Synthesis of panaxytriol and its stereoisomers as potential antitumor drugs

Article abstract of DOI:10.1016/j.tetasy.2016.03.005

An efficient synthesis of panaxytriol and its seven stereoisomers was achieved, and four unnatural diastereomers of 2a were prepared. The key steps involved the opening of vicinal hydroxy epoxides, the stereospecific opening of the epoxides with perchlori

Full text of DOI:10.1016/j.tetasy.2016.03.005

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of panaxytriol and its stereoisomers as potential antitumor
drugs
Jianyou Mao a, Jiangchun Zhong a, Bo Wang a, Jing Jin b, Shuoning Li a, Zidong Gao a, Hanze Yang b,
Qinghua Bian a,
⇑
a Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
b State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical
College, 1 Xian Nong Tan Street, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of panaxytriol and its seven stereoisomers was achieved, and four unnatural
diastereomers of 2a were prepared. The key steps involved the opening of vicinal hydroxy epoxides,
the stereospecific opening of the epoxides with perchloric acid, and the Cadiot–Chodkiewicz cross-cou-
pling of chiral terminal alkynes with bromoalkynes. Preliminary antitumor activity investigations indi-
cated that some synthetic panaxytriols exhibited promising cytotoxic activity against three human
cancer cell lines.
Received 5 February 2016
Accepted 10 March 2016
Available online xxxx
Ó 2016 Published by Elsevier Ltd.
OH
1. Introduction
O
Red ginseng, a thermally processed product of the root of Panax
ginseng C. A. Meyer, is a well-known traditional oriental medicine
and is commonly used for the treatment of cardiovascular disease,
diabetes, and various cancer.1 It contains several types of chiral
polyacetylenic alcohols, such as panaxydol 1, panaxytriol 2a, and
panaxynol 3 (Fig. 1).2 We are interested in panaxytriol because it
exhibits inhibitory activity against several kinds of tumor cell lines,
including human gastric adenocarcinoma types (MK-1),3 human
colon adenocarcinoma (SW620),4 and human breast carcinoma
(Breast M25-SF).5 In addition, one biological investigation showed
that panaxytriol suppressed the proliferation of mouse lymphoma
cells (P388D1).6
(3R,9R,10S)-panaxydol 1
OH
OH
OH
(3R,9R,10R)-panaxytriol 2a
OH
Panaxytriol 2a was isolated from red ginseng and the structure
was identified as heptadec-1-ene-4,6-diyne-3,9,10-triol (Fig. 1).7
Its absolute configuration was confirmed as (3R,9R,10R) by the
modified Mosher’s method and circular dichroism (CD) analy-
sis.2b,8 Since the first total synthesis of panaxytriol 2a from chiral
(3R,9Z)-panaxynol 3
D
-gluconolactone and D
-xylose reported by Cai et al.,9 a number
Figure 1. Chiral polyacetylenic alcohols in red ginseng.
of asymmetric syntheses have been reported. The main strategies
employed to introduce the chiral propargyl alcohol core involved
derivation from a chiral template,10 enantioselective reduction of
an enynone,11 enantioselective diynylation of an aldehyde,12 and
chemoenzymatic approach.13 For constructing the chiral vicinal
alcohol unit, synthetic approaches were devised from optically
active starting materials10,14 and Sharpless asymmetric
dihydroxylation.11,15
The important bioactivity of natural panaxytriol and potential
antitumor activities of its stereoisomers prompted us to search
for more efficient and convenient synthetic strategies. Herein, we
have accomplished an efficient synthesis and preliminary in vitro
⇑
Corresponding author. Tel.: +86 010 62731356; fax: +86 010 62820325.
E-mail address: bianqinghua@cau.edu.cn (Q. Bian).
http://dx.doi.org/10.1016/j.tetasy.2016.03.005
0957-4166/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

2
J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
A. Syntheses of 8a and 8b
cytotoxicity evaluations of panaxytriol and its seven stereoisomers.
Moreover, four unnatural diastereomers of 2a have been prepared
for the first time.
O
O
RO
RO
(S)
(R) (S)
(R)
6
6
4a: R = H, >99% ee
5a: R = Ts, 99%
TsCl, Et3N
DCM, 0 o
4b: R = H, >99% ee
5b: R = Ts, 99%
2. Results and discussion
C
cat. HClO4
The retrosynthetic analysis of (3R,9R,10R)-panaxytriol 2a is
depicted in Figure 2. The Cadiot–Chodkiewicz coupling reaction
of terminal alkyne 8a with bromoalkyne 9a was envisaged to form
the target long-chain acetylenic alcohol 2a. The key fragment vic-
inal alcohol 8a could be prepared via the opening of vicinal
hydroxy epoxide 7a with lithiumacetylide–ethylenediamine com-
plex. The triflate of chiral epoxy alcohol 4a could be transformed
into the intermediate 7a by stereospecific epoxide opening with
perchloric acid and SN2 displacement with potassium carbonate
in methanol.
DMSO, H2O, 10 o
C
'
OR
OR
'
(S)
TsO
(R)
TsO
(S)
(R)
6
6
OR
OR
'
'
6a: R' = H
6b: R' = H
(R)-MTPACl
79%, 92% ee
80%, 92% ee
DMAP, Et3N
6b': R' = (S)-MTPA
6a': R' = (S)-MTPA
DCM, 0 o
C
O
O
(R)
(S)
(S)
K2CO3
MeOH, 0 o
(R)
6
6
C
OH
OH
7b, 96%
7a, 95%
OH
Li-acetylide
EDA complex
(R)
OH
HMPA, THF, 0 o
C
OH
OH
(R)
(R)
(R)
(R)
(S)
(S)
6
6
OH
OH
8a, 80%
OH
(3R,9R,10R)-panaxytriol 2a
8b, 79%
Cadiot-ChodkIewicz
coupling
B.
Syntheses of 8c and 8d
OH
OH
O
O
(R)
(S)
(R)
RO
RO
(R)
(R)
6
(R)
6
(S)
OH
8a
9a
Br
TsCl, Et3N
DCM, 0 oC
4d: R = H, >99% ee
5d: R = Ts, 99%
4c: R = H, >99% ee
5c: R = Ts, 99%
vicinal hydroxy
epoxide opening
cat. HClO4
O
DMSO, H2O, 10 o
C
HC CLi.NH2CH2CH2NH2
(R)
(R)
OR'
OR
'
OH
7a
(S)
TsO
TsO
(R)
(R)
(S)
stereospecific
6
6
epoxide opening
OR '
OR
'
SN2 displacement
6d
: R' = H
O
6c: R' = H
(R)-MTPACl
78%, 94% ee
79%, 96% ee
HO
DMAP, Et3N
6c'
6d'
: R' = (S)-MTPA
: R' = (S)-MTPA
(R) (S)
DCM, 0 o
C
4a
O
O
Figure 2. Retrosynthetic analysis of (3R,9R,10R)-panaxytriol 2a.
