Tandem one-pot acetalation-acetylation for direct access to differentially protected thioglycosides and O-glycosides with p-toluenesulfonic acid

Article abstract of DOI:10.1055/s-0028-1087913

A new tandem one-pot acetalation-acetylation procedure is reported which streamlines routine protecting-group manipulation of carbohydrate molecules in production of differentially protected O- and thioglycosides. This new procedure eliminates the use of

Full text of DOI:10.1055/s-0028-1087913

LETTER
603
Tandem One-Pot Acetalation–Acetylation for Direct Access to Differentially
Protected Thioglycosides and O-Glycosides with p-Toluenesulfonic Acid
Synthesis of
Differ
w
entially Protecte
d
o
Thioglycosid
k
e
s
and
O
-G
l
-
ycosidesKong Tony Mong,* Chin-Sheng Chao, Min-Chun Chen, Chun-Wei Lin
Department of Applied Chemistry, National Chiao Tung University, 1001 Ta-Hsueh Road, Hsinchu 300, Taiwan
Fax +886(3)5723764; E-mail: tmong@mail.nctu.edu.tw
Received 23 September 2008
requires extra procedure rendering them less convenient
Abstract: A new tandem one-pot acetalation–acetylation proce-
dure is reported which streamlines routine protecting-group manip-
ulation of carbohydrate molecules in production of differentially
protected O- and thioglycosides. This new procedure eliminates the
in practice. Recently, iodine-catalyzed tandem acetonide
formation–acetylation was reported, but it is not useful for
making benzylidene acetal function.10 To overcome such
use of highly toxic pyridine, and p-toluenesulfonic acid is employed limitations and to develop a pyridine-free process, a new
as catalyst for acetalation and acetylation. Synthetic utility of the
one-pot procedure is required. Herein we report the devel-
new procedure is demonstrated in the expeditious preparation of
opment of a versatile tandem one-pot acetalation–acetyla-
differentially protected glycosides from a wide variety of carbohy-
tion, which expedites the preparation of differentially
drate substrates including unprotected O-glycosides, thioglyco-
protected O-glycosides and thioglycosides.
sides, and N-acetyl neuraminic acid ester.
The key to effect a one-pot procedure is to explore the ap-
propriate reaction conditions so that a practical acetyla-
tion rate is retained in the presence of the acid-labile acetal
Key words: tandem, acetals, glycosides, oligosaccharides, protect-
ing group
Preparation of carbohydrate building blocks has always
been necessary for oligosaccharide synthesis; thus expe-
ditious synthesis of such building blocks is highly desired.
A logical approach toward this goal is to merge two or
three sequential reactions into a tandem one-pot opera-
tion, which was realized in the preparation of peracetyl
glycosyl bromide,1 peracetyl glycosyl azide,2 peracetyl
glycosyl iodide,3 peracetyl thioglycoside,4 and regioselec-
tive one-pot protection of carbohydrates.5
OH
PhCH(OMe)2
Ac2O
O
Ph
O
O
O
HO
HO
AcO
cat. TsOH, MeCN
4 h, 90%
AcO
HO
OMe
OMe
2
methyl α-D-gluco-
pyranoside
Scheme 1 One-pot acetalation–acetylation of methyl a-D-glucopy-
ranoside
Acetalation and acetylation are routine synthetic steps for
protection of hydroxy function. Generally the former is
effected with a free6 or masked carbonyl function7–10 in
the presence of acid catalyst,11–17 while the latter is usually
promoted in the presence of excess pyridine.18 However,
owing to malodorous and toxic nature of pyridine, such
acetylation procedure is gradually superseded by various
acid-catalyzed protocols.19, 20 Sequential acetalation and
acetylation of unprotected glycoside substrates are widely
employed for production of differentially protected O-
glycosides and thioglycosides, and the latter constitutes a
major class of useful building blocks in oligosaccharide
synthesis.21 As both acetalation and acetylation are cata-
lyzed by acid, it is reasonable for us to merge them into a
tandem one-pot operation. Such strategy has been demon-
strated in one-pot acetalation–acetylation with immobi-
OH
O
OH
HO
OH
O
HO
HO
O
HO
HO
OR
HO
STol
OH
OH
R = (CH2)6Cl
AcHN
OMe
3
5
4
OH
O
OH
HO
HO
HO
O
HO
STol
HO
7
6
OH
STol
STol
OH
HO
OH
O
O
HO
O
HO
O
HO
HO
S
STol
OH
OH
OH
O
9
OH
8
OH
O
HO
HO
HO
HO
22
lized HClO4 and H2SO4.23 Though both reported
STol
NHTroc
NHTroc
methods are found useful for production of differentially
protected O-glycosides, preparation of synthetically use-
ful thioglycoside was less discussed in their investiga-
tions. In addition, immobilization of acid on silica
10
11
OH
HO
t-Bu
OH
HO
CO2Me
O
AcHN
HO
12
SYNLETT 2009, No. 4, pp 0603–0606
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087913; Art ID: W15008ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 O-Glycosides 3 and 4, thioglycosides 5–11, and NANA
ester 12

604
K.-K. T. Mong et al.
