The first total synthesis of telephiose A

Article abstract of DOI:10.1016/j.tetlet.2007.03.138

The first total synthesis of telephiose A (1), a novel trisaccharide ester having two acetyl groups and two benzoyl groups, was achieved by using glucosyl donor 6 and disaccharide acceptor 12. The crucial key step was the stereoselective construction of t

Full text of DOI:10.1016/j.tetlet.2007.03.138

Tetrahedron Letters 48 (2007) 3745–3748
The first total synthesis of telephiose A
Ken-ichi Sato,* Koudai Sakai, Keiko Tsushima and Shoji Akai
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1, Rokkakubashi,
Kanagawa-ku, Yokohama 221-8686, Japan
Received 26 December 2006; revised 15 March 2007; accepted 16 March 2007
Available online 27 March 2007
Abstract—The first total synthesis of telephiose A (1), a novel trisaccharide ester having two acetyl groups and two benzoyl groups,
was achieved by using glucosyl donor 6 and disaccharide acceptor 12. The crucial key step was the stereoselective construction of the
b-D-glucosidic linkage featuring the neighboring group participation of the 2-O-N-phenylcarbamoyl group (of donor 6), which can
be selectively deprotected in the presence of acetyl and benzoyl groups. Donor 6 was prepared from D-glucose in eight steps (33%
yield), whereas acceptor 12 was prepared from sucrose in six steps (35% yield). Precursors 6 and 12 were reacted in subsequent reac-
tions (five steps) to afford 1 in 22% yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Three new oligosaccharide esters (telephiose A–C,
Fig. 1) have been isolated from Polygala telephioides
WILLD, a plant, that is, widely distributed in southern
China and employed as a detoxification agent for heroin
poisoning in China. The structures of the esters have
been recently characterized using spectroscopic studies.1
Due to our interest in the detoxification activities and
the structures of these partially acylated oligosaccharide
esters, we decided to undertake the total synthesis of
telephiose A (1) via a key step in the stereoselective con-
struction of the b-D-glucosidic linkage via neighboring
group participation of 2-O-acyl type protecting group,
which could be deprotected in the presence of acyl
groups of the glucosyl donor.
In a previous Letter,2 we reported on the construction of
four types of glycosidic linkages via a universal glucosyl
donor that involves the neighboring group participation
of an N-phenylcarbamoyl (Car) group and the SN2 dis-
placement reaction at C-2. The Car group is stable from
pH 1 to 12 in aqueous solutions,3 and because of the dif-
ficulty in the deprotection, the Car group has yet to be
widely employed for the protection of hydroxyl groups.
To the best of our knowledge, the Car protecting group
has not been employed in the synthesis of complex nat-
ural products, which often require delicate chemical dif-
ferentiation of various protecting groups under mild
conditions. We have successfully developed a novel
deprotection procedure that does not affect acyl, silyl,
methoxymethyl, benzylidene acetal, and isopropylidene
acetal protecting groups,4 and therefore, has allowed
the Car group to become a valuable tool in natural
products syntheses.
OR1
O
BzO
HO
R3O
HO
O
O
O
HO
OH
HO
O
BzO
OR2
HO
Telephiose A (1) : R1 = R2 = Ac, R3 = H
Herein, we describe the practical synthesis of telephiose
A (1) from D-glucose and D-sucrose featuring the prop-
erties of the Car group.
B
C
: R1 =H, R2 = R3 = Ac
: R1 = R2 = R3 = H
Figure 1. The structures of telephioses.
As shown in Scheme 1, glucosyl donor 6 was prepared
from D-glucose in eight steps. Initially, phenyl 4,6-O-
benzylidene-1-thio-b-D-glucopyranoside (2)5 was pre-
pared from D-glucose in four steps (61% yield). Treat-
ment of 2 with methoxymethyl chloride (MOM–Cl,
Keywords: Telephiose; Total synthesis; Oligosaccharide esters;
N-Phenylcarbamoyl group.
*
Corresponding author. Tel.: +81 45 481 5661x3853; fax: +81 45 413
9770; e-mail: satouk01@kanagawa-u.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.138

3746
K. Sato et al. / Tetrahedron Letters 48 (2007) 3745–3748
the corresponding 2-O-Car derivative 4 in 92% yield.