(S)
(R)
(S)
K2CO3
(R)
6
MeOH, 0 oC
6
OH
7c, 87%
Recently, we accomplished the total synthesis of panaxydol and
its stereoisomers.16 Almost enantiomerically pure propargyl alco-
hols 9a and 9b (>99% ee) were obtained via the enantioselective
addition of trimethylsilyacetylene to acrolein.17 Moreover, the
Sharpless asymmetric epoxidation of allylic alcohol afforded chiral
epoxy alcohols 4a–d with high enantioselectivities.18
OH
7d, 90%
Li-acetylide
EDA complex
HMPA, THF, 0 o
C
OH
OH
(S)
(R)
(S)
(R)
6
6
Our study began with the enantioselective synthesis of chiral
vicinal alcohols 8 (Scheme 1). Treatment of 4a (>99% ee) and 4b
(>99% ee) with p-toluenesulfonyl chloride afforded their tosylates
5a,b quantitatively. Subsequent regioselective and stereospecific
ring-opening reaction of 2,3-epoxy 1-sulfonate esters 5a,b with
aqueous perchloric acid in DMSO gave 2,3-diol-l-sulfonate esters
6a (80% yield, 92% ee), and 6b (79% yield, 92% ee),19 determined
OH
OH
8c, 84%
8d, 84%
Scheme 1. Enantioselective syntheses of vicinal alcohols 8.
converted into tosylates (2R,3S)-6c (79%, 96% ee) and (2S,3R)-6d
(78%, 94% ee) via the above two-step protocol. The 1H NMR com-
parison of one proton signal at C-1 of Mosher esters 6c0,d0 derived
from 6c,d and (R)-(ꢀ)-MTPACl showed that there was 2% of disas-
tereomer 6d0 in 6c0. Correspondingly, 3% of disastereomer 6c0 was
1
by H NMR analysis of the Mosher esters 6a0,b0 derived from 6a,b
20
and (R)-(ꢀ)-MTPACl.
Comparison of the proton signal at C-2 of
both Mosher esters 6a0 and 6b0 showed that there was 4% of disas-
tereomer 6b0 in 6a0. In addition, 4% of disastereomer 6a0 was
1
observed in the H NMR of the Mosher ester 6d0, which indicated
1
observed in the H NMR of the Mosher ester 6b0, which indicated
that the ee value of 6d was 94% (Fig. 4). Next, 1,2-epoxy-3-o1 7a
was obtained in 95% yield by exposure of 6a to potassium
carbonate in methanol.21 Finally, the reaction of 7a with the
lithiumacetylide–ethylenediamine complex afforded the chiral
building block 8a in 80% yield.11a,22 Other stereoisomers 8b–d
that the ee value of 6b was 92% (Fig. 3). According to the study
of Hanson,19 this acid-catalyzed stereospecific epoxide cleavage
led to an inversion of configuration at C-3. Therefore, the configu-
ration of tosylate 6a was assigned as (2R,3R), and that of 6b was
(2S,3S). Almost enantiopure epoxy alcohols 4c and 4d were
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
(3R,9R,10R)-configuration. Three stereoisomers 2b–d were
obtained from 9a and 8b–d using a similar strategy. The Cadiot–
Chodkiewicz cross-coupling reaction of bromoalkyne 9b with vic-
inal alcohols 8a–d afforded (3S,9R,10R)-, (3S,9S,10S)-, (3S,9R,10S)-
and (3S,9S,10R)-panaxytriol 2e–h in good yields.
Ph
OCH3
F3C
(S)
O
O
(R)
TsO
The in vitro cytotoxicity evaluation of natural panaxydol and
their stereoisomers against human colon cancer cell line (HCT-
116), human lung cancer cell line (NCI-H1650) and human ovar-
ian cancer cell line (A2780) using a 3-(dimethyl-thiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay is shown in Table 1.24
The results showed that the stereoisomers 2e–h with an (S)-con-
figuration at C-3 were uniformly more cytotoxic than stereoiso-
mers 2b–d with an (R)-configuration at C-3 including natural
panaxytriol 2a. Importantly, (3S,9R,10R)- and (3S,9S,10S)-
panaxytriols 2e and 2f showed significant cytotoxic activity
(R)
O
O
(S)
Ph
H3CO
CF3
6a'
Ph
F3C
OCH3
(S)
O
O
against NCI-H1650 with IC50 values of 0.84 and 0.73 lM, respec-
(S)
TsO
(S)
tively. These results are very close to those of taxol, a well known
antitumor drug.25 Our biological investigations provide strong
evidence that some synthetic panaxytriols possess promising
anticancer activities.
O
O
(S)
Ph
H3CO
CF3
6b'
3. Conclusion
Figure 3. The representative 1H NMR spectra (300 MHz, CDCl3) of Mosher esters 6a0
and 6b0.
In conclusion, we have reported an efficient synthesis of natural
panaxytriol and its seven stereoisomers; furthermore, (3R,9R,10S)-,
(3R,9S,10R)-, (3S,9R,10S)-, (3S,9S,10R)-panaxytriols 2c, 2d, 2g, 2h
have been prepared for the first time. Our strategy includes the
opening of vicinal hydroxy epoxides, the stereospecific opening
of epoxides with perchloric acid, and the Cadiot–Chodkiewicz
cross-coupling of chiral terminal alkynes with bromoalkynes. Fur-
thermore, preliminary in vitro cytotoxicity investigations showed
that some synthetic panaxytriols possessed promising antitumor
activities, and were valuable for further exploration as potential
antitumor drugs.
Ph
F3C
OCH3
(S)
O
O
(S)
TsO
(R)
O
O
(S)
Ph
H3CO
CF3
4. Experimental
4.1. General
6c'
All reactions were conducted under a nitrogen atmosphere
unless otherwise noted, and using standard Schlenk techniques.
Solvents were dried according to standard procedures and distilled
prior to use. Melting points were measured on a STUART-SMP3
Melt-Temp apparatus without correction. Optical rotations were
obtained using a Perkin–Elmer PE-341 polarimeter. 1H and 13C
NMR spectra were recorded on a Bruker DP-X300 spectrometer.
Chemical shifts are reported in ppm, and tetramethylsilane (TMS)
served as an internal standard for 1H NMR and CDCl3 for 13C
NMR. High resolution mass spectrometry (HRMS) data were col-
lected on a Waters LCT PremierTM with an ESI mass spectrometer.
Ph
F3C
OCH3
(S)
O
O
TsO
(R)
(S)
O
O
(S)
Ph
H3CO
CF3
6d'
4.2. Experimental procedures and spectroscopic data
Figure 4. The representative 1H NMR spectra (300 MHz, CDCl3) of Mosher esters 6c0
and 6d0.
4.2.1. (2R,3S)-2,3-Epoxy-1-decanol tosylate 5a
To a stirred solution of epoxy alcohol 4a (2.06 g, 12 mmol) in
dry CH2C12 (40 mL) were added triethylamine (3.37 mL,
24.0 mmol) and p-toluene sulfonyl chloride (2.75 g, 14.4 mmol)
at 0 °C. The resulting mixture was stirred at 0 °C overnight. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography (n-hexane/ethyl
acetate 10:1 to 5:1) to give 5a (3.90 g, 99% yield) as a colorless
were prepared smoothly from tosylates 5b–d via
a similar
approach.
