Straightforward synthesis of panaxytriol: An active component of red Ginseng

Article abstract of DOI:10.1021/jo0341665

A total synthesis of (3R,9R,10R)-panaxytriol (1) was accomplished enantioselectively (40% overall yield; 30% for the longest sequence). A key step was a CadiotChodkiewicz cross-coupling reaction on two fragments containing, in the aggregate, three unprotected hydroxyl groups. One fragment was synthesized by a highly enantioselective reduction of an enynone. The other arose from a highly enantioselective dihydroxylation of an allylic alcohol.

Full text of DOI:10.1021/jo0341665

Str a igh tfor w a r d Syn th esis of P a n a xytr iol:
An Active Com p on en t of Red Gin sen g
Heedong Yun*,† and Samuel J . Danishefsky*,†,‡
Department of Chemistry, Columbia University,
Havemeyer Hall, 3000 Broadway,
New York, New York 10027, and Laboratory for Bioorganic
Chemistry, Sloan-Kettering Institute for Cancer Research,
F IGURE 1. Antitumor components ofPanax ginseng, pa-
naxytriol (1).
1
275 York Ave., New York, New York 10021
s-danishefsky@ski.mskcc.org
Received February 6, 2003
Abstr a ct: A total synthesis of (3R,9R,10R)-panaxytriol (1)
was accomplished enantioselectively (40% overall yield; 30%
for the longest sequence). A key step was a Cadiot-
Chodkiewicz cross-coupling reaction on two fragments con-
taining, in the aggregate, three unprotected hydroxyl groups.
One fragment was synthesized by a highly enantioselective
reduction of an enynone. The other arose from a highly
enantioselective dihydroxylation of an allylic alcohol.
F IGURE 2. Retrosynthetic analysis.
Red Ginseng (the steamed and dried root of Panax
ginseng C. A. Meyer), found in various Asian countries
including China, J apan, and Korea, has been used in
many folk medicines. Included among these are applica-
tions in what appear to be analeptic, erythropoietic, and
SCHEME 1. En a n tioselective Syn th esis of
Left-Ha n d P iece Usin g CBS Red u ction
a
1
cytotoxic contexts. Panaxytriol (1, Figure 1), an appar-
ently important contributor to the overall activity of Red
2
Ginseng, was isolated in 1983. After the structure of
panaxytriol was established,3 it was shown to have
inhibitory activity against MK-1 cells (IC50 = 8.5 ng/mL)
and to suppress the growth of B16 melanoma cells
a
Reaction conditions: (a) (R)-Me-CBS, BMS, -30 °C, 10 min,
7
5%, >99% ee; (b) NBS, cat. AgNO3, acetone, rt, 1 h, 100%.
4
transplanted into mice. Moreover, it was very effective
7
theses did not serve to answer these questions in a fully
convincing way using chemically based criteria.
