& Glycochemistry

Pyranoside-into-Furanoside Rearrangement: New Reaction inCarbohydrate Chemistry and Its Application in OligosaccharideSynthesis

Vadim B. Krylov,[a] Dmitry A. Argunov,[a] Dmitry Z. Vinnitskiy,[a] Stella A. Verkhnyatskaya,[a]

Alexey G. Gerbst,[a] Nadezhda E. Ustyuzhanina,[a] Andrey S. Dmitrenok,[a]

Johannes Huebner,[b] Otto Holst,[c] Hans-Christian Siebert,[d] and Nikolay E. Nifantiev*[a]

Abstract: Great interest in natural furanoside-containingcompounds has challenged the development of preparativemethods for their synthesis. Herein a novel reaction in car-bohydrate chemistry, namely a pyranoside-into-furanoside(PIF) rearrangement permitting the transformation of selec-tively O-substituted pyranosides into the corresponding fur-anosides is reported. The discovered process includes acid-promoted sulfation accompanied by rearrangement of thepyranoside ring into a furanoside ring followed by solvolytic

O-desulfation. This process, which has no analogy in organicchemistry, was shown to be a very useful tool for the synthe-sis of furanoside-containing complex oligosaccharides, whichwas demonstrated by synthesizing disaccharide derivativesa-d-Galp-(1!3)-b-d-Galf-OPr, 3-O-s-lactyl-b-d-Galf-(1!3)-b-d-Glcp-OPr, and a-l-Fucf-(1!4)-b-d-GlcpA-OPr related topolysaccharides from the bacteria Klebsiella pneumoniae andEnterococcus faecalis and the brown seaweed Chordariaflagelliformis.

Introduction

Different types of furanosyl residues are included in the struc-tures of a variety of natural compounds, especially bacterial,plant, and fungal polysaccharides.[1, 2] The synthesis of oligosac-charides related to these biopolymers, as well as glycoconju-gates thereof, is often dictated by the needs of vaccine and di-agnostics development.[3–6] Currently, the most widely usedmethods for furanoside synthesis are based on the initial trans-formation of unblocked monosaccharides by the Fischer reac-tion under kinetic control[7, 8] or their high-temperature acyla-tion.[7, 9] All of these reactions proceed with the formation ofa mixture of a- and b-furanosides and are contaminated by re-

spective pyranoside isomers that may require laborious chro-matography in order to separate the target products. It is alsonotable that further regioselective introduction of O-blockinggroups into furanosides can be more difficult than in the caseof related pyranoside derivatives.

The idea of pyranoside-into-furanoside (PIF) rearrangementcame from our recent observation[10] that an unusual oligosac-charide impurity with a terminal (at the “reducing end”) fura-noside residue (e.g. , disaccharide C on Figure 1) in addition tothe expected pyranoside product (e.g. , compound B) wasformed in acid-promoted O-sulfation[11] of oligofucosides (e.g. ,disaccharide A) related to seaweed fucoidans. It was shownthat per-O-sulfation by Py·SO3 complex was accompanied bythe formation of unexpected furanoside byproducts of type Conly in the presence of a strong acid (trifluoromethanesulfonicor chlorosulfonic acid), while no formation of such compoundswas observed, when a weaker acid promoter, particularly, thetrifluoroacetic acid, was used.[10]

Figure 1. Difucopyranoside A and the products of its acid-promoted O-sulfa-tion with pyranoside (B) and furanoside (C) terminal residues.[10]

[a] Dr. V. B. Krylov, D. A. Argunov, D. Z. Vinnitskiy, S. A. Verkhnyatskaya,Dr. A. G. Gerbst, Dr. N. E. Ustyuzhanina, Dr. A. S. Dmitrenok,Prof. Dr. N. E. NifantievLaboratory of Glycoconjugate ChemistryN.D. Zelinsky Institute of Organic Chemistry, Russian Academy of SciencesLeninsky prospect 47, 119991 Moscow (Russian Federation)E-mail : nen@ioc.ac.ru

[b] Prof. Dr. J. HuebnerDivision of Pediatric Infectious Diseases, Hauner Children’s HospitalLudwigs-Maximilian University, Munich (Germany)

[c] Prof. Dr. O. HolstResearch Center BorstelLeibniz-Center for Medicine and Biosciences, Borstel (Germany)

[d] Prof. Dr. H.-C. SiebertRI-B-NT - Research Institute of Bioinformatics and Nanotechnology24118 Kiel (Germany)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201405083.

