Diastereoselective Formal Synthesis of Polycyclic Meroterpenoid (±)-Cochlearol A

Article abstract of DOI:10.1021/acs.joc.1c00205

A formal synthesis of (±)-cochlearol A was accomplished. The synthesis features Suzuki coupling and Friedel-Crafts cyclization as a convergent strategy to the functionalized tetralone ring and an intramolecular construction of the C/D ring involving seque

Full text of DOI:10.1021/acs.joc.1c00205

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Diastereoselective Formal Synthesis of Polycyclic Meroterpenoid
( )-Cochlearol A
Telugu Venkatesh, Prathama S. Mainkar, and Srivari Chandrasekhar*
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ABSTRACT: A formal synthesis of ( )-cochlearol A was accomplished. The synthesis features Suzuki coupling and Friedel−Crafts
cyclization as a convergent strategy to the functionalized tetralone ring and an intramolecular construction of the C/D ring involving
sequential epoxide formation/acetal formation.
he Lingzhi mushroom, popularly called and regarded as the
“herb of spiritual potency” in China, belongs to the genus
dimethoxybenzene 4 through TMSOTf-promoted lactonization
to the formation of the desired lactone with a quaternary carbon
(Scheme 1a).2 Recently, Ishigami and co-workers have reported
a formal synthesis of ( )-cochlearol A in 15 steps involving the
stereoselective construction of perhydro-3,9a-epoxybenzo[c]-
oxepine by intramolecular acetal formation of the spiroepoxide,
which was prepared from lactone 5 (Scheme 1b).3 Herein, we
wish to report a new strategy to 2 starting from commercially
available boronic acid 6 and easily accessible compound 10 from
ethyl acetoacetate (Scheme 1c).
We conceived a totally modular strategy, wherein an aliphatic
framework 9 prepared from 7 will be appended to A ring in a
catalytic fashion, while the functionalities needed for B, C, and D
rings are all in the right place to obtain 8. This approach, in
principle, should provide access to a natural product in a shorter
number of steps with better yields (Scheme 2). The reaction
sequence is also expected to avoid the oxidation of the benzylic
position for the formation of a keto derivative. The synthesis of
the cis-fused five-membered ring was also facile due to the one-
pot conversion of olefin to epoxide and acetal formation.
Thus, commercially available 2,5-dimethoxyphenylboronic
acid 6 and readily accessible vinyl triflate 9 became key starting
materials toward the total synthesis. The vinyl triflate 9 has three
different ester-protecting groups, viz., acetate, ethyl ester, and t-
butyl ester, such that each functionality is released at the
appropriate stage, the unique design of this modular strategy.
T
Ganoderma. Many species of Ganoderma have shown very
important activities such as antiasthmatic and antihypertensive.
Significantly, G. lucidium and G. sinense are also a part of P R
China Pharmacopeia and American Herbal Pharmacopeia.
Recently, Cheng et al.1a have isolated cochlearols A and B, the
polycyclic meroterpenoids from the fungus Ganoderma cochlear,
exhibiting reno-protective activities.1b,c Cochlearol A has a novel
skeleton with a 5/6/6/6 tetracyclic framework with three
asymmetric carbons but isolated as a racemic mixture, which was
further separated by chiral HPLC for biological studies and
characterization. The synthetic challenges for cochlearol A
include the B/D 6/6 ring system containing an uncommon
dioxaspiro[4,5]decane, two quaternary carbons, and sensitive
acetal functionality (Figure 1).
Figure 1. Structures of cochlearol A (1) and its precursor 2.
