Total Synthesis of Kehokorins A-E, Cytotoxic p-Terphenyls

Article abstract of DOI:10.1021/acs.joc.7b00147

This paper describes a general method for the synthesis of kehokorins A-E, novel cytotoxic p-terphenyls. 2,4,6-Trihydroxybenzaldehyde served as a common building block for preparation of the central aromatic ring. Construction of their p-terphenyl skeletons was achieved by a stepwise Suzuki-Miyaura coupling, whereas the phenyldibenzofuran moiety was built up by an intramolecular Ullmann reaction. Introduction of an l-rhamnose residue into partly protected kehokorin B was performed by the trichloroacetimidate method.

Full text of DOI:10.1021/acs.joc.7b00147

Article
pubs.acs.org/joc
Total Synthesis of Kehokorins A−E, Cytotoxic p‑Terphenyls
Shunya Takahashi,*,† Yasuaki Suda,†,‡ Takemichi Nakamura,† Koji Matsuoka,‡ and Hiroyuki Koshino†
†RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan
‡Division of Material Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
S
* Supporting Information
ABSTRACT: This paper describes a general method for the
synthesis of kehokorins A−E, novel cytotoxic p-terphenyls.
2,4,6-Trihydroxybenzaldehyde served as a common building
block for preparation of the central aromatic ring. Con-
struction of their p-terphenyl skeletons was achieved by a
stepwise Suzuki−Miyaura coupling, whereas the phenyl-
dibenzofuran moiety was built up by an intramolecular
Ullmann reaction. Introduction of an L-rhamnose residue
into partly protected kehokorin B was performed by the
trichloroacetimidate method.
mainly determined by extensive NMR analyses, and the
presence of the L-rhamnose residue in 1 was confirmed by
enzymatic degradation studies. These natural products exhibit
cytotoxic activity against the HeLa human epithelial carcinoma
cell line, and the IC50 value of the most potent compound 1
was shown to be 1.5 μg/mL. In the antimicrobial assay, only 1
was reported to show a weak activity against Staphylococcus
aureus. These results suggest the importance of the sugar
residue. Although there are many p-terphenyls in nature, a
phenyldibenzofuran glycoside such as 1 was virtually
unknown.14 In connection with our studies on bioactive p-
terphenyls,15 the unique structure stimulated our interest.
Described herein is the first total synthesis of kehokorins A−E
(1−5), thus confirming the structures of the natural products.
INTRODUCTION
■
Terphenyls are a group of aromatic hydrocarbons consisting of
a chain of three benzene rings. Most of natural products
belonging to this family are p-terphenyls, in which two terminal
aromatic rings connect to the central ring at the p-position, and
are known to be present in fungi and lichens.1 Although their
research history is derived from the discovery of polyporic acid
as a pigment in 1877,2 recent studies have been mainly focused
on their diverse biological activities, such as potent
immunosuppressive,3 neuroprotective,4 antitumor,5 antialler-
gic,6 and 5-lipoxygenase7 inhibitory activities. On the other
hand, the presence of many aromatic sp2 carbons existing in
these molecules makes it difficult to study their structures, and
several papers on structural revision may emphasize the
significance of synthetic studies.8−12 Kehokorins A−E (1−5)
are novel p-terphenyls carrying a dibenzo[b,d]furan as a
common structural motif which were isolated from field-
collected fruit bodies of the myxomycetes Trichia favoginea by
Ishibashi et al. (Figure 1).13 Their p-terphenyl structures were
RESULTS AND DISCUSSION
■
As the most complex molecule in the kehokorin series is
kehokorin A (1), we initially designed a synthetic strategy
directed toward 1 as illustrated in Scheme 1. Removal of the L-
rhamnose residue in the target molecule leads to a benzoylated
L-rhamnose derivative 6 and 8-O-protected kehokorin B 7.
Cleavage of the internal ether linkage can revert 7 back to the
p-terphenyl 8. This could be synthesized by a stepwise Suzuki−
Miyaura coupling16 of 10 with a couple of boronic acid
derivatives, 9 and 11. The formyl group in 10 was introduced
for a regioselective functionalization of the central ring as well
as for an equivalent of a masked hydroxyl group, and 2,4,6-
trihydroxybenzaldehyde (12) was envisaged as the common
starting material. In addition, these retrosynthetic analyses
would enable us to prepare kehokorin C−E (3-5) by changing
the boronic acid derivatives employed in the Suzuki−Miyaura
coupling.
Received: January 20, 2017
Figure 1. Structures of kehokorins A−E (1−5).
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00147
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corresponding methyl ether to afford the central part 15. The
first Suzuki−Miyaura coupling of 15 with boronic acid 11 was
performed by the action of Pd(OAc)2 in the presence of XPhos
and potassium phosphate in aqueous THF, giving a biphenyl
16 in high yield. Its 6-O-benzyl group was removed by
magnesium bromide etherate19 giving 17 quantitatively. Its
triflation afforded a biphenyl block 18 in good yield. Prior to
the second Suzuki−Miyaura coupling, chloroboronic acid 20
was prepared from 5-chlorobenzo[d][1,3]dioxole (19) via
ortho-lithiation20 with LDA followed by trapping with
triisopropylborate. The selection of 20 as a coupling partner
stemmed from the ready availability of the starting material 19
and the expectation of an easy hydrolysis of the methylene
acetal moiety at a later stage.15 The coupling of 18 with 20,
however, gave unsatisfactory results. Among the conditions
tried (Table 1), a combination of Pd(PPh3)4 and potassium
phosphate in anhydrous 1,4-dioxane afforded the desired p-
terphenyl 21 in 24% yield. The low yield made us change the
boronic acid employed in the coupling.
Scheme 1. Synthetic Plan for Kehokorin A (1)
Next, as another precursor of the terminal aromatic ring,
methoxyphenylboronic acid derivavtive 28 with an acyclic
protecting group was designed that would be obtained easily
from 3-bromo-4-chloro-2-methoxyphenol (25)21 (Scheme 3).
It was obtained by a 1,4-addition of HCl to 5-bromo-6,6-
dimethoxycyclohexa-2,4-dien-1-one, but we found this method
to be unsuitable for our purpose because of the low yield (2%).
Therefore, direct chlorination of 22 was attempted. Treatment
with sulfuryl chloride in CHCl3 at 50 °C afforded a ca. 1:1
mixture of a p-chlorophenol derivative 25 and its o-isomer 24 in
78% yield, whereas Gustafson’s method using NCS−Ph3PS22
improved the selectivity (25/24 = 82/18, total 84% yield). As
the authors reported, the use of a BINAP derivative 2323 (0.1
mol equiv) instead of Ph3PS gave the desired product 25 in
high selectivity (25/24 = 93/7). When a small excess of NCS
(∼1.5 mol equiv) was employed according to the original
paper, the ratio of 25 was revealed to decrease due to the
The synthesis of 1 began with preparation of the central part
15. The dibenzyl ether 13 obtained by benzylation17 of 2,4,6-
trihydroxybenzaldehyde (12) was transformed into 14 (Scheme
2) via bromination. The structure, in particular the position of
the newly introduced bromine atom, was confirmed by 2D
NMR analyses.18 The free hydroxyl group was changed to the
Scheme 2. Synthesis of the Central Part 15 and Its
Conversion into p-Terphenyl 21
1
formation of the corresponding dichloride by the H NMR
analysis. Therefore, 1.0 equiv of NCS was employed in this
reaction. The phenol 25 thus obtained was transformed into
the corresponding MOM ether 26. Preparation24 of 28 from 26
was a troublesome step. As a Pd-catalyzed cross-coupling of 26
with bis(pinacolato)diboron25 resulted in a low yield of 28, a
route via transmetalation was examined. Different from the case
of its regioisomer,15b the anion generated by treatment of 26
with n-BuLi was found to be unstable. Consequently, a brief
(<5 min, −78 °C) treatment with the base followed by
immediate addition of 27 was needed to obtain 28 in a practical
yield. The second Suzuki−Miyaura coupling of 18 with the
boronate 28 was also effected by treatment with Pd(PPh3)4 in
the presence of potassium phosphate to give 29 in good yield.
