Efficient Intramolecular Glycosylation Supported by a Rigid Spacer

Article abstract of DOI:10.1021/jo990132e

The m-xylylene moiety was employed as rigid spacer in intramolecular glycoside bond formation. Fifteen-membered macrocycle formation starting from 6-O-linked donor and 6- and 4-O-linked acceptor (5a,b, 6b) led exclusively to β(1-4)- and β(1-6)-linked compounds 7β and 8β, respectively, which gave cellobioside and gentiobioside derivatives. The glycosylation yields could be improved by 14-membered macrocycle formation. In the four cases studied, the donor was 6-O-linked to the spacer. For the acceptor linkage to the spacer and the accepting hydroxy group, relative D-/L-threo- and D-/L-erythro-arrangements were chosen. Standard glycosylation conditions led in three cases (13, 14, 23) only to β-linkage in high yield (16β, 17β, 25β). For the transformation of 24, having a D-erythro-arrangement in the acceptor moiety, the α-anomer 26α was preferentially obtained. Limitation of the conformational space of the donor and the acceptor as in 31, which is stereochemically identical with 24, led to the corresponding α-glycoside 32α in 87% yield. Synthesis of a pseudo mirror image of 23 [having 6-(D)/3-(D-threo)-arrangement], namely 35, having 3(L)/6-(L-threo)-arrangement of the donor and acceptor moieties, expectedly gave only α-glycoside 36α in very high yield. Thus, the efficiency and versatility of this conceptual approach to intramolecular glycoside bond formation is exhibited.

Full text of DOI:10.1021/jo990132e

6190
J . Org. Chem. 1999, 64, 6190-6201
Efficien t In tr a m olecu la r Glycosyla tion
Su p p or ted by a Rigid Sp a cer
Matthias Mu¨ller, Ursula Huchel, Armin Geyer, and Richard R. Schmidt*
Fakulta¨t Chemie, Universita¨t Konstanz, Fach M 725, D-78457 Konstanz, Germany
Received J anuary 26, 1999
The m-xylylene moiety was employed as rigid spacer in intramolecular glycoside bond formation.
Fifteen-membered macrocycle formation starting from 6-O-linked donor and 6- and 4-O-linked
acceptor (5a ,b, 6b) led exclusively to â(1-4)- and â(1-6)-linked compounds 7â and 8â, respectively,
which gave cellobioside and gentiobioside derivatives. The glycosylation yields could be improved
by 14-membered macrocycle formation. In the four cases studied, the donor was 6-O-linked to the
spacer. For the acceptor linkage to the spacer and the accepting hydroxy group, relative D-/L-threo-
and D-/L-erythro-arrangements were chosen. Standard glycosylation conditions led in three cases
(13, 14, 23) only to â-linkage in high yield (16â, 17â, 25â). For the transformation of 24, having a
D-erythro-arrangement in the acceptor moiety, the R-anomer 26R was preferentially obtained.
Limitation of the conformational space of the donor and the acceptor as in 31, which is
stereochemically identical with 24, led to the corresponding R-glycoside 32R in 87% yield. Synthesis
of a pseudo mirror image of 23 [having 6-(D)/3-(D-threo)-arrangement], namely 35, having 3(L)/6-
(L-threo)-arrangement of the donor and acceptor moieties, expectedly gave only R-glycoside 36R in
very high yield. Thus, the efficiency and versatility of this conceptual approach to intramolecular
glycoside bond formation is exhibited.
Glycosyl transfer within the active site of an enzyme
are mainly based on attachment of the acceptor via a
spacer Y to the 2-hydroxy group of the donor3-10 (“func-
tional-substituent-based approach”) or, alternatively, to
the leaving group of the donor11-14 (“leaving-group-based
approach”), and varying results have been obtained. The
functional-substituent-based approach, generating five-
membered cyclic transition states (Y ) SiR2, CR2),3,5-7
resulted generally in good anomer selectivity. However,
the anomer selectivity is dependent on the configuration
of the 2-hydroxy group (â-2-OH f â-glycoside; R-2-OH
f R-glycoside), and depending on the spacer type, this
process may even violate the ring closure rules,15 thus
favoring unwanted competing reactions. With larger
spacer systems at the 2-hydroxy group (Y ) CO-CH2-
CH2-CO-)8 or at any other position of the donor,9,10 as
a result of missing steric constraints, often not only was
the anomer selectivity found to be low but also the yields
were modest. For some cases of leaving-group-based
reactions, an intermolecular reaction course could even
be verified, though model considerations favored in-
tramolecularity of the process.13
can be regarded as an intramolecular process in which
the anomeric center of the glycosyl donor and the
accepting moiety are held in close proximity to ensure
regio- and diastereoselective glycoside bond formation
(Scheme 1).1,2 To enforce a similar in vitro reaction
course, various approaches to intramolecular glycoside
bond formation have been studied.3-14 These approaches
(1) (a) Schmidt, R. R.; Dietrich, H. Angew. Chem. 1991, 109, 1348-
1349; Angew. Chem., Int. Ed. Engl. 1991, 30, 1328-1329. (b) Schmidt,
R. R.; Frische, K. Bioorg. Med. Chem. Lett. 1993, 3, 1747-1750. (c)
Amann, F.; Schaub, C.; Mu¨ller, B.; Schmidt, R. R. Chem. Eur. J . 1998,
4, 1106-1115.
(2) (a) Sinnott, L. M. Chem. Rev. 1990, 90, 1171-1202. (b) Legler,
G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319-384.
(3) Barresi, F.; Hindgaul, O. J . J . Am. Chem. Soc. 1991, 113, 9376-
9377; Synlett 1992, 759-761; Can. J . Chem. 1994, 72, 1447-1465.
(4) Preuss, R.; J ung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992,
377-382.
(5) Stork, G.; Kim, G. J . J . Am. Chem. Soc. 1992, 114, 1087-1088.
(6) Bols, M. J . Chem. Soc., Chem. Commun. 1992, 913-914; Acta
Chem. Scand. 1996, 50, 931-937.
(7) Ito, Y.; Ogawa, T. Angew. Chem. 1994, 106, 1843-1845; Angew.
Chem., Int. Ed. Engl. 1994, 33, 1765-1767; J . Am. Chem. Soc. 1997,
119, 5562-5566.
(8) (a) Ziegler, T.; Lau, R. Tetrahedron Lett. 1995, 36, 1417-1420.
(b) Lau, R.; Schu¨le, G.; Schwaneberg, U.; Ziegler, T. Liebigs Ann. 1995,
1745-1754. (c) Schu¨le, G.; Ziegler, T. Liebigs Ann. 1996, 1599-1607.
(d) Ziegler, T.; Lemanski, G. Eur. J . Org. Chem. 1998, 163, 3-170;
Angew. Chem. 1998, 110, 3367-3369; Angew. Chem., Int. Ed. Engl.
1998, 37, 3129-3132.
(9) (a) Valverde, S.; Gomez, A. M.; Hernandez, A.; Herradon, B.;
Lopez, J . C. J . Chem. Soc., Chem. Commun. 1995, 2005-2006. (b)
Valverde, S.; Gomez, A. M.; Lopez, J . C.; Herradon, B. Tetrahedron
Lett. 1996, 37, 1105-1108.
(10) Yamada, H.; Imamura, K.; Takahashi, T. Tetrahedron Lett.
1997, 38, 391-394.
The close proximity between glycosyl donor and gly-
cosyl acceptor in the active site of an enzyme is generated
by specific binding between the enzyme and the sub-
strate, leading to a structurally rigid array composed of
large rings that enforce (regio- and) diastereoselective
glycoside bond formation.16 To extend this concept to face-
selective intramolecular glycoside bond formation, a rigid
spacer concept was proposed by us (Scheme 1),17 which
(11) (a) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249-
1259. (b) Schmidt, R. R. In Carbohydrates - Synthetic Methods and
Applications in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami,
T., Eds.; Kodanasha Ltd.: Tokyo, 1992; 68-88. (c) Behrendt, M. E.;
Schmidt, R. R. Tetrahedron Lett. 1993, 34, 6733-6736.
(12) Iimori, T.; Shibazaki, T.; Ikegami, S. Tetrahedron Lett. 1996,
37, 2267-2270.
(14) Mukai, C.; Itoh, T.; Hanaoka, M. Tetrahedron Lett. 1997, 38,
4595-4598.
(15) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-736;
738-741.
(16) In a way, this phenomenon is also effective in the intramolecu-
lar transglycosidation in cyclodextrin formation.
(17) Huchel, U.; Schmidt, R. R. Tetrahedron Lett. 1998, 39, 7693-
7694.
(13) Scheffler, G.; Schmidt, R. R. Tetrahedron Lett. 1997, 38, 2943-
2946; J . Org. Chem. 1999, in press.
10.1021/jo990132e CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/29/1999

Intramolecular Glycosylation Supported by a Rigid Spacer
Sch em e 1
J . Org. Chem., Vol. 64, No. 17, 1999 6191
Ta ble 1. Tr a n sfor m a tion of 5a ,b in to 7â
NaH as base and 15-crown-5 as supporting reagent into
6-O-linked derivatives 3a and 3b, respectively (Scheme
3). Treatment of known 4,6-O-unprotected glucoside 420
with dibutyltin oxide in toluene and then reaction with
3a ,b in the presence of tetrabutylammonium iodide
afforded the desired 6a,6b-O-linked intermediates 5a and
5b (5a : 41%; 5b: 64%). Correspondingly, direct reaction
of 3b with 4 in the presence of NaH and 15-crown-5 gave,
besides 5b, the 4a,6b-O-linked intermediate 6b. Activa-
tion of 5a with N-iodo-succinimide (NIS, 1.3 equiv) and
trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.1
equiv)21 in CH2Cl2 at room temperature afforded the
desired (1-4)-linked disaccharide moiety, which is part
of the 15-membered macrocycle 7â, as the only mono-
meric product (Table 1). The â-configuration could be
assigned with the help of NMR data (2b-H: J 1,2 ) 7.4
Hz). Activation of the pentenyloxy group in 5b with NIS/
TMSOTf 19 afforded also 7â. The yield is, as expected,
concentration-dependent (Table 1), and intermolecular
oligomer formation seems to be the competing reaction.
Thus, it is exhibited that diastereofacial control in the
intramolecular glycosylation step is independent of the
glycosyl donor configuration and even at room temper-
ature one anomer is exclusively generated. Hydrogenolyt-
ic O-debenzylation of 7â and then O-acetylation afforded
known cellobioside 9â,22 which was structurally assigned
by homo- and heteronuclear NMR spectra.
conc
yield of
7â (%)
educt (mol/L)
reaction conditions
5a
0.01
NIS (1.3 equiv), TMSOTf (0.1 equiv),
CH2Cl2, room temperature
65
5b
0.1
NIS (1.3 equiv), TMSOTf (0.1 equiv),
Toluene, room temperature
46
0.05
0.01
56
63
as a result of geometrical constraints should lead to the
desired diastereocontrol.
This concept can be now verified with the m-xylylene
residue as rigid spacer.17 Attachment of the donor, for
instance, via the 6-hydroxy group of D-glucose corre-
sponding to â-face attachment [6(â)] (Scheme 2), can be
readily performed. In the acceptor, any cyclic 1,3- or 1,2-
threo- or -erythro-diol arrangement, structural entities
common to all sugar residues, will allow for attachment
to the spacer and will also provide the desired accepting
hydroxy group. As shown below, this design keeps the
reacting centers at proper distance and enforces the
desired diastereoselection in the glycosylation step via
the formation of macrocyclic rings (14- and 15-membered
rings) from which the products can be readily liberated.
Resu lts a n d Discu ssion
Gen er a tion of 15-Mem ber ed Ma cr ocycles. For the
investigation of this concept, ethyl â-thioglucoside 1a 18
and 4-penten-1-yl glucoside 1b (R:â ) 9:1)19 were trans-
formed with R,R′-dibromoxylene (2) in the presence of
(19) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U. E.; Fraser-Reid,
B. J . Am. Chem. Soc. 1988, 110, 5583-5584. (b) Hondier, S.; Vottero,
P. J . A. Angew. Chem. 1994, 106, 365-367; Angew. Chem., Int. Ed.
Engl. 1994, 33, 354-355.
(20) Bell, D. J .; Lorber, J . J . Chem. Soc. 1940, 453-455.
(21) (a) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J . H.
Tetrahedron Lett. 1990, 31, 1331-1334. (b) Konradsson, P.; Udodon,
U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313-4316.
(18) Garegg, P. J .; Kvarnstro¨m, I.; Niklasson, A.; Svensson, S. C. T.
J . Carbohydr. Chem. 1993, 12, 933-935.

