Mild and selective O-glycosylations of primary alcohols with the thioglucosaminide derivative promoted by N-iodosuccinimide and HBF4-adosrobed on silica gel

Article abstract of DOI:10.3987/COM-09-S(S)24

Selective glycosylations of primary alcohols with the thioglucosaminide 1 are achieved by using NIS and HBF₄-SiO₂- HBF₄-SiO₂ is a mild Bronsted acid which requires primary alcohols or phenols to effectively activate 1 with NIS at rt. A wide range of functional groups are tolerated under these conditions.

Full text of DOI:10.3987/COM-09-S(S)24

HETEROCYCLES, Vol. 80, No. 1, 2010
115
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 115 - 123. © The Japan Institute of Heterocyclic Chemistry
Received, 15th April, 2009, Accepted, 11th May, 2009, Published online, 12th May, 2009
DOI: 10.3987/COM-09-S(S)24
MILD AND SELECTIVE O-GLYCOSYLATIONS OF PRIMARY
ALCOHOLS WITH THE THIOGLUCOSAMINIDE DERIVATIVE
PROMOTED BY N-IODOSUCCINIMIDE AND HBF4-ADOSROBED ON
SILICA GEL
Michio Kurosu* and Kai Li
Dedicated to Professor Akira Suzuki on the occasion of his 80th birthday
Department of Microbiology, Immunology, and Pathology, College of
Veterinary Medicine and Biomedical Sciences, Colorado State University, 1682
Campus Delivery, Fort Collins, CO 80523-1682, USA
E-mail: michio.kurosu@colostate.edu
Abstract
–
Selective glycosylations of primary alcohols with the
thioglucosaminide 1 are achieved by using NIS and HBF4-SiO2. HBF4-SiO2 is a
mild Brønsted acid which requires primary alcohols or phenols to effectively
activate 1 with NIS at rt. A wide range of functional groups are tolerated under
these conditions.
Drug design in recent years has attempted to explore new chemical spaces resulting in more complex and
larger molecular weight molecules. These molecules often possess limited water solubility. In general,
these poorly soluble active new chemical entities present problems in drug administration and
formulation.1 Prodrug strategy has employed to improve the solubility profile of molecules, resulting in
increase of the intestinal absorption of poorly water-soluble hydrophobic compounds.2 Glycosylation is
one of the approaches for increasing water solubility and cellular uptake; a number of examples of the
enhancement in the solubility and efficacy of natural products via glycosylation have been reported.3
However, rational attempts to improve the oral absorption of poorly soluble active new chemical entities
by glycosylation(s) are complicated by the fact that the mechanisms by which new molecules are
transported from the gastro intestine to the blood are unknown. In addition, extensive regeneration studies
of inactive glycosyl prodrugs by the cellular enzymatic reaction of glycosidase (enzyme specific
activation) or hydrolysis in vivo are necessary. To date, glucuronide-, glucosyl- and galactosyl-prodrug
approaches have been applied to known chemical entities, and their transport and regeneration