Although the reaction was completed in a short time at a higher
temperature (100−110 °C), hydrolysis of 18 into 17 was
observed. In order to suppress the side reaction, the reaction
was conducted at a low temperature (∼75 °C) for a long time.
Construction of the dibenzo[b,d]furan skeleton was accom-
plished by the method15b previously reported. Thus, 29 was
initially oxidized with mCPBA in the presence of NaHCO3, and
then the resulting formate, without purification, was heated
with Cu2O26 in pyridine to furnish the desired dibenzofuran
derivative 30. Treatment with HCl led to 7. The benzyl group
in 7 was removed by hydrogenolysis with 10% Pd/C to give
kehokorin B (2), the spectral data of which were identical with
those of the natural product.13a On the other hand, the
B
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a
Table 1. Suzuki−Miyaura Coupling of 18 and 20
b
entry
catalyst (mol %)
ligand
base (equiv)
solvent
toluene
temp (°C)
products (% yield)
1
2
3
4
5
6
7
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
PdCl2(dppf) (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
−
−
−
−
Cs2CO3 (2.0)
K3PO4 (1.5)
K3PO4 (1.5)
Cs2CO3 (2.0)
K3PO4 (2.0)
KF (3.3)
110
100
75
17 (60), 21 (20)
complex mixture
21 (24)
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
100
65
17 (23), 21 (10)
c
PPh3
PCy3
PCy3
no reaction
c
THF
rt
no reaction
c
KF (3.3)
THF
55
no reaction
a
b
c
Boronic acid (1.3 equiv) was employed. A 15 mol % portion of ligand was employed. Triflate 18 was recovered in 86−95% yield.
Scheme 3. Total Synthesis of Kehokorins A (1) and B (2)
was isolated as 32 after debenzoylation.35 Finally, debenzylation
of 32 afforded kehokorin A (1). The physical and spectral data
of 1 matched well those of natural kehokorin A.13a
As we could establish a synthetic route to kehokorins A (1)
and B (2), we next turned our attention to kehokorin C (3).
Kehokorin C (3) lacks the 1-methoxy group of kehokorin B
(2). Therefore, boronic acid 33 instead of 28 was employed for
the second Suzuki−Miyaura coupling (Scheme 4). Reaction of
Scheme 4. Total Synthesis of Kehokorin C (3)
18 with 33 was effected by the use of PdCl2(dppf) in the
presence of Cs2CO3 (Table 2) to give p-terphenyl 34 in high
yield. Baeyer−Villiger oxidation of 34 followed by the Ullmann
reaction afforded 35, which underwent debenzylation to give 3,
the spectral data of which were consistent with those of natural
kehokorin C.13a
In a similar way, kehokorins D (4) and E (5) were
synthesized from 15 and 36 (Scheme 5). Thus, a mixture of
both compounds was treated with Pd(OAc)2 in the presence of
XPhos and potassium phosphate, affording biphenyl 37 in good
yield. Debenzylation and triflation of the resulting phenol 38
gave a pivotal intermediate 39. A Pd-catalyzed coupling of 39
with 33 or 40 provided 41 or 42, respectively. Upon the
indicated functionalization, each compound was transformed
into 43 and 44 and then kehokorins D (4) and E (5),
respectively. Spectral data for both compounds were identical
in all respects to those previously reported.13b
In conclusion, we achieved the total synthesis of kehokorin A
(1) through a stepwise Suzuki−Miyaura coupling, Ullmann
reaction, and stereoselective glycosidation as key steps. This
strategy also enabled us to prepare its congeners (2−5) and
therefore would be useful for preparing kehokorin A analogs
with a variety of sugars in aid of SARs. Furthermore, the
structures of the natural products were unambiguously
established by our synthetic work.
introduction of an L-rhamnose unit into 7 was needed for the
preparation of kehokorin A (1). Although several groups
reported the glycosidation employing a phenol with a
benzofuran moiety as a glycosyl acceptor,27−32 no paper has
appeared dealing with such reaction of a dibenzofuran
derivative. We adopted Schmidt’s procedure using 2,3,4-tri-O-
benzoyl-L-rhamnosyl trichloroacetimidate (31)33 as a glycosyl
donor. Reaction of 7 and 31 (2.2 equiv) in the presence of
TMSOTf (0.001 equiv) and MS4A in dichloromethane at −20
°C proceeded nicely to provide a glycosylated product34 in high
yield. This contained a considerable amount of the inseparable
imidate-derived byproducts so that the glycosylated product
C
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Article
a
Table 2. Suzuki−Miyaura Coupling of 18 and 33
b
entry
catalyst (mol %)
ligand
base (equiv)
solvent
temp (°C)
products (% yield)
c
1
1
2
3
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
PdCl2(dppf) (5)
Pd(OAc)2 (5)
−
−
−
Cs2CO3 (2.0)
K3PO4 (1.5)
Cs2CO3 (2.0)
KF (3.3)
toluene
110
75
no reaction
1,4-dioxane
1,4-dioxane
34 (41), 18 (43)
34 (96)
100
65
c
PCy3
THF/H2O (v/v; 12/1)
no reaction
a
b
c
Boronic acid (1.2 equiv) was employed. A 15 mol % portion of ligand was employed. Triflate 18 was recovered in 82−98% yield.
4,6-Bis(benzyloxy)-3-bromo-2-methoxybenzaldehyde (15).
To a stirred suspension of 14 (100 mg, 0.24 mmol) and potassium
carbonate (60.2 mg, 0.435 mmol) in N,N-dimethylformamide (0.5
mL) was added iodomethane (40 μL, 0.61 mmol) at rt, and the
mixture was stirred at rt for 16 h, diluted with water, and then
extracted with ether. The combined organic layers were washed
successively with water and brine and concentrated. The residue was
chromatographed on silica gel (n-hexane−ethyl acetate−dichloro-
methane = 4:1:1) to give 15 (103 mg, quant.) as a crystalline solid: mp
91−92 °C (n-hexane−ethyl acetate); IR (ZnSe) 2942, 2871, 1672,
Scheme 5. Total Synthesis of Kehokorins D (4) and E (5)
1
1578, 1198, 1168, 1101, 734 cm−1; H NMR (500 MHz, CDCl3) δ
10.36 (1H, s), 7.43−7.33 (10H, m), 6.40 (1H, s), 5.15 (2H, s), 5.11
(2H, s), 3.91 (3H, s); 13C NMR (125 MHz, CDCl3) δ 186.9, 161.8,
160.7, 160.5, 135.5, 135.2, 128.6, 128.5, 128.22, 128.20, 126.9, 126.8,
114.2, 100.3, 95.2, 71.0, 62.2; HRMS (EI+) calcd for C22H19BrO4 [M]+
426.0467, found 426.0469.
