Enantioselective total synthesis of (+)-isoaltholactone

Article abstract of DOI:10.1016/S0040-4020(02)00791-3

A facile enantioselective route to highly functionalized α,β-unsaturated -δ-lactones has allowed for the synthesis of (+)-isoaltholactone in 6.4% overall yield from furylmethanol. This approach derived its asymmetry by applying Sharpless kinetic resolution on racemic 2-furylmethanol. The resulting pyranone was produced in high enantioexcess and was stereoselectively transformed into (+)-isoaltholactone via a highly diastereoselective epoxidation and a key PPTS catalyzed intramolecular cyclization.

Full text of DOI:10.1016/S0040-4020(02)00791-3

Tetrahedron 58 (2002) 6799–6804
Enantioselective total synthesis of (1)-isoaltholactone
Xiaoshui Peng,a Anpai Li,a Jiangping Lu,a Qiaoling Wang,a Xinfu Pana and Albert S. C. Chan
b
,
*
aNational Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China
bDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, People’s Republic of China
Received 5 April 2002; revised 13 June 2002; accepted 4 July 2002
Abstract—A facile enantioselective route to highly functionalized a,b-unsaturated -d-lactones has allowed for the synthesis of (þ)-
isoaltholactone in 6.4% overall yield from furylmethanol. This approach derived its asymmetry by applying Sharpless kinetic resolution on
racemic 2-furylmethanol. The resulting pyranone was produced in high enantioexcess and was stereoselectively transformed into (þ)-
isoaltholactone via a highly diastereoselective epoxidation and a key PPTS catalyzed intramolecular cyclization. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
As a part of our continuing to synthesize biologically active
natural products12 and to extend our research for the
synthesis of a,b-unsaturated-d-lactones from cheap and
readily available 2-furylmethanol 2, we designed a flexible
route to synthesize the natural product (þ)-isoaltholactone
1. Retrosynthetically, our approach is shown in Scheme 1.
(þ)-Isoaltholactone 1 (Fig. 1), a furanopyrone member of
the styryllactone family, was isolated from the plants of
Goniothalamus malayanus, G. montanus and G. tapis.1 This
class of compounds feature 6-substituted a,b-unsaturated-
d-lactones. This family from various plants and fungi share
the common 5-oxygenated-5,6-dihydro-2H-pyran-2-one
structural motifs.2 These members include 5-acetoxy-
goniothalamin, goniodiol, altholactone and others.3 These
natural products have interesting biological activities
including anti-tumor, anti-fungal and anti-bacterial proper-
ties.4 Due to the wide distribution of this class of natural
product in the nature, many synthetic methodologies have
been employed to synthesize their core structure.5 Several
research groups have reported the synthesis of altho-
lactone.6–9 These synthesis ranged from 13 steps from
D-gluconolactone7 to 16 steps from D-glyceraldehyde
acetonide.8 Many of them derived their asymmetry from
carbohydrate derivatives,6–8 diethyl L-tartrate,10 a substi-
tuted benzaldehyde chromium(0) complex,11 or the Sharp-
less asymmetric dihydroxylation.9
2. Results and discussion
(þ)-Isoaltholactone 1 could be obtained via an intra-
molecular cyclization from epoxide 10 and subsequent
functional group transformations. Epoxide 10, in turn, could
be prepared from compound 8 via a diastereoselective
epoxidation.13 The stereochemistry in 8a could then be
established via a Sharpless kinetic resolution from readily
available 2-furylmethanol 2.14
The kinetic resolution of compound 2 was carried out with
t-butyl hydroperoxide (TBHP) (0.6 mol equiv.) and a
catalytic amount of L-(þ)-diisopropyl tartrate (L-(þ)-
DIPT) (30 mol%) and titanium tetraisopropoxide
[Ti(O-iPr)4] (20 mol%) in anhydrous CH2Cl2 in the
˚
presence of molecular sieves 4 A at 230 to 2408C under
argon atmosphere for 24 h to afford the pyranone 3 in 38%
yield.14 Protection the free hydroxyl group in lactol 3 with
ethyl vinyl ether gave a- and b-ethoxy ethyl ethers 4 and 5
in 74 and 10% yield and .76% ee, respectively. The
a-anomer 4 was reduced with NaBH4 and CeCl3·7H2O in
methanol at 2408C to furnish the allyl alcohols 6 and 7 in 78
and 4% yield, respectively, and .90% de.15 The stereo-
chemistry of the hydroxy group in the compound 6 could not
be determined at this stage; however, it was assumed to be
3R based on the results of similar works by Sammes et al.16
and was unambiguously established by converting 6 into the
natural product (þ)-isoaltholactone 1 as follows. The
Figure 1.
Keywords: total synthesis; (þ)-isoaltholactone; enantioselective and
stereoselective.
