Palladium-Catalyzed Cross-Coupling Reaction of Thioglycosides with (Hetero)aryl Halides

DOI: 10.1002/adsc.201200695

Palladium-Catalyzed Cross-Coupling Reaction of Thioglycosideswith (Hetero)aryl Halides

Etienne Brachet,a Jean-Daniel Brion,a Samir Messaoudi,a,* and Mouad Alamia,*a Univ Paris-Sud, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Th�rapeutique, Facult� de

Pharmacie, 5 rue J.-B. Cl�ment, 92296 Ch�tenay-Malabry, FranceFax: (+33)-146-83-58-28; e-mail: [email protected] or [email protected]

Received: August 3, 2012; Revised: November 7, 2012; Published online: February 1, 2013

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200695.

Abstract: a- and b-thioglycosides serve as effectivenucleophiles for Buchwald–Hartwig cross-couplingreactions using functionalized (hetero)aryl halides.The functional group tolerance on the electrophilicpartner is typically high, both benzyl and acetateprotecting groups on the carbohydrate are tolerated,and anomer selectivities of thioglycosides are high in

all cases studied. The efficiency of this general proto-col was well demonstrated by the synthesis of 4-methyl-7-thioumbelliferyl-b-d-cellobioside (MUS-CB).

Keywords: C�S bond formation; ACHTUNGTRENNUNG(hetero)aryl hal-ides; palladium catalysis; thioglycosides

Introduction

The biological relevance of sulfur-containing carbohy-drates is gaining substantial attention in a wide arrayof biological studies.[1] Thioglycoside derivatives havebeen investigated extensively as mimetics of biologi-cally relevant O-glycosides. S-glycosides are muchmore stable than O-glycosides to both chemical andenzymatic degradation and are utilized as enzyme in-hibitors in various biochemical studies.[2]

While much effort has been spent on constructionof specific thiooligosaccharides and thiopeptides,[1c]

relatively little attention has been devoted to synthe-sis of (hetero)arylthioglycosides. These derivatives aremore routinely prepared by treating per-O-acetylatedglycosyl precursors with a thiophenol in the presenceof a Lewis acid,[3] or by substituting the halogen atomof an acetohaloglycoside with a thiolate anion[4]

(Scheme 1a). These procedures suffer from the use ofan excess of harsh acidic reagents, and are generallyrestricted in substrate scope with respect to thiophe-

Scheme 1.

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nols. In addition, reactions can be lengthy, and unde-sired anomeric mixtures are occasionally observed.[5]

An appealing option to access (hetero)arylthioglyco-sides 3 would be the use of thioglycosides as nucleo-philes in transition metal-catalyzed reactions(Scheme 1b).

To the best of our knowledge, only one report de-scribed the preparation of arylthioglycosides by cou-pling of per-O-acetylated sugar thiols with activatedo-iodoaryltriazenes.[6] To be successful, the reactionrequired the use of stoichiometric amounts of CuI.Only activated o-iodoaryltriazenes were used, thuslimiting the scope of the reaction.[7] Attempted cou-plings with unactivated aryl iodides failed.[6] There-fore, the development of general and selective proto-cols to give a more efficient and direct access to (het-ero)arylthioglycosides 3 is still desirable.

Continuing our longstanding interest in developingnovel metal-catalyzed carbon-heteroatom bond form-ing reactions,[8] we decided to explore the ability of a-and b-thioglycosides to participate as nucleophiles ina Pd-catalyzed C�S[9] cross-coupling reaction witha wide variety of (hetero)aryl halides (Scheme 1b).From a synthetic viewpoint, this coupling is a substan-tially daunting task because of the added functionalityand stereochemical complexity of carbohydrates. Tothe best of our knowledge, there is no report describ-ing the formation of these (hetero)aryl thioglycosides(3) using this idea. Herein, we report our success inthe development of such a general and unprecedentedprotocol that accommodates a wider combination ofaglycon groups (e.g., aryl, heteroaryl, heterocyclic) atthe sulfur atom of thioglycosides. This selective cou-pling competes with the standard preparation of ar-ylthioglycosides by reaction of thiophenols with an ac-tivated sugar since, with respect to aryl partners, halo-genated (hetero)aromatic compounds are morewidely commercially available than thiophenol deriva-tives.[10]

Results and Discussion

To determinate the feasibility of this C�S bond for-mation process, we examined the coupling of perace-tylated b-thioglucose 1a with 4-iodoanisole 2a undervarious palladium catalysts, ligand sources, bases andsolvents. Representative results from this study aresummarized in Table 1. The reaction of 1a (1.5 equiv.)with 2a (1 equiv.) was first investigated under the con-ditions of our previously reported procedure[8a,b]

[Pd ACHTUNGTRENNUNG(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 100 8C].However, this transformation was inefficient and re-sulted in concomitant formation of the expected b-ar-ylthioglycoside 3a, together with by-product 3b in92:08 ratio (Table 1, entry 1). After a tedious separa-tion, 3a was isolated in an acceptable 66% yield. Of

note, compound 3b arises from the aryl migration be-tween the metal center and coordinated phosphine inthe Pd(II) complex. This reactivity is quite rare buthas nevertheless already been reported.[11] To circum-vent the formation of 3b, an extensive screening ofvarious reaction parameters (base, ligand and solvent)was conducted. Screening of other carbonate basessuch as K2CO3 gave a similar result (63%, entry 2).We were delighted to find that the use of organicbases such as (i-Pr)2NH, (i-Pr)2NEt or Et3N leads toimprovement of performance of the coupling reactionwith yields up to 98% (entries 3–5). With Et3N as thebase, the screening reactions with respect to theligand revealed that the bidentate phosphine Xant-phos L1 is superior to all other choices, providing 3ain a quantitative yield (entry 5). Other ligands weredetrimental to the reaction (entries 6–9). Finally, afterscreening other parameters (solvent and amount ofbase), optimal conditions were found to require 1a(1.5 equiv.), 2a (1 equiv.), PdACHTUNGTRENNUNG(OAc)2 (3 mol%), Xant-phos (1.5 mol%), NEt3 (1 equiv.), dioxane in a sealedSchlenk tube at 100 8C for 1 h (entry 11).[12] Accord-ingly, 3a was formed in 99% yield without any anome-rization. A control experiment revealed that both pal-ladium catalyst and ligand were necessary for the cou-pling to occur as no product could be formed in theabsence of Pd ACHTUNGTRENNUNG(OAc)2 or L1.

Motivated by these results, we next explored thescope of the coupling reaction of b-thioglucose 1awith various (hetero)aryl iodides and bromides. Grati-fyingly, all the arylations proceeded cleanly and selec-tively in excellent yields. As depicted in Table 2, 1awas readily coupled with aryl bromides and iodideshaving para and meta electron-donating or electron-withdrawing substituents to give thioglycosylatedproducts in good to excellent yields with complete b-selectivity (entries 1–3, 6–8 and 10–15). In addition,the sterically demanding ortho substitution patternwas tolerated toward the coupling reaction of 1a,leading to b-thioglycosylated derivatives in excellentyields (entries 4, 5 and 9), regardless of the electronicnature of the substituents. As shown in Table 2, thepresence of a free amino (entry 2) or hydroxy group(entries 3 and 15) on the aryl halides 2 did not inter-fere with the outcome of the present reaction. Inter-estingly, the thioglycosylation procedure was tolerantof a diverse array of electrophilic functional groups[e.g., NO2, CHO, CO2Et, COMe, CH=NAr, CONR2,C(Me)=NNHTs], providing the corresponding b-ar-ylthioglycosides with yields ranging from 61% to98%. Aryl halides 2l–n revealed an excellent chemicalselectivity of the C�I bond over the C�Br bond or N-tosylhydrazone function,[13] which could enjoy furthermetal-catalyzed functionalization processes[14] (en-tries 11–13). Extending the glycosylation method toheteroaromatic halides proved to be also successful(entries 16–21). Halopyridines 2q, 2r, 2-iodothiophene

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2s and 3-bromoquinoline 2t were good partners with1a under our optimized conditions, furnishing the de-sired heteroaromatic thioglycosides 3q–t in yieldsranging from 88 to 95% (entries 16–19). In addition,the reaction was found to proceed successfully whenheterocyclic halides were used, such as 3-iodoquino-lone 2u and 3-iodochromone 2v leading to glycosylat-ed products 3u and 3v in excellent yields (entries 20and 21).

In a further set of experiments, we investigated thescope and generality of the method for a range ofmono- and dithiosaccharides 1a–g (Figure 1).

As depicted in Scheme 2, coupling reactions pro-ceeded cleanly in high yields without any significantside reaction such as anomerization of the resultingarylthioglycosides. The reaction seems to be general

with respect to the sugar configuration as per-O-ace-tylated 1-thio-b-d-galactose 1e and 1-thio-b-d-ribose1f gave the corresponding products 4a–c in good toexcellent yields (76–99%). The coupling procedure isnot limited only to thiols with the anomeric b configu-ration, but also works successfully with thiols of thea configuration (Scheme 2, 4 ). Moreover, there wereno significant reactivity differences between a- and b-anomers, as similar yields were obtained from thecoupling of b-benzylated thioglucopyranose 1b and a-benzylated thioglucopyranose 1d with 4-iodoaceto-phenone (78% and 81% yields, respectively).

Importantly, there is no significant impact of pro-tecting groups on the reactivity of the thiosugar deriv-atives since benzyl-protected carbohydrate 1b reactssimilarly as the O-acetylated derivative 1a furnishing

Table 1. Optimization of the coupling reaction of 1a with 2a under various conditions.[a]

Entry Ligand Base Solvent Conversion[b] [%] Ratio[c] 3 a/3 b Yield[d] [%]

1 L1 Cs2CO3 dioxane 100 92:08 662 L1 K2CO3 dioxane 100 89:11 633 L1 ACHTUNGTRENNUNG(i-Pr)2NH dioxane 100 100:0 984 L1 ACHTUNGTRENNUNG(i-Pr)2NEt dioxane 100 100:0 985 L1 Et3N dioxane 100 100:0 996 L2 Et3N dioxane 52 – –7 L3 Et3N dioxane 0 – –8 L4 Et3N dioxane 0 – –9 L5 Et3N dioxane 0 – –10 L1 Et3N toluene 100 100:0 9511 L1 Et3N dioxane 100 100:0 99[e,f,g]

[a] Reaction conditions: 1a (0.375 mmol), 2a (0.25 mmol), PdACHTUNGTRENNUNG(OAc)2 (10 mol%), ligand (5 mol%), base (0.75 mmol) in sol-vent (1.5 mL) were heated in a sealed Schlenk tube at 100 8C.

