Iodine-catalyzed one-pot acetalation-esterification reaction for the preparation of orthogonally protected glycosides

Article abstract of DOI:10.1016/j.carres.2010.07.010

An iodine-catalyzed one-pot tandem acetalation-esterification reaction of thio- and O-glycosides has been developed providing a fast and mild route to orthogonally protected glycosides ready to be used as building blocks in glycosylation reactions.

Full text of DOI:10.1016/j.carres.2010.07.010

Carbohydrate Research 345 (2010) 1842–1845
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Iodine-catalyzed one-pot acetalation–esterification reaction
for the preparation of orthogonally protected glycosides
Rachel A. Jones a, Robert Davidson a, Anh Tuan Tran a, Nichola Smith b, M. Carmen Galan a,
*
a School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
b Novartis Institute for Biomolecular Research, Novartis Horsham Research Centre, Horsham RH12 5AB, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2010
Received in revised form 17 June 2010
Accepted 4 July 2010
Available online 30 July 2010
An iodine-catalyzed one-pot tandem acetalation–esterification reaction of thio- and O-glycosides has
been developed providing a fast and mild route to orthogonally protected glycosides ready to be used
as building blocks in glycosylation reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Orthogonal protection
Monosaccharide building blocks
Acetalation
Esterification
One-pot
1. Introduction
ation strategies, there are fewer examples of one-pot approaches
applied to the preparation of orthogonally protected glycosides.3
Carbohydrates and their glycoconjugates are one of the most
important classes of macrobiomolecules which play key structural
and functional roles in numerous biological recognition processes.1
Furthermore, carbohydrate moieties have also been employed as
useful chiral precursors in natural product synthesis.2 The synthe-
sis of structurally defined oligosaccharides in sufficient purity and
quantity remains essential for understanding glycan diversity and
function.
Oligosaccharide assembly relies on the ability to link monosac-
charide units in a chemo- and stereo-selective manner and this is
typically accomplished by the use of orthogonal protecting groups
that can be manipulated under different reaction conditions.3
The preparation of differentially protected monosaccharide
building blocks to be used as either synthetic chiral scaffolds or
glycosylation donors is still a very laborious endeavor. This process
is typically accomplished by the introduction of each protecting
group stepwise and tends to increase the linearity and decrease
the efficiency of the overall synthesis.
For instance, the groups of Beau and co-workers4 and Hung and
co-workers5 have developed a commendable regio-selective one-
pot protection strategy via a Lewis acid-catalyzed reaction on
per-O-trimethylsilylated glucosides, however, their approach was
unsuccessful with unprotected glycosides. Alternatively, a one-
pot benzylidination–acetylation reaction of sugar derivatives has
6
been reported under acidic condition using immobilized HClO4
and H2SO4,7 respectively, or p-toluenesulfonic acid8 in combination
with acetic anhydride. However, all of these strategies are based on
the use of harsh, costly, and in some cases difficult to handle, acidic
systems to catalyze the acetal formation step.
4,6-O-Arylidene acetalations which can undergo regio-selective
ring opening to provide a free 4-OH or 6-OH, correspondingly, or
afford both free hydroxyls upon acetal hydrolysis or hydrogenoly-
sis, are widely used on carbohydrate templates in combination
with acetylation at C-2 and C-3. This protecting group strategy pro-
vides a versatile set for orthogonal protection that allows for regio-
and stereo-isomer control in oligosaccharide assembly.3
One-pot synthetic strategies whereby several synthetic steps
can be performed in the same vessel without any need for work-
up and purification are an ideal alternative. However, though much
research has been focused in the development of one-pot glycosyl-
As previously described, benzylidenation is frequently catalyzed
by acidic catalysts, while esterification often requires excess acetic
anhydride, generally in the presence of toxic pyridine to act as both
solvent and catalyst of the reaction.9 Molecular iodine (I2) has been
previously used as an inexpensive, non-toxic, nonmetallic, and read-
ily available catalyst in organic reactions10 and also in carbohydrate
chemistry.11 In particular it has been used to catalyze reactions such
as acetonide,12 acetylation,13–15 isopropylidenation,16 and benzyli-
* Corresponding author. Tel.: +44 (0)1179287654; fax: +44 (0)1179298611.