4,6-Bis(benzyloxy)-3-(p-methoxyphenyl)-2-methoxybenzal-
dehyde (16). To a stirred mixture of 15 (4.08 g, 9.54 mmol), 11
(2.10 g, 13.8 mmol), potassium phosphate (6.10 g, 28.7 mmol), and
XPhos (685 mg, 1.43 mmol) in THF−water (12:1, 165 mL) was
added palladium acetate (107 mg, 0.476 mmol), and the mixture was
stirred at 65 °C for 7 h, cooled, diluted with water, and then extracted
with ethyl acetate. The combined organic layers were washed
successively with water and brine and concentrated. The residue was
chromatographed on silica gel (n-hexane−ethyl acetate−dichloro-
methane = 25:5:1 → 8:2:1) to give 16 (4.07g, 94%) as a crystalline
solid: mp 127−128 °C (n-hexane−ethyl acetate); IR (ZnSe) 2932,
1
1683, 1588, 1452, 1373, 1246, 1153, 1097, 1028, 734 cm−1; H NMR
(500 MHz, CDCl3) δ 10.44 (1H, s), 7.44−7.28 (10H, m), 7.20 (2H,
brd, J = 7.3 Hz), 6.95 (2H, brd, J = 8.9 Hz), 6.39 (1H, s), 5.13 (2H, s),
5.04 (2H, s), 3.86 (3H, s), 3.42 (3H, s); 13C NMR (125 MHz, CDCl3)
δ 188.1, 162.0, 161.8, 161.5, 158.6, 136.08, 136.06, 132.0, 128.7, 128.6,
128.3, 128.1, 128.0, 127.0, 126.5, 124.6, 118.3, 113.3, 94.6, 70.8, 70.4,
61.8, 55.2; HRMS (EI+) calcd for C29H26O5 [M]+ 454.1780, found
454.1778.
EXPERIMENTAL SECTION
General Procedures. All reactions were carried out under an
argon atmosphere, unless otherwise noted. Melting points are
uncorrected. IR spectra were recorded by the ATR method. The
■
1
NMR spectra were recorded at 500 or 600 MHz for H and 125 or
150 MHz for 13C. The 1H chemical shift was referenced to the residual
6-(Benzyloxy)-4-hydroxy-2,4′-dimethoxy-[1,1′-biphenyl]-3-
carbaldehyde (17). To a stirred solution of 16 (912 mg, 2.00 mmol)
in benzene-ether (7:1, 16 mL) was added magnesium bromide ethyl
etherate (622 mg, 2.41 mmol) and the mixture was stirred at 80 °C for
2.5 h and then cooled to rt. After addition of 4 M HCl at 0 °C, the
resulting mixture was stirred at 0 °C → rt for 12 h and then extracted
with ethyl acetate. The combined organic layers were washed
successively with water and brine and concentrated. The residue was
chromatographed on silica gel (n-hexane−ether = 6:1 → 4:1) to give
17 (719 mg, 98%) as an amorphous solid: IR (ZnSe) 3027, 2933,
solvent signal (δH 7.26 for CDCl3 or δH 2.04 for acetone-d6). The 13
C
chemical shift was referenced to the solvent signal (δC 77.0 for CDCl3
or δC 29.8 for acetone-d6). High-resolution mass spectra (HRMS)
were acquired in electron-impact mode (EI) or field desorption mode
(FD) using a time-of-flight mass spectrometer or gas chromatograph
time-of-flight mass spectrometer, respectively. The solvent extracts
were dried with magnesium sulfate, and the solutions were evaporated
under diminished pressure at 35−40 °C.
4,6-Bis(benzyloxy)-3-bromo-2-hydroxybenzaldehyde (14).
To a stirred solution of 13 (1.23 g, 3.69 mmol) in dichloromethane
(12 mL) was added dropwise bromine (0.19 mL, 3.7 mmol) at 0 °C
and the mixture was stirred at 0 °C for 1 h. After being quenched with
addition of saturated aqueous Na2S2O3, the resulting mixture was
extracted with ethyl acetate. The combined organic layers were washed
successively with saturated aqueous NaHCO3, water, and brine and
concentrated. The residue was treated with n-hexane−dichloro-
methane to give 14 (1.33 g, 87%) as a crystalline solid: mp 149−
150 °C (n-hexane−ethyl acetate); IR (ZnSe) 3031, 2880, 1634, 1604,
1
1632, 1607, 1578, 1289, 1245, 1176, 1095, 800, 775 cm−1; H NMR
(500 MHz, CDCl3) δ 12.26 (1H, s), 10.10 (1H, s), 7.34−7.23 (7H,
m), 6.96 (2H, d, J = 8.8 Hz), 6.32 (1H, s), 5.09 (2H, s), 3.86 (3H, s),
3.40 (3H, s); 13C NMR (125 MHz, CDCl3) δ 193.2, 164.43, 164.39,
162.0, 158.7, 135.8, 132.0, 128.6, 127.9, 126.5, 124.4, 115.9, 113.5,
109.2, 96.4, 70.3, 62.1, 55.2; HRMS (EI+) calcd for C22H20O5 [M]+
364.1311, found 364.1314.
6-(Benzyloxy)-3-formyl-2,4′-dimethoxy-[1,1′-biphenyl]-4-yl
Trifluoromethanesulfonate (18). To a stirred solution of 17 (50.5
mg, 0.139 mmol) in N,N-dimethylformamide (1.3 mL) were added N-
phenylbis(trifluoromethanesulfonimide) (54.5 mg, 0.152 mmol) and
potassium carbonate (21.0 mg, 0.152 mmol) at −17 °C, and the
mixture was stirred at −17 °C → rt for 6.5 h, poured into ice−water,
and then extracted with ether. The combined organic layers were
washed with water (2×) and brine and concentrated to give a white
1411, 1384, 1293, 1217, 1123, 1092, 722 cm−1; H NMR (600 MHz,
1
CDCl3) δ 12.94 (1H, s), 10.15 (1H, s), 7.41−7.36 (10H, m), 6.12
(1H, s), 5.19 (2H, s), 5.09 (2H, s); 13C NMR (150 MHz, CDCl3) δ
191.8, 162.7, 162.2, 161.5, 135.4, 135.3, 128.9, 128.8, 128.6, 128.4,
127.4, 126.9, 106.8, 91.8, 90.1, 71.1, 71.0; HRMS (EI+) calcd for
C21H17BrO4 [M]+ 412.0310, found 412.0309.
D
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Article
solid, which was treated with dichloromethane−ether to afford 18
(61.4 mg, 86%) as white needles. The mother liquid was chromato-
graphed on silica gel (n-hexane−ethyl acetate = 10:1 → 4:1) to give
additional 18 (5.4 mg, 8%) as white needles: mp 163−164 °C (n-
hexane−ethyl acetate); IR (ZnSe) 3027, 2954, 1692, 1595, 1427, 1189,
1122, 1028, 733 cm−1; 1H NMR (500 MHz, CDCl3) δ 10.28 (1H, s),
7.37−7.22 (7H, m), 7.00 (2H, d, J = 8.9 Hz), 6.67 (1H, s), 5.11 (2H,
s), 3.88 (3H, s), 3.44 (3H, s); 13C NMR (125 MHz, CDCl3) δ 186.5,
162.9, 161.5, 159.4, 147.7, 135.1, 131.6, 128.7, 128.3, 126.6, 125.2,
122.9, 118.7 (q, JCF = 321.4 Hz), 116.5, 113.7, 103.6, 71.1, 62.5, 55.3;
HRMS (EI+) calcd for C23H19F3O7S [M]+ 496.0804, found 496.0798.