[b] Conversion was determined by 1H NMR on the crude reaction mixture and is based on the chemical shift of the protonsignal (ppm) at the C-2 position of the aromatic ring (2a : d=6.68, 3a : d= 6.82).

[c] Ratio was determined by 1H NMR in the crude reaction mixture and is based on the chemical shift of the proton signal(ppm) at the anomeric position (3a : d=4.54, 3b : d=4.70).

[d] Yield of isolated product.[e] Reaction was carried out in the presence of Pd ACHTUNGTRENNUNG(OAc)2 (3 mol%), L1 (1.5 mol%) and Et3N (1 equiv.). Compound 3a was

formed in 95% yield when reaction was carried out with Pd2dba3 (3 mol%), L1 (3 mol%). No reaction occurred whenPd2dba3 (3 mol%) was used alone without L1.

[f] A 72% yield of 3a was obtained when using only 1 mol% of PdACHTUNGTRENNUNG(OAc)2 and (0.5 mol%) of Xantphos.[g] For control experiments, no conversion at all was observed in the absence of Pd ACHTUNGTRENNUNG(OAc)2 or L1 and in the absence of

Pd ACHTUNGTRENNUNG(OAc)2 and L1.

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Palladium-Catalyzed Cross-Coupling Reaction of Thioglycosides with (Hetero)aryl Halides


the coupling product 4d in a good 78% yield. Moreinterestingly, coupling of unprotected b-d-thioglucose1c with 4- iodoanisole under our optimized conditions

furnished exclusively b-anomer 4f in a good yield(66%, Scheme 2) without any significant side productresulting from O-arylation under Pd-catalysis.[15] A lit-

Table 2. Palladium-catalyzed coupling of b-thioglucose 1a with (hetero)aryl halides 2.[a]

Entry ACHTUNGTRENNUNG(Hetero)aryl hal-ides (2)

b-Arylthioglycosides(3)

Yield[%][b]

Entry ACHTUNGTRENNUNG(Hetero)aryl hal-ides (2)

b-Arylthioglycosides(3)

Yield[%][b]

1 99 12 84

2 90 13 90

3 99 14 87

4 98 15 72

5 98 16 84

6 91 17 88

7 61 18 88

8 86 19 95

9 98 20 88

10 96 21 89

11 95 22 86

[a] Reactions of 1a (0.375 mol) with (hetero)aryl haldies 2 (0.25 mmol) were performed in a sealed Schlenk tube at 100 8Cfor 1 h in dioxane (1.5 mL) in the presence of Pd ACHTUNGTRENNUNG(OAc)2 (5 mol%), Xantphos (2.5 mol%), and Et3N (0.25 mmol).

[b] Yield of isolated product.




erature search did not uncover any other metal-cata-lyzed coupling of a free thioglucose nucleophile withC ACHTUNGTRENNUNG(sp2) aryl halides.

Finally, the protocol was successfully applicable toperacetylated b-d-disaccharides 1h derived from d-cellobiose octaacetate. The exclusive 1,2-trans b-thio-glycoside 4g was obtained in 77% yield within 1 h andthe stereochemistry of the 1!4’ glycosidic bond re-mained intact.As depicted in Scheme 2, coupling reac-tions proceeded cleanly in high yields without any sig-nificant side reaction such as anomerization of the re-sulting arylthioglycosides. Ultimately, a major benefitof our thioglycosylation procedure its amenability tolate-stage synthetic applications. To demonstrate thispotential, biologically active molecules were subjectedto our coupling protocol to obtain their thioglycosideanalogues (Scheme 3). For instance, compounds 5 and6 which are analogues of isocombretastatin A-4

(isoCA-4),[16] and phenstatin,[17] two highly promisingcytotoxic and antitubulin agents, were each selectivelythioglycosylated with 1-thio-b-d-galactose 1e underour optimized conditions. The couplings furnished b-thioglycosides 7 and 8 with excellent efficiency (yieldsup to 97%). In addition, subjection of 6-iodocarbox-ACHTUNGTRENNUNGamide quinolinone 9 to 1a under our protocol similar-ly resulted in the rapid preparation of the thioglyco-side 10 analogue of 6BrCaQ, a potent hsp90 inhibitordeveloped in our group.[18] In the context of drug dis-covery, this strategy offers the potential for rapid test-ing of thioglycosylated analogues for biological activi-ty from a single late-stage synthetic product.

Finally, the synthetic potential of this protocol waswell illustrated by the preparation of 4-methyl-7-thio-umbelliferyl-b-d-cellobioside (MUS-CB),[19] a fluores-cent non-hydrolyzable substrate analogue for cellu-ACHTUNGTRENNUNGlases. The key step was the coupling of 7-iodocoumar-in 11[20] with peracetylated b-d-disaccharide 1g underour optimized conditions to give acetylated MUS-CB12 in an excellent 87% yield with exclusive b-selectiv-ity (Scheme 4). Further deprotection of acetoxygroups[19] furnished MUS-CB in 75% yield.

Conclusions

In conclusion, we have developed a general and selec-tive method for the thioglycosylation of highly func-tionalized (hetero)aryl halides. To the best of ourknowledge the C ACHTUNGTRENNUNG(sp2)�S bond was formed, for thefirst time, directly by using thioglycosides as a nucleo-phile partner in the presence of commercially avail-

Figure 1. Thiosaccharides 1a–g used in this study

Scheme 2. Palladium-catalyzed coupling of various thiosaccharides 1a–g with aryl iodides 2a.




able Pd ACHTUNGTRENNUNG(OAc)2/Xantphos as the catalyst system. Ouroptimized reaction conditions allow us to preparethio ACHTUNGTRENNUNGsugar-based derivatives 3 that accommodatea wider combination of aglycone groups (e.g., aryl,heteroaryl, heterocyclic) at the sulfur atom of thesugar moiety. The value of this transformation hasbeen highlighted via the thioglycosylation of biologi-cally active molecules. We expect this simple and gen-eral protocol to be of broad utility for the synthesisand development of new medicinal agents.

Experimental Section

General Experimental Methods

The compounds were all identified by usual physical meth-ods, e.g., 1H NMR, 13C NMR (J-MOD), IR, MS (ESI). 1Hand 13C NMR spectra were measured in CDCl3 or DMSO-d6

with a Bruker Avance-300. 1H chemical shifts are reportedin ppm from an internal standard TMS or of residual chloro-form (7.27 ppm). 13C chemical shifts are reported in ppmfrom the central peak of deuteriochloroform (77.14). IRspectra were measured on a Bruker Vector 22 spectropho-tometer. MS were recorded on a Micromass spectrometer.Analytical TLC was performed on Merck precoated silicagel 60F plates. Merck silica gel 60 (0.015–0.040 mm) wasused for column chromatography. Melting points were re-corded on a B�chi B-450 apparatus and are uncorrected.

High resolution mass spectra (HR-MS) were recorded ona Bruker MicroTOF spectrometer, using ESI with methanolas the carrier solvent. Nominal and exact m/z values are re-ported in Daltons. (Hetero)aryl halides are commerciallyavailable. Thiosaccharides 1a–f[21–23] were synthesized as ac-cording to literature protocols.

Analytical Data for Thioglycosides 1a–g

Compound 1a:[21] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl triacetate:1H NMR (300 MHz, CDCl3): d=5.13 (dt, J=19.2, 9.3 Hz,2 H), 4.96 (t, J=9.4 Hz, 1 H), 4.54 (t, J=9.8 Hz, 1 H), 4.24(dd, J=12.5, 4.8 Hz, 1 H), 4.11 (dd, J=12.4, 2.0 Hz, 1 H),3.71 (ddd, J=9.8, 4.7, 2.0 Hz, 1 H), 2.30 (d, J=9.9 Hz, 1 H),2.08 (s, 3 H), 2.07 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H).

Compound 1b:[22] (2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-thiol: 1H NMR(200 MHz, CDCl3): d= 7.44–7.09 (m, 20 H), 5.03–4.76 (m,5 H), 4.64–4.44 (m, 4 H), 3.76–3.60 (m, 3 H), 3.54–3.37 (m,2 H), 2.31 (d, J=8.0 Hz, 1 H).

Compound 1c:[21] (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triol: 1H NMR(300 MHz, methanol-d4): d=3.28 (m, 4 H), 3.64(dd, J=12.0,5.1 Hz, 1 H), 3.84 (dd, J=12.1, 1.8 Hz, 1 H), 4.41 (d,J=9.3 Hz, 1 H).

Compound 1d:[22] (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-thiol: 1H NMR(200 MHz, CDCl3): d= 7.45–7.00 (m, 20 H), 5.71 (t, J=

Scheme 3. Direct thioglycosylation of biologically active molecules.

Scheme 4. Synthesis of 4-methyl-7-thioumbelliferyl-b-d-cellobioside (MUS-CB).




4.7 Hz, 1 H), 4.94–4.38 (m, 9 H), 4.22–4.10 (m, 1 H), 3.90–3.45 (m, 4 H), 1.85 (d, J=4.7 Hz, 1 H).

Compound 1e:[21] Compound 1e: (2R,3S,4S,5R,6S)-2-(ace-toxymethyl)-6-mercaptotetrahydro-2H-pyran-3,4,5-triyl tria-cetate: 1H NMR (300 MHz, CDCl3): d= 5.42 (d, J= 3.3 Hz,1 H), 5.17 (t, J= 9.8 Hz, 1 H), 5.00 (dd, J= 10.1, 3.4 Hz, 1 H),4.52 (t, J=9.8 Hz, 1 H), 4.11 (d, J=6.7 Hz, 2 H), 3.93 (t, J=6.5 Hz, 1 H), 2.36 (d, J=9.9 Hz, 1 H), 2.15 (s, 3 H), 2.08 (s,3 H), 2.04 (s, 3 H), 1.97 (s, 3 H).

Compound 1f:[23] This substrate is not enough stable forits characterization and was used immediately after its prep-aration.

