Synthesis of (±)-pterosin A via Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tet.2013.01.055

A practical synthesis of (±)-pterosin A from commercially available 2-bromo-1,3-dimethyl-benzene 5 has been accomplished in 10% overall yield. The synthesis used Suzuki-Miyaura coupling reaction of C6-bromoindanone derivative 3 with potassium vinyltrifluoroborate 9, which provided the corresponding vinylindanone 2 in >85% yield. The vinylindanone 2 could be further elaborated to pterosin A by reduction with LAH, selective protection of primary alcohol with TESCl, hydroboration-oxidation of vinyl group, protection of primary alcohol with TIPSCl, oxidation of the secondary alcohol, and desilylation with TBAF.

Full text of DOI:10.1016/j.tet.2013.01.055

Tetrahedron 69 (2013) 2572e2576
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (ꢀ)-pterosin A via SuzukieMiyaura cross-coupling
reaction
,
Shao-Chien Hsu a, Mogili Narsingam a, Yi-Fang Lin a, Feng-Lin Hsu b, Biing-Jiun Uang a
*
a Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
b Graduate Institute of Pharmacognosy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthesis of (ꢀ)-pterosin A from commercially available 2-bromo-1,3-dimethyl-benzene 5 has
been accomplished in 10% overall yield. The synthesis used SuzukieMiyaura coupling reaction of C6-
bromoindanone derivative 3 with potassium vinyltrifluoroborate 9, which provided the corresponding
vinylindanone 2 in >85% yield. The vinylindanone 2 could be further elaborated to pterosin A by re-
duction with LAH, selective protection of primary alcohol with TESCl, hydroborationeoxidation of vinyl
group, protection of primary alcohol with TIPSCl, oxidation of the secondary alcohol, and desilylation
with TBAF.
Received 21 September 2012
Received in revised form 15 January 2013
Accepted 21 January 2013
Available online 29 January 2013
Keywords:
SuzukieMiyaura reaction
Vinylation
Ó 2013 Elsevier Ltd. All rights reserved.
Potassium vinyltrifluoroborate
Pterosin A
1. Introduction
construct both the indanone core and the C6-side chain in an ef-
ficient manner.
Pterosin family are sesquiterpenoids that existed in bracken fern
(Pteridium aquilinum).1 Some pterosins have been shown to possess
biological activity2 including antibacterial2,3 and cytotoxicity.3 Al-
though there had been some reports on the synthesis of
pterosins,4e6 the challenge of synthesizing pterosins usually was
restricted by the continuous functional groups that somehow in-
creased the complexity during the synthesis.7 We need some
substantial amount of pterosin A 1 (Fig.1) and its derivatives for our
biological studies. It needs a flexible methodology, that is, able to
The construction of indanone skeleton from benzene derivative
using FriedeleCrafts/Nazarov cyclization methodology is docu-
mented.8 Although this methodology has a drawback on the
regioselectivity, it remains as a useful method for the synthesis of
indanones from benzene derivatives.5,9
Taking the advantage of modern synthetic method using the
SuzukieMiyaura cross-coupling for the vinylation of aryl halides
with potassium vinyltrifluoroborate,10,11 we envisage that pterosin
A might be synthesized by the following manner (Fig. 1): (1) pre-
pare bromo-indanone 4 from 5 followed by ethoxycarbonylation
and alkylation to furnish C2-quaternary center, (2) use Suzu-
kieMiyaura cross-coupling reaction to install a vinyl group at C6 of
indanone 3 and it could be converted to the hydroxyethyl group to
furnish the synthesis of pterosin A or elaborate to its derivatives.
2. Results and discussion
Our synthesis of pterosin A 1 was started from the reaction of 2-
bromo-1,3-dimethylbenzene 5 with 3-chloro-propionyl chloride in
the presence of AlCl3. The reaction gave two isomeric products 6a
and 6b as described in the literature.5 The mixture of 6a and 6b was
heated directly with concd H2SO4 at 90 ꢁC to give the corresponding
indanones 4 and 7 (vide infra) in 39% and 40% yield, respectively,
(Scheme 1). However, it was found that the 1H and 13C NMR data of
either 4 or 7 did not match with that were reported in the literature
(Table 1).5 Assignments of their structures by NOE experiments
Fig. 1. Retrosynthesis of pterosin A.
* Corresponding author. E-mail address: bjuang@mx.nthu.edu.tw (B.-J. Uang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.055

S.-C. Hsu et al. / Tetrahedron 69 (2013) 2572e2576
2573
were unsuccessful. However, there is a weak correlation signal
between C1eH7 on the HMBC spectrum of 7 and no such correla-
tion signal for 4. To further confirm the structure of our prepared
products, X-ray crystallographic study was conducted and the
structure of 4 is confirmed as shown in Fig. 2.
