Total synthesis of (-)-isoaltholactone

Article abstract of DOI:10.1007/s11426-012-4823-3

A short and efficient stereoselective synthesis of a styryllactone (-)-isoaltholactone has been achieved in seven steps and 33% overall yield, starting from the readily available carbohydrate D-mannose. The key steps of our synthesis involve intramolecula

Full text of DOI:10.1007/s11426-012-4823-3

SCIENCE CHINA
Chemistry
July 2013 Vol.56 No.7: 928–932
doi: 10.1007/s11426-012-4823-3
• ARTICLES •
Total synthesis of ()-isoaltholactone
LIU Jun1*, ZHANG Xing1, 2, LIU Yi1, 2, BI JingJing1, 2 & DU YuGuo1, 2*
1State Key Laboratory of Environmental Chemistry and Eco-toxicology; Research Center for Eco-Environmental Sciences,
Chinese Academy of Sciences, Beijing 100085, China
2School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, China
Received November 17, 2012; accepted November 28, 2012; published online December 21, 2012
A short and efficient stereoselective synthesis of a styryllactone ()-isoaltholactone has been achieved in seven steps and 33%
overall yield, starting from the readily available carbohydrate D-mannose. The key steps of our synthesis involve intramolecu-
lar tetrahydrofuran cyclization and one-pot acetonide deprotection-lactonization.
total synthesis, styryllactone, isoaltholactone, carbohydrate
1 Introduction
Phytochemical studies on Goniothulumus species have led
to the isolation and characterization of a large number of
styryllactones, a diverse group of secondary metabolites,
which were found to possess significant biological activity
including antitumor and antifungal properties, as well as
antibiotic potential [1]. Altholactone (1, Figure 1), a
furanopyrone member of the styryllactone family, was first
isolated from the bark of an unnamed Polyathia (An-
nonaceae) species in 1977 [2]. This compound, named as
goniothalenol, was also isolated from the bark of the An-
nonacea plant, Goniothalamus giganteus, and showed anti-
tumor activity against a leukemia mouse in vivo [3]. Its dia-
stereomer, isoaltholactone (2), was subsequently isolated
from the plants of the Goniothalamus species [4]. The bio-
logical evaluation of isoaltholactone revealed that it also
displays important biological activities, including antitumor,
antifungal and antibacterial properties [4, 5a].
Figure 1 Structures of ()-altholactone (1) and ()-isoaltholactone (2).
drofuran framework bearing four consecutive stereogenic
centers. Their unusual structure and promising biological
activity have attracted immense interest from the synthetic
community. As a result, several elegant approaches toward
the total synthesis of (+) and ()-isoaltholactone as well as
its analogues have been reported to date [5]. As part of our
ongoing synthetic research into natural products from car-
bohydrate-based chiral building blocks [6], herein we report
the concise and stereoselective synthesis of ()-isoaltholac-
tone (2) from D-mannose.
Differing only in the configuration of the stereogenic
centers at C-2 and C-3, isoaltholactone and altholactone
consist of a similar 5-oxygenated-5,6-dihydro-2H-pyran-
2-one structural skeleton and a richly substituted tetrahy-
2 Experimental
2.1 General
Unless noted otherwise, commercially available materials
were used without further purification. All solvents were
dried according to the established procedures ahead of use.
*Corresponding authors (email: junliu@rcees.ac.cn; duyuguo@rcees.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