at inhibiting cellular respiration and energy balance of
a human breast carcinoma cell line.5 In addition, it
enhanced the cytotoxicity of mitomycin C against human
gastric adenocarcinoma cell lines.6
Our goals in this project were several. The first was to
accomplish an efficient total synthesis of panaxytriol,
which would allow for a systematic and extensive evalu-
ation of its promise. Moreover, it was hoped that mastery
of the total synthesis issues would lead us to molecules
that are more plausible looking drug candidates. Finally,
we sought a total synthesis that would lay to rest all
issues associated with relative and absolute stereochem-
istry of panaxytriol (1). Remarkably, the previous syn-
Our synthetic building blocks would ultimately be 4
and 10. These compounds would be linked using a key
Cadiot-Chodkiewicz cross-coupling reaction. As will be
seen, fragment 4 was to be synthesized by an oxazaboro-
lidine-catalyzed enantioselective reduction of an enynone
. Correspondingly, asymmetric dihydroxylation of a
TBS-protected allylic alcohol 6 would ultimately lead to
0. The program started with the preparation of the
known 2. Actually, enantiocontrolled reduction of this
type of 1-trimethylsilyl-4-alken-1-yn-3-one with a long
hydrocarbon chain at the â-position of the olefin had
previously been reported, albeit with only moderate
2
1
8
9
selectivity. By contrast, reduction of 2 with the com-
*
To whom correspondence should be addressed. Tel: +01-212-639-
mercially available (R)-Me-CBS reducing agent afforded
a 75% yield of 3 with a remarkably high enantiomeric
excess (>99%) (Scheme 1), as determined by Mosher ester
5
501. Fax: +01-212-772-8691.
†
Columbia University.
Sloan-Kettering Institute for Cancer Research.
‡
(
1) Saito, T.; Matsunaga, H.; Yamamoto, H.; Nagumo, F.; Fujito, H.;
Mori, M.; Katano, M. Biol. Pharm. Bull. 1994, 17, 798.
2) Kitagawa, I.; Yoshikawa, M.; Yoshihara, M.; Hayashi, T.;
Taniyama, T. Yakugaku Zasshi 1983, 103, 612.
3) Katagawa, I.; Taniyama, T.; Shibuya, H.; Noda, T.; Yoshikawa,
M. Yakugaku Zasshi 1987, 107, 495.
4) Katano, M.; Yamamoto, H.; Matsunaga, H.; Mori, M.; Takata,
K.; Nakamura, M. Gan To Kagakuyoho 1990, 17, 1045.
5) Matsunaga, H.; Saita, T.; Naguo, F.; Mori, M.; Katano, M. Cancer
Chemother. Pharmacol. 1995, 35, 291.
6) Matsunaga, H.; Katano, M.; Saita, T.; Yamamoto, H.; Mori, M.
Cancer Chemother. Pharmacol. 1994, 33, 291.
10
methodology. According to the Mosher precedents,
(
(7) (a) Satoh, M.; Takeuchi, N.; Fujimoto, Y. Chem. Pharm. Bull.
1997, 45, 1114. (b) Lu, W.; Zheng, G.; Gao, D.; Cai, J . Tetrahedron
1999, 55, 7157. (c) Gurjar, M. K.; Kumar, V. S.; Rao, B. V. Tetrahedron
1999, 55, 12563. (d) Yadav, J . S.; Maiti, A. Tetrahedron 2002, 58, 4955.
(e) Mayer, S. F.; Steinreiber, A.; Orru, R. V. A.; Faber K. J . Org. Chem
2002, 67, 9115.
(8) Malacria, M.; Roumestant, M. L. Tetrahedron 1977, 2813.
(9) (a) Garcia, J .; Lopez, M.; Romeu, J . Tetrahedron: Asymmetry
1999, 10, 2617. (b) Garcia, J .; Romeu, J . Synlett 1999, 4, 429.
(
(
(
(
1
0.1021/jo0341665 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003
J . Org. Chem. 2003, 68, 4519-4522
4519

F IGURE 3. A proposed model for the CBS reduction of 2.
SCHEME 2. En a n tioselective Syn th esis of
arising from the diamagnetic effect of the benzene ring,
the H NMR signals of (R)-MTPA ester should appear
Righ t-Ha n d P iece Usin g Sh a r p less Asym m etr ic
1
a
Dih yd r oxyla tion
upfield relative to those of the (S)-MTPA ester. Indeed,
the proton signals (δ 6.091, 5.868) of the corresponding
Mosher ester of compound 3 appeared at higher fields
than those (δ 6.119, 5.958) of the other Mosher ester.
