Total synthesis of laetevirenol A

Article abstract of DOI:10.1021/jo301345a

The first complete synthesis of laetevirenol A was performed in nine steps via intramolecular Friedel-Crafts alkylation in a trans-selective manner. The key phenanthrene intermediate was synthesized by a one-pot Suzuki-Miyaura coupling and an aldol condensation cascade reaction.

Full text of DOI:10.1021/jo301345a

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Note
Total Synthesis of Laetevirenol A
Young Lok Choi, Bum Tae Kim, and Jung-Nyoung Heo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301345a • Publication Date (Web): 04 Sep 2012
Downloaded from http://pubs.acs.org on September 6, 2012
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Total Synthesis of Laetevirenol A
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Young Lok Choi,†,# Bum Tae Kim,† and JungꢀNyoung Heo†,‡,*
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†Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, 141 Gajeongꢀro,
Daejeon 305ꢀ600 Korea, #Department of Chemistry, Korea University, 145 Anamꢀro, Seoul 105ꢀ600 Korea, and
‡Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehakꢀro,
Daejeon 305ꢀ764 Korea
heojn@krict.re.kr
Abstract
MeO
RO
RO
OMe
OR
p-TsOH
MeO
OMe
OMe
toluene
120 oC, 18 h
OR
OR
HO
43%
OMe
OR
17
23, R = Me
BBr3
99%
1, R = H (Laetevirenol A)
The first complete synthesis of laetevirenol A was performed in 9 steps via intramolecular FriedelꢀCrafts
alkylation in a transꢀselective manner. The key phenanthrene intermediate was synthesized by a oneꢀpot Suzukiꢀ
Miyaura coupling and an aldol condensation cascade reaction.
Laetevirenol A (1) was isolated from the roots and stems of P. laetevirens, along with laetevirenol B (2)−E, by
Pan et al. in 2008 (Figure 1).1 Laetevirenol A was observed strong antioxidant activities, most likely due to the
presence of a phenanthrene moiety acting as a free radical scavenger. Structurally, laetevirenol A belongs to a
large and diverse family of polyphenol compounds that includes resveratrol (3)ꢀbased natural products such as
quadranglularin A (4),2 parthenocissin A (5),3 and pauciflorol F (6).4 Members of this family of resveratrol
oligomers possess a wide range of biological activities including antitumor,5 antioxidant,6 antiꢀinflammatory,7
antiꢀHIV,8 antifungal,9 and neuroprotective activities.10
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OH
HO
HO
HO
OH
HO
OH
OH
OH
HO
OH
O
OH
OH
HO
Laetevirenol B (2)
Laetevirenol A (1)
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HO
OH
OH
O
OH
HO
HO
OH
OH
OH
OH
OH
HO
OH
OH
Pauciflorol F (6)
E = Quadranglularin A (4)
Z = Parthenocissin A (5)
Resveratrol (3)
Figure 1. Representative molecules of resveratrolꢀbased oligomers.
The complex molecular diversity of resveratrol oligomers has attracted considerable attention from
organic and medicinal chemists. Recently, Snyder et al. developed an elegant strategy that allowed them to
access several molecules of resveratrol oligomers via a programmable process. The process was initiated from a
simple, common intermediate.11 Thereafter, Nicolaou and Chen’s group reported the synthesis of hopeahainol A
and hopeanol by employing an intramolecular FriedelꢀCrafts alkylation.12
Our synthetic strategy began with the retrosynthetic analysis of laetevirenol A (1) to a triarylꢀ
substituted olefin intermediate, 7 (Scheme 1). At this late stage of cyclization, the FriedelꢀCrafts alkylation
would be appropriate to provide trans stereochemistry to laetevirenol A.13,14 Consequently, it was anticipated
that the triarylꢀsubstituted olefin 7 could be obtained through a Grignard addition of ketone 8, followed by acidꢀ
catalyzed dehydration. Furthermore, ketone 8 could, in turn, be prepared from phenanthrene carboxylic acid
through a Grignard reaction. Phenanthrene 9 was expected to be easily obtained using our previously performed
method, a oneꢀpot SuzukiꢀMiyaura coupling/aldol condensation cascade reaction of phenylacetonitrile 11 with
2ꢀformylphenylboronic acid 10.15
Scheme 1. Retrosynthetic Analysis for Laetevirenol A
HO
MeO
OH
OMe
HO
MeO
OH
OH
OMe
OH
Friedel-Crafts
OMe
Grignard/Dehydration
OMe
1
7
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MeO
MeO
MeO
MeO
OMe
Aldol
CHO
Suzuki-Miyaura
B(OH)2
+
Br
10
MeO
OMe
OH
O
O
MeO
CN
Grignard
OMe
9
OMe
8
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OMe
10
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For the preparation of phenanthrene 9, a oneꢀpot SuzukiꢀMiyaura coupling/aldol condensation cascade
reaction was employed. The substrate for this reaction, phenylacetonitrile 11, was easily prepared by
bromination of benzyl bromide 1216,11c with NBS, followed by cyanation with NaCN in DMF (Scheme 2).17
Based on the original procedure reported by our group,15a the oneꢀpot reaction of 11 with 2ꢀformylphenylboronic
acid 10 under microwave irradiation easily produced the phenanthrene 13 in 86% yield. Hydrolysis of the
phenanthrene nitrile 13 in basic conditions produced the corresponding acid 9 in excellent yield,18 which was
subsequently converted into the Weinreb amide 14 in 97% yield. The Grignard addition of 14 with
phenylmagnesium chloride 15 was then carried out to afford the ketone 8 in 81% yield.
