Total syntheses of 9-epoxyfalcarindiol and its diastereomer

Article abstract of DOI:10.1016/j.tetasy.2016.12.008

The first total syntheses of 9-epoxyfalcarindiol 1a and its diastereomer 1b have been achieved. Central to our approach were the Zn-cyclopropane-based amino alcohol catalyzed enantioselective alkynylation of acrolein, the diastereoselective addition of a diynic ester to an epoxy aldehyde, and the asymmetric Sharpless epoxidation of allylic alcohol catalyzed with L-(+)-diethyl tartrate and Ti(OiPr)₄.

Full text of DOI:10.1016/j.tetasy.2016.12.008

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total syntheses of 9-epoxyfalcarindiol and its diastereomer
Yun Zhou a, Yanli Huang b,c, Shuoning Li a, Pengfei Yang a, Jiangchun Zhong a, Jingwei Yin a, Kaijie Ji a,
Yanqing Yang a, Ning Ye d, Lifeng Wang a, Mingan Wang a, Min Wang a, Qinghua Bian a,
⇑
a Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
b School of Surveying and Land Information Engineering, Henan Polytechinic University, Jiaozuo, Henan 454000, PR China
c Institute of Soil and Water Conservation, Northwest A & F University, Yangling, Shanxi 454003, PR China
d Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total syntheses of 9-epoxyfalcarindiol 1a and its diastereomer 1b have been achieved. Central to
our approach were the Zn-cyclopropane-based amino alcohol catalyzed enantioselective alkynylation of
acrolein, the diastereoselective addition of a diynic ester to an epoxy aldehyde, and the asymmetric
Sharpless epoxidation of allylic alcohol catalyzed with L-(+)-diethyl tartrate and Ti(OiPr)4.
Ó 2016 Published by Elsevier Ltd.
Received 25 October 2016
Revised 30 November 2016
Accepted 6 December 2016
Available online xxxx
1. Introduction
ligands to afford optically active diynic alcohols.13 Herein, we dis-
close the first total syntheses of 9-epoxyfalcarindiol 1a and its
9-Epoxyfalcarindiol 1a (Fig. 1), also known as PQ-2, was first
isolated in 1991 from American Ginseng (Panax quinquefolium),1
a valuable anticancer herbal medicine.2 It was also found to exist
in other plants, such as Hedera rhombea,3 Panax notoginseng,4
Angelica sinensis,5 and Oenanthe fistulosa.6 Its structure was identi-
fied as 9,10-epoxy-heptadeca-1-ene-4,6-diyne-3,8-diol by analy-
ses of spectroscopic data.1 In 2009, the absolute configuration of
9-epoxyfalcarindiol was confirmed as (3R,8R,9S,10R) via the
modified Mosher’s method, and chemical correlation with
(3R,8S)-falcarindiol 2 (Fig. 1).6,7 The laboratory bioassays showed
that 9-epoxyfalcarindiol exhibited cytotoxic activities against leu-
kemia cells (L 1210)1 and two pathogenic strains of Mycobacterium
tuberculosis (H37Rv and Erdman).5b The investigation of Shigemori
et al. indicated that it could inhibit the shoot and root growth of
rice, perennial ryegrass, cockscomb, lettuce, and cress.3 Dall’Acqua
et al. reported that 9-epoxyfalcarindiol was also able to inhibit the
acetylcholinesterase (Ache).8 In addition, Atanasov et al. observed
that 9-epoxyfalcarindiol displayed the properties of selective par-
diastereomer 1b (Fig. 1) via implementing this strategy of alkyny-
lation of acrolein and diastereoselective addition of epoxy alde-
hyde. Moreover, the chiral epoxy moiety of 1a and 1b was
constructed with the enantioselective Sharpless epoxidation of
allylic alcohol.
2. Results and discussion
The retrosynthetic analysis of 9-epoxyfalcarindiol 1a is depicted
in Fig. 2. The epoxy 1,3-diynic alcohol ester 17a was envisioned to
be obtained via the diastereoselective addition of diynic ester 10 to
epoxy aldehyde 16. The Zn-cyclopropane-based amino alcohol cat-
alyzed enantioselective addition of TIPS diyne 3 to acrolein 4 was
expected to afford chiral TIPS enynic diol 7. On the other hand,
we thought that the Sharpless asymmetric epoxidation of 14 could
generate chiral epoxy alcohol 15. Subsequent Dess-Martin oxida-
tion of 15 would provide the key intermediate 16.
Our study started with the preparation of diynic ester 10
(Scheme 1). TIPS diyne 3 was synthesized smoothly according to
the procedure of Danheiser et al.,14 subsequent enantioselective
addition 3 to acrolein 4 catalyzed by zinc and our cyclopropane-
based amino alcohol (1S,3R)-L1 to afford (R)-8-methyl-8-((triiso-
propylsilyl)oxy)nona-1-en-4,6-diyn-3-ol 5 in 60% yield and with
81% ee.13 For the determination of the absolute configuration of
adduct 5, a modified Mosher’s method15 was applied. The reaction
tial peroxisome proliferator-activated receptor gamma (PPARc),
and was valuable for further exploration as pharmaceutical lead
or dietary supplement.9
The enantioselective alkynylzinc addition to aldehydes is one of
the most effective and convenient protocols to prepare optically
active propargylic alcohols.10–12 Recently, we have developed the
highly enantioselective addition of 1,3-diynes to aldehydes cat-
alyzed by zinc and our cyclopropane-based amino alcohol chiral
of 5 with (R)- and (S)-a-methoxy-a-(trifluoromethyl)-phenylacetic
acid chloride (MTPA-Cl) gave the (S)- and (R)-MTPA esters 18a and
18b, respectively. Analysis of the differences in 1H chemical shifts
⇑
Corresponding author. Tel.: +86 010 62731356; fax: +86 010 62820325.
E-mail address: bianqinghua@cau.edu.cn (Q. Bian).
(D
dH = dS À dR) between the (S)- and (R)-MTPA of 5 favored its
http://dx.doi.org/10.1016/j.tetasy.2016.12.008
0957-4166/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.12.008

2
Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
HO
HO
H
OTIPS
OTIPS
O
4
(R)
(R)
(S)
O
Me2Zn, (1S,3R)-L1
toluene, -20oC
60%, 81%ee
(R)
(R)
3
5
OH
OH
1a
OH
H
H
H
H
OTIPS
(R)
N-Boc-L-proline
(S)
(S)
(1) TBAF, THF, rt
EDCI, DMAP
O
(R)
(R)
DCM, rt
76%
(2) TIPSOTf, DCM
2,6-lutidine, 0 oC
OR
H
1b
6
: R = N-Boc-L-Pro
78%
NaOH, THF, rt
86%, 90% ee
HO
H
5: R = H
(S)
OH
(R)
KOH, benzene
TBAF
2
(R)
OH
H
(R)
reflux
72%
THF, rt
OTIPS
H
87%
OTIPS
H
7
8
Figure 1. The structures of 9-epoxyfalcarindiol 1a, its diastereomer 1b and (+)-
(3R,8S)-falcarindiol 2.