*
Corresponding author. Tel.: þ86-931-8912407; fax: þ86-931-8912582;
e-mail: panxf@lzu.edu.cn
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00791-3

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X. Peng et al. / Tetrahedron 58 (2002) 6799–6804
Scheme 1.
inversion of the anti-alcohol 6 into the syn-alcohol 7 was
accomplished via the Mitsunobu reaction by using
1.5 equiv. of Ph3P, DEAD and p-NO2C6H4COOH in
anhydrous THF, followed by hydrolysis of the correspond-
ing p-nitrobenzoate. 7 was thus obtained in 82% overall
yield.17 TBS protection of the hydroxy group in 7 (TBSCl,
Et3N, DMAP, CH2Cl2, 95%) followed by the treatment of
the resulted silyl ether with m-CPBA and NaHCO3 led to the
regioselective (.20:1) and diastereoselective (a–b.9.6:1)
formation of 9 in 82% yield. Deprotection of the TBS group
was easily achieved with tetra-n-butylammonium fluoride in
anhydrous THF, providing 10 in 80% yield. The stereo-
chemistry of epoxide 10 was assigned to a-facial epoxide on
the basis of the stereochemistry of the above reactions.
Epoxide 10 is unstable and decomposes into alcohol or
aldehyde in the presence of strong acids, such as CSA,
ZnBr2, BF3·Et2O, TiCl4, ZnCl2 and AlCl3 (Scheme 2).
Ac2O, pyridine and DMAP in anhydrous CH2Cl2 affording
12 in 92% yield. Deprotection of the ethoxy ethyl group and
oxidation the resulted allylic alcohol with CrO3/HOAc yield
in the same reactive flask provided 13 in 83% yield. Finally,
deprotection of the acetyl group with K2CO3 in methanol
afforded (þ)-isoaltholactone 1 in 78% yield.19 All physical
1
data (MS, H and 13C NMR, optical rotation, mp) of the
synthetic (þ)-isoaltholactone 1 were in full agreement with
those reported for the natural (þ)-isoaltholactone 1.1
3. Conclusion
We have successfully synthesized the natural (þ)-isoaltho-
lactone 1 in 6.4% overall yield from readily available
racemic 2-furylmethanol 2. The synthesis required only in
11 chemical operations and was highly enantio- and
diastereoselective. Sharpless kinetic resolution on racemic
2-furylmethanol 2, diastereoselective epoxidation of olefin
8 and PPTS catalyzed intramolecular cyclization of epoxide
alcohol 10 are the key steps for our synthesis. Our strategy
has provided a general and efficient access to a,b-
unsaturated d-lactones in their optically active form and is
expected to find more applications in the synthesis of other
related natural products such as altholactone, 3-acetylaltho-
lactone, goniothalesdiol.
For our synthesis of (þ)-isoaltholactone, the endo-cycliza-
tion reaction of compound 10 is the key reaction. We carried
out many experiments to establish the conditions for the
endo-cyclization reaction of 10, and found that excellent
stereoselectivity could be achieved by using catalytic
amount of PPTS in anhydrous CH2Cl2.18 The desired
bicyclic intermediate 11 was thus obtained in 90% yield.
Protection of the free hydroxy in 11 was accomplished with
i
˚
Scheme 2. (a) L-(þ)-DIPT, Ti(O- Pr)4, TBHP, 4 A MS, CH2Cl2, 230 to 2408C, 24 h, 38%; (b) ethyl vinyl ether, PPTS, CH2Cl2, 258C, 4 h, a (78%), b (10%);
(c) NaBH4, CeCl3·7H2O, MeOH, 230 to 2408C; 5 h, 6 (78%), 7 (4%); (d) DEAD, PPh3, p-NO2C6H5COOH, THF; then K2CO3, MeOH, rt, 10 h, 82%; (e)
TBSCl, Et3N, DMAP, CH2Cl2, 08C, 12 h, 95%; (f) m-CPBA, NaHCO3, CH2Cl2, 258C, 24 h, 82%, a–b.9.6:1; (g) TBAF, THF, 258C, 6 h, 80%; (h) PPTS,
CH2Cl2, 258C, 4 h, 90%; (i) Ac2O, Py, DMAP, 258C, 3.5 h, 92%; (j) CrO3/HOAc, 258C, 3 h, 83%; (k) K2CO3, MeOH, 258C, 5 h, 78%.

X. Peng et al. / Tetrahedron 58 (2002) 6799–6804
6801
4. Experimental
(20 mL) were added ethyl vinyl ether (11.90 g, 164.8 mmol)
and a catalytic amount of pyridium toluene-p-sulphonate at
room temperature. The reaction mixture was stirred for 3 h
at room temperature and poured into water (30 mL). The
phase were separated and the aqueous layer was extracted
with CH2Cl2 (5£30 mL). The organic layer was combined
and washed with brine, dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was
purified by column chromatography on silica gel using
petroleum ether–ethyl acetate (12:1, v/v) as eluent. The first
fraction gave the a-anomer 4 (3.51 g, 74%) as yellow oil.
[a ]2D0¼þ5.6 (c 0.15, CHCl3); nmax (KBr)/cm21 3040, 1720,
1680, 1640; m/z (EI) 243 (68, Mþ245), 216 (10), 198 (19),
131 (8), 115 (24), 103 (15), 84 (59), 77 (74); dH (400 MHz,
CDCl3) 1.22 and 1.25 (3H, each t, J¼7.2 Hz, CH2Me ), 1.43
and 1.45 (3H, each d, J¼4.8 Hz, CHMe ), 3.55–3.75 (2H,
m, CH2Me), 5.01 and 5.11 (1H, each q, J¼5.3 Hz, CHMe),
5.12 and 5.22 (1H, each dd, J¼5.4 and 1.7 Hz, EEO-
CHOCH ), 5.62 and 5.66 (1H, each d, J¼3.5 Hz, EEOCHO),
6.15 and 6.18 (1H, each d, J¼10.3 Hz, CHCHvCHCO),
6.40 and 6.45 (1H, each dd, J¼15.6 and 5.6 Hz,
CHvCHPh), 6.73 (1H, d, J¼15.6 Hz, CHvCH Ph), 6.90
and 6.92 (1H, each dd, J¼9.9 and 3.4 Hz, CHCHvCHCO)
