molecules Communication A One-Pot Approach to Novel Pyridazine C-Nucleosides Flavio Cermola 1,* , Serena Vella 2, Marina DellaGreca 1 , Angela Tuzi 1 and Maria Rosaria Iesce 1 1 Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario di M. Sant’Angelo, Via Cintia, 80126 Napoli, Italy; [email protected] (M.D.); [email protected] (A.T.); [email protected] (M.R.I.) 2 Erbagil s.r.l., Via L. Settembrini, 13, 82037 Telese Terme, Italy; [email protected] * Correspondence: [email protected] Abstract: The synthesis of glycosides and modified nucleosides represents a wide research field in organic chemistry. The classical methodology is based on coupling reactions between a glycosyl donor and an acceptor. An alternative strategy for new C-nucleosides is used in this approach, which consists of modifying a pre-existent furyl aglycone. This approach is applied to obtain novel pyridazine C-nucleosides starting with 2- and 3-(ribofuranosyl)furans. It is based on singlet oxygen [4+2] cycloaddition followed by reduction and hydrazine cyclization under neutral conditions. The mild three-step one-pot procedure leads stereoselectively to novel pyridazine C-nucleosides of pharmacological interest. The use of acetyls as protecting groups provides an elegant direct route to a deprotected new pyridazine C-nucleoside. Keywords: glycosyl furans; singlet oxygen; [4+2] cycloaddition; C-nucleosides; photooxygenation; pyridazines; reduction Citation: Cermola, F.; Vella, S.; 1. Introduction DellaGreca, M.; Tuzi, A.; Iesce, M.R. A The synthesis of nucleoside analogues has a prominent role in the field of organic One-Pot Approach to Novel chemistry and biology [1]. Among modified nucleosides, C-nucleosides represent a special Pyridazine C-Nucleosides. Molecules moiety of this compound class due to their higher stability towards enzymatic and chemical 2021, 26, 2341. https://doi.org/ hydrolysis than that of natural N-nucleosides, as well as owing to the interesting biolog- 10.3390/molecules26082341 ical and pharmacological properties of some of their derivatives [1,2]. The first natural C-nucleoside isolated was pseudouridine [3], followed by showdomycin [4], and oxazino- Academic Editor: Axel G. Griesbeck mycin [5]—all characterized by important pharmacological activities, from antitumor to antibacterial. C-nucleosides comprise a sugar moiety and a non-natural heterocyclic base Received: 1 April 2021 connected by a carbon–carbon bond. The stability of this bond and the broad structural Accepted: 13 April 2021 Published: 17 April 2021 variation in the heterocyclic base account for the high interest in this compound class [6–9]. The main synthetic approach for C-glycosides is based on coupling reactions between a Publisher’s Note: MDPI stays neutral glycosyl donor and an acceptor in the presence of a promoter [10]. Alternatively, structural with regard to jurisdictional claims in elaborations on a pre-existing aglycone are performed to afford the final C-glycoside [10]. In published maps and institutional affil- this context, the use of the furan as starting aglycone is of particular interest due to the easy iations. preparation and high versatility of this heterocycle [11]. We elaborated a green procedure based on the use of a furan aglycone as a building block and the [4+2] cycloaddition of singlet oxygen [12] by dye-sensitized photooxygenation as a strategy for providing the final desired structures. Indeed, singlet oxygen addition to furan systems offers various elegant routes to differently functionalized derivatives through structural elaborations of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the initial endoperoxides, the 2,3,7-trioxabicyclo[2.2.1]hept-5-enes [13]. Although the furan This article is an open access article endoperoxides are thermally unstable, their reactivity can be controlled and opportunely distributed under the terms and addressed by working at low temperatures. With this strategy, it is possible to synthe- conditions of the Creative Commons size novel glycosyl derivatives, such as glycals [14] and spiroketals of monosaccharides, Attribution (CC BY) license (https:// which are structural motifs of many products characterized by important and assorted creativecommons.org/licenses/by/ biological properties [15]. Pyridazine [16], pyrazoline [14], bis-epoxide [17], and spiro- 4.0/). cyclic C-nucleosides [17] were also obtained. Key intermediates are often unsaturated Molecules 2021, 26, 2341. https://doi.org/10.3390/molecules26082341 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 10 Molecules 2021, 26, 2341 2 of 10 epoxide [17], and spirocyclic C-nucleosides [17] were also obtained. Key intermediates are Zoften-1,4-enediones, unsaturated easily Z-1,4-enediones, obtained