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Observed PIF rearrangement has no analogy in organicchemistry and can be compared formally only with enzymaticisomerization of sugar nucleotides mediated by pyranose–fura-nose mutase (Scheme 1).[12] The discovered intriguing side pro-cess challenged us to study whether it can be performed ina straightforward way within the context of synthesizing oligo-saccharides bearing furanoside units. Herewith we report ourfirst results from this study.

Results and Discussion

To optimize the PIF rearrangement protocol, readily available3-O-benzyl-b-d-galactopyranoside (1)[13] was used as a modelsubstrate (Scheme 2).

It was treated under the conditions leading to the formationof furanoside byproducts from oligofucopyranosides.[10] It ap-peared that its treatment with the Py·SO3 complex in the pres-ence of chlorosulfonic acid in DMF at room temperature (seegeneral procedure in Experimental Section and Supporting In-formation) readily gave per-O-sulfated rearranged furanosideproduct 3 via the initial formation of per-O-sulfated derivative2, which was detected first by 1H NMR spectroscopy on thebasis of its characteristic downfield shifts of the H-2, H-4, andH-6 signals (see the Supporting Information). 13C NMR monitor-ing of the reaction mixture revealed that already after 10 minall of compound 1 had been transformed into sulfate 2(Figure 2), and after 2 h about 30 % of pyranoside 2 was rear-ranged into furanoside 3. Further prolongation of the treat-ment time up to 48 h afforded complete PIF rearrangement togive sulfated galactofuranoside 3. Its further O-desulfationunder conventional solvolysis[14, 15] by Py·HCl in a dioxane/DMFmixture gave galactofuranoside 4.

The structures of galactofuranoside derivatives 3 and 4 wereconfirmed by HR-mass and NMR spectroscopy data. Particular-ly, the HMBC spectrum of product 3 contained a correlationpeak between C-4 and H-1, while there were no correlationsbetween C-5 and H-1, clearly evidencing the presence of thefuranoside ring. In addition, the removal of the Bn group andreduction of allyl in 4 by catalytic hydrogenolysis gave propylb-d-galactofuranoside 5, whose 1H and 13C NMR spectra coin-cided well with the published spectra of n-octyl b-galactofura-noside.[16]

It is reasonable to assume that the rearrangement startswith the protonation of O-5 giving pre-reaction intermediate A(Scheme 2). Further transformation of the pyranoside ring in Awas studied employing ab initio RHF calculations (see the Sup-porting Information). It is supposed that the rate-determiningstep in the PIF rearrangement was the formation of open-ringintermediate C, which proceeded via transition state B. In thiscase, further recyclization of C accompanied by sulfate transfershould yield furanoside 3. The geometry of the transition state(B) obtained in the calculations led us to the conclusion thatthe sulfate group at O-2 might participate in the O(5)�C(1)bond cleavage, facilitating this process and contributing to the

Scheme 1. Conversion of UDP-Galp into UDP Galf by UDP-galactopyranosemutase.[12]

Scheme 2. The per-O-sulfation of b-d-galactopyranoside 1 followed by 2!3 isomerization and putative intermediate structures A–C.

Figure 2. 13C NMR spectroscopy monitoring of galactopyranoside 1 transfor-mation into galactofuranoside 3 : after 10 min (total conversion of 1 into tri-O-sulfated intermediate 2 with minor formation of 3), after 2 h (mixture of 2and 3, ~2:1), and after 48 h (complete formation of the furanoside 3).

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fixation of the anomeric configuration during therearrangement.

To confirm the crucial role of the sulfate group at O-2, weprepared 2-O-acetylated derivative 6 from galactoside 1 withintermediate 4,6-acetonation and hydrolysis steps (Scheme 3,for details see Supporting Information). As expected, the treat-ment of 2-O-acetylated derivative 6 under standard PIF condi-tions resulted only in totally sulfated pyranoside 7 without theformation of even traces of the furanoside derivative. Remarka-bly, the activation energy for 2-O-sulfated derivative 2 calculat-ed as the difference between A and B was 65 kJ mol�1

(Scheme 2); when the substituent at O-2 was changed to ace-tate in the calculations, the activation energy (difference be-tween E and D) was much higher, reaching 117 kJ mol�1

(Scheme 3). This fact supports the above discussed mechanismof the PIF rearrangement. Its further investigation is in prog-ress and will be reported elsewhere.