LETTER
function. Referring to the reported procedures, the amount was added to give the expected 2,3-di-O-acetyl-4,6-O-
of acid used in acetalation spans from 5–20 mol%.11,14,15 benzylidene a-D-gluco-pyranoside 2 in excellent 90%
Thus in our model study, a suspension of methyl a-D-glu- yield.
copyranoside and benzaldehyde dimethyl acetal in aceto-
Being encouraged by the preliminary result, we next ex-
nitrile were treated with 10 mol% of TsOH (0.05 M,
amined the one-pot acetalation–acetylation of unprotected
Scheme 1). The reaction proceeded smoothly at room
O-glycosides 3, 4,24 thioglycosides 5–11,25 and N-acetyl
temperature and upon complete conversion into acetal in-
termediate, acetic anhydride (Ac2O, 1.5 equiv per OH)
neuraminic acid ester (NANA ester) 1226 (Figure 1), and
the results were detailed in Table 1.27
Table 1 One-Pot Acetalation–Acetylation of O-Glycosides 3 and 4, Thioglycosides 5–11, and NANA ester 12
Entry
Substrate Product
TsOH (mol%, M)
Acetalation/acetyla- Time (h)
tion temp (°C)
Yield (%)
Ph
O
O
1
3
10 (0.031)
25/40
25/40
4
4
81
O
OR
O
AcO
OAc
13
O
Ph
O
AcO
2
3
4
5
10 (0.041)
10 (0.032)
76
77
AcHN
OMe
14
Ph
O
O
25/40
5
O
STol
AcO
OAc
15
O
Ph
O
O
4
5
6
7
STol
10 (0.032)
10 (0.01)
25/40
25/50
4.5
6
75
70
AcO
OAc
1623
OAc
O
O
Ph
O
AcO
STol
17
Ph
O
O
OAc
6
8
10 (0.014)
50/50
10
82
O
O
AcO
O
STol
AcO
OAc
OAc
1828
O
Ph
O
O
7
8
10
11
STol
32 (0.019)
10 (0.027)
25/40
25/40
4
6
70
75
AcO
NHTroc
1929
O
Ph
O
S
O
AcO
NHTroc
t-Bu
20
Synlett 2009, No. 4, 603–606 © Thieme Stuttgart · New York

LETTER
Synthesis of Differentially Protected Thioglycosides and O-Glycosides
605
Table 1 One-Pot Acetalation–Acetylation of O-Glycosides 3 and 4, Thioglycosides 5–11, and NANA ester 12 (continued)
Entry
9
Substrate Product
TsOH (mol%, M)
10 (0.023)
Acetalation/acetyla- Time (h)
tion temp (°C)
Yield (%)
70
OAc
O
O
5
40/40
25/40
25/40
12
STol
O
OAc
21
O
O
O
10
11
6
10 (0.023)
5 (0.018)
7
52
75
STol
AcO
OAc
STol
22
O
AcO
9
4
O
O
2322
O
O
OH
12
12
10 (0.021)
25/35
8
74
AcO
AcHN
O
CO2Me
AcO
24
One-pot benzylidenation–acetylation of unprotected gly- galactopyranosyl derivative. It should be mentioned that
coside substrates 3–8 and 10–11 produced the expected camphorsulfonic acid (CSA)32 and trimethylsilyl chloride
glycosyl acetal derivatives 13–20 in 70–82% yield within (TMSCl)33 were also employed as catalyst, though the re-
4–10 hours (Table 1, entries 1–8).30 Owing to variation in sults were inferior to those obtained by using TsOH cata-
physicochemical properties, optimization of reaction con- lyst. Isopropylidenation of thioglucopyranoside 6 gave
ditions was required for particular glycoside substrates. A 4,6-O-isopropylidene ketal derivative 22 as the single re-
point in case is the acetalation of mannopyranoside, which gioisomer in a modest 52% yield along with 15% per-O-
suffers from competitive formation of 2,3:4,6-O-bis(ace- acetyl thioglucopyranoside. Formation of the latter is at-
