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Total Synthesis of Natural Disaccharide Sambubiose Was Developed pharmaceuticals Article Total SynthesisSynthesis ofof NaturalNatural DisaccharideDisaccharide SambubioseSambubiose , Simone Lucarini *,†y, Maria, Maria Gessica Gessica Ciulla Ciulla †, Paolay , Paola Mestichelli Mestichelli and Andrea and Andrea Duranti Duranti * * Department of Biomolecular Sciences, University of Urbino Carlo Bo Piazza del Rinascimento, 6,6, 61029 Urbino,61029 Urbino, Italy; [email protected] Italy; [email protected] (M.G.C.); (M.G.C.); [email protected] [email protected] (P.M.) (P.M.) * Correspondence:Correspondence: [email protected] (S.L.); [email protected] (A.D.);(A.D.) Tel.:Tel.: +39-0722-303333+39-0722-303333 (S.L.); (S.L.); +39-0722-303501+39-0722-303501 (A.D.) (A.D.) These authors contributed equally to this work. †y These authors contributed equally to this work. Received: 23 23 June 2020; Accepted: 13 13 Augu Augustst 2020; 2020; Published: Published: 17 17 August August 2020 2020 Abstract: AA practical practical and and robust robust synthetic synthetic method method to toob obtaintain the the natural natural disaccharide disaccharide sambubiose sambubiose (2- (2-O-βO--Dβ-xylopyranosyl--D-xylopyranosyl-D-glucopyranose)D-glucopyranose) is reported, is reported, exploring exploring the the key key step step in in the the synthesis, synthesis, i.e., i.e., stereoselective OO-glycosylation.-glycosylation. Specifically, Specifically, the the best combinationsbest combinations of glycoside of glycoside donors anddonors acceptors and wereacceptors identified, were identified, stereospecific stereosp controlecific of the control reaction of the was reaction achieved was by achieved screening by several screening catalysts several and catalystsprotection and/deprotection protection/deprotection steps were evaluated steps andwere improved. evaluated The and best improved. result was obtainedThe best byresult coupling was obtainedallyl 3,5,6-tri- by Ocoupling-benzyl- β-D-glucofuranosideallyl 3,5,6-tri-O-benzyl- withβ-D 2,3,4-tri--glucofuranosideO-acetyl-D-xylopiranosyl- with 2,3,4-tri-Oα-acetyl--trichloroD- xylopiranosyl-acetimidate inα the-trichloro presence acetimidate of trimethylsilyl in the triflate presence as aof catalyst trimethylsilyl giving the triflate corresponding as a catalyst protected giving thetarget corresponding compound as protected a correct target single compound isomer. The as latter a correct was single transformed isomer. accordingly The latter was into transformed the desired accordinglyfinal product into by deprotectionthe desired final steps product (deallylation, by dep deacetylation,rotection steps and(deallylation, debenzylation). deacetylation, Sambubiose and wasdebenzylation). synthesized Sambubiose into a satisfactory was synthesized and higher into overall a satisfactory yield than and previously higher overall reported yield and than was previouslyalso characterized. reported and was also characterized. Keywords: chemopreventive phytochemicals; flavonoids;flavonoids; 2-O-xylosylvitexin; antiproliferative activity; carbohydrates; glycosylation;glycosylation; sambubiose; total synthesis 1. Introduction Introduction Chemopreventive phytochemicals phytochemicals (CPs) (CPs) occur occur naturally naturally in in some some plants plants and and have have been been shown shown to inhibitto inhibit all alllevels levels of carcinogenesis of carcinogenesis in both in both in viintro vitro andand in invivo vivo modelsmodels [1]. [1 Among]. Among CPs, CPs, flavonoid flavonoid 2- O2--xylosylvitexinO-xylosylvitexin (Figure (Figure 11),), which which is constitutedis constituted by carbohydrate by carbohydrate (sambubiose, (sambubiose, Figure1 )Figure and aglycone 1) and (apigenin,aglycone (apigenin, Figure1) Figure components, 1) componen was identifiedts, was identified for the firstfor the time first in timeCitrus in Citrus sinensis sinensisleaves leaves [2] and [2] andthen then in Beta in Beta vulgaris vulgarissub. sub.cycla cyclaleaves leaves and and seeds seeds [3] with [3] with the latterthe la containingtter containing the mostthe most abundant abundant and andefficacious efficacious CPs. CPs. OH O HO O OH OH O O O OH HO HO O O OH HO HO O HO O OH HO O OH OH OH OH Sambubiose Apigenin OH OH 2-O-Xylosylvitexin Figure 1. ChemicalChemical structures structures of sambubiose, 2- O-xylosylvitexin, and apigenin. Pharmaceuticals 2020, 13, 198;x; doi: doi: FOR10.3390 PEER/ph13080198 REVIEW www.mdpi.com/journal/pharmaceuticalswww.mdpi.com/journal/pharmaceuticals PharmaceuticalsPharmaceuticals 20202020,, 1313,, 198x FOR PEER REVIEW 22 ofof 1312 2-O-xylosylvitexin shows strong antiproliferative activity against human colon cell cancer lines 2-O-xylosylvitexin shows strong antiproliferative activity against human colon cell cancer