Total synthesis of riccardin C and (±)-cavicularin via Pd-catalyzed Ar-Ar cross couplings

Article abstract of DOI:10.1016/j.tet.2013.06.064

Riccardin C, a specific LXRα agonist, is a representative macrocyclic bisbibenzyl-type natural product. As part of our synthetic studies on macrocyclic bisbibenzyls, the synthesis of riccardin C and its analog cavicularin was examined. The total synthesis

Full text of DOI:10.1016/j.tet.2013.06.064

Tetrahedron 69 (2013) 6959e6968
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Total synthesis of riccardin C and (ꢀ)-cavicularin via Pd-catalyzed
AreAr cross couplings
Kenichi Harada a, Kosho Makino a, Naoki Shima a, Haruka Okuyama a, Tomoyuki Esumi a,
,
Miwa Kubo a, Hideaki Hioki b, Yoshinori Asakawa a, Yoshiyasu Fukuyama a
*
a Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
b Faculty of Education, Gunma University, Maebashi, Gunma 371-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2013
Received in revised form 15 June 2013
Accepted 18 June 2013
Available online 24 June 2013
Riccardin C, a specific LXRa agonist, is a representative macrocyclic bisbibenzyl-type natural product. As
part of our synthetic studies on macrocyclic bisbibenzyls, the synthesis of riccardin C and its analog
cavicularin was examined. The total synthesis of riccardin C was accomplished via a Pd-catalyzed in-
tramolecular SuzukieMiyaura coupling as the key macrocyclization step. This synthetic strategy was also
extended in the synthesis of (ꢀ)-cavicularin, which was then attained by constructing the dihy-
drophenanthrene moiety using a Pd-catalyzed AreAr coupling reaction.
Keywords:
Riccardin C
Ó 2013 Elsevier Ltd. All rights reserved.
Cavicuralin
SuzukieMiyaura reaction
Pd-catalyzed AreAr coupling reaction
1. Introduction
transcription.3 Interestingly, riccardin C acts as an antagonist, not
an agonist, of LXR
nuclear receptors, such as PPAR
RXR , and increases LXR-target gene expression in macrophages.
On the basis of these results, 1 has been expected to be a lead
compound for the treatment of cardiovascular-related diseases,
such as arteriosclerosis, because LXRs are thought to regulate
cholesterol metabolites.
b
. Moreover, it has no ability to activate other
Macrocyclic bisbibenzyls are natural products that occur mainly
in liverworts and feature two bibenzyl structures double-linked by
ether bonds and/or biphenyl bonds. It is known that macrocyclic
bisbibenzyl compounds exhibit a variety of biological activities.1
Riccardin C (1), originally isolated from Reboulia hemisphaerica, is
a representative bisbibenzyl compound with notable biological
activity2 (Fig. 1). Compound 1 was found to bind directly to the liver
g
, RAR , RAR , RAR , FXR, and
a
b
g
a
Investigation of the structureeactivity relationships of 1 is
a current important assignment, and riccardin C analogs and de-
X receptor
a
(LXR
a
), a member of the nuclear receptor super family,
/RXR-dependent reporter gene
leading to the activation of LXR
a
rivatives are also expected to be LXRa
agonist candidates.3,4 In
Fig. 1. Structures of riccardin C (1) and cavicularin (2).
particular, highly strained cavicularin (2), which is assumed to be
biosynthetically formed via an intramolecular oxidative coupling
between the 30 and 100 positions of riccardin C, has attracted
* Corresponding author. Tel.: þ81 88 602 8435; fax: þ81 88 655 3051; e-mail
address: fukuyama@ph.bunri-u.ac.jp (Y. Fukuyama).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.064

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K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
attention as not only a biologically active compound,1a but also
a synthetic target. Cavicularin was isolated from the liverwort
Cavicularia densa by Toyota and Asakawa in 19965 and is one of the
most interesting natural products from a synthetic perspective
(Fig. 1). The rigid cyclophane structure of 2 causes benzene ring A to
bend into a boat-like form with a dihedral angle of 212ꢁ; therefore,
2 is an optically active compound with planar chirality ([
c 0.25, MeOH).
a
]
21 þ168,
D
Thus, the intriguing structures and biological activity of the
macrocyclic bisbibenzyls have made them attractive synthetic tar-
gets.6 The synthesis of riccardin C has been reported by five groups
7
ꢀ
ꢀ
to date. Nogradi et al. achieved the first total synthesis of 1 in 1988.
They used Wurtz coupling to construct the 18-membered macro-
cyclic ring. Eicher et al.8 and Harrowven et al.9 separately applied
Wittig olefination reactions to the macrocyclization to accomplish
the total synthesis of 1. Recently, Suzuki et al.10 and Kagechika
et al.11 each reported syntheses of 1 that employed an SNAr reaction
for the key macrocyclization step. On the other hand, cavicularin
has been synthesized by just three groups. In 2005, Harrowven
et al. reported the first total synthesis of (ꢀ)-cavicularin by applying
a radical transannulation for the formation of the dihydrophenan-
threne moiety,9 and subsequently reported improvements to the
protocol in 2011.12 Dam and Baran applied an intramolecular [4þ2]
cyclization of ring A for the synthesis of 2.13,14 Recently, Zhao and
Beaudry reported a similar synthesis of 2 using a highly regiose-
lective DielseAlder reaction.15 We also have continued synthetic
studies of macrocyclic bisbibenzyl compounds using an in-
dependent strategy involving Pd-catalyzed macrocyclization and
previously reported the syntheses of plagiochin A and D,16 iso-
plagiochin D,17 and asterelin A.18 Herein, we describe the synthesis
of riccardin C4 and (ꢀ)-cavicularin by applying two types of Pd-
catalyzed reactions, one to form the 18-membered macrocyclic
rings, and the other to construct the highly strained dihy-
drophenanthrene moiety of 2.
The common synthetic strategy for riccardin C and cavicularin is
shown in Scheme 1. Starting units 3, 4, and 5 would be condensed
by HornereWadswortheEmmons (HWE) reactions. After bor-
ylation of the bromide on ring B, the macrocycles of 1 and 2 could
be formed via intramolecular SuzukieMiyaura coupling. For the
synthesis of cavicularin, regioselective iodination on the C-100 po-
sition would then be required, which would be made possible by
protecting the phenolic hydroxyl group at C-130 as a MOM ether.
After iodination, transannulation between C-30 and C-100 via Pd-
catalyzed AreAr coupling would construct the dihydrophenan-
threne embedded within the cavicularin skeleton. Although Pd-
catalyzed AreAr coupling has already proved to be an effective
method for the formation of a biphenyl bond,19 the synthetic
strategy based on Pd-chemistry described here is not only chal-
lenging, but also attractive for constructing the highly strained and
hindered cavicularin skeleton.
Scheme 1. Synthetic strategy for riccardin C (1) and cavicularin (2).
converted to a triflate with Tf2NPh and Cs2CO3. Subsequently,
chemoselective borylation21 of the bromide over the triflate of 18
was carried out with Pd(PPh3)4, bis(pinacolato)diboron, and K3PO4
in dioxane, giving rise to 19 in 95% yield.
With boron ester 19 successfully obtained, SuzukieMiyaura
coupling was attempted to achieve the 18-membered macro-
cyclization (Table 1). Firstly, 10 mol % Pd(PPh3)4/K3PO4/DMF, which
was effective for the synthesis of isoplagiochin D, was employed for
this cyclization. However, the desired product 20 was obtained in
only 9% yield (entry 1). Using 5 mol % Pd2(dba)3/SPhos/aqNa2CO3/
DMF, the yield was improved to 16% (entry 2). Then, it was found
that this macrocyclization is highly dependent on the base. Aque-
ous Na2CO3 enhanced the reactivity to give the desired product in
48% yield, along with 25% of the undesired cyclic dimer 21 (entry 3).
Other solvents such as toluene, THF, and DMSO were less effective
for this cyclization (entries 4e6).
2. Results and discussion
The synthesis of 1 commenced with commercially available 4-
bromobenzaldehyde (9), which corresponds to ring A (Scheme 2).
In the presence of CuO and K2CO3, the Ullmann coupling of 9 with
methyl 3-hydroxy-4-methoxybenzoate (10) afforded biphenyl
ether 3 in 76% yield. Next, the HWE reaction with phosphonate 4
proceeded smoothly to give 11. Successive LiAlH4 reduction of 11
and bromination of the resulting alcohol 12 with SOBr2 followed by
Arbuzov reaction of bromide 13 gave phosphonate 14 in 96% yield
over three steps. Subsequently, the HWE reaction of 14 with alde-
hyde 15 afforded 16, which contains all four of the arene rings of 1
and 2, in 87% yield. Reduction of the two alkenes and removal of the
MOM groups were achieved by treatment with Et3SiH in TFA to give
17 in 74% yield.20 The liberated hydroxy group of 17 was then
Finally, treatment of 20 with BBr3 in DCM completed the syn-
thesis of riccardin C. The spectroscopic data for synthetic 1 were
consistent with those for natural riccardin C (Scheme 3).