Based on biological profile as a renal protective agent, acting
on chronic kidney disease as an antifibrotic compound and
scarce availability of natural 1 for further studies, the total
synthesis of cochlearol A became a target of interest, and to date
only, two approaches are reported for ( )-cochlearol A. In 2019,
Qin et al. achieved the synthesis of 1 in 16 steps starting from
ethyl 4-tert-butoxyacetoaceate 3 and 2-(2-iodoethyl)-1,4-
Received: January 27, 2021
Published: March 22, 2021
https://doi.org/10.1021/acs.joc.1c00205
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5412−5416
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Scheme 1. Synthetic Approaches for the Precursor 2 of Cochlearol A (1)
Scheme 2. Retrosynthetic Analysis
Thus, ethyl acetoacetate 7 was subjected to alkylation with t-
butyl 2-bromoacetate in DMF and K2CO3 as a base to synthesize
10 by a known procedure.4 Second alkylation with 3-bromo-1-
propyl acetate again with K2CO3 as a base in DMF provided
compound 11. Ethyl acetoacetate can be converted to 11 in one
pot, with similar yields over two steps.5 The acyl group in 11 was
enolized with KHMDS and trapped as a triflate with PhN(Tf)2
in a 75% yield.6 The catalytic Suzuki coupling of vinyl triflate 9
with boronic acid 6 provided the late-stage intermediate 12 in
74% yield.7 With three differential protecting groups, the
selective deprotection of the t-butyl group with TFA provided
acid 13 in an 86% yield. The intramolecular Friedel−Crafts
reaction was achieved using (COCl)2 and AlCl3 to provide
decalone frame 14 in a 60% yield8a8b (Scheme 3). This had all of
the required functional groups in place including the benzylic
keto group.
The next steps of functionalizing were achieved by
deacetylation of 14 with K2CO3 in ethanol to achieve 15 in a
78% yield,9a which was further oxidized to aldehyde 8 using SO3·
pyridine as an oxidant.9b The one-pot epoxidation−acetalization
of 8 was performed using m-CPBA followed by exposure to
catalytic p-TSA to generate the desired tetracyclic product 16 in
a 60% yield.10 The reaction sequence involves epoxidation
followed by the opening of epoxide at the benzylic position with
carbonyl oxygen and then attack of epoxide oxygen at the
electrophilic carbonyl carbon to provide 16 as a single
diastereomer. In this reaction, the epoxide stereochemistry
does not show any effect on bicyclic acetal stereochemistry; i.e.,
both α/β-epoxides (∼1:1 diastereomer ratio) give a single
isomer of acetal 16. This is probably due to the fact that the π-
conjugating aryl group tends to favor the nucleophilic attack at
the benzylic position by stabilization of benzyl carbocation.3,11
Next, the ethyl ester functionality in 16 was hydrolyzed with
LiOH to generate 2 in an 85% yield,12 and the spectroscopic
data of 2 matched the literature values (Scheme 4). Compound
2 has already been converted by Qin et al. to ( )-cochlearol A
by oxidative demethylation with CAN, followed by hydrogen
Pd/C reduction, thus constituting the formal total synthesis of
the natural product in 9 steps.
In conclusion, a concise approach has been developed for the
formal synthesis of ( )-cochlearol A. The key steps involved in
the synthesis of precursor 2, in 9 steps with a 6% overall yield, are
one-pot epoxidation−acetalization and sequential Suzuki
coupling/Friedel−Crafts acylation. We believe that the strategy
will aid in synthesizing the molecule on a larger scale.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reagents were
used as received from commercial suppliers. All reactions were
performed under a nitrogen atmosphere and in flame-dried or oven-
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Scheme 3. Synthesis of Substituted Tetralone 14
Scheme 4. Formal Synthesis of ( )-Cochlearol-A
dried glassware with magnetic stirring. All solvents were dried before
use following the standard procedures. Reactions were monitored using
silica gel thin-layer chromatography (TLC). TLC plates were visualized
with UV light (254 nm), iodine treatment, or using ninhydrin stain.
Column chromatography was carried out using silica gel (100−200
mesh) packed in glass columns. NMR spectra were recorded at 400 and
500 MHz (H) and at 100 and 125 MHz (C), respectively. Chemical
shifts (δ) are reported in ppm, using the residual solvent peak in CDCl3
(H δ = 7.26 and C δ = 77.0 ppm) as an internal standard, and coupling
constants (J) are given in hertz (Hz). HRMS were recorded using ESI-
TOF techniques.
