Methylsulfonylethoxycarbonyl (Msc) and fluorous propylsulfonylethoxycarbonyl (FPsc) as hydroxy-protecting groups in carbohydrate chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.02.146

The methylsulfonylethoxycarbonyl (Msc) group is presented as a non-lipophilic, base-labile, participating protecting group for carbohydrate alcohols. It can be introduced using Msc-Cl and pyridine and is readily cleaved via β-elimination under mild basic

Full text of DOI:10.1016/j.tetlet.2009.02.146

Tetrahedron Letters 50 (2009) 2185–2188
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Tetrahedron Letters
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Methylsulfonylethoxycarbonyl (Msc) and fluorous
propylsulfonylethoxycarbonyl (FPsc) as hydroxy-protecting groups
in carbohydrate chemistry
Asghar Ali, Richard J. B. H. N. van den Berg, Herman S. Overkleeft, Dmitri V. Filippov,
*
*
Gijsbert A. van der Marel , Jeroen D. C. Codée
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The methylsulfonylethoxycarbonyl (Msc) group is presented as a non-lipophilic, base-labile, participating
protecting group for carbohydrate alcohols. It can be introduced using Msc–Cl and pyridine and is readily
cleaved via b-elimination under mild basic conditions. Its fluorous counterpart, the perfluorooctyl propyl-
sulfonylethoxycarbonyl (FPsc) group, is used in a ‘light fluorous’ trisaccharide synthesis sequence.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 December 2008
Revised 9 February 2009
Accepted 20 February 2009
Available online 25 February 2009
The development of new protecting groups is important in syn-
thetic organic chemistry.1 In the field of carbohydrate chemistry,
protecting groups occupy a central position and an effective pro-
tecting group strategy is at the heart of every complex oligosaccha-
ride synthesis.2 New protecting groups in carbohydrate chemistry
improve the efficiency with which oligosaccharides can be assem-
bled.3 In this respect, fluorous-protecting groups have attracted
considerable attention.4 Installment of a ‘light’ fluorous group in
a molecule allows for easy separation from non-fluorous com-
pounds using fluorous silica gel chromatography, in a so-called flu-
often for the protection of alcohols.18,19 We reasoned that Msc
could be a favorable alternative to 9-fluorenylmethyl carbonate
(Fmoc), which is becoming increasingly popular in carbohydrate
chemistry.20,21 It was expected that the Msc group could be cleaved
under similarly mild conditions as those used for Fmoc deprotec-
tion, but that it would be sterically less demanding and less lipo-
philic than bulky Fmoc. In addition, fluorous analogues of Msc
can be readily prepared.22
As a first objective, we investigated the installation and cleav-
age of the Msc group on a range of carbohydrate building blocks.
As depicted in Table 1, the Msc group is introduced readily using
methylsulfonylethoxycarbonyl chloride (Msc–Cl) and pyridine in
CH2Cl2, to both primary and secondary hydroxy functions in the
presence of various other functionalities (Table 1, entries 1–6). It
can also be introduced selectively to the primary position of a par-
tially protected pyranoside (Table 1, entry 7) by reaction at ꢀ20 °C.
Several basic cleavage conditions were examined to remove the
Msc group from glucofuranose 9 as summarized in Table 2. The
use of a catalytic amount of sodium methoxide (NaOMe, 0.1 equiv)
in methanol required 18 h to completely remove the Msc group
(Table 2, entry 1). Tetrabutylammonium fluoride (TBAF, 0.1 equiv)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.1 equiv) on the
other hand cleaved the Msc group within 30 min (Table 2, entries
2 and 3). b-Elimination using 30 equiv of triethylamine proceeded
slowly and complete deprotection took 20 h (Table 2, entry 4).
Cleavage of the Msc group from galacturonic acid lactone 1023
was accomplished with DBU without compromising the integrity
of the labile lactone ring to afford the deprotected alcohol in 97%
yield (Table 2, entry 5). Having established conditions for both
installation and cleavage of the Msc group, we next investigated
its orthogonality with the levulinoyl (Lev) ester. To this end alcohol
11 was levulinoylated to provide fully protected glucoside
12 (Scheme 1). The levulinoyl group can be cleaved from this
orous solid phase extraction (FSPE) process.5
A variety of
fluorinated protecting groups have been reported to date, includ-
ing fluorous analogues of benzyl6 and benzyloxycarbonyl,7 tert-
butyl8 and tert-butyloxycarbonyl,9 pentenyl,10 trityl,11 benzyli-
dene,12 and various acyl13 and silyl-based14 groups. We recently
introduced the fluorous methylsulfonylethoxycarbonyl (FMsc, 2,
Fig. 1)15 group as an amine-protecting group in peptide chemistry.
