An improved synthesis of chacotriose

Article abstract of DOI:10.1246/cl.2004.444

Glycosylation using the trichloroacetimidate method was investigated in order to synthetize chacotriose. In a continuation of previous studies we present here a shorter approach to the synthesis of chacotriose, α-L-rhamnopyranosyl-(1→2)-[α:-L-rhamnopyranosyl-(1→4)] -D-glucopyranose.

Full text of DOI:10.1246/cl.2004.444

444
Chemistry Letters Vol.33, No.4 (2004)
An Improved Synthesis of Chacotriose
y
ꢀyy
´
Vincent Lequart, Gerard Goethals, Joseph Banoub, Pierre Villa, and Patrick Martin
´
Laboratoire des Glucides, Universite de Picardie Jules Verne, F-80039
yDepartment of Biochemistry, Memorial University, St John’s, Canada
yy
`
´
´
´
Laboratoire de la Barriere Hemato Encephalique, Universite d’Artois-Institut Pasteur de Lille, F-62307
(Received January 7, 2004; CL-040028)
Glycosylation using the trichloroacetimidate method was in-
ous attempts showed that the proportion of disaccharide 8 is im-
portant except when using the BF3–Et2O at a temperature of
ꢁ60 ꢂC (Entry 4).
vestigated in order to synthetize chacotriose. In a continuation of
previous studies we present here a shorter approach to the syn-
thesis of chacotriose, ꢀ-L-rhamnopyranosyl-(1!2)-[ꢀ-L-rham-
nopyranosyl-(1!4)]-D-glucopyranose.
Table 2. Regiospecific glycosylation of compound 4
OR2
O
OPiv
OR1
O
O
O
The precise molecular structure of chacotriose represents a
typical structural pattern of steroidal glycoalkaloids,1 with a ꢁ-
D-glucopyranosyl group as the first sugar attached to a steroid,
which in turn is glycosylated with two ꢀ-L-rhamnopyranose
units substituted at the 2- and 4-positions. The many properties
of the glycosteroids2–5 and the difficulty of obtaining them in
great quantity drew our attention. In a previous publication,6
we described the preparation of the peracetylated chacotriose,
while herein we report an improved approach to the synthesis
of this type of trisaccharide.
The previous synthesis of peracetylated chacotriose6 con-
sisted of 13 steps starting from 1,2:5,6-di-O-isopropylidene-ꢀ-
D-glucofuranose.7 We initially undertook to reduce this number,
particularly in the preparation of glycosyl acceptor. The strategy
adopted was to partially protect the glucose unit leaving only the
2- and 4-hydroxy groups available for the glycosylation reaction
with the two L-rhamnopyranose units.
OR1
R3O
OPiv
O
OBn
R
AcO
O
CH3
OBn
OH
O
CH3
AcO
O
O
R3O
O
OBn
CH3
CH3
HO
OBn
OH
OR3
R3O
OAc
AcO
OAc
AcO
OR3
R3O
8
4
5: R = Br
7a: R1 = Bn, R2 = Piv, R3 =Ac
7b: R1 = H, R2 = Piv, R3 =Ac
7c: R1 = R2 = R3 =Ac
6: R = OC(NH)CCl3
Run
Donnor
Temp/ꢂC
Yield 7a
/%
7a-8
1
2
3
5a
6b
6b
20
45
29
53
74
63–37
37–63
72–28
100–0
ꢁ20
ꢁ40
ꢁ60
4
6b
a
b
AgOTf was used. BF3 Et2O was used.
Glycosylation of glucose derivative 4 with 2,3,4-tri-O-ace-
tyl-ꢀ-L-rhamnopyranosyl bromide (5)11 in the presence of
AgOTf by the method of Hanessian and Banoub12 mainly pro-
vided the desired di-O-glycosylated product 7a (45% yield).
However the disaccharide 4-O-glycosylated product 8 was also
obtained in 27% yield while no 2-O-glycosylated product was
isolated. The 13C NMR spectrum of 8 showed two anomeric car-
bons at ꢂ 100.2 and 97.1 ppm and a HMBC experiment indicated
a correlation between C-1 of the rhamnose unit and H-4 of the
glucose unit indicating (1!4) glycosylation in 8.