(5-Chlorobenzo[d][1,3]dioxol-4-yl)boronic Acid (20). To a
stirred solution of lithium diisopropylamide (LDA) prepared from
diisopropylamine (0.77 mL, 5.5 mmol) and n-butyllithium (1.6 M in n-
hexane, 3.43 mL, 5.50 mmol) in tetrahydrofuran (15 mL) was added
dropwise a solution of 19 (0.79 g, 5.0 mmol) in tetrahydrofuran (0.6
mL) at −78 °C. After 15 min, triisopropylborate (1.44 mL, 6.25 mL)
was added, and the mixture was stirred at −78 °C for 10 min and then
gradually warmed to 0 °C over 2 h with stirring. After addition of cold
1 M HCl, the resulting mixture was stirred vigorously for 15 min and
then extracted with ethyl acetate. The combined organic layers were
washed successively with water and brine and concentrated. The
residue was chromatographed on silica gel (n-hexane−ethyl acetate =
4:1 → 2:1 → 1:1) to give 20 (526 mg, 52%) as an amorphous solid: IR
(ZnSe) 3325, 2900, 1630, 1430, 1230, 1038, 947, 794 cm−1; 1H NMR
(500 MHz, CDCl3) δ 6.90 (1H, d, J = 8.3 Hz), 6.83 (1H, d, J = 8.3
Hz), 6.08 (2H, s), 5.95 (2H, s); 13C NMR (125 MHz, CDCl3) δ
153.7, 145.7, 130.2, 123.3, 111.3, 101.7; HRMS (EI+) calcd for
C7H6ClO4B [M]+ 200.0048, found 200.0039.
6-(Benzyloxy)-4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-2,4′-di-
methoxy-[1,1′-biphenyl]-3-carbaldehyde (21). To a stirred
mixture of 18 (15 mg, 30 μmol), 20 (8.0 mg, 39 μmol), and
potassium phosphate (9.0 mg, 45 μmol) in dioxane (0.5 mL) was
added tetrakis(triphenylphosphine)palladium (1.7 mg, 1.4 μmol), and
the mixture was stirred at 75 °C for 6.5 h, cooled, and concentrated.
The residue was purified by preparative TLC (n-hexane−ethyl acetate
= 4:1, and then benzene−ether = 30:1, two developments) to give 21
(3.7 mg, 24%) as a foam: IR (ZnSe) 2925, 2853, 1685, 1547, 1438,
1238, 1102, 932, 800, 734 cm−1; 1H NMR (500 MHz, CDCl3) δ 10.21
(1H, s), 7.45 (2H, d, J = 8.8 Hz), 7.31−7.22 (5H, m), 6.99 (2H, d, J =
8.8 Hz), 6.95 (1H, d, J = 8.3 Hz), 6.78 (1H, d, J = 8.3 Hz), 6.74 (1H,
s), 5.95 (1H, d, J = 1.5 Hz), 5.94 (1H, d, J = 1.5 Hz), 5.12 (2H, s),
3.88 (3H, s), 3.46 (3H, s); 13C NMR (125 MHz, CDCl3) δ 189.4,
162.3, 160.4, 158.9, 146.1, 146.0, 136.0, 135.5, 131.8, 128.5, 127.8,
126.6, 125.15, 125.11, 124.2, 122.0, 121.9, 121.1, 113.4, 111.7, 108.3,
101.8, 70.4, 62.1, 55.2; HRMS (EI+) calcd for C29H23ClO6 [M]+
502.1183, found 502.1183.
at 0 °C, and then the mixture was stirred at 0 °C → rt for 1.2 h. After
being quenched with addition of saturated aqueous NaHCO3, the
resulting mixture was extracted with ethyl acetate. The combined
organic layers were washed successively with water and brine and
concentrated. The residue was chromatographed on silica gel (n-
hexane−ether = 8:1) to give 26 (180 mg, 90%) as a syrup: IR (ZnSe)
2930, 1468, 1156, 1082, 992, 877 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.16 (1H, d, J = 9.1 Hz), 7.06 (1H, d, J = 9.1 Hz), 5.20 (2H, s), 3.88
(3H, s), 3.51 (3H, s); 13C NMR (125 MHz, CDCl3) δ 149.7, 148.8,
128.1, 125.1, 119.0, 116.4, 95.5, 60.7, 56.4; HRMS (EI+) calcd for
C9H10BrClO3 [M]+ 279.9502, found 279.9496.
2-(6-Chloro-2-methoxy-3-(methoxymethoxy)phenyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28). To a stirred
solution of 26 (377 mg, 1.34 mmol) in tetrahydrofuran (4.7 mL)
was added dropwise a 1.1 M solution of n-butyllithium (1.28 mL, 1.41
mmol) in hexane at −78 °C. After 5 min, 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (27) (0.38 mL, 1.9 mmol) was added,
and the mixture was stirred at −78 °C for 1 h and then gradually
warmed to 0 °C over 1 h with stirring. After addition of water, the
resulting mixture was extracted with ethyl acetate. The combined
organic layers were washed successively with water and brine and
concentrated. The residue was chromatographed on silica gel
(dichloromethane−ether = 200:1 → 0:1) to give 28 (229 mg, 52%)
as a syrup: IR (ZnSe) 2976, 1459, 1319, 1254, 1157, 1143, 998 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.05 (1H, d, J = 8.8 Hz), 6.98 (1H, d, J
= 8.8 Hz), 5.16 (2H, s), 3.85 (3H, s), 3.48 (3H, s), 1.40 (12H, s); 13C
NMR (125 MHz, CDCl3) δ 152.9, 148.2, 129.6, 124.7, 119.0, 95.3,
84.6, 61.5, 56.2, 24.7; HRMS (EI+) calcd for C15H22ClO5B [M]+
328.1249, found 328.1252.
5′-(Benzyloxy)-6-chloro-2,3′,4″-trimethoxy-3-(methoxyme-
thoxy)-[1,1′:4′,1″-terphenyl]-2′-carbaldehyde (29). To a stirred
mixture of 18 (185 mg, 0.372 mmol), 28 (147 mg, 0.447 mmol), and
potassium phosphate (119 mg, 0.561 mmol) in dioxane (3.5 mL) was
added tetrakis(triphenylphosphine)palladium (34 mg, 29 μmol), and
the mixture was stirred at 75 °C for 10 h, cooled, diluted with water,
and then extracted with ethyl acetate. The combined organic layers
were washed successively with water and brine and concentrated. The
residue was chromatographed on silica gel (n-hexane−ethyl acetate =
10:1 → 8:1 → 6:1) to give 29 (169 mg, 82%) as a foam: IR (ZnSe)
2934, 2833, 1685, 1547, 1463, 1364, 1244, 1114, 1002, 805, 739 cm−1;
1H NMR (500 MHz, CDCl3) δ 10.20 (1H, s), 7.49 (2H, d, J = 8.8
Hz), 7.31−7.21 (5H, m), 7.16 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.8
Hz), 7.01 (2H, d, J = 8.8 Hz), 6.65 (1H, s), 5.26 (1H, d, J = 6.6 Hz),
5.23 (1H, d, J = 6.6 Hz), 5.12 (1H, d, J = 11.3 Hz), 5.08 (1H, d, J =
11.3 Hz), 3.88 (3H, s), 3.56 (3H, s), 3.55 (3H, s), 3.48 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 189.4, 162.1, 160.3, 158.9, 149.1, 147.9,
138.4, 136.1, 134.1, 131.9, 128.4, 127.7, 126.5, 125.8, 124.6, 124.4,
122.0, 116.8, 113.3, 111.5, 95.4, 70.3, 62.1, 60.7, 56.3, 55.2; HRMS
(FD+) calcd for C31H29ClO7 [M]+ 548.1602, found 548.1605.
