Glycosyl disulfides: Novel glycosylating reagents with flexible aglycon alteration

Article abstract of DOI:10.1021/jo051374j

Glycosyl disulfides have been shown for the first time to be effective glycosyl donors. Glucosylation and galactosylation of a panel of representative alcohol acceptors allowed the formation of 28 simple glycosides, disaccharides, and glycoamino acids in yields of up to 90%. As well as providing a novel class of effective glycosyl donors, the ability to easily alter the nature of the aglycon and the ability to differently activate donors that differ only in their aglycon simply through altering conditions lends glycosyl disulfide donors to their use in latent-active reactivity tuning strategies.

Full text of DOI:10.1021/jo051374j

Glycosyl Disulfides: Novel Glycosylating Reagents with Flexible
Aglycon Alteration
Elizabeth J. Grayson,† Sarah J. Ward,‡ Alison L. Hall,† Phillip M. Rendle,‡
David P. Gamblin,‡ Andrei S. Batsanov,§ and Benjamin G. Davis*,‡
Department of Chemistry, University of Durham, South Road, Durham, U.K., DH1 3LE,
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, U.K. OX1 3TA, and Chemical Crystallography Laboratory,
Department of Chemistry, University of Durham, South Road, Durham, U.K. DH1 3LE
Ben.Davis@chem.ox.ac.uk
Received July 2, 2005
Glycosyl disulfides have been shown for the first time to be effective glycosyl donors. Glucosylation
and galactosylation of a panel of representative alcohol acceptors allowed the formation of 28 simple
glycosides, disaccharides, and glycoamino acids in yields of up to 90%. As well as providing a novel
class of effective glycosyl donors, the ability to easily alter the nature of the aglycon and the ability
to differently activate donors that differ only in their aglycon simply through altering conditions
lends glycosyl disulfide donors to their use in latent-active reactivity tuning strategies.
Introduction
hence easily automatable glycosylation method is yet
available for the synthesis of oligosaccharides.12,13 De-
velopment in this area therefore remains a vital challenge
to glycoscience.2 As part of the search for such a method,
a number of glycosyl donor systems have been developed
in which differences in their anomeric leaving groups
have an often critical effect on their reactivity.5 Two of
the most powerful, thioglycosides14 and glycosyl sulfox-
ides,15 utilize sulfur at the anomeric center, and therefore,
such donors are attractive in glycosylation strategies.
Thioglycosides, such as 1 (see Figure 1), in particular,
are one of the most popular donor systems.14 Strategies
for tuning16 their reactivity, including the use of armed/
disarmed donors,17,18 latent-active donors,5,19-21 or a
bulky leaving group,6,22 have culminated in elegant one-
Oligosaccharides are vital components in biological
systems, often attached to proteins on cell surfaces as
key cell-cell interaction mediators that initiate a number
of highly specific processes.1,2 To achieve a better under-
standing of the subtlety of the often highly specific nature
of these processes, there is a continuing need for access
to precise oligosaccharide structures. Although many
highly elegant and powerful approaches have been
developed,3-11 no generally applicable, selective, and
† Department of Chemistry, University of Durham.
‡ Department of Chemistry, University of Oxford.
§ Chemical Crystallography Laboratory, University of Durham.
(1) Varki, A. Glycobiology 1993, 3, 97-130.
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511.
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10.1021/jo051374j CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/25/2005
9740
J. Org. Chem. 2005, 70, 9740-9754

Glycosyl Disulfides
and trapped with aniline as an acceptor in this single,
yet encouraging, example. The lack of scrutiny may be
due to the paucity of efficient methods for the synthesis
of glycosyl disulfides. Although the use of a large excess
of aglycon thiol under oxidizing conditions can allow their
formation,36 this method is not compatible with the
efficient use of sensitive, scarce, or expensive aglycon
thiols or with solid-supported thiols. We now report the
efficient preparation of glucosyl and galactosyl disulfides
2 and an investigation of their behavior in representative
glycosylations. Part of this work has already been
published in a short, initial communication.37
FIGURE 1. Generalized structures of core glycosyl donors and
reagents used in this study.
pot glycosylation systems.16,18,22-34 In many of these
systems, the substituent on sulfur plays a key role in
modulating activity21,22 yet, once installed, is difficult to
alter.
Results and Discussion
Synthesis of Novel Disulfides as Potential Gly-
cosyl Donors. Representative ethyl disulfides 2a-d
were synthesized from the corresponding parent aldoses,
as shown in Scheme 1 through the use of four corre-
sponding methanethiosulfonates (MTS), 3, as powerful
mixed disulfide forming reagents.38-41 Benzyl-protected
bromides 5a,b were obtained from tetrabenzylglucose 4a
and -galactose 4b, respectively, by treatment with oxalyl
bromide using the method of Bundle and co-workers.42
Crude yields of 5a,b were approximately quantitative,
as judged by 1H NMR. However, owing to their instabil-
ity, the bromides were dried but not purified further
before immediate use in subsequent reactions. Tet-
raacetylglucosyl bromide 5c and tetraacetylgalactosyl
bromide 5d were prepared by reaction of pentaacetyl-
glucose and -galactose, respectively, with HBr in AcOH,
according to literature methods.43
Sodium methanethiosulfonate (NaMTS) for reaction
with bromides 5 was prepared through direct reaction
of sodium methanesulfinate with sulfur.44 Having sur-
veyed a range of alternative methods either for the
preparation of NaMTS38 or for the use of alternative MTS
ion sources, such as KMTS,45 we have found this method
and source of CH3SO2- to be the most efficient, although
different selectivities may be obtained with some alterna-
tive sources (vide infra). Heating the bromides 5a-d with
NaMTS in dioxan (for 3a,b), ethanol (for 3c), or toluene
(under phase-transfer conditions for 3d) furnished the
corresponding methanethiosulfonates 3 in moderate to
good yields. Many conditions were investigated, and
optimal conditions are shown in Table 1 (see Supporting
Information for further details of conditions).
With the aim of extending the scope of glycosyl donor
reagents with sulfur at the anomeric center, we have
examined the use of glycosyl disulfides, such as 2. It was
anticipated that glycosyl disulfides would exhibit reac-
tivities similar to those of their thioglycoside counterparts
but would have the added advantage that the disulfide
linkage could be readily cleaved and reformed. This
would usefully allow the variable adjustment of the
aglycon in reactivity tuning methods late in synthetic
routes for enhanced strategic flexibility and contrasts
with the typically early installation of the aglycon in
thioglycoside syntheses.5
Despite this potential attraction, very little has been
reported on the use of glycosyl disulfides as glycosyl
donors, and prior to this study, little was known of their
reactivity. Indeed, to the best of our knowledge, only one
example of any activation of glycosyl disulfides as glycosyl
donors had been demonstrated and it was for N- rather
than O-glycoside formation.35 Vasella and co-workers
successfully activated [(2,3:5,6)-di-O-isopropylidene-1-
thio-R-D-mannofuranosyl]methyl disulfide with bromine
(17) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J.
Am. Chem. Soc. 1988, 110, 5583.
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1993, 34, 8523.
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(20) Boons, G. J.; Burton, A.; Wyatt, P. Synlett 1996, 310-312.
(21) Cao, S. D.; Gan, Z. H.; Roy, R. Carbohydr. Res. 1999, 318, 75-
81.
(22) Geurtsen, R.; Holmes, D. S.; Boons, G. J. J. Org. Chem. 1997,
62, 8145-8154.
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Chem., Int. Ed. Engl. 1996, 35, 197-200.
(24) Cheung, M. K.; Douglas, N. L.; Hinzen, B.; Ley, S. V.; Pan-
necoucke, X. Synlett 1997, 257.
Perbenzylated MTS reagents 3a,b were obtained as
â-enriched anomer mixtures; the level of â-stereoselec-
tivity and yields were generally higher for gluco-MTS 3a
than for galacto-MTS 3b. Pure samples of the anomers
(25) Grice, P.; Ley, S. V.; Pietruszka, J.; Osborn, H. M. I.; Priepke,
H. W. M.; Warriner, S. L. Chem.-Eur. J. 1997, 3, 431-440.
(26) Grice, P.; Ley, S. V.; Pietruszka, J.; Priepke, H. W. M.; Warriner,
S. L. J. Chem. Soc., Perkin Trans. 1 1997, 351-363.
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Soc., Perkin Trans. 1 1998, 51-65.
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189-190.
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(29) Johnson, M.; Aries, C.; Boons, G. J. Tetrahedron Lett. 1998,
39, 9801-9804.
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Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734-753.
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Natl. Acad. Sci. U.S.A. 2003, 100, 797-802.
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C. H. Angew. Chem., Int. Ed. 2003, 42, 4657-4660.
(34) Lee, H. K.; Scanlan, C. N.; Huang, C. Y.; Chang, A. Y.; Calarese,
D. A.; Dwek, R. A.; Rudd, P. M.; Burton, D. R.; Wilson, I. A.; Wong, C.
H. Angew. Chem., Int. Ed. 2004, 43, 1000-1003.
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75, 557.
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9614-9615.
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Jones, J. B. Tetrahedron: Asymmetry 2000, 11, 245.
(42) Wessel, H.-P.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1
1985, 2251-2260.
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3.
J. Org. Chem, Vol. 70, No. 24, 2005 9741

Grayson et al.
SCHEME 1
TABLE 1. Preparation of Methanethiosulfonates 3a-d
TABLE 2. Preparation of Disulfides 2a-d and 7a from
Methanethiosulfonates 3a-d
MTS product
solvent
methodb
â:R ratio
yield (%)
76a
73a
62a
95
disulfide product
order of addition
yield (%)a
3a
3a
3b
3c
3d
dioxane
dioxane
dioxane
EtOH
A
D
A
F
G
7.5:1
1:5.9
4.5:1
100:0
100:0
2a
2b
2c
2c
2d
7a
inverse
inverse
normalb
inverse
inverse
inverse
79
82
65-74
96
82
67
toluene
80
a Over two steps from 4a,b. A: 70 °C, 15 h, split batch of 2 ×
∼1 g, with NaMTS. D as for B: 0.5 g with ∼1 equiv of Bu4NBr.
F: 90 °C, 25 min with NaMTS. G: reflux, 75 min, 0.1 equiv of
Bu4NI. See Supporting Information and Experimental Section for
further details of the effects of other conditions, B,C, and E.
b
a Based on â-3. b Addition of 3 to 6.
pling in CDCl3 is also inconclusive47 with a value of 1JCH
) 165 Hz. However, in deuterated acetone, the expected
4C1 conformation is observed and coupling constants
consistent with a â-MTS were observed. The structure
of 3d was unequivocally determined to be the â-anomer
by X-ray crystallography (Supporting Information); this
also indicated a 4C1 conformation in the solid state which
is adopted by both symmetrically independent molecules.
The observed formation of only â-anomers of the meth-
anethiosulfonates 3c,d with exclusive stereoselectivity is
consistent with neighboring group participation of the
C-2 acetate group.
To allow ready comparison with known ethyl thiogly-
coside glycosyl donors, ethyl glycosyl disulfides, 2, were
selected as model donor systems. The methanethiosul-
fonates 3a-d reacted with Et3N and ethanethiol (6a) to
give the corresponding â-ethyl disulfides 2a-d in good
yields (Table 2). Initially, a solution of 3c was added to
a solution of ethanethiol at room temperature in one
portion. This resulted in moderate yields (65-74%) of
desired glycosyl donor 2c. However, the best results were
achieved by carrying out the reaction in dichloromethane
at 0 °C and effecting dropwise addition of a dilute (∼0.04
M) solution of ethanethiol to 3c (“inverse addition”) over
∼30-40 min. The reaction was complete in 1 h to afford
2c as a stable white solid in an improved and excellent
yield of 96% (Scheme 1 and Table 2). Use of the same
dilute solution conditions and inverse addition order also
proved optimal for reactions of 3a,b,d. In all cases, the
anomeric configuration was unperturbed in the resulting
ethyl disulfides 2a-d. The structure of 2d was further
confirmed by X-ray crystallography (Supporting Informa-
of 3a,b could be obtained by column chromatography.
However, it should be noted that advantageously even
only â-enriched MTS mixtures under correct conditions
react in an exclusively â-selective manner with thiols
(vide infra), thereby allowing the ready formation of pure
â-disulfide products without the need for obtaining pure
â-MTS reagents. Carrying out the reaction of bromide
5a with NaMTS in the presence of organic-soluble
bromide source tetrabutylammonium bromide (Bu4NBr)
(conditions D) or the use of Bu4MTS as an MTS source
(conditions E, see Supporting Information) reversed
stereoselectivity to give highly R-enriched 3a (â:R )
1:4.2-1:5.9). Presumably, under these conditions, tet-
rabutylammonium serves as a solvating counterion for
bromide that in turn is able to catalyze in situ anomer-
ization of R-bromide 5a to its â-anomer. More rapid
reaction of this â-anomer with the MTS ion then leads
to preferential R-MTS formation in a manner akin to that
proposed for R-O-glycosides by Lemieux.46 Although
peracetylated gluco-MTS 3c was most readily prepared
according to our previously established methods through
the reaction of NaMTS in EtOH at 90 °C,41 this method
proved low yielding in the preparation of corresponding
peracetylated galacto-MTS 3d and ethyl 2,3,4,6-tetra-O-
acetyl-â-D-galactopyranoside was instead isolated as the
major product. However, reaction of bromide 5d in
refluxing toluene in the presence of catalytic Bu4NI as a
solid-solution phase-transfer catalyst successfully yielded
3d in 80% yield. The conformation of 3d in CDCl3 is
consistent with a 1C4 conformation and led to initial
confusion over the anomeric configuration; C1-H1 cou-
(46) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056-4062.
(47) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974,
293.
9742 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
SCHEME 2
labile protecting groups, primary acetonide, secondary
acetonide, Z, TBDMS, TBDPS, and COOMe groups were
also variously incorporated into these acceptors. More-
over, our selection and construction of glycosyl disulfides
2a-d and 7 as model systems was designed to test
various donor properties that are often critical to their
effectiveness:7 (i) the effect of the protecting group
(activating17 ether Bn (a,b) vs deactivating ester Ac (c,d)),
(ii) aglycon variation (active17 SSEt 2 vs latent SSpNP
7), and (iii) donor configuration (Glc (a,c) vs Gal (b,d)).
A. Glycosylation Using Iodonium-Source Activa-
tion. The utility of disulfides 2 as glycosyl donors was
first tested by exploring the reactions of glucosyl disul-
fides 2a and 2c with diacetone galactose (9b) as a model
acceptor using a series of activator systems based on
iodonium-source reagents in dichloromethane (DCM) or
acetonitrile (CH3CN) as solvent (Scheme 2, Table 3). The
selected activator systems (NIS, NIS/TfOH, NIS/
TMSOTf, I2, IBr, MeOTf, and NIS/TESOTf) have all been
used previously in successful activations of thioglyco-
sides.7 This initial optimization survey (Table 3) revealed
the use of 10 equiv NIS/0.5 equiv TESOTf in DCM as
giving the best yields of the corresponding disaccharides
11a and 11c (entries 8 and 12). In all cases, the use of
disarmed glycosyl donor 2c gives substantially lower
yields, up to 36% (entries 1-8), than armed donor 2a
(90%, entry 12), albeit with exclusive â-stereoselectivity
by virtue of the participatory Ac substituent on O-2.
