First enantioselective total synthesis of (-)-dysibetaine CPa and absolute configurations of natural product

Article abstract of DOI:10.1016/j.tetlet.2013.08.113

Here we report total synthesis of enantiomerically pure dysibetaine CPa, isolated from Micronesian marine sponge and expected to serve as a neuroactive agent. Starting from meso-cyclopropane triester, the synthesis was achieved in 12.8% overall yield over

Full text of DOI:10.1016/j.tetlet.2013.08.113

Tetrahedron Letters 54 (2013) 5911–5912
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First enantioselective total synthesis of (À)-dysibetaine CPa
and absolute configurations of natural product
⇑
Michihiro Sakai, Yuichi Ishikawa, Satoshi Takamizawa, Masato Oikawa
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report total synthesis of enantiomerically pure dysibetaine CPa, isolated from Micronesian
marine sponge and expected to serve as a neuroactive agent. Starting from meso-cyclopropane triester,
the synthesis was achieved in 12.8% overall yield over 10 steps including organocatalytic enantioselective
solvolysis of meso-succinic anhydride as a key step. This work established the absolute configurations of
the natural product as (3R,4R).
Received 12 July 2013
Revised 20 August 2013
Accepted 26 August 2013
Available online 4 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
Dysibetaine CPa
Enantioselective total synthesis
Quaternary ammonium group
Neuroactive natural product
Organocatalytic solvolysis
In 2004, a series of structurally interesting hydrophilic natural
products, such as dysibetaine CPa (1) and dysibetaine CPb (2)
(Fig. 1), have been isolated by Sakai et al. from Micronesian marine
sponge, Lendenfeldia chondrodes.1 The dysibetaines are trisubsti-
tuted cyclopropanes bearing carboxy and tetraalkylammonium
dysibetaine CPa. Acidic hydrolysis of triethyl ester 3 (6 M aq HCl,
95 °C) followed by treatment with Ac2O under microwave irradia-
tion conditions gave dianhydride 5 in high yield (98%).
With succinic anhydride 5 in hand, we then investigated cin-
chona alkaloid-mediated methanolysis. After several experiments,
it was found that Song’s bifunctional quinine-sulfonamide cata-
lyst7 showed acceptable level of asymmetric induction (83–88%
ee)8 to give monomethyl ester 7 in moderate yield (54–62%).9
The absolute stereochemistry was tentatively assigned as (3S,4S)
(dysibetaine CPa numbering) on the basis of the empirical rule
proposed by Bolm10 and Oda,11 and confirmed separately by sin-
gle-crystal X-ray analysis of the 4-bromobenzoyl ester derivative
(see the Supplementary data).
groups, and thus contain c-amino butyric acid (GABA) motif. Since
Sakai group had discovered dysiherbaine from the same sponge in
19972 which was later identified as a potent agonist selective to
GluK1, GluK2, and GluK3,3 the dysibetaines 1 and 2 are also
expected to serve as neuroactive agents. However, because of the
limited availability from natural resources, their biological activi-
ties have not been studied well. In addition, the absolute stereo-
chemistry of the natural products remains to be elucidated.
While total synthesis is the strategy often employed toward
elucidation of unknown configurations, two synthetic studies4,5
previously reported for racemic dysibetaine CPa were not applica-
ble to the enantioselective synthesis.
From dicarboxylic acid 7, (À)-dysibetaine CPa (1) was synthe-
sized as follows (Scheme 2). Esterification of 7 with tBuOH was
performed by modified Takeda–Gooben reaction (Boc2O, DMAP,
Here we report our preliminary results on the de novo asym-
metric synthesis of (À)-dysibetaine CPa (1), which culminated in
the structural determination of the natural product as (3R,4R).
As shown in Scheme 1, the asymmetric synthesis started with
known trans,meso-cyclopropanetricarboxylic acid triethyl ester
(3).6 We expected that organocatalytic solvolysis of meso cyclic
anhydride would discriminate between the anhydride carbonyl
groups and allow us to synthesize enantiomerically pure
5
COOH
COO
*
3
*
2
4
O
1
COO
*
6
NMe3
NMe3 NH2
1
2
(–)–dysibetaine CPa ( )
(+)–dysibetaine CPb ( )
absolute stereochemistry
of natural product
established in this work
*: relative stereochemistry
⇑
Corresponding author. Tel./fax: +81 45 787 2403.
E-mail address: moikawa@yokohama-cu.ac.jp (M. Oikawa).
Figure 1. Cyclopropane-containing betaines from Lendenfeldia chondrodes.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.113

