Asymmetric synthesis of (-)-muricatacin's analogue (4S,5R)-5-hydroxy-4- octadecanolide exhibiting the cytotoxicity against esphageal cancer cells

Article abstract of DOI:10.3987/COM-11-12397

An efficient and facile synthesis, in six steps and 50% overall yield from commercial D-(-)-lyxose as starting material via twice Wittig olefination and one-pot deisopropylidenation and intramolecular lactonization, of the enantiopure (4S,5R)-(+)-5-hydroxy-4-octadecanolide (2), analogue of (-)-muricatacin, and the cytotoxic activity against CE48T cell line (human esophageal carcinoma) are described and the biological activity is the first shown in the literature.

Full text of DOI:10.3987/COM-11-12397

HETEROCYCLES, Vol. 85, No. 2, 2012
299
HETEROCYCLES, Vol. 85, No. 2, 2012, pp. 299 - 304. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 22nd November, 2011, Accepted, 26th December, 2011, Published online, 10th January, 2012
DOI: 10.3987/COM-11-12397
ASYMMETRIC SYNTHESIS OF (-)-MURICATACIN’S ANALOGUE
(4S,5R)-5-HYDROXY-4-OCTADECANOLIDE
EXHIBITING
THE
CYTOTOXICITY AGAINST ESPHAGEAL CANCER CELLS
Yow-Fu Tsai,1* Chien-Cheng Huang,1 Shiau-Han Lin,1 Pei-Mei Su,1 Ying-Ju
Chen,2 and Tzong-Yuan Wu2
1
Department of Chemistry, Chung Yuan Christian University, Chung Li 32023,
2
Taiwan. E-mail: tsaiyofu@cycu.edu.tw; Fax: +886-3-2653399. Department of
Bioscience Technology, Chung Yuan Christian University, Chung Li 32023,
Taiwan
Abstract – An efficient and facile synthesis, in six steps and 50% overall yield
from commercial D-(-)-lyxose as starting material via twice Wittig olefination and
one-pot deisopropylidenation and intramolecular lactonization, of the enantiopure
(4S,5R)-(+)-5-hydroxy-4-octadecanolide (2), analogue of (-)-muricatacin, and the
cytotoxic activity against CE48T cell line (human esophageal carcinoma) are
described and the biological activity is the first shown in the literature.
Optically pure functionalized hydroxy--lactones possess important biological activities and are important
building blocks to synthesize a variety of natural products and biologically active compounds.1 Their
synthesis has attracted much interst from organic synthetic chemists. Although many useful synthetic
strategies have been reported,2 further investigations for facile and efficient entry to this type of
compounds are still required.
(-)-Muricatacin (1, Figure 1), a functionalized 5-hydroxy--lactone, was isolated from the seeds and bark
of the tropical plant Annona muricata.3 The synthesis of (-)-muricatacin (1) and its congeners has
attracted considerable attention of some organic synthetic laboratories4 over the past years due to
possessing diverse biological activities.3,5 Furthermore, the stereochemistry at C4 and C5 position of
(-)-muricatacin (1) and its congeners and the length of alkyl side chain which is more than thirteen
carbons were reported to show no significant effect on biological activity based on the structure-activity
relationship (SAR) studies.6 For the aforementioned reasons, (4S,5R)-(+)-5-hydroxy-4-octadecanolide (2,

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HETEROCYCLES, Vol. 85, No. 2, 2012
Figure 1), an unknown analogue of (-)-muricatacin, is chosen to be our synthetic target to develop an
asymmetric synthetic methodology, adopted chiral pool strategy from the commercially avaible
D-(-)-lyxose as the starting material, for efficiently preparing a variety of the enantiomerically pure
hydroxy--lactones.
(R)
( R)
(S)
( R)
(CH2)9Me
(CH2)10Me
O
O
O
O
OH
OH
(4R,5R)-(-)-muricatacin (1)
2
HO
( S)
(R)
(R)
(CH2)10Me
HO
(CH2)10Me
O
(S)
O
OAc
2-AC
OH
2-Tol
Figure 1. Structures of compound 1, 2, 2-AC, and 2-Tol
The total synthesis of (4S,5R)-(+)-5-hydroxy-4-octadec-anolide (2) is outlined in Scheme 1. The synthesis
of (4S,5R)-(+)-5-hydroxy-4-octadecanolide (2) started from the chemoselective isopropylidenation of
D-lyxose with anhydrous acetone in the presence of catalytic amount of concentrated H2SO4 as catalyst at
room temperature to furnish the 2,3-O-isopropylidene--D-lyxofuranose (3) as a single isolable anomer
in 86% yield.7 Determination of the stereochemistry of isopropylidene 3 at anomeric carbon was
compared to the literature results.7b The 1H and 13C NMR spectral data of compound 3 are well identical
with the literature data as well as melting point and specific rotation [3: mp 81-83 oC; []28D +28.0 (c 1.2,
H2O); lit.7b mp 80-82 oC; []21D +23.0 (CHCl3)]. Wittig olefination of 3 with dodecyl(triphenyl)phosphor
nium bromide/KHMDS led to the corresponding enediol 4 as a sole isolable Z-stereoisomer in 81% yield.
As for the stereochemistry of double bond in the 4, it was worked by the homodecouple technique of 1H
NMR to determine the coupling constant (J = 11.1 Hz) of both vinyl protons and confirmed the assigned
stereochemistry of double bond of the 4. In order to install the desired ester group and carbon chain by
Wittig reaction, oxidative cleavage of the enediol 4 was achieved by treatment with NaIO4 in EtOH/H2O
(2:1 (v/v)) to afford the aldehyde 5 as a syrup compound in 93% yield.8 Wittig olefination of the
aldehyde 5 with the appropriate C2-ylide (Ph3P=CHCO2Et) gave the syrup dienester 6 as a ca. 3.2:1.0
mixture of E- and Z-stereoisomers (monitored by 1H NMR, 6-2E: 6.78 (dd, J = 15.6, 5.6 Hz, 1H); 6-2Z:
 6.19 (dd, J = 12.0, 8.0 Hz, 1H)) in 82% yield. The diastereomer mixture without separation was
subsequently subjected to hydrogenation under H2/Pd/C condition to obtain the saturated ester 7 as a