Consistent with the disarmed and peracetylated nature
of 2c, moderate yields and acetyl migration side products
were obtained under a variety of conditions. The mass
balance of these reactions was made up of two major side
products, 1,3,4,6-tetra-O-acetyl-R-D-glucose and an acety-
lated acceptor.49,50 This indicated successful activation of
the donor but subsequent acetyl migration. The disarmed
nature of 2c was further confirmed by the lack of
reactivity with I251 (entry 9) but the efficient conversion
of 2c to acetobromoglucose 5c using IBr (entry 10). IBr
has been previously shown to be capable of activating
disarmed thioglycosides that cannot be activated under
other conditions.52
tion); the asymmetric unit comprises three molecules, all
adopting essentially the same core conformation. Al-
though perbenzylated glycomethanethiosulfonate, 3a,
could be obtained as its pure â-anomer, conveniently, the
use of glycomethanethiosulfonate 3a as a mixture of
anomers (93% â, 7% R) also allowed the formation of pure
â-ethyl disulfide 2a. Thus, using short reaction times,
complete reaction of only the â-anomers of 3a or 3b was
achieved, thus rendering anomer separation unnecessary
for 3a,b. Indeed, chromatographic separation of the
starting material recovered at this stage allowed the
convenient isolation of pure samples of the unreacted
R-anomers of 3a,b. Presumably, 1,3-diaxial interactions
render the R-anomer a poorer electrophile. To explore
aglycon variation, an example of a latent glycosyl donor
containing an electron deficient aglycon, the perben-
zylated p-nitrophenyl (pNP) glucosyl disulfide 7a, was
also prepared, and again, this was readily achieved by
reaction of the appropriate MTS 3a with Et3N and the
corresponding thiol, p-nitrothiophenol 6b.
Glycosylation Reactions Using Glycosyl Disul-
fides. To test the power of these novel disulfides 2a-d
and 7 as potential glycosyl donors, we evaluated their
utility in the glycosylation of a representative panel of
alcohol glycosyl acceptors, 9 (Scheme 2). These included
simple alcohols, MeOH (9a), primary carbohydrate alco-
hols 9b for disaccharide synthesis, a protected serine
derivative 9c,48 and three more hindered secondary
alcohol acceptors, 9d-f. To test the compatibility of
glycosylation conditions with a variety of potentially
Having established suitable activation conditions for
glucosyl donors 2a,c, we next probed their reactivity
toward our panel of representative acceptors (Scheme 2).
We were pleased to find that under the optimal
conditions elucidated for activation (10 equiv NIS, 0.5
equiv TESOTf, DCM, 0 °C), ethyl tetrabenzylglucosyl
disulfide 2a rapidly and smoothly gave methyl glucoside
10a in an excellent 90% yield. Furthermore, reaction with
more challenging acceptors 9b and 9c gave good yields
of disaccharide 11a53 and glycopeptide 12a54 O-gluco-
sides, respectively. Secondary alcohol acceptors proved
more challenging. A yield of 56% of 13a was obtained
from 9d through the inclusion of 1 equiv of the base tri-
(49) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190.
(50) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am.
Chem. Soc. 1998, 120, 13291.
(51) Kartha, K. P. R.; Aloui, M.; Field, R. A. Tetrahedron Lett. 1996,
37, 5175-5178.
(52) Kartha, K. P. R.; Field, R. A. Tetrahedron Lett. 1997, 38, 8233.
(53) Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N. Carbohydr. Res.
1973, 27, 55.
(48) Hwang, D.-R.; Helquist, P.; Shekhani, M. S. J. Org. Chem. 1985,
50, 1264.
(54) Lacombe, J. M.; Pavia, A. A.; Rocheville, J. M. Can. J. Chem.
1981, 59, 473.
J. Org. Chem, Vol. 70, No. 24, 2005 9743

Grayson et al.
TABLE 3. Glycosylation Reactions to Explore Varying Donor and Iodonium-Activation Conditions Using 2a,c with
Model Acceptor Diacetone Galactose (9b)
entry
N
activation
activator
equiv
time
(h)
temp
(°C)
yield
(%)
product
â:R ratio
donor
conditionsa
solvent
product
1
2
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2a
2a
2a
NISb
DCM
DCM
CH3CN
DCM
CH3CN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
2.5
2.5
10
10
10
3
24
reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
11c
11c
11c
11c
11c
11c
11c
11c
18
26
2
30
16
15
34
36
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
NIS, TfOHc
NIS, TfOHc
NIS, TMSOTfd
NIS, TMSOTfd
NIS, TESOTf
NIS, TESOTf
NIS, TESOTfe
I2
22
3
24
4
4.5
6
5
6
15
7
5
24
8
10
10
3
3
10
10
2
9
168
30 min
1.5
1
10
11
12
13
IBr
5c
82
70
90
75
0:100
1:1
9:14
9:11
NIS, TESOTff
NIS, TESOTfg
NIS, TESOTfg
11a
11a
11a
0
40 min
0
a 0.5 equiv of coactivator. b Activation method F in Experimental Section. c Activation method G in Experimental Section. d Activation
method H in Experimental Section. e Activation method D in Experimental Section. f Activation method B in Experimental Section.
g Activation method A in Experimental Section.
tert-butylpyrimidine (TTBP)55 to minimize Lewis-acid-
catalyzed acetonide deprotection of both the starting
material 9d and the product 13a. Activation condition
associated side products, succinimidyl glucoside deriva-
tive 16a (21%) and the 3-O-triethyl silylated glucofura-
noside 17 (23%), were also observed. Glycosylated suc-
cinimides, such as 16a, have been observed previously
in potent glycosylating systems30 with hindered accep-
tors, and it is a testament to the electrophilicity of the
intermediates generated that they are capable of glyco-
sylating such a nonnucleophilic imide species. To further
test the ability of 2a to glycosylate other less-nucleophilic
alcohol acceptors and to explore the compatibility of silyl
ether protection, secondary alcohol acceptors, 5-O-tert-
butyldimethylsilyl 9e56 and 5-O-tert-butyldiphenylsilyl-
1,2-diisopropylidenexylose 9f were tested. The disaccha-
ride coupling product 14a was obtained from 9e in 77%
yield and, remarkably, with exclusive R-stereoselectivity.
From the more bulky acceptor 9f, the glucosylated
product 15a was obtained in a lower 41% yield together
with succinimide adduct 16a (27%). Presumably, as for
9d, because this acceptor is particularly sterically hin-
dered, even succinimide can compete successfully as a
nucleophile.
TABLE 4. Glycosylation Reactions Using Donors 2a-d
and NIS/TESOTf Activation
entry
N
activation NIS
yield product
donor acceptor methoda equiv product (%) R:â ratio
1
2
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
2c
2d
9a
9b
9c
9d
9e
9f
9a
9b
9c
9d
9e
9f
A
A
A
C
B
B
B
C
B
C
B
B
D
D
D
D
10
10
10
10
3
10a
11a
12a
13a
14a
15a
10b
11b
12b
13b
14b
15b
10c
11c
12c
11d
90
9:15
90
9:14
3
73
1:1
4
56b
77c
41d
44e
39f
31g
34h
54i
56
1.6:1
100:0
3.4:1
1:2.4
1.4:1
100:0
100:0
3.6:1
5:1
5
6
3
7
2
3
1.5
3
3
3
10
10
10
10
8
9
10
11
12
13
14
15
16
9a
9b
9c
9b
24
0:100
0:100
0:100
0:100
36
34
43
a A: 10 equiv of NIS, 0.5 equiv TESOTf, DCM, 0 °C. B: as for
A with 1.5-3 equiv of NIS. C: as for A with 1.5-10 equiv of NIS
with TTBP. D: as for A at room temperature. b Also obtained 21%
succinimidyl adduct 16a and 23% triethyl silylated diacetone
glucose 17. c Also obtained 21% succinimidyl adduct 16a. d Also
obtained 27% succinimidyl adduct 16a. e Also obtained 22% suc-
cinimidyl adduct 16b. f Also obtained 27% succinimidyl adduct 16b
and 33% triethyl silylated diacetone galactose 18. g Also obtained
16% succinimidyl adduct 16b. h Also obtained 32% succinimidyl
adduct 16b and 36% triethylsilylated diacetone glucose 17. i Also
obtained 29% succinimidyl adduct 16b.
The glycosyl disulfide methodology was then tested for
galactosylation of a range of acceptors using ethyl tet-
rabenzylgalactosyl donor 2b. As has been observed for
other galactosyl donors,30 2b is more reactive than
glucosyl donor 2a and, as a result, the use of NIS/TESOTf
as an activator proved much less satisfactory (yields of
31-56%), with significant quantities of the corresponding
succinimide adduct 16b being formed even with less-
hindered primary alcohol acceptors 9a-c (Table 4).
Interestingly, slightly improved yields under these condi-
tions were, in fact, obtained using secondary over primary
hydroxyl acceptors: with diacetone glucose 9d buffered
(55) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(56) Krischna, P. R.; Kannan, V.; Ilangovan, A.; Sharma, G. V. M.
Tetrahedron: Asymmetry 2001, 12, 829-837.
(57) Hall, A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.; Wightman,
R. H. J. Chem. Soc., Perkin Trans. 1 2000, 329-343.
9744 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
TABLE 5. Glycosylation Reactions Using Donors 2a,b with Noniodonium Lewis Activation Sourcesa
entry
N
activator
equiv
yield
(%)
product
R:â ratio
donor
acceptor
activator
product
1
2
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2a
2a
2a
2a
2a
2a
2a
2b
2b
2a
2b
2a
2b
9a
9b
9c
9d
9d
9f
9a
9b
9c
9d
9f
9b
9e
9e
9e
9b
9b
9d
9e
9d
9b
9b
9b
9b
DMTST
5
10a
11a
12a
13a
13a
15a
10b
11b
12b
13b
15b
78
76
73
23b
39d
56
80
82
79
56e
66
1:2
DMTST
5
1:1
3
DMTST
5
1.7:1
2.3:1
1.6:1
3:1
1:1.7
1.3:1
2:1
4
DMTST
5
5
DMTSTc
DMTST
6
6
6
7
DMTST
5
8
DMTST
5
9
DMTST
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMTSTc
DMTST
6
1.8:1
6.5:1
4
MeOTf
1-10
5
DMTSTf
DMTSTf
DMTSTf
DMTSTf
DMTSTf
DMTSTf
DMTSTf
DMTSTf
NPCL/Tf2Og
NPCL/Tf2Og
Ph2SO/Tf2Oh
Ph2SO/Tf2Oh
14a
14a
14a
11b
11b
13a
14b
13b
11a
11b
11a
11b
49
61
42
80
78
76
46
69
75
65
41
20
7:1
4
6:1
3
5:1
4
1:1
3
1:1
4
1.6:1
9:1
4
4
2.5:1
1:1
1.3:1
1:1
1.4:1
1
1
1
1
a DMTST as the activator (method E). b Also obtained 23% monoacetone glucose deprotection side product. c Buffered by 1 equiv of
TTBP. d Also obtained 27% glycosylated migration side product 19a. e Also obtained 14% glycosylated migration side product 19b. f Bufffered
with 1.1 of equiv TTBP for every 1 equiv of DMTST. g 1.03 equiv of NPCL, 1.2 equiv of Tf2O, and 1.3 of equiv TTBP for 45 min at 0 °C.
h 1.03 equiv of Ph2SO, 1.2 equiv of Tf2O, and 1.3 equiv of TTBP for 2 h at 0 °C.
by 1 equiv of TTBP, the coupling product 13b was formed
in 34% yield (together with 32% succinimide adduct 16b
and 36% 3-O-triethylsilylated diacetone glucose 17) and
silylated acceptors 9e and 9f gave galactosylated products
14b and 15b in yields of 54% and 56% (with 29% and
32% 16b), respectively.
in good yields (73-82%, Table 5) to give glycosides,
disaccharides, and glycoamino acids 10-12a-c. With the
secondary alcohol acceptor diacetone glucose 9d, however,
even when buffered with 1 equiv of TTBP, the coupling
products 13a and 13b were formed from 2a and 2b,
respectively, in moderate yields of 39 and 56%, respec-
tively. These reactions of 9d were contaminated by
isomeric byproducts in yields of 27 and 14% that were
not the same as those formed using NIS/TESOTf. From
the glucosylation of 9d using 2a, 13C NMR resonances
at 100.81 and 100.95 of a side product obtained in 27%
yield were characteristic of a dimethylacetal carbon in a
dioxan ring.60,61 This indicated that rearrangement of 9d
to give 19a, as illustrated in Scheme 3, had taken place
in this case. Acetonide rearrangement reactions of 9d
using O-6 as a nucleophile rather than OH-3 to give
rearranged products in which the 5,6-dioxolane ring has
opened and reclosed with the 3-OH to form a dioxan ring
(Scheme 3) have been used as a general approach to
primary 6-halo-6-deoxyglucosides,62-64 and acetonides
may act as nucleophiles in intramolecular ether forma-
tion.65 However, to the best of our knowledge, this
Finally, the disarmed17 peracetylated donors 2c and
2d were also evaluated against several compounds of the
panel of glycosyl acceptors under conditions of NIS-
mediated activation. Only low yields (24-43%), albeit
with expected exclusive â-stereoselectivity, were observed
throughout (Table 4). As above, acetyl migration side
products were also observed.46,50
B. Minimizing Succinimidyl Adduct Formation:
Use of Alternative Noniodonium Activators. The
high levels (in some cases up to 32%) of succinimidyl
glucoside adducts in 16 prompted us to explore alterna-
tive activation methods devoid of such potentially com-
peting nucleophiles. Dimethylthiosulfonium triflate
(DMTST) has, like NIS/TESOTf, been established as an
effective activator for armed thioglycosides.58,59 It is
typically less reactive than NIS/TESOTf but has the
advantage of not producing unwanted byproducts (namely
succinimidyl adducts). By use of 5-6 equiv of DMTST
as activators, both armed donors 2a and 2b underwent
glycosylation with all the primary alcohol acceptors 9a-c
(60) Buchanan, J. G.; Chaco´n-Fuertes, M. E.; Edgar, A. R.; Moor-
house, S. J.; Rawson, D. I.; Wightman, R. H. Tetrahedron Lett. 1980,
21, 1793-1796.
(61) Saito, S.; Sasaki, Y.; Furumoto, T.; Sumita, S.; Hinomoto, T.
Carbohydr. Res. 1994, 258, 59-75.
(62) Smith, D. C. C. J. Chem. Soc. 1956, 1244.
(63) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 2163-
2170.
(58) Okuma, K.; Koike, T.; Yamamoto, S.; Takeuchi, H.; Yonekura,
K.; Ono, M.; Ohta, H. Bull. Chem. Soc. Jpn. 1992, 65, 2375-2380.
