Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation

Article abstract of DOI:10.1021/acs.joc.8b02595

The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.

Full text of DOI:10.1021/acs.joc.8b02595

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Note
Formal Total Synthesis of Hybocarpone Enabled
by Visible-Light-Promoted Benzannulation
Wei Chen, Renyu Guo, Zhen Yang, and Jianxian Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02595 • Publication Date (Web): 28 Nov 2018
Downloaded from http://pubs.acs.org on November 28, 2018
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Formal Total Synthesis of Hybocarpone Enabled by
Visible-Light-Promoted Benzannulation
Wei Chen,† Renyu Guo,† Zhen Yang,*,†,‡ and Jianxian Gong*,†
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†State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National La-
boratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing
100871, China
RECEIVED DATE
ABSTRACT: The formal total synthesis of hybocarpone was achieved in eight steps from commercially
available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannula-
tion to construct the key α-naphthol intermediate, and a modified CAN-mediated dimerization/hydration
cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The
total synthesis of boryquinone was also achieved in seven steps.
Naphthols and naphthoquinones are ubiquitous motifs present in many pharmaceuticals and natural
products and have attracted significant attention from the chemical and biological communities.1,2 Se-
lected examples 1–6 are shown in Figure 1. These naphthol and naphthoquinone-based natural products
have a broad range of biological activities, such as anti-cancer, anti-HIV, and anti-bacterial activities.3
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Figure 1. Naturally occurring naphthol and naphthoquinone-based products.
Hybocarpone (1), which is isolated from mycobiont cultures derived from the lichen Lecanora hy-
bocarpa, is a dimer of naphthazarin bearing a highly substituted pentacyclic ring and two vicinal qua-
ternary stereocenters. Hybocarpone was reported to be a potent cytotoxic agent against a murine masto-
cytoma cell line, with an IC50 value of 0.27 μM.3a
The first total synthesis of 1 was accomplished in 12 steps from a commercially available starting
material by Nicolaou and Gray in 2001 (Scheme 1a).4 The key steps in their elegant total synthesis are
a UV-light-promoted Diels-Alder reaction of substituted 6-methylbenzaldehyde 7 with methyl 2-meth-
ylenebutanoate 8, resulting in the formation of substituted tetrahydronaphthalene 10, followed by a ceric
ammonium nitrate (CAN)-mediated oxidative dimerization of substituted 3-hydroxy-naphthalene-1,4-
dione 11 for the formation of the hybocarpone core (1). The Chai group5 and Pettus group6 reported
different approaches for the construction of the key intermediate 11.
Recently, visible-light-mediated photoredox catalysis has emerged as a powerful tool for synthesizing
structurally diverse organic compounds.7 As part of our program aimed at forming the core structures of
biologically important natural products via visible-light-promoted reactions,8 we became interested in
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applying photoredox-catalyzed cascade radical cyclization as a key step in the total synthesis of hybocar-
pone (1). As shown in our retrosynthetic analysis (Scheme 1b), visible-light-promoted benzannulation
of α-bromocarbonyl 16 with vinyl pivalate 15 was envisioned for constructing naphthol 13, which could
be converted to the key intermediate 11 through a global oxidation event. Finally, CAN-mediated oxi-
dative dimerization of 11 could furnish hybocarpone methyl ether (12), facilitating the formal total syn-
thesis of hybocarpone (1).
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Scheme 1. Synthetic analysis of hybocarpone.
Our synthesis began with the development of a concise method for constructing naphthol 13. Naph-
thols are important intermediates in organic synthesis, and hence, intense effort has been devoted to their
synthesis.9 The emergence of visible-light photoredox catalysis has enabled the productive use of lower-
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energy radiation, leading to structurally diverse polycyclic compounds,10 which has attracted our atten-
tion. Substituted α-bromoketone has a tendency to generate α-ketone radicals under photoredox catalysis.
The radicals can couple with alkene to form functionalized building blocks.11 Therefore, we envisage
generating radical 14a through irradiation of α-bromoketone 16 under visible light in the presence of a
photosensitizer. This radical couples with vinyl pivalate 15 followed by benzannulation through inter-
mediate 14b to produce naphthol 13 (Scheme 1b).
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Table 1. Optimized reaction conditions.a
We began exploring this synthetic transformation to produce the proposed chemistry. To this end, we
synthesized α-bromoketone 16 in two steps from commercially available 1,2,4-trimethoxybenzene (see
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the Experimental Section). First, we examined this transformation with organic photoredox catalyst eo-
sin Y (*E1/2ox = ˗1.08 V vs SCE)12 as the photocatalyst (PC). However, the desired bicyclic product 13
was only observed at trace levels (Table 1, entries 1 and 2). We then evaluated other typical photosensi-
tizers (entries 3–5). Among them, fac-Ir(ppy)3, with its lower redox potential (*E1/2ox = ˗1.73 V vs SCE)13,
produced the best result (58%, entry 5). The yield slightly improved (66%, entry 6) when the base was
changed to potassium carbonate (K2CO3). In contrast, a decreased yield was observed when Na2HPO4
was used as a base (43%, entry 7). When using DMF as a solvent, only 30% yield of the desired product
13 could be isolated (entry 8). Control experiments revealed that the reaction did not proceed in the
absence of a photocatalyst or visible light irradiation (entries 9 and 10). Notably, this reaction could be
carried out on gram scale with a slightly decreased yield (see the Experimental Section).
