Total synthesis of panaxydol and its stereoisomers as potential anticancer agents

Article abstract of DOI:10.1016/j.tetasy.2015.12.001

An efficient total synthesis of natural panaxydol 1a and its seven stereoisomers 1b-h was accomplished; four diastereomers of the natural form were prepared for the first time. Our strategy involves the Cadiot-Chodkiewicz cross-coupling reaction of chiral terminal alkynes with bromoalkynes, the asymmetric alkynylation of aldehydes, and the enantioselective Sharpless epoxidation of allylic alcohols. Preliminary in vitro cytotoxicity evaluation indicated that some synthetic panaxydols possess anticancer activities, and (3S,9R,10S)-panaxydol 1e showed a particularly promising cytotoxic effect.

Full text of DOI:10.1016/j.tetasy.2015.12.001

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of panaxydol and its stereoisomers as potential
anticancer agents
Jianyou Mao a, Shuoning Li a, Jiangchun Zhong a, Bo Wang a, Jing Jin b, 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 total synthesis of natural panaxydol 1a and its seven stereoisomers 1b–h was accomplished;
four diastereomers of the natural form were prepared for the first time. Our strategy involves the
Cadiot-Chodkiewicz cross-coupling reaction of chiral terminal alkynes with bromoalkynes, the asymmet-
ric alkynylation of aldehydes, and the enantioselective Sharpless epoxidation of allylic alcohols.
Preliminary in vitro cytotoxicity evaluation indicated that some synthetic panaxydols possess anticancer
activities, and (3S,9R,10S)-panaxydol 1e showed a particularly promising cytotoxic effect.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 26 October 2015
Accepted 1 December 2015
Available online xxxx
1. Introduction
synthetic strategies to 1a include derivation from a chiral tem-
plate8,9 and Sharpless asymmetric dihydroxylation.10
As one of the most important traditional Asian medicines, red
ginseng, the root of Panax ginseng C. A. Meyer, is commonly used
for the treatment of cardiovascular disease, diabetes, and various
cancers.1 Panaxydol 1a (Fig. 1) is an important chiral polyacetylenic
alcohol isolated from red ginseng,2 which has been proven to pos-
sess significant antitumor activities.3–5 For instance, panaxydol
showed cytotoxicity against various cancer cells, such as human
breast cancer (MCF-7)4 and human melanoma (SK-MEL-1).5
Considering the important bioactivity of natural panaxydol and
the potential antitumor activities of its stereoisomers, we decided
to search for more efficient and convenient asymmetric synthetic
strategies. The enantioselective alkynylation of aldehydes is the
most convenient protocol to obtain chiral propargyl alcohols.11,12
However to the best of our knowledge, there are no reports which
synthesize these polyacetylenic alcohols using this asymmetric
catalytic methodology. Herein, we report an efficient total
synthesis of natural panaxydol and its seven stereoisomers via
enantioselective alkynylation of aldehydes; four diastereomers of
the natural form were prepared for the first time. Furthermore,
their preliminary antitumor activity was also investigated.
OH
O
2. Results and discussion
(3R,9R,10S)-panaxydol 1a
Our retrosynthetic analysis of (3R,9R,10R)-panaxydol 1a is out-
lined in Figure 2. The chiral polyacetylenic alcohol 1a could be
formed by the Cadiot-Chodkiewicz coupling reaction of terminal
alkyne 13a with bromoalkyne 7a. We envisaged that the chiral
propargyl alcohol moiety of fragment 7a could be introduced via
the enantioselective addition of trimethylsilylacetylene to acrolein
3. Correspondingly, the Sharpless asymmetric epoxidation of 10a
was expected to give chiral epoxy alcohol 11a, whose triflate was
envisioned to generate the key intermediate 13a.
Figure 1. The structure of natural Panaxydol 1a.
Since the isolation of panaxydol 1a from red ginseng and the
confirmation of its structure and absolute configuration,6,7 its total
synthesis has attracted much attention and interest from chemists.
In 1998, Cai et al. achieved the first total synthesis of (3R,9R,10R)-
panaxydol 1a from chiral (+)-diethyl tartrate.8 To date, the main
Our study began with the preparation of chiral bromoalkynes 7
(Scheme 1). The enantioselective addition reaction of alkynylzinc
⇑
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.2015.12.001
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001

2
J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
bromoalkyne 7a in 94% yield.15 A similar procedure for the synthe-
OH
sis of 7b was developed from the enantioselective alkynylation of
acrolein 3 with (R)-BINOL/Ti(OiPr)4 catalyst.
O
Next, the key intermediate allylic alcohols 10a and 10b were pre-
pared (Scheme 2). The alkylation of commercially available propar-
gyl alcohol 8 with 1-bromoheptane gave dec-2-yn-1-ol 9 in 95%
yield.16 Propargyl alcohol 9 was hydrogenated with Lindlar catalyst
to form (Z)-dec-2-en-1-ol 10a in 92% yield.17 By contrast, reduction
of 9 with LiAlH4 afforded (E)-2-decen-1-ol 10b in 85% yield.18
1a
(3R,9R,10S)-panaxydol
Cadiot-ChodkIewicz
coupling
OH
O
6
Br
7a
13a
n-BuLi, THF, HMPA
HO
HO
asymmetric
alkynylation
alkylation
CH3(CH2)6Br
-78 oC to rt
desilylation
8
9
, 95%
O
H2, Lindlar catalyst
EtOH, Py, rt
CHO
HO
TMS
HO
6
TMS
11a
3
10a , 92%
10b, 85%
Sharpless asymmetric
epoxidation
LiAlH4, THF, reflux
HO
HO
10a
Scheme 2. Synthesis of allylic alcohols 10a and 10b.
Figure 2. Retrosynthetic analysis of (3R,9R,10S)-panaxydol 1a.
As with allylic alcohols 10a and 10b, the preparation of chiral
epoxy alkynes 13a–d was studied (Scheme 3). Sharpless asymmet-
ric epoxidation with (ꢀ)-diisopropyl tartrate and Ti(OiPr)4 con-
verted cis-allylic alcohol 10a into (2R,3S)-2,3-epoxy-1-decanol
11a in 85% yield.19a Recrystallization of 11a from petroleum ether
improved the ee to over 99%, which was determined by 1H NMR
analysis of Mosher ester 11a0 derived from 11a and (R)-(ꢀ)-
MTPACl. Analysis of the terminal methylene proton region of
Mosher ester 11a0 indicated that there was no diastereomeric (S)-
MTPA ester of 11b (Fig. 3).19b The comparison with reported
specific rotation value and the governing precedents in the
Sharpless asymmetric epoxidation of allylic alcohols 10a19a both
supported the (2R,3S)-configuration of 11a. Similarly, optically
active epoxy alcohol (2S,3R)-11b was obtained when (+)-diethyl
tartrate was used. On the other hand, chiral epoxy alcohols
(2R,3R)-11c and (2S,3S)-11d were synthesized from the
enantioselective epoxidation of trans-allylic alcohol 10b with
(ꢀ)-diisopropyl tartrate/Ti(OiPr)4 and (+)-diethyl tartrate/Ti(OiPr)4
catalyst via a similar protocol, respectively.19c According to 1H
NMR analysis of the terminal methylene proton region of Mosher
esters 11c0,d0 derived from 11c,d and (R)-(ꢀ)-MTPACl, the ee
values for 11c and 11d were over 99%, within the detection
limit of 1H NMR (Fig. 4). We found that the alkylation
of (trimethylsilylethynyl)lithium with the corresponding
triflate generated from the treatment of 11a with
trifluoromethanesulfonic anhydride, furnished (4R,5S)-12a in 73%
yield over two steps.20 Finally, 12a was converted into 13a after
desilylation with potassium carbonate in methanol.10 Having
obtained terminal alkyne 13a, we prepared its enantiomer 13b
and diastereomeric isomers 13c and 13d by repeating the same
procedures.
