Superarming common glycosyl donors by simple 2-O-Benzoyl-3,4,6-tri-O-benzyl protection

Article abstract of DOI:10.1021/jo9021474

(Chemical Equation Presented) A complementary concept for superarming glycosyl donors through the use of common protecting groups was previously discovered with S-benzoxazolyl (SBox) glycosyl donors. As this strategy can be of benefit to existing oligosaccharide methodologies, it has now been expanded to encompass a wide array of common, stable glycosyl donors. The versatility of this developed technique has been further illustrated in application to a sequential chemoselective oligosaccharide synthesis, wherein a superarmed ethyl thioglycoside was incorporated into the conventional armed-disarmed strategy.

Full text of DOI:10.1021/jo9021474

pubs.acs.org/joc
Superarming Common Glycosyl Donors by Simple 2-O-Benzoyl-3,4,6-tri-
O-benzyl Protection
Hemali D. Premathilake, Laurel K. Mydock, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri;St. Louis, One University Boulevard,
St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received October 6, 2009
A complementary concept for superarming glycosyl donors through the use of common protecting
groups was previously discovered with S-benzoxazolyl (SBox) glycosyl donors. As this strategy can
be of benefit to existing oligosaccharide methodologies, it has now been expanded to encompass a
wide array of common, stable glycosyl donors. The versatility of this developed technique has been
further illustrated in application to a sequential chemoselective oligosaccharide synthesis, wherein a
superarmed ethyl thioglycoside was incorporated into the conventional armed-disarmed strategy.
Introduction
expeditious strategies for oligosaccharide assembly have
surfaced.4,5 Among these, the armed-disarmed strategy is
of particular interest.6,7 As first introduced by Fraser-Reid
and co-workers, this approach allows for the expeditious
synthesis of oligosaccharides while necessitating only one
type of anomeric leaving group. Thus, the reactivities of the
building blocks involved in such chemoselective activations
are differentiated by the electronic and/or torsional effects of
the protecting groups.8-10 Though initially discovered with
Only recently has the tremendous biological significance
and therapeutic potential of carbohydrates and conjugates
thereof (glycoproteins, glycolipids, proteoglycans, etc.) be-
gun to emerge.1 However, success in studying these fascinat-
ing biomolecules has proven to be directly correlated to the
availability of the involved carbohydrates. With the low
availability of pure natural isolates, the invention of efficient
chemical and enzymatic methods for the synthesis of com-
plex carbohydrates has become increasingly important. This
need has led to the development of many excellent new
methods for glycoside synthesis,2,3 from which a variety of
(5) Smoot, J. T.; Demchenko, A. V. Adv. Carbohydr. Chem. Biochem.
2009, 62, 161–250.
(6) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583–5584.
(7) Fraser-Reid, B.; Udodong, U. E.; Wu, Z. F.; Ottosson, H.; Merritt,
J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942 and
references therein.
(8) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem. Soc.,
Perkin Trans. 1 1998, 51–65.
(1) Essentials of Glycobiology, 2nd ed.; Varki, A., Cummings, R. D.,
Esko, J. D., Freeze, H. H., Bertozzi, C. R., Stanley, P., Hart, G. W., Etzler,
M. E., Eds.; CSH Laboratory Press: New York, 2009.
(2) Handbook of Chemical Glycosylation: Advances in Stereoselectivity
and Therapeutic Relevance; Demchenko, A. V., Ed.; Wiley-VCH: Weinheim,
2008.
(9) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.; Wong,
C. H. J. Am. Chem. Soc. 1999, 121, 734–753.
(3) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
(4) Boons, G. J. Tetrahedron 1996, 52, 1095–1121.
(10) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205–9213.
DOI: 10.1021/jo9021474
r
Published on Web 01/28/2010
J. Org. Chem. 2010, 75, 1095–1100 1095
2010 American Chemical Society

Premathilake et al.
JOCArticle
FIGURE 1. Cooperative arming and disarming effects.
O-pentenyl glycosides, the armed-disarmed concept has
since been proven with many other classes of glycosyl
donors.5
This strategy led to the commonly accepted belief that
benzylated derivatives are always significantly more re-
active than their benzoylated counterparts and that the
overall glycosyl donor reactivity is in direct correlation
with the total number of benzyl substituents.11 However,
this presumption was challenged with the discovery of the
O-2/O-5 cooperative effect, wherein it was observed that
glycosyl donors with mixed protecting group patterns
showed unexpected reactivity trends.12 This was the first
indication that the reactivity of the glycosyl donor was
not limited to the electron-withdrawing/-donating (or
torsional) effects of its protecting groups. Therein, it
was proposed that the reactivity of glycosyl donors was
also influenced by how well the glycosyl cation, formed
upon promoter (P)-assisted leaving group (LG) depar-
ture, could self-stabilize. As depicted in Figure 1, in the
case of the armed, benzylated glycosyl donor (B), stabili-
zation can be efficiently achieved via the oxacarbenium
intermediate through resonance with the electronically
“armed” lone pair electrons of O-5. However, in the case
of the per-benzoylated derivative (C), this type of stabili-
zation would be less likely due to the electron-withdraw-
ing substituents at C-4 and C-6. Instead, the acyl
substituent at C-2 allows for stabilization via the acylox-
onium intermediate. Therefore, the combination of these
two opposing effects results in the decreased reactivity of
disarmed donor (C) relative to B.