Next, our attention was focused on the synthesis of cavicularin
(Scheme 4). The synthesis began with the common intermediate
14. The HWE reaction with aldehyde 22, which contained a pro-
tected phenolic 3-OH group as the MOM ether, afforded 23 in 94%
yield. After diimide reduction22 of the two alkenes and removal of
the benzyl group to give 24, the liberated hydroxyl group was
converted to a triflate with Tf2O and DMAP. Selective borylation of
25 was carried out using the same conditions as described above,
giving rise to 26 in 81% yield. Subsequently, SuzukieMiyaura

K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
6961
Firstly, the MOM protecting group of 27 was removed under acidic
conditions to give rise to phenol 28, which was then regiose-
lectively iodinated at C-100 with NaI, NaClO, and NaOH in MeOH to
give 29 in good yield.23 In order to increase the reactivity of the
subsequent Pd-catalyzed AreAr coupling reaction and prevent the
undesired coordination of the Pd complex with the phenolic OH
group, 29 was acetylated, giving 30 in 97% yield.
We were now in a position to investigate the crucial Pd-
catalyzed AreAr coupling for construction of the dihydrophenan-
threne moiety. The reaction was first carried out under standard
conditions of 20 mol % Pd(OAc)2 and 2 equiv of Ag2CO3 in DMF at
120 ꢁC, which gave deiodinated 32 as the sole product (Table 2,
entry 1). In order to obtain the desired product 31, a range of ligands
were screened. The use of 40 mol % (o-tol)3P or t-Bu3P as the ligand
afforded only 32 (entries 2 and 3). However, 40 mol % n-Bu3P24 was
found to provide product 31 in 39% yield, along with 32 in 36% yield
(entry 4). The more compact ligand Et3P provided no desired
product, which may be due to its inability to reduce Pd(II) to Pd(0)
efficiently (entry 6). On the other hand, reducing the ligand load
from 40 mol % to 20 mol % increased the yield of 31 up to 50% (entry
5). It was also noted that microwave irradiation or the addition of
a pivalate salt (CsOPiv) was not effective for improving the yield of
31. Interestingly, some reactions using chiral ligands such as (S,S)-
chiraphos ((1S,2S)-(ꢂ)-bis(diphenylphosphino)butane), (S)-BINAP,
or (R,R)-Me-BPE ((þ)-1,2-bis((2R,5R)-2,5-dimethylphospholano)
ethane), gave 31 with low ee. However, a satisfactory ee has not
been obtained to date (entries 8e10).
Due to the electron rich character of ring C possessing one alk-
oxy and one aryloxy groups, there are three plausible reaction
mechanisms for this Pd-catalyzed transannulation (Scheme 6).26
The first is a true CeH activation mechanism that proceeds via
a four- (X¼I) or six- (X¼OAc) membered transition state. The sec-
ond is an electrophilic substitution mechanism. Both of these
mechanisms would conclude via reductive elimination. The third
possible mechanism is a Heck reaction-type carbopalladation.
Generally, this route would be improbable because anti-elimination
of HePdeX is required.19a However, in this case, elimination of the
PdeX moiety would be facilitated by the electron donation from
the alkoxy group. Although it is not clear, which particular mech-
anism is in effect, small ligands such as n-Bu3P and bidentate li-
gands are suitable for forming the above transition states and
intermediates inside of the macrocyclic ring.
Finally, hydrolysis of the acetyl group in (ꢀ)-32 followed by
treatment with BBr3 gave rise to (ꢀ)-cavicularin in 71% yield over
two steps (Scheme 7). The spectroscopic data for 2 were consistent
with those of natural cavicularin.
3. Conclusion
The total synthesis of riccardin C (1) and (ꢀ)-cavicularin (2) was
successfully accomplished in 11 steps and 17 steps, respectively.
Intramolecular SuzukieMiyaura coupling reactions were utilized
for the formation of the 18-membered macrocycles of 1 and 2, and
a Pd-catalyzed AreAr coupling reaction was employed for the
construction of the highly strained dihydrophenanthrene moiety of
2. The design and optimization of asymmetric catalysts for the Pd-
catalyzed transannulation are currently underway in order to re-
alize the synthesis of (þ)-cavicularin.
Scheme 2. Preparation of boronic ester 19.
coupling was attempted. Unfortunately, the 5 mol % Pd2(dba)3/
SPhos/aqNa2CO3/DMF (0.005 M) system that was employed in the
synthesis of riccardin C mainly brought about protonation of the
boronic ester moiety. This protonation may have been due to the
presence of H2O in the reaction mixture; therefore, anhydrous
Na2CO3 was used along with freshly distilled DMF under otherwise
identical conditions. To our delight, the reaction yield was im-
proved to 53%. Finally, by optimizing the reaction concentration
and the reaction time to 0.001 M and 15 h, respectively, a further
increase in the yield of 27 up to 72% was achieved.
4. Experimental section
4.1. General methods
Commercially available reagents, general solvents, and dry sol-
vents were used as received. Column chromatography was per-
The next step was the Pd-catalyzed AreAr coupling reaction to
construct the crucial dihydrophenanthrene structure (Scheme 5).
formed using silica gel (63e210, 45e75, and 40e50 m
m), 1H NMR

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K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
Table 1
Intramolecular SuzukieMiyaura coupling of 19
Entry
Catalyst
Ligand
Base
Solvent
20
21
a
1
2
3
4
5
6
Pd(PPh3)4
d
K3PO4
K3PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMF
DMF
DMF
Toluene
THF
9
16
48
2
34
3
0
0
25
28
24
0
b
b
b
b
b
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
SPhos
SPhos
SPhos
SPhos
SPhos
c
c
c
c
DMSO
a
10 mol %.
b
c
5 mol %.
2 M aqueous Na2CO3 solution was used.
Scheme 3. Completion of the synthesis of riccardin C (1).
spectra were recorded at 300, 400, and 500 MHz and chemical
shifts are referenced to TMS (
at 75, 100, and 125 MHz and chemical shifts are referenced to CDCl3
d
¼0). 13C NMR spectra were recorded
(
d
¼77.03). Coupling constants (J) are quoted in hertz (Hz). HRMS
were recorded on Magnetic Sector (Double Focusing) mass spec-
trometer equipped with EI, CI, and FAB source. FTIR spectra were
recorded with ATR.
4.2. Methyl 3-(4-formylphenoxy)-4-methoxybenzoate (3)
4-Bromobenzaldehyde (9) (4.05 g, 32.6 mmol), K2CO3 (1.06 g,
7.67 mmol), and copper(II) oxide powder (608 mg, 7.63 mmol) were
added to a solution of methyl 3-hydroxy-4-methoxybenzoate (10)
(995 mg, 5.46 mmol) in pyridine (10.0 mL). After stirring at reflux
for 16 h, the reaction mixture was filtered through CeliteÒ535RVS
and concentrated in vacuo. The residue was purified by column
chromatography eluted with toluene, to give 3 (1.18 g, 76%) as a pale
yellow prism. 1H NMR (300 MHz, CDCl3)
d 3.86 (3H, s), 3.89 (3H, s),
6.99 (2H, d, J¼8.6 Hz), 7.06 (1H, d, J¼8.6 Hz), 7.78 (1H, d, J¼2.0 Hz),
7.83 (2H, d, J¼8.6 Hz), 7.97 (1H, dd, J¼2.0, 8.6 Hz), 9.92 (1H, s); 13C
NMR (75 MHz, CDCl3)
d 52.1, 56.1, 112.1, 116.3, 123.4, 123.8, 128.5,
131.2, 131.9, 142.6, 155.5, 163.0, 166.0, 190.7; IR (ATR) 1716, 1692,
1600, 1579, 1504, 1437, 1280, 1226, 115, 1130, 1094, 1022, 833,
770 cmꢂ1; EIMS m/z (relative intensity) 286 [M]þ (100), 255 (94);
HR-EIMS m/z: [M]þ calcd for C16H14O5 286.0841; found 286.0850;
mp 94.5e96.2 ꢁC.
Scheme 4. Construction of the macrocycle of 2 and preparation of 27.

K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
6963
Scheme 5. Preparation of 30.
