Total synthesis and biological evaluation of an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid

Article abstract of DOI:10.1021/jo4013964

A convergent route has been developed to synthesize an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid and analogues. A Li/naphthalene- mediated reductive alkylation was employed for coupling β-cyclocitral and the corresponding benzyl chloride, while a BBr₃-mediated one-pot bis-demethylation and intramolecular Friedel-Crafts alkylation was used to assemble the tricyclic molecular skeleton. The structure-activity relationship of the diterpenoid was assessed on the basis of antiproliferation assays of the natural product and analogues against strains of pathogenic yeasts and filamentous fungi.

Full text of DOI:10.1021/jo4013964

Article
pubs.acs.org/joc
Total Synthesis and Biological Evaluation of an Antifungal Tricyclic
o‑Hydroxy‑p‑Quinone Methide Diterpenoid
†
‡
‡
,†
Jinhua Huang, Dylan Foyle, Xiaorong Lin, and Jiong Yang*
†Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
‡Department of Biology, Texas A&M University, College Station, Texas 77843-3258, United States
*
S Supporting Information
ABSTRACT: A convergent route has been developed to synthesize an
antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid and ana-
logues. A Li/naphthalene-mediated reductive alkylation was employed for
coupling β-cyclocitral and the corresponding benzyl chloride, while a BBr3-
mediated one-pot bis-demethylation and intramolecular Friedel−Crafts
alkylation was used to assemble the tricyclic molecular skeleton. The
structure−activity relationship of the diterpenoid was assessed on the basis
of antiproliferation assays of the natural product and analogues against strains of pathogenic yeasts and filamentous fungi.
INTRODUCTION
the clinical drugs amphotericin B and fluconazole. Our interest
■
was partially fueled by the increasing demand for new
Quinone methides are typically reactive electrophilic species
that are formed as transient intermediates in chemical
5
antifungal drugs. The increasing incidence of invasive fungal
infections associated with substantial mortality and high
financial burden, especially among immunocompromised
patient populations, rendered it increasingly important to
develop new classes of drugs to combat fungal infection.
1
transformations. However, in the presence of stabilizing
structural elements, such as extended conjugation, relatively
stable quinone methides may be formed. Indeed, a number of
o-hydroxy-p-quinone methide diterpenoids and triterpenoids,
such as fuerstion (1), taxodione (2) and its dimer (4),
pristimerin (5), celastrol (6), and tingenone (7), many of
which show interesting biological activities, have been isolated
RESULTS AND DISCUSSION
■
Whereas a number of approaches have been reported for the
synthesis of taxodione and related compounds, many employ-
6
2
from nature (Figure 1). As part of our efforts in investigating
natural products with useful pharmacological properties, we
ing linear synthetic routes starting from natural precursors, no
3
total synthesis had been reported for 3 since its isolation in
became interested in 3, an unnamed quinone methide
diterpenoid isolated from the root bark of Bobgunnia
5
a
2
000. To fully explore the biomedical potential of 3, we
envisioned a convergent synthetic approach that not only
would enable access of the natural product but also allow the
preparation of analogues for structure−activity relationship
4
madagascariensis. In particular, we were intrigued by its
reported potent antifungal activity, which even rivals that of
(
SAR) and mode-of-action studies. In this regard, we
envisioned that the o-hydroxy-p-quinone methide moiety of 3
could be prepared by oxidation of catechol 8 (Scheme 1). An
intramolecular Friedel−Crafts alkylation would be relied upon
to build the tricyclic core of 8. The corresponding precursor 9
would be assembled by coupling of benzyl chloride 10 and
commercially available β-cyclocitral. Herein we describe the
results of our study, which led to the first synthesis of (±)-3
and elucidation of its preliminary SAR.
Our synthesis started from the known bromobenzene 11,
available in four steps from commercial 3,4-dimethyoxytoluene
7
(
Scheme 2). Stille coupling of 11 and tributylvinyltin was
envisioned for introducing the ethylene group as a precursor to
the 2-hydroxyethyl functionality of 3. After extensive screening
of reaction conditions, the coupling was achieved using
8
Pd (dba)3 and P(t-Bu)3 to give 12 in 98% yield. The
2
Received: June 27, 2013
Published: August 19, 2013
Figure 1. Some o-hydroxy-p-quinone methide natural products.
©
2013 American Chemical Society
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The Journal of Organic Chemistry
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Scheme 1. Synthetic Design
Scheme 3. Hydroboration/Oxidation of 12
unsaturated ketone was achieved with NaBH(OAc) to give the
3
primary alcohol 23.
The generation of the tricyclic molecular skeleton of 3 by an
intramolecular Friedel−Crafts alkylation reaction is challenging,
because it requires simultaneous dearomatization and the
formation of an all-carbon quaternary center. Thus, to evaluate
the feasibility and to elucidate the nuance of this trans-
formation, we used 25 as a model substrate to test various
conditions for the cyclization. This substrate (i.e., 25) was
synthesized through Li/naphthalene-mediated coupling of the
known benzyl chloride 24 and β-cyclocitral followed by
reduction of ester 12 with DIBAL-H yielded benzyl alcohol 13,
which was converted to benzyl chloride 14 upon treatment with
SOCl . Whereas complex mixtures were obtained when Li/
2
naphthalene was used for coupling benzyl chloride 14 and β-
6
c
cyclocitral, no desired product (i.e., 15) could be isolated
from our attempts of coupling through the corresponding
Grignard and organolithium reagents of 14.
6j
oxidation with IBX (Scheme 5).
We speculated that the extended conjugation of 14 might be
responsible for the difficulty of the coupling. Thus, we explored
the possibility of furnishing the 2-hydroxyethyl group prior to
the coupling reactions. However, attempts to introduce the 2-
hydroxyethyl group of 17 through hydroboration/oxidation of
A number of achiral and chiral Brønsted/Lewis acids were
evaluated for the intramolecular Friedel−Crafts alkylation of
25. The combination of formic acid and phosphoric acid was
reported to be suitable for cyclizing 25 into 26 in 41% yield at
115 °C (not shown). Interestingly, an extended reaction
under such conditions led to formation of the undesired cis-
isomeric 28 as the major product (Table 1, entry 1), suggesting
its thermodynamic nature. The BINOL-based chiral phosphoric
acid 31c was also effective for the cyclization (entry 2), but no
enantioselectivity was observed under the harsh conditions
necessary for the reaction to proceed. A number of Lewis acids
were also tested (see the Supporting Information for a
6f
1
2 was only partially successful, as the undesired regioisomer
(i.e., 16) was formed as the major product under all conditions
9
except when BH I·Me S was used, which gave the desired
regioisomeric product 17 somewhat preferentially (2:1)
2
2
(
Scheme 3).
In order to improve the efficiency of the synthesis, we turned
to the allyl-substituted benzyl chloride 19, which was expected
to be compatible with the coupling reaction (Scheme 4). The
previously employed Stille reaction conditions also proved to
be effective for the coupling of 11 and allyltributyltin to give 18.
