Total synthesis of (±)-bruguierol A via an intramolecular [3+2] cycloaddition of cyclopropane 1, 1-diester

Article abstract of DOI:10.1016/j.tet.2010.05.057

Total synthesis of natural product (±)-bruguierol A was accomplished in 10-steps and with an overall 16.8% yield. The embedded unique 8-oxabicyclo[3.2.1]octane core skeleton in this natural product was constructed via a novel Sc(OTf)3-catalyzed intramolecular [3+2] cycloaddition of cyclopropane which was developed recently in this laboratory. This general synthetic strategy can be potentially applied to the synthesis of a broad range of structurally related natural products.

Full text of DOI:10.1016/j.tet.2010.05.057

Tetrahedron 66 (2010) 5671e5674
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Total synthesis of (ꢀ)-bruguierol A via an intramolecular [3þ2] cycloaddition of
cyclopropane 1,1-diester
*
Bao Hu, Siyang Xing, Jun Ren, Zhongwen Wang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2010
Received in revised form 10 May 2010
Accepted 14 May 2010
Available online 20 May 2010
Total synthesis of natural product (ꢀ)-bruguierol A was accomplished in 10-steps and with an overall
16.8% yield. The embedded unique 8-oxabicyclo[3.2.1]octane core skeleton in this natural product was
constructed via a novel Sc(OTf)3-catalyzed intramolecular [3þ2] cycloaddition of cyclopropane, which
was developed recently in this laboratory. This general synthetic strategy can be potentially applied to
the synthesis of a broad range of structurally related natural products.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bruguierol
Total synthesis
Nature product
Cycloaddition
Cyclopropane
1. Introduction
synthesis of racemic bruguierol A in 2008. The key bridged cyclic
framework was constructed using an intramolecular FriedeleCrafts
Bruguierols AeC (Fig. 1) were isolated and characterized by
Sattler and co-workers from the stem of Bruguiera gymnorrhiza tree
in 2005.1 These natural products have the unique structure char-
acterized by a 2,3-benzofused 8-oxabicyclo[3.2.1]octane core. With
the interesting structural features and potential biological activi-
ties, synthesis of bruguierols began to attract attention from the
synthetic community.2 Up to now, there are four synthetic routes
reported for the total synthesis of bruguierols. In 2007, Ramana and
co-workers2a reported the application of [2þ2þ2] alkyne cyclo-
trimerisation as the key step for the construction of benzannulated
8-oxabicyclo[3.2.1]octane skeleton to complete the total synthesis
of bruguierol A. Wu and co-workers2b have completed the total
alkylation with a ketal as the alkylating agent developed in their
group several years ago.3 A similar total synthesis of (þ)-bruguierol
C was also presented by Jennings and Solorio2c Recently, Fananás
ꢀ
and co-workers have applied an efficient tandem intramolecular
hydroalkoxylation/hydroarylation reaction for the construction of
the key bridged cyclic framework to the total synthesis of bru-
guierol A.2d
Recently, we have developed a general strategy for efficient
construction of bridged oxa- and aza-[n.2.1] skeletons via a Lewis
acid-catalyzed intramolecular [3þ2] cycloaddition of cyclopropane
1,1-diesters with carbonyls and imines, and successfully applied it
to the synthesis of platensimycin.4 In this paper, we wish to report
the application of this strategy to the total synthesis of (ꢀ)-bru-
guierol A (1).
OH
HO
HO
Bruguierol B
O
O
O
2. Results and discussion
HO
Bruguierol C
HO
Bruguierol A
Retrosynthetic analysis of (ꢀ)-bruguierol A (1) is shown in
Scheme 1. We envisioned that compound (ꢀ)-1 could be synthe-
sized by decarboxylation and demethylation of an intermediate 2.
The key step is the construction of the 8-oxabicyclo[3.2.1]octane
skeleton in 2 by an intramolecular [3þ2] cycloaddition of cyclo-
propane 3,4 which could be readily synthesized from commercially
available 3-bromoanisole.