Liu J, et al. Sci China Chem July (2013) Vol.56 No.7
929
All reagents were purchased from commercial corporations.
Flash chromatography (FC) was performed using silica gel
(200–300 mesh) according to the standard protocol. All
reactions under standard conditions were monitored by
thin-layer chromatography (TLC) on gel F254 plates. Opti-
cal rotations were measured using a polarimeter with a
thermally jacketed 5 cm cell at approximately 25 °C. High-
resolution mass spectrometry data (HRMS) were acquired
using a Q-TOF analyzer in acetone as solvent. 1H NMR and
13C NMR spectra were measured on 400 MHz or 100 MHz
spectrometers (NMR in CDCl3 with TMS as an internal
standard). Chemical shifts () are given in ppm relative to
residual solvent (usually chloroform;  7.26 for 1H NMR or
77.0 for proton decoupled 13C NMR), and coupling con-
stants (J) in Hz. Multiplicity is tabulated as s for singlet, d
for doublet, t for triplet, q for quadruplet, and m for multi-
plet and br when the signal is broadened.
was concentrated with toluene and poured into saturated aq.
CuSO4 (30 mL), then extracted with dichloromethane
(DCM) (2 × 30 mL). The combined organic phase was
washed with brine, dried over Na2SO4 and concentrated
under vacuum. The crude residue was purified by flash
column chromatography (hexanes/EtOAc 6:1) to give
compound 5 as a yellow oil (373 mg, 73%). []2D5 16.1 (c
1
2.2, CHCl3); H NMR (400 MHz): δ 1.38 (s, 3H), 1.40 (s,
3H), 1.44 (s, 3H), 1.58 (s, 3H), 3.88 (q, J = 4.0 Hz, 1H),
4.17–4.23 (m, 2H), 4.48–4.53 (m, 1H), 4.77 (dd, J = 6.0 Hz,
J = 4.0 Hz, 1H), 4.98 (dd, J = 6.0 Hz, J = 0.8 Hz, 1H), 5.20
(s, 1H), 7.28–7.37 (m, 5H); 13C NMR (100 MHz)  24.7,
25.2, 26.2, 26.9, 67.0, 73.5, 81.1, 81.3, 84.9, 87.5, 109.2,
112.8, 125.4, 127.4, 128.7, 138.3; HRMS (ESI-TOF) m/z:
Calcd for C18H24O5: 320.1624; Found 343.1525 ([M +
Na]+).
Synthesis of (R)-1-((3aS,4R,6R,6aR)-2,2-dimethyl-6-phenyl-
tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)ethane-1,2-diol (6)
2.2 Experimental procedures
To a solution of 5 (125 mg, 0.39 mmol) in dry DCM (8 mL)
was added solid FeCl3·6H2O (11 mg, 0.04 mmol) under an
N2 atmosphere. After stirring for 1.5–2 h at room tempera-
ture, the mixture was filtered through a pad of celite, and
the pad was washed with DCM (10 mL). The combined
organic phase was washed with brine, dried over Na2SO4
and concentrated under vacuum. The crude was purified by
flash column chromatography (hexanes/EtOAc 1:3) to give
compound 6 as a yellowish oil (90 mg, 82%). []2D5 +39.0 (c
Synthesis of (R)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl) ((4S,
5R)-5-((S)-hydroxy (phenyl) methyl)-2,2-dimethyl-1,3-dio-
xolan-4-yl) methanol (4)
To a solution of 2,3:5,6-di-O-isopropylidene-a-D-manno-
furanose [7] (2.08 g, 8 mmol) in dry THF (30 mL) was
added phenyl lithium (2 M in dibutyl ether, 26.4 mmol) via
syringe by three portions at 78 °C under N2 protection.
After 30 min, the solution was warmed to 40 °C and
stirred for another 12 h. The reaction was quenched by the
slow addition of aq. NH4Cl (30 mL, Caution!). The aqueous
layer was extracted with ether (3 × 40 mL). The combined
organic phase was washed with brine, dried over Na2SO4
and concentrated under vacuum. The crude residue was
purified by flash column chromatography (hexanes/EtOAc
3:2) to give compound 4 as a yellow oil (1.85 g, 68% for 4
and 19% for its diastereomer). []D25 22 (c 1.2, CHCl3); 1H
1
1.0, CHCl3); H NMR (400 MHz): δ 1.39 (s, 3H), 1.60 (s,
3H), 2.30–2.80 (br, 2H), 3.84–3.87 (m, 1H), 3.94–3.97 (m,
1H), 3.98 (q, J = 4.0 Hz 1H), 4.11–4.15 (m, 1H), 4.85 (dd, J =
6.0 Hz, J = 4.0 Hz, 1H), 4.96 (dd, J = 6.0 Hz, J = 0.8 Hz,
1H), 5.21 (s, 1H), 7.28–7.38 (m, 5H); 13C NMR (100 MHz)
 24.8, 26.2, 64.5, 70.5, 80.4, 81.6, 84.7, 87.3, 113.1, 125.4,
127.6, 128.7, 138.2; HRMS (ESI-TOF) m/z: Calcd for
C18H20O5: 280.1311; Found 303.1217 ([M + Na]+).
NMR (400 MHz):  1.26 (s, 3H), 1.32 (s, 3H), 1.39 (s, 3H),
1.59 (s, 3H), 3.36 (br s, 2H), 3.57 (d, J = 6.4 Hz, 1H),
3.99–4.09 (m, 3H), 4.36 (d, J = 7.2 Hz, 1H), 4.49 (dd, J =
7.2 Hz, J = 4.0 Hz, 1H), 4.95 (d, J = 4.0 Hz, 1H), 7.29–7.32
(m, 1H), 7.35–7.38 (m, 2H), 7.43–7.44 (m, 2H); 13C NMR
(100 MHz) δ 24.6, 25.3, 26.4, 26.7, 67.0, 70.1, 71.9, 75.7,
76.0, 80.1, 108.5, 109.2, 127.1, 128.2, 128.6, 140.5; HRMS
(ESI-TOF) m/z: Calcd for C18H26O6: 338.1729; Found
361.1601 ([M + Na]+).
Synthesis of (Z)-ethyl 3-((3aS,4R,6R,6aR)-2,2-dimethyl-
6-phenyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)acrylate (7)
To a solution of diol 6 (72 mg, 0.26 mmol) in MeOH (10
mL) was added solid NaIO4 (82 mg, 0.38 mmol) at room
temperature. After stirring for 45 min at room temperature,
the mixture was filtered through a pad of Celite, and the pad
was washed with MeOH (2 mL). To the resulting solution
was added (ethoxycarbonylmethylene) triphenylphospho-
rane (271 mg, 0.78 mmol) at 0 °C. After stirring at 0 °C for
8 h, the reaction mixture was concentrated under vacuum.
The crude residue was purified by flash column chromatog-
raphy (hexanes/EtOAc 5:1) to give compound 7 as a color-
less solid (66 mg, 79%). []D25 88 (c 0.5, CHCl3) [5h, 5i]; 1H
Synthesis of (3aS,4R,6R,6aR)-4-((R)-2,2-dimethyl-1,3-dio-
xolan-4-yl)-2,2-dimethyl-6-phenyl-tetrahydrofuro[3,4-d]
[1,3]dioxole (5)
To a solution of diol 4 (540 mg, 1.6 mmol) in dry pyridine
(12 mL) was added TsCl (671 mg, 3.51 mmol) in two por-
tions at 80 °C under N2 protection and the mixture was
stirred for 60–72 h. The reaction was quenched at room
temperature by the addition of MeOH (10 mL). The solution
NMR (400 MHz):  1.32 (t, J = 7.2 Hz, 3H), 1.35 (s, 3H),
1.57 (s, 3H), 4.27 (q, J = 7.2 Hz, 2 H), 4.99 (dd, J = 6.0 Hz,
J = 0.4 Hz, 1H), 5.04 (dd, J = 6.0 Hz, J = 4.0 Hz, 1H), 5.27
(s, 1H), 5.40–5.43 (m, 1H), 5.99 (dd, J = 11.6 Hz, J = 1.6

