Prearranged glycosides. Part 14: Intramolecular glycosylation of non-symmetrically tethered glycosides

Article abstract of DOI:10.1016/S0040-4039(00)02032-3

Partially benzylated 1-thio-β-D-glucopyranosides were tethered via position 2 to position 3 of methyl α-D-glucopyranosyl and benzyl 2-phthalimido-2-deoxy-β-D-glucopyranosyl derivatives, respectively, by non-symmetrical o-, m-, and p-methylbenzoate linkers. Intramolecular glycosylation of these prearrange glycosides lead to the corresponding non-symmetrically tethered α-(1→4)-linked disaccharides as the exclusive or main products. The tethers were regioselectively opened by the transesterification affording isomeric disaccharide acceptors which are susceptible for further elongation of the sugar chain at position 3 and 2′, respectively.

Full text of DOI:10.1016/S0040-4039(00)02032-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 569–572
Prearranged glycosides. Part 14: Intramolecular glycosylation of
non-symmetrically tethered glycosides
Thomas Ziegler,* Gregor Lemanski and Ju¨rgen Hu¨rttlen
Institute of Organic Chemistry, University of Cologne, Greinstraße 4, D-50939 Cologne, Germany
Received 13 November 2000
Abstract—Partially benzylated 1-thio-b-
D
-glucopyranosides were tethered via position 2 to position 3 of methyl a-
D-glucopyra-
nosyl and benzyl 2-phthalimido-2-deoxy-b-
D
-glucopyranosyl derivatives, respectively, by non-symmetrical o-, m-, and p-methyl-
benzoate linkers. Intramolecular glycosylation of these prearranged glycosides lead to the corresponding non-symmetrically
tethered a-(1“4)-linked disaccharides as the exclusive or main products. The tethers were regioselectively opened by transester-
ification affording isomeric disaccharide acceptors which are susceptible for further elongation of the sugar chain at positions 3
and 2%, respectively. © 2001 Elsevier Science Ltd. All rights reserved.
Intramolecular glycosylation by ring forming glycosyla-
tion reactions of tethered glycosyl donors and glycosyl
acceptors (prearranged glycosides) has been shown by
us1 and others2 to be a useful tool for the diastereose-
lective formation of O-glycosidic bonds. This strategy
of intramolecular glycosylation of prearranged gly-
cosides is especially powerful for the construction of
tive ring opening by transesterification. The latter sac-
charides B and B% could in turn be used directly as
glycosyl acceptors for further elongation of the sugar
chain. In this communication we would like to outline
briefly the use of non-symmetrical tethers for some
intramolecular a-glucosylation reactions as previously
performed with symmetrical tethers in order to demon-
strate the usefulness of this approach.
otherwise difficult to establish b-
D
-mannosidic and b-L-
rhamnosidic linkages1a,e and can be applied to oligosac-
charide syntheses as well.1h,2d Since only symmetrical
tethers have been used for this approach so far (i.e.
aliphatic and aromatic dicarboxylates and xylylene
groups) the deployment of non-symmetrical tethers
appeared to be desirable because such tethers would
allow for regioselective ring opening after the glycosyla-
tion step. Thus, it extends the applicability of this
strategy to the construction of higher oligosaccharides.
For example, isomeric prearranged glycosides of type A
and A% tethered by benzyl carboxylates (Scheme 1)
would result in saccharides B and B%, respectively, after
subsequent intramolecular glycosylation and regioselec-
As glycosyl donors and acceptors the readily available
partially benzylated 1-thio-b-
-glucosides 13 and the
D
glucoside derivatives 44a and 134b were used. First, 1a3a
was alkylated with t-butyl 2-bromomethyl benzoate5
2a, followed by acidic hydrolysis of the ester group to
give the corresponding glycosyl donor moiety 3a. Simi-
larly, 3-bromomethyl benzonitrile 2b, and 4-bro-
momethyl benzonitrile 2c were condensed with 1a to
afford 1-thio-glycosides 3b and 3c, respectively, after
saponification of the intermediate nitriles. It should be
noted that the condensation product of 1a and 2-bro-
momethyl benzonitrile could not be completely sa-
O
O
O
O
O
SR
HO
O
SR
HO
O
HO
O
O
O
O
OR'
O
O
O
OR'
OH
O
O
OR'
OR'
O
MeOOC
COOMe B'
A'
O
B
A
Scheme 1. Intramolecular glycosylation of isomeric prearranged glycosides using non-symmetrical tethers.
* Corresponding author. Fax: +49 (0)221 470 5057; e-mail: thomas.ziegler@uni-koeln.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02032-3

