DSpace at VNU: Expedient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones

Tetrahedron Letters xxx (2015) xxx–xxx Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Expedient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones Tuyet Anh Dang Thi a, Yves Depetter b, Karen Mollet b, Hoang Thi Phuong a, Doan Vu Ngoc a, Chinh Pham The a, Ha Thanh Nguyen a, Thu Ha Nguyen Thi a, Hung Huy Nguyen c, Matthias D’hooghe b, Tuyen Van Nguyen a,⇑ a Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, CauGiay, Hanoi, Vietnam SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium c Hanoi University of Science, 19-Le Thanh Tong str., Hoan Kiem, Hanoi, Vietnam b a r t i c l e i n f o Article history: Received 30 January 2015 Revised March 2015 Accepted 17 March 2015 Available online xxxx a b s t r a c t Heterocyclic naphthoquinones represent valuable scaffolds in medicinal chemistry In the present Letter, the efficient stereoselective synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones by means of one-pot multicomponent reactions using 2-hydroxy-1,4-naphthoquinone, an aromatic aldehyde and ethyl 4,4,4-trifluoroacetoacetate or a pyridinium bromide, respectively, is described Ó 2015 Elsevier Ltd All rights reserved Keywords: Pyranonaphthoquinones Furanonaphthoquinones Multicomponent reactions 2-Hydroxy-1,4-napthoquinones Introduction Heterocyclic naphthoquinones are widely distributed in nature, where they contribute to several biochemical processes in bacteria, fungi and plants Because of their pronounced biological and pharmacological properties, these scaffolds have attracted considerable attention from organic and medicinal chemists.1 For example, a-lapachone and b-lapachone 2, originally isolated from the bark of Tabebuia sp., are known to exhibit a wide range of biological activities including anticancer, antibacterial, antiplasmodial, antiangiogenic, trypanocidal and anti-inflammatory properties,2 and also their non-natural furano analogues and are known to show cytotoxic activity (Fig 1).3 Other examples include nanaomycin A 5, isolated from Streptomyces rosa notoensis, with antibiotic and antifungal properties,4 psychorubin 6, a cytotoxic pyranonaphthoquinone exhibiting antitumor, antibiotic and antileishmanial properties isolated from the roots of Psychotria rubra,5 kigelinone 7, a furanonaphthoquinone isolated from Kigelia pinnata with antitumor properties,6 and synthetic furanonaphthoquinone displaying antileishmanial activity.7 It is evident that the broad biological relevance of heterocyclic naphthoquinones inspired many chemists and prompted them to ⇑ Corresponding author Tel.: +84 917683979 E-mail address: ngvtuyen@hotmail.com (T Van Nguyen) develop approaches towards novel analogues, often within the framework of bioactive compound development.8 In continuation of our synthetic efforts related to functionalized heterocyclic naphthoquinones,9 the synthesis of new dihydropyrano- and dihydrofuranonaphthoquinones is investigated in the present Letter starting from 2-hydroxy-1,4-naphthoquinone using one-pot multicomponent reactions (MCRs) The deployment of 2hydroxy-1,4-naphthoquinone as a building block in MCRs has been the topic of many studies, often involving the use of aromatic aldehydes as reaction partners.10 In general, the application of multicomponent strategies has become very popular in recent years as they provide high structural diversity through multiple bond-forming reactions in a one-pot approach.11 In addition, structure-activity relationship studies concerning functionalized heterocyclic naphthoquinones have shown that the introduction of chemically diverse side chains to the heterocyclic ring can enhance the biological activities of these