(59) Ravenscroft, M.; Roberts, R. M. G.; Tillett, J. G. J. Chem. Soc.,
Perkin Trans. 2 1982, 1569-1572.
(64) Ponpipom, M. M.; Hanessian, S. Carbohydr. Res. 1971, 18, 342-
344.
J. Org. Chem, Vol. 70, No. 24, 2005 9745

Grayson et al.
SCHEME 3
rearrangement has not, until now, been used as a
strategy for accessing 6-O-glycosylated glucosides with
perbenzylated donors, although isolated examples have
been observed in low yield in Koenigs-Knorr glucosyla-
tions with peracetylated donors.61,66 We are currently
investigating this interesting and potentially useful
rearrangement further.
With secondary alcohol acceptor 9e as an acceptor,
extensive silyl migration occurred leading to a mixture
of coupling products arising from intra- and intermolecu-
lar migration of the TBDMS group. Such migrations are
known to occur in the presence of certain Lewis acids.67
However, with less labile tert-butyldiphenylsilylated 9f
as an acceptor, donors 2a and 2b gave the coupling
products 15a and 15b in fair yields of 56 and 66%,
respectively, without associated migration.
To reduce the migration that had been observed and
thus increase the efficiency of glycosyl disulfide donors
with testing acceptors such as 9d,e, addition of base
TTBP and reduced levels of the DTMST activator were
investigated (entries 13-20, Table 5). Interestingly, a
survey of the literature for activations of thioglycoside
donors using DMTST reveals a disparity in the numbers
of equivalents typically employed ranging from 2 to 12
equiv, with 4 equiv being most frequently employed.68-74
Testing acceptor 9e, which had failed to react success-
fully, previously gave improved yields with 2a when
treated with 3-5 equiv of DMTST (Table 5, entries 13-
15); 4 equiv proved optimal. Similarly, 4 equiv proved
optimal for glucosylation of 9b,d, with the latter being
formed in a dramatically improved yield (76% cf. 39%).
In general, the use of fewer equivalents of DMTST gave
rise to slower reactions. Although, with more nucleophilic
acceptors, such as 9b, the use of only 3 equiv of DMTST
proved possible with only a marginally reduced yield
(entry 17) and reaction times were greatly prolonged (18
h cf. 1 h for 4 equiv). Application of these conditions to
galactosylation of 9b,d with 2b (entries 19 and 20) also
proved successful.
Comparisons of other noniodonium-source activators
and an assessment of the effect of varying the level of a
given activator were also conducted. The use of triflic
anhydride in conjunction with diphenylsulfoxide75 and
N-(phenylthio)-ꢀ-caprolactam (NPCL)76 has been recently
revealed. However, using these alternative promoters, we
observed reduced yields only (Table 5, entries 21-24).
The nature of the cleavage products from the activation
of this novel class of donors has also intrigued us.
Although, in most cases, a mixture of aglycone-associated
products was isolated, making definitive accounting of
all mass balance difficult, these products strongly sug-
gested the formation of methyl polysulfides, presumably
as the product of a further reaction of released disulfides
and sulfenyliodides; in some cases, mass spectrometry
suggests that polysulfide species with degrees of polym-
erization (dp) as high as dp ) 10 are observed.
Competition Reactions. Having established effective
conditions for the glycosylation of a range of representa-
tive acceptors, we investigated the utility of glycosyl
disulfide donors in potential latent-active19,21 reactivity
tuning18 strategies through aglycon variation.
A. Comparison of the Reactivities of 2a and 1a.
Initially, ethyl glucosyl disulfide, 2a, was compared with
the corresponding thioglucoside 1a. Thus, 1 equiv of 2a,
1 equiv of 1a (prepared by a literature procedure77), and
4 equiv of representative acceptor diacetone galactose 9b
were treated with 6 equiv of DMTST at 0 °C, followed
by warming to room temperature, under the successful
conditions established previously for glycosylations with
DMTST. Activation with NIS/TESOTf under these condi-
tions was considered too rapid to be monitored effectively
by high-pressure liquid chromatography (HPLC) and was
plagued by succinimidyl side product formation. After 10
min, HPLC indicated all of thioglucoside 1a had reacted
whereas disulfide 2a remained. From this competition
reaction, the disaccharide coupling product 11a was
obtained in 85% yield based on 1 equiv of donor 1a,
slightly higher than the yield of 75-80% obtained in
(65) Ashlani-Shotorbani, G.; Buchanan, J. G.; Edgar, A. R.; Shahidi,
P. K. Carbohydr. Res. 1985, 136, 37-52.
(66) Lipta´k, A.; Na´sa´si, P.; Neszme´lyi, A.; Wagner, H. Carbohydr.
Res. 1980, 86, 133-136.
(67) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(68) Plettenburg, O.; Bodmer-Narkevitch, V.; Wong, C.-H. J. Org.
Chem. 2002, 67, 4559-4564.
(69) Lear, M. J.; Yoshimura, F.; Hirama, M. Angew. Chem., Int. Ed.
Engl. 2001, 40, 946-949.
(70) Drinnan, N.; West, M. L.; Broadhurst, M.; Kellam, B.; Toth, I.
Tetrahedron Lett. 2001, 42, 1159-1162.
(71) Bernlind, C.; Bennett, S.; Oscarson, S. Tetrahedron: Asymmetry
2000, 11, 481-492.
(72) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F. J. Am.
Chem. Soc. 1997, 119, 449-450.
(75) Codee, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft,
H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519-
1522.
(76) Duron, S. G.; Polat, T.; Wong, C.-H. Org. Lett. 2004, 6, 839-
841.
(77) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand. 1989, 43, 471.
(73) Krog-Jensen, C.; Oscarson, S. J. Org. Chem. 1996, 61, 4512-
4513.
(74) Andersson, F.; Fuegedi, P.; Garegg, P. J.; Nashed, M. Tetrahe-
dron Lett. 1986, 27, 3919-22.
9746 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
SCHEME 4
control, noncompetition reactions of 1a with 9b in the
absence of 2a under the same conditions. The unreacted
glycosyl disulfide donor was also recovered, in 69% yield.
Interestingly, this consisted of an inseparable mixture
of unreacted ethyl disulfide 2a (22% recovery) and the
methyl disulfide 8a (47%). These results show that,
contrary to earlier predictions,37 the disulfide 2a is
markedly less reactive than its counterpart thioglucoside
1a. Recovery of the methyl disulfide 8a may be explained
by the activation preequilibria with DMTST shown in
Scheme 4a via dithiosulfonium 20. This role of DMTST
as a source of “MeS+” also suggests the likely formation
of thiosulfoniums, such as 21 (Scheme 4b), similar to
dithiosulfonium 20 (Scheme 4a) in DMTST activation of
thioglycosides. This, in turn, highlights the potentially
common intermediacy of thiosulfoniums (e.g., 21) both
in the activation of thioglycosides (e.g., methyl thiogly-
cosides 22), known successful donors,14 by DMTST and
in the activation of glycosyl disulfides (e.g., 8 or 2) by a
source of “Me+”. However, despite this mechanistic
indication, treatment of 8 or 2a with 1-10 equiv of
MeOTf gave no reaction (entry 12, Table 5).
B. Comparison of the Reactivities of 2a and 7a.
It has been shown previously that partially protected
thioglycosides in which p-nitrophenyl is the aglycon
group are sufficiently unreactive as donors to be used
instead as acceptors. These may then be activated under
more strenuous conditions and therefore may, in effect,
be considered to be so-called latent donors19,21 whose
reactivity and hence function may be tuned by activation
conditions. To explore the potential of glycosyl disufides
in this regard, a competition reaction was therefore
carried out to compare the reactivity of ethyl disulfide
2a with corresponding p-nitrophenyl disulfide 7a. This
tested whether the p-nitrophenyl disulfide group could
be used as a leaving group in an analogous acceptor/
latent donor molecule strategy. As before, 1 equiv of 2a,
1 equiv of 7a, and 4 equiv of diacetone galactose 9b were
treated with 6 equiv of DMTST at 0 °C, followed by
warming to room temperature. After 20 min, HPLC
indicated that all the disulfide 2a had reacted whereas
disulfide 7a largely remained. From the reaction, 74%
of unreacted 7a was recovered, as well as the coupling
product 11a in 87% yield. Given this highly promising
TABLE 6. Temperature-Tuned Glycosylation Reactions
of Active 2a and Latent 7a with Diacetone Galactose 9b
and DMTSTa
yield (%)a
reaction
entry
N
time
(h)
temp
(°C)
recovered recovered
donor
coupled
donor
acceptor
1
2
3
4
5
6
2a
2a
7a
7a
7a
7a
5
4
5
4
-10
80
78
6
16
16
70
0
-10
0
80
60
58
94
50
70
20 min
20 h
0 f 20
0 f 20
a 5 equiv of DMTST (method E).
indication of differences in reactivity based only on
aglycon variation, further glycosylation reactions with
DMTST and diacetone galactose 9b were carried out
using 2a and 7a separately to find mild activating
conditions under which 2a reacted completely but 7a did
not and more strenuous activating conditions under
which 7a reacted completely. The results are shown in
Table 6.
Pleasingly, these results indicated that a suitably
protected sugar bearing a p-nitrophenyl disulfide group
on the anomeric carbon was poorly active (entry 3, Table
6) and could be used as an acceptor/latent donor at -10
°C with a short reaction time and as a donor at room
temperature with a longer reaction time (entry 6, Table
6). Importantly, under the same -10 °C mild conditions,
2a gave 80% disaccharide coupling product (entry 1,
Table 6).
The recovery of methyl p-nitrophenyl disulfide 23 from
the glycosylation of 7a (entry 6) may arise either through
direct transfer of -SMe from the thiophilic Lewis acid
activator DMTST, through transfer of -Me to the proxi-
mal, anomeric sulfur, or through post activation disulfide
J. Org. Chem, Vol. 70, No. 24, 2005 9747

Grayson et al.
cooled to 0-5 °C in an ice bath with stirring. Freshly distilled
methanesulfonyl chloride (23.3 mL, 34.5 g, 0.3 mol) was added
dropwise over 1 h. The mixture turned yellow, then orange-
brown, and finally colorless. Some sulfur was precipitated. The
mixture was heated under reflux for 18 h and then cooled. At
this stage, the reaction mixture was brown. The solution was
evaporated on a high-vacuum rotary evaporator giving a white
solid. The solid was dried for 24 h in a vacuum desiccator over
calcium chloride, ground with a pestle and mortar, and
replaced in the vacuum desiccator for an additional 24 h. The
white solid was extracted with dry ethanol (ca. 15 × 100 mL),
and the slurry was filtered after each extraction. The filtrate
was evaporated down to a thick slurry of precipitated sodium
methanethiosulfonate which was collected by filtration. The
filtrate thus obtained was evaporated further and refiltered.
Sodium methanethiosulfonate (32.5 g, 87%) was obtained as
white crystals.
scrambling of released disulfide and/or trisulfide prod-
ucts. The second possibility seems less likely given that
methyl triflate, a powerful Me+ donor, was found to be
inactive when tested as an activator for glycosyl disul-
fides (entry 12, Table 5).
Finally, although these results confirmed that the
p-nitrophenyl disulfide could be converted from a latent
into an active donor by simply altering temperature and
reaction time, the feasibility of chemically converting the
latent p-nitrophenyl disulfide group in 7a into the active
ethyl group to give 2a was also demonstrated. The
disulfide 7a was cleaved by PBu3 in a 6:3:1 mixture of
chloroform/dioxan/water78 to give the thiol 2479 in 95%
yield that was then reacted with ethyl methanethiosul-
fonate80 and Et3N in dichloromethane to give disulfide
2a in 74% overall yield (Scheme 1).
Method B.44 A mixture of sodium methanesulfinate (10 g,
98 mmol) and sulfur (3.14 g, 98 mmol) in dry methanol (1.2
L) was heated to reflux. After 20 min, the sulfur had dissolved
and the reaction was stopped. The solvent was removed under
reduced pressure, and the off-white residue was triturated
with dry ethanol. The remaining solvent was removed in
vacuo, affording the product as a pale yellow solid (10.04 g,
76%): mp 273-274 °C (lit.81 272-273 °C); 1H NMR (200 MHz,
D2O) δ 3.24 (s, SCH3);44 13C NMR (400 MHz, D2O) δ 54.9 (CH3);
MS-ES+ m/z (%) 156 (100) (M+ + Na).
Tetrabutylammonium Methanethiosulfonate. Sodium
methanethiosulfonate (0.3 g, 2.4 mmol) and tetrabutylammo-
nium bromide (0.772 g, 2.4 mmol) were stirred in dry acetone
(5 mL) under nitrogen at room temperature for 18 h. The
suspension was filtered, and the filtrate was evaporated to give
an oil, which was taken up in dried chloroform (10 mL) and
refiltered. The filtrate was reevaporated to give tetrabutylam-
monium methanethiosulfonate as a colorless oil (0.81 g, 95%)
which began to crystallize under vacuum: 1H NMR (250 MHz,
CDCl3) δ 0.95 (t, 12H, CH3CH2, J ) 7.1 Hz), 1.35-1.75 (m,
16H, CH3CH2), 3.25-3.4 (m, 11H, SCH3, NCH2).
Conclusions
Glycosyl disulfides have been shown for the first time
to be effective glycosyl donors. Glucosylation and galac-
tosylation of a panel of representative alcohol acceptors
allowed the formation of simple glycosides, disaccharides,
and glycoamino acids in yields of up to 90%. Although
NIS/TESOTf proved to be an effective activator for armed
glucosyl donors with good nucleophiles, the succinimide
side product competed as a nucleophile with poorer
nucleophiles such as secondary alcohol acceptors and
even with armed galactosyl donors. DMTST proved to be
a more effective activator that allowed generally efficient
glycosylation of this useful novel class of tunable glycosyl
donors. It should be noted that these glycosylation
reactions were intentionally optimized to be compatible
with relatively mild reaction conditions (typically room
temperature unlike many glycosylations that require, in
some cases, significant cooling). Improved yields were
possible in some glycosyl disulfide systems through the
use of much lower temperatures; however, these are
incompatible with our longer-term goals of readily trans-
lated methods for solid-phase and oligosaccharide as-
sembly. Although the preparative route from, e.g., pre-
cursor acetate to donor, is slightly longer for glycosyl
disulfides than for, e.g., thioglycosides, the overall yields
can be similarly efficient (up to 91% in this work) and
such donors can be readily accessed on a gram scale.
Advantageously, we have shown here that, once a given
donor aglycon unit has been installed, it may be easily
switched in only two steps to an alternative aglycon with
differing reactivity. We believe this additional switching
ability combined with effective relative glycosylation
reactivities holds great promise in novel reactivity tuning
strategies.
