Biomimetic synthesis of a leaf-opening factor, potassium isolespedezate, by direct formation of enol-glycoside

Article abstract of DOI:10.1246/cl.2004.976

Potassium isolespedezate (1) is a leaf-opening factor controlling the nyctinastic leaf-movement of leguminous plants. We carried out bioorganic studies on nyctinasty by using synthetic probes designed on the structure of 1 and its galactose analog (2). Ho

Full text of DOI:10.1246/cl.2004.976

976
Chemistry Letters Vol.33, No.8 (2004)
Biomimetic Synthesis of a Leaf-opening Factor, Potassium Isolespedezate,
by Direct Formation of Enol-glycoside
Takanori Sugimoto and Minoru Uedaꢀ
Tohoku University, Department of Chemistry, Aoba-ku, Sendai 980-8578
(Received May 19, 2004; CL-040573)
Potassium isolespedezate (1) is a leaf-opening factor con-
1) Old route
trolling the nyctinastic leaf-movement of leguminous plants.
We carried out bioorganic studies on nyctinasty by using
synthetic probes designed on the structure of 1 and its galactose
analog (2). However, 1 was synthesized via an indirect route be-
cause of the difficulty of direct formation of the enol-glycosidic
linkage. More efficiency is desired for the preparation of 1 and 2
which are necessary for the synthesis of probe compounds. In
this paper, we report the biomimetic synthesis of 1 containing
direct formation of an enol-glucosidic linkage. This efficient
route makes it possible to prepare 1 and 2 in large quantity.
OTBS
OTBS
KÖnigs-Knorr
OTBS
OAc
O
DDQ
AcO
AcO
+
OAc
O
OAc
O
AcO
AcO
AcO
AcO
O
HO
O
AcO
Br
OAc
OAc
COOMe
OH
COOMe
COOMe
OR
2) Biomimetic new route
OR
OP
O
OP
O
OH
O
PO
PO
PO
PO
HO
HO
O
HO
O
1
PO
X
PO
OH
COOR'
COOR'
OR
COOK
OH
X: leaving group
or
OP
Most leguminous plants close their leaves in the evening, as
if to sleep, and open them early in the morning according to the
circadian rhythm controlled by the biological clock.1 We have
revealed that nyctinasty is controlled by a pair of leaf-movement
factors: leaf-opening and leaf-closing substances.1 Recently, we
revealed the target cell2 and potential receptor protein3 of a leaf-
opening substance, potassium isolespedezate (1),4 by using syn-
thetic probe compounds designed on the structure of 1 and its
galactose analog (2).5 Syntheses of probe compounds need a
large amount of 1 and 2, which are the core skeletons of the
probes. However, 1 and 2 were synthesized via an indirect route
because of the difficulty of direct formation of the enol–glycosi-
dic linkage. The enol-glycosidic linkage was formed via 2 steps:
glycosidation and following oxidative olefination. Besides its in-
efficiency, oxidative olefination incurs an experimental problem
in the separation of the resulting coupling product from an ex-
cess amount of DDQ. Especially, this problem becomes serious
in large-scale synthesis. Then, more efficiency is desired for the
preparation of 1 and 2, which are necessary for the development
of probe compounds. In a biosynthetic pathway, 1 would be syn-
thesized via direct formation of the enol-glucosidic linkage cat-
alyzed by a glucosyltransferase. In this paper, we report a biomi-
metic synthesis of 1 and 2 via direct formation of the enol-
glycosidic linkage.
O
PO
PO
OH
OH
O
O
O
HO
O
OH
COOK
2
COOR'
Figure 1. Old synthetic route and Biomimetic new route to 1.
the other is epoxide (Figure 1).