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HETEROCYCLES, Vol. 80, No. 1, 2010
mechanisms at specific sites have been well studied.4 Although glucosaminyl or N-acetyl-glucosaminyl
prodrugs are known to exhibit beneficial physicochemical properties (i.e. shorter half-live of hydrolysis
(at pH 7.4), and susceptibility to -D-N-acetyl-glucosaminidase),5 applications of these prodrug systems
to complex molecules have been limited due in part to lack of robust selective glycosylations with
glucosamine derivatives. Herein, we report a mild and selective glycosylation of primary alcohols with
thioglucosaminide with N-Troc (2,2,2-trichloroethoxycarbonyl) group using NIS (N-iodosuccinimide)
and HBF4-SiO2.
Thioglycosaminide with N-Troc such as 1 has been widely utilized in synthesis of
N-acetylglucosamine-containing glycoconjugates.6 The thioglycoside 1 is generally coupled to primary or
secondary alcohols in good to excellent yields using a combination of NIS and TfOH7 or other variations
of triflate sources.8 The Troc group is reliably deprotected via a wide range of reductive elimination
conditions (i.e. Zn, Cd, or In in the presence of a mild Brønsted acid).9 Although reported
O-glycosylation conditions for 1 are useful for acyl- or benzyl-protected glycosyl acceptors, application
of glycosylation of 1 using NIS and strong Brønsted acids or strong acid salts to glycosyl acceptors
possessing acid sensitive groups (i.e. silyl or Boc group) generally requires laborious optimization efforts.
In our hands, the NIS/TfOH promoted glycosylation of 2h with 1 gave the desired product 3h in poor
yield due to desilylation of 2h or 3h (Scheme 1).10 In addition, no reliable condition for selective
glycosylations with 1 against primary alcohols of polyol molecules has been reported to date. In our
investigations of an alternative acid which can promote glycosylation of 2h with 1 and NIS, we observed
that HBF4-absorbed on silica gel (HBF4-SiO2)11 efficiently catalyzed the reaction to furnish 3h in over
95% yield within 3 h at rt. On the other hand, the glycosylation of the secondary alcohol 2s with 1 did not
O
O
OAc
NBOM
NBOM
OAc
O
AcO
AcO
HO
N
O
NIS, HBF4-SiO2
N
O
O
O
O
O
AcO
AcO
+
STol
CH2Cl2, 3 Å MS
95%
TrocNH
TrocNH
TBSO
OBn
OP
TBSO
OBn
1
2h
3h
OP
O
NHTroc
O
HO
NH
AcO
AcO
O
O
OAc
O
O
O
AcNH
Me
Me
AcNH
OBn
NIS, HBF4-SiO2
CH2Cl2, 3 Å MS
OBn
+
O
OAc
AcO
AcO
O
STol
NH
Cl
Cl
TrocNH
P=
Me
Me
O
SO2Ph
O
SO2Ph
O
O
Cl
Cl
OMe
1
2s
3s
Scheme 1. Investigation of a mild Brønsted acid to promote glycosylations of 1.

HETEROCYCLES, Vol. 80, No. 1, 2010
117
provide the disaccharide 3s under the same conditions even after prolonged reaction time. Interestingly, 1
and 2s could be recovered as their intact forms in almost quantitative yields (Scheme 1).12 The glycosyl
donor 1 is activated by using a NIS/TfOH condition in the absence of acceptor alcohols to furnish the
corresponding anomeric alcohol. Thus, an unusual reaction mechanism, the primary alcohol 2h efficiently
participates in the process of activation of 1, observed in Scheme 1 may be attributed to the preferential
glycosylation of the primary alcohol and tolerance of the silyl group in these reactions. Indeed,
HBF4-SiO2 1) no longer shows a strong Brønsted acid characteristic as observed for HBF4•OEt2 in aprotic
solvents, 2) does not catalyze the cleavage of acetal, and acid sensitive ether and Boc groups at ambient
temperatures, 3) has a strong affinity for alcohols, but a weak affinity for carbonyls,13 and 4) does not
cause HBF4 leaching from silica gel during the reactions or by washing with organic solvents including
MeOH.14 Thus, such a strongly bound HBF4 on SiO2 serves as a moderate to weak Brønsted acid.15
In order to generalize the use of NIS/HBF4-SiO2 for selective glycosylations with 1, a wide range of
model donor molecules, primary, secondary and phenolic alcohols, were examined. In these experiments,
acceptors (3~5 equiv against 1), NIS (2 equiv against 1), 3 Å MS (~two times its weight in 1),16 and
HBF4-SiO2 (0.8 mmol/g, 2 equiv against 1) were employed in the reactions in CH2Cl2 at rt. Selected
examples are summarized in Table 1 and 2. All primary and phenolic alcohols investigated were
glycosylated to furnish the corresponding -glycosides within 3 h. Reaction rates of the phenols 2b and
2c were faster than those of benzyl alcohol (2a) and alkanols (entries 1–8 in Table 1). Glycosylations of
structurally simple alcohols 2a–c resulted in the formation of corresponding -glycosides 3a–c in greater
than 95% yields. The -hydroxy ester 2d and serine derivatives, 2e and 2f, were coupled with 1, and the
desired products 3d, 3e, and 3f were isolated with good to moderate yields (entries 4, 5). The Boc group
of 2e was stable under these conditions, however, the isolated yield of 3e was 30% (>95% yield based on
recovering 2e) due in part to the attenuated nucleophilicity of the hydoxy group of 2e by forming a
hydrogen bond with the neighboring group. Similarly, glycosylation of the Fmoc-protected serine 2f
yielded 3f in 50 % yield. The primary alcohols of the pyranose and furanose derivatives 2g, i, j were
efficiently coupled with 1 to yield the corresponding -linked disaccharides 3g, i, j, respectively (entries
6–8). As observed in the reaction of 2s with 1 in Scheme 1, secondary alcohols showed poor reactivity
against 1 under the HBF4-SiO2 promoted glycosylation conditions (Table 2). Glycosylation of 2-proponol
(2k) with 1 provided the -linked glycoside 3k in less than 30% yield after 15 h (entry 9); no detectable
amount of 3k was identified on TLC within 1 h. However, trace amounts of 3k was formed after 3 h. Less
than 5% of the -cholesteryl glycoside was isolated after 15 h (entry 10). The threonine derivative 2m
and secondary alcohols of the pyranose and furanose derivatives 2n–p did not provide detectable amounts
of the corresponding products on TLC even after 15 h (entries 11–13).