O
3
(S)-BINOL
TMS
(R)-BINOL
Et2Zn, toluene
Ti(Oi-Pr)4, 25 o
C
OH
OH
(
S
)
(
)
R
TMS
4b
4a
TMS
80%, 91% ee
79%, 91% ee
3, 5-dinitrobenzoyl chloride
Et3N, DCM, 0-25 oC
OAr
OAr
Ar = 3,5-dinitrobenzoyl
(S)
(R)
R
R
5b
: R = TMS, 90%
5a: R = TMS, 92%
recryst. 73%, > 99% ee
AgNO3, NBS
acetone, 0-25 oC
recryst. 71%, > 99% ee
6a
: R = Br
6b: R = Br
90%, > 99% ee
87%, > 99% ee
2M NaOH
THF, 25 o
C
OH
OH
(
)
R
( )
S
Br
7b
Br
, 92%
7a, 94%
Scheme 1. Enantioselective synthesis of bromoalkynes 7a and 7b.
reagent, which was prepared in situ from trimethylsilylacetylene
and diethylzinc, to acrolein 3 catalyzed by (S)-BINOL/Ti(OiPr)4 gen-
erated (R)-5-(trimethylsilyl)pent-1-en-4-yn-3-ol 4a in 79% yield
and with 91% ee.11a The specific rotation of 4a13 and the governing
precedents in the enantioselective alkynylation of acroleins11a also
favored its absolute (R)-configuration. Our previous study14
demonstrated that recrystallization of the benzoate derived from
the chiral alcohol could improve the enantiomeric purity. 3,5-Dini-
trobenzoate 5a was prepared from alcohol 4a and recrystallized
from n-hexane–dichloromethane. The enantiomeric purity of 5a
was improved from 91% to over 99%. Subsequent in situ desilyla-
tion and bromination of alkyne 5a using NBS and AgNO3 afforded
optically active 6a in 90% yield.13 Finally, treating 6a with 2 M
sodium hydroxide in tetrahydrofuran resulted in the formation of
Having accessed chiral building blocks 7 and 13, eight panaxy-
dols 1a–h were prepared (Scheme 4). The Cadiot-Chodkiewicz
cross-coupling reaction of 7a and 13a resulted in the formation
of panaxydol 1a in 85% yield.21,22 The specific rotation measured
for 1a {[
a
]
20 = ꢀ94.8 (c 1.1, CHCl3)} was consistent with the value
D
of natural (3R,9R,10S)-panaxydol {[
a]
D = ꢀ81.8 (c 1.52, CHCl3)},7
which matched the configurations of chiral intermediates 7a and
13a. Bromoalkyne 7a and other epoxy alkynes 13b–d were merged
in Cadiot-Chodkiewicz cross-coupling reactions to afford
(3R,9S,10R)-, (3R,9R,10R)-, and (3R,9S,10S)-panaxydol 1b–d
stereoisomers. In addition, another four stereoisomers of natural
panaxydol 1e–h were also synthesized in good yields using a sim-
ilar approach from bromoalkyne 7b and epoxy alkynes 13a–d.
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J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
A.
13a
13b
Synthesis of
and
HO
O
Ph OMe
O
(R) (S)
(S)
F3C
10a
O
11a'
(-)-DIPT
(+)-DET
Ti(OiPr)4
t-BuOOH, 4Å MS
DCM, -10 oC
O
O
RO
11b
RO
(
) ( )
S R
(
) ( )
S
R
6
6
(R)-MTPACl
11a: R= H, 85%
: R= H, 87%
recryst. >99% ee
recryst. >99% ee
DMAP, Et3N
11a': R = (S)-MTPA
11b': R = (S)-MTPA
DCM, 0 o
C
TMS
TMS
O
O
(R) (S)
(1) 2,6-lutidine
DCM, Tf2O
O
Ph OMe
(
) ( )
S R
(2) TMS
n-BuLi, Et2O
6
O
6
(S) (R)
(S)
F3C
12b, 72% two steps
12a
, 73% two steps
O
11b'
K2CO3
MeOH, 0 o
C
O
O
(
S
)
( ) ( )
S R
(R)
6
6
13a
, 81%
13b
, 81%
B. Synthesis of 13c and 13d
HO
10b
(-)-DIPT
(+)-DET
Ti(OiPr)4
t-BuOOH, 4Å MS
DCM, -10 oC
O
O
(S)
(
R
)
RO
RO
6
(S)
6
(R)
Figure 3. The representative 1H NMR spectra (300 MHz, CDCl3) of Mosher esters
11a0 and 11b0.
(R)-MTPACl
11c
11d: R= H, 89%
: R= H, 90%
recryst. >99% ee
11c': R = (S)-MTPA
recryst. >99% ee
DMAP, Et3N
DCM, 0 oC
11d': R = (S)-MTPA
Ph OMe
O
TMS
(R)
TMS
(1) 2,6-lutidine
DCM, Tf2O
O
O
O
(S)
(R)
(S)
F3C
(R)
6
6
TMS
(2)
(S)
(
R
)
O
11c'
n-BuLi, Et2O
12d, 73% two steps
12c
, 74% two steps
K2CO3
MeOH, 0 oC
O
O
(
)
R
(S)
6
6
(R)
(S)
13d, 79%
13c, 78%
Scheme 3. Synthesis of epoxy alkynes 13.
The in vitro cytotoxicities of natural panaxydol and its
stereoisomers were evaluated against human colon cancer cell line
(HCT-116), human lung cancer cell line (NCI-H1650), and human
ovarian cancer cell line (A2780) using a 3-(dimethyl-thiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Table 1).23 The
results showed that the stereoisomers of natural panaxydol, except
for 1b, generally exhibited a stronger cytotoxic activity than the
natural one. It is noteworthy that (3S,9R,10S)-panaxydol 1e had a
good cytotoxic effect against HCT-116, NCI-H1650, and A2780 cells
Ph OMe
O
(S)
O
(S)
F3C
(S)
O
11d'
with IC50 values of 2.13, 4.97, and 1.92 lM, respectively, which
were close to the result with taxol, a well-known antitumor drug.24
These results show that some synthetic panaxydols are of value for
further exploration as potential anticancer agents.
3. Conclusion
In conclusion, we have conducted an efficient total synthesis of
natural panaxydol and seven of its stereoisomers. Meanwhile,
(3R,9R,10R)-, (3R,9S,10S)-, (3S,9R,10R)-, (3S,9S,10S)- panaxydol 1c,
Figure 4. The representative 1H NMR spectra (300 MHz, CDCl3) of Mosher esters
11c0 and 11d0.
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4
J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
OH
OH
OH
(
)
R
(R)
(R)
CuCl, n-BuNH2
O
7a
H2O, DCM
O
Br
6
O
NH2OH.HCl
(S) (
)
R
(R) (
)
S
6
6
(R) (S)
13a
MeOH, 0 o
C
(3R,9R,10S)-panaxydol 1a
(3R,9S,10R)-panaxydol 1b
83%, from 7a and 13b
85%
OH
OH
OH
(R)
(
)
R
(S)
O
O
O
(S)
(
)
R
(
R
)
(S)
6
6
(S)
(R)
6
(3S,9R,10S)-panaxydol 1e
81%, from 7b and 13a
(3R,9R,10R)-panaxydol 1c
82%, from 7a and 13c
(3R,9S,10S)-panaxydol 1d
7a
13d
and
86%, from
OH
OH
OH
(
S
)
(S)
(
S
)
O
O
O
(S)
(R)
(
S
)( )
R
(S)
6
6
6
( )
R
(3S,9S,10R)-panaxydol 1f
7b 13b
1g
(3S,9R,10R)-panaxydol
(3S,9S,10S)-panaxydol 1h
82%, from 7b and 13d
84%, from
and
7b 13c
85%, from
and
Scheme 4. Synthesis of panaxydols 1a–h via Cadiot-Chodkiewicz cross-coupling.
collected on an Agilent instrument using the TOF MS technique,
or a Waters LCT PremierTM with an ESI mass spectrometer.