570
T. Ziegler et al. / Tetrahedron Letters 42 (2001) 569–572
ponified and resulted in an o-benzamide derivative
corresponding to compounds 3 (details are not shown
here). Glycosides 3a–c were condensed with position 3
rides 11 which were transesterified to give saccharides
12 in 79–84% yield.7 The anomeric configuration of all
tethered disaccharides 6 and 11, respectively, were
unambiguously assigned by NMR spectroscopy which
of methyl a- -glucopyranoside derivative 4 and the
D
1
benzylidene groups of the intermediates were regioselec-
tively opened6 to afford the prearranged glycosides 57
(Scheme 2). As was expected from previous intramolec-
ular glucosylations of similarly tethered glycosides1
solely a-(1“4)-linked disaccharides 6 were obtained by
ring closing glycosylation of compounds 5. Finally,
regioselective opening of the non-symmetrical tether of
saccharides 6 was performed by NaOMe-catalyzed
transesterification in methanol to give disaccharides 7 in
80–85% yield.7
showed significant J-coupling constants9 of 169.6 Hz
(6a), 167.4 Hz (6b), 168.3 Hz (6c), 168.3 Hz (11a), 169.1
Hz (11b), and 170.0 Hz (11c). Compared to related
intermolecular 1,4-selective glycosylations with simi-
larly protected non-tethered 1-thio-glycosides10 dia-
stereoselectivities of intramolecular glycosylations of 5
and 10 were significantly increased or even inverted.
In a very similar sequence, phenyl 1-thio-glucoside 1b
was alkylated with methyl 2-bromomethyl benzoate 2e
and methyl 3-bromomethyl benzoate 2f to give directly
intermediates 3e and 3f. Condensation of the latter with
glucosamine derivative 13 followed by benzylidene ring
opening of the intermediates as outlined above gave the
prearranged glycosides 14.7 Intramolecular glycosyla-
tion of 14a and 14b having an o- and m-methylben-
zoate tether, respectively, resulted in a anomeric
mixtures of disaccharides 15 (Scheme 3).7 Both
anomers, however, could be separated by CC and the
anomeric configuration was unambiguously assigned by
the 3J1%,2%-coupling constants that showed 3.2 and 2.9 Hz
for the a-anomers and 8.4 Hz for the b-anomers of 15a
and 15b.7 Compared to the related ring closing glycosy-
lation of compound 6a (Scheme 2) the more bulky
phthalimido group must be responsible for the lower
anomeric selectivity in this case. Similar observations
For the preparation of disaccharides bearing the same
tethers at reversed positions of the donor and acceptor
part two approaches were tested. Esterification of 1a
with 2-bromomethyl benzoyl chloride8 afforded first
intermediate 8 which was subsequently condensed with
4 followed by regioselective ring opening of the benzyl-
idene moiety to give prearranged glycoside 10a.7 As
outlined above for the preparation of 5, glycosyl accep-
tor 4 was alkylated with 2b and 2c, respectively, and the
benzylidene groups of intermediates 9 were once again
opened to afford tethered glycosides 10b and 10c.7 Both
variants afforded the prearranged glycosides 10 in 21–
23% overall yield in three and four steps, respectively.
Final intramolecular glycosylation of the latter gave
once again the corresponding a-(1“4)-linked disaccha-
OBn
OBn
O
O
Ph
O
OBn
O
O
BnO
BnO
OBn
SEt
HO
BnO
BnO
O
SEt
BnO
BnO
O
4 BnO
ii
OH
SEt
HO
OMe
O
OBn
O
iii
BnO
BnO
1a
OBn
O
O
O
O
i
Br
5a (ortho)
5b (meta)
5c (para)
O
O
R
BnO
BnO
OMe
OMe
R
O
O
2a R=o-COOtBu
2b R=m-CN
2c R=p-CN
3a R=o-COOH
3b R=m-COOH
3c R=p-COOH
OBn
O
6a (ortho)
6b (meta)
6c (para)
iv
BnO
BnO
OBn
O
O
O
HO
OBn
MeOOC
Cl
O
BnO
OMe
O
BnO
BnO
SEt
7a (ortho)
7b (meta)
7c (para)
O
Br
O
vi
v
OBn
O
Br
2d
OBn
O
BnO
BnO
8
SEt
OBn
O
O
O
BnO
BnO
OBn
O
HO
O
Ph
iii
O
O
O
O
O
O
HOOC
10a (ortho)
10b (meta)
10c (para)
O
BnO
O
OMe
BnO
vii
viii
OMe
BnO
OMe
4
OBn
O
BnO
BnO
OBn
O
9b (meta)
9c (para)
12a (ortho)
12b (meta)
12c (para)
11a (ortho)
11b (meta)
11c (para)
HO
iv
O
MeOOC
O
BnO
OMe
Scheme 2. (i) (a) 1a+2a, NaH, DMF, 25°C, 1 h, (b) CF3COOH, CH2Cl2, 25°C, 3 h, 82% 3a; (a) 1a+2b,c NaH, DMF, 25°C, 1.5
h, (b) NaOH, EtOH, D, 8 h, 51% 3b, 47% 3c. (ii) (a) 3a–c+4, DCC, cat. DMAP, CH2Cl2, 25°C, 18 h; (b) NaCNBH3, HCl in Et2O,
THF, 0°C, 5 min, 49% 5a, 55% 5b, 48% 5c. (iii) NIS, cat. TMSOTf, CH2Cl2, −30°C, 15 min, 50% 6a, 78% 6b, 70% 6c, 53% 11a,
82% 11b, 71% 11c. (iv) NaOMe, MeOH, D, 4.5 h, 85% 7a, 80% 7b, 82% 7c, 84% 12a, 79% 12b, 82% 12c. (v) 1a+2d, pyridine, 25°C,
16 h, 60% 8. (vi) 4+8, NaH, DMF, 25°C, 1 h, (b) NaCNBH3, HCl in Et2O, THF, 0°C, 5 min, 37% 10a. (vii) (a) 4+2b,c NaH,
DMF, 25°C, 1 h, 78% 9b, 80% 9c. (viii) (a) 1a+9b,c, DCC, cat. DMAP, CH2Cl2, 25°C, 20 h; (b) NaCNBH3, HCl in Et2O, THF,
0°C, 5 min, 53% 10b, 44% 10c.

