Synthesis of Two Coumarins Isolated from Aster praealtus

Article abstract of DOI:10.1002/cjoc.201500295

Two coumarins isolated from Aster praealtus were synthesized via a direct coupling of the corresponding cyclohexyl carbinol with a coumarin-derived aryl bromide or iodide, a very difficult etherification due to the excess steric congestion around the carbinol and the low reactivity of the aryl halide that frustrated many seemingly feasible protocols. Unequivocal ¹H and ¹³C NMR data for these compounds were thus made available for the first time. Uncertainty and errors in ¹H and ¹³C NMR data in previous reports are also eliminated and revealed, respectively. These two long-known naturally occurring coumarins were synthesized via a direct coupling reaction, a very difficult etherification that frustrated many seemingly feasible protocols. Clear-cut spectroscopic data for these compounds were thus made available for the first time.

Full text of DOI:10.1002/cjoc.201500295

FULL PAPER
DOI: 10.1002/cjoc.201500295
Synthesis of Two Coumarins Isolated from Aster praealtus
Bo Wang,a,b Huijun Chen,a Yikang Wu,*,a and Bo Liu*,b
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemis-
try for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
b Key Laboratory of Green Chemical Technology of College of Heilongjiang Province, School of Chemical and
Environmental Engineering, Harbin University of Science and Technology, Harbin 150040, China
Two coumarins isolated from Aster praealtus were synthesized via a direct coupling of the corresponding cy-
clohexyl carbinol with a coumarin-derived aryl bromide or iodide, a very difficult etherification due to the excess
steric congestion around the carbinol and the low reactivity of the aryl halide that frustrated many seemingly feasi-
1
ble protocols. Unequivocal H and 13C NMR data for these compounds were thus made available for the first time.
Uncertainty and errors in 1H and 13C NMR data in previous reports are also eliminated and revealed, respectively.
Keywords alcohols, condensation, natural products, stereochemistry, ethers
Introduction
These two natural products were documented in the lit-
erature since 1968 and 1989,[4,5] respectively. Racemic 4
was also reported[6,7,8a] as a side/minor products of
Lewis acid mediated cyclization of a geranyl epoxide
(with the coumarin moiety already connected to the
primary OH of geraniol). Recently, a coumarin sharing
the same planar structure with 4 was also isolated[8b]
from roots of Cleme viscosa (L.).
During our recent study[1] on the synthesis of peroxy
chamigranoids[2] (such as 1, Figure 1), enantioselective
cyclization of geraniol 2 was once considered as a pos-
sible approach for construction of the cyclohexane ring
with the geminal dimethyl groups in the target structures.
Alternatives involving the potentially exploitable inter-
mediate cyclohexyl carbinol 3 were also examined.
Compound 5 (Praealtin C) was only obtained[5] as an
inseparable mixture with an acyl isomer (carrying a
2-methylbutanoyl instead of the 3-methylbutanoyl
group on the secondary hydroxyl group); its NMR
hence has never been secured to date. Therefore, it ap-
peared warranted to carry out a synthetic study of the
natural coumarins 4 and 5.
O
HO
HO
O
OH
O
OAc
H
H
1
2
3
14'
15'
13'
5
8
4
4a
8a
6
3
11' 12'
8'
9'
O
1'
O
O
O
HO
Results and Discussion
7
7'
4'
2
O
O
O
O
6'
2'
3'
1
Given optically active 3 (prepared using a literature[9]
procedure) already available, direct coupling with a
coumarin-related species such as 8 and 9 (Scheme 1)
appeared to be a straightforward entry to the target
compounds 4 and 5. However, to date there has been no
precedent for coupling of 8 or 9 with any aliphatic al-
cohols, although substituted phenols did undergo
smooth coupling[10] with 8; attachment of any alkyl
groups to the C-7 position of coumarin can be achieved
only either via alkylation of the OH of 7 with a halide
(often unhindered or activated) or a Mitsunobu reaction
with an unhindered alcohol.[11] These documented lit-
erature cases, when taken together, seemed to indicate
5'
10'
4
5 (Praealtin C)
AcO
O
O
O
X
O
O
6 (Praealtin A)
7 X = OH, 8 X = Br, 9 X = I
Figure 1 The structures for talaperoxide A 1, geraniol 2, the
carbinol 3, natural coumarins 4－6 and the building blocks 7－9.
