Synthesis of (+)-zeylenone from shikimic acid

Article abstract of DOI:10.1016/j.tet.2004.02.066

Starting from shikimic acid, the total synthesis of zeylenone was studied. The product was proved to be the (+)antipode of zeylenone through analysis and comparison of their respective spectra (including NMR, MS, IR and CD) and optical data. The absolute

Full text of DOI:10.1016/j.tet.2004.02.066

Tetrahedron 60 (2004) 3689–3694
Synthesis of (1)-zeylenone from shikimic acid
b
a
a
An Liu,a Zhan Zhu Liu,b Zhong Mei Zou,a Shi Zhi Chen, Li Zhen Xu and Shi Lin Yang
,
,
*
*
aInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100094,
People’s Republic of China
bInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050,
People’s Republic of China
Received 19 November 2003; revised 16 February 2004; accepted 20 February 2004
Abstract—Starting from shikimic acid, the total synthesis of zeylenone was studied. The product was proved to be the (þ)antipode of
zeylenone through analysis and comparison of their respective spectra (including NMR, MS, IR and CD) and optical data. The absolute
configuration of the natural product was thus determined to be (1S,2S,3R).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of the enantioisomer of zeylenone from shikimic
acid (2).5
A number of polyoxygenated cyclohexenes, which show
anticancer, antiviral and antibiotic activities, have been
isolated from the Uvaria genus.1 As a part of our project of
searching for the anticancer components from the plant
source, zeylenone (Fig. 1) was isolated from Uvaria
grandiflora, which showed remarkable inhibition of nucleo-
side transport in Ehrlich carcinoma cells and interesting
cytotoxicity to cultured cancer cells.2 The relative stereo-
chemistry of zeylenone was assigned on the basis of the
modern NMR techniques but the absolute configuration was
not elucidated. Kunio Ogasawara and co-workers syn-
thesized (2)tonkinenin A, which was isolated from Uvaria
tonkinensis,3 and corrected its structure to be the same as
zeylenone.4 As our continuous effort to confirm the
structure and to study the structure–activity relationship
of zeylenone, we report herein the enantioselective
The retrosynthetic analysis for zeylenone is outlined in
Scheme 1. Zeylenone could be obtained by oxidation of
olefin 3 with SeO2. The olefin 3 could be synthesized from
the trans diol 4, which could be derived from olefin 5 by
oxidation with OsO4. The olefin 5 could be obtained from
shikimic acid (2) by reduction and selective protection.
2. Results and discussion
Our synthesis of 1 began with the methylation of shikimic
acid (2), followed by regio-selective protection of trans
vicinal diol 6 with 2,3-butanedione, (^)-camphorsulfonic
acid (CSA, cat.) and trimethyl orthoformate in methanol at
reflux to give compound 7 in 87% yield.6 At the same time,
we obtained the protected cis diol 8 in 10%. Fortunately,
compound 8 could be converted into 7 with catalytic amount
of (^)-CSA in refluxing methanol under Ar for 18 h in 92%
yield, After introduction of tert-butyldimethylsilyl
(TBDMS) group,7 compound 9 was obtained in 97% yield
from the protected diol 7. After reduction of 9 with
diisobutylaluminum hydride (DIBAL-H), alcohol 10 was
obtained in 92% yield.8 Benzoylation of 10 with benzoyl
chloride afforded olefin 5 in 97% yield. The olefin 5 was
dihydroxylated with OsO4 and N-methylmorphorline-N-
oxide (NMO) in THF/H2O (1:1) under Ar to give
stereoselectively the sole diol isomer 11 in 94% yield.
The cis diol 11 was protected with 2,2-dimethylpropane to
give acetonide 12 in 99% yield,9 followed by selective
deprotection with TFA/H2O (1:1) to give the trans vicinal
diol 4(Scheme 2).10
Figure 1. The structures of zeylenone and shikimic acid.
Keywords: Zeylenone; Absolute configuration; Shikimic acid; Total
synthesis; Enantiomer.
*
Corresponding authors. Tel.: þ86-10-62899705 (L.Z.X.); tel.: þ86-10-
63165253 (Z.Z.L.);
e-mail addresses: liuan62@yahoo.com.cn; liuzhanzhu@imm.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.066

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A. Liu et al. / Tetrahedron 60 (2004) 3689–3694
Scheme 1.
The treatment of trans vicinal diol 4 with Ph3P, imidazole
and iodine in toluene at reflux gave cyclohexene 3 in 87%
yield.10,11 We have tried to oxidize cyclohexene 3 by CrO3/
t-BuOOH, PCC, CuBr/t-BuOOH, or SeO2 to synthesize
enone. Unfortunately, we could not get the desired product
17, only to obtain the TBDMS-deprotected enone 13
(Scheme 3).