DIBAL-H reduction followed by chlorination with SOCl2
converted 18 into benzyl chloride 19. As we had expected,
the coupling of benzyl chloride 19 and β-cyclocitral went
smoothly to give 20 (79% yield), which was converted to the
α,β-unsaturated ketone 21 through oxidation with IBX. After
complete list). Treatment of 25 with BBr led to one-pot bis-
3
demethylation, and an intramolecular Friedel−Crafts alkylation
1
0
gave 27 (entry 3), which could be oxidized with Ag O to give
2
6a
taxodione (i.e., 2, not shown). On the other hand, the starting
material was recovered when 25 was treated with BF ·Et O
3
2
(entry 4). Surprisingly, the one-pot demethylation and
Friedel−Crafts cyclization of 25 with TMSI led to diaster-
eoselective formation of the cis-isomeric product 30, with only
one of the methoxyl groups hydrolyzed (entry 5). In order to
impose enantioselection during the cyclization, the oxazabor-
oxidative cleavage of the alkene of 21 through OsO -catalyzed
4
dihydroxylation and subsequent oxidative cleavage of the vicinal
11
diol with NaIO , aldehyde 22 was obtained in 85% yield.
olidine-based Lewis acid 32 was also used. However, the
4
Selective reduction of the aldehyde in the presence of α,β-
cyclization proceeded with low yield and low enantioselectivity
Scheme 2. Synthesis of 14
9
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The Journal of Organic Chemistry
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Scheme 4. Synthesis of 23
Scheme 5. Synthesis of 25
1H and 13C NMR and MS spectra with those reported for the
natural product confirmed the identity of synthetic 3. Selective
monoetherification of 3 with dimethoxymethane gave the
analogue 33.
To evaluate the effect of the 2-hydroxyethyl group of 3 on
the antifungal activity, we also prepared analogue 37 from the
7
known carboxylic acid 34 (Scheme 7). Thus, reduction of 34
with borane−dimethyl sulfide complex followed by chlorination
with SOCl provided benzyl chloride 35. The coupling of 35
and β-cyclocitral went smoothly with Li/naphthalene to give
Table 1. Intramolecular Friedel−Crafts Alkylation of 25
2
the corresponding allyl alcohol, which was oxidized with IBX to
give enone 36. Compound 37 was obtained by BBr -mediated
3
one-pot bis-demethylation and intramolecular Friedel−Crafts
alkylation followed by oxidation of the resulting catechol with
Ag O.
2
With the compounds synthesized above in hand, we
evaluated their antifungal activity against strains of pathogenic
yeasts (Candida spp. and Cryptococcu spp.) and the mold
Aspergillus fumigatus. Candida, Cryptococcus, and Aspergillus
species are the major fungal pathogens of global significance
1
2
(
Table 2). The strains were chosen because of existing data
13,14
on their susceptibility to fluconazole or itraconazole,
two
azole drugs that are commonly used clinically to treat infections
caused by yeast and mold, respectively. Consistent with the
original report, the synthetic o-hydroxy-p-quinone methide 3
indeed was found to be potently cytotoxic toward all the yeast
strains tested, with MIC100 values ranging from 0.4 to 6.4 mg/L.
Interestingly, the values of MIC100 were found to be similar to
those of MFC (minimal fungicidal concentration). In contrast,
MFCs are often much higher than MICs for fungistatic drugs
such as fluconazole (Table 2). This finding indicates the
fungicidal rather than fungistatic nature of these compounds.
Compounds 3 and 37 are particularly effective against all the
yeast strains, including the Candida glabrata, Candida krusei,
and Candida parapsilosis strains that are resistant to the
yield (%)
[ee]
entry
conditions
T (°C)
115
time
12 h
product
1
2
3
4
5
6
HCO H, H PO
4
26 + 28
26 + 28
27
18 + 38
43 + 14
45
2
3
HCO H, 31c
110
96 h
2
BBr , CH Cl
2
−78 to 0
30 min
3
2
BF ·Et O, CH Cl −78 to rt 2 h
27
0
3
2
2
2
TMSI, toluene
70
4 h
30
54
32, BBr , CH Cl
2
0
20 min
27
20 [<20]
3
2
(
entry 6). A series of chiral Brønsted and Lewis acidic
conditions were also tested (see the Supporting Information).
However, no enantioselection was observed for the cyclization.
The application of the BBr -mediated one-pot reaction
conditions allowed the completion of the synthesis of 3. Thus,
treatment of 23 with BBr led to one-pot bis-demethylation and
cyclization to form a tricyclic catechol, which was subjected to
oxidation with Ag O to give 3 (Scheme 6). Comparison of the
1
4
commonly used antifungal fluconazole (Table 2). The lack of
any apparent correlation between the fungal susceptibility
against these new compounds and that against azole drugs
suggests that these compounds might differ in their mode of
action against fungi from the known drug fluconazole.
3
3
2
9
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The Journal of Organic Chemistry
Article
Scheme 6. Synthesis of 3 and 33
Scheme 7. Synthesis of 37
a
Table 2. Taxodione (2), 3, and Analogues Exhibiting Fungicidal Effects (mg/L)
3
37
2
33
azole
a
yeast/fungal strain
MIC100
MFC
MIC100
MFC
MIC100
MFC
MIC100
MFC
MIC90
MFC
Cryptococcus gattii R265
0.4
0.4
0.4
0.8
0.8
0.8
0.8
0.8
0.8
1.6
0.8
1.6
6.4
6.4
12.8
12.8
4
1
Cryptococcus neoformans H99α
Candida albicans SC5314
8
64
6.4
12.8
6.4
3.2
6.4
6.4
>12.8
>6.4
6.4
>12.8
6.4
>100
>12.8
>12.8
>100
>100
>100
0.2
8
Candida glabrata PAT2ISO3
Candida krusei DUMC132.91
Candida parapsilosis MMRL1594
Aspergillus fumigatus Af293
Aspergillus fumigatus CEA10
1.6
1.6
3.2
3.2
>64
64
1.6
1.6
1.6
3.2
3.2
12.8
12.8
100
64
>64
0.4
0.5
3.2
6.4
1.6
3.2
6.4
12.8
>64
12.8
-
25.6
25.6
25.6
25.6
17.1
17.1
17.1
17.1
>100
>100
>100
>100
100
a
MFC is defined as the lowest drug concentration at which at least 99% of cells were killed in comparison to the original inocula. Suspensions from
the microdilution assays after 24 h (for Candida species and Aspergillus fumigatus strains) or 48 h (for strains of Cryptococcus species) of incubation
were plated on a drug-free medium to obtain the values of colony forming units (CFU) to determine the minimal fungicidal concentration (MFC).
Successive 2× serial dilutions of the compounds were used. The data on the susceptibility of these strains against azole drugs (itraconazole for the
1
3−15
mold A. fumigatus and fluconazole for all yeast species) were obtained from previous studies.