E-mail addresses: M.C.Galan@bristol.ac.uk, chmcgh@bris.ac.uk (M. Carmen
Galan).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.07.010

R. A. Jones et al. / Carbohydrate Research 345 (2010) 1842–1845
1843
dene acetal17 formation, because of its known ability to interact with
Table 1
electron-rich centers of solvents and reagents as a Lewis acid. More
recently, I2 hasbeensuccessfullyusedtocatalyzethetandemisopro-
pylidenation–acetylation reaction of non-reducing sugars and sugar
glycosides under solvent-free conditions.18
Herein, we report the previously undisclosed one-pot tandem
iodine-catalyzed acetalation–esterification reaction for the effi-
cient preparation of orthogonally protected thio- and O-glycosides.
Entry
Starting material
Product
Yield (%)
Ph
O
O
O
OMe
1
1
75
80
BzO
OBz
11
O
pMPh
O
O
OMe
2
3
4
1
AcO
OAc
12
OH
Ph
O
O
O
O
SPh
2. Results and discussion
HO
AcO
89
78
SPh
HO
OAc
13
OH
4
For our initial experiments, commercially available methyl b-D-
pMPh
O
O
O
glucopyranoside 1 was reacted with benzylidene dimethyl acetal
and 0.1 equiv of I2 in acetonitrile.17 Unfortunately in our hands,
the reaction could not be driven to completion, even when reaction
temperature was raised to 50 °C. Increasing the equivalents of I2 to
0.4 produced the 4,6-benzylidene acetal derivative 2 within 2 h at
room temperature. Upon complete consumption of the starting
material, as shown by TLC, acetic anhydride (5 equiv)19 was added
into the reaction and the mixture was stirred at room temperature
for another 16 h to afford methyl 2,3-di-O-acetyl-4,6-O-benzyli-
SPh
4
AcO
14
OAc
HO
Ph
OH
O
O
SPh
HO
O
5
6
74
85
OH
5
O
SPh
AcO
OAc
15
pMPh
dene-b-D
-glucopyranoside 320 very cleanly in 77% yield after col-
O
O
umn chromatography. In the presence of catalytic amounts of
4-N-dimethylaminopyridine (DMAP) (5 mol %) the esterification
step was accelerated and the reaction was complete within 6 h
with the product isolated in similar yields (Scheme 1).
5
O
SPh
AcO
OAc
16
OH
O
OAc
O
HO
HO
Ph
Ph
O
Encouraged by these results, we decided to apply this method-
ology to the preparation of orthogonally protected thioglycosides,
which are a commonly used type of glycosyl donor for glycosyla-
tion reactions.21 Although epimerization of ‘armed’ thioglycosides
with iodine in the absence of an acceptor alcohol has been previ-
ously reported,22,23 as Fraser-Reid has shown,24 4,6-O-benzyli-
dene-protected pyranosyl systems, such as products 12–19, are
considered ‘disarmed’ glycosyl donors. Due to the greater strain
the conformational deformation imposes on the transfused
bicyclic nucleus, the formation of oxycarbenium cations is dis-
favored and thus no epimerization under the proposed reactions
conditions is expected.
O
7
8
60
75
SPh
SPh
SPh
HO
AcO
6
17
18
OH
O
O
O
O
SPh
HO
HO
AcO
NHTroc
NHTroc
7
OH
O
Ph
O
O
AcO
O
SPh
NHPhth
HO
HO
9
65a
SPh
NHPht
19
8
a
1 equiv I2 was used to catalyze acetal formation.
To this purpose, a series of unprotected thioglycosides 4,25 5,26
and 627 were prepared following the reported procedures and one-
pot tandem reactions were performed under the same conditions
as before to afford orthogonally protected thioglycosides 13,28
15,20 and 17,29 respectively, in good to excellent yields ranging
from 60% to 89% (Table 1, entries 3, 5, and 7). Similarly, the method
was successfully applied to N-trichloroethylchloroformate (N-Troc)
and N-phthalimido (N-Phth)-protected glucosamine thioglycosides
730 and 831 to yield products 1832 and 1920 in excellent yields of
75% and 65%, respectively, (Table 1, entries 8 and 9).
To explore the scope of the reaction, we decided to apply our
methodology to orthogonal protections with another set of
4,6-O-acetals and 2,3-di-O-ester groups. For instance, the
p-methoxybenzylidene acetal is a versatile protecting group for
diols that undergoes acid hydrolysis 10 times faster than the ben-
zylidene group.33 To that end, glycosides 1, 4, and 5 were treated
with our optimized protocol for the tandem acetalation–acetyla-
tion reaction and compounds 12,34 14, and 16 were obtained in
excellent yields of 80%, 78%, and 85%, respectively, after column
chromatography (Table 1, entries 2, 4, and 6). These results demon-
strate that our mild set of conditions is compatible with this more
labile class of acetals. On the other hand, the benzoyl ester group is
one of the most common alcohol-protecting groups, since benzo-
ates are less readily hydrolyzed than acetates and the tendency
for benzoate migration to adjacent hydroxyl is not as strong as
their acetate counterparts.35 Thus, reaction of 1 under the condi-
tions described above, but using benzoic anhydride instead of ace-
tic anhydride, afforded 1120 in a very good yield of 75% (Table 1,
entry 1).