As an extension of the work on the peroxy chami-
granoids, we also explored the synthesis of two other
natural products[3] related to 3, i.e. coumarins 4 and 5.
*
E-mail: yikangwu@sioc.ac.cn
Received April 10, 2015; accepted April 23, 2015; published online June 2, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500295 or from the author.
Chin. J. Chem. 2015, 33, 723—728
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Wang et al.
FULL PAPER
place the 1,10-phenanthroline as the ligand with K3PO4
as the base instead of Cs2CO3 as reported[17] by Xu and
Hu also failed to result any reactions.
that for some reasons the coupling of 8 or 9 with alco-
hols might be experimentally unfeasible.
Scheme 1 Coupling of 3 with coumarin-related aryl halides
However, under the CuI/Cs2CO3/1,10-phenanthro-
line/toluene/110 ℃ conditions[16] the coupling of 12[18]
with 3 proceeded smoothly (Scheme 2), affording the
corresponding coupling product 11 in 71% isolated
yield. Debenzylation of 13 could also be achieved satis-
factorily under Liu’s[19] Li/naphthalene conditions. En-
couraged by this model reaction, we next used 15[20a]
(which might allow for a late stage construction of the
coumarin ring through the aldehyde group) to run the
coupling under the same conditions. But unfortunately,
the yield for the expected 17 turned out to be only 40%.
And the product was no longer predominated by a sin-
gle isomer (containing a regio-isomer 17', where the
aryl group was on the secondary OH, cf. the discussion
below for 4' in Scheme 1). All these made this route
much less attractive than expected. The planned[20b]
subsequent steps were therefore not carried out.
HO
OH
cf. also text
X
O
O
3
8
9
X = Br, X = I
CuI/Cs2CO3
1,10-penanthroline
O
O
O
O
O
O
OH
OH
4'
4
inseparable
f rom each other
Solvent/temperature: tolunene/up to 120 °C (no reactions)
8 4 4'
3
)
or xylene/160 °C (11% from
or xylene/160 °C (20% from
,
/
= 5.9:1, 50% recovered
= 5.9:1, 40% recovered
9 4 4'
3
)
,
/
Scheme 2 Model reactions
OBn
HO
OH
Br
Br
O
OMe
O
O
CuI/Cs2CO3
11
10
1,10-penanthroline
3
(cf. text)
O
HO
toluene/110 °C
71%
Nevertheless, prompted by the potential advantage
such a direct coupling may offer to the coumarin syn-
thesis, also by the availability of 3, we decided to take
the challenge of the seemingly hopeless coupling any-
way.
I
OBn
13
12
Li/THF
94%
naphthlene
HO
O
OH
−78 °C
The initial experiment was performed under the
Buchwald’s[12] conditions, which were effective for
connection of a range of alcohols (even sterically hin-
dered ones) to different phenols. Thus, the bromide 8
(prepared according to a literature[13] procedure from the
commercially available coumarin 7) was treated with
alcohol 3 in the presence of Pd2(dba)2/BINAP and
Cs2CO3 in toluene at 90 ℃. Unfortunately, no reactions
could be detected even after 24 h. Addition of a
14
O
H
HO
OH
3
CuI/Cs2CO3
1,10-penanthroline
OBn
HO
O
+ 17'
CHO
toluene/110 °C
40%
17
I
OBn
3:1
inseparable
co-solvent such as MeO(CH2)2OMe or EtOAc did not
15
[14]
give any improvement. Use of Pd(OAc)2/K3PO4
in-
Nevertheless, the smooth coupling of 12 seemed to
suggest that the inertness of 8 or 9 in the coupling might
not be all caused by the steric crowding of the hydroxyl
group in 3; perhaps the electronic effects of the lactone
carbonyl group also contributed. It followed that break-
ing up the conjugate system by saturating the C—C
double bond might eliminate the possible negative in-
fluence of the carbonyl group on the aromatic ring and
thus improve the reactivity. With this thought in mind,
we next used 10 to replace 8 to perform the reaction
under the same conditions.
stead of Pd2(dba)2/Cs2CO3 to run the reaction under the
otherwise the same conditions also failed to lead to any
discernible changes.
