Enantioselective total syntheses of cedrelin A and methylated paralycolin B using Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols

Article abstract of DOI:10.1016/j.tet.2013.05.007

We report the first enantioselective total syntheses of cedrelin A and methylated paralycolin B, wherein Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols was the key step.

Full text of DOI:10.1016/j.tet.2013.05.007

Tetrahedron 69 (2013) 5913e5919
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective total syntheses of cedrelin A and methylated
paralycolin B using Pd-catalyzed asymmetric intramolecular
FriedeleCrafts allylic alkylation of phenols
*
Yuta Suzuki, Nobuaki Matsuo, Tetsuhiro Nemoto, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the first enantioselective total syntheses of cedrelin A and methylated paralycolin B, wherein
Pd-catalyzed asymmetric intramolecular FriedeleCrafts allylic alkylation of phenols was the key step.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 April 2013
Received in revised form 1 May 2013
Accepted 3 May 2013
Available online 18 May 2013
Keywords:
Asymmetric synthesis
Dihydrophenanthrenes
FriedeleCrafts alkylation
Palladium
Total synthesis
1. Introduction
targets in organic synthesis and medicinal chemistry. To date,
however, synthetic studies of these natural products have not been
Highly oxygenated 9,10-dihydrophenanthrenes are ubiquitous
structural motifs in biologically active natural products. In 1987,
Delle Monache and co-workers reported the isolation of a novel
dihydrophenanthrapyrane natural product from the root of Clusia
paralycola, paralycolin A (1a), which exhibits cytotoxicity against
KB and P388 cells (Fig. 1).1a The structurally related natural prod-
ucts cedrelin A (2a) and cedrelin B (2b) were isolated from the bark
of Cedrelinga catenaeformis Duke by Kakisawa and co-workers in
1991. Cedrelin A has cytotoxic activity against Staphylococcus aureus
(209P) and Bacillus subtilis (IAM1213).1b Paralycolin B (1b), whose
oxidation pattern differs from that of paralycolin A and cedrelins,
was also reported by Delle Monache et al. in 2002.1c This
natural product was isolated only as a methylated derivative (1c)
after treatment of an obtained mixture of paralycolin A and
paralycolin B with diazomethane. In addition to multiple oxygen
functionalities on the aromatic rings, these natural products com-
monly possess an isopropenyl group at the 10-position of the
9,10-dihydrophenanthrene skeleton. The reported bioactivities and
characteristic structure make these natural products attractive
reported. The development of an efficient and divergent synthetic
method would facilitate detailed studies of the bioactivities of
this class of dihydrophenanthrapyranes. Herein we report the
first enantioselective total syntheses of cedrelin A and methylated
paralycolin
B using Pd-catalyzed asymmetric intramolecular
FriedeleCrafts allylic alkylation of phenols.
* Corresponding author. Tel./fax: þ81 43 226 2920; e-mail addresses: hamada@
p.chiba-u.ac.jp, y-hamada@faculty.chiba-u.jp (Y. Hamada).
Fig. 1. Dihydrophenanthrapyrane natural products.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.007

5914
Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
2. Results and discussions
derivative 8 in 95% yield. After reduction of the ester unit with
DIBAL-H, the obtained alcohol was converted into allyl carbonate
derivative 9 in 85% yield in three steps.
Our plan for the enantioselective synthesis of cedrelins and
paralycolins is shown in Scheme 1. As part of our ongoing studies
aimed at developing novel synthetic methods based on intra-
molecular FriedeleCrafts-type reactions,2 we recently reported
a Pd-catalyzed asymmetric intramolecular FriedeleCrafts allylic
alkylation of phenols that provides 10-vinyl- or 10-isopropenyl-
substituted chiral 9,10-dihydrophenanthrenes in excellent yield
with high enantioselectivity.3,4 This catalytic asymmetric reaction
can be a powerful tool for constructing the core structure of target
natural products. We envisioned that the D-ring moiety could be
constructed in the late stage of the synthesis using diphenol-type
compounds I as key intermediates, which in turn would be ob-
tained in optically active forms by the Pd-catalyzed asymmetric
intramolecular FriedeleCrafts allylic alkylation of symmetric
3,5-dihydroxy biphenyl derivatives II. Biphenyl derivatives could be
prepared from the corresponding aryl bromides and arylboronate
using catalytic biaryl coupling reactions.
We next examined Pd-catalyzed asymmetric intramolecular
FriedeleCrafts allylic alkylation of 9 (Table 1). First, we performed
the reaction using 10 mol % of Pd(dba)2 and 12 mol % of (R,R)-
DCHA-phenyl Trost ligand7 10a in CH2Cl2/MeOH mixed solvent at
40 ꢀC, which were the optimum conditions for the previously re-
ported chiral 9,10-dihydrophenanthrene synthesis. The reaction
proceeded smoothly to give compound 11 in 94% yield, which was
determined by 1H NMR analysis of the crude mixture. Enantiomeric
purity of the product was, however, 29% ee (Entry 1). The solvent
system affected the reactivity, as well as the enantioselectivity.
When the reaction was performed in THF/MeOH mixed solvent, the
product was obtained in 88% yield with 60% ee (Entry 4). No re-
action occurred when other commercially available Trost ligands
were used (Entries 5 and 6).8 The addition of acetate salts slightly
increased the enantiomeric excess. Using 1.5 equiv of KOAc,
the reaction proceeded smoothly to provide 11 in 98% yield (94%
Scheme 1. Synthetic plan.
Synthetic studies toward cedrelin A started with the known
aldehyde 15 (Scheme 2). After temporary protection of the phenolic
hydroxyl group with a TBS group, a methylene-unit homologation
of the aldehyde moiety was performed via Wittig reaction using
phosphonium salt 2, followed by acidic hydrolysis, affording com-
pound 3 in 77% yield in three steps. Compound 3 was reacted with
isolated yield after silica gel column purification) with 66% ee. Less
satisfactory results were obtained when the reaction was per-
formed using 5 mol % of the Pd catalyst (Entry 10).
