Total Synthesis of Boletopsin 11 Enabled by Directed ortho-C(sp2)-H Arylation

Article abstract of DOI:10.1021/acs.joc.8b00792

A nine-step synthesis of boletopsin 11 (1), a bioactive fungal natural product, is disclosed. Key features include a one-pot [O]-oxa-Michael cascade to establish the polyoxygenated dibenzofuran core followed by a Pd-catalyzed directed ortho-C(sp²)-H arylation to complete the fully functionalized carbon skeleton. Exploration of the latter transformation led to the discovery of an unexpected tandem ortho-C(sp²)-H arylation event, and the scope of the directed ortho-C(sp²)-H reaction was further investigated with coupling partners varying in stereoelectronic properties.

Full text of DOI:10.1021/acs.joc.8b00792

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Total Synthesis of Boletopsin 11 Enabled by Directed ortho-C(sp2)−H
Arylation
Meng Yao Zhang and Russell A. Barrow*
Research School of Chemistry, Australian National University, Acton, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: A nine-step synthesis of boletopsin 11 (1), a bioactive fungal natural product, is disclosed. Key features include a
one-pot [O]-oxa-Michael cascade to establish the polyoxygenated dibenzofuran core followed by a Pd-catalyzed directed ortho-
C(sp2)−H arylation to complete the fully functionalized carbon skeleton. Exploration of the latter transformation led to the
discovery of an unexpected tandem ortho-C(sp2)−H arylation event, and the scope of the directed ortho-C(sp2)−H reaction was
further investigated with coupling partners varying in stereoelectronic properties.
oletopsins 1−14, isolated from the Boletopsis sp. of
group that we anticipated would slow undesired oxidative
Bmushrooms, are a family of natural products containing decomposition of the central C ring and serve as an enabling
group for the direct attachment of the D ring via a Pd-catalyzed
directed ortho-C(sp2)−H arylation, inspired by recent pub-
lications from the Yu laboratory7 and others.8 In this fashion,
the D ring of the boletopsin carbon framework was
disconnected from the rest of the molecule to reveal
benzaldehyde 4.
a p-terphenyl carbon skeleton and a highly functionalized 3-
phenyldibenzofuran core.1 A significant proportion of the
boletopsin family exhibit antibiotic properties,2 and several
boletopsins are identified as active ingredients in the fungi
utilized in Papua New Guinean medicine possessing in vitro
activity against a panel of human pathogenic bacteria.1b
Based on related studies published from within our group,9
we anticipated benzaldehyde 4 could be disconnected back to
catechol 5 via an [O]-oxa-Michael transform.10 We presumed
catechol 5 would be easily accessible through Suzuki−Miyaura
cross-coupling of known bromide 6 and commercially available
3,4-dimethoxyphenyl boronic acid followed by chemoselective
demethylation.
Given their medicinal properties and their intriguing
structures, the boletopsins (and related natural products)2,3
have attracted ongoing interest from synthetic chemists
(Scheme 1).4 The highly oxygenated nature of the boletopsins
and their fully substituted aromatic C ring renders their
synthesis a challenge. Several dibenzofuran p-terphenyl natural
products have been prepared previously by our group5 and that
of Takahashi,6 including the syntheses of boletopsins 7, 11 (1),
12 (2), and vialinin B (3), which were completed in either 13
or 14 steps. The p-terphenyl carbon scaffolds were constructed
via sequential Suzuki−Miyaura cross-coupling reactions, and
the dibenzofuran core was forged through Baeyer−Villiger
oxidation and intramolecular Ullmann coupling. Both synthetic
routes required the use of unstable intermediates, and boronic
acid cross-coupling partners that were not commercially
available, which hindered material throughput.
As part of our ongoing interest in the development of new
methods for the preparation of dibenzofuran natural products,
we sought to formulate a new modular approach to the
boletopsin scaffold that was more efficient and would mitigate
undesired decomposition pathways, which primarily stem from
the oxidation prone, electron-rich C ring. Herein we disclose a
successful realization of this goal that culminated in a nine-step
synthesis of boletopsin 11 (1). Our plan centered on the
strategic replacement of the C-4 methoxy group with a formyl
Our synthesis of boletopsin 11 began with the preparation of
aryl bromide 6 in two steps from sesamol.5,11 Suzuki−Miyaura
cross-coupling4c of aryl bromide 6 with commercially available
3,4-dimethoxyphenyl boronic acid using catalytic Pd(OAc)2
and triphenylphosphine furnished biphenyl 7 in 89% yield
(Scheme 2). The selective cleavage of the methyl ethers of 7, in
preference over the methylenedioxy moiety, was successfully
realized with boron tribromide in DCM. Initial subjection of
catechol 5 to sodium periodate in a biphasic DCM/water
reaction medium12 resulted in a successful [O]-oxa-Michael
reaction; however, the isolated yield was poor due to the
instability of the dibenzofuran catechol product 8. This
problem was ultimately circumvented by switching the oxidant
to iodobenzene diacetate and using a mixed solvent system of
DCM/MeOH, followed by in situ protection of the catechol
Received: March 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00792
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The Journal of Organic Chemistry
Note
leading to triaryl 11 in 3% yield. Presumably formed through
the transient seven-membered palladacycle,8g this tandem Pd-
catalyzed directed ortho-C(sp2)−H arylation sequence is
currently under further investigation in our laboratory and
could have great potential for the rapid synthesis of exotic
helical triaryls.14
Scheme 1. p-Terphenyl Natural Products and Retrosynthetic
Analysis
At this stage, our attention turned to the removal of the
methylenedioxy moiety of 10 and acetylation of the resulting
catechol functionality. Previous syntheses of the boletopsins
and related structures were compelled to undertake multiple
concession steps at this point to realize this goal. Anticipating
that the aldehyde functionality at C-5 would stabilize the
electron-rich catechol C ring upon deprotection, treatment of
10 with phosphorus pentachloride followed by hydrolysis
successfully cleaved the methylenedioxy group, and although
the intermediary catechol was isolable, we found it convenient
to simply acetylate the crude reaction mixture with acetic
anhydride and triethylamine, which furnished diacetate 12 in
83% yield over two steps from 10.