The FMsc-group was used as a purification tag for a peptide assem-
bled using Fmoc-based solid phase peptide synthesis. After purifi-
cation of the peptide using fluorous HPLC (FHPLC), in which the
fluorinated product was separated from non-fluorous deletion se-
quences, the FMsc group was removed using mild basic conditions.
We report here on the use of Msc (1, Fig. 1) and its fluorous coun-
terpart, perfluorooctyl propylsulfonylethoxycarbonyl (FPsc, 3,
Fig. 1) as hydroxy-protecting groups in carbohydrate chemistry.
Although Tesser’s methylsulfonylethoxycarbonyl (Msc)16 group
is popular for the protection of amino groups, and the methylsulfo-
nylethyl ester has been used to mask carboxylic acids,17 the related
sulfonylethoxycarbonate functionality has not been employed very
* Corresponding authors. Tel.: +31 71 5274280; fax: +31 71 5274307.
E-mail addresses: marel_g@chem.leidenuniv.nl (G.A. van der Marel), jcodee@
chem.leidenuniv.nl (J.D.C. Codée).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.146

2186
A. Ali et al. / Tetrahedron Letters 50 (2009) 2185–2188
O
O
O
O
O
O
O
O
O
S
S
F17C8
S
O
F17C8
O
O
1, Msc
2, FMsc
3, FPsc
Figure 1. The Msc, FMsc, and FPsc protecting groups.
Table 1
cleavage of the Msc group using a catalytic amount of DBU pro-
vided primary alcohol 13 almost quantitatively, showing that the
Msc and Lev groups are fully orthogonal.24,25
Installation of Msc on carbohydrate hydroxy groupsa
Entry
1
Product
Temperature
Time (h)
3
Yield (%)
98
We next investigated the applicability of Msc-protected carbo-
hydrates in a set of glycosylation reactions (Scheme 2). In the first
example, the Msc-protected thioglucoside 6 was condensed with
methyl glucoside 14 in the presence of N-iodosuccinimide (NIS)
and a catalytic amount of trimethylsilyl triflate (TMSOTf) to pro-
vide disaccharide 15 in 63% yield. The Msc group could be selec-
tively removed from this disaccharide leaving all the benzoyl
functionalities untouched. A second glycosylation employed thio-
glucose 7, with the Msc group at C2–OH, which was coupled to
acceptor 14. The b-linked dimer 17 was obtained in 74% yield,
showing that the methylsulfonylethoxy carbonyl group provided
efficient anchimeric assistance in the glycosylation reaction. When
this glycosylation was carried out using diphenylsulfoxide (Ph2SO)
in combination with trifluoromethanesulfonic anhydride (Tf2O)26
in the presence of excess tri-tert-butylpyrimidine (TTBP),27 disac-
charide 17 was isolated in similar yield (67%). Use of a catalytic
amount of DBU, quantitatively liberated the C20-hydroxy group in
17 to afford 18. The Msc group was also well tolerated when pres-
ent in an acceptor building block as shown in the glycosylations in
which the perbenzoylated S-phenyl glucoside 19 was coupled to
primary alcohol 20 and secondary alcohol 11, respectively. Disac-
charides 21 and 22 were isolated in 70% and 64% yields,
respectively.
Having established conditions to install and remove the Msc
group on carbohydrate alcohols and having studied their behavior
under glycosylation conditions, we next focused our attention on
the applicability of the fluorous Msc group (2, Fig. 1) in oligosac-
charide synthesis. Although the FMsc group can be introduced to
carbohydrate hydroxy functions under the above-mentioned con-
ditions for the introduction of the Msc group, it soon became
apparent that the resulting fluorous carbonate was rather labile.