Preparation of (2S,3S,4R,5S,6R)-2-(Acetoxymethyl)-6-{[(2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymeth-yl)-6-mercaptotetrahydro-2H-pyran-3-yl]oxy}tetra-hydro-2H-pyran-3,4,5-triyl Triacetate (1g)

Thiourea (5.5 g, 72.0 mmol, 1.5 equiv.) and 2,3,6,2’,3’,4’,6’-hepta-O-acetyl-a-cellobiosyl bromide[19] (48.0 mmol,1 equiv.) were dissolved in acetone (100 mL) under Ar. Thereaction mixture was heated to 60 8C. After 2 h, a whitesolid precipitated. This was removed by filtration and the fil-trate returned to reflux. This process was repeated until thesolid ceased to precipitate. (If the product does not precipi-tate after 4 h stirring, acetone was removed under vacuum).The solid 2,3,6,2’,3’,4’,6’-hepta-O-acetyl-a-cellobiosyl 1-iso-thiouronium bromide (22.6 mmol, 1 equiv.) formed andNa2S2O5 (6.0 g, 31.7 mmol, 1.4 equiv.) were added to a stirredmixture of DCM (100 mL) and H2O (50 mL). The reactionmixture was heated to reflux under Ar. After 3 h, T.L.C.(cyclohexane/ethyl acetate; 1:1) indicated the formation ofproduct (Rf 0.5) with complete consumption of the startingmaterial (Rf 0.0). The reaction mixture was cooled to roomtemperature and the phases separated. The aqueous layerwas re-extracted with DCM (2� 100 mL), dried overMgSO4, filtered and concentrated under vacuum to afford1g as a white crystalline solid; yield: 22.6 mmol (100%).Rf =0.5 (cyclohexane/AcOEt, 5:5); white-yellow solid; mp195–197 8C; [a]24

D : �103.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d= 5.42 (d, J=3.3 Hz, 1 H), 5.17 (t, J=9.8 Hz, 1 H), 5.00 (dd, J= 10.1, 3.4 Hz, 1 H), 4.52 (t, J=9.8 Hz, 1 H), 4.11 (d, J=6.7 Hz, 2 H), 3.93 (t, J= 6.5 Hz,1 H), 2.36 (d, J=9.9 Hz, 1 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 2.04(s, 3 H), 1.97 (s, 3 H); 13C NMR (75 MHz, CDCl3): d=170.61 ACHTUNGTRENNUNG(C=O), 170.44 (C=O), 170.33 (C=O), 170.00 (C=O),169.80 (C=O), 169.44 (C=O), 169.21 (C=O), 100.94 (CH),78.62 (CH), 77.33 (CH), 76.40 (CH), 73.89 (CH), 73.32(CH), 73.03 (CH), 72.12 (CH), 71.70 (CH), 67.87 (CH),62.22 (CH2), 61.67 (CH2), 21.00 (CH3), 20.86 (CH3), 20.79(CH3), 20.66 (4 CH3); IR (neat): n=3414, 3392, 3293, 3216,2216, 2146, 2033, 1964, 1734, 1367, 1210, 1034 cm�1; MS(APCI+): m/z=653.0 [M+ H]+.

General Procedure for Palladium-Catalyzed Couplingof b-Thioglucose 1a with (Hetero)aryl Halides 2

A flame-dried resealable Schlenk tube was charged withPd ACHTUNGTRENNUNG(OAc)2 (5 mol%), Xantphos (2.5 mol%), thiosugar1 (0.375 mmol), (hetero)aryl halide 2 (0.25 mmol), and Et3N(0.25 mmol). The Schlenk tube was capped with a rubberseptum, evacuated and backfilled with argon; then, dioxane

(1.5 mL) was added through the septum. The septum was re-placed with a teflon screwcap. The Schlenk tube was sealed,and the mixture was stirred at 100 8C for 1 h. The resultingsuspension was cooled to room temperature and filteredthrough celite eluting with ethyl acetate. The filtrate wasconcentrated and purification of the residue by silica gelcolumn chromatography gave the desired product 3.

Analytical Data for Arylthioglycosides 3

Compound 3a: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-methoxyphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.3 (cyclohexane/AcOEt, 5:5); white-yellow solid;mp 76–78 8C; [a]24

D : + 47.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.42 (d, J= 8.9 Hz, 2 H), 6.82 (d, J=8.9 Hz, 2 H), 5.18 (t, J=9.4 Hz, 1 H), 4.97 (t, J= 9.8 Hz, 1 H),4.86 (t, J= 9.6 Hz, 1 H), 4.54 (d, J=10.0 Hz, 1 H), 4.30–4.06(m, 2 H), 3.79 (s, 3 H), 3.72–3.60 (m, 1 H), 2.08 (s, 3 H), 2.05(s, 3 H), 1.98 (s, 3 H), 1.96 (s, 3 H); 13C NMR (75 MHz,CDCl3): d=170.63 (C=O), 170.27 (C=O), 169.46 (C=O),169.32 (C=O), 160.55 (C), 136.63 (2 CH), 120.96 (C), 114.51(2 CH), 85.77 (CH), 75.84 (CH), 74.18 (CH), 70.00 (CH),68.30 (CH), 62.18 (CH2), 55.43 (CH), 20.89 (CH3), 20.84(CH3), 20.68 (2 CH3); IR (neat): n=3457, 3361, 3262, 3193,2358, 2216, 2219, 1755, 1739, 1711, 1592, 1246, 1175 cm�1;HR-MS (ESI): m/z = 493.1128, calcd. for C21H26NaO10S;493.1139.

Compound 3b: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(phenylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.36 (cyclohexane:AcOEt, 7:3); white-yellow solid; mp 112–114 8C; [a]24

D : �16.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d=7.45–7.41 (m, 2 H), 7.31–7.18 (m, 3 H), 5.16 (t,J=9.3 Hz, 1 H), 4.94 (dt, J=19.3, 9.6 Hz, 2H), 4.65 (d, J=10.1 Hz, 1 H), 4.16 (dd, J=12.6, 5.2 Hz, 1 H), 4.11 (dd, J=12.5, 2.9 Hz, 1 H), 3.66 (ddd, J = 10.0, 4.9, 2.8 Hz, 1 H), 2.01(s, 3 H), 2.01 (s, 3 H), 1.95 (s, 3 H), 1.92 (s, 3 H); 13C NMR(75 MHz, CDCl3): d= 170.57 (C=O), 170.19 (C=O), 169.43(C=O), 169.28 (C=O), 133.17 (2 CH), 131.71 (C), 128.99(2 CH), 128.46 (CH), 85.76 (CH), 75.86 (CH), 74.03 (CH),70.02 (CH), 68.30 (CH), 62.20 (CH2), 20.77 (2 CH3), 20.62(2 CH3); IR (neat): n=3448, 3236, 2355, 2198, 1999, 1753,1741, 1482, 1366, 1250, 1090 cm�1.

Compound 3c: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-({3-[(tert-butyldimethylsilyl)oxy]-4-methoxyphenyl}thio)tetrahy-dro-2H-pyran-3,4,5-triyl triacetate: Rf =0.57 (cyclohex-ACHTUNGTRENNUNGane:AcOEt, 6:4); colorless oil; [a]24

D: �46.0 (c 1.0, CHCl3);1H NMR (300 MHz, CDCl3): d= 7.04 (dd, J= 8.3, 2.2 Hz,1 H), 6.98 (d, J=2.2 Hz, 1 H), 6.75 (d, J= 8.4 Hz, 1 H), 5.17(t, J=9.3 Hz, 1 H), 4.99 (t, J= 9.8 Hz, 1 H), 4.94–4.82 (m,1 H), 4.56 (d, J= 10.1 Hz, 1 H), 4.20 (dd, J=12.3, 4.9 Hz,1 H), 4.09 (dd, J= 12.3, 2.4 Hz, 1 H), 3.77 (s, 3 H), 3.64 (ddd,J=10.0, 4.8, 2.4 Hz, 1 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 1.97 (s,3 H), 1.95 (s, 3 H), 0.96 (s, 9 H), 0.13 (d, J= 2.0 Hz, 6 H);13C NMR (75 MHz, CDCl3): d=170.65 (C=O), 170.24 (C=O), 169.41 (C=O), 169.22 (C=O), 152.05 (C), 145.02 (C),128.36 (CH), 127.00 (CH), 121.40 (C), 112.07 (CH), 86.20(CH), 75.84 (CH), 74.11 (CH), 70.01 (CH), 68.21 (CH),62.14 (CH2), 55.48 (CH), 25.73 (CH3), 20.83 (CH3), 20.78(CH3), 20.64 (2CH3), 18.48, �4.57 (2 CH3); IR (neat): 3474,3260, 3174, 2194, 2013, 1991, 1756, 1502, 1442, 1304, 1271,1137, 1029, 949 cm�1.




Compound 3d: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-aminophenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.27 (cyclohexane/AcOEt, 5:5); white-yellowsolid; mp 73–75 8C; [a]24

D : �14.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.29 (d, J= 8.6 Hz, 2 H), 6.62 (d, J=8.6 Hz, 2 H), 5.18 (t, J=9.3 Hz, 1 H), 4.98 (t, J= 9.8 Hz, 1 H),4.93–4.76 (m, 1 H), 4.51 (d, J= 10.0 Hz, 1 H), 4.25–4.09 (m,2 H), 3.70–3.59 (m, 1 H), 3.34 (brs, NH2), 2.09 (s, 3 H), 2.07(s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H); 13C NMR (75 MHz,CDCl3): d=170.76 (C=O), 170.36 (C=O), 169.54 (C=O),169.41 (C=O), 145.33 (C), 136.59 (2 CH), 119.84 (C), 116.47(2 CH), 86.02 (CH), 75.87 (CH), 74.26 (CH), 70.05 (CH),68.37 (CH), 62.26 (CH2), 20.94 (2 CH3), 20.72 (2 CH3); IR(neat): n=3462, 3403, 3303, 3267, 2383, 2193, 1984, 1755,1741, 1709, 1645, 1598, 1566, 1550, 1499, 1428, 1366, 1207,1092 cm�1; HR-MS (ESI): m/z =478.1128, calcd. forC20H25NNaO9S: 478.1142.

Compound 3e: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(3-hydroxyphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.14 (DCM/AcOEt, 95:5); white-yellow solid; mp120–122 8C; [a]24

D : �10.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d= 7.15 (t, J= 7.8 Hz, 1 H), 7.05–6.94 (m, 2 H),6.85–6.73 (m, 1 H), 6.34 (brs, OH), 5.22 (t, J=9.3 Hz, 1 H),5.00 (dt, J=19.4, 9.8 Hz, 2 H), 4.70 (d, J=10.1 Hz, 1 H),4.30–4.17 (m, 2 H), 3.80–3.63 (m, 1 H), 2.09 (s, 3 H), 2.07 (s,3 H), 2.01 (s, 3 H), 1.98 (s, 3 H); 13C NMR (75 MHz, CDCl3):d= 171.33 (C=O), 170.43 (C=O), 169.63 (2 C=O), 156.26(C), 132.57 (C), 129.96 (CH), 124.91 (CH), 120.14 (CH),115.81 (CH), 85.39 (CH), 75.93 (CH), 74.11 (CH), 70.10(CH), 68.43 (CH), 62.29 (CH2), 20.86 (2CH3), 20.69 (2 CH3);IR (neat): n=3346, 2247, 2182, 2165, 1982, 1755, 1581, 1477,1441, 1366, 1251, 1092, 1034 cm�1; HR-MS (ESI): m/z =479.0989, calcd. for C20H24NaO10S: 479.0982.

