 and 4). An \u003cem\u003eN\u003c/em\u003e-glycosylated uronic ester is a valuable building block for the synthesis of Ningnanmycin-type antibiotics and Gougerotin.\u003csup\u003e44\u003c/sup\u003e Therefore, we are particularly interested in heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation with glycal epoxides derived from highly electron-deficient glucuronal\u003cstrong\u003e\u0026nbsp;S2\u0026nbsp;\u003c/strong\u003eand galactoronal\u003cstrong\u003e\u0026nbsp;S4\u0026nbsp;\u003c/strong\u003e(Figure 2). The epoxides obtained from these two glycals can be smoothly converted to the \u003cem\u003eN\u003c/em\u003e-glycosylated uracils in good yields (products \u003cstrong\u003e4\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e6\u003c/strong\u003e, \u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1). Next, we examined an array of electronically differentiated glucals and galactals, as well as a 6-deoxy glucal and a xylal: all of them are excellent substrates and the corresponding glycal epoxides can readily \u003cem\u003eN\u003c/em\u003e-glycosylate a bis-silylated uracil in excellent yield (products \u003cstrong\u003e7\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e13\u003c/strong\u003e,\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1). To probe for the functional-group compatibility and synthetic utility of this method, we subsequently evaluated a range of readily available, disaccharide-based glycosyl donors,\u003csup\u003e34\u003c/sup\u003e including the epoxides derived from glucosamine (GlcN)-a-1,6-glucose (Glu), GlcN-a-1,4-glucuronic acid (GlcA), GlcN-a-1,3-Glu, GlcN-b-1,3-Glu, as well as those from maltose and lactose. Using iron catalyst \u003cstrong\u003e1a\u003c/strong\u003e, the \u003cem\u003eN\u003c/em\u003e-glycosylation with all of these donors afforded single diastereomeric products in high yield (products \u003cstrong\u003e14\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e19\u003c/strong\u003e,\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1). It is also worth mentioning the bis-silylated thymine and \u003cem\u003eN\u003c/em\u003e-benzoyl cytosine are both compatible with this method affording \u003cem\u003eN\u003c/em\u003e-glycosylated thymines and cytosines in good yields (products \u003cstrong\u003e20\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e26\u003c/strong\u003e,\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1).\u003c/p\u003e\n\u003cp\u003eInterestingly, heterocycles with multiple Lewis-basic nitrogen atoms can directly participate in this iron-catalyzed stereospecific \u003cem\u003eN\u003c/em\u003e-glycosylation without BSTFA activation (Figure 4). 1,4-Dioxane is a necessary co-solvent for heterocycles that have low solubility in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e, and longer reaction time is often needed for full conversion. Ribosylated benzimidazoles are promising inhibitors of human cytomegalovirus (HCMV),\u003csup\u003e45\u003c/sup\u003e so we first evaluated benzimidazole \u003cem\u003eN\u003c/em\u003e-glycosylation with an array of functionalized, pyranose-based glycal epoxides. All of these glycosylations afford the desired products in good yield (products \u003cstrong\u003e27\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e33\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1). 1,2,4-Triazoles are synthetically valuable because of their relevance to antiviral medicine Ribavirin.\u003csup\u003e46\u003c/sup\u003e We observed that the catalytic \u003cem\u003eN\u003c/em\u003e-glycosylation occurs regioselectively at the triazole N1 position in decent yields (corresponding products \u003cstrong\u003e34\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e36\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1, see Supporting Information for details). Furthermore, we explored the \u003cem\u003eN\u003c/em\u003e-glycosylation of an indazole and a tetrazole: both of the regioselectively \u003cem\u003eN\u003c/em\u003e-glycosylated heterocycles were isolated in excellent yields (corresponding products \u003cstrong\u003e37\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e42\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cem\u003edr\u0026nbsp;\u003c/em\u003e\u0026gt;20:1, see Supporting Information for details).\u003c/p\u003e\n\u003cp\u003eMost known purine \u003cem\u003eN\u003c/em\u003e-glycosylation methods predominantly afford the \u003cem\u003eN\u003c/em\u003e9-glycosylated adenines. The\u0026nbsp;initially formed \u003cem\u003eN\u003c/em\u003e3-glycosylated adenine undergoes an irreversible \u003cem\u003eN\u003c/em\u003e3 to \u003cem\u003eN\u003c/em\u003e9 transglycosylation, presumably by formation of the\u0026nbsp;3,9-\u003cem\u003eN\u003c/em\u003e,\u003cem\u003eN\u003c/em\u003e\u0026apos;-diglycosylated adenine and cleavage of the \u003cem\u003eN\u003c/em\u003e3 glycoside.