Taxodione (2) showed potent activity as well. However, the
methoxymethyl ether of 3 (i.e., 33) significantly diminished the
growth inhibition activity. None of these compounds were
found to be effective against the mold A. fumigatus. It appears
that the cytotoxicity of these compounds is correlated with the
fungal growth mode (yeast versus mold) rather than their
evolutionary relatedness, given that Candida (yeast) and
Aspergillus (mold) spp. are closely related and their common
ancestors diverged from that of Cryptococcus (yeast) spp. about
one billion years ago. The cause of the differential cytotoxicities
of these compounds against yeasts and the filamentous fungal
stains is currently unknown.
mediated one-pot bis-demethylation/intramolecular Friedel−
Crafts alkylation to assemble the tricyclic molecular skeleton
and completed the synthesis of 3. Taxodione 2 and analogues
of 3 were also synthesized. Compounds 3, 37, and 2 showed
potent cytotoxicity against various strains of pathogenic yeasts
tested, but etherification of the 2-hydroxyethyl group led to
significantly attenuated activity. Surprisingly, these compounds
were found to be ineffective against the fungal strain Aspergillus
fumigatus. The cause of this discrepancy of activity against the
yeasts versus filamentous fungi is currently unknown.
EXPERIMENTAL SECTION
■
General Information. All moisture-sensitive reactions were
carried out in flame-dried flasks under a nitrogen atmosphere.
Dichloromethane and diethyl ether were dried using an activated
molecular sieve solvent purification system. Tetrahydrofuran was
freshly distilled over sodium and benzophenone. All other commercial
reagents were used as received. Reactions were monitored by TLC
performed on precoated glass-backed TLC plates, silica gel 60 F254
(EMD 250 μm thickness). Spots were visualized with UV or through
staining with an ethanolic solution of phosphomolybdic acid. Flash
CONCLUSION
■
In summary, we completed the first total synthesis of the
antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid 3.
A Stille reaction was used to introduce the allyl group as a
masked 2-hydroxyethyl side chain, whereas a Li/naphthalene-
mediated reductive alkylation was employed for coupling
benzyl chloride 19 and β-cyclocitral. We developed a BBr3-
9
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The Journal of Organic Chemistry
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column chromatography was performed using 60 Å silica gel (230−
silica (washed with ethyl acetate). After concentration, the residue was
purified by flash column chromatography (silica gel, eluted with ethyl
acetate/petroleum ether 1/5) to provide 18 (2.59 g, 98%) as a yellow
1
4
00 mesh) as the stationary phase. H NMR chemical shifts are
reported as δ values in ppm relative to CDCl (7.26 ppm) or acetone-
3
−
1
d6 (2.05 ppm), coupling constants (J) are reported in Hertz (Hz), and
oil: IR (film, cm ) 2949, 2842, 1717, 1596, 1484, 1330, 1211, 1099,
1
multiplicities follow the normal convention. CDCl (77.0 ppm) or
1045, 989; H NMR (500 MHz, CDCl ) δ 7.29 (s, 1H), 5.95−5.89
3
3
13
acetone-d (29.84 ppm) served as the internal standard for C NMR
(m, 1H), 5.00 (dd, J = 10.2, 1.8 Hz, 1H), 4.86 (dd, J = 17.1, 1.8 Hz,
6
spectra. Infrared (IR) spectra resonance frequencies are given as
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.49 (dt, J = 5.6, 1.8 Hz,
−1
13
wavenumbers in cm . HRMS spectra were recorded using a tandem
TOF spectrometer.
2H), 2.41 (s, 3H); C NMR (125 MHz, CDCl ) δ 168.6, 150.2,
3
150.0, 136.0, 133.3, 132.1, 126.1, 115.1, 112.2, 60.9, 55.7, 51.9, 30.8,
+
Methyl 4,5-Dimethoxy-2-methyl-3-vinylbenzoate (12). To a
16.1; HRMS (ESI) calcd for C H O [M + H ] 251.1283, found
14
18
4
suspension of ester 11 (1.57 g, 5.45 mmol), Pd (dba) (113 mg, 0.11
2
3
251.1274.
-Allyl-1-(chloromethyl)-4,5-dimethoxy-2-methylbenzene
mmol), and tributylvinyltin (1.75 mL, 6.0 mmol) in toluene (11 mL)
3
was added P(t-Bu) (0.22 mL, 0.22 mmol, 1 M in toluene) under
(19). To a solution of ester 18 (2.50 g, 10 mmol) in THF (50 mL)
was added DIBAL-H (1 M in hexanes, 30 mL, 30 mmol) at 0 °C
under nitrogen. The mixture was stirred at 0 °C for 4 h before it was
treated with ethyl acetate (5 mL) and saturated aqueous Rochelle salt
3
nitrogen. The reaction was stirred at 60 °C overnight. When the
reaction was complete on the basis of TLC, the solution was treated
with KF (4 g), Et O (30 mL), and activated carbon (4 g). The mixture
2
was stirred for 5 min before it was filtered through a short pad of silica
gel (washed with ethyl acetate). After concentration, the residue was
purified by flash column chromatography (silica gel, eluted with ethyl
acetate/petroleum ether 1/5) to provide 12 (1.26 g, 98%) as a yellow
(
50 mL). The mixture was stirred for another 1 h at room
temperature. The organic layer was separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic layers
were washed with brine and dried over Na SO . After concentration,
the residue was purified by flash column chromatography (silica gel,
eluted with ethyl acetate/petroleum ether 1/1) to provide allyl alcohol
S1 (2.01 g, 90%) as a colorless oil: IR (film, cm ) 3414, 2937, 1640,
1
CDCl ) δ 6.87 (s, 1H), 5.92 (ddt, J = 17.1, 10.1, 5.8 Hz, 1H), 4.99 (dd,
J = 10.2, 1.8 Hz, 1H), 4.90 (dd, J = 17.1, 1.9 Hz, 1H), 4.64 (d, J = 4.5
2
4
−1
oil: IR (film, cm ) 2999, 2955, 2842, 1723, 1590, 1478, 1427, 1324,
1
1
199, 1167, 1110, 983; H NMR (500 MHz, CDCl ) δ 7.32 (s, 1H),
3
6.71 (dd, J = 17.9, 11.6 Hz, 1H), 5.61 (dd, J = 11.6, 2.0 Hz, 1H), 5.52
−1
(
2
dd, J = 17.9, 2.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H),
1
599, 1487, 1309, 1232, 1111, 1042, 906, 850; H NMR (500 MHz,
.47 (s, 3H); 13C NMR (125 MHz, CDCl ) δ 168.4, 150.0, 149.7,
3
3
133.8, 131.2, 131.1, 126.3, 121.1, 112.9, 60.3, 55.9, 52.0, 17.6; HRMS
molecular ion not observed.