molecules,12 making the synthesis of new naphthoquinone-fused heterocycles through MCRs a relevant challenge in modern organic and medicinal chemistry Results and discussion The synthetic strategy used in this study towards new heterocyclic naphthoquinones is based on the above-described building http://dx.doi.org/10.1016/j.tetlet.2015.03.071 0040-4039/Ó 2015 Elsevier Ltd All rights reserved Please cite this article in press as: Dang Thi, T A.; et al Tetrahedron Lett (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.071 T A Dang Thi et al / Tetrahedron Letters xxx (2015) xxx–xxx O O OH O O O O O O O O OH O O O O O O O O O O O OH OH O O O O N N N Figure Examples of biologically active heterocyclic naphthoquinones block approach starting from 2-hydroxy-1,4-naphthoquinone via multicomponent reactions First, the synthesis of a number of dihydropyranonaphthoquinones using aromatic aldehydes, ethyl 4,4,4-trifluoroacetoacetate and ammonium acetate, is described Subsequently, the preparation of a variety of new dihydrofuranonaphthoquinones is pursued using pyridinium bromides and aromatic aldehydes For the synthesis of new dihydropyranonaphthoquinones 9a–f, a recently developed tandem multicomponent reaction starting from 2-hydroxy-1,4-naphthoquinone 10 was employed,13 with some minor adaptations in the reaction conditions (tBuOH was used as solvent instead of EtOH and NH4OAc was used instead of a NH4OAc/AcOH mixture) (Scheme 1, Table 1) By using an excess of ammonium acetate instead of a NH4OAc/AcOH mixture in a catalytic amount, the reaction mechanism is assumed not to proceed via acid catalysis but possibly through the formation of a trifluorinated enamine, formed in situ by imination of b-keto ester 12 with ammonium acetate.14 However, it should be noted that both approaches seem comparable with regard to product yield and efficiency In this way, six new dihydropyranonaphthoquinones 9a–f were obtained in 53–86% yield as single diastereoisomers.15 The relative stereochemistry of compound was confirmed by means of X-ray single crystal analysis and corroborated the stereochemistry as described in the literature.13 The use of 2-hydroxybenzaldehyde and indole-3-carbaldehyde in this approach did not lead to the premised derivatives In order to provide a convenient entry into the synthesis of the lower homologues of the above-mentioned dihydropyranonaphthoquinones, the preparation of dihydrofuranonaphthoquinones 14 as novel scaffolds was contemplated in the next part The synthesis of these novel furanonaphthoquinones 14a–l was conducted using a one-pot multicomponent reaction, for which triethylamine was added to a solution of 2-hydroxy-1,4-naphthoquinone 10, aromatic aldehyde 15 and pyridinium bromide 16 in tBuOH The mixture was heated under reflux for h, resulting in the selective formation of dihydrofuranonaphthoquinones 14a–l in 53-76% yield as single diastereoisomers (Scheme 2, Table 2).16 By varying the aromatic aldehyde and pyridinium bromide, 12 Table Preparation of ethyl 2-hydroxy-5,10-dioxo-2-trifluoromethyl-3,4,5,10-tetrahydro2H-benzo[g]chromene-3-carboxylates a O OH + 1.2 equiv O R1 H R1 Compound (yield)a 3-MeO–C6H4 2-MeO–C6H4 3,4-OCH2O–C6H3 Naphth-1-yl Fur-3-yl 1-Acetyl-indol-3-yl 9a (65%) 9b (63%) 9c (86%) 9d (81%) 9e (53%) 9f (65%) After purification by column chromatography (SiO2) new compounds were obtained, which were analysed using 1H NMR, 13C NMR, MS and IR techniques to confirm their molecular structure In the 1H NMR spectrum of compound 14a, two protons of the dihydrofuran moiety were seen as doublets at d = 4.96 and 6.09 ppm with a vicinal coupling constant of 5.5 Hz, indicating that the thermodynamically more stable trans diastereoisomer is formed.17 X-ray analysis