tal) derivative. As a consequence, previous one-pot aceta- tributed to the cleavage of inherently less stable 4,6-O-
lation–acetylation of methyl a-D-mannopyranoside met isopropylidene ketal function in conjunction with acetyla-
with difficulty.22 In our optimized one-pot procedure, a tion (Table 1, entry 10).34,35
‘diluted’ suspension of thiomannopyranoside 7 (1 g in 35
Other than glycoside substrates, the present procedure is
mL of MeCN) and a stoichiometric amount of acetalating
also applicable to carbohydrate hemiacetals as exempli-
agent [1.05 equiv of PhCH(OMe)2] were used. Gratify-
fied in the one-pot isopropylidenation–acetylation of
ingly, formation of bis(acetal) derivative was largely sup-
NANA ester 12, which gave NANA ester ketal derivative
24 in 74% yield (Table 1, entry 12). As previously report-
pressed and the desired 3-O-acetyl-4,6-O-benzylidene
thiomannopyranoside 17 was obtained in satisfactory
ed, the tertiary C-2 hydroxy function of 12 was unacety-
70% yield (Table 1, entry 5).
lated.20 To prove the suitability of the procedure for a
One-pot isopropylidenation–acetylation of carbohydrate larger scale operation, 10 g of per-O-acetyl thiolactoside
substrates 5, 6, 9, and 12 was conducted in acetone,31 from was deacetylated to thiolactoside 8, which after neutral-
which the corresponding glycosyl ketal derivatives 21–24 ization and purification, underwent the now routine one-
were furnished in 52–75% yield at reasonable time frames pot procedure to give lactosyl benzylidene acetal 18 in re-
(Table 1, entries 9–12). Isopropylidenation of thiogalacto- producible yield.36
pyranoside 5 at room temperature gave a mixture of 3,4-
O- and 4,6-O-isopropylidene ketal derivatives, while ele-
vating the reaction temperature to 40 °C led to the exclu-
sive formation of 3,4-O-isopropylidene ketal derivative
21 (Table 1, entry 9). Close examination revealed that 4,6-
O-isopropylidene ketal derivative was formed preferen-
In summary, an unprecedented TsOH-catalyzed one-pot
acetalation–acetylation was developed, which streamlines
the routine protecting-group manipulation procedures and
obviate the use of toxic pyridine in preparation of a wide
diversity of differentially protected thioglycosides.
tially in the beginning, but was gradually isomerized to
21. Thus, longer reaction time and higher reaction temper-
ature would favor the formation of 3,4-O-isopropylidene
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 4, 603–606 © Thieme Stuttgart · New York

606
K.-K. T. Mong et al.
LETTER
(22) Mukhopadhyay, B.; Russell, D. A.; Field, R. A. Carbohydr.
Res. 2005, 340, 1075.
Acknowledgment
We thank the National Science Council of Taiwan for financial sup-
port (Grant no. 96-2113-M-009-016) and Ms. C.-C. Chang of
NCTU for Inova 500 NMR spectroscopic analysis.
(23) Mukhopadhyay, B. Tetrahedron Lett. 2006, 47, 4337.
(24) Compound 4 was obtained by literature procedure reported
in: Ahn, Y. M.; Gray, G. R. Carbohydr. Res. 1997, 298, 279.