6192 J . Org. Chem., Vol. 64, No. 17, 1999
Mu¨ller et al.
Sch em e 2
Detailed NMR studies23 of compound 7â and molecular
mechanics simulations (MM+, HyperChem) showed that
the generally observed syn â(1-4)-arrangement of the
glucopyranose residues a and b is readily accessible
(Figure 1). There is also some flexibility between the
benzene ring on one side and the disaccharide moiety on
the other side. Thus, â-face attachment of the glycosyl
donor at the 6-position to the spacer which is linked via
the 6-hydroxy group to a 5,4-L-threo-arranged acceptor
moiety as in 5 [designation: 6(â)/6(5,4-L-threo)-arrange-
ment; see Table 2] provides â-face selective glycosylation.
However, also from model considerations, high confor-
mational flexibility in this system can be deduced.
Therefore, the intermolecular reaction can compete with
the formation of the 15-membered ring.
Not surprisingly, a similar result is obtained when the
attachment of the acceptor to the spacer is reversed as
in 6b, i.e., the donor/spacer combination 3b is linked via
the 4-hydroxy group to a 4,6-O-unprotected L-threo-
arranged acceptor to yield 6b [having 6(â)/4(4,5-L-threo)-
arrangement]. Activation of 6b with NIS/TMSOTf in
toluene at room temperature afforded the 15-membered
ring â(1-6)-linked 8â in 72% yield. The conformational
assignment (Figure 1) exhibited again, as observed for
7â, some flexibility between the benzene ring and the
disaccharide moiety.23 Hydrogenolytic O-debenzylation of
8â and then O-acetylation afforded known gentiobioside
derivative 10â,24 which was structurally assigned by
homo- and heteronuclear NMR spectra.
Gen er a tion of 14-Mem ber ed Ma cr ocycles. From
the preceding results, it can be concluded that only â-face
selective ring closure to a 15-membered ring is observed
for a system that has the m-xylylene residue as rigid
spacer, â-face attachment of the donor, and L-threo-1,3-
diol arrangement in the acceptor moiety. However, the
product yields of ∼70% in this system are not yet
satisfactory. On the basis of conformational studies with
7â and 8â,23 ring closure to a 14-membered ring was
envisaged to further limit the conformational space of the
donor and/or the acceptor moiety and to favor the
intramolecular reaction course. This idea was also sup-
ported by model considerations, which exhibited practi-
cally strain-free access to 14-membered rings that contain
the m-xylylene residue as rigid spacer.
To this end, donor/spacer-linked intermediate 3a was
treated with 2,3-O-unprotected glucose derivative 1125 in
the presence of NaH as base in DMF, affording mainly
2-O-linked compound 13 (Scheme 4; 2-O/3-O-attachment
) 5:1), which had 6(â)/2(2,3-L-threo)-arrangement. Gly-
cosylation under standard conditions furnished 14-
membered macrocycle 16â in 81% yield, thus resulting
in the desired high glycoside yield combined with exclu-
sive â-selectivity. Conformational studies with 16â, based
on NMR experiments and molecular mechanics simula-
tions (Figure 2), demonstrated that the glycosidic linkage
possesses the unusual anti-conformation.23 Hydrogenolyt-
ic O-debenzylation of 16â and then O-acetylation afforded
(22) Gi, C. T.; Ishihara, H.; Tejima, S. Chem. Pharm. Bull. 1978,
26, 1570-1575.
(23) (a) 1H and 13C assignments by DQF-COSY and HMQC spectra.
For details, see: Geyer, A.; Huchel, U.; Schmidt, R. R. Magn. Reson.
Chem. 1999, 37, 145-148. (b) The figures show energy minized average
conformations of a 100 ps molecular dynamics simulation. J -Coupling-
derived torsion angles and ROE-derived distances served as experi-
mental restraints. Ten snapshots from each calculation are also shown.
Three overlayed structures of 32R differ in the exocyclic torsion of ring
b, where conformational averaging was observed. NMR and modelling
procedures are described in ref 23a.
(24) Kochetkov, N. K.; Klimov, E. M.; Malysheva, N. N.; Demchenko,
A. V. Carbohydr. Res. 1991, 212, 77-91.
(25) Hall, D. M. Carbohydr. Res. 1980, 86, 158-160.

Intramolecular Glycosylation Supported by a Rigid Spacer
J . Org. Chem., Vol. 64, No. 17, 1999 6193
Sch em e 3
F igu r e 1. Energy minimized average conformations of 7â and
8â.23b
Ta ble 2. Gycosid e Bon d F or m a tion Resu lts
results
rel config
donor/acceptor
ring
compd size
yield
(%)
compd
linkage
5a ,b
6b
13
15
23
24
31
35
6(â)/6(5,4-L-threo)
6(â)/4(4,5-L-threo)
6(â)/2(2,3-L-threo)
7â
15 Glcâ(1-4)Glc
15 Glcâ(1-6)Glc
14 Glcâ(1-3)Glc
14 Glcâ(1-3)Gal
14 Glcâ(1-4)Glc
14 GlcR/â(1-4)Gal
14 GlcR(1-4)Gal
14 GlcR(1-4)Glc
65
72
81
84
84
77
87
93
8â
16â
6(â)/4(4,3-L-erythro) 17â
6(â)/3(3,4-D-threo)
25â
6(â)/3(3,4-D-erythro) 26r,â
6(â)3(3,4-D-erythro) 32r
3(â)/6(5,4-L-threo)
36
O-debenzylation of 17â and then O-acetylation led to
known â(1-3)-linked disaccharide 19â,27 which was struc-
turally assigned by homo- and heteronuclear NMR
spectra.
D-threo-Linkage in the acceptor moiety could also be
readily constructed from 3a : reaction with 3-O-unpro-
tected glucose derivative 2028 in the presence of NaH as
base and 15-crown-5 as supporting agent afforded the 3a-
O-alkylated intermediate 22 (Scheme 5). Ensuing reduc-
tive opening of the benzylidene group with NaCN‚BH3
in the presence of HCl in THF29 furnished 4a-O-
unprotected intermediate 23, which had the desired 6(â)/
3(3,4-D-threo)-arrangement. The same sequence of reac-
tions as described above led to exclusive â(1-4)-linkage,
affording 25â in 84% yield, and finally to known cello-
bioside 9â.22 The conformation of 25â depicted in Figure
223 shows syn-arrangement for the glycosidic linkage and
the limited flexibility of the benzene ring relative to the
disaccharide moiety.
known â(1-3)-linked disaccharide 18â,26 which was struc-
turally assigned by homo- and heteronuclear NMR
spectra.
Besides the 6(â)/2(L-threo)-arrangement, as in 14, the
other three stereochemically possible 1,2-diol arrange-
ments also were investigated in order to elucidate the
influence of the donor attachment (R and â) versus the
influence of the relative acceptor configuration (D,L-threo,
-erythro) on the facial selectivity in the glycosylation step.
To this end, 3a was treated with 4-O-unprotected galac-
tose derivative 12 in the presence of NaH as base and in
DMF as the solvent to afford 4a-O-linked intermediate
14; reaction with DDQ in CH2Cl2 furnished 3a-O-
unprotected 15, which had 6(â)/4(4,3-L-erythro)-arrange-
ment. Glycosylation under standard conditions afforded
the glycosidic linkage in 83% yield, and only â-product
17â was obtained. The preferred conformation is depicted
in Figure 2, exhibiting syn-conformation for the glycosidic
linkage in the 14-membered ring, which seems to be
accessible without any steric strain. Hydrogenolytic
Finally, D-erythro-linkage in the acceptor moiety was
investigated. To this end, 3,4-O-unprotected galactose
intermediate 2130 was treated with dibutyltin oxide in
toluene, and then 3a was added to furnish the 3-O-
linkage, thus providing the desired 6(â)/3(3,4-D-erythro)-
(27) Wozney, Y. V.; Backinowsky, L. V.; Kochetkov, N. K. Carbohydr.
Res. 1979, 73, 282-286.
(28) Qin, H.; Grindley, T. B. J . Carbohydr. Chem. 1996, 15, 95-
108.
(29) Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97-101.
(30) Schneider, J .; Lee, Y. C.; Flowers, H. M. Carbohydr. Res. 1974,
36, 159-166.
(26) Takeo, K. Carbohydr. Res. 1977, 59, 258-260.

6194 J . Org. Chem., Vol. 64, No. 17, 1999
Mu¨ller et al.
Sch em e 4
arranged intermediate 24. Already, model considerations
had exhibited that the â-face of the donor is less acces-
sible than the R-face, and this was proven by the
experiment: application of standard glycosylation condi-
tions to 24 led to glycoside bond formation in 77% yield.
However, for the first time a mixture of R/â-anomers
26R,â was obtained (R:â ) 3:1). The structural assign-
ments were supported by hydrogenolytic O-debenzylation
and then O-acetylation, yielding R/â(1-4)-linked disac-
charides 27R and 27â.
The four sterically different systems exhibit that high
glycosylation yields can be readily obtained in 14-
membered ring formation and that 6-(â-face)-attachment
of the donor to the m-xylylene residue as rigid spacer
system yields, for D- and L-threo- and L-erythro-attach-
ment of the acceptor, exclusively â-linkage; only for
D-erythro-attachment is preferential R-linkage formation
observed. These promising results led to two further
questions: (i) Can the glycosylation yields be increased
by further limiting the conformational space of the donor
and acceptor moieties? (ii) Can R- vs â-glycoside bond
formation in a 14-membered ring system be reached by
formally inverting the relative attachment of the donor
and the acceptor moieties to the rigid spacer system?
Answers to these questions are given below.
of the xylylene residue. Because of their geometry, phenyl
rings seemed to be particularly attractive as substituents
because they limit the conformational space of the
methylene groups but still permit SN2 reactions at the
methylene carbons to construct the required starting
materials. The envisaged spacer could be readily obtained
from known dimethyl-m-terphenyl 28;31 bromination with
N-bromo-succinimide (NBS) gave bis(bromomethyl)-
derivative 29 as the required precursor.
Investigation of the 6(â)/3(3,4-D-erythro)-arrangement
as in 24 seemed particularly attractive for this study
because in this case not only was an R/â-product mixture
obtained but also the yield was somewhat lower com-
pared with the other cases of 14-membered ring forma-
tion. Therefore, 29 was reacted with 1a in the presence
of NaH as base to afford 6-O-alkylated product 30
(Scheme 7). Treatment of 21 with dibutyltin oxide in
toluene, and then with 30, afforded the desired 3a-O-
alkylation product 31, which is structurally related to 24.
Glycosylation studies with 31 under the same conditions
not only led to a higher yield (87%) but also greatly
improved the face selectivity; only R-product 32R was
obtained. Hydrogenolytic O-debenzylation and then O-
acetylation afforded as expected 27R, and 28 could also
be recovered. Results of the conformational studies of 32R
are depicted in Figure 3.23 They exhibit syn-conformation
for the glycosidic part; 32R is the only cyclic compound
which exhibits rotational isomerism about the exocyclic
Lim ita tion of th e Con for m a tion a l Sp a ce of th e
Don or a n d Accep tor Moieties. The m-xylylene spacer
provides free rotation around the benzene carbon/meth-
ylene bonds, thus permitting conformations where the
reacting centers are far apart. Obviously, this large
conformational space can be reduced as shown in Scheme
6 with the help of substituents in the 4- and 6-position
(31) Chardonnens, L.; Chardonnens, H. Helv. Chim. Acta 1958, 41,
2109-2111.