The direct hydroxyethylation using Grignard reagent with eth-
ylene oxide is a straight forward way to construct C6 substitution.6 It
is difficult for us to receive ethylene oxide because this reagent is
a controlled chemical in our case. Besides, it limits the further
elaboration to other functional groups for the biological studies. The
incorporation of a vinyl group at C6 may provide an alternative so-
lution for the elaboration into hydroxyl group or other functional
groups. The vinylation of aryl bromide has been shown that it could
be achieved by using trivinylcyclotriboroxane,12 vinylpolysiloxanes13
or tributyl-vinyl-stannane in the palladium catalyzed coupling re-
action.14,15 However, the palladium catalyzed vinylation of 1,3-
dimethyl-2-bromobenzene derivatives usually suffer from low
yielding due to steric hindrance and the electron-rich nature that
caused by the ortho,ortho0-disubstituted methyl groups.11a Recently,
Molander’s group had established an efficient SuzukieMiyaura
Cross-Coupling reactions of potassium vinyltrifluoroborate 9 with
hindered aryl bromides, such as bromo mesitylene using RuPhos as
a ligand.10
Inspired by these reports, we tried to conduct vinylation by
SuzukieMiyaura cross-coupling reaction in our synthesis. The
ortho,ortho0-dimethyl groups could be an obstacle for the coupling
reaction if we uses less expensive PdCl2 as the catalyst. However,
the electron-withdrawing benzoyl carbonyl group could be a ben-
efit to this type of coupling reaction.10,11 Initially, treatment of the
bromoester 3 with potassium vinyltrifluoroborate 9 (1 equiv) in the
presence of 2 mol % of PdCl2, Cs2CO3 (3 equiv), and 6 mol % of PPh3
afforded an almost equal amount of coupling product 2 and bro-
moester 3 as an inseparable mixture in 87% yield (Table 2, entry 1,
Molander’s typical reaction condition).10b When the amount of
reagents and catalyst were doubled, the reaction gave a slightly
improved yield of vinylated product 2. However, some substantial
amount of 3 remained in the mixture (Table 2, entry 2). To force the
reaction toward completion and improve the yield of desired 2, the
catalyst loading was raised to 20 mol % for the coupling reaction
and it afforded product 2 in 88% yield as a mixture with inseparable
reduction product 10 (Table 2, entry 3). It was documented that the
increase of palladium catalyst loading could cause the formation of
reduction product.11a Through the optimization process, it was
observed that the ratio of 2 and 10 could be slightly improved by
decreasing the amount of Cs2CO3 (Table 2, entry 4). Decrease the
amount of base and increase the reaction concentration of the re-
action gave unsatisfactory results (Table 2, entries 5 and 6). There
was no apparent improvement found whether the reaction tem-
perature was lowered or raised (Table 2, entries 7 and 8). Attempt to
speed up the catalytic cycle of coupling reaction by increasing the
amount of PPh3 and shorten the reaction time (Table 2, entry 9), but
the reduction product 10 still can be found. Interestingly, when the
reaction was prolonged, it was found that the reaction can go to
completion with almost the same amount of reduction 10 was
produced (Table 2, entry 10). The ratio of 2 and 10 could be further
improved to 95:5 when the amount of potassium vinyl-
trifluoroborate 9 was decreased (Table 2, entries 11 and 12). How-
ever, the yield was decreased dramatically when the amount of 9
was decreased further (Table 2, entry 13).
Scheme 1. Reagents and conditions: (i) AlCl3, CH2Cl2, 0 ꢁC to rt, 12 h; (ii) concd H2SO4,
90 ꢁC, 1 h, 39% of 4.
Table 1
NMR chemical shifts (ppm) of indanone 4 and 7 (all measured in CDCl3)
Reported 45
4
7
1H NMR
13C NMR
1H NMR
13C NMR
1H NMR
13C NMR
2.45 (s, 3H)
2.65 (s, 3H)
2.9 (t, 2H)
3.04 (t, 2H)
7.26 (s, 1H)
19.46
24.25
36.85
122.65
133.6
136.7
138.54
152.83
205
2.46 (s, 3H)
2.66 (t, 2H)
2.72 (s, 3H)
2.95 (t, 2H)
7.17 (s, 1H)
17.32
24.41
24.88
2.41 (s, 3H)
2.45 (s, 3H)
2.67 (t, 2H)
3.02 (t, 2H)
7.45 (s, 1H)
18.86
24.09
25.23
37.09
36.25
125.75
127.88
133.29
138.72
144.51
154.38
206.24
121.97
134.97
135.28
136.06
137.88
152.24
206.32
Fig. 2. X-ray single crystal analysis of indanone 4.
