MMTr as an efficient anomeric S-protecting group for the synthesis of glycosyl thiols

Article abstract of DOI:10.1016/j.tetlet.2006.09.003

The 4-monomethoxytrityl (MMTr) group was introduced in high yields to anomeric sulfhydryl functions using commercially available MMTrCl. Significantly, it is stable to a variety of reaction conditions, including acids and bases, and is removable under ver

Full text of DOI:10.1016/j.tetlet.2006.09.003

Tetrahedron Letters 47 (2006) 7935–7938
MMTr as an efficient anomeric S-protecting group for the
synthesis of glycosyl thiols
Xiangming Zhu*
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland
Received 18 July 2006; revised 21 August 2006; accepted 1 September 2006
Available online 20 September 2006
Abstract—The 4-monomethoxytrityl (MMTr) group was introduced in high yields to anomeric sulfhydryl functions using commer-
cially available MMTrCl. Significantly, it is stable to a variety of reaction conditions, including acids and bases, and is removable
under very mild acidic conditions, which are compatible with the presence of a number of other acid-labile hydroxyl protecting
groups. The successful preparation of seven glycosyl thiols indicates that MMTr has potential application for the synthesis of com-
plex 1-thiosugars.
Ó 2006 Elsevier Ltd. All rights reserved.
The rapid development of glycobiology has created a
great demand for structurally defined carbohydrates
and their mimetics as biological probes. Among them,
thioglycosides have attracted considerable attention
due to their resistance to chemical and enzymatic hydro-
lysis and their similar solution conformation and biolog-
ical activities compared to native counterparts.1 As a
consequence, efforts have been devoted to synthesize
thioglycosides, including thiosaccharides and S-glyco-
conjugates, in order to provide valuable compounds
for biological studies.2 For instance, a series of 6-b-thio-
saccharide analogues of morphine-6-glucuronide (M6G)
have been synthesized and evaluated with the objective
of preparing an analogue of M6G with improved bio-
logical activity.3 Also, carbohydrate epitopes of conju-
gate vaccines have been modified to contain S-linked
residues and the resulting S-linked immunogens gener-
ated an antigen-specific immune response that even
exceeded the response to the native oligosaccharides.4
tage of the glycosyl thiol-based approach is the ready
availability and chemical stability of glycosyl thiols.
The preparation of glycosyl thiol dates from nearly half
a century ago6 and new preparative procedures are still
emerging.7 On the other hand, both a- and b-glycosyl
thiols are quite stable, and do not mutarotate even
under basic conditions,3 hence the anomeric stereochem-
istry is maintained during the glycosylation process.
Therefore, by utilizing glycosyl thiols, various thioglyco-
sides have been synthesized as stable glycoside ana-
logues and as potential agents for therapeutic
intervention.2,8 S-Glycopeptides have been synthesized
recently by two independent groups, in which glycosyl
thiols were utilized as sugar building blocks.8a,b
In addition to their wide application in thioglycoside
synthesis, glycosyl thiols are also useful in the synthesis
of many other carbohydrate contexts, such as C-glyco-
side synthesis,9 glycosyl sulfenamide and glycosyl sul-
fonamide synthesis,10 and glycosyl disulfide synthesis.11
Glycosyl thiols have been employed to prepare carbohy-
drate thionolactones12 which could be useful in the con-
struction of spiro-C/O-glycoside-containing natural
products. Moreover, novel sugar species have been
developed from glycosyl thiols, such as GTM-Cl,13
which could be applied in the synthesis of various neo-
glycoconjugates. Very recently, glycosyl thiol was used
to generate the transient species, glycosylsulfenic acid.14
Currently, glycosyl thiols or their precursors, such as
anomeric thioacetates, which can be S-deacetylated
in situ to generate the desired glycosyl thiols, are the
key building blocks for the construction of thioglyco-
sides,2 although thioglycosides can also be synthesized
conventionally from normal glycosyl donors and the
corresponding sulfur-containing acceptors.5 The advan-
Keywords: MMTr; S-Protecting group; Glycosyl thiol; Thioglycoside.
*
Although glycosyl thiol has exhibited great utility and
potential in contemporary carbohydrate chemistry, to
Tel.: +353 17162386; fax: +353 17162501; e-mail: Xiangming.Zhu@
ucd.ie
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.003