With chiral subunits 8 and 9 in hand, we next synthesized eight
stereoisomers of panaxytriol 2a–h (Scheme 2). Panaxytriol 2a was
obtained in 87% yield via Cadiot–Chodkiewicz cross-coupling reac-
tion of 8a with 9a.23 The NMR spectra and specific rotation of syn-
thetic chiral polyacetylenic alcohol 2a was were identical to the
natural (3R,9R,10R)-panaxytriol.8 Furthermore, the configurations
of the chiral fragments 8a and 9a also proposed that 2a had a
oil. [a]
20 = +15.1 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.84–
D
7.79 (m, 2H), 7.37–7.34 (m, 2H), 4.18 (dd, J = 11.1, 5.1 Hz, 1H),
4.09 (dd, J = 11.1, 6.3 Hz, 1H), 3.18–3.13 (m, 1H), 3.00–2.96 (m,
1H), 2.46 (s, 3H), 1.46–1.27 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

4
J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
OH
OH
OH
CuCl, n-BuNH2
(R)
H2O, DCM
(R)
OH
(R)
(R)
+
6
NH2OH HCl
MeOH, 0 oC
(R)
Br
(R)
8a
OH
9a
6
OH
(3R,9R,10R)-panaxytriol 2a, 87%
OH
OH
OH
(R)
(R)
(R)
OH
OH
OH
(S)
(S)
(R)
(R)
(S)
(S)
6
6
6
OH
OH
OH
(3R,9S,10S)-panaxytriol 2b
85%, from 9a and 8b
2c
(3R,9R,10S)-panaxytriol
86%, from 9a and 8c
(3R,9S,10R)-panaxytriol 2d
84%, from 9a and 8d
OH
OH
OH
CuCl, n-BuNH2
(S)
H2O, DCM
(R)
OH
(S)
(R)
+
6
(R)
NH2OH HCl
MeOH, 0 oC
Br
(R)
8a
OH
9b
6
6
OH
(3S,9R,10R)-panaxytriol 2e, 87%
OH
OH
OH
(S)
(S)
(S)
OH
OH
OH
(R)
(S)
(S)
(R)
(S)
(S)
6
6
OH
OH
OH
(3S,9S,10R)-panaxytriol 2h
82%, from 9b and 8d
(3S,9S,10S)-panaxytriol 2f
83%, from 9b and 8b
(3S,9R,10S)-panaxytriol 2g
88%, from 9b and 8c
Scheme 2. Synthesis of panaxytriols 2a–h via Cadiot–Chodkiewicz cross-coupling.
Table 1
4.2.3. (2R,3R)-2,3-Epoxy-1-decanol tosylate 5c
The in vitro cytotoxicities of natural panaxytriol and their stereoisomers against three
Following a similar procedure described for 5a, the esterifica-
tion of epoxy alcohol 4c (2.06 g, 12 mmol) with p-toluene sulfonyl
chloride (2.75 g, 14.4 mmol) afforded 5c (3.91 g, 99% yield) as a col-
human cancer cell linesa
Compound
IC50 (lM)
orless oil. [a] [a]D = +30.7 (c 1.17,
20 = +28.7 (c 1.7, CHCl3), lit.27
D
HCT-116
NCI-H1650
A2780
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.82–7.78 (m, 2H), 7.37–7.34
(m, 2H), 4.18 (dd, J = 11.3, 3.9 Hz, 1H), 3.98 (dd, J = 11.3, 5.8 Hz,
1H), 2.96–2.92 (m, 1H), 2.80–2.76 (m, 1H), 2.45 (s, 3H), 1.60–1.48
(m, 2H), 1.41–1.26 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 144.9, 132.8, 129.8, 127.9, 70.2, 56.7, 54.4,
31.6, 31.2, 29.1, 29.0, 25.6, 22.5, 21.5, 14.0; HRMS (ESI) calcd for
Natural panaxytriol 2a
(3R,9S,10S)-Panaxytriol 2b
(3R,9R,10S)-Panaxytriol 2c
(3R,9S,10R)-Panaxytriol 2d
(3S,9R,10R)-Panaxytriol 2e
(3S,9S,10S)-Panaxytriol 2f
(3S,9R,10S)-Panaxytriol 2g
(3S,9S,10R)-Panaxytriol 2h
Taxolb
>10
>10
>10
>10
0.25 0.14
1.49 0.97
1.97 0.64
1.31 0.86
0.03
2.45 1.06
3.72 0.94
2.46 0.69
2.30 0.58
0.84 0.04
0.73 0.18
2.72 0.58
1.57 0.86
0.36
>10
>10
>10
>10
0.70 0.08
0.69 0.13
0.71 0.08
0.44 0.06
0.061
C
17H27O4S [M+H]+ 327.1630, found 327.1633.
a
4.2.4. (2S,3S)-2,3-Epoxy-1-decanol tosylate 5d
MTT assay following 96 h inhibition. HCT-116 is a human colon cancer cell line.
Following a similar procedure described for 5a, the esterifica-
tion of epoxy alcohol 4d (2.06 g, 12 mmol) with p-toluene sulfonyl
chloride (2.75 g, 14.4 mmol) gave 5d (3.91 g, 99% yield) as color-
NCI-H1650 is human lung cancer cell line. A2780 is human ovarian cancer cell line.
b
Positive control.
less oil. [
a]
20 = ꢀ30.0 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3) d
D
7.82–7.78 (m, 2H), 7.37–7.34 (m, 2H), 4.18 (dd, J = 11.3, 3.9 Hz,
1H), 3.98 (dd, J = 11.3, 5.8 Hz, 1H), 2.96–2.92 (m, 1H), 2.80–2.76
(m, 1H), 2.45 (s, 3H), 1.60–1.48 (m, 2H), 1.45–1.26 (m, 10H),
0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 144.9, 132.8,
129.8, 127.9, 70.2, 56.7, 54.4, 31.6, 31.2, 29.1, 29.0, 25.6, 22.5,
21.5, 13.9; HRMS (ESI) calcd for C17H27O4S [M+H]+ 327.1630, found
327.1634.
NMR (75 MHz, CDCl3) d 145.0, 132.7, 129.9, 127.9, 68.1, 56.5, 52.9,
31.6, 29.2, 29.0, 27.6, 26.4, 22.5, 21.5, 13.9; HRMS (ESI) calcd for
C
17H27O4S [M+H]+ 327.1630, found 327.1630.
4.2.2. (2S,3R)-2,3-Epoxy-1-decanol tosylate 5b
Following a similar procedure described for 5a, the esterifica-
tion of epoxy alcohol 4b (2.06 g, 12 mmol) with p-toluene sulfonyl
chloride (2.75 g, 14.4 mmol) provided 5b (3.91 g, 99% yield) as a
colorless oil. [
a
]
20 = ꢀ13.5 (c 1.3, CHCl3), lit.26
[
a
]
20 = ꢀ12.6 (c 0.6,
4.2.5. (2R,3R)-1-Tosyloxy-2,3-decanediol 6a
D
D
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.84–7.80 (m, 2H), 7.37–7.35
(m, 2H), 4.18 (dd, J = 11.1, 5.1 Hz, 1H), 4.09 (dd, J = 11.1, 6.3 Hz,
1H), 3.18–3.13 (m, 1H), 2.98–2.96 (m, 1H), 2.46 (s, 3H), 1.46–
1.27 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
145.0, 132.7, 129.8, 127.9, 68.1, 56.5, 52.9, 31.6, 29.2, 29.0, 27.6,
26.4, 22.5, 21.5, 13.9; HRMS (ESI) calcd for C17H27O4S [M+H]+:
327.1630, found 327.1632.