With the optimized conditions in hand, the generality and scope of this visible-light-promoted ben-
zannulation were explored. The results are listed in Table 2.
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Table 2. Substrate scope of visible-light-promoted benzannulation.a
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As shown in Table 2, all the selected substrates could produce the expected naphthols (18a–18g) in
moderate to high yields, and substrates with electron-donating groups on their aromatic ring produced
higher yields (18b–18d) than those with electron-withdrawing groups (18e–18g).
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A proposed mechanism was depicted in Scheme 2. Initially, the excited state photocatalyst is gener-
ated from fac-Ir(ppy)3 under the visible light irradiation. The oxidative quenching may happen in pres-
ence of α-bromoketone 16 via a single-electron-transfer (SET) process and the resultant radical interme-
diate 14a (an electron deficient radical species) subsequently add to the electron rich double bond of
vinyl pivalate 15. The generated radical intermediate I can cyclize onto the aromatic ring system through
a homolytic-aromatic-substitution (HAS) process14 in presence of base to deliver the arene radical anion
II. Oxidation of II by the oxidized-state photocatalyst (E1/2Ir(IV)/Ir(III)= + 0.77 V vs SCE)13 will regenerate
the ground-state photocatalyst and afford the tetralone product 14b (path a). Alternatively, 14b can be
obtained via a chain-propagating electron transfer15 from another equivalent of substrate 16 (path b).
Finally, under the assistance of PTSA, 14b can be easily converted to the desired naphthol product 13.
Scheme 2. Proposed mechanism.
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Once the rapidly assembled key naphthol intermediate 13 was obtained, we investigated the prepara-
tion of advanced intermediate 11 (Scheme 3). To this end, naphthol 13 was treated with methyltriox-
orhenium (VII)16 in the presence of hydrogen peroxide (H2O2) and acetic acid in an aqueous solution;
the substituted 1,4-diquinone derivative 19 was obtained with 60% yield. Further oxidation of 19 with
H2O2 in the presence of Na2CO3 in EtOH followed by the treatment with H2SO417 afforded hydroxynaph-
thoquinone 11 with 66% overall yield. This is the key intermediate in the total synthesis of hybocarpone
(1), as reported by Nicolaou group.4
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Scheme 3. Synthesis of advanced intermediate 11.
With 11 in hand, we proceeded toward the total synthesis of hybocarpone (1). To this end, we first
removed the three methyl ether groups from substrate 11 through treatment with BBr3 in methylene
chloride at room temperature for 24 h, thus producing boryquinone (2) with 89% yield (Scheme 4).
Actually, compound 2 is a naturally occurring solid product with a deep red color, and the spectral data
for the synthesized compound were identical to those reported in the literature.3b,5
We then attempted to directly synthesize hybocarpone (1) from boryquinone (2) under different oxi-
dative coupling conditions. However, the desired hybocarpone (1) product could not be obtained (see
the Supporting Information for details). We believe that this transformation could be attributed to poly-
phenol groups in 2, which could be decomposed through oxidation.18 Therefore, we decided to use hy-
droxynaphthoquinone 11 as the substrate for constructing the pentacyclic core of compound 12, thus
realizing the formal total synthesis of hybocarpone (1). A modified version of the Nicolaou and Gray’s
method was used to isolate dimer product 12 as a single isomer with 25% yield together with 25%
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recovered starting material 11 and some unidentified products (Scheme 4). We could even isolated in-
termediate 12a using preparative thin layer chromatography (PTLC). Interestingly, 12a was found to
undergo a cascade hydration process, thus generating pentacycle product 12 in CDCl3 (see the Support-
ing Information for details). Nicolaou and Gray used 12 as a key intermediate in the total synthesis of
hybocarpone (1).4 Thus, we have achieved a formal total synthesis of hybocarpone (1) in eight steps
from commercially available starting compound.
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Scheme 4. Synthesis of boryquinone and advanced intermediate 12.
In conclusion, we developed a visible-light-promoted benzannulation strategy for a concise total syn-
thesis of boryquinone (2) in seven steps. We also used a modified CAN-mediated oxidative dimeriza-
tion/hydration cascade reaction to construct the sterically congested pentacyclic core of hybocarpone (1),
realizing a formal total synthesis of hybocarpone (1) in eight steps from commercially available 1,2,4-
trimethoxybenzene.