3-Bromo-6-chloro-2-methoxyphenol (24) and 3-Bromo-4-
chloro-2-methoxyphenol (25). To a stirred solution of 22 (200 mg,
0.985 mmol) and (R)-[1,1′-binaphthalene]-2,2′-diylbis-
(diphenylphosphine sulfide) (23) (68 mg, 99 μmol) in dichloro-
methane (1 mL) was added N-chlorosuccinimide (132 mg, 0.989
mmol) by portions, and the mixture was stirred at rt in the dark for 14
h and then directly poured into a column of silica gel (n-hexane).
Elution with n-hexane−ethyl acetate (1:0 → 20:1 → 10:1) gave 24
(10.7 mg, 5%) and 25 (158 mg, 67%).
8-(Benzyloxy)-1,6-dimethoxy-2-(methoxymethoxy)-7-(4-
methoxyphenyl)dibenzo[b,d]furan (30). To a stirred suspension
of 29 (43 mg, 78 μmol) and NaHCO3 (33 mg, 0.39 mmol) in
dichloromethane (1.2 mL) was added dropwise a solution of mCPBA
(70−75% assay; 100 mg, ca. 400 μmol) in dichloromethane (1.5 mL)
at 0 °C, and the mixture was stirred at 0 °C for 1 h. After being
quenched with saturated aqueous Na2S2O3, the resulting mixture was
extracted with ethyl acetate. The combined organic layers were washed
successively with saturated aqueous NaHCO3, water, and brine, dried,
and concentrated to give a solid (47.7 mg) which was dissolved in
pyridine (2.5 mL). Cu2O (56.2 mg, 0.393 mmol) was added, and the
mixture was heated under reflux with stirring for 5 h, cooled, and then
filtered through a pad of Celite. The filtrate was concentrated to give a
solid, which was chromatographed on silica gel (n-hexane−ethyl
acetate = 5:1 → 4:1) to give 30 (21.4 mg, 54%) as an amorphous
24: syrup; IR (ZnSe) 3382, 2952, 1455, 1415, 1201, 1142, 996, 786
1
cm−1; H NMR (500 MHz,CDCl3) δ 7.03 (1H, d, J = 8.8 Hz), 6.99
(1H, d, J = 8.8 Hz), 5.91 (1H, s), 3.93 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 146.6, 145.3, 125.8, 124.1, 119.9, 114.8, 61.1; HRMS (EI+)
calcd for C7H6BrClO2 [M]+ 235.9240, found 235.9243.
25: syrup; IR (ZnSe) 3408, 2940, 1576, 1466, 994, 896, 839, 809
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.15 (1H, d, J = 8.8 Hz), 6.89
(1H, d, J = 8.8 Hz), 5.68 (1H, brs), 3.91 (3H, s); 13C NMR (125
MHz, CDCl3) δ 148.4, 145.6, 126.05, 125.99, 117.1, 115.3, 61.1;
HRMS (EI+) calcd for C7H6BrClO2 [M]+ 235.9240, found 235.9236.
2-Bromo-1-chloro-3-methoxy-4-(methoxymethoxy)benzene
(26). To a stirred solution of 25 (168 mg, 0.707 mmol) and N,N-
diisopropylethylamine (0.22 mL, 1.3 mmol) in dichloromethane (1.5
mL) was added dropwise methoxymethyl chloride (70 μL, 0.92 mmol)
1
solid: IR (ZnSe) 2933, 1497, 1427, 1245, 1070, 1050, 831 cm−1; H
NMR (500 MHz, CDCl3) δ 7.43−7.41 (3H, m), 7.31−7.22 (7H, m),
7.00 (2H, brd, J = 8.8 Hz), 5.25 (2H, s), 5.08 (2H, s), 4.01 (3H, s),
3.95 (3H, s), 3.88 (3H, s), 3.59 (3H, s); 13C NMR (125 MHz, CDCl3)
δ 158.6, 152.9, 152.8, 145.15, 145.10, 143.4, 142.9, 137.4, 132.1, 128.4,
127.5, 126.9, 126.2, 123.6, 123.5, 118.8, 118.1, 113.3, 107.0, 101.9,
E
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The Journal of Organic Chemistry
Article
96.9, 71.6, 61.0, 60.8, 56.4, 55.2; HRMS (EI+) calcd for C30H28O7
[M]+ 500.1835, found 500.1835.
152.3, 146.2, 145.6, 143.7, 143.2, 133.0, 127.0, 124.5, 122.2, 119.4,
119.3, 114.1, 107.5, 103.3, 101.9, 73.6, 72.5, 71.9, 70.5, 61.3, 60.8, 55.5,
18.1; HRMS (FD+) calcd for C27H28O10 [M]+ 512.1683, found
512.1693.
8-(Benzyloxy)-1,6-dimethoxy-2-hydroxy-7-(4-methoxy-
phenyl)dibenzo[b,d]furan (7). Treatment of 30 (40.4 mg, 80.7
μmol) in dichloromethane (1.5 mL) with a 10% HCl solution in
methanol (1.5 mL) at rt for 1 h gave, after evaporation, a solid, which
was diluted with ethyl acetate; washed successively with saturated
aqueous NaHCO3, water, and brine; and concentrated. The residue
was chromatographed on silica gel (n-hexane−ethyl acetate = 4:1) to
give 7 (36.8 mg, quant.) as an amorphous solid: IR (ZnSe) 3390,
5,5′-Bis(benzyloxy)-2-chloro-3′,4″-dimethoxy-[1,1′:4′,1″-ter-
phenyl]-2′-carbaldehyde (34). To a stirred mixture of 18 (15 mg,
30 μmol), 33 (9.5 mg, 36 μmol), and cesium carbonate (20 mg, 61
μmol) in dioxane (0.5 mL) was added PdCl2(dppf) (1.8 mg, 2.4
μmol), and the mixture was stirred at 100 °C for 10 h, cooled, and
then concentrated. The residue was directly chromatographed on silica
gel (n-hexane−ethyl acetate = 8:1 → 4:1 → 0:1) to give 34 (16.4 mg,
96%) as a foam: IR (ZnSe) 3061, 3031, 2933, 2833, 1685, 1547, 1452,
1
2925, 1428, 1245, 1070, 1029, 803, 735 cm−1; H NMR (500 MHz,
CDCl3) δ 7.43 (2H, brd, J = 8.8 Hz), 7.31−7.28 (6H, m), 7.24 (1H,
brd, J = 8.8 Hz), 7.07 (1H, brd, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz),
5.46 (1H, s), 5.08 (2H, s), 3.96 (3H, s), 3.91 (3H, s), 3.89 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 158.7, 152.8, 151.5, 144.1, 143.6, 143.1,
140.4, 137.4, 132.0, 128.4, 127.6, 126.9, 126.1, 123.8, 122.6, 117.7,
115.0, 113.3, 107.9, 101.9, 71.8, 61.2, 60.8, 55.2; HRMS (EI+) calcd for
C28H24O6 [M]+ 456.1573, found 456.1579.
1
1243, 1166, 1011, 735 cm−1; H NMR (500 MHz, CDCl3) δ10.12
(1H, s), 7.47−7.22 (8H, m), 7.00 (2H, brd, J = 8.5 Hz), 6.96 (1H, dd,
J = 8.8, 3.2 Hz), 6.87 (1H, d, J = 3.2 Hz), 6.66 (1H, s), 5.10, 5.08 (2H,
each d, J = 12.2 Hz), 5.04 (2H, s), 3.88 (3H, s), 3.48 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 189.5, 161.6, 160.3, 158.9, 157.2, 142.6,
139.7, 136.4, 136.0, 131.9, 130.0, 128.6, 128.5, 128.1, 127.8, 127.6,
126.6, 124.8, 124.4, 124.3, 121.8, 116.8, 115.6, 113.4, 111.1, 70.4, 70.3,
62.0, 55.2; HRMS (FD+) calcd for C35H29ClO5 [M]+ 564.1704, found
564.1741.
