Study of the regioselectivity of intra- and intermolecular glycosylations of mannoside diol acceptors

Article abstract of DOI:10.1055/s-2005-865228

The intramolecular glycosylation of thiomannoside donors linked through C6′ by a phthaloyl group to C3 of a diol mannoside acceptor is described. The unexpected results led us to undertake a systematic analysis of the factors affecting the regioselectivity of the intermolecular process. The substituents on the diol mannoside acceptor have been found to play an important role.

Full text of DOI:10.1055/s-2005-865228

LETTER
1095
Study of the Regioselectivity of Intra- and Intermolecular Glycosylations of
Mannoside Diol Acceptors
Study of the
R
egiosele
.
ctivity of Ma
B
nnoside
D
iol Ac
e
c
eptors lén Cid,*1 Serafín Valverde,* J. Cristobal López, Ana M. Gómez, Mercedes García2
Instituto de Química Orgánica General, Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)4973966; E-mail: Belen.cid@uam.es
Received 25 October 2005
The results of our investigations into the regioselectivity
Abstract: The intramolecular glycosylation of thiomannoside do-
nors linked through C6¢ by a phthaloyl group to C3 of a diol man-
noside acceptor is described. The unexpected results led us to
undertake a systematic analysis of the factors affecting the regiose-
of the equivalent reaction in the context of intramolecular
glycosylation appeared to complement to those described
previously for intermolecular processes and led us to un-
lectivity of the intermolecular process. The substituents on the diol dertake a thorough examination of the factors involved.
mannoside acceptor have been found to play an important role.
Key words: glycosylation, regioselectivity, stereoselectivity
OBn
O
OAc
O
BnO
BnO
BnO
BnO
BnO
Ph
OTBDPS
O
Pent
BnO
2
3
O
O
OPent
Cl
C4/trisaccharide = 58/21
BnO
BnO
The interest in carbohydrate derivatives is increasing be-
cause of their function in many biological processes.3 The
preparation of complex oligosaccharides still requires
enormous effort by synthetic organic chemists, and
strategies that avoid protecting group manipulations
through regioselective processes would be a tremendous
advance.3c As a part of our program directed at developing
regio- and stereoselective glycosylation methods based on
intramolecular glycosylation4 we applied this approach to
the synthesis of a trimannan branched at C3 and C6,
through a combined intramolecular-intermolecular one-
pot glycosylation with minimal hydroxyl group protec-
tion.4d On the other hand, recent work by Fraser-Reid and
coworkers5b,6 has shown that the, normally overlooked,
substituent at O-2 plays an important role in determining
the regioselectivity on the glycosylation of diols. In this
work we have drawn the attention to the, normally un-
noticed, substituents at O-6 and O-3 in a mannoside-2,4-
diol. Furthermore, we have compared intramolecular with
intermolecular glycosylation processes.
1
OH
OH
O
AllO
HO
BnO
O
HO
BnO
Pent =
AllO
OMe
OMe
4a
4b
ref 3a
ref 3b
Figure 1 Regioselective glycosylations of mannoside acceptors 4
and donors with participating (1 and 3) and non-participating (2)
groups
We first investigated the regioselectivity of glycoside do-
nors in reactions with mannose diol acceptors analogous
to 4 in an intramolecular glycosylation of diols 5
(Figure 2). The effects of both participating and non-
participating groups at position C2 of the donors were
analyzed. The C6¢ and C3 positions were chosen as the
anchoring sites for the donor and acceptor, respectively.
In order to analyze the regioselectivity of the process for
C4 and C2, the hydroxyl group at C6 of the acceptor was
protected as a TBDPS group. Previous experience led us
to use thioglycosides as the glycosyl donors and a
phthaloyl group as the linker.4
The synthesis of mannosides branched at the C2 and C4
positions has been less studied than that of the 6,3- and
6,2-substituted oligomannosaccharides; however, some
interesting results regarding regioselectivity have been
published.5 For example, position 4 of acceptors 4a and
4b is glycosylated in a regioselective manner, respective-
ly, by donors 1 and 3, which have participating groups at
C2 (Figure 1).5a In contrast, when donor 2 with a non-par-
ticipating group is used, the C2 hydroxyl group of the
mannose acceptor 4a undergoes complete regioselective
glycosylation.5b It has also been shown that glucosamine
donors with phthalimide as the participating protecting
group at C2 also react regioselectively with the C4
hydroxyl group of the acceptor.7
OR
O
O
R = Me
R = Ac
RO
RO
OH
O
PO
HO
SPh
P = TBDPS
5
O
OMe
Figure 2 General structure of intramolecular glycosylation
precursors
Precursors 6a,b and 7 were used as the mannosyl
donors8,4d and acceptor,9 respectively, and were prepared
from mannose following reported procedures. The (6¢-3)
and (6¢-2) diester phthaloyl derivatives 8 and 9 were
obtained from 6 by acylation, formation of the corre-
SYNLETT 2005, No. 7, pp 1095–1100
0
2.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865228; Art ID: D31804ST
© Georg Thieme Verlag Stuttgart · New York