To complete the total synthesis of boletopsin 11, diacetate
12 was submitted to Baeyer−Villiger oxidation with m-CPBA
and sodium bicarbonate. Subsequent in situ formate hydrolysis
followed by treatment with excess potassium carbonate and
methyl iodide successfully effected methylation to deliver
boletopsin 11 (1), in a single-pot operation.
We were particularly intrigued by the versatility of the Pd-
catalyzed ortho-C(sp2)−H arylation reaction that enabled the
direct functionalization of a sterically encumbered benzalde-
hyde 4. In efforts to further evaluate the breadth of this
transformation, a brief substrate screen was conducted with aryl
iodides differing in electronics and substitution patterns to
examine the effects of electronic and steric properties of the aryl
iodide on the reaction outcome.
As shown in Scheme 3, the directed ortho-C(sp2)−H
arylation was performed on five additional examples. Both
electron-rich and -deficient ortho-substituted aryl iodides
performed poorly, presumably owing to steric effects (13 and
14), while reaction with 4-iodotoluene and 3-bromoiodoben-
zene exhibited modest reactivity (15 and 16).15 The best result
was obtained with 4-iodobenzoate, affording the adduct 17 in
72% isolated yield.
functionality. Thus, upon completion of the [O]-oxa-Michael
process, the byproducts including the solvent could be easily
removed under vacuum and the intermediary dibenzofuran
catechol subjected to dimethylation conditions using methyl
iodide and potassium carbonate, delivering benzaldehyde 4 in
two steps from biphenyl 7.
With benzaldehyde 4 in hand, the stage was set to complete
the boletopsin carbon skeleton and install the D ring via
directed ortho-C(sp2)−H arylation. We were delighted to find
that subjection of benzaldehyde 4 and p-iodoanisole to the
protocol developed by Yu and co-workers,7a using amino acid 9
as the transient directing group (DG), led to the isolation of the
desired product 10 in 51% yield, along with 26% of recovered
benzaldehyde 4. Attempts to push the reaction to completion
using a higher catalyst loading, prolonged reaction time, or
additional equivalents of silver trifluoroacetate proved un-
successful and resulted in diminished overall yield.13 It was
surmised that this process was hampered by the steric
encumbrance of both the transient DG 9 and the heavily
substituted benzaldehyde 4, impeding formation of the
intermediary five-membered palladacycle and subsequent
reaction with p-iodoanisole. To the best of our knowledge,
this is the first example of a 2,3,4,5-tetrasubstituted
benzaldehyde engaging in a Pd-catalyzed directed ortho-
C(sp2)−H arylation. Furthermore, during our attempts to
optimize this transformation by employing a large excess of p-
iodoanisole, a secondary directed C(sp2)−H arylation event
was discovered on the newly appended p-methoxyphenyl ring,
In summary, the total synthesis of boletopsin 11 (1) has been
completed in nine steps from sesamol. In comparison to the
previous route (13 steps),5 our synthesis is not only shorter but
also more robust, employing bench stable synthetic inter-
mediates and commercially available cross-coupling partners
that provide a more scalable route to the natural product. The
pivotal steps include a one-pot [O]-oxa-Michael addition
reaction to forge the dibenzofuran scaffold, followed by a
sterically challenging directed ortho-C(sp2)−H arylation
reaction that appends the D ring to complete the carbon
framework. The latter, to the best of our knowledge, is the first
application of this methodology in natural product synthesis.16
The key feature of our synthetic plan was the strategic
placement of the C-5 formyl group on the C ring, which served
as a stabilizing group as well as the synthetic handle to enact the
directed ortho-C(sp2)−H arylation. During the course of this
study, a secondary ortho-C(sp2)−H arylation reaction was
discovered, with the isolation of triaryl 11. Further explorations
into this tandem directed ortho-C(sp2)−H arylation reaction
focusing on induction of axial chirality employing chiral
directing groups8c,17 are currently ongoing in our laboratory.