Compound 3f: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(2-methoxyphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.27 (cyclohexane/AcOEt, 7:3); white-yellow solid;mp 117–119 8C; [a]24

D : + 5.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d= 7.46 (dd, J=7.7, 1.4 Hz, 1 H), 7.34–7.21 (m, 1 H), 6.98–6.78 (m, 2 H), 5.22 (t, J=9.3 Hz, 1 H),5.05(t, J=8.9 Hz, 1 H), 4.99 (t, J=8.9 Hz, 1 H), 4.79 (d, J=10.0 Hz, 1 H), 4.21 (dd, J=12.3, 5.2 Hz, 1 H), 4.12 (dd, J=12.2, 2.3 Hz, 1 H), 3.84 (s, 3 H), 3.77–3.62 (m, 1 H), 2.05 (s,3 H), 2.04 (s, 3 H), 2.01 (s, 3 H), 1.98 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=170.66 (C=O), 170.32 (C=O), 169.47(C=O), 169.38 (C=O), 158.59 (C), 133.74 (CH), 129.72(CH), 121.15 (CH), 120.14 (C), 111.16 (CH), 84.41 (CH),75.87 (CH), 74.25 (CH), 70.26 (CH), 68.44 (CH), 62.36(CH2), 55.87 (CH), 20.81 (2CH3), 20.70 (2 CH3); IR (neat):n=3321, 2357, 2330, 2208, 2169, 2046, 2000, 1984, 1754,1581, 1480, 1432, 1366, 1214, 1039 cm�1; HR-MS (ESI): m/z=493.1143, calcd. for C21H26NaO10S: 493.1139.

Compound 3g: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(o-tolylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf = 0.42(cyclohexane/AcOEt, 6:4); white-yellow solid; mp 102–104 8C; [a]24

D: �15.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d=7.51 (d, J=7.4 Hz, 1 H), 7.24–7.08 (m, 3 H), 5.23(dd, J=19.8, 10.5 Hz, 1 H), 5.11–4.96 (m, 2 H), 4.67 (d, J=10.1 Hz, 1 H), 4.21 (dd, J=12.3, 5.5 Hz, 1 H), 4.12 (dd, J=12.3, 2.5 Hz, 1 H), 3.72–3.59 (m, 1 H), 2.39 (s, 3 H), 2.07 (s,3 H), 2.05 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=170.60 (C=O), 170.24 (C=O), 169.46(C=O), 169.36 (C=O), 140.55 (C), 133.29 (CH), 132.00 (C),

130.51 (CH), 128.54 (CH), 126.70 (CH), 86.51 (CH), 75.81(CH), 74.08 (CH), 70.30 (CH), 68.45 (CH), 62.36 (CH2),21.01 (CH3), 20.79 (2 CH3), 20.68 (2 CH3); IR (neat): n=3458, 3399, 3351, 3138, 2372, 2185, 2127, 2008, 1971, 1755,1746, 1435, 1366, 1247, 1366, 1090 cm�1; HR-MS (ESI):m/z= 477.1190, calcd. for C21H26NaO9S: 477.1190.

Compound 3h: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-nitrophenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.71 (cyclohexane/AcOEt, 5:5); yellow solid; mp180–182 8C; [a]24

D : �63.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d= 8.14 (d, J= 9.0 Hz, 2 H), 7.58 (d, J=9.0 Hz, 2 H),5.32–5.20 (m, 1 H), 5.08 (d, J=9.3 Hz, 1 H), 5.02 (d, J=9.1 Hz, 1 H), 4.86 (d, J=10.1 Hz, 1 H), 4.34–4.12 (m, 2 H),3.93–3.59 (m, 1 H), 2.09 (s, 3 H), 2.07 (s, 3 H), 2.03 (s, 3 H),1.99 (s, 3 H); 13C NMR (75 MHz, CDCl3): d=170.49 (C=O),170.13 (C=O), 169.42 (C=O), 169.29 (C=O), 147.17 (C),141.79 (C), 131.16 (2 CH), 123.98 (2 CH), 84.46 (CH), 76.24(CH), 73.73 (CH), 69.73 (CH), 68.14 (CH), 62.18 (CH2),20.84 (CH3), 20.75 (CH3), 20.65 (2 CH3); IR (neat): n= 3475,3453, 3346, 2275, 2219, 2187, 2047, 1752, 1717, 1698, 1685,1651, 1558, 1542, 1476, 1375, 1342 cm�1; HR-MS (ESI):m/z= 508.0860, calcd. for C20H23NNaO11S: 508.0884.

Compound 3i: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-formylphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triacetate:Rf =0.17 (cyclohexane/AcOEt, 7:3); white-yellow solid; mp110–112 8C; [a]24

D : +37.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d=9.98 (s, 1 H), 7.80 (d, J=8.1 Hz, 2 H), 7.58 (d,J=8.2 Hz, 2 H), 5.26 (t, J=9.3 Hz, 1 H), 5.05 (td, J=9.5,7.0 Hz, 2 H), 4.86 (d, J= 10.1 Hz, 1 H), 4.24 (dd, J= 12.4,5.3 Hz, 1 H), 4.18 (dd, J=12.3, 2.4 Hz, 1 H), 3.90–3.65 (m,1 H), 2.08 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H);13C NMR (75 MHz, CDCl3): d=191.29 (CHO), 170.54 (C=O), 170.17 (C=O), 169.44 (C=O), 169.30 (C=O), 141.04 (C),135.39 (C), 131.00 (2 CH), 130.06 (2 CH), 84.74 (CH), 76.14(CH), 73.84 (CH), 69.83 (CH), 68.24 (CH), 62.25 (CH2),20.84 (CH3), 20.77 (CH3), 20.66 (2 CH3); IR (neat): n= 3435,3217, 2212, 2142, 2001, 1755, 1700, 1592, 1367, 1212, 1089,1039 cm�1; HR-MS (ESI): m/z =491.0973, calcd. forC21H24NaO10S: 491.0982.

Compound 3j: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[4-(ethoxycarbonyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyltriacetate: Rf =0.58 (cyclohexane/AcOEt, 5:5); white-yellowsolid; mp 112–114 8C; [a]24

D : +43.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.94 (d, J= 8.6 Hz, 2 H), 7.48 (d, J=8.6 Hz, 2 H), 5.23 (t, J= 9.3 Hz, 1 H), 5.10–4.90 (m, 2 H), 4.80(d, J= 10.0 Hz, 1 H), 4.35 (q, J=7.1 Hz, 2 H), 4.22 (dd, J=12.3, 5.2 Hz, 1 H), 4.15 (dd, J= 12.3, 2.5 Hz, 1 H), 3.76 (ddd,J=9.9, 5.1, 2.6 Hz, 1 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 2.00 (s,3 H), 1.97 (s, 3 H), 1.36 (t, J= 7.1 Hz, 3 H); 13C NMR(75 MHz, CDCl3): d=170.54 (C=O), 170.14 (C=O), 169.40(C=O), 169.25 (C=O), 166.01 (C=O), 138.42 (C), 131.08(2 CH), 130.00 (2 CH), 129.89 (C), 85.00 (CH), 76.03 (CH),73.88 (CH), 69.89 (CH), 68.24 (CH), 62.20 (CH2), 61.21(CH2), 20.78 (CH3), 20.75 (CH3), 20.62 (2CH3), 14.38 (CH3);IR (neat): n=3380, 3341, 3324, 3099, 2337, 2273, 2169, 2104,2016, 1757, 1716, 1216, 1040 cm�1; HR-MS (ESI): m/z =535.1246, calcd. for C23H28NaO11S: 535.1245.

Compound 3k: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[2-(ethoxycarbonyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyltriacetate: Rf = 0.29 (cyclohexane/AcOEt, 7:3); white-yellowsolid; mp 120–122 8C; [a]24

D : �53.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.86 (d, J= 7.8 Hz, 1 H), 7.56 (d, J=




8.1 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 7.26 (t, J= 7.5 Hz, 1 H),5.26 (t, J=8.8 Hz, 1 H), 5.15–5.03 (m, 2 H), 4.87 (d, J=10.1 Hz, 1 H), 4.40–4.27 (m, 2 H), 4.26–4.08 (m, 2 H), 3.86–3.73 (m, 1 H), 2.05 (s, 3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.98 (s,3 H), 1.36 (t, J= 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3):d= 170.54 (C=O), 170.20 (C=O), 169.44 (C=O), 169.18 (C=O), 166.44 (C=O), 136.72 (C), 132.18 (CH), 131.11 (C),130.79 (CH), 129.13 (CH), 126.32 (CH), 84.46 (CH), 75.81(CH), 74.07 (CH), 69.88 (CH), 68.43 (CH), 62.44 (CH2),61.48 (CH2), 20.77 (CH3), 20.69 (CH3), 20.65 (2 CH3), 14.31(CH3); IR (neat): n=3386, 2370, 2342, 2208, 2153, 2044,2029, 1752, 1708, 1467, 1367, 1290, 1251, 1213, 1110,1039 cm�1; HR-MS (ESI): m/z =535.1258, calcd. forC23H28NaO11S: 535.1245.

Compound 3l: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-acetylphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triacetate:Rf =0.42 (cyclohexane/AcOEt, 5:5); white-yellow solid; mp129–131 8C; [a]24

D : +54.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d= 7.86 (d, J= 8.3 Hz, 2 H), 7.51 (d, J=8.3 Hz, 2 H),5.24 (t, J=9.3 Hz, 1 H), 5.03 (dt, J=19.3, 9.6 Hz, 2 H), 4.82(d, J=10.0 Hz, 1 H), 4.23 (dd, J=12.4, 5.2 Hz, 1 H), 4.16 (dd,J=12.3, 2.4 Hz, 1 H), 3.78 (ddd, J=10.0, 5.1, 2.5 Hz, 1 H),2.57 (s, 3 H), 2.07 (s, 3 H), 2.06 (s, 3 H), 2.01 (s, 3 H), 1.98 (s,3 H); 13C NMR (75 MHz, CDCl3): d= 197.18 (C=O), 170.53(C=O), 170.14 (C=O), 169.42 (C=O), 169.27 (C=O), 138.89(C), 136.28 (C), 131.16 (2CH), 128.79 (2 CH), 84.87 (CH),76.06 (CH), 73.87 (CH), 69.86 (CH), 68.23 (CH), 62.20(CH2), 26.64 (CH3), 20.81 (CH3), 20.76 (CH3), 20.64 (2 CH3);IR (neat): n=3425, 3314, 3285, 3177, 3098, 3035, 2514, 1755,1682, 1368, 1214, 1039 cm�1; HR-MS (ESI): m/z= 505.1139,calcd. for C22H26NaO10S: 505.1132.