EXPERIMENTAL SECTION
General Experimental Information. Reagents were purchased at the highest commercial quality
(>95%) and used without further purification, unless otherwise stated. Anhydrous tetrahydrofuran (THF),
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toluene (PhMe) were distilled from sodium-benzophenone, dichloromethane (DCM), acetonitrile
(MeCN), and dimethylformamide (DMF) were distilled from calcium hydride. All reactions were carried
out with magnetic stirring, and if moisture or air sensitive, under an argon gas atmosphere with dry
solvents. External bath temperatures were used to record all reaction temperatures. Low temperature
reactions were carried out in a Dewar vessel filled with acetone/dry ice (–78 °C) or distilled water/ice
(0 °C). 3 W blue LEDs (λmax = 465 nm, model 12V 5050, purchased from Greenthink Co., Ltd.) was
used for light irradiation. Reactions were monitored by thin-layer chromatography (TLC) carried out on
0.25 mm Tsingdao silica gel glass-backed plates (60F-254) and visualized under UV light at 254 nm.
Staining was performed with an ethanolic solution of phosphomolybdic acid and heat as developing
agents. Tsingdao silica gel (60, particle size 0.040–0.063 mm) was used for flash column chromatog-
raphy. Yields refer to chromatographically, unless otherwise specified. NMR spectra were recorded on
Brüker Advance 500 (1H: 500 MHz, 13C 125 MHz), Brüker Advance 400 (1H: 400 MHz, 13C 100 MHz)
and Brüker Advance 300 (1H: 300 MHz, 13C 75 MHz). The spectra were reported as followed: chemical
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1
shift δ in ppm (multiplicity, coupling constant J in Hz, number of protons) for H NMR spectra and
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chemical shift δ in ppm for C NMR spectra. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combinations thereof.
Residual solvent peaks of CDCl3 (δ H = 7.26 ppm, δ C = 77.16 ppm) or CD3OD (δ H = 3.31 ppm, δ C =
48.00 ppm) was used as an internal reference, unless otherwise stated. High resolution mass spectromet-
ric (HRMS) data were recorded on Q-TOF-MS instruments (Brüker Apex IV RTMS and VG Auto Spec-
3000), respectively. Infrared spectra (IR) were recorded on an IR Prestige-21 FTIR spectrometer with a
KBr disc. Melting points (m.p.) are uncorrected and were recorded on a SGWX-4B apparatus.
Synthesis of 1,2,4-trimethoxy-3-methylbenzene. To a solution of 1,2,4-trimethoxybezene(14.9 mL,
100 mmol, 1.00 equiv) in THF (400 mL) was added nBuLi (50.0 mL of 2.5 M soln in hexanes, 125 mmol,
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1.25 equiv) dropwise over 5 min at -78 C under an argon atmosphere. After 15 min stirring at this
temperature, the reaction was allowed to warm to room temperature and keep stirring for another 1 h.
Then the reaction was cooled to -78 oC again and MeI (9.40 mL, 150 mmol, 1.50 equiv) was added. The
mixture was allowed to warm to room temperature again over 2 h and quenched with sat. aq. NH4Cl
(200 mL) solution. The aqueous layer was extracted with Et2O (3 x 250 mL). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by silica gel flash chromatography (19:1 hexanes:EtOAc) to afford 1,2,4-
trimethoxy-3-methylbenzene (18.2 g, 99%) as a colorless oil. Rf = 0.75 (silica gel, EtOAc/hexanes=
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1
1/16). H NMR (500 MHz, CDCl3) δ 6.71 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H),
3.81 (s, 3H), 3.79 (s, 3H), 2.17 (s, 3H). The spectroscopic data was identical to the one reported in the
literature.19
Synthesis of 2-bromo-1-(2,4,5-trimethoxy-3-methylphenyl)butan-1-one (16). (Strategy A: one-step
synthesis): To a stirred solution of AlBr3 (221 mg, 0.83 mmol, 1.50 equiv) in DCM (3.0 mL) was added
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2-bromobutanoyl chloride (76.5 μL, 0.66 mmol, 1.20 equiv) at 0 C under an argon atmosphere, the
resultant mixture was stirred at this temperature for 10 min. A solution of 1,2,4-trimethoxy-3-
methylbenzene (100 mg, 0.55 mmol, 1.00 equiv) in DCM (2.0 mL) was added dropwise and the reaction
was allowed to warm to room temperature and stirring was continued for 2 h. The reaction mixture was
quenched with sat. aq. NH4Cl (5.0 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel flash chromatography (19:1 hex-
anes:EtOAc) to afford 16 (81.6 mg, 45%) as a brown oil. (Strategy B: multi-gram scale synthesis):