4,5-Dimethoxy-2-methyl-3-vinylphenyl)methanol (13). To a
Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.47 (dt, J = 5.8, 1.8 Hz, 2H), 2.18
(
(
13
s, 3H); C NMR (125 MHz, CDCl ) δ 150.4 146.7, 136.5, 134.4,
3
stirred solution of ester 12 (1.24 g, 5.25 mmol) in THF (30 mL) was
added DIBAL-H (1 M in hexanes, 15.75 mL, 15.75 mmol) at 0 °C
under nitrogen. The mixture was stirred at 0 °C for 2 h before it was
quenched with ethyl acetate (3 mL) and saturated aqueous Rochelle
salt (30 mL). The mixture was stirred for another 1 h at room
temperature. The organic layer was separated, and the aqueous phase
was extracted with ethyl acetate. The combined organic layers were
washed with brine and dried over Na SO . After concentration, the
1
32.6, 127.5, 115.0, 110.5, 63.9, 60.9, 55.7, 30.9, 13.9; HRMS (ESI)
+
calcd for C H O [M + Li ] 229.1416, found 229.1406.
13
18
3
To a solution of S1 (1.85 g, 8.32 mmol) in CH Cl (40 mL) was
2
2
added SOCl (0.73 mL, 9.99 mmol) dropwise at 0 °C under nitrogen.
2
The reaction mixture was maintained at room temperature for 30 min
before it was carefully quenched with saturated aqueous NaHCO3.
The mixture was taken into CH Cl . The organic layer was separated,
washed with water and brine, and dried over Na SO . After
concentration, the residue was purified by flash column chromatog-
raphy (silica gel, eluted with ethyl acetate/petroleum ether 1/10) to
provide 19 (1.93 g, 97%) as a white amorphous solid: IR (film, cm )
2
2
2
2
4
2
4
residue was purified by flash column chromatography (silica gel, eluted
with ethyl acetate/petroleum ether 1/1) to provide 13 (992 mg, 91%)
−1
as a colorless oil: IR (film, cm ) 2934, 1587, 1475, 1318, 1235, 1116,
−1
1
9
74, 921, 944; H NMR (500 MHz, CDCl ) δ 6.92 (s, 1H), 6.74 (dd, J
3
1
940, 1602, 1484, 1330, 1226, 1108, 1045, 986, 912; H NMR (500
=
17.9, 11.7 Hz, 1H), 5.58 (dd, J = 11.7, 2.1 Hz, 1H), 5.54 (dd, J =
MHz, CDCl ) δ 6.79 (s, 1H), 5.92 (ddt, J = 17.1, 10.2, 5.8 Hz, 1H),
5.01 (dd, J = 10.2, 1.8 Hz, 1H), 4.89 (dd, J = 17.1, 1.8 Hz, 1H), 4.60
3
1
3
1
7.9, 2.1 Hz, 1H), 4.67 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.25 (s,
H); 13C NMR (125 MHz, CDCl ) δ 150.4, 146.3, 134.6, 132.9,
3
(s, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.48 (dt, J = 5.8, 1.8 Hz, 2H), 2.26
31.5, 126.6, 120.5, 111.2, 63.9, 60.2, 55.9, 15.1; HRMS (ESI) calcd
13
+
(s, 3H); C NMR (125 MHz, CDCl
1
calcd for C H ClO [M + H ] 241.0995, found 241.1003.
3
) δ 150.5, 147.7, 136.2, 133.1,
for C H O [M + Li ] 215.1259, found 215.1266.
12
16
3
31.0, 129.1, 115.1, 112.2, 60.9, 55.7, 45.9, 31.0, 14.3; HRMS (ESI)
1
-(Chloromethyl)-4,5-dimethoxy-2-methyl-3-vinylbenzene
+
(
14). To a solution of alcohol 13 (832 mg, 4.0 mmol) in CH Cl (20
13 17
2
2
2
2
-(3-Allyl-4,5-dimethoxy-2-methylphenyl)-1-(2,6,6-trime-
thylcyclohex-1-en-1-yl)ethanol (20). A mixture of naphthalene
3.61 g, 28.13 mmol) and lithium (196 mg, 28.13 mmol) in THF (30
mL) was added SOCl (0.35 mL, 4.8 mmol) dropwise at 0 °C under
2
nitrogen. The reaction mixture was stirred at room temperature for 30
min before it was carefully quenched with saturated aqueous NaHCO3
and taken into CH Cl . The organic layer was separated, washed with
(
mL) was stirred at room temperature under nitrogen for 1.5 h. The
mixture was then treated with a solution of β-cyclocitral (1.26 g, 8.25
mmol) and benzyl chloride 19 (1.80 g, 7.50 mmol) in THF (10 mL)
dropwise via syringe at 0 °C. After it was stirred at room temperature
for 2 h, the mixture was diluted with ether and treated with saturated
aqueous NH Cl. The organic phase was separated. The aqueous phase
was extracted with EtOAc. The combined organic layers were washed
with brine and dried over Na SO . After concentration, the residue was
purified by flash column chromatography (silica gel, eluted with ethyl
acetate/petroleum ether 1/4) to provide 20 (2.13 g, 79%) as a
2
2
water and brine, and dried over Na SO . After concentration, the
2
4
residue was purified by flash column chromatography (silica gel, eluted
with ethyl acetate/petroleum ether 1/20) to provide 14 (832 mg,
−
1
9
1
2%) as a yellow oil: IR (film, cm ) 3005, 2970, 2934, 2837, 1590,
1
478, 1318, 1238, 1116, 1045, 980, 927, 853; H NMR (500 MHz,
4
CDCl ) δ 6.84 (s, 1H), 6.73 (dd, J = 17.9, 11.7 Hz, 1H), 5.60 (dd, J =
3
1
(
1.7, 2.0 Hz, 1H), 5.54 (dd, J = 17.9, 2.1 Hz, 1H), 4.62 (s, 2H), 3.88
2
4
s, 3H), 3.76 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl ) δ
3
1
1
50.5, 147.4, 133.4, 131.3, 131.2, 128.2, 120.7, 113.0, 60.2, 55.9, 45.8,
5.4; HRMS molecular ion not observed.
