Total Synthesis of Dactylicapnosines A and B

Article abstract of DOI:10.1021/acs.joc.0c01900

Dactylicapnosines A and B, two natural products from Dactylicapnos scandens, exhibited potent anti-inflammatory and analgesic activities both in vitro and in vivo. In this paper, we report our second-generation synthesis of dactylicapnosine A and the first total synthesis of dactylicapnosine B. Our synthetic route features acid-induced isomerization of o-quinone (16), Co-mediated regioselective ring contraction of p-quinone (8b), and oxidative methoxylation of enone (18). This modified sequence provides dactylicapnosine A in 14 steps with an overall yield of 12% from a known compound (14a) and also offers opportunities to synthesize dactylicapnosine-like analogues for biological investigations.

Full text of DOI:10.1021/acs.joc.0c01900

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Total Synthesis of Dactylicapnosines A and B
Yinjiao Zhao, Yuda Li, Bei Wang, Jingfeng Zhao, Liang Li, Xiao-Dong Luo,* and Hongbin Zhang*
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sı Supporting Information
ABSTRACT: Dactylicapnosines A and B, two natural products from Dactylicapnos scandens, exhibited potent anti-inflammatory and
analgesic activities both in vitro and in vivo. In this paper, we report our second-generation synthesis of dactylicapnosine A and the
first total synthesis of dactylicapnosine B. Our synthetic route features acid-induced isomerization of o-quinone (16), Co-mediated
regioselective ring contraction of p-quinone (8b), and oxidative methoxylation of enone (18). This modified sequence provides
dactylicapnosine A in 14 steps with an overall yield of 12% from a known compound (14a) and also offers opportunities to
synthesize dactylicapnosine-like analogues for biological investigations.
INTRODUCTION
dactylicapnosine A through regioselective oxidative ring
contraction of the isocorydione derivative.
■
Dactylicapnosines A and B are two racemic natural products
isolated from Dactylicapnos scandens (Papaveraceae), a tradi-
tional Chinese medicinal herb used widely for treatment of
various pains in the southwest of China. The structures of
these two compounds are 9,10-seco-7-dehydroaporphines with
unprecedented highly oxygenated five-membered D-rings
Figure 1). Biosynthetically, dactylicapnosines A and B might
derive from oxidative D-ring contractions of isocorydione and
demethylsonodione, two known aporphine alkaloids present
also in Dactylicapnos scandens, respectively.
RESULTS AND DISCUSSION
■
1
Our retrosynthetic analysis for dactylicapnosine A and
dactylicapnosine B is indicated in Scheme 2. Dactylicapnosine
B could be prepared by regioselective demethylation of
dactylicapnosine A with the assistance of the neighboring
carbonyl group. The isocorydione derivative (8a) could be
obtained by oxidative formation of the p-quinone moiety and
oxidative aromatization of the B-ring. The aporphinoid
intermediate (11) can be synthesized by a palladium-mediated
coupling reaction of compound 12. Pictet−Spengler cycliza-
tion of aldehyde 14 (X = O) with commercially available
amine derivative 13 would lead to tetrahydroisoquinoline 12.
The highly oxy-substituted benzene derivative 14 (X = CH2)
could be accessed by Claisen rearrangement of intermediate
(
2
Dactylicapnosine A exhibited significant anti-inflammatory
activity in vitro by inhibition of the expression of TNF-α, IL-
β, and PGE2. In our previous studies, the in vivo anti-
1
1
inflammatory and analgesic activities of dactylicapnosine A
were also evaluated using samples provided by our bioinspired
total synthesis. Although the total synthesis of dactylicapnosine
A, with the key steps being oxidative aromatization of the
aporphinoid derivative (Scheme 1, 7) and oxidative rearrange-
ment of p-quinone (8), was completed in 10 steps with 5%
overall yield, the shortcoming associated with our first
generation synthetic route is the unbiased oxidative ring
contraction of p-quinone 8, which provided the desired
cyclopentanone (9) in only 32% yield (Scheme 1). The
undesired regioisomer (10) was also produced in similar yield.
To access the sample of dactylicapnosine A as well as its
analogues more for further biological evaluation, it is of our
interest to develop a regioselective strategy with better overall
yield. In this full paper, we report the first total synthesis of
dactylicapnosine B and our second-generation synthesis of
1
5c followed by a number of functional group manipulations.