Figure 1. Bruguierols AeC.
* Corresponding author. Tel.: þ86 22 23498191; e-mail address: wzwrj@nankai.
edu.cn (Z. Wang).
URL: http://wzw.nankai.edu.cn
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.057

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B. Hu et al. / Tetrahedron 66 (2010) 5671e5674
3. Conclusions
CO2Me
CO2Me
O
O
HO
In summary, a total synthesis of (ꢀ)-bruguierol A was success-
MeO
Bruguierol A (1)
fully accomplished from commercially available 3-bromoanisole in
10-steps and with an overall 16.8% yield. The key step, a Sc(OTf)3-
catalyzed intramolecular [3þ2] cycloaddition of cyclopropane 3
was employed for efficient construction of the 8-oxabicyclo[3.2.1]
octane core skeleton. This synthetic strategy also provides a general
protocol for synthesis of other structurally related natural and
unnatural products.
2
CO2Me
CO2Me
O
MeO
Br
MeO
3
3-bromoanisole
Scheme 1. Retrosynthetic analysis of 1.
4. Experimental section
4.1. General method
With the initial blueprint in mind, we started the synthesis of
bruguierol A as depicted in Scheme 2. FriedeleCrafts acylation of
3-bromoanisole afforded compound 4 in 72% yield.5 Protection
of acetophenone 4 gave ketal 5.6 Allylation of 5 using a Grignard
reagent only gave 20% yield of 6. A halogen/lithium exchange
method was applied successfully and compound 6 was obtained in
64% yield.7 Cyclopropanation of 6 with diazodimethyl-malonate
in the presence of Rh2(OAc)4 afforded cyclopropane 7 in a poor
yield (35%), together with a certain amount of recovered starting
material. Fortunately, when Rh2(esp)2 was used as the catalyst, the
yield of 7 was improved to 77%.8 Deprotection of the ketal 7 with
10% HCl in THF was successfully carried out (95%) and the product
ketone 3 was implemented to the subsequent reaction without
further purification. The 8-oxabicyclo[3.2.1]octane core skeleton
could be easily constructed by a Sc(OTf)3-catalyzed intramolecular
[3þ2] cycloaddition recently developed in our labarotary,4 and the
key intermediate 2 was almost quantitatively obtained. Attempts
to prepare carboxylic acid 9 by hydrolyzation and decarboxylation
of the germinal diesters in 2 under acidic conditions proved to be
unsuccessful.9 Fortunately, Krapcho decarboxylation10 of 2 was
successfully carried out to afford the corresponding monoester 8
(88%), which was then saponified to afford carboxylic acid 9 in 88%
yield. It should be noted that the Krapcho decarboxylation of 2
almost exclusively gave the single isomer 8. We proposed that the
stereochemistry of 8 is endo as showed in the synthesis of pla-
tensimycin.4 Finally, the total synthesis of (ꢀ)-bruguierol A was
achieved after the Barton decarboxylation11 and demethyla-
tion2b,12 of 9. The spectrum data were identical to those reported
in the literature.2a,b,d
All NMR spectra were recorded with
a spectrometer at
400 MHz (1H NMR) and 100 MHz (13C NMR) in CDCl3. The
chemical shifts were reported in parts per million referenced to
CDCl3
resonance (
(
d
¼7.26 ppm) for 1H NMR and relative to the central CDCl3
d
¼77.0 ppm) for 13C NMR spectroscopy. Column chro-
matography was performed on silica gel (100e200 or
200e300 mesh) using petroleum ether and EtOAc as eluent. Thin
layer chromatography (TLC) was performed on Merck silica gel
GF254 plates and visualized by UV light (254 nm). Melting points
were uncorrected. All solvents were purified and dried using
standard procedures. Abbreviations: AIBN¼2,20-azobisisobutyroni-
trile, DCE¼1,1-dichloroethane, DCM¼dichloromethane, DMAP¼N,N-
dimethylaminopyridine, DMF¼N,N-dimethylformamide, DMSO¼
dimethylsulfoxide, esp¼a,a,a0,a0-tetramethyl-1,3-benzenedipropa-
noate, THF¼tetrahydrofuran, Ts¼p-toluenesulfonyl.