To a stirred solution of tosylate 5a (3.91 g, 12 mmol) in a 60%
aqueous DMSO (60 mL), a solution of 70% HClO4 (0.25 mL) was
added. The resulting mixture was stirred for 72 h at 10 °C. The
reaction mixture was diluted with ethyl acetate (200 mL) and
washed with water. The organic phase was dried over Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (n-hexane/ethyl acetate 2:1) to
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
afford 6a (3.30 g, 80% yield, 92% ee, determined by 1H NMR analy-
sis of the ester 6a0 derived from (R)-(ꢀ)-MTPACl) as a white solid.
white solid. Mp 62.0–64.0 °C; [
a
]
20 = +4.6 (c 1.2, CHCl3); 1H NMR
D
(300 MHz, CDCl3) d 7.82–7.78 (m, 2H), 7.37–7.34 (m, 2H), 4.19
(dd, J = 10.5, 3.3 Hz, 1H), 4.13 (dd, J = 10.5, 6.7 Hz, 1H), 3.78–3.64
(m, 2H), 2.84 (d, J = 5.1 Hz, 1H), 2.45 (s, 3H), 2.28 (d, J = 4.9 Hz,
1H), 1.48–1.26 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 145.0, 132.4, 129.9, 127.9, 72.2, 72.1, 71.2,
32.3, 31.7, 29.4, 29.1, 25.6, 22.5, 21.5, 13.9; HRMS (ESI) calcd for
Mp 64.5–66.0 °C; [a]
20 = +8.0 (c 1.3, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 7.81–7.79 (m, 2H), 7.37–7.34 (m, 2H), 4.11 (dd, J = 10.3,
4.7 Hz, 1H), 4.05 (dd, J = 10.3, 6.5 Hz, 1H), 3.74–3.67 (m, 1H),
3.58–3.56 (m, 1H), 2.92 (d, J = 5.9 Hz, 1H), 2.45 (s, 3H), 2.40 (d,
J = 6.1 Hz, 1H), 1.50–1.26 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 145.0, 132.5, 129.8, 127.8, 71.39, 71.36,
70.7, 33.2, 31.7, 29.4, 29.1, 25.4, 22.5, 21.5, 13.9; HRMS (ESI) calcd
for C17H29O5S [M+H]+ 345.1736, found 345.1733.
C
17H29O5S [M+H]+ 345.1736, found 345.1737.
4.2.10. (S)-MTPA ester of 6c (6c0)
Following a similar procedure described for 6a0, the reaction
4.2.6. (S)-MTPA ester of 6a (6a0)
between 6c (51.6 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl (90
lL,
To
4-(dimethy1amino)pyridine (DMAP) (18 mg, 0.15 mmol) in CH2Cl2
(1 mL), was added 6a (51.6 mg, 0.15 mmol) at 0 °C. (R)-(ꢀ)-
Methoxy- -(trifluoromethy1)phenylacetyl chloride (MTPACl)
(90 L, 0.45 mmol) was then added, and the reaction solution
a
solution of triethylamine (100
lL, 0.7 mmol) and
0.45 mmol) yielded 6c0 as a colorless oil. [
a]
20 = ꢀ25.7 (c 1.2,
D
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.73–7.69 (m, 2H), 7.51–7.48
(m, 2H), 7.38–7.26 (m, 10H), 5.40–5.36 (m, 1H), 5.29–5.24 (m,
1H), 4.27 (dd, J = 11.5, 2.6 Hz, 1H), 4.03 (dd, J = 11.4, 8.2 Hz, 1H),
3.53 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 1.41–1.13 (m, 12H), 0.88 (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 165.9, 165.5, 145.4,
132.2, 131.8, 131.5, 130.0, 129.69, 129.65, 128.4, 127.9, 127.2,
127.1, 123.1 (q, J = 287.0 Hz), 84.6 (q, J = 27.6 Hz), 74.3, 73.7, 66.1,
55.7, 55.2, 31.5, 30.2, 29.0, 28.8, 24.6, 22.5, 21.6, 14.0; HRMS
(ESI) calcd for C37H42F6NaO9S [M+Na]+: 799.2351, found: 799.2350.
a
-
a
l
turned orange. The reaction solution was maintained at 0 °C until
complete consumption of 6a as monitored by TLC. The reaction
was quenched with 3-(dimethylamino)propylamine (50 lL) and
concentrated under reduced pressure. The residue was purified
by flash chromatography (n-hexane/ethyl acetate 5:1) to give 6a0
as a colorless oil. [
a]
D
20 = ꢀ40.7 (c 1.1, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.72–7.69 (m, 2H), 7.52–7.26 (m, 12H), 5.46–5.41 (m,
1H), 5.16–5.12 (m, 1H), 3.98 (d, J = 6.1 Hz, 2H), 3.46 (s, 3H), 3.42
(s, 3H), 2.44 (s, 3H), 1.48–1.14 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 165.7, 165.6, 145.4, 132.2, 131.6,
130.0, 129.8, 128.5, 127.9, 127.21, 127.18, 123.1 (q, J = 286.7 Hz),
84.5 (q, J = 17.9 Hz), 73.7, 71.7, 66.3, 55.5, 55.3, 31.6, 29.4, 29.0,
28.9, 24.9, 22.5, 21.6, 14.0; HRMS (ESI) calcd for C37H42F6NaO9S
[M+Na]+ 799.2351, found 799.2349.
4.2.11. (2S,3R)-1-Tosyloxy-2,3-decanediol 6d
Following a similar procedure described for 6a, the ring-open-
ing reaction of 5d (3.91 g, 12 mmol) with 70% HClO4 solution
(0.25 mL) afforded 6d (3.22 g, 78% yield, 94% ee, determined by
1H NMR analysis of the ester 6d0 derived from (R)-(ꢀ)-MTPACl)
as a white solid. Mp 61.0–63.0 °C; [
a]
20 = ꢀ4.6 (c 1.3, CHCl3); 1H
D
NMR (300 MHz, CDCl3) d 7.82–7.78 (m, 2H), 7.37–7.35 (m, 2H),
4.19 (dd, J = 10.5, 3.3 Hz, 1H), 4.13 (dd, J = 10.5, 6.7 Hz, 1H), 3.79–
3.63 (m, 2H), 2.69 (d, J = 5.0 Hz, 1H), 2.45 (s, 3H), 2.14 (d,
J = 4.9 Hz, 1H), 1.49–1.27 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 145.0, 132.5, 129.9, 127.9, 72.3, 72.1,
71.2, 32.4, 31.7, 29.4, 29.1, 25.6, 22.5, 21.5, 14.0; HRMS (ESI) calcd
for C17H29O5S [M+H]+ 345.1736, found 345.1734.
4.2.7. (2S,3S)-1-Tosyloxy-2,3-decanediol 6b
Following a similar procedure described for 6a, the ring-open-
ing reaction of 5b (3.91 g, 12 mmol) with 70% HClO4 solution
(0.25 mL) provided 6b (3.26 g, 79% yield, 92% ee, determined by
1H NMR analysis of the ester 6b0 derived from (R)-(ꢀ)-MTPACl)
as a white solid. Mp 64.5–66.5 °C; [
a
]
D
20 = ꢀ7.5 (c 1.3, CHCl3); 1H
4.2.12. (S)-MTPA ester 6d (6d0)
NMR (300 MHz, CDCl3) d 7.81–7.79 (m, 2H), 7.37–7.34 (m, 2H),
4.11 (dd, J = 10.4, 4.7 Hz, 1H), 4.05 (dd, J = 10.4, 6.5 Hz, 1H), 3.74–
3.67 (m, 1H), 3.58–3.56 (m, 1H), 2.87 (d, J = 5.3 Hz, 1H), 2.45 (s,
3H), 2.35 (d, J = 5.6 Hz, 1H), 1.47–1.26 (m, 12H), 0.88 (t,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 145.0, 132.5, 129.9,
127.9, 71.41, 71.37, 70.7, 33.2, 31.7, 29.4, 29.1, 25.4, 22.5, 21.5,
14.0; HRMS (ESI) calcd for C17H29O5S [M+H]+ 345.1736, found
345.1735.