Compound 15c could be obtained from commercially available
2
,3,4-trimethoxybenzaldehyde.
We began our investigations by preparing intermediate 7
1
(
Scheme 3) according to our previous procedure. Starting
from 2,3,4-trimethoxybenzaldehyde (15a), Baeyer−Villiger
Received: August 6, 2020
©
XXXX American Chemical Society
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A
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Figure 1. Alkaloids from Dactylicapnos scandens and a possible biosynthetic relationship.
Scheme 1. Bio-inspired synthesis of dactylicapnosine A
oxidation followed by allyl ether formation (to 15b) and
Claisen rearrangement afforded 14a in 89% overall yield in 3
steps. Treatment of phenol 14a with benzyl bromide in the
only epoxide 7a, the structure being established by X-ray
crystallography (see the Supporting Information), was isolated
when hydrogen peroxide was used in the presence of sodium
3
7
presence of potassium carbonate provided 14b in 99% yield.
After oxidative cleavage of the double bond, the resulting
aldehyde (14c) was then converted to its bromide 14d using
carbonate (Scheme 4). Other reaction conditions resulted in
decomposition of substrate 7. Although sodium perborate
tetrahydrate (NaBO ·4H O) and hydrogen peroxide (H O )
3
2
2
2
4
standard NBS conditions, with 74% yields in two steps.
could promote the oxidative ring-contraction of quinone 8 to
compounds 9, 9a, and 10 (structures of 9a and 10 were
confirmed by X-ray crystallography analysis, see the Supporting
Information) under mild reaction conditions, no improved
yields or regioselectivities were observed (Scheme 4).
Treatment of 14d with amine 13a in the presence of
trifluroacetic acid afforded tetrahydroisoquinoline 12a in yields
5
of 86%. With intermediate 12a in hand, we next conducted
the coupling reaction with palladium acetate and triphenyl-
6
phosphine under microwave conditions and the aporphinoid
Having failed to improve the regioselectivity, we decided to
derivative 11a was obtained in 78% yield (Scheme 3). After
removal of the benzyl-protecting group, oxidation of the
resulting phenol with iodobenzene diacetate (IBD) in
hexafluoroisopropanol (HFIP) gave quinone 7 in 86% yield
over two steps.
explore alternative ring contraction mediated by cobaltous
8
chloride. After removal of the Boc-protecting group under
acidic conditions, amine 11b was converted to intermediate
1
1c by treating with N-chlorosuccinimide, potassium tert-
9
1
butoxide, and methyl chloroformate (Scheme 5). Next,
palladium-catalyzed hydrogenolysis followed by oxidation
with IBX (o-iodoxybenzoic acid) afforded o-quinone 16 in
77% yield. To our delight, o-quinone 16 could be readily
isomerized to p-quinone 8b in the presence of sulfuric acid in
high yield (Scheme 5).
In our previous synthesis, compound 8 was obtained by
oxidative aromatization and used in the following sodium
periodate-mediated ring contraction (Schemes 3 and 1). In this
study, further attempts were made toward oxidative ring
contraction of quinones 7 and 8 using a range of oxidants
10
(
Oxone, KMnO , NaBO ·4H O, NaIO , and H O ); however,
4 3 2 4 2 2
B
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Scheme 2. Retrosynthetic Analysis of Dactylicapnosines A and B
Scheme 3. Synthesis of Intermediates 7 and 8
With intermediate 8b in hand, we next conducted a cobalt-
mediated ring contraction reaction. Treating p-quinone 8b
with cobaltous chloride in methanol and tetrahydrofuran
(THF) afforded cyclopentenone 17 in 68% yield. Dehydration