−1
colorless liquid: IR (film, cm ) 3500, 2931, 1593, 1484, 1291, 1229,
1111, 1048, 989, 906; H NMR (500 MHz, CDCl ) δ 6.70 (s, 1H),
1
Ethyl 3-Allyl-4,5-dimethoxy-2-methylbenzoate (18). To a
3
suspension of ester 11 (2.88 g, 10 mmol), Pd (dba) (275 mg, 0.30
mmol), and allyltributyltin (3.72 mL, 12 mmol) in toluene (15 mL)
5.94 (dd, J = 17.1, 10.1 Hz, 1H), 5.01 (dq, J = 10.1, 1.7 Hz, 1H), 4.93
(dq, J = 17.1, 1.8 Hz, 1H), 4.45 (dd, J = 10.0, 4.3 Hz, 1H), 3.87 (s,
3H), 3.80 (s, 3H), 3.49 (ddd, J = 5.8, 3.9, 1.9 Hz, 2H), 3.19 (dd, J =
14.2, 10.0 Hz, 1H), 2.88 (dd, J = 14.2, 4.3 Hz, 1H), 2.24 (s, 3H),
2.03−1.99 (m, 2H); 2.02 (s, 3H), 1.65−1.54 (m, 2H), 1.46−1.44 (m,
2
3
was added P(t-Bu) (1 M in toluene, 0.60 mL, 0.60 mmol) under
3
nitrogen. The reaction mixture was stirred at 60 °C overnight. When
the reaction was complete (monitored by TLC, ethyl acetate/
petroleum ether 1/10 for two to three times), KF (5 g) was added
2H), 1.11 (s, 3H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl
) δ
3
followed by Et O (30 mL) and activated carbon (5 g). The mixture
was stirred for 5 min, and then it was filtered through a short pad of
150.3, 146.0, 139.3, 136.7, 133.3, 132.4, 132.0, 128.3, 114.9, 113.0,
71.2, 60.9, 55.8, 40.5, 40.0, 34.8, 34.2, 31.2, 28.5, 28.3, 21.4, 19.3, 15.2;
2
9
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Article
+
HRMS (ESI) calcd for C H O [M + Na ] 381.2406, found
mixture was stirred at room temperature for 2 h, diluted with ether,
23
34
3
3
81.2388.
-(3-Allyl-4,5-dimethoxy-2-methylphenyl)-1-(2,6,6-trime-
thylcyclohex-1-en-1-yl)ethanone (21). A solution of alcohol 20
910 mg, 2.54 mmol) and IBX (1.07 g, 3.81 mmol) in DMSO (5 mL)
and then treated with saturated aqueous NH Cl. The organic phase
4
2
was separated, and the aqueous phase was extracted with EtOAc. The
combined organic layers were washed with brine and dried over
Na SO . After concentration, the residue was purified by flash column
(
2
4
was stirred at room temperature for 3 h. The reaction was quenched
with H O (5 mL) at 0 °C. The mixture was filtered, and the aqueous
phase was extracted with EtOAc. The combined organic layers were
washed with brine and dried over Na SO . After concentration in
vacuo, the residue was purified by column chromatography (silica gel,
eluted with ethyl acetate/petroleum ether 1/1) to provide 21 (780 mg,
chromatography (silica gel, eluted with ethyl acetate/petroleum ether
2
1/5) to provide allyl alcohol S2 (2.26 g, 85%) as a light yellow liquid:
1
H NMR (500 MHz, CDCl ) δ 6.70 (d, J = 1.9 Hz, 1H), 6.66 (d, J =
3
2
4
1.9 Hz, 1H), 4.42 (dd, J = 10.1, 3.6 Hz, 1H), 3.87 (s, 3H), 3.80 (s,
3
H), 3.34 (dt, J = 13.9, 6.9 Hz, 1H), 3.06 (dd, J = 13.9, 10.1 Hz, 1H),
2
.82 (dd, J = 13.9, 3.5 Hz, 1H), 2.05−1.94 (m, 2H), 1.96 (s, 3H),
−1
8
1
5
4
3
2
6
1
3
6%) as a yellow oil: IR (film, cm ) 2937, 1691, 1596, 1487, 1285,
1.62−1.53 (m, 2H), 1.46−1.42 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H),
1.10 (s, 3H), 0.97 (s, 3H); C NMR (125 MHz, CDCl ) δ 152.5,
1
13
226, 1113, 1048, 995; H NMR (500 MHz, CDCl ) δ 6.56 (s, 1H),
3
3
.93 (ddt, J = 17.1, 10.2, 5.7 Hz, 1H), 4.99 (dq, J = 10.1, 1.7 Hz, 1H),
.91 (dq, J = 17.1, 1.9 Hz, 1H), 3.87 (s, 2H), 3.82 (s, 3H), 3.78 (s,
H), 3.48 (dt, J = 5.7, 1.8 Hz, 2H), 2.11 (s, 3H), 1.99 (t, J = 6.5 Hz,
H), 1.72−1.67 (m, 2H), 1.63 (s, 3H), 1.48−1.46 (m, 2H), 1.11 (s,
144.9, 142.4, 138.9, 135.5, 131.8, 118.9, 110.7, 72.3, 60.9, 55.7, 43.4,
39.9, 34.8, 34.1, 28.6, 28.1, 26.8, 23.6, 23.5, 21.4, 19.3.
To a solution of S2 (370 mg, 1.07 mmol) in DMSO (4 mL) was
added IBX (449 mg, 1.60 mmol) at room temperature. The resulting
mixture was stirred at room temperature for 3 h before it was treated
H); 13C NMR (125 MHz, CDCl ) δ 207.8, 150.3, 146.4, 143.1,
3
36.6, 132.4, 129.5, 129.1, 128.4, 114.9, 112.9, 60.8, 55.8, 50.8, 39.0,
with H O (5 mL) at 0 °C. The mixture was filtered, and the aqueous
2
3.4, 31.3, 31.2, 28.8, 21.2, 18.9, 15.4; HRMS (ESI) calcd for
phase was extracted with EtOAc. The combined organic layers were
washed with brine and dried over Na SO . After concentration, the
+
C H O [M + H ] 357.2430, found 357.2423.
23
32
3
2
4
2
-(2,3-Dimethoxy-6-methyl-5-(2-oxo-2-(2,6,6-trimethylcy-
residue was purified by column chromatography (silica gel, eluted with
clohex-1-en-1-yl)ethyl)phenyl)acetaldehyde (22). To a solution
of alkene 21 (530 mg, 1.49 mmol) in acetone/H O (4/1, 15 mL) was
added NMO (262 mg, 2.23 mmol) and OsO (2.5 wt % solution in t-
BuOH, 758 mg, 7.45% mmol). After being stirred at room
temperature overnight, the mixture was concentrated in vacuo. The
residue was taken into EtOAc, washed with H O and brine, and dried
over Na SO . After concentration in vacuo, the crude reaction product
was dissolved in CH CN/H O (1/1, 16 mL) and treated with NaIO
ethyl acetate/petroleum ether 1/5) to provide 25 (285 mg, 77%) as a
1
2
yellow amorphous solid: H NMR (500 MHz, CDCl ) δ 6.66 (d, J =
3
4
2.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79
(
s, 2H), 3.33 (dt, J = 13.9, 6.9 Hz, 1H), 1.99−1.96 (m, 2H), 1.69−1.67
(m, 2H), 1.56 (s, 3H), 1.47−1.44 (m, 2H), 1.20 (s, 3H), 1.19 (s, 3H),
13
2
1.08 (s, 6H); C NMR (125 MHz, CDCl ) δ 152.3, 145.1, 143.1,
3
2
4
142.0, 129.7, 129.6, 119.7, 111.3, 60.9, 55.7, 52.2, 38.9, 33.4, 31.2, 28.8,
26.7, 23.5, 21.2, 18.8.