Kehokorin B (2). To a stirred solution of 7 (4.5 mg, 10 μmol) in
methanol (0.3 mL) was added 10% palladium on carbon (1.0 mg).
The mixture was stirred vigorously under a hydrogen atmosphere at rt
for 5 h, filtered through a pad of Celite, and then concentrated. The
residue was chromatographed on silica gel (benzene−ethyl acetate =
20:1) to give 2 (3.4 mg, 94%) as an amorphous solid: IR (ZnSe) 3513,
2,8-Bis(benzyloxy)-4-methoxy-3-(4-methoxyphenyl)-
dibenzo[b,d]furan (35). As described for the preparation of 30 from
29, treatment of 34 (42.7 mg, 75.6 μmol) with mCPBA (70−75%
assay; 37 mg, ca. 0.15 mmol) in dichloromethane (0.66 mL) afforded
the corresponding formate (44.1 mg), which was treated with Cu2O
(54.0 mg, 378 μmol) in pyridine (2.7 mL) at 110 °C for 4 h. The usual
workup followed by chromatography on silica gel (benzene−ethyl
acetate = 50:0 → 20:1) gave 35 (16.5 mg, 42%) as an amorphous
solid: IR (ZnSe) 3066, 3031, 2942, 2834, 1601, 1430, 1246, 1182,
1
3392, 2939, 2832, 1498, 1427, 1248, 1164, 1056, 953 cm−1; H NMR
(500 MHz, acetone-d6) δ 7.39 (1H, s), 7.36 (2H, brd, J = 8.8 Hz), 7.19
(1H, d, J = 8.8 Hz), 7.06 (1H, d, J = 8.8 Hz), 6.98 (2H, brd, J = 8.8
Hz), 4.02 (3H, s), 3.90 (3H, s), 3.84 (3H, s); 13C NMR (125 MHz,
acetone-d6) δ 159.8, 152.0, 151.9, 145.9, 143.7, 143.2, 142.5, 133.0,
127.1, 124.5, 121.9, 119.0, 117.3, 114.1, 107.6, 103.2, 60.9, 60.7, 55.5;
HRMS (EI+) calcd for C21H18O6 [M]+ 366.1103, found 366.1114.
Glycoside 32. To a stirred suspension of 7 (36.8 mg, 80.6 μmol),
31 (109 mg, 0.176 mmol), and MS4A (130 mg) in dichloromethane
(4.0 mL) was added trimethylsilyl trifluoromethanesulfonate (0.01
mL, 0.06 μmol) at −20 °C. After 30 min, more trimethylsilyl
trifluoromethanesulfonate (0.01 mL, 0.06 μmol) was added and
stirring was continued for additional 15 min. Triethylamine (0.11 mL,
0.79 mmol) was added, and the mixture was stirred at −10 °C for 15
min and then concentrated. The residue was passed through a short
column of silica gel (n-hexane−ethyl acetate = 8:1 → 4:1) to give a
solid (88.7 mg) which was dissolved in methanol−dichloromethane
(2:1, 1.5 mL). A 1.0 M solution of sodium methoxide in methanol
(0.02 mL) was added at rt, and the mixture was stirred at rt for 1 h,
made neutral with Dowex 50W X-8 (H+) resin, and filtered, and the
filtrate was concentrated. The residue was chromatographed on silica
gel (chloroform−methanol = 100:1 → 50:1 → 20:1) to give 32 (42.4
mg, 87%) as an amorphous solid: [α]2D5 −49 (c 0.41, CHCl3); IR
(ZnSe) 3406, 2973, 2912, 1236, 1087, 878 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.36 (2H, brd, J = 8.8 Hz), 7.31 (1H, s), 7.25−7.14 (7H,
m), 6.97 (2H, brd, J = 8.8 Hz), 5.56 (1H, brs), 4.98 (2H, s), 4.39 (1H,
brs), 4.20 (1H, brd, J = 7.8 Hz), 4.04 (1H, m), 3.93 (3H, s), 3.89 (3H,
s), 3.86 (3H, s), 3.76 (1H, m), 1.39 (3H, d, J = 5.8 Hz); 13C NMR
(125 MHz, CDCl3) δ 158.7, 153.0, 152.9, 144.8, 144.2, 143.4, 142.9,
137.3, 132.0, 128.3, 127.5, 126.9, 126.0, 123.8, 123.1, 119.0, 117.7,
113.3, 107.2, 101.7, 100.3, 73.2, 71.8, 71.5, 71.2, 69.3, 61.1, 60.7, 55.2,
17.6; HRMS (FD+) calcd for C34H34O10 [M]+ 602.2152, found
602.2125.
Kehokorin A (1). According to the method described for the
preparation of 2 from 7, compound 32 (12 mg, 20 μmol) was
hydrogenated over 10% palladium on carbon (2.0 mg) in methanol−
ethyl acetate (5:2, 0.7 mL) for 7 h and upon purification by
chromatography on silica gel (dichloromethane−methanol =100:1 →
50:1 → 10:1) gave 1 (9.4 mg, 92%) as an amorphous solid: [α]2D5 −54
(c 0.31, methanol); lit.13a [α]2D5 −49 (c 0.50, methanol); IR (ZnSe)
3406, 2919, 1236, 1088, 884, 830 cm−1; 1H NMR (500 MHz, acetone-
d6) δ 8.00 (1H, brs), 7.42 (1H, s), 7.37 (1H, d, J = 8.8 Hz), 7.36 (2H,
d, J = 8.8 Hz), 7.29 (1H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.47
(1H, s), 4.19 (1H, brs), 4.07 (3H, s), 3.94 (1H, brdd, J = 9.3, 2.5 Hz),
3.91 (3H, s), 3.89 (1H, m), 3.84 (3H, s), 3.53 (1H, t, J = 9.3 Hz), 1.23
(3H, d, J = 6.1 Hz); 13C NMR (125 MHz, acetone-d6) δ 159.8, 153.7,
1
1151, 1027, 737 cm−1; H NMR (500 MHz, CDCl3) δ 7.51−7.24
(14H, m), 7.21 (1H, s), 7.12 (1H, dd, J = 8.8, 2.5 Hz), 6.99 (2H, d, J =
8.6 Hz), 5.17 (2H, s), 5.07 (2H, s), 3.98 (3H, s), 3.88 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 158.6, 154.9, 152.8, 151.5, 143.9, 143.2,
137.3, 137.0, 132.1, 128.6, 128.4, 128.0, 127.6, 127.5, 126.8, 126.2,
124.9, 124.7, 123.7, 116.0, 113.2, 112.3, 104.9, 99.3, 71.5, 71.0, 60.8,
55.2; HRMS (EI+) calcd for C34H28O5 [M]+ 516.1937, found
516.1943.
Kehokorin C (3). According to the method described for the
preparation of 2 from 7, compound 35 (14.3 mg, 27.7 μmol) was
hydrogenated over 10% palladium on carbon (4.0 mg) in
tetrahydrofuran (1.0 mL) for 23 h and upon purification by
preparative TLC (benzene−ethyl acetate = 10:1, three developments)
gave 3 (7.6 mg, 81%) as an amorphous solid: IR (ZnSe) 3533, 3370,
2930, 2850, 1173, 1147, 1047, 796 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.41 (1H, d, J = 8.8 Hz), 7.36 (2H, brd, J = 8.8 Hz), 7.31
(1H, d, J = 2.4 Hz), 7.17 (1H, s), 7.07 (2H, brd, J = 8.8 Hz), 6.96 (1H,
dd, J = 8.8, 2.4 Hz), 4.92 (1H, s), 4.76 (1H, brs), 4.01 (3H, s), 3.89
(3H, s); 13C NMR (125 MHz, CDCl3) δ 159.6, 151.5, 151.2, 149.3,
142.9, 142.5, 131.9, 125.5, 125.1, 124.2, 119.9, 115.5, 114.8, 112.2,
106.2, 99.8, 60.8, 55.3; HRMS (EI+) calcd for C20H16O5 [M]+
336.0998, found 336.1004.