with trifluoroacetic anhydride in the presence of triethyl-
amine provided intermediate 18. Oxidation of the enone
8
11
C
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Scheme 4. Further Studies on Oxidative Ring Contraction
Scheme 5. Transformation of 11a to p-Quinone 8b
Scheme 6. Final Stage toward the Synthesis of Dactylicapnosines A and B
D
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system with hydrogen peroxide in the presence of potassium
carbonate led to the precursor of dactylicapnosine A in 87%
yield. After deprotection with sodium methoxide and
methylation with methyl iodide, dactylicapnosine A was
obtained in 70% yield. Finally, treatment of dactylicapnosine
Methyl-8-(benzyloxy)-1,2,9,10,11-pentamethoxy-4,5-dihydro-
6
H-dibenzo[de,g]quinoline-6- carboxylate (11c). Amine 11b (1.346
g, 2.82 mmol) was dissolved in THF (40 mL). To this solution, N-
chlorosuccinimide (NCS, 450 mg, 3.39 mmol) was added in a
nitrogen-filled glovebox. After being stirred at room temperature for 2
h, sodium tert-butoxide (2.710 g, 28.2 mmol) was introduced. The
reaction mixture was then stirred for 12 h before addition of methyl
chloroformate (2.664 g, 28.2 mmol). The resulting mixture was
allowed to stir at ambient temperature for 24 h. After thin-layer
chromatography (TLC) analysis, the mixture was diluted with water
(150 mL) and extracted with ethyl acetate (4 × 50 mL). The
combined organic phases were washed with brine (30 mL), dried over
12
A with boron trichloride, leading to an unstable diketone
intermediate (20, NMR spectra shown in the Supporting
Information), followed by methoxylation with 2,2-dimethox-
ypropane completed the first total synthesis of dactylicapno-
sine B (Scheme 6). The NMR spectra as well as physical data,
including X-ray analysis (of compounds 19 and 1), of our
synthetic dactylicapnosine A and dactylicapnosine B were
anhydrous MgSO , and concentrated under reduced pressure. The
4
1
residue was purified by column chromatography on silica gel
consistent with those of natural products.
(
petroleum ether/ethyl acetate = 5:1) to afford carbomate 11c (1.5
1
g, 90%) as a colorless syrup. H NMR (400 MHz, CDCl ): δ: 8.02 (s,
3
CONCLUSIONS
1
2
3
H), 7.62−7.60 (m, 2H), 7.43−7.32 (m, 3H), 7.05 (s, 1H), 5.16 (s,
■
H), 4.07−4.05 (m, 8H), 3.97 (s, 3H), 3.76 (s, 3H), 3.69 (s, 3H),
In summary, we have completed the total synthesis of two
bioactive natural alkaloids bearing a 9,10-seco-7-dehydroapor-
phinoid skeleton. Our second-generation synthetic route
toward dactylicapnosines A and B features acid-induced
isomerisation of o-quinone, a Co-mediated regioselective ring
contraction reaction of p-quinone, and oxidative methoxylation
of the enone system. This modified sequence led to the target
1
3
1
.63 (s, 3H), 3.16 (t, J = 4.8 Hz, 2H); C{ H} NMR (100 MHz,
CDCl ): δ: 155.2, 150.8, 149.2, 145.9, 145.1, 141.7, 137.8, 132.1,
3
1
7
3
1
28.5, 128.2, 127.9, 127.1, 124.5, 123.6, 120.3, 116.1, 112.8, 111.1,
−1
6.1, 61.6, 60.9, 60.8, 56.7, 53.0, 43.5, 30.3; IR (KBr, thin film, cm ):
030, 2993, 2940, 2844, 1704, 1619, 1584, 1496, 1456, 1447, 1390,
361, 1334, 1323, 1280, 1255, 1235, 1219, 1201, 1142, 1120, 1097,
+
+
1078, 1051, 1023, 988, 762, 735, 700; HRMS (ESI ) m/z [M + H] :
(
dactylicapnosine A) in 12% overall yields from a known
calcd for C H NO : 534.2122, found: 534.2121.
3
0
32
8
compound (14a), much better than our previous synthesis.
This new synthetic route should be useful in the future for the
synthesis of medicinally interesting dactylicapnosine-like
analogues.