o-Hydroxy-p-quinone Methide Diterpenoid 3. To a solution
of alcohol 23 (301 mg, 0.84 mmol) in dichloromethane (8 mL) was
3
2
4
(478 mg, 2.24 mmol) at 0 °C. The mixture was warmed to room
temperature and stirred for 1 h before it was filtered through a short
pad of silica gel (eluted with EtOAc). The filtrate was washed with
H O and brine and dried over Na SO . After concentration in vacuo,
the residue was purified by column chromatography (silica gel, eluted
with ethyl acetate/petroleum ether 1/5) to provide 22 (446 mg, 84%
added a freshly prepared solution of BBr (1 M in dichloromethane,
3
2
2
4
5.04 mL, 5.04 mmol) dropwise at −78 °C under nitrogen. The
reaction mixture was stirred for 30 min, warmed to 0 °C, and stirred
for another 2 h. The reaction was carefully quenched with saturated
−1
for two steps) as a white amorphous solid: IR (film, cm ) 2937, 1720,
aqueous NaHCO . The aqueous phase was extracted with EtOAc. The
3
1
1697, 1484, 1279, 1229, 1108, 1066; H NMR (500 MHz, CDCl ) δ
combined organic layers were washed with brine and dried over
Na SO . After concentration in vacuo, the residue was taken into
3
9
.68 (s, 1H), 6.62 (s, 1H), 3.89 (s, 2H), 3.84 (s, 3H), 3.81 (d, J = 2.0
2
4
Hz, 2H), 3.78 (s, 3H), 2.07 (s, 3H), 2.00 (t, J = 6.5 Hz, 2H), 1.72−
CHCl (10 mL) and treated with Ag O (223 mg, 0.90 mmol). The
3
2
13
1
.66 (m, 2H), 1.64 (s, 3H), 1.49−1.46 (m, 2H), 1.12 (s, 6H);
C
mixture was stirred at 50 °C for 30 min and filtered through a cotton
plug. The filtrate was concentrated and purified by column
chromatography (silica gel, eluted with ethyl acetate/petroleum
ether 1/1) to provide 3 (103 mg, 37% for 2 steps) as an orange
NMR (125 MHz, CDCl ) δ 207.6, 199.7, 150.2, 146.6, 143.0, 129.7,
3
129.2, 128.8, 125.7, 114.2, 60.5, 55.8, 50.8, 42.7, 38.9, 33.5, 31.3, 28.8,
+
21.2, 18.8, 16.1; HRMS (ESI) calcd for C H O [M + Li ] 365.2304,
22
30
4
−1
found 365.2312.
amorphous solid: IR (film, cm ) 3325, 2925, 1670, 1610, 1377, 1223,
1
2
-(3-(2-Hydroxyethyl)-4,5-dimethoxy-2-methylphenyl)-1-
1185, 1146, 1045; H NMR (500 MHz, acetone-d ) δ 8.32 (s, 1H),
6
(2,6,6-trimethylcyclohex-1-en-1-yl)ethanone (23). To a solution
6
.50 (s, 1H), 3.75 (t, J = 5.7 Hz, 1H), 3.63−3.59 (m, 2H), 3.05−3.02
m, 1H), 2.85−2.81 (m, 2H), 2.65 (s, 1H), 2.34 (s, 3H), 1.76−1.70
(m, 2H), 1.59−1.54 (m, 1H), 1.40−1.36 (m, 1H), 1.29−1.26 (m, 1H),
of aldehyde 22 (423 mg, 1.18 mmol) in benzene (10 mL) was added
NaBH(OAc) (376 mg, 1.77 mmol) and acetic acid (0.70 mL). After it
was stirred at room temperature under nitrogen for 6 h, the reaction
mixture was quenched with saturated aqueous NaHCO at 0 °C. The
aqueous phase was extracted with EtOAc. The combined organic
layers were washed with brine and dried over Na SO . After
concentration in vacuo, the residue was purified by column
chromatography (silica gel, eluted with ethyl acetate/petroleum
ether 1/1) to provide 23 (370 mg, 87%) as a white amorphous
(
3
1
1
.27 (s, 3H), 1.24 (s, 3H), 1.10 (s, 3H); H NMR (500 MHz, acetone-
3
d +D O) δ 6.52 (s, 1H), 3.59 (t, J = 7.1 Hz, 2H), 3.03 (d, J = 11.8 Hz,
6
2
1
H), 2.83 (t, J = 7.2 Hz, 2H), 2.66 (s, 1H), 2.33 (s, 3H), 1.73−1.66
2
4
(m, 2H), 1.56−1.53 (m, 1H), 1.37 (d, J = 11.7 Hz, 1H), 1.26 (s, 3H),
1
1
3
.23 (s, 3H), 1.10 (s, 3H); 13C NMR (125 MHz, acetone-d ) δ 201.1,
6
82.3, 146.4, 145.1, 142.0, 134.8, 131.3, 127.0, 62.3, 61.2, 43.0, 42.9,
7.7, 33.4, 33.3, 31.0, 22.2, 21.6, 19.3, 15.9; HRMS (ESI) calcd for
−1
+
solid: IR (film, cm ) 3446, 2934, 1694, 1596, 1492, 1300, 1229, 1116,
1
C H O [M − H ] 329.1753, found 329.1738.
20
26
4
1
048; H NMR (500 MHz, CDCl ) δ 6.55 (s, 1H), 3.88 (s, 2H), 3.83
(4bS,8aS)-4-Hydroxy-2-(2-(methoxymethoxy)ethyl)-
3
(
s, 3H), 3.82 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H),
1,4b,8,8-tetramethyl-4b,5,6,7,8,8a-hexahydrophenanthrene-
3,9-dione (33). To a solution of alcohol 3 (9.9 mg, 0.03 mmol) in
dichloromethane (2 mL) was added dimethyoxymethane (0.027 mL,
2
3
.16 (s, 3H), 2.00 (t, J = 6.4 Hz, 2H), 1.72−1.67 (m, 2H), 1.64 (s,
13
H), 1.49−1.46 (m, 2H), 1.12 (s, 6H); C NMR (125 MHz, CDCl )
3
δ 207.8, 150.1, 146.5, 143.0, 131.1, 129.6, 128.8, 128.8, 113.1, 62.7,
0.5, 55.7, 50.9, 38.9, 33.5, 31.3, 30.7, 28.8, 21.2, 18.8, 15.7; HRMS
0.3 mmol) and P
room temperature for 2 h before it was diluted with dichloromethane,
washed with saturated aqueous NaHCO , and then dried over
Na SO . After concentration, the residue was purified by column
chromatography (silica gel, eluted with ethyl acetate/petroleum ether
2 5
O (43 mg, 0.15 mmol). The solution was stirred at
6
+
(ESI) calcd for C H O [M + Li ] 367.2461, found 367.2469.