Scheme 2. Synthesis of Phenanthrene Ketone 8
Br
1) NBS, CH2Cl2
rt, 4 h
10
MeO
MeO
Br
Pd(PPh3)4
CN
86%
Cs2CO3
toluene/EtOH(2:1)
MW 150 oC, 10 min
86%
2) NaCN, DMF
rt, 3 h
OMe
OMe
93%
12
11
MeO
MeO
MeO
MeO(Me)NH. HCl
36% NaOH
O
MeO
OH
BOP, DIPEA
DMF, rt, 4 h
CN
HO
150 oC, 18 h
92%
O
97%
OMe
13
OMe
9
OMe
MeO
MeO
MeO
OMe
ClMg
OMe
OMe
N
MeO
15
OMe
O
O
THF, rt, 3 h
81%
OMe
OMe
14
8
Next, ketone 8 was subjected to the Grignard addition with benzylmagnesium chloride 16 to give the
expected tertiary alcohol 17 in 59% yield (Scheme 3).19 Dehydration of the tertiary alcohol 17 with pꢀTsOH in
toluene at room temperature afforded a triarylꢀsubstituted olefin 7 in 73% yield with an E/Z ratio of 5:1.20 Other
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Brønsted acids, including HCl, CSA, and TFA, proved to be less effective, resulting in an E/Z ratio of ~1:1.
With access to olefin 7 established, our efforts turned to implementing the key intramolecular FriedelꢀCrafts
alkylations. A small screening of Lewis acids revealed that exposure of olefin 7 to FeCl3 promoted
intramolecular oxidative cyclohydrogenation to provide a fully conjugated acephenanthrylene 18 in good
yield.21,22 Thus, we envisioned that further elaboration of 18 by catalytic hydrogenation would provide the cis
stereoisomer of laetevirenol A. Indeed, exposing 18 to the standard palladiumꢀcatalyzed hydrogenation
conditions led to the desired cis derivative 19 in quantitative yield.23
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Scheme 3. Synthesis of cis-isomer 19
MeO
OMe
OMe
ClMg
16
p-TsOH
MeO
8
OMe
OMe
THF, rt, 3 h
toluene
rt, 4 h
HO
59%
OMe
73%
17
MeO
MeO
MeO
MeO
OMe
OMe
FeCl3.6H2O
CH2Cl2
rt, 3 h
OMe
OMe
79%
OMe
OMe
OMe
OMe
7 (E/Z = 5:1)
18
MeO
OMe
H2, Pd/C
EtOH/EtOAc/CH2Cl2
(1:1:1)
MeO
OMe
OMe
rt, 3 h
99%
OMe
19
Given these findings, we then hypothesized that it might be possible to find FriedelꢀCrafts reaction
conditions to generate the quinone methide 22, which could be a stabilized resonance form of the secondary
benzylic cabocation 21 to produce the desired trans stereoisomer 23 (Scheme 4). After investigating numerous
reaction conditions, we were pleased to find that the oneꢀpot dehydration/FriedelꢀCrafts alkylation of 17 with pꢀ
TsOH in toluene at elevated temperature (120 °C). The desired transꢀcyclized product 23 was obtained as a
single isomer. However, the product was synthesized in moderate yield (43%), along with 18 and 24. At higher
temperatures, we believe that carbocations 20 and 21 may rapidly equilibrate via a 1,2ꢀhydride shift or
interconversion through olefin intermediate 7 due to the significant contribution of quinone methide 22 for the
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stabilization of 21. When olefin 7 (E/Z = 1.7:1) was treated with pꢀTsOH, a mixture of cyclized products 23 and
24 was obtained in a 2.5:1 ratio. We believe that this observation supports the hypothesis that the
interconversion between 20 and 21 proceeds through olefin 7. Finally, global demethylation of 23 using BBr3 in
CH2Cl2 provided laetevirenol A (1) in quantitative yield. The spectroscopic data of the synthetic laetevirenol A
were identical to those reported for the natural product.1 In the case in which the strong Brønsted acid TfOH is
used, the 9Hꢀindeno[2,1ꢀl]phenanthrene 24 could be exclusively obtained in 74% yield, probably through the
tertiary carbocation 20.24 Interestingly, the FriedelꢀCrafts cyclization of 17 seems to depend upon the pKa value
of the Brønsted acids.25 When methanesulfonic acid (pKa = ꢀ0.6) or pꢀTsOH (pKa = ꢀ2.8) was used, the reaction
provided a mixture of 23/24 in 1.4:1 or 5.3:1 ratio, respectively. Therefore, the much higher value of TfOH (pKa
= ꢀ14.0) perhaps resulted in significant stabilization of carbocation 20.