T. Ziegler et al. / Tetrahedron Letters 42 (2001) 569–572
571
OBn
O
O
Ph
O
OBn
O
O
OBn
BnO
OBn
O
BnO
BnO
HO
SPh
OBn
O
BnO
BnO
PhthN
SPh
1bOH
SPh
HO
iii
BnO
OBn
O
BnO
BnO
OBn
O
O
13
O
O
i
O
ii
OBn
OBn
O
O
Br
R
PhthN
PhthN
14a (ortho)
14b (meta)
O
O
R
2e R=o-COOMe
2f R=m-COOMe
3e R=o-COOH
3f R=m-COOH
OBn
O
iv 15a (ortho) α:β=87:13
15b (meta) α:β=50:50
BnO
BnO
OBn
O
O
O
HO
OBn
16a (ortho)
16b (meta)
AcNH
COOMe
OBn
O
OBn
O
O
Ph
O
OBn
O
O
OBn
BnO
BnO
SPh
BnO
BnO
O
OBn
OBn
HOOC
BnO
OBn
PhthN
O
O
iv BnO
O
O
O
O
O
v
ii
HO
O
OBn
OBn
HO
O
O
13
O
OBn
O
PhthN
PhthN
iii
AcNH
MeOOC
19 α:β=100:0
17
18
20
Scheme 3. (i) (a) 1b+2e,f, NaH, DMF, 25°C, 1.5 h then H2O, 55% 3e, 61% 3f. (ii) (a) 3e,f+13, 1b+17, DCC, cat. DMAP, CH2Cl2,
25°C, 15 h; (b) NaCNBH3, HCl in Et2O, THF, 0°C, 5 min, 42% 14a, 36% 14b, 39% 18. (iii) NIS, cat. TMSOTf, CH2Cl2, 0°C,
20 min, 76% 15a (a-anomer), 11% 15a (b-anomer), 19% 15b (a-anomer), 19% 15b (b-anomer), 67% 19. (iv) (a) N2H4, EtOH, D,
5 h; (b) Ac2O, pyridine, 25°C, 15 h; (c) NaOMe, MeOH/toluene, D, 6 h, 38% 16a, 40% 16b, 37% 20. (v) (a) 13+2e, NaH, DMF,
25°C, 3 h then H2O; (b) LiI, pyridine, D, 4 d, 42% 17.
Acknowledgements
have been previously made as well for symmetrically
tethered glucosamine acceptors.1d As encountered in
other cases1,2 this example also shows the strong depen-
dence of the anomeric diastereoselectivity of in-
tramolecular glycosylations from the ring size. Regiose-
lective ring opening of the tethers of saccharides 15
(only the a-anomers were used here) was achieved
under carefully optimized conditions by subsequent
hydrazinolysis of the phthaloyl group followed by
reacetylation of the formed amine and transesterifica-
tion of the benzoate as performed above. The resulting
disaccharide acceptors 16 were susceptible for further
elongation of the sugar chain at positions 3. The
inverted regioselectivity for the partial cleavage of the
tether was realized in an approach similar to that of
compounds 9b and 9c. Alkylation of 13 with 2d, con-
densation of intermediate 17 with 1b and benzylidene
ring opening gave prearranged glycoside 18.7 When the
latter was intramolecularly glycosylated solely a-(1“4)-
linked disaccharide 19 was obtained.7 This is in contrast
to the cyclizations of isomeric 14 which afforded
anomeric mixtures. The dependence of the anomeric
selectivity on the nature and position of the tether is
evident from this observation. Final opening of the
o-methyl benzoate tether gave disaccharide 20 which
can be used for chain elongation at position 2%.7
We thank Dr. H. Schmickler, and C. Schmitz, Univer-
sity of Cologne for performing the NMR spectra and
the elemental analyses. This work was financially sup-
ported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
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.