An armed-disarmed approach for blocking aglycon transfer of thioglycosides

Article abstract of DOI:10.1016/j.tetlet.2006.11.126

Thioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thioglycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this letter, it is shown that aglycon transfer can

Full text of DOI:10.1016/j.tetlet.2006.11.126

Tetrahedron Letters 48 (2007) 559–562
An armed–disarmed approach for blocking aglycon transfer
of thioglycosides
Zhitao Li and Jeffrey C. Gildersleeve*
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
Received 25 October 2006; revised 17 November 2006; accepted 21 November 2006
Available online 12 December 2006
Abstract—Thioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thio-
glycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this letter, it is shown that aglycon transfer
can be blocked by matching thioglycoside-containing acceptors with more armed glycosyl donors.
Published by Elsevier Ltd.
Thioglycosides are extremely useful derivatives for the
synthesis of oligosaccharides and glycosylated natural
products.1,2 The sulfide group is easy to install and sta-
ble to a wide range of reaction conditions. In addition,
thioglycosides can be activated directly as glycosyl do-
nors using a variety of activating agents such as mercury
salts, sulfenyl triflates, and alkylating agents.1,2 More-
over, thioglycosides can be readily converted into other
glycosyl donors such as glycosyl sulfoxides,3 sulfones,4
and halides.5 As a result, they are versatile intermediates
for carbohydrate synthesis. Thioglycosides have also
been investigated extensively as mimetics of biologically
relevant O-glycosides.6 S-Glycosides are much more sta-
ble than O-glycosides to both chemical and enzymatic
degradation and are typically much easier to synthesize.
As a result, S-glycosides have been developed as glycosyl
transferase inhibitors, agonists/antagonists for lectins,
and as carbohydrate-based vaccine antigens.7
One strategy to block aglycon transfer is to introduce
aglycon groups that decrease the nucleophilicity of the
sulfur atom through steric hindrance and/or electronic
deactivation such as the dicyclohexylmethyl group or
2,6-dimethylphenyl (DMP) group.16,17,22 While this
approach is effective in many synthetic routes, there
are a number of situations where the aglycon group
cannot be modified. For example, many S-glycoside
inhibitors and vaccine antigens have strict structural
requirements for the aglycon group. Therefore, an alter-
native strategy that minimizes or eliminates aglycon
transfer without modifying the aglycon is needed.
Several reports have shown that the aglycon transfer
process is affected by the protecting groups on the
O
O
O
SR
HO
N3
+
O
N3
O
X
SR
While being extremely useful, compounds containing
thioglycoside aglycon groups are prone to a detrimental
side reaction referred to as aglycon transfer.8–22 Strong
electrophilic species such as activated glycosyl donors
can react with the sulfur atom of a thioglycoside to pro-
duce a sulfonium ion (see Scheme 1). Cleavage of the
bond between the anomeric carbon and the sulfur atom
results in the transfer of the aglycon to the electrophilic
species. In the case of a glycosylation reaction, the agly-
con is transferred to the glycosyl donor.
Desired Disaccharide
Donor
Acceptor
N3
O
O
O
SR
N3
S+
HO
R
Aglycon Transfer
Product
Sulfonium Ion
Scheme 1. Aglycon transfer of thioglycosides.
*
Corresponding author. Tel.: +1 301 846 5699; fax: +1 301 846
6033; e-mail: gildersleevej@ncifcrf.gov
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.126