Because of the repeated failures with the Pd-catalyzed
coupling under the conditions exemplified above, we
next turned to Cu-catalyzed ones, which in many cases
effectively catalyzed[15] the coupling of aryl halides with
alcohols. Buchwald CuI/Cs2CO3/1,10-phenanthroline/
toluene/110 ℃[16] conditions, which were effective for
even secondary alcohols, were then tested. However,
with either 8 or 9 as the aryl halide no reactions oc-
curred at elevated temperatures up to 110 ℃ after 24 h.
Increasing the amount of the added CuI to 1 mol equiv-
alent (with respect to 3) or more did not result in any
discernible changes. Use of 8-hydroxyquinoline to re-
To our disappointment, the outcome was still nega-
tive, with no desired 4 could be detected. But somewhat
different from the situation with the reaction using 8
(where the starting 8 remained intact), the added 10
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Synthesis of Two Coumarins Isolated from Aster praealtus
completely disappeared in the end. We reasoned that
this was because the non-conjugate lactone was more
sensitive to base-mediated hydrolysis than the conjugate
one. To exclude the possibility of a failed coupling be-
ing caused by hydrolysis of 10, we next used 11 (which
should be reasonably stable to the basic conditions) to
re-run the coupling reaction.
two compounds) in the signals in the previous assign-
ments is also cleared. Since 4 and 5 co-exist in the same
plant, the two compounds are very likely to share the
same relative configuration.
Scheme 3 The TEMPO/BAIB oxidation
Without the interference from the hydrolysis, the
coupling of 11 with 3 indeed occurred, but only to a
negligible extent (＜3%) after heating at 110 ℃ for 37
h; the starting 3 and 11 were recovered in 95% and 85%,
respectively.
O
O
O
O
O
O
+
OH
OH
4
4'
Up to this point, it seemed that use of a direct cou-
pling of 3 to afford 4 would be a mission impossible;[21]
lack of similar coupling precedents in the literature in-
deed had its reasons. However, with all the reactants
still in hand, before giving up we decided to run the re-
action under more forcing conditions despite the very
likely excessive side reactions.
TEMPO/BAIB
CH2Cl2
O
O
O
O
O
O
O
+
Thus, with m-xylene to replace toluene as the reac-
tion solvent, we re-examined the coupling of 3 with 8 in
a sealed tube at 160 ℃ (bath) under otherwise the
same conditions. To our gratification, the desired 4 was
finally formed in 11% isolated yield (along with 50% of
recovered 3) after 24 h. If using 9 instead of 8, the yield
for 4 was 20% (along with 40% of recovered 3).
18
CHO
18'
BAIB = bis(acetoxy)iodobenzene
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy
Scheme 4 Acylation of 4
1
Careful examination of the H NMR of the 4 re-
O
vealed co-existence of two species (inseparable on silica
gel) in an approximately 5.9∶1 ratio. In the beginning
the possibility of epimerization under the high tempera-
ture was considered. However, acylation of the remain-
ing hydroxyl group indicated (through the changes in
Cl
O
O
O
O
O
O
O
O
OH
DMAP/CH2Cl2
0 °C/3 h
4
5
63%
1
the H NMR) that the unexpected isomer was more
It should be noted that the two[4,7] existing sets of 1H
NMR data for the synthetic 4 either were incomplete or
contained some errors. As for the recently reported[8b]
natural product that was assigned the same planar
structure as 4, its 1H NMR is partially incompatible with
that for the 4 from this work (a signal at ca. δ 3.5 was
missing and the two geminal methyl groups appeared at
ca. δ 0.3 to the downfield; cf. the tabular data compari-
son in the Supporting Information).
likely to be the regio-isomer 4' (Scheme 1).