1,2,4-trimethoxy-3-methylbenzene (15.5 g, 85.0 mmol, 1.00 equiv) and n-butyric acid (9.4 mL, 102
mmol, 1.20 equiv) were added into polyphosphate acid (PPA, 100 g) and the reaction mixture was
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stirred at 65 oC for 5 h. Ice water (500 mL) was poured into the mixture and extracted with DCM (3 x
300 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure, the residue was filtered through a short plug of silica gel (eluent: 10%
EtOAc in hexanes) to give the crude product as a yellow oil. The crude product was submitted to the
next step without further purification. To a solution of the crude product in ether (100 mL) was added
Br2 (4.1 mL, 85.0 mmol, 1.00 equiv) via addition funnel over 30 min at room temperature. When the
reddish color disappeared (about 2 h), the organic solvent was removed under reduced pressure. The
residue was diluted with DCM (100 mL) and washed with sat. aq. NaHCO3 (50 mL) and brine (100
mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by silica gel flash chromatography (19:1 hexanes:EtOAc) to afford the
16 (20.3 g, 72 % yield over two steps) as a brown oil. Rf = 0.58 (silica gel, EtOAc/hexanes= 1/8). 1H
NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 5.37 (dd, J = 7.8, 6.2 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.72
(s, 3H), 2.21 (s, 3H), 2.17 (dt, J = 14.6, 1H), 2.04 (dt, J = 14.6, 7.4 Hz, 1H), 1.07 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 196.6, 152.4, 152.0, 149.6, 126.3, 125.9, 111.0, 62.8, 60.5, 56.1, 54.6,
27.6, 12.4, 9.7; IR νmax (film) 2966, 1681, 1628, 1404, 1275, 1087, 1002; HRMS (ESI) m/z calcd for
C14H20O4Br [M+H]+:331.0539; found:331.0541.
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General procedure for bromide precursor synthesis: 20 To a stirred solution of commercially avail-
able ketones (10.0 mmol, 1.00 equiv) in AcOH (50 mL) was added Br2 (0.48 mL, 10.0 mmol, 1.00
equiv) dropwise. When the reddish color disappeared (about 1-2 h), the organic solvent was removed
under reduced pressure. The residue was diluted with DCM (50 mL) and washed with sat. aq. NaHCO3
(50 mL)and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under
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reduced pressure. The crude product was purified by silica gel flash chromatography (20:1 hex-
anes:EtOAc) to afford the corresponding precursors 17. Note: 17a was commercially available and
purchased from Aldrich (CAS No: 2114-00-3)
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2-bromo-1-(p-tolyl)propan-1-one (17b). 17b was synthesized following the general procedure. After
purification by silica gel flash chromatography, 17b was provided as a white solid (1.60 g, 71% yield
from 1-(p-tolyl)propan-1-one). Rf = 0.65 (silica gel, DCM/hexanes= 1/2). 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.28 (q, J = 6.6 Hz, 1H), 2.42 (s, 3H), 1.89 (d, J =
6.6 Hz, 3H). The spectroscopic data was identical to the one reported in the literature.20c
2-bromo-1-(4-methoxyphenyl)propan-1-one (17c). 17c was synthesized following the general pro-
cedure. After purification by silica gel flash chromatography, 17c was provided as a light yellow solid
(2.40 g, > 98% yield from 1-(4-methoxyphenyl)propan-1-one). Rf = 0.68 (silica gel, DCM/hexanes=
1/2). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.0 Hz, 2H), 7.06 – 6.86 (m, 2H), 5.26 (q, J = 6.6 Hz,
1H), 3.87 (s, 3H), 1.88 (d, J = 6.6 Hz, 3H).The spectroscopic data was identical to the one reported in
the literature.20a
1-(benzo[d][1,3]dioxol-5-yl)-2-bromobutan-1-one (17d). 17d was synthesized following the general
procedure. After purification by silica gel flash chromatography, 17d was provided as a white solid
(2.04 g, 85% yield from 1-(benzo[d][1,3]dioxol-5-yl)butan-1-one). Rf = 0.88 (silica gel, DCM/hex-
anes= 1/1). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 6.86
(d, J = 8.2 Hz, 1H), 6.06 (s, 2H), 4.99 (dd, J = 7.7, 6.5 Hz, 1H), 2.31 – 1.99 (m, 2H), 1.06 (t, J = 7.3
Hz, 3H).The spectroscopic data was identical to the one reported in the literature.20b
2-bromo-1-(4-chlorophenyl)propan-1-one (17e). 17e was synthesized following the general proce-
dure. After purification by silica gel flash chromatography, 17e was provided as a white solid (2.24 g,
91% yield from2-bromo-1-(4-chlorophenyl)propan-1-one). Rf = 0.85 (silica gel, DCM/hexanes= 1/1).