First, generation of enolate from properly protected aglycon
(3) was examined. We examined several bases such as DBU,
K2CO3, (NH4)2CO3, and t-BuOK. Then, it was revealed that on-
ly t-BuOK efficiently generated an enolate. Coupling of 3 and
2,3,4,6-tetra-O-acetyl-ꢀ-D-glucopyranosyl bromide (4) was car-
ried out by using t-BuOK as a base to give 5 in 31% yield (Table
1). No ꢀ-isomer and no C-glycosylated product were obtained in
this reaction. And no E-isomer was obtained in this reaction, be-
cause thermodynamically stable Z-enolate from 3 would pre-
dominatly exist under this condition. The low yield of coupling
product 5 in this reaction was due to ꢁ-elimination to give 6 in
22% yield. And use of tosylate 7,9 which has a good leaving
group on an anomeric position, as a glycosyl donor did not give
any coupling product at all (Table 1). Thus, it is expected that
without abstraction of 20-H in 4 by the enolate, the yield of cou-
pling product 5 would be improved. Using sterically hindered
glycosyl donor 8,10 a bulky pivaloyl group would prevent the ap-
proach of the enolate to the 20-H. However, coupling reaction us-
ing 8 gave the ꢁ-elimination product (10) predominantly and
coupling product (9) was obtained in lower yield than in the case
of 4 (Table 1). It was revealed that the competition between
glycosidation and ꢁ-elimination caused serious difficulty using
glucopyranosyl bromide as a glycosyl donor.
For the direct enol-glycoside formation, aglycon (3) should
be in a keto-enol equilibrium in dichloromethane (Figure 1),
which is usually used as a solvent in Konigs–Knorr reaction.
¨
However, no enol-glucoside was obtained under the usual
Konigs–Knorr glycosidation using 3 and 4. The 1H NMR spec-
¨
trum of 1 in CD2Cl2 revealed that the ratio of keto to enol was
>99 : 1, and almost no enol form of 1 existed in a nonpolar sol-
vent such as dichloromethane.
SN2-like glycosidation was studied by Rolando6 and Dani-
shefsky.7 Only one example on the SN2-type formation of
enol-glycoside with enolate has been reported so far.8 Then we
examined SN2-type glycosidation using enolate generated from
aglycon 3 by using some bases. And we examined two electro-
philes as a glycosyl donor: one is glucopyranosyl bromide and
Then, we prepared an epoxide-type glycosyl donor, 3,4,6-
tris-O-tert-butyldiemthylsilyl-1,2-anhydro-ꢀ-D-glucopyranose
(11) according to the method by Danishefsky.7 Glycosidation by
nucleophilic attack of the enolate from 5 to epoxide 11 gave
enol-glycoside. No E-isomer was obtained in this condition.
The coupling product 12, in which TBS group migrated to the
20 position, was obtained in 43% yield (Table 1). The structure
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.8 (2004)
977
of 12 was determined from the coupling between 30-hydroxy H
and 30-H in the 1H NMR spectrum. Stereochemistry of the olefin
in 12 was determined to be Z from the NOE between aromatic 2-
H and 20-H of sugar moiety (Scheme 1). And following depro-
tection gave potassium isolespedezate (1)3 in 35% yield in 3
steps from 11 (Table 1, Scheme 1).
Similarly, we examined the synthesis of potassium galacto-
isolespedezate (2) via direct formation of enol-glycoside. All
synthetic probes such as fluorescence-labeled probe and photoaf-
finity probe that are designed on the structure of 1 have a com-
mon skeleton 2 to circumvent the hydrolysis by ꢁ-glucosidase in
the plant body. Thus, efficient preparation of 2 is important for
the development of probe compounds exploring bioorganic stud-
ies on nyctinasty. Coupling reaction with 2,3,4,6-tetra-O-acetyl-
ꢀ-D-galactopyranosyl bromide (13) and 5 using t-BuOK as a
base gave coupling product 14 in 61% yield (Table 1). Stereo-
chemistry of the olefin in 14 was determined to be Z from the
NOE between aromatic 2-H and 20-H of sugar moiety (Scheme
1). Fortunately, no ꢁ-elimination product was obtained in this
case. This is because the abstraction of 20-H by the enolate would
be inhibited by steric hindrance due to the 40-acetyl group in 13.
Inhibition of the abstraction of 20-H in 13 would improve the
yield of the coupling product compared with the case of glucosyl
donor 4. And following deprotection gave potassium galactoiso-
lespedezate (2)11 in 55% yield in 3 steps from 13 (Table 1 and
Scheme 1).
On the other hand, coupling reaction with 3,4,6-tris-O-tert-
butyldiemthylsilyl-1,2-anhydro-ꢀ-D-galactopyranose (15)7 and
5 using t-BuOK as a base gave no coupling products (Table
1). It is assumed that steric hindrance between the TBS group
on the 40-position and enolate 5 might prevent the approach of
5 to the anomeric position of 15.
In summary, we have confirmed an efficient biomimetic
route to an important bioactive substance controlling nyctinasty,
that is important for the development of synthetic probes for
bioorganic study of nyctinasty.