4.1.1. 2-Bromo-3-methoxyacetophenone (4). Under an argon atmo-
sphere, a mixture of 3-bromoanisole (37.4 g, 0.2 mol), anhydrous
AlCl3 (32.0 g, 0.24 mol, 1.2 equiv), and 200 mL of dry CH2Cl2 was
cooled below 5 ꢁC with an ice-bath, and acetyl chloride (15.8 g,
14.4 mL, 0.2 mol, 1.2 equiv) was added dropwise. The mixture was
allowed to reach room temperature and stirred overnight, then
poured into 250 mL of ice-water containing 40 mL of concentrated
HCl and stirred to reach room temperature. The organic phase was
separated, and the aqueous layer was washed with CH2Cl2
(40 mLꢂ3). The combined organic phase was washed with H2O
(20 mLꢂ3), 10% aqueous NaOH (20 mLꢂ3), H2O (20 mLꢂ3), and
brine (20 mLꢂ3), dried over MgSO4, and the solvent was removed in
vacuo. The residue was distilled at 116e120 ꢁC (1 mmHg) to afford
the product 4 (33.08 g, 72%) as a colorless oil. 1H NMR (400 MHz,
O
O
O
CDCl3):
d
7.61 (d, J¼8.8 Hz, 1H, ArH), 7.16 (d, J¼2.0 Hz, 1H, ArH), 6.89
a
b
(dd, J¼2.0, 8.4 Hz, 1H, ArH), 3.85 (s, 3H, OCH3), 2.64 (s, 3H, CH3).
MeO
Br
MeO
d
Br
MeO
Br
5
3-bromoanisole
4
4.1.2. 2-(2-Bromo-4-methoxyphenyl)-2-methyl-1,3-dioxolane
(5).
To
a solution of 2-bromo-3-methoxyacetophenone (29.19 g,
O
O
O O
0.13 mol) in toluene (250 mL) at 25 ꢁC was added ethylene
glycol (11.79 g, 0.19 mol, 1.5 equiv) and p-TsOH (1.24 g, 6.5 mmol,
5 mol %). The solution was refluxed overnight with a Dean/Stark
trap. An additional 2 equiv (16.14 g, 0.26 mol) of ethylene glycol
was added in two equal portions and the solution was un-
ceasingly heated at reflux for 1 day. The toluene solution was
cooled to 25 ꢁC, water (200 mL) was added followed by ex-
traction with EtOAc (100 mLꢂ3). The combined organic layers
were washed with H2O (200 mLꢂ3) and brine (200 mLꢂ2),
dried over MgSO4, and then concentrated on a rotary evapora-
tor. The desired product 5 (33.27 g, 94%) was isolated as a yel-
CO2Me
CO2Me
e
c
MeO
MeO
6
7
O
CO2Me
CO2Me
CO2Me
CO2Me
f
O
MeO
g
MeO
3
2
CO2Me
h
CO2H
i
( )-1
O
O
MeO
MeO
8
9
lowish oil. 1H NMR (400 MHz, CDCl3):
d
7.37 (d, J¼8.8 Hz, 1H,
Scheme 2. Synthesis of (ꢀ)-bruguierol A. Reagents and conditions: (a) AlCl3, CH3COCl,
72%; (b) p-TsOH, ethylene glycol, 94%; (c) t-BuLi, Et2O, allyl bromide, 64%; (d) N2]C
(CO2Me)2, Rh2(esp)2, 77%; (e) 1 M HCl, THF, room temperature, 95%; (f) Sc(OTf)3, DCE,
98%; (g) LiCl, wet DMSO, 160 ꢁC, 88%; (h) LiOH, MeOH, H2O, THF, 88%; (i) (1) Barton
decarboxylation, then (2) NaSEt, DMF, 70% (two steps).