4.3. Dimethyl 2-bromo-5-methoxybenzylphosphonate (4)
A mixture of 1-bromo-2-(bromomethyl)-4-methoxybenzene
(10.0 g, 35.7 mmol) and trimethyl phosphite (13.0 mL, 107 mmol)
was stirred at reflux for 2 h. The reaction mixture was concentrated
in vacuo. The residue was purified by column chromatography
eluted with EtOAc, to give 4 (10.8 g, 98%) as a yellow oil. 1H NMR
Scheme 6. Plausible mechanisms for the Pd-catalyzed transannulation.
(300 MHz, CDCl3)
d
3.38 (2H, d, J¼22.0 Hz), 3.69 (3H, s), 3.74 (3H, s),
3.79 (3H, s), 6.69 (1H, dd, J¼2.8, 8.8 Hz), 7.00 (1H, d, J¼2.8 Hz), 7.44
(1H, d, J¼8.8 Hz); 13C NMR (75 MHz, CDCl3)
d 31.8, 33.7, 52.9, 55.4,
114.7, 115.1, 116.7, 132.2, 133.3, 158.7; IR (ATR) 3470, 2953, 2849,
1596, 1572, 1474, 1415, 1315, 1283, 1239, 1183, 1164, 1149, 1109, 1014,
942, 860, 803, 749, 732, 690, 665 cmꢂ1; CIMS m/z (relative in-
tensity) 311 [MþH]þ (91), 309 [MþH]þ (90), 229 (100); HR-CIMS
m/z: [MþH]þ calcd for C10H15O4BrP 308.9891; found 308.9908.
4.4. (E)-Methyl 3-(4-(2-bromo-5-methoxystyryl)phenoxy)-4-
methoxybenzoate (11)
To a solution of 4 (8.89 g, 28.6 mmol) in THF (26.0 mL) was
added a suspension of 60% NaH (1.53 g, 38.2 mmol) in THF
Table 2
Examination of the intramolecular Pd-catalyzed AreAr coupling for the synthesis of 2
Entry
Ligand
Mol % of L
31
32
ee25
1
2
3
4
5
6
7
8
9
10
d
20
40
40
40
20
40
20
20
20
20
0
0
0
39
50
0
41
23
18
12
74
81
78
36
31
0
43
0
0
d
d
d
d
(o-tol)3P
t-Bu3P
n-Bu3P
n-Bu3P
Et3P
d
d
11
7
Dppe
(S,S)-Chiraphos
(S)-BINAP
(R,R)-Me-BPE
0
6

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K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
at 100 ꢁC for 24 h, the reaction mixture was concentrated in vacuo.
The residue was purified by column chromatography eluted with
hexane/EtOAc (15:85) to give 14 (5.12 g, 98%) as a pale yellow oil. 1H
NMR (300 MHz, CDCl3)
d
3.07 (2H, d, J¼21.3 Hz), 3.65 (3H, s), 3.69
(3H, s), 3.82 (6H, s), 6.68 (1H, dd, J¼2.9, 8.8 Hz), 6.93 (2H, d,
J¼8.7 Hz), 6.95 (1H, d, J¼2.5 Hz), 6.96 (1H, d, J¼8.3 Hz), 6.97 (1H, d,
J¼16.4 Hz), 7.09 (1H, dd, J¼2.5, 8.3 Hz), 7.16 (1H, d, J¼2.9 Hz), 7.30
(1H, d, J¼16.4 Hz), 7.44 (1H, d, J¼8.8 Hz), 7.45 (2H, d, J¼8.7 Hz); 13C
NMR (75 MHz, CDCl3) d 31.2, 32.6, 52.9, 55.5, 56.0, 111.6, 113.0, 114.8,
116.8,117.3, 122.5, 122.6, 126.2, 128.1, 130.3, 130.8, 131.5, 133.5,137.9,
144.5, 150.5, 157.9, 159.0; IR (ATR) 2952, 2838, 1584, 1503, 1463,
1442, 1425, 1222, 1167, 1128, 1053, 1025, 961, 891, 852, 802, 772,
689, 664 cmꢂ1; EIMS m/z (relative intensity) 533 [M]þ (100), 343
(50); HR-EIMS m/z: [M]þ calcd for C25H27O6BrP 533.0687; found
533.0713.
Scheme 7. Completion of the synthesis of cavicularin (2).
(5.00 mL) at 0 ꢁC. After stirring at the same temperature for 1 h,
a solution of 3 (5.43 g, 19.0 mmol) in THF (5.00 mL) was added to
the mixture. After stirring at rt overnight, the reaction was
quenched with satd NH4Cl at 0 ꢁC and extracted with EtOAc. The
combined extracts were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography eluted
with hexane/EtOAc (10:1) to give 11 (8.74 g, 98%) as a colorless
4.7. 1-Bromo-4-methoxy-2-(4-(2-methoxy-5-(3-methoxy-4-
(methoxymethoxy)styryl)phenoxy)styryl)benzene (16)
prism. 1H NMR (300 MHz, CDCl3)
d 3.84 (3H, s), 3.86 (3H, s), 3.91
To a solution of 14 (595 mg, 3.03 mmol) in THF (5.00 mL) was
added 60% NaH (513 mg, 12.8 mmol). After stirring at 0 ꢁC for
10 min, 15 (1.30 g, 2.51 mmol) was added to the solution. After
stirring at 0 ꢁC for 3 h, the reaction mixture was quenched with
water and extracted with ether. The combined extracts were
washed with H2O and brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography
eluted with hexane/EtOAc (7:3) to give 16 (2.10 g, 87%) as a colorless
(3H, s), 6.66 (1H, dd, J¼2.7, 8.8 Hz), 6.93 (2H, d, J¼8.8 Hz), 6.96 (1H,
d, J¼16.2 Hz), 7.00 (1H, d, J¼8.5 Hz), 7.14 (1H, d, J¼2.7 Hz), 7.30 (1H,
d, J¼16.2 Hz), 7.42 (1H, d, J¼8.8 Hz), 7.48 (2H, d, J¼8.8 Hz), 7.68 (1H,
d, J¼2.1 Hz), 7.86 (1H, dd, J¼2.1, 8.5 Hz); 13C NMR (75 MHz, CDCl3)
d
51.9, 55.4, 56.0, 111.5, 111.8, 114.7, 114.8, 117.3, 122.1, 123.0, 126.3,
127.2, 128.1, 130.6, 131.7, 133.4, 137.7, 144.3, 155.2, 157.4, 158.9, 166.1;
IR (ATR) 2950, 2839, 1712, 1603, 1583, 1566, 1503, 1462, 1436, 1419,
1321, 1273, 1225, 1165, 1128, 1112, 1094, 1057, 1016, 992, 962, 909,
847, 815, 7634, 729, 694 cmꢂ1; CIMS m/z (relative intensity) 469
[MþH]þ(100), 468 [M]þ (60); HR-CIMS m/z: [MþH]þ calcd for
C24H22O5Br 469.0651; found 469.0637; mp 93.5e94.5 ꢁC.
oil. 1H NMR (400 MHz, CDCl3)
d 3.44 (3H, s), 3.77 (3H, s), 3.79 (3H,
s), 3.85 (3H, s), 5.16 (2H, s), 6.63 (1H, dd, J¼2.9, 8.8 Hz), 6.81 (2H, s),
6.91 (2H, d, J¼8.7 Hz), 6.92 (1H, d, J¼16.2 Hz), 6.93 (3H, m), 7.04 (1H,
d, J¼8.2 Hz), 7.11 (1H, d, J¼2.9 Hz), 7.13 (1H, d, J¼1.9 Hz), 7.20 (1H,
dd, J¼1.9, 8.2 Hz), 7.25 (1H, d, J¼16.2 Hz), 7.38 (1H, d, J¼8.8 Hz), 7.44
(1H, d, J¼8.7 Hz); 13C NMR (100 MHz, CDCl3)
d 55.5, 55.9, 56.1, 56.2,
95.5, 108.6, 109.2, 111.6, 112.9, 114.8, 116.3, 116.5, 117.3, 118.7, 119.5,
123.4, 126.2, 127.2, 128.2, 130.8, 131.1, 131.5, 132.0, 133.6, 138.0,
4.5. (E)-3-(4-(2-Bromo-5-methoxystyryl)phenoxy)-4-
methoxyphenylmethanol (12)
144.8, 146.2, 149.8, 150.9, 158.0, 159.0; IR (ATR) 2932, 1504 cmꢂ1
;
To a solution of 11 (1.36 g, 2.91 mmol) in THF (30.0 mL) was
added lithium aluminum hydride (209 mg, 2.91 mmol). After stir-
ring at 0 ꢁC for 30 min, the reaction mixture was quenched with
aqueous potassium sodium tartrate tetrahydrate and extracted
with EtOAc. The combined extracts were washed with H2O and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography eluted with hexane/EtOAc
(2:3) to give alcohol 12 (1.25 g, 98%) as a colorless prism. 1H NMR
EIMS m/z (relative intensity): 604 [M]þ (100), 602 [M]þ (96); HR-
EIMS m/z: [M]þ calcd for C33H31BrO6 602.1304; found 602.1299.