(25) Unprotected thioglycosides 5–10 were derived from the
corresponding peracetyl thioglycosides by Zemplèn
deacetylation. Peracetyl thioglycosides were prepared by
literature procedure reported in ref. 20.
(26) Compound 12 was obtained by literature procedure reported
in: Kondo, H.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc.
1992, 114, 8148.
References and Notes
(1) Kartha, K. P. R.; Jennings, H. J. J. Carbohydr. Chem. 1990,
9, 777.
(2) Kumar, R.; Tiwari, P.; Maulik, P. R.; Misra, A. K. Eur. J.
Org. Chem. 2006, 74.
(3) Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.; Field,
R. A. J. Org. Chem. 2004, 69, 7758.
(27) Preparatory procedures of compounds 3 and 11 were
described in supporting information.
(28) Larsen, K.; Olsen, C. E.; Motawia, M. S. Carbohydr. Res.
2003, 338, 199.
(29) Mong, T. K.-K.; Huang, C.-Y.; Wong, C.-H. J. Org. Chem.
2003, 68, 2135.
(4) (a) Tai, A.-A.; Kulkarni, S. S.; Hung, S.-C. J. Org. Chem.
2003, 68, 8719. (b) Tiwari, P.; Kumar, R.; Maulik, R.;
Misra, A. K. J. Carbohydr. Chem. 2005, 24, 723. (c) Lin,
C.-C.; Huang, L.-C.; Liang, P.-H. J. Carbohydr. Chem.
2006, 25, 303. (d) Dasgupta, S.; Rajput, V. K.; Roy, B.;
Mukhopadhyay, B. J. Carbohydr. Chem. 2007, 26, 91.
(e) Valerio, S.; Iadonisi, A.; Adinolfi, M.; Ravidà, A. J. Org.
Chem. 2007, 72, 6097.
(5) (a) 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 (London) 2007, 896. (b) Français, A.; Urban, D.;
Beau, J.-M. Angew. Chem. Int. Ed. 2007, 46, 8662.
(6) (a) De Belder, A. N. Adv. Carbohydr. Chem. Biochem. 1965,
20, 219. (b) De Belder, A. N. Adv. Carbohydr. Chem.
Biochem. 1977, 34, 179.
(7) Kihlberg, J.; Frejd, T.; Jansson, K.; Magnusson, G.
Carbohydr. Res. 1986, 152, 113.
(8) (a) Barili, P. L.; Berti, G.; Catelani, G.; Colonna, F.; Marra,
A. Tetrahedron Lett. 1986, 27, 2307. (b) Foster, A. B.;
Overend, W. G.; Stacey, M.; Wiggins, L. F. J. Chem. Soc.
1949, 2542.
(30) General One-Pot Benzylidenation–Acetylation
Procedure for the Preparation of 2 and 13–20
TsOH (10–32 mol%, Table 1) was added into a stirring
mixture of carbohydrate substrate (1.0 equiv of methyl a-D-
glucopyranoside, 3–8, 10, or 11) and PhCH(OMe)2 (1.5
equiv) in MeCN under N2. Upon complete conversion into
benzylidene acetal intermediate as assessed by TLC, Ac2O
(1.5 equiv per OH, total OH equals to the sum of OH of
acetal intermediate plus MeOH released from acetalating
reagent) was added, and the reaction temperature was
brought up to 40 or 50 °C (Table 1). Specific reaction
conditions are detailed in the supporting information. Upon
complete acetylation as assessed by TLC, excess EtOAc
(4 × volume of MeCN used) was added to the mixture, which
was then washed with sat. NaHCO3, brine, dried over
MgSO4, and concentrated for purification by flash column
chromatography over SiO2. Elution with EtOAc–hexane
mixture afforded the compounds 2 and 13–20.
(9) Hung, S.-C.; Chen, C.-S. J. Chin. Chem. Soc. 2000, 47,
(31) General One-Pot Isopropylidenation–Acetylation
1257.
Procedure for Preparation of 21–24
(10) Mukherjee, D.; Ali Shah, B.; Gupta, P.; Taneja, S. C. J. Org.