Ph
O
a) - d)
61%
e)
O
O
D-Glucose
Acid hydrolysis of 4 using 70% aq AcOH at 60 ꢁC for
1 h gave 4,6-diol derivative 5, which was then treated
with MOM–Cl (2.5 equiv) and N-ethyl-diisopropyl-
amine (2.5 equiv) in CH2Cl2 for 4 h to afford glucosyl
donor 66 in 71% yield (two steps).
SPh
HO
84%
OH
2
Ph
MOMO
O
Ph
O
f)
O
O
O
O
SPh
SPh
MOMO
92%
On the other hand, as showed in Scheme 2, acceptor 12
was prepared from sucrose in six steps. Following
Mannzo’s procedure,7 sucrose, acetone dimethylacetal
(10 equiv), and cerium(IV) ammonium nitrite (0.2 equiv)
were reacted to afford 2,10:4,6-di-O-isopropylidene-
sucrose (7) in 70% yield. The selective protection8 of
the 40,60-OH groups of 7 involved the addition of 1,3-di-
chloro-1,1,3,3-tetraisopropyldisiloxane (1.2 equiv) (in
three portions) to a mixture of 7 and imidazole
(1.0 equiv) in pyridine at 0 ꢁC. After maintaining the
reaction mixture for 8 h, and upon the disappearance
of 7 (determined by TLC), MeOH was added to the
reaction mixture. Typical work up procedures, followed
by purification using silica gel column chromatography
afforded 8 in 89% yield. Purified 8 was reacted with
MOM–Cl (1.2 equiv) and N-ethyldiisopropylamine
(1.2 equiv) in CH2Cl2 at rt for 6 h to give 3-O-meth-
oxymethyl derivative 9 (85% yield), which was treated
with benzoyl chloride (2.0 equiv) in pyridine to afford
OH
OCar
3
4
OH
OMOM
O
g)
e)
84%
O
HO
MOMO
MOMO
MOMO
SPh
OCar
SPh
OCar
84%
5
6
Scheme 1.9 Reagents and conditions: (a) Ac2O, AcONa; (b) PhSH,
BF3ÆEt2O/(ClCH2)2; (c) NaOMe/MeOH; (d) PhCH(OCH3)2, p-TsOH/
DMF; (e) MOM–Cl, i-Pr2NEt/CH2Cl2; (f) Ph–NCO/Py; (g) 70% aq
AcOH.
1.5 equiv) and N-ethyldiisopropylamine (1.2 equiv) in
CH2Cl2 at 0 ꢁC for 12 h afforded 3 (84% yield), which
was reacted with phenyl isocyanate (2.0 equiv) in pyri-
dine with stirring for 5 h at rt. Upon the addition of
MeOH, the reaction mixture was removed by evapora-
tion, and the crude product was recrystallized to give
O
O
O
O
O
O
OH
OH
HO
HO
c)
a)
b)
O
O
O
OH
O
O
Sucrose
i-Pr
i-Pr
70%
89%
85%
O
O
HO
Si
O
O
O
O
Si
i-Pr
i-Pr
7
8
OAc
O
OR
O
O
HO
MOMO
MOMO
O
HO
O
6
MOMO
O
OR
MOMO
O
O
HO
O
O
O
O
O
O
MOMO
i-Pr
i-Pr
e)
g)
57%
β-selective
O
i-Pr
O
O
MOMO
i-Pr
OCar
Si
Si
BzO
O
83%
i-Pr
O
OR
Si
O
i-Pr
O
Si
O
BzO
i-Pr
i-Pr
Si
O
OAc
i-Pr
i-Pr
d)
97%
9: R = H
Si
O
i-Pr
i-Pr
10: R = Bz
11: R = H
f)
83%
13
12: R = Ac
OAc
O
OAc
O
OAc
O
BzO
MOMO
BzO
BzO
HO
MOMO
MOMO
HO
HO
MOMO
O
O
OH
O
O
O
O
MOMO
MOMO
O
O
O
h)
98%
j)
MOMO
i-Pr
HO
MOMO
k)
OR
OH
O
HO
HO
O
92%
O
O
61%
Si
O
BzO
BzO
BzO
i-Pr
OAc
OAc
OAc
HO
Si
O
HO
i-Pr
16
1
i-Pr
14: R = Car
15: R = H
i)
71%
Scheme 2.9 Reagents and conditions: (a) Ce(N2H4)2(NO3)6, (CH3)2C(OCH3)2/DMF; (b) [[(CH3)2CH]2SiCl]–O–[ClSi[CH(CH3)2]2], imidazole/DMF;
(c) MOM–Cl, i-Pr2NEt/CH2Cl2; (d) BzCl, Py; (e) 0.1 M HCl–MeOH; (f) AcCl, Py; (g) NIS, TMSOTf, MS4A/CH2Cl2; (h) BzCl, Py; (i) Bu4NNO2/
DMF; (j) TBAF/THF; (k) 90% AcOH aq.

