New approach to the total synthesis of (-)-zeylenone from shikimic acid

Article abstract of DOI:10.1248/cpb.54.1459

The natural antitumor product (-)-zeylenone was prepared for the first time in a stereoselective synthesis from shikimic acid.

Full text of DOI:10.1248/cpb.54.1459

October 2006
Notes
Chem. Pharm. Bull. 54(10) 1459—1461 (2006)
1459
New Approach to the Total Synthesis of (ꢀ)-Zeylenone from Shikimic
Acid
c
Yi ZHANG,a An LIU,b Zu Guang YE,b Jia LIN,a Li Zhen XU,*,a and Shi Lin YANG
a Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College;
Beijing 100094, China: b State Research Center for R&D of TCM Multi-ingredient Drugs, Beijing Zhongyan Tongrentang
Chinese Medicine R&D Co., Ltd.; Beijing 100700, China: and c National Pharmaceutical Engineering Center for Solid
Preparation in Chinese Herbal Medicine; Nanchang 330006, China. Received May 29, 2006; accepted July 27, 2006
The natural antitumor product (ꢀ)-zeylenone was prepared for the first time in a stereoselective synthesis
from shikimic acid.
Key words zeylenone; shikimic acid; total synthesis
The polyoxygenated cyclohexanes, which have been iso- (TBDMS) group to increase the stereoselectivity.9) Consider-
lated from the Uvaria genus, show anticancer, antiviral and ing the target product 1 and the steric hindrance of the ben-
antibiotic activities.1—3) (ꢀ)-Zeylenone is one such example zoyl group, the two hydroxyl groups of compound 6 were di-
separated from Uvaria grandiflora and showed remarkable rectly benzoylated with benzoyl chloride in 99% yield10) after
inhibition of nucleoside transport in Ehrlich carcinoma cells the reduction of compound 5 with DIBAL-H in 90% yield.5)
and interesting cytotoxicity to cultured cancer cells.4) Assess- Fortunately, the olefin 7 was dihydroxylated with OsO4 and
ment of cytotoxicity of (ꢀ)-zeylenone was performed on the N-methylmorphorline (NMO) in THF/H2O (1 : 1) under Ar to
following human tumor cell lines: HCT-8 (a human colonic give stereoselectively the sole diol isomer 8 in 92% yield
tumor cell line), BGC-823 (a human gastric cancer cell line), (Chart 2).5) Therefore, the introduction and deprotection of
and Bel-7402 (a human liver cancer cell line); and the IC50 TBDMS group were avoided and the total yield was raised.
(nM) was 3.25, 5.26, and 4.69, accordingly.
The cis diol 8 had to be protected in the next steps.
We have built the total synthesis of (ꢁ)-zeylenone in our Though we had tried 2,2-dimethylpropane and chloromethyl
former research work.5) As our continuous effort to study the methyl ether, we could not get the desired protected products
structure-activity relationship of zeylenone, we improved the (Chart 3). In view of the following deprotection of the trans
route and report herein a new approach of the enantioselec-
tive synthesis of (ꢀ)-zeylenone from shikimic acid. The syn-
thesis is starting from a selective protected shikimic acid,
using Mitsunobu reaction, OsO4 catalyzed oxidation, cyclic
carbonates protection for the cis diol and a SeO2 oxidation of
olefin as the key steps (Chart 1).
We used shikimic acid as a starting compound, which
could be easily found in a number of natural plants. After
methylation of shikimic acid5) and regio-selective protection
of trans vicinal diol 3,5) we performed a stereospecific con-
version of the 3-OH of compound 4 with a Mitsunobu reac-
tion.6,7) The alcohol 4 is treated with triphenylphosphine, di-
ethyl azodicarboxylate (DEAD) and p-nitrobenzoic acid, fol-
(a) SOCl2, CH3OH, 10 °C, 93%; (b) (CH3CO)2, CH(OCH3)3, (ꢂ)CSA, CH3OH, Ar,
48 h, 90 °C, 90%; (c) DEAD, Ph3P, p-O2NC6H4COOH, THF, Ar, 5 h, rt; CH3ONa,
CH3OH, 2 h, rt, 91%; (d) DIBAL-H, toluene, ꢀ78 °C, 90%; (e) BzCl, DMAP, pyridine,
rt, 99%; (f) OsO4, NMO, THF/H2O (1 : 1), Ar, 92%.