and 7.25–7.45 (5H, m, C6H5); dC (100 MHz, CDCl3) 15.1,
21.7, 60.7, 85.8, 88.7, 97.6, 126.6, 126.7 (2), 127.2, 128.1,
128.8 (2), 129.6, 139.3, 143.8, 193.6; Found: C, 70.86; H,
6.92. C17H20O4 requires C, 70.83; H, 6.94%.
4.1. General
The melting point was measured with a X-4 apparatus. IR
spectra were recorded on a Nicolet 170 SXFT-IR
spretrometer. The H NMR data in CDCl3 solution were
1
recorded on a Brucker AM-400 MHz spectrometer. The
chemical shifts are reported in ppm relative to TMS. Mass
spectra were measured with a ZAB-HS mass spectrometer
(EI) by direct inlet at 70 eV and signal are given in m/z.
Optical rotation measurements were carried out on a
TASCO 20C polarimeter. All solvents were freshly purified
and dried by standard techniques prior to use. Purification of
products was performed by flash column chromatography
on silica gel (200–300 mesh) purchased from Qing Dao
Marine Chemical Co. (Qingdao, China) and eluting with a
solvent mixture (v/v) of petroleum spirit (60–908C) (bp)
and ethyl acetate (EA). TLC was performed on a glass plate
(2£5 cm) coated with GF254 purchased from Qing Dao
Marine Chemical Co. (Qingdao, China), and the compounds
were extracted with CH2Cl2 or AcOEt.
4.1.1. (2S )-6-Hydroxy-2-[(E )-styryl]-6H-pyran-3(2H )-
one (3). To a stirred solution of the furyl alcohol 2 (11 g,
0.055 mol) and L-(þ)-DIPT (1.93 g, 8.25 mmol) in anhy-
drous CH2Cl2 (120 mL) was added activated molecular
˚
sieves 4 A (1.84 g) at room temperature under argon. The
stirred mixture was cooled to 2308C, treated with
Ti(O-iPr)4 (1.57 g, 5.5 mmol), and stirring was continued
for 30 min at 2308C. The reaction mixture was treated with
TBHP (5.0–6.0 M, in nonane solution, 5.5 mL, 27.5 mmol)
and was then stirred for 24 h at the same temperature. A
freshly prepared solution of FeSO4·7H2O (4.62 g,
16.6 mmol) and tartaric acid (16.6 g, 110 mmol) in
deionized water (30 mL) was added to the reaction mixture
at 2308C. The resulting mixture was stirred at room
temperature until the mixture was clear. The phase were
separated and the aqueous layer was extracted with CH2Cl2
(5£40 mL). The organic layer was combined and washed
with brine and dried over anhydrous Na2SO4. Evaporation
of the solvent gave a residue, which was purified by column
chromatography on silica gel using petroleum ether–ethyl
acetate (4:1, v/v) as eluent to afford the pyranone 3 (4.51 g,
38%) as a brown oil; [a ]2D0¼þ126.3 (c 0.5, CHCl3); nmax
(KBr)/cm21 3350, 1720, 1680, 1640; m/z (EI) 216 (6, Mþ),
198 (8), 131 (16), 115 (29), 84 (84), 77 (19); dH (400 MHz,
CDCl3) 3.8–4.2 (1H, br s, OH ), 4.80 (0.2H, d, J¼5.9 Hz,
OCHCHvCHPh), 5.26 (0.8H, dd, J¼5.7 and 1.5 Hz,
OCHCHvCHPh), 5.77 (1H, br s, CHOH), 6.18 (1H, dd,
J¼10.3 and 1.5 Hz, CHCHvCHCO), 6.39 (0.8H, dd,
J¼15.8 and 5.72 Hz, CHvCHPh), 6.48 (0.2H, dd, J¼15.8
and 6.3 Hz, CHvCHPh), 6.75 (1H, dd, J¼15.8 and 1.9 Hz,
CHvCH Ph), 6.95 (0.8H, dd, J¼10.3 and 3.3 Hz,
CHCHvCHCO), 6.98 (0.2H, dd, J¼10.3 and 1.9 Hz,
CHCHvCHCO) and 7.25–7.45 (5H, m, C6H5); dC
(100 MHz, CDCl3) 86.3, 91.8, 125.8 (2), 126.5, 126.9,
127.4, 128.5 (2), 129.5, 131.2, 133.6, 190.2; Found: C, 72.4;
H, 5.57. C13H12O3 requires C, 72.2; H, 5.56%.