It then follows that a glycosyl donor wherein there is no
stabilization/participating group at C-2, and electron-with-
drawing groups at the remaining positions, would be even
further deactivated, as is the case for superdisarmed glycosyl
donor (D).12 Crich and Li additionally investigated this
phenomenon for the S-benzoxazolyl (SBox) glycosyl donors
of the D-gluco series, finding that in order for this C-2
stabilization to occur, a 1,2-trans anomeric configuration is
necessary.13 This suggests that the lone pair at C-2 must
also have access to the developing positive charge as the
leaving group departs implying that anchimeric assistance is
in part, if not fully, responsible for the observed C-2 effect.
Building upon this concept, we then determined that glycosyl
donors possessing a participating moiety at C-2 and an
electronically armed lone pair at O-5 (A) would have ex-
ceptionally high reactivity as the both stabilizing effects
would be combined.14,15
FIGURE 2. Glycosyl donors of the armed and superarmed series.
Results and discussion
This concept of superarming was previously explored
with benzoxazolyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-
D-glycopyranosides (SBox glycosides) of the D-gluco,
D-galacto, and D-manno series;14,15 however, it remained
unclear whether this principle could be applied to other
classes of leaving groups. Previously, the term “super-
armed” was coined by Bols and co-workers in their recent
publications in reference to conformationally modified glyco-
syl donors.16-18 Herein, we describe the investigation of stable
glycosyl donors of the armed (1) and superarmed (2) series,
bearing common leaving groups: O-pentenyl, S-ethyl, S-phen-
yl, S-tolyl, and S-thiazolinyl (STaz, Figure 2). All test glycosy-
lations were performed with the standard glycosyl acceptor 319
to afford disaccharides 420 and 520 from glycosyl donors of the
armed and superarmed series, respectively (Table 1). Addition-
ally, the obtained results were compared to the previously
investigated SBox glycosides 1a21 and 2a.14
It should be noted that the key feature of any chemose-
lective activation lies in choosing suitable reaction condi-
tions that will allow for the reactivity levels of the building
blocks to be differentiated. However, establishing a reacti-
vity differentiation becomes increasingly difficult with the
highly reactive superarmed and armed glycosyl donors. In
our previous work, we described that the reactivity of armed
and superarmed SBox glycosides, 1a and 2a, respectively,
can be effectively separated in the presence of dimethyl-
(methylthio)sulfonium trifluoromethansulfonate22 (DMTST)
as a promoter (Table 1, entries 1 and 2).14 Herein, we also
determined that an equally successful differentiation can be
achieved in the presence of copper(II) trifluoromethanesulfonate
(16) Pedersen, C. M.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2007,
129, 9222–9235.
(17) Jensen, H. H.; Pedersen, C. M.; Bols, M. Chem.;Eur. J. 2007, 13,
7576–7582.
(18) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Chem. Commun. 2008,
2465–2467.
(19) Kuester, J. M.; Dyong, I. Justus Liebigs Ann. Chem. 1975, 2179–
2189.
(20) Nguyen, H. M.; Chen, Y. N.; Duron, S. G.; Gin, D. Y. J. Am. Chem.
Soc. 2001, 123, 8766–8772.
(21) Kamat, M. N.; Rath, N. P.; Demchenko, A. V. J. Org. Chem. 2007,
72, 6938–6946.
(11) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155–173.
(12) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
(13) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115–4118.
(14) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2103–2106.
(15) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2107–2110.
(22) Ravenscroft, M.; Roberts, R. M. G.; Tillett, J. G. J. Chem. Soc.,
Perkin Trans. 2 1982, 1569–1972.
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Premathilake et al.
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TABLE 1. Comparative Activation of Armed (1) and Superarmed (2)
Glycosyl Donors
TABLE 2. Activation of Armed (1) and Superarmed (2) Glycosyl
Donors in the Presence of Iodine (3 Molar Equiv)
entry
donor
time (h)
product
yield (%)
ratio R/β
entry
D
P
temp (°C)
time
2 h
5 min
2 h
20 min
20 h
3 h
96 h
96 h
18 h
6 h
CP yield (%)
R/β
2:1
β only
2:1
β only
3:1
β only
2:1
β only
2:1
β only
2:1
1
2
3
4
5
6
7
8
1c
2c
1d
2d
1e
2e
1f
10
1
15
8
15
12
19
19
17
17
48
20
4
5
4
5
4
5
4
5
4
5
4
5
89
93
74
78
63
72
87
85
82
84
NRa
95
1:4
β only
1:2
β only
1:2
β only
1:2
β only
1:2.8
β only
1
2
3
4
5
6
7
8
9
1a DMTST
2a DMTST
1a Cu(OTf)2
2a Cu(OTf)2
1b IDCP
2b IDCP
1c IDCP
2c IDCP
1c MeOTf
2c MeOTf
1c DMTST
2c DMTST
0
0
0
4
5
4
5
4
5
4
5
4
5
4
5
92
86
99
96
62
53
82
78
95
96
90
89
0
-10
-10
-10
-10
0
0
-20
-20
2f
9
1b
2b
1a
2a
10
11
12
10
11
12
β only
1 h
10 min
aNR: no reaction, although glycosyl donor 1a smoothly reacted at rt
in 13 h affording disaccharide 4 in 95% (R:β=1:2).