4-bromo
benzoyl
chloride
(
S
)
Ph
Ph
(R)
(R)
(R)
Et3N
OAr
absolute (R)-configuration (Fig. 3).15 This result was consistent
with the governing precedents of enantioselective addition
between 1,3-diynes and aldehydes developed by our group.13 Pre-
vious reports16 demonstrated that N-tert-butoxycarbonyl-L-pro-
line (Boc-L-proline) could resolve racemic secondary alcohols. To
improve upon the enantiomeric optical of TIPS enynic alcohol 5,
OH
H
H
N
O
OH
DCM, 0 oC
Ar = 4-bromobenzoyl
L1
(1S,3R)-
75%, 90% ee
9
10
Scheme 1. Synthesis of diynic ester 10.
steps.17 Upon exposure to KOH in refluxing toluene, TIPS enynic
diol 7 was directly converted into TIPS enyne 8 in 72% yield.18
Finally, deprotection of secondary hydroxyl group at C-3 with TBAF
furnished (R)-hepta-1-en-4,6-diyn-3-ol 9 in 87% yield,19 followed
by the esterification of enynic alcohol 9 with 4-bromobenzoyl
chloride to obtain diynic ester 10 in 75% yield and with 90% ee.20
Next, we focused on the synthesis of chiral epoxy aldehyde
16 (Scheme 2). The alkylation of propargyl alcohol 12 with
the esterification of 5 with Boc-L-proline and the silica gel column
chromatography separation were conducted sequentially, which
provided enynic ester 6 in 76% yield. The resolving agent was then
cleaved with NaOH in THF, and gave TIPS enynic alcohol 5 in 86%
yield and with 90% ee.16 After deprotection of the tertiary hydroxyl
group at C-8 with TBAF, the secondary hydroxyl group at C-3 was
protected with TIPSOTf to afford (R)-2-methyl-7-((triisopropylsi-
lyl)oxy)nona-8-en-3,5-diyn-2-ol 7 in 78% yield over the two
HO
H
(R)
(R)
(S)
-0.003
+0.06
+0.12
+0.09
O
(R)
Si
O
1a
OH
H
hydrolysis
O
-0.01
O
18a (S)-MTPA ester of 5
18b (R)-MTPA ester of 5
HO
H
F3C
Ph
(R)
OMe
(R)
(S)
F3C
Ph
O
(R)
17a
OMe
O
diastereoselective
alkynylation
OAr
H
+0.01
+0.01
O
-0.04
+0.05
O
(R)
O
(R)
(R)
O
O
-0.002
O
-0.07
OAr
H
16
Dess-Martin
10
-0.01
20a
17a
(S)-MTPA ester of
20b (R)-MTPA ester of 17a
oxidation
Br
OH
F3C
Ph
(R)
HO
(S)
OMe
O
O
-0.01
-0.06
(R)
-0.01
O
OTIPS
15
H
7
+0.08
O
Sharpless
asymmetric
epoxidation
asymmetric
alkynylation
O
O
0.00
+0.06
OTIPS
0.00
20c
17b
(S)-MTPA ester of
O
HO
20d (R)-MTPA ester of 17b
Br
3
4
14
Figure 3. Confirmation of the absolute configurations of secondary alcohols 5, 17a
and 17b via the modified Mosher’s method.
dH (dS À dR) values are given in ppm.
Figure 2. Retrosynthetic analysis of 9-epoxyfalcarindiol 1a.
D
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Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
HO
HO
H
HO
12
HO
(R)
(R)
NaOH, THF, 0 o
78%
C
Br
(S)
17a
17b
HMPA, n-BuLi
THF, _78 oC to rt
95%
O
13
11
(R)
OH
OH
H
1a
NiAc2.4H2O
NaBH4, H2
Ti(OiPr)4, L-(+)-DET
tBuOOH, 4Å MS
DCM, _10 o
H
HO
NaOH, THF, 0 o
80%
C
(R)
(S)
NH2CH2CH2NH2
EtOH, rt
C
(S)
14
83%
O
(R)
82%
Dess-Martin
periodinane
1b
H
HO
O
DCM, rt
71%
O
Scheme 3. Synthesis of 9-epoxyfalcarindiol 1a and its diastereomer 1b.
O
16
15
recryst. 72%, > 99% ee
Scheme 2. Synthesis of chiral epoxy aldehyde 16.
was applied to assign the absolute configurations at C-8 of 17a
and 17b. Analysis of the differences in the 1H chemical shifts
(
D
dH = dS À dR) between the (S)- and (R)-MTPA of 17a suggested
1-bromoheptane (11) afforded dec-2-yn-1-ol 13 in 95% yield,21
which was reduced to (Z)-dec-2-en-1-ol 14 in 82% yield with
Brown’s P2-Nisystem.22 Sharplessasymmetricepoxidation of allylic
alcohol 14 catalyzed with L-(+)-diethyl tartrate and Ti(OiPr)4 gener-
ated (2S,3R)-2,3-epoxy-1-decanol (15) in 83% yield.23 Recrystalliza-
tion of 15 from petroleum ether improved the ee to over 99%, which
was determined by 1H NMR and 13C NMR analysis of (S)-MTPA ester
of 15.15 The final Dess-Martin oxidation converted epoxy alcohol 15
into (2R,3R)-2,3-epoxy decanal 16 in 71% yield.24
With the chiral building blocks 10 and 16 in hand, the diastere-
oselective addition of diynic ester 10 to epoxy aldehyde 16 was
studied (Table 1). In the absence of a chiral ligand, the addition
proceeded with a Felkin-Anh preference,25 providing a 3:1 mix-
tures of 17a and 17b at À20 °C (entry 2). When chiral ligand
(1S,3R)-L1 was used, diastereomeric ratios of 1:6 showed that
(1S,3R)-L1 was the matched case (entry 4). However, in the pres-
ence of enantiomeric ligand (1R,3S)-L1, the addition gave a 1:1
mixtures of 17a and 17b, thus indicating that (1R,3S)-L1 was a mis-
matched case (entry 6). A similar phenomenon was observed in the
diastereoselective vinyl ether addition to enantioenriched b-
hydroxy aldehydes by Walsh et al.26 Furthermore, we found that
increasing the temperature from À20 to 0 °C just increased the
yield, but had almost had no effect on the diastereomeric ratio
(entries 1,3,5 vs. 2,4,6). The same modified Mosher’s method15
the R configuration (Fig. 3). The absolute configuration at C-8 of
17b was confirmed as (S) by comparison of the chemical shifts of
the protons (DdH = dS-dR) neighboring the oxygenated methine on
the (S)- and (R)-MTPA of 17b (Fig. 3).15
The final hydrolysis of 17a with NaOH in THF afforded the tar-
get 9-epoxyfalcarindiol 1a in 78% yield (Scheme 3).20 The NMR
spectroscopic data and specific rotation of synthetic 1a were iden-
tical to those of the natural 9-epoxyfalcarindiol 1a isolated from
Panax quinquefolium.1 The similar hydrolysis of 17b gave the
diastereomer of 9-epoxyfalcarindiol 1b in 80% yield (Scheme 3),
and its structure was character with 1H NMR, 13C NMR and HRMS
spectra.