We judged this lability to be the result of the inductive electron-
withdrawing effect of the perfluoro chain, which makes the FMsc
carbonate very susceptible to b-elimination. Therefore, we decided
to develop a new fluorous version of the Msc group, in which the
perfluoro part is positioned further away from the sulfonyl group
by adding an extra ‘insulating’ three methylene units, in the form
of fluorous propylsulfonylethoxycarbonyl (FPsc, 3, Fig. 1).
MscO
O
BnO
BnO
SEt
0 °C–rt
OBn
4
BnO
O
MscO
RO
SPh
2
0 °C–rt
5
5 (R = Bn) 78
6 (R = Bz) 76
OR
5 R = Bn
6 R = Bz
Ph
O
O
O
SPh
OMsc
3
4
0 °C–rt
0 °C–rt
4
4
79
79
BnO
7
DMTO
O
MscO
BnO
BnO
OMe
8
O
O
H
O
O
5
6
0 °C–rt
3
3
5
95
88
90
O
MscO
O
9
SPh
O
0 °C–rt
O
MscO
OBn
10
MscO
O
HO
BnO
7
ꢀ20 °C to rt
BnO
OMe
11
a
Msc–Cl (2 equiv), pyridine (3 equiv), CH2Cl2 (0.2 M).
Table 2
Cleavage of the Msc group
Entry
Substrate
Conditions
Quantity (equiv)
Time
Yield (%)
The synthesis of fluorous propylsulfonylethoxycarbonyl chloride
(FPsc–Cl, 26) started from commercially available 3-(perfluoro-
octyl)propyl iodide,22 as depicted in Scheme 3. The primary iodide
was substituted with mercaptoethanol in refluxing tert-butyl alco-
hol to give thioether 24, which was oxidized to the corresponding
sulfone 25. Treatment of 25 with phosgene in THF transformed the
primary alcohol into the chlorocarbonate 26 (FPsc–Cl).
1
2
3
4
5
9
9
9
9
NaOMe, MeOH
TBAF, THF
DBU, DMF
Et3N, DCM
DBU, DMF
0.1
0.1
0.1
30
18 h
100
100
100
100
97
30 min
25 min
20 h
10
0.1
1 min
pyranoside without affecting the Msc-carbonate using hydrazine
hydrate in a mixture of pyridine and acetic acid. Alternatively,
The FPsc group was utilized in the assembly of trisaccharide 33
starting with the selective introduction of the fluorous propylsulf-
LevOH, DMAP,
EDC.HCl, CH2Cl2,
DBU, DMF,
HO
MscO
HO
MscO
LevO
BnO
1 h, 89%
25 min
95%
O
O
O
LevO
BnO
BnO
H2NNH2.H2O
pyridine/HOAc
5 min, 96%
BnO
BnO
BnO
11
12
13
OMe
OMe
OMe
Scheme 1. Orthogonality of the Msc and Lev groups.

A. Ali et al. / Tetrahedron Letters 50 (2009) 2185–2188
2187
NIS, TMSOTf,
CH2Cl2, -40 oC-RT,
1 h
BnO
BnO
BnO
MScO
BzO
BnO
O
O
O
RO
O
O
HO
BzO
SPh
SPh
+
+
BzO
BzO
BzO
63%
BzO
BzO
BzO
OMe
OMe
OMe
6
7
14
14
DBU, dioxane
30 min
15 R = MSc
16
R = H (100%)
NIS, TMSOTf,
CH2Cl2, -40 oC-RT,
1 h (74%)
Ph
O
Ph
O
BnO
O
O
BnO
O
O
O
O
HO
O
BnO
OR
BnO
BzO
BzO
or
OMsc
BzO
BzO
OMe
Ph2SO, Tf2O
TTBP, CH2Cl2,
-60 oC-RT (67%)
DBU, dioxane
30 min
17 R = MSc
18
R = H (100%)
NIS, TMSOTf,
CH2Cl2, -40 oC-RT,
1 h
BzO
HO
BzO
O
O
O
BzO
MscO
BzO
O
SPh
SPh
+
BzO
BzO
BnO
70%
O
BzO
BnO
BzO MscO
OMe
OMe
BnO
19
20
21
BnO
OMe
NIS, TMSOTf,
CH2Cl2, -40 oC-RT,
1 h
BzO
MscO
BzO
O
O
O
MscO
BzO
BzO
HO
BzO
BzO
+
O
O
BnO
64%
BnO
BzO
BnO
BzO
BnO
OMe
22
19
11
Scheme 2. Glycosylation reactions of Msc-containing carbohydrate building blocks.
