Zhang and Yu
TABLE 1. Glycosyla tion of Tor a la cton e 5 w ith Don or s 6a -g
entry
donor (equiv)
conditionsa
products (yield, %)
1
2
3
4
5
6a (1.2)
TMSOTf (0.3 equiv), PhCl, rt, 2 h
TMSOTf (1.5 equiv), DTBMP (2.5 equiv), PhCl, rt, 15 h
TMSOTf (0.2 equiv), ClCH2CH2Cl, rt, 24 h
BF3‚OEt2 (0.2-3.4 equiv), ClCH2CH2Cl, -78 °C to rt, 16 h
TMSOTf (0.2 equiv), CH2Cl2, 0 °C to rt, 2 h;
additional TMSOTf (0.6 equiv) was added, rt, 24 h
TBAB (1.2 equiv), borate buffer (pH ) 10.8), CHCl3, 52 °C, 12 h
TBAB (1.2 equiv), 0.06 M K2CO3, CHCl3, 40 °C, 24 h
CdCO3 (4.0 equiv), toluene, reflux, 19 h
25 (trace)
25 (<25)
6b (1.4)
6c (1.5)
26 (trace), 29
26 (no), 29
27 (trace)
27 (trace), 30
28 (<20)
6
7
8
6d (3.0)
(1.5)
28 (trace)
complex
(2.0)
9
6e (3.0)
6f (1.5)
(1.5)
(6.0)
(6.0)
6g (2.0)
(6.0)
BF3‚OEt2 (3.0-20.0 equiv), DTBMP (4.0 equiv), CH2Cl2, rt, 30 h
28 (no)
10
11
12
13
14
15
TMSOTf (0.6 equiv), CH2Cl2, 0-25 °C, 5 h
28 (<10), 31
28 (28), 31
28 (90), 31
28 (90), 31
28 (33)
TMSOTf (1.0 equiv), DTBMP (1.2 equiv), CH2Cl2, 0-25 °C, 9 h
TMSOTf (1.0 equiv), DTBMP (1.2 equiv), CH2Cl2, 0-25 °C, 9 h
TMSOTf (0.05 equiv), CH2Cl2, 0-25 °C, 14 h
TMSOTf (0.1 equiv), CH2Cl2, 0 °C to rt, 23 h
TMSOTf (0.1 equiv), CH2Cl2, 0 °C to rt, 23 h;
28 (<40)
28 (82)
additional TMSOTf (0.2 equiv) was added, 4 h
a
All reactions were carried out in the presence of 4 Å MS and a positive pressure of argon.
with 2,3,4-tri-O-Bz-6-O-TBS-D-glucopyranosyl trifluoro-
acetimidate 6c met with no success; the intramolecular
glycosidation with cleavage of the 6-O-TBS group readily
took place, producing 1,6-anhydro-2,3,4-tri-O-benzoyl-â-
D-glucopyranose 3028 as the major product (Table 1, entry
5). Therefore, a more robust protective group on the 6-OH
of the donor 6 is mandatory to achieve an effective
glycosylation of naphthol 5, which shows minimal nu-
cleophilicity.
Our attention was then focused on the 6-O-acetyl-2,3,4-
tri-O-benzoyl-D-glucopyranosyl donors 6d -g. The most
frequently employed protocol for glycosylation of phenols
relies on the SN2 displacement of the anomeric bromide
with phenolates generated in basic conditions.6,29 How-
ever, attempted coupling of toralactone 5 with glycosyl
bromide 6d under literature conditions, including the use
of tetrabutylammonium bromide (TBAB) as a phase-
transfer reagent29a-c and the use of CdCO3 as a base,24,29d,e
all failed to give considerable yields of the desired product
28 (Table 1, entries 6-8). Peracetylglucosyl fluoride
under the action of BF3‚OEt2 and DTBMP has been
reported as a successful protocol for glycosylation of
phenols.30 However, applying the literature conditions to
the coupling of 5 with glycosyl fluoride 6e gave no desired
28 (Table 1, entry 9).
glucal 3124 mainly. Attempts to modify the reaction
conditions, such as TMSOTf or BF3‚OEt2 equivalents,
“inverse” addition sequence,31 as well as concentration
and temperature, led to no appreciable improvement.