With optically active intermediate 11 (66% ee) in hand, we
examined the enantioselective total synthesis of cedrelin
A
(Scheme 3). First, to construct the D-ring moiety, 11 was reacted
with 3,3-dimethylacrolein in the presence of ethyl-
endiamine$2AcOH.9 The tetracyclic adduct with the desired mo-
lecular skeleton 12 was obtained in 51% yield, accompanied by the
formation of regioisomer 120 in 38% yield. Deprotection of the tosyl
stable ylide 4 to give a,b-unsaturated ester 5 (83% yield), which was
then transformed into the corresponding tosylate 6 in 90% yield.
SuzukieMiyaura cross-coupling6 of 6 with 7 proceeded smoothly
using 5 mol % of PdCl2(dppf) and K3PO4 as a base, affording biaryl
Scheme 2. Substrate preparation for the Pd-catalyzed asymmetric intramolecular FriedeleCrafts allylic alkylation.

Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
5915
Table 1
Pd-catalyzed asymmetric intramolecular FriedeleCrafts allylic alkylation of 9
Entry
Pd cat. (mol %)
Solvent
Chiral ligand
Additive
Yield (%)a
Ee (% ee)b
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
5
CH2Cl2/MeOH (4/1)
CH3CN/MeOH (4/1)
Toluene/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
THF/MeOH (4/1)
(R,R)-10a
(R,R)-10a
(R,R)-10a
(R,R)-10a
(R,R)-10b
(R,R)-10c
(R,R)-10a
(R,R)-10a
(R,R)-10a
(R,R)-10a
d
94
33
31
88
29
36
38
60
d
d
d
d
d
No reaction
No reaction
83
d
d
LiOAc
KOAc
Mg(OAc)2
KOAc
63
66
65
60
98 (94)c
75
10
45
a
Determined by 1H NMR analysis of the crude sample.
Determined by chiral HPLC analysis.
Isolated yield.
b
c
3. Conclusion
In conclusion, we successfully achieved the first enantiose-
lective total syntheses of cedrelin A and methylated paralycolin B
by Pd-catalyzed asymmetric intramolecular FriedeleCrafts allylic
alkylation of phenols. The present method provides access to syn-
thetic analogues of this class of dihydrophenanthrapyranes that are
of potential interest in medicinal chemistry. Further studies are in
progress.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR (Smiths
Detection, DuraSample IR II). NMR spectra were recorded on a JEOL
ecp 400 spectrometer, operating at 400 MHz for 1H NMR, and
100 MHz for 13C NMR. Chemical shifts in CDCl3, were reported
downfield from TMS (¼0 ppm) for 1H NMR. For 13C NMR, chemical
shifts were reported in the scale relative to the solvent signal [CHCl3
(77.0 ppm)] as an internal reference. ESI mass spectra were mea-
sured on JEOL AccuTOF LC-plus JMS-T100L. The enantiomeric ex-
cess (ee) was determined by HPLC analysis. HPLC was performed on
JASCO HPLC systems consisting of the following: pump, PU-980;
detector, UV-970, measured at 254 nm; column, DAICEL CHIR-
ALCEL OD-H; mobile phase: hexane/2-propanol. Reactions were
carried out in dry solvent under argon atmosphere. Other reagents
were purified by the usual methods.
Scheme 3. Total synthesis of cedrelin A.
group was performed under basic conditions to give cedrelin A in
74% yield (16.5% overall yield, 12 steps from 1)([
a
]
D
24 ꢁ54.9 [c 0.75,
CHCl3, 66% ee]; Literature data.1b
[
a]
D ꢁ20.8 [c 0.25, CHCl3]).10 The
NMR data (1H NMR and 13C NMR) were identical to the reported
data of 2a.1b
We next turned our attention to enantioselective total synthesis
of paralycolin B with different oxidation patterns on the A-ring
(Scheme 4). Compound 17 was prepared from commercially avail-
able 6-bromoveratraldehyde 13 using the same synthetic method
as that used for compound 9 (seven steps, 71% overall yield).
Asymmetric intramolecular FriedeleCrafts allylic alkylation of 17
proceeded using 2.5 mol % of Pd(dba)2 and 3 mol % of (R,R)-10a in
4.2. Enantioselective synthesis of (L)-cedrelin A
4.2.1. 2-(6-Bromo-3-hydroxy-2-methoxyphenyl)acetaldehyde
(3). To a stirred solution of 1 (7.44 g, 32.2 mmol) and imidazole
(2.85 g, 41.9 mmol) in DMF (32.2 mL) at 0 ꢀC was added TBSCl
(7.28 g, 48.3 mmol), and the resulting mixture was stirred for 1 h at
room temperature. After dilution with Et2O, the mixture was
washed with water (2 times), brine, and then dried over Na2SO4.
After concentration in vacuo, the obtained crude silylated
product was used for the next step without purification. To a stirred
solution of (methoxymethyl)triphenyl phosphonium chloride
CH2Cl2/MeOH mixed solvent, providing 18 in 98% yield with 92% ee.
23
Subsequent D-ring formation gave a mixture of 19 ([
a]
ꢁ94.0 [c
D
0.44, CHCl3]) and 190 in 55% yield and 28% yield, respectively.11 Fi-
nally, 19 was converted into methylated paralycolin B (1c) in 92%
yield (35.2% overall yield, 10 steps from 13).1c 1H NMR and 13C NMR
analyses of the synthetic sample were identical to the literature
data.12,13

5916
Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
Scheme 4. Total synthesis of methylated paralycolin B.
