Determination of the absolute configuration of nodulisporacid A by the concise synthesis of four stereoisomers via three-component reaction and one-pot construction of the framework

Article abstract of DOI:10.1016/j.tetlet.2010.03.064

Four stereoisomers of nodulisporacid A (1) were synthesized by the concise approach which includes three-component reaction and subsequent one-pot construction of the whole framework. The ¹H NMR comparison of the derivatives (10-12) revealed the absolute configuration of natural 1 to be 4R,4′R,6′R.

Full text of DOI:10.1016/j.tetlet.2010.03.064

Tetrahedron Letters 51 (2010) 2765–2767
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Determination of the absolute configuration of nodulisporacid A by the
concise synthesis of four stereoisomers via three-component reaction and
one-pot construction of the framework
Tatsunobu Sumiya a,b, Ken Ishigami a, Hidenori Watanabe a,
*
a Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bukyo-ku, Tokyo 113-8657, Japan
b Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi, Nogi-Machi, Shimotsuga-gun, Tochigi 329-0114, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Four stereoisomers of nodulisporacid A (1) were synthesized by the concise approach which includes
three-component reaction and subsequent one-pot construction of the whole framework. The 1H NMR
comparison of the derivatives (10–12) revealed the absolute configuration of natural 1 to be 4R,40R,60R.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 February 2010
Revised 16 March 2010
Accepted 18 March 2010
Available online 20 March 2010
Keywords:
Nodulisporacid A
Antiplasmodial activity
Three-component reaction
Determination of the absolute configuration
Nodulisporacid A (1) was isolated from a marine-derived fun-
gus, Nodulisporium sp. CRIF1, by Kittakoop et al. in 2008 as an anti-
plasmodial agent (Fig. 1).1 This compound was reported to exist as
a 1:1 equilibration mixture of the (E)- and (Z)-isomers. Although
the stereochemistry at the three asymmetric centers of nodulispor-
acid A (1) could not be clarified, the stereogenic centers were,
based on the spectroscopic similarity, assumed to be the same as
those of lowdenic acid (2),2 whose relative stereochemistry has
been elucidated by X-ray crystallographic analysis. Herein, we re-
port a synthesis of four stereoisomers of 1 and determination of
the absolute configuration of the natural product.
the tertiary alcohol as a TBS ether, treatment with periodic acid
caused a hydrolysis of acetonide followed by an oxidative cleavage
of the resulting glycol to afford (2S,4S)-7. Another isomer, (2R,4S)-
7, was also prepared in a similar manner starting from the enantio-
meric aldehyde [(S)-3].6
With two stereoisomers of 7 in hand, the three-component
reaction was investigated (Scheme 3). According to the procedure
reported by Mukaiyama, large excess amount of the simple alcohol
(e.g., MeOH and EtOH) was added to the premixed aldehyde, dike-
tene, and TiCl4 in CH2Cl2.3 However, we were pleased to find that
the amount of alcohol (dimethyl malate) could be minimized to
Our synthetic strategy is shown in Scheme 1. The framework of
the target molecule would be constructed by the successive intra-
molecular Claisen condensation, enol etherification of the resulting
acyltetramic acid derivative, and dehydration of A. Compound A, a
b-ketoester of malate, was expected to be prepared readily by the
three-component reaction reported by Mukaiyama.3
Two diastereomers of the aldehyde (7) were prepared as shown
in Scheme 2. A protected glyceraldehyde (R)-34 was reacted with a
Grignard reagent prepared from commercially available 4 (pur-
chased from Sigma–Aldrich) and the resulting alcohol was oxidized
to ketone 5 by Dess–Martin periodinane. Methylation in the mode
O
O
2'
5
3'
4'
6
3
O
4
1'
HO2C
HO2C
( 1 : 1 )
9'
2
O
O1
O
6'
7'
5'
O
O
8'
(Z)-isomer
(E)-isomer
Nodulisporacid A (1)
O
HO2C
of
a-chelation was performed in the presence of SnCl4 and 6 was
O
O
obtained in an excellent stereoselectivity (>20:1).5 After protecting
Lowdenic acid (2)
(relative stereochemistry)
O
n-C9H19
Figure 1. Structures of nodulisporacid A (1) and lawdenic acid (2).
* Corresponding author. Fax: +81 3 5841 8019.
E-mail address: ashuten@mail.ecc.u-tokyo.ac.jp (H. Watanabe).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.064