Methyl-1,2,10,11-tetramethoxy-8,9-dioxo-4,5,8,9-tetrahydro-6H-
dibenzo[de,g]quinoline-6- carboxylate (16). To a solution of
carbamate 11c (1.33 g, 2.495 mmol) in methanol (20 mL), palladium
on carbon (10% Pd/C, 270 mg, 2.495 mmol) was added. The
resulting mixture was stirred at room temperature in an autoclave
under a hydrogen atmosphere (0.4 MPa H ) for 12 h. The mixture
2
EXPERIMENTAL SECTION
was filtered through a short column of silica gel and washed with ethyl
acetate (ca. 50 mL). The filtrate was concentrated under reduced
pressure to give crude phenol, which was used for the next step
without further purification. The crude phenol was dissolved in
dimethyl sulfoxide (DMSO) (20 mL), and then, 2-iodoxybenzoic acid
■
General Experiments. All reactions were performed in oven-
dried glassware under a positive pressure of dry nitrogen. Anhydrous
THF was dried by distillation over metallic sodium and
benzophenone; dichloromethane and methanol were distilled from
calcium hydride. Starting materials and reagents used in reactions
were obtained commercially from Adamas-β, Aldrich, and Accela
ChemBio and were used without purification, unless otherwise
indicated. Nuclear magnetic resonances ( H NMR and C NMR)
spectra were recorded on either Bruker Avance 300 or 400
spectrometers. High-resolution mass spectra (HRMS) were recorded
on an Agilent G6230 TOF MS spectrometer. Melting points were
measured with a capillary melting point instrument and are
uncorrected.
(
0.838 g, 2.994 mmol) was added. The resulting mixture was allowed
to stir at room temperature for 24 h. After TLC analysis, silica gel (ca.
g) was added. The mixture was stirred at ambient temperature for 24
2
1
13
h, and at this time, the color of the mixture turned dark blue. The
mixture was filtered and washed with ethyl acetate. The filtrate was
diluted with water (100 mL) and extracted with ethyl acetate. (4 × 30
mL). The combined organic layer was dried over anhydrous MgSO4.
After removal of the solvents under reduced pressure, the residue was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 2:1 → 1:1) to yield o-quinone 16 (unstable, used as
8
-(Benzyloxy)-1,2,9,10,11-pentamethoxy-5,6,6a,7-tetrahydro-
H-dibenzo[de,g]quinoline (11b). To a solution of compound 11a
2 g, 3.466 mmol) in dichloromethane (20 mL), trifluoroacetic acid
10 mL) was added. The reaction mixture was stirred at room
4
soon as possible, 0.820 g, 77%) as a dark blue plate. Mp: 146−147
1
(
(
°C; H NMR (400 MHz, CDCl
3
): δ: 8.05 (s, 1H), 7.16 (s, 1H), 4.21
(s, 3H), 4.09 (t, J = 5.6 Hz, 2H), 4.02 (s, 3H), 3.88 (s, 3H), 3.87 (s,
1
3
1
temperature for 2 h. The mixture was quenched carefully by addition
of water (60 mL) and a 10% aqueous solution of sodium hydroxide,
until pH 13−14. The resulting mixture was then extracted with
dichloromethane (4 × 20 mL), and the combined organic phases
3H), 3.79 (s, 3H), 3.17 (t, J = 5.6 Hz, 2H); C{ H} NMR (100
MHz, CDCl ): δ: 179.7, 177.4, 163.5, 154.6, 150.4, 144.3, 137.8,
137.3, 129.0, 127.9, 127.2, 126.1, 124.1, 116.7, 113.4, 62.0, 61.2, 56.9,
3
−
1
53.8, 43.7, 30.2; IR (KBr, thin film, cm ): 2995, 2948, 2847, 1712,
were dried over anhydrous MgSO . After removal of the solvents
1661, 1622, 1604, 1538, 1508, 1456, 1441, 1405, 1380, 1349, 1308,
4
+
under reduced pressure, the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 1:1
1216, 1204, 1141, 1119, 1090, 1034, 1001, 906, 764; HRMS (ESI )
+
m/z [M + H] : calcd for C H NO : 428.1340, found: 428.1340.