3. Conclusion
In conclusion, we have accomplished the total syntheses of 9-
epoxyfalcarindiol 1a and its diastereomer 1b for the first time.
The key steps of our approach include the asymmetric alkynylation
of acrolein catalyzed by zinc and our cyclopropane-based amino
alcohol chiral ligand, the diastereoselective addition of diynic ester
to epoxy aldehyde, and the enantioselective Sharpless epoxidation
of allylic alcohol. Moreover, the epoxy 1,3-diynic alcohols 1a and
1b synthesized herein are potentially useful in the development
of antitumor drugs and dietary supplements.
Table 1
Diastereoselective addition of diynic ester 10 to epoxy aldehyde 16a
Me2Zn
(R)
(R)
+
O
toluene, -20 oC
(R)
O
OAr
10
H
16
Ar = 4-bromobenzoyl
R
R'
(R)
Ph
(R)
(
S
)
(
S
)
Ph
N
O
OH
(R)
17a
17b
: Ar = 4-bromobenzoyl, R = OH, R' = H
: Ar = 4-bromobenzoyl, R = H, R' = OH
OAr
H
(1R,3S)-L1
Entry
Ligand
Temp. (°C)
Yield (%)b
Dr (17a:17b)c
1
2
3
4
5
6
No
No
(1S,3R)-L1
(1S,3R)-L1
(1R,3S)-L1
(1R,3S)-L1
0
À20
0
48
28
63
60
64
58
3:1
3:1
1:5
1:6
1:1
1:1
À20
0
À20
a
b
c
Reactions were performed with 1 equiv epoxy aldehyde 16, 3 equiv diynic ester 10 and Me2Zn.
Isolated yields after chromatographic purification.
Determined by HPLC with a Daicel Chiralcel OJ-H column.
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4
Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
chromatography (petroleum ether/ethyl acetate 20:1) to give eny-
4. Experimental
4.1. General
nic ester 6 (0.5900 g, 76% yield) as a yellow oil. [
a]
24 = À7.7 (c 0.68,
D
CHCl3); 1H NMR (300 MHz, CDCl3) dH 6.02–5.82 (m, 2H), 5.58–5.52
(m, 1H), 5.37–5.33 (m, 1H), 4.28–4.24 (m, 1H), 3.59–3.40 (m, 2H),
2.24–2.20 (m, 1H), 1.99–1.86 (m, 3H), 1.53 (s, 6H), 1.43 (s, 9H),
1.15–1.06 (m, 21H); 13C NMR (75 MHz, CDCl3) dC 171.7, 153.7,
131.9, 119.8, 85.7, 80.1, 73.8, 71.3, 66.5, 64.9, 59.0, 46.3, 32.8,
30.8, 28.4, 28.3, 23.6, 18.2, 12.9; HRMS (ESI) m/z 518.3297 [M
+H]+ (calcd for C29H48NO5Si, 518.3302).
Melting points were measured on a STUART-SMP3 Melt-Temp
apparatus without correction. Optical rotations were obtained on
a PERKIN ELEMER 341 Polarimeter. NMR spectra were recorded
on a Bruker DP-X300 MHz spectrometer. Chemical shifts (d) were
relative to internal tetramethylsilane (TMS) for 1H NMR (dH = 0.00 -
ppm) and to CDCl3 for 13C NMR (dC = 77.00 ppm). High resolution
mass spectra (HRMS) were conducted on an Agilent time-of-flight
instrument. Enantiomeric excesses (ee) were determined on an
Agilent 1200 HPLC system with a Daicel Chiralcel OJ-H chiral-
phase column and elution with n-hexane and 2-propanol. All reac-
tions were performed under an argon atmosphere, and the stated
yields are isolated yields after chromatographic purification. Sol-
vents were purified and dried according to the standard proce-
dures before use. Unless otherwise stated, all commercially
available reagents were used without further purification.
4.4. Hydrolysis of enynic ester 6 to TIPS enynic alcohol 5
At first, NaOH aqueous solution (1.1 mL, 2 M, 2.2 mmol, 2 equiv)
and methanol (0.06 mL) were added to a solution of enynic ester 6
(0.5690 g, 1.1 mmol, 1 equiv) in THF (5 mL). The resulting mixture
was warmed to room temperature, and stirred for 5 h. The reaction
mixture was diluted with water (5 mL) and diethyl ether (5 mL).
The organic phase was separated and the aqueous phase was
extracted with diethyl ether (3 Â 15 mL). The combined organic
layers were washed with brine (15 mL), dried over anhydrous Na2-
SO4, and concentrated under reduced pressure to give a crude
product. The crude product was purified by silica gel column chro-
matography (petroleum ether/ethyl acetate 10:1) to obtain TIPS
enynic alcohol 5 (0.3032 g, 86% yield, 90% ee, measured on chi-
ral-phase HPLC analysis of its 3,5-dinitrobenzoate) as a yellow
oil. Enantiomeric excess was determined by HPLC with a Daicel
Chiralcel OD-H column (10% 2-propanol in n-hexane, 1.3 mL/min,
220 nm); minor (S)-enantiomer tr = 9.61 min, major (R)-enan-
tiomer tr = 12.52 min.