B
DOI: 10.1021/acs.joc.8b00792
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The Journal of Organic Chemistry
Note
Scheme 2. Total Synthesis of Boletopsin 11 (1)
a
b
1
Isolated yield (rsm (recovered starting material) yield of 4). Yield was determined by H NMR spectroscopy using dibromomethane as the
internal standard. The NMR yield of the tandem ortho-C(sp2)−H product 11 could be improved to 10% with reaction conditions: Pd(OAc)2 (10
mol %), DG 9 (40 mol %), AgTFA (2 equiv), ClCH2CO2H (10 equiv), p-iodoanisole (7 equiv), HFIP (0.2 M), 110 °C, 36 h.
7-bromo-6-hydroxybenzo[d][1,3]dioxole-5-carbaldehyde (6)11 were
prepared according to literature procedures.
7-(3,4-Dimethoxyphenyl)-6-hydroxybenzo[d][1,3]dioxole-5-car-
baldehyde (7). In a two-neck flask fitted with a condenser, aryl
EXPERIMENTAL SECTION
■
General Experimental Methods. NMR spectra were recorded at
298 K, 400 MHz for 1H, 100 MHz for 13C, on an Avance 400
instrument. Chemical shifts are reported in ppm (δ). NMR
experiments were run in CDCl3 or (CD3)2CO as indicated. 1H
NMR spectra are referenced to the resonance from residual CHCl3 at
7.26 ppm and CHD2COCD3 at 2.05 ppm. 13C NMR spectra are
referenced to the central peak in the signal from CDCl3 at 77.0 ppm
and (CD3)2CO at 29.8 ppm. The multiplicities of 1H NMR resonances
are expressed by abbreviations: br (broad), s (singlet), d (doublet), t
(triplet), quartet (q), m (multiplet), and combinations thereof for
highly coupled systems. 13C NMR spectra were run as proton
decoupled experiments. EI-MS were recorded on an Agilent HP 6890
series gas GC/MS with a 7683 series injector. HREI-MS data were
recorded on a Waters AutoSpec Premier spectrometer magnetic sector
instrument, operating at 70 eV. ESI-MS data were recorded on a ZMD
Micromass spectrometer with a Waters Alliance 2690 HPLC. HRESI-
MS were recorded on a Waters LCT Premier time-of-flight (TOF)
mass spectrometer and a Thermo Fisher Scientific Velos Pro Orbitrap
mass spectrometer. Mass spectra are displayed as mass/charge ratios
(m/z) and relative abundance (% of base peak intensity). Thin layer
chromatography (TLC) was run on Merck silica gel 60 F254 aluminum
backed plates, and details of the eluents are described in each
procedure. Plates were observed under UV light (254 nm) and/or
developed in a ceric phosphomolybdic acid dip followed by heating.
Flash column chromatography was run on silica gel (230−400 mesh)
using the eluent system detailed for each procedure. Anhydrous
solvents were obtained from commercial sources unless otherwise
noted. The petroleum ether (pet.) fraction used was 60−80 °C unless
otherwise stated. IR spectra were recorded on the Alpha Bruker Optics
FT-IR spectrometer or the PerkinElmer Spectrum Two FT-IR
spectrometer (neat), and all data were reported in wavenumbers.
Peak intensities are described by s (strong), m (medium), w (weak),
and br (broad). 6-Hydroxybenzo[d][1,3]dioxole-5-carbaldehyde5 and
bromide 6 (1.00 g, 4.08 mmol, 1.0 equiv), 3,4-dimethoxyphenyl
boronic acid (1.49 g, 8.19 mmol, 2.0 equiv), Pd(OAc)2 (64 mg, 0.285
mmol, 7 mol %), and triphenylphosphine (225 mg, 0.859 mmol, 21
mol %) were degassed and refilled with nitrogen. A 30 mL aliquot of
solvent (THF/n-propanol = 1:1, degassed by bubbling nitrogen) was
added to the solids and stirred for 10 min at which time 6 mL of
degassed 2 M Na2CO3 solution were added and the reaction was
heated to 80 °C in an oil bath for 17 h. The mixture was cooled to
room temperature and diluted with EtOAc and brine. The mixture was
extracted with EtOAc, washed with brine, dried with MgSO4, and
concentrated under reduced pressure. The crude material was
subjected to flash column chromatography on silica, using a gradient
elution of EtOAc/pet. = 1:3 to 1:2 to afford the title compound as a
yellow solid (1.10 g, 3.63 mmol, 89%). Rf (1:2 EtOAc/pet.) = 0.26. 1H
NMR (400 MHz, CDCl3) δ 12.3 (s, 1H), 9.68 (s, 1H), 7.20 (d, J = 2.0
Hz, 1H), 7.18 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.04 (s,
2H), 3.92 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
194.1, 158.7, 152.4, 148.9, 148.6, 141.0, 122.6, 122.4, 113.8, 113.3,
112.5, 110.9, 108.2, 102.0, 56.0, 55.9. IR: ν (cm−1) = 1626 (m), 1520
(m), 1256 (s), 1227 (s) 1025 (s). MS (EI) m/z 302 (100, [M]+•
C16H14O6). HRMS (EI) m/z: [M]+• calcd for C16H14O6 302.0790;
found 302.0788.