merceptoethanol,
t-BuOH, NaOH,
AcOOH,AcOH,
H2O, EtOAc, 2 h
reflux, 4 h
95%
F17C8
I
F17C8
S
OH
96%
23
24
phosgene,THF,
0 oC, 16 h
100%
O
O
O
O
O
F17C8
S
F17C8
S
OH
O
Cl
25
26
Scheme 3. Synthesis of FPsc–Cl.
onylethoxycarbonate to diol 27 (see Scheme 4).28 The primary
alcohol was selectively acylated using 1 equiv of FPsc–Cl 26 at
low temperature to give the acceptor glycoside 28 in 94% yield.
This monosaccharide was then treated with an excess of donor
29 (2.6 equiv), bearing a levulinoyl group at C4–OH. TLC analysis
showed formation of the desired disaccharide along with the for-
mation of several donor-derived side-products. The disaccharide
was purified by FSPE using a gradient of acetonitrile in water
(50–100%) to provide the fluorous product 30 in excellent yield.
Delevulinoylation of 30 did not affect the FPsc group and alcohol
1) NIS, TMSOTf,
FPsc-Cl (26), pyr,
CH2Cl2, 0 oC-RT,
1 h
HO
HO
BnO
FPscO
HO
BzO
RO
CH2Cl2, -40 oC-RT,
4 h
O
O
O
FPscO
O
O
2) FSPE
BzO
BnO
BnO
BnO
BnO
BzO
OMe
OMe
BnO
27
28
BzO
LevO
BzO
OMe
94%
O
SPh
1) H2NNH2.H2O
pyridine/HOAc
5 min
30 R = Lev (93%)
31
BzO
29
R = H (81%)
2) FSPE
Si
O
NPh
O
O
LevO
O
CF3
TCAHN
Si
O
O
32
BzO
O
O
FPscO
LevO
O
O
1) TfOH, CH2Cl2, -20 oC, 15 min
2) FSPE
BzO
O
TCAHN
BnO
BzO
BnO
OMe
33 (78%)
Scheme 4. Oligosaccharide synthesis using the FPsc group.

2188
A. Ali et al. / Tetrahedron Letters 50 (2009) 2185–2188
15. De Visser, P. C.; Van Helden, M.; Filippov, D. V.; Van der Marel, G. A.; Drijfhout,
J. W.; Van Boom, J. H.; Noort, D.; Overkleeft, H. S. Tetrahedron Lett. 2003, 44,
9013.
16. (a) Tesser, G. I.; Balvert-Geers, I. C. Int. J. Peptide Protein Res. 1975, 7, 295; (b)
Wolters, E. T. M.; Tesser, G. I.; Nivard, R. J. F. J. Org. Chem. 1974, 39, 3388; (c)
Also see Ref. 1.
31 was obtained uneventfully. Next, the disaccharide 31 was elon-
gated using an excess of (N-phenyl)trifluoroacetimidate glucosa-
mine 3229 (3 equiv) and a catalytic amount of TfOH at ꢀ20 °C.
After FSPE, trisaccharide 33 was isolated in 78% yield.30
In conclusion, we have reported on the successful introduction
of the methylsulfonylethoxycarbonyl (Msc) group as a non-lipo-
philic alcohol-protecting group in oligosaccharide synthesis. The
Msc carbonate can be introduced using standard conditions for
the formation of carbonates and can be cleaved using mild basic
conditions under which commonly used ester-protecting groups
are stable. The Msc group was shown to be fully orthogonal with
the levulinoyl group. The carbonate is completely stable to Lewis
acidic glycosylation conditions and provides anchimeric assistance
when situated at the C2–OH of a glycosyl donor. The fluorous ver-
sion of Msc proved to be very labile when used as an alcohol-pro-
tecting group, and thus the fluorous propylsulfonylethoxycarbonyl
(FPsc) group was developed. This fluorous carbonate was used suc-
cessfully in the assembly of a trisaccharide.
17. (a) Hardy, P. M.; Rydon, H. N.; Thompson, R. C. Tetrahedron Lett. 1968, 9, 2525;
(b) Miller, A. W. J. Chem. Soc., C. 1968, 2612; (c) Also see Ref. 1.
