Regioselective 6-detrimethylsilylation of per-O-TMS-protected carbohydrates in the presence of ammonium acetate

Article abstract of DOI:10.1016/j.tetlet.2013.05.039

A convenient methodology has been developed for the regioselective removal of primary trimethylsilyl group (TMS) of various per-O-TMS-protected carbohydrates by inexpensive ammonium acetate. After acetylation and trichloroacetimidation of 6-hydroxyl sugar 1b, other TMS groups of 1d and 1c were inert to ammonium acetate in the same conditions, and this approach was also successfully applied in TMS-protected sphingosine.

Full text of DOI:10.1016/j.tetlet.2013.05.039

Tetrahedron Letters 54 (2013) 3831–3833
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective 6-detrimethylsilylation of per-O-TMS-protected
carbohydrates in the presence of ammonium acetate
a
b
c
Yanli Cui a, , Zhaodong Cheng , Jianwei Mao , Yongping Yu
⇑
a Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
b Zhejiang Provincial Key Lab for Chem. & Bio. Processing Technology of Farm Produces, Hangzhou 310023, PR China
c College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient methodology has been developed for the regioselective removal of primary trimethylsilyl
group (TMS) of various per-O-TMS-protected carbohydrates by inexpensive ammonium acetate. After
acetylation and trichloroacetimidation of 6-hydroxyl sugar 1b, other TMS groups of 1d and 1c were inert
to ammonium acetate in the same conditions, and this approach was also successfully applied in TMS-
protected sphingosine.
Received 23 February 2013
Revised 26 April 2013
Accepted 10 May 2013
Available online 18 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Regioselectivity
Desilylation
Glycosides
Protecting groups
Regioselective modification of carbohydrates has always been a
focus in research of glycochemistry and glycobiology.1,2 However,
the achievement of this goal is often complicated, because the car-
bohydrate molecules contain a number of hydroxyl units which are
difficult to manipulate selectively.3 Single hydroxyl sugar deriva-
tives in 6-position and suitably protected 6-hydroxy sugars4,5 are
useful glycosyl acceptors for the preparation of several bioactive
molecules6 and some very important oligosaccharides.7 In the
early days, the synthetic routes of 6-hydroxy sugars need numer-
ous, wasteful manipulation processes. Usually the bulky groups
selectively hold up the 6-hydroxy position and are removed under
certain conditions after the other hydroxies have been protected.8
Therefore, an alternative approach is obligatory.
Per-O-TMS-protected glycosides were so sensitive to acid that
they can be readily deprotected via acidic methanolysis.9,10 The
TMS group, which is an unusual protecting group, did not get much
more attention for further research in earlier works. However, the
value of TMS in carbohydrate research has been significantly
increasing in recent years. Hung et al. have reported their regiose-
lective one-pot protection of mono-saccharides from per-O-trim-
ethylsilylated glycosides.11 Witschi and Gervay-Hague revealed a
method of regioselective nonenzymatic acetylation of mono-
saccharides.12
Currently we have applied considerable effort towards the con-
struction of galactosylceramide ( -GalCer) with per-O-TMS galac-
a
tosyl iodide.13 We accidentally observed the removal of the TMS
group at 6-position when per-O-trimethylsilylated galactose was
treated with ammonium acetate in methanol. Concerning salt cat-
alyst of detrimethylsilylation, Klaus and co-workers14 reported
that 6-O-TMS could be removed by potassium carbonate in meth-
anol at 0 °C in 1994, but Hai and co-workers15 stated that this
method did not always work.
We herein disclose our findings on the detrimethylsilylation of
carbohydrates under mild conditions (Scheme 1).
As a model system, per-O-trimethylsilylated a-D-galactose was
treated with varying amounts of ammonium acetate and reaction
solvent at room temperature. 2.0 equiv of NH4OAc in co-solvent
of CH2Cl2 and CH3OH (v/v = 1/1) at rt afforded 6-detrimethylsilylat-
ed galactose 1b in good to excellent yield.16 In order to explore
the application range,
a
series of TMS-protected mono and
OH
O
OTMS
O
NH4OAc ( 2.0 eq )
TMSO
TMSO
TMSO
X
X
CH2Cl2/MeOH ( v/v = 1/1 ),
rt, 9-12h
TMSO
OTMS
OTMS
X = OTMS, OPh, OCH3
⇑
Corresponding author. Tel./fax: +86 571 88486676.
E-mail address: hnzzcyl@hotmail.com (Y. Cui).
Scheme 1. 6-Detrimethylsilylation of carbohydrates.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.039