Following a similar procedure described for 6a0, the reaction
between 6d (51.6 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl (90
lL,
0.45 mmol) afforded 6d0 as a colorless oil. [
a]
D
20 = ꢀ30.0 (c 1.3,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.65–7.62 (m, 2H), 7.47–7.24
(m, 12H), 5.45–5.40 (m, 1H), 5.37–5.32 (m, 1H), 4.18 (dd, J = 11.3,
3.3 Hz, 1H), 3.80 (dd, J = 11.3, 7.7 Hz, 1H), 3.43 (s, 3H), 3.41 (s,
3H), 2.43 (s, 3H), 1.60–1.58 (m, 2H), 1.29–1.23 (m, 10H), 0.88 (t,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 165.7, 165.6, 145.3,
132.2, 131.7, 131.6, 130.0, 129.9, 129.71, 129.67, 128.9, 128.8,
128.5, 128.4, 128.0, 127.4, 127.2, 127.0, 123.1 (q, J = 286.8 Hz),
123.0 (q, J = 287.0 Hz), 84.7 (q, J = 27.6 Hz), 74.6, 73.4, 66.0, 55.4,
55.3, 31.5, 30.2, 29.0, 28.9, 25.0, 22.5, 21.6, 14.0; HRMS (ESI) calcd
for C37H42F6NaO9S [M+Na]+ 799.2351, found 799.2352.
4.2.8. (S)-MTPA ester of 6b (6b0)
Following a similar procedure described for 6a0, the reaction
between 6b (51.6 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl (90
lL,
0.45 mmol) produced 6b0 as a colorless oil. [
a]
20 = ꢀ20.7 (c 1.1,
D
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.65–7.26 (m, 14H), 5.55–
5.50 (m, 1H), 5.25–5.20 (m, 1H), 4.09 (dd, J = 10.8, 4.1 Hz, 1H),
3.91 (dd, J = 10.8, 8.0 Hz, 1H), 3.41 (s, 6H), 2.42 (s, 3H), 1.51–1.49
(m, 2H), 1.26–1.16 (m, 10H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 166.0, 165.8, 145.3, 132.0, 131.4, 131.1, 129.9,
129.81, 129.77, 129.5, 128.55, 128.52, 128.0, 127.6, 127.3, 123.1
(q, J = 286.8 Hz), 84.8 (q, J = 26.9 Hz), 73.7, 72.3, 66. 8, 55.3, 31.5,
30.1, 28.9, 28.8, 24.6, 22.5, 21.6, 14.0; HRMS (ESI) calcd for
4.2.13. (2R,3R)-1,2-Epoxy-3-decanol 7a
To a stirred solution of the 2,3-diol-1-sulfonate 6a (0.688 g,
2 mmol) in anhydrous methanol (15 mL) was added K2CO3
(0.553 g, 4 mmol) and stirred at 0 °C for 0.5 h. The reaction mixture
was concentrated under reduced pressure, and purified by flash
chromatography (n-hexane/ethyl acetate 2:l) to afford 7a
(0.327 g, 95% yield) as a colorless oil. [
a]
D
20 = ꢀ1.2 (c 1.2, CHCl3);
C
37H42F6NaO9S [M+Na]+ 799.2351, found 799.2352.
lit.11a
[a]
19.1 = ꢀ3.38 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) d
D
3.46–3.39 (m, 1H), 3.00–2.95 (m, 1H), 2.83 (dd, J = 4.9, 4.1 Hz,
1H), 2.71 (dd, J = 4.9, 2.8 Hz, 1H), 2.12–2.09 (m, 1H), 1.63–1.57
(m, 2H), 1.48–1.28(m, 10H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 71.7, 55.5, 45.0, 34.2, 31.7, 29.5, 29.1, 25.2,
22.5, 13.9; HRMS (ESI): calcd for C10H21O2 [M+H]+ 173.1542,
found 173.1538.
4.2.9. (2R,3S)-1-Tosyloxy-2,3-decanediol 6c
Following a similar procedure described for 6a, the ring-open-
ing reaction of 5c (3.91 g, 12 mmol) with 70% HClO4 solution
(0.25 mL) gave 6c (3.26 g, 79% yield, 96% ee, determined by 1H
NMR analysis of the ester 6c0 derived from (R)-(ꢀ)-MTPACl) as a
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

6
J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2.14. (2S,3S)-1,2-Epoxy-3-decanol 7b
Following a similar procedure described for 7a, the reaction
between 6b (0.69 g, 2 mmol) and K2CO3 (0.55 g, 4 mmol) afforded
amine complex (0.61 g, 6.6 mmol) gave 8c (0.27 g, 84% yield) as a
white solid. Mp 88.5–90.5 °C; [
20 = +1.2 (c 1.1, CHCl3); 1H NMR
a]
D
(300 MHz, CDCl3) d 3.74–3.70 (m, 2H), 2.51–2.45 (m, 2H), 2.40
(d, J = 4.3 Hz, 1H), 2.07 (t, J = 2.7 Hz, 1H), 2.00 (d, J = 4.3 Hz, 1H),
1.52–1.28 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 81.1, 73.4. 72.4, 70.8, 32.0, 31.8, 29.5, 29.2, 25.8, 22.6,
21.7, 14.00; HRMS (ESI) calcd for C12H23O2 [M+H]+ 199.1698, found
199.1696.
7b (0.33 g, 96% yield) as a colorless oil. [
a]
20 = +2.0 (c 1.4, CHCl3),
D
lit.28 D = +1.7 (c 1.2); 1H NMR (300 MHz, CDCl3) d 3.46–3.38
[a]
(m, 1H), 3.00–2.96 (m, 1H), 2.82 (dd, J = 4.9, 4.1 Hz, 1H), 2.71 (dd,
J = 4.9, 2.8 Hz, 1H), 2.19 (d, J = 5.8 Hz 1H), 1.64–1.57 (m, 2H),
1.48–1.26 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 71.7, 55.5, 45.0, 34.1, 31.6, 29.4, 29.0, 25.2, 22.4, 13.8;
HRMS (ESI) calcd for C10H21O2 [M+H]+ 173.1542, found 173.1535.