ArH), 6.96 (d, J¼2.4 Hz, 1H, ArH), 6.62 (dd, J¼2.4, 8.8 Hz, 1H,
ArH), 3.86 (t, J¼6.8 Hz, 2H, CH2), 3.61 (s, 3H, OCH3), 3.56 (t,
J¼6.8 Hz, 2H, CH2), 1.60 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
159.6, 133.1, 128.7, 120.9, 120.1, 112.7, 108.6, 64.2, 55.5, 25.5; IR

B. Hu et al. / Tetrahedron 66 (2010) 5671e5674
5673
(thin film):
n
¼2987, 2939, 2889, 1601, 1486, 1292, 1239, 1197,
1137, 1034, 824 cmꢃ1; HRMS (ESI) calcd for C19H24O7Na (MþNa)þ:
387.1414; found: 387.1414.
Method B: Under an argon atmosphere, a solution of dimethyl
diazomalonate (1.151 g, 7.28 mmol,1.1 equiv) in CH2Cl2 (28 mL) was
added via syringe pump (2 mL/hr) to a refluxing solution of
1038, 1021 cmꢃ1; HRMS (ESI) calcd for C11H13BrO3H (MþH)þ:
273.0121; found: 273.0127.
4.1.3. 2-(2-Allyl-4-methoxyphenyl)-2-methyl-1,3-dioxolane
(6).
Method A: Under an argon atmosphere, ketal 5 (2.73 g, 10 mmol)
was dissolved in 20 mL of diethyl ether, and the solution was
cooled to ꢃ80 ꢁC. To the mixture was slowly added 9.2 mL of
tert-butyllithium (12 mmol, 1.3 M in pentane). After stirring for
2 h, 2.5 mL of 3-bromopropene (30 mmol, 3.0 equiv) was added.
The reaction mixture was warmed slowly to room temperature
and stirred overnight prior to being quenched with saturated
NH4Cl solution. The product was extracted into portions of ether
(20 mLꢂ3). The combined organic phases were washed with
H2O (20 mLꢂ2) and brine (10 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate¼20:1 to 10:1) to afford 1.48 g (63%) of alkene 6 as
Rh2(OAc)4 (14.6 mg, 33 mmol, 0.5 mol %) and the alkene 6 (1.55 g,
6.62 mmol, 1 equiv) in CH2Cl2 (20 mL). The reaction mixture was
then refluxed for 23 h. After being cooled to room temperature, the
mixture was concentrated. The residue was purified by column
chromatography on silica gel, then was recrystallized to afford the
desired product 7 (0.847 g, 35%), which was identical to that pre-
pared by method A.
4.1.5. Dimethyl 2-(2-acetyl-5-methoxybenzyl)cyclopropane-1,1-di-
carboxylate (3). To a solution of ketal 7 (796 mg, 2.2 mmol) in THF
(20 mL) was slowly added 5.7 mL of 1 M HCl (5.7 mmol, 2.6 equiv)
below 10 ꢁC. The reaction solution was stirred overnight at room
temperature. Then saturated NH4Cl solution was added and
extracted with ether (20 mLꢂ3). The combined organic phases