Compound 3m: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(3-bromophenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf = 0.75 (cyclohexane/AcOEt, 5:5); white-yellowsolid; mp = 81–83 8C; [a]24

D : �23.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.64 (t, J=1.7 Hz, 1 H), 7.43 (ddd,J=8.0, 1.9, 1.0 Hz, 1 H), 7.47–7.34 (m, J= 13.9, 7.8, 1.7,1.0 Hz, 1 H), 7.39 (ddd, J=7.8, 1.6, 1.0 Hz, 1 H), 7.16 (t, J=7.9 Hz, 1 H), 5.22 (t, J=9.3 Hz, 1 H), 5.02 (t, J= 9.8 Hz, 1 H),4.98–4.90 (m, J= 10.0, 9.3 Hz, 1 H), 4.70 (d, J=10.1 Hz, 1 H),4.29–4.08 (m, 2 H), 3.74 (ddd, J=10.0, 5.0, 2.7 Hz, 1 H), 2.08(s, 3 H), 2.06 (s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=170.68 (C=O), 170.16 (C=O), 169.42(C=O), 169.26 (C=O), 135.30 (CH), 134.01 (C), 131.51(CH), 131.43 (CH), 130.27 (CH), 122.68 (C), 85.43 (CH),76.02 (CH), 73.92 (CH), 69.90 (CH), 68.19 (CH), 62.20(CH2), 20.87 (CH3), 20.77 (CH3), 20.63 (2 CH3); IR (neat):2361, 1755, 1737, 1577, 1559, 1432, 1366, 1246, 1087, 1062,1030 cm�1; HR-MS (ESI): m/z =541.0121, calcd. forC20H23BrNaO9S: 541.0138.

Compound 3n: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-({4-[(E)-(4-bromobenzylidene)amino]phenyl}thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.44 (cyclohexane/AcOEt, 7:3); white-yellow solid; mp 167–169 8C; [a]24

D :�39.0 (c 1.0, CHCl3); 1H NMR (300 MHz, acetone): d= 8.62(s, 1 H), 7.92 (d, J=8.5 Hz, 2 H), 7.72 (d, J=8.4 Hz, 2 H),7.58 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.5 Hz, 2 H), 5.34 (t, J=9.4 Hz, 1 H), 5.15–4.85 (m, 3 H), 4.24 (dd, J=12.3, 5.4 Hz,1 H), 4.17 (dd, J=12.3, 2.5 Hz, 1 H), 4.05 (ddd, J=9.8, 5.4,2.5 Hz, 1 H), 2.05 (s, 6 H), 2.00 (s, 3 H), 1.94 (s, 3 H);13C NMR (75 MHz, acetone): d=170.77 (C=O), 170.35 (C=O), 170.12 (C=O), 169.81 (C=O), 160.63 (CH), 152.62 (C),

136.63 (C), 134.54 (2 CH), 132.97 (2 CH), 131.47 (2 CH),130.57 (C), 126.37 (C), 122.53 (2CH), 85.85 (CH), 76.41(CH), 74.57 (CH), 70.93 (CH), 69.34 (CH), 63.07 (CH2),20.81 (2 CH3), 20.68 (CH3), 20.63 (CH3); IR (neat): n= 3477,3452, 3259, 2407, 2328, 2212, 2146, 2110, 2025, 2007, 1952,1755, 1626, 1583, 1488, 1367, 1248, 1217, 1039 cm�1; HR-MS(ESI): m/z = 622.0741,calcd. for C27H29BrNO9S: 622.0741.

Compound 3o: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[4-(1-{2-tosylhydrazono}ethyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.12 (cyclohexane/AcOEt,7:3); white-yellow solid; mp 204–206 8C; [a]24

D : +30.0 (c 1.0,CHCl3); 1H NMR (300 MHz, CDCl3): d=8.34 (s, 1 H), 7.88(d, J=8.3 Hz, 2 H), 7.55 (d, J= 8.5 Hz, 2 H), 7.41 (d, J=8.5 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 5.22 (t, J= 9.3 Hz,1 H), 5.07–4.89 (m, 2 H), 4.71 (d, J=10.1 Hz, 1 H), 4.21 (dd,J=12.3, 5.0 Hz, 1 H), 4.15 (dd, J= 12.3, 2.5 Hz, 1 H), 3.73(m, 1 H), 2.38 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 6 H), 2.00 (s,3 H), 1.96 (s, 3 H); 13C NMR (75 MHz, CDCl3): d= 170.53(C=O), 170.11 (C=O), 169.39 (C=O), 169.26 (C=O), 151.52(C=N), 144.17 (C), 137.17 (C), 135.46 (C), 133.40 (C), 132.30(2 CH), 129.62 (2 CH), 128.02 (2 CH), 126.65 (2 CH), 85.29(CH), 75.81 (CH), 73.84 (CH), 69.90 (CH), 68.17 (CH),62.12 (CH2), 21.58 (CH3), 20.71 (2CH3), 20.55 (2 CH3), 13.39(CH3); IR (neat): n=3468, 3381, 3332, 3131, 2169, 1755,1710, 1596, 1494, 1366, 1307, 1249, 1211, 1167, 1085 cm�1;HR-MS (ESI): m/z =651.1674, calcd. for C29H35N2O11S2:651.1677.

Compound 3p: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[4-(morpholine-4-carbonyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.45 (AcOEt); white-yellow solid;mp 101–103 8C; [a]24

D : �17.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.53 (d, J= 8.1 Hz, 2 H), 7.35 (d, J=8.1 Hz, 2 H), 5.23 (t, J= 9.3 Hz, 1 H), 5.11–4.91 (m, 2 H), 4.73(d, J=10.1 Hz, 1 H), 4.34–4.03 (m, 2 H), 3.92–3.29 (m, 9 H),2.08 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H);13C NMR (75 MHz, CDCl3): d=170.61 (C=O), 170.22 (C=O), 169.76 (C=O), 169.51 (C=O), 169.32 (C=O), 135.14 (C),134.46 (C), 132.66 (2 CH), 127.83 (2 CH), 85.49 (CH), 76.08(CH), 73.99 (CH), 69.96 (CH), 68.29 (CH), 66.99 (4CH2),62.24 (1 CH2), 20.85 (2 CH3), 20.69 (2 CH3); IR (neat): n=3266, 2361, 2154, 1981, 1755, 1740, 1710, 1631, 1596, 1430,1364, 1280, 1211, 1114 cm�1; HR-MS (ESI): m/z=576.11498,calcd. for C25H31NNaO11S: 576.1510.

Compound 3q: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[4-(3-hydroxybut-1-yn-1-yl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf = 0.64 (cyclohexane/AcOEt, 5:5);white-yellow solid; mp 139–141 8C; [a]24

D : + 45.0 (c 1.0,CHCl3); 1H NMR (300 MHz, CDCl3): d=7.42 (d, J= 8.5 Hz,2 H), 7.35 (d, J=8.4 Hz, 2 H), 5.22 (t, J= 9.3 Hz, 1 H), 5.10–4.88 (m, 2 H), 4.80–4.65 (m, 2 H), 4.30–4.02 (m, 2 H), 3.82–3.64 (m, 1 H), 2.09 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 1.99 (s,3 H), 1.55 (d, J= 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3):d= 170.65 (C=O), 170.27 (C=O), 169.49 (C=O), 169.35 (C=O), 132.56 (2CH), 132.46 (C), 132.14 (2 CH), 122.83 (C),92.56 (C), 85.53 (CH), 83.39 (C), 76.04 (CH), 74.02 (CH),70.02 (CH), 68.33 (CH), 62.28 (CH2), 58.99 (CH), 24.49(CH3), 20.86 (2 CH3), 20.70 (2CH3); IR (neat): n= 3492,2245, 2201, 2159, 2122, 1755, 1745, 1491, 1366, 1248, 1209,1088, 1032 cm�1; HR-MS (ESI): m/z =531.1291, calcd. forC24H28NaO10S: 531.1295.

Compound 3r: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(pyridin-4-ylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate:




Rf =0.10 (cyclohexane/AcOEt, 7:3); white-yellow solid; mp135–137 8C; [a]24

D : �16.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d=8.48 (brs, 2 H), 7.30 (d, J=4.9 Hz, 2 H), 5.29 (t,J=9.2 Hz, 1 H), 5.10 (td, J= 9.8, 2.9 Hz, 2 H), 4.95 (d, J=10.1 Hz, 1 H), 4.25 (dd, J=12.4, 5.5 Hz, 1 H), 4.18 (dd, J=12.4, 2.3 Hz, 1 H), 3.97–3.72 (m, 1 H), 2.08 (s, 3 H), 2.05 (s,3 H), 2.04 (s, 3 H), 2.00 (s, 3 H); 13C NMR (75 MHz, CDCl3):d= 170.52 (C=O), 170.15 (C=O), 169.45 (C=O), 169.34 (C=O), 149.34 (2 CH), 145.58 (C), 123.65 (2 CH), 83.70 (CH),76.21 (CH), 73.73 (CH), 69.74 (CH), 68.25 (CH), 62.29(CH2), 20.82 (CH3), 20.74 (CH3), 20.68 (2 CH3); IR (neat):n=3449, 2361, 2335, 2150, 1746, 1740, 1575, 1485, 1434,1409, 1366, 1209, 1089, 1063, 1033 cm�1; HR-MS (ESI):m/z= 442.1151, calcd. for C19H24NO9S: 442.1166.