So, the cyclohexene 3 was deprotected with tetra-butyl-
ammonium fluoride (TBAF) and benzoic acid in dry THF to
Scheme 2. (a) SOCl2, MeOH, 10 8C, 93%; (b) (CH3CO)2, CH(OMe)3, (^) CSA, MeOH, Ar, 48 h, 90 8C, 87%; (c) (^) CSA, MeOH, Ar, 18 h; (d) TBDMSCl,
imidazole, DMAP, CH2Cl2, room temperature, 24 h, 97%; (e) DIBAL-H, toluene, 278 8C, 92%; (f) BzCl, DMAP, pyridine, room temperature 97%; (g) OsO4,
NMO, THF/H2O (1:1), Ar, 94%; (h) (CH3)2C(OCH3)2, TsOH, CH2Cl2, Ar, room temperature, 99%; (i) TFA/H2O (1:1), CH2Cl2, 79%.

A. Liu et al. / Tetrahedron 60 (2004) 3689–3694
3691
Scheme 3. (j) Ph3P, imidazole, I2, reflux, 87%; (k) t-BuOOH, CrO3,
CH2Cl2, 36%.
Figure 2. The CD spectra of zeylenone.
zeylenone and (2)-tonkinenin A were the same natural
products. Further work on the synthesis of the authentic
natural product and its analogues is in progress.
give alcohol 14,12 followed by the protection with benzoyl
group to give olefin 15. The enone 16 was obtained from 15
by oxidation with SeO2 in dry THF at reflux for 24 h 40%
yield.13 Subsequent deprotection of 15 with TFA/H2O (9:1)
in CH2Cl2 at room temperature provided the target
compound 1 in 85% yield (Scheme 4).
4. Experimental
4.1. General
The spectral data (including NMR, MS and IR) of
compound 1 were identical with those of natural zeyleone,
which indicated that the relative stereochemistry of 1 was
the same as that of the natural product. The positive Cotton
effect14 of the synthetic product 1 suggested the absolute
stereochemistry of 1 to be of (1R,2R,3S). But the value and
sign of the optical rotation of the compound 1 {[a]2D0¼þ118
(c 0.56, CHCl3), [a]2D0¼þ26 (c 0.23, CH3OH)} were
opposite to those of the natural product {lit.2
[a]D20¼2126.5 (c 0.747, CHCl3); lit.3 [a]2D0¼226.0 (c
0.89, MeOH); [a]D20¼2120 (c 0.60, CHCl3), [a]2D0 226 (c
0.26, CH3OH)}. In addition, Cotton effects in CD spectra of
the two compounds were opposite too (Fig. 2). All the data
proved that compound 1 is the (þ)-antipode of the natural
product. So the absolute configuration of the natural product
was determined to be (1S,2S,3R). This also proved that
zeylenone and (2)-tonkinenin A were the same natural
products.
Melting points were obtained on a Yanaco apparatus and
were uncorrected. Infrared spectra were measured on a
1
Perkin–Elmer 683 spectrometer. H and 13C NMR spectra
were recorded on a JEOL FX-90Q spectrometer. Chemical
shifts were reported in ppm with tetramethylsilane as the
internal standard and J values in Hz. Mass spectra and high-
resolution mass data were obtained on a VGZAB-2F
spectrometer. Silica gel was used for flash column
chromatography. All solvents were purified and dried by
standard techniques or used as supplied from commercial
sources as appropriate.
4.1.1. (3R,4S,5R)-3,4,5-Trihydroxy-1-cyclohexene-1-car-
boxylate methyl ester (6). To a solution of shikimic acid
(2) (20 g, 0.11 mol) in MeOH, SOCl2 (15 mL, 0.21 mol)
was added dropwise during 1 h at 0 8C. Then the reaction
mixture was warmed to room temperature and stirred
overnight. Removal of the solvent and recrystallization from
EtOAc afforded 6 as white solid (19.9 g, 93%). Mp 112–
113 8C, [a]2D0¼2125 (c 1.8, EtOH), IR (KBr): 3330, 2900,
3. Conclusion
1
1716, 1658, 1435, 1244, 1095, 1068, 930, 746 cm21; H
NMR (CDCl3, 300 MHz) d 6.71–6.73 (m, 1H, H-2), 4.83 (s,
3H, OCH3), 4.31 (br s, 1H, H-3), 3.93 (dd, 1H, J¼12.3,
5.1 Hz, H-5), 3.61–3.65 (m,1H, H-4), 3.25 (s, 1H, OH),
2.60–2.67 (m, 1H, H-6b), 2.17 (dd, 1H, J¼18.0, 5.1 Hz,
H-6a).
In summary, we have achieved the asymmetric total
synthesis of (þ)-antipode of zeylenone via a multi-step
enantioselective route starting from shikimic acid. Our
study shows the absolute configuration of the natural
product zeylenone was proved to be (1S,2S,3R) and that
Scheme 4. (l) TBAF, benzoic acid, THF, room temperature, 94%; (m) BzCl, DMAP, pyridine, room temperature, 99%; (n) SeO2, THF, reflux, 40%; (o)
TFA/H2O (9:1), CH2Cl2, 85%.

