Tetrahedron Letters 53 (2012) 702–704

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Tetrahedron Letters

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Free-radical hydrothiolation of glycals: a thiol-ene-based synthesisof S-disaccharides

Samuele Staderini a, Angela Chambery b, Alberto Marra a,⇑, Alessandro Dondoni b,⇑a Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italyb Dipartimento di Scienze della Vita, II Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy

a r t i c l e i n f o a b s t r a c t

Article history:Received 8 November 2011Revised 28 November 2011Accepted 30 November 2011Available online 7 December 2011

Keywords:AllalGalactalGlucalGulalSugar thiols

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.11.140

⇑ Corresponding authors. Tel.: +39 0532 455176; faE-mail address: adn@unife.it (A. Dondoni).

A method for the synthesis of a new family of 1-deoxy S-disaccharides has been established via free-radical hydrothiolation of glycals by sugar thiols (thiol-ene coupling). The photoinduced couplingbetween four tri-O-acetyl-D-glycals and three different sugar thiols reveals that the reaction efficiencyand stereoselectivity are highly dependent on the stereochemistry of the OAc groups at C3 and C4 ofthe glycal.

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Glycans and their conjugates deeply influence many fundamen-tal biological processes in living organisms.1 They mediate a vari-ety of events, including inflammation, immunological response,fertilization, cancer metastasis, and viral and bacterial infection.2

Hence, there is an urgent need to provide usable quantities ofnatural carbohydrates with a well defined structure and composi-tion to be used in studies of those phenomena at molecular levels.There is, however, substantial difficulty to obtain complex naturalO-linked oligosaccharides in a pure and homogeneous form fromnatural sources because of the presence of mixtures of glycosylatedspecies (glycoforms). Moreover, these compounds display anintrinsic instability toward chemical and enzymatic degradationdue to the readily hydrolizable exocylic carbon–oxygen bond.Therefore, synthetic efforts have been directed toward the supplyof carbon- and sulfur-linked isosteres, that is, compounds bearinga methylene group or a sulfur atom in place of the oxygen atomof the glycosidic bond that is present in natural products. Thus,simple C-disaccharides3 and S-disaccharides4 have been preparedbecause these products can be used as probes of recognition spec-ificity and may provide important insight into the mechanism ofglycoside elaboration by carbohydrate processing enzymes. Inturn, these glycomimetics may become effective inhibitors of thoseenzymes and therefore evolve into lead compounds of pharmaceu-tical relevance. It has to be noted, however, that for biological stud-ies, S-oligosaccharides may be more suitable than C-analogues

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because the sulfur derivatives, despite some differences in C–Sand C–O bond lengths, as well as in C–S–C and C–O–C bond an-gles,5 represent the smallest step away from natural O-glycosidesin the backbone space.6 While several chemical syntheses ofS-disaccharides have been established over the second half of lastcentury,4 the free-radical thiol-ene coupling (TEC) between alkenylsugars and sugar thiols was reported7 for the first time by ourgroup in 2009. Under optimized conditions (irradiation time,reagent ratio, and solvent) TEC afforded S-linked disaccharides inelevated yields. Given our ongoing research in the use of TEC inglycochemistry8 as a very efficient metal-free click process,9 wewould like to report here on a new TEC-based approach toS-disaccharides by using glycals as ene partners. Protected glycalsare well known precursors to functionalized carbohydrates due tothe occurrence of a variety of addition reactions to the endocycliccarbon–carbon double bond.10 Epoxidation is probably the mostimportant of these addition reactions11 because the so-called gly-cal epoxides that are formed are precursors to O- and C-glycosidesand glycoconjugates. Other reactions, however, such as azidationreactions12 bear substantial importance because of the easytransformation of the 2-azido substituted products into 2-aminoderivatives. Quite surprisingly, to the best of our knowledge thereis only a single example that has been reported in 1970 on thefree-radical hydrothiolation of a glycal.13 This consists of the ther-mal addition of thiolacetic acid to D-glucal triacetate in thepresence of the free-radical initiator cumene hydroperoxide. Thereaction afforded a mixture of two diastereomers in 70:30 ratiowith the major product featuring the axial SAc group and the

SR

OAcOSR

OAcO

(AcO)2 (AcO)2

AGRax AGReq

Figure 1. Anomeric glycosyl radical (AGR) intermediates formed by addition of athiyl radical to glycals.