lowed by hydrolyzed with CH3ONa, to give the alcohol 5 in
91% yield.8) As in our former work, before the reduction of
methyl ester with diisobutylaluminum hydride (DIBAL-H),
there should be an introduction of tert-butyldimethylsilyl Chart 2. Reagents and Conditions
(g) (CH3)2C(OCH3)2, TsOH, CH2Cl2, Ar, rt; (h) i-Pr2NEt, MOMCl, CH2Cl2, Ar, rt.
Chart 1. Retrosynthesic Analysis
Chart 3. Reagents and Conditions
∗ To whom correspondence should be addressed. e-mail: xulizhen2002@hotmail.com
© 2006 Pharmaceutical Society of Japan

1460
Vol. 54, No. 10
room temperature and then the solvent was removed. The residue was solved
in 150 ml MeOH and a new-made sodium methoxide was added dropwise to
the solution. After being stirred for 2 h at room temperature, the mixture was
treated with NH4Cl and stirred for 10 min. And then the solvent was re-
moved and the product was purified by column chromatography (acetone/pe-
troleum ether 1 : 9), which yield 5 as white solids (10.8 g, 91%). mp 62—
1
64 °C; H-NMR (CDCl3) d: 6.70 (1H, m, H-2), 4.44 (1H, ddd, Jꢃ2.1, 4.2,
8.4 Hz, H-5), 3.81 (1H, dt, Jꢃ6.3, 10.5 Hz, H-3), 3.75 (3H, s, OCH3), 3.62
(1H, dd, Jꢃ8.4, 10.8 Hz, H-4), 3.28 (3H, s, OCH3), 3.25 (3H, s, OCH3), 2.70
(1H, dd, Jꢃ4.2, 17.1 Hz, H-6a), 2.35 (1H, m, H-6b), 1.32 (3H, s, CH3), 1.30
(3H, s, CH3); 13C-NMR (CDCl3) d: 166.4, 138.2, 128.6, 99.3, 99.1, 74.0,
69.8, 65.3, 52.1, 48.0, 47.9, 29.6, 17.7 (Cꢄ2). [a]D20ꢃꢁ84° (cꢃ0.064,
CHCl3).
(i) triphosgene, pyridine, CH2Cl2, Ar, ꢀ78 °C, 91%; (j) TFA, CH2Cl2, rt, 87%; (k)
Ph3P, imidazole, I2, reflux, 86%; (l) i SeO2, THF, reflux; ii pyridine/H2O (1 : 1), reflux,
0.5 h, 37%.
Chart 4. Reagents and Conditions
((2S,3S,4aR,8S,8aS)-8-(Benzoyloxy)-2,3-dimethoxy-2,3-dimethyl-
2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxin-6-yl)methyl benzoate (7)
Benzoyl chloride (12.2 ml, 0.1 mol) was added dropwise to a solution of
alcohol 6 (8.3 g, 30.3 mmol) and catalytic amount of DMAP (0.05 g, 0.4
mmol) in dry pyridine (250 ml) at room temperature during a period 20 min.
