Synthesis of 2,3,6-trideoxysugar-containing disaccharides by cyclization and glycosidation through the sequential activation of sulfoxide and methylsulfanyl groups in a one-pot procedure

Article abstract of DOI:10.1002/anie.200250218

A one-pot procedure for the synthesis of 2,3,6-trideoxyglycosides 1 has been developed, based on the sequential activation of a sulfoxide group and a methylsulfanyl group in 2, cyclization, and subsequent glycosidation with a glycosyl acceptor 3.

Full text of DOI:10.1002/anie.200250218

Angewandte
Chemie
Deoxyglycoside Synthesis
Synthesis of 2,3,6-Trideoxysugar-Containing
Disaccharides by Cyclization and Glycosidation
through the Sequential Activation of Sulfoxide
and Methylsulfanyl Groups in a One-Pot Proce-
dure**
Toru Amaya, Daisuke Takahashi, Hiroshi Tanaka, and
Takashi Takahashi*
Deoxysugars are often found in the polysaccharide domains
of biologically active (anticancer, antibiotic, and cardiotonic)
natural products.[1] The important role that the oligosaccha-
ride moiety plays in this class of natural products has become
apparent.[1,2] Like many deoxysugars, 2,3,6-trideoxysugars
exist in important antibiotics,[3] such as landomycin A[4] and
PI-080.[5] Several problems arise in the synthesis of 2,3,6-
trideoxyglycosides.[6] Glycosyl donors with a leaving group at
the anomeric center are quite sensitive compounds, and the
2,3,6-trideoxyglycosidic linkage formed by glycosylation is
also labile under the acidic conditions used. Generally, the
fewer oxygen atoms present in the pyranoside, the lower its
acid stability.[7] Thus, the glycosylation method chosen should
be applicable to the glycosylation of other deoxysugars and
take into account their acid lability. 2,3,6-Trideoxysugars are
not commercially available, as is true for deoxysugars in
general. Therefore, the development of an efficient synthetic
strategy, including the preparation of deoxysugars, introduc-
tion of the leaving group, and glycosylation, is particularly
important.
Our attention has been focused on a strategy based on the
idea that a sulfur atom can stabilize a carbanion at the
a position, whereas a sulfenium ion can be used to generate a
carbocation at the same position. Hanessian et al. and Trost
et al. elegantly utilized these features in the synthesis of
nucleosides.[8] We recently demonstrated that alkylation of an
a-phenylsulfanyllactone followed by intramolecular acetal
formation (glycosylation) provided a sialyl glycolactone.[9]
Herein we report a novel and convenient one-pot method
for the synthesis of disaccharides that contain 2,3,6-trideoxy-
sugars, from acyclic compounds with a sulfoxide and a
methylsulfanyl group.[10]
The synthetic strategy is illustrated in Scheme 1. Alkyla-
tion of methyl (methylsulfanyl)methyl sulfoxide (formalde-
hyde mercaptal sulfoxide; FAMSO) (4)[11] with 3,4-dialkoxy-
1-iodopentane 5, followed by selective deprotection, provides
[*] Prof. Dr. T. Takahashi, T. Amaya, D. Takahashi, Dr. H. Tanaka
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2884
E-mail: ttakashi@o.cc.titech.ac.jp
[**] This study was supported by Special Coordination Funds for
Promoting Science and Technology from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, to whom we are
deeply indebted.