General Procedure for Bromides 5a,b.42 Tetrabenzyl-
glucose or -galactose, 4a or 4b (2 g, 3.7 mmol), was dissolved
in a mixture of dry dichloromethane (12 mL) and dry DMF
(0.8 mL) under argon. Oxalyl bromide (6 mL, 2 M in DMF, 12
mmol) was added via a syringe very carefully over 5-10 min
to the stirred solution. The reaction mixture foamed. Stirring
1
was continued for 1 h. At the end of this time, the H NMR
spectrum of a small aliquot showed complete conversion of the
starting material into product. The solvent was removed in
vacuo, and the residue was taken up in dichloromethane (50
mL). The dichloromethane solution was washed with saturated
aqueous sodium bicarbonate (2 × 20 mL) to render it alkaline,
with water (20 mL), with and brine (20 mL). The dichlo-
romethane solution was dried (MgSO4) and evaporated. The
residue was taken up in toluene (30 mL) and reevaporated
under high vacuum. This procedure was repeated to give 5a
or 5b as a yellow-brown oil in approximately quantitative yield.
They were used without purification either immediately or
after storage for up to 15 h in a deep freeze. The procedure
gave the same results on larger (4 g) scales.
Data for 2,3,4,6-tetra-O-benzyl-R-D-glucopyranosyl bromide
5a:42,82 1H NMR (400 MHz, CDCl3, COSY) δ 3.57 (dd, 1H, H-2,
J(H-1,H-2) ) 3.5 Hz, J(H-2,H-3) ) 9.1 Hz), 3.68 (dd, 1H, H-6,
J(H-6, H-5) ) 2.1 Hz, J(H-6,H-6′) ) 11.0 Hz), 3.79-3.84 (m,
2H, H-4, H-6′), 4.07 (t, 1H, H-3, J ) 9.1 Hz), 4.07-4.11 (m,
1H, H-5), 4.47-4.62 (m, 3H, PhCH2), 4.74 (s, 2H, PhCH2),
4.84-4.89 (m, 2H, PhCH2), 5.10 (d, 1H, PhCHH′, J ) 11.1 Hz),
6.46 (d, 1H, H-1, J(H-1,H-2) ) 3.7 Hz), 7.15-7.40 (m, 20H,
Ar-H); 13C NMR (125.7 MHz, CDCl3, HSQC) δ 67.5 (C-6), 72.8
(C-5), 73.5 (PhCH2), 75.2 (PhCH2), 75.8 (PhCH2), 76.0 (PhCH2),
79.6 (C-2), 82.1 (C-3), 91.9 (C-1), 127.8-128.4 (Ar-CH), 137.3-
138.2 (Ar-C) (30C).
Experimental Section
Sodium Methanethiosulfonate.44,81 Method A. Sodium
sulfide nonahydrate (72.1 g, 0.3 mol) was dissolved in water
(80 mL) with gentle heating to about 60 °C. The solution was
(78) Kiefel, M. J.; Thomson, R. J.; Radovanovic, M.; Itzstein, M. v.
J. Carbohydr. Chem. 1999, 18, 937-959.
(79) Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2000, 65, 4607-
4617.
(80) Berglund, P.; DeSantis, G.; Stabile, M. R.; Shang, X.; Gold, M.;
Bott, R. R.; Graycar, T. P.; Lau, T. H.; Mitchinson, C.; Jones, J. B. J.
Am. Chem. Soc. 1997, 119, 5265-5266.
(81) Shaked, Z.; Szajewski, R. P.; Whitesides, G. M. Biochemistry
1980, 19, 4156-4166.
(82) Ernst, B.; Winkler, T. Tetrahedron Lett. 1989, 30, 3081-3084.
9748 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
General Procedures for Methanethiosulfonates 3a,b.
Method A. The crude bromide 5a or 5b (ca. 2.28 g, 3.7 mmol)
was divided into two roughly equal portions. They were placed
under argon, and a portion of sodium methanethiosulfonate
(total 1.48 g, 11.04 mmol) was added to each portion followed
by dry dioxan (7.5 mL) (total 15 mL). The mixtures were
stirred thoroughly and then heated to 70 °C for 15 h. They
were combined, filtered, and evaporated to give a yellow oil
which was then purified by flash column chromatography on
silica gel (hexane/ethyl acetate 8:2).
Method B. The procedure described in method A was
repeated but as a single batch using bromide 5a or 5b (ca. 4.5
g, 7.2 mmol), sodium methanethiosulfonate (2.96 g, 22.08
mmol), and dry dioxan (30 mL).
(dd, 1H, H-6′, J(H-6′,H-6) ) 12.4 Hz, J(H-6′,H-5) ) 2.2 Hz),
5.06 (t, 1H, H-4, J ) 9.7 Hz), 5.08 (dd, 1H, H-2, J(H-2,H-1) )
10.2 Hz, J(H-2,H-3) ) 9.2 Hz), 5.26 (d, 1H, H-1, J(H-1,H-2) )
10.2 Hz), 5.31 (t, 1H, H-3, J ) 9.2 Hz); MS-ES+ m/z (%) 465
(100) (M+ + Na).
General Procedure for Disulfide Syntheses for 2a-d.
Methanethiosulfonate 3 (â-anomer or â-enriched) was dis-
solved in dry dichloromethane (15 mL). Triethylamine (221
µL, 1.59 mmol) was added, and the resulting solution was
cooled to 0 °C. A dilute solution of ethanethiol (39.7 mL, 0.04
M, 1.59 mmol) was added dropwise with stirring over 40 min.
The reaction mixture was allowed to warm to room temper-
ature and was stirred for 2 h. Volatile materials were removed
in vacuo, and the residue was purified by column chromatog-
raphy. Elution with hexane/ethyl acetate 9:1 furnished 2.
Further elution with hexane/ethyl acetate 7:3 allowed isolation
of pure samples of the unreacted R-anomer of 3 in the cases of
3a and 3b.
Method C. The procedure described in method A was
repeated but as a single batch using bromide 5a or 5b (0.136
g, 0.225 mmol), sodium methanethiosulfonate (0.110 g, 0.820
mmol), and dry dioxan (2 mL).
Ethyl 2,3,4,6-Tetra-O-benzyl-â-D-glucopyranosyl Di-
sulfide 2a. 3a (1.25 g, estimated â-content 1.59 mmol) gave
â-2a (0.78 g, 79% based on â-3a) as a white solid: mp 62-64
°C; [R]25D -80.0 (c 3.0, CH3OH); IR (KBr, disk) 3024 (Ar C-H),
2980, 2927, 2899, 2868, 2789 (C-H), 1953, 1864, 1818 (weak,
Method D. The procedure described in method B was
repeated using the bromide 5a (ca. 0.59 g, ca. 0.91 mmol),
sodium methanethiosulfonate (0.3 g, 2.4 mmol), and anhydrous
dioxan (4 mL). Tetrabutylammonium bromide (0.297 g, 0.925
mmol) was also placed in the reaction flask with the bromide
5a before the dioxan was added. 3a was obtained in 73% yield
(â:R ) 1:5.9).
Method E. Bromide 5a (ca. 0.56 g, ca. 0.86 mmol) was placed
under nitrogen, and a solution of tetrabutylammonium meth-
anethiosulfonate (ca. 0.81 g, ca. 2.2 mmol) in anhydrous dioxan
(4 mL) was added. The mixture was heated with stirring at
70 °C for 15 h. Workup as described in method A furnished
3a in 73% yield (â:R ) 1:4.2).
1
Ar C-C) cm-1; H NMR (500 MHz, CDCl3, COSY) δ 1.33 (t,
3H, SCH2CH3, J ) 7.8 Hz), 2.88 (m, 2H, SCH2CH3), 3.53 (ddd,
1H, H-5, J(H-5,H-4) ) 9.5 Hz, J(H-5,H-6) ) 4.0 Hz, J(H-5,H-
6′) ) 2.0 Hz), 3.72 (pd, 1H, H-6, J(H-6,H-6′) ) 9.0 Hz), 3.74-
3.77 (m, 2H, H-2, H-4), 3.78 (pd, 1H, H-6′, J(H-6′,H-6) ) 9.0
Hz), 3.84 (t, 1H, H-3, J ) 8.7 Hz), 4.48 (d, 1H, H-1, J(H-1,H-
2) ) 9.5 Hz), 4.58 (d, 1H, PhCHH′, J ) 12.0 Hz), 4.63 (d, 1H,
PhCHH′, J ) 12.0 Hz), 4.65 (d, 1H, PhCHH′, J ) 10.6 Hz),
4.83 (d, 1H, PhCHH′, J ) 10.5 Hz), 4.89 (d, 1H, PhCHH′, J )
10.7 Hz), 4.92 (d, 1H, PhCHH′, J ) 10.3 Hz), 4.92 (d, 1H,
PhCHH′, J ) 10.8 Hz), 4.98 (d, 1H, PhCHH′, J ) 10.8 Hz),
7.22-7.40 (m, 20H, Ar-H); 13C NMR (125 MHz, CDCl3, HSQC)
δ 14.3 (SCH2CH3), 34.2 (SCH2CH3), 69.3, 73.7, 79.4, 79.8, 86.9,
(C-2,3,4,5,6), 90.1 (C-1); MS-ES+ m/z (%) 639 (3) (M+ + Na);
HRMS-ES calcd for C36H40O5S2NH4 (M+ + NH4) 634.2661,
found 634.2661. Anal. Calcd for C36H40O5S2: C, 70.10; H, 6.54.
Found: C, 70.06; H, 6.67.
2,3,4,6-Tetra-O-benzyl-â-D-glucopyranosyl Methane-
thiosulfonate 3a. 3a was prepared using methods A, B, and
C as a mixture of anomers in yields of 76% (â:R ) 7.5:1), 78%
(â:R ) 6.2:1), and 70% (â:R ) 93:7), respectively. The mixed
product could be further purified by column chromatography
(hexane/ethyl acetate 9:1) to afford pure 2,3,4,6-tetra-O-benzyl-
â-D-glucopyranosyl methanethiosulfonate 3a as a white crys-
talline solid: mp 135-137 °C; [R]23 -6.9 (c 1, CHCl3); IR
D
(Nujol) 3028 (Ar C-H), 1325, 1130 (S-SO2) cm-1
;
1H NMR
Pure R-3a was also isolated in the chromatographic proce-
dure as a white crystalline solid: mp 130-133 °C; [R]23.8
(400 MHz, CDCl3, COSY) δ 3.36 (s, 3H, SCH3), 3.60 (dd, 1H,
H-6, J(H-6,H-6′) ) 10.0 Hz, J(H-6,H-5) ) 2.4 Hz), 3.45 (m,
4H, H-2, H-4, H-5, H-6′), 3.78 (pt, 1H, H-3, J ) 8.6 Hz), 4.49
(d, 1H, PhCHH′, J ) 11.6 Hz), 4.51 (d, 1H, PhCHH′, J ) 10.4
Hz), 4.58 (d, 1H, PhCHH′, J ) 10.8 Hz), 4.74 (d, 1H, PhCHH′,
J ) 10.4 Hz), 4.78 (d, 1H, PhCHH′, J ) 10.8 Hz), 4.85 (d, 1H,
PhCHH′, J ) 10.8 Hz), 4.88 (d, 1H, PhCHH′, J ) 11.2 Hz),
4.93 (d, 1H, PhCHH′, J ) 10.8 Hz), 5.12 (d, 1H, H-1, J(H-1,H-
2) ) 10.0 Hz), 7.19-7.22, 7.31-7.37 (m, 20H, Ar-H); 13C NMR
(100 MHz, CDCl3, APT) δ 52.9 (CH3), 68.7 (C-6), 72.3 (PhCH2),
73.1 (PhCH2), 73.2 (PhCH2), 73.5 (PhCH2), 78.3 (C-5), 78.8 (C-
2), 79.3 (C-4), 86.4 (C-3), 87.5 (C-1), 127.7-128.6 (16 × Ar-
CH), 137.0, 137.5, 137.6, 138.0 (Ar-C); MS-ES+ m/z (%) 652
(100) (M+ + NH4), 657 (98) (M+ + Na); HRMS-ES calcd for
C35H38O7S2NH4 (M+ + NH4) 652.2403, found 652.2408.
D
+146.7 (c 1, CHCl3); IR (KBr, disk) 3087, 3063, 3028, 3002
(Ar C-H), 2917, 2868, 2809 (C-H), 1322, 1130 (S-SO2) cm-1
;
1H NMR (500 MHz, CDCl3, COSY) δ 3.30 (s, 3H, CH3), 3.51
(t, 1H, H-4, J ) 9.4 Hz), 3.59 (t, 1H, H-3, J ) 8.8 Hz), 3.63
(dd, 1H, H-6′, J(H-6′,H-5) ) 5.7 Hz, J(H-6′,H-6) ) 10.1 Hz),
3.70 (dd, 1H, H-6, J(H-6,H-5) ) 2.0 Hz, J(H-6,H-6′) ) 10.4
Hz), 3.95 (dd, 1H, H-2, J(H-2,H-1) ) 5.7 Hz, J(H-2,H-3) ) 9.5
Hz), 4.10 (ddd, 1H, H-5, J(H-5,H-6) ) 1.8 Hz, J(H-5,H-6′) )
5.9 Hz, J(H-5,H-4) ) 10.2 Hz), 4.46 (d, 1H, PhCHH′, J ) 11.3
Hz), 4.49 (d, 1H, PhCHH′, J ) 12.0 Hz), 4.52 (d, 1H, PhCHH′,
J ) 12.0 Hz), 4.61 (d, 1H, PhCHH′, J ) 11.3 Hz), 4.75 (d, 1H,
PhCHH′, J ) 11.3 Hz), 4.78 (d, 1H, PhCHH′, J ) 11.3 Hz),
4.84 (d, 1H, PhCHH′, J ) 11.3 Hz), 4.93 (d, 1H, PhCHH′, J )
11.3 Hz), 6.25 (d, 1H, H-1, J(H-1,H-2) ) 5.7 Hz), 7.15-7.19,
7.26-7.39 (m, 20H, Ar-H); 13C NMR (125 MHz, CDCl3, HSQC)
δ 52.1 (CH3), 68.9 (C-6), 72.3 (PhCH2), 73.1 (C-5), 73.5 (PhCH2),
75.2 (PhCH2), 75.7 (PhCH2), 76.7 (C-4), 78.3 (C-2), 82.3 (C-3),
90.0 (C-1), 127.86, 127.89, 127.93, 127.97, 128.18, 128.25,
128.42, 128.46, 128.56 (Ar-CH), 136.66, 137.38, 137.57, 138.06
(Ar-C). MS-ES+ m/z (%): 1291.2 (15) (2M+ + Na), 657.1 (100)
(M+ + Na); HRMS-ES calcd for C35H38O7S2NH4 (M+ + NH4)
652.2403, found 652.2407. Anal. Calcd for C35H38O7S2: C,
66.22; H, 6.03. Found: C, 66.41; H, 6.07.
2,3,4,6-Tetra-O-acetyl-â-D-glucopyranosyl Methane-
thiosulfonate 3c.41 A mixture of 5c (0.800 g, 1.9 mmol) and
sodium methanethiosulfonate (0.390 g, 2.9 mmol) in ethanol
(7 mL) was stirred at 90 °C under nitrogen. The reaction was
followed on thin-layer chromatography (TLC) (ethyl acetate/
hexane 9:11) which revealed conversion of starting material
(Rf ) 0.3) into product (Rf ) 0.2). After 25 min, the resulting
suspension was cooled, and the solvent was removed in vacuo.