Table 1
The in vitro cytotoxicities of natural panaxydol and their stereoisomers against three
human cancer cell linesa
4.2. Experimental procedures and spectroscopic data
Compound
IC50 (lM)
HCT-116
NCI-H1650
A2780
4.2.1. (R)-5-Trimethylsilyl-1-penten-4-yn-3-ol 4a
Natural panaxydol 1a
(3R,9S,10R)-Panaxydol 1b
(3R,9R,10R)-Panaxydol 1c
(3R,9S,10S)-Panaxydol 1d
(3S,9R,10S)-Panaxydol 1e
(3S,9S,10R)-Panaxydol 1f
(3S,9R,10R)-Panaxydol 1g
(3S,9S,10S)-Panaxydol 1h
Taxolb
>10
>10
>10
To a stirred solution of trimethylsilylethyne (3.31 mL, 24 mmol)
in toluene (12 mL), was slowly added diethylzinc (16 mL, 1.5 M in
n-hexane, 24 mmol) under a nitrogen atmosphere at room temper-
ature. The resulting mixture was refluxed for 1 h. After cooling to
room temperature, (S)-BINOL (0.68 g, 2.4 mmol), Et2O (96 mL),
and Ti(OiPr)4 (1.71 g, 6.0 mmol) were added sequentially and the
mixture was stirred for an additional 1 h. Acrolein 3 (0.4 mL,
6 mmol) was then added and the reaction solution was stirred
for 4 h at room temperature. The reaction was quenched with sat-
urated NH4Cl (20 mL), and the aqueous phase was extracted with
CH2Cl2 (3 ꢁ 40 mL). The combined organic phases were dried over
Na2SO4, and concentrated under reduced pressure. The crude pro-
duct was purified by silica gel chromatography (n-hexane/ethyl
acetate 10:1) to provide 4a (0.73 g, 79% yield, 91% ee) as a colorless
>10
>10
>10
2.13 0.42
3.58 0.03
>10
>10
0.03
>10
>10
7.2 1.30
1.94 0.30
4.97 0.24
>10 ꢁ 10ꢀ6
>10 ꢁ 10ꢀ6
>10 ꢁ 10ꢀ6
0.36
3.99 0.10
9.38 1.20
1.92 0.14
3.58 0.92
>10
>10
0.061
a
MTT assay following 96 h inhibition. HCT-116 is a human colon cancer cell line.
NCI-H1650 is human lung cancer cell line. A2780 is human ovarian cancer cell line.
b
Positive control.
1d, 1g, 1h were prepared for the first time. The key steps of our
approach include the asymmetric addition of alkynylzinc reagent
to aldehydes, the enantioselective Sharpless epoxidation of allylic
alcohols and the Cadiot-Chodkiewicz cross-coupling reactions.
Moreover, preliminary in vitro cytotoxicity evaluations indicated
that some synthetic panaxydols have potential utility in the devel-
opment of antitumor drugs.
oil. [
a]
20 = ꢀ37.6 (c 1.3, CHCl3), lit.13
[
a]
D
20 = ꢀ24.1 (c 1, CHCl3). 1H
D
NMR (300 MHz, CDCl3) d 5.97 (ddd, J = 17.0, 10.1, 5.3 Hz), 5.51–
5.45 (m, 1H), 5.26–5.22 (m, 1H), 4.90–4.86 (m, 1H), 1.92–1.89
(m, 1H), 0.19 (s, 9H); 13C NMR (75 MHz, CDCl3) d 136.7, 116.6,
104.0, 91.1, 63.5, ꢀ0.23; HRMS (APCI-TOF) calcd for C8H15OSi
[M+H]+ 155.0892, found: 155.0894. Enantiomeric excess was
determined by HPLC with a Chiralcel OJ-H column (99:1 n-hexane/
2-propanol, 0.8 mL/min, 220 nm); major (R)-enantiomer tr = 10.96
min, minor (S)-enantiomer tr = 12.91 min.
4. Experimental
4.1. General
4.2.2. (S)-5-Trimethylsilyl-1-penten-4-yn-3-ol 4b
All reactions were performed using standard Schlenk tech-
niques, and under a nitrogen atmosphere unless otherwise noted.
Solvents were dried following standard procedures and distilled
before use. Melting points were measured on a STUART-SMP3
Melt-Temp apparatus and were uncorrected. Optical rotations
were recorded on a Perkin–Elmer PE-341 polarimeter. Enan-
tiomeric excesses (ee) were determined on an Agilent 1100 HPLC
system with a chiral column (Chiralcel OJ-H, Chiralcel OD-H or Chi-
ralpak AD-H column), and 2-propanol–n-hexane was the eluent. 1H
and 13C NMR spectra were obtained on a Bruker DP-X300 spec-
trometer. Chemical shifts are reported in ppm, and tetramethylsi-
lane (TMS) served as an internal standard for 1H NMR and
13C NMR. High resolution mass spectrometry (HRMS) data were
Similar asymmetric alkynylation as described for 4a from
trimethylsilylethyne (3.31 mL, 24 mmol), diethylzinc (16 mL,
1.5 M in n-hexane, 24 mmol), and acrolein 3 (0.4 mL, 6 mmol), cat-
alyzed by (R)-BINOL (0.68 g, 2.3 mmol) and Ti(OiPr)4 (1.71 g,
6.0 mmol) afforded 4b (0.74 g, 80% yield, 91% ee) as a colorless
oil. [a]
20 = +36.2 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.97
D
(ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.50–5.44 (m, 1H), 5.25–5.21 (m,
1H), 4.88–4.86 (m, 1H) 2.12–2.10 (m, 1H), 0.19 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 136.7, 116.5, 104.1, 91.1, 63.5, ꢀ0.24; HRMS
(APCI-TOF) calcd for C8H15OSi [M+H]+ 155.0892, found: 155.0896.
Enantiomeric excess was determined by HPLC with a Chiralcel
OJ-H column (99:1 n- hexane/2-propanol, 0.8 mL/min, 220 nm);
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J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
minor (R)-enantiomer tr = 10.94 min, major (S)-enantiomer
tr = 12.51 min.
AgNO3 (0.57 g, 3.4 mmol) to afford 6b (5.24 g, 87% yield, >99% ee)
as a white solid. Mp 90.0–90.5 °C; [
20 = +47.4 (c 1.2, CHCl3); 1H
a]
D
NMR (300 MHz, CDCl3) d 9.26–9.19 (m, 3H), 6.20–6.18 (m, 1H),
6.05 (ddd, J = 16.8, 10.0, 6.0 Hz, 1H), 5.71 (d, J = 16.9 Hz, 1H), 5.51
(d, J = 10.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 161.3, 148.8,
133.3, 131.3, 129.7, 122.7, 121.2, 74.4, 67.6, 50.0; HRMS (APCI-
TOF) calcd for C12H7BrN2O6 [M]– 353.9487, found: 353.9491. Enan-
tiomeric excess was determined by HPLC with a Chiralpak AD-H
column (98:2 n-hexane/2-propanol, 1.0 mL/min, 254 nm); major
(S)-enantiomer tr = 14.39 min.
4.2.3. (R)-5-Trimethylsilyl-1-penten-4-yn-3-yl 3,5-dinitrobenzo-
ate 5a
To a stirred solution of 4a (2.07 g, 13.5 mmol), triethylamine
(2.8 mL, 20 mmol) in CH2Cl2 (40 mL) was added 3,5-dinitrobenzoyl
chloride (3.73 g, 16 mmol) at 0 °C under nitrogen atmosphere. The
resulting mixture was stirred for 30 min at room temperature and
the reaction was quenched with water (15 mL). The aqueous layer
was extracted with CH2Cl2 (3 ꢁ 30 mL) and the combined organic
layers were dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(n-hexane/diethyl ether 5:1) to furnish 5a (4.32 g, 92% yield) as a
white solid. Slow recrystallization of 5a from n-hexane–dichloro-
methane (15:1, 80 mL) improved the enantiomeric purity to over
99% ee, and gave enantiomerically pure 5a (3.15 g, 73% yield) as
4.2.7. (R)-5-Bromo-1-penten-4-yn-3-ol 7a
To a stirred solution of 6a (1.770 g, 5 mmol) in THF (20 mL) was
added 2 M NaOH (12.5 mL, 25 mmol). The reaction mixture was
stirred for 2 h at room temperature and then diluted with Et2O
(15 mL). The aqueous phase was extracted with Et2O (3 ꢁ 20 mL).