Intramolecular Glycosylation Supported by a Rigid Spacer
J . Org. Chem., Vol. 64, No. 17, 1999 6195
To test this hypothesis, 2 was reacted with 3-O-
unprotected thioglycoside 33, in the presence of NaH as
base, to afford 34 (Scheme 9). For the acceptor attach-
ment, 4,6-O-unprotected glucoside 420 was treated with
dibutyltin oxide in toluene, and then 34 was added to
give the desired intermediate 35. Glycosylation under
standard conditions gave exclusively the R-anomer 36R
in 93% yield. Results of the conformational studies of 36R
are shown in Figure 3. The unexpectedly weak transg-
lycosidic NOE corresponds to a gauche orientation of both
glycosidic angles with φ (H1-C1-O4-C4) ) -67° and
ψ (C1-O4-C4-H4) ) -55°. Further structural proof for
36R was obtained from hydrogenolysis and then O-
acetylation, leading to known maltoside 9R,32 which was
structurally assigned by homo- and heteronucleoar NMR
spectra.
Con clu sion
The rigid m-xylylene spacer permits, at room temper-
ature, highly face-selective and efficient intramolecular
glycoside bond formation. This is particularly noteworthy
because high anomeric control is generally not observed
for glucopyranosyl and galactopyranosyl donors at room
temperature unless there is anchimeric assistance. In the
high yielding 14-membered ring formation, competing
intermolecular glycoside bond formation plays, if at all,
only a minor role. As exhibited, further potential for this
intramolecular reaction is available by further limiting
the conformational space of the glycosyl donor and
acceptor moiety. Formal inversion of the relative stere-
ochemical attachment of the donor and the acceptor
moiety yields either R- or â-glycosides, as desired. There-
fore, a powerful methodology for oligosaccharide synthe-
sis in general can be based on this new conceptual
approach.
Exp er im en ta l Section
F igu r e 2. Energy minimized average conformations of 16â,
17â, and 25â.23b
Solvents were purified in the usual way; boiling range of
petroleum ether: 35-60 °C. Melting points are uncorrected.
Thin-layer chromatography (TLC): plastic sheets, silica gel
60 F254 (layer thickness 0.2 mm). Flash chromatography: silica
gel (30-60 µm). Optical rotations: 1 dm cell, 20 °C. NMR
spectra: DQF-COSY, HMQC, and compensated ROESY spec-
tra were acquired on a 600 MHz NMR spectrometer at 300 K,
internal standard tetramethylsilane (TMS). MALDI-MS: posi-
tive mode, 2,5-dihydroxybenzoic acid (DHB) matrix; FAB-
MS: positive mode, 3-nitrobenzyl alcohol (NBOH)/NaI matrix.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
3a ,b. To a solution of 2 (528 mg, 2.0 mmol) and 1a ,b (1.0 mmol)
in dry dichloromethane (10 mL) at -17 °C are added 15-
crown-5 (220 µL, 1.1 mmol) and sodium hydride (26 mg, 1.1
mmol), and the mixture is stirred for 8 h at -17 °C. Evapora-
tion of the solvent and chromatography (toluene/ethyl acetate
30:1) of the residue affords compounds 3a ,b.
Eth yl 2,3,4-Tr i-O-ben zyl-6-O-(3-br om om eth ylben zyl)-
1-th io-â-D-glu cop yr a n osid e (3a ). Treatment of compound
1a 18 (495 mg) according to the general procedure affords 3a
(280 mg, 41%) as a colorless oil. TLC (toluene/ethyl acetate
6:1): Rf 0.68; [R]D +16 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): δ 1.34 (t, 3 H, SCH2CH3), 2.68-2.88 (m, 2 H, SCH2-
CH3), 3.41-3.80 (m, 6 H, 2-H, 3-H, 4-H, 5-H, 2 6-H), 4.42-
4.93 (m, 11 H, 1-H, 2 7′-H, 2 8′-H, 3 PhCH2), 7.16-7.41 (m, 19
H, 3 Ph, 2′-H, 4′-H, 5′-H, 6′-H); FAB-MS: m/z 699 (M + Na)+.
Anal. Calcd for C37H41BrO5S (677.71): C, 65.58; H, 6.09.
Found: C, 65.28; H, 6.12.
5-6-bond of ring b. The main conformation (50%) popu-
lates the gg rotamer (3J 5b-6bproR ) 5.9 Hz, 3J 5b-6bproS ) 7.0
Hz).
F or m a l In ver sion of th e Ster eoch em istr y of Do-
n or a n d Accep tor Atta ch m en t to th e Rigid Sp a cer .
Inversion of the relative stereochemistry of acceptor
attachment can be obtained by changing the attachment
site in a 1,2- or 1,3-erythro-diol system or by choosing
enantiomeric threo-1,2- or 1,3-diol arrangement. For
stereochemically different donor attachment, formally
two alternatives exist: either inversion of the configu-
ration of the attachment site is performed, thus going
from â-face to R-face attachment and vice versa, or the
face of the attachment is retained. However, the attach-
ment site is on the opposite half of the pyranose plane.
This pseudo-inversion of the relative stereochemistry is
exhibited in Scheme 8 where, for instance, a 6(â)/3(D-
threo)-arrangement should lead via transition state Aq
to the â-linked disaccharide. This experiment was already
performed by the transformation of 23 into 25â, furnish-
ing only â-linkage in 84% yield. Changing the donor
attachment site to the 3(â)-oxygen and selecting for the
acceptor attachment an L-threo-1,3-diol system, to retain
14-membered ring formation, should then lead via tran-
sition state Bq to the R-anomer.
(32) Dick, W. E., J r.; Weisleder, D.; Hodge, J . E. Carbohydr. Res.
1971, 18, 115-123.

6196 J . Org. Chem., Vol. 64, No. 17, 1999
Mu¨ller et al.
Sch em e 5
Sch em e 6
Sch em e 7
4-P en ten -1-yl 2,3,4-Tr i-O-ben zyl-6-O-(3-br om om eth yl-
ben zyl)-r/â-D-glu cop yr a n osid e (3b). Treatment of com-
pound 1b19 (518 mg) according to the general procedure affords
3b (544 mg, 78%) as a colorless oil. TLC (toluene/ethyl acetate
6:1): Rf 0.69; [R]D +24 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): δ 1.69 (m, 2 H, CH2CH2CH), 2.12 (m, 2 H, CH2CH2-
CH2), 3.39-3.81 (m, 7 H, 2-H, 3-H, 4-H, 5-H, 2 6-H, 1/2 OCH2-
CH2), 3.96 (m, 1 H, 1/2 OCH2CH2), 4.45-5.08 (m, 13 H, 1-H,
2 7′-H, 2 8′-H, 3 PhCH2, CH2CHdCH2), 5.81 (m, 1 H, CH2CHd
CH2), 7.11-7.43 (m, 19 H, 3 Ph, 1′-H, 3′-H, 4′-H, 5′-H). Anal.
Calcd for C40H45BrO6 (701.69): C, 68.47; H 6.46. Found: C,
68.72; H, 6.37.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
5a ,b. Compound 420 (374 mg, 1.0 mmol) and dibutyltin oxide
(274 mg, 1.1 mmol) are refluxed in toluene (10 mL) for 3 h in
an apparatus for the azeotropic removal of water. Toluene (5
mL) is distilled off, and the solution is cooled to room
temperature. Tetrabutylammonium iodide (406 mg, 1.1 mmol)
and 3a ,b (1.0 mmol) are added. Stirring for 6 h at 90 °C,
evaporation of the solvent, and chromatography (toluene f
toluene/ethyl acetate 6:1) of the residue affords 5a ,b.
Eth yl 6-O-[3-(Meth yl 2,3-d i-O-ben zyl-r-D-glu cop yr a n o-
sid e-6-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-1-th io-â-D-
glu cop yr a n osid e (5a ). Treatment of compound 3a (678 mg)

Intramolecular Glycosylation Supported by a Rigid Spacer
J . Org. Chem., Vol. 64, No. 17, 1999 6197
Sch em e 9
F igu r e 3. Energy minimized average conformations of 32R
and 36R.23b
Sch em e 8
and then the mixture is stirred for 5 min at room temperature.
Compound 3b (702 mg, 1.0 mmol) in dichloromethane (5 mL)
is added and stirred for 2 h. The solution is neutralized with
an ion-exchange resin (Amberlite IR 120, H+ form), filtered,
and concentrated in vacuo. Chromatography (toluene/ethyl
acetate 7:1) of the residue affords 5b (448 mg, 45%) and 6b
(150 mg, 15%) as a colorless oil. TLC (toluene/ethyl acetate
2:1): Rf 0.45; [R]D +34 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): δ 1.69 (m, 2 H, CH2CH2CH), 2.12 (m, 2 H, CH2CH2-
CH2), 3.43 (s, 3 H, OCH3), 3.49-3.82 (m, 13 H, 2a-H, 3a-H,
4a-H, 5a-H, 2 6a-H, 2b-H, 3b-H, 4b-H, 5b-H, 2 6b-H, 1/2 OCH2-
CH2), 3.95 (m, 1 H, 1/2 OCH2CH2), 4.36-5.08 (m, 18 H, 1a-H,
1b-H, 2 7′-H, 2 8′-H, 5 PhCH2, CH2CHdCH2), 5.79 (m, 1 H,
CH2CHdCH2), 7.08-7.48 (m, 29 H, 5 Ph, 2′-H, 4′-H, 5′-H, 6′-
H); MALDI-MS: m/z 1018 (M + Na)+. Anal. Calcd for
C61H70O12 (995.22): C, 73.61; H, 7.09. Found: C, 73.68; H, 7.10.
Meth yl 6,6′-O-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-â-D-glu -
cop yr a n osyl)-(1′f4)-2,3-d i-O-b en zyl-r-D-glu cop yr a n o-
sid e (7â). (a) Trimethylsilyl trifluoromethanesulfonate (5 µL)
is added under argon at room temperature to a solution of 5b
(100 mg, 0.1 mmol) and N-iodosuccinimide (29 mg, 0.13 mmol)
in dry toluene (10 mL); the mixture is stirred for 15 min. The
solution is neutralized with triethylamine, sodium dithionite
is added, and then stirring is continued until the solution is
colorless. The solid is filtered off, and the solution is concen-
trated in vacuo. Chromatography (toluene f toluene/ethyl
acetate 8:1) of the residue affords 7â (57 mg, 63%) as a colorless
oil.
according to the general procedure affords 5a (621 mg, 64%)
as a colorless oil. TLC (toluene/ethyl acetate 6:1): Rf 0.29; [R]D
+26 (c 1, CH2Cl2); 1H NMR (250 MHz, CDCl3): δ 1.35 (t, 3 H,
SCH2CH3), 2.76-2.81 (m, 2 H, SCH2CH3), 3.40 (s, 3 H, OCH3),
3.46-4.95 (m, 28 H, 1a-H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6a-H,
1b-H, 2b-H, 3b-H, 4b-H, 5b-H, 2 6b-H, 2 7′-H, 2 8′-H, 5 PhCH2),
7.20-7.39 (m, 29 H, 5 Ph, 2′-H, 4′-H, 5′-H, 6′-H); FAB-MS:
m/z 994 (M + Na)+. Anal. Calcd for C58H66O11S (971.25): C,
71.73; H, 6.85. Found: C, 71.57; H, 6.52.
4-P en ten -1-yl 6-O-[3-(Meth yl 2,3-d i-O-ben zyl-r-D-glu -
cop yr a n osid e-6-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-
r/â-D-glu cop yr a n osid e (5b). Treatment of compound 3b (702
mg) according to the general procedure affords 5b (408 mg,
41%) as a colorless oil. TLC (toluene/ethyl acetate 2:1): Rf 0.46;
[R]D +38 (c 1, CH2Cl2); 1H NMR (250 MHz, CDCl3): δ 1.67 (m,
2 H, CH2CH2CH), 2.09 (m, 2 H, CH2CH2CH2), 3.36 (s, 3 H,
OCH3), 3.52-3.60 (m, 13 H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6-H,
2b-H, 3b-H, 4b-H, 5b-H, 2 6-H, 1/2 OCH2CH2), 4.43 (m, 1 H,
1/2 OCH2CH2), 4.45-4.95 (m, 18 H, 1a-H, 1b-H, 2 7′-H, 2 8′-
H, 5 PhCH2, CH2CHdCH2), 5.78 (m, 1 H, CH2CHdCH2), 7.08-
7.28 (m, 29 H, 5 Ph, 2′-H, 4′-H, 5′-H, 6′-H); MALDI-MS: m/z
1018 (M + Na)+. Anal. Calcd for C61H70O12 (995.22): C, 73.61;
H 7.09. Found: C, 73.79; H, 7.13.
(b) Trifluoromethanesulfonic acid (5 µL) is added under
argon at room temperature to a solution of 5a (97 mg, 0.1
mmol) and N-iodosuccinimide (29 mg, 0.13 mmol) in dry
dichloromethane (10 mL), and the mixture is stirred for 15
min. The solution is neutralized with triethylamine and
washed with aqueous Na2S2O4 solution. The water phase is
4-P en ten -1-yl 6-O-[3-(Meth yl 2,3-d i-O-ben zyl-r-D-glu -
cop yr a n osid e-4-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-
r/â-D-glu cop yr a n osid e (6b). To a solution of 420 (374 mg,
1.0 mmol) in dry dichloromethane (5 mL) are added 15-crown-5
(220 µL, 1.1 mmol) and sodium hydride (26 mg, 1.1 mmol),