The residue was triturated with ether and dried to afford 3c
as a white solid (0.800 g, 95%): mp 148-151 °C (lit.41 mp 151-
152 °C); [R]22 -22 (c 1.0, CHCl3) (lit.41 [R]27 -19 (c 1.24,
Ethyl 2,3,4,6-Tetra-O-acetyl-â-D-glucopyranosyl Disul-
fide 2c. 3c (1.0 g, 2.2 mmol) gave â-2c (0.930 g, 96%) as a
D
D
CHCl3); IR (KBr, disk) 1742 (CdO), 1331, 1139 (S-SO2) cm-1
;
white solid: mp 100-102 °C; [R]24 -178 (c 1.0, CH3OH); IR
D
1H NMR (200 MHz, CDCl3) δ 2.02, 2.06, 2.07, 2.09 (4 × s, 12H,
OAc), 3.45 (s, 3H, SCH3), 3.84 (ddd, 1H, H-5, J(H-5,H-4) )
9.9 Hz, J(H-5,H-6) ) 5.8 Hz, J(H-5,H-6′) ) 2.2 Hz), 4.10 (dd,
1H, H-6, J(H-6,H-6′) ) 12.4 Hz, J(H-6,H-5) ) 5.8 Hz), 4.33
(KBr, disk) 3031 (C-H), 1728 (CdO) cm-1; 1H NMR (500 MHz,
CDCl3, COSY) δ 1.30 (t, 3H, SCH2CH3, J ) 7.2 Hz), 2.00, 2.03,
2.04, 2.07 (4 × s, 12H, OAc), 2.79 (m, 2H, SCH2CH3), 3.73 (ddd,
1H, H-5, J(H-5,H-4) ) 7.8 Hz, J(H-5,H-6) ) 4.8 Hz, J(H-5,H-
J. Org. Chem, Vol. 70, No. 24, 2005 9749

Grayson et al.
6′) ) 2.4 Hz), 4.15 (dd, 1H, H-6, J(H-6,H-6′) ) 12.3 Hz, J(H-
6,H-5) ) 2.4 Hz), 4.22 (dd, 1H, H-6′, J(H-6′,H-6) ) 12.3 Hz,
J(H-6′,H-5) ) 4.8 Hz), 4.51 (pt, 1H, H-2), 5.09 (m, 1H, H-4),
Method C. The disulfide 2 (0.081 mmol), NIS (1.5-10 equiv),
the acceptor 9 (1 equiv), TTBP (1 equiv), and activated
powdered 4 Å molecular sieves (0.15 g) were stirred in dry
dichloromethane (3 mL) under argon at room temperature for
1 h and then cooled to 0 °C. TESOTf (0.5 equiv) was added.
The mixture was allowed to warm to room temperature and
was stirred until TLC (hexane/ethyl acetate 8:2 and 6:4)
showed the disappearance of all starting materials. It was then
diluted with dichloromethane (15 mL), washed with aqueous
sodium thiosulfate (2 × 15 mL), saturated aqueous sodium
bicarbonate (15 mL), water (15 mL), and brine (15 mL), and
dried (MgSO4). Evaporation gave the crude product, which was
purified by column chromatography on silica gel using hexane/
ethyl acetate mixtures.
Method D. The disulfide 2 (0.081 mmol), NIS (10 equiv),
the acceptor 9 (1 equiv), and activated powdered 4 Å molecular
sieves (0.15 g) were stirred in dry dichloromethane (3 mL)
under argon at room temperature for 1 h. TESOTf (0.5 equiv)
was added. The mixture was stirred until TLC (hexane/ethyl
acetate 3:2) showed the disappearance of all starting materials.
It was then diluted with dichloromethane (15 mL), washed
with aqueous sodium thiosulfate (2 × 15 mL), saturated
aqueous sodium bicarbonate (15 mL), water (15 mL), and brine
(15 mL), and dried (MgSO4). Evaporation gave the crude
product, which was purified by column chromatography on
silica gel using hexane/ethyl acetate mixtures.
5.25 (d, 1H, H-1, J(H-1, H-2) ) 8.4 Hz), 5.24 (pt, 1H, H-3); 13
C
NMR (100 MHz, CDCl3, DEPT, HMQC) δ 14.2 (SCH2CH3),
20.5, 20.6, 20.7 × 2 (CH3CO), 34.0 (SCH2CH3), 62.0 (C-6), 68.0
(C-4), 69.1 (C-2), 73.8 (C-3), 75.9 (C-5), 88.0 (C-1), 169.2, 169.4,
170.3, 170.6 (CdO); MS-ES+ m/z (%) 871 (10) (2M+ + Na),
447 (100) (M+ + Na); HRMS-ES calcd for C16H24O9S2H
[M+H]+ 425.0940, found 425.0936. Anal. Calcd for C16H24-
O9S2: C, 45.27; H, 5.70. Found: C, 45.57; H, 5.86.
p-Nitrophenyl 2,3,4,6-Tetra-O-benzyl-r,â-D-glucopyra-
nosyl Disulfide 7a. The methanethiosulfonate 3a (0.11 g,
estimated â-content 0.10 mmol) was placed under nitrogen,
and a solution of triethylamine (12.5 µL, 0.09 mmol) in distilled
dichloromethane (2 mL) was added. The mixture was stirred
and cooled to 0 °C in an ice bath. A solution of p-nitrothiophe-
nol (0.014 g, 0.09 mmol) in dichloromethane (8 mL) was added
dropwise over 1 h. With each drop, a bright orange coloration
appeared transiently. At the end of the addition, the solution
was very pale yellow. All volatile materials were removed in
vacuo leaving an orange oil. The oil was purified by column
chromatography on silica gel using hexane/ethyl acetate 9:1
giving 7a (0.047 g, 73%) (â:R ) 9:1). Further chromatographic
purification gave pure â-7a as a pale yellow solid (67%): mp
104.5-105.5 °C; [R]23.7 -182.2 (c 1, CHCl3); IR (KBr, disk)
D
3027 (ArC-H), 2900 (C-H), 1515, 1340 (NO2) cm-1; 1H NMR
(500 MHz, CDCl3, COSY) δ 3.37-3.41 (m, 1H, H-5), 3.49-3.65
(m, 4 H, H-3, H-4, H-6, H-6′), 3.65 (t, 1H, H-2, J ) 8.7 Hz),
4.29 (d, 1H, PhCHH′, J ) 11.9 Hz), 4.33 (d, 1H, PhCHH′, J )
11.9 Hz), 4.44 (d, 1H, H-1, J(H-1, H-2) ) 8.7 Hz), 4.48 (d, 1H,
PhCHH′, J ) 10.8 Hz), 4.72 (d, 1H, PhCHH′, J ) 10.8 Hz),
4.76 (d, 1H, PhCHH′, J ) 10.4 Hz), 4.80 (d, 1H, PhCHH′, J )
10.4 Hz), 4.81 (d, 1H, PhCHH′, J ) 10.9 Hz), 4.84 (d, 1H,
PhCHH′, J ) 10.9 Hz), 7.05-7.31 (m, 20H, Ar-H), 7.65 (d, 2H,
o-C6H4NO2, J ) 8.8 Hz), 7.87 (d, 2H, m-C6H4NO2, J ) 8.8 Hz);
13C NMR (125 MHz, CDCl3, HSQC) δ 68.8 (C-6), 73.5 (PhCH2),
75.1 (PhCH2), 75.6 (PhCH2), 75.8 (PhCH2), 77.4 (C-3), 79.3 (C-
5), 79.8 (C-4 or C-2), 86.5 (C-4 or C-2), 89.5 (C-1), 123.5, 126.91,
127.44, 127.68, 127.76, 127.85, 127.90, 128.07, 128.13, 128.35,
128.41, 128.47, 128.49 (Ar-CH), 137.50, 137.70, 137.74, 138.14,
146.20, 146.72 (Ar-C); MS-ES+ m/z (%) 732.3 (100) (M+ + Na);
HRMS-ES calcd for C40H39NO7S2NH4 (M+ + NH4) 727.2512,
found 727.2509.
General Procedures for Glycosylations with Disul-
fides 2. Method A. The disulfide 2 (0.081 mmol), NIS (10
equiv), the acceptor 9 (1 equiv), and activated powdered 4 Å
molecular sieves (0.15 g) were stirred in dry dichloromethane
(3 mL) under argon at room temperature for 1 h and then
cooled to 0 °C. TESOTf (0.5 equiv) was added. The mixture
was stirred at 0 °C until TLC (hexane/ethyl acetate 8:2 and
6:4) showed the disappearance of all starting materials. It was
then diluted with dichloromethane (15 mL), washed with
aqueous sodium thiosulfate (2 × 15 mL), saturated aqueous
sodium bicarbonate (15 mL), water (15 mL), and brine (15 mL),
and dried (MgSO4). Evaporation gave the crude product, which
was purified by column chromatography on silica gel using
hexane/ethyl acetate mixtures.
Method B. The disulfide 2 (0.081 mmol), NIS (1.5-3 equiv),
the acceptor 9 (1 equiv), and activated powdered 4 Å molecular
sieves (0.15 g) were stirred in dry dichloromethane (3 mL)
under argon at room temperature for 1 h and then cooled to 0
°C. TESOTf (0.5 equiv) was added. The mixture was allowed
to warm to room temperature and was stirred until TLC
(hexane/ethyl acetate 8:2 and 6:4) showed the disappearance
of all starting materials. It was then diluted with dichlo-
romethane (15 mL), washed with aqueous sodium thiosulfate
(2 × 15 mL), saturated aqueous sodium bicarbonate (15 mL),
water (15 mL), and brine (15 mL), and dried (MgSO4).
Evaporation gave the crude product, which was purified by
column chromatography on silica gel using hexane/ethyl
acetate mixtures.
Method E. The disulfide 2 (0.081 mmol), the acceptor 9 (1
equiv), and activated powdered 4 Å molecular sieves (0.15 g)
were stirred in dry dichloromethane (3 mL) under argon at
room temperature for 1 h and then cooled to 0 °C. A freshly
prepared solution of DMTST58,59 (3,4,5, or 6 equiv) was added.
The mixture was allowed to warm to room temperature and
was stirred until TLC (hexane/ethyl acetate 8:2 and 6:4)
showed the disappearance of all starting materials. It was then
diluted with dichloromethane (15 mL), washed with saturated
aqueous sodium bicarbonate (15 mL), water (15 mL), and brine
(15 mL), and dried (MgSO4). Evaporation gave the crude
product, which was purified by column chromatography on
silica gel using hexane/ethyl acetate mixtures.
Method F. The disulfide 2 (0.23 mmol) and the acceptor 9
(1 equiv) were refluxed with molecular sieves (4 Å beads, 200
mg) in dichloromethane (4 mL) under nitrogen. After 20 min,
N-iodosuccinimide (2.5 equiv) was added. The reaction was
followed by TLC (hexane/ethyl acetate 3:2) to show consump-
tion of starting materials. Solids were removed by filtration,
and the filtrate was diluted with dichloromethane (50 mL),
washed with aqueous sodium thiosulfate (20 mL), and dried
(Na2SO4). The solvent was removed in vacuo, and the crude
product was purified by column chromatography (hexane/ethyl
acetate mixtures).
Method G. The disulfide 2 (0.23 mmol) and the acceptor 9
(1 equiv) with molecular sieves (4 Å beads, 200 mg) were
stirred in dichloromethane (6 mL), or acetonitrile (6 mL) was
stirred under argon at room temperature. To this was added
N-iodosuccinimide (2.5 equiv) and a solution of trifluo-
romethanesulfonic acid in dichloromethane (0.15 M, 1 mL).
The reaction was followed by TLC (hexane/ethyl acetate 3:2)
to show consumption of starting materials. Solids were re-
moved by filtration, and the filtrate was diluted with dichlo-
romethane (50 mL), washed with aqueous sodium thiosulfate
(20 mL) and saturated sodium bicarbonate solution (2 × 20
mL), and dried (Na2SO4). If acetonitrile was used, then this
was removed first in vacuo. The solvent was removed in vacuo,
and the crude product was purified by column chromatography
(hexane/ethyl acetate, mixtures).
Method H.83 The disulfide 2 (0.18 mmol) and the acceptor 9
(1 equiv) with molecular sieves (3 Å beads, 100 mg) were
stirred in dry dichloromethane (5 mL), or acetonitrile (5 mL)
was stirred under argon at room temperature. After 2 h,
N-iodosuccinimide (10 equiv) and trimethylsilyltrifluoro-
(83) Demchenko, A.; Stauch, T.; Boons, G.-J. Synlett 1997, 818.
9750 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
methanesulfonate (0.5 equiv) were added. The reaction was
followed by TLC (hexane/ethyl acetate 3:2) to show consump-
tion of starting materials. Solids were removed by filtration
and the filtrate was diluted with dichloromethane (50 mL),
washed with aqueous sodium thiosulfate (20 mL) and water
(3 × 20 mL), and dried (Na2SO4). If acetonitrile was used, then
this was removed first in vacuo. The solvent was removed in
vacuo, and the crude product was purified by column chro-
matography (hexane/ethyl acetate, mixtures).
gave 11a (R:â ) 1:1) (0.048 g, 76%). Using method E with 4
equiv of DMTST and 4.4 equiv of TTBP, a reaction time of 1
h, 2a (0.04 g, 0.065 mmol), and 9b (0.015 g, 0.065 mmol) gave
11a (R:â ) 1:1) (0.041 g, 80%).
N-(Benzyloxycarbonyl)-O-(2,3,4,6-tetra-O-benzyl-râ-D-
glucopyranosyl)-L-serine Methyl Ester (12a). Using method
A, a reaction time of 1.5 h, 2a (0.117 g, 0.19 mmol), and 9c48
(0.048 g, 0.19 mmol) gave 12a (0.042 g, 73%) and TLC
conversion (ethyl acetate /hexane 2:3); Rf ) 0.7 f 0.3,0.4 as a
mixture of anomers (R:â ) 1:1) after column chromatography
(hexane/ethyl acetate 8:2) as a clear oil. Additional column
chromatography (hexane/ethyl acetate 8:2) furnished a pure
sample of R-12a as a colorless oil: IR (thin film) 3339 (C-H),
2918 (N-H), 1725 (br, CdO, amide I), 1512 (amide II), 737-
In Situ Preparation of DMTST.58,59 Dimethyl disulfide
(36 µL, 0.40 mmol) was added to a stirred solution of methyl
triflate (45 µL, 0.40 mmol) in dry dichloromethane (1 mL) at
0 °C. The mixture was then stirred at room temperature for
2-3 h and used immediately.