According to this analysis, compound 3 was assigned to
have the (R) configuration. The sense of the reduction
(
vide infra) is also consistent with that proposed for
1
1
alkynone substrates in the Corey model. Applying this
logic, the double bond of 2 is placed furthest from the
B-methyl function to rationalize the result. To the best
of our knowledge, this is the first example of attainment
of such high enantioselectivity with an enynone system.12
Following in situ deprotection of the C-silyl function and
bromination of the terminal alkyne using NBS and
3
AgNO , component 4 was in hand (100%). The route to
the subunit containing the vicinal diol building block,
commenced with the commercially available trans-2-
decen-1-ol (5), which was protected as its tert-butyldi-
methylsilyl ether 6 (99%). Sharpless asymmetric dihy-
droxylation13 of 6, using AD-mix-â, afforded 7 in ca. 99%
ee (100%). The assignment of the absolute configuration
of compound 7 rests on several lines of evidence. First,
governing precedents in Sharpless asymmetric dihy-
droxylation lead to the expectation that the principal
product would have the (R,R) configuration.13 Further-
more, the result of an application of the analytical Mosher
ester methodology10 to 7 is in accord with this assign-
ment. The proton signals (δ 5.355, 5.282) of the corre-
sponding bis-Mosher ester of compound 7 appeared at
higher fields than those (δ 5.430, 5.291) of the other
component. Accordingly, compound 7 was assigned to
have the (R,R) configuration. Temporary protection of the
diol as its isopropylidene derivative was followed by in
situ deprotection of the primary alcohol and conversion
of the primary hydroxyl function to a bromide (see
compound 8, 90% for 2 steps). Acid-induced cleavage of
the acetonide linkage, followed by treatment of the diol
bromide with potassium carbonate led to 9 (89% for 2
steps). The epoxide linkage (possibly activated by the
adjacent oxy function) of 9,14 served to alkylate lithium
a
Reaction conditions: (a) TBSCl, imidazole, DMF, 0 °C to rt, 6
t
h, 99%; (b) AD-mix-â, CH3SO2NH2, BuOH/H2O 1:1, 0 °C, 1 day,
1
(
00%, >99% ee; (c) (1) (CH3)2C(OCH3)2, p-TsOH, CH2Cl2, rt, 1 h,
2) PPh3, Br2, CH2Cl2, 30 min, 90% for 2 steps; (d) (1) 1 N HCl, rt,
3 days, (2) K CO , rt, overnight, 89% for 2 steps; (e) Li-acetylide
EDA complex, HMPA, THF, 0 °C to rt, overnight, 80%
2
3
SCHEME 3. Ca d iot-Ch od k iew icz Cr oss-cou p lin g
Rea ction
a
a
Reaction condition: (a) CuCl, EtNH2, NH2OH‚HCl, MeOH, 0
°
C, 1 h, 63%.
acetylide, under the conditions shown, to afford building
block 10 (80%). The defining step of the synthesis was
the last one. Thus, the nonprotected key subunits 4 and
1
0 were merged in a Cadiot-Chodkiewicz cross-coupling
15
reaction (Scheme 3) to produce a 63% yield of panaxy-
triol (1). The NMR spectrum of the fully synthetic product
was identical with that obtained from an authentic
sample of panaxytriol, kindly provided by Dr. Yun-Lian
Lin.16 This identity establishes that our fully synthetic
(
10) (a) Sullivan, G. R.; Dale, J . A.; Mosher, H. S. J . Org. Chem.
973, 38, 2143. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J . Am. Chem. Soc. 1991, 113, 4092.
11) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc.
1
(14) Compare: Danishefsky, S.; Tsai, M.; Kitahara, T. J . Org. Chem.
1977, 42, 394.
(
1
987, 109, 5551. (b) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1995,
6, 9153. (c) Helal, C. J .; Magriotis, P. A.; Corey, E. J . J . Am. Chem.
(15) (a) Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819. (b) Chod-
kiewicz, W. Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Deker:
New York, 1969; p 597. (c) Brandsma, L. Preparative Acetylenic
Chemistry, 2nd ed.; Elsevier: Amsterdam, 1988; pp 212-214. (d) For
recent work in this area, see: Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew. Chem., Int. Ed. 2000, 39, 2632.