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HETEROCYCLES, Vol. 80, No. 1, 2010
Table 1. NIS/HBF4-SiO2 promoted glycosylations of 1 with primary alcohols.17
OAc
OAc
O
NIS, HBF4-SiO2
O
AcO
AcO
AcO
AcO
O
+
R-OH
STol
R
CH2Cl2, 3 Å MS
rt, 3 h
TrocNH
TrocNH
2a~j
3a~j
1
product
OAc
yield (%)
>95
entry
1
acceptor
O
OH
AcO
AcO
O
O
TrocNH
OAc
3a
3b
2a
O
OH
2
3
4
5
>95
>95
85
AcO
AcO
TrocNH
OAc
2b
O
AcO
AcO
O
O
TrocNH
OH
O
2c
3c
3d
O
OAc
Cl
O
HO
O
AcO
AcO
O
O
O
O
Cl
2d
TrocNH
OAc
O
O
NHR
O
a
AcO
AcO
3e:
30 (>95)
55 (>95)a
HO
O
NHR
OH
TrocNH
3f:
O
2e: R=Boc,
2f: R=Fmoc
3e: R=Boc,
3f: R=Fmoc
OAc
O
AcO
AcO
O
O
87
6
7
BnO
O
TrocNH
OAc
BnO
BnO
BnO
BnO
OMe
O
BnO
2g
3g
OMe
O
NBOM
NBOM
O
O
AcO
AcO
HO
O
3h:
3i:
N
N
>95
>95
O
O
O
TrocNH
RO
OBn
RO
OBn
2h: R=TBS,
3h: R=TBS,
3i: R=Me
2i: R=Me
O
O
OAc
O
NBOM
NBOM
O
AcO
AcO
HO
N
O
O
N
O
>95
8
O
TrocNH
O
O
2j
O
O
3j
a Yield based on recovering starting material.