S. Staderini et al. / Tetrahedron Letters 53 (2012) 702–704 703

minor one having the same group equatorial. The product distribu-tion was interpreted on the basis of the different stability of glyco-syl radical intermediates. We were, thus, spurred to investigate inmore detail the substrate scope and stereochemical outcome of thephotoinduced addition of sugar thiols to isomeric glycals en routeto 1-deoxy S-disaccharides and the relevant results are reportedbelow.

We first investigated the model reaction between 3,4,6-tri-O-acetyl-D-glucal 1a and peracetylated 1-thio-b-D-glucopyranose 2a(Table 1) under previously established standard conditions forS-disaccharide synthesis via TEC,7 that is, irradiation at wavelengthclose to visible light (kmax 365 nm) in the presence of catalytic2,2-dimethoxy-2-phenylacetophenone (DPAP) as radical initiator.The reaction was carried out at room temperature in a glass vialwithout any caution to exclude air and moisture. After someexperimentation optimized reaction conditions were established.These entailed using 6 equiv of 2a, 1 h irradiation and 20:1EtOH–CH2Cl2 as the solvent. Under these conditions the glucal 1awas totally consumed (100% conversion) to give a mixture ofproducts 3a and 4a in 80% isolated overall yield and 57:43 ratio.The use of a lower excess of 2a (4 equiv) or a shorter irradiationtime (30 min) resulted in a partial conversion of glucal 1a (73%and 33%, respectively) with consequent significant lower overallyield of 3a and 4a (53% and 33%, respectively). These productswere formed in about 1:1 ratio also under these conditions. Hence,the reaction was essentially lacking in stereoselectivity while itappeared to be totally regioselective with the thiyl radicalgenerated from thiol 2a attacking exclusively the C2 carbon ofthe glucal 1a. In agreement with that suggested for the additionof thiolacetic acid to 1a,13 these results are consistent with theinitial formation of two anomeric glycosyl radical (AGR)

Table 1Hydrothiolation of glycals 1a

OOAc

(AcO)2 SHO

AcOAcO

OAc

AcO(APh

MeO OMe

O

Ph

hν (365 nm)

DPAP

+

1 a2

a Glycal Conversion (%) Product(s)

O

OAc

AcOAcO

1a

100

SO

AcO

3a

OAc

O OAcAcO

OAcAcOAcO

O

OAc

AcO

AcO

1b

100S

O

AcO

3b

OAc

O OAcAcO

OAcAcO

AcO

O

OAc

AcO

AcO

1c

40

SO

AcO

3c

OAc

O OAcAcO

OAcAcO

AcO

O

OAcAcO

AcO

1d

35

SO

AcO

3d

OAc

O OAcAcO

OAcAcO

AcO

a Reaction conditions: 6 equiv of 2a, 0.6 equiv of DPAP, 20:1 EtOH–CH2Cl2, 1 h.b Overall yield of products isolated by column chromatography on silica gel.c Ratio determined by 1H NMR.

intermediates stabilized by the adjacent oxygen atom, namelyAGRax in which the RS group is axial and AGReq in which the samegroup is equatorial (Fig. 1). In the present case these intermediatesmust have comparable energies with the consequence that theproducts 16 and 17 are formed in essentially equal amounts.

It was soon realized that the relative amounts of AGRax andAGReq depended considerably on the stereochemistry of the OAcgroups at C3 and C4 in the starting glycal. Accordingly, the additionof the sugar thiol 2a to the D-galactal triacetate 1b under the abovestandard conditions afforded a mixture of diastereomeric sulfides3b and 4b in good yield and with a net excess of the latter display-ing the equatorially linked RS group (Table 1). This is consistentwith the preferential formation of AGReq over AGRax due to theshielding exerted by the axial OAc group at C4 in 1b. This stereo-chemical outcome was completely reversed in the hydrothiolationof D-allal triacetate 1c by 2a as this reaction afforded exclusivelythe axially substituted sulfide 3c although in only fair yield (Table1). Thus, it appears that in this case the axial OAc group at C3 of 1cinduces the exclusive formation of the AGRax radical intermediatevia an addition of the thiyl radical to the double bond anti to thealkoxy group at C-3 of the glycal to give a 2,3-trans-diaxial substi-tuted product.