4.8. 4-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-
methoxyphenethyl)-2-methoxyphenol (17)
To a solution of 16 (1.20 g, 2.05 mmol) in TFA (36.0 mL) was
added Et3SiH (18.2 mL, 114 mmol). After stirring at 60 ꢁC for 2.5 h,
the mixture was concentrated in vacuo. The residue was purified by
column chromatography eluted with hexane/EtOAc (7:3) to give 17
(300 MHz, CDCl3)
d 3.77 (3H, s), 3.78 (3H, s), 4.54 (2H, s), 6.63 (1H,
dd, J¼3.0, 8.8 Hz), 6.88 (2H, d, J¼8.6 Hz), 6.91 (1H, d, J¼16.1 Hz), 6.93
(1H, d, J¼8.6 Hz), 6.96 (1H, d, J¼1.9 Hz), 7.09 (1H, dd, J¼1.9, 8.6 Hz),
7.10 (1H, d, J¼3.0 Hz), 7.24 (1H, d, J¼16.1 Hz), 7.39 (1H, d, J¼8.8 Hz),
(853 mg, 74%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 2.78
(4H, s), 2.86 (2H, m), 2.97 (2H, m), 3.74 (3H, s), 3.81 (3H, s), 3.82 (3H,
s), 5.48 (1H, s), 6.59 (1H, dd, J¼1.9, 6.0 Hz), 6.60 (1H, m), 6.65 (1H,
dd, J¼2.9, 8.8 Hz), 6.70 (1H, d, J¼2.9 Hz), 6.73 (1H, d, J¼1.4 Hz), 6.80
(1H, d, J¼8.1 Hz), 6.83 (2H, d, J¼8.8 Hz), 6.89 (1H, d, J¼1.5 Hz), 7.13
(2H, d, J¼8.8 Hz), 7.42 (1H, d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
7.42 (2H, d, J¼8.6 Hz); 13C NMR (75 MHz, CDCl3)
d 55.6, 56.1, 64.7,
111.6, 112.8, 114.8, 117.4, 120.0, 123.7, 126.2, 128.2, 130.4, 130.8, 131.5,
133.5, 134.0, 137.9, 144.8, 150.9, 157.9, 159.0; IR (ATR) 3377, 2934,
1505, 1463, 1440, 1425, 1271, 1227, 1167, 1124, 1015, 961, 844, 808,
729, 633, 625, 608 cmꢂ1; CIMS m/z (relative intensity) 441 [MþH]þ
(40), 440 [M]þ (70), 361 (100); HR-CIMS m/z: [MþH]þ calcd for
C23H22O4Br 441.0701; found 441.0721; mp 82.8e83.2 ꢁC.
d
35.4, 37.3, 37.6, 38.7, 55.4, 55.8, 56.1, 111.1, 112.7, 113.4, 114.2, 114.9,
116.2, 117.3, 120.8, 121.1, 124.2, 129.5, 133.3, 133.4, 134.8, 135.5, 141.9,
143.7, 145.1, 146.2, 149.4, 156.1, 158.9; IR (ATR) 3522, 2933,
1503 cmꢂ1; EIMS m/z (relative intensity): 562 [M]þ (54), 363 (100),
137 (96); HR-EIMS m/z: [M]þ calcd for C31H31O5Br 562.1355; found
562.1362.
4.6. (E)-Dimethyl 3-(4-(2-bromo-5-methoxystyryl)phenoxy)-
4-methoxybenzylphosphonate (14)
To a solution of alcohol 12 (4.31 g 9.85 mmol) in toluene
(100 mL) was added thionyl bromide (1.00 mL, 12.8 mmol) at 0 ꢁC.
After stirring at the same temperature for 2 h, the reaction mixture
was quenched with water and extracted with EtOAc. The combined
extracts were washed with H2O and brine, and dried over Na2SO4
and concentrated in vacuo. To a solution of the residue in benzene
was added trimethyl phosphite (5.85 mL, 49.5 mmol). After stirring
4.9. 4-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-
methoxyphenethyl)-2-methoxyphenyl tri-
fluoromethanesulfonate (18)
To a solution of 17 (639 mg, 1.14 mmol) in MeCN/DMF¼9:1
(30 mL) was added Tf2NPh (614 mg, 1.72 mmol) and CsCO3 (565 mg,
1.72 mmol). After stirring at rt for 8 h, the reaction mixture was

K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
6965
quenched with satd NaHCO3 and extracted with ether. The com-
bined extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography eluted with hexane/EtOAc (4:1) to give 18 (754 mg,
1268, 1214, 811, 750 cmꢂ1; FABMS m/z: 933 [Mþ1]þ; HR-FABMS m/
z: [Mþ1]þ calcd for C62H61O8 933.4366; found 933.4347.
4.12. Riccardin C (1)
96%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 2.84 (6H, m), 2.97
(2H, m), 3.74 (3H, s), 3.83 (3H, s), 3.83 (3H, s), 6.63 (1H, dd, J¼3.1,
8.8 Hz), 6.70 (1H, d, J¼3.1 Hz), 6.71 (1H, d, J¼8.8 Hz), 6.72 (1H, m),
6.73 (1H, d, J¼2.0 Hz), 6.84 (2H, d, J¼8.6 Hz), 6.86 (1H, dd, J¼2.2,
8.6 Hz), 6.89 (1H, br s), 7.08 (1H, d, J¼8.0 Hz), 7.13 (2H, d, J¼8.6 Hz),
To a cooled solution of 20 (19.3 mg, 63.0
was added BBr3 (1 M DCM solution, 550
m
mol) in DCM (5.00 mL)
m
L, 550 mol). After stir-
m
ring at 0 ꢁC for 24 h, the reaction mixture was quenched with H2O
and extracted with DCM. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography eluted with hex-
ane/EtOAc (3:2) to give 1 (25.9 mg, 97%) as a colorless prism. 1H
7.42 (1H, d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d 35.4, 36.6, 37.8,
38.7, 55.4, 56.1, 56.1, 112.7, 113.3, 114.8, 116.1, 117.1, 117.3, 120.3, 120.6,
120.7, 122.1, 124.2, 129.5, 133.3, 133.9, 135.6, 137.0, 141.8, 143.2, 145.3,
149.6, 151.0, 156.0, 158.9; IR (ATR) 2935, 1504 cmꢂ1; EIMS m/z (rel-
ative intensity): 694 [M]þ (47), 696 (54), 495 (100), 425 (33); HR-
EIMS m/z: [M]þ calcd for C32H30BrF3O7S 694.0848; found 694.0877.
NMR (400 MHz, CDCl3)
d 2.68 (5H, m), 2.93 (2H, m), 3.04 (1H, m),
4.75 (1H, s), 4.88 (1H, s), 5.35 (1H, d, J¼2.0 Hz), 5.58 (1H, s), 6.23
(1H, dd, J¼1.8, 7.7 Hz), 6.39 (1H, d, J¼1.5 Hz), 6.74 (1H, dd, J¼2.0,
8.1 Hz), 6.77e6.87 (6H, m), 6.92 (1H, d, J¼8.0 Hz), 6.98 (1H, d,
4.10. 2-Methoxy-4-(4-methoxy-3-(4-(5-methoxy-2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phenoxy)phe-
nethyl)phenyl trifluoromethanesulfonate (19)
J¼2.5 Hz), 7.05 (1H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 34.9,
37.1, 37.8, 38.1, 114.3, 114.9, 116.0, 116.0, 117.5, 121.7, 122.2, 122.5,
122.5, 124.3, 128.2, 129.5, 129.5, 131.4, 132.9, 133.1, 139.8, 142.0,
143.3, 143.8, 146.3, 151.8, 152.5, 155.9; IR (ATR) 3422, 2925,
1506 cmꢂ1; CIMS m/z (relative intensity): 425 [Mþ1]þ (82), 424
[M]þ (100); HR-CIMS m/z: [M]þ calcd for C28H24O4 424.1675; found
424.1679; mp 189.3e190.6 ꢁC.