The second fraction gave b-anomer 5 (0.47 g, 10%) as
yellow oil. [a ]D20¼þ19.6 (c 0.15, CHCl3); nmax (KBr)/cm21
3040, 1720, 1680, 1640; m/z (EI) 243 (68, Mþ245), 216
(10), 198 (19), 131 (8), 115 (24), 103 (15), 84 (59), 77 (72);
dH (400 MHz, CDCl3) 1.19 and 1.25 (3H, each t, J¼7.2 Hz,
CH2Me ), 1.38 and 1.45 (3H, each d, J¼5.0 Hz, CHMe ),
3.35–3.75 (2H, m, CH2Me), 4.82 and 4.98 (1H, each d,
J¼6.5 Hz, EEOCHOCH ), 5.01 and 5.13 (1H, each q,
J¼6.3 Hz, CHMe), 5.64–5.76 (1H, m, EEOCHO), 6.13–
6.28 (1H, m, CHCHvCHCO), 6.44 and 6.65 (1H, each dd,
J¼15.6 and 6.6 Hz, CHvCHPh), 6.70 and 6.73 (1H, each d,
J¼15.6 Hz, CHvCH Ph), 6.90 and 6.95 (1H, each dd,
J¼9.9 and 3.4 Hz, CHCHvCHCO) and 7.25–7.45 (5H, m,
C6H5); dC (100 MHz, CDCl3) 15.3, 21.2, 60.9, 85.6, 88.7,
97.3, 126.5, 126.7 (2), 127.4, 128.1, 128.8 (2), 129.6, 139.1,
143.6, 192.9; Found: C, 70.84; H, 6.96. C17H20O4 requires
C, 70.83; H, 6.94%.
4.1.3. (2S,3R,6S)- and (2S,3S,6S )-6-(1-Ethoxyethoxy)-2-
[(E)-styryl]-3,6-dihydro-2H-pyran-3-ol (6) and (7). To a
stirred solution of the enone 4 (3.5 g, 12.2 mmol) and
CeCl3·7H2O (4.52 g, 12.2 mmol) in MeOH (40 mL) at 230
to 2408C was added powdered sodium borohydride
(0.464 g, 12.2 mmol). The reaction mixture was stirred for
1 h at room temperature. After dilution with brine (30 mL)
the mixture was extracted with ethyl acetate (5£30 mL).
The organic layer was washed with brine and dried over
anhydrous Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on
silica gel using petroleum ether–ethyl acetate (5:1, v/v) as
eluent. The first fraction gave the compound 6 (2.75 g, 78%)
as a green oil, [a]2D0¼231.2 (c 0.2, CHCl3); nmax
(KBr)/cm21 3434, 1640, 1600; m/z (EI) 218 (26,
Mþ272), 176 (49), 151 (26), 131 (79), 115 (12), 103
(35), 77 (23); dH (400 MHz, CDCl3) 1.18 and 1.23 (3H, each
4.1.2. (2S,6S)- and (2S,6R )-6-(1-Ethoxyethoxy)-2-[(E )-
styryl]-6H-pyran-3(2H )-one (4) and (5). To a stirred
solution of the lactol 3 (3.56 g, 16.48 mmol) in CH2Cl2

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X. Peng et al. / Tetrahedron 58 (2002) 6799–6804
t, J¼7.2 Hz, CH2Me), 1.36 and 1.38 (3H, each d, J¼5.7 Hz,
CHMe ), 1.86–1.92 (1H, br s, OH ), 3.48–3.73 (2H, m,
CH2Me), 4.08–4.10 (1H, br s, CHOH), 4.27 and 4.33 (1H,
each dd, J¼9.2 and 6.7 Hz, OCHCHvCHPh), 4.93 and 5.0
(1H, each q, J¼5.4 Hz, CHMe), 5.26 and 5.35 (1H, each br
s, EEOCHO), 5.73 and 5.81 (1H, each dt, J¼11.2 and
2.4 Hz, EEOCHCHvCH), 6.0 (1H, dd, J¼11.2 and 1.2 Hz,
EEOCHCHvCH ), 6.32 (1H, ddd, J¼16.1, 6.5 and 3.1 Hz,
CHvCHPh), 6.74 (1H, d, J¼16.1 Hz, CHvCH Ph) and
7.25–7.43 (5H, m, C6H5); dC (100 MHz, CDCl3) 15.3, 21.5,
63.2, 71.5, 77.5, 91.5, 98.8, 125.5 (2), 126.3, 127.5, 127.9,
128.1 (2) 128.8, 129.5, 133.1; Found: C, 70.32; H, 7.60.
C17H22O4 requires C, 70.34; H, 7.59%.