2766
T. Sumiya et al. / Tetrahedron Letters 51 (2010) 2765–2767
Nodulisporacid A (1)
a. Claisen condensation
CO2Me
TBSO
MeO2C
a
b
O
(2S, 4S)-7
b. enol ether formation
O
O
OH
c. dehydration
8
b
CO2R
a
RO2C
HO
O
O
O
O
O
O
O
MeO2C
MeO2C
O
O
OH
OH
OH
c
O
O
A
TBSO
HO
E
F
three-component
reaction
O
CO2R
RO2C
4
4'
RO2C
D
OH
O
O
aldol
6'
RO
esterification
O
O
OHC
O
(4S,4'S,6'S)-9 (R=Me)
(4S,4'S,6'S)-1 (R=H)
B
c
C
Scheme 1. Retrosynthetic analysis.
Scheme 3. Synthesis of (4S,40S,60S)-1. Reagents and conditions: (a) diketene
(2 equiv), TiCl4 (1.2 equiv), CH2Cl2, ꢁ78 °C, 15 min then dimethyl (S)-malate
(2 equiv), ꢁ78 to 0 °C, over 3 h, 62%; (b) TBAF (1 equiv), THF, 0 °C to rt, 1 h, then
TBAF (2 equiv), rt, 20 h, then concd HCl, rt, 5 h, 51%; (c) 6 N HCl, 1,4-dioxane, rt, 97%.
2 equiv which enabled the easier isolation of the product, and 8
was obtained in 62% yield as a single isomer (stereochemistry
not determined). The next step, one-pot reaction for the construc-
tion of the whole framework, could be carried out successfully by
the successive treatment with TBAF7 and HCl in 51% yield. During
the reaction, stepwise generation of intermediates (E and F) could
be monitored on TLC, and after the complete deprotection, the
reaction mixture was acidified by the addition of HCl to cause
the enol ether formation. It should be noted that when the TBAF
treatment was carried out at higher temperature (80 °C), partial
epimerization at C-4 has taken place. The methyl ester of
(4S,40S,60S)-9 was then hydrolyzed to afford (4S,40S,60S)-1 as a 1:1
mixture of (E)- and (Z)-isomers.
Similarly, by changing the combination of stereoisomers of 7
and dimethyl malate, four diastereomeric methyl esters (9) of 1
were synthesized and their 1H NMR spectral data were compared
with those reported for the methyl ester of natural nodulisporacid
A.1 Among the four isomers, only (4S,40S,60S)-9 showed complete
accordance with the natural product derivative while other iso-
O
O
4
4
MeO2C
4'
MeO2C
4'
O
O
O
O
6'
6'
*
O
O
(4S,4'R,6'S)-9
[α]2D7 –1.62 (c 0.30, CHCl3)
[lit. [α]2D7 –11.4 (c 1.00, CHCl3)]
O
O
4
4
*
MeO2C
4'
MeO2C
4'
O
O
O
O
6'
6'
*
O
O
(4R,4'S,6'S)-9
(4R,4'R,6'S)-9
Figure 2. Synthesized stereoisomers of nodulisporacid A methyl ester.
O
recryst'n
Z
HO2C
O
1:1 E/Z mixture
O
O
MeOH
r.t., 3h
a, b
CHO
of (4S,4'S,6'S)-1
+
O
O
Br
O
O
O
(Z)-isomer
[α]2D8 –0.96 (c 1.00, MeOH)
[α]D28 +9.03 (c 1.00, MeOH)
[lit. [α]2D7 –20.6 (c 1.10, MeOH)]
(R)-3
4
5
Scheme 4. Recrystallization and isomerization of 1.
HO
O
c
d, e
TBSO
OHC
O
mers showed different chemical shifts of protons on the asterisked
carbons (Fig. 2). However, the specific rotation of our synthetic
(2S,4S)-7
6
(4S,40S,60S)-9 (½a 2D7
ꢁ1.62) was much smaller than the reported
ꢀ
data (½a 2D7
ꢀ
ꢁ11.4)1 and the absolute configuration of the natural
product could not be established.
Similarly:
In addition to that, the specific rotations of synthetic
(4S,40S,60S)-1 and natural nodulisporacid A were also different
CHO
TBSO
OHC
(½a 2D8
ꢀ
ꢁ0.96 and ½a 2D7
ꢀ
ꢁ20.6,1 respectively). Although the natural
+
O
O
Br
1 was reported to be an amorphous solid, synthetic (4S,40S,60S)-1
could be recrystallized from i-Pr2O–CHCl3–CCl4 as a single (Z)-iso-
(S)-3
4
(2R,4S)-7
mer (mp 124–125 °C) whose [a] value was +9.03 immediately
D
Scheme 2. Preparation of aldehyde 7. Reagents and conditions: (a) Mg, THF, 0 °C to
rt, 30%; (b) Dess–Martin periodinane, CH2Cl2, rt, 89%; (c) SnCl4 (1 equiv), MeLi
(4 equiv), CH2Cl2, ꢁ78 °C, 60% (75% brsm); (d) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 97%;
(e) HIO4ꢂ2H2O, EtOAc, rt, 99%.
after dissolution in methanol and gradually decreased to ꢁ0.96
in 3 h at rt by the isomerization (Scheme 4). From these values,
the specific rotation of (E)-isomer was estimated to be ꢁ11.0. It