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A. Liu et al. / Tetrahedron 60 (2004) 3689–3694
4.1.2. Methyl (3R,4S,5R)-3-hydroxy-4,5-(2,3-dimethoxy-
butan-2,3-dioxy)-cyclohex-1-ene-1-carboxylate (7) and
methyl (3R,4S,5R)-5-hydroxy-3,4-(2,3-dimethoxybutan-
2,3-dioxy)-cyclohex-1-ene-1-carboxylate (8). Trimethyl
orthoformate (60 g, 0.57 mol) was added to a mixture of 6
(17.8 g, 0.095 mol), 2,3-butanedione (20 g, 0.23 mol) and
catalytic amount of DMAP (0.12 g, 0.1 mmol) in MeOH
(200 mL), and the whole mixture was refluxed under Ar for
48 h. After being cooled to room temperature, NaHCO3
(20 g) was added to the mixture and stirred for 10 min.
Removal of the solvent and purification of the residue by
column chromatography (acetone/petroleum ether 1:5)
afforded colorless oil 7 (24.9 g, 87%) and white solid 8
(3.7 g, 12%). Compound 7: [a]2D0¼þ23.1 (c 0.89, CHCl3),
1H NMR (CDCl3, 300 MHz) d 6.90 (dd, 1H, J¼5.1, 2.7 Hz,
H-2), 4.39 (t, 1H, J¼4.8 Hz, H-3), 4.06–4.15 (m, 1H, H-5),
3.76 (s, 3H, OCH3), 3.62 (dd, 1H, J¼10.8, 4.5 Hz, H-4),
3.28 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.84 (dd, 1H,
J¼17.7, 5.7 Hz, H-6a), 2.25 (ddd, 1H, J¼17.7, 7.5, 2.7 Hz,
H-6b), 1.34 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR
(CDCl3, 75 MHz) d 166.6, 135.0, 131.8, 100.0, 99.2, 70.5,
65.0, 62.4, 52.1, 48.0, 47.9, 30.0, 17.8, 17.7; EIMS m/z: 271,
213, 154, 139, 125, 101, 95, 75; FAB-HRMS: cacld for
C14H22O7Na [MþNa]þ: 325.1263, found 325.1283. Com-
pound 8: mp 137–138 8C, [a]2D0¼2144.2 (c 0.26, CHCl3),
1H NMR (CDCl3, 300 MHz) d 6.98 (s, 1H, H-2), 4.39 (d,
1H, J¼1.2 Hz, H-3), 4.17 (br s, 1H, H-5), 4.11 (br s, 1H,
H-4), 3.73 (s, 3H, COOCH3), 3.27 (s, 3H, OCH3), 3.26 (s,
3H, OCH3), 2.64 (ddd, 1H, J¼18.3, 6, 3 Hz, H-6b), 2.40 (d,
H, J¼18.3 Hz, H-6a), 1.27 (s, 3H, CH3), 1.24 (s, 3H, CH3).
EIMS m/z: 271, 154, 139, 122, 101, 95, 75. FAB-HRMS:
cacld for C14H22O7Na [MþNa]þ: 325.1263, found
325.1283.
CH3); 13C NMR (CDCl3, 75 MHz) d 167.1, 136.8, 129.7,
99.5, 98.7, 70.8, 66.0, 62.4, 52.0, 47.8, 47.6, 30.4, 25.8
(C£3), 18.3, 17.9, 17.7, 24.70 (C£2); HRFABMS: cacld
for C20H36O7SiNa [MþNa]þ: 439.2122, found 439.2127.
4.1.4. (3R,4S,5R)-3-O-tert-Butyldimethylsilyl-4,5-(2,3-
dimethoxybutan-2,3-dioxy)-cyclohex-1-ene-1-methanol
(10). A solution of diisobutylaluminium hydride (1 M,
58 mL) in toluene was added dropwise to the solution of 9
(12.1 g, 29 mmol) in dry toluene under Ar at 278 8C. After
being stirred for 20 min, water (100 mL) was added to the
reaction mixture to quench the reaction. The mixture was
extracted with diethyl ether (3£100 mL), washed with brine
(50 mL) and dried (MgSO4). The solvent was removed in
vacuo and purified by column chromatography (acetone/
petroleum ether 1:6) to yield alcohol 10 (11.3 g, 92%) as
white solid. Mp 90–91 8C, [a]2D0¼þ8.6 (c 0.11, CHCl3),
KBr
max
IR n
cm21:: 3244, 2971, 1685, 1255, 1124, 839, 775,
673 cm21 1H NMR (CDCl3, 300 MHz) d 5.69 (d, 1H,
;
J¼4.5 Hz, H-2), 4.22 (t, 1H, J¼4.5 Hz, H-3), 4.14 (td, 1H,
J¼10.5, 6.0 Hz, H-5), 4.02 (s, 2H, H-7), 3.48 (dd,
1H, J¼10.8, 3.9 Hz, H-4), 3.24 (s, 3H, OCH3), 3.22 (s,
3H, OCH3), 2.34 (dd, 1H, J¼16.8, 6.0 Hz, H-6a), 2.09 (dd,
1H, J¼16.8, 10.5 Hz, H-6b), 1.27 (s, 6H, CH3£2), 0.90 (s,
9H, CH3£3), 0.09 (6H, s, CH3£2); 13C NMR (CDCl3,
75 Hz) d 138.2, 128.2, 99.4, 98.6, 71.3, 66.4, 65.9, 62.1,
48.2, 47.7, 31.5, 25.7 (C£3), 18.4, 17.9, 17.7, 24.6, 24.8.
