An improved synthesis of methyl protodioscin. II. A direct E-ring opening by BF3-Et2O/Ac2O from dioscin ester

Article abstract of DOI:10.1246/cl.2012.1015

A direct E-ring opening of dioscin ester by BF₃-Et ₂O/Ac₂O was studied, and methyl protodioscin was synthesized from dioscin ester in three steps with a total yield of 44%. The details of the E-ring opening reaction was di

Full text of DOI:10.1246/cl.2012.1015

doi:10.1246/cl.2012.1015
Published on the web September 8, 2012
1015
An Improved Synthesis of Methyl Protodioscin. II.
A Direct E-ring Opening by BF3-Et2O/Ac2O from Dioscin Ester
Bo Wang, Yang Liu,* Xin Liu, and Mao-sheng Cheng*
Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education,
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
(Received June 12, 2012; CL-120641; E-mail: mscheng@syphu.edu.cn)
A direct E-ring opening of dioscin ester by BF3-Et2O/Ac2O
was studied, and methyl protodioscin was synthesized from
dioscin ester in three steps with a total yield of 44%. The details
of the E-ring opening reaction was discussed, and a prominent
stability of C16-OAc was obversed.
OMe
26
22
E
O
OH
O
1
O
16
OH
O
OH
HO
HO
O
O
HO
O
1
O
HO
O
HO
HO
Methyl protodioscin (1, Figure 1), a representative natural
furostanol saponin, has received increasing attentions due to its
potential anticancer activity.1-3 Because of its relative scarcity
from nature, scientists are attemping to synthesize this furostanol
saponin.
OH
HO
OH
Figure 1. The chemical structure of methyl protodioscin.
Former work: five steps
Yield < 20%
O
Retrosynthetically, this bisglycoside can be divided into
three parts: a furostanol aglycone and two sugar moieties. In the
synthesis of methyl protodioscin, there are two difficulties that
we have to overcome: constructing the furostanol stuctrure
efficiently and adding the chacotriose at the C3-OH of the
aglycone in the naturally occurring configuration. In our first
attempt,4 a convergent strategy was applied. In the glycosylation
via a chacotriosyl thioglycoside, the right ¢-configuration was
confirmed though the lack of a neighboring participatory group.
In the subsequent work,5 direct access to the 3-O-substituted
kryptogenin from dioscin ester was established, and this new
synthesis saved one deprotection step compared with the former
method. Even with the elimination of this step, this new method
still involved five steps®DMDO oxidation, Zn/KI/HOAc
reduction, glycosylation, NaBH4 selective reduction, and de-
protection®starting from dioscin ester to synthesize methyl
protodioscin, with a total yield lower than 20% (Figure 2).
Obviously, this synthetic route is inefficient. Herein we report a
highly efficient synthetic route for methyl protodioscin in which
the key step is direct E-ring opening by BF3-Et2O/Ac2O. This
synthesis represents a new method to construct furostanol
aglycones.
O
Methyl Protodioscin
OPiv
O
5
This work: three steps
Yield = 44%
RO
R=
O
PivO
O
O
BzO
O
BzO
OBz
BzO
BzO
OBz
Figure 2. An improved method toward methyl protodioscin.
O
OBz
O
O
OR
O
O
CCl3
BzO
BzO
OBz
O
b
NH RO
2
3
RO
R = Bz
OR
a
HO
R = OH
NH
CCl3
O
O
BzO
OPiv
O
BzO
c
OBz
5
O
HO
PivO
d
4
OH
As shown in Scheme 1, dioscin ester 5 was prepared from
diosgenin. First, a perbenzoylated glucosyl trichloroacetimidate
was introduced onto the C3-OH of diosgenin. This reaction
guaranteed that the linkage between the aglycone and the sugar
moiety would be in the ¢ orientation due to the neighboring
participatory benzoyl group.6 After a global deprotection, the
3,6-diol of the glucose was selectively shielded by pivaloyl,7
followed by the introduction of two benzoylated rhamnose
moieties onto the two remaining free hydroxy groups.
As shown in Scheme 2, the E-ring in compound 5 was
directly opened by a combination of BF3-Et2O and acetic
anhydride in dichloromethane, followed by glycosylation with
perbenzoylated glucose trichloroacetimidate to give the impor-
tant bisglycoside intermediate 8. Once C16-OAc in 8 was
deprotected under basic conditions, the newly formed hydroxy
group automatically attacked the C22-carboyl group to produce
Scheme 1. (a) TMSOTf, CH2Cl2, 0 °C, 1 h, 92%; (b) NaOMe,
MeOH-CH2Cl2, 1 h; (c) PivCl, pyridine, 6 h, 0 °C, 75% over two
steps; (c) TMSOTf, CH2Cl2, r.t., 3 h, 79%.
a C22-OH furostanol saponin. As reported,8 when cation-
exchange resin was used to neutralize the solution, C22-OH was
converted into C22-OMe, yielding methyl protodioscin. The
analytical data, including MS, optical rotation, 1H and 13C NMR
data, for the synthesized methyl prododioscin were identical to
those of the natural product.9,12