6198 J . Org. Chem., Vol. 64, No. 17, 1999
Mu¨ller et al.
extracted with dichloromethane (3 × 5 mL), and the combined
organic extracts are dried (NaSO4) and concentrated in vacuo.
Chromatography (toluene f toluene/ethyl acetate 8:1) of the
residue affords 7â (59 mg, 65%) as a colorless oil. TLC (toluene/
1.99, 2.02, 2.04, 2.07, 2.09, 2.14 (7 s, 21 H, COCH3), 3.38 (s, 3
H, OCH3), 3.65 (ddd, 1 H, J 5,6 ) 2.5, 4.4 Hz, J 5,4 ) 10.0 Hz,
5b-H), 3.73 (dd, 1 H, J 4,5 ) J 4,3 ) 9.7 Hz, 4a-H), 3.89 (ddd, 1
H, J 5,6 ) 1.9, 4.7 Hz, J 5,4 ) 10.0 Hz, 5a-H), 4.05 (ddd, 1 H, J 6,6
) 12.5 Hz, J 6,5 ) 2.5 Hz, 6b-H), 4.14 (dd, 1 H, J 6,6 ) 12.2 Hz,
J 6,5 ) 5.0 Hz, 6a-H), 4.37 (dd, 1 H, J 6,6 ) 12.4 Hz, J 6,5 ) 4.4
Hz, 6b-H), 4.48 (dd, 1 H, J 6,6 ) 12.2 Hz, J 6,5 ) 2.2 Hz, 6a-H),
4.52 (d, 1 H, J 1,2 ) 8.0 Hz, 1b-H), 4.82 (dd, 1 H, J 2,1 ) 3.9 Hz,
2a-H), 4.86 (d, 1 H, J 1,2 ) 3.6 Hz, 1a-H), 4.93 (dd, 1 H, J 2,1 8.0
) Hz, J 2,3 ) 9.1 Hz, 2b-H), 5.07 (dd, 1 H, J 4,3 ) J 4,5 ) 9.7,
4b-H), 5.14 (dd, 1 H, J 3,4 ) J 3,2 ) 9.4 Hz, 3b-H), 5.45 (dd, 1 H,
J 3,2 ) J 3,4 ) 9.7 Hz, 3a-H).
1
ethyl acetate 2:1): Rf 0.64; [R]D +11 (c 1, CH2Cl2); H NMR
3
3
(600 MHz, CDCl3): δ 3.06 (dd, 1 H, J 4,3 ) J 4,5 ) 9.5 Hz, 4b-
3
3
H), 3.21 (dd, 1 H, J 5,6 ) J 5,4 ) 9.5 Hz, 5b-H), 3.36 (dd, 1 H,
3
3J 2,3 ) 9.1 Hz, J 2,1 ) 7.4 Hz, 2b-H), 3.38 (s, 3 H, OCH3), 3.39
(dd, 1 H, 3J 3,2 ) 3J 3,4 ) 9.5 Hz, 3b-H), 3.47 (dd, 1 H, 3J 2,3 ) 9.6
3
Hz, J 2,1 ) 3.7 Hz, 2a-H), 3.58-3.63 (m, 2 H, 5a-H, 6a-H),
3.71-3.81 (m, 3 H, 3a-H, 6a-H, 6b-H), 4.22-5.02 (m, 17 H,
1a-H, 1b-H, 6b-H, 2 7′-H, 2 8′-H, 5 PhCH2), 6.89-7.39 (m, 28
H, 5 Ph, 4′-H, 5′-H, 6′-H), 7.81 (m, 1 H, 2′-H); 13C NMR (150
MHz, CDCl3): δ 69.3 (6a-C), 70.4 (5a-C), 73.6 (5b-C), 78.3 (4b-
C), 78.9 (2a-C), 79.9 (3a-C), 83.5 (2b-C), 84.8 (3b-C), 98.5 (1a-
C), 99.8 (1b-C); MALDI-MS: m/z 931 (M + Na)+. Anal. Calcd
for C56H60O11 (909.11): C, 73.98; H, 6.65. Found: C, 73.89; H,
6.70.
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-
(1f6)-2,3,4-tr i-O-a cetyl-r-D-glu cop yr a n osid e (10â). Treat-
ment of compound 8â (18 mg) according to the general
procedure and chromatography (toluene/ethyl acetate 2:1) of
the residue affords known 10â24 (11 mg, 85%) as a colorless
1
oil. H NMR (600 MHz, CDCl3): δ 2.00, 2.02, 2.03, 2.05, 2.07,
Meth yl 4,6′-O-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-â-D-glu -
cop yr a n osyl)-(1′f6)-2,3-d i-O-b en zyl-r-D-glu cop yr a n o-
sid e (8â). Trimethylsilyl trifluormethanesulfonate (5 µL) is
added under argon at room temperature to a solution of 6b
(100 mg, 0.1 mmol) and N-iodosuccinimide (29 mg, 0.13 mmol)
in dry toluene (10 mL), and the mixture is stirred for 15 min.
The solution is neutralized with triethylamine, sodium dithion-
ite is added, and then stirring is continued until the solution
is colorless. The solid is filtered off, and the solution is
concentrated in vacuo. Chromatography (tolueneftoluene/
ethyl acetate 8:1) of the residue affords 8â (65 mg, 72%) as a
colorless oil. TLC (toluene/ethyl acetate 2:1): Rf 0.68; [R]D +13
(c 1, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 3.11 (dd, 1 H,
2.08, 2.09 (7 s, 21 H, COCH3), 3.39 (s, 3 H, OCH3), 3.55 (dd, 1
H, J 6,6 ) 10.8 Hz, J 6,5 ) 6.4 Hz, 6a-H), 3.69 (ddd, 1 H, J 5,6
)
2.8 Hz, 4.7 Hz, J 5,4 ) 10.0 Hz, 5b-H), 3.91 (dd, 1 H, J 6,6 ) 10.8
Hz, J 6,5 ) 2.0 Hz, 6a-H), 3.95 (ddd, 1 H, J 5,6) 2.2 Hz, 6.4 Hz,
J 5,4 ) 10.2 Hz, 5a-H), 4.13 (dd, 1 H, J 6,5 ) 2.8 Hz, J 6,6 ) 12.5
Hz, 6b-H), 4.27 (dd, 1 H, J 6,5 ) 4.7 Hz, J 6,6 ) 12.4 Hz, 6b-H),
4.55 (d, 1 H, J 1,2 ) 8.0 Hz, 1b-H), 4.84 (dd, 1 H, J 2,1 ) 3.6 Hz,
J 2,3 ) 10.2 Hz, 2a-H), 4.91 (m, 2 H, 1a-H, 4a-H), 5.01 (dd, 1 H,
J 2,1 ) 8.0 Hz, J 2,3 ) 9.7 Hz, 2b-H), 5.08 (dd, 1 H, J 4,3 ) J 4,5
)
9.7 Hz, 4b-H), 5.20 (dd, 1 H, J 3,2 ) J 3,4 ) 9.4 Hz, 3b-H), 5.46
(dd, 1 H, J 3,2 ) J 3,4 ) 9.7 Hz, 3a-H).
Meth yl 2,6-Di-O-ben zyl-3-O-(4-m eth oxyben zyl)-r-D-ga -
la ctop yr a n osid e (12). Compound 2130 (3.74 g, 10.0 mmol)
and dibutyltin oxide (2.74 g, 11.0 mmol) are refluxed in toluene
(50 mL) for 5 h in an apparatus for the azeotropic removal of
water. The solution is cooled to room temperature, and
tetrabutylammonium iodide (4.06 g, 11.0 mmol) and p-meth-
oxybenzyl chloride (1.57 g, 10.0 mmol) are added. Stirring for
1 h at 90 °C, evaporation of the solvent in vacuo, and
chromatography (toluene f toluene/ethyl acetate 9:1) of the
residue affords 12 (3.54 g, 72%) as a colorless oil. TLC (toluene/
ethyl acetate 1:1): Rf 0.65; [R]D +25 (c 1, CHCl3); 1H NMR
(250 MHz, CDCl3): δ 3.30 (s, 3 H, OCH3), 3.54-3.93 (m, 10
H, 2-H, 3-H, 4-H, 5-H, 2 6-H, OH, PhOCH3), 4.43-4.76 (m, 7
H, 1-H, 3 PhCH2), 6.79 (m, 2 H, Ph), 7.19-7.30 (m, 12 H, Ph);
MALDI-MS: m/z 518 (M + Na)+. Anal. Calcd for C29H34O7
(494.58): C, 70.43; H, 6.93. Found: C, 70.29; H, 6.84.
3
3J 4,3 ) J 4,5 ) 9.9 Hz, 4a-H), 3.28 (s, 3 H, OCH3), 3.31-3.42
3
(m, 5 H, 6a-H, 2b-H, 4b-H, 5b-H, 6b-H), 3.46 (dd, 1 H, J 2,1
)
3
3
2
3.6 Hz, J 2,3 ) 9.5 Hz, 2a-H), 3.56 (dd, 1 H, J 3,2 ) J 3,4 ) 9.1
Hz, 3b-H), 3.87-3.97 (m, 3 H, 3a-H, 5a-H, 6b-H), 4.31 (d, 1 H,
3J 1,2 ) 7.6 Hz, 1b-H), 4.40-4.97 (m, 16 H, 1a-H, 6a-H, 2 7′-H,
2 8′-H, 5 PhCH2), 6.91-7.34 (m, 28 H, 5 Ph, 4′-H, 5′-H, 6′-H),
7.70 (m, 1 H, 2′-H); 13C NMR (150 MHz, CDCl3): δ 70.8 (5a-
C), 74.3 (5b-C), 78.2 (4b-C), 79.7 (4a-C), 79.9 (2a-C), 82.0 (3a-
C), 82.2 (2b-C), 84.4 (3b-C), 97.4 (1a-C), 101.8 (1b-C); MALDI-
MS: m/z 931 (M + Na)+. Anal. Calcd for C56H60O11 (909.11):
C, 73.98; H, 6.65. Found: C, 73.61; H, 6.40.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
9r, 10â, 18â, 19â, a n d 27r,â. A mixture of 8â, 16â, 17â, 26R/
â, 32R, 36R (0.02 mmol), and palladium on carbon (10%, 10
mg) in methanol/ethyl acetate (4 mL, 1:1) and formic acid (0.2
mL) is stirred under hydrogen for 20 h. After filtration and
concentration in vacuo, the residue is dissolved in pyridine/
acetic anhydride (4 mL, 1:1), and the mixture is stirred for 20
h. The solution is concentrated in vacuo and coevaporated with
toluene.
Eth yl 6-O-[3-(Meth yl 4,6-O-ben zylid en e-r-D-glu cop y-
r an oside-2-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-1-th io-
â-D-glu cop yr a n osid e (13). Compound 3a (678 mg, 1.0 mmol)
in dry dimethylformamide (5 mL) is added at 0 °C to a
suspension of 11 (565 mg, 2.0 mmol) and sodium hydride (26
mg, 1.1 mmol) in dry dimethylformamide (10 mL), and the
mixture is stirred for 15 h at 0 °C. Concentration of the solution
in vacuo and chromatography (toluene/ethyl acetate 9:1) of the
residue affords 13 (404 mg, 46%) as a colorless oil. TLC
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-r-D-glu cop yr a n osyl)-
(1f4)-2,3,6-tr i-O-a cetyl-r-D-glu cop yr a n osid e (9r). Treat-
ment of compound 35R (16 mg) according to the general
procedure and chromatography (toluene/ethyl acetate 2:1) of
the residue affords known 9R32 (11 mg, 85%) as a colorless oil.
1H NMR (600 MHz, CDCl3): δ 1.94, 1.96, 1.98, 1.99, 2.04, 2.08
(6 s, 21 H, COCH3), 3.35 (s, 3 H, OCH3), 3.89-3.92 (m, 3 H,
4a-H, 5a-H, 5b-H), 3.98 (dd, 1 H, J 6,6 ) 12.5 Hz, J 6,5 ) 2.4 Hz,
1
(toluene/ethyl acetate 6:1): Rf 0.23; [R]D +20 (c 1, CHCl3); H
NMR (250 MHz, CDCl3): δ 1.29 (t, 3 H, SCH2CH3), 2.57 (d, 1
3
H, J OH,3 ) 2.0 Hz, 3a-OH), 2.69-2.75 (m, 2 H, SCH2CH3),
3.32-3.77 (m, 13 H, OCH3, 2a-H, 4a-H, 5a-H, 6a-H, 2b-H, 3b-
3
3
H, 4b-H, 5b-H, 2 6b-H), 4.09 (ddd, 1 H, J 3,2 ) J 3,4 ) 9.3 Hz,
3J 3,OH ) 2.0 Hz, 3a-H), 4.20 (dd, 1 H, 2J 6,6 ) 9.7 Hz, 3J 6,5 ) 4.4
Hz, 6a-H), 4.39-4.99 (m, 12 H, 1a-H, 1b-H, 2 7′-H, 2 8′-H, 3
PhCH2), 5.45 (s, 1 H, PhCH), 7.11-7.45 (m, 24 H, 4 Ph, 2′-H,
4′-H, 5′-H, 6′-H); MALDI-MS: m/z 902 (M + Na)+. Anal. Calcd
for C51H58O11S (879.08): C, 69.78; H, 6.65. Found: C, 69.48;
H, 6.65.
6c-H), 4.18-4.20 (m, 2 H, 6a-H, 6b-H), 4.38 (dd, 1 H, J 6,6
)
12.1 Hz, J 6,5 ) 1.8 Hz, 6b-H), 4.71 (dd, 1 H, J 2,3 ) 10.2 Hz, J 2,1
) 3.6 Hz, 2a-H), 4.77-4.81 (m, 2 H, 1a-H, 2b-H), 5.00 (dd, 1
H, J 4,3 ) J 4,5 ) 9.9 Hz, 4b-H), 5.30 (dd, 1 H, J 3,2 ) J 3,4 ) 9.9
Hz, 3b-H), 5.36 (d, 1 H, J 1,2 ) 4.0 Hz, 1b-H), 5.46 (m, 1 H,
3a-H).
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-
(1f4)-2,3,6-tr i-O-a cetyl-r-D-glu cop yr a n osid e (9â). A mix-
ture of 7â, 25â (50 mg, 0.055 mmol), and palladium on carbon
(10%, 8 mg) in methanol/ethyl acetate (3 mL, 1:1) and formic
acid (0.3 mL) is stirred under hydrogen for 20 h. After filtration
and concentration in vacuo, the residue is dissolved in pyridine/
acetic anhydride (6 mL, 1:1) and is stirred for 7 h. The solution
is concentrated in vacuo and coevaporated with toluene.
Chromatography (toluene/ethyl acetate 2:1) affords known 9â22
Eth yl 6-O-[3-(Meth yl 2,6-d i-O-ben zyl-3-O-(4-m eth oxy-
ben zyl)-r-D-ga la ct op yr a n osid e-4-yloxym et h yl)-b en zyl]-
2,3,4-tr i-O-ben zyl-1-th io-â-D-glu cop yr a n osid e (14). Com-
pound 12 (544 mg, 1.1 mmol) in dry dimethylformamide (5
mL) is added at 0 °C to a suspension of 3a (678 mg, 1.0 mmol)
and sodium hydride (26 mg, 1.1 mmol) in dry dimethylforma-
mide (10 mL). The mixture is warmed to room temperature
and stirred for 5 h. Concentration of the solution in vacuo and
chromatography (petroleum ether/ethyl acetate 5:1 f 4:1) of
the residue affords 14 (665 mg, 61%) as a colorless oil. TLC
1
(32 mg, 89%) as a colorless oil. H NMR (600 MHz, CDCl3): δ