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Scheme 4. Synthesis of laetevirenol A (1)
MeO
OMe
MeO
OMe
OMe
OMe
7
MeO
MeO
MeO
MeO
MeO
MeO
OMe
OMe
OMe
p-TsOH
17
OMe
OMe
OMe
OMe
OMe
OMe
toluene
120 oC, 18 h
OMe
OMe
OMe
20
21
22
43%
MeO
MeO
HO
MeO
MeO
OMe
OH
OMe
BBr3
HO
CH2Cl2
rt, 18 h
OMe
OMe
OH
OH
OMe
OMe
99%
OMe
OH
OMe
24
1
23
In summary, we have successfully achieved the first complete synthesis of laetevirenol A in 9 steps,
starting from the commercially available benzyl bromide 12, in an overall 12% yield. The intramolecular
FriedelꢀCrafts alkylation was employed as the final key step. The synthesis of the phenanthrene ketone
intermediate 8 involves a Grignard addition and a oneꢀpot SuzukiꢀMiyaura coupling/aldol condensation reaction.
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Notably, this route makes it possible to access the cisꢀisomer 19 and indeno[2,1ꢀl]phenanthrene 24 of
laetevirenol A natural product analogues. Our strategy can be considered as a simple and rapid synthesis of this
family of interesting natural products.
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Experimental Section
2-Bromo-1-(bromomethyl)-3,5-dimethoxybenzene. To a solution of 1ꢀ(bromomethyl)ꢀ3,5ꢀdimethoxybenzene
12 (2.0 g, 8.7 mmol) in CH2Cl2 (26 mL) at 0 °C was added NBS (1.53 g, 8.7 mmol) in several portions. The
solution was gradually warmed to room temperature and stirred for 4 h. The reaction mixture was quenched
with saturated NaS2O3 solution and extracted with CH2Cl2. The organic layers were washed with H2O and brine,
dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column
chromatography (10% EtOAc/hexanes) to afford 2ꢀbromoꢀ1ꢀ(bromomethyl)ꢀ3,5ꢀdimethoxybenzene (2.3 g, 86%)
as a white solid. 1H NMR (300 MHz, CDCl3) δ 6.63 (1H, d, J = 2.7 Hz), 6.44 (1H, d, J = 2.5 Hz), 4.60 (2H, s),
3.87 (3H, s), 3.82 (3H, s); 13C NMR (75 MHz, CDCl3) δ 159.9, 157.3, 138.7, 107.3, 105.2, 100.2, 56.6, 55.8,
34.0; MS (EI) m/z 307 (M+, 7%), 229 (72), 135 (77); HRMS (EI) calcd for C9H10Br2O2 [M+] 307.9048, found
307.9048.
2-(2-Bromo-3,5-dimethoxyphenyl)acetonitrile (11). To
a solution of 2ꢀbromoꢀ1ꢀ(bromomethyl)ꢀ3,5ꢀ
dimethoxybenzene (26.0 g, 84 mmol) in DMF (138 mL) was added sodium cyanide (12.33 g, 252 mmol). The
resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with H2O and extracted with
EtOAc (3 × 100 mL). The combined extracts were washed with H2O and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20%
1
EtOAc/hexanes) to afford phenylacetonitrile 11 (20.0 g, 93%) as a white solid. H NMR (300 MHz, CDCl3) δ
6.70 (1H, d, J = 2.7 Hz), 6.47 (1H, d, J = 2.7 Hz), 3.89 (3H, s), 3.84 (3H, s); 13C NMR (75 MHz, CDCl3) δ
160.1, 157.2, 131.6, 117.1, 105.9, 103.9, 99.4, 56.4, 55.7, 25.3; MS (EI) m/z 255 (M+, 100%), 212 (18), 146 (19);
HRMS (EI) calcd for C10H10BrNO2 [M++2] 256.9874, found 256.9856.