To confirm this, the coupling product was subjected
to oxidation of TEMPO/BAIB[22] (Scheme 3); the prod-
uct mixture did show an aldehyde signal in 1H NMR. If
only a limited amount of TEMPO was employed with
the reaction time carefully controlled, only 4' was oxi-
dized while most of the 4 remain intact. The unreacted 4
could be easily separated from 18'.
It is noteworthy that as shown by the formation of 4',
the reactivity difference between the primary and the
secondary OH groups in 3 appeared much less than one
might expect. This unexpected phenomenon may stem
from a substantially increased steric congestion around
the primary OH caused by the additional (allylic) me-
thyl group.
More definite rejecting evidence is found in the 13C
NMR, where practically all signals from the aliphatic
moiety of the natural sample are completely incompati-
ble with those for the synthetic 4. Therefore that[8b] nat-
ural product and 4 (of the cis configuration) must be
1
different compounds. And as the H NMR for the natu-
ral product[8b] is also incompatible with those reported[4]
for the anti isomer (e.g., the geminal methyl groups), it
is concluded that even the planar structure assigned for
that natural sample is incorrect.
Using pure 4 as the substrate, target compound 5 was
readily obtained via a simple acylation (Scheme 4).
The synthetic samples of 4 and 5 allowed for collec-
1
tion of unambiguous H and 13C NMR data as well as
the optical rotations for the first time. Although direct
data comparison for 4 is not possible,[23] the H and C
NMR recorded on a mixture of 5 and its (acyl) isomer
allowed for unequivocal confirmation of the previously
assigned structure and relative configuration for 5.
Some uncertainty (because the sample was a mixture of
1
13
Conclusions
In summary, synthesis of naturally-occurring cou-
marins, i.e. compounds 4 and 5 were attempted through
a direct coupling reaction between a cyclohexyl carbinol
Chin. J. Chem. 2015, 33, 723—728
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725

Wang et al.
FULL PAPER
of unequivocal relative and absolute configurations and
a proper coumarin-derived aryl bromide or iodide. Be-
cause of the excess steric congestion of the alcohol and
the reduced reactivity of the halides, the coupling did
not occur under the literature conditions. The seemingly
impossible coupling was eventually achieved in a sealed
tube at 160 ℃. The synthetic samples of 4 and 5 not
only provided clear-cut spectroscopic data for these two
long-known compounds for the first time, but also re-
vealed some errors and ambiguity in the previous stud-
ies. A recently reported natural product, which was re-
portedly to have the same planar structure as 4, is also
proven to be erroneously assigned.
above was employed. Yield: 7%. Data for 9: M.p. 178－
1
180 ℃ (lit.[24] m.p. 172 ℃). H NMR (500 MHz,
CDCl3) δ: 7.72 (d, J＝1.2 Hz, 1H), 7.65 (d, J＝9.6 Hz,
1H), 7.62 (dd, J＝8.1, 1.6 Hz, 1H), 7.19 (d, J＝8.1 Hz,
1H), 6.45 (d, J＝9.6 Hz, 1H); EI-MS m/z (%): 272 (M＋,
100), 244 (52), 127 (6), 117 (17), 89 (32).