7936
X. Zhu / Tetrahedron Letters 47 (2006) 7935–7938
Table 1. Deprotection of thioglycosides 5–11 with TFA/TESHa
Entry
1
Substrate
Product
Yieldb (%)
96
OMe
O
OMe
O
MeO
MeO
SMMTr
SMMTr
SH
MeO
MeO
OMe
OMe
5
12
OBn
OBn
O
O
BnO
BnO
BnO
BnO
2
3
4
86
83
83
SH
OBn
OBn
6
13
OBn
OBn
BnO
BnO
Ph
BnO
BnO
O
O
SMMTr
SMMTr
SH
SH
OBn
OBn
7
14
Ph
O
O
O
O
O
O
AcO
AcO
OAc
OAc
8
15
OTBDPS
O
OTBDPS
O
BzO
BzO
BzO
5
6
88
93
SMMTr
SH
BzO
OBz
O
OBz
O
9
16
O
O
O
O
Ph
Ph
SMMTr
SH
PivO
PivO
OAc
OAc
10
17
O
O
O
O
TBDPSO
AcO
TBDPSO
AcO
7
84
O
O
SMMTr
11
SH
18
a All reactions were conducted with 0.8% TFA in CH2Cl2 containing 1% TESH at 0 °C; see Ref. 21 for details.
b Yield of pure, isolated product with correct analytical and spectral data.
the best of our knowledge, only a few papers describe
the development of sulfhydryl protecting groups, which
could allow access to glycosyl thiols with enhanced
structural diversity and complexity. The xanthenyl
(Xan) group has been reported as a S-protecting
group,15 however, its application in thioglycoside
synthesis is limited due to the harsh protection and
deprotection conditions. Reactions to introduce the
triphenylmethyl (Tr) group onto an anomeric sulfhydryl
group were troublesome and low yielding, besides, the
strong acidic conditions required for its removal would
also cleave other acid-sensitive protecting groups on
the sugar ring.16 The triisopropylsilyl (TIPS) group has
also been used to protect glycosyl thiols,8b however, its
application is limited in view of the fact that the silyl
group is one of the most popular O-protecting groups
in carbohydrate chemistry.
Although the MMTr protecting group has been well
studied in both nucleoside and peptide chemistry,17 little
is known about this group in carbohydrate chemistry.
MMTr was reported to be cleaved under very mild
acidic conditions in peptide synthesis, however, its com-
patibility with common acid-labile hydroxyl protecting
groups on a sugar ring remains to be tested. To clarify
this issue, we prepared a range of monomethoxyltrityl
thioglycosides 5–11, as depicted in Table 1, which bear
typical acid-labile carbohydrate protecting groups, such
as benzyl, benzylidene, tert-butyldiphenylsilyl and iso-
propylidene. In practice, the corresponding per-acetyl
glycosyl thiols, such as mannosyl thiol 118 (Scheme 1),
were prepared as starting materials and then treated
with commercially available MMTrCl in pyridine at
room temperature to give the desired per-acetyl thiogly-
coside intermediates,19 such as compound 2, in very high
yields. Subsequently, deacetylation of these intermedi-
ates with NaOMe in MeOH followed by protecting
group manipulations, such as methylation with MeI un-
der the action of NaH; benzylation with BnBr in the
presence of NaH; benzylidenation with PhCH(OMe)2
catalyzed by p-TsOH; silylation with TBDPSCl in
pyridine and isopropylidenation with Me2C(OMe)2
catalyzed by p-TsOH, furnished substrates 5–11 in
generally very good yields.
Under these circumstances, the development of a new
and efficient protecting group for the synthesis of glyco-
syl thiols is of great interest. As part of our ongoing
interest in S-glycoconjugates,8a we report here the 4-
monomethoxytrityl (MMTr) group as a practical pro-
tecting group for glycosyl thiols, which can be easily
introduced and selectively removed under very mild
conditions.