3. Summary
In summary, we have demonstrated that inexpensive molecular
iodine can be used as a cheap, non-toxic, general, and fast catalyst
OH
O
Ph
O
Ph
O
O
a)
O
b)
O
O
HO
HO
OMe
OMe
HO
OMe
AcO
OH
OAc
OH
2
3
1
not isolated
77%
Scheme 1. Reagents: (a) PhCH(OMe)2 (1.5 equiv), I2 (0.4 equiv) CH3CN; (b) Ac2O (5 equiv), DMAP.

1844
R. A. Jones et al. / Carbohydrate Research 345 (2010) 1842–1845
for one-pot tandem acetalation–esterification reactions of glyco-
sides in good to excellent yields without the need for purification
after each reaction step. Furthermore, the addition of catalytic
DMAP can be used to accelerate the esterification step and thus
shorten reaction times. The method is mild and compatible with
different thio- and O-glycosides, applicable to the formation of
4,6-O-benzylidene and 4,6-O-p-methoxybenzylidene acetals in
tandem with either 2,3-O-di-acetate or 2,3-O-di-benzoate esters
and also amenable to commonly used amino-protecting groups
(Phth and Troc). This approach simplifies the preparation of
orthogonally protected building blocks ready to be used in glyco-
sylation reactions.
4.2.1. Phenyl 2,3-di-O-acetyl-4,6-O-p-methoxybenzylidene-1-thio-b-
D
-glucopyranoside 14
½
a 2D3
ꢀ
ꢁ33 (c 0.03, CH2Cl2); 1H NMR (CDCl3, 400 MHz, ppm):
d = 7.50–7.48 (m, 2H, Ph), 7.35 (d, 2H, J = 8.5 Hz, pMPh), 7.35–
7.33 (m, 3H, Ph), 6.88 (d, 2H, J = 8.5 Hz, Ph), 5.46 (s, 1H, pMPhCH),
5.34 (t, 1H, J2,3 = J3,4 = 9.5 Hz, H-3), 5.01 (dd, 1H, J2,3 = 9.5 Hz,
J1,2 = 10.0 Hz, H-2), 4.82 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.37 (dd, 1H,
J5,6a = 5.0 Hz, J6a,6b = 10.5 Hz, H-6a), 3.80 (s, 3H, OMe), 3.78 (t, 1H,
J5,6b = J6a,6b = 10.5 Hz, H-6b), 3.66 (t, 1H, J3,4 = J4,5 = 9.5 Hz, H-4),
3.60–3.54 (m, 1H, H-5), 2.11 (s, 3H, CH3 OAc), 2.03 (s, 3H, CH3
OAc). 13C NMR (CDCl3, 100 MHz): d = 170.1, 169.5 (CO), 160.2 (C-
OMe, pMPh), 133.0 (Cq, pMPh), 131.8 (Cq, Ph), 129.2, 129.0, 128.4,
127.5, 113.6 (pMPh), 101.5 (pMPhCH) 86.6 C-1), 78.1 (C-4), 72.9
(C-2), 70.8 (C-3), 70.7 (C-5), 68.4 (C-6), 55.3 (OMe), 20.8 (CH3
OAc). HRMS-ESI (C24H26O8SNa+) calcd: 497.1241, found: 497.1246.