Angew. Chem. Int. Ed. 2003, 42, 1833 – 1836
DOI: 10.1002/anie.200250218
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1833

Communications
one-pot sequential cyclization and
subsequent glycosidation
OTr
OTr
Y
OTr
Y
O
a
b
X
H
I
HO
1
2
X
X
O
3
O
OH
X
(S)-9
10 (X = OH, Y = H)
11 (X = H, Y = OH)
12 (X = OBn, Y = H)
13 (X = H, Y = OBn)
O
SOMe
SMe
HO
O
OH
OR
1
SOMe
SMe
c
alkylation
2
Y
X
14 (X = OBn, Y = H)
15 (X = H, Y = OBn)
OP
I
SOMe
Scheme 2. Preparation of the key intermediates. a) 1) vinyl magnesium
bromide, THF, 92% (syn (11)/anti (10)=2:3); b) 1) BnBr, NaH, THF,
quant. (12 and 13); 2) BH3·THF, then NaOH, H2O2, 53% (12), 48%
(13); 3) I2, PPh3, benzene, imidazole, 93% (12), 94% (13);
c) 1) FAMSO, NaH, THF, 758C; 2) CSA, MeOH, 2 steps, 70% (14),
80% (15). Tr=triphenylmethyl (trityl), Bn=benzyl, CSA=camphorsul-
fonic acid.
–
SMe
(FAMSO)
OR
5
4
OH
Tf2O
2
TfOSMe
SMe
+
O
ROH, Tf2O (1.1 equiv based on
OR
X
OR
HO
1'
O
donor), CH2Cl2, ms (4Å)
X
14 or 15
6
3
4'
2'
Y
O
O
BnO
BnO
X
TfOSMe
SMe
Glc-C6 =
+
O
HO
BnO
3
O
OMe
1
RO
RO
18 (X = OBn, Y = H, R = Glc-C6)
20 (X = H, Y = OBn, R = Glc-C6)
7
8
R1O
BnO
BnO
BnO
BnO
Glc-C2 =
BnO
O
O
ROH =
R2O
Scheme 1. Synthetic strategy and mechanism of formation of deoxy-
sugar-containing disaccharide 1.
OMe
OMe
16 (R1 = H, R2 = Bn)
or 17 (R1 = Bn, R2 = H)
19 (X = OBn, Y = H, R = Glc-C2)
21 (X = H, Y = OBn, R = Glc-C2)
2. Selective activation of the sulfoxide group[12] in 2 with
trifluoromethanesulfonic anhydride (Tf2O)[13] leads to the
formation of a sulfenium species 6, which undergoes intra-
molecular acetalization to form thioglycopyranoside 7. Con-
comitant activation of the methylsulfanyl group in 7 with the
TfOSMe present affords the oxonium intermediate 8, which
undergoes glycosidation with 3, leading to disaccharide 1
(Scheme 1).[14] As the labile glycosyl donor 7 is formed in situ,
the need for its tedious isolation is avoided. If this reaction is
carried out in the presence of a leaving group X on the
glycosyl acceptor 3, then further elongation of the glycoside is
feasible, that is, orthogonal glycosylation,[15] one-pot glyco-
sylation,[16,17] or two-directional glycosylation.[18]
1,2-Addition of a vinyl Grignard reagent to aldehyde (S)-
9, prepared from ethyl (S)-lactate, afforded the diastereomers
10 and 11 (3:2, 92%), and these were separated on silica
gel.[19] After benzylation of 10, hydroboration, followed by
iodination, afforded iodide 12 (Scheme 2). Alkylation of
FAMSO with 12 was performed at 758C in the presence of
NaH. Removal of the trityl group provided the key inter-
mediate 14 in 70% yield for the two steps.[20] The syn
diastereomer 15 was prepared from 11 by a similar procedure
(Scheme 2).
Scheme 3. One-pot sequential cyclization and glycosidation. ms=mo-
lecular sieves.
was added to a mixture of the acyclic donor 14 and the
acceptor 16 in CH2Cl2 at ꢀ788C. After a few minutes, TLC
analysis showed that the starting substrate had almost
disappeared. After workup and column chromatography the
desired disaccharide 18 was obtained in 83% yield (a/b =
1.2:1) (Table 1, entry 1).[21] The glycosidations of donor 14
with acceptor 17, and donor 15 with acceptors 16 and 17, were
performed under the same conditions to provide the corre-
sponding disaccharides 19, 20, and 21 in 28%, 72%, and 40%
yields, respectively (Table 1, entries 6, 4, and 9). We observed
that glycosidations at the C6 hydroxy group occurred in
moderate yield, whereas glycosidations at the C2hydroxy
group gave the products in poor yield. We believe that the
glycosidation step is the rate-determining step as the sub-
strates disappeared at ꢀ788C within a few minutes. There-
fore, the reaction temperature was allowed to rise slowly from
ꢀ788C to room temperature, which significantly improved
the yields of the reactions at both the C6 and C2hydroxy
groups. Under these conditions, anomerization occurred, with
dominant formation of the a-glycosides as the reaction
temperature increased. When excess donor was used in the
One-pot sequential cyclization and glycosidation was
carried out as follows (Scheme 3, Table 1): Tf2O (1.1 equiv)
1834
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Chemie
Table 1: One-pot sequential cyclization and glycosidation of acyclic
donor precursors 14 and 15 with acceptors 16 and 17.