2
2
22
8
→
DCM/MeOH = 5:1) to afford amine 11b (1.58 g, 96%) as a pale
Methyl-9-hydroxy-1,2,10-trimethoxy-8,11-dioxo-4,5,8,11-tetra-
1
yellow syrup. H NMR (300 MHz, CDCl ): δ: 7.46−7.34 (m, 5H),
hydro-6H- dibenzo[de,g]quinoline-6-carboxylate (8b). To a sol-
3
6
3
3
1
1
1
3
1
1
.66 (s, 1H), 5.02 (s, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.87 (s, 3H),
.76 (s, 3H), 3.65 (s, 3H), 3.44−3.40 (m, 1H), 3.31−3.30 (m, 1H),
.14−3.08 (m, 1H), 2.95−2.93 (m, 2H), 2.68−2.64 (m, 1H), 2.05−
ution of o-quinone 16 (427 mg, 1 mmol) in acetonitrile (CH
CN, 10
3
mL), concentrated sulphuric acid (H SO , 10 drops) was added, and
2
4
the resulting mixture was stirred at room temperature for 1 h. The
reaction mixture was then diluted with water (50 mL) and extracted
with ethyl acetate (4 × 30 mL). The combined organic layer was
.86 (m, 2H); 13C{ H} NMR (75 MHz, CDCl ): δ: 151.6, 148.8,
1
3
46.4, 145.5, 145.4, 143.7, 137.4, 130.1, 128.5, 128.3, 128.0, 127.6,
26.4, 124.2, 120.6, 111.9, 75.5, 61.3, 61.1, 60.9, 60.8, 56.0, 53.9, 43.0,
1.2, 28.7; IR (KBr, thin film, cm ): 2940, 2839, 1661, 1596, 1563,
515, 1462, 1409, 1379, 1354, 1328, 1296, 1261, 1195, 1119, 1104,
082, 1065, 1039, 1023, 972, 755, 734, 700; HRMS (electrospray
dried over anhydrous MgSO . After removal of the solvents under
4
−
1
reduced pressure, the residue was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 1:1 → DCM/MeOH =
5:1) to afford p-quinone 8b (392 mg, 95%) as a red solid. Mp: 210−
+
+
1
ionization (ESI )) m/z [M + H] : calcd for C H NO : 478.2224,
211 °C; H NMR (400 MHz, CDCl ): δ: 8.17 (s, 1H), 7.14 (s, 1H),
2
8
32
6
3
found: 478.2223.
6.64 (br s, 1H), 4.23 (s, 3H), 4.09 (t, J = 5.6 Hz, 2H), 4.00 (s, 3H),
E
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.98 (s, 3H), 3.89 (s, 3H), 3.17 (t, J = 5.6 Hz, 2H); 13C{ H} NMR
1
733; HRMS (ESI ) m/z [M + H] : calcd for C H NO : 476.1551,
+
+
3
2
3
26
10
(
100 MHz, CDCl ): δ: 182.2, 181.9, 154.7, 151.2, 143.6, 142.2, 140.1,
found: 476.1551.
3
1
5
1
1
38.9, 129.9, 128.7, 127.9, 126.1, 123.2, 116.3, 111.9, 61.2, 60.3, 56.7,
Dactylicapnosine A (1). To a solution of compound 19 (48 mg,
0.1 mmol) in methanol (2 mL), sodium methoxide (6 mg, 0.11
mmol) was added. After being stirred at room temperature for 2 h, the
mixture was filtered through a short column of silica gel and washed
with a solution of triethylamine in ethyl acetate (v/v = 1:100, ca. 20
mL). The filtrate was concentrated under reduced pressure to give
crude amine, which was used for the next step without further
purification. The crude amine product was transferred to a sealable
tube (Teflon cap) together with potassium carbonate (138 mg, 1
mmol), methyl iodide (142 mg, 1 mmol), and anhydrous THF (2
mL). The sealed reaction mixture was allowed to stir at 100 °C (oil
bath) for 30 h. After TLC analysis, the mixture was filtered through a
short column of silica gel and washed with a solution of triethylamine
in ethyl acetate (v/v = 1: 100, ca. 30 mL). The filtrate was
concentrated under reduced pressure, and the residue was purified by
column chromatography on silica gel (petroleum ether/acetone = 2:1
−
1
3.7, 43.9, 30.1; IR (KBr, thin film, cm ): 3383, 2949, 1713, 1683,
658, 1603, 1584, 1510, 1443, 1405, 1380, 1346, 1310, 1254, 1229,
214, 1205, 1141, 1120, 1097, 1084, 1030, 1012, 996, 963, 908, 764;
+
+
HRMS (ESI ) m/z [M + H] : calcd for C H NO : 414.1183,
found: 414.1182.