β only
(Table 1, entries 3 and 4). This result offers further signifi-
cance, as Cu(OTf)2 is a promoter unique to thioimidoyl
leaving groups.
MeOTf at 0 °C or DMTST at -20 °C, wherein a 3- and 6-fold
increase in reactivity was achieved, respectively (Table 1,
entries 9-12). Additionally, the yields for both armed and
superarmed glycosyl donors were good to excellent across
the board. Upon investigating a variety of other known
thioglycoside promoters,28-30 we found results with molec-
ular iodine, introduced by Field as a mild promoter for the
activation of methyl thioglycosides,31 at -25 °C to be the
most impressive. Thus, while activation of the armed glyco-
syl donor 1c required at least 10 h, the reaction of its super-
armed counterpart 2c completed in less than 1 h, displaying a
10-fold reactivity increase (Table 2, entries 1 and 2). Encour-
aged by these results, iodine was tested as the promoter in
subsequent studies with O-pentenyl donors (1b and 2b), as
well as common classes of thioglycoside donors,28-30 S-
phenyl (1d32 and 2d33), S-tolyl (1e34 and 2e), and STaz
glycosides (1f35 and 2f). Although we observed that the
superarmed glycosyl donors of both the S-phenyl and
S-tolyl series reacted faster (Table 2, entries 3-6), no signi-
ficant differentiation was achieved under these reaction
conditions.
In order to differentiate between armed and superarmed
O-pentenyl glycosides, 1b23 and 2b,24 respectively, we chose
iodonium(di-γ-collidine)perchlorate25 (IDCP), as this mild
promoter has proven effective for chemoselectively activat-
ing armed pentenyl glycosides over their disarmed counter-
parts at rt.6 However, these reaction conditions were found
to be too powerful, as both glycosyl donors 1b and 2b were
activated in a matter of minutes at rt. Additionally,
no significant difference in reactivity was observed when
O-pentenyl glycosides were investigated in the presence of
NIS (rt), NBS (45 °C), or NIS/TfOH (-20 °C), albeit in a
majority of the comparative glycosylations, superarmed donor
1b was slightly more reactive (the extended experimental
results are available as a part of the Supporting Information).
Ultimately, the application of IDCP at low temperature
(-10 °C) was deemed the most successful in terms of the
differential activation of O-pentenyl glycosides. Thus, 20 h
was required for the glycosidation of 1b, whereas the glyco-
sidation of 2b was complete in about 3 h (Table 1, entries 5
and 6). The yields obtained with both armed and superarmed
pentenyl glycosides under these reaction conditions, how-
ever, remained modest (62% and 53%, respectively).
Consequently, we investigated S-ethyl glycosides 1c26 and
2c27 in the presence of relatively mild promoters, including
IDCP, DMTST, and MeOTf at reduced temperatures
(Table 1, entries 7-12). While reactions in the presence of
IDCP showed an insufficient difference in reactivity (Table 1,
entries 7 and 8), the best differentiation was achieved with
Furthermore, no reactivity differentiation could be estab-
lished in the presence of iodine between the armed and
superarmed STaz glycosyl donors 1f and 2f, or between O-
pentenyl glycosides 1b and 2b, respectively (Table 2, entries
(28) Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft,
H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34, 769–782.
(29) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 179–205.
(30) Zhong, W.; Boons, G.-J. In Handbook of Chemical Glycosylation;
Wiley-VCH: Weinheim, 2008; pp 261-303.
(31) Kartha, K. P. M.; Aloui, M.; Field, R. A. Tetrahedron Lett. 1996, 37,
5175–5178.
(32) Pfaeffli, P. J.; Hixson, S. H.; Anderson, L. Carbohydr. Res. 1972, 23,
195–206.
(33) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.;
Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem.;Eur. J. 1999, 5, 2648–
2667.
(23) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1 1989,
1805–1810.
(24) Mach, M.; Schlueter, U.; Mathew, F.; Fraser-Reid, B.; Hazen, K. C.
Tetrahedron 2002, 58, 7345–7354.
(25) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190–2198.
(26) Andersson, F.; Fugedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron
Lett. 1986, 27, 3919–3922.