It is crucial to use a proper amount of potassium vinyl-
trifluoroborate 9 in SuzukieMiyaura reaction to suppress the re-
duction product. The reduction product 10 was eliminated by
decreasing the amount of 9.11a However, it is contrary to Wyatt’s
report that the reduction product was eliminated by increasing the
amount of 9 (Table 2, entries 2, 10, and 11). These opposite findings
may be due to the catalyst systems are different.16 The result of
entry 12 in Table 2 is compatible with Wyatt’s result in terms of
yield.11a This condition was selected for the preparation of vinyl-
indanone 2.
Treatment of indanone 4 with sodium hydride and diethyl car-
bonate in refluxing toluene gave 8 in 88% yield. Subsequently,
treatment of 8 with sodium hydride in THF and iodomethane
afforded 3 in 86% yield (Scheme 2).
With the advanced intermediate 2 in hand, we continued our
Scheme 2. Reagents and conditions: (i) NaH, diethyl carbonate, toluene, reflux, 88%;
(ii) NaH, MeI, THF, 0 ꢁC to rt, 86%.
effort to construct 20-hydroxyethyl group at C6 position. It is

2574
S.-C. Hsu et al. / Tetrahedron 69 (2013) 2572e2576
Table 2
Optimization of the SuzukieMiyaura reaction17
Entrya
9 (equiv)
Cs2CO3 (equiv)
PPh3 (mol %)
PdCl2 (mol %)
Temp (oC)
THF:H2O (9:1)/mL
Time (h)
Ratioc (3:2:10)
Yield (%)d
1
2
3
4
5
6
7
8
1
2
3
3
3
3
3
3
3
3
2
1.5
1.2
3
6
6
4
2
2
4
4
4
4
4
4
4
6
12
30
30
30
30
30
30
60
60
30
30
30
2
4
85
85
85
85
85
3
3
3
3
1
1
1
1
1
1
3
3
3
48
48
48
48
48
60
48
48
24
48
48
48
48
47:53:0
40:60:0
0:85:15
0:89:11
44:52:4
26:68:6
29:60:11
0:86:14
13:77:10
0:91:9
87
80
88
90
92
93
91
93
93
91
90
90
92
20
20
30
30
30
30
30
30
20
20
20
85
65
105b
85
9
10
11
12
13
85
85
85
85
0:93:7
0:95:5
22:72:6
a
All reactions were conducted with 300 mg of 3.
THF was replaced by DME (1,2-dimethoxyethane).
Ratios were determined by 1H NMR of the isolated mixture.17
Isolated yield of the mixture (2þ3þ10).
b
c
d
reasonable to control the regiochemistry on the hydration of vinyl
group by using hydroboration/oxidation sequence (Scheme 3).
However, treatment of 2 with borane etherate followed by H2O2/
NaOH gave a complex mixture. There is no carbonyl signal in IR
coupling reaction in the presence of PdCl2 can be achieved in high
yield. We have accomplished the synthesis of (ꢀ)-pterosin A in 9
steps and 10% overall yield. Although the overall yield of our syn-
thetic pterosin A is lower than the reported synthesis,6 vinyl-
indanone 2 will be more versatile for the further elaboration to
pterosin A derivatives for the biological and StructureeActivity
Relationship studies.
spectrum of the reaction product. To minimize the complexity, b-
keto ester 2 was reduced to the corresponding diol by LAH then
followed by a selective protection of the primary alcohol to provide
11 as a w1:1 diastereomeric mixture. When 11 was treated with
borane etherate followed by an oxidation using H2O2 and 2 N
NaOH, an equal amount of the desired compound 12 and undesired
regioisomer were detected. To improve the regioselectivity, 9-BBN
was tested for the reaction. Unfortunately, no sign of reaction was
observed. Finally, diol 12 was obtained as a diastereomeric mixture
in 81% yield when dicyclohexylborane was used to react with 11
followed by oxidation with H2O2/2 N NaOH. Selective protection of
the primary alcohol in 12 by using triisopropylsilyl chloride (TIPSCl)
afforded 13 in 82% yield. The benzylic hydroxyl group of 13 was
oxidized by using PDC to give keto compound 14. Subsequently,
both TIPS and TES groups of 14 were removed by using tetrabuty-
lammonium fluoride (TBAF) in THF to give (ꢀ)-pterosin A 1 in 85%
yield. Both 1H and 13C NMR spectra and other physical data of our
synthetic compound 1 were in agreement with the known litera-
ture data.6
4. Experimental section
4.1. General information
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a BRUKER AV-400 (400 MHz) or a Varian Mercury-400
(400 MHz). Data were reported in the following order; chemical
shift as
d values referenced to CDCl3 (7.24), integration, multiplicity
(s¼singlet,
d¼doublet,
t¼triplet,
q¼quartet,
br¼broad,
m¼multiple), coupling constants in Hertz. Carbon nuclear mag-
netic resonance (13C NMR) spectra were recorded on a Varian
Mercury-400 (100 MHz). Chemical shifts are reported in
d values
and referenced to CDCl3 (77.00). High resolution mass spectra
(HRMS) were recorded with Mass spectrometers in m/z, re-
spectively, in NSC Instrumentation Center at NTHU. IR spectra were
obtained on a Bomen MB 100FT spectrometer. Thin-layer chroma-
tography was performed on silica gel G60 F254 (Merck) with short-
wavelength UV light for visualization. Silica Gel 60 (particle size
63w200 um, purchased from Merck) was used for column
chromatography.