1096
M. B. Cid et al.
LETTER
sponding acid chloride and coupling with the dialkylstan- 12a/13a = 21:37:37:5) in 62% yield. The intramolecular
nylene derivative of 7 prepared by microwave irradiation glycosylation of diol 8b took place upon treatment with
as described previously by us (Scheme 1).4d The acetylat- NIS/AgOTf (entry 3) to give a 75:25 mixture of the a(1-
ed donor 6b furnished the (6¢-3) linked diester 8b in 52% 2) and a(1-4) disaccharides 10b and 12b in 46% yield.11
yield and the permethylated derivative gave a 70:30 mix-
The formation of different ratios of stereoisomers depend-
ing on the activation procedure (NIS/TfOTMS or TfOMe)
was also observed by Ziegler and co-workers when study-
ture of the (6¢-3) and (6¢-2) diesters 8a and 9a, which
could be separated readily by flash chromatography.10
ing intramolecular (1-4) glycosylation of 3¢- and 6¢-linked
O
mannoside donors with different acceptors.12 Although
several methods have been described recently for the
preparation of b-mannosides in an intermolecular man-
ner,13 an intramolecular approach has once again proved
to be a complementary alternative for the formation of this
difficult kind of linkage.14
RO
O
MeO
O
O
O
O
OR
O
HO
RO
RO
RO
MeO
MeO
SPh
PhS
i–ii
SPh
RO
+
OTBDPS
OH
HO
O
O
O
O
6a R = Me
6b R = Ac
O
O
TBDPSO
OMe
HO
OH
TBDPSO
HO
9a (23%)
The result obtained in the glycosylation reaction of diester
8b (entry 3) contrasts with those observed by Fraser-Reid
and Ogawa, who observed the opposite regioselectivity in
the intermolecular glycosylation of donors 1 and 3 bearing
participating substituents at C2 with acceptors 4a and 4b
(Figure 1).5 An important difference between the intermo-
lecular glycosylations studied by Ogawa and Fraser-Reid
(Figure 1) and the intramolecular version studied by us
(Table 1) lies in the protecting groups of the acceptor moi-
ety. Since various factors, such as the type and position of
the bridging group between the glycosyl donor and accep-
tor, can influence the regio- and stereoselectivity of in-
tramolecular glycosylations, these results are difficult to
rationalize. Therefore, with the aim of determining
whether the intramolecular nature of the process was the
only factor responsible for the different regioselectivity
observed, several intermolecular glycosylations were
carried out and are summarized in Table 2.
MeO
O
HO
HO
8a R = Me (51 %)
8b R = Ac (52 %)
OMe
7
O
O
i)
, Et3N, CH2Cl2, 80%
O
ii) a) Cl2SO (5 equiv) DMF cat., Tol,
b) 7, n-Bu2SnO, toluene, microwave, then 6a or 6b
Scheme 1
The intramolecular glycosylation of diester 8a, which
bears the fully methylated donor, was studied under two
different sets of reaction conditions (Table 1). When NIS
was used as the only promoter (entry 1) the b(1-2) disac-
charide 11a was isolated in 39% yield and the a(1-2), a(1-
4) and b(1-4) disaccharides 10a, 12a and 13a were ob-
tained after acetylation in 6, 8 and 8% yield, respectively.
The NIS/AgOTf system (entry 2) led to a mixture of the
a(1-2), b(1-2), a(1-4) and b(1-4) disaccharides (10a/11a/
Table 1 Intramolecular Glycosylation
O
OR
OTBDPS
O
OR
O
OR
OR
O
O
O
O
O
O
OTBDPS
OH
OH
O
O
RO
RO
O
RO
RO
RO
RO
O
O
RO
RO
O
O
TBDPSO
O
+
i
TBDPSO
O
+
O
+
8
MeO
HO
O
O
CH2Cl2
HO
O
O
O
O
O
O
MeO
O
MeO
MeO
a R = Me
b R = Ac
10a
10b
12a
12b
11a
13a
i) Method A: NIS (3 equiv), r.t., 48 h; method B: NIS (3 equiv), TfOAg (0.1 equiv), –40 °C to r.t., 24 h; method C: NIS (3 equiv), TfOAg (1
equiv), 0 ºC, 10 min.
Entry
Substrate
Conditions (yield, %)
Ratio of products
a(1-2) 10
b(1-2) 11
64 (39)
37
a(1-4) 12
13 (8)
37
b(1-4) 13
13 (8)
5
1
2
3
R = Me 8a
R = Me 8a
R = Ac 8b
Method A (61)a
Method B (62)
Method C (46)
10 (6%)
21
75
25
a Yields given for acetylated products.
Synlett 2005, No. 7, 1095–1100 © Thieme Stuttgart · New York

LETTER
Study of the Regioselectivity of Mannoside Diol Acceptors
1097
Table 2 Intermolecular Glycosylations
R1O
R2O
R1O
R2O
R1O
OR1
O
O
OR1
O
R2O
R1O
OH
O
R1O
R4O
HO
R2O
R1O
R1O
R1O
R1O
OR4
OH
R1O
R4O
O
R2O
R1O
NIS (3 equiv)
R1O
R3O
+
+
O
+
O
O
OR4
O
SPh
TfOAg (0.1 equiv)
CH2Cl2
O
OMe
R1O
O
HO
R3O
R3O
O
O
14a R1 = Me, R2 = Bz
14b R1 = R2 = Ac
3
4
15 R = Bz, R = TBDPS
19 R3 = R4 = Bz
4a R3 = R4 = All
4b R3 = R4 = Bn
OMe
R3O
OMe
α(1–2)
α(1–4)
OMe
16a
16b
20
17a
21
23
18a
18b
22
24
Entry
Substrates (donor/acceptor)
Conditions
Yield of glycosylation (%)
a(1-2) a(1-4)
12 (16a/17a = 3:1)
Trisaccharide
1
2
3
4
5
6
R1 = Me, R2 = Bz (14a)/
0 °C to r.t., 48 h
0 °C to r.t., 1 h
3 (18a)
R3 = Bz, R4 = TBDPS (15)
R1 = R2 = Ac (14b)/
23 (16b)
26 (20)
–
21 (18b)
5 (22)
R3 = Bz, R4 = TBDPS (15)
R1 = R2 = Ac (14b)/
R3 = R4 = Bz (19)
0 °C to r.t., 20 min (38%)a
22 (21)
28 (21)
R1 = R2 = Ac (14b)/
R3 = R4 = Bz (19)
–40 °C to 0 °C, 3 h (23%)a
–40 °C to 0 °C, 24 h
19 (20)
21 (22)
R1 = R2 = Ac (14b)/
R3 = R4 = All (4a)
Complex mixture
–
R1 = R2 = Ac (14b)/
R3 = R4 = Bn (4b)
–35 °C to 0 °C, 6 h 30 min (26%)a
51 (23)
12 (24)
a Recovered acceptor.
