Synthesis and characterization of altaicadispirolactone

Article abstract of DOI:10.1080/00397910500287900

Altaicadispirolactone was synthesized via a simple route. In this route, levulinic acid was used as a starting material, and bromination followed by hydrolysis and BF₃·OEt₂-catalyzed cyclization were carried out. A single-crystal ORTEP drawing has been created and more detailed crystallographic data of the compound has been obtained from X-ray analysis. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500287900

w
Synthetic Communications , 35: 2729–2733, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500287900
Synthesis and Characterization of
Altaicadispirolactone
Yan Zhang, Linbo Wu, Feng Li, and Bo-Geng Li
Department of Chemical and Biochemical Engineering, State Key
Laboratory of Chemical Engineering, Zhejiang University,
Hangzhou, China
Abstract: Altaicadispirolactone was synthesized via a simple route. In this route,
levulinic acid was used as a starting material, and bromination followed by hydrolysis
.
and BF OEt -catalyzed cyclization were carried out. A single-crystal ORTEP
3 2
drawing has been created and more detailed crystallographic data of the compound
has been obtained from X-ray analysis.
Keywords: Altaicadispirolactone, 5-hydroxylevulinic acid, lactonization, levulinic
acid
INTRODUCTION
In general, synthesis of hydroxy acids or esters and conversion to lactones or
[1]
macrolides are important processes in organic synthesis because many of
these compounds can be used as potential bioactive substances or polymeriz-
able monomers. For an example, compounds containing g-butyrolactone often
[
2]
show interesting biological activities. Altaicadispirolactone 1, or 1,6,9,13-
tetraoxadispiro[4.2.4.2]tetradecane-2,10-dione, is a dispirolactone with two
g-butyrolactone rings. It was first isolated in 1986 from Anemone altaica
[
3]
C.A. May, a traditional Chinese medicinal herb. It is a dimer of 5-hydroxy-
[3]
levulinic acid (5-HLA, 2), which was isolated from the same plant.
Received in Japan April 11, 2005
Address correspondence to Bo-Geng Li, Department of Chemical and Biochemical
Engineering, State Key Laboratory of Chemical Engineering, Zhejiang University,
Hangzhou 310027, China. Tel.: þ86-571-8795-2623; Fax: þ86-571-8795-1612;
E-mail: bgli@zju.edu.cn
2
729

2730
Y. Zhang et al.
Anemone altaica C.A. May is usually used to decrease the amplitude,
[4]
frequence, and spike rate of the fast wave and slow wave of gut, and 1
[5]
may play a critical role in its therapeutic function. In 1996, S. Li and Y. Li
first reported a six-step total synthesis of this compound using succinic
anhydride as a starting material. In this article, we report a simple three-
step synthesis of 1 using levulinic acid (LA, 3) as a starting material.
Because 3 can be produced from biomass such as cellulose or lignin in
large scale and at low cost and can be used to synthesize many useful
chemicals, it is frequently proposed as a potential platform chemical
[
6]
derived from biomass. Therefore, our synthesis route may be a more econ-
omical and environmentally friendly one. Our synthesis approach is outlined
in Scheme 1.
First, 3 was brominated using Br as a bromating agent in methanol at 408C,
2
a condition under which the methyl is preferentially brominated. Pure methyl
5-bromolevulinate (5-MBL, 4) was obtained in 38% yield after the bromina-
tion reaction and a subsequent low-temperature recrystallization process.
Then, 2 was obtained by a one-step hydrolysis of the Br-C and ester bonds
.
of 4 in boiling water in 69% yield. Finally, cyclization of 2 using BF3 OEt2
as catalyst gave 1 in 77% yield.
The spectroscopic data of 1 are identical with those of the natural and
[3]
[
5]
the previously chemically synthesized products. A single crystal of 1 was
cultured in a dilute methylene chloride solution and used for X-ray analysis.
The ORTEP drawing of 1 is shown in Fig. 1, which demonstrates that two
saturated g-butyrolactone rings are connected to the dioxane ring in a
dispiro arrangement.
[7–9]
Although the first two steps have been reported separately in the literature.
the reaction and purification processes were both modified in our synthetic
route. In the bromination reaction, a methanol-drying procedure reported in
[7]
literature was omitted for convenience and no unfavorable effect was
observed on the yield. In the hydrolysis step, a modified one-step hydrolysis
of the Br-C and ester bonds of 4 and a subsequent continuous extraction of
Scheme 1. Synthesis route of 1 using 3 as a starting material.