(16.8 g, 48.9 mmol) in THF (120 mL) at 0 ꢀC was added KOt-Bu
(12.8 g, 114.0 mmol). The resulting mixture was stirred at the same
temperature for 30 min. A solution of the crude silylated product in
THF (40 mL) was added to the reaction, and then the resulting
mixture was stirred at room temperature. After 2 h, the reaction
was quenched with 1 N aq HCl, and the mixture was diluted with
AcOEt. After separation of the aqueous layer, the organic layer was
washed with brine, dried over Na2SO4, and then evaporated in
vacuo. The obtained crude methyl vinyl ether derivative was used
for the next step without purification. To a stirred solution of the
crude product in THF (72 mL) at room temperature was added 1 N
aq HCl (10 mL). The resulting solution was refluxed for 3 h. After
evaporation of the organic solvent in vacuo, water was added to the
mixture, and the resulting slurry was extracted with AcOEt. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The obtained residue
was purified by flash column chromatography (SiO2, hexane/
AcOEt¼3/1) to give 3 (7.10 g, 90% yield over three steps) as white
(s, 3H), 4.18 (q, J¼7.2 Hz, 2H), 5.69 (br s, 1H), 6.71 (td, J¼1.6 Hz,
7.0 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 7.23 (d, J¼8.4 Hz, 1H); 13C NMR
(CDCl3):
d 12.7, 14.1, 29.9, 60.7, 61.2, 114.3, 115.8, 128.2, 128.5, 132.4,
139.2, 146.4, 148.7, 168.4; (þ)-ESI-LRMS m/z 351 (MþNaþ), 353
(Mþ2þNaþ); (þ)-ESI-HRMS. Calcd for C14H17BrNaOþ4 (MþNaþ):
351.0202. Found: 351.0184.
4.2.3. (E)-Ethyl 4-(6-bromo-2-methoxy-3-(tosyloxy)phenyl)-2-
methylbut-2-enoate (6). To
a stirred solution of 5 (1.09 g,
3.30 mmol) and triethylamine (0.55 mL, 3.96 mmol) in CH2Cl2
(6.6 mL) at 0 ꢀC was added p-toluenesulfonyl chloride (1.66 g,
13.5 mmol), and the resulting mixture was stirred at room tem-
perature. After 1 h, the reaction was quenched with water, and the
mixture was diluted with AcOEt. After separation of the aqueous
layer, the organic layer was washed with brine, dried over Na2SO4,
and then evaporated in vacuo. The obtained residue was purified by
flash column chromatography (SiO2, hexane/AcOEt¼4/1) to give 6
(1.42 g, 90% yield) as white solids. Mp 70e71 ꢀC; IR (ATR)
n
2980,
d 1.28
solids. Mp 74e75 ꢀC; IR (ATR)
1287, 1179, 1030, 998, 807 cmꢁ1
n
3379, 2943, 2836, 1713, 1466, 1427,
1H NMR (CDCl3):
3.71 (s, 3H),
1707,1466,1378,1254,1178,1007, 818 cmꢁ1; 1H NMR (CDCl3):
;
d
(t, J¼7.2 Hz, 3H),1.94 (d, J¼1.2 Hz, 3H), 2.46 (s, 3H), 3.59 (d, J¼6.8 Hz,
2H), 3.71 (s, 3H), 4.18 (q, J¼7.2 Hz, 2H), 6.55 (td, J¼1.2 Hz, 6.8 Hz,
1H), 6.95 (d, J¼8.8 Hz, 1H), 7.27 (d, J¼8.8 Hz, 1H), 7.32 (d, J¼8.6 Hz,
3.91 (d, J¼1.2 Hz, 2H), 6.24 (br s, 1H), 6.80 (d, J¼9.0 Hz, 1H), 7.23 (d,
J¼9.0 Hz, 1H), 9.75 (t, J¼1.2 Hz, 1H); 13C NMR (CDCl3):
d 44.8, 61.3,
114.8, 116.8, 126.9, 128.6, 146.8, 148.5, 199.0; (þ)-ESI-LRMS m/z 267
(MþNaþ), 269 (Mþ2þNaþ); (þ)-ESI-HRMS. Calcd for C9H9BrNaOþ3
(MþNaþ): 266.9627. Found: 266.9628.
2H), 7.73 (d, J¼8.6 Hz, 2H); 13C NMR (CDCl3):
d 12.7, 14.3, 21.7, 30.2,
60.6, 61.5, 123.1, 123.3, 128.0, 128.4 (2C), 128.7, 129.7 (2C), 132.5,
134.4, 137.7,145.7, 151.7,167.9; (þ)-ESI-LRMS m/z 505 (MþNaþ), 507
(Mþ2þNaþ); (þ)-ESI-HRMS. Calcd for C21H23BrNaO6Sþ (MþNaþ):
505.0291. Found: 505.0313.
4.2.2. (E)-Ethyl 4-(6-bromo-3-hydroxy-2-methoxyphenyl)-2-
methylbut-2-enoate (5). To
a stirred solution of aldehyde 3
(980 mg, 4.00 mmol) in CH2Cl2 (20 mL) at room temperature was
added a Wittig reagent 4 (1.66 g, 13.5 mmol), and the resulting
mixture was stirred for 1 h at the same temperature. After evapo-
ration of the solvent, the obtained residue was purified by flash
column chromatography (SiO2, hexane/AcOEt¼4/1) to give
(1.09 g, 83% yield) as colorless oil. IR (ATR) 3370, 2981, 1685, 1467,
1293, 1257, 1176, 1001, 907, 808, 728 cmꢁ1; 1H NMR (CDCl3):
1.27
(t, J¼7.2 Hz, 3H), 2.02 (d, J¼1.6 Hz, 3H), 3.66 (d, J¼7.0 Hz, 2H), 3.77
4.2.4. (E)-Ethyl 4-(30,50-bis((tert-butyldimethylsilyl)oxy)-3-methoxy-
4-(tosyloxy)-[1,10-biphenyl]-2-yl)-2-methylbut-2-enoate (8). A mix-
ture of 6 (2.78 g, 5.76 mmol), 7 (3.21 g, 6.91 mmol), PdCl2(dppf)
(170 mg, 0.29 mmol), and K3PO4 (3.67 g, 17.3 mmol) in toluene
(5 mL) and H2O (5 mL) was stirred for 24 h at 90 ꢀC. After the re-
action was quenched with water, AcOEt was added to the mixture.