X. Zhu / Tetrahedron Letters 47 (2006) 7935–7938
7937
References and notes
OAc
O
OAc
AcO
AcO
AcO
AcO
AcO
AcO
O
MMTrCl, Py
84%
1. (a) Driguez, H. ChemBioChem. 2001, 2, 311–318; (b) Jahn,
M.; Marles, J.; Warren, R. A. J.; Withers, S. G. Angew.
Chem., Int. Ed. 2003, 42, 352–354; (c) Uhrig, M. L.;
Manzano, V. E.; Varela, O. Eur. J. Org. Chem. 2006, 162–
168.
2
SH
1
SMMTr
68%
i. NaOMe, MeOH
(2 steps) ii. TBDPSCl, Py
2. Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106,
160–187.
3. MacDougall, J. M.; Zhang, X. D.; Polgar, W. E.;
Khroyan, T. V.; Toll, L.; Cashman, J. R. J. Med. Chem.
2004, 47, 5809–5815.
O
O
OH
O
TBDPSO
HO
Me2C(OMe)2
TBDPSO
p-TsOH, CH3CN
HO
HO
O
95%
4
SMMTr
3
SMMTr
4. (a) Rich, J. R.; Bundle, D. R. Org. Lett. 2004, 6, 897–900;
(b) Bundle, D. R.; Rich, J. R.; Jacques, S.; Yu, H. N.;
Nitz, M.; Ling, C. C. Angew. Chem., Int. Ed. 2005, 44,
7725–7729.
Ac2O, Py
99%
5. For one example, see: Zhu, X.; Pachamuthu, K.; Schmidt,
R. R. J. Org. Chem. 2003, 68, 5641–5651.
6. Cerny´, M.; Vrkocˇ, J.; Staneˇk, J. Collect. Czech. Chem.
O
O
O
O
TBDPSO
AcO
TFA, TESH
CH2Cl2
TBDPSO
AcO
ˇ
O
O
84%
Commun. 1959, 24, 64–69.
SMMTr
SH
11
18
7. For one very recent procedure for the synthesis of glycosyl
thiols, see: Bernardes, G. J. L.; Gamblin, D. P.; Davis,
B. G. Angew. Chem., Int. Ed. 2006, 45, 4007–4011.
8. For some recent examples, see: (a) Zhu, X.; Schmidt, R. R.
Scheme 1. An example of MMTr as an S-protecting group for the
synthesis of glycosyl thiols. Synthesis of mannosyl thiol 18.
´
Chem. Eur. J. 2004, 10, 875–887; (b) Galonic, D. P.; van der
Donk, W. A.; Gin, D. Y. Chem. Eur. J. 2003, 9, 5997–6006;
´
(c) Galonic, D. P.; van der Donk, W. A.; Gin, D. Y. J. Am.
Next, we examined the deprotection of the MMTr
group on the above compounds 5–11. It is well known
that the removal of trityl-type protecting groups, such
as Tr, MMTr, and DMTr, from sulfur is reversible
due to the high stability of the trityl cation and the
strongly nucleophilic nature of the sulfhydryl group.
As a result, a cation scavenger is usually necessary to
drive the detritylation to completion. After screening
several conditions,20 0.8% trifluoroacetic acid (TFA) in
CH2Cl2 containing 1% triethylsilane (TESH) was chosen
to effect all the deprotections shown in Table 1. All the
reactions were performed at 0 °C. Under these condi-
tions,21 glycosyl thiols 12–18 were obtained in very high
to excellent yields. It is important to note that all the
acid-labile protecting groups present, including benzyl,
benzylidene, silyl, and isopropylidene, which are fre-
quently used in carbohydrate chemistry, were unaf-
fected. Most notably, the benzylidene protecting group
survived the present conditions as indicated by the good
to excellent yields of thiols 15 and 17.
Chem. Soc. 2004, 126, 12712–12713; (d) Thayer, D. A.; Yu,
H. N.; Galan, M. C.; Wong, C. H. Angew. Chem., Int. Ed.
2005, 44, 4596–4599; (e) Avenoza, A.; Busto, J. H.; Jimenez-
´
´
Oses, G.; Peregrina, J. M. Synthesis 2006, 641–644.
9. Taylor, R. J. K.; McAllister, G. D.; Franck, R. W.
Carbohydr. Res. 2006, 341, 1298–1311.
10. Knapp, S.; Darout, E.; Amorelli, B. J. Org. Chem. 2006,
71, 1380–1389.
11. Davis, B. G.; Ward, S. J.; Rendle, P. M. Chem. Commun.
2001, 189–190.
12. Chayajarus, K.; Fairbanks, A. J. Tetrahedron Lett. 2006,
47, 3517–3520.
13. Zhu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69, 1081–
1085.
14. Aversa, M. C.; Barattucci, A.; Bilardo, M. C.; Bonaccorsi,
P.; Giannetto, P.; Rollin, P.; Tatiboue¨t, A. J. Org. Chem.
2005, 70, 7389–7396.
15. Falconer, R. A. Tetrahedron Lett. 2002, 43, 8503–8505.
16. Greffe, L.; Jensen, M. T.; Chang-Pi-Hin, F.; Fruchard, S.;
O’Donohue, M. J.; Svensson, B.; Driguez, H. Chem. Eur.
J. 2002, 8, 5447–5455.
17. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed; John Wiley and Sons: New
York, 1999.
In summary, the 4-monomethoxytrityl group has been
employed as a new S-protecting group for the synthesis
of glycosyl thiols, which can be installed conveniently
and cleaved selectively in the presence of other acid-
labile hydroxyl protecting groups. In view of these
attributes, together with the recent use of the more
acid-labile dimethoxytrityl protecting group under
glycosidation conditions,22 the monomethoxytrityl
group described herein may find valuable and versatile
use in thioglycoside chemistry. Its application toward
the synthesis of complex oligosaccharidyl thiols is
currently underway.
18. Haque, M. B.; Roberts, B. P.; Tocher, D. A. J. Chem.
Soc., Perkin Trans. 1 1998, 2881–2890.
19. Typical procedure for the introduction of the MMTr group.
To a solution of the thiol 1 (1.45 g, 3.98 mmol) in dry
pyridine (18 mL) was added MMTrCl (1.36 g, 4.34 mmol).
The resulting mixture was stirred overnight at room
temperature. Pyridine was then removed in vacuo and the
residue was purified by flash column chromatography
(hexane/EtOAc, 3:1) to give the desired tritylated com-
pound 2 (2.13 g, 84%) as a white foam: TLC Rf = 0.29
(hexane/EtOAc, 2:1); [a]D +83.2 (c 0.9, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.28 (m, 12H, ArH), 6.81 (d,
J = 8.8 Hz, 2H, ArH), 5.29 (dd, J = 3.2, 1.6 Hz, 1H, H-
2), 5.26 (m, 2H, H-3, H-4), 4.82 (d, J = 1.6 Hz, 1H, H-1),
4.28 (m, 2H, H-5, H-6a), 3.93 (dt, J = 10.0, 3.6 Hz, 1H, H-
6b), 3.78 (s, 3H, OMe), 2.11, 2.03, 2.02, 1.97 (4s, 12H, Ac);
13C NMR (100 MHz, CDCl3) d 170.9, 170.0, 169.9, 169.7
(4MeCO), 158.7, 144.7, 144.6, 136.3, 131.3, 130.03, 130.00,
Acknowledgement
X.Z. thanks University College Dublin for financial
support.