S

OAcO

SO

AcO

cO)2

(AcO)2+

3 4

OAc

O OAcAcO

OAc

OAc

O OAcAcO

OAc

Yieldb (%) 3:4 ratioc

S

OAcO

4aOAc

O OAcAcO

OAcAcOAcO

80 57:43

S

OOAc

4bOAc

O OAcAcO

OAc

AcO

AcO 59 37:63

— 38 100:0

— 20 100:0

Table 2Hydrothiolation of glucal 1a and galactal 1b by different sugar thiolsa

Glycal Thiol Products Conversion (%) Yieldb (%) 5:6 ratioc

O

OAc

AcOAcO

1a

SHO

AcOAcO

OAcAcO

2bS

OAcO

SO

AcO

5a 6a

AcO

O

OAcAcO

OAc

AcO

O

OAcAcO

OAcAcO

AcO

AcOAcO 100 100 54:46

O

OAc

AcOAcO

1a

SHO

AcOAcHN

OAc

AcO

2cS

OAcO

SO

AcO

5b 6b

OAc

O OAcAcHN

OAc

OAc

O OAcAcHN

OAcAcO

AcO

AcOAcO

100 82 74:26

O

OAcAcO

AcO

1b

SHO

AcOAcO

OAcAcO

2bS

OOAc

SO

AcO

5c 6c

AcO

O

OAcAcO

OAc

AcO

O

OAcAcO

OAcAcO

AcO

AcO

AcO 100 100 38:62

O

OAc

AcO

AcO

1b

SHO

AcOAcHN

OAc

AcO

2cS

OOAc

SO

AcO

5d 6d

OAc

O OAcAcHN

OAc

OAc

O OAcAcHN

OAcAcO

AcO

AcO

AcO 100 100 50:50

a Reaction conditions: 6 equiv of 2a, 0.6 equiv of DPAP, 20:1 EtOH–CH2Cl2, 1 h.b Overall yield of products isolated by column chromatography on silica gel.c Ratio determined by 1H NMR.

704 S. Staderini et al. / Tetrahedron Letters 53 (2012) 702–704

An identical stereoselectivity was observed in the reaction of 2awith D-gulal triacetate 1d to give diastereoisomer 3d despite thepresence of the axial OAc group at C4 (Table 1). This, however, af-fected the kinetics of the process as shown by the incomplete con-version of glycal 1d and the low yield of isolated S-disaccharide 3d.

Next, the substrate scope of the reaction was investigated byconsidering the addition of two more thiols 2b and 2c to glucal1a and galactal 1b (Table 2). The choice of thiol 2c relied on the factthat the 2-acetamidoglucosyl moiety (GlcNAc) is a key structuralmotif that is present in numerous biologically active carbohy-drates. Moreover the presence of the NHAc group might serve tovalidate the stability of this important functionality under the con-ditions of TEC. Thus, it was with our great delight that the photo-induced hydrothiolation of 1a and 1b by thiols 2b and 2c underthe above optimized conditions occurred with essentially quantita-tive conversion of the glycals to give the corresponding pairs ofdiastereoisomers 5a–6a, 5b–6b, 5c–6c ,and 5d–6d in very high iso-lated yields. All reactions, however, were scarcely stereoselectiveas the two S-disaccharides 5 and 6 were formed in comparableor even equal amounts. Thus, it appears that the substitution pat-tern in the thiol exerts scarce or no effect on the stereochemicalcourse of the reaction.

In conclusion, it has been demonstrated for the first time thatglycals can undergo a photoinduced addition of glycosylthiyl radi-cals with total regioselectivity to give 1-deoxy S-disaccharides ingood to excellent yields. While the addition of three different sugarthiols to D-glucal and D-galactal leads to pairs of S-disaccharide dia-stereoisomers in comparable amounts, the additions of a sugarthiol to D-allal and D-gulal are totally stereoselective as they bothafford a single product although in low yields.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.11.140.

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