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Z. Li, J. C. Gildersleeve / Tetrahedron Letters 48 (2007) 559–562
glycosyl acceptor and donor. For one to effectively uti-
lize a protecting group strategy for blocking aglycon
transfer, it is critical to understand how changes to pro-
tecting groups affect transfer and how best to implement
this approach.
boring group participation. Second, one would like a
rational means to control the relative reactivities of the
activated species. However, the nature of the activated
intermediate(s) and the factors that determine the rela-
tive stabilities are not well understood. Nevertheless,
one can approximate the relative stabilities via an
armed–disarmed analysis. The terms armed and dis-
armed refer to the relative ease or difficulty of activating
a sugar as a glycosyl donor.23,24 In general, disarmed
sugars have protecting groups that would destabilize
an oxocarbenium ion such as electron withdrawing
esters and azides. Armed sugars typically have protect-
ing groups that are less destabilizing such as benzyl
ethers or silyl ethers. Since the rates of activation can
be evaluated experimentally, there is extensive informa-
tion in the literature regarding factors that affect the
armed–disarmed nature of a sugar.25
Aglycon transfer is thought to proceed via glycosylation
of the sulfur atom to form a sulfonium ion followed by
cleavage to give the transfer product. In principle, this
process is reversible, which raises two important issues.
First, the transfer process provides a pathway for cleav-
age and reformation of the bond between the anomeric
carbon and the sulfur atom. Therefore, it provides a
pathway for anomerization of the linkage. We recently
showed that anomerization does in fact occur.22 Second,
the transfer process permits equilibration between the
activated species derived from the glycosyl donor and
the activated species derived from the thioglycoside.
Therefore, the relative energies of the two activated
intermediates could have a significant effect on the trans-
fer process with the reaction driven to the more stable
intermediate(s). If this were true, one could avoid trans-
fer by controlling the relative stabilities of the activated
intermediates.
To evaluate the armed–disarmed strategy, a series of
glycosylations were carried out with the aim of synthe-
sizing a GalNAca1–3Gal derivative. This disaccharide
is known to be expressed in humans and was needed
as a glycan for our group’s carbohydrate micro-
array.26–28 The relative armed–disarmed nature of the
glycosyl donor and acceptor was systematically varied.
First, the disarmed donor 129 was coupled with armed
acceptor 230 (see Scheme 2).31 One would anticipate that
an oxocarbenium ion (or other activated intermediate)
derived from armed 2 would be more stable than an
To effectively implement this approach, two important
challenges must be addressed. First, one would have to
prevent anomerization. This could be achieved by addi-
tion of a group that controls stereoselectivity via neigh-
OBn
AcO
OAc
O
BnO
AcO
N3
OAc
O
TMS-OTf
O
No
AcO
+
+
+
+
HO
SPh
AcO
Disaccharide
N3
SPh
-20 ˚C, DCM
BnO
O
CCl3
1
2
3
NH
Disarmed
Armed
85% Transfer
OAc
AcO
AcO
AcO
OAc
OBz
BzO
O
AcO
O
OAc
O
OBz
AcO
TMS-OTf
O
OBz
N3
HO
SPh
N3
O
AcO
O
CCl3
NH
O
SPh
SPh
-20 ˚C, DCM
BzO
N3
OBz
1
4
5
3
Disarmed
BnO
Disarmed
40% Disaccharide
30% Transfer
OBn
OBn
BnO
HO
BnO
N3
OBn
O
TMS-OTf
O
O
No
BnO
SPh
BnO
SPh
Disaccharide
N3
O
CCl3
-20 ˚C, DCM
BnO
6
7
NH
2
Armed
30% Transfer
Armed
OBn
BnO
BnO
OBz
BnO
N3
OBn
BzO
O
O
TMS-OTf
OBz
O
BzO
4
BnO
OBz
O
No
HO
SPh
N3
transfer
O
CCl3
NH
O
SPh
-20 ˚C, DCM
OBz
6
8
Armed
79% Disaccharide
Disarmed
Scheme 2. Effects of varying the armed–disarmed nature of the glycosyl donor and acceptor on the outcome of the glycosylation reaction.

