Efficient synthesis of a group of saponins via orthogonal protection-deprotection glycosylation

Article abstract of DOI:10.1246/cl.2006.84

One new building block of tigogenyl glycoside with orthogonal protective groups has been efficiently synthesized. Using the building block as the key synthon, a small library of saponins with branched sugar moieties was built in an efficient way. Copyrigh

Full text of DOI:10.1246/cl.2006.84

84
Chemistry Letters Vol.35, No.1 (2006)
Efficient Synthesis of a Group of Saponins via Orthogonal Protection–Deprotection Glycosylation
Shujie Hou, Chuanchun Zou, Liang Zhou, Pingsheng Lei,ꢀ and Dequan Yu
Key Laboratory of Bioactivity Substance and Resources Utilization of Chinese Herbal Medicine, Ministry of Education of China,
Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100050, P. R. China
(Received October 11, 2005; CL-051289; E-mail: lei@imm.ac.cn)
One new building block of tigogenyl glycoside with orthog-
onal protective groups has been efficiently synthesized. Using
the building block as the key synthon, a small library of saponins
with branched sugar moieties was built in an efficient way.
uenesulfonic acid monohydrate, then the sterically hindered 3-
OH was masked by a benzyl ether to produce 12 in a yield of
73% of three steps. Treatment of 12 with 80% HOAc at 70 ꢁC
for 2 h, followed by monosilylation with TBDMS afforded 13,
which was turned into 14 in the presence of chloroacetic anhy-
dride. With the key compound 14 in hand, attentation was turned
to examining the orthogonality of the three chosen protective
groups. As anticipated, chloroacetyl group was removed off in
the presence of thiourea to give 13. At the condition of H2/
Pd–C, the building block 14 was hydrogenated giving 15. 14
was treated with CAN leading to clean conversion to 16 in a
yield of 80%. Interestingly, during to purify 16 with CH2Cl2–
MeOH (30:1) and 1% Et3N as eluent, part of chloroacetyl group
in 16 migrated to C06. At the same time, under the condition
of HOAc–THF–H2O (3:1:1) at room temperature for 2 h, the
silyl ether was removed completely. However, a stimultaneous
migration of the chloroacetyl group was observed.
It was well-established that natural products are an excellent
sources of chemical structures with a broad of promising biolog-
ical activities, including anticancer activity.1 Saponins, a struc-
turally and biologically diverse class of natural glycosides pres-
ent in a wide variety of plants, has been opened as a new field of
investigation of potential anticancer compounds.
As a result of the development of various glycosylation pro-
cedure, many natural saponins and their analogues have been
synthesized.2 To synthesis the natural glycosides with compli-
cated branched sugar moieties, the new challenge is to increase
the efficiency of the oligosaccharide assembly. To tackle this
problem, Wong and co-workers developed the strategy of or-
thogonal protection–deprotection glycosylation and built an
oligosaccharide pool in an efficient way.3
Both natural and synthesized compounds containing glucos-
amine have been demonstrated with potent bioactivities.4 In or-
der to study the structur-activity relationship of tigogenyl glyco-
sides, a group of new structurally tigogenyl glycosides having
glucosamine was designed (Figure 1) and synthesized by utiliza-
tion of orthogonal protection–deprotection protocol.
As described in Scheme 1, building block 14 was provided
from tigogenyl monosaccharide 11.5 Removal of the acetyl
groups from 11 gave a triol, which was treated with p-methoxy-
benzaldehyde dimethyl acetal and a catalytic amount of p-tol-
O
O
Tigo
Tigo
O
O
O
O
AcO
O
O
TBDMSO
O
d, e
a, b, c
NthPh
NthPh
NthPh
MP
HO
AcO
O
OAc
OBn
OBn
f
13
12
11
g
Tigo
Tigo
Tigo
O
O
O
O
O
O
TBDMSO
HO
ClAcO
h
i
TBDMSO
ClAcO
NthPh
NthPh
NthPh
ClAcO
OH
OBn
OBn
16
14
15
Scheme 1. Reagents and conditions: a) 0.1 mol Lꢂ1 MeONa–
MeOH, reflux, 87%. b) p-methoxybenzaldehyde dimethyl
acetal, p-TsOH, DMF, 50 ꢁC, 82%. c) BnBr, NaH, DMF, 73%.
d) 80% HOAc, 70 ꢁC, 89%. e) TBDMSiCl, DMAP, imidazole,
DMF, 94%. f) ClAc2O, pyridine, 62%. g) thiourea, CH2Cl2,
73%. h) H2, 10% Pd/C, CH2Cl2–EtOH, 73%. i) CAN, CH2Cl2–
MeOH, 80%.