K. Sato et al. / Tetrahedron Letters 48 (2007) 3745–3748
3747
the corresponding 30-O-benzoate derivative as an oil
Supplementary data
(97% yield); the structure of 10 was confirmed using
1H NMR spectroscopy [downfield shift of H-30(fruc)
and elemental analysis. Direct mono-benzoylation of
10 gave 3-O-benzoate (glc) instead 30-O-benzoyl (glc)
derivative, by the way. Selective hydrolysis of 10 at rt
using 0.1 M HCl–MeOH, followed by neutralization
using Dowex (OHꢀ form), afforded de-O-isopropylidene
11 (83% yield), which was treated with acetyl chloride
(1.5 equiv) in pyridine at 0 ꢁC for 30 min to afford
6,10-di-O-acetate 12 as an oil6 (83% yield). The struc-
ture of 12 was confirmed using 1H NMR spectro-
scopy [downfield shift of H-6 and H-10] and elemental
analysis.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.03.138.
References and notes
1. Li, J.-C.; Masateru, O.; Toshihiro, N. Chem. Pharm. Bull.
2000, 48, 1223–1225.
2. Sato, K.; Akai, S.; Sakai, K.; Kojima, M.; Murakami, H.;
Idoji, T. Tetrahedron Lett. 2005, 46, 7411–7414.
3. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999.
Using donor 6 and disaccharide acceptor 12, telephiose
A (1) was synthesized as follows: to a stirred mixture of
6 (1.0 equiv), 12 (0.9 equiv), and MS 4A in CH2Cl2
(after stirring for 30 min under argon at rt) was added
(dropwise) dry N-iodosucinimide (1.5 equiv), followed
by trimethylsilyl trifluoromethanesulfonate (TMSOTf,
0.3 equiv) at ꢀ40 ꢁC. Upon disappearance of the start-
ing material using TLC (1 h), the reaction mixture was
neutralized with Et3N, filtered, diluted with CHCl3,
and washed with aq NaHCO3, aq Na2S2O3, brine, and
water. The organic layer was dried over anhydrous
MgSO4, removed by evaporation, then purified using sil-
ica gel column chromatography to give trisaccharide 13
as an oil [1H NMR, J1,2 = 9.7 Hz, H-1 (b-linkage)] (57%
yield). In addition to the main product, the formation of
a small amount of a side product, the 4-O-glucoside
(10%), was observed. Benzoylation of the 4-OH group
of 13 with benzoyl chloride (1.5 equiv) in pyridine gave
4. Akai, S.; Nishino, N.; Iwata, Y.; Hiyama, J.; Kawashima,
E.; Sato, K.; Ishido, Y. Tetrahedron Lett. 1998, 39, 5583–
5586.
5. Blom, P.; Ruttens, B.; Van Hoof, S.; Hubrecht, I.; Van der
Eycken, J.; Sas, B.; Van hemel, J.; Vandenkerckhove, J. J.
Org. Chem. 2005, 70, 10109–10112.
6. IR (KBr, neat), 1H NMR, and other physical data of
compound 6, 12, and 1.