were washed with H2O (20 mLꢂ2) and brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure. The ketone 3
(671 mg, 95%) was obtained as a white solid, which was not purified
further and was used directly in the next step. Mp 86e87 ꢁC; 1H
a colorless oil. 1H NMR (400 MHz, CDCl3):
d
7.49 (d, J¼8.4 Hz, 1H,
ArH), 6.76 (d, J¼2.4 Hz, 1H, ArH), 6.71 (dd, J¼2.4, 8.4 Hz, 1H,
ArH), 6.04e5.91 (m, 1H, CH2]CH), 5.08 (d, J¼5.2 Hz, 1H, CH2]
CH), 5.04 (s, 1H, CH2]CH), 4.05e3.98 (m, 2H, CH2), 3.79 (s, 3H,
OCH3), 3.76e3.71 (m, 2H, CH2), 3.63 (d, J¼6.4 Hz, 2H, CH2), 1.67
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
159.1, 139.2, 138.2,
NMR (400 MHz, CDCl3):
d
7.77 (d, J¼8.4 Hz, 1H, ArH), 6.82 (s, 1H,
132.6, 127.6, 116.7, 115.6, 110.8, 109.3, 64.1, 55.2, 37.4, 27.6; IR
ArH), 6.80 (d, J¼8.8 Hz, 1H, ArH), 3.85 (s, 3H, OCH3), 3.75 (s, 3H,
CO2CH3), 3.71 (s, 3H, CO2CH3), 3.20 (dd, J¼6.4, 14.8 Hz, 1H, ArCH2),
2.85 (dd, J¼7.6, 14.8 Hz, 1H, ArCH2), 2.55 (s, 3H, COCH3), 2.37e2.22
(m, 1H, CH-cyclopropane), 1.64e1.53 (m, 1H, CH2-cyclopropane),
1.44 (dd, J¼4.8, 9.2 Hz, 1H, CH2-cyclopropane); 13C NMR (100 MHz,
(thin film):
n
¼2988, 2953, 2889, 1607, 1246, 1192, 1034 cmꢃ1
;
HRMS (ESI) calcd for C14H18O3H (MþH)þ: 235.1329; found:
235.1336.
Method B: Under an argon atmosphere, 3-bromopropene
(1.27 mL, 15 mmol, 1.5 equiv) was added to a solution of the
Grignard reagent prepared by adding a solution of ketal 5 (2.73 g,
10 mmol) in THF (30 mL) to a suspension of magnesium powder
(0.288 g, 12 mmol, 1.2 equiv) and I2 in THF (10 mL). The reaction
mixture was refluxed for 1 h, cooled, and quenched with a satu-
rated solution of NH4Cl. After being diluted with H2O (30 mL), the
mixture was extracted with ether (20 mLꢂ3). The combined ex-
tracts were washed with H2O (20 mLꢂ2) and brine (10 mL), dried
over Na2SO4, and concentrated to a residue. The residue was sub-
sequently purified by flash column chromatography on silica gel to
give 0.471 g (20%) of the desired product 6, which was identical to
that prepared by method A.
CDCl3):
d 199.3, 170.5, 168.6, 162.2, 143.4, 132.9, 129.3, 116.5, 110.9,
55.3, 52.6, 52.5, 34.2, 32.9, 29.1, 28.1, 21.1; IR (KBr):
n
¼2961, 2938,
1772, 1670, 1436, 1321, 1291, 1249, 1212, 1134, 1066 cmꢃ1; HRMS
(ESI) calcd for C17H20O6Na (MþNa)þ: 343.1153; found: 343.1152.