4. Experimental
4.1. General
4.2.2. Phenyl 2,3-di-O-acetyl-4,6-O-p-methoxybenzylidene-1-thio-b-
D
-galactopyranoside 16
½ ꢀ
Chemicals were purchased from Aldrich and Fluka and used
without further purification. Molecular sieves were activated at
350 °C for 3 h and cooled under vacuum. Dry solvents, where nec-
essary, were obtained by distillation using standard procedures or
by passage through a column of anhydrous alumina using equip-
ment from Anhydrous Engineering (University of Bristol) based
on the Grubbs’ design. Reactions requiring anhydrous conditions
were performed under an atmosphere of dry nitrogen; glassware,
syringes, and needles were either flame dried immediately prior
to use or placed in an oven (150 °C) for at least 2 h and allowed
to cool either in a desiccators or under an atmosphere of dry nitro-
gen; liquid reagents, solutions, or solvents were added via a syr-
inge or a cannula through rubber septa; solid reagents were
added via Schlenk-type adapters. Typical reactions were carried
out in 40–50 mg scale. Reactions were monitored by TLC on Kiesel-
gel 60 F254 (Merck). Detection was by examination under UV light
(254 nm) and by charring with 10% sulfuric acid in methanol. Flash
chromatography was performed using silica gel [Merck, 230–400
a 2D3
+18 (c 0.06, CH2Cl2); 1H NMR (CDCl3, 400 MHz, ppm): d
= 7.62–7.60 (m, 2H, Ph), 7.31 (d, 2H, J = 8.5 Hz, pMPh), 7.30–7.26
(m, 3H, Ph), 6.88 (d, 2H, J = 8.5 Hz, Ph), 5.42 (s, 1H, pMPhCH),
5.34 (t, 1H, J1,2 = J2,3 = 10.0 Hz, H-2), 4.99 (dd, 1H, J3,4 = 3.5 Hz,
J2,3 = 10.0 Hz, H-3), 4.70 (d, 1H, J1,2 = 10.0 Hz, H-1), 4.35 (dd, 1H,
J5,6a = 1.5 Hz, J6a,6b = 12.5 Hz, H-6a), 4.35 (dd, J4,5 = 1.0 Hz,
J3,4 = 3.5 Hz, H-4), 4.00 (dd, J5,6b = 1.5 Hz, J6a,6b = 12.5 Hz, H-6b),
3.83 (s, 3H, OMe), 3.57–3.56 (m, 1H, H-5), 2.09 (s, 3H, CH3 OAc),
2.02 (s, 3H, CH3 OAc). 13C NMR (CDCl3, 100 MHz): d = 170.7,
169.0 (CO), 160.2 (C-OMe, pMPh), 137.8 (Cq, pMPh), 133.6 (Cq,
Ph), 131.3, 130.1, 129.0, 128.8, 128.2, 128.1, 127.9, 125.3 (CH,
Ph), 113.5 (pMPh), 101.0 (pMPhCH), 85.2 (C-1), 73.4 (C-4), 73.2
(C-3), 69.7 (C-5), 69.0 (C-6), 66.8 (C-2), 55.3 (OMe), 20.9 (CH3
OAc). HRMS-ESI (C17H19O7SNa+) calcd: 497.1241, found: 497.1243.
Acknowledgments
We gratefully acknowledge financial support from Novartis,
EPSRC, and The Royal Society.
mesh (40–63 lm)], the crude material was applied to the column
as a solution in CH2Cl2 or by pre-adsorption onto silica, as appro-
priate. Extracts were concentrated under reduced pressure using
both a Büchi rotary evaporator (bath temperatures up to 40 °C)
at a pressure of either 15 mmHg (diaphragm pump) or 0.1 mmHg
(oil pump), as appropriate, and a high vacuum line at room tem-
perature. Optical rotations were recorded on a Bellingham and
Stanley APP220 polarimeter using a 10-cm cell in the solvent and
temperature stated. 1H NMR and 13C NMR spectra were measured
in the solvent stated at 400 on JEOL Eclipse 400 or Varian INOVA
500 instruments, respectively. Chemical shifts quoted in parts
per million from SiMe4 and coupling constants (J) given in hertz.
Multiplicities are abbreviated as br (broad), s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or combinations thereof.
References
1. Varki, A.; Lowe, J. B. In Essentials of Glycobiology; Varki, A., Ed.; Cold Spring
Harbor Laboratory Press: Cold Spring Harbor (NY), 2009. Part I, Chapter 6.
2. Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576–1624.
3. Filice, M.; Guisan, J. M.; Palomo, J. M. Curr. Org. Chem. 2010, 14, 516–532.
4. Francais, A.; Urban, D.; Beau, J. M. Angew. Chem., Int. Ed. 2007, 46, 8662–8665.
5. Wang, C. C.; Lee, J. C.; Luo, S. Y.; Kulkarni, S. S.; Huang, Y. W.; Lee, C. C.; Chang, K.
L.; Hung, S. C. Nature 2007, 446, 896–899.
6. Mukhopadhyay, B.; Russell, D. A.; Field, R. A. Carbohydr. Res. 2005, 340, 1075–
1080.