The combined organic phases were dried over NaSO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel chromatography (n-hexane/ethyl acetate 10:1) to furnish 7a
colorless crystals. Mp 99.0–100.0 °C; [
a
]
20 = ꢀ49.6 (c 1.1, CHCl3);
D
1H NMR (300 MHz, CDCl3)
d
9.25–9.20 (m, 3H), 6.20 (d,
J = 5.9 Hz), 6.04 (ddd, J = 16.8, 10.0, 5.9 Hz), 5.71 (d, J = 16.9 Hz,
1H), 5.48 (d, J = 10.0 Hz, 1H), 0.22 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 161.3, 148.7, 133.6, 131. 8, 129.6, 122.6, 120.7, 98.5, 94.3, 67.3,
ꢀ0.4; HRMS (ESI) calcd for C15H17N2O6Si [M+H]+ 349.0856, found:
349.0845. Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (95:5 n-hexane/2-propanol, 1.0 mL/min,
254 nm); major (R)-enantiomer tr = 6.55 min.
(0.76 g, 94% yield) as a colorless oil. [
a
]
20 = ꢀ41.8 (c 1.4, CHCl3),
D
lit.13
[
a]
D
20 = ꢀ31.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CHCl3) d
5.95 (ddd, J = 17.0, 10.2, 5.4 Hz, 1H), 5.50–5.44 (m, 1H), 5.28–5.24
(m, 1H), 4.92–4.88 (m, 1H), 2.18–2.16 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 136.2, 116.9, 78.8, 63.9, 46.8; HRMS (APCI-
TOF) calcd for C5H4BrO [MꢀH]+ 158.9446, found: 158.9439.
4.2.8. (S)-5-Bromo-1-penten-4-yn-3-ol 7b
4.2.4. (S)-5-Trimethylsilyl-1-penten-4-yn-3-yl 3,5-dinitrobenzo-
ate 5b
A similar procedure as described for 7a was accomplished from
6b (3.97 g, 11.2 mmol) and 2 M NaOH (22.4 mL) to give 7b (1.65 g,
A similar procedure as described for 5a was accomplished from
3,5-dinitrobenzoyl chloride (3.92 g, 17.0 mmol) and 4b (2.18 g,
14.2 mmol) to give 5b (4.46 g, 90% yield) as a white solid. Slow
recrystallization of 5b from n-hexane–dichloromethane (10:1,
85 mL) improved the enantiomeric purity to over 99% ee, and gave
enantiomerically pure 5b (3.17 g, 71% yield) as colorless crystals.
92% yield) as a colorless oil. [
[a]
D
a]
20 = +36.0 (c 1.3, CHCl3), lit.25
D
20 = 38.0 (c 1.9, CHCl3); 1H NMR (300 MHz, 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),
4.93–4.88 (m, 1H), 1.98 (d, 6.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 136.2, 117.0, 78.8, 64.0, 46.9; HRMS (APCI-TOF) calcd for C5H4BrO
[M-H]+ 158.9446, found: 158.9448.
Mp 99.5–100.5 °C; [a]
20 = +49.4 (c 1.3, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 9.25–9.20 (m, 3H), 6.22–6.19 (m, 1H), 6.10–6.00 (m, 1H),
5.74–5.68 (m, 1H), 5.50–5.46 (m, 1H), 0.22 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 161.3, 148.7, 133.6, 131.8, 129.6, 122.6, 120.7,
98.6, 94.3, 67.3, ꢀ0.39; HRMS (ESI) calcd for C15H17N2O6Si [M+H]+
349.0856, found: 349.0843. Enantiomeric excess was determined
by HPLC with a Chiralcel OD-H column (95:5 n-hexane/2-propanol,
1.0 mL/min, 254 nm); major (S)-enantiomer tr = 6.53 min.
4.2.9. 2-Decyn-1-ol 9
To a solution of propargyl alcohol 8 (5.32 mL, 90 mmol) and
HMPA (39.5 mL, 225 mmol) in THF (50 mL) was added n-BuLi
(72 mL, 2.5 M in n-hexane, 180 mmol) at ꢀ78 °C. The resulting
mixture was warmed to ꢀ30 °C and stirred for 3 h. Next, 1-bromo-
heptane (7 mL, 45 mmol) was added and the reaction mixture was
warmed to room temperature and stirred for another 21 h. The
reaction mixture was quenched with saturated aqueous NH4Cl
(30 mL). The aqueous layer was extracted with Et2O (3 ꢁ 50 mL).
The combined organic layers were dried over Na2SO4, and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (n-hexane/diethyl ether 5:1) to give 9 (6.6 g,
95% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) d 4.27–4.23
(m, 2H), 2.24–2.18 (m, 2H), 1.68 (t, J = 6.0 Hz, 1H), 1.56–1.46 (m,
2H), 1.39–1.27 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 86.4, 78.3, 51.2, 31.7, 28.8, 28.7, 28.6, 22.6, 18.7, 14.0;
HRMS (APCI-TOF) calcd for C10H19O [M+H]+ 155.1436, found:
155.1428.
4.2.5. (R)-5-Bromo-1-penten-4-yn-3-yl 3,5-dinitrobenzoate 6a
To a stirred solution of N-bromosuccinimide (1.90 g, 10.7 mmol)
and AgNO3 (0.57 g, 3.4 mmol) in acetone (35 mL) was added 5a
(3.1 g, 8.9 mmol) at 0 °C. The reaction flask was covered with alu-
minum foil and the reaction mixture was stirred for 5 h at room
temperature. The reaction was quenched with water (20 mL), and
the aqueous layer was extracted with Et2O (3 ꢁ 30 mL). The com-
bined organic phases were dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel chro-
matography (n-hexane/diethyl ether 5:1) to afford 6a (2.84 g, 90%
yield, >99% ee) as a white solid. Mp 89.0–90.0 °C; [
a
]
20 = ꢀ45.2 (c
D
1.3, CHCl3); 1H NMR (300 MHz, CDCl3) d 9.25–9.19 (m, 3H), 6.19
(d, J = 6.0 Hz, 1H), 6.04 (ddd, J = 16.6, 9.9, 6.0 Hz, 1H), 5.71 (d,
J = 16.8 Hz, 1H), 5.51 (d, J = 9.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 161.3, 148.7, 133.2, 131.3, 129.6, 122.7, 121.1, 74.4, 67.5, 49.9;
HRMS (APCI-TOF) calcd for C12H7BrN2O6 [M]ꢀ 353.9487, found:
353.9481. Enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (98:2 n-hexane/2-propanol, 1.0 mL/min,
254 nm); major (R)-enantiomer tr = 16.29 min.
4.2.10. (Z)-2-Decen-1-ol 10a
To a solution of pyridine (22 mL) and Lindlar catalyst (0.67 g) in
EtOH (120 mL) was added alkyne 9 (6.93 g, 45 mmol) under a
hydrogen gas atmosphere. Next, the reaction mixture was stirred
at room temperature for 1 h. The mixture was filtered through a
Celite pad, and the filtrate was concentrated under reduced pres-
sure. The crude product was purified by silica gel chromatography
(n-hexane/diethyl ether 5:1) to provide 10a (6.52 g, 92% yield) as a
yellow oil. 1H NMR (300 MHz, CDCl3) d 5.64–5.50 (m, 2H), 4.21–
4.18 (m, 2H, 2.10–2.04 (m, 2H), 1.38–1.27 (m, 11H), 0.88 (t,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 133.2, 128.3, 58.5,
4.2.6. (S)-5-Bromo-1-penten-4-yn-3-yl 3,5-dinitrobenzoate 6b
A similar procedure as described for 6a was accomplished from
5b (5.9 g, 17 mmol), N-bromosuccinimide (3.63 g, 20.4 mmol), and
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001

6
J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
31.8, 29.6, 29.1, 29.1, 27.4, 22.6, 14.0; HRMS (ESI) calcd for
10H20KO [M+K]+ 195.1151, found: 195.1146.
22.6, 14.0; HRMS (ESI) calcd for C20H27F3NaO4 [M+Na]+ 411.1759,
found: 411.1751.