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1H NMR (400 MHz, CDCl3) δ 8.06 – 7.89 (m, 2H), 7.53 – 7.38 (m, 2H), 5.22 (q, J = 6.6 Hz, 1H), 1.90
(d, J = 6.6 Hz, 3H).The spectroscopic data was identical to the one reported in the literature.20c
2-bromo-1-(4-fluorophenyl)propan-1-one (17f). 17f was synthesized following the general proce-
dure. After purification by silica gel flash chromatography, 17f was provided as a colorless oil (2.06 g,
90% yield from 1-(4-fluorophenyl)propan-1-one). Rf = 0.68 (silica gel, DCM/hexanes= 1/2). 1H NMR
(400 MHz, CDCl3) δ 8.06 – 7.87 (m, 2H), 7.11 (dd, J = 11.8, 5.4 Hz, 2H), 5.23 (q, J = 6.6 Hz, 1H),
1.86 (d, J = 6.6 Hz, 3H).The spectroscopic data was identical to the one reported in the literature.20c
2-bromo-1-(4-(trifluoromethyl)phenyl)propan-1-one (17g). 17g was synthesized following the gen-
eral procedure. After purification by silica gel flash chromatography, 17g was provided as a colorless
oil (2.28 g, 82% yield from 1-(4-(trifluoromethyl)phenyl)propan-1-one). Rf = 0.70 (silica gel,
DCM/hexanes= 1/2). 1H NMR (400 MHz, CDCl3) δ 8.12 (t, J = 6.5 Hz, 2H), 7.75 (t, J = 7.5 Hz, 2H),
5.26 (qd, J = 6.6, 2.1 Hz, 1H), 1.92 (t, J = 6.0 Hz, 3H).The spectroscopic data was identical to the one
reported in the literature.20a
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General procedure for visible-light-promoted benzannulation. A mixture of α-bromocarbonyl 17a-
17g (100 mg, 1.00 equiv), vinyl pivalate 15 (1.20 equiv), K2CO3 (2.00 equiv), fac-Ir(ppy)3 (5 mol %)
was charged with MeCN (2 mL) in round-bottom flask under an argon atmosphere, the resultant mix-
ture was stirred at room temperature for 8 h under irradiation with visible light from a 3 W blue LEDs
at a distance of 5.0 cm. Upon completion of the reaction by TLC monitor, the reaction mixture was
filtered through a pad of silica gel (eluent: EtOAc). The organic layer was washed with brine and dried
over anhydrous Na2SO4, which was removed under reduced pressure and the resultant residue was
dissolved in toluene (2 mL). PTSA (2.00 equiv) was added and the reaction was refluxed for 2-3 h with
a Dean-stark apparatus. When starting material was totally consumed (monitored by TLC), the reaction
mixture was allowed to cool to room temperature and neutralized with sat. aq. NaHCO3, then extracted
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with DCM (2 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The crude product was purified by silica gel flash chromatography to
obtain the corresponding naphthols 18a-18g.
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2-ethyl-5,6,8-trimethoxy-7-methylnaphthalen-1-ol (13). The synthesis of naphthol 13 was carried
out on 1.0 g scale following the general procedure above but 1 mol % fac-Ir(ppy)3 was used and the
reaction time was prolonged to 24 h. After purification by silica gel flash chromatography (50:1 hex-
anes:EtOAc), 13 was provided as a brown oil (446 mg, 53% yield from 16). Rf = 0.68 (silica gel,
EtOAc/hexanes= 1/8). 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.27 (d, J
= 8.8 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.89 (s, 3H), 2.79 (q, J = 7.6 Hz, 2H), 2.35 (s, 3H), 1.28 (t, J
= 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.0, 149.6, 147.7, 144.1, 128.4, 124.6, 121.9, 114.8,
112.3, 105.4, 62.4, 61.0, 60.7, 23.0, 14.5, 9.8; IR νmax (film) 2995, 1769, 1759, 1376, 1247, 1241, 1058;
HRMS (ESI) m/z calcd for C16H21O4 [M+H]+: 277.1434; found: 277.1433.
2-methylnaphthalen-1-ol (18a). 18a was synthesized following the general procedure. After purifica-
tion by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18a was provided as a brown
1
powder (16.8 mg, 53% yield from 17a). Rf = 0.45 (silica gel, EtOAc/hexanes= 1/8). H NMR (500
MHz, CDCl3) δ 8.13 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.38 (d, J = 8.3
Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.11 (s, 1H), 2.42 (s, 3H). The spectroscopic data was identical to
the one reported in the literature.20
2,6-dimethylnaphthalen-1-ol (18b). 18b was synthesized following the general procedure. After pu-
rification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18b was provided as a
o
brown powder (18.9 mg, 55% yield from 17b). m.p.: 75-77 C. Rf = 0.5 (silica gel, EtOAc/hexanes=
1/8). 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.35 – 7.27 (m, 2H), 7.21 (d,
J = 8.3 Hz, 1H), 5.05 (s, 1H), 2.50 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 148.7, 135.1,
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133.9, 129.2, 127.7, 126.9, 122.7, 120.9, 119.7, 115.6, 21.7, 15.7; IR νmax (film) 2995, 1755, 1249,
1240, 764, 748; HRMS (ESI) m/z calcd for C12H11O [M-H]-: 171.0815; found: 171.0813.