4.2.20. (4S,5R)-1-Dodecyne-4,5-diol 8d
Following a similar procedure described for 8a, the reaction
between 7d (0.31 g, 1.8 mmol) and lithiumacetylide–ethylenedi-
amine complex (0.66 g, 7.2 mmol) provided 8d (0.30 g, 84% yield)
4.2.15. (2R,3S)-1,2-Epoxy-3-decanol 7c
Following a similar procedure described for 7a, the reaction
between 6c (0.69 g, 2 mmol) and K2CO3 (0.55 g, 4 mmol) gave 7c
as a white solid. Mp 88.0–90.0 °C; [
a]
20 = ꢀ1.5 (c 1.1, CHCl3); 1H
D
(0.30 g, 87% yield) as a colorless oil. [
a
]
D
20 = +17.8 (c 1.3, CHCl3);
NMR (300 MHz, CDCl3) d 3.74–3.70 (m, 2H), 2.51–2.45 (m, 2H),
2.42 (d, J = 4.1 Hz, 1H), 2.07 (t, J = 2.7 Hz, 1H), 2.03 (d, J = 3.9 Hz,
1H), 1.51–1.28 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 81.1, 73.4, 72.4, 70.8, 32.0, 31.8, 29.5, 29.2
25.8, 22.6, 21.7, 14.0; HRMS (ESI) calcd for C12H23O2 [M+H]+
199.1698, found 199.1699.
1H NMR (300 MHz, CDCl3) d 3.84–3.78 (m, 1H), 3.03–2.99 (m,
1H), 2.82–2.80 (m, 1H), 2.73 (dd, J = 5.1, 4.0 Hz, 1H), 2.07 (d,
J = 2.2 Hz, 1H), 1.62–1.28 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 68.5, 54.5, 43.4, 33.5, 31.7, 29.6, 29.1,
25.2, 22.6, 14.0; HRMS (ESI) calcd for C10H21O2 [M+H]+ 173.1542,
found 173.1534.
4.2.21. (3R,9R,10R)-Panaxytriol 2a
4.2.16. (2S,3R)-1,2-Epoxy-3-decanol 7d
To a stirred solution of CuCl (4.0 mg, 0.04 mmol), n-BuNH2
Following a similar procedure described for 7a, the reaction
between 6d (0.69 g, 2 mmol) and K2CO3 (0.55 g, 4 mmol) afforded
(55 lL) and H2O (125 lL) in methanol (0.7 mL) and CH2Cl2
(0.6 mL), were added a few crystals of NH2OHꢂHCl to discharge
the blue color. Vicinal alcohol 8a (40 mg, 0.2 mmol) was then
added and stirred for 5 min. Next, bromoalkyne 9a (48 mg,
0.3 mmol) in CH2Cl2 (0.3 mL) was slowly added at 0 °C. After stir-
ring for 30 min, the reaction was quenched with water (5 mL).
The aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic phases were dried over Na2SO4, and concen-
trated under reduced pressure. The crude product was purified
by silica gel chromatography (n-hexane/ethyl acetate 2:1) to give
7d (0.31 g, 90% yield) as a colorless oil. [
a]
D
20 = ꢀ18.5 (c 1.4, CHCl3),
lit.29
[
a]
20 = ꢀ15.3 (c 1.42, CH2Cl2); 1H NMR (300 MHz, CDCl3) d
D
3.84–3.79 (m, 1H), 3.03–3.00 (m, 1H), 2.81 (dd, J = 5.1, 2.9 Hz,
1H), 2.73 (dd, J = 5.0, 4.0 Hz, 1H), 1.99 (d, J = 2.5 Hz, 1H), 1.62–
1.28 (m, 12H, 4-H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 68.5, 54.5, 43.4, 33.5, 31.8, 29.6, 29.2, 25.3, 22.6, 14.0;
HRMS (ESI) calcd for C10H21O2 [M+H]+ 173.1542, found 173.1536.
4.2.17. (4R,5R)-1-Dodecyne-4,5-diol 8a
2a (48.4 mg, 87% yield) as a white solid. Mp 85.5–87.5 °C;
To a cooled solution of lithiumacetylide–ethylenediamine com-
plex (0.70 g, 7.6 mmol) in THF (20 mL), were added HMPA (0.5 mL,
2.9 mmol) and 7a (0.33 g, 1.9 mmol) sequentially at 0 °C. The
resulting mixture was stirred for 24 h at the same temperature,
and quenched with saturated NH4Cl (15 mL). The aqueous layer
was extracted with diethyl ether (3 ꢁ 20 mL). The combined
organic phases were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography (n-hexane/ethyl acetate 3:1)
to give compound 8a (0.3 g, 80% yield) as a white solid. Mp 54.5–
[a]
20 = ꢀ18.1 (c 1.1, CHCl3), lit.8
[a
]
D = ꢀ19.0 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3) d 5.95 (ddd, J = 17.0, 10.1, 5.4 Hz, 1H),
5.50–5.44 (m, 1H,=CH2), 5.28–5.24 (m, 1H), 4.93–4.92 (m, 1H),
3.67–3.59 (m, 2H), 2.60–2.58 (m, 2H), 2.32 (d, J = 5.8 Hz, 1H),
1.97 (d, J = 5.6 Hz, 1H), 1.92 (d, J = 6.8 Hz, 1H), 1.52–1.28 (m,
12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 136.1,
117.1, 78.2, 74.9, 73.1, 72.2, 70.9, 66.4, 63.4, 33.5, 31.8, 29.5,
29.2, 25.6, 24.9, 22.6, 14.0; HRMS (ESI) calcd for C17H26NaO3 [M
+Na]+ 301.1780, found 301.1772.
56.5 °C; [
a]
20 = +10.7 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d
4.2.22. (3R,9S,10S)-Panaxytriol 2b
D
3.63–3.62 (m, 2H), 2.50–2.46 (m, 3H), 2.16 (d, J = 5.0 Hz, 1H),
2.07 (t, J = 2.7 Hz, 1H), 1.53–1.29 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 80.7, 73.0, 72.1, 70.6, 33.4, 31.7, 29.5,
29.2, 25.6, 23.9, 22.6, 14.0; HRMS (ESI) calcd for C12H23O2 [M+H]+
199.1698, found 199.1698.
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8b (40 mg, 0.2 mmol) with 9a (48 mg,
0.3 mmol) furnished 2b (47 mg, 85% yield) as a white solid. Mp
70.0–72.0 °C; [
a
]
20 = ꢀ43.9 (c 1.1, CHCl3), lit.10a
[
a
]
D = ꢀ49.2 (c
D
0.90, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.95 (ddd, J = 17.0,
10.1, 5.3 Hz, 1H), 5.50–5.44 (m, 1H), 5.28–5.24 (m, 1H), 4.94–
4.90 (m, 1H), 3.67–3.58 (m, 2H), 2.60–2.58 (m, 2H), 2.46 (d,
J = 5.7 Hz, 1H), 2.15 (d, J = 6.5 Hz, 1H), 2.08 (d, J = 5.5 Hz, 1H),
1.52–1.29 (m, 12H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 136.1, 117.1, 78.2, 74.9, 73.1, 72.2, 70.9, 66.5, 63.4, 33.5,
31.8, 29.5, 29.2, 25.6, 24.9, 22.6, 14.1; HRMS (ESI) calcd for
4.2.18. (4S,5S)-1-Dodecyne-4,5-diol 8b
Following a similar procedure described for 8a, the reaction
between 7b (0.33 g, 1.9 mmol) and lithiumacetylide–ethylenedi-
amine complex (0.72 g, 7.8 mmol) afforded 8b (0.30 g, 79% yield)
as a white solid. Mp 54.0–56.0 °C; [
a
]
20 = ꢀ11.9 (c 1.1, CHCl3); 1H
D
NMR (300 MHz, CDCl3) d 3.63–3.62 (m, 2H), 2.58 (d, J = 5.0 Hz,
1H), 2.49–2.46 (m, 2H), 2.29 (d, J = 4.5 Hz, 1H), 2.07 (t, J = 2.5 Hz,
1H), 1.52–1.28 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 80.7, 73.0, 72.1, 70.7, 33.4, 31.7, 29.5, 29.2,
25.6, 23.9, 22.6, 14.0; HRMS (ESI) calcd for C12H23O2 [M+H]+
199.1698, found 199.1697.