4.1.6. 5-Methoxyl-1-methyl-12-oxatricyclo-[7.2.1.02,7]dodeca-2,4,6-
triene-11,11-dicarboxylic acid dimethyl ester (2). Ketone 3 (602 mg,
1.9 mmol) was dissolved in 15 mL DCE, 185 mg of Sc(OTf)3
(0.38 mmol, 20 mol %) was added to the solution at room temper-
ature under an argon atmosphere. The reaction mixture was stirred
overnight. After filtration through Celite, the organics were con-
centrated under reduced pressure and the residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate¼5:1) to afford 590 mg (98%) of the desired product 2 as
4.1.4. Dimethyl 2-(5-methoxy-2-(2-methyl-1,3-dioxolan-2-yl)benzyl)
cyclopropane-1,1-dicarboxylate (7). Method A: Under an argon at-
a white solid. Mp 88e89 ꢁC; 1H NMR (CDCl3, 400 MHz):
d 7.13 (d,
mosphere, Rh2(esp)2 (4 mg, 5
m
mol, 0.1 mol %) and 5 mL of CH2Cl2
J¼8.4 Hz, 1H, ArH), 6.65 (dd, J¼2.4, 8.8 Hz, 1H, ArH), 6.56 (d,
J¼2.4 Hz, 1H, ArH), 4.81e4.73 (m, 1H, OCH), 3.77 (s, 3H, OCH3), 3.76
(s, 3H, CO2CH3), 3.54 (s, 3H, CO2CH3), 3.36 (dd, J¼4.8, 16.4 Hz, 1H,
ArCH2), 2.79 (dd, J¼8.0, 13.6 Hz, 1H, ArCH2), 2.59 (d, J¼16.8 Hz, 1H,
CH2), 2.47 (dd, J¼2.4, 13.6 Hz, 1H, CH2), 1.86 (s, 3H, CH3); 13C NMR
were placed in a 50-mL three-necked flask equipped with a mag-
netic stir bar. The compound 6 (1.171 g, 5 mmol, 1 equiv) was
added and the reaction mixture was then cooled to below 3 ꢁC in
a water/ice bath. After 5 min, a solution of diazodimethylmalonate
(1.028 g, 6.5 mmol, 1.3 equiv) in CH2Cl2 (5.0 mL) was added by
syringe pump (1.5 mL/hr). The resulting solution was kept in the
bath for 10 min and then stirred overnight. After being cooled to
room temperature, the mixture was concentrated. The residue was
then purified by column chromatography on silica gel (petroleum
ether/ethyl acetate¼10:1 to 5:1) to afford 1.408 g (77%) of the
desired product 7 as a white solid. Mp 72e73 ꢁC; 1H NMR
(CDCl3, 100 MHz):
d 170.6, 169.0, 159.0, 133.6, 131.8, 127.6, 113.6,
111.5, 83.8, 72.7, 70.9, 55.1, 52.7, 52.4, 38.7, 37.3, 20.9; IR (KBr):
n
¼2953, 1745, 1720, 1247, 1082, cmꢃ1; HRMS (ESI) calcd for
C17H20O6Na (MþNa)þ: 343.1153; found: 343.1152.
4.1.7. 5-Methoxyl-1-methyl-12-oxatricyclo-[7.2.1.02,7]dodeca-2,4,6-
triene-11-carboxylic acid methyl ester (8). Diester
2 (358 mg,
(400 MHz, CDCl3):
d
7.47 (d, J¼8.4 Hz, 1H, ArH), 6.87 (d, J¼2.4 Hz,
1.11 mmol) and lithium chloride (474 mg, 11.14 mmol, 10.0 equiv)
were dissolved in wet DMSO (15 mL) and heated to 160 ꢁC for 4 h.
The solution was cooled to room temperature, diluted with 50 mL
of water and extracted with EtOAc (15 mLꢂ3). The organic layers
were combined and washed with brine (20 mLꢂ2), dried over
Na2SO4 and evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate¼10:1 to 5:1). Monoester 8 (256 mg, 88%) was
obtained as a colorless oil and as a single endo diastereoisomer; 1H
1H, ArH), 6.71 (dd, J¼2.4, 8.4 Hz, 1H, ArH), 4.01 (t, J¼6.4 Hz, 2H,
OCH2), 3.79 (s, 3H, OCH3), 3.75 (s, 3H, CO2CH3), 3.73 (s, 3H,
CO2CH3), 3.71 (t, J¼6.4 Hz, 2H, OCH2), 3.12 (dd, J¼5.6, 15.2 Hz, 1H,