6-methoxy-2-methylnaphthalen-1-ol (18c). 18c was synthesized following the general procedure. Af-
ter purification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18c was provided as a
yellow solid (21.1 mg, 56% yield from 17c). m.p.: 83-85 oC. Rf = 0.53 (silica gel, EtOAc/hexanes= 1/8).
1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.3 Hz,
1H), 7.12 (dd, J = 9.1, 2.5 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 5.04 (s, 1H), 3.91 (s, 3H), 2.38 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 157.6, 149.0, 134.9, 129.8, 122.9, 119.9, 119.2, 118.0, 114.2, 106.0, 55.4,
15.5; IR νmax (film) 2995, 1595, 1275, 1259, 764, 749; HRMS (ESI) m/z calcd for C12H13O2[M+H]+:
189.0910; found: 189.0910.
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6-ethylnaphtho[2,3-d][1,3]dioxol-5-ol (18d). 18d was synthesized following the general procedure.
After purification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18d was provided
as a brown solid (26.8 mg, 62% yield from 17d). m.p.: 108-110 oC. Rf = 0.48 (silica gel, EtOAc/hexanes=
1/8). 1H NMR (500 MHz, CDCl3) δ 7.46 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.05
(s, 1H), 6.02 (s, 2H), 4.98 (s, 1H), 2.73 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 147.9, 147.5, 130.6, 125.8, 121.8, 121.2, 119.8, 103.9, 101.1, 98.3, 23.0, 14.5; IR νmax (film)
2993, 1754, 1279, 1259, 764, 749; HRMS (ESI) m/z calcd for C13H13O3 [M+H]+: 217.0859; found:
217.0860.
6-chloro-2-methylnaphthalen-1-ol (18e). 18e was synthesized following the general procedure. After
purification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18e was provided as a
o
brown solid (20.7 mg, 54% yield from 17e). m.p.: 118-123 C. Rf = 0.53 (silica gel, EtOAc/hexanes=
1/8). 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 9.0,
2.1 Hz, 1H), 7.31 – 7.23 (m, 2H), 5.09 (s, 1H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 149.0, 134.3,
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131.6, 130.4, 126.4, 126.2, 123.3, 122.8, 119.5, 116.7, 15.7; IR νmax (film) 2989, 1275, 1261, 1241, 764,
749; HRMS (ESI) m/z calcd for C11H8OCl [M-H]-: 191.0269; found: 191.0268.
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6-fluoro-2-methylnaphthalen-1-ol (18f). 18f was synthesized following the general procedure. After
purification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18f was provided as a
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brown oil (17.2 mg, 49% yield from 17f). Rf = 0.55 (silica gel, EtOAc/hexanes= 1/8). H NMR (500
MHz, CDCl3) δ 8.16 (dd, J = 9.2, 5.7 Hz, 1H), 7.37 (dd, J = 10.0, 2.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H),
7.25 (dd, J = 8.9, 2.3 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 5.12 (s, 1H), 2.39 (s, 3H); 19F NMR (376
MHz, CDCl3) δ -114.9, -116.2 ; 13C NMR (125 MHz, CDCl3) δ 160.9 (d, 1JCF = 243.8 Hz, C-F), 149.1,
134.5 (d, 3JCF = 8.8 Hz, CH),130.46, 124.1 (d, 3JCF = 8.8 Hz, CH), 121.7, 119.6 (d, 4JCF = 5.0 Hz, CH),
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115.9, 115.6 (d, JCF = 25.0 Hz, CH), 110.7 (d, JCF = 21.3 Hz, CH), 15.5; IR νmax (film) 1275, 1261,
1241, 764, 749; HRMS (ESI) m/z calcd for C11H8OF [M-H]-: 175.0564; found: 175.0565.
2-methyl-6-(trifluoromethyl)naphthalen-1-ol (18g). 18g was synthesized following the general pro-
cedure. After purification by silica gel flash chromatography (20:1→10:1 hexanes:EtOAc), 18g was
o
provided as a brown solid (20.8 mg, 46% yield from 17g). m.p.: 87-90 C. Rf = 0.50 (silica gel,
EtOAc/hexanes= 1/8). 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.62 (dd, J
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= 8.8, 1.6 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 5.15 (s, 1H), 2.44 (s, 3H); F
13
NMR (376 MHz, CDCl3) δ -62.3; C NMR (125 MHz, CDCl3) δ 148.9, 132.4, 130.5, 127.6, 125.7,
125.5 (q, 2JCF = 24.5 Hz, C-CF3), 123.6, 122.6, 121.2, 121.0 (q, 1JCF = 237.5 Hz, CF3), 118.8, 15.9; IR
νmax (film) 1318, 1274, 1261, 1105, 1095, 764, 749; HRMS (ESI) m/z calcd for C12H8OF3 [M-H]-:
225.0532; found: 225.0538.