Intramolecular Glycosylation Supported by a Rigid Spacer
J . Org. Chem., Vol. 64, No. 17, 1999 6199
3
(petroleum ether/ethyl acetate 3:1): Rf 0.25; [R]D +10 (c 1,
CHCl3); 1H NMR (250 MHz, CDCl3): δ 1.30 (t, 3 H, SCH2CH3),
2.69-2.79 (m, 2 H, SCH2CH3), 3.35 (s, 3 H, OCH3), 3.39-4.02
(m, 15 H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6a-H, 2b-H, 3b-H, 4b-H,
5b-H, 2 6b-H, OCH3), 4.35-4.95 (m, 18 H, 1a-H, 1b-H, 2 7′-H,
2 8′-H, 6 PhCH2), 6.85 (m, 2 H, Ph), 7.14-7.38 (m, 31 H, Ph,
2′-H, 4′-H, 5′-H, 6′-H). Anal. Calcd for C66H74O12S (1091.37):
C, 72.64; H, 6.89. Found: C, 72.38; H, 6.75.
(m, 2 H, 1a-H, 1/2 PhCH2), 4.59 (d, 1 H, J 1,2 ) 7.8 Hz, 1b-H),
4.69 (d, 1 H, 2J ) 12.4 Hz, 1/2 PhCH2), 4.81-4.94 (m, 7 H,
7′-H, 8′-H, 2 1/2 PhCH2), 5.00 (d, 1 H, 2J ) 11.6 Hz, 7′-H),
5.10 (d, 1 H, 2J ) 11.9 Hz, 1/2 PhCH2), 7.00 (m, 1 H, 5′-H),
7.19-7.37 (m, 27 H, 5 Ph, 4′-H, 6′-H), 8.05 (s, 1 H, 2′-H); 13C
NMR (125 MHz, CDCl3): δ 55.1 (OCH3), 68.7 (6b-C), 69.9 (5a-
C), 70.7 (6a-C), 70.9 (8′-C), 71.6 (4a-C), 72.6 (7′-C), 73.3, 73.5,
74.0 (4 C, 4 PhCH2), 74.4 (5b-C), 75.0, 75.6 (2 C, 2 PhCH2),
76.0 (2a-C), 76.9 (4b-C), 81.5 (2b-C), 82.1 (3a-C), 84.2 (3b-C),
98.6 (1a-C), 106.0 (1b-C); FAB-MS: m/z 931 (M + Na)+. Anal.
Calcd for C56H60O11 (909.08): C, 73.99; H 6.65. Found:C, 73.61;
H 6.71.
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-
(1f3)-2,4,6-tr i-O-acetyl-r-D-galactopyr an oside (18â). Treat-
ment of compound 16â (16 mg) according to the general
procedure and chromatography (toluene/ethyl acetate 3:2 f
1:1) of the residue affords known 18â26 (12 mg, 92%) as a
colorless oil. 1H NMR (600 MHz, CDCl3): δ 1.91, 1.94, 1.97,
1.99, 2.03, 2.08 (6 s, 21 H, COCH3), 3.34 (s, 3 H, OCH3), 5.58
(ddd, 1 H, J 5,6 ) 2.1 Hz, 4.1 Hz, J 5,4 ) 9.7 Hz, 5b-H), 3.85 (m,
1 H, 5a-H), 3.98 (dd, 1 H, J 6,6 ) 12.3 Hz, J 6,5 ) 1.9 Hz, 6b-H),
4.05-4.08 (m, 2 H, 3a-H, 6a-H), 4.12 (dd, 1 H, J 6,6 ) 12.3 Hz,
J 6,5 ) 4.7 Hz, 6a-H), 4.27 (dd, 1 H, J 6,6 ) 12.3 Hz, J 6,5 ) 4.4
Hz, 6b-H), 4.59 (d, 1 H, J 1,2 ) 8.1 Hz, 1b-H), 4.79 (d, 1 H, J 1,2
) 3.6 Hz, 1a-H), 4.82-4.85 (m, 2 H, 2a-H, 2b-H), 4.92 (dd, 1
H, J 4,3 ) J 4,5 ) 9.7 Hz, 4a-H), 4.99 (dd, 1 H, J 4,3 ) J 4,5 ) 9.7
Hz, 4b-H), 5.05 (dd, 1 H, J 3,2 ) J 3,4 ) 9.4 Hz, 3b-H).
Eth yl 6-O-[3-(Meth yl 2,6-d i-O-ben zyl-r-D-ga la ctop yr a -
n osid e-4-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-1-th io-
â-D-glu cop yr a n osid e (15). A mixture of 14 (546 mg, 0.5
mmol) and 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-di-
carbonitrile (DDQ, 159 mg, 0.7 mmol) in dichloromethane (20
mL) and water (2 mL) is stirred at room temperature for 4 h.
Dichloromethane (20 mL) is added, and the mixture is washed
with aqueous NaHCO3 solution (10 mL) and water (10 mL).
Concentration of the solution in vacuo and chromatography
(toluene/ethyl acetate 6:1) of the residue affords 15 (437 mg,
90%) as a colorless oil. TLC (toluene/ethyl acetate 3:1): Rf 0.36;
1
[R]D +22 (c 1, CHCl3); H NMR (250 MHz, CDCl3): δ 1.30 (t,
3 H, SCH2CH3), 2.70-2.77 (m, 2 H, SCH2CH3), 3.31 (s, 3 H,
OCH3), 3.38-4.06 (m, 12 H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6a-H,
2b-H, 3b-H, 4b-H, 5b-H, 2 6b-H), 4.42-4.93 (m, 16 H, 1a-H,
1b-H, 2 7′-H, 2 8′-H, 5 PhCH2), 7.13-7.38 (m, 29 H, 5 Ph, 2′-
H, 4′-H, 5′-H, 6′-H); MALDI-MS: m/z 995 (M + Na)+, 1011
(M + K)+. Anal. Calcd for C58H66O11S (971.22): C, 71.73; H,
6.85. Found: C, 71.64; H, 6.70.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
16â, 17â, 25â, 26r/â, 32r, a n d 36r. Trifluoromethanesulfonic
acid (5 µL) is added under argon at room temperature to a
solution of 13, 15, 23, 24, 31, 34 (0.05 mmol), and N-
iodosuccinimide (22 mg, 0.10 mmol) in dry dichloromethane
(5 mL), and the mixture is stirred for 30 min. The solution is
washed with aqueous NaHCO3 solution (1 mL) and aqueous
Na2S2O3 solution (1 mL), dried (MgSO4), and concentrated in
vacuo.
Meth yl 2,6′-O-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-â-D-glu -
cop yr a n osyl)-(1′f3)-4,6-O-ben zylid en e-r-D-glu cop yr a n o-
sid e (16â). Treatment of compound 13 (44 mg) according to
the general procedure and chromatography (petroleum ether/
ethyl acetate 7:1) of the residue affords 16â (33 mg, 81%) as a
colorless oil. TLC (petroleum ether/ethyl acetate 3:1): Rf 0.32;
[R]D +30 (c 1, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 3.21 (d,
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-
(1f3)-2,4,6-tr i-O-acetyl-r-D-galactopyr an oside (19â). Treat-
ment of compound 17â (18 mg) according to the general
procedure and chromatography (toluene/ethyl acetate, 2/1) of
the residue affords known 19â27 (11 mg, 85%) as a colorless
1
oil. H NMR (600 MHz, CDCl3): δ 1.92, 1.95, 2.00, 2.04, 2.07
(5 s, 21 H, COCH3), 3.33 (s, 3 H, OCH3), 3.56 (ddd, 1 H, J 5,6
)
2.6 Hz, 3.8 Hz, J 5,6 ) 9.8 Hz, 5b-H), 3.98 (dd, 1 H, J 6,6 ) 10.5
Hz, J 6,5 ) 6.7 Hz, 6a-H), 4.06-4.12 (m, 4 H, 3a-H, 5a-H, 6a-
H, 6b-H), 4.19 (dd, 1 H, J 6,6 ) 12.3 Hz, J 6,5 ) 2.4 Hz, 6b-H),
4.59 (d, 1 H, J 1,2 ) 7.9 Hz, 1b-H), 4.82-4.85 (m, 2 H, 1a-H,
2b-H), 5.01 (dd, 1 H, J 4,3 ) J 4,5 ) 9.6 Hz, 4b-H), 5.05-5.09 (m,
3 H, 2a-H, 3b-H, 4b-H), 5.37 (d, 1 H, J ) 3.0 Hz, 4a-H).
Eth yl 6-O-[3-(Meth yl 2-O-ben zyl-4,6-O-ben zylid en e-r-
D-glu cop yr a n osid e-3-yloxym et h yl)-b en zyl]-2,3,4-t r i-O-
ben zyl-1-th io-â-D-glu cop yr a n osid e (22). To a suspension
of 2028 (137 mg, 0.36 mmol) and sodium hydride (10 mg, 0.4
mmol) in dichloromethane (3 mL) are added first 15-crown-5
(80 µL, 0.4 mmol) and then 3a (250 mg, 0.36 mmol) in
dichloromethane (2 mL). The solution is stirred for 12 h,
neutralized with acetic acid, and concentrated in vacuo.
Chromatography (toluene/ethyl acetate 15:1) of the residue
affords 22 (176 mg, 50%) as a colorless oil. TLC (toluene/ethyl
acetate 6:1): Rf 0.57; [R]D +12 (c 1, CH2Cl2); 1H NMR (250
MHz, CDCl3): δ 1.28 (t, 3 H, SCH2CH3), 2.62-2.82 (m, 2 H,
SCH2CH3), 3.37 (s, 3 H, OCH3), 3.39-4.92 (m, 26 H, 1a-H, 2a-
H, 3a-H, 4a-H, 5a-H, 2 6a-H, 1b-H, 2b-H, 3b-H, 4b-H, 5b-H, 2
6b-H, 2 7′-H, 2 8′-H, 4 PhCH2), 7.19-7.38 (m, 24 H, 4 Ph, 2′-
H, 4′-H, 5′-H, 6′-H). Anal. Calcd for C58H64O11S (969.25): C,
71.87; H, 6.65. Found: C, 71.41; H, 6.61.
3
2
3
1 H, J 5,4 ) 9.6 Hz, 5b-H), 3.33 (dd, 1 H, J 6,6 ) 10.4 Hz, J 6,5
3
) 1.7 Hz, 6b-H), 3.42 (s, 3 H, OCH3), 3.53 (dd, 1 H, J 3,2
)
3J 3,4 ) 9.1 Hz, 3b-H), 3.60-3.68 (m, 3 H, 2b-H, 4a-H, 6a-H),
3
3.79-3.86 (m, 3 H, 2a-H, 5a-H, 6b-H), 3.93 (dd, 1 H, J 4,3
)
3J 4,5 ) 9.6 Hz, 4b-H), 4.22 (dd, 1 H, J 6,6 ) 10.1 Hz, J 6,5 ) 4.9
2
3
Hz, 6a-H), 4.28 (d, 1-H, 2J ) 14.5 Hz, 8′-H), 4.44 (dd, 1 H, 3J 3,2
) 3J 3,4 ) 9.8 Hz, 3a-H), 4.47 (d, 1 H, J ) 13.7 Hz, 7′-H), 4.60
2
2
3
(d, 1 H, J ) 11.3 Hz, 1/2 PhCH2), 4.65 (d, 1 H, J 1,2 ) 3.6 Hz,
1a-H), 4.69-4.76 (m, 3 H, 1b-H, PhCH2), 4.83-4.88 (m, 3 H,
2
8′-H, PhCH2), 4.98 (d, 1 H, J ) 11.3 Hz, 1/2 PhCH2), 5.04 (d,
2
1 H, J ) 13.7 Hz, 7′-H), 5.41 (s, 1 H, PhCH), 7.06-7.26 (m,
21 H, 3 Ph, m-, p-benzylidene-H, 4′-H, 5′-H, 6′-H), 7.37 (m, 2
H, o-benzyliden-H), 8.04 (s, 1 H, 2′-H); 13C NMR (125 MHz,
CDCl3): δ 55.2 (OCH3), 62.6 (5a-C), 66.3 (6b-C), 68.7, 68.9 (2
C, 6a-C, 7′-C), 70.5 (8′-C), 72.5 (2a-C), 74.0 (5b-C), 74.5, 75.0
(2 C, 2 PhCH2), 75.3, 75.4 (3 C, PhCH2, 3a-C, 4a-C), 76.4 (4b-
C), 82.5 (2b-C), 84.4 (3b-C), 98.1 (1a-C), 98.7 (1b-C), 100.8
(PhCH); FAB-MS: m/z 839 (M + Na)+. Anal. Calcd for
C49H52O11 (816.35): C, 72.04; H, 6.42. Found: C, 71.48; H, 6.22.
Meth yl 4,6′-O-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-â-D-glu -
cop yr a n osyl)-(1′f3)-2,6-d i-O-ben zyl-r-D-ga la ctop yr a n o-
sid e (17â). Treatment of compound 15 (49 mg) according to
the general procedure and chromatography (petroleum ether/
ethyl acetate 7:1 f 6:1) of the residue affords 17â (38 mg, 84%)
as a colorless oil. TLC (petroleum ether/ethyl acetate 3:1): Rf
0.32; [R]D +14 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δ 3.07
Eth yl 6-O-[3-(Meth yl 2,6-d i-O-ben zyl-r-D-glu cop yr a n o-
sid e-3-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-1-th io-â-D-
glu cop yr a n osid e (23). A solution of hydrogen chloride
(saturated in diethyl ether) is added at room temperature to
a suspension of 22 (155 mg, 0.16 mmol) and sodium cy-
anoborohydride (82 mg, 1.3 mmol) in dry tetrahydrofuran (5
mL). At pH 1, the mixture is stirred for 1 h, water (5 mL) and
diethyl ether (10 mL) are added, and the water phase is
extracted with diethyl ether (3 × 10 mL). The combined
organic extracts are washed with aqueous NaHCO3 solution
and water, dried (MgSO4), and concentrated in vacuo. Chro-
matography (toluene/ethyl acetate 6:1) of the residue affords
23 (105 mg, 68%) as a colorless oil. TLC (toluene/ethyl acetate
6:1): Rf 0.28; [R]D +19 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): δ 1.05 (t, 3 H, SCH2CH3), 2.48-2.59 (m, 2 H, SCH2-
CH3), 3.11 (s, 3 H, OCH3), 3.14-3.54 (m, 12 H, 2a-H, 3a-H,
4a-H, 5a-H, 2 6a-H, 2b-H, 3b-H, 4b-H, 5b-H, 2 6b-H), 4.17-
4.73 (m, 16 H, 1b-H, 1a-H, 2 7′-H, 2 8′-H, 5 PhCH2), 6.87-
2
3
(dd, 1 H, J 6,6 ) 10.5 Hz, J 6,5 ) 3.9 Hz, 6a-H), 3.25 (s, 3 H,
OCH3), 3.36 (m, 2 H, 5b-H, 6b-H), 3.50 (m, 2 H, 2b-H, 6a-H),
3.65 (dd, 1 H, 3J 3,2 ) 3J 3,4 ) 9.2 Hz, 3b-H), 3.74 (m, 2 H, 4a-H,
3
3
5a-H), 3.84 (dd, 1 H, J 3,2 ) 10.3 Hz, J 3,4 ) 2.9 Hz, 3a-H),
3
3
3.98 (dd, 1 H, J 2,3 ) 10.3 Hz, J 2,1 ) 3.7 Hz, 2a-H), 4.11 (m, 2
H, 4b-H, 6b-H), 4.32-4.41 (m, 3 H, 8′-H, PhCH2), 4.49-4.51