ArCH2), 2.66 (dd, J¼8.4, 15.2 Hz, 1H, ArCH2), 2.13e2.18 (m, 1H, CH-
cyclopropane), 1.66 (dd, J¼5.6, 8.0 Hz, 1H, CH2-cyclopropane), 1.62
(s, 3H, CH3), 1.50 (dd, J¼4.8, 9.2 Hz, 1H, CH2-cyclopropane); 13C
NMR (100 MHz, CDCl3):
d 170.7, 168.7, 159.2, 138.9, 132.8, 127.6,
115.8, 111.0, 109.2, 64.1, 64.0, 55.2, 52.7, 52.6, 34.3, 31.3, 29.2, 27.5,
21.6; IR (KBr):
¼2993, 2956, 2898, 1736, 1723, 1322, 1276, 1214,
n
NMR (CDCl3, 400 MHz):
d
6.93 (d, J¼8.4 Hz, 1H, ArH), 6.63 (d,

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B. Hu et al. / Tetrahedron 66 (2010) 5671e5674
J¼2.4 Hz,1H, ArH), 6.61 (s, 1H, ArH), 4.70 (t, J¼6.0 Hz,1H, OCH), 3.75
(s, 3H, OCH3), 3.49 (s, 3H, CO2CH3), 3.37 (dd, J¼5.2, 16.4 Hz, 1H,
CHCO2Me), 3.06 (dd, J¼6.8, 10.8 Hz, 1H, ArCH2), 2.59 (d, J¼16.4 Hz,
1H, ArCH2), 2.50e2.37 (m, 1H, CH2), 2.30e2.19 (m, 1H, CH2), 1.86 (s,
20 mmol) were added, and the slurry was stirred for 1.5 h. To this
slurry, a solution of the above Barton decarboxylation product in
DMF (15 mL) was added, and the mixture was heated to 150 ꢁC for
45 h. After being cooled to room temperature, the mixture was
acidified with 1 N HCl (5 mL) and extracted with Et2O (5 mLꢂ3).
The combined organic layers were washed successively with water
(5 mL) and brine (5 mL), dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate¼1:10 to 1:5) to yield
115 mg (two steps, 70%) of pure compound (ꢀ)-1 (Bruguierol A) as
3H, CH3); 13C NMR (CDCl3, 100 MHz):
d 171.3, 158.7, 133.6, 131.7,
124.8, 114.0, 111.4, 81.8, 73.7, 58.7, 55.1, 51.8, 37.2, 33.3, 23.1; HRMS
(ESI) calcd for C15H18O4Na (MþNa)þ: 285.1097; found: 285.1105.
4.1.8. 5-Methoxyl-1-methyl-12-oxatricyclo-[7.2.1.02,7]dodeca-2,4,6-
triene-11-carboxylic acid (9). A solution of monoester 8 (256 mg,
0.98 mmol) was dissolved in MeOH (20 mL) and water (20 mL), and
to this solution LiOH/H2O (410 mg, 9.8 mmol, 10 equiv) was added.
The mixture was stirred at room temperature for 17.5 h. The MeOH
was evaporated, and the aqueous mixture was acidified by a careful
addition of 1 M HCl to adjust the pH value to 2e3. NaCl was added
to saturate the aqueous solution which was then extracted with
ether (15 mLꢂ5). The combined organic extracts were dried over
MgSO4, and the solvent was evaporated to afford carboxylic acid 9
(214 mg, 88%) as a white solid, which was used in the subsequent
transformation without further purification. Mp 153e154 ꢁC. 1H
a yellow oil. 1H NMR (CDCl3, 400 MHz):
d: 7.08 (br s, 1H), 6.89 (d,
J¼8.4 Hz, 1H), 6.51 (dd, J¼8.4, 2.4 Hz, 1H), 6.38 (d, J¼2.4 Hz, 1H),
4.65 (t, J¼6.0 Hz, 1H), 3.17 (dd, J¼16.8, 5.2 Hz, 1H), 2.31 (d,
J¼16.8 Hz, 1H), 2.23e2.10 (m, 1H), 1.97e1.87 (m, 1H), 1.84e1.71 (m,
1H), 1.69e1.55 (m, 1H), 1.64 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d
154.9, 135.5, 133.2, 124.0, 115.8, 113.2, 81.0, 74.5, 42.9, 37.5, 30.4,
22.8; IR (thin film):
n
¼3303, 2975, 1611, 1584, 1499, 1456, 1287,
1261, 1236, 1090, 1030, 994, 858, 816 cmꢃ1; HRMS (ESI) calcd for
C12H13O2 (MꢃH)ꢃ: 189.0921; found: 189.0926.