(34) Balavoine, G.; Berteina, S.; Gref, A.; Fischer, J. C.; Lubineau, A.
J. Carbohydr. Chem. 1995, 14, 1217–1236.
(35) Pornsuriyasak, P.; Demchenko, A. V. Chem.;Eur. J. 2006, 12,
6630–6646.
(27) Ekelof, K.; Oscarson, S. J. Org. Chem. 1996, 61, 7711–7718.
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TABLE 3. Competitive Activations of S-Ethyl Glycosyl Donors: 1c
(Armed) vs 2c (Superarmed)
SCHEME 1. Sequential Activation of Differently Protected
S-Ethyl Building Blocks: Synthesis of Tetrasaccharide 10
yield of
4b (%)
(R/β)
yield of
5b (%)
(R/β)
temp
(°C)
time
(h)
ratio
4:5a
entry
1
2
3
4
rt
-10
-25
-35
1
1
3
24
1:0.8
1:2.4
1:4
53 (1:1.7)
22 (1:4)
14 (1:4)
11 (1:5)
45 (β only)
51 (β only)
62 (β only)
26 (β only)
1:1.5
aDetermined by comparing integral intensities of the corresponding
signals in the NMR spectra recorded for the crude reaction mixtures.
bIsolated yields.
7-10). Although both O-pentenyl and STaz glycosides easily
react in accordance with the conventional armed-disarmed
activation scheme,6,36 we have found the differentiation
between the more closely positioned superarmed and armed
glycosides to be challenging. It is possible that the protecting
group effect is decreased in cases of remote activation,37 as is
typical for both the O-pentenyl and STaz glycosides (alkene7
and nitrogen atom of the thiazoline ring,38 respectively) and
is opposite in cases of direct activation21 cases (anomeric
sulfur atom of S-ethyl and SBox glycosyl donors).
Following this rationale, we additionally tested the armed
and superarmed SBox donors (1a and 2a, respectively)
wherein we found that the reactivity difference between
them in the presence of iodine at -25 °C was remarkable
(Table 2, entries 11 and 12). While no reaction took place
with the armed glycosyl donor 1a, the superarmed glycosyl
donor 2a reacted very smoothly and afforded the corre-
sponding disaccharide 5 in 20 h (95%). It should be noted
that the armed SBox glycoside 1a can also be activated with
iodine, but this was only accomplished at rt. Interestingly,
the fact that the SBox glycosides reacted much slower than
their S-ethyl counterparts was rather unanticipated, as SBox
glycosides are typically much more reactive and can be
selectively activated in the presence of alkyl/aryl thioglyco-
sides.21,39
As verification of the promising results obtained with
S-ethyl glycosides in the presence of iodine, we set up direct
competitive glycosylations. To optimize the reaction condi-
tions for a chemoselective oligosaccharide assembly, the
competitive glycosylations were investigated at a variety of
reaction temperatures (Table 3). These reactions were car-
ried out by placing equimolar amounts (1.1 equiv each) of the
armed 1c and superarmed 2c glycosyl donors in the same
reaction vessel with glycosyl acceptor 3 (1 equiv). Upon
addition of iodine (3 equiv), both glycosyl donors competed
for the same acceptor to form either disaccharide 4 or 5. The
highest product ratio in these competitive glycosylations was
also obtained at -25 °C, wherein the 1,2-trans-linked dis-
accharide 5 (derived from superarmed glycosyl donor 2c)
was isolated in 62% yield (Table 3, entry 3). Conversely, the
disaccharide 4 (derived from armed glycosyl donor 1c) was
isolated in only 14% yield (R/β = 1:4).
Having investigated the superarming and arming effects in
direct competitive glycosylations with glycosyl donors of the
S-ethyl series, we now turned our attention to a sequential
tetrasaccharide synthesis. To begin, the chemoselective acti-
vation of the superarmed glycosyl donor 2c over the “armed”
glycosyl acceptor 640 was successfully carried out in the
presence of iodine at -25 °C (Scheme 1). Subsequently, the
resulting armed disaccharide 7, obtained in 80% yield, was
coupled with “disarmed” glycosyl acceptor 8.41 This chemo-
selective activation was also performed in the presence of
iodine, but this time at rt. The resulting trisaccharide 9,
obtained in 55% yield (R/β = 1:2.6), was then reacted with
glycosyl acceptor 3 in the presence of NIS/TfOH, and the
resulting tetrasaccharide 10 was isolated in 72% yield. Over-
all, this synthesis serves as ultimate proof of the utility of this
superarmed approach in chemoselective oligosaccharide
synthesis.
In conclusion, a promising new concept for superarming
glycosyl donors through the use of common protecting
groups has now been extended to encompass a range of
common glycosyl donors. Although it was initially necessary
to fine-tune the reaction conditions and carefully select an
adequate (mild) promoter, once established, the reactivity of
the superarmed glycosyl donors was able to be exploited.