HETEROCYCLES, Vol. 80, No. 1, 2010
119
Table 2. NIS/HBF4-SiO2 promoted glycosylations of 1 with secondary alcohols or a diol or a triol.
OAc
OAc
O
NIS, HBF4-SiO2
O
AcO
AcO
AcO
AcO
O
+
R-OH
STol
R
CH2Cl2, 3 Å MS
rt, 15 h
TrocNH
TrocNH
2k~r
3k~r
1
product
yield (%)
<30
entry
9
acceptor
OAc
O
OH
AcO
AcO
O
TrocNH
OAc
2k
3k
O
10
11
<5
_
AcO
AcO
cholesterol
O
cholesteryl
TrocNH
2l
3l
O
_
HO
O
NHBoc
2m
OBn
O
HO
BnO
_
_
_
_
11
12
BnO
OMe
2n
Ph
O
O
O
HO
BnO
O
OMe
2o
NBOM
O
TrO
N
_
_
13
O
HO
OH
OAc
O
2p
AcO
AcO
O
O
TrocNH
HO
OH
MeO
O
7
:
70 (3qa)
10 (3qb)
14
HO
MeO
MeO
OMe
OMe
3qa
OAc
O
MeO
MeO
OMe
2q
1
MeO
AcO
AcO
O
O
TrocNH
OH
3qb
O
O
OAc
O
NBOM
O
NBOM
O
HO
15
N
AcO
AcO
72 (3r)
O
N
O
O
TrocNH
18 (other
regioisomers)
HO
OH
HO
OH
2r
3r

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HETEROCYCLES, Vol. 80, No. 1, 2010
Having considered the observation in which secondary alcohols are not effectively coupled with 1 under
the NIS/HBF4-SiO2 conditions, we explored selectivities (primary vs. secondary alcohol) of
glycosylations of a diol and a triol such as 2q and 2r. Glycosylation of 2q furnished a 7:1 mixture of
-glycosides, 3qa and 3qb, in 80% yield (entry 14). Similar selectivity against the primary alcohol was
observed in glycosylation of 2r, and the disaccharide 3r was isolated in 72% yield (entry 15). In both
cases the over-reaction products were not isolated and the regioisomer is the only byproduct in these
reactions. It is worthwhile mentioning that the product selectivities of the reaction with 2q and 2r were
not improved by shortening the reaction time (3 h) or lowering the reaction temperatures (-20–0 oC). Less
primary/secondary selectivities observed in glycosylations of the glucose and ribose derivatives, 2q and
2r, are not clear. Nonetheless, we observed useful level of selectivity against primary alcohol in
glycosylation of a diol and a triol.
The NIS/HBF4-SiO2 promoted selective glycosylations of primary alcohols observed for 1 were
applicable to the other tolyl thioglycosides such as 4 and 5. However, the orthoesters 6 and 7 were formed
in almost quantitative yields within 10 min,18 and 6 and 7 were not rearranged to the corresponding
glycosides 8 and 9 even after 15 h. Isolated 6 and 7 could be completely converted to 8 and 9,
respectively, via HBF4•OEt2 in CH2Cl2 (Scheme 2). The experimental data summarized in Scheme 2
confirm that HBF4-SiO2 is a mild Brønsted acid and acid-sensitive orthoesters 6 and 7 are not hydrolyzed
by HBF4-SiO2.
OAc
OAc
O
H3C
OAc
OAc
AcO
AcO
MeO
OBn
N
O
O
O
AcO
AcO
AcO
O
O
O
AcO
AcO
O
O
O
O
>90%
OEt2
NBOM
STol
HO
MeO
OBn
4
NBOM
8
6
N
NIS, HBF4-SiO2
O
HBF4
ꢀ
O
or
OAc
+
CH2Cl2, 3 Å MS
O
CH2Cl2, 3 Å MS
rt, 3 h
OAc
0
oC,12 h
O
O
MeO
OBn
MeO
OBn
AcO
AcO
OAc
O
AcO
AcO
2i
STol
NBOM
O
>95 %
O
O
O
AcO
AcO
>90%
O
O
N
OAc
O
O
H3C
5
OAc
7
9
MeO
OBn
Scheme 2. NIS/HBF4-SiO2 promoted glycosylations of 4 and 5.
In conclusion, we have demonstrated NIS/HBF4-SiO2 promoted selective glycosylations of primary
alcohols with thioglucosaminide 1. Interestingly, HBF4-SiO2 requires the thioglycosides (glycosyl
acceptors) and primary or phenolic alcohols to efficiently activate NIS.19 As demonstrated in Scheme 1
and 2, a wide range of functional groups are tolerated under NIS/HBF4-SiO2 promoted glycosylation