To a stirred solution of the compound 7 (1.72 g,
5.93 mmol) in anhydrous CH2Cl2 (30 mL) was added
Et3N (4.12 mL) in a round bottom flask and cooled to
08C. A catalytic amount of DMAP was added and followed
by addition of tert-butyldimethylsilyl chloride (1.07 g,
7.12 mmol). The solution was stirred for 8 h at 08C. The
reaction was quenched with Et2O (50 mL) and saturated
aqueous NaHCO3 (20 mL). The phase were separated and
the aqueous layer was extracted with Et2O (5£20 mL). The
organic fractions were combined, washed with saturated
aqueous NaHCO3 and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was
purified by column chromatography on silica gel using
petroleum ether–ethyl acetate (35:1, v/v) as eluent to afford
the compound 8 (2.28 g, 95%) as colorless oil. [a]2D0¼þ64
(c 2.8, CHCl3); nmax (KBr)/cm21 2932, 1384, 1099, 998;
m/z (EI) 332 (7, Mþ272), 315 (41), 289 (6), 272 (16), 258
(6), 243 (4), 200 (67), 143 (23), 131 (25), 91 (49), 77 (51),
73 (100), 45 (13); dH (400 MHz, CDCl3), 0.91 (9H, s, C
(Me )3), 0.10 (3H, s, SiCH3), 0.06 (3H, s, SiCH3), 1.14 and
1.24 (3H, each t, J¼7.2 Hz, CH2Me ), 1.35 and 1.38 (3H, d,
J¼6.0 Hz, CHMe ), 3.46–3.82 (2H, m, OCH2Me), 4.66–
4.69 (1H, m, CHCHvCHPh), 4.90 and 4.98 (1H, each q,
J¼5.4 Hz, OCHMe), 5.32 (1.5H, m, CHOTBS and
EEOCHO), 5.43 (0.5H, br s, EEOCHO), 5.86–6.07 (2H,
m, EEOCHCHvCH ), 6.36 (1H, dd, J¼16.2 and 7.2 Hz,
CHvCHPh), 6.64 (1H, d, J¼16.2 Hz, CHvCH Ph), 7.24–
7.42 (5H, m, C6H5); dC (100 MHz, CDCl3) 24.6 (2), 15.1,
15.3, 21.5, 25.9 (3), 64.7, 72.9, 77.2, 91.7, 99.8, 126.8 (2),
127.3, 127.8, 128.5, 129.8 (2), 130.1, 131.9, 136.8; Found:
C, 68.34; H, 8.89. C23H36SiO4 requires C, 68.32; H, 8.91%.
The second fraction gave the compound 7 (0.14 g, 4%) as
green oil. [a ]D20¼214.7 (c 0.2, CHCl3); nmax (KBr)/cm21
3434, 1640, 1600; m/z (EI) 218 (26, Mþ272), 176 (49), 151
(21), 131 (79), 115 (8), 103 (35), 77 (23); dH (400 MHz,
CDCl3) 1.16 and 1.23 (3H, each t, J¼7.4 Hz, CH2Me ), 1.36
and 1.38 (3H, each d, J¼5.8 Hz, CHMe ), 1.90–2.10 (1H, br
s, OH ), 3.46–3.82 (2H, m, CH2Me), 4.05–4.12 (1H, br s,
CHOH), 4.25 and 4.31 (1H, m, OCHCHvCHPh), 4.92 and
5.0 (1H. each q, J¼5.3 Hz, CHMe), 5.35 (1H, br s,
EEOCHO), 5.82 and 5.85 (1H, each t, J¼2.3 Hz,
EEOCHCHvCH),
6.04
(1H,
d,
J¼10.5 Hz,
EEOCHCHvCH ), 6.32 (1H, dd, J¼16.2 and 6.7 Hz,
CHvCHPh), 6.76 (1H, d, J¼16.2 Hz, CHvCH Ph) and
7.25–7.45 (5H, m, C6H5); dC (100 MHz, CDCl3) 15.2, 21.3,
63.2, 71.7, 77.3, 91.5, 98.7, 125.5 (2), 126.5, 127.8, 127.9,
128.2 (2) 128.7, 129.8, 133.1; Found: C, 70.33; H, 7.60.
C17H22O4 requires C, 70.34; H, 7.59%.
4.2. To invert the anti-alcohol (6) into the syn-alcohol (7)
4.2.2. (2S,3S,6S )-3-tert-Butyldimethylsilanyloxy-6-(1-
ethoxyethoxy)-2-[(3R )-3-phenyloxiranyl]-3, 6-dihydro-
2H-pyran (9). To a stirred solution of compound 8
(2.10 g, 5.2 mmol) and NaHCO3 (2.62 mg, 31.2 mmol) in
CH2Cl2 (20 mL) was added the power of m-CPBA (1.79 g,
10.4 mmol). The reaction was stirred for 10 h at room
temperature. The reaction was then quenched with Et2O
(40 mL) and saturated aqueous NaHCO3 (20 mL). The
phase were separated and the aqueous layer was extracted
with Et2O (5£30 mL). The organic fractions were combined
and dried over anhydrous Na2SO4. Evaporation of the
solvent gave a residue, which was purified by column
chromatography on silica gel using petroleum ether–ethyl
acetate (40:1–35:1, v/v) as eluent to afford the compound 9
(1.79 g, 82%) as a white solid. Mp 114–1168C; [a]2D0¼þ28
(c 2.4, CHCl3); nmax (KBr)/cm21 3390, 2928, 1384, 1068;
m/z (EI) 348 (6, M272), 331 (12), 273 (5), 261 (19), 245 (5),
235 (21), 200 (61), 131 (13), 91 (77), 77 (12), 73 (100), 45
(18); dH (400 MHz, CDCl3), 0.90 (9H, s, C(CH3)3), 0.15
(3H, s, SiCH3), 0.12 (3H, s, SiCH3), 1.16 and 1.22 (3H, each
t, J¼7.2 Hz, CH2Me ), 1.36 and 1.38 (3H, d, J¼6.0 Hz,
CHMe ), 3.44 (1H, dd, J¼6.8 and 2.0 Hz, CH(O)CHPh),
3.46–3.80 (2H, m, CH2Me), 3.95 (1H, d, J¼2.0 Hz,
CH(O)CH Ph), 4.28–4.35 (1H, m, CHCH(O)CHPh), 4.75
(1H, m, CHOTBS), 4.90 and 4.96 (1H, each q, J¼5.4 Hz,
CHMe), 5.34 (1H, br s, EEOCHO), 5.85–6.03 (2H, m,
EEOCHCHvCH ), 7.21–7.35 (5H, m, C6H5); dC
(100 MHz, CDCl3) 24.8 (2), 15.1, 18.2, 21.5, 25.7 (3),
57.6, 58.5, 61.1, 71.3, 77.3, 91.3, 99.6, 125.7, 127.6, 128.2
(2), 128.4 (2), 131.2, 134.6; Found: C, 65.69; H, 8.48.