by easily photooxygenation obtained by photooxygenation and followed by in and situ followed reduction by ofin thesitu corresponding reduction of the endoperoxides corresponding [14– 17endo] atperoxides low temperatures. [14–17] at In low many temperatures. cases, the pho- In tochemicalmany cases, approach the photochemical represents approach an alternative repres toents other an methods.alternative As to an other example, methods. Maeba As describedan example, the synthesisMaeba ofdescribed 3-(20,30,50 -tri-theO -benzoyl-synthesisβ -ribofuranosyl)pyridazineof 3-(2′,3′,5′-tri-O-benzoyl- throughβ-ribo- a seriesfuranosyl)pyridazine of reactions involving through the a oxidation series of ofreactions the furan involving ring by brominethe oxidation and methanol of the furan [18]. Wering obtained by bromine an analogue and methanol 4-(20,3 0[18].,50-tri- WeO-acetyl- obtainedβ-ribofuranosyl)-3,6-dimetylpyridazine an analogue 4-(2′,3′,5′-tri-O-acetyl-β-ri- in 70%bofuranosyl)-3,6-dimetylpyridazine yield (based on starting furan) by in oxygenation, 70% yield (based followed on starting by diethyl furan) sulfide by reductionoxygena- andtion, hydrazine followed by hydrochloride diethyl sulfide cyclization reduction [ 16and]. Thehydrazine efficient hydrochloride formation of thiscyclization compound [16]. promptedThe efficient us toformation explore theof this possibility compound of extending prompted this us approach to explore to novelthe possibility furans in of order ex- totending synthesize this approach 3- and 4-(ribofuranosyl)pyridazines. to novel furans in order to synthesize The pyridazine 3- and ring4-(ribofuranosyl)pyr- is recognized as aidazines. versatile The pharmacophore. pyridazine ring Inis recognized the last years, as a particularversatile pharmacophore. attention has been In the devoted last years, to developingparticular attention novel synthetic has been approaches devoted to thisdeve system,loping novel starting synthetic with new approaches precursors to or this by utilizingsystem, starting green methodologies with new precursors [19–22]. or by utilizing green methodologies [19–22]. 2. Results and Discussion For thisthis purpose,purpose, the the suitable suitable furans furans2a ,2ab were,b were initially initially prepared prepared by the byβ the-stereoselective β-stereose- reductionlective reduction [23] of the [23] corresponding of the corresponding furyl ketoses furyl1a ketoses,b (Scheme 1a,b 1(Scheme). The latter 1). The were latter obtained were byobtained coupling by reactionscoupling betweenreactions 2,3,5-tri- betweenO -benzyl-2,3,5-tri-O-D-ribono-1,4-lactonebenzyl-D-ribono-1,4-lactone as the glycosyl as the donor, gly- andcosyl 2- donor, or 3-furyllithium, and 2- or 3-furyllithium, according to aaccord previouslying to reporteda previously procedure reported [15 procedure]. [15]. OBn O BnO O Et SiH, CH CN O BnO 3 3 BF Et O, 40 °C r.t. OH OBn O 3 2 overnight BnO OBn 1a 2a O OBn O BnO Et SiH, CH CN O BnO 3 3 BF Et O, 40 °C r.t. OH OBn 3 2 O overnight BnO OBn 1b 2b Scheme 1. Stereoselective synthesis of 2-2- andand 3-(3-(ββ-ribofuranosyl)furans 2a,,b.. The reduction times were particularly long (overnight), probably owing to the open- chain structuresstructures of of the the furyl furyl derivatives derivatives1a 1a,b,inb in equilibrium equilibrium with with very very small small amounts amounts of the of 1 correspondingthe corresponding cyclic cyclic structures, structures, as evidenced as evidenced by their by their proton proton spectra. spectra. Although Although the theH- NMR1H-NMR spectra spectra of both of both crude crude reaction reaction mixtures mixtures showed showed only the only presence the presence of products of products2a,b, a considerable2a,b, a considerable loss of loss material of material occurred occurred during during purification purification by silica by gelsilica chromatography, gel chromatog- even if performed under N , as reported in the literature for 2a [24]. Firstly, 2a was photo- raphy, even if performed under2 N2, as reported in the literature for 2a [24]. Firstly, 2a was oxygenated at −20 ◦C in dichloromethane with methylene blue as the sensitizer (Scheme2 ). photo-oxygenated at −20 °C in dichloromethane 1with methylene blue as the sensitizer When the reaction was complete (90 min, TLC or H-NMR), Et12S (1.2 equiv.) was added (Scheme 2). When the reaction was complete (90 min, TLC or H-NMR), Et2S (1.2 equiv.) − ◦ towas the added crude to mixture, the crude which mixture, was which kept atwas 20keptC at to −20 avoid °C to thermal avoid thermal rearrangement rearrangement of the intermediate endoperoxide [12–17]. of the intermediate endoperoxide [12–17]. Molecules 2021, 26, x FOR PEER REVIEW 3 of 10 Molecules 2021, 26, 2341