25
Compound 6: mp 173.5–174.0 ꢁC (hexane–EtOH); ½aꢁD
+20.8 (c 0.7, CHCl3); mNH 2928 cmꢀ1, mC@O 1738 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 7.54–7.05 (5H, m, Ph), 6.83
(1H, s, –NH–), 5.15 (1H, dd, J2,1 = 9.7 Hz, J2,3 = 9.2 Hz,
H-2), 4.82, 4.72 (2H, each d, JAB = 7.4 Hz, CH2OCH3),
4.74, 4.68 (2H, each d, JAB = 7.8 Hz, CH2OCH3), 4.72, 4.67
(2H, each d, JAB = 6.2 Hz, CH2OCH3), 4.68 (1H, d, H-1),
3.84 (1H, dd, J6a,5 = 2.2 Hz, J6a,6b = 11.5 Hz, H-6a), 3.73
(1H, dd, J6b,5 = 5.1 Hz, H-6b), 3.68 (1H, dd, J3,4 = 9.7 Hz,
H-5), 3.57 (1H, dd, J4,5 = 9.2 Hz, H-4), 3.41 (1H, ddd, H-
5), 3.36, 3.33, 3.30 (9H, each s, OCH3). Anal. Calcd for
C25H33NO9S (523.60): C, 67.86; H, 5.34; N, 2.39. Found: C,
67.91; H, 5.54; N, 2.37.
1
14 (98% yield), which was confirmed using H NMR
spectroscopy [down field shift of H-4 (glc)] and elemen-
tal analysis. The 2-O-N-phenylcarbamoyl group of 14
was removed using Bu4NNO2 (3.0 equiv) in DMF at
90 ꢁC for 12 h under argon to give 15 as an oil (71%
yield), which was treated with Bu4NF (TBAF) in THF
to afford de-O-silylated 16 as an oil (92% yield). Depro-
tection conditions of the MOM groups using 90% aq
AcOH at rt resulted in a mixture of 1 (yield 61%) and
a side product (cleavage of the fructosyl linkage, ca.
20%). Purification using silica gel column chromatogra-
phy (CHCl3–MeOH) afforded pure 1; the optical rota-
26
Compound 12: ½aꢁD ꢀ15.0 (c 0.7, CHCl3); IR (KBr, neat)
m
C@O 1732 cmꢀ1, 1738 cmꢀ1, 1746 cmꢀ1, mOH 3455 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d 8.08–7.27 (5H, m, Ph), 5.61
(1H, d, J3 ,4 = 8.6 Hz, H-30), 5.52 (1H, d, J1,2 = 3.4 Hz, H-
1), 4.76 (1H, dd, J6a,5 = 8.6 Hz, J6a,6b = 8.3 Hz, H-6a), 4.71,
4.58 (2H, each d, JAB = 6.9 Hz, CH2OCH3), 4.43 (1H, d,
0
0
J1a ,1b = 12.0 Hz, H-1a0), 4.32 (1H, d, H-1b0), 4.31 (1H, dd,
J6b,5 = 9.5 Hz, H-6b), 4.06–4.05 (2H, m, H-40, H-50), 3.94–
3.90 (2H, m, H-6a0, H-3), 3.56–3.50 (2H, m, H-5, H-6b0),
3.41 (3H, s, OCH3), 3.39–3.32 (2H, m, H-2, H-4), 2.08 (6H,
s, COCH3 · 2), 1.12–0.95 (24H, m, TIPDS); Anal. Calcd
for C37H60O16Si2 (817.03): C, 54.39; H, 7.40. Found: C,
54.51; H, 7.64.
0
0
1
tion values and H NMR data are in good agreement
with those reported.1,6
24
Telephiose (1): [Synthetic]: colorless syrup; ½aꢁD ꢀ14.8 (c
0.36, MeOH) 1H NMR (600 MHz, Pyridine-d5) d 8.31–7.41
(10H, m, Ph), 6.30 (1H, d, J1,2 = 3.9 Hz, H-1 (Glc1)), 6.28
(1H, d, J3,4 = 8.9 Hz, H-3 (Fruc)), 5.69 (1H, dd,
J4,3 = 9.9 Hz, J4,5 = 9.9 Hz, H-4 (Glc1)), 5.17 (1H, dd,
J4,5 = 8.0 Hz, H-4 (Fruc)), 5.14 (1H, d, J2,3 = 12.2 Hz, H-2
(Fruc)), 5.09 (1H, d, J1,2 = 8.0 Hz, H-1 (Glc2)), 4.87 (1H,
m, H-5 (Glc1)), 4.69 (1H, m, H-5 (Fruc)), 4.62 (1H, m,
J1,2 = 12.2 Hz, H-1 (Fruc)), 4.59 (1H, dd, J3,2 = 9.9 Hz, H-
3 (Glc1)), 4.54–4.48 (3H, m, H-6 (Glc1), H-60 (Glc1), H-6
Herein, we described the first total synthesis of telephi-
ose A using a glucosyl donor (based on D-glucose) and
a disaccharide acceptor (based on sucrose). Our syn-
thetic methodology illustrates the usefulness of a Car
protecting group in the synthesis of oligosaccharide
esters.