3832
Y. Cui et al. / Tetrahedron Letters 54 (2013) 3831–3833
Table 1
6-Detrimethylsilylation of carbohydrates using NH4OAca
Entry
Substrates
Products
Time (h)
9
Yieldb (%)
91
OTMS
O
OH
O
TMSO
TMSO
TMSO
1
TMSO
TMSO
OTMS
TMSO
OTMS
1a
2a
3a
1b
OTMS
OH
TMSO
TMSO
O
TMSO
TMSO
O
2
3
9
9
86
85
TMSO
TMSO
OTMS
OTMS
2b
OTMS
O
OH
O
TMSO
TMSO
TMSO
TMSO
TMSO
TMSO
OMe
OMe
3b
OTMS
O
OH
O
TMSO
BnO
TMSO
BnO
4
5
6
9
90
85
65
TMSO
OTMS
TMSO
OTMS
4a
5a
4b
OTMS
O
OH
O
TMSO
TMSO
TMSO
TMSO
O
O
9
Ph
Ph
TMSO
TMSO
TMSO
5b
OTMS
OTMS
TMSO
OH
OTMS
TMSO
TMSO
TMSO
TMSO
TMSO
TMSO
O
O
12
O
O
O
O
TMSO
OH
6b
7b
OTMS
TMSO
6a
OTMS
O
OH
O
TMSO
TMSO
TMSO
TMSO
TMSO
TMSO
O
OTMS
OTMS
O
7
10
71
OH
O
O
TMSO
TMSO
OTMS
OTMS
OTMS
7a
OTCA
TMSO
TMSO
O
c
8
nr
nr
nr
nr
24
24
24
24
0
0
0
0
TMSO
1dc
OTMS
OAc
O
TMSO
TMSO
9
TMSO
OTMS
1c
OAc
O
TMSO
TMSO
10
11
TMSO
OMe
3c
8a
TMSO
O
TMSO
TMSO
OTMS
nr: No reaction.
a
With 2.0 equiv of NH4OAc in the co-solvent of CH2Cl2 and CH3OH (v/v = 1/1) at rt.
Isolated yield.
TCA = trichloroacetimidate.
b
c
disaccharides were subjected to the detrimethylsilylation reactions
and the results are presented in Table 1.
same condition. Likewise, the primary O-TMS groups of disaccha-
rides were selectively removed by ammonium acetate. Product
6b and 7b were separated in yield of 65% and 71%, respectively.
To confirm the position of free hydroxyl, 1b was then added
with Ac2O in the presence of pyridine to afford 1c in high yield
(Scheme 2). All proton assignment was accomplished using COSY,
and the position of Ac was determined via HMQC NMR data.
Now that ammonium acetate could selectively remove the
primary O-TMS, what about secondary O-TMS? Firstly the free hy-
droxyl of 1b reacted with Cl3CCN in the presence of NaH to afford
To our delight, only 6-O-TMS of per-O-trimethylsilylated
mono-saccharides (entries 1–5) were selectively removed with
good to excellent yields. Even the 3-O-Bn group (3a) did not have
any influence on the selectivity of removing 6-O-TMS (entry 4).
Additionally, we wanted to know whether the same results could
be observed when disaccharides were treated under the same con-
ditions. Per-O-trimethylsilylated lactose and trehalose (entries 6
and 7), both consist two primary O-TMS, were subjected to the

