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Chemical Synthesis of Core Structures
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
A different approach to the synthesis of the heptose-Kdo region related to important epitopes of lipooligosaccharides from Neisseria meningitidis was developed by van Boom’s group on the basis of iodonium ion-promoted glycosidations of thioglycosides (51–53). A thioglycoside group may be maintained as a temporary protection for the anomeric center through multistep reaction sequences, yet it may be selectively activated to serve as a versatile anomeric leaving group for glycosidation (Fig. 6). Thus, an aglyconic spacer-arm unit was introduced via glycosylation of N-benzyloxycarbonyl (Z) protected 3-aminopropanol with methyl or ethyl 2-thioglycosides of Kdo in the presence of N-iodosuccinimide (NIS) and catalytic amounts of triflic acid (TfOH) in yields of 50–80%, albeit with low anomeric selectivity not exceeding a ratio of 3:1 in favor of the a-anomer (51). Transformation of the protecting groups gave the 4-O-benzyl-7,8-O-isopropylidene-protected Kdo acceptor 44, which was reacted with the ethyl 1-thioheptopyranosyl donor 43 under promotion with NIS/TfOH to furnish the α-(l-→5)-linked disaccharide 45 in excellent yield (87%) and anomeric stereo-control. Deprotection of 45 was effected in three steps, namely deacetonation in acetic acid, debenzoylation, and catalytic hydrogenolysis on palladium-carbon, which gave, after Sephadex S-100 chromatography, the homogeneous disaccharide l-α-d-Hepp-(l→5)-α-Kdo-2-O-(CH2)3NH2 46. Proceeding toward epitopes containing also outer core determinants, the 2,3-O-isopropylidene-protected heptosyl donor 47 allowing for selective chain extension at O-4 was obtained from the ethyl 1-thio heptopyranosyl donor 43 in a few steps. Subsequent trimethylsilyl triflate-mediated glycosylation of 47 with the benzoyl-protected lactosyl trichloroacetimidate 48 afforded the trisaccharide ethyl 1-thioglycoside 49 in 91% yield. Exchange of the 2,3-O-isopropylidene group for benzoates afforded the trisaccharide donor 50, which was coupled in the presence of the thiophilic promoter system NIS/TfOH with the Kdo acceptor 44 to give the a -(l→5)-linked tetrasaccharide derivative 51 in excellent yield (55%). Removal of the blocking groups and final purification of the product on Sephadex S-100 furnished the tetrasaccharide p-d-Galp-(1→4)-β-d-G1cp-(1 →4)-l-α-DHepp-(l→5)-α-Kdo-2-O-(CH2)3NH252 corresponding to inner core determinant from N. meningitidis immunotypes L1–L9, which was subsequently used for the preparation of a synthetic vaccine.
Alkyl rhamnosides, a series of amphiphilic materials exerting broad-spectrum anti-biofilm activity against pathogenic bacteria via multiple mechanisms
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Guanghua Peng, Xucheng Hou, Wenxi Zhang, Maoyuan Song, Mengya Yin, Jiaxing Wang, Jiajia Li, Yajie Liu, Yuanyuan Zhang, Wenkai Zhou, Xinru Li, Guiling Li
The synthesis of nonionic alkyl rhamnosides via the Fischer type of glycosylation reaction between unprotected, unactivated l-rhamnose and fatty alcohols was promoted by triflic acid immobilized on silica gel (TfOH-SiO2) as described by Yu and Chen with some modifications [10]. First, TfOH (3.06 g, 20 mmol) was added to a suspension of silica gel (10 g, mesh no. 300-400) in ether (40 mL). The mixture was stirred magnetically for 30 min at room temperature. Ether was removed under reduced pressure and the residue was heated at 100 °C for 24 h under vacuum to afford TfOH-SiO2 (2 mmol/g) as a free-flowing powder [11]. Thin-layer chromatography (TLC) was performed on precoated Merck silica gel 60 F254 plates (Merck, Kenilworth, NJ) using CH2Cl2:MeOH (10:1; v/v) as developing solvent and visualized by 10% (v/v) H2SO4 in ethanol. Column chromatography was performed on silica gel (200–300 mesh, Qingdao, China). Solutions were concentrated at a temperature <50 °C under diminished pressure.