(16) We thank Dr. Yun-Lian Lin, National Research institute of
Chinese Medicine, Taipei 112, Taiwan, for sending us a specimen
sample of panaxytriol.
3
Soc. 1996, 118, 10938. (d) Corey, E. J .; Helal, C. J . Angew. Chem., Int.
Ed. 1998, 37, 1986.
(12) At the present writing, it is not clear to us why the reduction
of 2 is significantly more selective than the model cases in ref 9, which
bear substitution at the â-carbon of the olefin.
(13) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
4
520 J . Org. Chem., Vol. 68, No. 11, 2003

product is in the same diastereomer family as is natural
ether. The extract was washed with water and brine, dried over
MgSO , and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/ether
panaxytriol. The magnitude and sense of optical rota-
4
tion17 ([R]
25
D
3
-21.8, c ) 0.8, CHCl ) of fully synthetic
4
0
:1) to give compound 4 (212 mg, 100%) as a colorless oil: R
f
product confirms that our fully synthetic material is in
the same enantiomeric class as panaxytriol.18 The ster-
eochemistry of panaxytriol (1) is thus rigorously estab-
lished through chemical synthesis.
20.4
1
.49 (hexane/ether 2:1); [R]
D
-31.61 (c ) 1, CHCl
3
); H NMR
(
400 MHz, CDCl
(d, 1H, J ) 10.1), 4.88 (d, 1H, J ) 5.34), 2.44 (br, 1H); C NMR
(125 MHz, CDCl ) δ 136.7, 117.4, 79.3, 64.3, 47.2; IR (neat) ν
3
) δ 5.94 (m, 1H), 5.47 (d, 1H, J ) 17.0), 5.24
1
3
3
-
1
3
1
361.2, 2918.7, 2852.9, 2356.6 cm ; HRMS calcd 161.00, found
In summary, the synthesis of 1 was accomplished in
61.0334.
3
0% overall yield (40% for the largest linear sequence,
Com p ou n d 6. To a DMF solution of compound 5 (4.0 mL,
1.6 mmol) was added imidazole (2.0 g, 25.9 mmol) at room
comprising 8 steps). Parenthetically, the synthesis teaches
the feasibility of achieving high enantioselectivity of an
enynone such as 2 with appropriate CBS technology.
Moreover, it establishes the relative and absolute ster-
eochemistry of panaxytriol beyond reasonable doubt.
Finally, it underscores the power of the Cadiot-Chod-
kiewicz cross-coupling reaction even in the setting of
three nonprotected hydroxyl functions.19
2
temperature, and the resulting reaction mixture was cooled to
0 °C. Then TBSCl (4.0 g, 25.9 mmol) was slowly added to the
reaction mixture at 0 °C. Following warming room temperature,
the resulting mixture was stirred at room temperature for 6 h.
Water was added, and the organic phase was extracted with
ether, washed with brine, dried over MgSO , and concentrated
4
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane only to hexane/ethyl acetate
1
0:1) to give compound 6 (5.78 g, 99%) as a colorless oil: R
f
0.35
1
(
1
hexane only); H NMR (400 MHz, CDCl ) δ 5.6 (m, 1H), 5.5 (m,
3
Exp er im en ta l Section
H), 4.12 (dd, 2H, J ) 5.25, 1.19), 2.00 (dd, 2H, J ) 13.5, 6.57),
13
Com p ou n d 3. (R)-Me-CBS reagent (2.14 mL, 2.14 mmol, 1.0
M in toluene solution) was transferred into a freshly flame-dried
flask, and toluene was completely removed in vacuo for 1 day.