4.1.5. (3R,4S,5R)-1-Benzoyloxymethyl-3-O-tert-butyl-
dimethylsilyl-4,5-(2,3-dimethoxybutan-2,3-dioxy)-cyclo-
hex-1-ene (5). Benzoyl chloride (5.3 mL, 43.5 mmol) was
added dropwise to a solution of alcohol 10 (11.0 g,
28.4 mol) and catalytic amount of DMAP (0.05 g,
0.4 mmol) in dry pyridine (200 mL) at room temperature
during a period 20 min. Stirring was continued for another
2 h and then saturated aqueous NaHCO3 (100 mL) was
added to the reaction mixture to quench the reaction. The
mixture was extracted with CH2Cl2 (3£100 mL), washed
with brine (30 mL) and dried (MgSO4). The solvent was
removed and the product purified by column chromato-
graphy (acetone/petroleum ether 1:10), which yielded
protected alcohol 5 (13.8 g, 97%) as white solid. Mp 59–
60 8C, [a]2D0¼þ2.8 (c 0.64, CHCl3); IR nmKBaxr cm21:: 2947,
2854, 1720, 1452, 1375, 1267, 1140, 1076, 1039, 987, 901,
A solution of 8 (1.0 g, 3.3 mmol) and catalytic amount of
(^)-CSA was stirred in MeOH (20 mL) at reflux under Ar
for 18 h. After being cooled to room temperature, NaHCO3
(0.5 g) was added to the mixture and stirred for 5 min.
Removal of the solvent and purification of the residue by
column chromatography (acetone/petroleum ether 1:5)
afforded colorless oil 7 (0.92 g, 92%).
4.1.3. Methyl (3R,4S,5R)-3-O-tert-butyldimethylsilyl-4,5-
(2,3-dimethoxybutan-2,3-dioxy)- cyclohex-1-ene-1-car-
boxylate (9). To a solution of 7 (10.0 g, 33.1 mmol),
imidazole (3.8 g, 55.4 mmol) and catalytic amount of
dimethylaminopyridine (DMAP, 0.05 g, 0.4 mmol) in dry
CH2Cl2 (300 mL), tert-butyldimethyl-silyl chloride (5.0 g,
33.2 mmol) was added, and the mixture was stirred at room
temperature for 24 h. After quenching the reaction with
saturated aqueous NH4Cl (150 mL), the reaction mixture
was extracted with CH2Cl2 (3£150 mL), washed with brine
(50 mL), and dried (MgSO4). The solvent was removed and
the product was purified by column chromatography
(acetone/petroleum ether 1:10), which yielded 9 as white
solid (13.3 g, 97%). Mp 71–72 8C, [a]2D0¼215.6 (c 0.18,
CHCl3), 1H NMR (CDCl3, 300 MHz) d 6.75 (dd, 1H, J¼5.7,
2.7 Hz, H-2), 4.29 (t, 1H, J¼4.5 Hz, H-3), 4.10 (dt, 1H,
J¼10.5, 6 Hz, H-5), 3.73 (s, 3H, OCH3), 3.46 (dd, 1H,
J¼10.2, 4.5 Hz, H-4), 3.23 (s, 3H, OCH3), 3.21 (s, 3H,
OCH3), 2.88 (dd, 1H, J¼17.4, 6 Hz, H-6a), 2.20 (ddd, 1H,
J¼17.4, 10.2, 2.7 Hz, H-6b), 1.27 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 0.87 (s, 9H, CH3£3), 0.11 (s, 3H, CH3), 0.08 (s, 3H,
1
860, 833, 781, 719 cm21; H NMR (CDCl3, 300 MHz) d
8.06 (d, 2H, J¼7.5 Hz, H-20 and 60), 7.55 (d, 1H, J¼7.5 Hz,
H-40), 7.45 (t, 2H, J¼7.5 Hz, H-30 and 50), 5.80 (d, 1H,
J¼3.9 Hz, H-2), 4.75 (s, 2H, H-7), 4.22–4.27 (m, 1H, H-3),
4.19 (dd, 1H, J¼10.5, 4.3 Hz, H-5), 3.53 (dd, 1H, J¼10.8,
3.9 Hz, H-4), 3.25 (s, 6H, OCH3£2), 2.44 (dd, 1H, J¼17.5,
6.3 Hz, H-6a), 2.30 (ddd, 1H, J¼17.5, 10.2, 1.8 Hz, H-6b),
1.28 (s, 6H, CH3£2), 0.88 (s, 9H, CH3£3), 0.10 (s, 3H,
CH3), 0.09 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d
166.2, 133.8, 133.1, 130.0, 129.7 (C£2), 128.4 (C£2),
125.9, 99.4, 98.7, 71.0, 67.8, 66.3, 62.6, 47.8, 47.7, 32.1,
25.8 (C£3), 18.3, 17.9, 17.7, 24.6, 24.8.