4-(tert-Butyl) 1-Ethyl 2-(3-acetoxypropyl)-2-acetylsuccinate (11).
To a solution of 10 (20.00 g, 81.96 mmol, 1.0 equiv) and 3-
bromopropyl acetate (16.31 g, 90.16 mmol, 1.1 equiv) in DMF (250
mL) are added K2CO3 (22.62 g, 163.93 mmol, 2.0 equiv) and the
mixture was stirred at room temperature for 15 h. The reaction was
quenched by the addition of H2O (100 mL), and mixture was extracted
with ethyl acetate (2 × 150 mL). The organic layer was washed with
H2O (2 × 150 mL) and brine (200 mL), dried over Na2SO4, and
concentrated to afford the crude. The crude was purified by flash
chromatography (hexane/EtOAc 9:1) to afford 11(18.32 g, 65% yield)
as a pale yellow oil: Rf = 0.3 (hexane/EtOAc 9:1); 1H NMR (400 MHz,
CDCl3) δ 4.05 (qd, J = 7.1, 1.3 Hz, 2H), 3.87 (t, J = 6.4 Hz, 2H), 2.68 (s,
2H), 2.07 (s, 3H), 1.94−1.76 (m, 5H), 1.40−1.29 (m, 2H), 1.25 (s,
9H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
203.3, 170.8, 170.5, 169.5, 81.0, 63.7, 61.4, 60.8, 37.9, 29.1, 27.6, 26.4,
23.3, 20.6, 13.8; IR (neat) γmax 2979, 1716, 1453, 1363, 1232, 1193,
1150, 1105, 1037, 950, 914, 852, 753, 634, 606, 578 cm−1; HRMS (ESI)
m/z [M + Na]+ calcd for C17H28O7Na 367.1733, found 367.1726.
4-(tert-Butyl) 1-Ethyl 2-(3-acetoxypropyl)-2-(1-
(((trifluoromethyl)sulfonyl)oxy)vinyl)-succinate (9). To a solution of
11 (15.00 g, 43.60 mmol, 1.0 equiv) in THF (100 mL) was added
KHMDS (1.0 M in THF, 48 mL, 47.96 mmol, 1.1 equiv) at −78 °C.
After stirring for 1 h, a solution of PhN(Tf)2 (17.12 g, 47.96 mmol, 1.1
equiv) in THF (50 mL) was added at −78 °C. The mixture was stirred
for 3 h at −78 °C and quenched with the saturated NH4Cl solution
(150 mL). The aqueous layer was extracted with EtOAc (2 × 150 mL).
The combined organic layer was dried over Na2SO4, filtered, and
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evaporated under a vacuum. The residue was purified by flash
chromatography on silica gel (hexane/EtOAc, 9:1) to give triflate 9
(15.56 g, 75% yield) as pale yellow oil: Rf = 0.4 (hexane/EtOAc 9:1);
1H NMR (500 MHz, CDCl3) δ 5.34 (d, J = 5.0 Hz, 1H), 5.16 (d, J = 5.0
Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H), 2.80 (d, J =
15.4 Hz, 1H), 2.64 (d, J = 15.4 Hz, 1H), 2.00−1.89 (m, 5H), 1.64−1.47
(m, 2H), 1.37 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.9, 170.1, 168.4, 154.3, 118.2 (q, J = 319.3 Hz),
104.9, 81.7, 63.7, 62.0, 52.8, 38.3, 29.0, 27.8, 23.3, 20.7, 13.7.IR
(neat):γmax2982, 1729, 1658, 1418, 1368, 1216, 1141, 1033, 930, 856,
769, 747, 666, 604 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C18H28F3O9S 477.1406, found 477.1404.