This approach ultimately provides an additional synthetic
building block that can be integrated into the conventional
chemoselective armed-disarmed strategy. Results obtained
herein were both consistent and high yielding, thus, offering
this is a general methodology for cases wherein a 1,2-trans
linkage must to be introduced prior to other linkages.
(36) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem.,
Int. Ed. 2005, 44, 7123–7126.
(37) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80,
c17–c22.
(38) Kaeothip, S.; Pornsuriyasak, P.; Rath, N. P.; Demchenko, A. V. Org.
Lett. 2009, 11, 799–802.
(39) Kamat, M. N.; De Meo, C.; Demchenko, A. V. J. Org. Chem. 2007,
72, 6947–6955.
(40) Fei, C.; Chan, T. H. Acta Chim. Sin., Engl. Ed. 1989, 258–264.
(41) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275–
278.
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Premathilake et al.
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Additionally, the superarmed glycosyl donors can be easily
obtained by conventional synthetic methods. Currently,
further application of this superarmed concept toward se-
lective activation and orthogonal approaches to oligosac-
charide synthesis is under pursuit in our laboratory.
11.0 Hz, CH2Ph), 5.55 (dd, 1H, J2,3 = 8.5 Hz, H-2), 5.67 (d, 1H,
J1,2 = 10.3 Hz, H-1), 7.22-8.20 (m, 20H, aromatic) ppm; 13C
NMR δ 35.6, 64.3, 68.8, 72.4, 73.6, 75.3, 75.5, 77.8, 80.0, 83.1,
84.3, 127.8, 127.9, 128.0, 128.1 (ꢀ2), 128.1 (ꢀ2), 128.2 (ꢀ2),
128.5 (ꢀ2), 128.6 (ꢀ3), 128.6 (ꢀ2), 129.7, 130.1 (ꢀ2), 133.5,
137.9, 138.2, 138.3, 163.7, 165.4 ppm; HR-FAB MS [M þ Na]þ
calcd for C37H37NO6S2Naþ 678.1959, found 678.1977.
Experimental Section
Preparation of Di- And Oligosaccharides (4, 5, 7, 9, and
10). Method A: Typical DMTST-Promoted Glycosylation Pro-
cedure. A mixture containing the glycosyl donor (0.11 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
Preparation of Superarmed Glycosyl Donors 2e and 2f.
p-Methylphenyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-glu-
copyranoside (2e). The title compound was obtained using a
modified protocol similar to that previously reported.7,8,14
CH2Cl2 (9.0 mL) and p-toluenethiol (1.6 g, 13.03 mmol) were
added to 3,4,6-tri-O-benzyl-1,2-O-(methylorthobenzoate) R-D-
glucopyranoside14 (740 mg, 1.31 mmol) and molecular sieves
˚
sieves (4 A, 200 mg) in 1,2-dichloroethane (DCE, 1.6 mL) was
stirredunderargonfor 1 h. The mixturewas chilled to0 or -20 °C
(see Table 1), DMTST22 (0.33 mmol) was added, and the
reaction mixture was stirred for 5 min to 2 h (see Table 1).
Upon completion, the mixture was diluted with CH2Cl2, and
the solid was filtered off and rinsed successively with CH2Cl2.
The combined filtrate (30 mL) was washed with 20% aq
NaHCO3 (10 mL) and water (3 ꢀ 10 mL). The organic phase
was separated, dried, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl
acetate-hexane gradient elution).
˚
(3 A, 850 mg), and the resulting mixture was stirred under argon
for 45 min. Trimethylsilyl trifluoromethanesulfonate (6 μL,
0.328 mmol) was added, and the reaction mixture was stirred
under argon for 16 h at rt. After that, the reaction mixture was
neutralized by the addition of triethylamine (∼0.1 mL) and
diluted with CH2Cl2, and the solid was filtered off and rinsed
successively with CH2Cl2. The combined filtrate (∼30 mL) was
washed with water (10 mL), 20% aq NaHCO3 (10 mL), and
water (3 ꢀ 10 mL). The organic phase was separated, dried, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate/hexanes gradient
elution) to afford the title compound 2e as a white solid in 70%
yield. Analytical data for 2e: Rf = 0.54 (ethyl acetate/hexanes, 3/
Method B: Typical Cu(OTf)2-Promoted Glycosylation Proce-
dure. A mixture containing the glycosyl donor (0.11 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
˚
sieves (4 A, 200 mg) in DCE (1.6 mL) was stirred under argon for
1 h followed by the addition of freshly conditioned Cu(OTf)2
(0.22 mmol). The reaction mixture was stirred for 20 min to 2 h
at 0 °C (see Table 1) and then diluted with CH2Cl2, the solid was
filtered off and rinsed successively with CH2Cl2. The combined
filtrate (30 mL) was washed with 20% aq NaHCO3 (10 mL) and
water (3 ꢀ 10 mL). The organic phase was separated, dried, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexane gradient
elution).