As a key step in this synthesis, direct E-ring opening allows
the efficient conversion of the spirostanol into a cholesteric
structure, which was then converted into the corresponding
protodioscin via an automatic cyclization during deprotection.
The effects of two key factors, 1) the amounts and ratio of BF3-
Chem. Lett. 2012, 41, 1015-1017
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1016
O
Table 1. Direct E-ring opening by BF3-Et2O/Ac2O from
dioscin ester 5a
O
OR1
E
O
O
OAc
b
O
a
OR1
R
1 = H
6
5
BF3-Et2O/Ac2O
O
7 R1 = Ac
RO
RO
6 R1 = H
OAc
5
CH2Cl2
1 = Ac
7
R
O
OR2
Yieldb/%
OH
BF3-Et2O/Ac2O
(mmol/mmol)
Time
/min
Entry
c
OAc
O
OR4
5
6
7
1
2
3
4
6.4/9.5c
6.4/19.1
6.4/9.5
5
5
10
5
22
20
9
50
51
45
75
20
22
35
22
8
R3O
RO
OPiv
O
BzO
R2=
12.8/19.1
none
O
OBz
OBz
R=
O
PivO
O
O
aGeneral reaction procedure: The mixture of BF3-Et2O and
Ac2O was added to an ice-cooled solution of 5 (1 mmol) in
CH2Cl2 (5 mL). After the reaction, 30% MeOH in water
(10 mL) was added, and the mixture was stirred for 30 min.
bYields based on purification by column chromatography.
cAmounts taken from Refs. 10 and 11.
Dowex+
BzO
R3= Chacotriose
O
BzO
OBz
BzO
Methyl Protodioscin
BzO
BzO
R4= Glucose
OBz
Scheme 2. (a) BF3-Et2O/Ac2O, CH2Cl2, 0 °C, 10 min, then
30% MeOH in water, 30 min, 75%; (b) glucose imidate,
TMSOTf, CH2Cl2, r.t., 83%; (c) NaOMe, MeOH, reflux, 24 h,
then Dowex 50 (H+), r.t., 15 min, 71%.
O
O
Et2O/Ac2O and 2) the reaction time, on this reaction were
investigated. The prominent stability of 16C-OAc was observed
during deprotection.
OR1
OR3
OAc
OAc
NaOMe
r.t.
R2O
During the E-ring opening reaction of dioscin ester 5, the
function of BF3-Et2O and acetic anhydride is to form a complex
that promotes the formation of an oxacarbenium-ion intermedi-
ate from 5. Then, the hydrolysis of this intermediate occurs by
attack at C-22 by water used in the quenching step to give 6. It is
worth noting that under these conditions, the intramolecular
cyclization from the C26-OH to the C22-oxo group of 6 does
not take place. Therefore, the major by-product is diacetate 7,
resulting from the acetylation of 6 by the remaining acetic
anhydride. To reduce the amount of this by-product and to
consume the starting material completely, the reaction time and
the concentration of acetic anhydride were optimized. As shown
in Table 1, the yield was not satisfactory when using the initial
amounts of BF3-Et2O/Ac2O (Entry 1),10,11 leaving approxi-
mately 20% of the starting material unreacted. We assumed that
the intermediate 5, which contains a bulky protected trisaccha-
ride on its C3-OH, was difficult to approach, and therefore,
more reagent was needed. When using the same time (Entry 2),
the yields of the target compound, and the by-product and the
amount of remaining 5 were generally unaffected when the
amount of acetic anhydride was doubled. In addition, Entry 3
demonstrates that the reaction time is a major factor affecting the
proportions of 5, 6, and 7. Although the prolongation of the
reaction time resulted in almost complete consumption of the
starting material, longer reaction times also resulted in the
conversion of the desirable monoacetate 6 into the undesirable
diacetate 7. The optimal reagent amounts and reaction time were
determined to be those used in Entry 4, giving a 75% yield of
the desired compound.
8
9
RO
OPiv
O
OPiv
O
R2=
O
R=
O
PivO
PivO
O
O
O
O
O
O
HO
BzO
HO
OH
BzO
OBz
HO
BzO
HO
BzO
OH
OBz
HO
BzO
O
R3=
R1=
O
OH
OBz
OH
OBz
HO
BzO
¹1
Scheme 3. Deprotection of 8 by 1 mol L NaOMe in MeOH
at room temperature.
1H NMR data demonstrated that only the benzoyl groups in 8
were cleaved under these reaction conditions, giving 9 in an
excellent yield (Scheme 3). Only when a higher temperature was
used, as shown in Scheme 2, was the desired final product,
methyl protodioscin, obtained.
In conclusion, a highly efficient method for the synthesis of
methyl protodioscin was established with the key step of direct
E-ring opening by BF3-Et2O/Ac2O, followed by automatic
cyclization during deprotection. The total yield (44% from
dioscin ester and 24% from diosgenin as the starting material,
respectively) was increased considerably relative to that reported
previously.
The authors acknowledge the Ph.D. Scientific Research
Opening Foundation of Liaoning Province (No. 20091081) for
financial support for this research.
During the deprotection of 8, an interesting phenomenon
was observed. Usually the hydrolysis rates of acyl groups can be
ordered from fast to slow as follows: chloroacetyl > acetyl >
¹1
benzoyl > pivaloyl. However, when 8 was treated with 1 mol L
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