C
4.2.11. (E)-2-Decen-1-ol 10b
4.2.14. (2S,3R)-2,3-Epoxy-1-decanol 11b
To a suspension of LiAlH4 (3.42 g, 90 mmol) in dry THF (100 mL)
was added alkyne 9 (9.24 g, 60 mmol) at 0 °C. After the addition
was completed, the reaction mixture was refluxed for 20 h and
cooled to 0 °C. Next, 5% aqueous HCl (30 mL) was slowly added
to the mixture, and the aqueous layer was extracted with Et2O
(3 ꢁ 50 mL). The combined organic layers were dried over Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/ethyl acetate
7:1) to give 10b (7.95 g, 85% yield) as a colorless oil. 1H NMR
Similar asymmetric epoxidation as described for 11a from (Z)-
2-decen-l-ol 10a (6.6 g, 42 mmol) and TBHP (15 mL, 5.6 M in
decane, 84 mmol), catalyzed by (+)-diethyl tartrate (1.21 g,
5.8 mmol) and Ti(OiPr)4 (1.19 g, 4.2 mmol) afforded 11b (6.3 g,
87% yield) as a white solid. Recrystallization from petroleum ether
(30 mL) provided a white solid 11b (4.1 g, 65% yield, >99% ee,
1
determined by H NMR analysis of the ester 11b0 derived from
(R)-(ꢀ)-MTPACl). Mp 43.0–44.5 °C; [
a
]
20 = ꢀ4.9 (c 1.3, CHCl3), lit.19a
D
[a]
25 = ꢀ4.8 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 3.90–3.82
D
(300 MHz, CDCl3)
d
5.75–5.58 (m, 2H), 4.10–4.07 (m, 2H),
(m, 1H), 3.71–3.63 (m, 1H), 3.18–3.13 (m, 1H), 3.06–3.00 (m,
1H), 1.94–1.90 (m, 1H), 1.60–1.27 (m, 12H), 0.89 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 60.8, 57.2, 57.0, 31.6, 29.3, 29.1,
27.9, 26.5, 22.5, 13.9; HRMS (ESI) calcd for C10H21O2 [M+H]+
173.1542, found: 173.1533.
2.07–2.00 (m, 2H), 1.39–1.27 (m, 11H), 0.88 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 133.5, 128.8, 63.7, 32.2, 31.8, 29.1,
22.6, 14.0 (Two resonances were not observed due to overlapping
resonances); HRMS(TOF) calcd for C10H20NaO [M+Na]+ 179.1412,
found: 179.1409.
4.2.15. (S)-MTPA ester of 11b (11b0)
4.2.12. (2R,3S)-2,3-Epoxy-1-decanol 11a
A similar procedure as described for (S)-MTPA ester of 11a was
accomplished from 11b (25.8 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl
To a cooled solution of powered activated 4 Å molecular sieves
(5 g) in CH2Cl2 (140 mL), were added (ꢀ)-diisopropyl tartrate
(2.1 g, 9.0 mmol) and Ti(OiPr)4 (1.8 g, 6.4 mmol) sequentially at
0 °C. After the mixture was cooled to ꢀ23 °C, tert-butyl hydroper-
oxide (TBHP) (23 mL, 5.6 M in decane, 128 mmol) was added
slowly. The resulting mixture was stirred for 1 h, and (Z)-2-
decen-1-ol 10a (1.0 g, 64 mmol) was added. The reaction mixture
was warmed to ꢀ10 °C and stirred for 72 h. The reaction was
quenched with water (10 mL) at 0 °C, and the resulting mixture
was stirred for 1 h. After the mixture was warmed to room temper-
ature, a solution of 30% aqueous NaOH (40 mL) was added. The
solution was stirred vigorously until phase separation occurred.
The aqueous layer was extracted with CH2Cl2 (3 ꢁ 50 mL). The
combined organic layers were dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (n-hexane/diethyl ether 2:1) to afford 11a (9.4 g,
85% yield) as a white solid. Recrystallization from petroleum ether
(100 mL) provided a white solid 11a (6.39 g, 68% yield, >99% ee,
(60
l
L, 0.3 mmol) to produce the title compound 11b0 as a colorless
oil. [a
]
D
20 = ꢀ33.2 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.56–
7.52 (m, 2H), 7.44–7.39 (m, 3H), 4.51 (dd, J = 12.0, 4.6 Hz, 1H), 4.35
(dd, J = 11.8, 6.8 Hz, 1H), 3.57 (s, 3H), 3.26–3.20 (m, 1H), 3.05–3.00
(m, 1H), 1.58–1.28 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 166.5, 132.0, 129.7, 128.4, 127.3, 123.2 (q,
J = 286.7 Hz), 84.7 (q, J = 27.7 Hz), 64.5, 56.6, 55.5, 52.9, 31.7,
29.3, 29.1, 27.9, 26.5, 22.5, 14.0; HRMS (ESI) calcd for C20H27F3NaO4
[M+Na]+ 411.1759, found: 411.1749.
4.2.16. (2R,3R)-2,3-Epoxy-1-decanol 11c
A similar asymmetric epoxidation as described for 11a from (E)-
2-decen-l-ol 10b (6.24 g, 40 mmol) and TBHP (14.5 ml, 5.6 M in
decane, 80 mmol), catalyzed by (ꢀ)-diisopropyl tartrate (0.68 g,
2.9 mmol) and Ti(OiPr)4 (0.56 g, 2 mmol) gave 11c (6.19 g, 90%
yield) as a white solid. Recrystallization from petroleum ether
(40 mL) provided a white solid 11c (4.64 g, 75% yield, >99% ee,
1
1
determined by H NMR analysis of the ester 11a0 derived from
determined by H NMR analysis of the ester 11c0 derived from
(R)-(ꢀ)-MTPACl). Mp 43.0–44.0 °C; [
a
]
20 = +4.7 (c 0.9, CHCl3), lit.19a
(R)-(+)-MTPACl). Mp 49.0–50.0 °C; [a]
20 = +35.7 (c 1.4, CHCl3),
D
D
[a
]
D
25 = ꢀ4.8 (c 2.0, CHCl3) for (2S,3R)-2,3-epoxy-1-decanol (11b);
lit.19c
[
a]
20 = ꢀ34.8 (c 1.1, CHCl3) for (2S,3S)-2,3-epoxy-1-decanol
D
1H NMR (300 MHz, CDCl3) d 3.89–3.82 (m, 1H), 3.71–3.63 (m,
1H), 3.18–3.13 (m, 1H), 3.06–3.00 (m, 1H), 2.14–2.10 (m, 1H),
1.60–1.27 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 60.9, 57.3, 56.8, 31.7, 29.3, 29.1, 27.9, 26.6, 22.6, 14.0;
HRMS (ESI) calcd for C10H21O2 [M+H]+ 173.1542, found: 173.1536.
11d; 1H NMR (300 MHz, CDCl3) d 3.95–3.88 (m, 1H), 3.66–3.58
(m, 1H), 2.98–2.90 (m, 2H), 1.90–1.86 (m, 1H), 1.61–1.28 (m,
12H), 0.88 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d
61.8, 58.6, 56.0, 31.6, 31.4, 29.2, 29.1, 25.8, 22.5, 13.9; HRMS
(ESI) calcd for C10H21O2 [M+H]+ 173.1542, found: 173.1534.
4.2.13. (S)-MTPA ester of 11a (11a0)
4.2.17. (S)-MTPA ester of 11c (11c0)
To a stirred solution of 4-(dimethy1amino)pyridine (DMAP)
A similar procedure as described for (S)-MTPA ester of 11a was
accomplished from 11c (25.8 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl
(18 mg, 0.15 mmol) and triethylamine (100
lL, 0.7 mmol) in
CH2Cl2 (1 mL), was added 11a (25.8 mg, 0.15 mmol) at 0 °C.
(60 l
L, 0.3 mmol) to give the title compound 11c0 as a colorless oil.