Synthesis of 14 via coupling of 3 with 12 followed by
debenzylation of 13
Alcohol 3[24] ([α]D26 −52.0 (c 2.0, CH2Cl2) (lit.[25]
0
[α]2D −51.7 (c 2, CH2Cl2)), (100 mg, 0.59 mmol), m-
benzy-loxy-iodo-benzene (182 mg, 0.59 mmol), Cs2CO3
(385 mg, 1.18 mmol), 1,10-phenanthroline (22 mg,
0.118 mmol), CuI (11 mg, 0.059 mmol) and a magnetic
stirring bar were added to a thick wall/heavy-duty reus-
able sealed tube equipped with a Teflon screw cap. Dry
toluene (2 mL) was then added. The flask was flushed
with argon and sealed with the screw cap. The flask was
placed in in a 110 ℃ bath for 24 h (with magnetic stir-
ring). After being cooled to ambient temperature, water
was added (10 mL). The mixture was extracted with
EtOAc (80 mL×3). The combined organic layers were
washed with water (10 mL) and brine (10 mL) before
being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatog-
raphy [V(PE)/V(EtOAc)＝7∶1] on silica gel furnished
13 as a colorless oil (147 mg, 0.42 mmol, 71%), from
which the following data were collected: 1H NMR (500
MHz, CDCl3) δ: 7.50－7.27 (m, 5H), 7.18 (t, J＝8.1 Hz,
1H), 6.60 (dd, J＝7.9, 2.3 Hz, 1H), 6.57 (t, J＝1.9 Hz,
1H), 6.54 (dd, J＝8.1, 2.7 Hz, 1H), 5.46 (s, 1H), 5.03 (s,
2H), 4.23 (dd, J＝9.8, 3.7 Hz, 1H), 4.03 (dd, J＝9.9, 2.9
Hz, 1H), 3.45－3.39 (m, 1H), 3.22 (d, J＝9.2 Hz, 1H),
2.38 (d, J＝18.0 Hz, 1H), 2.17 (d, J＝17.7 Hz, 1H),
2.04 (s, 1H), 1.75 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 160.0, 159.3, 136.9, 131.7,
130.0, 128.6, 128.0, 127.6, 120.7, 107.7, 107.4, 102.1,
72.7, 70.1, 66.1, 48.9, 37.2, 32.0, 29.7, 28.1, 22.4, 21.9.
ESI-MS m/z: 375.4 ([M＋Na]＋).
Experimental
The NMR spectra were recorded on either an Agilent
500/54 NMR spectrometer (operating at 500 MHz for
1H) or an Agilent 400/54 instrument (operating at 400
1
MHz for H). IR spectra were measured on a Nicolet
380 Infrared spectrophotometer. ESI-MS data were ac-
quired on a Shimadzu LCMS-2010EV mass spectrome-
ter. EI-MS were collected using an Agilent Technologies
5973N instrument. ESI-HRMS data were obtained with
a Thermo Fisher Scientific LTQ FT Ultra spectrometer.
EI-HRMS were recorded on a Waters Micromass GCT
Premier. Optical rotations were measured on a Jasco
P-1030 polarimeter. Melting points were uncorrected
(measured on a hot stage melting point apparatus
equipped with a microscope). Toluene, m-xylene and
CH2Cl2 were dried with activated 4 Å MS (molecular
sieves). All chemicals were reagent grade and used as
purchased. Column chromatography was performed on
silica gel (300－400 mesh) under slightly positive pres-
sure. PE＝petroleum ether (b.p. 60－90 ℃).
Synthesis of 8[13]
With cooling (ice-water bath) and stirring, concd.
H2SO4 (1.3 mL, 0.024 mmol) was added dropwise to a
mixture of malic acid (520 mg, 3.9 mmol) and
m-bromo-phenol (1.0 g, 5.8 mmol) in a flask (equipped
with a condenser). After completion of the addition, the
mixture was heated (with magnetic stirring) in a 120 ℃
bath for 6 h. The dark mixture was then cooled to am-
bient temperature. The mixture was extracted with
EtOAc (50 mL×3). The combined organic layers were
washed with water (10 mL) and brine (10 mL) before
being dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatog-
raphy [V(PE)/V(EtOAc)＝7∶1] on silica gel gave 8 as
a white solid (338 mg, 1.52 mmol, 39%): M.p. 121－
123 ℃ (lit.[13a] m.p. 121－123 ℃, lit.[13b] m.p. 123.5
℃). 1H NMR (500 MHz, CDCl3) δ: 7.66 (d, J＝9.6 Hz,
1H), 7.52 (d, J＝1.7 Hz, 1H), 7.42 (dd, J＝8.3, 1.8 Hz,
1H), 7.35 (d, J＝8.3 Hz, 1H), 6.44 (d, J＝9.6 Hz, 1H).