4.2. (R)-8-Methyl-8-((triisopropylsilyl)oxy)nona-1-en-4,6-diyn-
3-ol 5
To a solution of cyclopropane-based amino alcohol (1S,3R)-L1
(0.2106 g, 0.6 mmol, 0.2 equiv) in toluene (6 mL) was added TIPS
diyne 3 (2.3802 g, 9 mmol, 3 equiv) at 0 °C under an argon atmo-
sphere. A solution of Me2Zn (7.5 mL, 1.2 M in toluene, 9 mmol,
3 equiv) was then added slowly via syringe at the same tempera-
ture. After the resulting mixture was stirred for 1.5 h at 0 °C, the
mixture was cooled to À20 °C. Acrolein 4 (0.1682 g, 3 mmol,
1 equiv) was added slowly via syringe, and the reaction mixture
was maintained for 48 h at À20 °C. The reaction was quenched
with water (10 mL) and filtered through a Celite pad. The organic
phase was separated and the aqueous phase was extracted with
diethyl ether (3 Â 20 mL). The combined organic layers were
washed with brine (20 mL), dried over anhydrous Na2SO4, and con-
centrated under reduced pressure to get crude product. The crude
product was purified by silica gel column chromatography (petro-
leum ether/ethyl acetate 10:1) to afford TIPS enynic alcohol 5
(0.5751 g, 60% yield, 81% ee, measured on chiral-phase HPLC anal-
ysis of its 3,5-dinitrobenzoate) as a yellow oil. Enantiomeric excess
was determined by HPLC with a Daicel Chiralcel OD-H column
(10% 2-propanol in n-hexane, 1.3 mL/min, 220 nm) minor (S)-
enantiomer tr = 9.76 min; major (R)-enantiomer tr = 12.52 min.
4.5. (R)-2-Methyl-7-((triisopropylsilyl)oxy)nona-8-en-3,5-diyn-
2-ol 7
To a solution of TIPS enynic alcohol 5 (0.2564 g, 0.8 mmol,
1 equiv) in THF (3 mL) was added TBAF (1.2 mL, 1.0 M in THF,
1.5 equiv) at 0 °C under an argon atmosphere. The resulting mix-
ture was warmed to room temperature and stirred for 12 h. The
reaction mixture was then cooled to 0 °C and quenched with water
(3 mL). The organic phase was separated and the aqueous phase
was extracted with diethyl ether (3 Â 10 mL). The combined
organic layers were washed with brine (15 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to afford
the crude enynic diol.
The crude enynic diol was dissolved in CH2Cl2 (6 mL), and
cooled to 0 °C. 2,6-Lutidine (0.1114 g, 1.04 mmol, 1.3 equiv) and
TIPSOTf (0.3187 g, 1.04 mmol, 1.3 equiv) were then added sequen-
tially. After the reaction mixture was stirred for 1 h at 0 °C, the
reaction was quenched with saturated aqueous NH4Cl solution
(4 mL). The organic phase was separated and the aqueous phase
was extracted with CH2Cl2 (3 Â 20 mL). The combined organic lay-
ers were washed with brine (20 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to get crude product. The
crude product was purified by silica gel column chromatography
[
a
]
24 = À2.1 (c 1.9, CHCl3); 1H NMR (300 MHz, CDCl3) dH 5.99
D
(ddd, J = 17.0, 10.1, 5.4 Hz, 1H), 5.54 (dd, J = 17.0, 0.5 Hz, 1H),
5.30 (dd, J = 10.1, 0.3 Hz, 1H), 5.01–4.97 (m, 1H), 2.01 (d,
J = 6.5 Hz, 1H), 1.57 (s, 6H), 1.12–1.10 (m, 21H); 13C NMR
(75 MHz, CDCl3) dC 136.0, 117.2, 85.5, 77.5, 70.5, 66.6, 66.5, 63.6,
32.8, 18.3, 12.9; HRMS (ESI) m/z 321.2238 [M+H]+ (calcd for
C19H33O2Si, 321.2250).
4.3. 1-(tert-Butyl)2-((R)-8-methyl-8-((triisopropylsilyl)oxy) nona-
1-en-4,6-diyn-3-yl) (S)-pyrrolidine-1,2-dicarboxylate 6
(petroleum ether/ethyl acetate 10:1) to afford TIPS enynic diol 7
24
(0.1999 g, 78% yield) as a yellow oil. [
a
]
+17.2 (c 1.3, CHCl3); 1H
D
Under an argon atmosphere, TIPS enynic alcohol 5 (0.4808 g,
1.5 mmol, 1 equiv) was added slowly to a solution of N-Boc-L-pro-
line (0.3875 g, 1.8 mmol, 1.2 equiv), EDCI (0.3738 g, 1.95 mmol,
1.3 equiv), and DMAP (0.0916 g, 0.75 mmol, 0.5 equiv) in CH2Cl2
(6 mL) at 0 °C. The reaction mixture was warmed to room temper-
ature and stirred for 12 h. The reaction was quenched with water
(5 mL), and the organic phase was separated. The aqueous phase
was extracted with CH2Cl2 (3 Â 15 mL). The combined organic lay-
ers were washed with brine (15 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to obtain crude
product. The crude product was purified by silica gel column
NMR (300 MHz, CDCl3) dH 5.89 (ddd, J = 17.0, 10.1, 5.1 Hz, 1H),
5.41 (d, J = 17.0 Hz, 1H), 5.18 (d, J = 10.1 Hz, 1H), 5.01 (dd, J = 3.7,
1.4 Hz, 1H), 2.13 (s, 1H), 1.53 (s, 6H), 1.10–1.07 (m, 21H); 13C
NMR (75 MHz, CDCl3) dC 137.0, 115.4, 83.7, 79.3, 69.1, 66.6, 65.6,
64.0, 31.0, 17.9, 12.2; HRMS (ESI) m/z 321.2237 [M+H]+ (calcd for
C19H33O2S, 321.2250).
4.6. (R)-(Hepta-1-en-4,6-diyn-3-yloxy)triisopropylsilane 8
To
a suspension of powdered KOH (0.0617 g, 1.1 mmol,
2.2 equiv) in benzene (25 mL) was added slowly TIPS enynic diol
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Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
7 (0.5 mmol, 0.1603 g, 1 equiv) under an argon atmosphere. The
resulting mixture was heated at reflux for 0.5 h, and then cooled
to room temperature. The reaction mixture was filtered through
a Celite pad eluting with petroleum ether. The filtrate was concen-
trated under reduced pressure to obtain a crude product. The crude
product was purified by silica gel column chromatography (petro-
leum ether/ethyl acetate 200:1) to give TIPS enyne 8 (0.0942 g, 72%
60 mmol, 6 equiv) in THF (10 mL) at À78 °C. The resulting mixture
was warmed to À30 °C and stirred for 3 h. 1-Bromoheptane 11
(1.7910 g, 10 mmol, 1 equiv) was then added slowly, and the reac-
tion mixture was stirred for 30 min at À30 °C. After the reaction
mixture was warmed to room temperature and stirred for 24 h,
the reaction was quenched with saturated aqueous NH4Cl
(10 mL). The organic phase was separated and the aqueous phase
was extracted with diethyl ether (3 Â 30 mL). The combined
organic phases were washed with brine (30 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to obtain
a crude product. The crude product was purified by silica gel chro-
matography (petroleum ether/ethyl acetate 10:1) to afford propar-
gyl alcohol 13 (1.4647 g, 95% yield) as a yellow oil. 1H NMR
(300 MHz, CDCl3) dH 4.26 (dt, J = 6.0, 2.2 Hz, 2H), 2.22 (tt, J = 7.2,
2.2 Hz, 2H), 1.99 (t, J = 5.9 Hz, 1H), 1.52–1.50 (m, 2H), 1.33–1.28
(m, 8H), 0.90 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 86.6,
78.3, 51.4, 31.7, 28.8, 28.7, 28.6, 22.6, 18.7, 14.0; HRMS (APCI-
TOF) m/z 155.1436 [M+H]+ (calcd for C10H19O 155.1436).