Next, (R)-(ꢀ)-
a
l
-methoxy-
a
-(trifluoromethy1)phenylacetyl chloride
[a]
20 = ꢀ40.2 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.55–7.52
D
(MTPACl) (60
L, 0.3 mmol) was added immediately into the mix-
(m, 2H), 7.44–7.39 (m, 3H), 4.53 (dd, J = 12.0, 3.5 Hz, 1H), 4.23 (dd,
J = 12.0, 6.2 Hz, 1H), 3.57 (s, 3H), 3.00–2.97 (m, 1H), 2.85–2.81 (m,
1H), 1.58–1.26 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 166.4, 132.1, 129.7, 128.5, 127.3, 123.2 (q, J = 286.7 Hz),
84.7 (q, J = 27.8 Hz), 66.3, 56.8, 55.5, 54.5, 31.7, 31.4, 29.3, 29.1,
25.8, 22.6, 14.0; HRMS (ESI) calcd for C20H27F3NaO4 [M+Na]+
411.1759, found: 411.1796.
ture. After the reaction solution turned orange, it was stirred at 0 °C
until the reaction was completed as monitored by TLC. The reac-
tion was quenched with 3-(dimethylamino)propylamine (50 lL)
and concentrated under reduced pressure. The residue was puri-
fied by flash chromatography (n-hexane/ethyl acetate 5:1) to give
the title compound 11a0 as a colorless oil. [
a
]
D
20 = ꢀ48.1 (c 1.2,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.55–7.52 (m, 2H), 7.43–7.39
(m, 3H), 4.45 (dd, J = 12.0, 4.6 Hz, 1H), 4.38 (dd, J = 12.0, 6.8 Hz,
1H), 3.58 (s, 3H), 3.23–3.17 (m, 1H), 3.05–3.00 (m, 1H), 1.60–1.39
(m, 12H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
166.5, 132.0, 129.7, 128.5, 127.3, 123.2 (q, J = 286.6 Hz), 84.7
(q, J = 27.5 Hz), 64.5, 56.6, 55.5, 53.0, 31.7, 29.3, 29.1, 27.9, 26.5,
4.2.18. (2S,3S)-2,3-Epoxy-1-decanol 11d
A similar asymmetric epoxidation as described for 11a from
(E)-2-decen-l-ol 10b (6.24 g, 40 mmol) and TBHP (14.5 ml, 5.6 M
in decane, 80 mmol), catalyzed by (+)-diethyl tartrate (0.60 g,
2.9 mmol) and Ti(OiPr)4 (0.57 g, 2 mmol) furnished 11d (6.12 g,
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001

J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
89% yield) as a white solid. Recrystallization from petroleum ether
9H); 13C NMR (75 MHz, CDCl3) d 101.6, 86.9, 57.0, 54.9, 31.7,
29.4, 29.2, 27.6, 26.4, 22.60, 14.0, ꢀ0.026. HRMS (ESI) calcd for
(40 mL) provided a white solid 11d (4.53 g, 74% yield, >99% ee,
1
determined by H NMR analysis of the ester 11d0 derived from
C
15H29OSi [M+H]+ 253.1988, found: 253.1975.
(R)-(ꢀ)-MTPACl). Mp 49.5–50.5 °C; [
a
]
20 = ꢀ39.7 (c 1.2, CHCl3),
D
lit.19a
[
a]
25 = ꢀ36.5 (c 2.8, CHCl3); 1H NMR (300 MHz, CDCl3) d
4.2.22. (4R,5R)-4,5-Epoxy-1-trimethylsilyl-1-decyne 12c
A similar procedure as described for 12a was accomplished
from 11c (344.0 mg, 2.0 mmol), trimethylsilylethyne (392.8 mg,
4.0 mmol), and n-BuLi (1.44 mL, 2.5 M in n-hexane, 3.6 mmol) to
D
3.95–3.88 (m, 1H), 3.66–3.58 (m, 1H), 2.98–2.90 (m, 2H), 1.93–
1.89 (m, 1H), 1.61–1.28 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 61.8, 58.6, 56.0, 31.7, 31.5, 29.3, 29.1,
25.9, 22.5, 14.0; HRMS (ESI) calcd for C10H21O2 [M+H]+ 173.1542,
found: 173.1535.
afford 12c (373.0 mg, 74% yield) as a colorless oil. [a]
20 = +0.1 (c
D
1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 2.87–2.80 (m, 2H), 2.63
(dd, J = 17.4, 4.4 Hz, 1H), 2.41 (dd, J = 16.5, 5.4 Hz, 1H), 1.59–1.26
(m, 12H), 0.88 (t, J = 7.0 Hz, 3H), 0.16 (s, 9H); 13C NMR (300 MHz,
CDCl3) d 101.3, 86.9, 58.4, 56.0, 31.7, 31.6, 29.3, 29.2, 25.9, 23.5,
22.6, 14.0, ꢀ0.042; HRMS (ESI) calcd for C15H29OSi [M+H]+
253.1988, found: 253.1992.
4.2.19. (S)-MTPA ester of 11d (11d0)
A similar procedure as described for (S)-MTPA ester of 11a was
accomplished from 11d (25.8 mg, 0.15 mmol) and (R)-(ꢀ)-MTPACl
(60 l
L, 0.3 mmol) to give the title compound 11d0 as a colorless oil.
[
a
]
20 = ꢀ24.7 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.55–7.52
D
(m, 2H), 7.44–7.40 (m, 3H), 4.58 (dd, J = 12.1, 3.5 Hz, 1H), 4.22 (dd,
J = 12.1, 5.8 Hz, 1H), 3.57 (s, 3H), 3.03–3.00 (m, 1H), 2.87–2.82 (m,
1H), 1.57–1.27 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 166.4, 132.0, 129.7, 128.5, 127.3, 123.2 (q, J = 286.7 Hz),
84.7 (q, J = 27.3 Hz), 66.0, 56.6, 55.5, 54.5, 31.7, 31.4, 29.2, 29.1,
4.2.23. (4S,5S)-4,5-Epoxy-1-trimethylsilyl-1-decyne 12d
A similar procedure as described for 12a was accomplished
from 11d (344.0 mg, 2.0 mmol), trimethylsilylethyne (392.8 mg,
4.0 mmol), n-BuLi (1.44 mL, 2.5 M in n-hexane, 3.6 mmol) to give
12d (367.6 mg, 73% yield) as a colorless oil. [
a
]
20 = ꢀ0.3 (c 1.3,
D
25.8, 22.6, 14.0; HRMS (ESI) calcd for
389.1940, found: 389.1938.
C
20H28F3O4 [M+H]+
CHCl3); 1H NMR (300 MHz, CDCl3) d 2.87–2.80 (m, 2H), 2.63 (dd,
J = 17.4, 4.4 Hz, 1H), 2.41 (dd, J = 17.4, 5.4 Hz, 1H), 1.60–1.28 (m,
12H), 0.88 (t, J = 7.0 Hz, 3H), 0.16 (s, 9H). 13C NMR (75 MHz, CDCl3)
d 101.3, 86.9, 58.4, 56.0, 31.7, 31.6, 29.3, 29.2, 25.9, 23.5, 22.6, 14.0,
ꢀ0.040; HRMS (ESI) calcd for C15H29OSi [M+H]+ 253.1988, found:
253.1974.
4.2.20. (4R,5S)-4,5-Epoxy-1-trimethylsilyl-1-decyne 12a
To a stirred solution of epoxide 11a (344 mg, 2 mmol) in anhy-
drous CH2Cl2 (8 mL) were added dropwise 2,6-lutidine (0.328 mL,
3 mmol) and trifluoromethanesulfonic anhydride (848.4 mg,
3 mmol) at ꢀ78 °C under argon. The resulting mixture was
warmed slowly to ꢀ40 °C and stirred. Next, the reaction mixture
was recooled to ꢀ78 °C and stirred for an additional 1 h. The reac-
tion was quenched with saturated aqueous NH4Cl (5 mL), and the
aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/ethyl acetate 30:1) to
afford the crude triflate of 11a as a colorless oil, which was used
in the subsequent reaction without further purification.