3
22
32
4
2
-(3-Isopropyl-4,5-dimethoxyphenyl)-1-(2,6,6-trimethylcy-
clohex-1-en-1-yl)ethanone (25). A mixture of naphthalene (4.92 g,
8.35 mmol) and lithium (266 mg, 38.35 mmol) in THF (40 mL) was
2
4
−1
3
1/5) to provide 33 (7.4 mg, 66%) as a yellow liquid: IR (film, cm )
1
stirred at room temperature for 1.5 h before it was treated with a
3322, 2934, 1670, 1611, 1380, 1152, 1116, 1025; H NMR (500 MHz,
solution of β-cyclocitral (1.28 g, 8.44 mmol) and benzyl chloride 24
CDCl ) δ 7.53 (s, 1H), 6.51 (s, 1H), 4.60 (s, 2H), 3.62 (t, J = 6.9 Hz,
3
(
1.75 g, 7.67 mmol) in THF (10 mL) dropwise at 0 °C. The resulting
2H), 3.33 (s, 3H), 2.98−2.95 (m, 1H), 2.93−2.88 (m, 2H), 2.59 (s,
9
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The Journal of Organic Chemistry
Article
1
(
H), 2.29 (s, 3H), 1.74−1.70 (m, 2H), 1.62−1.59 (m, 2H), 1.44−1.40
m, 1H), 1.28 (s, 3H), 1.26 (s, 3H), 1.13 (s, 3H); 13C NMR (125
MHz, CDCl ) δ 201.2, 181.5, 146.1, 143.7, 141.1, 133.5, 131.1, 126.6,
40.0, 39.5, 34.8, 34.2, 28.5, 28.3, 21.4, 19.6, 19.3; HRMS (ESI) calcd
+
for C H O [M + Li ] 325.2355, found 325.2339.
20
30
3
A solution of S3 (960 mg, 3.03 mmol) in DMSO (6 mL) was
3
9
1
3
6.3, 65.9, 62.2, 55.2, 42.6, 42.4, 37.1, 33.2, 32.7, 27.2, 21.9, 21.7, 18.6,
treated with IBX (1.27 g, 4.55 mmol) and stirred at room temperature
+
5.8; HRMS (ESI) calcd for C H O [M + Li ] 381.2248, found
for 2 h. The reaction mixture was treated with H O (6 mL) at 0 °C
22
30
5
2
81.2262.
and filtered. The aqueous phase was extracted with EtOAc. The
combined organic layers were washed with brine and dried over
Na SO . After concentration in vacuo, the residue was purified by
(
4bS,8aR)-4-Hydroxy-2-isopropyl-3-methoxy-4b,8,8-tri-
methyl-4b,5,6,7,8,8a-hexahydrophenanthren-9(10H)-one (30).
2
4
A mixture of hexamethyldisilizane (0.25 mL, 1.2 mmol) and iodine
column chromatography (silica gel, eluted with ethyl acetate/
(
305 mg, 1.2 mmol) was heated at 65 °C for 20 min under nitrogen.
petroleum ether 1/3) to provide 36 (701 mg, 73%) as a light yellow
−1
After the mixture was cooled to room temperature, a solution of
ketone 25 (69 mg, 0.2 mmol) in toluene (1 mL) was added. The
reaction mixture was stirred at 70 °C for 4 h before it was concentrated
in vacuo. The residue was purified by flash column chromatography
amorphous solid: IR (film, cm ) 2931, 1700, 1516, 1460, 1270, 1229,
1
1108, 1039, 998; H NMR (500 MHz, CDCl ) δ 6.71 (s, 1H), 6.61 (s,
3
1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 2H), 2.23 (s, 3H), 1.99 (t, J =
6.4 Hz, 2H), 1.71−1.66 (m, 2H), 1.62 (s, 3H), 1.48−1.46 (m, 2H),
(
silica gel, eluted with ethyl acetate/petroleum ether 1/5) to provide
1.11 (s, 6H); 13C NMR (125 MHz, CDCl ) δ 208.0, 147.8, 146.8,
3
−1
3
2
0 (35.9 mg, 54%) as a yellow amorphous solid: IR (film, cm ) 3414,
143.0, 129.5, 129.4, 124.5, 113.7, 113.6, 56.0, 55.8, 49.7, 38.9, 33.4,
1
+
955, 2931, 1694, 1448, 1418, 1300, 1229, 1057, 1033, 998; H NMR
31.2, 28.8, 21.1, 19.6, 18.8; HRMS (ESI) calcd for C H O [M + H ]
20
28
3
(
500 MHz, CDCl ) δ 6.67 (s, 1H), 5.77 (s, 1H), 3.80 (s, 3H), 3.65 (d,
317.2117, found 317.2126.
3
J = 22.9, 1.1 Hz, 1H), 3.47 (d, J = 22.9 Hz, 1H), 3.27 (dt, J = 13.9, 6.9
Hz, 1H), 3.03−2.99 (m, 1H), 1.98 (s, 1H), 1.61−1.15 (m, 5H), 1.26
(4bS,8aS)-4-Hydroxy-1,4b,8,8-tetramethyl-4b,5,6,7,8,8a-
hexahydrophenanthrene-3,9-dione (37). To a solution of ketone
(
d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.9 Hz, 3H), 1.24 (s, 3H), 0.94 (s,
36 (95 mg, 0.30 mmol) in CH
2
Cl
2
(3 mL) was added a freshly
Cl , 1.80 mL, 1.80 mmol)
3
1
3
H), 0.30 (s, 3H); 13C NMR (125 MHz, CDCl ) δ 213.1, 145.8,
44.9, 133.7, 130.4, 126.4, 122.3, 68.5, 61.9, 44.0, 42.2, 40.1, 37.4, 34.4,
prepared solution of BBr (1 M in CH
3
2
2
3
dropwise at −78 °C under nitrogen. The reaction mixture was stirred
for 30 min, warmed to 0 °C, and further stirred for 3 h. The reaction
2.4, 31.9, 27.2, 22.8, 22.5, 22.4, 20.2; HRMS (ESI) calcd for
+
was carefully quenched with saturated aqueous NaHCO . The aqueous
C H O [M + H ] 331.2268, found 331.2264.