Finally, we proposed that employing a large excess
amount of the donor 6f in the reaction would give a
higher yield of the coupling product 28, if trifluoroace-
timidate 6f, which readily underwent elimination, could
still provide enough of the glycosyl oxacarbenium inter-
mediate over a sufficient period for consumption of
naphthol 5. To our delight, applying 6.0 equiv of 6f to
the previous coupling conditions (1.0 equiv of TMSOTf,
1.2 equiv of DTBMP, 4 Å MS, CH2Cl2, 0-25 °C) generated
28 in a remarkable 90% yield (Table 1, entry 12). The
presumed role of DTBMP, to activate the phenolic O-H
bond, thus enhancing the nucleophilicity of the oxygen,
was not consistent with the observation that addition of
DTBMP into 5 did not change the 1H NMR chemical
shifts of 9-OH and 10-OH. In addition, when we did not
add DTBMP and decreased the amount of TMSOTf to
0.05 equiv, i.e., the previous typical glycosylation condi-
tions for glycosyl trifluoroacetimidate,5 coupling of 5 with
6.0 equiv of 6f afforded 28 in 90% yield (Table 1, entry
13). In comparison, we also tried the trichloroacetimidate
counterpart 6g for glycosylation of 5. Similar results as
glycosylation with trifluoroacetimidate donor 6f were
obtained (Table 1, entries 14 and 15). The obvious
difference noticed was that trichloroacetimidate 6g did
not undergo ready elimination to produce glucal 31, but
instead predominantly generated the corresponding 1-OH
derivative.
Our last resort was the use of 6-O-acetyl-2,3,4-tri-O-
benzoyl-D-glucopyranosyl trifluoroacetimidate 6f as the
donor for glycosylation of toralactone 5. We expect that
it would give an increased yield of the coupling product
from donor 6a bearing a labile 6-O-trityl group. However,
under conditions similar to those for the coupling of 6a
with 5 (Table 1, entries 10 and 11), glycosylation of 5
with 6f did not improve the coupling yield. In addition,
trifluoroacetimidate 6f was found to be eliminated into
With the toralactone glucoside 28 being successfully
prepared, the completion of the synthesis of Cassiaside
C2 is straightforward (Scheme 6). The primary 6-O-
acetate on 28 was selectively removed with 1% HCl in
MeOH/CH2Cl2 (85%), which was then coupled with the
trisaccharide trifluoroacetimidate 3 under the usual
conditions (0.1 equiv of TMSOTf, 4 Å MS, CH2Cl2, 0 °C
to rt) to provide the tetrasaccharide 32 in a satisfactory
73% yield. Finally, removal of the acetate and benzoate
groups on 32 in the presence of K2CO3 in MeOH/THF
(3:2) at room temperature afforded the target molecule
(27) Oikawa, M.; Shintaku, T.; Sekljic, H.; Fukase, K.; Kusumoto,
S. Bull. Chem. Soc. J pn. 1999, 72, 1857.
(28) Ohrui, H.; Horiki, H.; Kishi, H.; Meguro, H. Agric. Biol. Chem.
1983, 47, 1101.
(29) (a) Grabley, S.; Gareis, M.; Bo¨ckers, W.; Thiem, J . Synthesis.
1992, 1078. (b) Dess, D.; Kleine, H. P.; Weinberg, D. V.; Kaufman, R.
J .; Sidhu, R. S. Synthesis 1981, 883. (c) Li, M.; Han, X.; Yu, B.
Tetrahedron Lett. 2002, 43, 9467. (d) Tsujihara, K.; Hongo, M.; Saito,
K.; Inamasu, M.; Arakawa, K.; Oku, A.; Matsumoto, M. Chem. Pharm.
Bull. 1996, 44, 1174. (e) Dick, W. E., J r. Carbohydr. Res. 1979, 70,
313.
(30) Oyama, K.-I.; Kondo, T. Synlett 1999, 1627.
(31) Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 32, 3353.
6312 J . Org. Chem., Vol. 68, No. 16, 2003