The aqueous layer was separated and the resulting organic layer
was washed with brine, dried over Na2SO4, and then evaporated in
5
n
d

Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
5917
vacuo. The obtained residue was purified by flash column chro-
matography (SiO2, hexane/AcOEt¼30/1) to give 8 (4.18 g, 98% yield)
(s, 1H), 5.53 (br s, 1H), 5.80 (br s, 1H), 6.38 (d, J¼2.4 Hz, 1H), 6.76 (d,
J¼8.0 Hz, 1H), 7.04 (d, J¼8.0 Hz, 1H), 7.25 (d, J¼2.4 Hz, 1H), 7.29 (d,
as white solids. Mp 107e108 ꢀC; IR (ATR)
n
2931, 1714, 1585, 1379,
0.18 (s, 12H),
J¼8.4 Hz, 1H), 7.76 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3):
d 21.0, 21.7,
1255, 1166, 1029, 831, 781 cmꢁ1
;
1H NMR (CDCl3):
d
25.6, 37.1, 61.2,103.1,103.8,112.2,117.0,119.8,121.3,128.4 (2C),129.6
(2C), 130.2, 132.6, 134.4, 135.5, 141.8, 145.2, 145.3, 149.6, 154.1, 155.4;
(þ)-ESI-LRMS m/z 475 (MþNaþ); (þ)-ESI-HRMS. Calcd for
0.97 (s, 18H), 1.26 (t, J¼6.8 Hz, 3H), 1.67 (d, J¼1.2 Hz, 3H), 2.47 (s,
3H), 3.38 (d, J¼6.8 Hz, 2H), 3.73 (s, 3H), 4.14 (q, J¼6.8 Hz, 2H), 6.32
(s, 2H), 6.32 (s, 1H), 6.53 (dt, J¼1.2 Hz, 6.8 Hz, 1H), 6.90 (d, J¼8.2 Hz,
1H), 7.04 (d, J¼8.2 Hz, 1H), 7.35 (d, J¼8.4 Hz, 2H), 7.82 (d, J¼8.4 Hz,
C25H24NaO6Sþ (MþNaþ): 475.1186. Found: 475.1199; [
a
]
14 ꢁ71.8 (c
D
1.27, CHCl3, 66% ee). The enantiomeric excess was determined by
chiral HPLC analysis (DAICEL CHIRALCEL OD-H, hexane/2-
propanol¼80/20, flow rate: 1.0 mL/min, tR 9.3 min [(R)-(ꢁ)-iso-
mer] and 13.1 min [(S)-(þ)-isomer], detection at 254 nm).
2H); 13C NMR (CDCl3):
d
ꢁ4.5 (4C), 12.3, 14.3, 18.1 (2C), 21.7, 25.6
(6C), 27.6, 60.3, 61.1, 111.1, 114.4 (2C), 121.7, 125.1, 127.5, 128.4 (2C),
129.7 (2C), 132.3, 133.1, 140.2, 141.7, 141.9, 142.2, 145.4, 150.8, 156.3
(2C), 167.8; (þ)-ESI-LRMS m/z 763 (MþNaþ); (þ)-ESI-HRMS. Calcd
for C39H56NaO8SSiþ2 (MþNaþ): 763.3127. Found: 763.3166.
4.2.7. (R)-7-Hydroxy-4-methoxy-10,10-dimethyl-6-(prop-1-en-2-
yl ) - 6 ,10 - d i hy d ro - 5 H - n a p ht h o [ 2 ,1 -g ] ch ro m e n - 3 - yl 4 -
methylbenzenesulfonate (12). To a stirred solution of 11 (25.3 mg,
0.081 mmol) and ethylendiamine diacetate (0.7 mg, 0.0041 mmol)
4.2.5. (E)-3’,5’-Dihydroxy-3-methoxy-2-(4-((methoxycarbonyl)oxy)-
3 - m e t h y l b u t - 2 - e n - 1 - y l ) - [ 1 , 1 0- b i p h e n y l ] - 4 - y l 4 -
methylbenzenesulfonate (9). To a stirred solution of 8 (4.08 g,
6.95 mmol) in CH2Cl2 (35 mL) at ꢁ78 ꢀC was added DIBAL-H
(17.4 mL, 1 M solution in hexane, 17.4 mmol). After the solution
was stirred for 2.5 h at ꢁ78 ꢀC, and 30 min at room temperature, the
reaction was quenched by the addition of aq 1 M Rochelle salt. After
being stirred for 1 h, the mixture was extracted with AcOEt. The
combined organic layers were washed with brine, dried over
Na2SO4, and then concentrated in vacuo. The obtained crude alco-
hol was used for the next step without purification. To a stirred
solution of crude alcohol and DMAP (170 mg, 1.39 mmol) in CHCl3
(11.6 mL) and pyridine (2.3 mL) at 0 ꢀC was added methyl chlor-
oformate (1.34 mL, 17.4 mmol), and the resulting mixture was kept
stirring for 3 h at room temperature. The reaction was quenched
with 1 N HCl at 0 ꢀC, and then the resulting mixture was extracted
with AcOEt. The combined organic layers were washed with brine,
dried over Na2SO4, and then concentrated in vacuo. The obtained
residue was used for the next reaction without further purification.