Compound 3s: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(3-nitropyridin-2-yl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.25 (cyclohexane/AcOEt, 6:4); white-yellowsolid; mp 67–69 8C; [a]24

D: +113.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=8.69 (dd, J= 4.6, 1.6 Hz, 1 H), 8.49(dd, J= 8.3, 1.5 Hz, 1 H), 7.30 (dd, J= 8.3, 4.6 Hz, 1 H), 6.03(d, J=10.3 Hz, 1 H), 5.42–5.21 (m, 2 H), 5.13 (t, J= 9.5 Hz,1 H), 4.19 (dd, J=12.5, 4.6 Hz, 1 H), 4.03 (dd, J= 12.4,2.2 Hz, 1 H), 3.93–3.82 (m, 1 H), 2.00 (s, 3 H), 1.99 (s, 3 H),1.98 (s, 3 H), 1.97 (s, 3 H); 13C NMR (75 MHz, CDCl3): d=170.49 (C=O), 170.14 (C=O), 169.34 (C=O), 169.22 (C=O),154.21 (C), 153.05 (CH), 142.30 (C), 133.98 (CH), 120.17(CH), 79.83 (CH), 75.94 (CH), 74.34 (CH), 68.89 (CH),68.21 (CH), 61.88 (CH2), 20.64 (2 CH3), 20.57 (2 CH3); IR(neat): n=3457, 3410, 3316, 3099, 2264, 2204, 2182, 2040,2019, 1963, 1755, 1747, 1588, 1559, 1520, 1402, 1367, 1342,1249, 1214, 1061 cm�1; HR-MS (ESI): m/z=509.0829, calcd.for C19H22N2NaO11S: 509.0837.

Compound 3t: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(thiophen-2-ylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate:Rf =0.26 (cyclohexane/AcOEt, 7:3); white-yellow solid; mp85–87 8C; [a]24

D : +15.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d=7.44 (dd, J=5.4, 1.2 Hz, 1 H), 7.20 (dd, J= 3.6,1.2 Hz, 1 H), 7.01 (dd, J=5.4, 3.6 Hz, 1 H), 5.19 (t, J=9.4 Hz, 1 H), 4.99 (t, J=9.8 Hz, 1 H), 4.91 (t, J= 9.6 Hz, 1 H),4.50 (d, J=9.9 Hz, 1 H), 4.31–4.08 (m, 2 H), 3.81–3.56 (m,1 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H);13C NMR (75 MHz, CDCl3): d=170.71 (C=O), 170.30 (C=O), 169.48 (C=O), 169.32 (C=O), 136.76 (CH), 131.69 (CH),127.62 (CH), 127.25 (C), 85.62 (CH), 76.03 (CH), 74.11(CH), 69.76 (CH), 68.21 (CH), 62.13 (C), 20.89 (2CH3),20.70 (2CH3); IR (neat): n= 3433, 3365, 3000, 2359, 2042,2019, 1755, 1738, 1365, 1247, 1207, 1090, 1059 cm�1; HR-MS(ESI): m/z =469.0607, calcd. for C18H22NaO9S2: 469.0603.

Compound 3u: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(quinolin-3-ylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate:Rf =0.37 (cyclohexane/AcOEt, 5:5); white-yellow solid; mp69–71 8C; [a]24

D : �22.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d= 8.96 (s, 1 H), 8.42 (s, 1 H), 8.19 (d, J= 8.5 Hz,1 H), 7.85 (d, J= 8.2 Hz, 1 H), 7.79 (t, J=7.7 Hz, 1 H), 7.62(t, J=7.5 Hz, 1 H), 5.22 (t, J=9.3 Hz, 1 H), 4.96 (dd, J= 18.4,9.4 Hz, 2 H), 4.71 (d, J=10.0 Hz, 1 H), 4.20 (m, 2 H), 3.81–3.64 (m, 1 H), 2.13 (s, 3 H), 2.03 (s, 3 H), 2.00 (s, 3 H), 1.97 (s,3 H); 13C NMR (75 MHz, CDCl3): d= 170.73 (C=O), 170.21(C=O), 169.43 (C=O), 169.40 (C=O), 154.23 (CH), 147.41(C), 142.24 (CH), 130.72 (CH), 129.31 (CH), 128.02 (C),127.91 (CH), 127.55 (CH), 124.43 (C), 84.90 (CH), 76.17(CH), 73.90 (CH), 70.03 (CH), 68.16 (CH), 62.00 (CH2),

20.88 (CH3), 20.79 (CH3), 20.66 (2 CH3); IR (neat): n= 3427,3340, 3199, 2559, 2368, 2209, 2162, 2032, 1993, 1755, 1367,1213, 1038 cm�1; HR-MS (ESI): m/z =492.1321, calcd. forC23H26NO9S: 492.1323.

Compound 3v: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(1-benzyl-4-oxo-1,4-dihydroquinolin-3-yl)thio]tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.17 (cyclohexane/AcOEt,5:5); white-yellow solid; mp 90–92 8C; [a]24

D : �30.0 (c 1.0,CHCl3); 1H NMR (300 MHz, CDCl3): d= 8.43 (dd, J= 8.0,1.3 Hz, 1 H), 8.14 (s, 1 H), 7.57–7.46 (m, 1 H), 7.39–7.27 (m,5 H), 7.14 (m, 2 H), 5.35 (s, 2 H), 5.29–5.13 (m, 1 H), 5.07–4.92 (m, 3 H), 4.12 (dd, J= 12.3, 4.7 Hz, 1 H), 4.00 (dd, J=12.3, 2.2 Hz, 1 H), 3.60 (ddd, J=10.0, 4.6, 2.3 Hz, 1 H), 2.11(s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H), 1.80 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=176.03 (C=O), 170.52 (C=O), 170.06(C=O), 169.94 (C=O), 169.50 (C=O), 149.57 (CH), 139.77(C), 134.91 (C), 132.46 (CH), 129.37 (2 CH), 128.57 (CH),127.54 (CH), 126.70 (C), 126.14 (2CH), 124.65 (CH), 116.35(CH), 109.46 (C), 82.57 (CH), 75.79 (CH), 74.14 (CH), 70.23(CH), 68.46 (CH), 61.86 (CH2), 56.70 (CH2), 20.94 (CH3),20.65 (2 CH3), 20.55 (CH3); IR (neat): n= 3469, 3354, 3128,2334, 2196, 1967, 1753, 1622, 1601, 1546, 1487, 1225 cm�1;HR-MS (ESI): m/z=620.1562, calcd. for C30H31NNaO10S:620.1566.

Compound 3w: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-phenyl-2H-chromen-3-yl)thio]tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.35 (cyclohexane/AcOEt, 7:3); white-yellow solid; mp 170–172 8C; [a]24

D : + 37.0 (c 1.0, CHCl3);1H NMR (300 MHz, CDCl3): d= 7.46–7.31 (m, 3 H), 7.21–7.05 (m, 3 H), 6.87 (d, J=8.1 Hz, 1 H), 6.79 (td, J= 7.5,1.0 Hz, 1 H), 6.65 (dd, J=7.7, 1.5 Hz, 1 H), 5.16 (t, J=9.3 Hz, 1 H), 5.04 (d, J=9.8 Hz, 1 H), 5.00 (s, 2 H), 4.88 (t,J=9.6 Hz, 1 H), 4.55 (d, J=10.2 Hz, 1 H), 4.26–4.11 (m,2 H), 3.71 (ddd, J= 9.9, 5.4, 2.7 Hz, 1 H), 2.11 (s, 3 H), 2.02(s, 3 H), 1.96 (s, 3 H), 1.68 (s, 3 H); 13C NMR (75 MHz,CDCl3): d=170.75 (C=O), 170.23 (C=O), 169.47 (C=O),169.25 (C=O), 153.99 (C), 141.28 (C), 136.13 (2 CH), 129.93(CH), 128.25 (2 CH), 128.00 (CH), 126.96 (CH), 124.68 (C),121.66 (CH), 121.66 (C), 116.05 (2CH), 85.79 (CH), 76.07(CH), 73.78 (CH), 70.14 (CH), 69.41 (CH2), 68.30 (CH),62.32 (CH2), 20.81 (CH3), 20.68 (2 CH3), 20.47 (CH3); IR(neat): n=3470, 3157, 2157, 2024, 1973, 1755, 1682, 1592,1483, 1453, 1365, 1090 cm�1; HR-MS (ESI): m/z= 593.1458,calcd. for C29H30NaO10S: 593.1452.

General Procedure for Palladium-Catalyzed Couplingof Thioglycosides 1b–g with Aryl Iodides 2

A flame-dried resealable Schlenk tube was charged withPd ACHTUNGTRENNUNG(OAc)2 (5 mol%), Xantphos (2.5 mol%), thiosugar 1b–g(0.375 mmol), (hetero)aryl halide 2 (0.25 mmol), and Et3N(0.25 mmol). The Schlenk tube was capped with a rubberseptum, evacuated and backfilled with argon; then, dioxane(1.5 mL) was added through the septum. The septum was re-placed with a teflon screwcap. The Schlenk tube was sealed,and the mixture was stirred at 100 8C for 1 h. The resultingsuspension was cooled to room temperature and filteredthrough celite eluting with ethyl acetate. The filtrate wasconcentrated and purification of the residue by silica gelcolumn chromatography gave the desired product 4.




Analytical Data for Arylthioglycosides 4

Compound 4a: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-[(4-methoxyphenyl)thio]tetrahydro-2H-pyran-3,4,5-triyl triace-tate: Rf =0.28 (cyclohexane/AcOEt, 7:3); colorless oil ; [a]24

D :�13.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d= 7.47(d, J=8.4 Hz, 2 H), 6.85 (d, J= 8.4 Hz, 2 H), 5.38 (d, J=3.2 Hz, 1 H), 5.17 (t, J=9.9 Hz, 1 H), 5.02 (dd, J= 9.9,3.3 Hz, 1 H), 4.56 (d, J= 9.8 Hz, 1 H), 4.17 (dd, J= 11.2,6.9 Hz, 1 H), 4.09 (dd, J= 11.2, 6.4 Hz, 1 H), 3.88 (t, J=6.6 Hz, 1 H), 3.80 (s, 3 H), 2.11 (s, 3 H), 2.09 (s, 3 H), 2.03 (s,3 H), 1.96 (s, 3 H); 13C NMR (75 MHz, CDCl3): d= 170.49(C=O), 170.30 (C=O), 170.19 (C=O), 169.54 (C=O), 160.41(C), 136.06 (2 CH), 122.19 (C), 114.50 (2 CH), 87.12 (CH),74.47 (CH), 72.23 (CH), 67.49 (CH), 67.38 (CH), 61.67(CH2), 55.48 (CH3), 21.02 (CH3), 20.81 (CH3), 20.74 (2 CH3);IR (neat): n=3488, 3404, 3221, 2574, 2252, 2014, 1749, 1370,1244, 1220 cm�1; HR-MS (ESI): m/z =493.1135, calcd. forC21H26NaO10S: 493.1139.