Stirring was continued for another 4 h and then saturated aqueous NaHCO3
(100 ml) was added to the reaction mixture to quench the reaction. The mix-
ture was extracted with CH2Cl2 (3ꢄ100 ml), washed with brine (20 ml) and
dried (MgSO4). The solvent was removed in vacuum and purified by column
chromatography (acetone/petroleum ether 1 : 10), which yielded benzoylated
alcohol 7 as white solids (14.4 g, 99%). mp 102—104 °C; 1H-NMR (CDCl3)
d: 8.00—8.11, 7.54—7.59, 7.39—7.48 (4H, 2H, 4H, m, H of phenyl), 5.75
(1H, br s, H-2), 5.73 (1H, m, H-3), 4.78 (1H, d, Jꢃ13.2 Hz, H-7a), 4.70 (1H,
d, Jꢃ13.2 Hz, H-7b), 4.06 (1H, m, H-4), 4.02 (1H, m, H-5), 3.30 (3H, s,
OCH3), 3.28 (3H, s, OCH3), 2.41 (2H, m, H-6), 1.31 (3H, s, CH3), 1.27 (3H,
vicinal diol with acid and the less stereo hindrance, we de-
cided to choose the cyclic carbonate, which was steady under
acidic conditions and smaller in stereo hindrance, as the pro-
tection for the cis vicinal diol. The compound 8 was treated
with triphosgene and pyridine in CH2Cl2 at ꢀ78 °C under N2
to give the cyclic carbonate 9 in 91% yield, followed by de-
protection with TFA in CH2Cl2 to give the trans vicinal diol
10 in 87% yield. After that, compound 10 was treated with
Ph3P, imidazole and iodine in toluene at reflux to give the cy-
clohexene 11 in 86% yield.5) Afterwards the cyclohexene 11
was oxidized by SeO2 in dry THF at reflux for a day in 39%
yield, and then the residue was deprotected with
pyridine/H2O at reflux for 20 min to give the target com- s, CH3); 13C-NMR (CDCl3) d: 166.1, 165.9, 134.3, 133.6, 133.2, 133.0,
130.1, 129.7 (Cꢄ4), 128.4 (Cꢄ4), 123.0, 99.3, 99.2, 72.5, 71.4, 66.8, 65.6,
pound 1 in 90% yield. On account of the lower yield of the
oxidation, we decided to bring the oxidation together with
the deprotection and obtained the higher total yield of 37%
48.1, 47.8, 30.9, 17.7, 17.6. [a]D20ꢃꢁ144° (cꢃ0.066, CHCl3).
((2S,3S,4aR,6S,7S,8S,8aS)-8-(Benzoyloxy)-6,7-dihydroxy-2-oxo-2,3-
dimethoxy-2,3-dimethyloctahydrobenzo[b][1,4]dioxin-6-yl)methyl ben-
(Chart 4).
The melting point of the mixture of compound 1 and the
zoate (9) To a stirred solution of 8 (6.3 g, 12.2 mmol) in dried CH2Cl2, was
added dropwise a solution of triphosgene (3.6 g, 12.1 mmol) in dried CH2Cl2
after dropping dried pyridine (10 ml, 12.5 mmol) under Ar at ꢀ78 °C. Once
addition was completed, the reaction mixture was then allowed to warm to
room temperature. The resultant homogeneous solution was quenched with
1 N HCl, then washed with saturated aqueous NaHCO3 and brine, and dried
(MgSO4). The solvent was removed in vacuum and purified by column chro-
matography (acetone/petroleum ether 1 : 9) to yield 9 (6.0 g, 91%) as white
solids. mp 97—99 °C; 1H-NMR (CDCl3) d: 7.97—8.06, 7.53—7.59, 7.40—
7.45 (4H, 2H, 4H, m, H of phenyl), 5.42 (1H, dd, Jꢃ6.3, 10.5 Hz, H-3), 4.79
(1H, d, Jꢃ6.3 Hz, H-2), 4.52 (1H, d, Jꢃ11.7 Hz, H-7a), 4.38 (1H, d, Jꢃ
11.7 Hz, H-7b), 4.01 (1H, m, H-5), 3.77 (1H, t, Jꢃ10.2 Hz, H-4), 3.27 (3H,
s, OCH3), 3.15 (3H, s, OCH3), 2.49 (1H, dd, Jꢃ4.8, 15.0 Hz, H-6a), 1.92
(1H, dd, Jꢃ12.0, 15.0 Hz, H-6b), 1.28 (3H, s, CH3), 1.20 (3H, s, CH3); 13C-
NMR (CDCl3) d: 165.7, 164.9, 152.7, 133.8, 133.4, 129.9 (Cꢄ2), 129.8
(Cꢄ2), 129.3 (Cꢄ2), 128.7 (Cꢄ2), 128.5 (Cꢄ2), 99.5, 99.4, 82.6 (C-2),
81.2 (C-1), 75.1 (C-3), 69.0 (C-4), 67.9 (C-7), 62.8 (C-5), 48.2, 47.9, 31.7
(C-6), 17.5, 17.4. [a]D20ꢃꢁ155° (cꢃ0.082, CHCl3).