To a stirred solution of the crude sample in THF (35 mL) at 0 ꢀC was
added TBAF (17.4 mL, 1 M solution in THF, 0.73 mmol). After being
stirred for 1 h at room temperature, the reaction mixture was di-
luted with AcOEt. The obtained mixture was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The ob-
tained residue was purified by flash column chromatography (SiO2,
hexane/AcOEt¼2/1) to give 9 (3.10 g, 85% yield over three steps) as
in toluene (1.60 mL), was added 3-methyl crotonaldehyde (12.4 mL,
0.121 mmol), and the resulting mixture was refluxed for 6 h. Then,
the solvent was removed in vacuo, and the obtained residue was
purified by flash column chromatography (SiO2, hexane/AcOEt¼4/1
to 3/1) to give 12 (15.6 mg, 51% yield) as a brown oil, and 120
(11.6 mg, 38% yield) as a brown oil. IR (ATR)
n
3528, 2925, 1470,
1.42
1373, 1255, 1175, 1122, 827, 771, 734 cmꢁ1; 1H NMR (CDCl3):
d
(s, 3H), 1.48 (s, 3H), 1.54 (s, 3H), 2.44 (s, 3H), 2.72 (dd, J¼7.2 Hz,
16.0 Hz, 1H), 3.29 (dd, J¼2.4 Hz, 16.0 Hz, 1H), 3.64 (dd, J¼2.4 Hz,
7.2 Hz,1H), 3.70 (s, 3H), 4.54 (s, 1H), 4.69 (s,1H), 4.99 (br-s,1H), 5.64
(d, J¼10.0 Hz, 1H), 6.65 (d, J¼10.0 Hz, 1H), 6.86 (s, 1H), 7.05 (d,
J¼8.6 Hz, 1H), 7.28 (d, J¼8.4 Hz, 2H), 7.33 (d, J¼8.6 Hz, 1H), 7.74 (d,
J¼8.4 Hz, 2H); 13C NMR (CDCl3):
d 20.4, 21.7, 25.7, 27.5, 28.0, 38.5,
61.2, 75.9, 105.1, 110.0, 112.8, 116.1, 116.4, 119.7, 121.5, 128.5 (2C),
129.4, 129.5 (2C), 129.9, 132.8, 134.2, 134.3, 141.8, 145.2, 145.9, 148.9,
149.6, 152.7; (þ)-ESI-LRMS m/z 541 (MþNaþ); (þ)-ESI-HRMS. Calcd
26
for C30H30NaO6Sþ (MþNaþ): 541.1655. Found: 541.1635; [
ꢁ68.8 (c 1.93, CHCl3, 66% ee).
a]
D
4.2.8. (R)-12-Hydroxy-7-methoxy-3,3-dimethyl-5-(prop-1-en-2-yl)-
5 , 6 - d i h y d r o - 3 H - n a p h t h o [ 1, 2 - h ] c h r o m e n - 8 - y l 4 -
methylbenzenesulfonate (120). IR (ATR)
n
3464, 2973, 1474, 1409,
1371, 1255, 1190, 1175, 1120, 1060, 967, 829, 775, 731 cmꢁ1; 1H NMR
(CDCl3): 1.30 (s, 3H), 1.45 (s, 3H), 1.57 (s, 3H), 2.43 (s, 3H), 2.51 (dd,
d
amorphous solids. IR (ATR)
n
3420, 2955, 1721, 1598, 1472, 1442,
1H NMR (CDCl3):
J¼6.4 Hz, 15.6 Hz, 1H), 3.26 (d, J¼16.0 Hz, 1H), 3.67 (s, 3H), 3.80 (d,
J¼6.4 Hz, 1H), 4.14 (s, 1H), 4.49 (s, 1H), 5.26 (br s, 1H), 5.62 (d,
J¼10.0 Hz,1H), 6.62 (s, 1H), 6.66 (d, J¼10.0 Hz, 1H), 7.07 (d, J¼8.2 Hz,
1H), 7.22 (d, J¼8.2 Hz, 1H), 7.27 (d, J¼8.4 Hz, 2H), 7.75 (d, J¼8.4 Hz,
1370, 1254, 1189, 1174, 1154, 983, 749, 668 cmꢁ1
;
d
1.47 (s, 3H), 2.46 (s, 3H), 3.18 (d, J¼5.6 Hz, 2H), 3.73 (s, 3H) 3.78
(s, 3H), 4.47 (s, 2H), 5.32 (t, J¼5.6 Hz, 1H), 6.16e6.25 (m, 4H), 6.36
(d, J¼2.0 Hz, 1H), 6.86 (d, J¼8.4 Hz, 1H), 7.00 (d, J¼8.4 Hz, 1H), 7.33
2H); 13C NMR (CDCl3):
d 21.5, 21.7, 25.5, 27.1, 28.1, 35.9, 61.2, 75.9,
(d, J¼7.6 Hz, 2H), 7.79 (d, J¼7.6 Hz, 2H); 13C NMR (CDCl3):
d
13.7,
103.0, 109.5, 111.4, 116.7, 119.1, 119.3, 121.2, 128.5 (2C), 129.5, 129.5
(2C), 130.7, 132.7, 133.9, 134.5, 141.7, 145.1, 145.2, 149.7, 150.2, 150.8;
21.7, 26.7, 55.1, 61.2, 73.6, 101.7, 108.8 (2C), 121.3, 125.1, 128.4 (2C),
129.2, 129.6, 129.7, 129.7 (2C), 132.9, 133.4, 141.6, 142.2, 145.4, 150.6,
156.2, 156.7 (2C); (þ)-ESI-LRMS m/z 551 (MþNaþ); (þ)-ESI-HRMS.
Calcd for C27H28NaO9Sþ (MþNaþ): 551.1346. Found: 551.1369.
(þ)-ESI-LRMS m/z 541 (MþNaþ); (þ)-ESI-HRMS. Calcd for
26
C30H30NaO6Sþ (MþNaþ): 541.1655. Found: 541.1635; [
(c 1.64, CHCl3, 66% ee).