C
17H26NaO3 [M+Na]+ 301.1780, found 301.1779.
4.2.23. (3R,9R,10S)-Panaxytriol 2c
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8c (40 mg, 0.2 mmol) with 9a (48 mg,
0.3 mmol) gave 2c (47.8 mg, 86% yield) as a white solid. Mp
73.0–75.0 °C; [
a
]
20 = ꢀ31.6 (c 1.1, CHCl3); 1H NMR (300 MHz,
D
4.2.19. (4R,5S)-1-Dodecyne-4,5-diol 8c
Following a similar procedure described for 8a, the reaction
between 7c (0.28 g, 1.63 mmol) and lithiumacetylide–ethylenedi-
CDCl3) d 5.95 (ddd, J = 17.0, 10.1, 5.4 Hz, 1H), 5.51–5.44 (m, 1H),
5.28–5.24 (m, 1H), 4.94–4.91 (m, 1H), 3.78–3.73 (m, 2H),
2.61–2.56 (m, 2H), 2.27 (d, J = 4.6 Hz, 1H), 1.96 (d, J = 6.6 Hz, 1H),
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
1.90 (d, J = 4.3 Hz, 1H), 1.51–1.29 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 136.1, 117.1, 78.7, 74.8, 73.6, 72.5, 70.9,
66.5, 63.4, 32.0, 31.8, 29.6, 29.2, 25.8, 22.8, 22.6, 14.1; HRMS (ESI)
calcd for C17H26NaO3 [M+Na]+ 301.1780, found 301.1777.
2.58–2.56 (m, 2H), 2.33 (d, J = 4.5 Hz, 1H), 2.04 (d, J = 6.5 Hz, 1H),
1.95 (d, J = 4.0 Hz, 1H), 1.50–1.29 (m, 12H), 0.88 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 136.1, 117.1, 78.7, 74.8, 73.5,
72.5, 70.9, 66.5, 63.4, 32.0, 31.8, 29.5, 29.2, 25.8, 22.8, 22.6, 14.1;
HRMS (ESI) calcd for
301.1778.
C
17H26NaO3 [M+Na]+ 301.1780, found
4.2.24. (3R,9S,10R)-Panaxytriol 2d
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8d (40 mg, 0.2 mmol) with 9a (48 mg,
0.3 mmol) generated 2d (46.7 mg, 84% yield) as a white solid. Mp
4.3. In vitro cytotoxicity evaluations
77.0–79.0 °C; [
a
]
D
20 = ꢀ28.6 (c 0.8, CHCl3); 1H NMR (300 MHz,
The HCT-116 (human colon cancer), NCI-H1650 (human lung
cancer) and A2780 (human ovarian cancer) cell lines were obtained
from Cell Culture Center at the Institute of Basic Medical Sciences,
Chinese Academy of Medical Sciences or American Type Culture
Collection (ATCC, Manassas, VA). These cells suspension in DMEM
(Dulbecco’s modified Eagle medium) containing 10% fetal bovine
CDCl3) d 5.95 (ddd, J = 17.0, 10.1, 5.4 Hz, 1H), 5.51–5.44 (m, 1H),
5.28–5.24 (m, 1H), 4.95–4.91 (m, 1H), 3.78–3.71 (m, 2H), 2.59–
2.56 (m, 2H), 2.26 (d, J = 4.6 Hz, 1H), 1.94 (d, J = 6.6 Hz, 1H), 1.89
(d, J = 4.3 Hz, 1H), 1.50–1.29 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 136.1, 117.1, 78.7, 74.8, 73.5, 72.5, 70.9,
66.5, 63.4, 32.0, 31.8, 29.5, 29.2, 25.8, 22.7, 22.6, 14.1; HRMS
(ESI) calcd for C17H26NaO3 [M+Na]+ 301.1780, found 301.1779.
serum (FBS), streptomycin (100 lg/mL) and penicillin (100 U/mL)
were seeded at 2.0 ꢁ 103/well into 96-well plate and incubated
for 24 h at 37 °C in a 5% CO2 humidified air. The cells were then
treated with different concentrations of tested compounds for
4.2.25. (3S,9R,10R)-Panaxytriol 2e
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8a (40 mg, 0.2 mmol) with 9b (48 mg,
0.3 mmol) gave 2e (48.3 mg, 87% yield) as a white solid. Mp
96 h. MTT (5 mg/mL, 20 lL) solution was added to each cell and
incubated for another 4 h at 37 °C to form formazan crystals. After
the supernatants were removed, dimethyl sulfoxide (DMSO) was
added to dissolve the formazan crystals. The plates were read at
570 nm on a microplate reader (Biotek Instruments, Inc. USA).
Taxol was used as positive control for all tests, and IC50 value is
the drug concentration for which vitality is 50%.
69.0–71.0 °C; [a]
20 = +50.0 (c 0.7, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 5.95 (ddd, J = 17.0, 10.1, 5.4 Hz, 1H), 5.51–5.44 (m, 1H),
5.28–5.24 (m, 1H), 4.95–4.91 (m, 1H), 3.67–3.58 (m, 2H), 2.60–
2.58 (m, 2H), 2.32 (d, J = 5.7 Hz, 1H), 1.96 (d, J = 5.6 Hz, 1H), 1.92
(d, J = 6.6 Hz, 1H), 1.57–1.29 (m, 12H), 0.89 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 136.0, 117.1, 78.2, 74.8, 73.1, 72.1, 70.9,
66.5, 63.4, 33.5, 31.8, 29.5, 29.2, 25.6, 24.9, 22.6, 14.1; HRMS
(ESI) calcd for C17H26NaO3 [M+Na]+ 301.1780, found 301.1773.
Acknowledgments
We thank the National Key Technology Research and Develop-
ment Program (No. 2015BAK45B01) and New Century Excellent
Talents in University (NCET-12-0528) for the financial support.
We also appreciate Prof. Mingan Wang for helpful discussion con-
cerning NMR.
4.2.26. (3S,9S,10S)-Panaxytriol 2f
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8b (40 mg, 0.2 mmol) with 9b (48 mg,
0.3 mmol) furnished 2f (46.1 mg, 83% yield) as a white solid. Mp
86.0–88.0 °C; [a] [a]D = +18.7 (c
20 = +19.1 (c 0.7, CHCl3), lit.15a
D
Supplementary data
0.21, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.95 (ddd, J = 17.0,
10.1, 5.3 Hz 1H), 5.50–5.44 (m, 1H), 5.28–5.24 (m, 1H), 4.94–4.90
(m, 1H), 3.67–3.58 (m, 2H), 2.60–2.58 (m, 2H), 2.34 (d, J = 5.7 Hz,
1H), 1.98 (d, J = 1.8 Hz, 1H), 1.96 (d, J = 3.0 Hz, 1H), 1.52–1.29 (m,
12H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 136.1,
117.1, 78.2, 74.8, 73.1, 72.1, 70.9, 66.5, 63.5, 33.6, 32.0, 29.5,
29.2, 25.6, 25.0, 22.6, 14.1; HRMS (ESI) calcd for C17H26NaO3 [M
+Na]+ 301.1780, found 301.1775.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.03.