C23H36SiO5 requires C, 65.71; H, 8.50%.
To a stirred solution of the anti-alcohol 6 (2.1 g, 7.24 mmol)
in anhydrous THF (40 mL) was added powered Ph3P
(2.85 g, 10.86 mmol) and p-NO2C6H4COOH (1.82 g,
10.86 mmol) at room temperature. After 20 min, the
mixture was cooled to 08C and added a solution of DEAD
(1.87 g, 10.86 mmol) in anhydrous THF (10 mL) under
argon. The reaction mixture was stirred for 10 h at room
temperature. The solvent was removed under reduced
pressure to give a residue. Ethyl ether (50 mL) was added
and the white precipitate was filtered off. The filtrate was
evaporated to dryness to give a crude product, which was
purified by column chromatography on silica gel using
petroleum–ethyl acetate (15:1, v/v) as eluent to afford 2.8 g
(quant.) the p-nitrobenzoate of the compound 6 as yellow oil.
At room temperature to the stirred solution of the p-
nitrobenzoate of compound 6 (2.8 g, 6.14 mmol) in MeOH
(30 mL) was added K2CO3 (1.02 g, 7.37 mmol) and the
reaction mixture was stirred for 10 h. After the addition of
H2O (20 mL) and dilution with CH2Cl2 (50 mL), the phase
were separated and the aqueous layer was extracted with
CH2Cl2 (5£30 mL). The organic layer was washed with
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent gave a residue, which was purified by column
chromatography on silica gel with petroleum ether–ethyl
acetate (5:1) as eluent to afford the alcohol 7 (1.72 g, 82%).
4.2.1. (2S,3S,6S )-3-tert-Butyldimethylsilanyloxy-6-(1-
ethoxyethoxy)-2-[(E)-styryl]-3,6-dihydro-2H-pyran (8).

X. Peng et al. / Tetrahedron 58 (2002) 6799–6804
6803
4.2.3. (2S,3S,6S )-6-(1-Ethoxyethoxy)-2-[(3R )-3-phenyl-
oxiranyl]-3,6-dihydro-2H-pyran-3-ol (10). To a stirred
solution of compound 9 (1.72 g, 4.1 mmol) and TBAF
(2.68 g, 10.25 mmol) was dissolved in THF (30 mL) at
room temperature. The reaction was stirred for 2 h at room
temperature. The reaction was then quenched with Et2O
(40 mL) and saturated aqueous NaHCO3 (20 mL). The
phase were separated and the aqueous layer was extracted
with Et2O (5£20 mL). The organic fractions were combined
and dried over anhydrous Na2SO4. Evaporation of the
solvent gave a residue, which was purified by column
chromatography on silica gel with petroleum ether–ethyl
acetate (8:1, v/v) as eluent to afford the compound 10 (1.0 g,
80%) as colorless oil. [a]2D0¼þ39 (c 3.92, CHCl3); nmax
(KBr)/cm21 3418, 2980, 1388, 1083, 1001; m/z (EI) 306 (8,
Mþ), 289 (21), 261 (2), 234 (20), 199 (15), 158 (9), 149 (14),
131 (18), 91 (94), 77 (41), 73 (100), 45 (70); dH (400 MHz,
CDCl3), 1.16 and 1.24 (3H, each t, J¼7.0 Hz, CH2Me ), 1.36
and 1.38 (3H, d, J¼5.8 Hz, CHMe ), 2.62 (1H, br s, OH ),
3.46–3.81 (2H, m, CH2Me), 3.54 (1H, dd, J¼5.8 and
1.8 Hz, CH(O)CHPh), 3.98 (1H, d, J¼1.8 Hz,
CH(O)CH Ph), 4.08 (1H, dd, J¼5.8 and 3.0 Hz, CHOH),
4.22–4.24 (1H, m, CHCH(O)CHPh), 4.92 and 4.98 (1H,
each q, J¼5.5 Hz, CHMe), 5.37 (1H, br s, EEOCHO), 5.80
and 5.84 (1H, each t, J¼2.6 Hz, EEOCHCHvCH), 6.15
(1H, d, J¼10.4 Hz, EEOCHCHvCH ), 7.23–7.37 (5H, m,
C6H5); dC (100 MHz, CDCl3) 15.2, 21.4, 56.8, 57.2, 61.8,
70.6, 77.3, 91.4, 99.6, 125.6, 126.1, 128.4 (2), 128.7 (2),
129.6, 136.8; Found: C, 66.65; H, 7.20. C17H22O5 requires
C, 66.67; H, 7.19%.