Z. Li, J. C. Gildersleeve / Tetrahedron Letters 48 (2007) 559–562
561
R.; Field, R. A. Tetrahedron Lett. 1997, 38, 8233–8236; (c)
Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713–2715.
6. (a) For some recent reviews, see: Driguez, H., Thiooligo-
saccharides in glycobiology. In Glycoscience Synthesis of
Substrate Analogs and Mimetics; 1997; Vol. 187, pp 85–
116; (b) Witczak, Z. J. Curr. Med. Chem. 1999, 6, 165–178;
(c) Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106,
160–187.
7. For some recent examples, see: (a) Knapp, S.; Myers, D. S.
J. Org. Chem. 2002, 67, 2995–2999; (b) Bundle, D. R.;
Rich, J. R.; Jacques, S.; Yu, H. N.; Nitz, M.; Ling, C. C.
Angew. Chem., Int. Ed. 2005, 44, 7725–7729; (c) Thayer,
D. A.; Yu, H. N.; Galan, M. C.; Wong, C. H. Angew.
Chem., Int. Ed. 2005, 44, 4596–4599.
8. Kihlberg, J.; Eichler, E.; Bundle, D. R. Carbohydr. Res.
1991, 211, 59–75.
9. Knapp, S.; Nandan, S. R. J. Org. Chem. 1994, 59, 281–283.
10. Leigh, D. A.; Smart, J. P.; Truscello, A. M. Carbohydr.
Res. 1995, 276, 417–424.
11. Belot, F.; Jacquinet, J. C. Carbohydr. Res. 1996, 290,
79–86.
12. Du, Y. G.; Lin, J. H.; Linhardt, R. J. J. Carbohydr. Chem.
1997, 16, 1327–1344.
13. Zhu, T.; Boons, G. J. Carbohydr. Res. 2000, 329, 709–715.
14. Yu, H.; Yu, B.; Wu, X. Y.; Hui, Y. Z.; Han, X. W. J.
Chem. Soc., Perkin Trans. 1 2000, 9, 1445–1453.
15. Sherman, A. A.; Yudina, O. N.; Mironov, Y. V.; Sukhova,
E. V.; Shashkov, A. S.; Menshov, V. M.; Nifantiev, N. E.
Carbohydr. Res. 2001, 336, 13–46.
16. Cheshev, P. E.; Kononov, L. O.; Tsvetkov, Y. E.;
Shashkov, A. S.; Nifantiev, N. E. Russ. J. Bioorg. Chem.
2002, 28, 419–429.
17. Geurtsen, R.; Boons, G. J. Tetrahedron Lett. 2002, 43,
9429–9431.
18. Tanaka, H.; Adachi, M.; Takahashi, T. Tetrahedron Lett.
2004, 45, 1433–1436.
oxocarbenium ion derived from disarmed 1. Therefore,
aglycon transfer was expected to be favorable. In fact,
aglycon transfer was the major pathway (85% of 3,32
a:b = 2.5:1) and no disaccharide was formed. Next, we
examined disarming the thioglycoside by substituting
the benzyl ethers with electron-withdrawing benzoyl es-
ters. In addition to disarming the thioglycoside, the ben-
zoyl ester at the 2 position should maintain the beta
stereochemistry at the anomeric center via neighboring
group participation. Glycosylation of disarmed acceptor
426 with disarmed donor 1 produced the desired disac-
charide (5)26 in 40% yield along with 30% of transfer
product 3 (a:b = 1:1). Next, armed donor 629 was cou-
pled with armed acceptor 2. The reaction produced a
very complex mixture of products. From this mixture,
the transfer product (7, all b)33 could be isolated in
30% yield, but the desired product was not obtained.
The extensive formation of side products may have
resulted from polymerization and/or anomerization.
Finally, we coupled disarmed thioglycoside 4 with
armed donor 6. Based on the mechanistic analysis, this
is the preferred matching and transfer should be
unfavorable. Indeed, disaccharide 834 was produced in
79% yield and no transfer product was observed.
The results demonstrate that aglycon transfer can be
avoided by modifying the protecting groups on the
glycosyl donor and acceptor to ensure that the thio-
glycoside acceptor is more disarmed than the glycosyl
donor. The approach provides a complement to existing
strategies based on modifying the aglycon group. Given
the work involved in changing protecting groups, this
approach is best implemented in the planning stages of
a synthesis.
19. Xue, J.; Khaja, S. D.; Locke, R. D.; Matta, K. L. Synlett
2004, 861–865.
20. Codee, J. D. C.; Stubba, B.; Schiattarella, M.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der
Marel, G. A. J. Am. Chem. Soc. 2005, 127, 3767–3773.
21. Sun, J. S.; Han, X. W.; Yu, B. Org. Lett. 2005, 7, 1935–
1938.
Acknowledgement
Financial support from the intramural research program
of the NIH, NCI is gratefully acknowledged.
22. Li, Z.; Gildersleeve, J. C. J. Am. Chem. Soc. 2006, 128,
1161–11619.
23. Fraser-Reid, B.; Wu, Z. F.; Udodong, U. E.; Ottosson, H.
J. Org. Chem. 1990, 55, 6068–6070.
24. Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J. Am. Chem. Soc. 1988, 110, 5583–5584.
25. For some nice examples, see: (a) Zhang, Z.; Ollmann, I.
R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J.
Am. Chem. Soc. 1999, 121, 734–753; (b) Jensen, H. H.;
Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004, 126,
9205–9213, and references cited therein.
References and notes
1. Garegg, P. J. In Advances In Carbohydrate Chemistry And
Biochemistry; Academic Press: New York, 1997; Vol. 52,
pp 179–205.
2. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
3. For some examples and key references, see: (a) Kahne, D.;
Walker, S.; Cheng, Y.; Engen, D. J. Am. Chem. Soc. 1989,
111, 6881–6882; (b) Kakarla, R.; Dulina, R. G.; Hat-
zenbuhler, N. T.; Hui, Y. W.; Sofia, M. J. J. Org. Chem.
1996, 61, 8347–8349; (c) Chen, M. Y.; Patkar, L. N.; Chen,
H. T.; Lin, C. C. Carbohydr. Res. 2003, 338, 1327–1332;
(d) Chen, M. Y.; Patkar, L. N.; Lin, C. C. J. Org. Chem.
2004, 69, 2884–2887; (e) Agnihotri, G.; Misra, A. K.
Tetrahedron Lett. 2005, 46, 8113–8116.
26. Manimala, J.; Li, Z.; Jain, A.; VedBrat, S.; Gildersleeve, J.
C. ChemBioChem 2005, 6, 2229–2241.
27. Manimala, J. C.; Roach, T. A.; Li, Z.; Gildersleeve, J. C.
Angew. Chem., Int. Ed. 2006, 45, 3607–3610.
28. Podolsky, D. K. J. Biol. Chem. 1985, 260, 8262–8271.
29. Schmidt, R. R.; Grundler, G. Angew. Chem., Int. Ed. Engl.
1982, 21, 781–782.
30. Kanie, O.; Ito, Y.; Ogawa, T. Tetrahedron Lett. 1996, 37,
4551–4554.
31. Procedure for the glycosylation reactions: A mixture of
donor 6 (98 mg, 0.16 mmol, 2 equiv) and acceptor 4
(46 mg, 0.08 mmol, 1 equiv) was dried under vacuum for
1 h and then dissolved in dichloromethane (1 mL). Mole-
cular sieves were added to the solution and the reaction
was cooled to ꢀ20 °C. TMSOTf (1 drop) was added and
4. For examples, see: (a) Chang, G. X.; Lowary, T. L. Org.
Lett. 2000, 2, 1505–1508; (b) Brown, D. S.; Ley, S. V.;
Vile, S.; Thompson, M. Tetrahedron 1991, 47, 1329–1342.
5. For some examples and key references, see: (a) Nicolaou,
K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J.
Am. Chem. Soc. 1984, 106, 4189–4192; (b) Kartha, K. P.