6200 J . Org. Chem., Vol. 64, No. 17, 1999
Mu¨ller et al.
7.13 (m, 24 H, 2′-H, 4′-H, 5′-H, 6′-H, 4 Ph). C58H66O11S (971.25)
FAB-MS: m/z 994 (M + Na)+.
27â: TLC (toluene/acetone 2:1): Rf 0.45; [R]D +7 (c 0.5,
1
CHCl3); H NMR (250 MHz, CDCl3): δ 2.00, 2.02, 2.05, 2.06,
Eth yl 6-O-[3-(Meth yl 2,6-d i-O-ben zyl-r-D-ga la ctop yr a -
n osid e-3-yloxym eth yl)-ben zyl]-2,3,4-tr i-O-ben zyl-1-th io-
â-D-glu cop yr a n osid e (24). Compound 2130 (449 mg, 1.2
mmol) and dibutyltin oxide (324 mg, 1.3 mmol) are refluxed
in toluene (10 mL) for 5 h in an apparatus for the azeotropic
removal of water. The solution is cooled to room temperature,
and then tetrabutylammonium bromide (322 mg, 1.0 mmol)
and 3a (678 mg, 1.0 mmol) are added. Stirring for 20 h at 90
°C, evaporation of the solvent, and chromatography (toluene
f toluene/ethyl acetate 6:1) of the residue affords 24 (610 mg,
63%) as a colorless oil. TLC (toluene/acetone 4:1): Rf 0.40; [R]D
2.08, 2.09 (6 s, 21 H, COCH3), 3.34 (s, 3 H, OCH3), 3.60 (m, 1
H, 5b-H), 3.96-4.25 (m, 6 H, 4a-H, 5a-H, 2 6a-H, 2 6b-H), 4.45
3
3
(d, 1 H, J 1,2 ) 7.8 Hz, 1b-H), 4.82 (d, 1H, J 2,1 ) 2.8 Hz, 1a-
H), 4.85-5.22 (m, 5 H, 2a-H, 3a-H, 2b-H, 3b-H, 4b-H).
C
27H38O18 (650.59) FAB-MS: m/z 973 (M + Na)+.
4′,6′-Bis(br om om eth yl)-m -ter p h en yl (29). A suspension
of 2831 (1.29 g, 5.0 mmol), N-bromosuccinimide (3.56 g, 10.0
mmol), and azobisisobutyronitrile (20 mg) in tetrachlo-
romethane (10 mL) is refluxed for 24 h. After the mixture cools
to room temperature, the solid is filtered off and washed with
tetrachloromethane. The filtrate is concentrated in vacuo.
Chromatography (petroleum ether/tetrachloromethane 9:1) of
the residue affords 29 (1.27 g, 61%) as colorless crystals; mp
101-103 °C. TLC (petroleum ether/tetrachloromethane 4:1):
Rf 0.38; 1H NMR (250 MHz, CDCl3): δ 4.48 (s, 4 H, 2 PhCH2-
Br), 7.17 (s, 1 H, 5′-H), 7.36 (m, 10 H, 2 Ph), 7.70 (s, 1 H, 2′-
H). Anal. Calcd for C20H10Br2 (416.15): C, 57.75; H, 3.88.
Found: C, 57.54; H, 3.91.
1
+14 (c 1, CHCl3); H NMR (250 MHz, CDCl3): δ 1.31 (t, 3 H,
SCH2CH3), 2.72-2.77 (m, 2 H, SCH2CH3), 3.36 (s, 3 H, OCH3),
3.39-4.04 (m, 12 H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6a-H, 2b-H,
3b-H, 4b-H, 5b-H, 2 6b-H), 4.43-4.93 (m, 16 H, 1a-H, 1b-H, 2
7′-H, 2 8′-H, 5 PhCH2), 7.12-7.39 (m, 29 H, 5 Ph, 2′-H, 4′-H,
5′-H, 6′-H); MALDI-MS: m/z 995 (M + Na)+, 1011 (M + K)+.
Anal. Calcd for
C58H66O11S (971.22): C, 71.73; H, 6.85.
Found: C, 71.52; H, 6.89.
Eth yl 2,3,4-Tr i-O-ben zyl-6-O-(3-br om om eth yl-4,6-diph e-
n ylb en zyl)-1-t h io-â-D-glu cop yr a n osid e (30). Compound
1a 18 (495 mg, 1.0 mmol) in dry dimethylformamide (3 mL) is
added at 0 °C to a suspension of 29 (624 mg, 1.5 mmol) and
sodium hydride (26 mg, 1.1 mmol) in dry dimethylformamide
(10 mL), and the mixture is stirred for 20 h at 0 °C.
Concentration of the solution in vacuo and chromatography
(petroleum ether/ethyl acetate 19:1) of the residue affords 30
(456 mg, 55%) as a colorless oil. TLC (petroleum ether/ethyl
acetate 3:1): Rf ) 0.64; [R]D +5 (c 1, CHCl3); 1H NMR (250
MHz, CDCl3): δ 1.26 (t, 3 H, SCH2CH3), 2.69-2.73 (m, 2 H,
SCH2CH3), 3.39-3.71 (m, 6 H, 2-H, 3-H, 4-H, 5-H, 2 6-H),
4.42-4.93 (m, 11 H, 1-H, 2 7′-H, 2 8′-H, 3 PhCH2), 7.18-7.46
(m, 26 H, 5 Ph, 5′-H), 7.70 (s, 1 H, 2′-H); MALDI-MS: m/z
Meth yl 3,6′-O-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-â-D-glu -
cop yr a n osyl)-(1′f4)-2,3-d i-O-b en zyl-r-D-glu cop yr a n o-
sid e (25â). Treatment of compound 23 (50 mg) according to
the general procedure and chromatography (toluene f toluene/
ethyl acetate 9:1) of the residue affords 25â (38 mg, 84%) as a
colorless oil. TLC (toluene/ethyl acetate 2:1): Rf 0.64; [R]D +24
(c 1, CH2Cl2); 1H NMR (600 MHz, CDCl3): δ 3.18 (m, 1 H, 5b-
H), 3.36-3.45 (m, 6 H, 6a-H, 2b-H, 3b-H, OCH3), 3.51-3.52
(m, 3 H, 2a-H, 5a-H, 6b-H), 3.80-3.99 (m, 5 H, 3a-H, 4a-H,
6a-H, 4b-H, 6b-H), 4.24-4.98 (m, 16 H, 1a-H, 1b-H, 2 7′-H, 2
8′-H, 5 PhCH2), 7.18-7.36 (m, 23 H, 4′-H, 5′-H, 6′-H, 5 Ph),
8.51 (s, 1 H, 2′-H); 13C NMR (150 MHz, CDCl3): δ 70.3 (5a-C),
74.3 (5b-C), 76.9 (4b-C), 77.9 (4a-C), 80.0 (3a-C), 81.0 (2a-C),
82.7 (2b-C), 84.7 (3b-C), 98.1 (1a-C), 103.3 (1b-C). C56H60O11
(909.11) FAB-MS: m/z 932 (M + Na)+.
851, 853 (M + Na)+, 867, 869 (M + K)+. Anal. Calcd for C49H49
-
BrO5S (829.91): C, 70.92; H, 5.96. Found: C, 70.95; H, 6.07.
Eth yl 6-O-[3-(Meth yl 2,6-d i-O-ben zyl-r-D-ga la ctop yr a -
n osid e-3-yloxym et h yl)-4,6-d ip h en ylb en zyl]-2,3,4-t r i-O-
ben zyl-1-th io-â-D-glu cop yr a n osid e (31). Compound 21 (374
mg, 1.0 mmol) and dibutyltin oxide (274 mg, 1.1 mmol) are