4,6-Bis(benzyloxy)-3-phenyl-2-methoxybenzaldehyde (37).
According to the procedure described for the preparation of 16, a
mixture of 15 (50.0 mg, 0.117 mmol) and 36 (20.0 mg, 0.164 mmol)
in THF−water (12:1, 2.0 mL) was treated with palladium acetate (1.3
mg, 5.7 μmol) in the presence of potassium phosphate (75 mg, 0.35
mmol) and XPhos (8.5 mg, 18 μmol) at 65 °C for 10 h. The usual
workup followed by chromatography on silica gel (benzene−ethyl
acetate = 100:1 → 50:1) gave 37 (44.5 mg, 89%) as an amorphous
solid: IR (ZnSe) 2931, 2856, 1672, 1579, 1173, 1096, 1009, 733 cm−1;
1H NMR (500 MHz, CDCl3) δ 10.44 (1H, s), 7.46−7.40 (8H, m),
7.37−7.28 (5H, m), 7.19 (2H, brd, J = 8.1 Hz), 6.40 (1H, s), 5.14 (2H,
s), 5.04 (2H, s), 3.43 (3H, s); 13C NMR (125 MHz, CDCl3) δ 188.0,
161.83, 161.75, 161.7, 136.0, 132.5, 130.9, 128.7, 128.55, 128.47,
128.12, 128.06, 127.9, 127.8, 127.2, 127.0, 126.4, 118.7, 113.2, 94.5,
70.8, 70.3, 61.9; HRMS (EI+) calcd for C28H24O4 [M]+ 424.1675,
found 424.1665.
6-(Benzyloxy)-4-hydroxy-2-methoxy-[1,1′-biphenyl]-3-car-
baldehyde (38). According to the procedure described for the
F
DOI: 10.1021/acs.joc.7b00147
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Article
preparation of 17, compound 37 (338 mg, 0.796 mmol) was treated
with magnesium bromide ethyl etherate (268 mg, 1.04 mmol) in
benzene−ether (7:1, 16 mL) at 80 °C for 3 h. The usual workup
followed by chromatography on silica gel (n-hexane−ethyl acetate =
1:0 → 15:1) gave 38 (235 mg, 88%) as a crystalline solid: mp 120−
121 °C (n-hexane−ether); IR (ZnSe) 3024, 2939, 2867, 1603, 1362,
Hz), 7.18 (1H, s), 6.96 (1H, dd, J = 8.8, 2.7 Hz), 4.91 (1H, s), 4.88
(1H, s), 4.02 (3H, s); 13C NMR (125 MHz, CDCl3) δ 151.5, 151.3,
149.1, 142.8, 142.4, 132.5, 130.7, 129.3, 128.4, 125.8, 125.0, 120.2,
115.6, 112.2, 106.2, 100.1, 60.8; HRMS (EI+) calcd for C19H14O4 [M]+
306.0892, found 306.0880.
5′-Benzyloxy-2-chloro-5,3′-dimethoxy-[1,1′:4′,1″-terphen-
yl]-2′-carbaldehyde (42). According to the procedure described for
the preparation of 34, a mixture of 39 (50.0 mg, 0.107 mmol) and 40
(26.0 mg, 0.139 mmol) in dioxane (1.6 mL) was treated with
PdCl2(dppf) (6.3 mg, 8.6 μmol) in the presence of cesium carbonate
(70 mg, 0.21 mmol) at 95 °C for 10 h. The usual workup followed by
chromatography on silica gel (n-hexane−ethyl acetate = 15:1 → 8:1)
gave 42 (36.5 mg, 74%) as a crystalline solid: mp 136−138 °C (n-
hexane−ether); IR (ZnSe) 3029, 2935, 1684, 1542, 1366, 1137, 1020,
1
1265, 1172, 1052, 1004, 943, 811, 734 cm−1; H NMR (500 MHz,
CDCl3) δ 12.28 (1H, s), 10.11 (1H, s), 7.44−7.26 (8H, m), 7.21 (2H,
brd, J = 8.1 Hz), 6.33 (1H, s), 5.10 (2H, s), 3.40 (3H, s); 13C NMR
(125 MHz, CDCl3) δ 193.2, 164.6, 164.3, 162.0, 135.8, 132.4, 131.0,
128.5, 128.0, 127.9, 127.3, 126.5, 116.4, 109.2, 96.5, 70.3, 62.3; HRMS
(EI+) calcd for C21H18O4 [M]+ 334.1205, found 334.1195.
6-(Benzyloxy)-3-formyl-2-methoxy-[1,1′-biphenyl]-4-yl Tri-
fluoromethanesulfonate (39). According to the procedure
described for the preparation of 18, compound 38 (181 mg, 0.541
mmol) was treated with N-phenylbis(trifluoromethanesulfonimide)
(213 mg, 0.596 mmol) and potassium carbonate (82 mg, 0.60 mmol)
at −20 °C for 3.5 h. The usual workup followed by chromatography
on silica gel (dichloromethane−ether = 1:0 → 15:1) gave 39 (253 mg,
quant.) as a crystalline solid: mp 146−148 °C (n-hexane−ethyl
acetate); IR (ZnSe) 3061, 2947, 2897, 1692, 1595, 1427, 1200, 1117,
1036, 987, 843, 733 cm−1; 1H NMR (500 MHz, CDCl3) δ 10.29 (1H,
s), 7.50−7.43 (5H, m), 7.36−7.29 (3H, m), 7.23 (2H, brd, J = 7.8 Hz),
6.70 (1H, s), 5.12 (2H, s), 3.44 (3H, s); 13C NMR (125 MHz, CDCl3)
δ 186.5, 162.9, 161.4, 148.0, 135.0, 131.0, 130.3, 128.7, 128.4, 128.3,
128.2, 128.1, 126.5, 125.5, 118.6 (q, JCF = 320.5 Hz), 116.4, 103.5,
71.0, 62.7; HRMS (EI+) calcd for C22H17F3O6S [M]+ 466.0698, found
466.0689.
5,5′-Bis(benzyloxy)-2-chloro-3′-methoxy-[1,1′:4′,1″-ter-
phenyl]-2′-carbaldehyde (41). According to the procedure
described for the preparation of 34, a mixture of 39 (50.0 mg, 0.107
mmol) and 33 (37.0 mg, 0.139 mmol) in dioxane (1.6 mL) was
treated with PdCl2(dppf) (6.3 mg, 8.6 μmol) in the presence of cesium
carbonate (70 mg, 0.21 mmol) at 95 °C for 4 h. The usual workup
followed by chromatography on silica gel (n-hexane−ethyl acetate =
100:0 → 20:1 → 10:1) gave 41 (50.7 mg, 88%) as a crystalline solid:
mp 134−135 °C (n-hexane−ethyl acetate); IR (ZnSe) 3031, 2939,
1684, 1546, 1371, 1266, 1145, 1013, 733 cm−1; H NMR (500 MHz,
CDCl3) δ 10.13 (1H, s), 7.52 (2H, brd, J = 8.6 Hz), 7.48−7.34 (9H,
m), 7.32−7.25 (3H, m), 7.20 (2H, brd, J = 8.3 Hz), 6.97 (1H, dd, J =
8.8, 3.2 Hz), 6.89 (1H, d, J = 3.2 Hz), 6.67 (1H, s), 5.11, 5.08 (2H,
each d, J = 12.5 Hz), 5.05 (2H, s), 3.49 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 189.4, 161.5, 160.1, 157.3, 143.0, 139.7, 136.4, 136.0, 132.3,
130.7, 130.0, 128.6, 128.5, 128.1, 127.9, 127.8, 127.56, 127.52, 126.5,
125.2, 124.4, 121.7, 116.8, 115.6, 111.1, 70.3, 62.2; HRMS (FD+) calcd
for C34H27ClO4 [M]+ 534.1598, found 534.1566.