yield) as a white solid (mp 95−97 °C): Rf = 0.5 (hexane/EtOAc 1:1);
1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 9.2 Hz, 1H), 6.80 (d, J = 9.2
Hz, 1H), 5.79 (s, 1H), 5.56 (s, 1H), 4.04−3.97 (m, 2H), 3.97−3.82 (m,
2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.31 (d, J = 16.0 Hz, 1H), 2.28 (d, J =
17.6 Hz, 1H), 2.15−2.01 (m, 1H), 1.97 (s, 3H), 1.81−1.48 (m, 2H),
1.46 (dd, J = 6.6, 5.6 Hz, 1H), 0.88 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 194.9, 173.2, 170.9, 153.5, 149.8, 139.5, 131.3,
122.1, 118.4, 116.5, 112.3, 64.1, 61.0, 56.6, 56.4, 52.6, 48.0, 31.5, 23.7,
20.8, 13.7; IR (neat) γmax 3018, 2837, 1724, 1680, 1582, 1476, 1437,
1390, 1367, 1258, 1215, 1054, 1034, 920, 867, 808, 742, 665, 608 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C21H27O7 391.1757, found
391.1749.
4-(tert-Butyl) 1-Ethyl 2-(3-acetoxypropyl)-2-(1-(2,5-
dimethoxyphenyl)vinyl)-succinate (12). To a solution of triflate 9
(15.0 g, 31.51 mmol, 1.0 equiv) and 2,5-dimethoxyphenylboronicacid 6
(11.47 g, 63.02 mmol, 2.0 equiv) in THF (200 mL) were added
Pd(PPh3)4 (1.81 g, 1.57 mmol, 0.05 equiv) and K2CO3 (8.69 g, 63.02
mmol, 2.0 equiv) at room temperature. The combined mixture was
stirred at 60 °C in an oil bath for 12 h. After completion of the starting
material, monitored by TLC, the reaction was quenched by adding
saturated aqueous NH4Cl (50 mL). The mixture was extracted with
ethyl acetate (2 × 200 mL). The organic layer was washed with H2O (2
× 150 mL) and brine (200 mL), dried over Na2SO4, and concentrated
to afford the crude. The crude was purified by flash chromatography
(hexane/EtOAc 4:1) to afford 12 (10.82 g, 74% yield) as a pale yellow
oil: Rf = 0.3 (hexane/EtOAc 9:1); 1H NMR (500 MHz, CDCl3) δ 6.74
(dd, J = 7.8, 5.6 Hz, 2H), 6.59 (dd, J = 2.7, 0.6 Hz, 1H), 5.39 (s, 1H),
5.15 (s, 1H), 4.11 (qd, J = 7.1, 2.7 Hz, 2H), 4.02 (dt, J = 11.5, 6.5 Hz,
2H), 3.72 (s, 3H), 3.67 (s, 3H), 2.93 (d, J = 16.0 Hz, 1H), 2.50 (d, J =
16.0 Hz, 1H), 2.05−1.93 (m, 5H), 1.87−1.80 (m, 1H), 1.66−1.50 (m,
1H), 1.38 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.9, 171.1, 170.4, 153.0, 150.9, 146.4, 131.0, 118.4, 117.5,
113.0, 111.4, 80.7, 65.0, 60.8, 55.8, 55.6, 52.4, 39.5, 29.9, 28.0, 23.6,
21.0, 14.0; IR (neat) γmax 3020, 1724, 1495, 1463, 1418, 1391, 1366,
1215, 1152, 1046, 917, 861, 743, 667, 610 cm−1; HRMS (ESI) m/z [M
+ Na]+ calcd for C25H36O8Na487.2308, found 487.2299.