3,5,7-Trimethoxyphenanthrene-9-carbonitrile (13). To
a
thickꢀwell microwave vial was added
phenylacetonitrile 11 (256 mg, 1.0 mmol), (2ꢀformylꢀ5ꢀmethoxyphenyl)boronic acid 10 (198 mg, 1.1 mmol),
Pd(PPh3)4 (46 mg, 4 mol %), and Cs2CO3 (978 mg, 3.0 mmol) sequentially. The mixture was suspended in
toluene/EtOH (4 mL/2 mL). Then, the reaction vial was sealed and placed into a microwave reactor and
irradiated at 150 °C for 10 min. After being cooled to room temperature, the mixture was diluted with EtOAc
and filtered through a short Celite pad. The solution was concentrated in vacuo and the residue was purified by
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silica gel flash column chromatography (20% EtOAc/hexanes) to afford phenanthrene 13 (252 mg, 86%) as a
white solid. mp 201−202 °C; 1H NMR (300 MHz, CDCl3) δ 9.06 (1H, d, J = 2.5 Hz), 8.18 (1H, s), 7.80 (1H, d, J
= 8.7 Hz), 7.30 (1H, d, J = 2.5 Hz), 7.23 (1H, dd, J = 8.7, 2.5 Hz), 6.83 (1H, d, J = 2.5 Hz), 4.12 (3H, s), 4.01
(6H, s); 13C NMR (75 MHz, CDCl3) δ 160.8, 160.4, 159.7, 137.0, 133.9, 133.1, 130.8, 124.4, 119.1, 116.0, 115.4,
109.8, 106.2, 100.6, 98.9, 56.13, 55.8, 55.5; MS (EI) m/z 293 (M+, 17%), 277 (17), 234 (10), 198 (6); HRMS (EI)
calcd for C18H15NO3 [M+] 293.1052, found 293.1053.
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3,5,7-Trimethoxyphenanthrene-9-carboxylic acid (9). A solution of 3,5,7ꢀtrimethoxyphenanthreneꢀ9ꢀ
carbonitrile 13 (700 mg, 2.4 mmol) in a mixture of 36 % aq NaOH solution (7 mL) and 2ꢀmethoxy ethanol (21
o
mL) was heated at 150 C for 18 h. Upon cooling, the solution was acidified with 6 N HCl solution and
extracted with EtOAc (3 × 100 mL). The combined extracts were washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. Triturating of the crude product with Et2O gave the carboxylic acid 9 (683
mg, 92%) as a white solid. mp 227−228 °C; 1H NMR (300 MHz, CDCl3) δ 9.10 (1H, d, J = 2.5 Hz), 8.66 (1H, s),
8.34 (1H, d, J = 2.6 Hz), 7.87 (1H, d, J = 8.7 Hz), 7.21 (1H, dd, J = 8.8, 2.5 Hz), 6.83 (1H, d, J = 2.6 Hz), 4.12
(3H, s), 4.02 (3H, s), 4.01 (3H, s); 13C NMR (75 MHz, DMSOꢀd6) δ 169.5, 160.2, 160.1, 159.0, 133.7, 133.3,
133.1, 131.8, 124.4, 124.0, 115.6, 115.3, 109.6, 100.4, 99.5, 56.5, 55.6 (2); MS (EI) m/z 312 (M+, 100%), 279
(6), 210 (8), 139 (6); HRMS (EI) calcd for C18H16O5 [M+] 312.0998, found 312.0992.
N,3,5,7-Tetramethoxy-N-methylphenanthrene-9-carboxamide (14). A solution of carboxylic acid 9 (633 mg,
2.03 mmol), N,Oꢀdimethylhydroxylamine hydrochloride (218 mg, 2.23 mmol), BOP (1.08 g, 2.44 mmol) and
DIPEA (1.1 mL, 8.12 mmol) in DMF (6 mL) was stirred at 25 °C for 4 h. The reaction mixture was quenched
with H2O and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with H2O and brine,
dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column
chromatography (30% EtOAc/hexanes) to afford Weinreb amide 14 (702 mg, 97%) as a white solid. mp
126−127 °C; 1H NMR (300 MHz, CDCl3) δ 9.08 (1H, d, J = 2.6 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.70 (1H, s), 7.19
(1H, dd, J = 8.7, 2.6 Hz), 6.93 (1H, d, J = 2.5 Hz), 6.78 (1H, d, J = 2.5 Hz), 4.11 (3H, s), 4.00 (3H, s), 3.93 (3H,
s), 3.62 (3H, s), 3.36 (3H, s); 13C NMR (75 MHz, CDCl3) δ 160.2, 158.9, 158.7, 132.2, 132.1, 130.0, 129.1,
127.1, 124.9, 115.6, 115.2, 109.6, 99.5, 98.5, 61.3, 55.9, 55.4, 55.3; MS (EI) m/z 355 (M+, 2%), 295 (100), 252
(24); HRMS (EI) calcd for C20H21NO5 [M+] 355.1420, found 355.1437.