yield) as a yellow oil. [a]
24 = +2.1 (c 1.2, CHCl3); 1H NMR (300 MHz,
D
CDCl3) dH 5.90 (ddd, J = 17.0, 10.1, 5.1 Hz, 1H), 5.43 (dt, J = 17.0,
1.4 Hz, 1H), 5.21 (dt, J = 10.1, 1.4 Hz, 1H), 5.00 (dt, J = 4.0, 1.0 Hz,
1H), 2.2 (d, J = 1.0 Hz, 1H), 1.14–1.08 (m, 18H), 0.88–0.84 (m,
3H); 13C NMR (75 MHz, CDCl3) dC 136.7, 115.6, 76.0, 69.4, 68.4,
67.6, 63.9, 17.9, 12.2; HRMS (ESI) m/z 263.1820 [M+H]+ (calcd for
C16H27OSi, 263.1831).
4.7. (R)-Hepta-1-en-4,6-diyn-3-ol 9
To a solution of TIPS enyne 8 (0.0787 g, 0.3 mmol, 1 equiv) in
THF (1.5 mL) was added TBAF (0.45 mL, 1.0 M in THF, 0.45 mmol,
1.5 equiv) at 0 °C under an argon atmosphere. The resulting mix-
ture was warmed to room temperature and stirred for 25 min.
The reaction was then cooled to 0 °C and quenched with water
(2 mL). The organic phase was separated and the aqueous phase
was extracted with diethyl ether (3 Â 10 mL). The combined
organic layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to give a
crude product. The crude product was purified by silica gel column
chromatography (petroleum ether/ethyl acetate 10:1) to afford
4.10. (Z)-Dec-2-en-1-ol 14
Under an H2 atmosphere, a suspension of NaBH4 (0.3594 g,
9.5 mmol, 1 equiv) in ethanol (10 mL) was added slowly to a stir-
red solution of NiAc2Á4H2O (1.679 g, 9.5 mmol, 1 equiv) in ethanol
(10 mL) at 25 °C. The resulting mixture was warmed to room tem-
perature and stirred for 1 h. Ethylenediamine (2.2838 g, 38 mmol,
4 equiv) was then added and stirred for an additional 5 min. Next,
propargyl alcohol 13 (1.4649 g, 9.5 mmol, 1 equiv) was added
slowly. After the reaction mixture was maintained for another
6 h, the reaction mixture was filtered through a celite pad. The fil-
trate was concentrated under reduced pressure to get crude prod-
uct. The crude product was purified by silica gel chromatography
(petroleum ether) to afford allylic alcohol 14 (1.2153 g, 82% yield)
as a colorless oil. 1H NMR (300 MHz, CDCl3) dH 5.63–5.56 (m, 2H),
4.22–4.21 (m, 2H), 2.13–2.06 (m, 2H), 1.53 (br s, 1H), 1.40–1.30 (m,
10H), 0.91 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 133.0,
128.4, 58.5, 31.8, 29.6, 29.1, 29.0, 27.4, 22.6, 14.0; HRMS (APCI-
TOF) m/z 157.1581 [M+H]+ (calcd for C10H21O 157.1592).
enynic alcohol
9 (0.0275 g, 87% yield) as a yellow oil.
[
a]
D
20 = À38.2 (c 1.3, CHCl3). Lit6
[
a]
24 = À31.6 (c 0.75, CH2Cl2). 1H
D
NMR (300 MHz, CDCl3) dH 5.93 (ddd, J = 17.0, 10.1, 5.4 Hz, 1H),
5.50 (dd, J = 17.0, 0.9 Hz, 1H), 5.27 (dd, J = 10.1, 0.3 Hz, 1H), 4.91
(s, 1H), 2.42 (br s, 1H), 2.23 (d, J = 1.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) dC 135.6, 117.5, 74.7, 70.4, 69.0, 67.3, 63.3; HRMS(APCI-
TOF) m/z 107.0506 [M+H]+ (calcd for C7H7O, 107.0497).
4.8. (R)-Hepta-1-en-4,6-diyn-3-yl 4-bromobenzoate 10
To a solution of enynic alcohol 9 (0.0954 g, 0.9 mmol, 1 equiv)
and triethylamine (0.1366 g, 1.35 mmol, 1.5 equiv) in CH2Cl2
(5 mL) was added 4-bromobenzoyl chloride (0.2350 g, 1.08 mmol,
1.2 equiv) in CH2Cl2 (3 mL) via a syringe pump over 3 h at 0 °C.
The reaction solution was stirring for 3 h at the same temperature,
and quenched with water (5 mL). The organic phase was separated
and the aqueous phase was extracted with CH2Cl2 (3 Â 10 mL). The
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure
to give a crude product. The crude product was purified by silica
gel column chromatography (petroleum ether/ethyl acetate
200:1) to afford diynic ester 10 (0.1948 g, 75% yield, 90% ee) as a
yellow oil. Enantiomeric excess was determined by HPLC with a
Chiralcel OJ-H column (1% 2-propanol in n-hexane, 1.0 mL/min,
4.11. (2S,3R)-2,3-Epoxy-1-decanol 15
Under an argon atmosphere, L-(+)-diethyl tartrate (0.2245 g,
1.0887 mmol, 0.14 equiv) and Ti(OiPr)4 (0.2210 g, 0.7777 mmol,
0.1 equiv) were added sequentially to a suspension of powdered
activated 4 Å molecular sieves (0.6076 g) in CH2Cl2 (20 mL) at
0 °C. The resulting mixture was cooled to À23 °C, and tert-butyl
hydroperoxide (TBHP) (2.8 mL, 5.5 M in decane, 15.4 mmol,
2 equiv) was then added slowly. After the mixture was stirred for
1 h at À23 °C, allylic alcohol 14 (1.2153 g, 7.7769 mmol, 1 equiv)
was added. The reaction mixture was warmed to À10 °C and stir-
red for an additional 72 h, followed by quenching with water
(10 mL) at 0 °C. After stirring for 1 h, NaOH aqueous solution
(40 mL, 30%) was added and stirred vigorously until the phase sep-
aration was occurred at room temperature. The organic phase was
separated and the aqueous layer was extracted with CH2Cl2
(3 Â 50 mL). The combined organic layers were dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to give
crude product. The crude product was purified by silica gel chro-
matography (petroleum ether/diethyl ether 2:1) to afford epoxy
alcohol 15 (1.1120 g, 83% yield) as a white solid. M.p. 43.0–
44.0 °C; Recrystallization from petroleum ether (100 mL) provided
a white solid (0.8006 g, 72% yield, >99% ee, determined by 1H NMR
220 nm); minor (S)-enantiomer tr = 12.48 min, major (R)-enan-
20
tiomer tr = 13.32 min.