Altaicadispirolactone
2731
Figure 1. View of the molecule 1 with the atom-labeling scheme.
the concentrated hydrolysis product were performed so that a yield (69%)
much higher than the result (38%) of the two-step hydrolysis reported in lit-
[
9]
erature
was obtained. In the third step, boron trifluoride etherate
[5]
.
BF3 OEt ) was used as catalyst instead of p-toluene sulphonic acid, and
2
(
consequently a higher yield (77%) was obtained.
EXPERIMENTAL
The melting point of the purified product 2 was measured by Perkin-Elmer 7
DSC. IR spectra (n
2
in cm ) were recorded on a Nicolet 560 FT-IR spec-
1
max
1
trometer. H NMR spectra were obtained with a Brucker AVANCE 500-M
spectrometer using tetramethylsilane as internal standard. Mass spectra were
determined on a Thermofinnigan 1A-1112 spectrometer. A single crystal of
compound 2 was measured on a Rigaku RAXIS-RAPID single-crystal
diffractometer.
Methyl 5-Bromolevulinate 4
Bromine (160 g, 1 mol) was added to a solution of 3 (116 g, 1 mol) in methanol
(
500 ml) at 30 8C for 30 min. The reaction mixture was then stirred at 408C for
h. After removing the methanol under reduced pressure, the residue was
dissolved in diethyl ether (500 ml) and washed with water and then with
8
sodium bicarbonate aqueous solution. After the ethereal layer was dried
˚
(
Na SO and 4 A molecular sieve), the ether was distilled off. The residue
2 4
was dissolved in diethyl ether/cyclohexane (1:1, 800 ml), and the solution
was then cooled at 220 to 2408C. After recrystallization for 2 h, filtration,
and washing, 4 (80 g) was obtained in 38% yield as colorless acicular
2
1
crystals. Melting point: 198C. nmax, (cm ) 2953, 1735, 594. dH (CDCl3)
.64–2.97 (4H, brs,. CH CH ), 3.68 (3H, s, COOCH ), 3.98 (3H, s, BrCH ).
2
2
2
3
2

2732
Y. Zhang et al.
5
-Hydroxylevulinic Acid 2
A mixture of 4 (20 g) and water (300 ml) were heated to reflux for 4 h before
evaporation and concentration. The residue mixture was continuously
extracted with diethyl ether with a modified extractor for 48 h. The resultant
ethereal solution was dried with magnesium sulphate. After evaporation of
the ether, a crude crystalline product (12 g) (mp 98.6–99.68C) was obtained.
Recrystallization from chloroform (60 ml/g) gave 9.2 g of colorless crystals
2
1
(
mp 100–1018C). nmax (cm ) 3427(OH), 1696, 1409. d (CDCl )
H
3
2
COCH O). Calc. for C H O : C, 48.13; H, 5.76. Found: C, 48.20; H, 5.84.
.61–2.81 (2H, dm, CH COC), 2.44 (2H, M, CH COO), 4.06–4.28 (2H, ds,
2 2
2
5 8 4
Altaicadispirolactone 1
.
BF3 OEt (0.5 ml) was added to a solution of 2 (4 g) in CH Cl (300 ml), and
2
2
2
the mixture was refluxed for 4 h in a 500-ml round-bottomed flask equipped
with a Deam–Sbark apparatus. The reaction mixture was washed with
deionized water. The organic layer was dried (with Na SO ) and then evapor-
2
4
ated to obtain 3.1 g of white powder. After recrystallization in CH Cl , 3 g of
2
2
2
1
granulous crystals were obtained in 77% yield. nmax (cm ) 1766, 1226; 1049.
d (CDCl ) 2.09–2.14, 2.30–2.35, 2.69–2.75, 2.91–2.97 (8H, 4 m, 3, 4, 11,
H
3
Figure 2. Crystal structure of 1 viewed along the b axis.

Altaicadispirolactone
2733
1
2H), 3.83–3.85 (2H, d, 7a, 14a, H), 4.14–4.16 (2H, d, 7a, 14a, H). dc
CDCl ) 180.7 (C 55 O), 105.3 (O–C–O), 77.3 (CH –O), 65.3 (CH –C 55 O),
(
3
2
2
2
9.8, 28.0. Calc. for C H O : C, 52.63; H, 5.30. Found: C, 52.63; H, 5.27.
10 12 6
˚
Crystal data for 1: monoclinic, space group P21/n, a ¼ 8.898(5)A,
˚
˚
˚
b ¼ 6.010(2)A, c ¼ 9.897(4)A, b ¼ 111.70(1)A, z ¼ 2, radiation ¼ MoK
˚
(
0.71069 A), final R ¼ 0.048. The final R is better than that of crystallographic
data reported in Ref. 10, where the R ¼ 0.065. Its crystal packing is shown in
Fig. 2. Within the crystal lattice, the molecules are arranged along the diagonal
of a–c axis in a parallel fashion occupying the crystallographic plane. The
crystallographic data for the structures 1 in this article have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publi-
cation number CCDC261917.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from the Chinese
National Science Fund for Distinguished Young Scholars (20125617), the
National Natural Science Foundation of China (20304012), the Specialized
Research Fund for Doctoral Program of China (20020335101), and the
Prior Special Fund for National Basic Research Program of China
(2004CCA05500). We extend our thanks to Gu Jian-Ming and Liu Tong-
Bao for their help with the X-ray crystallographic analysis.
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2
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