(3,5-Dimethoxyphenyl)(3,5,7-trimethoxyphenanthren-9-yl)methanone (8). To a solution of Weinreb amide
14 (100 mg, 0.3 mmol) in THF (1 mL) at 0 °C was added a solution of (3,5ꢀdimethoxyphenyl)magnesium
chloride 15 (1.4 mL, 1.4 mmol, 1 M in THF). The reaction mixture was allowed to warm at 25 °C and stirred for
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3 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 ×
10 mL). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The
resulting residue was purified by silica gel flash column chromatography (20% EtOAc/hexanes) to afford ketone
8 (105 mg, 81%) as a white solid. mp 170−172 °C; 1H NMR (300 MHz, CDCl3) δ 9.11 (1H, d, J = 2.5 Hz), 7.80
(1H, s), 7.74 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 2.5 Hz), 7.18 (1H, dd, J = 8.8, 2.5 Hz), 7.05 (2H, d, J = 2.3
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Hz), 6.80 (1H, d, J = 2.5 Hz), 6.70 (1H, t, J = 2.3 Hz), 4.12 (3H, s), 4.01 (3H, s), 3.84 (3H, s), 3.79 (6H s); 13
C
NMR (75 MHz, CDCl3) δ 198.0, 160.7, 160.1, 159.7, 158.7, 140.9, 133.2, 133.1, 132.0, 131.8, 130.8, 124.2,
115.9, 115.3, 109.6, 108.0, 105.7, 99.8, 99.5, 55.9, 55.6, 55.35, 55.30; MS (EI) m/z 432 (M+, 100%), 373 (11),
295 (17), 252 (7); HRMS (EI) calcd for C26H24O6 [M+] 432.1573, found 432.1570.
1-(3,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)-1-(3,5,7-trimethoxyphenanthren-9-yl)ethanol (17). To a
solution of ketone 8 (100 mg, 0.2 mmol) in THF (1 mL) at 0 °C was added a solution of (4ꢀ
methoxybenzyl)magnesium chloride 16 (2 mL, 0.5 mmol, 0.25 M in THF). The reaction mixture was allowed to
warm gradually to 25 °C and stirred for 3 h. The reaction mixture was quenched with a saturated aqueous
NH4Cl solution and extracted with EtOAc (3 × 15 mL). The organic extracts were washed with H2O and brine,
dried over MgSO4, concentrated under reduced pressure. The residue was purified by silica gel flash column
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chromatography (20% EtOAc/hexanes) to give alcohol 17 (75mg, 59%) as a white solid. mp 183−184 °C; H
NMR (300 MHz, CDCl3) δ 9.08 (1H, d, J = 2.6 Hz), 8.06 (1H, s), 7.80 (1H, d, J = 8.7 Hz), 7.30−7.24 (1H, m),
7.20 (1H, dd, J = 8.7, 2.6 Hz), 6.70 (4H, s), 6.65 (1H, d, J = 2.5 Hz), 6.39 (2H, d, J = 2.3 Hz), 6.27 (1H, t, J =
2.3 Hz), 4.05 (3H, s), 4.00 (3H, s), 3.85 (1H, d, J = 12.8 Hz), 3.74 (3H, s), 3.65 (1H, d, J = 12.7 Hz), 3.60 (6H,
s), 3.56 (3H, s); 13C NMR (75 MHz, CDCl3) δ 160.6, 160.2, 158.6, 158.6, 149.3, 136.0, 132.2, 131.8, 130.3,
128.0, 127.2, 125.4, 117.0, 115.0, 113.3, 109.6, 104.8, 101.7, 99.0, 98.8, 78.5, 77.4, 55.9, 55.4, 55.4, 55.3; MS
(EI) m/z 554 (M+, 1%), 433 (59), 295 (27), 252 (8), 165 (100), 137 (19), 121 (44); HRMS (EI) calcd for
C34H34O7 [M+] 554.2305, found 554.2305.
(E)-10-(1-(3,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)vinyl)-2,4,6-trimethoxyphenanthrene (7E). To
a
solution of alcohol 17 (84 mg, 0.156 mmol) in toluene (1.5 mL) was added pꢀTsOH.6H2O (13 mg, 0.8 mmol)
and stirred at rt for 4 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with
EtOAc (3 × 10 mL). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by prep HPLC using an XTerra C18 OBDTM (5 m) column (30%
H2O/ACN, 40 mL/min) to afford olefin 7E (50 mg, 61%) as a yellow solid (retention time = 15.0 min). mp
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202−204 °C; H NMR (300 MHz, CDCl3) δ 9.08 (1H, d, J = 2.5 Hz), 7.78 (1H, d, J = 8.8 Hz), 7.76 (1H, s,),
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7.21−7.17 (3H, m), 7.07 (1H, d, J = 2.5 Hz), 6.85 (1H, s), 6.77 (2H, dd, J = 8.8, 2.0 Hz), 6.67 (1H, d, J = 2.5
Hz), 6.47 (2H, d, J = 2.3 Hz), 6.30 (1H, t, J = 2.3 Hz), 4.07 (3H, s), 4.00 (3H, s), 3.80 (3H, s), 3.67 (3H, s), 3.58
(6H, s); 13C NMR (75 MHz, CDCl3) δ 160.7, 160.1, 158.6, 158.2, 157.8, 142.7, 141.0, 137.7, 134.8, 131.5,
130.9, 130.6, 129.9, 129.7, 129.6, 126.0, 115.8, 114.8, 113.5, 109.6, 107.9, 100.6, 99.5, 98.9, 55.8, 55.3, 55.2 (2),
55.1; MS (EI) m/z 534 (M+, 100%), 401 (29), 295 (16); HRMS (EI) calcd for C34H32O6 [M+] 536.2199, found
536.2188.