3-O-Benzyl-b-d-galactopyranoside (1) was used as a modelsubstrate to optimize the protocol for the PIF rearrangement,because its furanoside isomer 4 was regarded as a convenientprecursor for the planned synthesis of disaccharide 11 repre-senting the repeating unit of the O-specific polysaccharide

(OPS) of Klebsiella pneumonia (Scheme 4). This bacteriumcauses pneumonia, bacteremia, and urinary tract infectionswith high incidence and mortality.[17] The OPS chain is built upof the disaccharide repeating unit [!3)-a-d-Galp-(1!3)-b-d-Galf-(1! ] .[18, 19] Disaccharide 11, representing this repeatingunit, was prepared as a molecular probe to study the topologyof OPS recognition by lysozyme and other proteins of theimmune system.

Silylation of compound 4 with TBSCl in DMF followed by hy-drogenolysis gave monohydroxy derivative 8 (Scheme 4). Itsglycosylation with ethylthio galactopyranoside 9[20] gave a-linked disaccharide 10, the deprotection of which afforded thetarget disaccharide 11 in a yield of 75 %.

The applicability of PIF rearrangement was also demonstrat-ed by the synthesis of disaccharide 20, related to fucoidanfrom the brown seaweed Chordaria flagelliformis[21] (Scheme 5).Polysaccharide fucoidans from brown seaweeds demonstratepromising types of biological activity[22–27] that stimulate thepreparation of related oligosaccharides as models for QSARstudies.

Scheme 3. The preparation of non-rearrangeable 2-O-acetylated derivative 6and structures of putative protonated structures D and E.

Scheme 4. The synthesis of disaccharide 11 related to OPS of K. pneumonia.

Scheme 5. The synthesis of disaccharide 20 related to fucoidan from C. flagelliformis.

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3-O-Benzoylated allyl b-l-fucofuranoside (14) was chosen asthe main precursor towards disaccharide 20 with the aim ofexploring the remote stereocontrolling effect[28, 29] of the 3-O-benzoyl group for efficient a-fucofuranosylation during disac-charide assembly (Scheme 5). Compound 13 was prepared inhigh yield by the regioselective benzoylation of triol 12[30] viaintermediate generation of an organoboron intermediate.[31]

Further PIF rearrangement of pyranoside 13 proceededsmoothly with formation of the required furanoside 14. Itsbenzylation followed by anomeric deallylation and imidate for-mation gave the fucofuranosyl donor 16. Coupling of mono-saccharides 16 and 18 (obtained from diol 17[32] by regioselec-tive oxidation of the primary OH group at C-6, see the Sup-porting Information) in the presence of TMSOTf gave stereose-lectively a-linked disaccharide 19. Deprotected disaccharide 20was obtained by hydrogenolysis and saponification of product19, which can be regarded as a convenient block for the as-sembly of larger oligosaccharides via O-deallylation followedby transformation into glycosyl donor derivatives.

The synthetic potential of PIF rearrangement was also dem-onstrated by the preparation of mono- (30) and disaccharides(34) related to the diheteroglycan polysaccharide of Enterococ-cus faecalis, which is built up from repeating disaccharide unitswith the formula [!6)-3-O-lactyl-b-d-Galf-(1!3)-b-d-Glcp-(1!] .[33] Enterococci are currently the third most commonpathogen (among Gram-positive bacteria) causing hospital-as-sociated infections in the US, and are the second mostcommon pathogen isolated from intensive care unit patientsworldwide.[34] Oligosaccharides related to the heteroglycanchain are regarded as promising components for vaccinedesign.[33]

Selectively substituted galactopyranoside 25 bearing the 3-O-lactyl group was used as a substrate for PIF rearrangement(Scheme 6).

Its preparation was performed by regioselective 6-O-silyla-tion with TBSCl of readily available allyl b-d-galactopyranoside21[35] followed by alkylation of triol 22 with racemic ethyl 2-bromopropionate via an organotin intermediate[36] (see theSupporting Information). These reactions gave a mixture of bi-cyclic lactones dominated by compounds 23 and 24, which

were isolated in their individual forms. Their structures, includ-ing the configurations of lactic units, were assessed by NMRspectroscopy with NOE experiments (shown in the SupportingInformation). These demonstrated the spatial proximity of theHLA and H-4 protons in 23 but of HLA and H-2 in 24. Based onthese data, the S- and R configurations of lactic units were as-cribed to compounds 23 and 24, respectively. The lactones in23 and 24 were further transformed into isomeric esters 25and 26 under treatment with MeONa in anhydrous MeOH.Compound 25 was used for the further preparation of furano-side derivatives 30 and 34 (Scheme 7). Thus, PIF rearrangementof 25 gave intermediate product 27, the solvolytic O-desulfa-tion of which in a DMF/dioxane mixture in the presence ofPy·HCl followed by saponification gave target monosaccharide30.