7. Mukhopadhyay, B. Tetrahedron Lett. 2006, 47, 4337–4341.
8. Mong, K. K. T.; Chao, C. S.; Chen, M. C.; Lin, C. W. Synlett 2009, 603–606.
9. Hudson, C. S.; Dale, J. K. J. Am. Chem. Soc. 1915, 37, 1280–1282.
10. Togo, H.; Iida, S. Synlett 2006, 2159–2175.
11. Vaino, A. R.; Szarek, W. A. Adv. Carbohydr. Chem. Biochem. 2001, 56, 9–63.
12. Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415–3416.
13. Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11753–11766. 1997, 53,
11753–11766.
4.2. General procedure for theone-pot tandem benzylidenation–
acetylation
14. Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.; Field, R. A. J. Org. Chem. 2004,
69, 7758–7760.
15. Biswas, A.; Selling, G.; Appell, M.; Woods, K. K.; Willett, J. L.; Buchanan, C. M.
Carbohydr. Polym. 2007, 68, 555–560.
16. Zhao, G. L.; Zhang, Y.; Wang, J. W. Collect. Czech. Chem. Commun. 2007, 72,
1214–1218.
17. Panchadhayee, R.; Misra, A. K. J. Carbohydr. Chem. 2008, 27, 148–155.
18. Mukherjee, D.; Shah, B. A.; Gupta, P.; Taneja, S. C. J. Org. Chem. 2007, 72, 8965–
8968.
19. Note: 5 equiv of acetic anhydride are needed to ensure completion of the
reaction since 2 equiv of methanol are being generated during the acetalation
with dimethoxybenzaldehyde.
20. Tiwari, P.; Misra, A. K. Carbohydr. Res. 2006, 341, 339–350.
21. Oscarson, S.. In Carbohydrates in Chemistry and Biology; Wiley-VCH: Weinheim,
2000; Vol. 1.
To a mixture of unprotected glycosides 1–10 in acetonitrile
(0.1 mmol in 1 mL) were added benzaldehyde dimethyl acetal
(1.5 mmol, 1.5 equiv) and iodine (0.4 mmol, 0.4 equiv) and stirred
at room temperature until TLC showed consumption of starting
material (2 h). Acetic anhydride or benzoic anhydride (1.5 equiv
per OH group in the reaction mixture + 2 equiv) and DMAP
(0.05 mmol) were added. The mixture was then stirred for another
6 h before the reaction being quenched with Et3N and the mixture
was evaporated under reduced pressure. The residue was purified
by flash chromatography to give the corresponding products in
good to excellent yields of 60–89%.

R. A. Jones et al. / Carbohydrate Research 345 (2010) 1842–1845
1845
22. Boons, G.-J.; Stauch, T. Synlett 1996, 906–908.
23. Kartha, K. P. R.; Cura, P.; Aloui, M.; Readman, S. K.; Rutherford, T. J.; Field, R. A.
Tetrahedron: Asymmetry 2000, 11, 581–593.
24. Andrews, C. W.; Rodebaugh, R.; FraserReid, B. J. Org. Chem. 1996, 61, 5280–5289.
25. Zissis, E.; Clingman, A. L.; Richtmyer, N. K. Carbohydr. Res. 1966, 2, 461–469.
26. Sarkar, A. K.; Matta, K. L. Carbohydr. Res. 1992, 233, 245–250.
27. Maity, S. K.; Dutta, S. K.; Banerjee, A. K.; Achari, B.; Singh, M. Tetrahedron 1994,
50, 6965–6974.
30. Ikeda, K.; Miyajima, K.; Shimizu, T.; Achiwa, K. Chem. Pharm. Bull. 2000, 48, 32–
40.
31. Ogawa, T.; Nakabayashi, S.; Sasajima, K. Carbohydr. Res. 1981, 95, 308–312.
32. Galan, M. C.; Tran, T. A.; Whitaker, S. Chem. Commun. 2010, 46, 2106–2108.
33. Smith, M.; Khorana, H. G.; Rammler, D. H.; Goldberg, I. H. J. Am. Chem. Soc.
1962, 84, 430–440.
34. Rye, C. S.; Withers, S. G. J. Org. Chem. 2002, 67, 4505–4512.
35. Advances in Carbohydrate Chemistry and Biochemistry; Haines, A. H.; Tipson, R.
S.; Horton, D., Eds.; Illus. Academic Press: New York, NY, USA, London, England,
1976; Vol. 33. X+464p, pp. 11–109.
28. Roen, A.; Padron, J. I.; Vazquez, J. T. J. Org. Chem. 2003, 68, 4615–4630.
29. Deng, S.; Gangadharmath, U.; Chang, C.-W. T. J. Org. Chem. 2006, 71, 5179–5185.