Donors 14a and 14b, prepared following standard proce- The reaction of the disarmed donor 14b with acceptor 15
dures,15 were chosen as analogues of diesters 8a and 8b, afforded the a(1-2) disaccharide 16b and trisaccharide
respectively, and used in equivalent intermolecular glyco- 18b in 23 and 21% yield, respectively; 19% of acceptor 15
sylations. Mannosyl acceptor 15 presents maximum simi- was recovered (entry 2). The regioselectivity observed in
larity with the acceptor used in the intramolecular version this case was lower than that of the analogous intramolec-
of the reaction.16
ular process (entry 3, Table 1). This result is also in con-
trast with the regioselectivity observed with glycosyl
donors 1 and 3, with participating groups at C2, for the C4
position of the mannosyl acceptors 4 (Figure 1).5 This ob-
servation seems to indicate that the preference for C2 over
C4 in the intramolecular reaction (entry 3, Table 1) could
in part be a consequence of the different substituents on
the acceptor and not only an effect of the intramolecular
nature of the process.
The glycosylation reaction of the armed donor 14a with
acceptor 15 afforded an inseparable 3:1 mixture of a(1-2)
and a(1-4) disaccharides 16 and 17 in a poor 12% yield;
the corresponding trisaccharide 18a formed by double
glycosylation was also isolated in 3% yield (entry 1).17 In
spite of the low yield, the tendency towards reaction at the
C2 position is in agreement with the result obtained by
Fraser-Reid with donor 2 (Figure 1).5b This result also
illustrates the influence of the protecting groups on the ac- We reasoned that the volume of the bulky TBDPS protect-
ceptor in the reactivity of the diol system when compared ing group at C6 of the acceptor could be responsible for
to the results obtained with acceptor 4a.5b Comparison be- this poor regioselectivity, and it was substituted for a ben-
tween Table 1 (entries 1 and 2) and Table 2 (entry 1), zoyl group. Nevertheless, the reaction of the disarmed do-
where similar glycosyl acceptors gave strikingly different nor 14b with acceptor 1918 gave all three possible
yield of disaccharides, indicate that the intramolecular glycosylation products. Mixtures of the a(1-2) disaccha-
glycosylation process is clearly superior, avoids the ride 20, a(1-4) regioisomer 21 and trisaccharide 22 were
formation of trisaccharides and allows the reaction to be formed in different ratios depending on the reaction con-
carried out in the absence of TfOAg. A plausible conse- ditions (entries 3 and 4).
quence of this is that the intramolecular strategy could be
With the aim of determining unambiguously whether the
specially well suited for coupling unreactive glycosyl
leaving group of the glycosyl donor or the nature of the
partners.
Synlett 2005, No. 7, 1095–1100 © Thieme Stuttgart · New York

1098
M. B. Cid et al.
LETTER
(6) (a) Fraser-Reid, B.; López, J. C.; Radhakrishanan, K. V.;
substituents on the acceptor were responsible for this dif-
ferent reactivity, the acceptors 4a and 4b used by Ogawa
and Fraser-Reid were prepared,19 and their glycosylation
reaction with disarmed donor 14b studied. The allylated
acceptor 4a gave a complex mixture of products, as the al-
lyl groups also react under the reaction conditions (entry
5). Nevertheless, the benzylated acceptor 4b showed a
clear tendency to undergo glycosylation at the C4 position
when it reacts with the thioglycoside donor 14b, affording
23 and trisaccharide 24 in 51 and 12% yield, respectively
(entry 6). Therefore, the results in Table 2 (entries 4 and
6) clearly illustrate how the mere switch from a benzoyl to
a benzyl protecting group at O-3 and O-6 of the acceptor
has an important influence on the regiochemistry of the
process.
Mach, M.; Schlueter, U.; Gómez, A. M.; Uriel, C. Can. J.
Chem. 2002, 80, 1075. (b) Fraser-Reid, B.; López, J. C.;
Radhakrishanan, K. V.; Mach, M.; Schlueter, U.; Gómez, A.
M.; Uriel, C. J. Am. Chem. Soc. 2002, 124, 3198.
(c) Fraser-Reid, B.; Anilkumar, G. N.; Nair, L. G.;
Radhakrishanan, K. V.; López, J. C.; Gómez, A. M.; Uriel,
C. Aust. J. Chem. 2002, 55, 123. (d) Fraser-Reid, B.; López,
J. C.; Radhakrishanan, K. V.; Nandakumar, M. V.; Gómez,
A. M.; Uriel, C. Chem. Commun. 2002, 2104. (e) López, J.
C.; Gómez, A. M.; Uriel, C.; Fraser-Reid, B. Tetrahedron
Lett. 2003, 44, 1417. (f) Uriel, C.; Gómez, A. M.; López, J.
C.; Fraser-Reid, B. Synlett 2003, 2203. (g) Fraser-Reid, B.;
López, J. C.; Gómez, A. M.; Uriel, C. Eur. J. Org. Chem.
