Photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines: antifungal and anti-inflammatory activities

Photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines: antifungal and anti-inflammatory activities | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 20 January 2026 V1 Latest version Share on Photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines: antifungal and anti-inflammatory activities Authors : Xiao-Ying Huang , Jing-Ru Li , Xue-Ru Li , Jin-Hui Bao , Fuxing Yang , Wengui Duan , and Ying-Ming Pan 0000-0002-3625-7647 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176889251.18265471/v1 143 views 83 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A visible-light-driven [3+3] cycloaddition of α-nitroketones with 1,4-dithiane-2,5-diol has been developed for the efficient synthesis of novel 1,4,2-oxathiazine scaffolds. This photochemical transformation proceeds via in situ-generated electron donor-acceptor (EDA) complexes derived from α-nitroketones, LiO t Bu, and HFIP, eliminating the need for external photocatalysts or transition metals and enabling a green approach to O,N,S-containing heterocycles. Notably, the synthesized heterocycles exhibit significant biological activities, including potent antifungal activity against Candida albicans (MIC = 32.84 ± 0.53 μM) and anti-inflammatory potential. Cite this paper: Chin. J. Chem. 2026 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX Photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines: antifungal and anti-inflammatory activities Xiao-Ying Huang, a,b,c Jing-Ru Li, b Xue-Ru Li, b Jin-Hui Bao, b Fuxing Yang,* , d Wen-Gui Duan,* , a and Ying-Ming Pan* , b a School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People’s Republic of China b State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, People’s Republic of China c College of Materials and Chemical Engineering, Guangxi Key Laboratory of Calcium Carbonate Resources Comprehensive Utilization, Hezhou University, Hezhou 542899, People’s Republic of China d Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin 541199, People’s Republic of China Photocatalysis | 1,4,2-Oxathiazines | Donor–acceptor (EDA) complexes | [3+3] Cycloaddition | Biological activities | Comprehensive Summary A visible-light-driven [3+3] cycloaddition of α-nitroketones with 1,4-dithiane-2,5-diol has been developed for the efficient synthesis of novel 1,4,2-oxathiazine scaffolds. This photochemical transformation proceeds via in situ-generated electron donor-acceptor (EDA) complexes derived from α-nitroketones, LiO t Bu, and HFIP, eliminating the need for external photocatalysts or transition metals and enabling a green approach to O,N,S-containing heterocycles. Notably, the synthesized heterocycles exhibit significant biological activities, including potent antifungal activity against Candida albicans (MIC = 32.84 ± 0.53 μM) and anti-inflammatory potential. Background and Originality Content Oxathiazines, a class of heterocycles incorporating oxygen, sulfur, and nitrogen atoms, constitute privileged structural motifs in medicinal and agrochemical research (Scheme 1a). 1 For instance, 1,2,3-oxathiazines ( I ) function as an estrone sulfatase inhibitor; 2 while 1,4,3-oxathiazines ( II ) demonstrate potent 11 β -HSD1 inhibition. 3 Synthetic routes to 1,3,5- and 1,5,2-oxathiazines ( III and IV ) have also been established. 4 In contrast, the isomeric 1,4,2-oxathiazine scaffold ( V ) has received scant attention, with neither reliable synthetic methods nor systematic pharmacological studies reported. The construction of multi-heteroatom heterocycles often requires specific synthetic strategies. 5 Therefore, the development of straightforward, efficient, and sustainable methods for one-step construction of 1,4,2-oxathiazines, along with the exploration of their biological profiles, is highly desirable. Scheme 1 Representative examples of oxathiazines and strategies for the photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines α-Nitroketones are valuable synthons in the synthesis of natural products and bioactive compounds. 6 Their unique reactivity has inspired extensive methodological developments, enabling efficient access to structurally diverse and high-value scaffolds. 7 In the past decades, a common strategy involves the activation of α-nitroketones to nitrile oxides, which participate in 1,3-dipolar cycloadditions with alkenes or alkynes to afford various isoxazole derivatives (Scheme 1b). 