7-(3,4-Dihydroxyphenyl)-6-hydroxybenzo[d][1,3]dioxole-5-car-
baldehyde (5). Boron tribromide (1.0 M solution in DCM, 8.34
mmol, 2.1 equiv) was added dropwise to a solution of biphenyl 7 (1.20
g, 3.97 mmol, 1.0 equiv) in 45 mL of anhydrous DCM at 0 °C under
nitrogen. The solution was slowly warmed to room temperature and
stirred for 1.5 h at which time it was poured into ice water. The
mixture was extracted exhaustively with EtOAc, and the combined
organic layers were washed with brine, dried with MgSO4 and
concentrated under reduced pressure. The residue was purified via
flash column chromatography on silica using EtOAc/pet. = 3:2 as the
C
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Note
103.4, 103.3, 102.9, 95.7, 56.6, 56.3. IR: ν (cm−1) = 1671 (m), 1503
(m), 1396 (m), 1261 (s), 1112 (s). MS (EI) m/z 300 (100, [M]+•
C16H12O6). HRMS (EI) m/z: [M]+• calcd for C16H12O6 300.0634;
found 300.0633.
Scheme 3. Scope of the Directed ortho-C(sp2)−H Arylation
a
Reaction with Benzaldehyde 4
8,9-Dimethoxy-4-(4-methoxyphenyl)benzo[b][1,3]dioxolo[4,5-e]-
benzofuran-5-carbaldehyde (10). In a sealed tube, benzaldehyde 4
(137 mg, 0.457 mmol, 1.0 equiv), p-iodoanisole (214 mg, 0.914 mmol,
2.0 equiv), Pd(OAc)2 (10.3 mg, 0.0457 mmol, 10 mol %), DG 9 (18.8
mg, 0.183 mmol, 40 mol %), AgTFA (202 mg, 0.914 mmol, 2.0 equiv),
and ClCH2CO2H (432 mg, 4.57 mmol, 10 equiv) were suspended in
2.3 mL of HFIP, and the mixture was stirred for 10 min and then
heated to 100 °C in an oil bath covered in aluminum foil to minimize
exposure to light. After 22 h, the reaction was cooled to room
temperature and 3.00 g of sodium bicarbonate were added. The
suspension was stirred vigorously for 10 min and then filtered through
Celite using EtOAc, and the filtrates were concentrated in vacuo.
Purification was achieved via flash column chromatography on silica
using DCM/pet/EtOAc = 8:2:1 as the eluent affording the title
compound as a brown amorphous solid (94 mg, 0.246 mmol, 51%
isolated yield, 26% recovered starting material). Rf (1:1 EtOAc/pet.) =
0.30. 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.43−7.41 (m, 2H),
7.34 (s, 1H), 7.29 (s, 1H), 7.04−7.02 (m, 2H), 6.23 (s, 2H), 4.00 (s,
3H), 3.98 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
188.7, 159.8, 153.8, 152.2, 150.3, 146.7, 143.8, 140.9, 132.2, 123.8,
123.6, 113.9, 112.9, 111.5, 109.3, 103.1, 102.7, 96.1, 56.6, 56.3, 55.4.
IR: ν (cm−1) = 2926 (w), 1683 (m), 1597 (m), 1475 (m), 1249 (s),
1199 (s), 1174 (s), 1124 (s). MS (ESI) m/z 445 (55, [M + K]+
C23H18O7K), 429 (100, [M + Na]+ C23H18O7Na), 407 (20, [M + H]+
C23H19O7). HRMS (ESI) m/z: [M + Na]+ calcd for C23H18O7Na
429.0950; found 429.0951.
4-(4′,5-Dimethoxy-[1,1′-biphenyl]-2-yl)-8,9-dimethoxybenzo[b]-
[1,3]dioxolo[4,5-e]benzofuran-5-carbaldehyde (11). In a sealed tube,
benzaldehyde 4 (35 mg, 0.12 mmol, 1.0 equiv), p-iodoanisole (192
mg, 0.819 mmol, 7.0 equiv), Pd(OAc)2 (2.6 mg, 0.012 mmol, 10 mol
%), DG 9 (4.8 mg, 0.047 mmol, 40 mol %), AgTFA (51.7 mg, 0.234
mmol, 2.0 equiv), and ClCH2CO2H (111 mg, 1.17 mmol, 10 equiv)
were suspended in 0.6 mL of HFIP, and the mixture was stirred for 10
min and then heated to 110 °C in an oil bath covered in aluminum foil
to minimize exposure to light. After 36 h, the reaction was cooled to
room temperature and 300 mg of sodium bicarbonate were added.