Table 1. Reaction conditions of SN2-type glycosidation
OSEM
base
product
glycosyl donor
DMF
O
t
COO Bu
3
glycosyl donor / equiv.
AcO
Base/ equiv.
Temp/Time
product / yield
OSEM
AcO
AcO
O
AcO
AcO
O
AcO
+
AcO
AcO
AcO
t
0 °C/ 2 hrs
BuOK
O
AcO
O
AcO
Br
(2.5 equiv.)
AcO
t
COO Bu
(31%)
4 (2 equiv.)
(37 %)
5
6
AcO
AcO
AcO
O
t
BuOK
–
rt/ 24 hrs
AcO
(2.5 equiv.)
OTs
7 (2 equiv.)
OSEM
+
PivO
PivO
PivO
PivO
PivO
PivO
O
O
t
PivO
PivO
PivO
BuOK
rt/ 5 hrs
O
PivO
O
PivO
Br
(2.5 equiv.)
PivO
t
COO Bu
8 (2 equiv.)
9 (18 %)
10 (52 %)
OSEM
TBSO
TBSO
HO
TBSO
TBSO
TBSO
t
BuOK (1.2 equiv.)
O
O
O
rt/ 6 hrs
18-Crown-6 (1.2 eqiuv.)
OTBS
O
t
COO Bu
11 (5 equiv.)
12 (43 %)
This work was financially supported by the Ministry of
Education, Culture, Sports, Science and Technology, Japan
Grant-in-Aid for Scientific Research (No. 15681013).
OSEM
OAc
OAc
OAc OAc
O
t
AcO
BuOK
O
0 °C/ 1 hr
AcO
O
(5 equiv.)
AcO
Br
AcO
t
COO Bu
References
13 (4 equiv.)
14 (61%)
1
2
3
4
5
6
M. Ueda and S. Yamamura, Angew. Chem., Int. Ed., 39,
1400 (2000).
T. Sugimoto, Y. Wada, S. Yamamura, and M. Ueda,
Tetrahedron, 57, 9817 (2001).
T. Sugimoto, T. Fujii, Y. Idutu, S. Yamamura, and M. Ueda,
Tetrahedron Lett., 45, 335 (2004).
H. Shigemori, N. Sakai, E. Miyoshi, Y. Shizuri, and S.
Yamamura, Tetrahedron Lett., 30, 3991 (1989).
M. Ueda, Y. Sawai, and S. Yamamura, Tetrahedron, 55,
10925 (1999).
OTBS
TBSO
TBSO
t
O
BuOK(1.2 equiv.)
rt/ 24 hrs
–
18-Crown-6 (1.2 equiv.)
O
15 (5 equiv.)
OSEM
4.6%
OH
COOK
OH
TFA-CH Cl
2
2
H
RO
HO
HO
H
O
O
O
RO
HO
O
then K CO
2
HO
3
M. Bouktaib, A. Atmani, and C. Rolando, Tetrahedron Lett.,
43, 6263 (2002); K. Tatuta and K. Toshima, Chem. Rev., 93,
1503 (1993).
OR
OH
1
t
(quant.)
COO Bu
12 (R=TBS)
16 (R=H)
TBAF-AcOH
THF (84 %)
7
8
9
R. L. Halcomb and S. J. Danishefsky, J. Am. Chem. Soc.,
111, 6661 (1989).
S. Sato, S. Sumita, Y. Kanda, and Y. Sasaki, Tetrahedron
Lett., 33, 7381 (1992).
OSEM
6.8%
TFA-CH Cl
then K CO
2
2
2
OH
OR
RO
OH
HO
3
H
O
H
O
O
(93 %)
O
A. Wisniewski, J. Madaj, E. Skorupowa, and J. Sokolowski,
J. Carbohydr. Chem., 13, 873 (1994).
10 S. Velarde, J. Urbina, and M. R. Pena, J. Org. Chem., 61,
HO
OH
2
COOK
OR
t
COO Bu
14 (R=Ac)
17 (R=H)
NaOMe
Me|OH
(95 %)
9541 (1996).
11 M. Ueda, Y. Sawai, and S. Yamamura, Tetrahedron Lett., 40,
3757 (1999).
Scheme 1. Synthesis of 1 and 2.
Published on the web (Advance View) July 5, 2004; DOI 10.1246/cl.2004.976