8 Nevertheless, the transformation of α-nitroketones into other heterocyclic classes remains limited. From the perspective of sustainable chemistry, establishing green and efficient reactions between α-nitroketones and new types of dipolarophiles would significantly expand the toolbox for heterocycle synthesis. Photocatalysis has emerged as a powerful and sustainable platform for organic synthesis. 9 Photochemical reactions offer distinct advantages, include novel mechanistic pathways, mild conditions, and the ability to assemble thermodynamically disfavored structures. Among various activation modes, photoreactions mediated by electron donor-acceptor (EDA) complexes are particularly attractive, as they frequently proceed without external photocatalysts or transition metal. These transient complexes form via weak non-covalent interactions between donor and acceptor molecules, inducing a bathochromic shift in their absorption profiles and thereby enabling direct excitation by visible light. 10 Despite progress, the construction of multi-heteroatom heterocyclic systems via photoreactions of α-nitroketones remains relatively undeveloped. This unmet challenge is primarily attributed to limitations in activation strategies and a lack of readily available, compatible dipolarophiles. 11 To address this, we envisioned an EDA-complex strategy to facilitate the photocatalytic dehydration of α-nitroketones, which would generate nitrile oxides—a classic class of 1,3-dipoles—as key intermediates. Notably, under basic conditions, 1,4-dithiane-2,5-diol can undergo in situ transformation to furnish two molecules of 2-mercaptoacetaldehyde. This bifunctional reagent possesses both nucleophilic and electrophilic sites, making it an ideal bipolar coupling partner. 12 Building on this foundation, we have achieved a metal-free photocatalytic [3+3] cycloaddition between α-nitroketones and 1,4-dithiane-2,5-diol, offering a new route for the efficient construction of 1,4,2-oxathiazine scaffolds. Results and Discussion Table 1 Optimization of reaction conditions a Entry Variation from standard conditions Yield b 1 none 87 2 380 nm instead of 410 nm 42 3 395 nm instead of 410 nm 65 4 425 nm instead of 410 nm 34 5 LiO t Bu (5 mol%) 49 6 LiO t Bu (15 mol%) 76 7 air instead of argon 75 8 O 2 instead of argon 43 9 without base n.d. 10 without light n.d. a Conditions: 1a (0.2 mmol, 1.0 eq.), 2 (0.11 mmol, 0.55 eq.) and LiO t Bu (0.02 mmol, 10 mol%) were stirred in HFIP (2.0 mL) at argon atmosphere at 31 °C for 7 h under 410 nm irradiation of 40 W. b Isolated yields. n.d. = not detected. We initiated our study by exploring the visible-light-mediated [3+3] cycloaddition between benzoylnitromethane ( 1a ), serving as a nitrile oxide precursor, and 1,4-dithiane-2,5-diol ( 2 ) to construct 1,4,2-oxathiazine derivatives. Employing lithium tert -butoxide (LiO t Bu) as the base in hexafluoroisopropanol (HFIP) under an argon atmosphere and irradiation with a 40 W LED lamp (λmax = 410 nm) at 31 °C proved optimal, delivering the desired product 3a in 87% yield after 7 hours (Table 1, entry 1). The reaction efficiency was found to be highly dependent on the irradiation wavelength, as switching to 380, 395, or 425 nm LEDs resulted in notably diminished yields (entries 2–4). Subsequent optimization revealed that deviations from the optimal stoichiometry of the base, either lower or higher, adversely affected the outcome (entries 5 and 6). Control experiments under an air or pure oxygen atmosphere led to inferior results, with oxygen exerting a particularly strong inhibitory effect—presumably by intercepting the reactive nitrile oxide intermediate (entries 7 and 8). The transformation was completely suppressed in the absence of either the photocatalyst or the base, underscoring the essential role of both components in the catalytic cycle (entries 9 and 10). With the optimized conditions established, we examined the substrate scope of α-nitroketones (Scheme 2). Substrates possessing phenyl rings with electron-donating groups (EDGs; e.g., methyl, tert -butyl, methoxy) all underwent smooth conversion, delivering products 3b–3g in excellent yields ranging from 79% to 89%. The reaction also tolerated multiply substituted arenes, exemplified by a 3-chloro-5-methoxyphenyl substrate furnishing 3h in 59% yield. Arenes bearing electron-withdrawing substituents were compatible, with 4-(trifluoromethoxy)phenyl and 3-(methoxycarbonyl)phenyl derivatives affording products 3i and 3j in 73% and 84% yield, respectively. This protocol extended