2
1
20
8
Dimethyl -8-hydroxy-1,2,9-trimethoxy-10-oxo-4,8,9,10-
tetrahydrobenzo[de]cyclopenta[g]quinoline-6,8(5H)-dicarboxylate
(17). To a sealable tube (Teflon cap), p-quinone 8b (207 mg, 0.5
mmol), anhydrous methanol (10 mL), THF (1 mL), and cobaltous
chloride (CoCl , 649 mg, 5 mmol) were added. The resulting mixture
2
was sealed and was allowed to stir at 80 °C (oil bath) for 24 h. The
reaction mixture was cooled to room temperature. After TLC analysis,
the mixture was filtered through a short column of silica gel and
washed with ethyl acetate (ca. 40 mL). The filtrate was concentrated
under reduced pressure, and the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to
→
1:1) to yield dactylicapnosine A (30 mg, 70%) as a pale yellow
yield the ring contraction product 17 (152 mg, 68%) as a pale yellow
solid. Mp: 202−203 °C; H NMR (400 MHz, CDCl ): δ: 7.75 (s,
1
plate. Mp: 179−180 °C; H NMR (300 MHz, CDCl ): δ: 6.91 (s,
1
3
3
1
8
H), 6.39 (s, 1H), 3.99−3.94 (m, 7H), 3.65 (s, 3H), 3.52−3.45 (m,
1
4
3
1
9
H), 7.12 (s, 1H), 4.66 (s, 1H), 4.46 (s, 1H), 4.22−4.16 (m, 1H),
.07−4.00 (m, 7H), 3.87 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H), 3.22−
13 1
H), 3.15 (t, J = 6.3 Hz, 2H), 3.10 (s, 3H); C{ H} NMR (75 MHz,
): δ: 187.6, 171.4, 155.4, 152.5, 152.0, 143.7, 129.5, 126.6,
17.9, 117.4, 111.7, 102.0, 95.8, 81.2, 61.6, 56.5, 53.5, 52.0, 51.7, 50.2,
.17 (m, 2H); 1 C{ H} NMR (100 MHz, CDCl ): δ: 192.4, 172.8,
54.7, 151.8, 149.9, 143.9, 142.9, 129.6, 125.7, 120.9, 114.5, 110.9,
2.3, 80.2, 61.7, 60.7, 56.7, 54.1, 53.7, 43.9, 30.6; IR (KBr, thin film,
3
1
CDCl
3
3
1
4
−1
0.4, 29.8; IR (KBr, thin film, cm ): 3442, 2925, 1735, 1583, 1525,
+
−
1
1459, 1411, 1344, 1303, 1165, 1104, 1069; HRMS (ESI ) m/z [M +
Na] : calcd for C H NNaO : 454.1472, found: 454.1472.
cm ): 3594, 3469, 1727, 1604, 1516, 1465, 1440, 1404, 1345, 1312,
276, 1253, 1228, 1209, 1147, 1105, 1092, 1040, 1008, 989, 960, 765;
+
2
2
25
8
1
+
+
Dactylicapnosine B (2). Dactylicapnosine A (1, 19 mg, 0.044
mmol) was dissolved in anhydrous dichloromethane (2 mL), and this
solution was cooled to −78 °C. Boron trichloride in dichloromethane
HRMS (ESI ) m/z [M + H] : calcd for C H NO : 446.1446,
found: 446.1447.
2
2
24
9
Dimethyl-1,2,9-trimethoxy-10-oxo-4,10-dihydrobenzo[de]-
(1M, 0.5 mL, 0.5 mmol) was then added, and the resulting mixture
cyclopenta[g]quinoline- 6,8(5H)-dicarboxylate (18). Compound 17
was allowed to stir at −78 °C for 3 h. After TLC analysis, the mixture
was diluted with water (5 mL) and the organic layer was separated.
The aqueous layer was extracted with dichloromethane (6 × 5 mL).
The combined organic phases were dried over anhydrous MgSO4.
After filtration and concentration under reduced pressure, the crude
(
143 mg, 0.32 mmol) was dissolved in dichloromethane (10 mL) and
triethylamine (1.5 mL). The solution was cooled to 0 °C before
addition of trifluoroacetic anhydride (0.5 mL). The resulting mixture
was then stirred for 2 h. After TLC analysis, the reaction mixture was
quenched with water (15 mL) and the organic layer was separated.
The aqueous layer was extracted with dichloromethane (3 × 10 mL).