3. Conclusions
In summary, the vinylation of hindered aryl bromide by using
potassium vinyltrifluoroborate 9 in the SuzukieMiyaura cross-
Scheme 3. Reagents and conditions: (i) LAH, THF, ꢂ78 ꢁC, 3 h then TESCl, Imidazole, CH2Cl2, 6 h, 2 steps 88%; (ii) Cy2BH, 0 ꢁC to rt, 12 h; then 2 N NaOH, H2O2, 0 ꢁC, 4 h, 81%; (iii)
TIPSCl, imidazole, 0 ꢁC to rt, 3 h, 82%; (iv) PDC, CH2Cl2, 0 ꢁC to rt, 4 h, 81%; (v) TBAF, THF, 0 ꢁC to rt, 3 h, 85%.

S.-C. Hsu et al. / Tetrahedron 69 (2013) 2572e2576
2575
4.2. Procedure for the preparation of pterosin A (1)
13C NMR:
d 13.94, 17.57, 21.12, 24.97, 38.58, 56.59, 61.39, 125.59,
128.37, 131.12, 139.87, 145.43, 151.92, 171.88, 202.79; HRMS: calcd for
C15H17BrO3: 324.0361, found: 324.0355. IR (KBr) 1740, 1708, 1590,
1454.
4.2.1. 6-Bromo-5,7-dimethyl-1-indanone 4. To a stirred mixture of
AlCl3 (20.2 g, 151 mmol) and 3-chloro-propionyl chloride (16.5 g,
129 mmol) in CH2Cl2 (80 mL) was dropwise added 2-bromo-1,3-
dimethylbenzene 2 (20.0 g, 108 mmol) in CH2Cl2 (40 mL) through
an addition funnel over 40 min at 0 ꢁC .The reaction mixture was
warmed to room temperature and stirred for 12 h then quenched
with ice (200 g) and 12 M HCl (50 mL). The mixture was stirred for
15 min then extracted with ethyl acetate (2ꢃ300 mL). The com-
bined extract was successively washed with water (400 mL), brine
(500 mL) dried (Na2SO4), and concentrated in vacuo. The residue
was added concd H2SO4 (165 mL), and stirred at 90 ꢁC for 1 h. After
the reaction mixture was cooled to room temperature, it was
quenched with the addition of ice (400 g). The reaction mixture was
extracted with ethyl acetate (2ꢃ400 mL), and the combined extract
was washed with water (500 mL), brine (500 mL), dried (anhydrous
Na2SO4), and concentrated in vacuo. The crude product was puri-
fied by silica gel column chromatography (hexane/ethyl acetate,
12:1, v/v) to give pure 4 (10.1 g, 39%) as solid and 7 (10.3 g, 40%).
4.2.4. 2,5,7-Trimethyl-1-oxo-6-vinyl-indan-2-yl-carboxylic acid ethyl
ester 2. A solution of potassium vinyltrifluoroborate, 9 (186 mg,
1.38 mmol), PdCl2 (33 mg, 0.18 mmol), PPh3 (73 mg, 0.27 mmol),
Cs2CO3 (1.2 g, 3.7 mmol), and compound 3 (0.30 g, 0.92 mmol) in
THF/H2O (9:1) (3 mL) was heated at 85 ꢁC with stirring under an
argon atmosphere in a sealed tube for 48 h. After cooled to room
temperature, the reaction mixture was diluted with H2O (6 mL) and
extracted with ethyl acetate (3ꢃ10 mL). The combined extract was
dried (anhydrous Na2SO4), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (4% EtOAc in
petroleum ether as eluent) to give an inseparable mixture of
compounds 2 and 10 (0.23 g, 90% in total yield). Compound 2: 1H
NMR:
d
1.21 (t, J¼7.2 Hz, 3H), 1.46 (s, 3H), 2.33 (s, 3H), 2.59 (s, 3H),
2.83 (d, J¼16.8 Hz, 1H), 3.58 (d, J¼16.8 Hz, 1H), 4.15 (m, 2H), 5.22
(dd, J¼18.0, 2.0 Hz, 1H), 5.61 (dd, J¼11.2, 2.0 Hz, 1H), 6.61 (dd,
Compound 4: mp: 81w86 ꢁC; 1H NMR:
d
2.46 (s, 3H), 2.66 (t,
J¼11.2, 18.0 Hz, 1H), 7.11 (s, 1H); 13C NMR:
d 13.94, 14.05, 21.21,
J¼6 Hz, 2H), 2.72 (s, 3H), 2.95 (t, J¼6 Hz, 2H), 7.17 (s, 1H); 13C NMR:
21.80, 38.84, 56.26, 61.21, 120.71, 124.92, 130.13, 133.80, 137.46,
138.49, 143.90, 151.93, 172.30, 203.8; HRMS: calcd for C17H20O3:
272.1412, found: 272.1416; IR (KBr) 3083, 1736, 1705, 1439.