successfully to fused aromatic systems, with biphenyl- and naphthalen-2-yl-based substrates providing adducts 3k and 3l in 82% and 68% yield. Furthermore , a variety of heteroaromatic α-nitroketones derived from 2-thienyl, 6-methoxypyridin-3-yl, 5-methylisoxazol-3-yl, and benzo[b]thiophen-2-yl groups proved Scheme 2 The substrate scope for the synthesis of 1,4,2-oxathiazines Reaction conditions: 1 (0.2 mmol, 1.0 eq.), 2 (0.11 mmol, 0.55 eq.), and LiO t Bu (0.02 mmol, 10 mol%) were stirred in HFIP (2.0 mL) under an argon atmosphere at 31 °C for 7 h under 410 nm irradiation of 40 W. Yield of isolated products. Scheme 3 Scale-up reaction and synthetic transformations to be suitable substrates, yielding the corresponding products 3m–3p in 48–81% yield. Aliphatic α-nitroketones participated effectively in the transformation, affording products 3q–3s in good yields. Pleasingly, an adamantane-containing substrate—a motif frequently encountered in medicinal chemistry—was successfully incorporated, delivering 3t satisfactorily. Nitroacetate esters were also suitable reaction partners, with methyl and ethyl esters providing 3u and 3v in 74% and 71% yield, respectively. However, nitroacetic acid and N -methyl- N -phenyl-2-nitroacetamide proved unreactive under the present conditions, yielding no desired products ( 3w , 3x ). Next, we successfully performed a scale-up reaction using 1.0 mmol of 1a, which afforded product 3a in 79% yield (Scheme 3a). To demonstrate the synthetic utility of this methodology, we further conducted product transformations (Scheme 3b) . 13 The oxidation led to the formation of sulfoxide 4 in 53% yield. Moreover, a condensation reaction between 3a and p -nitrophenyl-hydrazine under acidic conditions provided hydrazone 5 in 58% yield. Additionally, treatment of 3a with 2-methylacryloyl chloride under basic conditions resulted in ring-opening to give product 6 in 74% yield. To probe the reaction mechanism, we conducted a series of control experiments (Scheme 4). The UV-vis data, as evidenced by a bathochromic shift, suggest the formation of an EDA complex from α-nitroketone, LiO t Bu, and HFIP (Figure 1). Intermediates Figure 1. UV−vis absorption spectra of various compositions in HFIP. Scheme 4 Control experimentes 7-10 were detected by HRMS analysis under standard conditions in the absence of 1,4-dithiane-2,5-diol 2 (Scheme 4a). Additionally, these same intermediates were observed when the reaction of 1a with 2 was analyzed after 3 h (Scheme 4b). Furthermore, upon addition of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), only a trace amount of product 3a were observed, while TEMPO- coupled compounds 11 and 12 were detected by HRMS (Scheme 4c). These results indicate that α-nitroketone forms a nitrile oxide intermediate in this photochemical transformation. Based on the experimental results and literature precedents, 14 a plausible mechanism was proposed as shown in Scheme 5. The process initiates with the formation of an EDA complex B among α-nitroketone, LiO t Bu, and HFIP. This complex facilitates Scheme 5 Proposed reaction mechanism the decomposition of substrate 1 into intermediate C (the nitrite catalyst). Subsequently, intermediate C then reacts with compound 1 to generate intermediate D , which undergoes dehydration to form intermediate E . Subsequent conversion of Intermediate E yields nitrile oxide F (with regeneration of intermediate C ), which participates in a [3+3] cycloaddition with intermediate H (derived from 2 ), ultimately leading to the formation of oxathiazine 3 . Critical evidence for this pathway comes from HRMS detection of furoxan intermediate G during the reaction of 1 and 2 , confirming nitrile oxide generation. 15 Figure 2 Biological activity evaluation. We conducted biological activity assays on a series of products. 16 Initial evaluation of the antimicrobial activity of target compounds was performed using the broth dilution method. Fluconazole (FLC) or penicillin G (PG) was used for comparison. The results demonstrated that compounds 3b , 3i , and 3k exhibited inhibitory activity against both Candida albicans ATCC10231 and Staphylococcus aureus , but were inactive toward Escherichia coli (see SI). Through serial dilution assays, the minimum inhibitory concentration (MIC) of compound 3b against Candida was determined to be 32.84 ± 0.53 μM (Figure 2a). Furthermore, we evaluated the inhibitory effects of target compounds on nitric oxide (NO) production using the Griess assay. After treatment with various concentrations