18. (a) Balgobin, N.; Josephson, S.; Chattopadyaya, J. B. Tetrahedron Lett. 1981, 22,
3667; (b) Josephson, S.; Balgobin, N.; Chattopadyaya, J. B. Tetrahedron Lett.
1981, 22, 4537.
19. For a review on alkyl carbonates, see: Parrish, J. P.; Salvatore, R. N.; Woon Jung,
K. Tetrahedron 2000, 56, 8207.
20. (a) Gioeli, C.; Chattopadyaya, J. B. J. Chem. Soc., Chem. Commun. 1982, 672; (b)
Nicolaou, K. C.; Winssinger, N.; Pastor, J.; de Roose, F. J. Am. Chem. Soc. 1997,
119, 449; (c) Roussel, F.; Knerr, L.; Grathwohl, M.; Schmidt, R. R. Org. Lett. 2000,
5, 3043.
21. During introduction and cleavage of the Fmoc group, dibenzofulvene polymers
can be formed which can complicate purification.
22. Fluorous Fmoc–Cl is commercially available from Fluorous Techonologies Inc.
for $95/mmol. 3-(Perfluorooctyl)propyl iodide (22, Scheme 3) used for the
synthesis of fluorous propylsulfonylethoxycarbonyl chloride (FPsc-Cl, 25) is
available from Fluorous Techonologies Inc. for $15/mmol. See http://
www.fluorous.com.
23. Van den Bos, L. J.; Litjens, R. E. J. N.; Van den Berg, R. J. B. H. N.; Overkleeft, H. S.;
Van der Marel, G. A. Org. Lett. 2005, 7, 2007.
Acknowledgments
24. Zhu, T.; Boons, G.-J. Tetrahedron: Asymmetry 2000, 11, 199.
25. The corresponding 6-O-levulinoylated product was isolated in 2% yield as a
result of acyl migration from the secondary C4–OH to the primary C6–OH.
26. (a) Codée, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft, H. S.; Van
Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1519; (b) Codée, J. D. C.;
Litjens, R. E. J. N.; Van den Bos, L. J.; Overkleeft, H. S.; Van Boom, J. H.; Van der
Marel, G. A. Tetrahedron 2004, 60, 1057.
We thank the Higher Education Commission of Pakistan (HEC)
and the Netherlands Organisation for Scientific Research (NWO)
for financial support (S120114 to A.A. and VENI fellowship to
J.D.C.C., respectively).
27. Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
28. For F-tag oligosaccharide synthesis, see for example: (a) Miura, T.; Satoh, A.;
Goto, K.; Murakami, Y.; Imai, N.; Inazu, T. Tetrahedron. Asymmetry 2005, 16, 3;
(b) Manzoni, L.; Castelli, R. Org. Lett. 2006, 8, 955; (c) Jaipuri, F. A.; Pohl, N. L.
Org. Biomol. Chem. 2008, 6, 2686; (d) Tojino, M.; Mizuno, M. Tetrahedron Lett.
2008, 49, 5920; (e) Mizuno, M.; Goto, K.; Miura, T.; Inazu, T. QSAR Comb. Sci.
2006, 25, 742. and references cited therein.
Supplementary data
Supplementary data (Detailed experimental procedures and
analytical data for all new compounds) associated with this Letter
can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.146.
29. Dinkelaar, J.; Gold, H.; Overkleeft, H. S.; Codée, J. D. C.; Van der Marel, G. A. J.
Org. Chem., submitted for publication.
30. When this glycosylation was run at 0 °C a fluorous side-product was formed,
which was separated from fluorous trimer 32 by silica gel column
chromatography and was determined to be the dehydroglucosamine-coupled
product 34. Formation of this product can be explained by b-elimination of the
imidate group of donor 31, followed by a Ferrier glycosylation on the resulting
glycal. Although formation of this kind of side-product is uncommon, it has
been reported before.31
References and notes
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H. S.; Van Boom, J. H. Tetrahedron Lett. 2002, 43, 7809.
Si
O
O
O
BzO
TCAHN
O
O
FPScO
O
O
BzO
8. Pardo, J.; Cobas, A.; Guitián, E.; Castedo, L. Org. Lett. 2001, 3, 3711.
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BnO
34
BzO
BnO
OMe
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