was then performed on dihydrofuranonaphthoquinone 14b to secure the relative stereochemistry of these new molecular frameworks (Fig 2) As demonstrated in Table 2, a set of 12 new derivatives 14a–l was prepared through variation of the substitution pattern of the starting aldehyde 15 and pyridinium bromide 16 In that respect, both electron-donating and electron-withdrawing substituents present on the phenyl moieties were selected to assess their influence on the reaction outcome However, no major effects were observed, leading to comparable yields in all cases A possible mechanistic explanation for this multicomponent reaction starts with a Knoevenagel condensation of 2-hydroxy1,4-naphthoquinone 10 with aromatic aldehydes 15, followed by dehydration resulting in the formation of 1,2,3,4-tetrahydro1,2,4-naphthalenetriones 18 The next step is a Michael addition of pyridinium ylides 19, formed in situ by deprotonation of pyridinium bromides 16 by triethylamine, across Michael acceptors 18 The obtained naphthoquinones 20/21 undergo a cyclization to produce the desired substituted dihydrofuranonaphthoquinones O 1.2 equiv Entry O F3 C OEt 12 O equiv NH4 OAc 13 tBuOH, Δ, h O O 10 11 R1 O OEt CF3 O OH 9a-f (53-86%) Scheme Synthesis of dihydropyranonaphthoquinones 9a–f Please cite this article in press as: Dang Thi, T A.; et al Tetrahedron Lett (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.071 T A Dang Thi et al / Tetrahedron Letters xxx (2015) xxx–xxx O OH + 1.2 equiv O R1 O 1.2 equiv N + H R2 Br O 1.2 equiv Et3 N O O 10 R2 R1 14a-l (53-76%) 16 15 O O tBuOH, Δ, h Scheme Synthesis of dihydrofuranonaphthoquinones 14a–l Table Preparation of 2,3-dihydronaphtho[2,3-b]furan-4,9-diones 14 a Entry R1 R2 Compound (yield)a 10 11 12 C6H5 C6H5 C6H5 C6H5 4-Br–C6H4 3-Br–C6H4 3-Br–C6H4 4-Cl–C6H4 4-MeO–C6H4 4-MeO–C6H4 3-MeO–C6H4 Naphth-2-yl C6H5 3-NO2–C6H4 4-NO2–C6H4 4-F–C6H4 3-NO2–C6H4 C6H5 3-NO2–C6H4 4-F–C6H4 C6H5 3-NO2–C6H4 4-F–C6H4 C6H5 14a (69%) 14b (67%) 14c (69%) 14d (66%) 14e (62%) 14f (53%) 14g (76%) 14h (65%) 14i (60%) 14j (70%) 14k (68%) 14l (70%) Acknowledgments The authors are indebted to the Vietnamese National Foundation for Science and Technology Development (NAFOSTED, code: 104.01-2013.27) and to Ghent University—Belgium (BOF) for financial support After purification by column chromatography (SiO2) References and notes O O O NO2 O In conclusion, the efficient diastereoselective synthesis of a variety of functionalized dihydropyrano- and dihydrofuranonaphthoquinones has been described using one-pot multicomponent reactions These heterocyclic naphthoquinones could represent interesting new structures within the pursuit of biologically active compounds 14b Figure X-ray crystal structure of compound 14b 14 (Scheme 3) The proposed mechanism was further supported through analysis of the reaction mixtures using LC–MS providing evidence for the presence of intermediates 18 and 20/21, although other alternative routes cannot be ruled out completely No major effects of the substrate scope on the yields could be observed, and the proposed mechanism seems to be consistent with the use of aromatic aldehydes and aromatic pyridinium bromides (a) Thomson, R H Naturally Occurring Quinones, 2nd ed.; 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Estévez-Braun, A.; Ravelo, A G.; Ferro, E A.; Tokuda, H.; Mukainaka, T.; Nishino, H Bioorg Med Chem 2003, 11, 483–488; (b) de Castro, S L.; Emery, F S.; Da Silva, E N., Junior Eur J Med Chem 2013, 69, 678–700 13 Duan, Y.; Wang, X.; Xu, X.; Kang, Z.; Zhang, M.; Song, L.; Deng, H Synthesis 2013, 45, 2193–2200 14 Roy, P J.; Dufresne, C.; Lachance, N.; Leclerc, J.