2.81 mmol), a catalytic amount of 4-dimethylaminopyri-
dine, acetic anhydride (860 mg, 8.43 mmol) and a drop wise
pyridine in CH2Cl2 (15 mL) was stirred for 5 h at room
temperature and then poured into water (10 mL). The crude
product was extracted with CH2Cl2 (5£20 mL), and the
organic layer was washed using brine and dried over
anhydrous Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on
silica gel with petroleum ether–ethyl acetate (10:1, v/v) as
eluent to afford the acetate 12 (978 mg, 92%) as a white
solid. Mp 132–1348C; [a]2D0¼26 (c 0.8, CHCl3); nmax
(KBr)/cm21 3412, 3382, 2975, 1742, 1378, 1082; m/z (EI)
276 (3, Mþ272), 261 (6), 216 (32), 198 (5), 191 (17), 169
(6), 107 (5), 91 (17), 77 (34), 73 (100), 45 (20); dH
(400 MHz, CDCl3), 1.13 and 1.20 (3H, each t, J¼7.0 Hz,
CH2Me ), 1.26 and 1.36 (3H, d, J¼6.0 Hz, CHMe), 2.62
(3H, s, OCOMe ), 3.42–3.90 (2H, m, CH2Me), 4.82 (1H, m,
CHOCHPh), 4.94 and 4.98 (1H, each q, J¼5.7 Hz, CHMe),
4.96 (1H, d, J¼5.3 Hz, CHOAc), 5.15 (1H, dd, J¼5.3 and
2.4 Hz, OCHCOAc), 5.35 (1H, dd, J¼4.2 and 2.2 Hz,
CH Ph), 5.38 (1H, br s, EEOCHO), 5.80 and 5.84 (1H, each
t, J¼3.0 Hz, EEOCHCHvCH), 6.11 (1H, d, J¼10.4 and
4.2 Hz, EEOCHCHvCH ), 7.25–7.37 (5H, m, C6H5); dC
(100 MHz, CDCl3) 15.5, 19.7, 21.1, 61.6, 72.7, 76.8, 80.3,
89.7, 98.5, 125.7, 125.9, 128.3, 128.5 (2), 128.7 (2), 130.7,
138.9, 170.7; Found: C, 65.49; H, 6.87. C19H24O6 requires
C, 65.52; H, 6.90%.
4.2.6. 3-Acetyl-isoaltholactone (13). To a stirred solution
of the compound 12 (960 mg, 2.76 mmol) in HOAc (5 mL)
was added the solution of CrO3/HOAc (3.32 mmol). The
reaction mixture was stirred for 5 h at room temperature.
The mixture was poured into water (20 mL) and extracted
with CH2Cl2 (5£20 mL). The organic layer was washed
with brine and saturated aqueous NaHCO3 and dried over
anhydrous Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on
silica gel using petroleum ether–ethyl acetate (2:1, v/v) as
eluent to afford the lactone 13 (627 mg, 83%) as a white
solid. Mp 153–1568C; [a ]2D0¼þ66 (c 1.1, EtOH); nmax
(KBr)/cm21 2924, 1736, 1228, 1032, 1070; m/z (EI) 215 (5,
[MþH2OHCOCH3]þ), 199 (8), 163 (5), 126 (52), 122 (6),
107 (10), 105 (17), 97 (27), 95 (12), 77 (21); dH (400 MHz,
CDCl3), 2.08 (3H, s, COMe ), 4.91 (1H, t, J¼5.2 Hz,
CHOCHPh), 4.96 (1H, d, J¼4.2 Hz, CHOAc), 5.06 (1H, t,
J¼5.2 Hz, OCHCHOAc), 5.36 (1H, dd, J¼4.2 and 2.2 Hz,
CH Ph), 6.23 (1H, d, J¼9.8 Hz, OCOCHvCH), 6.92 (1H,
dd, J¼9.8 and 5.2 Hz, OCOCHvCH ), 7.21–7.42 (5H, m,
C6H5); dC (100 MHz, CDCl3) 170.4, 161.2, 141.8, 138.2,
128.8 (2), 128.6 (2), 125.6, 122.4, 81.8, 78.4, 76.4, 68.2,
20.8; Found: C, 65.65; H, 5.14. C15H14O5 requires C, 65.67;
H, 5.11%.
4.2.4. 6S-6-(1-Ethoxyethoxy)-isoaltholactone (11). The
compound 10 (980 mg, 3.2 mmol) was dissolved in CH2Cl2
(15 mL) and a catalytic amount of PPTS was added to the
solution at room temperature. The reaction was stirred for
4 h at room temperature. The reaction was quenched with
Et2O (30 mL) and saturated aqueous NaHCO3 (10 mL). The
phase were separated and the aqueous layer was extracted
with Et2O (5£20 mL). The organic fractions were combined
and dried over anhydrous Na2SO4. Evaporation of the
solvent gave a residue, which was purified by column
chromatography on silica gel using petroleum ether–ethyl
acetate (5:1, v/v) as eluent to afford the compound 11
(882 mg, 90%) as
a white solid. Mp 138–1418C;
[a]2D0¼þ32 (c 1.4, CHCl3); nmax (KBr)/cm21 3405, 3394,
2924, 1382, 1066; m/z (EI) 234 (6, [M272]þ), 217 (11), 126
(8), 122 (20), 107 (43), 105 (9), 97 (83), 95 (13), 91 (17), 77
(65); dH (400 MHz, CDCl3), 1.10 and 1.21 (3H, each t,
J¼7.2 Hz, CH2Me ), 1.27 and 1.34 (3H, each d, J¼5.8 Hz,
CHMe ), 2.1 (1H, br s, OH ), 3.38–3.92 (2H, m, OCH2Me),
4.28 (1H, m, CHOH), 4.51 (1H, d, J¼7.6 Hz, OCH Ph), 4.83
(1H, m, CHOCHPh), 4.93 and 4.99 (1H, each q, J¼5.6 Hz,
CHMe), 5.14 (1H, dd, J¼6.2, 5.8 Hz, OCHCHOH), 5.37
(1H, br s, EEOCHO), 5.82 and 5.85 (1H, each t, J¼2.8 Hz,
EEOCHCHvCH), 6.11 (1H, dd, J¼10.4, 4.0 Hz,
EEOCHCHvCH ), 7.22–7.45 (5H, m, C6H5); dC
(100 MHz, CDCl3) 142.8, 138.3, 128.6 (2), 128.5, 128.4
(2), 125.7, 87.9, 85.6, 78.9, 77.6, 67.4, 64.3, 21.2, 15.5, 14.2;
Found: C, 66.68; H, 7.21. C17H22O5 requires C, 66.67; H,
7.19%.