refluxed in toluene (10 mL) for 4 h in an apparatus for the
azeotropic removal of water. The solution is cooled to room
temperature, and then tetrabutylammonium bromide (355 mg,
1.1 mmol) and 30 (415 mg, 0.5 mmol) are added. Stirring for
4 h at 90 °C, evaporation of the solvent, and chromatography
(toluene f toluene/ethyl acetate 19:1) of the residue affords
31 (298 mg, 53%) as a colorless oil. TLC (toluene/ethyl acetate
4:1): Rf ) 0.57; [R]D -1 (c 0.7, CHCl3); 1H NMR (250 MHz,
CDCl3): δ 1.18 (t, 3 H, SCH2CH3), 2.28 (s, 1H, OH), 2.50-
2.56 (m, 2 H, SCH2CH3), 3.27-3.75 (m, 15 H, 2a-H, 3a-H, 4a-
H, 5a-H, 2 6a-H, 2b-H, 3b-H, 4b-H, 5b-H, 2 6b-H, OCH3), 4.32-
4.81 (m, 16 H, 1a-H, 1b-H, 2 7′-H, 2 8′-H, 5 PhCH2), 7.11-
Meth yl 3,6′-(1,3-Xylylen e)-(2,3,4-tr i-O-ben zyl-r/â-D-glu -
cop yr a n osyl)-(1′f4)-2,6-d i-O-ben zyl-r-D-ga la ctop yr a n o-
sid e (26r/â). Treatment of compound 24 (49 mg) according to
the general procedure and chromatography (petroleum ether/
ethyl acetate 9:1) of the residue affords 26R/â (35 mg, 77%) as
a colorless oil. TLC (petroleum ether/ethyl acetate 3:1): Rf 0.27;
1H NMR (600 MHz, CDCl3): δ 3.18 (m, 1 H, 4b-H), 3.30 (m,
2b-Hâ), 3.37, 3.39 (2 s, 3 H, OCH3), 3.47 (m, 2b-HR, 5b-Hâ),
3.61-4.03 (m, 8 H, 2a-H, 3a-H, 5a-H, 2 6a-H, 3b-H, 2 6b-H),
4.27-5.11 (m, 1a-H, 4a-H, 5b-HR, 2 7′-H, 2 8′-H, 5 PhCH2),
3
3
5.12 (d, J 1,2 ) 2.9 Hz, 1b-HR), 5.35 (d, J 1,2 ) 7.7 Hz, 1b-Hâ),
6.95-7.34 (m, 28 H, 5 Ph, 4′-H, 5′-H, 6′-H), 8.34 (s, 1 H, 2′-H);
13C NMR (125 MHz, CDCl3): δ 55.1, 55.2 (OCH3), 69.2 (6a-C),
70.1 (5a-C), 70.8-75.1 (7 C, 7′-C, 8′-C, 5 PhCH2), 72.1 (5b-CR),
72.1 (5b-Câ), 73.8 (6b-C), 77.0 (4a-C), 77.4 (2a-C), 78.1 (3a-C),
78.6 (4b-Câ), 80.2 (2b-CR), 80.9 (2b-CR, 3b-CR), 83.2 (2b-Câ), 84.7
(3b-Câ), 98.1 (1a-C), 98.2 (1b-CR), 99.9 (1b-Câ); FAB-MS: m/z
931 (M + Na)+. Anal. Calcd for C56H60O11 (909.08): C, 73.99;
H, 6.65. Found: C, 73.74; H, 6.76.
7.37 (m, 36 H, 7 Ph, 5′-H), 7.64 (s, 1H, 2′-H). C70H74O11
S
(1123.41) FAB-MS: m/z 1145 (M + Na)+.
Meth yl 3,6′-O-(4,6-Dip h en yl-1,3-xylylen e)-(2,3,4-O-tr i-
b en zyl-r-D-glu cop yr a n osyl)-(1′f4)-2,6-d i-O-b en zyl-r-D-
ga la ctop yr a n osid e (32r). Treatment of compound 31 (56 mg)
according to the general procedure and chromatography
(petroleum ether/ethyl acetate 9:1 f 7:1) of the residue affords
32R (46 mg, 87%) as a colorless oil. TLC (petroleum ether/
Meth yl O-(2,3,4,6-Tetr a -O-a cetyl-r-D-glu cop yr a n osyl)-
(1f4)-2,3,6-tr i-O-acetyl-r-D-galactopyr an oside (27r). Meth -
yl O-(2,3,4,6-Tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-(1f4)-
2,3,6-tr i-O-a cetyl-r-D-ga la ctop yr a n osid e (27â). (a) Treat-
ment of compound 26R/â (18 mg) according to the general
procedure and chromatography (toluene/ethyl acetate 3:1 f
2:1) of the residue affords first 27R (8 mg, 61%) as a colorless
solid and then 27â (3 mg, 23%) as a colorless oil.
1
ethyl acetate 5:1): Rf 0.18; [R]D +16 (c 0.8, CHCl3); H NMR
3
3
(600 MHz, CDCl3): δ 3.10 (dd, 1 H, J 4,3 ) J 4,5 ) 9.3 Hz, 4b-
3
3
H), 3.29 (s, 3 H, OCH3), 3.37 (dd, 1 H, J 4,3 ) J 4,5 ) 9.3 Hz,
2
3
(b) Treatment of compound 32R (22 mg) according to the
general procedure and chromatography (toluene/ethyl acetate
9:1 f 2:1) of the residue affords first 28 (4 mg, 77%) as a
colorless solid and then 27R (10 mg, 77%) as a colorless oil.
27R: TLC (toluene/acetone 2:1): Rf 0.50; [R]D +36 (c 0.5,
2b-H), 3.46 (dd, 1 H, J 6,6 ) 11.2 Hz, J 6,5 ) 7.9 Hz, 6b-H),
2 3
3.53 (dd, 1 H, J 6,6 ) 10.0 Hz, J 6,5 ) 7.0 Hz, 6a-H), 3.72 (dd,
2
3
2
1 H, J 6,6 ) 11.2 Hz, J 6,5 ) 3.0 Hz, 6b-H), 3.76 (dd, 1 H, J 6,6
3
) 10.2 Hz, J 6,5 ) 5.9 Hz, 6a-H), 3.85-3.88 (m, 2 H, 3a-H, 5a-
3
3
H), 3.95 (dd, 1 H, J 3,2 ) J 3,4 ) 9.3 Hz, 3b-H), 4.00 (dd, 1 H,
1
3
3
CHCl3); H NMR (250 MHz, CDCl3): δ 1.99, 2.04, 2.05, 2.06,
3J 2,1 ) 3.5 Hz, J 2,3 ) 10.0 Hz, 2a-H), 4.16 (dd, 1 H, J 4,3 ) 2.0
3
2.08, 2.09 (6 s, 21 H, COCH3), 3.41(s, 3 H, OCH3), 4.03-4.17
(m, 4 H, 4a-H, 5a-H, 6a-H, 6b-H), 4.25-4.40 (m, 3 H, 5b-H,
6a-H, 6b-H), 4.88-4.97 (m, 3 H, 1a-H, 1b-H, 2b-H), 5.11-5.18
Hz, J 4,5 < 1.0 Hz, 4a-H), 4.25 (d, 1 H, 2J ) 12.1 Hz, 1/2
PhCH2), 4.32 (m, 3 H, 3/2 PhCH2), 4.40 (m, 1 H, 5b-H), 4.47
2
2
(d, 1 H, J ) 10.7 Hz, 1/2 PhCH2), 4.52 (d, 1 H, J ) 11.9 Hz,
3
3
(m, 2 H 3a-H, 4b-H), 5.27 (dd, 1 H, J 2,1 ) 3.5 Hz, J 2,3 ) 11.2
1/2 PhCH2), 4.61-4.70 (m, 7 H, 3 PhCH2, 1a-H), 4.78 (d, 1 H,
3
3
Hz, 2a-H), 5.48 (dd, J 3,2
)
3J 3,4 ) 9.7 Hz, 3b-H). C27H38O18
2J ) 10.9 Hz, 1/2 PhCH2), 5.02 (d, 1 H, J 1,2 ) 3.0 Hz, 1b-H),
(650.59) FAB-MS: m/z 973 (M + Na)+.
5.13 (d, 1 H, J ) 13.2 Hz, 1/2 PhCH2), 7.00-7.32 (m, 36 H, 7
2