3
21
30
3
phase was extracted with EtOAc. The combined organic layers were
1-(Chloromethyl)-4,5-dimethoxy-2-methylbenzene (35). To
washed with brine and dried over Na SO . After concentration in
a solution of carboxylic acid 34 (1.0 g, 5.10 mmol) in THF (9 mL) was
added a solution of borane−dimethyl sulfide complex (2 M in THF,
2
4
vacuo, the residue was taken into CHCl (10 mL) and treated with
3
Ag O (104 mg, 0.45 mmol). The mixture was stirred at 50 °C for 30
4
.08 mL, 8.15 mmol) at 0 °C. The solution was warmed to room
2
min and filtered through a plug of cotton. The filtrate was
concentrated and purified by column chromatography (silica gel,
eluted with ethyl acetate/petroleum ether 1/4) to provide 37 (35.9
temperature and stirred overnight. The reaction mixture was carefully
quenched with H O, and the resulting mixture was diluted with
2
EtOAc. The organic phase was separated, washed with H O, and dried
2
−1
mg, 42% for 2 steps) as an orange amorphous solid: IR (film, cm )
over Na SO . After concentration, the residue was purified by flash
2
4
1
3
432, 2925, 1673, 1626, 1413, 1380, 1356, 1223, 1146, 773; H NMR;
column chromatography (silica gel, eluted with ethyl acetate/
petroleum ether 1/1) to provide the benzyl alcohol (836 mg, 90%)
as a white amorphous solid.
δ 7.42 (s, 1H), 6.43 (s, 1H), 6.42 (d, J = 1.2 Hz, 1H), 2.97−2.94 (m,
1
1
1
1
3
−
H), 2.59 (s, 1H), 2.26 (d, J = 1.3 Hz, 3H), 1.77−1.66 (m, 2H), 1.62−
.57 (m, 1H), 1.43−1.39 (m, 1H), 1.27 (s, 3H), 1.26 (s, 3H), 1.24−
The benzylic alcohol (1.82 g, 10 mmol) was taken into CH Cl (20
2
2
.16 (m, 1H), 1.12 (s, 3H); 13C NMR (125 MHz, CDCl ) δ 201.1,
mL) and treated with SOCl (0.87 mL, 12 mmol) dropwise at 0 °C
3
2
81.6, 150.3, 144.5, 140.9, 131.3, 126.9, 126.4, 62.4, 42.9, 42.4, 37.1,
under nitrogen. The mixture was stirred at room temperature for 30
min before it was carefully quenched with saturated aqueous NaHCO3.
The organic phase was separated, and the aqueous phase was extracted
with CH Cl . The combined organic layers were dried over Na SO
3.2, 32.8, 21.9, 21.7, 19.8, 18.6; HRMS (ESI) calcd for C H O [M
18 22
3
+
H ] 285.1496, found 285.1501.
Taxodione (2). To a solution of ketone 25 (103 mg, 0.30 mmol)
in CH Cl (3 mL) was added a freshly prepared solution of BBr (1 M
2
2
2
4
and concentrated. The residue was purified by flash column
chromatography (silica gel, eluted with ethyl acetate/petroleum
ether 1/5) to provide 35 (1.90 g, 95%) as a yellow oil: IR (film,
2
2
3
in CH Cl , 1.80 mL, 1.80 mmol) at −78 °C under nitrogen. The
2
2
reaction mixture was stirred for 30 min, warmed to 0 °C, and stirred
−1
1
for another 30 min. The reaction was carefully quenched with
cm ) 2963, 2934, 1611, 1519, 1466, 1338, 1282, 1226, 1105, 998; H
saturated aqueous NaHCO . The aqueous phase was extracted with
NMR (500 MHz, CDCl ) δ 6.84 (s, 1H), 6.71 (s, 1H), 4.60 (s, 2H),
3
3
13
EtOAc. The combined organic layers were washed with brine and
dried over Na SO . After concentration in vacuo, the residue was taken
3
1
.89 (s, 6H), 2.38 (s, 3H); C NMR (125 MHz, CDCl ) δ 149.1,
3
2
4
47.0, 129.8, 127.3, 113.7, 113.0, 56.0, 55.9, 45.2, 18.4; HRMS (ESI)
+
into CHCl (10 mL) and treated with Ag O (104 mg, 0.45 mmol).
3
2
calcd for C H O Cl [M + H ] 201.0682, found 201.0692.
10
13
2
The mixture was stirred at 50 °C for 30 min before it was filtered
through a plug of cotton. The filtrate was concentrated and purified by
column chromatography (silica gel, eluted with ethyl acetate/
petroleum ether 1/4) to provide 2 (36.8 mg, 39% for two steps) as
an orange amorphous solid.
2
-(4,5-Dimethoxy-2-methylphenyl)-1-(2,6,6-trimethylcyclo-
hex-1-en-1-yl)ethanone (36). A mixture of naphthalene (5.77 g, 45
mmol) and lithium (313 mg, 45 mmol) in THF (50 mL) was stirred at
room temperature under nitrogen for 1.5 h. To this mixture was added
a solution of β-cyclocitral (1.51 g, 9.9 mmol) and benzyl chloride 35
(
1.80 g, 9 mmol) in THF (10 mL) via syringe at 0 °C. The mixture
was then stirred at room temperature for 2 h before it was diluted with
ether and treated with saturated aqueous NH Cl. The organic phase
was separated, and the aqueous phase was extracted with EtOAc. The
combined organic layers were washed with brine and dried over
Na SO . After concentration, the residue was purified by flash column
ASSOCIATED CONTENT
Supporting Information
■
4
*
S
Figures giving some other conditions tested for the Friedel−
1
13
Crafts alkylation of 26 and H and C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2
4
chromatography (silica gel, eluted with ethyl acetate/petroleum ether
/5) to provide allyl alcohol S3 (2.17 g,76%) as a light yellow
1
−1
amorphous solid: IR (film, cm ) 3538, 2934, 1608, 1513, 1466, 1270,
1
1
1
226, 1102, 998; H NMR (500 MHz, CDCl ) δ 6.74 (s, 1H), 6.69 (s,
AUTHOR INFORMATION
Corresponding Author
E-mail for J.Y.: yang@mail.chem.tamu.edu.
3
■
*
H), 4.44 (dd, J = 10.2, 4.1 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.14
(
3
(
dd, J = 14.2, 10.2 Hz, 1H), 2.79 (dd, J = 14.2, 4.1 Hz, 1H), 2.33 (s,
H), 2.03−1.94 (m, 2H), 2.00 (s, 3H), 1.62−1.53 (m, 2H), 1.45−1.42
m, 2H), 1.10 (s, 3H), 0.94 (s, 3H); 13C NMR (125 MHz, CDCl )
Notes
3
147.3, 147.0, 139.3, 131.9, 129.6, 128.8, 113.8, 113.7, 71.4, 56.1, 55.9,
The authors declare no competing financial interest.
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172
dx.doi.org/10.1021/jo4013964 | J. Org. Chem. 2013, 78, 9166−9173

The Journal of Organic Chemistry
Article
ACKNOWLEDGMENTS
■
We thank Mr. Gaines Taylor (NSF REU student) of the
University of Maryland, Baltimore County, for preparing some
of the starting materials. Financial support was provided by the
Robert A. Welch Foundation (A-1700 to J.Y.), the National
Science Foundation (CHE-1150606 to J.Y., CHE-1062840 to
G.T.), the Norman Hackerman Advanced Research Program
(
grant 01957 to X.L.), and the National Institute of Allergy and
Infectious Diseases (AI097599 to X.L.).
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