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(Z)-10-(1-(3,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)vinyl)-2,4,6-trimethoxyphenanthrene (7Z). The
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product (10 mg, 12%) was obtained by the above prep HPLC (retention time = 10.5 min). mp 235−236 °C; H
NMR (300 MHz, CDCl3) δ 9.14 (1H, d, J = 2.6 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.57 (1H, s), 7.23 (1H, s), 7.16
(1H, dd, J = 8.7, 2.6 Hz), 6.99 (1H, d, J = 2.5 Hz), 6.94 (2H, dd, J = 6.8, 1.9 Hz), 6.72 (1H, d, J = 2.5 Hz), 6.57
(2H, d, J = 2.3 Hz), 6.53 (2H, dd, J = 6.8, 2.1 Hz), 6.35 (1H, t, J = 2.3 Hz), 4.12 (3H, s), 4.01 (3H, s), 3.69 (6H,
s), 3.67 (3H, s), 3.64 (3H, s); 13C NMR (75 MHz, CDCl3) δ 160.7, 160.2, 158.5, 158.3, 158.2, 145.6, 138.9,
134.8, 133.4, 131.5, 130.5, 129.8, 129.72, 129.67, 126.4, 116.0, 114.7, 113.6, 109.5, 105.1, 99.7, 99.1, 98.9,
55.8, 55.3 (2), 55.2, 55.1; MS (EI) m/z 536 (M+, 95%), 505 (57), 214 (51), 108 (100); HRMS (EI) calcd for
C34H32O6 [M+] 536.2199, found 536.2199.
5-(3,5-Dimethoxyphenyl)-1,3,9-trimethoxy-4-(4-methoxyphenyl)acephen-anthrylene (18). To a solution of
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olefin 7E (8 mg, 0.015 mmol) in CH2Cl2 (0.7 mL) at rt was added FeCl3 6H2O (8 mg, 0.03 mmol) and stirred for
3 h. The reaction mixture was treated with H2O (10 mL) and extracted with CH2Cl2 (2 × 20 mL). The extracts
were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel
flash column chromatography (20% EtOAc/hexanes) to give acephenanthrylene 18 (6.3 mg, 79%) as a yellow
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solid. mp 137−138 °C; H NMR (300 MHz, CDCl3) δ 8.87 (1H, d, J = 2.7 Hz), 8.09 (1 H, s), 7.91 (1H, d, J =
8.8 Hz), 7.40 (2H, d, J = 8.7 Hz), 7.20 (1H, dd, J = 8.8, 2.7 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.72 (1H, s), 6.53 (2H,
d, J = 2.3 Hz), 6.39 (1H, t, J = 2.3 Hz), 4.22 (3H, s), 4.03 (3H, s), 3.86 (3H, s), 3.84 (3H, s), 3.68 (6H, s); 13C
NMR (75 MHz, CDCl3) δ 161.7, 160.5, 159.3, 158.6, 156.1, 139.0, 138.0, 135.3, 133.4, 132.3, 131.9, 131.8,
129.3, 127.9, 126.6, 117.3, 114.8, 112.9, 112.3, 109.5, 108.7, 99.1, 95.7, 56.30, 59.28, 55.5, 55.4; MS (EI) m/z
534 (M+, 100%), 519 (22), 284 (16); HRMS (EI) calcd for C34H30O6 [M+] 534.2042, found 534.2039.
cis-5-(3,5-Dimethoxyphenyl)-1,3,9-trimethoxy-4-(4-methoxyphenyl)-4,5-dihydroacephenanthrylene (19).
To a solution of acephenanthrylene 18 (20 mg, 0.037 mmol) in a mixture of EtOAc/EtOH/CH2Cl2 (0.6 mL/0.6
mL/0.6 mL) was added 10% Pd/C (20 mg, 10 wt %). The resulting suspension was stirred at rt for 3 h under an
atmosphere of hydrogen (balloon). The reaction mixture was filtered through a short Celite pad and
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concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (20%
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EtOAc/hexanes) to afford cisꢀdihydroacephenanthrylene 19 (18 mg, 99%) as a white solid. mp 182−183 °C; H
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NMR (300 MHz, CDCl3) δ 8.95 (1H, d, J = 2.6 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.23 (1H, s), 7.15 (1H, dd, J = 8.7,
2.7 Hz), 6.85 (1H, s), 6.51−6.37 (5H, m), 6.19 (1H, t, J = 2.4 Hz), 6.09 (2H, d, J = 2.3 Hz), 5.16−5.04 (2H, m),
4.20 (3H, s), 4.02 (3H, s), 3.83 (3H, s), 3.64 (3H, s), 3.55 (6H, s); 13C NMR (75 MHz, CDCl3) δ 160.1, 159.1,
157.85, 157.82, 154.3, 142.7, 141.7, 141.5, 134.0, 130.5, 129.6, 129.5, 128.5, 122.5, 122.0, 114.4, 112.9, 112.8,
109.8, 108.4, 99.0, 97.4, 56.8, 56.5, 56.3, 55.6, 55.3, 55.2, 52.7; MS (EI) m/z 536 (M+, 100%), 505 (11), 428
(18); HRMS (EI) calcd for C34H32O6 [M+] 536.2199, found 536.2183.