O
O
O
HO
D-galactopyranosyl =
OH
HO
R3O
O
O
OH
O
When three sugar receptors 13, 15, and 16 were prepared,
six tigogenyl disaccharides were synthesized in an efficient
way described as in shown Scheme 2. Using 2,3,4,6-tetra-O-ace-
tyl-ꢀ-D-galactopyranosyl trichloroacetimidate6 as the sugar do-
nor to couple with 13, 15, and 16 were afforded 17, 19, and
21, respectively. Using the methods described above, TBDMS
group and Bn were efficiently removed off. Treatment of the
three intermediates with hydrazine hydrate and then Ac2O–
MeOH, furnished the target saponins 1, 3, and 5. Using a similar
way with 2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl trichloroace-
timidate7 as donor, disaccharide saponin 2, 4, and 6 were pre-
pared from 13, 15, and 16, respectively.
R2O
NHAc
L-rhamnopyranosyl =
HO
OH
OR1
OH
1. R1 = β-D-galactopyranosyl, R2 = R3= H;
2. R1 = α-L-rhamnopyranosyl, R2 = R3 = H;
3. R2 = β-D-galactopyranosyl, R1 = R3 = H;
4. R2 = α-L-rhamnopyranosyl, R1 = R3 = H;
5. R3 = β-D-galactopyranosyl, R1 = R2 = H;
6. R3 = α-L-rhamnopyranosyl, R1 = R2 = H;
7. R3 = β-D-galactopyranosyl, R2 = α-L-rhamnopyranosyl, R1 = H;
8. R3 = β-D-galactopyranosyl, R1 = α-L-rhamnopyranosyl, R2 = H;
9. R3 = α-L-rhamnopyranosyl, R2 = β-D-galactopyranosyl, R1 = H;
10. R3 = α-L-rhamnopyranosyl, R1 = β-D-galactopyranosyl, R2 =H;
As shown in Scheme 3 as the example, saponins with com-
plete branched sugar moieties were synthesized in an efficient
Figure 1. Small library of tigogenyl glycosides.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.1 (2006)
85
Tigo
In a summary, the tactics of orthogonal protection–deprotec-
tion glycosylation was fist used to synthesized branched sapo-
nins, which was proved to be an efficient way to build the library
of saponins.
Tigo
Tigo
O
O
O
O
O
O
TBDMSO
CAcO
a
TBDMSO
CAcO
b
HO
HO
NthPh
NthPh
NHAc
OR
OH
OR
17, 18
1, 2
13
Tigo
Tigo
Tigo
O
O
O
O
O
O
TBDMSO
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 20372085) is gratefully
acknowledged by the authors.
TBDMSO
c
HO
RO
a
NthPh
NthPh
NHAc
RO
HO
OBn
OBn
OH
19, 20
3, 4
15
Tigo
Tigo
Tigo
References and Notes
G. M. Cragg, D. J. Newman, Expert Opin. Invest. Drugs
2000, 9, 2738.
O
O
O
O
O
O
a
RO
d
RO
HO
HO
1
NthPh
NHAc
NthPh
CAcO
CAcO
OBn
OH
OBn
2
a) B. Yu, B. Li, G. W. Xing, Y. Z. Hui, J. Comb. Chem. 2001,
3, 404. b) S. J. Hou, C. C. Zou, L. Zhou, P. S. Lei, D. Q. Yu,
Chem. Lett. 2005, 34, 1220. c) C. C. Zou, S. J. Hou, P. S. Lei,
X. T. Liang, Carbohydr. Res. 2003, 338, 721.
C. H. Wong, X. S. Ye, Z. Y. Zhang, J. Am. Chem. Soc. 1998,
120, 7137.