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Liu J, et al. Sci China Chem July (2013) Vol.56 No.7
Hz, 1H), 6.45 (dd, J = 11.6 Hz, J = 6.8 Hz, 1H), 7.26–7.38
(m, 5H); 13C NMR (100 MHz) δ 14.1, 24.9, 26.3, 60.3, 78.2,
83.0, 85.1, 87.3, 112.7, 120.9, 125.5, 127.5, 128.6, 138.4,
145.5, 165.7; HRMS (ESI-TOF) m/z: Calcd for C18H22O5:
318.1467; Found 341.1377 ([M + Na]+).
Synthesis of ()-isoaltholactone (2)
To a solution of ester 7 (36 mg, 0.11 mmol) in THF (1 mL)
was added 50% trifluoroacetic acid (TFA) (2 mL) at room
temperature. The mixture was stirred for 48 h and concen-
trated with toluene under vacuum. The crude residue was
purified by flash column chromatography (hexanes/EtOAc
1:1) to give ()-isoaltholactone (2) (22.5 mg, 88%) as white
solid, []D25 27 (c 0.5, EtOH); 1H NMR (400 MHz):  3.32
(br s, 1H), 4.27–4.29 (m, 1 H), 4.78 (d, J = 7.2 Hz, 1H), 4.88
(t, J = 5.2 Hz, J = 4.8 Hz, 1H), 5.06 (t, J = 5.6 Hz, 1H), 6.21
(d, J = 10.0 Hz, 1H), 6.87 (dd, J = 10.0 Hz, J = 4.4 Hz, 1H),
7.27–7.41 (m, 5H); 13C NMR (100 MHz)  67.8, 78.4, 78.6,
83.1, 122.5, 125.6, 128.1, 128.5, 138.6, 141.7, 162.0;
HRMS (ESI-TOF) m/z: Calcd for C13H12O4: 232.0736;
Found 255.0624 ([M + Na]+).
Scheme 1 Retrosynthetic analysis of ()-isoaltholactone (2).
The synthesis of stereochemically pure tetrasubstituted
tetrahydrofuran subunit 5 was initiated from di-O-isopropy-
lidene-a-D-mannofuranose (3), as shown in Scheme 2. The
known di-O-isopropylidene-a-D-mannofuranose (3) was
easily obtained from D-mannose in excellent yield accord-
ing to a reported procedure [7]. According to a modified
procedure from Mekki [8], excess phenyllithium was added
to 3 in dry THF leading to a syn product 4 as a separable
mixture of diastereoisomers in 87% yield (dr = 3.7:1 by
NMR, syn-4 being the major isomer) [9].
3 Results and discussion
In the initial attempt for the synthesis of the -C-
furanoside 5, we examined the Mitsunobu cyclization of the
diol 4 [10]. Unfortunately, the Tsunoda modification of the
Mitsunobu reaction revealed no desired product. In the
conventional cyclization method utilizing TsCl and pyridine
[11], the diol 4 was tosylated at 80 °C and furnished
-C-furanoside 5 as a single product in 73% yield. No
The retrosynthetic strategy for ()-isoaltholactone (2) is
depicted in Scheme 1. We envisaged that 2 could be ob-
tained from functionalized (Z)-,-unsaturated ethyl ester 7
via acidic one-pot acetonide deprotection/lactonization
(Scheme 1). The (Z)-,-unsaturated ester 7, which contains
all of the four required stereocenters of the natural product,
could be prepared from the key diol 4 by intramolecular
tetrahydrofuran cyclization at C5 with inversion of config-
uration at C2 followed by cis-Wittig olefination at C6. De-
tails of the studies thus undertaken are described below.
1
-C-furanoside product was detected by careful H NMR
analysis of the crude product. The -C-furanoside 5 was
resulted from the initial mesylation of the benzylic hydroxyl
group (C2) of diol 4 and subsequent intramolecular cycliza-
Scheme 2 Total synthesis of ()-isoaltholactone.