After the CBS reagent was diluted with THF, the resulting
1.38-1.27 (m, 10H), 0.91-0.86 (m, 12H), 0.05 (s, 6H); C NMR
(125 MHz, CDCl ) δ 131.7, 129.4, 64.6, 32.8, 32.4, 29.9, 29.8,
3
26.6, 23.3, 19.0, 14.7, -4.4; IR (neat) ν 2957.0, 2928.1, 2856.7,
-
1
1471.8, 1255.3, 1103.1, 836.7, 775.6 cm ; HRMS calcd 270.53,
found 270.2403.
8
solution was transferred to a flask of compound 2 (163 mg, 1.07
mmol) at room temperature, and the reaction temperature cooled
Com p ou n d 7. A flask, equipped with a magnetic stirrer, was
charged with 1:1 tert-butyl alcohol/water solution, and AD-mix-â
to -30 °C. At -30 °C, BH
3
2
‚Me S (BMS) (0.589 mL, 1.18 mmol)
was slowly added over 10 min. After addition of BMS, TLC
analyses indicated complete reaction. Methanol was slowly
added, and reaction mixture was slowly warmed to room
temperature. The reaction mixture was diluted with diethyl
(42.8 g) and MeSO NH2 (2.91 g, 30.6 mmol). The mixture was
2
stirred at room temperature until both phases were clear and
then cooled to 0 °C, and a 1:1 tert-butyl alcohol/water solution
of compound 6 (8.24 g, 30.5 mmol) was added. The heterogeneous
slurry was stirred vigorously at 0 °C for 1 day. The reaction was
quenched at 0 °C by addition of sodium sulfite (45.7 g), warmed
to room temperature, and stirred for 1 h. The reaction mixture
was extracted with dichloromethane, washed with 2 N KOH,
ether, washed with 2:1 (v:v) NaOH/saturated NaHCO
until the aqueous phase was clear, and then washed with brine.
After being dried over MgSO , solvent was removed. The
3
solution
4
resulting organic phase was diluted with diethyl ether, and to
this was added 0.5 M HCl in methanol solution (4.5 mL, 2.14
mmol). Precipitates were removed by filtration, and solvent was
removed. The crude product was purified by silica gel column
chromatography (hexane/ether 5:1) to give compound 3 (0.123
dried over MgSO , and concentrated under reduced pressure.
4
The residue was purified by silica gel column chromatography
(hexane/ethyl acetate 5:1) to give compound 7 (9.56 g, 100%) as
a yellow oil: R 0.35 (hexane/ethyl acetate 5:1); [R]19.9 +9.72
f
D
g, 75%) as a colorless oil: R
f
0.4 (hexane/dichloromethane 2:1);
(c ) 1, CHCl );
1
H NMR (400 MHz, CDCl ) δ 3.76 (m, 1H), 3.68
3
3
2
0.0
1
[
(
R]
ddd, 1H, J ) 17.0, 10.1, 5.29), 5.46 (d, 1H, J ) 17.0), 5.21 (d,
H, J ) 10.1), 4.86 (d, 1H, J ) 3.87), 2.17 (br, 1H), 0.16 (s, 9H);
D
-24.1 (c ) 1, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 5.95
(m, 1H). 3.62 (m, 1H), 3.46 (m, 1H). 2.57 (br, 1H), 1.52-1.25
(m, 12H), 0.88 (m, 12H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl )
3
1
δ 73.5, 72.8, 66.4, 34.1, 32.4, 30.2, 29.8, 29.2, 26.1, 23.2, 14.7,
1
3
C NMR (125 MHz, CDCl
3
) δ 137.0, 116.8, 104.9, 91.3, 63.9,
-4.7; IR (neat) ν 3394.3, 2954.4, 2930.7, 2859.3, 1468.4, 1260.3,
0
8
.2; IR (neat) ν 3368.7, 2961.3, 2927.0, 2855.3, 2174.4, 1250.9,
1111.7, 838.8 cm-1; HRMS calcd 304.54, found 305.2540.
-
1
43.7 cm ; HRMS calcd 154.28, found 154.0817.