1
733 cm−1; H NMR (500 MHz, CDCl3) δ 10.12 (1H, s), 7.52 (2H,
brd, J = 8.0 Hz), 7.47 (2H, brt, J = 7.9 Hz), 7.40 (1H, m), 7.36 (1H, d,
J = 8.8 Hz), 7.32−7.25 (3H, m), 7.20 (2H, brd, J = 8.0 Hz), 6.89 (1H,
dd, J = 8.8, 2.9 Hz), 6.79 (1H, d, J = 2.9 Hz), 6.69 (1H, s), 5.13, 5.09
(2H, each d, J = 12.0 Hz), 3.81 (3H, s), 3.49 (3H, s); 13C NMR (125
MHz, CDCl3) δ 189.4, 161.4, 160.1, 158.0, 143.1, 139.6, 136.0, 132.3,
130.7, 129.9, 128.4, 128.0, 127.8, 127.5, 126.5, 125.2, 124.1, 121.7,
115.9, 114.7, 111.1, 70.3, 62.2, 55.5; HRMS (FD+) calcd for
C28H23ClO4 [M]+ 458.1285, found 458.1289.
2-Benzyloxy-4,8-dimethoxy-3-phenyldibenzo[b,d]furan
(44). According to the procedure described for the preparation of 30,
treatment of 42 (33.9 mg, 73.9 μmol) with mCPBA (70−75% assay;
90 mg, ca. 0.37 mmol) in the presence of NaHCO3 (31.0 mg, 369
μmol) in dichloromethane (2.7 mL) afforded the corresponding
formate (38.2 mg), which was treated with Cu2O (53.0 mg, 369 μmol)
in pyridine (2.0 mL) at 110 °C for 5 h. The usual workup followed by
chromatography on silica gel (n-hexane−ethyl acetate−dichloro-
methane = 20:2:1) gave 44 (16.8 mg, 55%) as an amorphous solid:
IR (ZnSe) 2934, 2831, 1602, 1480, 1422, 1265, 1183, 1149, 1064,
1
1027, 732 cm−1; H NMR (500 MHz, CDCl3) δ 7.50−7.45 (5H, m),
7.40−7.37 (1H, m), 7.37 (1H, d, J = 2.7 Hz), 7.32−7.22 (6H, m), 7.06
(1H, dd, J = 9.1, 2.7 Hz), 5.08 (2H, s), 4.00 (3H, s), 3.93 (3H, s); 13C
NMR (125 MHz, CDCl3) δ 155.8, 152.7, 151.3, 143.8, 143.1, 137.2,
134.1, 130.9, 128.3, 127.7, 127.5, 127.0, 126.7, 125.0, 124.9, 123.9,
115.3, 112.3, 103.3, 99.2, 71.5, 60.8, 56.0; HRMS (EI+) calcd for
C27H22O4 [M]+ 410.1518, found 410.1512.
Kehokorin E (5). According to the method described for the
preparation of 2, compound 44 (11.6 mg, 28.3 μmol) was
hydrogenated over 10% palladium on carbon (3.0 mg) in
tetrahydrofuran (0.7 mL) for 16 h, and purification by chromatog-
raphy on silica gel (n-hexane−ethyl acetate = 5:1) gave 5 (7.6 mg,
84%) as an amorphous solid: IR (ZnSe) 3419, 2936, 2831, 1586, 1481,
1422, 1267, 1188, 1146, 1026, 760 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.55 (2H, brt, J = 7.5 Hz), 7.47−7.44 (4H, m), 7.35 (1H, d,
J = 2.7 Hz), 7.21 (1H, s), 7.05 (1H, dd, J = 9.0, 2.7 Hz), 4.90 (1H,
brs), 4.03 (3H, s), 3.92 (3H, s); 13C NMR (125 MHz, CDCl3) δ
155.7, 151.4, 149.1, 142.7, 142.3, 132.5, 130.7 129.3, 128.4, 126.1,
124.7, 120.0, 115.5, 112.2, 103.6, 99.9, 60.8, 56.0; HRMS (EI+) calcd
for C20H16O4 [M]+ 320.1049, found 320.1045.
2,8-Bis(benzyloxy)-4-methoxy-3-phenyldibenzo[b,d]furan
(43). According to the procedure described for the preparation of 30,
treatment of 41 (36.7 mg, 68.6 μmol) with mCPBA (70−75% assay;
84 mg, ca. 0.34 mmol) in the presence of NaHCO3 (29 mg, 0.34
mmol) in dichloromethane (2.7 mL) afforded the corresponding
formate (31.9 mg), which was treated with Cu2O (40.5 mg, 283 μmol)
in pyridine (1.7 mL) at 110 °C for 4 h. The usual workup followed by
chromatography on silica gel (benzene−ethyl acetate = 100:1) gave 43
(14.2 mg, 50%) as an amorphous solid: IR (ZnSe) 2926, 2851, 1602,
ASSOCIATED CONTENT
* Supporting Information
■
1
1478, 1448, 1424, 1264, 1182, 1150, 1016, 732 cm−1; H NMR (500
S
MHz, CDCl3) δ 7.52−7.37 (12H, m), 7.32−7.21 (6H, m), 7.13 (1H,
dd, J = 8.9, 2.5 Hz), 5.18 (2H, s), 5.07 (2H, s), 3.99 (3H, s); 13C NMR
(125 MHz, CDCl3) δ 154.9, 152.7, 151.5, 143.8, 143.1, 137.2, 137.0,
134.1, 131.0, 128.6, 128.3, 128.0, 127.7, 127.6, 127.5, 127.1, 126.7,
125.0, 124.9, 124.0, 116.1, 112.4, 104.9, 99.2, 71.5, 71.0, 60.8; HRMS
(EI+) calcd for C33H26O4 [M]+ 486.1831, found 486.1852.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00147.
NMR spectra of 1−5, 7, 14−18, 20, 21, 24−26, 28−30,
32, 34, 35, 37−39, and 41−44 and 2D NMR spectra of
14 (PDF)
Kehokorin D (4). According to the method described for the
preparation of 2, compound 43 (10.1 mg, 20.8 μmol) was
hydrogenated over 10% palladium on carbon (2.8 mg) in
tetrahydrofuran (0.6 mL) for 19 h, and purification by preparative
TLC (n-hexane−ethyl acetate = 1:1, two developments) gave 4 (5.0
mg, 79%) as an amorphous solid: IR (ZnSe) 3386, 2942, 1609, 1479,
1426, 1180, 1146, 1051, 799, 701 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.55 (2H, brt, J = 7.8 Hz), 7.47−7.41 (4H, m), 7.31 (1H, d, J = 2.7
AUTHOR INFORMATION
Corresponding Author
*E-mail: shunyat@riken.jp
ORCID
■
Shunya Takahashi: 0000-0001-9148-9814
G
DOI: 10.1021/acs.joc.7b00147
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
15K07421.
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H
DOI: 10.1021/acs.joc.7b00147
J. Org. Chem. XXXX, XXX, XXX−XXX