Alternatively to the above-described solvolytic protocol, O-desulfation can be also performed by acetolysis to give corre-sponding per-acetylated derivatives (see transformation 27!28 in Scheme 7). Acetolysis of the sulfate groups is accompa-nied by the cleavage of the glycoside bond with the formationof the corresponding acetate, which is a valuable precursor inthe preparation of various furanosyl donors. Thus, acetolysis of27 in the presence of AcOH/Ac2O/H2SO4 gave tetraacetate 28as a mixture of a- and b-isomers (a/b= 1:3). Selective removalof the anomeric acetate in compound 28 followed by treat-ment with N-phenyltrifluoroacetimidoyl chloride afforded gal-actofuranoside donor 29. The spacer-armed glycosyl acceptor32 was prepared from the known diol 31[37] by regioselective2-O-benzoylation by the method of Szeja[38] as modified byKrepinsky.[39] Coupling of acceptor 32 and the galactofuranosyldonor 29 proceeded smoothly and gave disaccharide 33 ingood yield. Its deprotection gave the spacer-armed disacchar-ide 34. The application of compounds 30 and 34 in immuno-bacteriological investigations as well as in the structural assess-ment of diheteroglycan of E. faecalis will be publishedelsewhere.

The described examples of PIF rearrangement demonstrateits applicability for the transformation of monosaccharide de-rivatives with allyl, benzyl, benzoyl, and lactyl substituents.Moreover, it turned out that the discovered procedure couldalso be used for PIF rearrangement of oligosaccharides. Thus,the treatment of disaccharide 36 (Scheme 8) afforded the rear-ranged product 37 bearing the furanoside residue at the “re-ducing end”. Its hydrogenolysis gave disaccharide 11, revealingan alternate synthesis strategy towards this compound in addi-tion to that shown in Scheme 4. Substrate 36 was preparedfrom the known disaccharide 35[40] by acidic hydrolysis withaqueous TFA as described in Supporting Information.

It is remarkable that the PIF rearrangement proceeds withthe retention of the anomeric configuration. Thus, only a-fura-nosides were obtained from a-pyranosides (see compounds Aand C in Figure 1).[10] Similarly, all b-pyranoside substrates de-scribed above gave exclusively b-furanosides (see transforma-tion 1!4 on Scheme 2, 13!14 on Scheme 5, 25!30 onScheme 7 and 36!37 on Scheme 8).

Scheme 6. The synthesis of galactopyranosides 25 and 26 bearing 3-O-lactylsubstituent.

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Conclusion

In conclusion, a new reaction, namely, PIF rearrangement, wasdiscovered. It has no analogy in organic chemistry and can becompared only to enzymatic isomerization by action of pyra-nose mutases. PIF rearrangement provides a very good and ad-vantageous alternative to known methods of furanoside oligo-saccharide synthesis as demonstrated by the describedexamples.

Experimental Section

General methods

All solvents for reactions were dried according to conventional pro-cedures[41] or purchased as dry. Dichloromethane (CH2Cl2) was dis-tilled over CaH2, and methanol (MeOH) was distilled overMg(OMe)2. Dimethylformamide (DMF) and acetonitrile (CH3CN)were purchased as dry and used without further purification. Re-agents for synthesis were commercial and used without further pu-rification. All reactions involving air- or moisture-sensitive reagentswere carried out using dry solvents under dry argon. Molecularsieves for glycosylation reactions were activated prior to use at

180 8C in vacuum of an oil pump during 2 h. Thin-layer chromatog-raphy (TLC) was carried out on aluminum plates coated with silicagel 60 F254 (Merck). Analysis TLC plates were inspected by UV light(l= 254 nm) and developed by the treatment with a mixture of15 % H3PO4 and orcinol (1.8 g L�1) in EtOH/H2O (95:5, v/v) followedby heating. Silica gel column chromatography was performed withSilica Gel 60 (40–63 mm, Merck). Gel filtration was performed ona Sephadex G-15 column (35 � 500 mm) by elution with water ata flow rate of 1 mL min�1 or on a column of TSK HW-40 (S) gel(25 � 400 mm) in 0.1 m AcOH at a flow rate of 0.7 mL min�1.