The combined organic phases were dried over anhydrous MgSO4.
After removal of the solvents under reduced pressure, the residue was
purified by column chromatography on silica gel (petroleum ether/
product was obtained (17 mg) as a red solid. This crude product was
added to a sealable tube (Teflon cap) together with anhydrous
methanol (1 mL), 2,2-dimethoxypropane (1 mL), and p-toluene-
sulfonic acid (17 mg). The resulting mixture was then sealed and was
allowed to stir at 80 °C (oil bath) for 16 h. The solvents were
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (petroleum ether/acetone =
ethyl acetate = 2:1) to afford enone 18 (125 mg, 92%) as a brown
1
solid. Mp: 170−171 °C; H NMR (300 MHz, CDCl ): δ: 8.15 (s,
3
1
3
H), 6.86 (s, 1H), 4.30 (s, 3H), 4.07 (t, J = 5.4 Hz, 2H), 3.96 (s, 3H),
1
.91 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.10 (t, J = 5.4 Hz, 2H);
2:1) to afford dactylicapnosine B (2, 8 mg, 42%) as a yellow syrup. H
1
3
1
C{ H} NMR (75 MHz, CDCl ): δ: 187.1, 164.1, 155.7, 154.7,
NMR (300 MHz, CDCl
3
): δ: 12.55 (s, 1H), 6.90 (s, 1H), 6.38 (s,
3
1
1
51,9, 149.7, 143.9, 142.0, 130.1, 127.7, 119.7, 113.2, 112.8, 112.0,
1H), 4.05(s, 1H), 3.98 (s, 3H), 3.70 (s, 3H), 3.58 (t, J = 6.6 Hz, 2H),
1
3
1
11.8, 61.5, 60.5, 56.7, 53.6, 51.8, 44.2, 30.5; IR (KBr, thin film,
3.52 (s, 3H), 3.50 (s, 3H), 3.14 (dd, J = 6.3, 10.5 Hz, 2H); C{ H}
NMR (75 MHz, CDCl ): δ: 192.2, 170.9, 157.5, 154.2, 147.5, 143.0,
−
1
cm ): 3400, 1704, 1622, 1608, 1574, 1523, 1464, 1439, 1405, 1338,
3
+
1
307, 1275, 1261, 1205, 1160, 764, 750; HRMS (ESI ) m/z [M +
124.0, 121.5, 116.8, 115.9, 111.6, 101.0, 96.0, 82.5, 56.4, 53.7, 52.2,
+
−1
H] : calcd for C H NO : 428.1340, found: 428.1340.
51.7, 50.5, 40.6, 28.8; IR (KBr, thin film, cm ): 3410, 2962, 2924,
22
22
8
Dimethyl-8-hydroxy-1,2,9,9-tetramethoxy-10-oxo-4,8,9,10-
2853, 1739, 1630, 1573, 1528, 1460, 1425, 1584, 1316, 1243, 1179,
+
+
tetrahydrobenzo[de]cyclopenta[g]quinoline-6,8(5H)-dicarboxylate
1072, 1046; HRMS (ESI ) m/z [M + H] : calcd for C H NO :
2
1
24
8
(
19). To a solution of compound 18 (43 mg, 0.1 mmol) in methanol
2 mL), hydrogen peroxide (30%, 2 drops) was added followed by
418.1496, found: 418.1495.
(
sodium carbonate (16 mg, 0.15 mmol). The resulting mixture was
then stirred at room temperature for 1 h. The mixture was filtered
through a short column of silica gel and washed with ethyl acetate (ca.
ASSOCIATED CONTENT
■
*
sı
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01900.