T. Sumiya et al. / Tetrahedron Letters 51 (2010) 2765–2767
2767
δ 7.40 and 7.52
H
O
O
H
N
a
b
2'
4
Ph
4'
HO2C
S
O
O
O
O
O
O
6'
O
O
10
(4S,4'S,6'S)-1
(4R,4'R,6'R)-1
(natural nodulisporacid A)
δ 7.42 and 7.51
H
O
H
N
2'
Ph
Figure 3. Absolute stereochemistry of nodulisporacid A.
R
O
O
O
11
lute configuration of the natural compound is 4R,40R,60R as de-
picted in Figure 3.
In summary, four stereoisomers of nodulisporacid A (1) were
synthesized efficiently by the three-component reaction and one-
pot construction of the whole framework. The NMR comparison
of the methyl esters (9) enabled the determination of the relative
stereochemistry and the absolute configuration was then estab-
lished to be 4R,40R,60R by the derivatization to amides (10–12).
δ 7.42 and 7.51
H
O
a
H
N
2'
Natural 1
Ph
S
O
O
O
O
12
Scheme 5. Determination of the absolute configuration of nodulisporacid A (1) by
1H NMR data comparison of (S)- or (R)-1-phenyethylamine derivative. Reagents and
conditions: (a) (S)-1-phenylethylamine, EDCI, Et3N, CH2Cl2; (b) (R)-1-phenylethyl-
amine, EDCI, Et3N, CH2Cl2.
Acknowledgment
We thank Dr. Kittakoop of Chulabhorn Research Institute for
generous gift of natural nodulisporacid A.
was therefore difficult to determine the absolute configuration by
the sign of rotation.
References and notes
To determine the absolute configuration of the natural product
unambiguously, amides (10–12) with (S)- or (R)-1-phenylethyam-
ines were prepared from synthetic (4S,40S,60S)-1 and natural 1 and
their 1H NMR spectra were compared (Scheme 5). As shown in
Scheme 5, olefinic protons at C-20 of 10 and 11 appeared at the dif-
ferent chemical shifts and the optical purity of synthetic
(4S,40S,60S)-1 was found to be pure. On the other hand, 12 showed
good accordance with 11. From these results, we concluded that
(4S,40S,60S)-1 was an enantiomer of nodulisporacid A and the abso-
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3. Izawa, T.; Mukaiyama, T. Chem. Lett. 1975, 161–164.
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