4.2.24. (4R,5S)-4,5-Epoxy-1-decyne 13a
To a solution of 12a (320 mg, 1.3 mmol) in methanol (9 mL) was
added potassium carbonate (390 mg, 2.8 mmol) at 0 °C. After stir-
ring for 5 h at room temperature, the mixture was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (n-hexane/diethyl ether 60:1) to provide 13a
(190 mg, 81% yield) as a colorless oil. [
a
]
20 = ꢀ42.8 (c 1.5, CHCl3),
D
lit.10
[
a]
25 = ꢀ53.8 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) d
D
3.18–3.12 (m, 1H), 3.00–2.95 (m, 1H), 2.64–2.55 (m, 1H), 2.33–
2.24 (m, 1H), 2.06 (t, J = 2.7 Hz, 1H), 1.55–1.28 (m, 12H) 0.89 (t,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 79.4, 70.2, 56.9, 54.7,
31.7, 29.4, 29.1, 27.5, 26.4, 22.6, 18.4, 14.0; HRMS (ESI) calcd for
To
a stirred solution of trimethylsilylethyne (392.8 mg,
4.0 mmol) in anhydrous diethyl ether (8 mL) was slowly added
n-BuLi (1.44 mL, 2.5 M in n-hexane, 3.6 mmol) at ꢀ78 °C under
argon. After the resulting mixture was stirred for 1.5 h at the same
temperature, a solution of the triflate of 11a in anhydrous diethyl
ether (1.5 mL) was added at ꢀ78 °C. The reaction mixture was
warmed slowly to ꢀ40 °C, continued to be warmed to ꢀ25 °C
and stirred overnight. The reaction was quenched with saturated
aqueous NH4Cl (5 mL) and the aqueous layer was extracted with
diethyl ether (3 ꢁ 10 mL). The combined organic layers were dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (n-hex-
ane/diethyl ether 60:1) to give 12a (367.9 mg, 73% yield) as a col-
C
12H20NaO [M+Na]+ 203.1412, found: 203.1411.
4.2.25. (4S,5R)-4,5-Epoxy-1-decyne 13b
A similar deprotection as described for 13a from 12b (530 mg,
2.1 mmol) and potassium carbonate (580 mg, 4.2 mmol) gave
13b (310 mg, 81% yield) as a colorless oil. [
a]
20 = +45.4 (c 1.4,
D
CHCl3), lit.7 25 = 53.9 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3)
[a]
D
d 3.18–3.13 (m, 1H), 3.00–2.95 (m, 1H), 2.64–2.55 (m, 1H), 2.32–
2.24 (m, 1H), 2.06 (t, J = 2.7 Hz, 1H), 1.55–1.28 (m, 12H), 0.89 (t,
J = 6.9 Hz, 3H); 13C NMR (300 MHz, CDCl3) d 79.4, 70.3, 57.0, 54.7,
31.7, 29.4, 29.1, 27.5, 26.4, 22.6, 18.5, 14.0. HRMS (ESI) calcd for
orless oil. [
a
]
20 = ꢀ33.6 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3) d
C
12H20NaO [M+Na]+ 203.1412, found: 203.1405.
D
3.17–3.11 (m, 1H), 2.99–2.93 (m, 1H), 2.64 (dd, J = 17.3, 5.4 Hz, 1H),
2.31 (dd, J = 17.3, 7.3 Hz, 1H), 1.61–1.26 (m, 12H), 0.89 (t, J = 6.9 Hz,
3H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) d 101.6, 86.8, 56.9, 54.9,
31.7, 29.4, 29.2, 27.6, 26,4, 22.6, 19.9, 14.0, ꢀ0.045; HRMS (ESI)
calcd for C15H29OSi [M+H]+ 253.1988, found: 253.1984.
4.2.26. (4R,5R)-4,5-Epoxy-1-decyne 13c
A similar deprotection as described for 13a from 12c (1.53 g,
6.1 mmol), potassium carbonate (1.68 g, 12.2 mmol) afforded 13c
(0.86 g, 78% yield) as a colorless oil. [a]
20 = +14.6 (c 1.2, CHCl3).
D
1H NMR (300 MHz, CDCl3) d 2.89–2.84 (m, 2H), 2.65–2.57 (m,
1H), 2.47–2.39 (m, 1H), 2.04 (t, J = 2.7 Hz, 1H), 1.57–1.28 (m,
12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (300 MHz, CDCl3) d 78.9,
70.3, 58.2, 55.6, 31.7, 31.5, 29.3, 29.1, 25.9, 22.6, 21.9, 14.0; HRMS
(ESI) m/z calcd for C12H20KO [M+K]+ 219.1151, found: 219.1138.
4.2.21. (4S,5R)-4,5-Epoxy-1-trimethylsilyl-1-decyne 12b
A similar procedure as described for 12a was accomplished
from 11b (344.0 mg, 2.0 mmol), trimethylsilylethyne (392.8 mg,
4.0 mmol), and n-BuLi (1.44 mL, 2.5 M in n-hexane, 3.6 mmol) to
give 12b (362.9 mg, 72% yield) as a colorless oil. [a]
20 = +38.2 (c
D
1.2, CHCl3); 1H NMR (300 MHz, CDCl3) d 3.17–3.11 (m, 1H), 2.99–
2.93 (m, 1H), 2.64 (dd, J = 17.3, 5.4 Hz, 1H), 2.31 (dd, J = 17.3,
7.3 Hz, 1H), 1.59–1.28 (m, 12H), 0.89 (t, J = 7.0 Hz, 3H), 0.16 (s,
4.2.27. (4S,5S)-4,5-Epoxy-1-decyne 13d
A similar deprotection as described for 13a from 12d (1.71 g,
6.8 mmol) and potassium carbonate (1.88 g, 13.6 mmol) furnished
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001

8
J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
13d (0.97 g, 79% yield) as a colorless oil. [
a
]
20 = ꢀ14.4 (c 1.3,
4.2.32. (3S,9R,10S)-Panaxydol 1e
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7b (48.3 mg, 0.3 mmol) and 13a (36 mg, 0.2 mmol) gave 1e
D
CHCl3); 1H NMR (300 MHz, CDCl3) d 2.89–2.84 (m, 2H), 2.65–2.57
(m, 1H), 2.47–2.38 (m, 1H), 2.04 (t, J = 2.7 Hz, 1H), 1.59–1.28 (m,
12H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (300 MHz, CDCl3) d 78.9,
70.3, 58.2, 55.6, 31.7, 31.5, 29.3, 29.1, 25.9, 22.6, 21.9, 14.0; HRMS
(ESI) calcd for C12H20KO [M+K]+ 219.1151, found: 219.1146.
(42.1 mg, 81% yield) as a colorless oil. [
a
]
20 = ꢀ43.4 (c 0.6, CHCl3),
D
lit.10
[
a]
25 = ꢀ57.7 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3) d
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), 4.95–4.91 (m, 1H), 3.18–3.12 (m, 1H), 2.98–2.96 (m,
1H), 2.75–2.67 (m, 1H), 2.43–2.35 (m, 1H), 1.95 (d, 6.7 Hz, 1H),
1.54–1.29 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 136.0, 117.1, 76.7, 74.9, 70.8, 66.2, 63.4, 57.0, 54.3, 31.7,
29.4, 29.1, 27.5, 26.4, 22.6, 19.5, 14.1; HRMS (ESI) calcd for
4.2.28. (3R,9R,10S)-Panaxydol 1a
To a stirred solution of CuCl (4.0 mg, 0.04 mmol), n-BuNH2
(55 lL), and H2O (125 lL) in methanol (0.7 mL) and CH2Cl2
(0.6 mL), were added a few crystals of NH2OH.HCl to discharge
the blue color. Epoxy alkyne 13a (36 mg, 0.2 mmol) was then
added and stirred for 5 min. Next, bromoalkyne 7a (48.3 mg,
0.3 mmol) in CH2Cl2 (0.3 mL) was added slowly over 30 min at
0 °C. After stirring for 30 min, the reaction was quenched with
water (3 mL). The aqueous layer was extracted with CH2Cl2
(3 ꢁ 10 mL), the combined organic phases were dried over Na2SO4,
concentrated, and purified by silica gel chromatography (n-hex-
ane/ethyl acetate 5:1) to give 1a (44.3 mg, 85% yield) as a colorless
C
17H24NaO2 [M+Na]+ 283.1674, found: 283.1663.