[
a]
À69.3 (c 0.9, CHCl3); 1H NMR
D
(300 MHz, CDCl3) dH 7.91 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz,
2H), 6.12 (dd, J = 5.7, 1.1 Hz, 1H), 5.97 (ddd, J = 15.9, 10.0, 5.6 Hz,
1H), 5.63 (d, J = 16.9 Hz, 1H), 5.41 (d, J = 10.0 Hz, 1H), 2.25 (d,
J = 0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) dC 164.3, 131.8, 131.7,
131.3, 128.75, 128.2, 120.2, 71.4, 71.1, 69.4, 67.1, 65.0; HRMS
(ESI) m/z 288.9902 [M+H]À (calcd for C14H10BrO2, 288.9864).
4.9. Dec-2-yn-1-ol 13
analysis of the ester derived from (R)-MTPACl). [
a
]
D
20 = À0.8 (c 0.48,
Under an argon atmosphere, n-BuLi (16 mL, 2.5 M in n-hexane,
40 mmol, 4 equiv) was added slowly to a stirred solution of propar-
gyl alcohol 12 (1.1214 g, 20 mmol, 2 equiv) and HMPA (10.752 g,
CHCl3). 1H NMR (300 MHz, CDCl3) dH 3.84 (ddd, J = 11.7, 7.5, 4.0 Hz,
1H), 3.66 (ddd, J = 12.0, 6.9, 4.8 Hz, 1H), 3.14 (dt, J = 6.9, 4.2 Hz, 1H),
3.02 (dt, J = 6.9, 4.2 Hz, 1H), 1.86 (dd, J = 7.4, 4.8 Hz, 1H), 1.54–1.27
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.12.008

6
Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
(m, 12H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CD Cl3) dC 60.9,
57.3, 56.8, 31.7, 29.4, 29.1, 27.9, 26.6, 22.6, 14.0; HRMS (APCI-TOF)
173.1533 [M+H]+ (calcd for C10H21O2 173.1542).
1.62 (m, 2H), 1.56–1.52 (m, 2H), 1.36–1.29 (m, 8H), 0.91 (t,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 164.4, 131.8, 131.7,
131.4, 128.7, 128.3, 120.2, 78.5, 74.8, 71.0, 70.0, 65.2, 60.7, 58.0,
57.8, 31.5, 29.3, 29.1, 27.5, 26.5, 22.6, 14.0; HRMS (APCI-TOF) m/z
459.1176 [M+H]+ (calcd for C24H28BrO4 459.1171).
4.12. (2R,3R)-2,3-Epoxy decanal 16
To a solution of epoxy alcohol 15 (0.1723 g, 1 mmol, 1 equiv) in
CH2Cl2 (5 mL) at 0 °C, was added slowly Dess-Martin periodinane
(0.5938 g, 1.4 mmol, 1.4 equiv). The reaction mixture was warmed
to room temperature and stirred for 1 h. Next, the reaction was
quenched with 5% Na2S2O3 in saturated aqueous NaHCO3
(15 mL). The organic phase was separated and the aqueous phase
was extracted with diethyl ether (3 Â 25 mL). The combined
organic phases were washed with brine (25 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to obtain
the crude product. The crude product was purified by silica gel
4.14. (S)-MTPA ester 18a of 5
At first, TIPS enynic alcohol 5 (16.0 mg, 0.05 mmol, 1 equiv) was
added slowly to a solution of DMAP (6.1 mg, 0.05 mmol, 1 equiv)
and triethylamine (25.3 mg, 0.25 mmol, 5 equiv) in CH2Cl2 (2 mL)
at 0 °C. (R)-(À)-a-Methoxy-a-(trifluoromethy1) phenylacetyl chlo-
ride (MTPACl) (25.3 mg, 0.1 mmol, 2 equiv) was then added, and
the reaction mixture turned yellow. The reaction was maintained
at 0 °C, and monitored by TLC. The reaction was quenched with
water (3 mL), and the organic phase was separated. The aqueous
phase was extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to give
crude product. The crude product was purified by thin layer chro-
matography to afford 18a (15.2 mg, 57% yield) as a yellow oil. 1H
NMR (300 MHz, CDCl3) dH 7.54–7.52 (m, 2H), 7.43–7.41 (m, 3H),
6.13–6.11 (m, 1H), 5.94 (ddd, J = 16.9, 10.0, 6.0 Hz, 1H), 5.62 (dd,
J = 16.9, 0.3 Hz, 1H), 5.43 (dd, J = 10.0, 0.06 Hz, 1H), 3.57 (s, 3H),
1.54 (s, 6H), 1.15–1.05 (m, 21H).
chromatography (petroleum ether/ethyl acetate 10:1) to afford
20
epoxy aldehyde 16 (0.1208 g, 71% yield) as a colorless oil. [
a]
=
D
+47.0 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) dH 9.48 (d,
J = 5.3 Hz, 1H), 3.35 (dd, J = 6.9, 4.8 Hz, 1H), 3.27 (dt, J = 6.9,
4.8 Hz, 1H), 1.77–1.64 (m, 4H), 1.39–1.30 (m, 8H), 0.90 (t,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 199.0, 59.1, 57.9,
31.6, 29.1, 28.9, 28.1, 26.5, 22.5, 13.9; HRMS (APCI-TOF) m/z
171.1371 [M+H]+ (calcd for C10H19O2 171.1385).