To a solution of 18 (71.3 mg, 100
was added tetrakis(triphenylphosphine)palladium(0) (11.8 mg,
10.0 mol), bis(pinacolato)diboron (61.8 mg, 240 mol), and K3PO4
(66.2 mg, 310
mmol) in dioxane (1.00 mL)
m
m
m
mol). After stirring at 100 ꢁC for 4 h, the reaction
mixture was filtered through CeliteÒ535RVS and concentrated in
vacuo. The residue was purified by preparative TLC eluted with
hexane/DCM (3:7) to give 19 (72.0 mg, 95%) as a pale yellow oil. 1H
4.13. 4-(Benzyloxy)-3-hydroxybenzaldehyde
To a solution of 3,4-dihydroxybenzaldehyde (2.03 g, 14.7 mmol)
in acetone (150 mL) was added K2CO3 (3.05 g, 22.1 mmol) and
benzyl bromide (1.74 mL, 14.7 mmol). After stirring at reflux for 4 h,
the reaction mixture was filtered through CeliteÒ535RVS and
concentrated in vacuo. The residue was purified by column chro-
matography eluted with toluene/EtOAc (13:1) to give 4-(benzy-
loxy)-3-hydroxybenzaldehyde (2.12 g, 63%) as a colorless prism. 1H
NMR (400 MHz, CDCl3)
d 1.35 (12H, s, Me), 2.78e2.87 (6H, m), 3.13
(2H, m), 3.80 (3H, s), 3.84 (6H, s), 6.72 (1H, dd, J¼2.3, 11.2 Hz),
6.70e6.76 (3H, m), 6.77 (1H, d, J¼2.1 Hz), 6.85 (2H, d, J¼8.7 Hz),
6.85 (1H, dd, J¼2.1, 8.4 Hz), 7.08 (1H, d, J¼8.0 Hz), 7.20 (2H, d,
J¼8.7 Hz), 7.79 (1H, d, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3)
d 24.9,
36.7, 37.8, 38.9, 39.0, 55.0, 56.1, 56.1, 83.2, 110.6, 112.7, 113.3, 115.2,
117.2, 120.6, 120.7, 122.1, 124.1, 129.5, 133.9, 137.0, 137.0, 138.4, 143.2,
145.4, 149.7, 151.0, 151.4, 155.7, 161.8; IR (ATR) 2976, 1602,
1348 cmꢂ1; CIMS m/z (relative intensity): 643 (100), 743 [Mþ1]þ
(42), 742 [M]þ (68); HR-CIMS m/z: [M]þ calcd for C38H42O9F3SB
742.2595; found 742.2566.
NMR (300 MHz, CDCl3)
d 5.21 (2H, s), 5.77 (1H, s), 7.05 (1H, d,
J¼8.2 Hz), 7.37e7.43 (7H, m), 9.86 (1H, s); 13C NMR (75 MHz)
d 71.2,
111.5 114.4,124.4,127.9, 128.8, 128.9, 130.8,135.2,146.3,150.9, 191.0;
IR (ATR) 3201, 1671, 1604, 1577, 1511, 1454, 1389, 1343, 1283, 1165,
1151, 1015, 962, 874, 811, 786, 738, 698, 678 cmꢂ1; EIMS m/z (rel-
ative intensity) 228 [M]þ (40), 91 (100); HR-EIMS m/z: [M]þ calcd
for C14H12O3 228.0786; found 228.0789; mp 120.0e122.0 ꢁC.
4.11. Trimethylriccardin C (20)
To a solution of 19 (32.8 mg, 44.0
added 2 M Na2CO3 (67.0 L, 134 mol), tris(dibenzylideneacetone)
dipalladium(0) (4.0 mg, 4.3 mol), and SPhos (3.6 mg, 8.7 mol).
m
mol) in DMF (8.8 mL) was
4.14. 4-(Benzyloxy)-3-(methoxymethoxy)benzaldehyde (22)
m
m
m
m
To a solution of 4-(benzyloxy)-3-hydroxybenzaldehyde (2.60 g,
11.4 mmol) in DCM (114 mL) was added MOMCl (1.73 mL,
22.8 mmol) and DIPEA (3.98 mL, 22.8 mmol). After stirring at 0 ꢁC for
12 h, the reaction mixture was quenched with water and extracted
with DCM. The combined extracts were washed with H2O and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified bycolumn chromatographyeluted with hexane/EtOAc(3:1)
After stirring at 100 ꢁC for 12 h, the reaction mixture was filtered
through CeliteÒ535RVS and concentrated in vacuo. The residue was
purified by recycle HPLC eluted with CHCl3 to give 20 (10.0 mg, 48%)
as a colorless solid and 21 (5.1 mg, 25%) as a colorless amorphous.
Compound 20: 1H NMR (400 MHz, CDCl3)
d 2.63 (3H, br s), 2.82 (2H,
br s), 2.86 (2H, br s), 3.08 (1H, br s), 3.64 (3H, s), 3.88 (3H, s), 3.94
(3H, s), 5.36 (1H, d, J¼1.9 Hz), 6.24 (1H, dd, J¼1.5, 7.6 Hz), 6.44 (1H, d,
J¼1.5 Hz), 6.73e6.83 (6H, m), 6.83 (1H, d, J¼7.6 Hz), 6.89 (1H, d,
J¼8.3 Hz), 6.96 (1H, d, J¼2.8 Hz), 7.06 (1H, d, J¼8.5 Hz); 13C NMR
to give 22 (2.44 g, 84%) as a yellow oil.1H NMR (300 MHz)
d 3.50 (3H,
s), 5.21 (2H, s), 5.26 (2H, s), 7.00 (1H, d, J¼8.4 Hz), 7.36e7.47 (6H, m),
7.66 (1H, d, J¼1.9 Hz), 9.80 (1H, s); 13C NMR (75 MHz)
d 56.3, 70.7,
(100 MHz, CDCl3)
d
35.6, 36.6, 37.5, 38.6, 55.2, 55.4, 56.1, 110.9, 111.0,
95.3, 113.0, 116.0, 126.6, 127.1, 128.1, 128.6, 130.1, 135.9, 147.1, 154.2,
190.6; IR (ATR) 2826, 1685, 1582, 1505, 1454, 1434, 1389, 1258, 1151,
1126, 1075, 990, 918, 808, 779, 730, 695, 628 cmꢂ1; EIMS m/z (rela-
tive intensity) 272 [M]þ (78), 227 (35), 181 (40), 91 (100); HR-EIMS
m/z: [M]þ calcd for C16H16O4 272.1049; found 272.1041.
112.6, 114.4, 116.9, 120.3, 120.9, 124.4, 127.8, 129.2, 130.7, 131.3, 131.5,
134.8, 136.4, 142.0, 142.3, 145.0, 149.7, 156.0, 156.7, 158.9; IR (ATR)
2932, 2833, 1505, 1463, 1230, 1128, 729 cmꢂ1; EIMS m/z (relative
intensity): 466 [M]þ (100), 239 (75); HR-EIMS m/z: [M]þ calcd for
C31H30O4 466.2144; found 466.2163. Compound 21: 1H NMR
(400 MHz, CDCl3)
d
2.62e2.95 (16H, m), 3.78 (6H, s), 3.79 (6H, s),
4.15. 1-(Benzyloxy)-4-((E)-3-(4-((E)-2-bromo-5-
methoxystyryl)phenoxy)-4-methoxystyryl)-2-(methox-
ymethoxy)benzene (23)
3.85 (6H, s), 6.70 (2H, br s), 6.71e6.83 (16H, m), 6.87 (2H, d,
J¼2.0 Hz), 6.89 (2H, d, J¼2.5 Hz), 7.00 (2H, d, J¼7.5 Hz), 7.10 (2H, d,
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 36.5, 36.6, 37.5, 38.6, 55.2,
55.4, 56.1, 110.9, 111.0, 112.6, 114.4, 116.9, 120.3, 120.9, 124.4, 127.8,
129.2, 130.7, 131.3, 131.5, 134.8, 136.4, 142.0, 142.3, 145.0, 149.7, 156.0,
156.7, 158.9; IR (ATR) 3006, 2925, 2853, 1604, 1575, 1503, 1463, 1418,
To a solution of 14 (5.44 g, 8.95 mmol) in THF (90.0 mL) was
added 60% NaH (716 mg, 17.9 mmol). After stirring at 0 ꢁC for 1 h, 22
(2.92 g, 10.7 mmol) was added to the solution. After stirring at 0 ꢁC

6966
K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
for 24 h, the reaction mixture was quenched with satd NH4Cl and
extracted with EtOAc. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography eluted with hex-
ane/EtOAc (4:1) to give 23 (5.70 g, 94%) as a pale yellow oil. 1H NMR
and DMAP (9.0 mg, 121
m
mol). After stirring at ꢂ78 ꢁC for 1 h, the
reaction mixture was quenched with satd NaHCO3 and extracted
with DCM. The combined extracts were washed with water and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography eluted with DCM/hexane
(1:1) to give 25 (42.2 mg, 96%) as a colorless oil. 1H NMR (400 MHz,
(400 MHz, CDCl3)
d 3.54 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 5.16 (2H,
s), 5.26 (2H, s), 6.67 (1H, dd, J¼3.0, 8.8 Hz), 6.84e6.81 (3H, m),
CDCl3) d 2.80e2.95 (6H, m), 2.95e2.97 (2H, m), 3.49 (3H, s), 3.74
6.97e7.03 (5H, m), 7.17e7.52 (13H, m); 13C NMR (100 MHz, CDCl3)
(3H, s), 3.83 (3H, s), 5.18 (2H, s), 6.68 (1H, dd, J¼3.2, 8.8 Hz), 6.70
(1H, d, J¼2.8 Hz), 6.73 (1H, d, J¼1.6 Hz), 6.77 (1H, dd, J¼2.4, 8.4 Hz),
6.84e6.91 (3H, m), 7.00 (1H, d, J¼1.6 Hz), 7.09 (1H, d, J¼8.4 Hz), 7.15
(2H, d, J¼8.8 Hz), 7.42 (1H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d
55.5, 56.1, 56.3, 71.0, 95.7, 111.6, 112.8, 114.5, 114.8, 117.3, 118.7,
121.1, 123.4, 126.1, 127.1, 126.2, 127.2, 127.9, 128.2, 128.6, 130.8, 131.1,
131.2, 131.4, 133.5, 137.0, 138.0, 144.8, 147.2, 148.7, 150.9, 158.0,
159.0; IR (ATR) 1588, 1503, 1461, 1267, 1226, 1166, 1125, 1075, 1000,
959, 847, 808, 735, 697, 660 cmꢂ1; EIMS m/z (relative intensity): 678
[M]þ (20), 91 (100), 41 (70); HR-EIMS m/z: [M]þ calcd for
C39H35BrO6 678.1585; found 678.1601.