Table 1. Preparation of glycosyl acceptor
O
OR2
O
O
O
OR1
OBn
OBn
O
HO
O
OH
R1
H
Bn
R2
H
Piv
α
/
β
3:1
1:0
1
2
3
4
To increase the yield, we have used another glycosylation
method described by Schmidt.14 Glycosylation of diol 4 with
2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl trichloroacetimidate
(6)13 under the promotion of BF3–Et2O (Table 2, Runs 2–4) pro-
vided a mixture of tri and disaccharide (7a and 8, respectively).
As the temperature was decreased, the yield of the 4-O-glycosy-
lated product diminished until, at ꢁ60 ꢂC, we did not observe the
disaccharide and we obtained the desired protected chacotriose15
in 74% yield.
Protected trisaccharide 7a was treated with hydrogen in the
presence of Pd/C (10%) to give 7b and then with NaOH to re-
move the benzyl and acetyl groups and subsequently acetylated
to give the desired peracetylated chacotriose 7c.16
Compound 4 was prepared in 3 steps (Table 1) starting from
1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose 1.7 Compound
2 was prepared by condensing 1 with benzyl bromide8 in 83%
yield. Removal of the isopropylidene groups with 3:2 AcOH–
H2O followed by selective protection of the anomeric hydroxyl
with benzyl alcohol in the presence of acetyl chloride9 afforded
compound 3 (71% yield). Position 6 was then selectively pro-
tected with pivaloyl chloride10 in pyridine to give the benzyl
3-O-benzyl-6-O-pivaloyl-ꢀ-D-glucopyranoside 4 in 82% yield.
The 2- and 4-hydroxy groups of glucose acceptor 4 were
glycosylated (Table 2) following two methods: either with
2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl bromide (5)11 by using
AgOTf as promoter,12 or with the 2,3,4-tri-O-acetyl-ꢀ-L-rham-
nopyranosyl trichloroacetimidate (6)13 by using BF3–Et2O as
promoter14 to give the fully protected chacotriose 7a. The vari-
In conclusion, we have devised an improved method for the
synthesis of chacotriose starting from the 1,2:5,6-di-O-isopropy-
lidene-ꢀ-D-glucofuranose with a total yield of 17%. In order to
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.4 (2004)
445
establish structure-activity relations, our objective is now to
synthesize some chacotriose analogues.
[(2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl-(1!4)]-3-O-ben-
zyl-6-O-pivaloyl-ꢀ-D-glucopyranoside (7a): white solid.
26
1
74% yield. mp 91–95 ꢂC; ½ꢀꢃD ꢁ5:7ꢂ (c 1.0, CHCl3); H
References and Notes
H. Ripperger and K. Schreiber, The Alkaloids, Academic
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NMR (300 MHz, CDCl3): ꢂ glucose 4.98 (d, 1H, J1;2
3:4 Hz, H-1), 4.91, 4.32 (2d, 2H, CH2-Ph), 4.76, 4.55 (2d,
¼
1
2H, CH2-Ph), 4.45 (dd, 1H, J5,6a ¼ 2:2 Hz, J6a,6b
¼
2
K. W. Kuo, S. H. Hsu, Y. P. Li, W. L. Lin, L. F. Liu, L. C.
Chang, C. C. Lin, C. N. Lin, and H. M. Sheu, Biochem.
Pharmacol., 60, 1865 (2000).
12:4 Hz, H-6a), 4.22 (dd, 1H, J5,6b ¼ 3:3 Hz, H-6b), 4.01
(t, 1H, J3;4 ¼ 9:3 Hz, H-3), 3.90 (m, 1H, H-5), 3.78 (t, 1H,
J4;5 ¼ 9:1 Hz, H-4), 3.71 (dd, 1H, J2;3 ¼ 9:6 Hz, H-2),
2.21–2.03 (3s, 9H, CH3), rhamnose 5.32 (dd,0 1H,
3
J. G. Roddick, M. Weissenberg, and A. L. Leonard,
Phytochemistry, 56, 603 (2000).