Spectroscopic methods

NMR spectra were recorded at 293–305 K using Bruker AM 300(300 MHz), Bruker AMX400 (400 MHz), Bruker DRX-500 (500 MHz),or Bruker AV600 (600 MHz) spectrometers. Shifts are referenced rel-ative to deuterated solvent residual peaks. NMR spectra of free oli-gosaccharides were measured for solutions in D2O using acetone(dH = 2.225 ppm, dC = 31.45 ppm) as an internal standard. The fol-lowing abbreviations are used to explain the observed multiplici-ties: s, singlet; d, doublet; t, triplet ; m, multiplet and br t, broadtriplet. Assignments were deduced from 2D experiments (COSY,HSQC, HMBC and TOCSY). Optical rotations were measured usinga JASCO DIP-360 polarimeter at ambient temperature in solvents

Scheme 7. The synthesis of mono- (30) and disaccharide (34) fragments related to polysaccharide from E. faecalis.

Scheme 8. The alternative synthesis of disaccharide 11.

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specified. High-resolution mass spectra (HR-MS) were measured ona Bruker micrOTOF II instrument using electrospray ionization(ESI).[42] The measurements were performed in a positive ion mode(interface capillary voltage �4500 V) or in a negative ion mode(3200 V); mass range from m/z 50 to m/z 3000 Da; external or in-ternal calibration was made with Electrospray Calibrant Solution(Fluka). A syringe injection was used for solutions in a mixture ofacetonitrile and water (50:50 v/v, flow rate 3 mL min�1). Nitrogenwas applied as a dry gas; interface temperature was set at 180 8C.

Computational details

Calculations were carried out using the NWChem v. 6.3 software[43]

and RHF approach with 6–31 + G* basis set. Starting structureswere obtained as stationary points after geometry optimization.Transition states were located using saddle point search as struc-tures having exactly one negative vibrational frequency corre-sponding to C1�O5 bond cleavage. Activation energies were esti-mated as differences between full energies of the found transitionstates and were used uncorrected for zero-point vibrationalenergy. Energies of both starting and saddle point structures wereconverged to RMS gradient less than 10�4.

General procedure for pyranoside-into-furanoside (PIF)transformation

O-Sulfation and rearrangement

HSO3Cl (26 mL, 0.39 mmol) was added dropwise to a stirred solu-tion of the pyranoside derivative (0.10 mmol) and Py·SO3 complex(159 mg, 1.00 mmol) in DMF (1.2 mL). The reaction mixture waskept for 48 h at 20 8C and then quenched with aqueous NaHCO3

(266 mg in 3 mL H2O, 3.17 mmol) and evaporated twice withwater. The residue was dissolved in a minimal amount of waterand then an excess of MeOH was added to result in precipitationof inorganic salts, the mixture was filtrated, the solid was washedwith MeOH, and the filtrate was concentrated and used for thenext step without additional purification.

O-Desulfation

Crude sulfated furanoside obtained as described above and Py·HCl(51 mg, 0.5 mmol) were dissolved in DMF (1 mL), and then dioxane(5 mL) was added. The mixture was stirred at 80 8C for 30 min andthen cooled to room temperature. The reaction mixture was dis-solved in CHCl3 (15 mL) and washed with saturated aqueous NaCl(15 mL). The organic layer was concentrated, and the residue waspurified by column chromatography on silica gel to give the fura-noside derivative.

NMR monitoring of PIF rearrangement

To a stirred solution of pyranoside 1 (30 mg, 0.097 mmol) in DMF(1.2 mL) Py·SO3 complex (159 mg, 1.00 mmol) and HSO3Cl (26 mL,0.39 mmol) were added. The reaction mixture was kept at 20 8C.After 10 min, 2 h and 48 h the sample of the resulted solution(250 mL) was taken from the reaction mixture and quenched withan aqueous solution of NaHCO3 (0.5 m, 1.32 mL). The resulting solu-tion was concentrated in vacuo and then co-evaporated twice withH2O and then lyophilized with D2O. The resulting white solid resi-due was dissolved in D2O and used for recording the NMRspectrum.

Full experimental procedures, characterization for all new com-pounds and copies of 1H, 13C NMR and HRMS spectra are providedin the Supporting Information.

Acknowledgements

This work was supported by RSF grant 14-23-00199 (NEN). Wethank Dr. Y. E. Tsvetkov for reading this manuscript and valua-ble comments, and Dr. A. O. Chizhov for recording high resolu-tion mass spectra at the Department of Structural Studies ofthe Zelinsky Institute of Organic Chemistry, Moscow.

Keywords: carbohydrates · furanoside · glycosylation ·rearrangement · sulfation

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Received: September 1, 2014Published online on October 15, 2014

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