Table 2: One-pot sequential cyclization and glycosidation with methyl 4-
O-benzoyl-a-d-olivoside (25).
Entry Donor
(equiv)
Acceptor Product
(equiv)
T
[8C]
Yield a/b
[%]
O
BzO
HO
O
BzO
O
OMe
25
1
2
3
14 (1.0) 16 (3.0)
14 (1.0) 16 (3.0)
14 (1.5) 16 (1.0)
18
18
18
ꢀ78
83
1.2:1[a],[c]
1.7:1[a],[c]
2.0:1[a],[c]
(1.0 equiv)
OMe
O
1'
15
ꢀ78!RT 79
Tf2O (1.1 equiv based on
2'
ꢀ78!RT 92
26
BnO
donor), CH2Cl2, ms (4Å),
4
5
15 (1.0) 16 (3.0)
15 (2.0) 16 (1.0)
20
20
ꢀ78
72
4.5:1[b],[d]
3.4:1[b],[d]
Entry
15 [equiv]
T [8C]
Yield [%]
a/b ratio of 26
ꢀ78!RT 88
1
2
3
1.5
1.5
3.0
ꢀ78
20
dec.[b]
63
3.1:1[a]
–
6.9:1[a]
6
7
8
14 (1.0) 17 (3.0)
14 (1.0) 17 (3.0)
14 (1.5) 17 (1.0)
19
19
19
ꢀ78
28
1.2:1[a],[e]
a only[a],[e]
22:1[b],[e]
ꢀ78!RT
ꢀ78!ꢀ50
ꢀ78!RT 65
ꢀ78!RT 73
[a] Ratio determined by HPLC analysis. Assignments of the anomeric
proton signals for a- and b-l-rhodinosides: d=4.88 ppm (br d,
9
10
15 (1.0) 17 (3.0)
15 (1.5) 17 (1.0)
21
21
ꢀ78
40
a only[b],[f]
38:1[b],[f]
J1’,2’ =2.9 Hz) for 26a, d=4.47 ppm (dd, J1’,2’ax =9.2 Hz, J1’,2’eq =1.9 Hz)
ꢀ78!RT 74
for 26b. [b] Decomposed.
[a] The ratio was determined by HPLC analysis. [b] The ratio was
determined by integration of the H-4’ signals in the 1H NMR (400 MHz,
CDCl3) spectrum. [c] Assignments of the anomeric proton signals for a-
and b-l-amicetosides: (400 MHz, CDCl3) d=4.65 ppm (br d,
methyl 4-O-benzoyl-a-d-olivoside (25). Glycosidation at
ꢀ788C for 1 h gave the desired deoxyglycoside 26 in low
yield (20%; Table 2, entry 1). The product decomposed when
the reaction mixture was allowed to warm to room temper-
ature (Table 2, entry 2). However, the desired deoxyglycoside
26 was obtained in moderate yield (63%) when the reaction
temperature was kept at ꢀ508C for 2h (Table 2, entry 3).