The suspension was stirred vigorously for 10 min, then filtered
through Celite, and concentrated in vacuo. The NMR yields were
determined using dibromomethane as the internal standard. The NMR
yields of benzaldehydes 4, 10, and 11 were 10%, 41%, and 10%,
respectively. Separation of 10 and 11 proved to be difficult due to the
highly similar Rf values, and a pure sample for characterization could
be obtained via flash column chromatography using a gradient eluent
a
Reaction conditions: benzaldehyde 4 (0.110 mmol, 1 equiv), aryl
iodide (3 equiv), Pd(OAc)2 (10 mol %), DG 9 (40 mol %),
ClCH2CO2H (10 equiv), AgTFA (2 equiv), HFIP (0.6 mL), 110 °C,
20 h. Isolated yields (rsm yields). Reaction conditions: benzaldehyde
4 (0.457 mmol, 1 equiv), p-iodoanisole (2 equiv), Pd(OAc)2 (10 mol
%), DG 9 (40 mol %), ClCH2CO2H (10 equiv), AgTFA (2 equiv),
HFIP (2.3 mL), 100 °C, 22 h. Isolated yields (rsm yields).
b
eluent, affording the title compound as a yellow solid (889 mg, 3.24
mmol, 82%). Rf (2:1 EtOAc/pet.) = 0.48. 1H NMR (400 MHz,
(CD3)2CO) δ 12.4 (br s, 1H), 9.76 (s, 1H), 7.97 (br s, 2H), 7.15 (d, J
= 2.0 Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J = 8.2, 2.0 Hz, 1H), 6.88 (d, J =
8.2 Hz, 1H), 6.11 (s, 2H); 13C NMR (100 MHz, (CD3)2CO) δ 196.1,
159.4, 153.5, 145.9, 145.4, 142.1, 123.0, 122.8, 118.2, 115.6, 114.8,
113.3, 109.0, 103.1. IR: ν (cm−1) = 3486 (m), 3283 (br), 1608 (s),
1409 (s), 1307 (s), 1249 (s), 1039 (s). MS (EI) m/z 274 (100, [M]+•
C14H10O6). HRMS (EI) m/z: [M]+• calcd for C14H10O6 274.0477;
found 274.0476.
8,9-Dimethoxybenzo[b][1,3]dioxolo[4,5-e]benzofuran-5-carbal-
dehyde (4). Biphenyl catechol 5 (274 mg, 1.00 mmol, 1.0 equiv) was
dissolved in 58 mL of solvent (DCM/MeOH = 7:1) at 0 °C under
nitrogen. PhI(OAc)2 (451 mg, 1.40 mmol, 1.4 equiv) was added to the
solution in one portion and stirred for 1 h at which time an additional
0.2 equiv of PhI(OAc)2 was added. After 0.5 h, the solvent was
removed in vacuo and the residue was redissolved in 10 mL of DMF.
Potassium carbonate (1.38 g, 10.0 mmol, 10 equiv) was added to the
solution followed by methyl iodide (1.14 g, 8.00 mmol, 8.0 equiv), and
the mixture was stirred at room temperature under nitrogen for 17 h,
at which time the reaction was diluted with water and EtOAc. The
reaction mixture was extracted with EtOAc, and the combined organic
layers were washed with brine, dried with MgSO4, and concentrated
under reduced pressure. Purification was achieved using flash column
chromatography on silica using DCM/pet/EtOAc = 8:2:1 as the
eluent affording the title compound as a colorless solid (135 mg, 0.451
mmol, 45%). Rf (1:1 EtOAc/pet.) = 0.32. 1H NMR (400 MHz,
CDCl3) δ 10.40 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.15 (s, 1H), 6.22
(s, 2H), 3.99, (s, 3H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
186.1, 155.9, 151.8, 150.4, 146.7, 145.3, 143.8, 114.2, 111.7, 109.9,
1
system (pet/EtOAc = 5:1 to 4:1). Rf (1:4 EtOAc/pet.) = 0.06. H
NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H),
7.29 (s, 1H), 7.25 (s, 1H), 7.09−7.07 (m, 2H), 7.02−6.98 (m, 2H),
6.70−6.68 (m, 2H), 6.12 (d, J = 1.1 Hz, 1H), 5.80 (d, J = 1.1 Hz, 1H),
3.97 (s, 3H), 3.96 (s, 3H), 3.90 (s, 3H), 3.71 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 188.4, 160.0, 158.7, 153.9, 152.1, 150.3, 146.7, 143.74,
143.65, 141.2, 133.1, 132.9, 130.1, 123.4, 122.4, 115.5, 113.4, 113.0,
112.6, 111.5, 109.3, 103.1, 102.5, 96.2, 56.6, 56.3, 55.4, 55.1. IR: ν
(cm−1) = 2930 (w), 1685 (m), 1603 (m), 1494 (m), 1475 (m), 1309
(m), 1248 (m), 1200 (s), 1175 (s), 1127 (s). MS (ESI) m/z 551 (20,
[M + K]+ C30H24O8K), 535 (100, [M + Na]+ C30H24O8Na), 513 (30,
[M + H]+ C30H25O8). HRMS (ESI) m/z: [M + H]+ calcd for
C30H25O8 513.1544; found 513.1538.