2
0 mL). The filtrate was concentrated under reduced pressure, and
the residue was purified by column chromatography on silica gel
petroleum ether/ethyl acetate = 2:1) to provide product 19 (41 mg,
(
1
8
1
4
7%) as a pale yellow syrup. H NMR (300 MHz, CDCl ): δ: 7.75 (s,
1H and 13C NMR spectra of new compounds; X-ray
crystallographic data of 7a (CCDC2018119), 9a
(CCDC2018120), 10 (CCDC2018122), 19
3
H), 7.11 (s, 1H), 4.26−4.18 (m, 1H), 4.08 (s, 3H), 3.99−3.94 (m,
H), 3.84 (s, 3H), 3.67 (s, 3H), 3.56 (s, 3H), 3.47 (s, 3H), 3.20−3.15
m, 2H); 1 C{ H} NMR (75 MHz, CDCl ): δ: 189.0, 170.9, 154.6,
3
1
(
3
(
CCDC2018123), and 1 (CCDC2018121 for synthetic
1
1
52.1, 151.8, 143.6, 143.1, 129.8, 125.9, 125.5, 120.8, 114.2, 111.2,
dactylicapnosine A) (PDF)
02.7, 80.9, 61.6, 56.6, 53.7, 52.2, 51.9, 44.0, 30.5; IR (KBr, thin film,
−
1
cm ): 3484, 2951, 2844, 1733, 1604, 1515, 1464, 1440, 1404, 1348,
312, 1253, 1228, 1212, 1164, 1107, 1075, 1043, 1011, 991, 895, 763,
Combined.cif (CIF)
1
F
https://dx.doi.org/10.1021/acs.joc.0c01900
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
W.-L.; Cong, K.; Wang, X.; Dong, Y.; Cai, J.; Zhang, J.-L.; Zhang, G.-
H.; Yang, J.-L.; Yang, S.-C.; Fan, W. Identification of candidate genes
involved in isoquinoline alkaloids biosynthesis in Dactylicapnos
scandens by transcriptome analysis. Sci. Rep. 2017, 7, No. 9119.
AUTHOR INFORMATION
Corresponding Authors
■
Xiao-Dong Luo − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China; State Key Laboratory
of Phytochemistry and Plant Resources in West China, Kunming
Institute of Botany, Chinese Academy of Sciences, Kunming
(3) Bochicchio, A.; Cefola, R.; Choppin, S.; Colobert, F.; Noia, M.
A. D.; Funicello, M.; Hanquet, G.; Pisano, I.; Todisco, S.;
Chiummiento, L. Selective Claisen rearrangement and iodination
for the synthesis of polyoxygenated allyl phenol derivatives.
Tetrahedron Lett., 2016, 57, 4053.
(4) Duchek, J.; Piercy, T. G.; Gilmet, J.; Hudlicky, T. Chemo-
6
50201, P. R. China; orcid.org/0000-0002-6768-5679;
enzymatic total synthesis of ent-neopinone and formal total synthesis
of ent-codeinone from β-bromoethylbenzene. Can. J. Chem. 2011, 89,
Email: xdluo@mail.kib.ac.cn
Hongbin Zhang − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China; orcid.org/0000-
7
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09.
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syntheses to azafluoranthene and dehydroaporphine alkaloids. Eur.
J. Org. Chem. 2015, 2015, 6324.
Email: zhanghb@ynu.edu.cn
Authors
Yinjiao Zhao − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology and Center for Life
Sciences, School of Life Sciences, Yunnan University, Kunming,
Yunnan 650091, P. R. China
Yuda Li − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan Province, School of
Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
Bei Wang − State Key Laboratory of Phytochemistry and Plant
Resources in West China, Kunming Institute of Botany, Chinese
Academy of Sciences, Kunming 650201, P. R. China
Jingfeng Zhao − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan Province,
School of Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
Liang Li − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan Province, School of
Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
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arylation of unactivated arenes: application to the synthesis of
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Tetrahedron Lett. 2016, 57, 1040.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01900
(10) (a) Ozanne, A.; Pouysegu, L.; Depernet, D.; Francois, B.;
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Application of the combined C−H activation/Cope rearrangement as
a key step in the total syntheses of the assigned structure of
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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+)-elisabethadione and a (+)-p-benzoquinone natural product.
Tetrahedron 2006, 62, 10477.
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Synthesis of (-)-Stenine. Angew. Chem., Int. Ed., 2012, 51, 1024.
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This work was supported by grants from the National Natural
Science Foundation of China (U1702286 and 21572197), the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT17R94), the Lingjun scholar of
Yunnan Province, and the Postdoctoral Science Foundation of
Yunnan Province (C6193105).
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(
total synthesis of (±)-renieramycin A. Tetrahedron Lett. 1990, 31,
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https://dx.doi.org/10.1021/acs.joc.0c01900
J. Org. Chem. XXXX, XXX, XXX−XXX