Benzofuran–appended 4-aminoquinazoline hybrids as epidermal growth factor receptor tyrosine kinase inhibitors: synthesis, biological evaluation and molecular docking studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Malose J. Mphahlele, Marole M. Maluleka, Abimbola Aro, Lyndy J. McGaw, Yee Siew Choong
The benzofuran-aminoquinazolines 10a–j and the corresponding intermediates were prepared following the reaction sequence outlined in Scheme 2 and their yields are listed in Table 1. The initial task of this investigation involved the preparation of 5-bromo-2-hydroxy-3-iodoacetophenone 5 to serve as a substrate for the tandem palladium catalyzed Sonogashira cross-coupling with arylacetylenes and subsequent endo-dig Csp–O cyclization to afford the requisite 7-acetyl–substituted 2-aryl-5-bromobenzofurans. Recourse to the literature revealed that 5-bromo-2-hydroxy-3-iodoacetophenone has been prepared before by treatment of the commercially available 5-bromo-2-hydroxyacetophenone with pyridinium iodochloride (1 equiv.) in methanol under reflux for 2 h19. We opted for the use of commercially available 2-hydroxyacetophenone 4 (purchased from Sigma-Aldrich) as a substrate for initial halogenation with 1 equivalent of N-bromosuccinimide (NBS) in acetic acid under reflux for 1.5 h to afford 5-bromo-2-hydroxyacetophenone in 59% yield (Scheme 2). The latter was, in turn, subjected to iodination with N-iodosuccinimide (NIS) in acetic acid under reflux for 1 h to afford 5-bromo-2-hydroxy-3-iodoacetophenone 5. Sonogashira cross-coupling of 5 with terminal acetylenes afforded the corresponding 1–(5-bromo-2-arylbenzofuran-7-yl)ethanones 6a–e in appreciable yields. Oximation of compounds 6a–e with hydroxylamine hydrochloride in pyridine under reflux for 1 h followed by aqueous work-up and recrystallization afforded the corresponding oximes 7a–e. The Beckmann rearrangement of these oximes with 20% mol equivalent of trifluoromethanesulfonic acid (triflic acid, TfOH) in acetonitrile under reflux for 4 h afforded compounds characterized using a combination of NMR, IR and mass spectrometric techniques as the 7-aminobenzofuran derivatives 8a–e. The latter are the result of the initial Beckmann rearrangement via aryl carbon migration followed by an in situ acid-mediated hydrolysis of the intermediate 7-acetamido-2-aryl-5-bromobenzofuran derivatives. Hitherto, Cacchi et al.23 had reported a method for the synthesis of the 7-aminobenzofuran derivatives which makes use of the Buchwald-Hartwig C–N bond formation of the intermediate 7-bromobenzofurans with the primary and secondary amines. Despite what looks like a simple molecular framework, we found that no attempts have been made before towards the synthesis of benzofuran-quinazoline hybrids in which the two pharmacophores are linked through a heteroatom bridge. Consequently, we reacted the nucleophilic 7-aminobenzofurans 8a–e with the electrophilic 6-bromo-4-chloro-2–(4-halogenophenyl)quinazoline 9a (X = F) or 9 b (X = Cl) in the presence of 5% HCl in isopropanol (iPrOH) under reflux for 4 h to afford the corresponding benzofuran-aminoquinazoline hybrids 10a–e or 10f–j, respectively. Dechloroamination was confirmed by the presence of increased number of proton and carbon signals in the aromatic region of the 1H- and 13C-NMR spectra of compounds 10a–j.