005.
References
1. (a) Steve, H. Altern. Med. Rev. 2004, 9, 259–274; (b) Jadhav, N. R.; Powar, T.;
Shinde, S.; Nadaf, S. Asian J. Pharm. 2014, 8, 58–69; (c) Smith, A. R.; Andreansky,
S. Med. Sci. 2014, 2, 1–22; (d) Oh, M.-R.; Park, S.-H.; Kim, S.-Y.; Back, H.-I.; Kim,
M.-G.; Jeon, J.-Y.; Ha, K.-C.; Na, W.-T.; Cha, Y.-S.; Park, B.-H.; Park, T.-S.; Chae, S.-
W. BMC Complement. Altern. Med. 2015, 14, 231–237.
2. (a) Hirakura, K.; Morita, M.; Nakajima, K.; Ikeya, Y.; Mitsuhashi, H.
Phytochemistry 1991, 30, 3327–3333; (b) Kobayashi, M.; Mahmud, T.;
Umezome, T.; Wang, W.; Murakami, N.; Kitagawa, I. Tetrahedron 1997, 53,
15691–15700; (c) Xu, G.-H.; Choo, S.-J.; Ryoo, I.-J.; Kim, Y.-H.; Paek, K.-Y.; Yoo,
I.-D. Nat. Prod. Sci. 2008, 14, 177–181.
3. Matsunaga, H.; Katano, M.; Saita, T.; Yamamoto, H.; Mori, M. Cancer Chem.
Pharm. 1994, 33, 291–297.
4. Matsunaga, H.; Katano, M.; Yamamoto, H.; Mori, M.; Takata, K. Chem. Pharm.
Bull. 1989, 37, 1279–1281.
5. Matsunaga, H.; Saita, T.; Nagumo, F.; Mori, M.; Katano, M. Cancer Chem. Pharm.
1995, 35, 291–296.
6. Kim, J. Y.; Lee, K.-W.; Kim, S.-H.; Wee, J. J.; Kim, Y.-S.; Lee, H. J. Planta Med. 2002,
68, 119–122.
4.2.27. (3S,9R,10S)-Panaxytriol 2g
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8c (40 mg, 0.2 mmol) with 9b (48 mg,
0.3 mmol) gave 2g (48.9 mg, 88% yield) as a white solid. Mp
78.0–79.5 °C; [a]
20 = +29.4 (c 0.8, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 5.94 (ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.50–5.44 (m, 1H),
5.28–5.24 (m, 1H), 4.94–4.90 (m, 1H), 3.77–3.73 (m, 2H),
2.58–2.56 (m, 2H), 2.50 (d, J = 4.5 Hz, 1H), 2.32 (d, J = 6.5 Hz, 1H),
2.10 (d, J = 3.8 Hz, 1H), 1.51–1.29 (m, 12H), 0.88 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 136.1, 117.1, 78.7, 74.8, 73.5,
72.5, 70.9, 66.5, 63.4, 32.0, 31.8, 29.5, 29.2, 25.8, 22.8, 22.6, 14.1;
HRMS (ESI) calcd for
301.1777.
C
17H26NaO3 [M+Na]+ 301.1780, found
7. Kitagawa, I.; Yoshikawa, M.; Yoshihara, M.; Hayashi, T.; Taniyama, T. Yakugaku
Zasshi 1983, 103, 612–622.
8. Kobayashi, M.; Mahmud, T.; Umezome, T.; Kitagawa, I. Chem. Pharm. Bull. 1995,
43, 1595–1597.
9. Lu, W.; Zheng, G. R.; Cai, J. C. Synlett 1998, 737–738.
10. (a) Lu, W.; Zheng, G.; Gao, D.; Cai, J. Tetrahedron 1999, 55, 7157–7168; (b)
Yadav, J. S.; Maiti, A. Tetrahedron 2002, 58, 4955–4961.
11. (a) Yun, H.; Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519–4522; (b) Yun, H.;
Chou, T.-C.; Dong, H.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Org. Chem. 2005, 70,
10375–10380.
4.2.28. (3S,9S,10R)-Panaxytriol 2h
Following a similar procedure described for 2a, the Cadiot–
Chodkiewicz coupling of 8d (40 mg, 0.2 mmol) with 9b (48 mg,
0.3 mmol) generated 2h (45.6 mg, 82% yield) as a white solid. Mp
73.5–75.5 °C; [a]
20 = +29.0 (c 0.8, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 5.95 (ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.51–5.44 (m, 1H),
5.28–5.24 (m, 1H), 4.94–4.91 (m, 1H), 3.78–3.73 (m, 2H),
12. Trost, B. M.; Chan, V. S.; Yamamoto, D. J. Am. Chem. Soc. 2010, 132, 5186–5192.
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005

8
J. Mao et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
13. Mayer, S. F.; Steinreiber, A.; Orru, R. V. A.; Faber, K. J. Org. Chem. 2002,
67, 9115–9121.
21. Kang, S. K.; Kim, Y. S.; Lim, J. S.; Kim, K. S.; Kim, S. G. Tetrahedron Lett. 1991, 32,
363–366.
14. Prasad, K. R.; Swain, B. Tetrahedron: Asymmetry 2011, 22, 1261–1265.
15. (a) Gurjar, M. K.; Kumar, V. S.; Rao, B. V. Tetrahedron 1999, 55, 12563–12576;
(b) Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257–259; (c) Yu, H.-J.; Sun, C.-M.; Chen,
C.-C.; Wu, T.-C.; Wei, C.-L.; Shen, C.-C. Heterocycles 2004, 62, 857–868.
16. Mao, J.; Li, S.; Zhong, J.; Wang, B.; Jin, J.; Gao, Z.; Yang, H.; Bian, Q. Tetrahedron:
Asymmetry 2016, 27, 69–77.
17. Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143–4146.
18. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
22. Danishefsky, S.; Tsai, M.-Y.; Kitahara, T. J. Org. Chem. 1977, 42, 394–396.
23. (a) Chodkiewicz, W.; Cadiot, P. Compt. Rend. 1955, 241, 1055–1057; (b) Fang, Z.;
Wills, M. Org. Lett. 2014, 16, 374–377.
24. Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.
25. (a) Bai, Z.-G.; Qu, X.; Han, W.; Ma, X.-M.; Zhao, X.-M.; Zhang, Z.-T. Mol. Med.
Rep. 2010, 3, 1071–1078; (b) Kim, R.-K.; Uddin, N.; Hyun, J.-W.; Kim, C.; Suh, Y.;
Lee, S.-J. Toxicol. Appl. Pharmacol. 2015, 286, 143–150.
26. Gansaeuer, A.; Fan, C.-A.; Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129, 3484–3485.
27. Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J. Org. Chem. 1995, 60, 4803–4812.
28. Soulie, J.; Boyer, T.; Lallemand, J. Y. Tetrahedron: Asymmetry 1995, 6, 625–636.
29. Behrens, C. H.; Ko, S. Y.; Sharpless, K. B.; Walker, F. J. J. Org. Chem. 1985, 50,
5687–5696.
19. Hanson, R. M. Tetrahedron Lett. 1984, 25, 3783–3786.
20. Goto, T.; Urabe, D.; Masuda, K.; Isobe, Y.; Arita, M.; Inoue, M. J. Org. Chem. 2015,
80, 7713–7726.
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.005