Synthesis of 2-ethyl-5,6,8-trimethoxy-7-methylnaphthalene-1,4-dione (19). To a stirred solution of
13 (318 mg, 1.15 mmol, 1.00 equiv) and methyltrioxorhenium(VII) MeReO3 (15 mg, 0.06 mmol, 5
mol %) in AcOH (5. 0 mL) was added 30% aqueous hydrogen peroxide H2O2 (0.6 mL, 5.75 mmol, 5.00
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equiv) dropwise at 0 oC. The reaction was allowed to warm to room temperature and stirring was con-
tinued for 3 h, quenched with sat. aq. Na2SO3 (10 mL) and subsequently extracted with DCM (3 x 20
mL). The combined organic layer was washed with sat. aq. NaHCO3 (2 x 10 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash
chromatography (15:1→10:1 hexanes:EtOAc) to afford 1,4-naphthoquinone 19 (200 mg, 60%) as a yel-
low oil. Rf = 0.55 (silica gel, EtOAc/hexanes= 1/4). 1H NMR (400 MHz, CDCl3) δ 6.60 (t, J = 1.5 Hz,
1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.54 (qd, J = 7.4, 1.5 Hz, 2H), 2.27 (s, 3H), 1.16 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 184.9, 184.5, 158.4, 156.3, 152.7, 149.9, 134.6, 134.0, 124.6,
121.7, 61.5, 61.4, 61.0, 22.5, 11.9, 10.0; IR νmax (film) 2995, 1770, 1383, 1247, 1058, 749; HRMS (ESI)
m/z calcd for C16H19O5[M+H]+:291.1227; found:291.1222.
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Synthesis of 2-ethyl-3-hydroxy-5,6,8-trimethoxy-7-methylnaphthalene-1,4-dione (11). To a solution
of 19 (800 mg, 2.76 mmol, 1.00 equiv) in EtOH (20 mL) was added 30% aqueous hydrogen peroxide
H2O2 (5.6 mL, 55.2 mmol, 20.0 equiv) dropwise at 0-5 oC. A solution of Na2CO3 (292 mg, 2.76 mmol,
1.00 equiv) in cold water (3.0 mL) was added and the reaction mixture was allowed to stir until the
yellow color disappeared (about 3 h), then quenched with sat. aq. Na2SO3 (10 mL) and subsequently
extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to give the crude product as a deep yellow oil.
The crude product was submitted to the next step without further purification. The sulfuric acid (5.0 mL)
was added into the flask containing the crude product and resulted bright red solution, stirred at 0-5 oC
for 20 min. The reaction mixture was slowly added to chilled water and extracted with DCM (3 x 30
mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The crude product was purified by silica gel flash chromatography (15:1
→8:1 hexanes:EtOAc) to afford naphthazarin 11 (554 mg, 66%) as a reddish solid. m.p.: 105-107 oC. Rf
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= 0.48 (silica gel, EtOAc/hexanes= 1/4). 1H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 3.93 (s, 3H), 3.90
(s, 3H), 3.82 (s, 3H), 2.56 (q, J = 7.5 Hz, 2H), 2.28 (s, 3H), 1.12 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 183.8, 180.6, 157.3, 156.4, 151.8, 150.9, 137.0, 125.4, 121.7, 121.4, 61.4, 61.3, 61.0, 17.0,
12.8, 10.2; IR νmax (film) 2995, 1768, 1759, 1383, 1247, 1057; HRMS (ESI) m/z calcd for
C16H19O6[M+H]+:307.1176; found:307.1175.
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Synthesis of boryquinone (2). To a stirred solution of 11 (100 mg, 0.33 mmol, 1.00 equiv) in dry DCM
(5.0 mL) was added BBr3 (1.65 mL of 1 M soln in DCM, 1.65 mmol, 5.00 equiv) under an argon gas
atmosphere at -78 oC. The reaction mixture was allowed to warm to room temperature and stirred for 24
h, then quenched with chilled water (5.0 mL) and subsequently extracted with DCM (3 x 10 mL). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel flash chromatography (1:1 hex-
anes:EtOAc) to give boryquinone 2 (76.7 mg, 89%) as a reddish solid, which was sparingly soluble in
CDCl3 and totally soluble in EtOAc or CD3OD. m.p.: 179-182 oC (lit. 180-184 oC)5. Rf = 0.45 (silica gel,
EtOAc/hexanes= 1/1). 1H NMR (500 MHz, CDCl3/EtOAc) δ 13.47 (s, 1H), 11.75 (s, 1H), 6.76 (s, 1H),
6.72 (s, 1H), 2.68 (q, J = 7.5 Hz, 2H), 2.15 (s, 3H), 1.15 (t, J = 7.5 Hz, 3H); 1H NMR (400 MHz, CD3OD)
δ 2.65 (q, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3/EtOAc) δ
173.7, 173.0, 171.2 (CH3C(O)OCH2CH3), 164.6, 164.4, 151.5, 151.2, 128.5, 122.9, 108.4, 104.1, 60.5
(CH3C(O)OCH2CH3), 21.1 (CH3C(O)OCH2CH3), 16.8, 14.4 (CH3C(O)OCH2CH3), 12.8, 8.6; 13C NMR
(100 MHz, CD3OD) δ 173.7, 172.7, 166.0, 165.6, 153.8, 153.4, 127.5, 121.8, 109.0, 103.5, 16.2, 12.1,
7.4; IR νmax (film) 2995, 1769, 1755, 1247, 1055; HRMS (ESI) m/z calcd for C13H13O6[M+H]+: 265.0707;
found: 265.0709.