H. Myszka, D. Bednarczyk, M. Najder, W. Kaca, Carbo-
hydr. Res. 1979, 338, 133.
S. J. Hou, C. C. Zhou, P. S. Lei, D. Q. Yu, Chin. Chem. Lett.
2004, 15, 781.
5, 6
16
21,22
17, 19, 21: R = 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl;
1, 3, 5: R = β-D-galactopyranosyl
18, 20, 22: R = 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl,
2, 4, 6: R = α-L-rhamnopyranosyl
3
4
5
6
7
.
ꢀ
Scheme 2. Reagents and conditions: a) BF3 Et2O, CH2Cl2, 4 A
MS, ꢂ40 ꢁC ! rt, 75% for 17, 65% for 18, 89% for 19, 87%
for 20, 46% for 21, 55% for 20. b) (i). CAN, CH2Cl2–MeOH;
. .
(ii). 85% NH2 NH2 H2O, CH2Cl2–EtOH, reflux (iii). Ac2O–
MeOH, rt; 43% for 1, 47% for 2 over three steps. c) (i). H2, 10%
U. Lemieux, T. Takeda, B. Y. Chung, Am. Chem. Soc. Series
1976, 39, 90.
Pd/C, CH2Cl2–MeOH; (ii). CAN, CH2Cl2–MeOH; (iii). 85%
. .
NH2 NH2 H2O, CH2Cl2–EtOH, reflux (iv). Ac2O–MeOH, rt;
37% for 3 and 33% for 4 over four steps. d) (i). H2, 10% Pd/C,
CH2Cl2–MeOH; (ii). 85% NH2 NH2 H2O, CH2Cl2–EtOH, reflux
(iii). Ac2O–MeOH, rt. 41% for 5 and 39% for 6 over three steps.
I. Kitagawa, N. I. Back, K. Ohashi, M. Sakagami, M.
Yoshikawa, H. Shibuya, Chem. Pharm. Bull. 1989, 37,
1131; T. Fujiwara, K. Aria, Carbohydr. Res. 1979, 69, 305.
The spectral data of 7: 13C NMR (75 MHz, pyridine-d5) ꢁ
170.4, 109.2, 105.4, 103.1, 100.1, 81.1, 80.7, 78.0, 76.9,
75.2, 75.1, 74.1, 73.8, 72.6, 72.4, 72.2, 70.5, 70.1, 68.8,
66.8, 63.0, 62.1, 58.4, 56.3, 55.0, 54.3, 44.5, 41.9, 40.7,
40.1, 37.1, 35.7, 35.2, 32.3, 32.0, 31.7, 30.5, 29.9, 29.2,
28.9, 23.6, 21.2, 18.4, 17.3, 16.5, 15.0, 12.2. FAB-MS
(m=z): 950.6 ðM þ NaÞþ HRMS (FAB-MS) m=z: calcd for
C47H77NO17Na ðM þ NaÞþ 950.5089, found: 950.5114.
The spectral data of 8: 13C NMR (75 MHz, pyridine-d5) ꢁ
170.8, 109.2, 105.9, 102.2, 100.3, 82.5, 80.0, 78.4, 77.0,
74.9, 74.8, 73.8, 73.6, 72.6, 72.2, 69.8, 69.6, 67.2, 66.7,
62.8, 61.8, 57.0, 56.2 (2 ꢃ C, overlap), 54.1, 44.5, 41.8,
40.6, 39.9, 36.9, 35.6, 35.0, 32.2 (2 ꢃ C, overlap), 31.9,
31.6, 30.4, 29.8, 29.1, 28.7, 23.4, 21.1, 18.5, 17.2, 16.4,
14.9, 12.1. FAB-MS (m=z): 950.4 ðM þ NaÞþ HRMS
(FAB-MS) m=z: calcd for C47H77NO17Na ðM þ NaÞþ
950.5089, found: 950.5099.
. .