4-Formyl-7,8-dimethoxy-3-(4-methoxyphenyl)dibenzo[b,d]furan-
1,2-diyl Diacetate (12). Compound 10 (46.7 mg, 0.115 mmol, 1.0
equiv) was suspended in 1.0 mL of toluene, and phosphorus
pentachloride (79.8 mg, 0.384 mmol, 3.3 equiv) was added. The
mixture was then heated to 60 °C in an oil bath under nitrogen. After
2 h, the temperature was increased to 80 °C and 0.8 mL of 1 M
HCl(aq) solution was added and stirred for 0.5 h at which time 2 mL
of sat. NaHCO3(aq) solution and 2 mL of EtOH were added and
heated to 90 °C for 1.5 h. The mixture was cooled to room
temperature, acidified with 1 M HCl(aq) solution, and extracted with
D
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EtOAc. The organic layers were washed with brine, dried with MgSO4,
and concentrated under reduced pressure to afford the crude which
was immediately subjected to the next step. The crude material was
dissolved in 1.5 mL of DCM under nitrogen at 0 °C, and acetic
anhydride (32.8 mg, 0.322 mmol, 2.8 equiv) was added slowly.
Subsequently, triethylamine (116 mg, 1.15 mmol, 10 equiv) was added
dropwise and the reaction was stirred at room temperature for 15 min
at which time sat. NH4Cl(aq) solution was added and extracted with
EtOAc. The organic layer was washed with brine, dried with MgSO4,
and concentrated under reduced pressure. The crude material was
subjected to flash column chromatography on silica using a gradient
elution of EtOAc/pet. = 3:2 to 1:1, affording the title compound as a
pale yellow paste (45.7 mg, 0.0956 mmol, 83% over two steps). Rf (1:1
EtOAc/pet.) = 0.23. 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.32
(s, 1H), 7.30−7.28 (m, 2H), 7.17 (s, 1H), 7.00−6.98 (m, 2H), 3.99 (s,
3H), 3.97 (s, 3H), 3.88 (s, 3H), 2.51 (s, 3H), 2.03 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 189.3, 168.5, 167.0, 159.9, 153.2, 152.6, 151.1,
146.9, 140.1, 136.9, 136.2, 132.0, 124.2, 120.0, 118.4, 113.7, 112.2,
103.2, 96.2, 56.6, 56.3, 55.4, 20.5, 20.1. IR: ν (cm−1) = 2937 (w), 1779
(m), 1477 (m), 1201 (s), 1171 (s), 1124 (s). MS (ESI) m/z 501 (100,
[M + Na]+ C26H22O9Na). HRMS (ESI) m/z: [M + Na]+ calcd for
C26H22O9Na 501.1162; found 501.1167.
benzaldehyde 4 following the general procedure, using 2-iodobenzoate
as the aryl iodide. Flash column chromatography on silica using
DCM/pet./EtOAc = 8:2:1 afforded compound 13 (2.0 mg, 0.0046
mmol, 4%) along with recovered benzaldehyde 4 (26.2 mg, 0.0873
1
mmol, 79%). Rf (8:2:1 DCM/pet./EtOAc) = 0.30. H NMR (400
MHz, CDCl3) δ 9.99 (s, 1H), 8.13 (dd, J = 7.7, 1.1 Hz, 1H), 7.65−
7.61 (m, 2H), 7.56−7.52 (m, 2H), 7.38 (dd, J = 7.0, 1.0 Hz, 1H), 7.36
(s, 1H), 7.27 (s, 1H), 6.17 (s, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.70 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 187.5, 166.7, 154.7, 152.2,
150.3, 146.7, 143.7, 140.9, 133.8, 132.3, 132.0, 130.7, 130.6, 128.7,
122.4, 112.7, 111.7, 109.5, 103.2, 102.8, 96.0, 56.6, 56.3, 52.1. IR: ν
(cm−1) = 2926 (w), 1725 (m), 1685 (m), 1606 (m), 1476 (m), 1310
(m), 1256 (m), 1200 (s), 1127 (s). MS (ESI) m/z 473 (45, [M + K]+
C24H18O8K), 457 (100, [M + Na]+ C24H18O8Na), 435 (15, [M + H]+
C24H19O8). HRMS (ESI) m/z: [M + H]+ calcd for C24H19O8
435.1074; found 435.1074.
8,9-Dimethoxy-4-(2-methoxyphenyl)benzo[b][1,3]dioxolo[4,5-e]-
benzofuran-5-carbaldehyde (14). Compound 14 was obtained from
benzaldehyde 4 following the general procedure, using o-iodoanisole as
the aryl iodide. Flash column chromatography on silica using DCM/
pet./THF = 25:10:1 afforded compound 14 (1.2 mg, 0.030 mmol, 3%)
along with recovered benzaldehyde 4 (23.9 mg, 0.0800 mmol, 72%). Rf
1
(25:10:1 DCM/pet./THF) = 0.23. H NMR (400 MHz, CDCl3) δ
Boletopsin 11 (1). Dibenzofuran 12 (56.6 mg, 0.118 mmol, 1.0
equiv) was dissolved in 1.7 mL of DCM, and sodium bicarbonate
(49.7 mg, 0.592 mmol, 5.0 equiv) was added followed by m-CPBA
(40.8 mg, 0.236 mmol, 2.0 equiv). The mixture was stirred under
nitrogen at room temperature for 18 h at which time potassium
carbonate (65.2 mg, 0.472 mmol, 4.0 equiv) and 1.5 mL of EtOH and
0.4 mL of water were added and stirred at room temperature for 6 h.