4.1.6. (1R,2R,3R,4S,5R)-1-Benzoyloxymethyl-1,2-di-
hydroxy-3-O-tert-butyldimethylsilyl-4,5- (2,3-dimethoxy-
butan-2,3-dioxy)-cyclohexane (11).
A suspension of
olefin 5 (13 g, 26 mmol), N-methylmorpholine-N-oxide
(NMO, 5.7 g, 42.0 mmol), and catalytic amount of OsO4
(70.0 mg, 0.28 mmol) in THF/H2O (250 mL, v/v 1:1) under

A. Liu et al. / Tetrahedron 60 (2004) 3689–3694
3693
Ar was stirred violently at room temperature for 12 h. The
solid Na2S2O3 (25 g) and EtOAc (100 mL) were added to
the reaction mixture and stirred for another 30 min. The
mixture was loaded onto a flash chromatographic column
and washed with EtOAc. Removal of the EtOAc and
purification of the residue by column chromatography
(acetone/petroleum ether 1:3) afforded white solid 11
(13.1 g, 94%). Mp 136–138 8C, [a]2D0¼þ73 (c 0.64,
(300 MHz, CDCl3, J in Hz) d 8.05 (2H, d, J¼7.5 Hz), 7.57
(1H, t, J¼7.5 Hz), 7.44 (2H, t, J¼7.5 Hz), 4.66 (1H, d,
J¼12.3 Hz, H-7a), 4.38 (1H, t, J¼3 Hz, H-3), 4.18–4.25
(1H, m, H-2), 4.20 (1H, d, J¼12.3 Hz, H-7b), 3.74–3.80
(1H, m, H-5), 3.69 (1H, dd, J¼9.3, 3 Hz, H-4), 2.25 (1H, dd,
J¼13.5, 4.2 Hz, H-6a), 2.03 (1H, t, J¼13.5 Hz, H-6b), 1.50
(3H, s, CH3), 1.35 (3H, s, CH3), 0.86 (9H, s, CH3£3), 0.14
(3H, s, CH3), 0.10 (3H, s, CH3); 13C NMR (CDCl3, 75 MHz)
d 166.1, 133.1, 129.9, 129.6 (C£2), 128.4 (C£2), 108.9,
80.4, 77.9, 73.9, 70.9, 67.2, 65.9, 38.1, 28.2, 26.7, 25.8
(C£3), 18.0, 24.8, 25.0; HRFABMS: cacld for
C23H37O7Si [MþH]þ: 453.2303, found 453.2306.
1
CHCl3), H NMR (300 MHz, CDCl3, J in Hz) d 4.85 (d,
1H, J¼12 Hz, H-7a), 4.45 (d, 1H, J¼12 Hz, H-7b), 4.16 (t,
1H, J¼3.3 Hz, H-3), 3.90–3.96 (m, 1H, H-5), 3.83 (dd, 1H,
J¼10.5, 3.3 Hz, H-4), 3.81 (d, 1H, J¼3.3 Hz, H-2), 2.42–
2.50 (m, 1H, H-6a), 1.85–1.93 (m, 1H, H-6b), 3.25 (s, 3H,
OCH3), 3.22 (s, 3H, OCH3), 1.29 (s, 3H, CH3), 1.27 (s, 3H,
CH3), 0.88 (s, 9H, CH3£3), 0.15 (s, 3H, CH3), 0.08 (s, 3H,
CH3), benzoyl groups: d 8.04 (d, 2H, J¼7.5 Hz), 7.59 (t, 1H,
J¼7.5 Hz), 7.46 (d, 2H, J¼7.5 Hz); 13C NMR (75 MHz,
CDCl3, J in Hz) d 167.2, 133.4, 129.7, 129.5 (2C), 128.5
(2C), 99.7, 99.0, 77.4, 77.0, 76.6, 74.2, 73.5, 71.9, 69.5, 62.4
(C£2), 47.8, 47.6, 34.1, 25.7 (C£3), 18.2, 17.8, 17.6, 24.9,
25.3; TOFMS m/z: 405, 315, 297, 237, 199, 197, 181, 169,
122, 105, 75; HRTOFMS: cacld for C26H42O9SiNa
[MþNa]þ: 549.2490, found 549.2479.
