First total synthesis of panaxytriol, a potent antitumor agent isolated from Panax ginseng

Article abstract of DOI:10.1055/s-1998-1775

Panaxytriol 1, a potent antitumor agent isolated from Panax ginseng, was first synthesized, and its stereostructure was confirmed to be (3R, 9R, 10R)-heptadec-1-ene-4,6-diyne-3,9,10-triol.

Full text of DOI:10.1055/s-1998-1775

July 1998
SYNLETT
737
First Total Synthesis of Panaxytriol, a Potent Antitumor Agent Isolated from Panax Ginseng
*
Wei Lu, Guangrong Zheng, Junchao Cai
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China
E-mail: jccaiqserver.shcnc.ac.cn
Received 24 March 1998
9
Abstract: Panaxytriol 1, a potent antitumor agent isolated from Panax
ginseng, was first synthesized, and its stereostructure was confirmed to
be (3R, 9R, 10R)-heptadec-1-ene-4,6-diyne-3,9,10-triol.
to protect the hydroxy group in 4 obtaining the compound 5. 5 was
10
dehomologated with H IO in EtOAc, and the resulting aldehyde 6
5
6
was treated with
a mixture of triphenylphosphine and carbon
tetrabromide in the presence of zinc dust to give the dibromoalkene 7
in 82% yield. However, the reaction of dibromide 7 with 2 equiv of n-
11
Panax ginseng C.A. Meyer is one of the most important oriental
11
butyllithium in THF at -78°C gave the desired alkyne 8 in a low yield
medicinal plants. Its many uses include psychiatric and neurologic and
(45-51%). It was reported that 1,1’-dibromoalkenes treated with
NaHMDS can give very cleanly and quantitatively bromoalkyne, and
exchanged with n-butyllithium, the corresponding alkynes could be
1
diabetes mellitus treatment in China, Japan and Korea. The
biologically active constituents of ginsengs have been pursued
extensively and, recently, many polyacetylene compounds, including
12
trapped in high yields. We used LDA to examine the possibility of
2
panaxytriol 1, were isolated. These polyacetylene compounds have
affecting complete change of dibromoalkene 7 to the alkyne 8. Addition
1.5 equiv of LDA to 7 in THF at -78°C, followed by 2.2 equiv of n-
butyllithium afforded the alkyne 8 in 91% yield.
received attention as a potential new type of antitumor agents.
2c
The plane structure of panaxytriol 1 was elucidated. The absolute
configuration of C-3 in panaxytriol 1 was confirmed to be R by the
Mosher method, and the absolute configurations of C-9 and C-10 were
3
defined as 9R, 10R by the CD analysis. However, Fujimoto and his
4
group reported that the absolute stereostructure of panaxytriol 1 has 9S
and 10S configurations on the basis of synthetic study.
In this communication, we describle the first total synthesis of optically
pure panaxytriol 1, and that the absolute stereostructure of it has been
confirmed to be (3R, 9R, 10R)-heptadec-1-ene-4,6-diyne-3,9,10-triol.
Reagents and conditions: a) p-TsCl, Py, rt. b) NaI, acetone, reflux 24hr.
c) Zn, ethanol, reflux 2hr., 81% in three steps; d) TBDPSCl, imidazole,
CH Cl , rt., 96%, e) H IO , EtOAc, rt. f) CBr , PPh , Zn, CH Cl , 0°C,
82% in two steps, g) i 1.5eq LDA, THF, -78°C, 30min, then 0°C, 30min,
ii 2.2eq n-BuLi, -78°C, 2hr, 91%.
2
2
5
6
4
3
2
2
Polyacetylene compounds are usually obtained through coupling of two
5
acetylenic fragments. Among the coupling methods available, the
6
Cadiot-Chodkiewicz reaction is one of the most general. In this
Scheme 2
reaction,
a
copper salt catalyses the crossing-coupling of
a
bromoacetylene with
a
terminal acetylene. When applied to
Next, fragment B of (9R, 10R) one hydroxy protected synthon 16 was
retrosynthetic analysis of panaxytriol 1, the reaction led to two
obtained as depicted in Scheme 3. Diisopropylene D-arabinose 9 was
fragments, one being acetylene A, the other, bromoacetylene B (Scheme
1).
13
prepared according to the well-known procedure
from D-
gluconolactone. The aldehyde was then subjected to the Wittig reaction
+
-
with n-C H P Ph Br to provide alkene 10, subsequently catalytic ally
6
13
3
hydrogenated with H / 10%Pd-C in ethanol yielding saturated
2
10
compound 11. Selective cleavage of the terminal isopropylidene
group of 11, and then reduction of the resulted aldehyde with NaBH
4
gave the primary alcohol 12, which on successive treatment with p-TsCl
in pyridine, acidic methanol and excess K CO in methanol led to
2
3
epoxy alcohol 13 in 81% yield. The secondary hydroxy group of 13 was
14
protected as a tert-butyldimethylsilyl(TBS) ether to yield 14, which
Scheme 1
was subjected to the coupling reaction with trimethylsilyl acetylene
15
lithium in the presence of boron trifluoride etherate to afford
Firstly, the fragment A of (3R)-(t-butyldiphenylsilyloxy)pent-1-en-4-
yne 8 was synthesized by using D-xylose as a chiral template shown in
Scheme 2. D-Xylose was transformed to 2,3; 4,5-diisopropylene D-
silylacetylene 15. By treatment with NBS and AgNO , 15 was
3
16
converted to the bromoacetylene 16 in one pot in high yield.
7
xylitol 2 according to the known procedure. The bisacetonide 2 was
converted to iodide 3 via its tosylate, and the iodide on interaction with
Finally, bromoacetylene 16 on coupling with alkyne 8 using Cadiot-
6,17
activated zinc dust in refluxing ethanol underwent a facile elimination to
Chodkiewicz procedure
at 0°C provided coupling product 17.
8
afford compound 4. We chose tert-butylchlorodiphenylsilane(TBDPS)
Subsequently, deprotection of the TBS and TBDPS group with