Chem. 2007, 72, 8965.
(11) Freudenberg, K.; Hixon, R. M. Ber. Dtsch. Chem. Ges. 1923,
56, 2119.
(12) Winnik, F. M.; Carver, J. P.; Krepinsky, J. J. J. Org. Chem.
1982, 47, 2701.
(13) Wood, H. B. Jr.; Diehl, H. W.; Fletcher, H. G. Jr. J. Am.
Chem. Soc. 1957, 79, 1986.
TsOH (5–10 mol%, Table 1) was added into a stirring
mixture of unprotected thioglycoside (1.0 equiv of 5, 6, 9, or
NANA ester 12), and Me2CH(OMe)2 (1.5 equiv) in acetone.
The mixture was stirred at r.t. or 40 °C under N2. Upon
complete conversion into glycosyl ketal intermediate as
assessed by TLC, Ac2O (1.5 equiv per OH, total OH equals
to OH from glycosyl acetal intermediate plus MeOH
released from acetalating reagent) was added, and the
reaction temperature was brought up to 35 or 40 °C
(Table 1). Specific reaction conditions for preparation of
compounds 21–24 were detailed in the supporting
information. Upon complete acetylation as assessed by TLC,
excess EtOAc (4 × volume of MeCN used) was added to the
mixture, which was then washed with sat. NaHCO3, brine,
dried over MgSO4, and concentrated for purification by flash
column chromatography over SiO2. Elution with EtOAc–
hexane mixture afforded compounds 21–24.
(14) Lipták, A.; Imre, J.; Nanási, P. Carbohydr. Res. 1981, 92,
154.
(15) Boulineau, F. P.; Wei, A. Carbohydr. Res. 2001, 334, 271.
(16) Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415.
(17) (a) Chen, C.-T.; Weng, S.-S.; Kao, J.-Q.; Lin, C.-C.; Jan,
M.-D. Org. Lett. 2005, 7, 3343. (b) Tsunoda, T.; Suzuki,
M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(18) (a) Chen, C.-T.; Weng, S.-S.; Kao, J.-Q.; Lin, C.-C.; Jan,
M.-D. Org. Lett. 2005, 7, 3343. (b) Tsunoda, T.; Suzuki,
M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(19) Bizier, N. P.; Atkins, S. R.; Helland, L. C.; Colvin, S. F.;
Twitchell, J. T.; Cloninger, M. J. Carbohydr. Res. 2008, 343,
1814; and references therein.
(32) Ziegler, T.; Herold, G. Liebigs Ann. Chem. 1994, 859.
(33) Nishida, Y.; Dohi, H.; Uzawa, H.; Kobayashi, K.
Tetrahedron Lett. 1998, 39, 8681.
(34) In Monosaccharides: Their Chemistry and their Roles in
Natural Products; Collins, P. M.; Ferrier, R. J., Eds.; John
Wiley and Sons: New York, 1996, 389–405.
(35) Lu, K.-C.; Hseih, S.-Y.; Patkar, L. N.; Chen, C.-T.; Lin,
C.-C. Tetrahedron 2004, 60, 8967.
(36) For acid-catalyzed one-pot acetalation–acetylation,
unnecessary prolonged reaction time would compromise the
yield of reaction due to the cleavage of the acetal function.
(20) Chao, C.-S.; Chen, M.-C.; Lin, S.-C.; Mong, K.-K. T.
Carbohydr. Res. 2008, 343, 957; and references therein.
(21) (a) Qiu, D.; Koganty, R. R. Tetrahedron Lett. 1997, 38, 45.
(b) Mong, T. K.-K.; Wong, C.-H. Angew. Chem. Int. Ed.
2002, 41, 4087. (c) Fan, R.-H.; Achkar, J.; Hernández-
Torres, J. M.; Wei, A. Org. Lett. 2005, 7, 5095. (d) Lopin,
C.; Jacquinet, J.-C. Angew. Chem. Int. Ed. 2006, 45, 2547.
(e) Manabe, S.; Ishii, K.; Ito, Y. J. Org. Chem. 2007, 72,
6107.
Synlett 2009, No. 4, 603–606 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.