4.2.7. (1)-Isoaltholactone (1). To a stirred solution of the
compound 13 (610 mg, 2.23 mmol) in MeOH (15 mL) was
added K2CO3 (0.46 g, 3.34 mmol) at room temperature. The
mixture was stirred for 6 h at room temperature. The
reaction was quenched with Et2O (30 mL) and water
(10 mL). The phase were separated and the aqueous layer
was extracted with Et2O (5£20 mL). The organic phrase
were combined, washed with water and dried over
anhydrous Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on
4.2.5. (3S,6S )-3-Acetyl-6-(1-ethoxyethoxy)-isoaltholac-
tone (12). A stirred solution of the alcohol 11 (860 g,

6804
X. Peng et al. / Tetrahedron 58 (2002) 6799–6804
Coleman, M. T. A.; Rivett, D. E. Progress in the Chemistry of
Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Tamm, Ch., Eds.; Springer: New York, 1989; Vol. 55,
pp 1–35.
silica gel using petroleum ether–ethyl acetate (1:1, v/v) as
eluent to afford the natural product 1 (403 mg, 78%) as a
needle solid. Mp 101.5–103.28C; [a ]2D0¼þ35 (c 0.80,
EtOH); nmax (KBr)/cm21 3500, 3030, 1730, 1645; m/z (EI)
232 (8, Mþ), 126 (8), 122 (13), 107 (28), 97 (100), 91 (14),
77 (25); dH (400 MHz, CDCl3), 2.86 (1H, br s, OH ), 4.28
(1H, m, CHOH), 4.80 (1H, d, J¼7.5 Hz, CH Ph), 4.89 (1H, t,
J¼5.5 and 4.5 Hz, CHOCHPh), 5.07 (1H, t, J¼5.5 Hz,
OCHCHOH), 6.23 (1H, dd, J¼10.2 and 1.1 Hz,
OCOCHvCH), 6.89 (1H, dd, J¼10.2 and 4.8 Hz,
OCOCHvCH ), 7.26–7.42 (5H, m, C6H5); dC (100 MHz,
CDCl3) 162, 142, 138, 129 (2), 128, 126 (2), 123, 84, 79, 78,
68; Found: C, 67.26; H, 5.14. C13H12O4 requires C, 67.24;
H, 5.17%. Its spectroscopic data are identical with those
reported.1
5. (a) See Ref. 2. (b) Schlessing, R. H.; Gillman, K. W.
Tetrahedron Lett. 1999, 40, 1257–1260. (c) Tsubuki, M.;
Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55, 2493.
(d) Gomez, A. M.; Lopez, U. B.; Valverde, S.; Lopez, J. C.
J. Chem. Soc., Chem. Commun. 1997, 1647. (e) Yang, Z. C.;
Zhou, W. S. Tetrahedron Lett. 1995, 36, 5617–5618.
6. (a) Gesson, J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron
Lett. 1987, 28, 3945–3948. (b) Gesson, J. P.; Jacquesy, J. C.;
Mondon, M. Tetrahedron 1989, 45, 2627–2640.
7. Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H. J. Org. Chem. 1995,
60, 3121–3130.
8. (a) Tsubuki, M.; Kanai, K.; Honda, T. Synlett 1993, 653–655.
(b) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
Tetrahedron 1999, 55, 2493–2514.
Acknowledgments
9. Joel, M. H.; O’Doherty, G. A. Org. Lett. 2000, 2, 2983–2986.
10. Somfa, P. Tetrahedron 1994, 50, 11315–11320.
11. Mukai, C.; Hirai, S.; Kim, I. J.; Hanaoka, M. Tetrahedron Lett.
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We are grateful to the National Science Foundation of China
(No. 20172023) for financial support. In addition, we thank
Dr Yun He and Professor Teng-Kuei Yang for careful
reading and helpful comment on the manuscript.
12. (a) Peng, X. S.; Li, A. P.; Zhang, C. L.; Wang, H.; Pan, X. F.
J. Chem. Res. 2002. in press. (b) Peng, X. S.; Li, A. P.; Shen,
H.; Wang, H.; Pan, X. F. J. Chem. Res. 2002. in press.
13. Chaomin, L.; Emily, A. P.; Mei, C. L.; Emil, L.; Thomas,
D. G.; John, A. P. J. J. Am. Chem. Soc. 2001, 123,
11308–11309.
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