a]
ꢁ62.3
D
4.2.6. (R)-6,8-Dihydroxy-1-methoxy-9-(prop-1-en-2-yl)-9,10-
d i h y d ro p h e n a n t h re n - 2 - yl 4 - m e t hyl b e n z e n e s u l fo n a t e
(11). Compound 9 (123 mg, 0.233 mmol), Pd(dba)2 (13.4 mg,
0.0233 mmol), (R,R)-10a (19.3 mg, 0.0279 mmol), and KOAc
(34.2 mg, 0.349 mmol) were dissolved in THF (3.7 mL) and MeOH
(0.93 mL) under argon atmosphere, and the resulting solution was
stirred at 40 ꢀC. After 12 h, the reaction was quenched with water,
and the mixture was extracted with AcOEt. The combined organic
layers were washed with brine, dried over Na2SO4, and then con-
centrated in vacuo. The obtained residue was purified by flash
column chromatography (SiO2, CHCl3/MeOH¼30/1) to give 11
4.2.9. (ꢁ)-Cedrelin A. Solution of potassium hydroxide (3.0 g) in
water (50 mL) and ethanol (50 mL) was prepared. 12 (38.6 mg,
0.074 mmol) was dissolved in 2.0 mL of the alkaline solution, and
the resulting mixture was stirred at 80 ꢀC. After 1 h, the solution
was cooled, and neutralized with acetic acid. The mixture was
extracted with ether, washed with aqueous NaHCO3 and brine,
dried over Na2SO4, and concentrated in vacuo. The obtained residue
was purified by flash column chromatography (SiO2, hexane/
AcOEt¼7/1) to give cedrelin A (20.0 mg, 74% yield) as pale yellow
oil; IR (ATR)
n
3441, 2973, 1604, 1558, 1474, 1291, 1167, 1121, 1027,
1.43 (s, 3H), 1.48 (s, 3H), 1.62 (s,
899, 753 cmꢁ1; 1H NMR (CDCl3):
d
(99.0 mg, 94% yield) as amorphous solids. IR (ATR)
1465, 1362, 1254, 1174, 1011, 967, 830, 754, 668 cmꢁ1
(CDCl3): 1.58 (s, 3H), 2.44 (s, 3H), 2.56e2.62 (m, 1H), 3.28 (d,
J¼16.0 Hz, 1H), 3.69 (s, 3H), 3.73 (d, J¼6.0 Hz, 1H), 4.29 (s, 1H), 4.59
n
3461, 1616,
3H), 2.89 (dd, J¼7.2 Hz, 15.6 Hz, 1H), 3.32 (dd, J¼2.8 Hz, 15.6 Hz, 1H),
3.96e3.71 (m, 1H), 3.78 (s, 3H), 4.64 (s, 1H), 4.73 (s, 1H), 4.98 (s, 1H),
5.62 (d, J¼10.0 Hz, 1H), 5.64 (s, 1H), 6.65 (d, J¼10.0 Hz, 1H), 6.86 (s,
1H), 6.86 (d, J¼8.4 Hz, 1H), 7.35 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3):
;
1H NMR
d

5918
Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
26
d
20.4, 26.4, 27.5, 28.0, 38.7, 61.2, 75.8, 104.3, 109.0, 112.8, 113.6,
313.1454; [
a]
ꢁ105.5 (c 0.52, MeOH, 92% ee). The enantiomeric
D
115.1,116.5,120.9,127.6,127.7,129.2,135.2,144.3,146.4,148.4,148.9,
excess was determined by chiral HPLC analysis (DAICEL CHIRALCEL
OD-H, hexane/2-propanol¼80/20, flow rate: 1.0 mL/min, tR
13.5 min [(S)-(þ)-isomer] and 24.0 min [(R)-(ꢁ)-isomer], detection
at 254 nm).
152.7; (þ)-ESI-LRMS m/z 365 (MþHþ); (þ)-ESI-HRMS. Calcd for
C23H25Oþ4 (MþHþ): 365.1747. Found: 365.1761; [
a
]
24 ꢁ54.9 (c 0.75,
D
CHCl3, 66% ee). The enantiomeric excess was determined by chiral
HPLC analysis (DAICEL CHIRALCEL OD-H, hexane/2-propanol¼90/
10, flow rate: 0.75 mL/min, tR 14.7 min [(S)-(þ)-isomer] and
17.4 min [(R)-(ꢁ)-isomer], detection at 254 nm).
4.3.5. (R)-2,3-Dimethoxy-10,10-dimethyl-6-(prop-1-en-2-yl)-6,10-
dihydro-5H-naphtho[2,1-g]chromen-7-ol (19). Compound 19 was
prepared from compound 18 according to the experimental pro-
cedures described in Section 4.2.7 (19: 55% yield, 190: 28% yield).
4.3. Enantioselective total synthesis of paralycolin B
Pale brown amorphous solids; IR (ATR)
n
3431, 2970, 2926, 1606,
1.44 (s,
4.3.1. (E)-Ethyl 4-(2-bromo-4,5-dimethoxyphenyl)-2-methylbut-2-
enoate (15). Compound 15 was prepared from commercially
available 13 according to the experimental procedures described in
Sections 4.2.1 and 4.2.2 (82% yield, three steps). White solids. Mp
1552, 1515, 1433, 1258, 1216, 1126 cmꢁ1; 1H NMR (CDCl3):
d
3H), 1.50 (s, 3H), 1.63 (s, 3H), 2.91 (dd, J¼2.4 Hz, 15.6 Hz, 1H), 3.11
(dd, J¼7.0 Hz, 15.6 Hz, 1H), 3.65 (dd, J¼2.4 Hz, 7.0 Hz, 1H), 3.89 (s,
3H), 3.91 (s, 3H), 4.67 (s, 1H), 4.75 (s, 1H), 5.06 (br s, 1H), 5.61 (d,
J¼9.6 Hz, 1H), 6.66 (s, 1H), 6.67 (d, J¼9.6 Hz, 1H), 6.86 (s, 1H), 7.17 (s,
35e36 ꢀC; IR (ATR)
n 2934, 1707, 1507, 1440, 1381, 1255, 1219, 1164,
1116, 1071, 1032, 800 cmꢁ1; 1H NMR (CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H),
1H); 13C NMR (CDCl3):
d 20.3, 27.6, 28.1, 33.1, 39.4, 55.9, 55.9, 75.9,
1.98 (s, 3H), 3.56 (d, J¼7.2 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.19 (q,
104.0, 107.1, 108.9, 111.1, 112.6, 115.3, 116.6, 126.3, 127.0, 128.9, 135.3,
J¼7.2 Hz, 2H), 6.69 (s, 1H), 6.79 (t, J¼7.2 Hz, 1H), 7.02 (s, 1H); 13C
146.9, 147.8, 148.7, 149.2, 152.6; (þ)-ESI-LRMS m/z 379 (MþHþ);
NMR (CDCl3):
d
12.7, 14.2, 35.0, 56.1, 56.2, 60.6, 113.0, 114.2, 115.7,
(þ)-ESI-HRMS. Calcd for C24H27Oþ4 (MþHþ): 379.1904. Found:
23
128.8, 130.5, 138.9, 148.3, 148.6, 167.9; (þ)-ESI-LRMS m/z 365
(MþNaþ), 367 (Mþ2þNaþ); (þ)-ESI-HRMS. Calcd for C15H19BrNaOþ4
(MþNaþ): 365.0359. Found: 365.0365.