7, v/v); mp 134-135 °C (diethyl ether/hexanes); [R]22 þ32.5
D
(c = 1, CHCl3); 1H NMR δ 2.18 (s, 3H, SPhCH3), 3.48 (m, 1H,
J
5,6a = 1.9 Hz, J5,6b = 3.6 Hz, H-5), 3.62 (dd, 1H, J4,5 = 9.5 Hz,
H-4), 3.65-3.78 (m, 3H, H-3, 6a, 6b), 4.42-4.75 (m, 6H, 3 ꢀ
CH2Ph), 4.61 (d, 1H, J1,2 = 10.0 Hz, H-1), 5.14(dd, 1H, J2,3
=
9.0 Hz, H-2), 6.80-8.00 (m, 24H aromatic) ppm; 13C NMR δ
21.3, 69.1, 72.7, 73.7, 75.2, 75.5, 76.8, 77.2, 77.4, 77.7, 78.0, 79.7,
84.5, 86.4, 127.7 (ꢀ3), 127.8 (ꢀ3), 127.8 (ꢀ3), 128.0, 128.1 (ꢀ2),
128.3, 128.4 (ꢀ2), 128.5 (ꢀ2), 128.7 (ꢀ2), 128.8 (ꢀ2), 128.9 (ꢀ2),
128.9 (ꢀ3), 129.1, 130.0 (ꢀ2), 130.3 (ꢀ2), 130.4, 133.6, 133.9
(ꢀ3), 138.1, 138.4, 138.5, 138.7, 165.3 ppm; HR-FAB MS [M þ
Na]þ calcd for C41H40O6SNaþ 683.2443, found 683.2624.
Thiazolinyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-gluco-
pyranoside (2f). The title compound was obtained using a
modified protocol similar to that previously reported.42 3,4,6-
Tri-O-benzyl-1,2-O-(methylorthobenzoate) R-D-glucopyrano-
side14 (200 mg, 0.35 mmol) was mixed with molecular sieves (3
Method C: Typical IDCP-Promoted Glycosylation Procedure.
A mixture containing the glycosyl donor (0.11 mmol), glycosyl
acceptor (0.10 mmol), and freshly activated molecular sieves (4
˚
A, 200 mg) in DCE (1.6 mL) was stirred under argon for 1 h. The
reaction mixture was then chilled to -10 °C, IDCP25 (0.22
mmol) was added, and the reaction mixture was stirred for
3-96 h (see Table 1). Upon completion, the mixture was diluted
with CH2Cl2, and the solid was filtered off and rinsed succes-
sively with CH2Cl2. The combined filtrate (30 mL) was washed
with 20% NaHCO3 (10 mL) and water (3 ꢀ 10 mL). The organic
phase was separated, dried, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(ethyl acetate-hexane gradient elution).
˚
A, 1.2 g) and 2-mercaptothiazoline (420 mg, 3.52 mmol) and
dried in vacuo for 15 min. Acetonitrile (2.6 mL) was added, and
the resulting mixture was stirred under argon for 1 h. Mercuric
bromide (13 mg, 0.035 mmol) was added, and the resulting
reaction mixture was heated at reflux for 16 h. The volatiles were
evaporated under reduced pressure, the residue was diluted with
CH2Cl2, and the solid was filtered off and rinsed successively
with CH2Cl2. The combined filtrate (30 mL) was washed with
1 N aq NaOH (10 mL) and water (3 ꢀ 10 mL). The organic phase
was separated, dried, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl
acetate/hexane gradient elution) to afford the title compound 2f
as a white solid in 70% yield. Analytical data for 2f: Rf = 0.47
(ethyl acetate/hexane, 4/6, v/v); mp 141-143 °C (diethyl
Method D: Typical MeOTf-Promoted Glycosylation Proce-
dure. A mixture containing the glycosyl donor (0.13 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
˚
sieves (3 A, 200 mg) in DCE (1.6 mL) was stirred under argon for
1 h. The mixture was chilled to 0 °C, MeOTf (0.39 mmol) was
added, and the reaction mixture was stirred for 6-18 h (see
Table 1). The mixture was then diluted with CH2Cl2, the solid
was filtered off, and the residue was rinsed successively with
CH2Cl2. The combined filtrate (30 mL) was washed with 20%
NaHCO3 (10 mL) and water (3 ꢀ 10 mL). The organic phase was
separated, dried, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acet-
ate-hexane gradient elution).
ether-hexanes); [R]22 þ81.2 (c = 1, CHCl3); 1H NMR δ
D
3.43 (m, 2H, NCH2), 3.82 (m, 1H, H-5), 3.88-3.98 (m, 2H, H-
6a, 6b), 4.03 (dd, 1H, J4,5 = 9.1 Hz, H-4), 4.05 (dd, 1H, J3,4 =
Method E: Typical Iodine-Promoted Glycosylation Procedure.