1
Methyl 2,3,4,6-Tetra-O-benzyl-râ-D-glucopyranoside
(10a). Using method A, a reaction time of 1 h, 2a (0.080 g,
0.13 mmol), and 9a (4 µL, 0.13 mmol) gave 10a (0.065 g, 90%)
and TLC conversion (EtOAc/hexane 4:1); Rf ) 0.5 f 0,2,0.3
as a mixture of anomers (R:â ) 9:15) after column chroma-
tography (hexane/ethyl acetate 9:1). The spectroscopic and
analytical data were in agreement with those reported in the
literature.84,85 Additional column chromatography (dichlo-
romethane/ethyl acetate 20:1) furnished a pure sample of the
668 (ArCH) cm-1; H NMR (400 MHz, CDCl3, COSY) δ 3.53
(dd, 1H, H-2, J(H-2,H-3) ) 9.6 Hz, J(H-2,H-1) ) 4.0 Hz), 3.61
(dd, 1H, CHH′CH, J ) 14.0 Hz, J ) 4.4 Hz), 3.62 (pt, 1H, H-4,
J ) 6.0 Hz), 3.70 (s, 3H, OCH3), 3.81 (m, 1H, H-5), 3.83 (dd,
1H, H-6, J(H-6,H-6′) ) 10.8 Hz, J(H-6,H-5) ) 3.6 Hz), 3.85
(m, 1H, CHH′CH), 3.89 (pt, 1H, H-3, J ) 9.4 Hz), 4.13 (dd,
1H, H-6′, J(H-6′,H-6) ) 10.6 Hz, J(H-6′,H-5) ) 3.2 Hz), 4.41
(d, 1H, PhCHH, J ) 12.0 Hz), 4.46 (d, 1H, PhCHH, J ) 10.8
Hz), 4.52 (d, 1H, PhCHH, J ) 10.8 Hz), 4.53 (m, 1H, CH2CH),
4.59 (d, 1H, PhCHH, J ) 11.6 Hz), 4.70 (d, 1H, PhCHH, J )
12.0 Hz), 4.74 (d, 1H, H-1, J(H-1,H-2) ) 3.6 Hz), 4.79 (d, 1H,
PhCHH, J ) 10.8 Hz), 4.81 (d, 1H, PhCHH, J ) 10.8 Hz), 4.93
(d, 1H, PhCHH, J ) 11.2 Hz), 5.11 (s, 2H, PhCH2), 6.03 (d,
1H, NH, J ) 9.2 Hz), 7.28-7.42 (m, 25H, Ar-H); MS-ES+ m/z
(%) 798 (100) (M+ + Na). The spectroscopic and analytical data
were in agreement with those reported in the literature.54,84
â-anomer as a colorless oil: [R]23 +12.0 (c 1.0, CHCl3); 1H
D
NMR (500 MHz, CDCl3, COSY) δ 3.45 (pt, 1H, H-2, J ) 8.3
Hz), 3.45-3.50 (m, 1H, H-5), 3.59 (s, 3H, OCH3), 3.60 (pt, 1H,
H-4, J ) 9.0 Hz), 3.66 (pt, 1H, H-3, J ) 8.7 Hz), 3.70 (dd, 1H,
H-6, J(H-6,H-6′) ) 11.0 Hz, J(H-6,H-5) ) 5.0 Hz), 3.77 (dd,
1H, H-6′, J(H-6′,H-6) ) 11.0 Hz, J(H-6′,H-5) ) 2.0 Hz), 4.32
(d, 1H, H-1, J(H-1,H-2) ) 7.5 Hz), 4.54 (d, 1H, PhCHH′, J )
10.5 Hz), 4.57 (d, 1H, PhCHH′, J ) 12.5 Hz), 4.63 (d, 1H,
PhCHH′, J ) 12.0 Hz), 4.72 (d, 1H, PhCHH′, J ) 11.0 Hz),
4.80 (d, 1H, PhCHH′, J ) 11.0 Hz), 4.83 (d, 1H, PhCHH′, J )
10.5 Hz), 4.93 (d, 1H, PhCHH′, J ) 11.0 Hz), 4.94 (d, 1H,
PhCHH′, J ) 10.5 Hz), 7.15-7.17, 7.27-7.36 (m, 20H, Ar-H);
MS-ES+ m/z (%) 577 (100) (M+ + Na).
Using method E, a reaction time of 1.5 h, 2a (0.05 g, 0.081
mmol), and 9c (0.020 g, 0.081 mmol) gave 12a (R:â ) 1.7:1)
(0.047 g, 73%).
1,2:3,4-Di-O-isopropylidene-3-O-(2,3,4,6-tetra-O-benzyl-
râ-D-glucopyranosyl)-r-D-glucopyranose (13a). Using
method C, a reaction time of 21 h, 2a (0.05 g, 0.081 mmol), 9d
(0.021 g, 0.081 mmol), and NIS (0.18 g, 0.81 mmol) gave 13a
(R:â ) 1.7:1) (0.036 g, 56%) after column chromatography
(hexane/ethyl acetate 8:2). Repeated column chromatography
furnished pure samples of the R- and â-anomers as colorless
oils. Data for R-13a: [R]26D +43.8 (c 0.55, CHCl3); IR (thin film)
3087, 3063, 3030 (Ar C-H), 2986, 2932 (C-H) cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.16, 1.18, 1.34, 1.41 (4 × s, 12H, CH3),
3.49 (dd, 1H, H-2′, J(H-2′,H-1′) ) 3.5 Hz, J(H-2′,H-3′) ) 9.8
Hz), 3.54 (t, 1H, H-4′, J ) 9.5 Hz), 3.61-3.67 (m, 2H, H-6′),
3.70-3.75 (m, 1H, H-5′), 3.87 (t, 1H, H-3′, J ) 9.3 Hz), 3.95-
4.01 (m, 2H, H-6), 4.06 (dd, 1H, H-4, J(H-4,H-3) ) 2.8 Hz, J(H-
4,H-5) ) 8.2 Hz), 4.16 (d, 1H, H-3, J(H-3,H-4) ) 2.8 Hz), 4.38
(d, 1H, PhCHH′, J ) 10.7 Hz), 4.39-4.44 (m, 1H, H-5), 4.42
(d, 1H, PhCHH′, J ) 12.1 Hz), 4.55 (d, 1H, PhCHH′, J ) 12.1
Hz), 4.59 (d, 1H, H-2, J(H-2,H-1) ) 3.6 Hz), 4.63 (d, 1H,
PhCHH′, J ) 11.8 Hz), 4.68 (d, 1H, PhCHH′, J ) 11.9 Hz),
4.73 (d, 1H, PhCHH′, J ) 10.8 Hz), 4.77 (d, 1H, PhCHH′, J )
10.5 Hz), 4.89 (d, 1H, PhCHH′, J ) 11.1 Hz), 5.18 (d, 1H, H-1′,
J(H-1′,H-2′) ) 3.5 Hz), 5.80 (d, 1H, H-1, J(H-1,H-2) ) 3.6 Hz),
7.03-7.30 (m, 20H, Ar-H); 13C NMR (125 MHz, CDCl3, HSQC)
δ 25.5, 26.1, 26.8, 27.0 (CH3), 67.0 (C-6), 68.5 (C-6′), 71.2 (C-
5′), 72.3 (C-5), 73.0 (PhCH2), 73.5 (PhCH2), 75.3 (PhCH2), 75.6
(PhCH2), 77.6 (C-4′), 79.9 (C-2′), 80.6 (C-3), 81.2 (C-4), 81.5
(C-3′), 83.7 (C-2), 97.9 (C-1′), 105.2 (C-1), 109.0, 111.8 ((CH3)2C),
127.55, 127.59, 127.69, 127.74, 127.87, 127.93, 128.02, 128.06,
128.38, 128.39, 128.45 (Ar-CH), 137.80, 137.91, 138.13, 138.62
(Ar-C); MS-ES+ m/z (%) 805.3 (100) (M+ + Na). Data for
Using method E, a reaction time of 2 h, 2a (0.05 g, 0.081
mmol), and 9a (23 µL, 0.81 mmol) gave 10a (R:â ) 1:2) (0.036
g, 78%).
1,2:3,4-Di-O-isopropylidene-6-O-(2,3,4,6-tetra-O-benzyl-
râ-D-glucopyranosyl)-r-D-galactopyranose (11a). Using
method A, a reaction time of 40 min, 2a (0.080 g, 0.13 mmol),
and 9b (0.034 g, 0.13 mmol) gave 11a (0.076 g, 75%) and TLC
conversion (ethyl acetate/hexane 2:3); Rf ) 0.3 f 0.6 as a
mixture of anomers (R:â ) 9:11) after column chromatography
(hexane/ethyl acetate 8:2). Additional column chromatography
(dichloromethane/ethyl acetate 20:1) furnished a pure sample
of the â-anomer as a colorless oil: 1H NMR (300 MHz, C6D6)
δ 1.02, 1.12, 1.44, 1.47 (4 × s, 12H, CH3), 3.29 (ddd, 1H, H-5′,
J(H-5′,H-4) ) 9.3 Hz, J(H-5′,H-6) ) 3.9 Hz, J(H-5′,H-6′) ) 2.1
Hz), 3.60 (dd, 1H, H-2′, J(H-2′,H-1′) ) 5.7 Hz, J(H-2′,H-3′) )
3.6 Hz), 3.64 (dd, 1H, H-6′b, J(H-6′b,H-6′a) ) 11.6 Hz, J(H-
6′b,H-5′) ) 2.1 Hz), 3.74 (dd, 1H, H-3′, J(H-3′,H-2′) ) 11.4 Hz,
J(H-3′,H-4′) ) 9.0 Hz), 3.90 (dd, 1H, H-6b, J(H-6b,H-6a) ) 7.8
Hz, J(H-6b,H-5) ) 1.5 Hz), 4.03 (dd, 1H, H-3, J(H-3,H-2) )
10.6 Hz, J(H-3,H-4) ) 7.6 Hz), 4.16 (dd, 1H, H-4, J(H-4,H-5)
) 4.8 Hz, J(H-4,H-3) ) 2.4 Hz), 4.24 (ddd, 1H, H-5, J(H-5,H-
4) ) 7.5 Hz, J(H-5,H-6a) ) 4.5 Hz, J(H-5,H-6b) ) 1.8 Hz), 4.43
(dd, 1H, H-6a, J(H-6a,H-6b) ) 7.8 Hz, J(H-6a,H-5) ) 2.1 Hz),
4.50 (dd, 1H, H-6′a, J(H-6′a,H-6′b) ) 7.5 Hz, J(H-6′a,H-5′) )
1.8 Hz), 4.51 (d, 1H, H-1′, J(H-1′,H-2′) ) 11.0 Hz), 4.38, 4.46,
4.50, 4.81, 4.86, 4.90, 5.06 (8 × d, 8H, PhCH2), 5.55 (d, 1H,
H-1, J(H-1,H-2) ) 4.8 Hz), 7.07-7.61 (m, 20H, Ar-H); MS-
ES+ m/z (%) 805 (45) (M+ + Na). The spectroscopic and
analytical data were in agreement with those reported in the
literature.53,84
â-13a: [R]26.1 +7.9 (c 0.5, CHCl3); IR (thin film) 3063, 3030
D
(Ar C-H), 2985 (C-H) cm-1
;
1H NMR (500 MHz, CDCl3) δ
3.31 (t, 1H, H-2′, J(H-2′,H-1′) ) 8.3 Hz), 3.34-3.38 (m, 1H,
H-5′), 3.55-3.58 (m, 2H, H-3′, H-4′), 3.64 (d, 2H, H-6′, J(H-
6′,H-5′) ) 2.9 Hz), 4.00 (d, 2H, H-6, J(H-6,H-5) ) 6.2 Hz), 4.27
(d, 1H, H-3, J(H-3,H-4) ) 3.1 Hz), 4.31 (dd, 1H, H-4, J(H-4,H-
5) ) 4.4 Hz, J(H-4,H-3) ) 2.8 Hz), 4.37 (dt, 1H, H-5, J(H-5,H-
6) ) 6.2 Hz, J(H-5,H-4) ) 4.6 Hz), 4.39 (d, 1H, H-1′, J ) 7.9
Hz), 4.42 (d, 1H, H-2, J(H-2,H-1) ) 3.8 Hz), 4.48 (d, 1H,
Using method E with 5 equiv of DMTST, a reaction time of
30 min, 2a (0.05 g, 0.081 mmol), and 9b (0.021 g, 0.081 mmol)
(84) Vankayalapati, H.; Singh, G.; Tranoy, I. Tetrahedron: Asym-
metry 2001, 12, 1373-1381.
(85) Briner, K.; Vasella, A. Helv. Chim. Acta 1992, 75, 621-635.
J. Org. Chem, Vol. 70, No. 24, 2005 9751

Grayson et al.
PhCHH′, J ) 12.3 Hz), 4.51 (d, 1H, PhCHH′, J ) 12.1 Hz),
4.55 (d, 1H, PhCHH′, J ) 12.0 Hz), 4.66 (s, 2H, PhCH2), 4.74
(d, 1H, PhCHH′, J ) 10.8 Hz), 4.75 (d, 1H, PhCHH′, J ) 11.00
Hz), 4.83 (d, 1H, PhCHH′, J ) 11.00 Hz), 5.70 (d, 1H, H-1,
J(H-1,H-2) ) 3.8 Hz), 7.03-7.14, 7.16-7.33 (m, 20H, Ar-H);
13C NMR (125 MHz, CDCl3, HSQC) δ 25.3, 26.1, 26.5, 26.7
(CH3), 65.8 (C-6), 68.5 (C-6′), 73.5 (PhCH2), 73.6 (C-5), 75.0
(PhCH2), 75.1 (PhCH2), 75.4 (PhCH2), 75.7 (C-5′), 77.6 (C-3′
or C-4′), 80.2 (C-3 and C-4), 82.1 (C-2′), 82.6 (C-2), 84.6 (C-3′
or C-4′), 101.3 (C-1′), 105.1 (C-1), 108.5, 111.8 ((CH3)2C),
127.89, 127.92, 128.01, 128.09, 128.29, 128.64, 128.66, 128.69,
128.74 (Ar-CH), 138.23, 138.37, 138.45, 138.70 (Ar-C); MS-
ES+ m/z (%) 805.3 (100) (M+ + Na), 503.2 (95). The spectro-
scopic and analytical data were in agreement with those
reported in the literature.84,86
Calcd for C48H62O10Si: C, 69.70; H, 7.56. Found: C, 69.45; H,
7.61. 16a (0.011 g, 21%) was also obtained.
Using method E with 4 equiv of DMTST and 4.4 equiv of
TTBP, a reaction time of 18 h, 2a (0.04 g, 0.065 mmol), and
9e (0.02 g, 0.065 mmol) gave 14a (R:â ) 6:1) (0.033 g, 61%).