2004, 1387.
(7) (a) Arnap, J.; Haraldsson, M.; Lönngren, J. J. Chem. Soc.,
Perkin Trans. 1 1985, 535. (b) Ogawa, T.; Nakabayashi, S.
Agric. Biol. Chem. 1981, 45, 2329.
In summary, it has been shown that the intramolecular
glycosylation of the studied mannoside diol acceptors is a
reliable alternative when the intermolecular approach
gives poor yields providing complementary stereoselec-
tivities. The presence of the anchoring spacer avoids the
undesired trisaccharides obtained in the intermolecular
glycosylation of polyol systems. It has also been demon-
strated that subtle changes in the substituents on the
glycosyl acceptor have a very important effect on the
regiochemistry of glycosylation reactions.
(8) Lemanski, G.; Ziegler, T. Tetrahedron 2000, 56, 563.
(9) Arias-Perez, M. S.; Santos, M. J. Tetrahedron 1996, 52,
10785.
(10) General Method for the Formation of Diesters 8 and 9.
A solution of 6a or 6b, phthalic anhydride (2 equiv) and Et3N
(5 equiv) in 20 mL of CH2Cl2 was stirred at r.t. for 4 h. Then,
a sat. solution of NH4Cl was added, the mixture was stirred
for 15 min, the aqueous layer was extracted with CH2Cl2 (3
ꢀ 100 mL), and the combined organic layers were washed
with brine, dried over MgSO4 and evaporated to give the
corresponding triethylamine salt. This salt was dissolved in
toluene and treated with SOCl2 (5 equiv) and 3 drops of
DMF, and the mixture was stirred under reflux for 4 h. The
reaction mixture was then co-evaporated with toluene
several times under vacuum to give the corresponding acid
chloride as a yellow oil, which was treated with a solution of
the tin derivative (1.1 equiv) prepared as follows: methyl 6-
O-tert-butyldimethylsilyl-a-D-mannopyranoside (7) was
dissolved in anhyd toluene in an Erlenmeyer flask, then
dibutyltin oxide (1.1 equiv) was added. The suspension was
heated in a microwave oven (domestic microwave oven LG
intellowave 700 W) for periods of 2 min until the solid was
completely dissolved. The solution was allowed to reach r.t.,
then was added to the freshly prepared acid chloride, and the
mixture was stirred for 20 h. Silica gel was then added, the
slurry was stirred for 1 h, the solvent was evaporated under
vacuum, and the solid was directly loaded into a column for
flash chromatography.
Acknowledgment
This research was supported by the Dirección General de Investig-
ación Científica y Técnica (Grant BQU2002-00120). MBC thanks
MCyT (Ministerio de Ciencia y Tecnología) for a Ramón y Cajal
contract and Nicole Frost for proof reading this manuscript.
References
(1) Present address: Departamento de Química Orgánica,
Universidad Autónoma de Madrid, Cantoblanco 28049,
Spain.
(2) Present address: DDW-Medicinal Chemistry II,
GlaxoSmithKline, 28770 Tres Cantos, Madrid, Spain.
(3) (a) Dwek, R. A. Chem. Rev. 1996, 96, 683. (b) Varki, A.
Glycobiology 1993, 3, 97. (c) Carbohydrates in Chemistry
and Biology, Vol. 1-4; Ernst, B.; Hart, G. W.; Sinaÿ, P., Eds.;
Wiley-VCH: Weinheim, 2000. (d) Glycoscience, Vol. 1-3;
Fraser-Reid, B.; Tatsuta, K.; Thiem, J., Eds.; Springer-
Verlag: Berlin, Heidelberg, 2001.
(4) (a) Valverde, S.; Gómez, A. M.; Hernandez, A.; Herradón,
B.; López, J. C. J. Chem. Soc., Chem. Commun. 1995, 2005.
(b) Valverde, S.; Gómez, A. M.; López, J. C.; Herradón, B.
Tetrahedron Lett. 1996, 37, 1105. (c) Valverde, S.; García,
M.; Gómez, A. M.; López, J. C. Synlett 2000, 22.
(d) Valverde, S.; García, M.; Gómez, A. M.; López, J. C.
Chem. Commun. 2000, 813.
Phenyl 2,3,4-tri-O-methyl-6-O-[methyl-O-(6-O-tert-
butyldimethylsilyl-a-D-mannopyranos-3-yloxy)-2-
carbonylbenzoyl]-1-thio-a-D-mannopyranoside (8a):
[a]D +36 (c 0.63, CHCl3). 1H NMR (300 MHz, CDCl3): d =
7.83–7.11 (m, 19 H, Ar), 5.65 (d, 1 H, J = 1.2 Hz, H1¢), 5.27
(dd, 1 H, J = 9.8, 3.1 Hz, H3), 4.72 (d, 1 H, J = 1.3 Hz, H1),
4.53 (m, 2 H, H5¢ and H6¢), 4.31 (m, 2 H, H4¢ and H2), 4.11 (td,
1 H, J = 9.7, 2.6 Hz, H4), 3.97 (dd, 1 H, J = 9.3, 4.9 Hz, H6),
3.91 (dd, 1 H, J = 9.3, 4.9 Hz, H6), 3.89 (br t, 1 H, J = 1.2 Hz,
H2¢), 3.79 (dt, 1 H, J = 9.7, 4.9 Hz, H5), 3.53–3.41 (m, 2 H,
H3¢ and H6¢), 3.54 (s, 3 H, OMe), 3.52 (s, 3 H, OMe), 3.44 (s,
3 H, OMe), 3.37 (s, 3 H, OMe), 3.14 (d, 1 H, J = 2.6 Hz,
C4OH), 2.91 (d, 1 H, J = 4.7 Hz, C2OH), 1.05 (s, 9 H, 3 Me).