A mixture containing the glycosyl donor (0.11 mmol), glycosyl
acceptor (0.10 mmol), and freshly activated molecular sieves
8.8 Hz, H-3), 4.30 (m, 2H, CH2S), 4.75 (dd, 2H, J2 = 11.9 Hz,
CH2Ph), 4.85 (dd, 2H, J2 = 10.9 Hz, CH2Ph), 4.87 (dd, 2H, J2 =
˚
(3 A, 200 mg) in DCE (1.6 mL) was stirred under argon for 16 h.
The mixture was chilled to -25 °C (or as indicated in Table 3 or
Scheme 1), iodine (0.33 mmol) was added, and the reaction
mixture was stirred for 1-48 h (see Table 2). Upon completion,
(42) Beignet, J.; Tiernan, J.; Woo, C. H.; Benson, M. K.; Cox, L. R.
J. Org. Chem. 2004, 69, 6341–6356.
J. Org. Chem. Vol. 75, No. 4, 2010 1099

Premathilake et al.
JOCArticle
the mixture was quenched with Et3N and diluted with CH2Cl2,
the solid was filtered off, and the residue was rinsed successively
with CH2Cl2. The combined filtrate (30 mL) was washed with
10% Na2S2O3 (10 mL) and water (3 ꢀ 10 mL). The organic
phase was separated, dried, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(ethyl acetate-toluene gradient elution).
method E (rt) in 55% yield (R/β = 1:2.6). Analytical data for 9:
Rf = 0.3 (ethyl acetate/hexane, 3/7, v/v); 1H NMR (selected data
for β-9) δ 1.13 (t, 3H, J = 8.0 Hz, SCH2CH3), 2.65 (m, 2H,
SCH2CH3), 3.26 (dd, 1H, J2 ,3 = 8.9 Hz, H-20), 3.30-3.58 (m,
0
0
4H, H-30, 40, 50, 6a), 3.62-4.20 (m, 9H, H-300, 400, 5, 500, 6a0, 6a00,
0
6b, 6b0, 6b00), 4.35 (d, 1H, J1 ,2 = 7.7 Hz, H-1 ), 4.35-4.95 (m,
0
0
14H, H-1, 100, 12 ꢀ CH2Ph), 5.32 (dd, 1H, J2 ,3 = 9.5 Hz,
00 00
Method F: Typical NIS/TfOH-Promoted Glycosylation Pro-
cedure. A mixture containing the glycosyl donor (0.11 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
H-200), 5.38 (dd, 1H, J4,5 = 7.0 Hz, H-4), 5.49 (dd, 1H, J2,3 = 9.7
Hz, H-2), 5.86 (dd, 1H, J3,4 = 9.7 Hz, H-3), 7.05-8.15 (m, 50H
aromatic) ppm; 13C NMR δ 15.0 (ꢀ2), 24.4, 29.9, 69.0, 70.4,
70.9, 73.7 (ꢀ2), 74.1, 74.4, 74.9 (ꢀ2), 75.2, 75.2, 75.4, 75.6, 77.7,
78.1, 78.4 (ꢀ2), 82.3, 83.0, 83.9, 84.6, 101.4, 103.9, 127.6 (ꢀ2),
127.8(ꢀ2), 127.8(ꢀ2), 127.9, 128.0, 128.1 (ꢀ4), 128.2(ꢀ2), 128.4,
128.4 (ꢀ4), 128.5 (ꢀ4), 128.6 (ꢀ5), 128.7, 129.0, 129.1, 129.5,
129.9(ꢀ2), 130.0, 130.0(ꢀ2), 130.1, 133.2, 133.4 (ꢀ2), 133.6(ꢀ2),
138.1 (ꢀ2), 138.2 (ꢀ2), 138.3, 138.4 (ꢀ2), 138.8 (ꢀ4), 165.3 (ꢀ2),
165.4 (ꢀ2), 165.6 (ꢀ3), 166.0 (ꢀ2) ppm; HR-FAB MS [M þ Na]þ
calcd for C90H88O19SNaþ 1527.5538, found 1527.5558.
˚
sieves (4 A, 200 mg) in DCE (1.6 mL) was stirred under argon for
16 h. NIS (0.22 mmol) and TfOH (0.022 mmol) were added, and
the reaction mixture was stirred for 1 h. Upon completion, the
mixture was diluted with CH2Cl2, the solid was filtered off, and the
residue was rinsed successively with CH2Cl2. The combined filtrate
(30mL) waswashedwith10%Na2S2O3 (10 mL) and water (3 ꢀ 10
mL). The organic phase was separated, dried, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (ethyl acetate-toluene gradient elution).
Methyl O-(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl)-(1 f 6)-
2,3,4-tri-O-benzyl-r-D-glucopyranoside (4). The spectroscopic
and analytical data for the title compound were in good agree-
ment with those reported previously.20
Methyl O-(2-O-Benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyrano-
syl)-(1 f 6)-O-(2,3,4-tri-O-benzyl-D-glucopyranosyl)-(1 f 6)-
O-(2,3,4-tri-O-benzoyl-β-D-glucopyranosyl)-(1 f 6)-2,3,4-tri-O-
benzyl-r-D-glucopyranoside (10). The title compound was ob-
tained as a colorless syrup 3 and 9 by method F in 72% yield.