562
Z. Li, J. C. Gildersleeve / Tetrahedron Letters 48 (2007) 559–562
the mixture was stirred at ꢀ20 °C for 0.5 h. The reaction
acetate/hexanes); 1H NMR (CDCl3): d 8.08–8.01 (m, 6H),
7.61–7.50 (m, 5H), 7.48–7.43 (m, 4H), 7.33–7.17 (m,
18H), 7.10–7.08 (m, 2H), 5.91 (d, J = 3.2 Hz, 1H), 5.64
(t, J = 10.0 Hz, 1H), 5.24 (d, J = 3.6 Hz, 1H), 4.85 (d,
J = 10.0 Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 4.58 (dd,
J = 11.6, 7.2 Hz, 1H), 4.46–4.36 (m, 3H), 4.30–4.21 (m,
4H), 4.12 (m, 1H), 3.74 (m, 1H), 3.70 (dd, J = 10.4,
3.2 Hz, 1H), 3.44 (dd, J = 10.8, 2.8 Hz, 1H), 3.38 (dd,
J = 9.6, 7.2 Hz, 1H), 3.23 (d, J = 1.2 Hz), 3.17 (dd,
J = 9.6, 5.6 Hz, 1H); 13C NMR (CDCl3): d 166.0, 165.7,
164.7, 138.1, 138.0, 137.5, 133.3, 133.2, 131.9, 130.1, 129.9,
129.8, 129.5, 129.4, 129.1, 128.8, 128.5, 128.44, 128.42,
128.36, 128.32, 128.16, 128.1, 127.97, 127.8, 127.7, 127.6,
127.5, 94.2, 86.0, 77.4, 75.0, 74.4, 73.7, 73.3, 73.2, 72.5,
70.1, 69.1, 68.9, 65.6, 62.7, 59.2; HRMS, Calcd for
[MNH4]+ C60H59N4O12S: 1059.3850. Found: 1059.3873.
was quenched by the addition of saturated NaHCO3
(1 mL). The organic layer was separated, dried over
Na2SO4, and concentrated in vacuo. The crude product
was purified by column chromatography (1:1 ethyl
acetate/hexanes) to give the desired product, phenyl
(2-azido-3,4,6-tri-O-benzyl-2-deoxy-a-D-galactopyranosyl)-
(1 ! 3)-2,4,6-tri-O-benzoyl-1-thio-b-D-galactopyranoside
(8), (64 mg, 79% yield).
32. Andreotti, A. H.; Kahne, D. J. Am. Chem. Soc. 1993, 115,
3352–3353.
33. Suzuki, K.; Ohtsuka, I.; Kanemitsu, T.; Ako, T.; Kanie,
O. J. Carbohydr. Chem. 2005, 24, 219–236.
34. Phenyl (2-azido-3,4,6-tri-O-benzyl-2-deoxy-a-D-galacto-
pyranosyl)-(1 ! 3)-2,4,6-tri-O-benzoyl-1-thio-b-D-galacto-
pyranoside (8), (64 mg, 79% yield): Rf = 0.4 (1:2 ethyl