379.1918; [
a]
ꢁ94.0 (c 0.44, CHCl3, 92% ee).
D
4.3.6. (R)-8,9-Dimethoxy-3,3-dimethyl-5-(prop-1-en-2-yl)-5,6-
dihydro-3H-naphtho[1,2-h]chromen-12-ol (190). White solids mp
4.3.2. (E)-Ethyl 4-(30,50-bis((tert-butyldimethylsilyl)oxy)-4,5-
dimethoxy-[1,10-biphenyl]-2-yl)-2-methylbut-2-enoate
(16). Compound 16 was prepared from compound 15 and aryl-
boronate 7 according to the experimental procedures described in
160e161 ꢀC; IR (ATR)
n
3441, 2962, 1514, 1431, 1264, 1206, 1114,
1067, 1036 cmꢁ1; 1H NMR (CDCl3):
d
1.31 (s, 3H), 1.47 (s, 3H), 1.68 (s,
3H), 2.89 (dd, J¼0 Hz, 15.6 Hz, 1H) 3.03 (dd, J¼6.8 Hz, 15.6 Hz, 1H),
3.84 (dd, J¼0 Hz, 6.8 Hz, 1H), 3.90 (s, 3H), 3.92 (s, 3H), 4.30 (s, 1H),
4.58 (s, 1H), 4.78 (br s, 1H), 5.62 (d, J¼10.0 Hz, 1H), 6.65 (d,
J¼10.0 Hz, 1H), 6.68 (s, 1H), 6.70 (s, 1H), 7.12 (s, 1H); 13C NMR
4.2.4 (92% yield). White solids. Mp 70e71 ꢀC; IR (ATR)
n
2930, 1711,
1584, 1516, 1432, 1256, 1164, 1028, 832, 781 cmꢁ1; 1H NMR (CDCl3):
d
0.20 (s, 12H), 0.98 (s, 18H), 1.27 (t, J¼7.2 Hz, 3H), 1.78 (d, J¼1.2 Hz,
(CDCl3): d 21.6, 27.1, 28.2, 32.7, 36.8, 55.8, 56.0, 75.8, 102.1, 106.8,
3H) 3.42 (d, J¼7.2 Hz, 2H), 3.87 (s, 3H), 3.90 (s, 3H), 4.16 (q, J¼7.2 Hz,
2H), 6.33 (t, J¼2.4 Hz,1H), 6.39 (d, J¼2.4 Hz, 2H), 6.72 (s, 1H), 6.74 (s,
108.4, 111.3, 111.7, 116.6, 118.7, 126.3, 128.5, 129.0, 135.1, 146.0, 147.6,
148.7, 150.0, 151.0; (þ)-ESI-LRMS m/z 379 (MþHþ); (þ)-ESI-HRMS.
26
1H), 6.79 (td, J¼1.2 Hz, 7.2 Hz, 1H); 13C NMR (CDCl3):
d
ꢁ4.4 (4C),
Calcd for C24H27Oþ4 (MþHþ): 379.1904. Found: 379.1919; [
ꢁ27.2 (c 1.18, CHCl3, 92% ee).
a]
D
12.4, 14.2, 18.2 (2C), 25.6 (6C), 32.3, 56.0, 56.0, 60.4, 110.7, 112.3,
113.1, 114.7 (2C), 127.7, 128.7, 134.2, 141.0, 142.9, 147.2, 148.4, 156.2
(2C), 167.9; (þ)-ESI-LRMS m/z 623 (MþNaþ); (þ)-ESI-HRMS. Calcd
for C33H52NaO6Siþ2 (MþNaþ): 623.3195. Found: 623.3222.
4.3.7. (R)-2,3,7-Trimethoxy-10,10-dimethyl-6-(prop-1-en-2-yl)-6,10-
dihydro-5H-naphtho[2,1-g]chromene (methylated paralycolin B)
(1c). To a stirred mixture of 19 (10.0 mg, 0.0264 mmol) and K2CO3
(11.0 mg, 0.0793 mmol) in DMF (0.5 mL) at 0 ꢀC was added iodo-
4.3.3. (E)-4-(3’,5’-Dihydroxy-4,5-dimethoxy-[1,10-biphenyl]-2-yl)-2-
methylbut-2-en-1-yl methyl carbonate (17). Compound 17 was
prepared from compound 16 according to the experimental pro-
cedures described in Section 4.2.5 (94% yield). Amorphous solids; IR
methane (5.0 mL), and the resulting mixture was kept stirring for
5 h. After dilution of the reaction mixture with Et2O, the mixture
was washed with water and brine, and then dried over Na2SO4.