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trans-5-(3,5-Dimethoxyphenyl)-1,3,9-trimethoxy-4-(4-methoxyphenyl)-4,5-dihydroacephenanthrylene (23).
To a solution of alcohol 17 (277 mg, 0.5 mmol) in toluene (10 mL) was added pꢀTsOH.6H2O (95 mg, 0.5 mmol).
The resulting mixture was sealed and stirred at 120 °C for 18 h. After cooling to room temperature, the mixture
was quenched with H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined extracts were washed
with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel
flash column chromatography (20% EtOAc/hexanes) to afford the desired trans isomer 23 (115 mg, 43%) as a
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white solid. mp 179−180 °C; H NMR (300 MHz, CDCl3) δ 8.93 (1H, d, J = 2.6 Hz), 7.66 (1H, d, J = 8.7 Hz),
7.14 (1H, dd, J = 8.7, 2.6 Hz), 6.99 (2H, d, J = 8.4 Hz), 6.80 (2H, d, J = 4.0 Hz), 6.78 (1H, d, J = 5.9 Hz), 6.34
(1H, t, J = 2.3 Hz), 6.28 (2H, d, J = 2.3 Hz), 4.72 (1H, d, J = 3.7 Hz), 4.46 (1H, d, J = 2.7 Hz), 4.17 (3H, s), 4.01
(3H, s), 3.78 (3H, s), 3.76 (3H, s), 3.70 (6H, s); 13C NMR (75 MHz, CDCl3) δ 160.9, 158.9, 158.0, 157.7, 154.1,
148.04, 142.0, 141.0, 137.9, 130.4, 129.4, 128.4, 128.1, 122.5, 122.0, 114.3, 113.7, 112.8, 109.6, 105.9, 98.25,
97.4, 77.4, 77.2, 77.0, 76.6, 61.1, 57.3, 56.3, 56.2, 55.4, 55.3 (2), 55.2; MS (EI) m/z 536 (M+, 100%), 505 (55),
488 (16); HRMS (EI) calcd for C34H32O6 [M+] 536.2199, found 536.2197.
Laetevirenol A (1). To a solution of transꢀdihydroacephenanthrylene 23 (20 mg, 0.037 mmol) in CH2Cl2 (1 mL)
at 0 °C was added a solution of BBr3 (745 µL, 0.75 mmol, 1 M in CH2Cl2). The reaction mixture was stirred at
25 °C for 24 h and quenched with MeOH. The resulting mixture was diluted with EtOAc (50 mL), washed with
brine, dried over MgSO4. The solution was concentrated in vacuo and purified by silica gel flash column
chromatography (10% MeOH/CH2Cl2) to afford laetevirenol A (18 mg, 99%) as a yellow solid. mp 143−144 °C;
1H NMR (500 MHz, acetoneꢀd6) δ 9.37 (1H, s), 8.93 (1H, d, J = 2.5 Hz), 8.44 (1H, s), 8.13 (1H, s), 8.09 (2H, s),
7.96 (1H, s), 7.64 (1H, d, J = 8.6 Hz), 7.17 (1H, d, J = 1.3 Hz), 7.03 (1H, dd, J = 8.5, 2.5 Hz), 6.89 (2H, d, J =
8.5 Hz), 6.79 (1H, s), 6.71 (2H, d, J = 8.5 Hz), 6.20 (1H, d, J = 2.1 Hz), 6.10 (2H, d, J = 2.3 Hz), 4.63 (1H, d, J
= 3.0 Hz), 4.28 (1H, dd, J = 3.2, 1.5 Hz); 13C NMR (125 MHz, acetoneꢀd6) δ 159.5, 156.9, 156.6, 156.1, 152.5,
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149.6, 142.6, 142.4, 137.5, 132.1, 129.9, 128.8, 128.1, 122.1, 120.0, 115.9, 115.3, 112.5, 111.7, 106.6, 104.9,
101.5, 62.0, 57.8; MS (EI) m/z 451 (M+, 1%), 167 (23), 149 (100); HRMS (EI) calcd for C28H19O6 [M+]
451.1182, found 451.1178.