4.2.33. (3S,9S,10R)-Panaxydol 1f
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7b (48.3 mg, 0.3 mmol) and 13b (36 mg, 0.2 mmol) gave 1f
(43.7 mg, 84% yield) as a colorless oil. [
a]
20 = +90.0 (c 0.5, CHCl3),
D
lit.10 25 = +103 (c 3.0, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.95
[a]
D
(ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.51–5.44 (m, 1H), 5.28–5.24 (m,
1H), 4.95–4.91 (m, 1H), 3.18–3.12 (m, 1H), 2.98–2.96 (m, 1H),
2.75–2.67 (m, 1H), 2.43–2.35 (m, 1H), 1.99–1.96 (m, 1H) 1.60–
1.25 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) d 136.0, 117.1, 76.7, 74.5, 70.8, 66.2, 63.4, 57.0, 54.3, 31.7,
29.4, 29.1, 27.5, 26.4, 22.6, 19.4, 14.1; HRMS (ESI) calcd for
oil. [a]
20 = ꢀ94.8 (c 1.1, CHCl3); lit.7 [
a]
D = ꢀ81.8 (c 1.52, CHCl3); 1H
D
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), 4.95–4.91 (m, 1H), 3.17–
3.12 (m, 1H), 3.00–2.94 (m, 1H), 2.75–2.67 (m, 1H), 2.43–2.35
(m, 1H), 1.99–1.96 (m, 1H), 1.59–1.25 (m, 12H), 0.89
(t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 136.0, 117.1, 76.7,
74.9, 70.8, 66.3, 63.5, 57.0, 54.3, 31.7, 29.4, 29.1, 27.5, 26.4, 22.6,
19.4, 14.1; HRMS (ESI) calcd for C17H24NaO2 [M+Na]+ 283.1674,
found: 283.1666.
C
17H24NaO2 [M+Na]+ 283.1674, found: 283.1670.
4.2.34. (3S,9R,10R)-Panaxydol 1g
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7b (48.3 mg, 0.3 mmol) and 13c (36 mg, 0.2 mmol) afforded 1g
4.2.29. (3R,9S,10R)-Panaxydol 1b
(44.2 mg, 85% yield) as a colorless oil. [a]
20 = +45.6 (c 1.2, CHCl3);
D
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7a (48.3 mg, 0.3 mmol) and 13b (36 mg, 0.2 mmol) afforded 1b
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), 2.89–
2.82 (m, 2H), 2.76–2.68 (m, 1H), 2.57–2.49 (m,1H), 1.99–1.97 (m,
1H), 1.61–1.25 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 136.0, 117.2, 76.4, 74.8, 70.9, 66.3, 63.5, 58.4,
55.3, 31.7, 31.5, 29.3, 29.2, 25.8, 22.9, 22.6, 14.1; HRMS (ESI) calcd
for C17H24NaO2 [M+Na]+ 283.1674, found: 283.1661.
(43.2 mg, 83% yield) as a colorless oil. [
a]
20 = +41.2 (c 1.2, CHCl3),
D
lit.10 25 = +51.2 (c 1.7, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.95
[a]
D
(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), 3.17–3.12 (m, 1H), 2.99–2.94 (m, 1H),
2.75–2.67 (m, 1H), 2.43–2.34 (m, 1H), 1.98 (d, 6.6 Hz, 1H), 1.59–
1.29 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
136.0, 117.1, 75.0, 70.7, 66.3, 63.4, 57.0, 54.3, 31.7, 29.4, 29.1,
27.4, 26.4, 22.6, 19.4, 14.1; HRMS (ESI) calcd for C17H24NaO2 [M
+Na]+ 283.1674, found: 283.1665.
4.2.35. (3S,9S,10S)-Panaxydol 1h
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7b (48.3 mg, 0.3 mmol) and 13d (36 mg, 0.2 mmol) gave 1h
(42.6 mg, 82% yield) as a colorless oil. [a]
20 = +37.0 (c 1.2, CHCl3);
D
4.2.30. (3R,9R,10R)-Panaxydol 1c
A similar Cadiot-Chodkiewicz coupling as described for 1a
from 7a (48.3 mg, 0.3 mmol) and 13c (36 mg, 0.2 mmol) gave
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), 2.88–
2.82 (m, 2H), 2.76–2.68 (m, 1H), 2.57–2.49 (m, 1H), 1.94 (d,
6.6 Hz, 1H), 1.59–1.22 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 136.0, 117.2, 76.3, 74.8, 70.9, 66.3, 63.5, 58.4,
55.3, 31.7, 31.5, 29.3, 29.2, 25.8, 22.9, 22.6, 14.1; HRMS (ESI) calcd
for C17H24NaO2 [M+Na]+ 283.1674, found: 283.1669.
1c (42.6 mg, 82% yield) as a colorless oil. [
a
]
20 = ꢀ35.6 (c 0.7,
D
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), 2.89–2.82 (m, 2H), 2.75–2.68 (m, 1H), 2.56–2.49
(m,1H), 1.94–1.91 (m, 1H), 1.59–1.28 (m, 12H), 0.89 (t,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 136.0, 117.1, 76.4,
74.8, 70.9, 66.3, 63.5, 58.4, 55.3, 31.7, 31.5, 29.3, 29.2, 25.8,
4.3. Antitumor activity investigations
22.9, 22.6, 14.0; HRMS (ESI) calcd for
283.1674, found: 283.1667.
C
17H24NaO2 [M+Na]+
The HCT-116 (human colon cancer), NCI-H1650 (human lung
cancer), and A2780 (human ovarian cancer) cell lines were
obtained from American Type Culture Collection (ATCC, Manassas,
VA) or Cell Culture Center at the Institute of Basic Medical Sciences,
Chinese Academy of Medical Sciences. These cells were incubated
in DMEM (Dulbecco’s modified Eagle medium) containing 10% fetal
4.2.31. (3R,9S,10S)-Panaxydol 1d
A similar Cadiot-Chodkiewicz coupling as described for 1a from
7a (48.3 mg, 0.3 mmol) and 13d (36 mg, 0.2 mmol) provided 1d
(44.7 mg, 86% yield) as a colorless oil. [
a
]
D
20 = ꢀ43.0 (c 1.4, CHCl3);
bovine serum (FBS), streptomycin (100 lg/mL), and penicillin
1H NMR (300 MHz, CDCl3) d 5.95 (ddd, J = 17.0, 10.2, 5.3 Hz, 1H),
5.50–5.44 (m, 1H), 5.27–5.23 (m, 1H), 4.93–4.90 (m, 1H), 2.89–
2.82 (m, 2H), 2.75–2.68 (m, 1H), 2.56–2.49 (m,1H), 2.15 (br s,
1H), 1.58–1.28 (m, 12H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 136.0, 116.9, 76.2, 74.9, 70.7, 66.3, 63.3, 58.4,
55.3, 31.7, 31.4, 29.2, 29.1, 25.8, 22.8, 22.5, 14.0; HRMS (ESI) calcd
for C17H24NaO2 [M+Na]+ 283.1674, found: 283.1662.
(100 U/mL), at 37 °C and a 5% CO2 humidified air. The cells were
seeded at 2.0 ꢁ 103/well into 96-well plate and incubated for
24 h. After the cells were treated with different concentrations of
tested compounds for 96 h, 20 lL MTT (5 mg/mL) solution was
added to each cell and incubated for 4 h at 37 °C to form formazan
crystals. Then, the medium was carefully removed, and dimethyl
sulfoxide (DMSO) was added to each well to dissolve the formazan
Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001

J. Mao et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
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microplate reader (Biotek Instruments, Inc. USA). The IC50 value
is the drug concentration for which vitality is 50%, and the results
are summarized in Table 1. For all tests, taxol was used as positive
control.
Acknowledgments
12. (a) Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.;
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We thank New Century Excellent Talents in University (NCET-
12-0528), the National Key Technology Research and Development
Program (No. 2015BAK45B01) and National Natural Science Foun-
dation of China (81102340) for the financial support. We also
thank Prof. Mingan Wang for helpful discussion concerning NMR.
Supplementary data
Supplementary data (NMR and HPLC data) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetasy.2015.12.001.
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Please cite this article in press as: Mao, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.12.001