4.13. (3R,8R,9S,10R)-9,10-epoxy-8-hydroxyheptadeca-1-en-4,6-
diyn-3-yl 4-bromobenzoate 17a and(3R,8S,9S,10R)-9,10-epoxy-
8-hydroxyheptadeca-1-en-4,6-diyn-3-yl 4-bromobenzoate 17b
4.15. (R)-MTPA ester 18b of 5
According to the similar procedure of synthesis of 18a, (S)-(À)-
To a solution of cyclopropane-based amino alcohol (1S,3R)-L1
(0.0014 g, 0.04 mmol, 0.2 equiv) in toluene (2 mL) was added
epoxy aldehyde 16 (0.0341 g, 0.2 mmol, 1 equiv) at 0 °C under an
argon atmosphere. A solution of Me2Zn (0.5 mL, 1.2 M in toluene,
0.6 mmol, 3 equiv) was added slowly via syringe at the same tem-
perature. After the resulting mixture was stirred for 1.5 h at 0 °C,
diynic ester 10 (0.1735 g, 0.6 mmol, 3 equiv) was added slowly
via syringe at À20 °C. The reaction mixture was then stirred for
48 h at the same temperature, and quenched with water (5 mL),
followed by filtering through a Celite pad. The organic phase was
separated and the aqueous phase was extracted with diethyl ether
(3 Â 8 mL). The combined organic layers were washed with brine
(8 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure to get the crude product. The crude product
was purified by silica gel column chromatography (petroleum
ether/ethyl acetate 5:1) to afford a mixture of two diastereoiso-
mers 17a and 17b (0.0551 g, 60% yield, d.r. 1:6) as a yellow oil.
The diastereoisomers were separated by silica gel column chro-
matography (n-hexane/ethyl acetate 15:1) to afford pure 17a
(0.0065 g) and 17b (0.039 g). The diastereomeric ratio was deter-
mined by HPLC with a Daicel Chiralcel OJ-H column (5% 2-propanol
in n-hexane, 1 mL/min, 220 nm); minor 17a tr = 16.68 min, major
a
-methoxy-a-(trifluoromethy1) phenylacetyl chloride (MTPACl)
(25.3 mg, 0.1 mmol, 2 equiv) and TIPS enynic alcohol 5 (16.0 mg,
0.05 mmol, 1 equiv) gave 18b (13.2 mg, 49% yield) as a yellow
oil. 1H NMR (300 MHz, CDCl3) dH 7.55–7.52 (m, 2H), 7.45–7.39
(m, 3H), 6.16–6.14 (m, 1H), 5.81 (ddd, J = 16.9, 10.1, 5.7 Hz, 1H),
5.53 (dd, J = 17.0, 0.7 Hz, 1H), 5.37 (dd, J = 10.1, 0.7 Hz, 1H), 3.61
(s, 3H), 1.55 (s, 6H), 1.12–1.06 (m, 21H).
4.16. (S)-MTPA ester 19 of 15
According to the similar procedure of synthesis of 18a, (R)-(À)-
a
-methoxy-a-(trifluoromethy1) phenylacetyl chloride (MTPACl)
(50.6 mg, 0.2 mmol, 2 equiv) and epoxy alcohol 15 (17.2 mg,
0.1 mmol, 1 equiv) gave 19 (20.2 mg, 52% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3) dH 7.59–7.56 (m, 2H), 7.46–7.44 (m,
3H), 4.55 (dd, J = 11.9, 4.6 Hz, 1H), 4.38 (dd, J = 11.9, 6.8 Hz, 1H),
3.61 (d, J = 1.2 Hz, 3H), 3.27 (dt, J = 6.9, 4.5 Hz, 1H), 3.06 (dt,
J = 6.9, 4.5 Hz, 1H), 1.61–1.31 (m, 12H), 0.92 (t, J = 6.7 Hz, 3H). 13C
NMR (75 MHz, CDCl3) dC 166.5, 132.0, 129.7, 128.5, 127.3, 123.2
(q, J = 287.1 Hz), 84.7, 64.5, 56.6, 55.5, 53.0, 31.7, 29.3, 29.1, 27.9,
26.5, 22.6, 14.0. HRMS (APCI-TOF) m/z 389.1967 [M+H]+ (calcd
for C20H28F3O4 389.1940).
17b tr = 21.83 min. 17a: [
a]
20 = À85.3 (c 1.2, CHCl3); 1H NMR
D
(300 MHz, CDCl3) dH 7.96 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz,
2H), 6.19 (d, J = 5.9 Hz, 1H), 6.00 (ddd, J = 16.9, 10.0, 5.7 Hz, 1H),
5.67 (d, J = 16.9 Hz, 1H), 5.46 (d, J = 10.1 Hz, 1H), 4.32 (d,
J = 7.5 Hz, 1H), 3.22 (dd, J = 7.5, 4.3 Hz, 1H), 3.09 (dt, J = 9.8,
4.9 Hz, 1H), 2.47 (br s, 1H), 1.61–1.52 (m, 2H), 1.40–1.30 (m,
10H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 164.4,
131.9, 131.7, 131.4, 128.7, 128.2, 120.2, 76.6, 75.1, 70.8, 70.5,
65.2, 62.1, 59.5, 57.4, 31.7, 29.3, 29.1, 28.1, 26.6, 22.6, 14.0. HRMS
4.17. (S)-MTPA ester 20a of 17a
According to the similar procedure of synthesis of 18a, (R)-(À)-
a
-methoxy-a-(trifluoromethy1) phenylacetyl chloride (MTPACl)
(11.1 mg, 0.04 mmol, 2 equiv) and 17a (9.0 mg, 0.02 mmol,
1 equiv) gave 20a (7.3 mg, 54% yield) as a yellow oil. 1H NMR
(300 MHz, CDCl3) dH 7.96 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz,
2H), 7.59–7.56 (m, 2H), 7.46–7.44 (m, 3H), 6.20 (d, J = 5.5 Hz,
1H), 6.04 (ddd, J = 17.0, 9.9, 5.7 Hz, 1H), 5.67 (d, J = 16.8 Hz, 1H),
5.51 (d, J = 5.4 Hz, 1H), 5.48 (d, J = 7.6 Hz, 1H), 3.63 (s, 3H), 3.30
(dd, J = 8.1, 4.3 Hz, 1H), 3.08 (dt, J = 10.9, 4.9 Hz, 1H), 1.32–1.29
(m, 12H), 0.89 (t, J = 7.9 Hz, 3H). HRMS (ESI) m/z 697.1369 [M
+Na]+ (calcd for C34H34BrF3NaO6 697.1389).
(APCI-TOF) m/z 459.1167 [M+H]+ (calcd for C24H28BrO4 459.1171).