738
LETTERS
SYNLETT
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Takata, K. Chem. Pharm. Bull., 1989, 37, 1279; e) Hirakura, K.;
Morita, M.; Nakajina, K.; Ikeya, Y.; Mitsuhashi, H.
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Kirisawa, M.; Satoh, M.; Takeuchi, N. Phytochemistry, 1992, 31,
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3.
a) Kitagawa, I.; Umezome, T.; Mahmud, T.; Kobayashi, M.;
Chem. Pharm. Bull., 1995, 43, 1595; b) Kobayashi, M.; Mahmud,
T.; Umezome, T.; Wang, W. Q.; Murakami, N.; Kitagawa, I.
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4.
5.
6.
7.
Satoh, M.; Takeuchi, N.; Fujimoto, Y. Chem. Pharm. Bull., 1997,
45, 1114.
Rutlege, T. F. Acetylenic Compounds, Preparation and
Substitution Reactions, Reinhold Book Corp., New York, 1968.
Chodkiewicz, W. Chemistry of Acetylenes, Viehe, H. G. Ed.; M.
Deker, 1969, p597
a) Rollin, P.; Pougny, J. R. Tetrahedron, 1986, 42, 3479. b) Yadav,
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8.
9.
Howes, D. A.; Brookes, M. H.; Coates, D.; Golding, B. T.;
Hudson, A. T. J. Chem. Research(s), 1983, 9.
Scheme 3
Hanessian, S.; Lavellee, P. Can. J. Chem., 1975, 53, 2975.
10. Xie, M.; Berges, D. A.; Robins, M. J. J. Org. Chem., 1996, 61,
5178.
11. Corey, E. J.; Fuchs, P.L. Tetrahedron Lett., 1972, 3769.
12. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett., 1994, 35,
3524.
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Bas., 1987, 106, 461.
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1981, 22, 4775.
Scheme 4
15. Yamaquchi, M.; Hirao, I. Tetrahedron Lett., 1983, 24, 391.
tetrabutylammonium fluoride afforded the panaxytriol 1, (3R, 9R, 10R)-
heptadec-1-ene-4,6-diyne-3,9,10-triol, in 83% yield (Scheme 4).
16. Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett.,
1994, 485.
17. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett, 1992, 33,
1
13
18
Synthetic 1 showed H NMR and C NMR spectra in agreement with
the reported data
5355.
2c,3
of the natural product. Moreover, the optical
18. Data of 1. α - 21.2 (c=0.55, CHCl ), -18.9 (c=0.60 MeOH)
D
3
rotation of synthetic 1 was nearly identical to that reported for the
natural sample: synthetic 1, α - 21.2 (c=0.55, CHCl ), -18.9 (c=0.60,
MeOH), and the natural, α -25.4 (c=1.54, CHCl ), -19.0 (c=1.0,
CHCl ). Consequently, the absolute stereostructure of panaxytriol 1
was confirmed to be (3R, 9R, 10R)-heptadec-1-ene-4,6-diyne-3,9,10-
triol. This approach gives an access to synthesize the other similar
polyacetylenes isolated from Panax ginseng C.A. Meyer, and this work
is now in progress in our group.
-1
IR(KBr) 3327, 2256 cm
HNMR(300MHz, CDCl )
3
D
3
1
δ
0.88(3H, t, J=6.7Hz), 1.25-
H
3b
3
D
3
1.38(10H, m), 1.51(2H, m), 1.96(3H, br), 2.59(2H, d, J=5.6Hz),
3.60(1H, m), 3.65(1H, m), 4.92(1H, d, J=5.4Hz), 5.25(1H, ddd,
J=1.1, 2.2, 10.1Hz), 5.47(1H, ddd, J=1.1, 2.3, 17.1Hz), 5.95(1H,
3a
3
ddd, J=5.4, 10.1, 17.0Hz) ppm
13
CNMR(300MHz, CDCl ) δ 136.0(C-2), 117.2(C-1), 78.1(C-
3
C
7), 74.7(C-4), 73.1(C-10), 72.1(C-9), 70.9(C-5), 66.5(C-6),
63.5(C-3), 33.5(C-11), 31.8(C-15), 29.5(C-13), 29.2(C-14),
References and notes:
25.6(C-8), 25.0(C-12), 22.6(C-16), 14.1(C-17)
+
1.
Chang, H. M.; But, P. P. Pharmacology and Application of
Chinese Materia Medica, 1986, 1, 17, World Scientific,
Singapore.
EIMS(m/z) 261(MH -H O), 243, 159, 145, 102
2
Anal. Calcd for C H O : C, 73.35; H, 9.41 found: C, 73.17; H,
17 26 3
9.34.