The solvent was removed in vacuo, and the residue was redissolved in
4 mL of acetone, which was subsequently treated with potassium
carbonate (130 mg, 0.944 mmol, 8.0 equiv) and methyl iodide (134
mg, 0.944 mmol, 8.0 equiv); the suspension was stirred under nitrogen
at room temperature for 17 h. The mixture was filtered through a small
plug of silica (DCM/pet/EtOAc = 8:2:1 as the eluent), and the filtrate
was concentrated under reduced pressure. The crude was purified by
flash column chromatography on silica using DCM/pet/EtOAc =
8:2:1 as the eluent, affording boletopsin 11 (1) as a colorless solid
(26.0 mg, 0.0542 mmol, 46%). Spectral data match the previously
reported data of the isolated natural product.1b Rf (8:2:1 DCM/pet./
9.83 (s, 1H), 7.48−7.43 (m, 1H), 7.39 (dd, J = 7.6, 1.9 Hz, 1H), 7.36
(s, 1H), 7.29 (s, 1H), 7.12−7.08 (m, 1H), 7.04−7.02 (m, 1H), 6.24 (d,
J = 1.1 Hz, 1H), 6.19 (d, J = 1.1 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H),
3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.9, 157.0, 153.6,
152.3, 150.3, 146.7, 144.1, 141.2, 132.0, 130.5, 120.7, 120.6, 119.8,
112.8, 111.6, 111.0, 109.6, 103.2, 102.7, 96.2, 56.6, 56.3, 55.6. IR: ν
(cm−1) = 2936 (w), 1687 (m), 1597 (m), 1476 (m), 1310 (m), 1245
(m), 1199 (s), 1127 (s). MS (ESI) m/z 445 (35, [M + K]+
C23H18O7K), 429 (100, [M + Na]+ C23H18O7Na), 407 (20, [M +
H]+ C23H19O7). HRMS (ESI) m/z: [M + H]+ calcd for C23H19O7
407.1125; found 407.1121.
8,9-Dimethoxy-4-(p-tolyl)benzo[b][1,3]dioxolo[4,5-e]benzofuran-
5-carbaldehyde (15). Compound 15 was obtained from benzaldehyde
4 following the general procedure, using 4-iodotoluene as the aryl
iodide. Flash column chromatography on silica using DCM/pet./THF
= 25:10:1 afforded compound 15 (7.4 mg, 0.019 mmol, 17%) along
with recovered benzaldehyde 4 (10 mg, 0.033 mmol, 30%). Rf
1
1
(25:10:1 DCM/pet./THF) = 0.30. H NMR (400 MHz, CDCl3) δ
EtOAc) = 0.48. H NMR (400 MHz, CDCl3) δ 7.32−7.30 (m, 2H),
9.96 (s, 1H), 7.39−7.37 (m, 2H), 7.35 (s, 1H), 7.32−7.28 (m, 3H),
6.22 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 2.44 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 188.7, 153.8, 152.3, 150.4, 146.7, 143.8, 140.9, 138.6,
130.8, 129.1, 128.7, 123.8, 112.9, 111.5, 109.4, 103.1, 102.8, 96.2, 56.6,
56.3, 21.3. IR: ν (cm−1) = 2923 (w), 1684 (m), 1597 (m), 1476 (m),
1309 (m), 1199 (s), 1176 (s), 1126 (s). MS (ESI) m/z 429 (65, [M +
K]+ C23H18O6K), 413 (100, [M + Na]+ C23H18O6Na). HRMS (ESI)
m/z: [M + H]+ calcd for C23H19O6 391.1176; found 391.1169.
4-(3-Bromophenyl)-8,9-dimethoxybenzo[b][1,3]dioxolo[4,5-e]-
benzofuran-5-carbaldehyde (16). Compound 16 was obtained from
benzaldehyde 4 following the general procedure, using 3-bromoiodo-
benzene as the aryl iodide. Flash column chromatography on silica
using DCM/pet./THF = 25:10:1 afforded compound 16 (11.8 mg,
0.0259 mmol, 24%) along with recovered benzaldehyde 4 (8.3 mg,
7.15−7.14 (m, 2H), 6.97−6.95 (m, 2H), 3.99 (s, 3H), 3.963 (s, 3H),
3.956 (s, 3H), 3.86 (s, 3H), 2.47 (s, 3H), 2.02 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.7, 168.0, 159.0, 151.6, 151.0, 146.4, 145.9, 140.7,
136.0, 131.5, 131.1, 125.4, 124.9, 119.3, 113.8, 113.5, 103.5, 95.7, 61.0,
56.5, 56.3, 55.2, 20.5, 20.2. 1H NMR (400 MHz, (CD3)2CO) δ 7.37 (s,
1H), 7.28 (s, 1H), 7.28−7.26 (m, 2H), 7.03−7.00 (m, 2H), 3.97 (s,
3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 2.49 (s, 3H), 2.01 (s,
3H); 13C NMR (100 MHz, (CD3)2CO) δ 168.9, 168.7, 160.2, 152.5,
152.2, 148.0, 146.6, 141.3, 137.4, 132.5, 132.3, 126.5, 125.9, 120.2,
114.3, 114.2, 104.7, 96.9, 61.3, 56.8, 56.6, 55.5, 20.4, 20.2. IR: ν (cm−1)
= 2937 (w), 1773 (m), 1478 (m), 1280 (m), 1208 (s), 1189 (s), 1172
(s). MS (ESI) m/z 519 (50, [M + K]+ C26H24O9K), 503 (100, [M +
Na]+ C26H24O9Na), 481 (10, [M + H]+ C26H25O9). HRMS (ESI) m/
z: [M + Na]+ calcd for C26H24O9Na 503.1318; found 503.1321.