d
35.4, 36.4, 37.7, 38.7, 55.4, 56.1, 56.5, 95.0, 112.7, 113.4, 114.8, 116.1,
116.6,117.4,120.6,122.0,122.1,124.2,129.5,133.3,133.9,135.6,137.3,
141.8, 143.3, 145.2, 148.8, 149.6, 156.0, 158.9; IR (ATR) 2924, 2851,
1604, 1504, 1470, 1420, 1270, 1245, 1211, 1141, 1104, 1078, 992, 924,
880, 814, 773, 702 cmꢂ1; EIMS m/z (relative intensity): 724 [M]þ
(20), 525 (40), 45 (100); HR-EIMS m/z: [M]þ calcd for
C33H32BrF3O8S 724.0956; found 724.0989.
4.16. 1-(Benzyloxy)-4-(3-(4-(2-bromo-5-methoxyphenethyl)
phenoxy)-4-methoxyphenethyl)-2-(methoxymethoxy)ben-
zene (23a)
4.19. 4-(4-Methoxy-3-(4-(5-methoxy-2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenethyl)phenoxy)phenethyl)-2-
(methoxymethoxy)phenyl trifluoromethanesulfonate (26)
To a solution of 23 (5.13 g, 7.55 mmol) in EtOCH2CH2OH (75.0 mL)
was added p-toluenesulfonyl hydrazide (14.0 g, 75.5 mmol) and
NaHCO3 (6.34 g, 75.5 mmol). After stirring at 135 ꢁC for 3 h, the re-
action mixture was filtered through CeliteÒ535RVS and the solution
was washed with water and brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by HPLC eluted with hex-
ane/EtOAc (9:1) to give 23a (5.00 g, 97%) as a colorless oil. 1H NMR
To a solution of 25 (12.0 mg, 166
added tetrakis(triphenylphosphine)palladium(0) (2.0 mg,1.66
bis(pinacolato)diboron (8.4 mg, 332 mol), and K3PO4 (10.5 mg,
500
mmol) in dioxane (1.00 mL) was
mmol),
m
m
mol). After stirring at 100 ꢁC for 12 h, the reaction mixture was
(400 MHz, CDCl3)
d
2.77 (4H, s), 2.85e2.97 (4H, m), 3.50 (3H, s), 3.74
filtered through CeliteÒ535RVS and concentrated in vacuo. The resi-
due was purified by preparative TLC eluted with hexane/EtOAc (4:1)
to give 26 (10.4 mg, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
(3H, s), 3.82 (3H, s), 5.11 (2H, s), 5.18 (2H, s), 6.68 (1H, dd, J¼3.5,
8.8 Hz), 6.67 (1H, d, J¼2.0 Hz), 6.69 (1H, d, J¼3.2 Hz), 6.75 (1H, d,
J¼1.3 Hz), 6.79e6.91 (6H, m), 7.13 (2H, dd, J¼2.0, 8.5 Hz), 7.29e7.43
d
1.35 (12H, s), 2.79e3.15 (8H, m), 3.49 (3H, s), 3.80 (3H, s), 3.83 (3H, s),
(6H, m); 13C NMR (100 MHz, CDCl3)
d
35.4, 37.0, 37.3, 38.7, 55.4, 56.1,
5.18 (2H, s), 6.71 (1H, d, J¼2.4 Hz), 6.74 (1H, dd, J¼2.4, 8.4 Hz), 6.76 (1H,
d, J¼2.0 Hz), 6.77 (1H, dd, J¼2.0, 8.4 Hz), 6.85 (1H, dd, J¼2.0, 8.4 Hz),
6.86 (2H, d, J¼8.4 Hz), 6.90(1H, d,J¼8.4 Hz), 7.01 (1H, d,J¼2.0Hz), 7.09
(1H, d, J¼8.4 Hz), 7.21 (2H, d, J¼8.4 Hz), 7.79 (1H, d, J¼8.4 Hz);13C NMR
56.2, 71.1, 95.7,112.6,113.3,114.5,114.8,116.1,117.3,117.8,120.8,122.3,
124.2, 127.2, 127.8, 128.5, 129.5, 133.2, 134.7, 135.0, 135.4, 137.3, 141.9,
145.0,146.8,147.3,149.4,156.1,158.8; IR (ATR) 2928,1589,1504,1469,
1423, 1265, 1222, 1154, 1125, 1076, 1006, 922, 805, 736, 697 cmꢂ1
;
(100 MHz, CDCl3) d 24.9, 36.6, 37.6, 38.8, 38.9, 55.0, 56.1, 56.4, 83.2,
EIMS m/z (relative intensity): 682 [M]þ (10), 91 (100), 45 (30); HR-
EIMS m/z: [M]þ calcd for C39H39BrO6 682.1930; found 682.1903.
95.0, 110.6, 112.7, 115.2, 116.6, 117.1, 120.6, 121.9, 122.0, 124.1, 129.5,
133.9, 136.9, 137.3, 138.3, 143.3, 145.4, 148.8, 149.6, 151.4, 155.8, 161.8;
IR (ATR) 2930, 1601, 1505, 1421, 1380, 1348, 1271, 1212, 1143, 1077,
1034, 994, 861, 612 cmꢂ1; EIMS m/z (relative intensity): 772 [M]þ (20),
615 (30), 525 (40), 359 (60), 45 (100); HR-EIMS m/z: [M]þ calcd for
C39H44F3O10SB 772.2700; found 772.2712.
4.17. 4-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-
methoxyphenethyl)-2-(methoxymethoxy)phenol (24)
To a solution of 23a (45.3 mg, 66.3
m
mol) in CHCl3/MeOH¼9:1
(2.50 mL) was added Pd(OH)2/C (4.0 mg). After stirring vigorously
under hydrogen atmosphere at rt for 10 min, the reaction mixture
was filtered through CeliteÒ535RVS and concentrated in vacuo. The
residue was purified by column chromatography eluted with DCM
to give the phenol 24 (36.6 mg, 93%) as a yellow oil. 1H NMR
4.20. Dimethylmethoxymethylriccardin C (27)
To a solution of 26 (79.2 mg, 103
added Na2CO3 (32.6 mg, 308 mol), tris(dibenzylideneacetone)
dipalladium(0) (9.4 mg, 10.3 mol), and SPhos (8.3 mg, 20.7 mol).
mmol) in DMF (100 mL) was
m
m
m
(400 MHz, CDCl3)
d
2.76 (4H, s), 2.85e2.97 (4H, m), 3.49 (3H, s), 3.74
After stirring at 100 ꢁC for 15 h, the reaction mixture was filtered
through CeliteÒ535RVS and concentrated in vacuo. The residue was
purified by HPLC eluted with hexane/EtOAc (9:1) to give 27
(36.5 mg, 72%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
(3H, s), 3.82 (3H, s), 5.13 (2H, s), 5.78 (1H, s), 6.63 (1H, dd, J¼3.2,
8.8 Hz), 6.68 (1H, dd, J¼2.0, 8.0 Hz), 6.70 (1H, d, J¼5.6 Hz), 6.72 (1H, d,
J¼1.6 Hz), 6.83 (4H, m), 6.89 (2H, m), 7.13 (2H, d, J¼8.4 Hz), 7.42 (1H,
d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d
35.4, 37.2, 37.4, 38.7, 55.4,
d 2.52e2.62 (3H, m), 2.82e2.88 (3H, m), 2.95e2.99 (1H, m),
56.1, 56.4, 96.0, 112.7, 113.3, 115.0, 115.8, 116.1, 117.3, 120.8, 123.0,
124.2,129.5,133.3,133.6,134.7,135.4,141.9,144.2,144.4,145.0,149.4,
156.1, 158.8; IR (ATR) 3447, 2931, 1604, 1505, 1471, 1270, 1226, 1153,
1125, 1078, 1054, 998, 924, 813 cmꢂ1; EIMS m/z (relative intensity):
592 [M]þ (69), 560 (74), 435 (96) 361 (96), 211 (100); HR-EIMS m/z:
[M]þ calcd for C32H33BrO6 592.1461; found 592.1469.