Liu J, et al. Sci China Chem July (2013) Vol.56 No.7
931
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4
5
FeCl3-mediated selective hydrolysis of the acetonide
group in 5 at room temperature for 2–3 h furnished the diol
6 (82%) [12]. Oxidative cleavage of the diol in 6 with NaIO4
in methanol gave the corresponding aldehyde in almost
quantitative yield, and when followed by cis-Wittig olefina-
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in dry methanol afforded the (Z)-,-unsaturated ester 7 in
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Z:E > 5.5:1) [13]. Finally, one-pot acetonide deprotection/
lactonization was achieved with 50% trifluoroacetic acid in
THF at room temperature, delivering ()-isoaltholactone (2)
in 88% yield [5i].
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The spectroscopic data (1H, 13C NMR, HRMS) and opti-
cal rotation {[]D25 27 (c 0.5, EtOH); []2D0 32.2 (c 0.3,
EtOH), [5h]; []D23 24.5 (c 0.2, EtOH), [5i]} of our syn-
thetic sample are essentially identical to those in the litera-
ture [5].
4 Conclusion
We have succeeded in the synthesis of the styryllactone
()-isoaltholactone from readily available chiral pool D-
mannose in only seven steps and 33% overall yield, includ-
ing intramolecular tetrahydrofuran cyclization and one-pot
deprotection-lactonization as key steps, which represents
the shortest route and highest overall yield to isoalt-
holactone so far as we know. This route also allowed us to
prepare other aromatic analogues of isoaltholactone.
This work was supported by the MOST of China (2012ZX09502001-001),
and the National Natural Science Foundation of China (2012CB822101,
21072217 and 21202193).
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