A solution of the above obtained 13 (117 mg, 0.33
mmol) in dry THF (2 mL) was added to a mixture of
Li/naphthalene (prepared by stirring Li cuts (5 mg, 2.02
mmol) and naphthalene (168 mg, 1.34 mmol) in dry
THF (2 mL) at ambient temperature under argon for 30
min before use) and stirred at −25 ℃ under argon
(balloon). After the addition, the mixture was stirred at
−25 ℃ for 3 h (when TLC showed completion of the
reaction). Aq. sat. NH4Cl (10 mL) was added carefully.
The mixture was extracted with EtOAc (80 mL×3).
The combined organic layers were washed with water
(10 mL) and brine (10 mL) before being dried over an-
hydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography [V(PE)/
V(EtOAc)＝5∶1] on silica gel furnished 14 as a color-
5
less oil (82 mg, 0.31 mmol, 94%): [α]2D −66.5 (c 0.5,
1
CHCl3). H NMR (500 MHz, CDCl3) δ: 7.11 (t, J＝8.2
Synthesis of 9
Hz, 1H), 6.57 (s, 1H), 6.49－6.44 (m, 2H), 6.40 (t, J＝
2.2 Hz, 1H), 5.49 (s, 1H), 4.21 (dd, J＝9.8, 3.6 Hz, 1H),
The same procedure for the preparation of 8 given
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Chin. J. Chem. 2015, 33, 723—728

Synthesis of Two Coumarins Isolated from Aster praealtus
4.13－4.02 (a lump, 1H, OH), 4.04 (dd, J＝9.8, 2.5 Hz,
1H), 3.44 (s, 1H), 2.40 (ddd, J＝18.3, 4.8, 2.4 Hz, 1H),
2.22 (d, J＝17.2 Hz, 1H), 2.20 (s, 1H), 1.75 (s, 3H),
1.10 (s, 3H), 1.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ: 158.7, 157.8, 131.0, 130.2, 120.7, 109.5, 104.8, 102.7,
72.2, 65.5, 48.7, 37.1, 31.9, 28.6, 23.1, 22.4; FT-IR
(film) vmax: 3378, 2961, 2924, 1597, 1483, 1466, 1287,
1174, 1149, 1075, 1010, 906, 769, 689 cm−1; EI-MS m/z
(%): 262 (M＋, 3), 149 (16), 135 (18), 121 (15), 110
(100). EI-HRMS calcd for C16H22O3 (M＋) 262.1569,
found 262.1571.
31.9 (CH), 27.3 (CH3), 22.4 (CH3), 20.9 (CH3); FT-IR
(film) vmax: 3473 (br), 2964, 2914, 1732, 1614, 1555,
1508, 1403, 1280, 1231, 1125, 835 cm−1; ESI-MS m/z:
315.2 ([M＋H]＋); ESI-HRMS calcd for C19H23O4 ([M
＋H]＋) 315.1596, found 315.1590.