8
Tigo
Tigo
Tigo
O
O
O
O
O
O
RO
R1O
RO
R1O
RO
b
c
NthPh
a
NHAc
NthPh
HO
Tigo
O
O
OBn
OH
OBn
RO
21b, 22b
7, 8
21a, 22a
NthPh
CAcO
a1
OBn
Tigo
Tigo
21, 22
Tigo
O
O
O
O
O
O
d
RO
CAcO
RO
RO
CAcO
b
NthPh
NHAc
NthPh
HO
9
OR1
OR1
OH
21A, 22A
21B, 22B
9, 10
21, 21a, 21A: R = 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl;
21b, 21B: R = 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl, R1 = 2,3,4-
tri-O-acetyl-α-L-rhamnopyranosyl,
7, 9: R = β-D-galactopyranosyl, R1 = α-L-rhamnopyranosyl;8,10
22, 22a, 22A: R = 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl
22b, 22B: R = 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl, R1 = 2,3,4,6-
tetra-O-acetyl-β-D-galactopyranosyl
10 The spectral data of 9: 13C NMR (75 MHz, pyridine-d5) ꢁ
170.2, 109.1, 105.8, 103.2, 99.8, 82.3, 81.0, 77.9, 76.9,
75.2, 73.7, 72.6, 72.5, 72.4, 70.6, 70.1, 69.7, 66.7, 62.9,
62.2, 57.2, 56.3, 56.0, 54.2, 44.4, 41.9, 40.6, 40.0, 37.0,
35.6, 35.1, 35.0, 34.8, 32.2, 32.0, 31.5, 30.5, 29.9, 29.1,
28.8, 23.3, 21.1, 18.4, 17.3, 16.5, 14.9, 12.2. FAB-MS
(m=z): 950 ðM þ NaÞþ HRMS (FAB-MS) m=z: calcd for
C47H77NO17Na ðM þ NaÞþ 950.5089, found: 950.5126.
11 The spectral data of 10: 13C NMR (75 MHz, pyridine-d5) ꢁ
171.3, 109.1, 105.8, 102.6, 99.9, 86.0, 81.0, 78.1, 77.3,
76.1, 75.0, 73.9, 72.2, 72.3, 70.4, 70.0, 69.8, 68.0, 66.8,
62.9, 62.0, 56.6, 56.3, 54.2, 44.4, 41.4, 40.7, 40.0, 37.0,
35.7, 35.1, 35.0, 32.3, 32.0, 31.7, 31.5, 30.5, 29.9, 29.2,
28.9, 23.7, 21.2, 18.6, 17.4, 16.5, 15.0, 12.2. FAB-MS
(m=z): 950.5 ðM þ NaÞþ HRMS (FAB-MS) m=z: calcd for
C47H77NO17Na ðM þ NaÞþ 950.5089, found: 950.5126.
8, 10: R = α-L-rhamnopyranosy, R1 = β-D-galactopyranosyl9,11
Scheme 3. Reagents and conditions: a) thiourea, CH2Cl2, 73%. b)
ꢁ
.
ꢀ
BF3 Et2O, CH2Cl2, 4 A MS, ꢂ40 C ! rt, 65% for 21b, 63% for
22b, 79% for 21B, 62% for 22B. c) (i). H2, 10% Pd/C, CH2Cl2–
. .
MeOH; (ii). 85% NH2 NH2 H2O, CH2Cl2–EtOH, reflux (iii).
Ac2O–MeOH, rt; 51% for 7 and 47% for 8 over three steps. d)
. .
(i). 85% NH2 NH2 H2O, CH2Cl2–EtOH, reflux (ii). Ac2O–
MeOH, rt, 68% for 9 and 72% for 10 over two steps.
way. With the synthon 21 in hand, sugar receptors 21a and 21A
were furnished. Using 2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl
trichloroacetimidate as the sugar donor to couple with 21a and
21A, trisaccharide saponins 21b and 21B were afforded respec-
tively. By deprotection of 21b and 21B, target saponins 7 and 9
were produced. According to the same procedure, 8 and 10 were
synthesized from 22.
Published on the web (Advance View) December 10, 2005; DOI 10.1246/cl.2006.84