Y. Cui et al. / Tetrahedron Letters 54 (2013) 3831–3833
3833
OAc
O
deprotected free hydroxyl could be used as glycosyl acceptor or
nucleophile for further chemical transformation.9
TMSO
TMSO
TMSO
a
OH
O
OTMS
TMSO
TMSO
Acknowledgments
1c
The work was supported financially by the National Natural Sci-
ence Foundation of China (No. 30870553) and the Key Interna-
tional S&T Cooperation Project, China (No. 2010DFA34370).
TMSO
1b
OTMS
b
OTCA
O
TMSO
TMSO
TMSO
OTMS
References and notes
1d
1. The Essentials of Glycobiology; Varki, A., Cummings, R., Esko, J., Freeze, H., Hart,
G., Marth, J., Eds.; Cold Spring Harbor Laboratory Press: New York, 1999.
2. (a) Lee, D.; Taylor, M. S. Synthesis 2012, 44, 3421–3431; (b) Schmidt, R. R.
Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235.
Scheme 2. Reagents and conditions: (a) Ac2O, pyridine, 2 h, rt 87%; (b) Cl3CCN, NaH
(60%), CH2Cl2, rt 2 h, 91%.
3. Pierre, C.; Isabel, H.; David, P. G.; Bo, L.; Rebecca, A. J.; Romano, T. K.; Lavina, C.
S.; Anthony, J. F.; Benjamin, G. D.; John, P. S. J. Am. Chem. Soc. 2006, 128, 1976–
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4. Dulayymi, J. R.; Baird, M. S.; Maximiliano, M. I.; Beken, S. V.; Grooten, J.
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834.
6. Veerapen, N.; Reddington, F.; Salio, M.; Cerundolo, V.; Besra, G. S. Bioorg. Med.
Chem. 2011, 19, 221–228.
N3 OTMS
C14H29
OTMS
9a
N3 OH
C14H29
OH
9
c
TMSO
HO
d
7. (a) Li, H.; Li, B.; Song, H.; Breydo, L.; Baskakov, L. V.; Wang, L. X. J. Org. Chem.
2005, 70, 9990–9996; (b) Deng, L. M.; Liu, X.; Liang, X. Y.; Yang, J. S. J. Org. Chem.
2012, 77, 3025–3027; (c) Mensah, E. A.; Azzarelli, J. M.; Nguyen, H. M. J. Org.
Chem. 2009, 74, 1650–1657.
8. (a) Reynolds, D. D.; Evans, W. L. Org. Synth. 1942, 22, 56; (b) Haider, A.;
Williams, C. K. C.R. Chim. 2011, 14, 736–744; (c) Latli, B.; Hrapchak, M.;
Seetharama, R.; Krishnamurthy, D.; Senanayake, C. H. J. Labelled Compd.
Radiopharm. 2011, 54, 337–339; (d) Zhang, Z.; Yu, B. J. Org. Chem. 2003, 68,
6309–6313.
N3 OTMS
C14H29
HO
OTMS
9b
Scheme 3. Reagents and conditions: (c) TMSCl, HMDS, pyridine, 90%; (d) 2.0 equiv
of NH4OAc, MeOH/CH2Cl2, 10 h, rt, 82%.
9. Jervis, P. J.; Cox, L. R.; Besra, G. S. J. Org. Chem. 2011, 76, 320–323.
10. Du, W. J.; Kulkarni, S. S.; Gervay-Hague, J. Chem. Commun. 2007, 23, 2336–2338.
11. (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 2007, 446, 896–899; (b) Wang, C. C.; Kulkarni, S.
S.; Lee, J. C.; Luo, S. Y.; Hung, S. C. Nat. Protoc. 2008, 3, 97–113; (c) Chang, K. L.;
Zulueta, M. M. L.; Lu, X. A.; Zhong, Y. Q.; Hung, S. C. J. Org. Chem. 2010, 75,
7424–7427; (d) Huang, T. Y.; Zulueta, M. M. L.; Hung, S. C. Org. Lett. 2011, 13,
1506–1509; (e) Hu, Y. P.; Lin, S. Y.; Huang, C. Y.; Zulueta, M. M. L.; Liu, J. Y.;
Chang, W.; Hung, S. C. Nat. Chem. 2011, 3, 557–563.
12. Witschi, M. A.; Gervay-Hague, J. J. Org. Lett. 2010, 12, 4312–4315.
13. Schombs, M.; Park, F. E.; Du, W.; Kulkarni, S. S.; Gervay-Hague, J. J. Org. Chem.
2010, 75, 4891–4898.
14. Ronnow, T. E. C. L.; Meldal, M.; Bock, K. Carbohydr. Res. 1994, 260, 323–328.
15. Fan, W.; Wu, Y.; Li, X. K.; Yao, N.; Li, X.; Yu, Y. G.; Hai, L. Eur. J. Med. Chem. 2011,
46, 3651–3661.
16. Ammonium acetate (185.9 mg, 2.41 mmol) was added to a solution of 1a
(653.0 mg, 1.21 mmol) in the co-solvent of CH2Cl2 (5.0 mL) and CH3OH
(5.0 mL) at rt. The mixture was stirred and monitored by TLC. Upon
consumption of starting substrate, the solvent was evaporated and the
residue was dissolved in hexane (50 mL) and the organic phase was washed
with water (3 Â 50 mL), brine, dried with MgSO4 and concentrated in vacuum.
The mixture was purified by flash column chromatography (petroleum ether/
ethyl acetate = 20:1) on silica gel to afford the desired product 1b as a white
solid (515.3 mg, 91%). Rf = 0.38 (petroleum ether/ethyl acetate = 15:1). dH
(400 MHz, CDCl3) 5.01 (1H, d, J = 3.0), 3.82–3.64 (4H, m), 3.46 (1H, t, J = 9.1),
3.34 (1H, dd, J = 9.1, 3.0), 1.78 (1H, t, J = 6.1 Hz), 0.23–0.07 (36H, m). dC
(101 MHz, CDCl3) 93.88, 73.95, 73.49, 71.94, 71.67, 61.64, 1.08, 0.76, 0.47, 0.27,
0.03, À0.27. ESI-MS: m/z = 491.1 [M+23]+.
1d. Compound 3c was obtained with the same process of 1c. Then
1c, 1d and 3c (entries 8–10) were treated, respectively, in the co-
solvent of CH2Cl2 and CH3OH with ammonium acetate at rt for
24 h. To our surprise, no reaction was detected by TLC. As well,
per-O-trimethylsilylated arabinose (8a) (entry 11) was stirred with
ammonium acetate, and also no reaction was monitored via TLC.
Does this methodology selectively remove primary O-TMS in a
molecule which is not a sugar? The experiment was extended to
per-silylated sphingosine (9a) (Scheme 3). The sphingosine was
per-silylated by trimethyl chlorosilane. Sequentially, only the pri-
mary O-TMS was removed in the presence of ammonium acetate
in good yield to afford 9b, which is known as a key intermediate
for the preparation of a-GalCer.
In summary, we have developed a method for the regioselective
removal of primary O-TMS from an array of mono and disaccha-
rides in mild conditions and the new method has been successfully
applied to the building of sphingosine intermediate (9b). The
ammonium acetate could be easily removed by aqueous workup
and the reaction is highly scalable due to the inexpensive cost of
ammonium acetate. This approach offers high versatility that the