Compound 4b: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-{[4-(trifluoromethyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyltriacetate: Rf =0.45 (cyclohexane/AcOEt, 6:4); white-yellowsolid; mp 70–72 8C; [a]24

D : �14.0 (c 1.0, CHCl3); 1H NMR(300 MHz, CDCl3): d=7.58 (d, J= 8.4 Hz, 2 H), 7.52 (d, J=8.5 Hz, 2 H), 5.48–5.33 (m, 1 H), 5.21 (t, J= 9.9 Hz, 1 H), 5.04(dd, J=9.9, 3.3 Hz, 1 H), 4.76 (d, J= 9.9 Hz, 1 H), 4.12 (m,2 H), 3.97 (dd, J=9.5, 3.4 Hz, 1 H), 2.08 (s, 3 H), 2.05 (s,3 H), 2.01 (s, 3 H), 1.94 (s, 3 H); 13C NMR (75 MHz, CDCl3):d= 170.30 (C=O), 170.08 (C=O), 169.97 (C=O), 169.39 (C=O), 137.55 (C), 131.80 (2 CH), 129.90 (q, J= 33.0 Hz, C),125.66 (CH), 125.66 (CH), 123.88 (q, J=258.75 Hz, C),85.44 (CH), 74.69 (CH), 71.89 (CH), 67.22 (CH), 67.07(CH), 61.71 (CH2), 20.76 (CH3), 20.63 (CH3), 20.55 (2 CH3);19F NMR (188 MHz, CDCl3): d=�60.94; IR (neat): n =3465, 3361, 2574, 2347, 2252, 2197, 2014, 1986, 1749, 1370,1244, 1220 cm�1; HR-MS (ESI): m/z =531.0919, calcd. forC21H23F3NaO9S: 531.0907.

Compound 4c: (2R,3R,4R,5S)-2-(acetoxymethyl)-5-[(4-methoxyphenyl)thio]tetrahydrofuran-3,4-diyl diacetate: Rf =0.58 (cyclohexane/AcOEt, 5:5); colorless oil; [a]24

D : �18.0 (c1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d= 7.40 (d, J=8.9 Hz, 2 H), 6.84 (d, J= 8.9 Hz, 2 H), 5.49 (m, 1 H), 5.05–4.93 (m, 2 H), 4.88 (dd, J=7.2, 2.9 Hz, 1 H), 4.12 (dd, J=11.6, 4.2 Hz, 1 H), 3.79 (s, 3 H), 3.77–3.68 (m, 1 H), 2.10 (s,3 H), 2.08 (s, 3 H), 2.03 (s, 3 H); 13C NMR (75 MHz, CDCl3):d= 169.88 (C=O), 169.76 (C=O), 169.37 (C=O), 160.38 (C),135.97 (2 CH), 121.47 (C), 114.74 (2 CH), 84.19 (CH), 68.29(CH), 67.54 (CH), 66.57 (CH), 63.56 (CH2), 55.44 (CH3),20.88 (CH3), 20.83 (2CH3); IR (neat): n= 3288, 3221, 2448,2365, 2214, 2167, 2086, 2032, 2012, 1748, 1593, 1495, 1372,1248, 1067 cm�1; HR-MS (ESI): m/z =421.0916, calcd. forC18H22NaO8S: 421.0928.

Compound 4d: 1-(4-{[(2S,3R,4S,5R,6R)-3,4,5-tris(benzy-loxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]thio}-phenyl)ethanone: Rf =0.27 (cyclohexane/AcOEt, 7:3);white-yellow solid; mp 118–120 8C; [a]24

D : �13.0 (c 1.0,CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68 (d, J= 8.2 Hz,2 H), 7.51 (d, J=8.3 Hz, 2 H), 7.31–6.98 (m, 20 H), 4.91–4.60(m, 6 H), 4.58–4.34 (m, 3 H), 3.81–3.34 (m, 6 H), 2.45 (s,3 H); 13C NMR (75 MHz, CDCl3): d= 197.37 (C=O), 141.43(C), 138.41 (C), 138.29 (C), 138.05 (C), 137.89 (C), 135.41(C), 129.86 (CH), 128.88 (CH), 128.59 (12 CH), 128.51(2 CH), 128.29 (CH), 128.07 (CH), 128.01 (2 CH), 127.89

(2 CH), 127.82 (2CH), 86.80 (CH), 86.39 (CH), 80.90 (CH),79.31 (CH), 77.88 (CH), 75.99 (CH2), 75.67 (CH2), 75.24(CH2), 73.60 (CH2), 69.16 (CH2), 26.65 (CH3); IR (neat): n =3324, 3255, 3226, 3206, 2168, 1756, 1680, 1589, 1496, 1453,1398, 1358, 1263, 1213, 1096 cm�1; HR-MS (ESI): m/z =697.2588, calcd. for C42H42NaO6S: 697.2594.

Compound 4e: 1-(4-{[(2R,3R,4S,5R,6R)-3,4,5-tris(benzy-loxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]thio}-phenyl)ethanone: Rf = 0.20 (cyclohexane/AcOEt, 9:1);white-yellow solid; mp 59–61 8C; [a]24

D : + 59.0 (c 1.0, CHCl3);1H NMR (300 MHz, CDCl3): d=7.73 (d, J= 8.4 Hz, 2 H),7.44 (d, J= 8.4 Hz, 2 H), 7.35–6.97 (m, 21 H), 5.70 (d, J=4.6 Hz, 1 H), 4.92 (d, J= 10.8 Hz, 1 H), 4.75 (t, J= 10.3 Hz,2 H), 4.69–4.57 (m, 2 H), 4.49 (d, J= 11.9 Hz, 1 H), 4.42 (d,J=10.8 Hz, 1 H), 4.33 (d, J= 11.9 Hz, 1 H), 4.23–4.08 (m,1 H), 3.92–3.75 (m, 2 H), 3.72–3.57 (m, 2 H), 3.50 (dd, J=10.7, 1.5 Hz, 1 H), 2.47 (s, 3 H); 13C NMR (75 MHz, CDCl3):d= 197.41 (C=O), 141.98 (C), 138.68 (C), 138.24 (C), 137.90(C), 137.61 (C), 135.10 (C), 129.51 (CH), 128.80 (CH),128.61 (CH), 128.53 (11 CH), 128.26 (CH), 128.16 (CH),128.12 (CH), 128.00 (4 CH), 127.87 (CH), 127.82 (CH),85.72 (CH), 82.67 (CH), 79.68 (CH), 77.41 (CH), 75.95(CH2), 75.28 (CH2), 73.55 (CH2), 72.92 (CH2), 71.62 (CH),68.63 (CH2), 26.63 (CH3); IR (neat): n= 3345, 3157, 2369,2356, 2230, 2125, 2013, 1982, 1915, 1681, 1588, 1453, 1359,1262, 1097 cm�1; HR-MS (ESI): m/z =697.2582, calcd, forC42H42NaO6S: 697.2594.

Compound 4f: (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-[(4-methoxyphenyl)thio]tetrahydro-2H-pyran-3,4,5-triol : Rf =0.38 (DCM/MeOH, 85:15); white oil; 1H NMR (300 MHz,acetone): d= 7.52 (d, J=8.8 Hz, 2 H), 6.88 (d, J= 8.8 Hz,2 H), 4.46 (d, J=9.6 Hz, 1 H), 4.41 (brs, 2 H), 3.83 (d, J=10.2 Hz, 1 H), 3.78 (s, 3 H), 3.66 (d, J=12.3 Hz, 1 H), 3.50–3.40 (m, 1 H), 3.32 (d, J= 5.4 Hz, 2 H), 3.16 (t, J= 9.1 Hz,1 H), 3.03 (s, 2 H); 13C NMR (75 MHz, acetone): d= 160.61(C), 135.89 (2 CH), 124.15 (C), 115.05 (2 CH), 89.02 (CH),81.38 (CH), 79.38 (CH), 73.19 (CH), 71.26 (CH), 62.90(CH2), 55.59 (CH3); IR (neat): n=3331, 3240, 3155, 2533,2202, 2119, 2020, 2002, 1756, 1592, 1494, 1460, 1287, 1218,1177, 1106 cm�1; HR-MS (ESI): m/z =325.0708, calcd. forC13H18NaO6S: 325.0716.

Compound 4g: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-[(4-methoxyphenyl)thio]tetrahydro-2H-pyran-3-yl]oxy}tetrahy-dro-2H-pyran-3,4,5-triyl triacetate: Rf =0.36 (cyclohexane/AcOEt, 5:5); white-yellow solid; mp 190–192 8C; [a]24

D :�20.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d= 7.38(d, J= 8.5 Hz, 2 H), 6.79 (d, J= 8.6 Hz, 2 H), 5.18–4.96 (m,3 H), 4.82 (dt, J= 19.3, 8.9 Hz, 2 H), 4.57–4.41 (m, 3 H), 4.32(dd, J= 12.5, 4.1 Hz, 1 H), 4.08–3.92 (m, 2 H), 3.76 (s, 3 H),3.69–3.48 (m, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 2.02 (s, 3 H),1.97 (s, 3 H), 1.96 (s, 6 H), 1.93 (s, 3 H); 13C NMR (75 MHz,CDCl3): d=170.46 (C=O), 170.21 (2 C=O), 169.76 (C=O),169.53 (C=O), 169.29 (C=O), 168.99 (C=O), 160.41 (C),136.59 (2 CH), 121.05 (C), 114.37 (2 CH), 100.75 (CH), 85.51(CH), 76.78 (CH), 76.28 (CH), 73.72 (CH), 72.97 (CH),71.99 (CH), 71.65 (CH), 70.16 (CH), 67.84 (CH), 61.87(CH2), 61.58 (CH2), 55.36 (CH3), 20.89 (CH3), 20.84 (CH3),20.65 (CH3), 20.56 (4CH3); IR (neat): n= 3354, 3248, 3206,3111, 3081, 2313, 2168, 2089, 1986, 1970, 1757, 1496, 1368,1215, 1041 cm�1; HR-MS (ESI): m/z =781.1970, calcd. forC33H42NaO18S: 781.1984.




General Procedure for Palladium-Catalyzed Couplingof Thioglycosides with Biologically Active Molecules5, 6, 9 and 11

A flame-dried resealable Schlenk tube was charged withPd ACHTUNGTRENNUNG(OAc)2 (5 mol%), Xantphos (2.5 mol%), thiosugar1 (0.375 mmol), 5, 6, 9 or 11 (0.25 mmol), and Et3N(0.25 mmol). The Schlenk tube was capped with a rubberseptum, evacuated and backfilled with argon; then, dioxane(1.5 mL) was added through the septum. The septum was re-placed with a teflon screwcap. The Schlenk tube was sealed,and the mixture was stirred at 100 8C for 1 h. The resultingsuspension was cooled to room temperature and filteredthrough celite eluting with ethyl acetate. The filtrate wasconcentrated and purification of the residue by silica gelcolumn chromatography gave the desired product 7, 8, 10and 12.