Following the Mosher’s protocols, the corresponding bis-
Following the appropriate protocols, the corresponding Mosher
10
Mosher ester was prepared using (R)-MTPA-Cl. The proton
1
0
ester was prepared using (R)-MTPA-Cl. The proton signals (δ
signals (δ 5.355, 5.282) of the corresponding bis-Mosher ester
of 7 appeared at higher fields than those (δ 5.430, 5.291) of the
other (S,S)-isomer.
Com p ou n d 8. Compound 7 (1.00 g, 3.28 mmol), 2,2-
dimethoxypropane (0.6 mL, 4.93 mmol) and p-TsOH (catalytic)
in dichloromethane were stirred at room temperature for 1 h.
The reaction was neutralized with triethylamine and concen-
trated under reduced pressure. The crude product was used for
a further step without additional purification. To a suspension
6
.091, 5.868) of the corresponding Mosher ester of 3 appeared
at higher fields than those (δ 6.119, 5.958) of the other (S)-
isomer.
Com p ou n d 4. Compound 3 (204 mg, 1.32 mmol) was dis-
solved in acetone. NBS (353 mg, 1.98 mmol) and silver nitrate
(45 mg, 0.26 mmol) were added to this solution. The reaction
mixture was stirred at room temperature for 1 h. The mixture
was cooled to 0 °C, mixed with cold water, and extracted with
3 2
of Ph PBr in dichloromethane was added a solution of crude
(
17) Interestingly, the magnitude of optical rotation of synthetic
product in the previous reaction in dichloromethane at room
temperature, and the resulting mixture was stirred at room
temperature for 30 min. Subsequently, dichloromethane was
1
9.1
panaxytriol seems to sharply depend on its concentration ([R]
D
-13,
3
c ) 1.5, CHCl ).
(
18) The absolute configuration of panaxytriol shown in structure
is consistent with following well-precedented trends: (i) the sense
of CBS reduction of 2; (ii) the sense of asymmetric dihydroxylation of
4
added, and the solution washed with water, dried over MgSO ,
1
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate 5:1) to give compound 8 (0.834 g, 90%) as a yellow oil.
This material was used directly without further purification.
Com p ou n d 9. Compound 8 (0.834 g, 2.84 mmol) and 1 N HCl
in ethanol was stirred at room temperature for 3 days and
neutralized with potassium carbonate (0.4 g). More potassium
carbonate (0.8 g) was then added to the reaction mixture, and
the pH adjusted to around 8-9. The reaction mixture was
vigorously stirred at room temperature overnight. Ethanol was
1
0
6
; (iii) the chemical shift patterns of the Mosher esters of 3 and 7;
and (iv) the sign of the optical rotation of 3, assigned here as (R), with
a recently reported, closely related (S) compound. For the absolute
configuration of panaxytriol to be opposite to that shown, all of these
precedents would have to be inapplicable.
2
0
(
19) A related Cadiot-Chodkiewicz cross-coupling reaction was
reported in the process of total synthesis of panaxytriol (ref 7b). The
novelty of our case lies in its application to a setting containing three
nonprotected resident hydroxyl groups.
(
20) Ratnayake, A. S.; Hemscheidt, T. Org. Lett. 2002, 4, 4667.