20
17b: [
a
]
+30.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) dH 7.96
D
(d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.19 (d, J = 5.6 Hz, 1H),
6.00 (ddd, J = 16.9, 10.1, 5.7 Hz, 1H), 5.67 (d, J = 16.9 Hz, 1H), 5.45
(d, J = 10.1 Hz, 1H), 4.40 (dd, J = 6.9, 3.9 Hz, 1H), 3.17 (dd, J = 7.3,
3.9 Hz, 1H), 3.08 (dt, J = 5.7, 3.9 Hz, 1H), 2.28 (br s, 1H), 1.68–
Please cite this article in press as: Zhou, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.12.008

Y. Zhou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
4.18. (R)-MTPA ester 20b of 17a
4.22. (3R,8S,9S,10R) 9,10-Epoxy-heptadeca-1-en-4,6-diyn-3,8-
diol 1b (diastereomer of 9-epoxy-falcarindio1)
According to the similar procedure of synthesis of 18a, (S)-(À)-
a
-methoxy-
a
-(trifluoromethy1) phenylacetyl chloride (MTPACl)
According to the similar procedure of synthesis of 1a, 4-bro-
mobenzoate 17b (0.0689 g, 0.15 mmol, 1 equiv) and aqueous solu-
tion NaOH (0.15 mL, 2 M, 3 mmol, 2 equiv) gave the diastereomer
of 9-epoxy-falcarindio1 1b (0.0332 g, 80% yield) as a yellow oil.
(11.1 mg, 0.04 mmol, 2 equiv) and 17a (9.1 mg, 0.02 mmol,
1 equiv) gave 20b (6.7 mg, 50% yield) as a yellow oil. 1H NMR
(300 MHz, CDCl3) dH 7.96 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz,
2H), 7.57–7.56 (m, 2H), 7.46–7.44 (m, 3H), 6.19 (d, J = 5.7 Hz,
1H), 6.03 (ddd, J = 17.0, 10.1, 5.7 Hz, 1H), 5.67 (d, J = 17.0 Hz, 1H),
5.48 (d, J = 10.1 Hz, 1H), 5.43 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.34
(dd, J = 8.5, 4.3 Hz, 1H), 3.15 (dt, J = 11.3, 6.2 Hz, 1H), 1.32–1.29
(m, 12H), 0.90 (t, J = 7.0 Hz, 3H). HRMS (ESI) m/z 675.1554 [M
+H]+ (calcd for C34H35BrF3O6 675.1569).
[a
]
D
20 = À57 (c 0.4, CH2Cl2); 1H NMR (300 MHz, CDCl3) dH 5.94
(ddd, J = 17.0, 10.2, 5.3 Hz, 1H), 5.48 (dd, J = 17.1, 0.9 Hz, 1H),
5.27 (dd, J = 10.2, 1.2 Hz, 1H), 4.94 (t, J = 4.6 Hz, 1H), 4.36 (dd,
J = 7.2, 3.9 Hz, 1H), 3.14 (dd, J = 7.2, 3.9 Hz, 1H), 3.05 (dt, J = 7.2,
3.9 Hz, 1H), 2.17 (d, J = 4.5 Hz, 1H), 2.05 (d, J = 6.3 Hz, 1H), 1.56–
1.46 (m, 4H), 1.32–1.24 (m, 8H), 0.88 (t, J = 3.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) dC 135.7, 117.4, 78.6, 78.0, 70.2, 70.0, 63.5, 60.8,
58.0, 57.9, 31.7, 29.4, 29.1, 27.5, 26.5, 22.6, 14.0; HRMS (APCI-
TOF) m/z 277.1797 [M+H]+ (calcd for C17H25O3 277.1804).
4.19. (S)-MTPA ester 20c of 17b
According to the similar procedure of synthesis of 18a, (R)-(À)-
a
-methoxy-a-(trifluoromethy1) phenylacetyl chloride (MTPACl)
Acknowledgments
(5.4 mg, 0.02 mmol, 2 equiv) and 17b (4.6 mg, 0.01 mmol, 1 equiv)
gave 20c (5.1 mg, 75% yield) as a yellow oil. 1H NMR (300 MHz,
CDCl3) dH 7.97 (dd, J = 6.8, 1.8 Hz, 2H), 7.64 (dd, J = 6.7, 1.8 Hz,
2H), 7.56–7.54 (m, 2H), 7.46–7.44 (m, 3H), 6.19 (d, J = 5.8 Hz,
1H), 6.02 (ddd, J = 16.8, 10.0, 5.8 Hz, 1H), 5.67 (d, J = 17.0 Hz, 1H),
5.47 (d, J = 10.1 Hz, 1H), 5.42 (d, J = 7.7 Hz, 1H), 3.58 (s, 3H), 3.33
(dd, J = 7.7, 3.8 Hz, 1H), 3.09 (dt, J = 8.6, 4.9 Hz, 1H), 1.30–1.28
(m, 12H), 0.91 (t, J = 6.2 Hz, 3H). HRMS (ESI) m/z 675.1546 [M
+H]+ (calcd for C34H35BrF3O6 675.1569).
We thank the National Key Technology Research and Develop-
ment Program (No. 2015BAK45B01), National Training Program
of Innovation and Entrepreneurship for Undergraduates
(201510019142), and Beijing Training Program of Innovation and
Entrepreneurship
2015bj144) for the financial support.
for
Undergraduates
(2015bj128
and
A. Supplementary data
4.20. (R)-MTPA ester 20d of 17b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.12.
008.
According to the similar procedure of synthesis of 18a, (S)-(À)-
a
-methoxy-a-(trifluoromethy1) phenylacetyl chloride (MTPACl)
(5.4 mg, 0.02 mmol, 2 equiv) and 17b (4.6 mg, 0.01 mmol, 1 equiv)
gave 20d (4.9 mg, 73% yield) as a yellow oil. 1H NMR (300 MHz,
CDCl3) dH 7.97 (d, J = 8.6 Hz, 2H), 7.63 (dd, J = 8.6, 1.8 Hz, 2H),
7.54–7.53 (m, 2H), 7.45–7.43 (m, 3H), 6.20 (d, J = 5.7 Hz, 1H),
6.03 (ddd, J = 17.1, 10.1, 5.8 Hz, 1H), 5.73 (d, J = 16.9 Hz, 1H), 5.47
(d, J = 10.1 Hz, 1H), 5.42 (d, J = 7.9 Hz, 1H), 3.62 (s, 3H), 3.25 (dd,
J = 7.9, 3.8 Hz, 1H), 3.03 (dt, J = 6.4, 3.1 Hz, 1H), 1.30–1.28 (m,
12H), 0.91 (t, J = 5.7 Hz, 3H). HRMS (ESI) m/z 675.1548 [M+H]+
(calcd for C34H35BrF3O6 675.1569).
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