1,2-Di-O-isopropylidene-5-O-tert-butyldiphenylsilyl-3-
O-(2,3,4,6-tetra-O-benzyl-râ-D-glucopyranosyl)-r-D-xylo-
furanose (15a). Using method B, a reaction time of 18 h, 2a
(0.05 g, 0.081 mmol), 9f (0.034 g, 0.081 mmol), and NIS (0.054
g, 0.243 mmol) gave, after column chromatography (hexane/
ethyl acetate 9:1), 15a (0.032 g, 41%) as a colorless oil
consisting of an inseparable mixture of anomers (R:â ) 3.4:1):
[R]26.9 +14.05 (c 1, CHCl3); IR (thin film) 3087, 3065, 3030
D
(Ar C-H), 2930, 2891, 2857 (C-H) cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.05, 1.07 (2 × s, 9H, (CH3)3C), 1.22, 1.27, 1.40, 1.52
(4 × s, 6H, (CH3)2C), 3.29-4.96 (m, ca. 19H), 5.08 (d, HR-1′,
J(HR-1′,HR-2′) ) 3.3 Hz), 5.75 (d, Hâ-1, J(Hâ-1,Hâ-2) ) 3.9 Hz),
5.87 (d, HR-1, J(HR-1,HR-2) ) 3.7 Hz), 7.09-7.48, 7.60-7.77
(m, 30H, Ar-H). 1H NMR (500 MHz, CDCl3, assignments were
made for the ring protons of the individual isomers using two-
dimensional COSY, HSQC, and TOCSY experiments) R-15a:
δ 3.43 (dd, 1H, H-2′, J(H-2′,H-1′) ) 3.5 Hz, J(H-2′,H-3′) ) 9.7
Hz), 3.49 (dd, 1H, H-4′, J(H-4′,H-3′) ) 9.2 Hz, J(H-4′,H-5′) )
9.8 Hz), 3.61 (m, 2H, H-6a′, H-6b′), 3.71 (m, 1H, H-5′), 3.80
(dd, 1H, H-3′, J ) 9.2 Hz, J ) 9.3 Hz), 3.89 (dd, 1H, H-5a, J
) 3.6 Hz, J ) 8.9 Hz), 4.07 (m, 1H, H-5b), 4.09 (m, 1H, H-3),
4.11 (m, 1H, H-4), 4.60 (d, 1H, H-2, J(H-2,H-1) ) 3.6 Hz), 4.99
(d, 1H, H-1′, J(H-1′,H-2′) ) 3.3 Hz), 5.78 (d, 1H, H-1, J(H-
1,H-2) ) 3.7 Hz). â-15a: δ 3.25 (dd, 1H, H-2′, J ) 7.9 Hz, J )
8.9 Hz), 3.35 (m, 1H, H-4′), 3.56 (m, 4 H, H-3′, H-5′, H-6a′,
H-6b′), 3.85 (dd, 1H, H-5a, J(H-5a,H-4) ) 5.9 Hz, J(H-5a,H-
5b) ) 10.6 Hz), 3.94 (dd, 1H, H-5b, J(H-5b,H-4) ) 6.2 Hz, J(H-
5b,H-5a) ) 10.6 Hz), 4.32 (m, 1H, H-4), 4.36 (m, 1H, H-3), 4.41
(d, 1H, H-1′, J(H-1′,H-2′) ) 7.8 Hz), 4.49 (d, 1H, H-2, J(H-
2,H-1) ) 3.8 Hz), 5.66 (d, 1H, H-1, J(H-1,H-2) ) 3.9 Hz); 13C
NMR (125 MHz, CDCl3, HSQC, assignable signals) δ 19.1
((CH3)3CSi), 26.1-26.9 ((CH3)2C, (CH3)3CSi), 68.6 (CR-6′), 68.9
(Câ-6′), 71.2 (CR-5′), 72.8-75.6 (PhCH2), 77.5 (CR-4′), 77.7 (Câ-
5′), 79.1 (Câ-3), 79.7 (CR-2′), 80.6 (CR-3), 80.7 (Câ-4), 81.0 (CR-
4), 81.5 (CR-3′ and CR-5), 81.7 (Câ-2′), 82.1 (Câ-2), 83.3 (CR-2),
84.6 (Câ-3′), 98.1 (CR-1′), 100.8 (Câ-1′), 104.8 (Câ-1), 104.9 (CR-
1), 115.6 ((CH3)2C), 127.5-133.5 (Ar-CH), 135.4-138.6 (Ar-
C); MS-ES+ m/z (%) 973.5 (100) (M+ + Na); HRMS-ES calcd
for C58H66O10SiNH4 (M+ + NH4) 968.4764, found 968.4774. 16a
(0.014 g, 27%) was also obtained.
A byproduct, the succinimidyl adduct 16a (0.011 g, 21%),
was also obtained as a colorless oil consisting of an inseparable
mixture of anomers: [R]23.6D +23.2 (c 1, CHCl3); IR (thin film)
3062, 3028 (Ar C-H), 2927, 2867 (C-H), 1715 (CdO) cm-1
;
1H NMR (500 MHz, CDCl3 COSY, assignments made for the
major, â-anomer) δ 2.49-2.54 (m, 4 H, (CH2)2), 3.54-3.65 (m,
3H, H-4, H-6, H-6′), 3.92 (dd, 1H, H-2, J(H-2,H-1) ) 7.4 Hz,
J(H-2,H-3) ) 9.0 Hz), 4.08 (ddd, 1H, H-5, J ) 2.2 Hz, J ) 3.5
Hz, J ) 10.0 Hz), 4.36-4.58 (m, 5 H, PhCH2), 4.55 (t, 1H, H-3,
J ) 9.1 Hz), 4.72-4.87 (m, 3H, PhCH2), 5.95 (d, 1H, H-1, J(H-
1,H-2) ) 7.5 Hz), 7.06-7.27 (m, 20H, Ar-H); 13C NMR (125
MHz, CDCl3) δ 28.1 (CH2)2), 68.8 (C-6), 73.3 (PhCH2), 73.4
(PhCH2), 74.5 (C-3), 75.2 (PhCH2), 75.9 (C-1), 75.9 (C-5), 77.3
(C-4), 78.4 (C-2), 83.1, 127.43-128.39 (Ar-CH), 137.44, 137.86,
138.39, 138.82 (Ar-C), 177.6 (CdO); MS-ES+ m/z (%) 1266.6
(10) (2M+ + Na), 644.7 (100) (M+ + Na); HRMS-ES calcd for
C38H39NO7NH4 (M+ + NH4) 639.3065, found 639.3061.
Using method E with 4 equiv of DMTST and 4.4 equiv of
TTBP, a reaction time of 18 h, 2a (0.04 g, 0.065 mmol), and
9d (0.015 g, 0.065 mmol) gave 13a (R:â ) 1.6:1) (0.039 g, 76%).
1,2-Di-O-isopropylidene-5-O-tert-butyldimethylsilyl-3-
O-(2,3,4,6-tetra-O-benzyl-râ-D-glucopyranosyl)-r-D-xylo-
furanose (14a). Using method B, a reaction time of 22 h, 2a
(0.05 g, 0.081 mmol), 9e (0.024 g, 0.081 mmol), and NIS (0.054
g, 0.243 mmol) gave, after column chromatography with
hexane/ethyl acetate 8:2, 14a (R-anomer only) as a colorless
oil which slowly solidified to give white crystals (0.052 g,
77%): mp 105-108 °C; [R]27.1D +24.5 (c 0.85, CHCl3); IR (thin
film) 3087, 3063, 3030 (Ar C-H), 2951, 2928, 2883, 2856 (C-
H) cm-1; 1H NMR (500 MHz, CDCl3, COSY) δ 0.00, 0.026 (2 ×
s, 6H, (CH3)2Si), 0.84 (s, 9H, (CH3)3C), 1.19, 1.45 (2 × s, 6H,
(CH3)2C), 3.50 (dd, 1H, H-2′, J(H-2′,H-1′) ) 3.4 Hz, J(H-2′,H-
3′) ) 9.7 Hz), 3.56 (t, 1H, H-4′, J ) 9.5 Hz), 3.62-3.70 (m, 2H,
H-6′), 3.75-3.80 (m, 1H, H-5′), 3.82 (dd, 1H, H-5a, J(H-5a,H-
4) ) 5.3 Hz, J(H-5a,H-5b) ) 10.5 Hz), 3.90 (t, 1H, H-3′, J )
9.4 Hz), 4.03 (dd, 1H, H-5b, J(H-5b,H-4) ) 7.5 Hz, J(H-5b,H-
5a) ) 10.6 Hz), 4.15-4.17 (m, 1H, H-3), 4.17-4.21 (m, 1H,
H-4), 4.42 (d, 1H, PhCHH′, J ) 10.8 Hz), 4.45 (d, 1H, PhCHH′,
J ) 12.1 Hz), 4.57 (d, 1H, PhCHH′, J ) 12.1 Hz), 4.63 (d, 1H,
PhCHH′, J ) 12.5 Hz), 4.65 (d, 1H, H-2, J(H-2,H-1) ) 3.7 Hz),
4.69 (d, 1H, PhCHH′, J ) 12.0 Hz), 4.75 (d, 1H, PhCHH′, J )
11.0 Hz), 4.79 (d, 1H, PhCHH′, J ) 10.6 Hz), 4.90 (d, 1H,
PhCHH′, J ) 10.9 Hz), 5.07 (d, 1H, H-1′, J(H-1′,H-2′) ) 3.4
Hz), 5.84 (d, 1H, H-1, J(H-1,H-2) ) 3.5 Hz), 7.07-7.14, 7.20-
7.31 (m, 20H, Ar-H); 13C NMR (125 MHz, CDCl3, HSQC) δ
-5.28, -5.15 ((CH3)Si), 18.2 ((CH3)3CSi), 25.9 ((CH3)3CSi), 26.2,
26.8 ((CH3)2C), 59.9 (C-5), 68.5 (C-6′), 71.1 (C-5′), 73.0 (PhCH2),
73.5 (PhCH2), 75.2 (PhCH2), 75.6 (PhCH2), 77.6 (C-4′), 79.9
(C-2′), 80.7 (C-3), 81.0 (C-4), 81.5 (C-3′), 83.4 (C-2), 98.1 (C-
1′), 105.9 (C-1), 111.6 ((CH3)2C), 127.56, 127.67, 127.69, 127.71,
127.80, 127.89, 127.92, 127.98, 128.00, 128.32, 128.36, 128.38,
128.42, 128.44 (Ar-CH), 137.83, 137.99, 138.12, 138.67 (Ar-
C); MS-ES+ m/z (%) 894.4 (100) (M+ + Na); HRMS-ES calcd
for C48H62O10SiNa (M+ + Na) 849.4010, found 849.4001. Anal.
Using method E, a reaction time of 27 h, 2a (0.05 g, 0.081
mmol), and 9f (0.034 g, 0.081 mmol) gave 15a (R:â ) 3:1) (0.044
g, 56%).
Methyl 2,3,4,6-Tetra-O-acetyl-â-D-glucopyranoside (10c).
Using method D, a reaction time of 15 min, 2c (0.080 g, 0.19
mmol), and 9a (6 µL, 0.19 mmol) gave 10c (â-anomer only)
and TLC conversion (hexane/EtOAc 3:2; Rf ) 0.3 f 0.2) (0.031
g, 24%) after column chromatography (hexane/ethyl acetate
1
1:1); IR (thin film) 3352 (C-H), 1730 (CdO) cm-1; H NMR
(200 MHz, CDCl3) δ 2.00, 2.02, 2.04, 2.05 (4 × s, 12H, OAc),
3.50 (s, 3H, OCH3), 3.64-3.74 (m, 2H), 4.42 (d, 1H, H-1, J(H-
1,H-2) ) 8.0 Hz), 4.14 (dd, 1H, H-6, J(H-6,H-6′) ) 12.2 Hz,
J(H-6,H-5) ) 2.4 Hz), 4.28 (dd, 1H, H-6′, J(H-6′,H-6) ) 12.2
Hz, J(H-6′,H-5) ) 4.5 Hz), 4.94-5.21 (m, 2H); MS-ES+ m/z
(%) 701 (6) (2M+ + Na), 484 (100), 385 (2) (M+ + Na). The
spectroscopic and analytical data were in agreement with those
reported in the literature.87,88
1,2:3,4-Di-O-isopropylidene-6-O-(2,3,4,6-tetra-O-acetyl-
â-D-glucopyranosyl)-r-D-galactopyranose (11c). Using
method D, a reaction time of 2 h, 2c (0.10 g, 0.23 mmol), and
9b (0.061 g, 0.23 mmol) gave 11c (â-anomer only) (0.05 g, 36%)
after column chromatography (hexane/ethyl acetate 1:1). The
spectroscopic and analytical data were in agreement with those
reported in the literature:89 mp 138-142 °C (lit.90 140-141
°C); [R]21 -35 (c 2.25, CH3OH) (lit.91 [R]27 -53 (c 1.05,
D
D
CHCl3)); 1H NMR (300 MHz, CDCl3) δ 1.30, 1.42, 1.48 (3 × s,
(86) Garegg, P. J.; Ortega, C.; Samuelsson, B. Acta Chem. Scand. B
1981, 35, 631-633.
12H, CH3), 1.98, 2.00, 2.05, 2. 05 (4 × s, 12H, OAc), 3.66 (dd,
9752 J. Org. Chem., Vol. 70, No. 24, 2005

Glycosyl Disulfides
1H, H-6b, J(H-6b,H-6a) ) 11.4 Hz, J(H-6b,H-5) ) 7.2 Hz), 3.68
(m, 1H, H-5′), 3.91 (m, 1H, H-5), 4.00 (dd, 1H, H-6a, J(H-6a,H-
6b) ) 11.4 Hz, J(H-6a,H-5) ) 3.3 Hz), 4.11 (m, 1H, H-6b′), 4.16
(dd, 1H, H-4, J(H-4,H-3) ) 7.8 Hz, J(H-4,H-5) )1.9 Hz), 4.23
(pd, 1H, H-6a′), 4.27 (dd, 1H, H-2, J(H-2,H-3) ) 5.1 Hz, J(H-
2,H-1) ) 2.4 Hz), 4.56 (dd, 1H, H-3, J(H-3,H-2) ) 8.1 Hz, J(H-
3,H-4) ) 2.4 Hz), 4.60 (d, 1H, H-1, J(H-1,H-2) ) 8.1 Hz), 4.98
(dd, 1H, H-2′, J(H-2′,H-3′) ) 9.6 Hz, J(H-2′,H-1′) ) 7.8 Hz),
5.06 (pt, 1H, H-3′), 5.20 (pt, 1H, H-4′), 5.48 (d, 1H, H-1, J(H-
1,H-2) ) 4.8 Hz); MS-ES+ m/z (%) 613 (100) (M+ + Na);
HRMS-ES calcd for C26H38O15Na (M+ + Na) 613.2108, found
613.2109.
Using method F, a reaction time of 24 h, 2c (0.10 g, 0.23
mmol), and 9b (0.061 g, 0.23 mmol) gave 11c (â-anomer only)
(0.026 g, 18%) after column chromatography (hexane/ethyl
acetate 1:1).
Using method G in DCM, a reaction time of 22 h, 2c (0.10
g, 0.23 mmol), and 9b (0.061 g, 0.23 mmol) gave 11c (â-anomer
only) (0.036 g, 26%) after column chromatography (hexane/
ethyl acetate 1:1).