d
17.32, 24.41, 24.88, 37.09, 125.75, 127.88, 133.29, 138.72, 144.51,
154.38, 206.24; HRMS: calcd for C11H11BrO: 237.9993, found:
237.9993. IR (KBr) 3011, 1706, 1590, 1441; Compound 7: 1H NMR:
d
2.41 (s, 3H), 2.45 (S, 3H), 2.67 (t, J¼6 Hz, 2H), 3.02 (t, J¼6 Hz, 2H),
4.2.5. 2,5,7-Trimethyl-2-triethylsilanyloxymethyl-6-vinyl-indan-1-ol
11. To a stirred dry THF (10 mL) solution containing compound 2
(1.3 g, 4.7 mmol) was added lithium aluminum hydride (0.212 g,
5.73 mmol) at ꢂ78 ꢁC under argon atmosphere. The reaction
mixture was stirred for 3 h then warmed to 0 ꢁC and quenched with
ethyl acetate at 0 ꢁC. The mixture was washed with 2 M potassium
sodium tartrate solution (20 mL) and extracted with ethyl acetate
(3ꢃ20 mL). The combined extract was washed with brine (20 mL),
dried (anhydrous Na2SO4), and concentrated in vacuo. The crude
residue was directly used for next step without purification. To
7.45 (s, 1H); 13C NMR:
d
18.86, 24.09, 25.23, 36.25, 121.97, 134.97,
135.28, 136.06, 137.88, 152.24, 206.32 IR (KBr) 1689, 1598, 1435.
4.2.2. 6-Bromo-5,7-dimethyl-1-oxo-indan-2-yl-carboxylic acid ethyl
ester 8. A mixture containing sodium hydride (60% dispersion, 5.0 g,
125 mmol) and diethyl carbonate (30.5 mL, 251 mmol) in toluene
(100 mL) was stirred mechanically with reflux. 1-Indanone 4 (10.0 g,
41.8 mmol) in toluene (50 mL) was added slowly to the above
refluxing solution over a period of 3 h. The addition funnel was
washed with toluene (20 mL) and the solution was added to the
reaction mixture. The reaction mixture was refluxed for an addi-
tional 0.5 h then added slowly into a saturated aqueous NH4Cl so-
lution. The aqueous layer was extracted with ethyl acetate
(3ꢃ100 mL) and the combined ethyl acetate extracts were washed
with brine, dried (anhydrous Na2SO4), and concentrated in vacuo.
The crude product was purified by silica gel column chromatography
(hexane/ethyl acetate, 15:1, v/v) to give 8 (11.5 g, 88.4%) as solid. Mp:
a
stirred solution containing above crude product (0.85 g,
3.66 mmol) in dry CH2Cl2 (20 mL) was added imidazole (0.50 g,
7.3 mmol) and TESCl (0.60 mL, 3.6 mmol) sequentially at 0 ꢁC under
argon atmosphere. The mixture was stirred at same temperature
for 6 h, then was diluted with H2O (20 mL) followed by extraction
with CH2Cl2 (3ꢃ10 mL). The combined extract was washed with
brine (25 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel column chromatography (10%
EtOAc in petroleum ether as eluent) to give 11 (0.85 g, 88%) as
108 ꢁC 1H NMR:
(dd, J¼8.4, 17.2 Hz, 1H), 3.39 (dd, J¼4.0, 17.2 Hz, 1H), 3.69 (dd, J¼4.0,
8.4 Hz, 1H), 4.24 (m, 2H), 7.2 (s, 1H); 13C NMR:
14.10, 17.52, 24.97,
28.92, 54.03, 61.56, 125.58, 128.34, 131.63, 139.59, 145.57, 152.87,
169.15, 198.89; HRMS: calcd for C14H15BrO3: 310.0205, found:
310.0200. IR (KBr) 1738, 1709.
d
1.29 (t, J¼7.2 Hz, 3H), 2,48 (s, 3H), 2.71 (s, 3H), 3.19
a syrup. 1H NMR:
d
0.52 (q, J¼8.4 Hz, 6H), 0.94 (t, J¼8.4 Hz, 9H), 1.18
d
(s, 3H), 2.27 (s, 3H), 2.35 (s, 3H), 2.57e2.68 (m, 2H), 3.34e3.42 (m,
2H), 4.98 (d, J¼6.4 Hz, 1H), 5.19 (d, J¼17.6 Hz, 1H), 5.51 (d, J¼11.2 Hz,
1H), 6.64 (dd, J¼11.2, 17.6 Hz, 1H), 6.85 (s, 1H); 13C NMR:
d 4.32 (3C),
6.72 (3C), 16.26, 18.04, 21.16, 40.37, 48.50, 69.55, 79.13, 119.28,
123.97, 133.62, 135.27, 136.18, 136.65, 140.15, 140.87; HRMS: calcd
for C21H34O2Si: 346.2328, found: 346.2332. IR (KBr) 3325, 3082,
1607, 1457.
4.2.3. 6-Bromo-2,5,7-trimethyl-1-oxo-indan-2-yl-carboxylic acid ethyl
ester 3. To a stirred solution of compound 8 (5.00 g, 16.1 mmol) in
dry THF (50 mL) was added sodium hydride (60% dispersion, 1.42 g,
35.4 mmol) in portions at 0 ꢁC by a solid addition funnel. The re-
action mixture was warmed to room temperature and stirred for
another 1 h, then was added MeI (2.0 mL, 32.1 mmol) dropwise at
0 ꢁC under argon atmosphere. The reaction mixture was warmed to
room temperature again and stirred for 5 h, then was quenched with
saturated aqueous NH4Cl solution at 0 ꢁC. The mixture was stirred for
15 min and extracted with ethyl acetate (3ꢃ100 mL). The combined
extract was washed with water (100 mL), brine (100 mL), dried
(anhydrous Na2SO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate,
4.2.6. 6-(20-Hydroxy-ethyl)-2,5,7-trimethyl-2-triethylsilanyloxy-methyl
-indan-1-ol 12. To a stirred dry THF (25 mL) solution containing 11
(0.85 g, 2.4 mmol) was added (Cy)2BH (0.87 g, 4.9 mmol) slowly at
0
ꢁC under argon atmosphere. The mixture was warmed to room
temperature and stirred for 12 h then was added 2 N NaOH (6 mL)
and H2O2 (3 mL) at 0 ꢁC. After stirred for 4 h the reaction mixture was
extracted with ethyl acetate (3ꢃ20 mL). The extract was washed with
water (10 mL), brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(10% EtOAc in petroleum ether as eluent) to give 12 (0.72 g, 81%) as
15:1, v/v) to give 3 as solid (4.5 g, 86%). Mp¼69 ꢁC; 1H NMR:
d
1.17 (t,
a gummy syrup. 1H NMR:
9H), 1.15 (s, 3H), 2.29 (s, 3H), 2.37 (s, 3H), 2.56, 2.63 (ABq, JAB¼16.4 Hz,
2H), 2.9 (t, J¼7.2 Hz, 2H), 3,33, 3.38 (ABq, JAB¼9.2 Hz, 2H), 3.66 (t,
d
0.52 (q, J¼8.4 Hz, 6H), 0.94 (t, J¼8.4 Hz,
J¼7.2 Hz, 3H),1.46 (s, 3H), 2.48 (s, 3H), 2.72 (s, 3H), 2.82 (d, J¼17.2 Hz,
1H), 3.53 (d, J¼17.2 Hz, 1H), 4.12 (dq, J¼7.2, 2.0 Hz, 2H), 7.18 (s, 1H);

2576
S.-C. Hsu et al. / Tetrahedron 69 (2013) 2572e2576
J¼7.2 Hz, 2H), 4.91 (s,1H), 6.82 (s, 1H); 13C NMR:
d
4.29 (3C), 6.70 (3C),
125.80, 131.55, 135.01, 138.10, 144.98, 152.38, 212.00; HRMS: calcd
for C15H20O3: 248.1412, found: 248.1408. IR (KBr) 3387, 1686, 1599,
1042.
15.18, 18.05, 20.49, 32.53, 40.35, 48.38, 61.65, 69.56, 79.13,124.4, 133.1,
134.8, 137.2, 140.4, 140.5; HRMS: calcd for C21H36O3Si: 364.2434,
found: 364.2427. IR (KBr) 3297, 1238, 1092, 1015, 741.