natural product zeylenone was the same as that of zeylenone
at 150—152 °C. The spectra data (including NMR, MS and
IR) of compound 1 were identical with those of natural
zeylenone. Moreover the value and sign of the optical rota-
tion of the compound 1 {[a]D20ꢃꢀ25.0° (cꢃ0.30, CH3OH),
[a]D20ꢃꢀ119.5° (cꢃ0.41, CHCl3)} were almost the same as
those of the natural product {lit.4) [a]D20ꢃꢀ26.0° (cꢃ0.89,
CH3OH), [a]D20ꢃꢀ126.5° (cꢃ0.747, CHCl3); lit.11) [a]D20ꢃ
ꢀ26.0° (cꢃ0.26, CH3OH), [a]D20ꢃꢀ120° (cꢃ0.60, CHCl3)}.
All the above proved that compound 1 and the natural
zeylenone were the same products and the absolute configu-
ration of the compound 1 was thus determined to be
(1S,2S,3R).
In summary, we have described a new approach to the
asymmetric total synthesis of (ꢀ)-zeylenone via a multi-step
route starting from shikimic acid in 16% yield, which enables
the synthesis of a wide variety of the analogues in relatively
good yields. Further work on the synthesis of the analogues
is in progress.
((3aS,5R,6S,7R,7aS)-7-(Benzoyloxy)-5,6-dihydroxy-2-oxohexahy-
drobenzo[d][1,3]dioxol-3a-yl)methyl benzoate (10) To
a vigorously
stirred solution of 9 (3.7 g, 6.8 mmol) in CH2Cl2 (200 ml), TFA (7 ml) was
added. After 6 h, 100 ml of 5% aqueous NaHCO3 was added to the reaction
mixture. Stirring for 5 min, the mixture was extracted with CH2Cl2 (3ꢄ
100 ml), washed with brine (30 ml) and dried (MgSO4). Removal of the sol-
vent and purification of the residue by column chromatography (acetone/pe-
troleum ether 1 : 4) gave diol 10 (2.5 g, 86%) as white solids. mp 124—
1
Experimental
125 °C; H-NMR (CDCl3) d: 7.94—7.98, 7.49—7.54, 7.19—7.40 (4H, 2H,
General Experimental Procedures Optical rotations were measured 4H, m, H of phenyl), 5.17 (1H, t, Jꢃ7.5 Hz, H-3), 4.83 (1H, d, Jꢃ7.2 Hz, H-
using a JASCO DIP-360 digital polarimeter. NMR spectra were recorded on 2), 4.62 (1H, d, Jꢃ12.0 Hz, H-7a), 4.35 (1H, d, Jꢃ12.0 Hz, H-7b), 4.00 (1H,
a JEOL JNM-AL300 spectrometer. The FABMS were obtained on a Micro- m, H-5), 3.66 (1H, t, Jꢃ7.2 Hz, H-4), 2.50 (1H, dd, Jꢃ3.6, 15.0 Hz, H-6a),
mass ZabSpec mass spectrometer. Precoated Silica gel plates (Qingdao 1.95 (1H, dd, Jꢃ9.3, 15.0 Hz, H-6b); 13C-NMR (CDCl3) d: 166.9, 165.8,
Haiyang Chem. Co.) were employed for TLC. For column chromatography, 153.1, 133.9, 133.8, 130.0, 129.9 (Cꢄ2), 128.7 (Cꢄ3), 128.6 (Cꢄ3), 128.5,
Silica gel (Qingdao Haiyang Chem. Co.) and Sephadex LH 20 (Pharmacia)
were used.
(2S,3S,4aR,8S,8aR)-Methyl-8-hydroxy-2,3-dimethoxy-2,3-dimethyl-
82.7 (C-2), 79.0 (C-1), 77.8 (C-4), 74.9 (C-3), 68.1 (C-5), 67.9 (C-7), 32.8
(C-6). [a]D20ꢃꢀ46° (cꢃ0.050, CHCl3).