-P.; Boisvert, M.; Wang, Z.; Leblanc, Y Synthesis 2005, 2751–2757 15 General procedure for the synthesis of dihydropyranonaphthoquinones 9: a mixture of 2-hydroxy-1,4-naphthoquinone 10 (1 equiv), aromatic aldehyde 11 (1.2 equiv), ethyl 4,4,4-trifluoroacetoacetate 12 (1.2 equiv) and ammonium acetate 13 (3 equiv) in tBuOH was heated under reflux for h Then, the reaction mixture was extracted three times with EtOAc and the combined organic phases were washed with a saturated aqueous solution of NaHCO3, dried (MgSO4) and evaporated in vacuo to afford the crude reaction mixture, which was purified by means of column chromatography on silica gel (n-hexane/EtOAc, 4/1) Ethyl (2S⁄,3S⁄,4R⁄)-2-hydroxy-4-(3-methoxyphenyl)-5,10-dioxo-2-trifluoromethyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-3-carboxylate 9a: red-yellow solid, 65% yield Mp 130–133 °C IR (KBr): m 3564; 3500; 2986; 2786; 1731; 1674; 1590; 1486; 1454; 1353; 1188; 1096; 986; 847; 729 cmÀ1 1H NMR (CDCl3, 500 MHz): d 8.12 (1H, d, J = 1.5, 7.0 Hz); 7.90 (1H, d, J = 1.0, 7.0 Hz); 7.66–7.72 (2H, m); 7.22 (1H, d, J = 8.0 Hz); 6.79 (1H, dd, J = 2.0, 8.0 Hz); 6.71 (1H, d, J = 8.0 Hz); 6.68 (1H, d, J = 2.0 Hz); 4.35 (1H, d, J = 11.5 Hz); 4.12 (2H, q, J = 7.0 Hz); 3.76 (3H, s); 3.15 (1H, d, J = 11.5 Hz); 1.07 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 125 MHz): d 182.3; 177.8; 172.1; 160.0; 150.7; 140.6; 134.3; 133.6; 131.8; 130.7; 130.1; 126.5; 126.4; 123.4; 122.7 (q, J = 285 Hz); 119.7; 113.3; 112.6; 94.4 (q, J = 33 Hz); 62.7; 55.2; 49.3; 40.1; 13.7 HRMS (ESI) [M+H]+: Calcd for C24H20F3O7: 477.1156, Found: 477.1167 16 General procedure for the synthesis of dihydrofuranonaphthoquinones 14: to a solution of 2-hydroxy-1,4-naphthoquinone 10 (1 equiv), aromatic aldehyde 15 (1.2 equiv) and pyridinium bromide 16 (1.2 equiv) in tBuOH was added 1.2 equiv of triethylamine at room temperature The mixture was heated under reflux for h, followed by extraction (three times) with EtOAc The combined organic phases were washed with a saturated aqueous solution of NaHCO3, dried (MgSO4) and evaporated in vacuo to afford the crude reaction mixture, which was purified by means of column chromatography on silica gel (nhexane/EtOAc, 4/1) (2R⁄,3R⁄)-2-Benzoyl-3-phenyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione 14a: yellow solid, 69% yield Mp 191–193 °C IR (KBr): m 3451; 2931; 1693; 1630; 1584; 1446; 1362; 1191; 1060; 965; 859; 699 cmÀ1 1H NMR (CDCl3, 500 MHz): d 8.12 (1H, dd, J = 2.0, 7.5 Hz); 7.95 (1H, dd, J = 2.0, 7.5 Hz); 7.92 (2H, dd, J = 1.0, 8.5 Hz); 7.68–7.69 (2H, m); 7.63 (1H, t, J = 7.5 Hz); 7.48 (2H, t, J = 8.0 Hz); 7.31–7.40 (5H, m); 6.09 (1H, d, J = 5.5 Hz); 4.96 (1H, d, J = 5.5 Hz) 13 C NMR (CDCl3, 125 MHz): d 190.1; 181.0; 177.5; 159.1; 139.4; 134.3; 133.2; 132.9; 131.6; 130.8; 129.3; 129.2; 129.1; 128.7; 128.4; 126.3; 126.2; 126.1; 91.4; 48.5 HRMS (ESI) [M+H]+: Calcd for C25H17O4: 381.1121, Found: 381.1133 17 (a) Antonioletti, R.; Malancona, S.; Bovicelli, P Tetrahedron 2002, 58, 8825– 8831; (b) Yilmaz, M.; Bicer, E.; Ustalar, A.; Pekel, A T Arkivoc 2014, v, 225–236 Please cite this article in press as: Dang Thi, T A.; et al Tetrahedron Lett (2015), http://dx.doi.org/10.1016/j.tetlet.2015.03.071 ... dihydropyranonaphthoquinones using aromatic aldehydes, ethyl 4,4,4-trifluoroacetoacetate and ammonium acetate, is described Subsequently, the preparation of a variety of new dihydrofuranonaphthoquinones is... chromatography (SiO2) References and notes O O O NO2 O In conclusion, the efficient diastereoselective synthesis of a variety of functionalized dihydropyrano- and dihydrofuranonaphthoquinones has been... performed on dihydrofuranonaphthoquinone 14b to secure the relative stereochemistry of these new molecular frameworks (Fig 2) As demonstrated in Table 2, a set of 12 new derivatives 14a–l was prepared