4.1.9. (1R,2R,3S)-1-Benzoyloxymethyl-1,2-O,O-iso-
propylidine-3-O-tert-butyldimethylsilyl- cyclohex-4-ene
(3). To a solution of diol 4 (2.0 g, 4.4 mmol) in toluene
(100 mL) were added triphenylphosphine (4.6 g,
18.0 mmol), imidazole (1.2 g, 18.0 mmol) and iodine
(3.4 g, 13.0 mmol). The mixture was heated under reflux
for 4 h. After cooling, the reaction mixture was diluted with
EtOAc and washed successively with 10% aqueous sodium
thiosulfate solution, saturated NaHCO3 solution, brine and
dried (MgSO4). Removal of the solvent and purification of
the residue by column chromatography (EtOAc/petroleum
ether 1:10) gave olefin 3 (1.6 g, 87%) as colorless oil:
[a]2D0¼þ48 (c 0.19, CHCl3), 1H NMR (300 MHz, CDCl3, J
in Hz) d 8.08 (2H, d, J¼7.5 Hz), 7.57 (1H, t, J¼7.5 Hz),
7.44 (2H, t, J¼7.5 Hz), 5.80–5.90 (2H, m, H-3 and 4), 4.46
(1H, d, J¼11.4 Hz, H-7a), 4.35–4.43 (1H, m, H-6), 4.27
(1H, d, J¼11.4 Hz, H-7b), 4.20 (1H, d, J¼3.3 Hz, H-5),
2.44 (1H, dd, J¼15.9, 3.3 Hz, H-6a), 2.30 (1H, t,
J¼15.9 Hz, H-6b), 1.42 (3H, s, CH3), 1.40 (3H, s, CH3),
0.86 (9H, s, CH3£3), 0.09 (3H, s, CH3), 0.08 (3H, s, CH3);
13C NMR (CDCl3, 75 MHz) d 166.2, 133.0, 130.0, 129.7
(C£2), 129.3, 128.3 (C£2), 126.5, 108.8, 80.8, 79.9, 68.1,
67.9, 32.3, 28.1, 27.1, 25.7 (C£3), 18.2, 24.7, 24.9;
HRFABMS: cacld for C23H35O5Si [MþH]þ: 419.2248,
found 419.2236.
4.1.7. (1R,2R,3R,4S,5R)-1-Benzoyloxymethyl-1,2-O,O-
isopropylidine-3-O-tert-butyldimethyl- silyl-4,5-(2,3-
dimethoxybutan-2,3-dioxy)-cyclohexane (12). Dimethoxy-
propane (1.2 g, 11.4 mmol) was added to the solution of diol
11 (3.0 g, 5.7 mmol) and catalytic amount of p-toulene-
sulfonic acid (19 mg, 0.11 mmol) in dried CH2Cl2
(100 mL), and the mixture was stirred under Ar at room
temperature for 3 h. After adding 10% aqueous NaHCO3
(50 mL), the reaction mixture was stirred for 5 min and then
extracted with CH2Cl2 (3£50 mL). The organic layers were
combined, washed with brine, and dried (MgSO4). The
solvent was removed and the residue was purified by
column chromatography (acetone/petroleum ether 1:10) to
yield 12 as white solid (3.2 g, 99%). Mp 148–150 8C,
[a]2D0¼þ19 (c 0.25, CHCl3), 1H NMR (300 MHz, CD3Cl, J
in Hz) d 8.05 (d, 2H, J¼7.8 Hz), 7.58 (t, 1H, J¼7.8 Hz),
7.44 (t, 2H, J¼7.8 Hz), 4.65–4.73 (m, 1H), 4.2–4.4 (m,
4H), 3.94–4.03 (m, 1H), 3.31 (s, 3H, OCH3), 3.30 (s, 3H,
OCH3), 2.10–2.20 (m, 1H, H-6a), 1.85–1.94 (m, 1H, H-6b),
1.52 (s, 6H, CH3), 1.36 (s, 3H, CH3), 1.32 (s, 3H, CH3), 0.84
(s, 9H, CH3), 0.14 (s, 3H, CH3), 0.17 (s, 3H, CH3); 13C
NMR (CDCl3, 75 MHz) d 166.1, 133.1, 130.0, 129.7 (C£2),
128.4 (C£2), 109.0, 99.9, 96.5, 80.6, 70.5, 69.8, 66.0, 62.6,
48.3, 48.4, 36.6, 28.1, 26.7, 25.6 (C£3), 23.6, 18.1, 18.0
(C£2), 24.5, 25.3.
4.1.10. (1R,2S)-1-Benzoyloxymethyl-1,2-O,O-isopropyl-
idine-cyclohex-4-en-3-one (13). A solution of 3 (72.0 mg
0.17 mmol) in dried CH2Cl2 was added to a solution of 70%
t-BuOOH (0.25 mL, 1.8 mmol) and catalytic amount of
CrO3 (1.7 mg, 0.017 mmol) in CH2Cl2 (2 mL) under Ar.
The reaction mixture was stirred at room temperature for
24 h, and then poured into column chromatography washing
with EtOAc. The solvent was removed and the residue was
purified by column chromatography (acetone/petroleum
ether 1:15), to give enone 13 as a white solid (30 mg, 56%).