In summary, we have developed a novel method for the
synthesis of 2,3,6-trideoxyglycosides by sequential activation
of the sulfoxide and methylsulfanyl groups in a one-pot
procedure. This method does not require anomeric depro-
tection and the activation steps have been incorporated
within traditional glycosylation strategies. Only three steps
are required for the synthesis of disaccharides from oxygen-
functionalized alkyl halides, a variety of which can be readily
prepared as building blocks. Furthermore, this reaction
proceeds in the presence of a phenylsulfanyl group and
glycosyl fluoride, and is applicable to the synthesis of a
deoxyglycoside linked to another deoxyglycoside. Thus, the
reaction should be extremely useful for the diversity-oriented
synthesis of oligosaccharides containing 2-deoxysugars as well
as 2,3,6-trideoxysugars.
J1’,2’ =2.0 Hz) for 18a, d=4.70 ppm (dd, J1’,2’ax =9.2 Hz, J1’,2’eq =1.9 Hz)
for 18b. [d] Assignments of the anomeric proton signals for a- and b-l-
rhodinosides: (400 MHz, [D6]benzene) d=4.80 ppm (br d, J1’,2’ =2.0 Hz)
for 20a, d=4.51 ppm (dd, J1’,2’ax =9.2 Hz, J1’,2’eq =2.0 Hz) for 20b.
[e] Assignments of the anomeric proton signal for a-l-amicetoside:
(400 MHz, CDCl3) d=4.97 ppm (br d, J1’,2’ =2.9 Hz) for 19a.
[f] Assignment of the anomeric proton signal for a-l-rhodinoside:
(400 MHz, CDCl3) d=5.07 ppm (br d, J1’,2’ =2.9 Hz) for 21a.
6'
O
O
1'
22 (1.5 equiv)
BnO
6
2'
Tf2O (1.1 equiv based on donor),
CH2Cl2, ms (4 Å),
O
14
MBzO
MBzO
X
MBzO
–78 °C → RT
23 a (X = SPh): 76%, α/β = 5.5:1
23 b (X = F): 94%, α/β = 3.8:1
HO
O
MBzO
X
ROH =
MBzO
MBzO
22 a (X = SPh)
22 b (X = F)
6'
O
O
1'
ROH (22 a (1.8 equiv), 22 b (1.6 equiv)),
Tf2O (1.1 equiv based on donor),
CH2Cl2, ms (4 Å), –78 °C → RT
4'
2'
BnO
O
MBzO
MBzO
Received: September 23, 2002
Revised: December 20, 2002 [Z50218]
15
X
MBzO
24 a (X = SPh): 80%, α/β = 6.7:1
24 b (X = F): 90%, α/β = 5.9:1
Keywords: carbohydrates · chemoselectivity · cyclization ·
glycosylation · oligosaccharides
.
Scheme 4. Chemoselective glycosidation. MBz=4-methylbenzoyl
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yields (92% for 18 (Table 1, entry 3), 73% for 19 (entry 8)).
We next examined chemoselective glycosidation to dem-
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with phenylthioglycoside 22a or glycosyl fluoride 22b as the
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group or the fluoride (76% for 23a, 94% for 23b, 80% for
24a, 90% for 24b) (Scheme 4).[22]
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Angew. Chem. Int. Ed. 2003, 42, 1833 – 1836
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Communications
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mild, acidic conditions (catalytic amount of CSA in methanol at
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[21] In an attempt to isolate the methylsulfanylpyranoside, the
acyclic donor 14 was treated with Tf2O in the presence of 4-
allyl-1,2-dimethoxybenzene[14a], which can trap TfOSMe. How-
ever, this reaction gave a complex mixture.
[22] The a/b ratios were determined by integration after complete
assignment of chemical shifts from 1H,1H-COSY spectra: 23a
((6’-H) a: d = 1.16 ppm, b: d = 1.20 ppm); 23b (6-H) a: d =
3.90 ppm, b: d = 3.81 ppm); 24a (6’-H) a: d = 1.09 ppm, b: d =
1.55 ppm; 24b (6’-H) a: d = 1.09 ppm, b: d = 1.55 ppm. Chemical
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=
2.9 Hz) for 23b, d = 4.79 ppm (br d, J1’,2’ = 1.9 Hz) for 24a, d =
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1836
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Angew. Chem. Int. Ed. 2003, 42, 1833 – 1836