0
(Glc2)), 4.47 (1H, dd, J5,6 = 6.4 Hz, J6,6 = 12.3 Hz, H-6
Acknowledgments
(Fruc)), 4.38 (1H, dd, J5,6 = 3.2 Hz, H-60 (Fruc)), 4.30 (1H,
dd, J5,6 = 5.8 Hz, J6 ,6 = 12.1 Hz, H-60(Glc2)), 4.17–3.98
(4H, m, H-4 (Glc2), H-3 (Glc2), H-2 (Glc2), H-2 (Glc1)),
3.93 (1H, m, H-5 (Glc2)), 2.10, 1.91 (6H, each s,
COCH3 · 2).
0
0
This work was partially supported by a ‘Science Fron-
tier Project of Kanagawa University’ from the Ministry
of Education, Science, Sports and Culture, Japan.
The authors thank Professor Nakagawa for helpful
discussions.
24
[Natural]: syrup; ½aꢁD ꢀ11.0 (c 0.45, MeOH) 1H NMR
(300 MHz, Pyridine-d5) d 8.26–7.40 (10H, m, Ph), 6.31 (1H,

3748
K. Sato et al. / Tetrahedron Letters 48 (2007) 3745–3748
J6 ,6 = 11.9 Hz, H-60 (Glc2)), 4.13–4.03 (4H, m, H-4 (Glc2),
H-3 (Glc2), H-2 (Glc2), H-2 (Glc1)), 3.91 (1H, m, H-5
(Glc2)), 2.07, 1.89 (6H, each s, COCH3 · 2).
0
d, J1,2 = 3.7 Hz, H-1 (Glc1)), 6.30 (1H, d, J3,4 = 8.6 Hz, H-
3 (Fruc)), 5.67 (1H, dd, J4,3 = 9.8 Hz, J4,5 = 9.8 Hz, H-4
(Glc1)), 5.15 (1H, dd, J4,5 = 7.9 Hz, H-4 (Fruc)), 5.12 (1H,
d, J2,3 = 12.2 Hz, H-2 (Fruc)), 5.08 (1H, d, J1,2 = 7.9 Hz,
H-1 (Glc2)), 4.87 (1H, m, H-5 (Glc1)), 4.68 (1H, m, H-5
(Fruc)), 4.60 (1H, m, J1,2 = 12.2 Hz, H-1 (Fruc)), 4.59 (1H,
dd, J3,2 = 9.8 Hz, H-3 (Glc1)), 4.51-4.50 (3H, m, H-6
(Glc1), H-60 (Glc1), H-6 (Glc2)), 4.43 (1 H, dd,
7. Mannzo, E.; Barone, G.; Parrilli, M. Synlett 2000, 887–889.
8. Poschalko, A.; Rohr, T.; Gruber, H.; Bianco, A.; Guichard,
G.; Briand, J.; Weber, V.; Falkenhagen, D. J. Am. Chem.
Soc. 2003, 125, 13415–13426.
9. For experimental procedure and their physical data of
compounds 3–5, 7–11, and 13–16, see Supplementary data
at doi:10.1016/j.tetlet.2007.03.138.
0
J5,6 = 6.4 Hz, J6,6 = 12.4 Hz, H-6 (Fruc)), 4.37 (1H, dd,
J5,6 = 3.4 Hz, H-60 (Fruc)), 4.31 (1H, dd, J5,6 = 5.8 Hz,
0