General Procedure for the Synthesis of Compounds 13−
17.7a In a sealed tube, benzaldehyde 4 (33.0 mg, 0.110 mmol, 1.0
equiv), aryl iodide (0.330 mmol, 3.0 equiv), Pd(OAc)2 (2.5 mg, 0.011
mmol, 10 mol %), DG 9 (4.5 mg, 0.044 mmol, 40 mol %),
ClCH2CO2H (104 mg, 1.10 mmol, 10 equiv), and AgTFA (48.6 mg,
0.220 mmol, 2.0 equiv) were dissolved in 0.6 mL of HFIP and the
mixture was stirred at room temperature for 10 min. The tube was
then sealed and heated to 110 °C in an oil bath for 20 h covered in
aluminum foil. The mixture was then cooled to room temperature, and
300 mg of sodium bicarbonate were added. The suspension was
vigorously stirred for 10 min and filtered through Celite using EtOAc
as the eluent. The filtrate was concentrated and subjected to flash
column chromatography to afford the various p-terphenyl products.
Methyl 2-(5-Formyl-8,9-dimethoxybenzo[b][1,3]dioxolo[4,5-e]-
benzofuran-4- yl)benzoate (13). Compound 13 was obtained from
1
0.028 mmol, 25%). Rf (25:10:1 DCM/pet./THF) = 0.35. H NMR
(400 MHz, CDCl3) δ 10.00 (s, 1H), 7.67−7.66 (m, 1H), 7.59 (ddd, J
= 7.4, 1.8, 1.7 Hz, 1H), 7.42−7.33 (m, 3H), 7.29 (s, 1H), 6.24 (s, 2H),
4.00 (s, 3H), 3.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.8,
154.2, 152.4, 150.6, 146.8, 144.0, 141.0, 134.0, 133.5, 131.6, 129.8,
129.6, 122.5, 121.4, 112.5, 111.3, 109.9, 103.2, 103.0, 96.1, 56.6, 56.4.
IR: ν (cm−1) = 2927 (w), 1686 (m), 1606 (m), 1472 (m), 1310 (m),
1200 (s), 1127 (s). MS (ESI) m/z 479 (99, [M + 2 + Na]+
C22H15O681BrNa), 477 (100, [M + Na]+ C22H15O679BrNa). HRMS
(ESI) m/z: [M + 2 + H]+ calcd for C22H16O681Br 457.0104; found
457.0100.
Methyl 4-(5-Formyl-8,9-dimethoxybenzo[b][1,3]dioxolo[4,5-e]-
benzofuran-4-yl)benzoate (17). Compound 17 was obtained from
benzaldehyde 4 following the general procedure, using 4-iodobenzoate
as the aryl iodide. Flash column chromatography on silica using
E
DOI: 10.1021/acs.joc.8b00792
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
DCM/pet./EtOAc = 8:2:1 afforded compound 17 (34.8 mg, 0.0802
mmol, 72%) along with recovered benzaldehyde 4 (4.8 mg, 0.016
mmol, 14%). Rf (8:2:1 DCM/pet./EtOAc) = 0.43. H NMR (400
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1
MHz, CDCl3) δ 10.00 (s, 1H), 8.16 (m, 2H), 7.57 (m, 2H), 7.34 (s,
1H), 7.28 (s, 1H), 6.23 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 3.96 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 187.7, 166.6, 154.3, 152.4,
150.6, 146.9, 144.0, 141.0, 136.8, 130.9, 130.1, 129.5, 121.8, 112.4,
111.3, 109.9, 103.2, 102.9, 96.1, 56.6, 56.3, 52.3. IR: ν (cm−1) = 2952
(w), 1720 (s), 1685 (m), 1608 (m), 1435 (m), 1310 (s), 1277 (s),
1201 (s), 1127 (s). MS (ESI) m/z 473 (25, [M + K]+ C24H18O8K),
457 (100, [M + Na]+ C24H18O8Na), 435 (20, [M + H]+ C24H19O8).
HRMS (ESI) m/z: [M + Na]+ calcd for C24H18O8Na 457.0899; found
457.0895.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00792.
1H and 13C NMR spectra of novel compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: rab@anu.edu.au.
■
ORCID
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Russell A. Barrow: 0000-0002-3248-1246
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was undertaken with the support of the Research
School of Chemistry at the Australian National University and
an NHMRC project grant (1028092). M.Y.Z. acknowledges the
Australian National University for an Australian Postgraduate
Award. We are thankful to the people of Kiovi village for
sharing their traditional knowledge and staff of the Center of
Natural Resource Research and Development, University of
Goroka, for assistance with collection. Dr. Lara Malins
(Australian National University) is thanked for helpful
discussions.
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