Acknowledgements
4.2.7. 2,5,7-Trimethyl-2-triethylsilanyloxymethyl-6-(2-triisopro-pylsily-
loxy-ethyl)-indan-1-ol 13. To a stirred solution of 12 (0.70 g, 1.9 mmol)
in dry CH2Cl2 (5 mL) was added imidazole (262 mg, 3.84 mmol) and
TIPSCl (0.45 mL, 2.11 mmol) sequentially at 0 ꢁC under argon atmo-
sphere. The reaction mixture was warmed to room temperature and
stirred for 3 h, then was diluted with H2O (10 mL) followed by ex-
traction with CH2Cl2 (3ꢃ10 mL). The combined organic layer was
washed with brine (10 mL), dried (anhydrous Na2SO4), and concen-
trated in vacuo. The residue was purified by silica gel column chro-
matography (4% EtOAc in petroleum ether as eluent) to give 13
We thank the National Science Council, Taiwan (ROC) for fi-
nancial support. (NSC 99-2323-B-038-002 and 101N2010E1).
Supplementary data
Crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre (de-
position number: CCDC 885874). Supplementary data related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2013.01.055.
(0.82 g, 82%). 1H NMR:
d
0.52 (q, J¼8.4 Hz, 6H), 0.94 (t, J¼8.4 Hz, 9H),
0.98e1.07 (m, 21H), 1.1 (s, 3H), 1.53 (d, J¼4.8 Hz, 1H), 2.34 (s, 3H), 2.39
(s, 3H), 2,57, 2.64 (ABq, JAB¼16 Hz, 2H), 2.93 (t, J¼7.6 Hz, 2H), 3,34, 3.39
(ABq, JAB¼9.6 Hz, 2H), 3.71 (t, J¼7.2 Hz, 2H), 4.91 (d, J¼4.8 Hz 1H), 6.81
References and notes
1. (a) Kuroyanagi, M.; Fukuoka, M.; Yoshihira, K.; Natori, S. Chem. Pharm. Bull. 1974,
22, 723; (b) Yoshihira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S.; Umeda, M.;
Morohoshi, T.; Enomoto, M.; Saito, M. Chem. Pharm. Bull. 1978, 26, 2346; (c)
Takashi, M.; Fuchino, H.; Sekita, S.; Satake, M. Phytother. Res. 2004, 18, 573; (d)
Fletcher, M. T.; Hayes, P. Y.; Somerville, M. J.; De Voss, J. J. Tetrahedron Lett. 2010,
51, 1997; (e) Ouyang, D. W.; Ni, X.; Xu, H. Y.; Chen, J.; Yang, P. M.; Kong, D. Y.
Planta Med. 2010, 76, 1896.
(s, 1H); 13C NMR:
d 4.34 (3C), 6.74 (3C), 11.96 (3C), 15.17, 17.97 (6C),
18.09, 20.52, 33.11, 40.33, 48.448, 62.30, 69.61, 79.32, 124.332, 133.75,
134.79, 137.30, 140.19, 140.44; HRMS: calcd for C30H56O3Si2: 520.3768,
found: 520.3763. IR (KBr) 3322, 1608, 1462, 1238, 1098, 1013.
2. Kobayashi, A.; Egawa, H.; Koshimizu, K.; Mitsui, T. Biol. Chem. 1975, 39, 1851.
3. (a) Kobayashi, A.; Koshimizu, K. Agric. Biol. Chem. 1980, 44, 393; (b) McMorris,
T.; Kelner, M.; Wang, W.; Estes, L.; Momotoya, M.; Taetle, R. J. Org. Chem. 1992,
57, 6876; (c) Bardouille, V.; Mootoo, B. S.; Hirotsu, K.; Clardy, J. Phytochemistry
1978, 17, 275; (d) Evans, E. T. R.; Evans, W. C.; Hughes, L. E. Vet. Rec. 1951, 63,
444; (e) Evans, W. C.; Patel, W. C.; Koohy, Y. Proc. R. Soc. Edinburgh, Sect. B: Biol.
1982, 81, 29; (f) Chen, Y. H.; Chang, F. R.; Lu, M. C.; Hsieh, P. W.; Wu., M. J.; Du, Y.
C.; Wu, Y. C. Molecules 2008, 13, 255.
4. (a) McMorris, T.; Liu, M.; White, R. H. Lloydia 1977, 40, 221; (b) Hyashi, Y.;
Nishizawa, M.; Harita, S.; Sakan, T. Chem. Lett. 1972, 375; (c) Neeson, S.; Ste-
venson, P. Tetrahedron 1989, 45, 6239; (d) Curtis, E.; Sandanayaka, V.; Padwa, A.
Tetrahedron Lett. 1995, 36, 1989; (e) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J.
Org. Chem. 1996, 61, 73; (f) Farrell, R.; Kelleher, F.; Sheridan, H. J. Nat. Prod. 1996,
59, 446.