HETEROCYCLES, Vol. 80, No. 1, 2010
121
conditions. Although mechanism of the reactions associated with HBF4-SiO2 is far from understood,
beneficial features of NIS/HBF4-SiO2 described above can be applied to selective glycosylations of
primary alcohols of target molecules, which are difficult to be glycosylated selectively using previously
reported conditions.6
ACKNOWLEDGEMENTS
We thank the National Institutes of Health and Colorado State University for generous financial support.
Mass spectra were obtained on instruments supported by the NIH Shared Instrumentation Grant
GM49631.
REFERENCES AND NOTES
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M. L. Citro, J. J. Barchi, J. R. Deschamps, D. Parrish, S. El-Gayar, U. Schleicher, C. Bogdan, and L. K.
Keefer, J. Med. Chem., 2008, 51, 3961.
6. (a) M. Imoto, H. Yoshimura, T. Shimamoto, N. Sakaguchi, S. Kusumoto, and T. Shibata, Bull. Chem.
Soc. Jpn., 1987, 60, 2205; (b) H. Paulsen and C. Krogmann, Liebigs Ann. Chem., 1989, 1203; (c) H.
Paulsen and B. Helpap, Carbohydr. Res., 1991, 216, 289; (d) W. Dullenkopf, J. C. Castro-Palomino, E.
I. Ibrahim, E. H. El-Ashry, and R. R. Schmidt, Eur. J. Org. Chem., 1998, 2305; (e) G. K. I. Nilsson,
Tetrahedron Lett., 1997, 38, 133; (f) Z. Zhang, I. Ollmann, X.-S. Ye, R. Wischnat, T. Baasov, and C.
H. Wong, J. Am. Chem. Soc., 1999, 121, 734.

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7. (a) G. H. Veeneman and J. H. van Boon, Tetrahedron Lett., 1990, 31, 275; (b) G. H. Veeneman, S. H.
van Leeuwen, and J. H. van Boom, Tetrahedron Lett., 1990, 31, 1331; (c) P. Konradsson, U. E.
Udodong, and B. Fraser-Reid, Tetrahedron Lett., 1990, 31, 4313.
8. (a) K. Fukase, A. Hasuoka, I. Kinoshita, Y. Aoki, and S. Kusumoto, Tetrahedron, 1995, 51, 4923; (b)
N. Tanaka, F. Ohnishi, D. Uchihata, S. Torii, and J. Nokami, Tetrahedron Lett., 2007, 48, 7383 and
references cited therein.
9. (a) A. J. Pearson and W. R. Roush, Ed.; Handbook of Reagents for Organic Synthesis: Activating and
Agents and Protecting Groups. Wiley, New York, 1999; (b) T. W. Greene and P. G. M. Wuts, In
Protective Groups in Organic Synthesis. 3rd Ed. John Wiley and Sons: New York, 1999.
10. p-Tolylsulfenyl trifluoromethanesulfonate (p-TolSOTf) was effective in promoting the glycosylation
of 2h with 1. However, addition of ScCO3 was indispensable to avoid desialylation of the TBS group,
see: M. Kurosu and K. Li, J. Org. Chem., 2008, 73, 9767.
11. Anhydrous HBF4 on SiO2 can readily be obtained by a simple procedure of mixing SiO2 with ~48% aq.
HBF4 and subsequent removal of H2O, and is not hygroscopic.
Preparation of HBF4-SiO2: To a magnetically stirred suspension of silica gel (20 g, 230–400 mesh) in
Et2O (100 mL), HBF4 (48% in water, 2.1 mL, 16 mmol) was added at rt. After 3 h, the mixture was
concentrated and the residue was dried under high vacuum (1~5 mmHg) at 110 °C for 72 h to give
anhydrous HBF4-SiO2 (HBF4: 0.8 mmol/g). Titration studies of the recovered HBF4-SiO2 and
washing solvents supported that negligible amounts of HBF4 from SiO2 are leached during the
reactions or washing.
12. In our laboratory, the glycopeptide core of lipid II 3s has been synthesized via NIS/AgBF4 in CH2Cl2.
Under these conditions a gram quantity of 3s was synthesized with >80 % yield (based on 2s).
13. Taking advantage of strong affinity of HBF4-SiO2 against primary or phenolic alcohols, we have used
HBF4-SiO2 as an affinity matrix for separating primary or phenolic alcohols out of crude materials.
14. Titrations were performed with an analytical 0.1 N NaOH solution and phenolphtalene as an indicator.
15. Recently, HBF4-SiO2 was demonstrated for synthesis of acetals from aldehydes or thiiranes from
oxiranes, see: (a) V. T. Kamble, B. P. Bandgar, N. S. Joshi, and V. S. Jamode, Synlett, 2006, 2719; (b)
B. P. Bandgar, P. V. Abasaheb, V. T. Kamble, and J. V. Totre, J. Mol. Catal. A: Chem., 2007, 273, 114.
For a study of glycosylations with thioglycosides promoted by NIS and HClO4-SiO2, see: (c) B.
Mukhopadhyay, B. Collet, and R. A. Field, Tetrahedron Lett., 2005, 46, 5923.
16. MS 3 Å is not indispensable. In order not to obtain inconsistent results caused by adventitious water,
activated MS 3 Å (~two times its weight in 1) was added in all reactions.
17. The following example represents typical experimental procedure: To a stirred suspension of 2i (282
mg, 0.6 mmol), 1 (117 mg, 0.2 mmol) and 3Å MS (550 mg) in dry CH2Cl2 (10 mL) under N2