Compound 7: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-({2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)vinyl]phenyl}thio)te-trahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.43 (cyclohex-ane/AcOEt, 7:3); white-yellow solid; mp 84–86 8C; [a]24

D :+22.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d= 7.57(d, J= 2.2 Hz, 1 H), 7.23 (dd, J=8.5, 2.2 Hz, 1 H), 6.84 (d,J=8.5 Hz, 1 H), 6.53 (s, 2 H), 5.44–5.22 (m, 4 H), 5.07 (dd,J=9.9, 3.4 Hz, 1 H), 4.83 (d, J=10.0 Hz, 1 H), 4.06 (dd, J=6.7, 3.4 Hz, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.81 (s, 6 H), 2.11(s, 3 H), 2.06 (s, 3 H), 1.98 (s, 3 H), 1.97 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=170.42 (C=O), 170.33 (C=O), 170.13(C=O), 169.52 (C=O), 158.08 (C), 153.04 (2C), 149.15 (C),137.17 (C), 134.37 (C), 132.86 (CH), 129.42 (CH), 120.70(C), 113.08 (C), 110.63 (CH), 105.82 (2CH), 85.36 (CH),74.49 (CH), 72.14 (CH), 67.52 (CH), 67.29 (CH), 61.42(CH2), 60.98 (CH), 56.30 (2CH3), 56.03 (CH3), 20.87(2 CH3), 20.70 (2 CH3); IR (neat): n=3431, 3379, 3159, 3095,2482, 224, 2128, 1922, 1753, 1368, 1223, 1126 cm�1; HR-MS(ESI): m/z =663.2098, calcd. for C32H39O13S: 663.2166.

Compound 8: (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-{[2-methoxy-5-(3,4,5-trimethoxybenzoyl)phenyl]thio}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf =0.32 (cyclohexane/AcOEt, 9:1); white-yellow solid; mp 108–110 8C; [a]24

D :+61.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d= 8.01(d, J= 2.1 Hz, 1 H), 7.71 (dd, J=8.5, 2.1 Hz, 1 H), 6.98 (s,2 H), 6.91 (d, J=8.6 Hz, 1 H), 5.45–5.36 (m, 1 H), 5.27 (t, J=10.0 Hz, 1 H), 5.06 (dd, J=9.9, 3.4 Hz, 1 H), 4.88 (d, J=10.0 Hz, 1 H), 3.99–4.02 (m, 2 H), 3.93 (s, 3 H), 3.90 (s, 3 H),3.85 (s, 6 H), 2.10 (s, 3 H), 2.05 (s, 3 H), 1.95 (s, 3 H), 1.93 (s,3 H); 13C NMR (75 MHz, CDCl3): d= 193.91 (C=O), 170.43(C=O), 170.29 (C=O), 170.06 (C=O), 169.57 (C=O), 161.13(C), 152.91 (C), 141.89 (C), 134.03 (CH), 132.88 (C), 131.86(CH), 130.74 (C), 122.10 (C), 109.88 (CH), 107.52 (2CH),84.69 (CH), 74.49 (CH), 71.96 (CH), 67.18 (CH), 61.40(CH2), 61.02 (CH), 56.39 (3CH3), 56.23 (CH3), 20.87 (CH3),20.69 (CH3), 20.63 (2CH3); IR (neat): n= 3439, 3323, 3270,3204, 3131, 2358, 2159, 2027, 1942, 1751, 1647, 1582, 1502,1413, 1368, 1225 cm�1; HR-MS (ESI): m/z=687.1708, calcd.for C31H36NaO14S: 687.1718.

Compound 10: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[3-(4-methoxybenzamido)-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl]thio}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf = 0.4(cyclohexane/AcOEt, 5:5); white-yellow solid; mp 107–109 8C; [a]24

D : �35.0 (c 1.0, in CHCl3); 1H NMR (300 MHz,CDCl3): d= 9.27 (s, 1 H), 8.80 (s, 1 H), 7.88 (d, J= 8.7 Hz,

2 H), 7.76 (d, J= 1.6 Hz, 1 H), 7.56 (dd, J=8.7, 1.7 Hz, 1 H),7.28 (d, J= 10.3 Hz, 1 H), 6.96 (d, J=8.7 Hz, 2 H), 5.21 (dd,J=15.2, 5.7 Hz, 1 H), 4.93 (dt, J= 29.5, 9.7 Hz, 2 H), 4.73–4.57 (m, 1 H), 4.29–4.07 (m, 2 H), 3.85 (s, 3 H), 3.80 (s, 3 H),3.82–3.73 (m, 1 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 1.98 (s, 3 H),1.94 (s, 3 H); 13C NMR (75 MHz, CDCl3): d=170.71 (C=O),170.17 (C=O), 169.42 (C=O), 165.29 (C=O), 162.87 (C=O),158.13 (C=O), 135.77 (C), 134.22 (CH), 134.09 (CH), 129.20(2 CH), 128.60 (C), 126.28 (C), 124.82 (C), 121.71 (C),119.31 (CH), 114.52 (CH), 114.08 (2 CH), 85.34 (CH), 76.17(CH), 75.96 (CH), 73.98 (CH), 69.78 (CH), 68.03 (CH),62.04 (CH2), 55.56 (CH3), 30.56 (CH3), 20.86 (2 CH3), 20.64(2 CH3); IR (neat): n=3416, 3215, 3014, 2219, 2181, 2044,1965, 1755, 1674, 1640, 1527, 1485, 1363, 1248, 1212,1176 cm�1; HR-MS (ESI): m/z =693.1724, calcd. forC32H34N2NaO12S: 693.1725.

Compound 12: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-{[(2R,3R,4S,5R,6S)-4,5-diacetoxy-2-(acetoxymethyl)-6-[(4-methyl-2-oxo-2H-chromen-7-yl)thio]tetrahydro-2H-pyran-3-yl]oxy}tetrahydro-2H-pyran-3,4,5-triyl triacetate: Rf = 0.45(cyclohexane/AcOEt, 4:6); white-yellow solid; mp 210–212 8C; [a]24

D : �5.0 (c 1.0, CHCl3); 1H NMR (300 MHz,CDCl3): d= 7.46 (m, 2 H), 7.23 (dd, J=8.3, 1.7 Hz, 1 H), 6.24(d, J= 1.0 Hz, 1 H), 5.35–4.85 (m, 5 H), 4.79 (d, J= 10.1 Hz,1 H), 4.56 (d, J=11.5 Hz, 1 H), 4.50 (d, J= 7.9 Hz, 1 H), 4.35(dd, J=12.5, 4.2 Hz, 1 H), 4.11 (dd, J=11.9, 5.3 Hz, 1 H),4.01 (dd, J= 12.4, 2.0 Hz, 1 H), 3.81–3.69 (m, 2 H), 3.65 (ddd,J=9.7, 4.0, 2.1 Hz, 1 H), 2.39 (s, 3 H), 2.18 (s, 3 H), 2.04 (s,6 H), 2.02 (s, 3 H), 1.98 (s, 6 H), 1.95 (s, 3 H); 13C NMR(75 MHz, CDCl3): d=170.58 (C=O), 170.51 (C=O), 170.24(C=O), 169.72 (C=O), 169.53 (C=O), 169.38 (C=O), 169.15(C=O), 160.25 (C=O), 153.63 (C), 151.92 (C), 138.04 (C),126.45 (CH), 124.70 (CH), 119.20 (C), 118.36 (CH), 115.20(CH), 100.90 (CH), 84.67 (CH), 77.16 (CH), 76.29 (CH),73.51 (CH), 73.00 (CH), 72.10 (CH), 71.67 (CH), 69.83(CH), 67.85 (CH), 62.12 (CH2), 61.63 (CH2), 20.94 (CH3),20.76 (CH3), 20.72 (CH3), 20.61 (4 CH3), 18.65 (CH3); IR(neat): n=3339, 2197, 2110, 2045, 2021, 1740, 1709, 1603,1384, 1364, 1210, 1167, 1032, 955 cm�1; HR-MS (ESI): m/z =811.2102, calcd. for C36H43O19S: 811.2114.

Procedure for Deprotection of Compound 12

A solution of compound 12 (0.150 g, 0.185 mmol) underargon was dissolved in methanol (12 mL) and a solution[1M] of sodium methoxide (1 mL) was added at 0 8C. Theresultant mixture was stirred continuously for 8 h at roomtemperature. The solution was treated with Amberlyst15(H+) resin until pH 5 and filtered through celite elutingwith methanol. Then, the filtrate was concentrated anddried under vacuum to give the desired MUS-CB product;yield: 0.72 g (75%).

Compound MUS-CB: 7-{[(2S,3R,4R,5S,6R)-3,4-dihy-droxy-6-(hydroxymethyl)-5-{[(2S,3R,4S,5S,6R)-3,4,5-trihy-droxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}te-trahydro-2H-pyran-2-yl]thio}-4-methyl-2H-chromen-2-one:Rf =0 (AcOEt); white-yellow oil; 1H NMR (300 MHz,DMSO/D2O, 9:1): d=7.66 (d, J=8.3 Hz, 1 H), 7.43–7.31 (m,2 H), 6.29 (d, J=1.0 Hz, 1 H), 4.88 (d, J= 9.8 Hz, 1 H), 4.28(d, J=7.8 Hz, 1 H), 3.78–3.34 (m, 14 H), 3.19 (m, 3 H), 3.11–2.91 (m, 2 H), 2.37 (s, 3 H). 13C NMR (75 MHz, DMSO):d= 159.69 (C=O), 153.10 (2C), 140.62 (C), 125.47 (CH),




124.31 (CH), 117.50 (C), 115.39 (CH), 113.56 (CH), 103.07(CH), 85.28 (CH), 79.75 (CH), 78.89 (CH), 76.84 (CH),76.50 (CH), 76.28 (CH), 73.34 (CH), 72.19 (CH), 70.07(CH), 61.07 (CH2), 60.24 (CH2), 18.03 (CH3). IR (neat): n=3400, 3369, 3303, 3286, 3161, 2953, 1569, 2460, 2078, 1973,1718, 1601, 677 cm�1; HR-MS (ESI): m/z =539.1170, calcd.for C22H28NaO12S: 539.1199.

Acknowledgements

The CNRS is gratefully acknowledged for financial supportof this research and Minist�re (MENRT) for a doctoral fel-lowship to EB. Our laboratory BioCIS-UMR 8076 isa member of the Laboratory of Excellence LERMIT sup-ported by a grant from ANR (ANR-10-LABX-33).

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