Mp 43–45 8C, 1H NMR (CDCl3, 300 MHz, J in Hz) d 8.00
(d, 2H, J¼7.2 Hz), 7.58 (t, 1H, J¼7.2 Hz), 7.44 (t, 2H,
J¼7.2 Hz), 6.90–7.01 (m, 1H, H-5), 6.24 (td, 1H, J¼10.5,
2.1 Hz, H-4), 4.40 (d, 1H, J¼11.4 Hz, H-7a), 4.39 (s, 1H,
H-2), 4.34 (d, 1H, H-7b), 2.79–2.87 (m, 2H, H-6), 1.50 (s,
3H, CH3), 1.34 (s, 3H, CH3); IR nKmBaxr cm21: 3430, 1720,
1698, 1271, 1113, 714;
4.1.8. (1R,2R,3R,4S,5R)-1-Benzoyloxymethyl-1,2-O,O-
isopropylidine-3-O-tert-butyldimethyl- silyl-4,5-di-
hydroxy-cyclohexane (4). To a violently stirred solution
of 12 (3.1 g, 5.6 mmol) in CH2Cl2 (150 mL), 50% aqueous
TFA (v/v, 1:1, 10.0 mL) was added. After 6 h, 100 mL 5%
aqueous NaHCO3 was added to the reaction mixture.
Stirring for 5 min, the mixture was extracted with CH2Cl2
(3£100 mL), washed with brine (50 mL) and dried
(MgSO4). Removal of the solvent and purification of the
residue by column chromatography (acetone/ petroleum
ether 1:5) gave diol 4 (2.0 g, 80%) as white solid. Mp 46–
48 8C, [a]2D0¼240 (c 0.20, CHCl3), IR nmKBaxr cm21: 3465,
4.1.11. (1R,2R,3S)-1-Benzoyloxymethyl-1,2-O,O-iso-
propylidine-3-hydroxy-cyclohex-4-ene (14). Tetrabutyl-
ammonium fluoride (1.0 M in THF, 14.4 mL, 14.4 mmol)
and benzoic acid (2.0 g, 14.4 mmol) were added to the
solution of 3 (1.5 g, 3.6 mmol) in dry THF (60 mL). The
solution was stirred at room temperature for 24 h, and then
1
2931, 1726, 1275, 1097, 1066, 839, 712 cm21; H NMR

3694
A. Liu et al. / Tetrahedron 60 (2004) 3689–3694
was evaporated under reduced pressure to leave a residue,
which was partitioned between water and EtOAc. The
organic layer was dried (MgSO4). Removal of the solvent
and purification of the residue by column chromatography
(acetone/petroleum ether 1:5) gave alcohol 14 (1.0 g, 94%)
4.1.14. (1)-Zeyleone (1). TFA/H2O (9:1, v/v, 0.2 mL,
2.2 mmol) was added to the solution of 15 (70 mg,
0.18 mmol) in CH2Cl2 (5 mL). The reaction mixture was
stirred violently for 6 h. Then, 5 mL 5% aqueous NaHCO3
was added to the reaction mixture and stirred for 5 min. The
mixture was extracted with CH2Cl2 (3£10 mL), washed
with brine (3 mL) and dried (MgSO4). Removal of the
solvent and purification of the residue by column chroma-
tography (acetone/petroleum ether 1:5) yielded 1 as white
solid (54 mg, 85%). Mp 150–152 8C; [a]2D0¼þ118 (c 0.56,
1
as colorless oil: [a]2D0¼24.7 (c 0.32, CHCl3), H NMR
(300 MHz, CDCl3, J in Hz) d 8.06 (2H, d, J¼7.5 Hz), 7.53
(1H, t, J¼7.5 Hz), 7.40 (2H, t, J¼7.5 Hz), 5.87 (2H, m, H-4
and 5), 4.37–4.43 (1H, m, H-2), 4.39 (1H, d, J¼11.7 Hz,
H-7a), 4.31 (1H, d, J¼11.7 Hz, H-7b), 4.20 (1H, d,
J¼3.3 Hz, H-3), 2.52 (1H, dd, J¼17.1, 5.4 Hz, H-6a),
2.29 (1H, d, J¼17.1 Hz, H-6b), 1.45 (3H, s, CH3), 1.42 (3H,
s, CH3); 13C NMR (CDCl3, 75 MHz) d 166.5, 147.7, 133.5,
129.7 (C£2), 129.0, 128.5 (C£2), 126.8, 109.2, 81.6, 79.7,
68.4, 67.9, 32.4, 28.3, 27.2; HRFABMS: cacld for
C17H20O5Na [MþNa]þ: 327.1203, found 327.1221.
1
CHCl3), [a]2D0¼þ26 (c 0.23, CH3OH); H NMR (CDCl3,
300 MHz) d 4.38 (dd, 1H, J¼3.3, 1.5 Hz, H-2), 4.59 (d, 1H,
J¼11.4 Hz, H-7a), 4.86 (d, 1H, J¼11.4 Hz, H-7b), 5.95 (td,
1H, J¼4.2 Hz, 0.9, H-3), 6.35 (dd, 1H, J¼10.2, 0.9 Hz,
H-5), 6.96 (ddd, 1H, J¼10.2, 4.2, 0.9 Hz, H-4), two benzoyl
groups: d 7.93–8.06 (m, 4H), 7.53–7.60 (m, 2H), 7.26–
7.45 (m, 4H); 13C NMR (CDCl3, 75 MHz) d 65.5 (C-7),
69.1 (C-3), 71.6 (C-2), 77.2 (C-1), 128.6 (C-5), 142.6 (C-4),
196.2 (C-6), two benzoyl groups: d 128.4, 128.5, 128.7
(C£2), 129.7 (C£2), 129.8 (C£2), 133.4, 133.7, 165.3,
166.2; IR nKmBaxr cm21: 3421, 1716, 1693, 1271, 1113, 714;
EIMS m/z: 282, 260, 220, 136, 122, 105, 94; HRMS (TOF):
cacld. for C21H19O7 [Mþ1]þ 383.1125, found 383.1126.