J03;4 ¼ 10:0 Hz, H0-3, Rh-(1!2)), 5.23 (m, 2H, J 2;3
¼
¼
4
5
B. E. Cham and B. Daunter, Cancer Lett., 55, 221 (1990).
T. Ikeda, H. Miyashita, T. Kajimoto, and T. Nohara,
Tetrahedron Lett., 42, 2353 (2001); Y. Du, G. Gu, G. Wei,
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M. Morillo, V. Lequart, E. Grand, G. Goethals, A.
Usubillaga, P. Villa, and P. Martin, Carbohydr. Res., 334,
281 (2001).
3:5 Hz, J00 ¼ 9:2 Hz, H0-2, H00-3), 5.16 (d, 1H, J00
2;3
3:4 Hz, H003-;24 , Rh-(1!4)), 5.03 (t, 1H, J04;5 ¼ 9:9 Hz, H0-
4), 5.00 (t, 1H, J00 ¼ 9:7 Hz, H00-4), 4.96 (m, 2H, H0-1,
4;5
H00-1), 4.06 (m, J05;6 ¼ 6:1 Hz, H0-5), 3.70 (m, 1H, J00
¼
5;6
6
6:4 Hz, H00-5), 1.32–1.21 (6s, 18H, CH3), 1.00 (d, 3H, H00-
6), 0.92 (d, 3H, H0-6); 13C NMR (75 MHz, CDCl3): ꢂ glu-
cose 170.3–169.0 (CO-), 139.2–127.6 (Ph), 100.3 (C-1),
81.1 (C-3), 79.6 (C-2), 76.1 (C-4), 76.0 et 69.8 (CH2-Ph),
69.1 (C-5), 62.6 (C-6), 39.3 (CMe3), 27.6 (CMe3), rhamnose
97.2, 97.1 (C-10), 71.1 (2 C-4), 70.2, 70.0, 69.9, 69.3 (C-2,
C-3), 67.7, 67.3 (C-5), 22.0, 21.9 (CH3-CO), 17.7, 17.5
(C-6). Anal. Calcd for C49H64O21 (989.54): C, 59.51, H,
6.52. Found: C, 59.47, H, 6.50.
7
8
9
I. Regnault, P. Villa, and G. Ronco, Fr. Patent 89 15985
(1989).
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13, 679 (1994).
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hydr. Res., 201, 261 (1990).
10 L. Jiang and T. K. Chan, J. Org. Chem., 63, 6035 (1998).
11 R. K. Ness, Jr., H. G. Fletcher, and C. S. Hudson, J. Am.
Chem. Soc., 73, 296 (1951).
12 S. Hanessian and J. Banoub, Adv. Chem. Ser., 39, 36 (1976).
13 C. Li, B. Yu, and Y. Hui, J. Carbohydr. Chem., 18, 1107
(1999).
14 R. R. Schmidt and W. Kinzy, Adv. Carbohydr. Chem.
Biochem., 50, 21 (1994).
15 Benzyl-2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl-(1!2)-
16 2,3,4-Tri-O-acetyl-ꢀ-L-rhamnopyranosyl-(1!2)-[2,3,4-
tri-O-acetyl-ꢀ-L-rhamnopyranosyl-(1!4)]-1,3,6-tri-O-ace-
tyl-D-glucopyranose (7c):. white solid. 79% yield (ꢀ=ꢁ 2:1);
25
mp 95–98 ꢂC; ½ꢀꢃD þ1:5ꢂ (c 1.1, CHCl3), ESI-Q-TOF-MS
and ESI-Q-TOF-MS-MS: [M+Na]þ m=z 874, [M + Na -
AcOH]þ m=z 814, [M + Na - 2AcOH]þ m=z 754, [M +
Na - 2AcOH - C12H16O7]þ m=z 482, [M + Na - AcOH -
C12H16O7]þ m=z 542. Anal. Calcd for C36H50O23 (850.78):
C, 50.82, H, 5.92. Found: C, 50.76, H, 5.89%.
Published on the web (Advance View) March 20, 2004; DOI 10.1246/cl.2004.444