Synthesis of hybocarpone methyl ether (12). Under an argon gas atmosphere, a solution of CAN (113
mg, 0.21 mmol, 1.20 equiv) in MeCN (2.0 mL) was stirred at 0oC. In a separated flask, hydroxyl quinone
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11(52 mg, 0.17 mmol, 1.00 equiv) was dissolved in degassed MeCN (2.0 mL) and cooled to 0 oC. This
solution was then added to the solution of CAN in one portion and the reaction mixture was stirred for
2 min. During this time, the color of the reaction mixture changed from black to a light yellow. Water
(2.0 mL) was added to the reaction mixture and subsequently extracted with DCM (3 x 5.0 mL). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was carefully purified by silica gel flash chromatography
(10:1→5:1→2:1, hexanes:EtOAc) to give 12 (13 mg, 25%) as colorless oil, and the starting material 11
(13 mg, 25%). Notably, 12 was isolated as a single isomer. Rf = 0.15 (silica gel, EtOAc/hexanes= 1/3).
1H NMR (400 MHz, CDCl3) δ 5.11 (s, 2H), 3.95 (s, 6H), 3.92 (s, 6H), 3.81 (s, 6H), 2.36 (dq, J = 12.9,
7.3 Hz, 2H), 2.31 (s, 6H), 1.88 (dq, J = 12.9, 7.3 Hz, 2H), 0.59 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 192.9, 192.0, 157.8, 156.0, 149.4, 136.6, 128.2, 123.8, 101.9, 70.0, 62.8, 62.1, 61.6, 26.5, 11.1,
10.5; IR νmax (film) 2995, 1769, 1383, 1247, 1058, 913, 744; HRMS (ESI) m/z calcd for
C32H36O13Na[M+Na]+: 651.2048; found: 651.2053.
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2,2'-diethyl-5,5',6,6',8,8'-hexamethoxy-7,7'-dimethyl-[2,2'-binaphthalene]-1,1',3,3',4,4'(2H,2'H)-
hexaone (12a). 12a was isolated for characterization purpose by taking an aliquot from the above reac-
tion mixture and filtering it through a short plug of silica (eluent: EtOAc), followed by concentration
under reduced pressure and the residue was purified by PTLC (silica gel, 1:1 hexanes:EtOAc, with two
drops of NEt3) to give 12a as a colorless oil. 12a was observed to undergo hydration to give the penta-
cycle product 12 in CDCl3 (See the Supporting Information for details). Rf = 0.45 (silica gel, EtOAc/hex-
anes= 1/3). 1H NMR (500 MHz, CDCl3) δ 3.97 (s, 6H), 3.95 (s, 6H), 3.69 (s, 6H), 2.59 (dq, J = 15.3, 7.6
Hz, 2H), 2.38 – 2.27 (dq, J = 15.3, 7.6 Hz, 2H), 2.24 (s, 6H), 0.73 (t, J = 7.6 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 198.7, 191.5, 179.3, 158.2, 154.6, 150.5, 136.2, 126.5, 124.8, 73.3, 62.4, 62.3, 61.1,
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27.9, 10.8, 10.5; IR νmax (film) 2995, 1769, 1247, 1058, 913, 743; HRMS (ESI) m/z calcd for
C32H35O12[M+H]+:611.2123; found:611.2123.
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The Supporting Information is available free of charge on the ACS Publications website at DOI: Full
spectroscopic data for all new compounds and crystallographic data (PDF)
AUTHOR INFORMATION
Corresponding Author
zyang@pku.edu.cn
gongjx@pku.edu.cn
ACKNOWLEDGMENT
This work was supported by National Science Foundation of China (Grant Nos. 21772008, 21632002,
21572009, and U1606403), Guangdong Natural Science Foundation (Grant No. 2016A030306011 and
2017TQ04R032), Shenzhen Basic Research Program (Grant Nos. JCYJ20170818090044432 and
JCYJ20160226105337556).
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