((1S,5R,6S)-5-(Benzoyloxy)-1,6-dihydroxy-2-oxocyclohex-3-
2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxine-6-carboxylate (5) Triphen- enyl)methyl benzoate (1) A suspension of olefin 11 (0.5 g, 1.3 mmol) and
ylphosphine (12.6 g, 0.048 mol) and p-nitrobenzoic acid (8.1 g, 0.048 mol)
was added to a solution of compound 4 (11.9 g, 0.039 mol) in dry THF
SeO2 (0.57 g, 5.2 mmol) in dried THF were stirred under reflux for 24 h.
After cooling, the reaction mixture was poured into a flash chromatography
(100 ml), and the whole mixture was stirred under Ar. After being cooled to and washed with EtOAc. After removing the solvent, the residue was dis-
0 °C, a solution of diethyl azodicarboxylate (2.2 M, 20 ml) in toluene was
added dropwise to the mixture. The reaction mixture was stirred for 5 h at
solved in pyridine/H2O (v/v, 1 : 1, 10 ml) and stirred under reflux for 20 min.
Removal of the solvent and purification of the residue by column chro-

October 2006
1461
matography (acetone/petroleum ether 1 : 5) yielded 1 as white solids
(183 mg, 37%). mp 150—152 °C; H-NMR (CDCl3) d: 7.95—8.08, 7.56—
Prod. Rep., 11, 219—224 (1994).
2) Yu D. Q., Pure Appl. Chem., 71, 1119—1122 (1999).
1
7.62, 7.41—7.49 (4H, 2H, 4H, m, H of phenyl), 6.92 (1H, dd, Jꢃ2.4, 10.5
Hz, H-4), 6.31 (1H, dd, Jꢃ2.4, 10.5 Hz, H-5), 6.11 (1H, dd, Jꢃ2.4, 9.0 Hz,
H-3), 4.75 (1H, d, Jꢃ11.4 Hz, H-7a), 4.67 (1H, d, Jꢃ11.4 Hz, H-7b), 4.35
(1H, d, Jꢃ9.0 Hz, H-2); 13C-NMR (CDCl3) d: 197.3, 166.0 (Cꢄ2), 146.4
(C-4), 133.7, 133.5, 129.9 (Cꢄ2), 129.7 (Cꢄ2), 129.2, 129.0, 128.6 (Cꢄ4),
3) Thebtaranonth C., Thebtaranonth Y., Acc. Chem. Res., 19, 84—90
(1986).
4) Liao Y. H., Xu L. Z., Yang S. L., Dai J., Zhen Y. S., Sun N. J., Phyto-
chemistry, 45, 729—732 (1997).
5) Liu A., Liu Z. Z., Zou Z. M., Chen S. Z., Xu L. Z., Yang S. L., Tetra-
hedron, 60, 3689—3694 (2004).
6) Mitsunobu O., Synthesis, 1, 1—28 (1981).
7) Nicolaou K. C., Boddy C. N. C., Natarajan S., Yue T.-Y., Li H., Bräse
S., Ramanjulu J. M., J. Am. Chem. Soc., 119, 3421—3422 (1997).
8) Mashimo K., Sato Y., Tetrahedron, 26, 803 (1970).
9) Hiroya K., Ogasawara K., Chem. Commun., 8, 2197—2198 (1999).
10) Haines A. H., Adv. Carbohydx Chem. Biochem., 33, 11—109 (1976).
11) Zhao W. M., Qin G. W., Yang R. Z., Jiang T. Y., Li W. X., Scott L.,
Snyder J. K., Tetrahedron, 52, 12373—12380 (1996).
128.0 (C-5), 79.3 (C-2), 77.4 (C-1), 61.8 (C-3), 64.3 (C-7). IR (KBr) cmꢀ1
:
3408, 1712, 1701, 1258. FAB-MS m/z: 383.0 [Mꢁ1]ꢁ. [a]D20ꢃꢀ25.0° (cꢃ
0.30, CH3OH), [a]D20ꢃꢀ119.5° (cꢃ0.41, CHCl3).
Acknowledgements We are grateful to the National Natural Science
Foundation of China (No. 30472077) and the Beijing Natural Science Foun-
dation (No. 7052049) for financial support.
Reference
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