J . Org. Chem, Vol. 68, No. 11, 2003 4521

removed under reduced pressure, and the residue was extracted
with ether, washed with water, dried over MgSO , and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate 10:1 to 7:1)
to give compound 9 (0.354 g, 89% based on recovered starting
compound 10 (41 mg, 0.207 mmol) at room temperature. A
dichloromethane solution of compound 4 (24.4 mg, 0.151 mmol)
was added dropwise to reaction mixture at 0 °C over 1 h using
a syringe pump. For an additional 1 h, reaction mixture was
stirred at 0 °C. The reaction mixture was quenched by water,
extracted with dichloromethane, washed with brine, dried over
4
material) as a yellow oil and starting material (0.158 g): R
f
0.6
); H NMR
) δ 3.44 (m, 1H), 2.94 (m, 1H), 2.77 (d, 1H, J )
.84), 2.67 (d, 1H, J ) 4.93), 2.45 (br, 1H), 1.62-1.26 (m, 12H),
.84 (t, 3H, J ) 6.72); 13C NMR (125 MHz, CDCl
) δ 72.1, 55.9,
5.5, 34.6, 32.1, 29.9, 29.5, 25.6, 22.9, 14.4; IR (neat) ν 3443.0,
1
9.1
1
(
(
hexane/ethyl acetate 1:1); [R]
D
-3.38 (c ) 1, CHCl
3
MgSO , and concentrated under reduced pressure. The residue
4
400 MHz, CDCl
3
was purified by silica gel column chromatography (hexane/ethyl
4
0
4
2
1
acetate 2:1) to give panaxytriol (1) (26.6 mg, 63% isolated) and
3
compound 10 (12.4 mg): R
0.13 (hexane/ethyl acetate 2:1); [R]
25
f
D
1
-21.8 (c ) 0.8, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 5.94 (ddd,
-
1
933.6, 2858.9, 2342.6, 1466.4, 1255.8, 923.0 cm ; HRMS calcd
72.26, found 171.1388.
1
5
H, J ) 17.0, 10.1, 5.35), 5.47 (ddd, 1H, J ) 17.0, 1.31, 1.21),
.25 (ddd, 1H, J ) 10.4, 1.25, 1.15), 4.92 (d, 1H, J ) 5.35), 3.62
Com p ou n d 10. To a solution of lithiumacetylide-ethylene-
(m, 2H), 2.58 (d, 2H, J ) 5.78), 2.11 (br, 3H), 1.51-1.25 (m, 12H),
diamine complex (0.330 g, 3.58 mmol) in THF and HMPA (0.2
mL) was added compound 9 (0.206 g, 1.19 mmol) at 0 °C. The
reaction mixture was stirred at that temperature overnight,
quenched with saturated ammonium chloride, extracted with
13
0
7
2
3
.88 (t, 3H, J ) 6.73); C NMR (125 MHz, CDCl ) δ 136.4, 117.6,
8.5, 75.1, 73.5, 72.5, 71.3, 66.9, 63.9, 34.0, 32.2, 29.9, 29.6, 26.0,
5.4, 23.0, 14.5; IR (neat) ν 3524.8, 2930.7, 2854.8, 2360.0, 1457.1
-
1
cm ; HRMS calcd 278.39, found 261.1047.
4
ethyl acetate, washed with brine, dried over MgSO , and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate 4:1)
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (grant HL25848).
to give compound 10 (0.189 g, 80%) as a yellow oil: R
f
0.24
); H
1
9.7
1
(
hexane/ethyl acetate 3:1); [R]
D
+0.1131 (c ) 1, CHCl
3
NMR (400 MHz, CDCl
2
NMR (125 MHz, CDCl ) δ 81.0, 73.6, 72.5, 71.4, 34.1, 32.4, 30.1,
3
2
2
3
) δ 3.61 (m, 2H), 2.47 (m, 2H), 2.31 (br,
H), 2.06 (s, 1H), 1.50-1.24 (m, 12H), 0.87 (t, 3H, J ) 6.75); 13
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterizations for all new compounds
including panaxytriol (1). This material is available free of
charge via the Internet at http://pubs.acs.org.
C
9.8, 26.2, 24.7, 23.3, 14.7; IR (neat) ν 3392.1, 2924.1, 2855.1,
-1
362.0, 1653.2, 1457.1 cm ; HRMS calcd 198.30, found 181.2777.
P a n a xytr iol (1). CuCl (1.5 mg), NH OH‚HCl (10 mg) and
ethylamine(0.23 mL) were added to a methanol solution of
2
J O0341665
4
522 J . Org. Chem., Vol. 68, No. 11, 2003