4.2.8. 2,5,7-Trimethyl-2-triethylsilanyloxymethyl-6-(2-triisopro-pylsi-
lyloxy-ethyl)-indan-1-one 14. To a stirred solution of compound 13
(0.80 g, 1.5 mmol) in dry CH2Cl2 (5 mL) was added pyridinium di-
chromate (1.15 g, 3.07 mmol) at 0 ꢁC under argon atmosphere. The
reaction mixture was warmed to room temperature and stirred for
4 h, then was concentrated in vacuo. The residue was purified by
silica gel column chromatography (3% EtOAc in petroleum ether as
eluent) to give 14 (0.64 g, 81%) as a colorless syrup. 1H NMR:
d 0.48
(q, J¼8.4 Hz, 6H), 0.83 (t, J¼8.4 Hz, 9H), 0.98e1.07 (m, 21H), 1.08 (s,
3H), 2.41 (s, 3H), 2.6e2.65 (m, 4H), 2.96 (t, J¼7.6 Hz, 2H), 3.34 (d,
J¼17.2, 1H), 3.48 (d, J¼9.6 Hz,1H), 3.69e3.72 (m, 3H), 7.05 (s,1H); 13C
5. Sheridan, H.; Lemon, S.; Frankish, N.; McArdle, P.; Higgins, T.; James, P.;
Bhandrai, P. Eur. J. Med. Chem. 1990, 25, 603.
NMR: d 4.26 (3C), 6.56 (3C), 11.91 (3C), 13.66, 17.90 (6C), 20.63, 21.35,
32.21, 36.72, 51.64, 62.20, 68.07, 125.44, 132.14,135.01, 137.71, 144.24,
152.43, 210.58; HRMS: calcd for C30H54O3Si2: 518.3611, found:
518.3602. IR (KBr) 3388, 1703, 1601, 1462, 1013.
6. Ng, K.; McMorris, T. Can. J. Chem. 1984, 62, 1945.
7. Wessig, P.; Teuhner, J. Synlett 2006, 1543.
8. Hart, R. T.; Tebbe, R. F. J. Am. Chem. Soc. 1950, 72, 3286.
9. (a) Finkielsztein, L. M.; Bruno, A. M.; Renou, S. G.; Iglesia, G. M. Bioorg. Med.
Chem. 2006, 14, 1863; (b) Finkielsztein, L. M.; Castro, E. F.; Fabian, L. E.; Mol-
trasio, G. Y.; Campos, R. H.; Cavallaro, L. V.; Moglioni, A. G. Eur. J. Med. Chem.
2008, 43, 1767.
4.2.9. 6-(2-Hydroxy-ethyl)-2-hydroxymethyl-2,5,7-trimethyl-indan-
1-one 1. To a stirred solution of 14 (0.64 g, 1.2 mmol) in dry THF
(5 mL) was added tetra-n-butylammonium fluoride (0.65 g,
2.4 mmol) in THF (5 mL) at 0 ꢁC. The mixture was stirred at room
temperature for 3 h then added H2O (10 mL) followed by extraction
with ethyl acetate (3ꢃ20 mL). The combined organic layer was
washed with brine (10 mL), dried (anhydrous Na2SO4), and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (20% EtOAc in petroleum ether as eluent) to give 1
10. (a) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107; (b) Molander, G. A.;
Brown, A. R. J. Org. Chem. 2006, 71, 9681.
11. For the vinylation of sterically hindered aryl halides, please see: (a) Carter, R. R.;
Wyatt, J. K. Tetrahedron Lett. 2006, 47, 6091; (b) Brooker, M. D.; Cooper, S. M., Jr.;
Hodges, D. R.; Carter, R. R.; Wyatt, J. K. Tetrahedron Lett. 2010, 51, 6748.
12. Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968.
13. Denmark, S. E.; Bulter, C. R. Org. Lett. 2006, 8, 63.
14. Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343.
15. Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119.
16. Although PdCl2(dppf)$CH2Cl2 system allows the reaction can be done without
using seal tube,11a the PdCl2 system was chosen because of its lower cost.
17. Product ratios were determined from the 1H NMR spectra by peaks integration
(0.26 g, 85%). 1H NMR:
d 1.19 (s, 3H), 2.4 (s, 3H), 2.62 (s, 3H), 2.72 (d,
J¼16.8 Hz, 1H), 2.97 (t, J¼7.2 Hz, 2H), 3.06 (d, J¼17.2 Hz, 1H), 3.57 (d,
of aryl hydrogens at chemical shifts d 7.18 (s, 1H, starting materials 3) 7.11 (s, 1H,
vinylindanone 2), 7.05 (s, 1H) and 6.94 (s, 1H, reduction product 10) of the
partially purified reaction mixture.
J¼10.8 Hz, 1H), 3.7 (t, J¼7.2 Hz, 2H), 3.76 (d, J¼10.8 Hz, 1H), 7.08 (s,
1H); 13C NMR:
d 13.72, 20.95, 21.29, 31.71, 36.67, 50.77, 61.29, 67.84,