Selected analytical data for β-10: Rf = 0.66 (ethyl acetate/
Methyl O-(2-O-Benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl)-
(1 f 6)-2,3,4-tri-O-benzyl-r-D-glucopyranoside (5). The spectro-
scopic and analytical data for the title compound were in good
agreement with those reported previously.20
hexane, 2/3, v/v); 1H NMR δ 4.24 (d, 1H, J1 ,2 = 7.8 Hz, H-
00 00
100), 4.29 (d, 1H, J1,2 = 3.3 Hz, H-1), 4.44 (d,1H, H-10), 4.47 (d,
1H, H-1000) ppm; 13C NMR δ 55.7, 67.7, 68.4, 68.8, 69.8, 70.0,
72.2, 73.3, 73.9, 74.3, 74.8, 74.9, 75.0, 75.4, 75.6, 75.8, 77.6 (ꢀ2),
77.9, 78.2, 79.6 (ꢀ2), 80.1, 82.2, 83.1, 98.3, 98.5, 101.0, 101.6,
127.4 (ꢀ3), 127.8, 128.0 (ꢀ3), 128.2 (ꢀ6), 128.3 (ꢀ4), 128.3 (ꢀ4),
128.4, 128.5 (ꢀ3), 128.7 (ꢀ5), 128.7 (ꢀ6), 128.8 (ꢀ7), 128.8 (ꢀ7),
128.8 (ꢀ6), 129.0 (ꢀ5), 129.1, 129.2, 129.4 (ꢀ3), 129.4, 129.6,
130.0, 130.1 (ꢀ3), 130.3, 130.4, 133.5, 133.6, 133.9, 136.2, 138.1,
138.3, 138.4, 138.6, 138.8, 139.3, 165.2, 165.4, 165.8, 166.1 ppm;
HR-FAB MS [M þ Na]þ calcd for C116H114O25Naþ 1929.7547,
found 1929.7583.
Ethyl O-(2-O-Benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl)-
(1 f 6)-2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (7). The
title compound was obtained as a colorless syrup from 1c26 and
640 by method E in 80% yield. Analytical data for 7: Rf = 0.4
(ethyl acetate/hexanes, 3/7, v/v); [R]23D þ18.4 (c = 1, CHCl3);
1H NMR δ 1.13 (t, 3H, J = 8.0 Hz, SCH2CH3), 2.51 (m, 2H,
SCH2CH3), 3.31 (dd, 1H, J2,3 = 9.0 Hz, H-2), 3.32-3.46 (m,
2H, H-4, 5), 3.48-3.65 (m, 3H, H-3, 50, 6a), 3.67-3.82 (m, 4H,
H-30, 40, 6a0, 6b0), 4.10 (d, 1H, J5,6b = J6a,6b = 10.5 Hz, H-6b),
4.32 (d, 1H, J1,2 = 9.7 Hz, H-1), 4.40-4.87 (m, 13H, H-10, 6 ꢀ
CH2Ph), 5.31 (br dd, 1H, H-20), 7.05-8.00 (m, 35H, aromatic)
ppm; 13C NMR δ 15.2, 24.7, 29.9, 68.4, 69.2, 74.0, 75.4, 75.7,
75.8, 75.8, 76.0, 77.6, 78.4, 79.1, 82.0, 83.3, 84.9, 86.9, 101.4,
128.0 (ꢀ2), 128.1 (ꢀ4), 128.2 (ꢀ3), 128.2 (ꢀ4), 128.4 (ꢀ4), 128.4
(ꢀ4), 128.6 (ꢀ3), 128.8 (ꢀ6), 128.8 (ꢀ5), 128.8 (ꢀ5), 130.2 (ꢀ2),
138.2, 138.4 (ꢀ2), 138.5, 166.0 ppm; HR-FAB MS [M þ Na]þ
calcd for C63H66O11SNaþ 1053.4224, found 1053.4238.
Acknowledgment. This work was supported by awards
from the NIGMS (GM077170) and NSF (CHE-0547566).
We thank Ms. Mercy Kiiru for experimental assistance and
Dr. R. E. K. Winter and Mr. J. P. Kramer (all UM;St.
Louis) for HRMS determinations.
Supporting Information Available: Extended experimental
Ethyl O-(2-O-Benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl)-
(1 f 6)-O-(2,3,4-tri-O-benzyl-D-glucopyranosyl)-(1 f 6)-2,3,4-
tri-O-benzoyl-1-thio-β-D-glucopyranoside (9). The title com-
pound was obtained as a pale yellow syrup from 7 and 841 by
1
data, general experimental procedures, and H and 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1100 J. Org. Chem. Vol. 75, No. 4, 2010