\u003csup\u003e47-48\u003c/sup\u003e However, the iron-catalyzed glycosylation of bis-(\u003cem\u003eN\u003c/em\u003e6-Boc)-protected adenine \u003cstrong\u003eS24\u003c/strong\u003e affords both the \u003cem\u003eN\u003c/em\u003e9- (\u003cstrong\u003e43a\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e45a\u003c/strong\u003e) and the \u003cem\u003eN\u003c/em\u003e3-glycosylated adenines (\u003cstrong\u003e43b\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e45b\u003c/strong\u003e) in excellent combined yield. Notably, \u003cstrong\u003e43a\u003c/strong\u003e and \u003cstrong\u003e43b\u003c/strong\u003e do not interconvert under the reaction conditions (Figure S7) and they are readily separable by column chromatography, providing an expedient way for the synthesis of 3-isoadenosine analogs. Interestingly, the iron-catalyzed \u003cem\u003eN\u003c/em\u003e-glycosylation of a protected guanine \u003cstrong\u003eS27\u003c/strong\u003e exclusively generated the \u003cem\u003eN\u003c/em\u003e9-glycosylated guanines (\u003cstrong\u003e46\u003c/strong\u003e and \u003cstrong\u003e47\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIn conclusion, we have developed an iron-catalyzed highly stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation method with pyranose-based glycal epoxides. This method is effective for a wide variety of glycals and heterocycles and it is compatible with an array of functional groups often used in complex-glycan synthesis. Our current effort focuses on applications of this method in rapid synthesis of small-molecule therapeutics.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eASSOCIATED CONTENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExperimental procedure, characterization data for all new compounds and selected NMR spectra. The Supporting Information is available free of charge on the ACS Publications website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorresponding Author\u003c/p\u003e\n\u003cp\u003e* [email protected] ORCID: 0000-0001-5029-8392\u003c/p\u003e\n\u003cp\u003eNotes\u003c/p\u003e\n\u003cp\u003eThe subject matter described in this article is included in patent applications filed by Brandeis University.\u003c/p\u003e\n\u003ch2\u003eACKNOWLEDGMENT\u003c/h2\u003e \u003cp\u003eThis research was supported by the National Institutes of Health (GM134926). We thank NIH Shared Instrumentation grant S10OD034395 (NMR) for the instrument support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNiedballa U, Vorbr\u0026uuml;ggen H (1970) A General Synthesis of Pyrimidine Nucleosides. 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Tetrahedron 62:10123\u0026ndash;10129\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"6fcdda10-f1d0-476d-a1b2-ed99d351595b","identifier":"10.13039/100000057","name":"National Institute of General Medical Sciences","awardNumber":"GM134926","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Brandeis University","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":"","lastPublishedDoi":"10.21203/rs.3.rs-8650471/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8650471/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStereospecific \u003cem\u003eN\u003c/em\u003e-glycosylation of heterocycles with glycal epoxides could readily provide valuable building blocks for drug discovery, but heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation with a pyranose-based glycal epoxide is still difficult using existing methods. We report herein an iron-catalyzed, stereospecific heterocycle \u003cem\u003eN\u003c/em\u003e-glycosylation method for these glycal epoxides in high yields and with low catalyst loadings. This method is functional-group tolerant and effective for a wide variety of functionalized, complex glycal epoxides and heterocycles.\u003c/p\u003e","manuscriptTitle":"Iron-Catalyzed Stereospecific Heterocycle N-Glycosylation with Glycal Epoxides","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-21 15:28:44","doi":"10.21203/rs.3.rs-8650471/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":"9db2d3e4-754b-4b81-80e7-e724998a688a","owner":[],"postedDate":"January 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61445246,"name":"Organic Chemistry"}],"tags":[],"updatedAt":"2026-01-21T15:28:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-21 15:28:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8650471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8650471","identity":"rs-8650471","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}