HETEROCYCLES, Vol. 80, No. 1, 2010
123
atmosphere was added NIS (45 mg, 0.2 mmol) and HBF4-SiO2 (250 mg, 0.2 mmol). After 3 h at rt, the
reaction mixtures were filtrated and washed with EtOAc (5 mL). The combined organic phase was
evaporated in vacuo. Purification by silica gel chromatography (hexanes/EtOAc = 2/1) gave the 3i
(178 mg, 96 %). Data for 3i: [α]20D +37o (c 1.0, CHCl3); IR (film): 1746, 1710, 1666, 1070 cm-1; 1H
NMR (400 MHz, CDCl3)  7.79 (d, J = 8.4 Hz, 1H), 7.43-7.28 (m, 10H), 5.97 (s, 1H), 5.80 (d, J = 8.0
Hz, 1H), 5.48 (s, 2H), 5.17 (m, 2H), 5.09 (m, 1H), 4.88 (d, J = 12.4 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H),
4.73 (m, 1H), 4.72 (s, 2H), 4.60 (d, J = 8.8 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.33-4.26 (m, 3H), 4.10
(dd, J = 2.0, 12.4 Hz, 1H), 4.03 (d, J = 3.6 Hz, 1H), 3.75-3.69 (m, 3H), 3.63 (m, 1H), 3.24 (s, 3H), 2.09
(s, 3H), 2.04 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3)  171.1, 170.9, 169.5, 163.0, 154.2,
151.0, 139.1, 138.0, 137.5, 128.6, 128.5, 128.2, 127.9, 101.8, 101.1, 95.5, 89.2, 80.5, 78.8, 76.5, 74.6,
72.3, 72.1, 71.9, 70.3, 68.4, 67.5, 61.9, 58.2, 56.6, 20.9, 20.8, 20.7; HRMS (ESI) Calcd. for
C40H46Cl3N3NaO16 (M + Na)+: 952.1841, found: 952.1848.
18. The formation of orthoesters has previously been reported with a number of different glycosyl donors
which contain a 2-O-acetyl group, see: A. H. Harreus and H. Kunz, Liebigs Ann. Chem., 1986, 717.
19. The reaction mechanism of the HBF4-SiO2 promoted glycosylations with 1 and NIS remains far from
understood. However, we speculate that primary alcohols interact with HBF4-SiO2 and alcohol
protons would activate NIS by coordination with the imido carbonyl of NIS.