HETEROCYCLES, Vol. 85, No. 2, 2012
301
white solid in 99% yield. The desired targeted compound (4S,5R)-(+)-5-hydroxy-4-octadecanolide (2)
[[]28 +10.0 (c 0.4, CHCl3)] was provided by means of one-pot deprotection and intramolecular
D
lactonization of ester 7 with hydrochloric acid in THF/H2O (10:3 (v/v)) in 88% yield.9,10
OH
O
H
OH
O
HO
a
b
HO
OH
HO
HO
OH
(CH2)10Me
O
O
O
O
O
D
-(-)-lyxose
3
4
O
O
c
d
EtO
(CH2)10Me
H
(CH2)10Me
O
O
O
5
6
O
f
e
(CH2)10Me
(S)
(R)
EtO
(CH2)10Me
O
O
O
O
OH
2
7
Scheme 1. Reagents and conditions: (a) acetone, H2SO4, rt, 2 h, 86%; (b) Ph3P(CH2)11MeBr,
KHMDS, rt, 7 h, 81%; (c) NaIO4, EtOH:H2O/2:1, rt, 3 h, 100%; (d) Ph3P=CHCO2Et, CH2Cl2,
rt, 3 h, 82%; (e) H2, Pd/C, EtOH, rt, 1 h, 99%; (f) HCl, THF:H2O/10:3, rt, 3 h, 88%
After completing the asymmetric synthesis of hydroxyl lactone 2, the antitumor effect was examined.
Furthermore, in order to understanding the effect of the hydroxyl group and lactone scaffold on biological
activity, we also prepared the (4S,5R)-(+)-5-acetoxy-4-octadecanolide (2-AC) and optically pure
(4S,5R)-octadecane-1,4,5-triol (2-Tol) (Figure 1). Herein, the cytotoxicities of lactone 2, 2-AC and 2-Tol
against the CE48T cell line (human esophageal cancer cell) in vitro were evaluated by measuring the
inhibition of cell proliferation. As shown in Figure 2, incubation of esophageal cancer cells with 2 and
2-AC for 24 h at a concentration range of 0.01-0.05 mg/mL caused a dose-dependent inhibition of cell
proliferation. This result demonstrated both 2 and 2-AC exhibited cytotoxicity against esophageal cancer
cells. The IC50 values were 20 and 25 g/mL for 2 and 2-Ac, respectively. Besides, significant changes
in the cell morphology were also observed after treatment with 2 and 2-AC for 24 h at 30 g/mL.
However, the triol 2-Tol did not show cytotoxicity against esophageal cancer cells. These results were
consistent with previous studies6 on the cytotoxicity of the lacton derivatives toward cancer cells and
demonstrated the core structure of lactone is maybe essential for inhibiting the growth of esophageal
cancer cells.

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conc. (mg/mL)
Figure 2. Viability of CE48T cell at a Concentration Range of 0.01-0.05 mg/mL of Lactones 2,
2-AC and 2-Tal (trace of DMSO was added to increase the solubility of 2, 2AC and 2-Tal in
water), and blank test (DMSO)
In conclusion, the synthesis of (4S,5R)-(+)-5-hydroxy-4-octadecanolide (2) has been achieved in six steps
from the chiral pool D-(-)-lyxose as the starting material in 50% overall yield and the cytotoxicity against
esophageal cancer cells is the first shown in the literature for hydroxy--lactone. Exploration of a facile
and flexible methodology to prepare the other three stereoisomers of hydroxy--lactone from the chiral
pool D-(-)-lyxose and examination of their biological activities are in progress.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support in part from the National Science Council, Taiwan (NSC
100-2119-M-033 -001), and (NSC 100-2120-M-033 -001).
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o
10. (S)-5-((1R)-1-hydroxytetradecyl)-dihydrofuran-2(3H)-one (2): mp 48-50 C; []28 +10.0 (c 0.4,
D
CHCl3); FT-IR (neat) cm-1: 3539, 3413, 2954, 2917, 2848, 2360, 2341, 1757, 1460, 1189 cm-1 1H
;
NMR (300 MHz, CDCl3): 4.44 (td, J = 7.2 Hz, 1H), 4.00-3.90 (m, 1H), 2.70-2.40 (m, 2H),
13
2.40-2.00. (m, 2H), 1.86 (s, 1H), 1.70-1.40 (m, 2H), 1.26 (bs, 22H), 0.88 (t, J = 6.0 Hz, 3H); C
NMR (100 MHz, CDCl3): 177.6 (C), 82.9 (CH), 71.3 (CH), 31.9 (CH2), 31.8 (CH2), 29.7 (CH2),
29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.5 (CH2), 29.5 (CH2) 29.32 (CH2), 28.7 (CH2), 25.6 (CH2),
22.7 (CH2), 21.0 (CH2), 14.1 (CH3); HRMS-ESI [M + Na]+ Calcd for C18H34O3Na 321.2400, Found
321.2400.