3.09e3.14 (1H, m), 3.33 (3H, s), 3.90 (3H, s), 3.94 (3H, s), 4.93 (1H, d,
J¼6.0 Hz), 5.00 (1H, d, J¼6.0 Hz), 5.38 (1H, d, J¼1.9 Hz), 6.25 (1H, dd,
J¼1.5, 7.5 Hz), 6.66 (1H, br), 6.72 (1H, d, J¼1.5 Hz), 6.72 (1H, br), 6.77
(1H, br), 6.78 (1H, dd, J¼1.9, 8.0 Hz), 6.82 (1H, br s), 6.83 (1H, d,
J¼7.5 Hz), 6.88 (1H, d, J¼8.0 Hz), 6.91 (1H, br), 6.96 (1H, d, J¼2.7 Hz),
7.04 (1H, d, J¼8.3 Hz); 13C NMR (125 MHz, CDCl3)
d 35.7, 37.2, 37.9,
38.2, 55.2, 56.1, 56.2, 95.1, 111.4, 111.7, 115.2, 115.4, 116.6, 121.5, 122.3,
122.5, 123.5, 128.8, 129.0, 129.6, 131.1, 132.3, 132.5, 133.7, 139.6,
141.3, 143.2, 146.8, 148.5, 152.7, 153.8, 159.1; IR (ATR) 2931, 2840,
1605, 1505, 1442, 1420, 1395, 1261, 1230, 1152, 1128, 1077, 1012, 907,
851, 808, 730 cmꢂ1; EIMS m/z 497 [MþH]þ (51), 496 [M]þ (100), 451
(66), 225 (51); HR-EIMS m/z: [M]þ calcd for C32H32O5 496.2250;
found 496.2250.
4.18. 4-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-
methoxyphenethyl)-2-(methoxymethoxy)phenyl tri-
fluoromethanesulfonate (25)
To a solution of phenol 24 (35.9 mg, 60.6
mmol) in DCM (1.00 mL)
was added trifluoromethanesulfonic anhydride (12.0
mL, 121 mol)
m

K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
6967
4.21. Dimethylriccardin C (28)
and n-Bu3P (0.3
m
L, 14.5
m
mol). After stirring at 120 ꢁC for 6 h, the
reaction mixture was filtered through CeliteÒ535RVS and concen-
trated in vacuo. The residue was purified by preparative TLC eluted
with hexane/Et2O (3:1) to give 31 (1.6 mg, 50%) as a colorless oil and
32 (1.0 mg, 31%) as a colorless oil. Compound 31: 1H NMR
To a solution of 27 (39.0 mg, 81.6
m
mol) in MeOH/EtOAc¼2:1
(1.00 mL) was added DowexÒ. After stirring at 70 ꢁC for 3 h, the
reaction mixture was filtered through CeliteÒ535RVS and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy eluted with hexane/DCM (1:1) to give 28 (32.4 mg, 83%) as
(500 MHz, CDCl3)
d
2.30 (1H, ddd, J¼3.0, 14.0, 14.0 Hz), 2.52 (1H,
ddd, J¼3.0, 12.0, 12.0 Hz), 2.64e2.78 (4H, m), 2.90 (2H, m), 3.87 (3H,
s), 3.94 (3H, s), 6.01 (1H, dd, J¼2.5, 8.5 Hz), 6.08 (1H, dd, J¼2.0,
8.5 Hz), 6.40 (1H, dd, J¼2.0, 8.5 Hz), 6.66 (1H, s), 6.73 (1H, dd, J¼2.5,
8.5 Hz), 6.75 (1H, dd, J¼2.5, 8.5 Hz), 6.79 (1H, d, J¼8.5 Hz), 6.84 (1H,
d, J¼2.5 Hz), 6.85 (1H, s), 6.94 (1H, d, J¼8.0 Hz), 7.04 (1H, d,
a colorless oil. 1H NMR (400 MHz, CDCl3)
d 2.60e2.81 (5H, m),
2.82e3.01 (2H, m), 3.03e3.16 (1H, m), 3.90 (3H, s), 3.94 (3H, s), 4.79
(1H, s), 5.42 (1H, d, J¼2.1 Hz), 6.28 (1H, dd, J¼1.6, 7.7 Hz), 6.43 (1H,
d, J¼1.6 Hz), 6.80 (6H, m), 6.88 (2H, dd, J¼2.6, 8.4 Hz), 7.03 (1H, d,
J¼2.7 Hz), 7.10 (1H, d, J¼8.5 Hz); 13C NMR (125 MHz, CDCl3)
d
35.1,
J¼8.0 Hz); 13C NMR (125 MHz, CDCl3)
d 20.7, 29.7, 30.1, 30.3, 37.6,
37.0, 37.7, 38.2, 55.4, 56.0, 111.7, 112.6, 115.9, 116.3, 116.6, 121.4, 121.6,
122.5, 122.7, 124.5, 128.0, 129.0, 129.3, 131.5, 132.6, 133.8, 139.3,
142.0, 143.6, 146.8, 148.6, 151.9, 152.9, 160.0; IR (ATR) 3462, 2929,
2854,1605,1504,1442,1420,1346,1259,1228,1165,1127,1032, 983,
898, 851, 807, 734, 701 cmꢂ1; EIMS m/z 452 [M]þ (100), 255 (70);
HR-EIMS m/z: [M]þ calcd for C30H28O4 452.1988; found m/z
452.1990.
38.1, 55.2, 56.7, 111.2, 111.5, 114.2, 115.4, 117.9, 119.8, 122.3, 123.8,
127.3, 129.4, 130.1, 130.3, 130.5, 130.7, 132.1, 133.1, 134.3, 139.3, 141.1,
145.6, 151.6, 154.4, 158.8, 168.8; IR (ATR) 2921, 2852, 1749, 1606,
1505, 1437, 1418, 1258, 1244, 1197, 1097, 1042, 805, 667, 637,
606 cmꢂ1; EIMS m/z 492 [M]þ (43), 450 (100), 359 (33); HR-EIMS
m/z: [M]þ calcd for C32H28O5 492.1937; found 492.1931. Com-
pound 32: 1H NMR (500 MHz, CDCl3)
d 2.01 (3H, s), 2.56e2.74 (3H,
m), 2.79e2.89 (3H, m), 2.96e3.08 (2H, m), 3.88 (3H, s), 3.95 (3H, s),
5.33 (1H, d, J¼2.0 Hz), 6.51 (1H, dd, J¼2.0, 7.5 Hz), 6.62 (1H, dd,
J¼2.0 Hz), 6.67 (1H, br d, J¼8.0 Hz), 6.74 (1H, br d, J¼8.0 Hz), 6.78
(1H, dd, J¼2.0, 8.5 Hz), 6.79e6.82 (1H, m), 6.81 (1H, dd, J¼2.0,
8.5 Hz), 6.89 (1H, d, J¼8.5 Hz), 6.92 (1H, br s), 6.90e6.95 (1H, m),
6.94 (1H, d, J¼7.5 Hz), 6.95 (1H, d, J¼2.0 Hz), 6.99 (1H, d, J¼8.5 Hz);
4.22. 100-Iodo-dimethylriccardin C (29)
To a solution of 28 (13.4 mg, 29.6
30.0 mol) and NaOH (4.6 mg, 32.9 mol) in MeOH (1.00 mL) was
added NaOCl (6.2 L, 88.8 mol). After stirring at rt for 3 h, the
mmol) and NaI (4.50 mg,
m
m
m
m
reaction mixture was quenched with aq Na2S2O3 and 2 N HCl and
extracted with DCM. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography eluted with
toluene to give 29 (12.9 mg, 75%) as a colorless oil. 1H NMR
13C NMR (125 MHz, CDCl3)
d 20.8, 35.3, 37.2, 37.6, 38.2, 55.3, 56.1,
111.5, 115.5,115.8, 116.5, 121.5, 122.3, 122.5, 122.8, 127.5, 129.2, 129.5,
129.7, 131.5, 132.2, 132.4, 133.4, 139.5, 141.4, 142.5, 146.9, 147.4,
148.5, 152.8, 159.4, 169.3; IR (ATR) 2927, 2855, 1761, 1606, 1505,
1420, 1368, 1261, 1231, 1203, 1128, 1014, 920, 810, 731, 639 cmꢂ1
;
(500 MHz, CDCl3)
d
2.67e2.82 (4H, m), 2.90e3.03 (4H, m), 3.90
EIMS m/z 494 [M]þ (92), 452 (100), 225 (60); HR-EIMS m/z: [M]þ
(3H, s), 3.95 (3H, s), 4.87 (1H, s), 5.36 (1H, d, J¼2.1 Hz), 6.37 (1H, s),
calcd for C32H30O5 494.2093; found 494.2106.