5912
M. Sakai et al. / Tetrahedron Letters 54 (2013) 5911–5912
CO2H
CO2Et
purification by chiral HPLC (Daicel CHIRALPAK IC column).
6
M aq. HCl
Bromination (CBr4, PPh3) gave 11 in 82% yield, ready for introduc-
tion of the trimethylammonium group at the C1-position. Accord-
ing to our racemate synthesis,5 we employed a stepwise reaction
also here because of the poor reactivity of bromide 11 toward
trimethylamine. Thus, amination with Me2NH at 120 °C gave 12,
which, in turn, reacted with dimethyl sulfate to deliver trimethy-
lammonium salt 13 successfully in 58% yield over two steps. For
the N-methylation, other agents were impractical; MeI caused
decomposition of the tert-butyl ester, and dimethyl carbonate
was unreactive even at elevated temperature (50 °C). Finally, acidic
hydrolysis (6 M aq HCl) followed by the removal of the
monomethyl sulfate ion by ion-exchange chromatography (Dowex
1-X8) provided (3R,4R)-dysibetaine CPa, which was chromato-
graphically and spectroscopically identical with natural product,1
including the optical rotation data (À8.0 for synthetic, and À8.1
for authentic materials). Our total synthesis thus unequivocally
established the absolute configurations of natural dysibetaine
CPa as (3R,4R). Overall yield was 12.8% over 10 steps from trans,-
meso-cyclopropanetricarboxylic acid triethyl ester (3). Evaluation
of the bioactivity as well as syntheses of the analogs is currently
underway in our laboratory.
95 °C
100%
EtO2C
CO2Et
HO2C
MeOH
CO2H
3
4
CO2Ac
CO2H
Ac2O
catalyst 6
(3S)
(4S)
microwave
(100 W), 10 min
98%
Et2O, rt
54–62%
MeO2C
CO2H
O
O
O
5
7
(83–88% ee)
OMe
H
N
CF3
CF3
NH
S
H
N
O
O
6
bifunctional quinine-sulfonamide catalyst
Scheme 1. Asymmetric synthesis of cyclopropane dicarboxylic acid 7 by organo-
catalytic methanolysis.
Acknowledgments
Mr. Shota Sasaki (Yokohama City University) is gratefully
acknowledged for his investigation during the early stage of this
research. The authors thank Professor Ryuichi Sakai (Hokkaido
University, Japan) for invaluable discussions, and Professor Shigeru
Nishiyama (Keio University, Japan) for access to the HRMS facility.
This work was supported by the grant for 2010–2012 Strategic
Research Promotion (Nos. T2202, T2309, T2401) of Yokohama City
University, Japan.
Boc2O
CO2tBu
CO2tBu
DMAP
LiOH
7
tBuOH
40 °C
93%
MeOH
H2O
84%
MeO2C
HO2C
CO2tBu
CO2tBu
8
9
CO2tBu
CO2tBu
1) BH3•THF
THF
CBr4
PPh3
Supplementary data
1
CO2tBu
CO2tBu
11
Supplementary data (X-ray diffraction experiment of
4-bromobenzoate of 10) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
113.
2) chiral HPLC
81%
CH2Cl2
82%
OH
Br
10 (100% ee)
CO2tBu
CO2tBu
CO2tBu
dimethyl
References and notes
O
O
OMe
O
Me2NH
sulfate
S
1. Sakai, R.; Suzuki, K.; Shimamoto, K.; Kamiya, H. J. Org. Chem. 2004, 69, 1180–
1185.
2. Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc. 1997, 119,
4112–4116.
3. Sakai, R.; Swanson, G. T.; Shimamoto, K.; Green, T.; Contractor, A.; Ghetti, A.;
Tamura-Horikawa, Y.; Oiwa, C.; Kamiya, H. J. Pharmacol. Exp. Ther. 2001, 296,
650–658.
CO2tBu
toluene
120 °C
sealed tube
80%
toluene
40 °C
73%
NMe3
NMe2
12
13
4. Siddiquee, T. A.; Lukesh, J. M.; Lindeman, S.; Donaldson, W. A. J. Org. Chem.
2007, 72, 9802–9803.
5. Oikawa, M.; Sasaki, S.; Sakai, M.; Sakai, R. Tetrahedron Lett. 2011, 52, 4402–
4404; Oikawa, M.; Sasaki, S.; Sakai, M.; Ishikawa, Y.; Sakai, R. Eur. J. Org. Chem.
2012, 5789–5802.
6. Aggarwal, V. K.; Smith, H. W.; Hynd, G.; Jones, R. V. H.; Fieldhouse, R.; Spey, S. E.
J. Chem. Soc., Perkin Trans. 1 2000, 3267–3276.
7. Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew.
Chem., Int. Ed. 2008, 47, 7872–7875.
COOH
1) 6
M aq. HCl
(3R)
90 °C
(4R)
COO
2) ion-exchange
chromatography
(basic)
NMe3
(–)–dysibetaine CPa (1)
[α]D22 -8.0 (c 0.10, H2O)
lit:1 [α]D18 -8.1 (c 0.12, H2O)
80%
8. Enantiomeric purity was determined by chiral HPLC analysis of triester 8 later
(0.46 Â 25 cm Daicel CHIRALPAK IC column, EtOH/hexane = 10:90, 1.0 mL/
min).
9. Dimethyl ester was also obtained in 30–46% yield as a byproduct (structure not
shown).
10. Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984–
6991.
Scheme 2. Total synthesis of (À)–dysibetaine CPa (1) with natural configurations.
11. Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Perkin Trans. 1 1987,
1053–1058.
12. Held, I.; Von den Hoff, P.; Stephenson, D. S.; Zipse, H. Adv. Synth. Catal. 2008,
350, 1891–1900.
tBuOH)12 to provide triester 8 in 93% yield. Selective hydrolysis of
methyl ester 8 (LiOH, H2O, 84%) and reduction of the carboxyl
group furnished enantiomerically pure alcohol 10 in 81% yield after