13C NMR (75 MHz, CDCl3): d = 167.8 (CO), 167.2 (CO),
135.5 (2 CH), 134.0, 133.1, 133.0, 132.2, 131.1, 130.6,
129.7, 139.6, 129.1, 129.0, 127.6, 127.3, 100.6, 84.1, 81.5,
78.1, 77.0, 76.4, 71.7, 70.5, 68.3, 66.7, 64.8, 64.8, 61.0, 58.0,
57.5, 54.8, 26.8 (3 C), 19.1 (C). MS (ES): m/z (%) = 894
(100) [M + 18], 899 (75) [M + 23].
(5) (a) Ogawa, T.; Sasajima, K. Carbohydr. Res. 1981, 93, 67.
(b) Anikumar, G.; Nair, L. G.; Fraser-Reid, B. Org. Lett.
2000, 2, 2587.
Synlett 2005, No. 7, 1095–1100 © Thieme Stuttgart · New York

LETTER
Phenyl 2,3,4-tri-O-acetyl-6-O-[methyl-O-(6-O-tert-
Study of the Regioselectivity of Mannoside Diol Acceptors
1099
6.0 Hz, H6¢), 4.77 (d, 1 H, J = 2.7 Hz, H1), 4.67 (d, 1 H,
J = 1.6 Hz, H1¢), 4.49 (dd, 1 H, J = 15.0, 2.7 Hz, H2), 4.22
(dd, 1 H, J = 16.0, 2.7 Hz, H6¢), 3.88 (ddd, 1 H, J = 13.3, 5.9,
3.8 Hz, H5), 3.73 (m, 2 H, 2 H6), 3.71 (dd, 1 H, J = 4.2, 1.6
Hz, H2¢), 3.59 (s, 3 H, OMe), 3.53 (dd, 1 H, J = 13.5, 13 Hz,
H4¢), 3.46 (s, 3 H, OMe), 3.44 (s, 3 H, OMe), 3.43 (s, 3 H,
OMe), 3.44–3.37 (m, 1 H, H5¢), 3.19 (dd, 1 H, J = 13.0, 4.2,
H3¢), 1.96 (s, 3 H, Me), 1.02 (s, 9 H, t-Bu). 13C NMR (75
MHz, CDCl3): d = 169.9 (CO), 168.8 (CO), 167.4 (CO),
136.0 (2 CH), 136.0 (2 CH), 134.2, 133.6, 131.9, 131.6,
130.6, 130.1, 128.5, 128.1 (2 CH), 128.0 (2 CH), 99.3 (C1,
JC-H = 168 Hz), 98.6 (C1¢, JC-H = 156 Hz), 83.1 (C3¢), 76.0
(C4¢, C2¢), 73.3 (C5¢), 71.9, 71.8, 71.6 (C3, C2 and C5), 67.6
(C4), 63.4 (C6), 62.0 (C6¢), 61.4 (OMe), 61.1 (OMe), 57.3
(OMe), 55.2 (OMe), 27.0 (3 Me), 21.1 (Me), 19.6 (C). MS
(ES): m/z (%) = 809(7) [M + 1], 826 (100) [M + 18], 831
(63) [M + 23].
butyldimethylsilyl-a-D-mannopyranos-3-yloxy)-2-
carbonylbenzoyl]-1-thio-a-D-mannopyranoside (8b):
[a]D +32.2 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d =
7.75 (d, 1 H, J = 7.8 Hz, Ar), 7.68–7.51 (m, 7 H, Ar), 7.45–
7.19 (m, 9 H, Ar), 7.14–7.11 (m, 2 H, Ar), 5.43–5.41 (m, 2
H, H1¢, H2¢), 5.35 (t, 1 H, J = 9.9 Hz, H4¢), 5.26 (m, 1 H, H3),
5.22 (dd, 1 H, J = 9.9, 3.1 Hz, H3¢), 4.65 (d, 1 H, J = 1.5 Hz,
H1), 4.54 (ddd, 1 H, J = 9.9, 7.8, 3.5 Hz, H5¢), 4.35 (dd, 1 H,
J = 7.8, 3.5 Hz, H6¢a and H6¢b), 4.20 (m, 1 H, H2), 4.0 (dt, 1 H,
J = 9.7, 2.8 Hz, H4), 3.91 (dd, 1 H, J = 10.7, 4.7 Hz, H6a),
3.85 (dd, 1 H, J = 10.7, 5.3 Hz, H6b), (m, 1 H, H5) 3.41 (s, 3
H, OMe), 3.14 (d, 1 H, J = 2.9 Hz, C4-OH), 2.88 (d, 1 H,
J = 4.7 Hz, C2-OH), 2.02 (s, 3 H, Me), 1.94 (s, 3 H, Me), 1.93
(s, 3 H, Me), 0.98 (s, 9 H, t-Bu). 13C NMR (50 MHz, CDCl3):
d = 170.0 (CO), 169.7 (2 ꢀ CO), 167.6 (CO), 167.1 (CO),
135.6, 131.8, 130.7, 129.7, 129.5, 129.4, 129.2, 128.0,
127.7, 100.7, 86.6, 77.0, 71.9, 70.9, 69.4, 69.2, 68.6, 66.9,
66.5, 64.9 (C-6), 63.9 (C-6), 54.8 (OMe), 26.8 (t-Bu), 20.7
(2 ꢀ Me), 20.6 (Me), 19.2. ESI+ [M + Na]+: 983.6; ESI– [M
+ Cl]–: 995.4.