4.1.12. (1R,2R,3S)-1-Benzoyloxymethyl-1,2-O,O-iso-
propylidine-3-benzoyloxy-cyclohex-4-ene (15). Benzoyl
chloride (0.38 mL, 3.3 mmol) was added dropwise to a
solution of alcohol 14 (0.66 g, 2.2 mol) and catalytic
amount of DMAP (5 mg, 0.04 mmol) in dry pyridine
(20 mL) at room temperature during a period 5 min. Stirring
was continued for another 2 h and then saturated aqueous
NaHCO3 (10 mL) was added to the reaction mixture to
quench the reaction. The mixture was extracted with
CH2Cl2 (3£10 mL), washed with brine (5 mL) and dried
(MgSO4). The solvent was removed and the product was
purified by flash chromatography (acetone/petroleum ether
1:5), to yield alcohol 15 (0.88 g, 99%) as colorless oil:
[a]2D0¼þ114 (c 0.24, CHCl3), 1H NMR (CDCl3, 300 MHz)
d 8.03 (2H, d, J¼7.5 Hz), 7.96 (2H, d, J¼7.5 Hz), 7.50–
7.57 (2H, m), 7.33–7.50 (4H, m), 6.00–6.07 (2H, m, H-4
and 5), 5.70 (1H, s, H-3), 4.55 (1H, d, J¼11.7 Hz, H-7a),
4.48–4.52 (1H, m, H-2),4.38 (1H, d, J¼11.7 Hz, H-7b),
2.43–2.58 (2H, m, H-6), 1.49 (3H, s, CH3), 1.45 (3H, s,
CH3); 13C NMR (CDCl3, 75 MHz) d 166.2, 165.6, 133.2,
133.1 (C£2), 129.7 (C£4), 129.4 (C£2), 128.5 (C£4),
124.7, 109.4, 79.3, 77.9, 69.4, 67.4, 32.2, 28.0, 27.3;
HRFABMS: cacld for C24H25O6 [MþH]þ: 409.1646, found
409.1650.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (No. 39970084) and the Chinese Doctoral Grants
of the Ministry of Science and Technology of China (No.
96-901-96-54) for financial support.
References and notes
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propylidine-3-benzoyloxy-cyclohex-4-en-one (16).
A
3. Zhao, W.-M.; Qin, G.-W.; Yang, R.-Z.; Jiang, T.-Y.; Li, W.-X.;
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´
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suspension of olefin 15 (0.20 g, 0.49 mmol) and SeO2
(0.22 g, 2.0 mmol) in dried THF were stirred under reflux
for 24 h. After cooling, the reaction mixture was poured into
a flash chromatography and washed with EtOAc. The
solvent was removed and the product purified by flash
chromatography (acetone/petroleum ether 1:10), which
yielded enone 16 (83 mg, 40%) as colorless oil:
[a]2D0¼þ132 (c 0.12, CHCl3); IR nmKBaxr cm21: 2989, 1726,
1691, 1452, 1273, 1093, 860, 710; 1H NMR (CDCl3,
300 MHz, J in Hz) d 7.94 (2H, d, J¼7.5 Hz), 7.84 (2H, d,
J¼7.5 Hz), 7.42–7.54 (2H, m), 7.36–7.42 (2H, m), 7.24–
7.34 (2H, m), 7.04 (1H, ddd, J¼1.5, 4.8 Hz, 10.2, H-4), 6.38
(1H, d, J¼10.2 Hz, H-5), 5.97 (1H, d, J¼4.05 Hz, H-3),
4.70 (1H, d, J¼11.4 Hz, H-7a), 4.67–4.69 (1H, m, H-2),
4.62 (1H, d, J¼11.4 Hz, H-7b), 1.48 (3H, s, CH3), 1.41 (3H,
s, CH3); 13C NMR (CDCl3, 75 MHz) d 195.5, 165.6, 165.2,
141.4, 133.6, 133.4 (C£2), 130.6 (C£2), 130.3 (C£4), 128.4
(C£4), 110.0, 80.0, 77.7, 66.0, 63.9, 27.4, 26.4; HRFABMS:
cacld for C24H23O7 [MþH]þ: 423.1438, found 423.1441.
7. Shing, T. K. M.; Tam, E. K. W. J. Org. Chem. 1998, 63,
1547–1554.
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1997, 1755–1758.
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