lines while also enhancing apoptosis, increasing cells in the G1 phase and reducing cells in the S phase as while also enhancing apoptosis, increasing cells in the G1 phase and reducing cells in the S phase as well as the proliferation of human fibroblasts [4]. well as the proliferation of human fibroblasts [4]. Sambubiose, on the other hand, is formed by glucopyranose and xylopyranose units linked Sambubiose, on the other hand, is formed by glucopyranose and xylopyranose units linked through a 1,2-trans bond in 2-position and was first isolated as a component of anthocyanins from through a 1,2-trans bond in 2-position and was first isolated as a component of anthocyanins from elderberry (Sambucus nigra) [5], a plant with therapeutic properties [6,7]. In addition, sambubiose is elderberry (Sambucus nigra)[5], a plant with therapeutic properties [6,7]. In addition, sambubiose is also a constituent of the other major anthocyanins from black raspberries (Rubus occidentalis L.) [8], also a constituent of the other major anthocyanins from black raspberries (Rubus occidentalis L.) [8], red red currants, Davidson’s plums, and small red beans, and is linked to minor anthocyanins from açai currants, Davidson’s plums, and small red beans, and is linked to minor anthocyanins from açai and and Vaccinium padifolium blueberries [9]. Vaccinium padifolium blueberries [9]. To date, to the best of our knowledge, only one synthesis of sambubiose has been reported [10]; To date, to the best of our knowledge, only one synthesis of sambubiose has been reported [10]; however, the method followed by Erbing and Lindberg [10] (Scheme 1) and subsequently applied by however, the method followed by Erbing and Lindberg [10] (Scheme1) and subsequently applied by Dick et al. [11] has several drawbacks and improvements could be made in the reagents and Dick et al. [11] has several drawbacks and improvements could be made in the reagents and conditions. conditions. SchemeScheme 1.1. Reagents and conditions: ( i) NaOH, BnCl, reflux, reflux, 7 h, 78%; (ii, iii) BnOH,BnOH, HCl,HCl, reflux,reflux, 44 hh thenthen AcAc22O, pyridine, rt, 24 h, 6%; (iv) MeONa, MeOH,MeOH, rt,rt, 1212 h,h, 22%;22%; ((vv,, vivi)) Hg(CN)Hg(CN)22//HgBrHgBr22, MeCN, MeCN, rt, 44 hh thenthen MeONa,MeONa, MeOH,MeOH, rt,rt, 1212 h,h, 54%;54%; ((viivii)H) H22, PdPd/C/C 10%, EtOH, rt, 2222 h,h, 43%.43%. Firstly,Firstly, the the purification purification of of benzyl benzyl 3,5,6-tri- 3,5,6-tri-O-benzyl-O-benzyl-α-Dα-glucofuranoside-D-glucofuranoside (4a) to (4a eliminate) to eliminate high- high-boilingboiling benzyl benzyl alcohol alcohol from the from reaction the crude reaction mixture crude was mixture extremely was difficult extremely both dibyffi distillationcult both byand/or distillation by chromatography. and/or by chromatography.Erbing and Lindberg Erbing [10], therefore, and Lindberg had to [10employ], therefore, acetylation had and to employdeacetylation acetylation as additional and deacetylation synthetic assteps additional via benzyl synthetic 2-O steps-acetyl-3,5,6-tri- via benzylO-benzyl- 2-O-acetyl-α-D- 3,5,6-tri-glucofuranosideO-benzyl- (3aα)-D-glucofuranoside to purify 4a (Scheme (3a 1,) “iii” to purify and “iv”4a (Schemesteps). Secondly,1, “iii” and the “iv” use of steps). the intrinsically Secondly, theunstable use of donor the intrinsically 2,3,4-tri-O-acetyl- unstableα- donorD-xylopyranosyl 2,3,4-tri-O -acetyl-bromideα-D-xylopyranosyl (5a), which must bromidebe freshly (5a prepared), which mustand recrystallized be freshly prepared because and of recrystallized its low stability, because even of its when low stability,refrigerated, even whenwas also refrigerated, problematic. was alsoMoreover, problematic. Erbing Moreover,and Lindberg Erbing [10] and used Lindberg a stoichiometric [10] used a amount stoichiometric of mercuric amount cyanide of mercuric as a cyanideglycosylation as a glycosylation promoter. promoter.This reactant This reactantshould shouldnot be notused be usedbecause because of its of itshigh high toxicity toxicity and dangerousness.dangerousness. Furthermore, Hg(CN)Hg(CN)22 does not allow a stereospecificstereospecific controlcontrol ofof glycosylation:glycosylation: 6 [[12]12] mustmust bebe separatedseparated from from its its anomer anomer since since the the output output of theof the reaction reaction is an is αan- and α- andβ-mixture. β-mixture. Finally, Finally, and importantly,and importantly, the authors the authors did not did fully not characterize fully characterize the natural the disaccharide natural disaccharide sambubiose sambubiose [10]. Hence, [10]. the aimHence, of this the investigation aim of this investigation was to develop was an to improved develop eanffi cientimproved strategy efficient to synthesize strategy our to targetsynthesize
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