Intramolecular Glycosylation Supported by a Rigid Spacer
J . Org. Chem., Vol. 64, No. 17, 1999 6201
Ph, 5′-H), 8.53 (s, 1 H, 2′-H); 13C NMR (125 MHz, CDCl3): δ
55.2 (OCH3), 69.2 (6a-C), 70.1 (5a-C), 71.8 (PhCH2), 71.9 (5b-
C), 72.3, 72.9, 73.2, 73.7, 73.9 (6 PhCH2), 74.0 (6b-C), 75.3
(PhCH2), 77.6 (2a-C), 77.8 (2 C, 3a-C, 4a-C), 78.3 (2b-C), 80.8
(3b-C), 80.9 (4b-C), 97.9 (1a-C), 98.6 (1b-C). C68H68O11 (1061.28)
FAB-MS: m/z 1083 (M + Na)+.
Meth yl 6,3′-O-(1,3-Xylylen e)-(2-O-ben zyl-4,6-O-ben zyl-
idene-r-D-glucopyranosyl)-(1′f4)-2,3-di-O-benzyl-r-D-gluco-
p yr a n osid e (36r). Treatment of compound 35 (44 mg) ac-
cording to the general procedure and chromatography (petro-
leum ether/ethyl acetate 5:1 f 4:1) of the residue affords 36R
(38 mg, 93%) as a colorless oil. TLC (toluene/ethyl acetate
4:1): Rf 0.40; [R]D +22 (c 1, CHCl3); 1H NMR (600 MHz,
CDCl3): δ 3.26 (dd, 1 H, J 6,6 ) 10.6 Hz, J 6,5 ) 7.6 Hz, 6a-H),
3.32 (dd, 1 H, 3J 2,1 ) 2.9 Hz, 3J 2,3 ) 10.0 Hz, 2b-H), 3.36-3.40
(m, 5 H, 4b-H, 5b-H, OCH3), 3.44-3.48 (m, 2 H, 2a-H, 4a-H),
3.52 (dd, 1 H, 3J 6,6 ) 3J 6,5 ) 10.0 Hz, 6b-H), 3.75 (dd, 1 H, 2J 6,6
E t h yl 2-O-Ben zyl-4,6-O-b en zylid en e-6-O-(3-b r om om -
eth ylben zyl)-1-th io-â-D-glu cop yr a n osid e (34). Compound
33 (403 mg, 1.0 mmol) in dry dimethylformamide (5 mL) is
added at 0 °C to a suspension of 2 (792 mg, 3.0 mmol) and
sodium hydride (29 mg, 1.2 mmol) in dry dimethylformamide
(10 mL), and the mixture is stirred for 2 h at 0 °C. Concentra-
tion of the solution in vacuo and chromatography (petroleum
ether/ethyl acetate 19:1 f 14:1) of the residue affords 33 (316
mg, 54%) as a colorless oil. TLC (petroleum ether/ethyl acetate
3:1): Rf 0.59; [R]D -31 (c 1, CHCl3); 1H NMR (250 MHz,
CDCl3): δ 1.31 (t, 3 H, SCH2CH3), 2.68-2.83 (m, 2 H, SCH2-
CH3), 3.39-3.49 (m, 2 H, 2-H, 5-H), 3.66-3.81 (m, 3 H, 3-H,
3
3
3
2
) 10.3 Hz, J 6,5 < 1.0 Hz, 6a-H), 3.92 (dd, 1 H, J 5,6 ) 7.6 Hz,
3J 5,4 ) 10.6 Hz, 5a-H), 3.97-4.00 (m, 2 H, 3a-H, 6b-H), 4.23
3
3
2
(dd, 1 H, J 3,4 ) J 3,2 ) 9.4 Hz, 3b-H), 4.43 (d, 1 H, J ) 13.2
2
Hz, 7′-H), 4.46 (d, 1 H, J ) 10.9 Hz, 1/2 PhCH2), 4.51-4.54
3
(m, 2 H, 4.51 (d, 1 H, J 1,2 )3.8 Hz, 1a-H), 1/2 PhCH2), 4.55
(d, 1 H, 2J ) 12.5 Hz, 1/2 PhCH2), 4.62-4.66 (m, 2 H, PhCH2),
2
4.73 (d, 1 H, J ) 13.2 Hz, 1/2 PhCH2), 4.85-4.94 (m, 3 H, 2
3
3
4-H, 6-H), 4.32-4.38 (m, 3 H, 6-H, 2 7′-H), 4.56 (d, 1 H, J 1,2
8′-H, 1/2 PhCH2), 5.21 (d, 1 H, J 1,2 ) 2.3 Hz, 1b-H), 5.36 (s, 1
) 9.8 Hz, 1-H), 4.74-4.92 (m, 4 H, PhCH2, 2 8′-H), 5.56 (s, 1
H, PhCH), 7.22-7.49 (m, 14 H, 2 Ph, 2′-H, 4′-H, 5′-H, 6′-H);
H, PhCH), 7.16-7.32 (m, 23 H, 4 Ph, 4′-H, 5′-H, 6′-H), 7.58 (s,
1 H, 2′-H); 13C NMR (125 MHz, CDCl3): δ 55.2 (OCH3), 65.7
(5b-C), 67.3 (6a-C), 68.9 (6b-C), 70.0 (3b-C), 70.2 (5a-C), 71.5
(7′-C), 72.1 (4a-C), 73.2, 73.3, 73.5, 74.2 (3 PhCH2, 8′-C), 78.3
(3a-C), 79.0 (2b-C), 80.8 (2a-C), 81.4 (4b-C), 94.6 (1b-C), 97.6
(1a-C), 101.3 (PhCH); FAB-MS: m/z 839 (M + Na)+. Anal.
Calcd for C49H52O11 (816.35): C, 72.04; H, 6.42. Found: C,
71.58; H, 6.42.
MALDI-MS: m/z 607, 609 (M + Na)+. Anal. Calcd for C30H32
-
BrO5S (585.57): C, 61.53; H, 5.68. Found: C, 61.60; H 5.64.
Eth yl 3-O-[3-(Meth yl 2,3-d i-O-ben zyl-r-D-glu cop yr a n o-
side-6-yloxym eth yl)-ben zyl]-2-O-ben zyl-4,6-O-ben zyliden e-
1-th io-â-D-glu cop yr a n osid e (35). Compound 4 (374 mg, 1.0
mmol) and dibutyltin oxide (274 mg, 1.1 mmol) are refluxed
in toluene (10 mL) for 4 h in an apparatus for the azeotropic
removal of water. The solution is cooled to room temperature,
and then tetrabutylammonium bromide (355 mg, 1.1 mmol)
and 34 (293 mg, 0.5 mmol) are added. Stirring for 20 h at 90
°C, evaporation of the solvent, and chromatography (toluene
f toluene/ethyl acetate 19:1) of the residue affords 35 (286
mg, 65%) as a colorless oil. TLC (toluene/ethyl acetate 4:1):
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie.
Su p p or t in g In for m a t ion Ava ila b le: HMQC spectra
(Mu¨ller, L. J . Am. Chem. Soc. 1979, 101, 4481) of macrocyclic
compounds 7â, 8â, 16â, 17â, 25â, 32R, and 36â and of protected
disaccharides 9R, 9â, 10â, 18â, and 19â. HMQC spectra were
acquired at 600 MHz (1H) and 300 K in CDCl3. Signal
assignments are based on DQF-COSY and ROESY spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
Rf 0.36; [R]D -17 (c 1, CHCl3); H NMR (250 MHz, CDCl3): δ
3
1.23 (t, 3 H, SCH2CH3), 2.23 (d, 1 H, J ) 2.3 Hz, OH), 2.64-
2.70 (m, 2 H, SCH2CH3), 3.27 (s, 3 H, OCH3), 3.29-3.72 (m,
11 H, 2a-H, 3a-H, 4a-H, 5a-H, 2 6a-H, 2b-H, 4b-H, 2 6b-H),
4.25-4.93 (m, 13 H, 1a-H, 1b-H, 3b-H, 2 7′-H, 2 8′-H, 3 PhCH2),
5.48 (s, 1 H, PhCH), 7.16-7.40 (m, 24 H, 4 Ph, 2′-H, 4′-H, 5′-
H, 6′-H). C51H58O11S (879.08) FAB-MS: m/z 901 (M + Na)+.
J O990132E