of the compounds, absorbance was measured at 540 nm using a microplate reader, and NO levels were calculated based on a standard curve. The results demonstrated that compounds 3l , 3k , 3r , and 5 all significantly suppressed NO activity (Figure 2b). To investigate whether the NO inhibition mechanism was associated with the expression of inflammation-related proteins, we further performed Western blot analysis. BV-2 microglial cells were first stimulated with LPS for 24 hours, followed by treatment with 10 and 40 μM concentrations of compounds 3l , 3k , 3r , and 5 . The results revealed that compounds 3l and 3k at 40 μM effectively inhibited the expression levels of inducible nitric oxide synthase (iNOS, P<0.0001, Figure 2c) and cyclooxygenase-2 (COX-2, P<0.0001, Figure 2d). Conclusions In summary, we have developed an efficient and transition-metal-free photocatalytic strategy for the synthesis of 1,4,2-oxathiazine derivatives from α-nitroketones and 1,4-dithiane-2,5-diol under visible-light irradiation. This green approach leverages in situ-formed EDA complexes—generated from α-nitroketones, LiO t Bu, and HFIP—as organic photocatalysts, enabling straightforward access to novel N,O,S-containing heterocyclic scaffolds in good yields (up to 89%) with high atom economy. Furthermore, biological evaluation identified promising bioactivities: compound 3b showed potent antifungal activity against Candida albicans (MIC = 32.84 ± 0.53 μM), while 3l and 3k exhibited significant anti-inflammatory effects. These results underscore both the environmental advantages and synthetic utility of this catalytic system for constructing multi-heteroatom heterocycles, while also advancing the understanding of the pharmacological potential of 1,4,2-oxathiazines and providing a foundation for developing novel bioactive derivatives. Experimental A 10 mL Schlenk tube was charged with α-nitroketone 1 (0.20 mmol, 1.0 eq.), 1,4-dithiane-2,5-diol 2 (0.11 mmol, 0.55 eq.), LiO t Bu (0.02 mmol, 0.1 eq.), and HFIP (2.0 mL). The reaction vessel was purged with argon (three cycles). The mixture was stirred at 31 °C under irradiation with a 40 W, 410 nm LED lamp for 7 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 6:1 to 3:1) to afford the product 3 . Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.70XXX. Acknowledgement This work is supported by the Guangxi Science and Technology Base and Talent Project (High level Innovative Talents and Team Training) (Guike AD23026094), the National Natural Science Foundation of China (22161008), the Postdoctoral Science Foundation of China (2025MD784095), and Guangxi Higher Education Institutions Young and Middle-aged Teachers’ Research Basic Ability Enhancement Program (2020KY18013) References 1. (a) Chee, G.-L.; Bhattarai, B.; Gietz, R. D.; Alrushaid, S.; Nitiss, J. L.; B. Hasinoff, B. Chemical Reactivity and Microbicidal Action of Bethoxazin. Bioorg. Med. Chem. 2012 , 20 , 1494−1501; (b) W. G. Brouwer, A. R. Bell, A. R. Blem and R. A. Davis, 3-Aryl-5,6-dihydro-1,4,2-oxathizines and their oxides. US4569690 , 1986 ; (c) De Witte, L. A. A.; Valcke, R. A.; Van der Flaas, M. A.; Willems, W. M. 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Information & Authors Information Version history V1 Version 1 20 January 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords 1 2-oxathiazines 4 [3+3] cycloaddition biological activities donor–acceptor (eda) complexes photocatalysis Authors Affiliations Xiao-Ying Huang Guangxi University School of Chemistry and Chemical Engineering View all articles by this author Jing-Ru Li Guangxi Normal University View all articles by this author Xue-Ru Li Guangxi Normal University View all articles by this author Jin-Hui Bao Guangxi Normal University View all articles by this author Fuxing Yang Guilin Medical University View all articles by this author Wengui Duan Guangxi University School of Chemistry and Chemical Engineering View all articles by this author Ying-Ming Pan 0000-0002-3625-7647 [email protected] Guangxi Normal University View all articles by this author Metrics & Citations Metrics Article Usage 143 views 83 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xiao-Ying Huang, Jing-Ru Li, Xue-Ru Li, et al. Photocatalyzed [3+3] cycloaddition for 1,4,2-oxathiazines: antifungal and anti-inflammatory activities. Authorea . 20 January 2026. DOI: https://doi.org/10.22541/au.176889251.18265471/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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