NMR (CDCl3, 400 MHz):
d
6.99 (d, J¼9.2 Hz, 1H, ArH), 6.61 (s, 2H,
Acknowledgements
ArH), 4.71 (t, J¼6.0 Hz, 1H, OCH), 3.76 (s, 3H, OCH3), 3.37 (dd, J¼4.8,
16.4 Hz, 1H, CHCO2H), 3.07 (dd, J¼7.2, 10.8 Hz, 1H, ArCH2), 2.59 (d,
J¼16.8 Hz, 1H, ArCH2), 2.50e2.38 (m, 1H, CH2), 2.15 (dd, J¼7.2,
12.8 Hz, 1H, CH2), 1.85 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz):
We thank the National Natural Science Foundation of China (No.
20972069), National Key Project of Scientific and Technical Sup-
porting Programs (973 Program) (No. 2010CB126106), and the
Ministry of Education of China (RFDF20070055022) for financial
support.
d
176.3, 158.8, 133.4, 131.2, 125.4, 113.9, 111.5, 81.9, 73.6, 58.7, 55.1,
37.2, 32.9, 22.9; IR (KBr):
n¼2997, 2957, 1728, 1613,1502,1252,1205,
1109, 1032, 1016 cmꢃ1; HRMS (ESI) calcd for C14H16O4Na (MþNa)þ:
271.0941; found: 271.0944.
Supplementary data
4.1.9. (ꢀ)-Bruguierol A (1). A solution of carboxylic acid 9 (214 mg,
0.86 mmol) in CH2Cl2 (20 mL) was treated at 10 ꢁC with DMF (two
drop) and oxalyl chloride (888 mg, 0.60 mL, 7.00 mmol, 8.0 equiv).
The reaction mixture was warmed to room temperature and stirred
for 2 h, after which all volatiles were removed in vacuo. The crude
acyl chloride was redissolved in THF (20 mL) at room temperature
in a round-bottom flask shielded from light with aluminum foil.
With stirring, 2-mercaptopyridine N-oxide sodium salt (207 mg,
1.39 mmol,1.6 equiv) and DMAP (21 mg, 0.17 mmol, 20 mol %) were
added to the above solution, and the mixture was stirred in the dark
for 2 h. Upon completion, the solvent was evaporated. To a solution
of the residue in benzene (30 mL) were added Bu3SnH (751 mg,
0.70 mL, 2.58 mmol, 3.0 equiv) and AIBN (22 mg, 0.16 mmol,
18 mol %), and the mixture was heated to reflux with vigorous stir
for 4 h. Additional Bu3SnH (250 mg, 0.23 mL, 0.86 mmol, 1.0 equiv)
and AIBN (15 mg, 0.09 mmol, 10 mol %) were added to the reaction
mixture, which was kept at reflux overnight. After being cooled to
room temperature, the mixture was treated with saturated aqueous
NH4Cl solution (20 mL) and vigorously stirred for an additional 1 h.
The organic layer was separated. The water layer was extracted
with ether (20 mLꢂ2). The combined organic phases were washed
with H2O (20 mLꢂ2) and brine (20 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was filtered
through a short pad of silica gel to obtain crude Barton de-
carboxylation product as a yellow oil, which was used for the next
step without further purification.
Electronic Supplementary data (ESI) copies of 1H and 13C NMR
spectra are available. Supplementary data associated with this ar-
ticle can be found, in the online version, at doi:10.1016/j.
tet.2010.05.057. These data include MOL files and InChIKeys of the
most important compounds described in this article.
References and notes
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Under an argon atmosphere, a 100 mL three-necked round-
bottom flask was charged with NaH (60% in mineral oil, 826 mg,
21 mmol) and washed with petroleum ether for several times to
remove mineral oil. DMF (25 mL) and ethanethiol (1.07 g, 1.5 mL,