6.79e6.91 (7H, m), 7.03 (1H, d, J¼2.5 Hz), 7.09 (1H, d, J¼9.0 Hz),
7.40 (1H, s); 13C NMR (125 MHz, CDCl3)
d 35.0, 36.1, 38.2, 41.7, 55.4,
4.25. Determination of ee by HPLC
56.1, 89.3, 111.9, 112.7, 116.1, 116.7, 117.9, 121.7, 122.6, 122.9, 126.3,
127.3, 129.0, 129.3, 132.1, 133.1, 139.2, 141.6, 143.7, 143.9, 147.0,
149.0, 152.3, 153.0, 160.2; IR (ATR) 3458, 2947, 1605, 1506, 1420,
1383, 1261, 1230, 1127, 1046, 851, 734 cmꢂ1; EIMS m/z 578 [M]þ
(100), 452 (28); HR-EIMS m/z: [M]þ calcd for C30H27O4I 578.0954;
found 578.0958.
Column¼Kromasil 3-CelluCoat 150 mmꢃ4.6 mm, hexane/
iPrOH¼10:1, flow rate¼1 mL/min.
4.26. Cavicularin (2)
4.23. 100-Iodo-dimethylacetylriccardin C (30)
To a solution of 31 (1.2 mg, 2.43
mmol) in MeOH (1.00 mL) was
added K2CO3 (1.0 mg, 7.31 mol). After stirring at rt for 5 h, the
m
To a solution of 29 (7.0 mg, 12.1
m
mol) and DMAP (1.5 mg,
reaction mixture was quenched with 2 N HCl and extracted with
EtOAc. The combined extracts were washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography eluted with hexane/EtOAc
(4:1) to give dimethylcavicularin (1.1 mg) as colorless oil. Sub-
sequently, to a cooled solution of dimethylcavicularin (1.8 mg,
12.2 mol) in THF (1.00 mL) was added Ac2O (2
m
m
L, 21.2 mol). After
m
stirring at rt for 2 h, the reaction mixture was quenched with satd
NaHCO3 and extracted with EtOAc. The combined extracts were
washed with water and brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography
eluted with hexane/EtOAc (4:1) to give 30 (7.3 mg, 97%) as a col-
39.9
10.2
m
mol) in DCM (1.00 mL) was added BBr3 (1 M DCM solution,
orless oil. 1H NMR (400 MHz, CDCl3)
d
2.03 (3H, s), 2.64 (1H, dd,
mL, 10.2 mol). After stirring at rt for 24 h, the reaction mixture
m
J¼10.6, 10.6 Hz), 2.76e3.00 (7H, m), 3.88 (3H, s), 3.95 (3H, s), 5.27
(1H, d, J¼2.0 Hz), 6.56 (1H, s), 6.76e6.82 (4H, m), 6.87 (1H, dd,
J¼2.8, 8.4 Hz), 6.89e6.93 (2H, m), 6.95 (1H, d, J¼2.8 Hz), 6.97 (1H, d,
was quenched with H2O and extracted with DCM. The combined
extracts were washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography eluted with hexane/EtOAc (7:3) to give 2 (1.2 mg, 71%
over two steps) as an amorphous solid. 1H NMR (500 MHz, CDCl3)
J¼8.8 Hz), 7.58 (1H, s); 13C NMR (100 MHz, CDCl3)
d 20.8, 35.3, 36.5,
38.2, 41.5, 55.3, 56.1, 97.6,111.7,112.0,115.7,121.8,122.5,122.7,124.2,
127.8, 129.4, 129.5, 132.0, 132.8, 133.8, 139.5, 142.6, 143.0, 143.9,
147.0, 147.7, 149.1, 152.7, 159.8, 169.1; IR (ATR) 2933, 1762, 1606,
1506, 1470, 1365, 1260, 1231, 1200, 1150, 1128, 1046, 1010, 909, 852,
730 cmꢂ1; EIMS m/z 620 [M]þ (100), 578 (44); HR-EIMS m/z: [M]þ
calcd for C32H29O5I 620.1060; found 620.1067.
d
2.28 (1H, ddd, J¼3.5, 12.5, 14.0 Hz), 2.55 (1H, ddd, J¼3.5, 12.5,
14.0 Hz), 2.63e2.78 (4H, m), 2.92e2.98 (2H, m), 4.75 (1H, s), 4.85
(1H, s), 6.10 (1H, dd, J¼2.5, 8.5 Hz), 6.12 (1H, s), 6.15 (1H, dd, J¼2.5,
8.5 Hz), 6.40 (1H, s), 6.47 (1H, dd, J¼2.5, 8.5 Hz), 6.68 (1H, s), 6.72
(1H, dd, J¼2.5, 8.5 Hz), 6.76 (1H, dd, J¼2.5, 8.5 Hz), 6.83 (1H, d,
J¼8.5 Hz), 6.88 (1H, d, J¼2.5 Hz), 6.94 (1H, d, J¼8.0 Hz), 6.98 (1H, d,
4.24. Dimethylacetylcavicularin (31)
J¼8.0 Hz); 13C NMR (125 MHz, CDCl3)
d 30.2, 30.5, 37.4, 38.1, 113.0,
113.3, 114.7, 115.1, 116.9, 117.8, 123.0, 123.3, 124.0, 124.0, 127.8, 128.9,
130.0, 131.1, 131.7, 131.7, 135.0, 138.5, 140.5, 141.6, 147.9, 150.2, 153.8,
155.5; IR (ATR) 3394, 2923, 2853, 1605, 1505, 1438, 1238, 1185, 995,
To a solution of 30 (4.0 mg, 6.45
mmol) in DMF (1.00 mL) was
added Ag2CO3 (1.8 mg, 7.09 mol), Pd(OAc)2 (0.3 mg, 1.34
m
mmol),

6968
K. Harada et al. / Tetrahedron 69 (2013) 6959e6968
815, 720, 636, 618, 607 cmꢂ1; EIMS m/z 420 [M]þ (100), 331 (35);
HR-EIMS m/z: [M]þ calcd for C28H22O4 422.1518; found 422.1521.
4. Hioki, H.; Shima, N.; Kawaguchi, K.; Harada, K.; Kubo, M.; Esumi, T.; Nishimaki-
Mogami, T.; Sawada, J.; Hashimoto, T.; Asakawa, Y.; Fukuyama, Y. Bioorg. Med.
Chem. Lett. 2009, 19, 738.
5. Toyota, M.; Yoshida, T.; Kan, Y.; Takaoka, S.; Asakawa, Y. Tetrahedron Lett. 1996,
37, 4745.
6. Recent review for synthetic studies on macrocyclic bisbibenzyls: Harrowven,
Acknowledgements
D. C.; Kostiuk, S. L. Nat. Prod. Rep. 2012, 29, 223.
7. Gottsegen, A.; Nogradi, M.; Vermes, B.; Kajtar-peredy, M.; Bihatsi-karsai, E.
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
We are grateful to Professor Masao Toyota, Tokushima Bunri
University, for providing the spectra of cavicularin. We also thank
Professor Masami Tanaka and Dr. Yasuko Okamoto, Tokushima
Bunri University, for the measurement of NMR and MS spectra. This
work was supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and Technology
of Japan (22590029) and a grant from MEXT-Senryaku.
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1H and 13C NMR spectra for all new compounds. Supplementary
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at http://dx.doi.org/10.1016/j.tet.2013.06.064.
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