Methyl O-(2¢,3¢,4¢-tri-O-methyl-a-d-mannopyranosyl)-
(1-4)-2-O-acetyl-6-O-tert-butyldiphenylsilyl-a-D-
mannopyranoside-3,6¢-phthalate (12a): 1H NMR (300
MHz, CDCl3): d = 7.96 (dd, 1 H, J = 7.4, 1.1 Hz, Ar), 7.75–
7.35 (m, 13 H, Ar), 5.89 (dd, 1 H, J = 10.7, 3.6 Hz, H3), 5.68
(t, 1 H, J = 2.2 Hz, H2), 5.19 (d, 1 H, J = 3.7 Hz, H1¢), 5.04
(d, 1 H, J = 9.3 Hz, H6 or H6¢), 4.72 (d, 1 H, J = 2.2 Hz, H1),
5.58 (t, 1 H, J = 10.3 Hz, H4), 4.04 (dd, 1 H, J = 10.7, 3.0, H6
or H6¢), 3.96–3.85 (m, 5 H, 2 H6 or 2 H6¢, H5¢ H5 and H4¢), 3.51
(s, 3 H, OMe), 3.42 (s, 3 H, OMe), 3.41 (s, 3 H, OMe), 3.30
(m, 1 H, H2¢), 3.27 (s, 3 H, OMe), 3.19 (dd, 1 H J = 9.3, 5.5
Hz, H3¢), 2.17 (s, 3 H, Me), 1.05 (s, 9 H, t-Bu). 13C NMR (75
MHz, CDCl3): d = 170.3 (CO), 168.2 (CO), 165.5 (CO),
135.7 (2 CH), 135.6 (2 CH), 135.2, 133.5, 133.3, 132.4,
131.2, 130.0, 129.7, 129.6, 127.6 (2 CH), 127.6 (2 CH), 98.2
(C1, JC-H = 172 Hz), 92.6 (C1¢, JC-H = 160 Hz), 79.2 (C2¢),
77.1 (C3¢), 71.1, 69.8, 69.7, 69.2, 68.8 (H4), 64.9 (CH2), 62.3
(CH2), 59.2 (OMe), 58.2 (OMe), 57.9 (OMe), 55.3 (OMe),
26.7 (3 Me), 20.7 (Me), 19.4 (C). After desilylation of 12
with TBAF and treatment with pyridine–Ac2O: 13C NMR
(75 MHz, CDCl3): d = 98.6 (C1, JC-H = 177 Hz), 93.3 (C1¢,
JC-H = 166 Hz). MS (ES): m/z (%) = 809 (2) [M + 1], 826
(100) [M + 18], 831 (40) [M + 23].
(11) Procedure for Intramolecular Glycosylation Reactions.
Method A: diester 8a was co-evaporated 3 times with
toluene, 4 Å molecular sieves were added, and the residue
was dried under vacuum for 3 h. The mixture was dissolved
in CH2Cl2 under argon, and NIS (3 equiv) was added as solid
under a stream of argon at r.t. The reaction mixture was
stirred for 48 h, then NaHCO3 and Na2S2O3 were added as
solids. The mixture was stirred at r.t. for 30 min, then filtered
through a short pad of celite, the solvent was evaporated, and
the crude product was purified by flash chromatography.
Method B: as for method A, but with the addition of 0.1
equiv of TfOAg after the addition of NIS. In this case the
reaction mixture was stirred at –40 °C for 2 h, was left to
reach r.t. over a period of 12 h, and was then stirred at r.t. for
a further 4 h.
Method C: as for method A, but with the addition of 1 equiv
of TfOAg after the addition of NIS and stirring the reaction
mixture at 0 °C for 10 min.
Methyl O-(2¢,3¢,4¢-tri-O-methyl-a-D-mannopyranosyl)-
(1-2)-6-O-tert-butyldiphenylsilyl-a-D-mannopyranoside-
3,6¢-phthalate (10a): [a]D +43 (c 0.21, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.88 (dd, 1 H, J = 6.6, 2.2 Hz, Ar),
7.58–7.33 (m, 13 H, Ar), 5.57 (d, 1 H, J = 4.4, H1¢), 5.32 (dd,
1 H, J = 10.2, 3.4 Hz, H3), 4.78–4.74 (m, 2 H, H1 and H6¢),
4.58 (m, 1 H, H2), 4.43–4.33 (m, 2 H, H6¢ and H4), 4.12 (m,
2 H, 2 H6), 3.83 (m, 1 H, H5¢), 3.78 (dt, J = 9.3, 4.1 Hz, 1 H,
H5), 3.53–3.51 (m, 1 H, H2¢), 3.50 (s, 3 H, OMe), 3.45–3.35
(m, 2 H, H4¢ and H3¢), 3.41 (s, 3 H, OMe), 3.37 (s, 3 H, OMe),
3.36 (s, 3 H, OMe), 2.82 (d, 1 H, J = 3.5 Hz, C4OH), 1.08 (s,
9 H, t-Bu). 13C NMR (75 MHz, CDCl3): d = 168.1 (CO),
168.0 (CO), 136.1 (4 CH), 133.5, 133.4, 132.9, 132.8, 132.0,
131.4, 130.5, 130.1, 129.7, 128.8, 128.1 (2 CH), 128.0 (2
CH), 101.4 (C1, JC-H = 166 Hz), 98.0 (C1¢, JC-H = 175 Hz),
80.6 (C2¢), 78.9 (C4¢), 77.6 (C3), 76.0 (C3¢), 74.6 (C5¢), 73.0
(C5), 71.8 (C2), 66.8 (C4), 66.3 (C6), 64.8 (C6¢), 60.5 (OMe),
59.1 (OMe), 58.0 (OMe), 55.1 (OMe), 28.9 (C), 27.2 (3Me).