7938
X. Zhu / Tetrahedron Letters 47 (2006) 7935–7938
128.3, 127.4, 113.5 (aromatic carbons), 83.2 (C-1), 72.5
84%) as a colorless syrup: TLC Rf = 0.51 (hexane/EtOAc,
3:1); [a]D +31.4 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.69 (m, 4H, Ph), 7.40 (m, 6H, Ph), 5.78 (d,
J = 6.4 Hz, 1H, H-1), 5.23 (dd, J = 10.0, 6.8 Hz, 1H, H-4),
4.26 (m, 2H, H-2, H-3), 4.11 (ddd, J = 9.8, 4.8, 2.9 Hz, 1H,
H-5), 3.76 (dd, J = 11.5, 4.9 Hz, 1H, H-6a), 3.72 (dd,
J = 11.4, 2.8 Hz, 1H, H-6b), 2.13 (d, J = 6.4 Hz, 1H, SH),
1.98 (s, 3H, Ac), 1.57 (s, 3H, Me), 1.36 (s, 3H, Me), 1.07 (s,
(C-2), 71.2 (C-5), 70.0 (CSAr), 69.7, 66.2 (C-3, C-4), 62.6
(C-6), 55.5 (CH3O), 21.0, 20.9, 20.8 (CH3CO); ESI-MS
m/z 659.2 [M+Na+].
20. Deprotection was unsuccessful using dichloroacetic acid
and anisole as the alternative to acid and cation scaveng-
ers, respectively.
21. Typical procedure for cleavage of the MMTr group. To a
stirred solution of the thioglycoside 11 (268 mg,
0.34 mmol) in CH2Cl2 (34 mL) at 0 °C was added drop-
wise TFA (0.27 mL) followed by Et3SiH (0.34 mL). The
mixture was stirred at 0 °C for 80 min, after which time
TLC indicated the disappearance of the starting material.
The mixture was then concentrated in vacuo at room
temperature, and azeotroped with toluene to give a
residue, which was purified by flash column chromato-
graphy (hexane/EtOAc, 8:1) to give the thiol 18 (148 mg,
t
9H, Bu); 13C NMR (100 MHz, CDCl3) d 169.7 (MeCO),
136.0, 135.9, 133.53, 133.49, 129.91, 129.87, 127.90, 127.85
(aromatic carbons), 110.6 (Me2C), 78.2 (C-2), 76.3 (C-1),
75.8 (C-3), 71.1 (C-5), 69.7 (C-4), 62.9 (C-6), 27.8 (Me2C),
27.0 (Me3C), 26.8 (Me2C), 21.1 (MeCO), 19.5 (Me3C);
ESI-MS m/z 517.3 [M+H+], 539.2 [M+Na+], 555.2
[M+K+].
22. Adinolfi, M.; Iadonisi, A.; Schiattarella, M. Tetrahedron
Lett. 2003, 44, 6479–6482.