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3,5,7,11,13-pentamethoxy-9-(4-methoxybenzyl)-9H-indeno[2,1-l]phenanthrene (24). To a solution of alcohol
17 (277 mg, 0.5 mmol) in toluene (10 mL) at room temperature was added TfOH (44 µL, 0.5 mmol). The
reaction mixture was sealed and stirred at 120 °C for 18 h. The reaction mixture was quenched with a saturated
aqueous NaHCO3 solution and extracted with EtOAc (3 × 100 mL). The extracts were washed with H2O and
brine, dried over MgSO4. The mixture was concentrated in vacuo and purified by silica gel flash column
chromatography (20% EtOAc/hexanes) to afford 9Hꢀindeno[1,2ꢀl]phenanthrene 24 (199 mg, 74%) as a white
solid. mp 96−97 °C; 1H NMR (300 MHz, CDCl3) δ 9.29 (1H, d, J = 9.3 Hz), 9.19 (1H, d, J = 2.7 Hz), 7.21 (1H,
dd, J = 9.3, 2.8 Hz), 7.14 (1H, d, J = 2.4 Hz), 6.94 (2H, d, J = 8.6 Hz), 6.75 (1H, d, J = 2.4 Hz), 6.72 (2H, d, J =
8.6 Hz), 6.54 (1H, d, J = 2.2 Hz), 6.27 (1H, d, J = 2.1 Hz), 4.43 (1H, dd, J = 9.0, 3.6 Hz), 4.13 (3H, s), 4.03 (3H,
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s), 4.02 (3H, s), 3.93 (3H, s), 3.74 (3H, s), 3.73 (3H, s), 3.69−3.65 (1H, m), 2.64 (1H, dd, J = 13.9, 9.0 Hz); 13
C
NMR (75 MHz, CDCl3) δ 160.3, 159.5, 158.4, 158.2, 157.2, 155.0, 152.7, 138.4, 137.2, 133.0, 132.4, 131.5,
130.6, 129.9, 123.8, 122.8, 115.3, 113.5, 113.4, 109.6, 103.0, 99.3, 98.1, 98.0, 56.4, 56.1, 55.5, 55.5, 55.4, 55.3,
49.9, 39.9; MS (EI) m/z 536 (M+, 100%), 505 (11), 428 (18); HRMS (EI) calcd for C34H32O6 [M+] 536.2199,
found 536.2188.
Acknowledgment
Financial support provided by the KRICT and Ministry of Knowledge Economy, Korea is gratefully
acknowledged. This work is dedicated to Prof. William R. Roush on the occasion of his 60th birthday.
Supporting Information
1H NMR and 13C NMR spectra for compounds 7−9, 11−14, 17−19, 23−24, and 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
† Korea Research Institute of Chemical Technology.
‡ Chungnam National University
# Korea University.
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13. For reviews, (a) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973. (b) Olah, G. A.;
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Oxford, 1991; pp. 293−339.
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Navarro, R.; Reisman, S. E. Angew. Chem. Int. Ed. 2011, 50, 9447. (b) Sun, B.ꢀF.; Hong, R.; Kang, Y.ꢀB.; Dong,
L. J. Am. Chem. Soc. 2009, 131, 10384. (c) Patil, D. V.; Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 5820. (d)
Zhang, Z.ꢀW.; Li, W.ꢀD. Z. Org. Lett. 2010, 12, 1649.
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15. (a) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J.ꢀN. J. Org. Chem. 2008, 73, 495. (b) Kim, J. K.; Kim,
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16. Compound 12 is commercially available. Also it can be readily prepared from the corresponding benzyl
alcohol by following the literature procedure. See: ref. 11(c).
17. Molander, G. A.; Pack, S. K. Tetrahedron 2003, 59, 10581.
18. Magnus, P.; Morris, J. C.; Lynch, V. Synthesis 1997, 506.
19. Suzuki, K.; Kobayashi, T.; Nishikawa, T.; Hori, Y.; Hagiwara, T. EP 1,167,372 (2002).
20. The E/Z isomers of 7 were separated by prep. HPLC and the relative stereochemistry was identified by nOe
experiments. For details, see the Supporting Information.
21. Other transition metalꢀbased Lewis acids such as Bi(OTf)3, Sc(OTf)3, AgOTf, and Yb(OTf)3 were proved
less efficient.
22. (a) Jeffrey, J. L.; Sarpong, R. Tetrahedron Lett. 2009, 50, 1969. (b) Levi, Z. U.; Tilley, T. D. J. Am. Chem.
Soc. 2010, 132, 11012. (c) Feng, X.; Wu, J.; Enkelmann, V.; Mullen, K. Org. Lett. 2006, 8, 1145.
23. All attempts for global demethylation of 19 with BBr3 or BCl3 failed to afford the cisꢀlaetevirenol A isomer.
24. Compound 24 is highly unstable at ambient conditions and readily decomposed to a mixture of unknown
compounds.
25. (a) Ordwell, F. B. Acc. Chem. Res. 1988, 21, 456. (b) Guthrie, J. P. Can. J. Chem. 2009, 30, 799.
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