After treatment with pyridine–Ac2O: 1H NMR (300 MHz,
CDCl3): d = 5.55 (t, 1 H, J = 10.0 Hz, H4). MS (ES): m/z
(%) = 809 (14) [M + 1], 826 (100) [M + 18], 831 (28) [M +
23].
Methyl O-(2¢,3¢,4¢-tri-O-methyl-b-D-mannopyranosyl)-
(1-4)-2-O-acetyl-6-O-tert-butyldiphenylsilyl-a-D-
mannopyranoside-3,6¢-phthalate (13a): [a]D –15 (c 0.17,
CHCl3), 1H NMR (300 MHz, CDCl3): d = 7.70–7.30 (m, 14
H, Ar), 5.69 (dd, 1 H, J = 6.3, 3.7 Hz, H3), 5.46 (t, 1 H,
J = 3.7 Hz, H2), 4.95 (dd, 1 H, J = 11.5, 2.7 Hz, H6¢), 4.78 (d,
1 H, J = 4.7 Hz, H1), 4.41 (s, 1 H, H1¢), 4.28 (dd, 1 H, J = 9.8,
6.3 Hz, H4), 4.12 (dd, 1 H, J = 11.5, 6.6 Hz, H6¢), 4.00–3.88
(m, 2 H, 2 H6), 3.85–3.78 (m, 1 H, H5), 3.52 (s, 3 H, OMe),
3.46 (s, 3 H, OMe), 3.44 (s, 3 H, OMe), 3.43 (s, 3 H, OMe),
3.50–3.26 (m, 2 H, H5¢ and H2¢), 3.34 (t, 1 H, J = 8.8 Hz, H4¢),
3.01 (dd, 1 H, J = 8.8, 2.9 Hz, H3¢), 2.07 (s, 3 H, Me), 1.09
(s, 9 H, 3 Me). 13C NMR (75 MHz, CDCl3): d = 170.7 (CO),
167.8 (CO), 167.1 (CO), 136.4 (2 CH), 136.1 (2 CH), 134.3,
133.6, 133.1, 131.8, 131.7, 131.3, 130.4, 129.6, 128.3 (2
CH), 128.2 (2 CH), 102.4 (C1¢, JC-H = 157 Hz), 99.1 (C1,
JC-H = 172 Hz), 83.8 (C3¢), 77.1 (C4¢), 76.8 (C5¢), 74.9 (C4),
74.0 (C3), 73.8 (C2¢), 72.1 (C5), 70.2 (C2), 64.1 (C6¢), 63.7
(C6), 61.8 (OMe), 61.2 (OMe), 57.9 (OMe), 55.7 (OMe),
27.1 (3 Me), 21.4 (Me), 19.7 (C). MS (ES): m/z (%) = 809
(5) [M + 1], 826 (100) [M + 18], 831 (16) [M + 23].
Methyl O-(2¢,3¢4¢-tri-O-acetyl-a-d-mannopyranosyl)-(1-
2)-a-D-mannopyranoside-3,6¢-phthalate: formed by
treatment of 10b with TBAF. 1H NMR (400 MHz, CDCl3):
d = 7.94–7.93 (m, 1 H, Ar), 7.55–7.50 (m, 3 H, Ar), 5.69 (d,
1 H, J = 4.7 Hz, H1¢), 5.33 (dd, 1 H, J = 10.6, 3.7 Hz, H3),
5.24 (dd, 1 H, J = 7.0, 3.8 Hz, H3¢), 5.06–5.00 (m, 2 H, H2¢,
Methyl O-(2¢,3¢,4¢-tri-O-methyl-b-D-mannopyranosyl)-
(1-2)-4-O-acetyl-6-O-tert-butyldiphenylsilyl-a-D-
mannopyranoside-3,6¢-phthalate (11a): [a]D –19 (c 1.07,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.78–7.62 (m, 5
H, Ar), 7.56–7.28 (m, 9 H, Ar), 5.45 (dd, 1 H, J = 16.0, 4.8
Hz, H3), 5.36 (t, 1 H, J = 15.0, H4), 5.07 (dd, 1 H, J = 16.0,
Synlett 2005, No. 7, 1095–1100 © Thieme Stuttgart · New York

1100
M. B. Cid et al.
LETTER
H4¢), 4.78 (dd, 1 H, J = 12.3 , 5.0 Hz, H6¢a), 4.73 (d, 1 H,
J = 1.3 Hz, H1), 4.46 (dd, 1 H, J = 3.5, 1.2 Hz, H2), 4.28–
4.22 (m, 2 H, H4, H6¢b), 4.17–4.14 (m, 1 H, H5¢), 3.82–3.78
(m, 2 H, H6a and H6b), 3.64 (ddd, 1 H, J = 9.7, 6.7, 3.4 Hz,
H5), 3.34 (s, 3 H, OMe), 2.81 (d, 1 H, J = 5.3 Hz, C4OH),
(14) (a) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087.
(b) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447.
(c) Ito, Y.; Ohnishi, Y.; Ogawa, T.; Nakahara, Y. Synlett
1998, 1102. (d) Fairbanks, A. J. Synlett 2003, 1945.
(e) Abdel-Rahman, A. A. H.; El Ashry El, S. H.; Schmidt, R.
R. Carbohydr. Res. 2002, 337, 195. (f) For a review of
intramolecular glycosylation see: Jung, K.-H.; Müller, M.;
Schmidt, R. R. Chem. Rev. 2000, 100, 4423.