After concentration under reduced pressure, the obtained residue
was purified by flash column chromatography (SiO2, hexane/
AcOEt¼6/1) to give 1c (9.5 mg, 92% yield) as white solids. Mp
(ATR)
n
3418, 2959, 1724, 1600, 1507, 1442, 1255, 1156, 1059, 1000,
776 cmꢁ1
;
1H NMR (CDCl3):
d
1.56 (s, 3H), 3.22 (d, J¼6.4 Hz, 2H),
3.79 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 4.53 (s, 2H), 5.59 (t, J¼6.4 Hz,
2H), 6.00 (br s, 2H), 6.33 (d, J¼2.0 Hz, 2H), 6.36 (t, J¼2.0 Hz,1H), 6.72
157e158 ꢀC IR (ATR)
n
2958,1604,1550,1514,1469,1455,1261,1224,
(s, 1H), 6.73 (s, 1H); 13C NMR (CDCl3):
d
13.8, 32.0, 55.0, 55.9, 55.9,
1080, 849 cmꢁ1; 1H NMR (CDCl3):
d 1.45 (s, 3H), 1.50 (s, 3H), 1.74 (s,
73.7, 101.2, 109.1 (2C), 112.6, 112.8, 129.1, 130.0, 130.6, 133.9, 143.5,
146.9, 148.1, 156.1, 156.6 (2C); (þ)-ESI-LRMS m/z 411 (MþNaþ);
(þ)-ESI-HRMS. Calcd for C21H24NaOþ7 (MþNaþ): 411.1414. Found:
411.1430.
3H), 2.89 (dd, J¼0 Hz, 15.6 Hz, 1H), 3.03 (d, J¼6.4 Hz, 15.6 Hz, 1H),
3.76 (s, 3H), 3.81 (dd, J¼0 Hz, 6.4 Hz, 1H), 3.89 (s, 3H), 3.92 (s, 3H),
4.26 (s, 1H), 4.64 (s, 1H), 5.65 (d, J¼10.0 Hz, 1H), 6.60 (d, J¼10.0 Hz,
1H), 6.66 (s, 1H), 6.98 (s, 1H), 7.18 (s, 1H); 13C NMR (CDCl3):
d 21.7,
27.7, 28.0, 32.8, 37.9, 55.8, 55.9, 62.3, 75.9, 106.8, 107.0, 111.5, 112.9,
113.4, 117.4, 123.5, 126.5, 127.7, 129.8, 135.8, 146.1, 147.7, 148.6, 152.6,
153.6; (þ)-ESI-LRMS m/z 393 (MþHþ); (þ)-ESI-HRMS. Calcd for
4 . 3 . 4 . ( R ) - 6 , 7 - D i m e t h o x y - 10 - ( p ro p - 1 - e n - 2 - yl ) - 9 ,10 -
dihydrophenanthrene-1,3-diol (18). Compound 18 was prepared
from compound 17 according to the experimental procedures de-
scribed in Section 4.2.6 (98% yield, 92% ee). White solid. Mp
C25H29Oþ4 (MþHþ): 393.2060. Found: 393.2075; [
a
]
D
26 þ15.5 (c 0.36,
CHCl3, 92% ee).
139e140 ꢀC; IR (ATR)
n
3409, 2938, 1606, 1578, 1515, 1464, 1257,
1.67 (s, 3H), 2.93 (dd,
1205,1139,1012, 756 cmꢁ1; 1H NMR (CDCl3):
d
Acknowledgements
J¼2.8 Hz, 15.2 Hz, 1H), 3.09 (dd, J¼7.2 Hz, 15.2 Hz, 1H), 3.72 (dd,
J¼2.8 Hz, 7.2 Hz, 1H), 3.91 (s, 3H), 3.94 (s, 3H), 4.53 (s, 1H), 4.72 (s,
1H), 4.78 (s, 1H), 4.98 (s, 1H), 6.31 (d, J¼2.6 Hz, 1H), 6.69 (s, 1H), 6.83
This work was supported by a Grant-in Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan, the Research Foundation for Pharmaceutical
Sciences, and the Inohana Foundation (Chiba university). We thank
Prof. Delle Monache for sending 1H and 13C NMR charts of meth-
ylated paralycolin B.
(d, J¼2.6 Hz, 1H), 7.15 (s, 1H); 13C NMR (CDCl3):
d 21.9, 33.8, 38.5,
56.4, 56.8, 102.2, 102.5, 109.2, 111.6, 113.4, 117.7, 128.8, 130.0, 137.4,
147.0, 149.0, 150.0, 156.6, 157.8 (þ)-ESI-LRMS m/z 313 (MþHþ);
(þ)-ESI-HRMS. Calcd for C19H21Oþ4 (MþHþ): 313.1434. Found:

Y. Suzuki et al. / Tetrahedron 69 (2013) 5913e5919
5919
Lett. 2012, 14, 2579 See also: (e) Rousseaux, S.; García-Fortanet, J.; Del Aguila
Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282.
5. Bandichhor, R.; Lowell, A. N.; Kozlowski, M. C. J. Org. Chem. 2011, 76, 6475.
6. For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Su-
zuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
7. For reviews on the asymmetric allylic alkylation using the Trost ligands, see: (a)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (b) Trost, B. M.; Ma-
chacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.05.007.
References and notes
8. Examinations using other chiral ligands gave less satisfactory results.
9. Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46, 7539.
10. Enantiomeric excess of the synthetic cedrelin A was determined by chiral HPLC
analysis. To increase the enantiomeric purity by recrystallization, we attempted
to transform 11 or 12 into a crystalline compound by derivatizing the phenol
moiety. However, crystalline adducts for this purpose could not be obtained.
11. Absolute configuration of (ꢁ)-19 was assigned by comparing the CD spectrum
with that of (ꢁ)-cedrelin B. See Supplementary data for the detail.
12. The 1H and 13C NMR data of methylated paralycolin B (1c), reported by Delle
Monache and co-workers in 2002 (Ref. 1c), were measured in C6D6, not in
CDCl3. Prof. Delle Monache kindly informed us this error information and
provided us the NMR charts of methylated paralycolin B, measured in both
C6D6 and CDCl3. NMR data of our synthetic sample were identical to the pro-
vided data.
13. We examined deprotection of the methyl groups in 19 under several reaction
conditions. When 19 was treated with 5 mol % of B(C6F5) and 3 equiv of
Et3SiH in CH2Cl2 at room temperature, paralycolin B (1b) was obtained in 52%
yield, accompanied by the formation of 6-isopropyl derivative (21%) as in-
separable mixtures. These yields were determined by 1H NMR analysis of the
isolated mixture. The use of other deprotection protocols gave unsatisfactory
results.
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