Using method G in CH3CN, a reaction time of 22 h, 2c (0.10
g, 0.23 mmol), and 9b (0.061 g, 0.23 mmol) gave 11c (â-anomer
only) (2 mg, 2%) after column chromatography (hexane/ethyl
acetate 1:1).
Using method H in DCM, a reaction time of 22 h, 2c (80
mg, 0.18 mmol), and 9b (0.050 g, 0.18 mmol) gave 11c
(â-anomer only) (0.032 g, 30%) after column chromatography
(hexane/ethyl acetate 1:1).
Using method H in CH3CN, a reaction time of 22 h, 2c (0.10
g, 0.23 mmol), and 9b (0.061 g, 0.23 mmol) gave 11c (â-anomer
only) (0.022 g, 16%) after column chromatography (hexane/
ethyl acetate 1:1).
the reaction mixture was diluted with dichloromethane (15
mL), washed with saturated aqueous sodium bicarbonate (15
mL), water (15 mL), and brine (15 mL), and dried (MgSO4).
Evaporation, followed by column chromatography (hexane/
ethyl acetate 8:2 to 1:1) furnished 0.034 g of a mixture of 2a
1
(22%) and 8a (47%) as a white solid: selected H NMR (400
MHz, CDCl3) δ 1.22 (t, SCH2CH3 in 2a, J ) 7.5 Hz), 2.44 (s,
SCH3 in 8a), 2.71-2.83 (m, SCH2CH3 in 2a); selected 13C NMR
(100 MHz, CDCl3) δ 14.30 (SCH2CH3 in 2a), 24.76 (s, SCH3 in
8a), 34.09 (SCH2CH3 in 2a), 89.70, 89.75 (C-1 in 2a and 8a);
MS-ES+ m/z (%) 639.7 (15) (M+(2a) + Na), 625.6 (100) (M+-
(8a) + Na). 11a (0.05 g, 85% based on quantity of 1a used)
and unreacted 9b (0.036 g) were also obtained.
Competition Reaction Between 2a and 7a. 2a (0.05 g,
0.081 mmol), 7a (0.057 g, 0.081 mmol), and activated powdered
4 Å molecular sieves (0.15 g) were placed under argon. A
solution of 9b (0.084 g, 0.34 mmol) in dry dichloromethane (2
mL) was added. The mixture was stirred at room temperature
for 1 h, and a sample was removed and analyzed by HPLC.
The reaction mixture was then cooled to 0 °C. A solution of
freshly prepared DMTST (from dimethyl disulfide (43 µL, 0.48
mmol) and methyl triflate (54 µL, 0.48 mmol)) in dry dichlo-
romethane (1 mL) was added. The ice bath was removed, and
the reaction mixture was allowed to warm to room tempera-
ture. After 20 min, HPLC showed that 2a had reacted
completely but that some 7a remained. After 2 h, there was
no further change and the reaction mixture was diluted with
dichloromethane (15 mL), washed with saturated aqueous
sodium bicarbonate (15 mL), water (15 mL), and brine (15 mL),
and dried (MgSO4). Evaporation, followed by column chroma-
tography (hexane/ethyl acetate 17:3, then 8:2, then 11:9),
furnished unreacted 7a (0.035 g, 74%), 11a (0.045 g, 87% based
on quantity of 2a used), and unreacted 9b (0.028 g).
Reactivity Testing Experiments with 2a (Table 6). A.
2a (0.05 g, 0.081 mmol) and activated powdered 4 Å molecular
sieves (0.15 g) were placed under argon, and a solution of 9b
(0.021 g, 0.081 mmol) in dry dichloromethane (2 mL) was
added. The mixture was stirred at room temperature for 1 h
and then cooled to 0 °C. A solution of freshly prepared DMTST
(from dimethyl disulfide (43 µL, 0.48 mmol) and methyl triflate
(54 µL, 0.48 mmol)) in dry dichloromethane (1 mL) was added.
The reaction mixture was stirred at 0 °C and monitored by
TLC (hexane/ethyl acetate 8:2 and 6:4). After 4 h, TLC showed
complete consumption of starting materials so the reaction
mixture was diluted with dichloromethane (15 mL), washed
with saturated aqueous sodium bicarbonate (15 mL), water
(15 mL), and brine (15 mL), and dried (MgSO4). Evaporation,
followed by column chromatography using hexane/ethyl ac-
etate 8:2, furnished 11a (0.050 g, 78%).
N-(Benzyloxycarbonyl)-O-(2,3,4,6-tetra-O-acetyl-â-D-
glucopyranosyl)-L-serine Methyl Ester (12c). Using method
D, a reaction time of 24 h, 2d (0.090 g, 0.21 mmol), and 9c48
(0.054 g, 0.21 mmol) gave 12c (â-anomer only) (0.042 g, 34%)
after column chromatography with hexane/ethyl acetate 1:1.
The spectroscopic and analytical data were in agreement with
those reported in the literature:92 IR (thin film) 3352 (C-H),
2955 (N-H), 1745 (CdO), 1653 (amide I), 1522 (amide II) cm-1
;
1H NMR (400 MHz, CDCl3, COSY) δ 1.99, 2.02, 2.07 (4 × s,
12H, OAc), 3.62 (ddd, 1H, H-5, J(H-5,H-4) ) 9.6 Hz, J(H-5,H-
6) ) 4.8 Hz, J(H-5,H-6′) ) 2.8 Hz), 3.76 (s, 3H, OCH3), 3.88
(dd, 1H, CHH′CH, J(H,H′) ) 10.6 Hz, J ) 3.4 Hz), 4.10 (dd,
1H, H-6, J(H-6,H-6′) ) 12.0 Hz, J(H-6,H-5) ) 2.4 Hz), 4.24
(m, 2H, H-6′, CHH′CH), 4.48 (d, 1H, H-1, J(H-1,H-2) ) 8.0
Hz), 4.93 (dd, 1H, H-2, J(H-2,H-3) ) 9.2 Hz, J(H-2,H-1) ) 8.0
Hz), 5.05 (pt, 1H, H-4, J ) 9.6 Hz), 5.13 (m, 3H, CH2CH,
PhCH2), 5.16 (pt, 1H, H-3, J ) 8.8 Hz), 5.57 (d, 1H, NH, J )
7.6 Hz), 7.31-7.37 (m, 5H, Ar-H); MS-ES+ m/z (%) 276 (100)
(ZSerOMe+ + Na), 606 (32) (M+ + Na).
B. The procedure described in A was repeated at -10 °C.
In this case, TLC showed complete consumption of starting
materials after 5 h. 11a (0.051 g, 80%) was obtained.
Competition Reaction Between 1a and 2a. 1a (0.047 g,
0.081 mmol), 2a (0.05 g, 0.081 mmol), and activated powdered
4 Å molecular sieves (0.15 g) were placed under argon, and a
solution of 9b (0.084 g, 0.34 mmol) in dry dichloromethane (2
mL) was added. The mixture was stirred at room temperature
for 1 h and then cooled to 0 °C. A solution of freshly prepared
DMTST (from dimethyl disulfide (43 µL, 0.48 mmol) and
methyl triflate (54 µL, 0.48 mmol)) in dry dichloromethane (1
mL) was added. The ice bath was removed, and the reaction
mixture was allowed to warm to room temperature. After 10
min, HPLC indicated that 1a had reacted completely but that
2a remained. After 1 h, the HPLC trace was little changed so
Reactivity Testing Experiments with 7a (Table 6). A.
7a (0.055 g, 0.078 mmol) and activated powdered 4 Å molecular
sieves (0.15 g) were placed under argon. A solution of 9b (0.020
g, 0.078 mmol) in dry dichloromethane (2 mL) was added. The
mixture was stirred at room temperature for 1 h and then
cooled to 0 °C. A solution of freshly prepared DMTST (from
dimethyl disulfide (43 µL, 0.48 mmol) and methyl triflate (54
µL, 0.48 mmol)) in dry dichloromethane (1 mL) was added.
The ice bath was removed, and the reaction mixture was
allowed to warm to room temperature. The reaction was
monitored by TLC (hexane/ethyl acetate 8:2 and 6:4). After
20 h, TLC showed complete consumption of starting materials.
The reaction mixture was diluted with dichloromethane (15
mL), washed with saturated aqueous sodium bicarbonate (15
mL), water (15 mL), and brine (15 mL), and dried (MgSO4).
Evaporation, followed by column chromatography using hex-
ane/ethyl acetate 8.5:1.5, furnished 11a (0.043 g, 70%) and
methyl p-nitrophenyl disulfide (0.015 g, 95%) as a yellow
solid: mp 36-38 °C (lit.93 42.9-44.3 °C); 1H NMR (200 MHz,
CDCl3) δ 2.48 (s, 3H, CH3), 7.65 (d, 2H, ArC-H, J ) 9.2 Hz),
(87) Mukherjee, D.; Ray, P. K.; Chowdhury, U. S. Tetrahedron 2001,
57, 7701-7704.
(88) Ikemoto, N.; Kim, O. K.; Lo, L.-C.; Satyanarayana, V.; Chang,
M.; Nakanishi, K. Tetrahedron Lett. 1992, 33, 4295-4298.
(89) Freudenberg, K.; Noe¨, A.; Knopf, E. Chem. Ber. 1927, 60, 238.
(90) Kreuzer, M.; Thiem, J. Carbohydr. Res. 1986, 149, 347.
(91) Du, Y.; Pan, Q.; Kong, F. Carbohydr. Res. 2000, 323, 28-35.
(92) Vafina, M. G.; Derevitskaya, V. A.; Kochetkov, N. K. Bull. Acad.
Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1965, 1777.
J. Org. Chem, Vol. 70, No. 24, 2005 9753

Grayson et al.
8.20 (d, 2H, ArC-H, J ) 9.0 Hz). The spectroscopic and
analytical data were in agreement with those reported in the
literature.93
of starting material. The solution was evaporated, and the
residue was purified by rapid column chromatography using
hexane/ethyl acetate 9:1 to furnish thiol 24 (0.017 g, 95%) as
a colorless oil: 1H NMR (200 MHz, CDCl3) δ 2.24 (d, 1H, SH,
J ) 8.3 Hz), 3.24-3.71 (m, 6H), 4.35-4.92 (m, 9H), 7.02-7.34
(m, 20H, Ar-H). 24 (0.017 g, 0.030 mmol) was then immediately
dissolved in dichloromethane (1.5 mL) and added dropwise to
a stirred solution of ethyl methanethiosulfonate 1780 (0.004 g,
0.035 mmol) and triethylamine (4.2 µL, 0.030 mmol) in
dichloromethane (0.5 mL) at 0 °C under nitrogen. The ice bath
was removed, and the reaction mixture was allowed to warm
to room temperature. After 1 h, TLC (hexane/ethyl acetate 8:2)
indicated complete consumption of 24. The reaction mixture
was evaporated, and the residue was purified by column
chromatography using hexane/ethyl acetate 9:1, furnishing 2a
(0.014 g, 74%).
B. 7a (0.055 g, 0.078 mmol) and activated powdered 4 Å
molecular sieves (0.15 g) were placed under argon. A solution
of 9b (0.020 g, 0.078 mmol) in dry dichloromethane (2 mL)
was added. The mixture was stirred at room temperature for
1 h and then cooled to 0 °C. A solution of freshly prepared
DMTST (from dimethyl disulfide (43 µL, 0.48 mmol) and
methyl triflate (54 µL, 0.48 mmol)) in dry dichloromethane (1
mL) was added. The ice bath was removed, and the reaction
mixture was allowed to warm to room temperature over 20
min. It was then worked up as described in A. Evaporation,
followed by column chromatography using hexane/ethyl ac-
etate 8.5:1.5 furnished unreacted 7a (0.032 g, 58%), 11a (0.010
g, 16%), and unreacted 9b (0.014 g, 70%).
Ethyl Methanethiosulfonate.80 Ethyl bromide (1.8 mL,
24 mmol) was added to a stirred suspension of sodium
methanethiosulfonate (0.5 g, 4.0 mmol) in dry ethanol (5 mL)
under argon. The reaction mixture was heated to 50 °C for 8
h and then cooled. The ethanol was evaporated, and the
residue was stirred with dichloromethane (20 mL) and then
filtered. The filtrate was evaporated. Column chromatography
of the residue using hexane/ethyl acetate 8:2 gave the title
product (0.498 g, 89%) as a colorless oil: 1H NMR (200 MHz,
CDCl3) δ 1.47 (t, 3H, SCH2CH3, J ) 7.5 Hz), 3.22 (q, 2H, SCH2-
CH3, J ) 7.3 Hz), 3.34 (s, 3H, SCH3).
C. 7a (0.055 g, 0.078 mmol) and activated powdered 4 Å
molecular sieves (0.15 g) were placed under argon. A solution
of 9b (0.020 g, 0.078 mmol) in dry dichloromethane (2 mL)
was added. The mixture was stirred at room temperature for
1 h and then cooled to 0 °C. A solution of freshly prepared
DMTST (from dimethyl disulfide (43 µL, 0.48 mmol) and
methyl triflate (54 µL, 0.48 mmol)) in dry dichloromethane (1
mL) was added. The reaction mixture was stirred at 0 °C for
4 h. It was then worked up as described in A. Evaporation,
followed by column chromatography using hexane/ethyl ac-
etate 8.5:1.5, furnished unreacted 7a (0.033 g, 60%), 11a (0.010
g, 16%), and unreacted 9b (0.010 g, 50%).
D. The procedure described in C was repeated but with a
reaction temperature of -10 °C and a reaction time of 5 h.
Column chromatography of the crude product furnished un-
reacted 7a (0.044 g, 80%), 11a (0.004 g, 6%), and unreacted
9b (0.019 g, 94%).
Conversion of 7a into 2a. 7a (0.023 g, 0.032 mmol) was
dissolved in a mixture of chloroform (0.6 mL), dioxan (0.3 mL),
and water (0.1 mL) under nitrogen. Nitrogen was bubbled
through the solution for 30 min. Tributylphosphine (11.9 µL,
0.048 mmol) was added. The reaction mixture immediately
became deep orange but faded rapidly to yellow. After 5 min,
TLC (hexane/ethyl acetate 7:3) showed complete consumption
Acknowledgment. We thank Justin Marston and
Dr. Andrew Cowley for technical assistance, Professor
J. Grant Buchanan for helpful discussions, the EPSRC
UK (S.J.W. and D.P.G.), the HEFCE UK (A.L.H.), the
Daphne Jackson Trust for a fellowship funded by the
Royal Commission for the Exhibition of 1851 (E.J.G.),
and the University of Oxford (P.M.R. and D.P.G.) for
funding.
Supporting Information Available: General experimen-
tal, experimental details for the D-galacto donor series, spectra
of reported compounds, and crystallographic information files
(CIF) for 2d and 3d. This material is available free of charge
via the Internet at http://pubs.acs.org.
(93) Baerlocher, F. J.; Baerlocher, M. O.; Langler, R. F.; MacQuarrie,
S. L.; Marchand, M. E. Aust. J. Chem. 2000, 53, 1-5.
JO051374J
9754 J. Org. Chem., Vol. 70, No. 24, 2005