Acylation of 4 to furnish 5
A solution of isopentanoyl chloride (470 μL, 0.038
mmol, of a stock solution prepared by dissolving 100
μL of isopentanoyl chloride in 10 mL of CH2Cl2) was
added to a solution of 4 (8 mg, 0.025 mmol) and DMAP
(12 mg, 0.10 mmol) in dry CH2Cl2 (0.5 mL) stirred in
an ice-water bath for 3 h (TLC showed completion of
the reaction). The mixture was diluted with EtOAc,
washed with water (5 mL) and brine (5 mL) before be-
ing dried over anhydrous Na2SO4. Removal of the sol-
vent by rotary evaporation and column chromatography
[V(PE)/V(EtOAc)＝5∶1] on silica gel furnished 5 as a
white wax (6 mg, 0.017 mmol, 62%): [α]2D5 −53.0 (c
Coupling of 3 with 8 to afford 4
Alcohol 3 (34 mg, 0.20 mmol), 8 (54 mg, 0.24
mmol), Cs2CO3 (130 mg, 0.40 mmol), 1,10-phenan-
throline (8 mg, 0.04 mmol), CuI (8 mg, 0.04 mmol) and
a magnetic stirring bar were added to a thick wall/
heavy-duty reusable sealed tube equipped with a Teflon
screw cap. Dry m-xylene (2 mL) was then added. The
flask was flushed with argon and sealed with the screw
cap. The flask was placed in a 160 ℃ bath for 24 h
(with magnetic stirring). After being cooled to ambient
temperature, water was added (10 mL). The mixture
was extracted with EtOAc (80 mL×3). The combined
organic layers were washed with water (10 mL) and
brine (10 mL) before being dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography [V(PE)/V(EtOAc)＝3∶1]
on silica gel furnished an approximately 5.9∶1 (as
shown by 1H NMR) inseparable mixture of 4 and 4' as a
colorless oil (8 mg, 0.025 mmol, 11%), along with re-
covered 3 (50%).
1
0.5, CHCl3); H NMR (500 MHz, CDCl3) δ: 7.64 (d,
J＝9.1 Hz, 1H), 7.37 (d, J＝8.8 Hz, 1H), 6.84 (dd, J＝
8.8, 2.3 Hz, 1H), 6.81 (d, J＝1.9 Hz, 1H), 6.25 (d, J＝
9.6 Hz, 1H), 5.39 (br s, 1H), 4.76 (t, J＝5.5 Hz, 1H),
4.37 (dd, J＝9.8, 4.4 Hz, 1H), 4.08 (dd, J＝9.8, 4.8 Hz,
1H), 2.42－2.34 (m, 1H), 2.28 (br s, 1H), 2.19 (br d,
J＝6.7 Hz, 2H), 2.14－2.07 (m, 2H), 1.79 (s, 3H), 1.04
(s, 3H), 1.03 (s, 3H), 0.96 (d, J＝6.0 Hz, 3H), 0.95 (d,
13
J＝6.8 Hz, 3H); C NMR (125 MHz, CDCl3) δ: 172.6,
162.0, 161.2, 156.0, 143.4, 133.4, 128.7, 119.7, 113.10,
113.07, 112.5, 101.3, 75.5, 68.5, 48.9, 44.0, 35.8, 28.8,
26.1, 25.9, 22.7, 22.5, 22.4, 20.1; FT-IR (film) vmax
:
2962, 2929, 2866, 1735, 1613, 1406, 1292, 1230, 1121,
834 cm−1; EI-MS m/z (%): 398 (M＋, 1.05), 296 (13),
176 (23), 162 (15), 135 (100), 121 (53), 119 (34), 107
(31), 93 (51), 85 (37); EI-HRMS calcd for C24H30O5 (M
＋) 398.2093, found 398.2096.
Coupling of 3 with 9 to afford 4
The same procedure given above for the coupling of
3 with 8 was used. Yield (4/4'＝5.9∶1): 20%, along
with 40% of recovered 3.
Acknowledgement
Removal of 4' in 4 by TEMPO oxidation
A solution of the mixture of 4 and 4' (18 mg, 0.05
mmol), BAIB (21 mg, 0.066 mmol) and TEMPO (5 mg,
0.028 mmol) in dry CH2Cl2 (1 mL) was stirred at ambi-
ent temperature for 3 h. The mixture was concentrated
on a rotary evaporator. The residue was purified by
column chromatography [V(PE)/V(EtOAc)＝3∶1] on
silica gel to give pure 4 as a colorless oil (14 mg, 0.038
mmol, 77%). Data for 4 (after removal of 4' by TEMPO
This work was supported by the National Natural
Science Foundation of China (Nos. 21172247,
21372248) and the Chinese Academy of Sciences.
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728
www.cjc.wiley-vch.de
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 723—728