2.01 (s, 3 H, Me), 2.00 (s, 3 H, Me), 1.78 (s, 3 H, Me). 13
C
NMR (75 MHz, CDCl3): d = 165.7 (CO), 165.5 (CO), 165.1
(CO), 163.7 (CO), 162.6 (CO), 128.7 (C), 127.7, 126.6,
126.4, 124.7 (C), 123.4, 96.6, 89.1, 72.9, 72.7, 72.5, 72.1,
68.8, 68.4, 68.3, 65.5, 64.4, 63.8, 60.6, 60.4, 57.4, 50.6
(OMe), 16.3 (2 ꢀ Me), 15.9 (Me).
Methyl O-(2¢,3¢4¢-tri-O-acetyl-a-d-mannopyranosyl)-(1-
4)-a-D-mannopyranoside-3,6¢-phthalate: formed by
treatment of 12b with TBAF. 1H NMR (400 MHz, CDCl3):
d = 7.98 (m, 1 H, Ar), 7.62 (dt, 1 H, J = 7.5, 1.5 Hz, Ar), 7.55
(dt, 1 H, J = 7.5, 1.5 Hz, Ar), 7.43 (m, 1 H, Ar), 5.70 (dd, 1
H, J = 10.7, 3.5 Hz, H3), 5.33 (dd, 1 H, J = 10.0, 3.3 Hz, H3¢),
5.33 (s, 1 H, H1¢), 5.24 (t, 1 H, J = 10.0 Hz, H4¢), 5.01 (dd, 1
H, J = 3.3, 1.5 Hz, H2¢), 4.83 (dd, 1 H, J = 11.5, 1.2 Hz, H6¢a),
4.75 (d, 1 H, J = 2.0 Hz, H1), 4.41–4.34 (m, 2 H, H2, H4),
(15) Kametani, T.; Kawamura, K.; Honda, T. J. Am. Chem. Soc.
1987, 109, 3010.
(16) Methyl 3-O-benzoyl-6-O-tert-butyldimethylsilyl-a-D-
mannopyranoside (15) was prepared starting from methyl-a-
D-mannopyranoside by silylation of the C6 hydroxyl group
followed by benzoylation of the dialkylstannylene derivative
formed by microwave irradiation. This compound had been
prepared previously by: Chung, S.-K.; Yu, S.-H. Bioorg.
Med. Chem. Lett. 1996, 6, 1461.
(17) Intermolecular glycosylations were carried out following
procedure B, previously described for an intramolecular
glycosylation reaction using 1 equiv each of the
corresponding glycosyl donor and acceptor, at the
temperature and for the reaction times specified in the text.
The structures of all oligosaccharides were assigned by
means of 2D NMR spectroscopy (COSY, HMQC) and mass
spectrometry. Regioisomers were identified based on
variations in the 1H chemical shift of the free hydroxyl
groups after acetylation. The assignment of the
4.20 (br t, 1 H, J = 10.0 Hz, H5¢), 3.95–3.87 (m, 3 H, H6¢b
,
H6a, H6b), 3.83– 3.77 (m, 1 H, H5), 3.38 (s, 3 H, OMe), 2.16
(s, 3 H, Me), 2.10 (s, 3 H, Me), 2.08 (s, 3 H, Me), 2.07 (s, 3
H, Me), 2.11 (s, 3 H, Me), 2.06 (s, 3 H, Me), 1.96 (s, 3 H,
Me). 13C NMR (75 MHz, CDCl3): d = 166.0 (CO), 165.8
(CO), 165.3 (CO), 164.2 (CO), 160.7 (CO), 130.5 (C),
128.3, 125.8, 125.6, 123.1, 122.9 (C), 95.8, 87.5, 66.5, 66.4,
66.2, 66.0, 64.4, 64.2, 63.5, 61.7, 59.2 (C6), 57.3 (C6), 51.1
(OMe), 16.4 (Me), 16.2 (Me), 16.1 (Me). After treatment
with pyridine–Ac2O: 1H NMR (300 MHz, CDCl3): d = 5.56
configuration (a or b) was based on the CH coupling
constant at the anomeric center (JCH ≈ 160Hz for b-
mannosides and JCH ≈ 170 Hz for a-mannosides).
(18) Compound 19 was synthesized from methyl-a-D-
mannopyranoside under standard benzoylation conditions in
the presence of two equivalents of benzoyl chloride. This
methylmannoside 19 had been previously prepared by:
Meyers, H. V.; Ojika, M.; Wiesler, W. T.; Nakanishi, K.
Carbohydr. Res. 1990, 197, 15.
(m, 1 H, H2). 13C NMR (75 MHz, CDCl3): d = 98.2 (JC-H
170 Hz), 91.7 (JC-H = 167 Hz).
(12) (a) Ziegler, T.; Lemanski, G. Angew. Chem. Int. Ed. 1998,
3129. (b) Ziegler, T.; Lemanski, G. Eur. J. Org. Chem. 1998,
163. (c) Ziegler, T.; Lemanski, G.; Rakoczy, A. Tetrahedron
Lett. 1995, 36, 8973.
(13) (a) Abel-Rahman, A. A.-H.; Jonke, S.; El Ashry El, S. H.;
Schmidt, R. R. Angew. Chem. Int. Ed. 2002, 41, 2972.
(b) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(c) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J.
Am. Chem. Soc. 2001, 123, 8477.
=
(19) Alais, J. O.; Veyrières, A. J. Chem. Soc., Perkin Trans. 1
1981, 377.
Synlett 2005, No. 7, 1095–1100 © Thieme Stuttgart · New York