Ethyl 2-(3-Hydroxypropyl)-5,8-dimethoxy-1-methylene-4-oxo-
1,2,3,4-tetrahydro-naphthalene-2-carboxylate (15). To a solution
of 14 (2 g, 5.13 mmol, 1.0 equiv) in EtOH (30 mL) was added K2CO3
(7.07 g, 51.28 mmol, 10.0 equiv) at room temperature. The mixture was
stirred at same temperature for 16 h. The reaction was quenched by the
addition of saturated aqueous NH4Cl (10 mL), and the mixture was
extracted with CH2Cl2 (2 × 30 mL). The organic layer was washed with
brine (30 mL), dried over Na2SO4, and concentrated to afford the
crude. The crude was purified by flash chromatography (hexane/
EtOAc 1:2) to afford 15 (1.4 g, 78% yield) as a white solid (mp 102−
104 °C): Rf = 0.2 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) δ
7.00 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 5.73 (s, 1H), 5.56 (s,
1H), 3.95−3.76 (m, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.62−3.47 (m,
2H), 3.28 (dd, J = 17.7, 0.8 Hz, 1H), 2.78 (s, 1H), 2.22 (dd, J = 17.7, 0.9
Hz, 1H), 2.03 (td, J = 12.6, 3.1 Hz, 1H), 1.75 (td, J = 12.7, 3.8 Hz, 1H),
1.54 (dt, J = 12.1, 5.2 Hz, 1H), 1.40−1.25 (m, 1H), 0.81 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 173.5, 153.4, 149.7,
139.5, 131.5, 121.9, 118.6, 116.5, 112.2, 62.2, 60.8, 56.6, 56.2, 52.6,
48.0, 31.3, 27.3, 13.6; IR (neat) γmax 3494, 3013, 2929, 2838, 1722,
1678, 1581, 1476, 1437, 1392, 1259, 1217, 1183, 1128, 1093, 1053, 913,
867, 809, 744, 664, 616 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C19H25O6 349.1651, found 349.1647.
Ethyl 5,8-Dimethoxy-1-methylene-4-oxo-2-(3-oxopropyl)-
1,2,3,4-tetrahydrona- phthalene-2-carboxylate (8). To a solution
of 15 (1.4 g, 4.02 mmol, 1.0 equiv) in CH2Cl2 (20 mL) were added
DMSO (1.71 mL, 24.14 mmol, 6.0 equiv), DIPEA (7.0 mL, 40.23
mmol, 10.0 equiv), and SO3·Py (1.92 g, 12.06 mmol 3.0 equiv),
respectively, at 0 °C. The reaction mixture was stirred for 2 h at the
same temperature. After completion of the starting material, monitored
by TLC, the reaction was quenched by adding excess water and
extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts
were dried over Na2SO4 and concentrated to give crude. The crude was
purified by flash chromatography (hexane/EtOAc 1:1), which afforded
8 (1.14 g, 82% yield) as a white solid (mp 99−101 °C): Rf = 0.4
(hexane/EtOAc 1:1); 1H NMR (500 MHz, CDCl3) δ 9.69 (t, J = 0.9
Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 5.80 (s, 1H),
5.56 (s, 1H), 4.00−3.83 (m, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.26 (d, J =
17.5 Hz, 1H), 2.55 (dddd, J = 18.1, 10.3, 5.4, 0.8 Hz, 1H), 2.43−2.33
(m, 1H), 2.33−2.23 (m, 2H), 2.03 (ddd, J = 14.0, 10.3, 5.5 Hz, 1H),
0.89 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.5,
194.4, 173.0, 153.5, 149.9, 138.9, 131.1, 121.9, 118.5, 116.8, 112.4, 61.1,
56.6, 56.4, 52.1, 48.0, 39.0, 26.7, 13.7; IR (neat) γmax 3018, 2837, 1722,
1681, 1582, 1477, 1436, 1260, 1215, 1128, 1090, 1056, 1035, 920, 857,
809, 743, 665, 627 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C19H23O6 347.1495, found 347.1488.
6-Acetoxy-3-(1-(2,5-dimethoxyphenyl)vinyl)-3-(ethoxycarbonyl)-
hexanoic Acid (13). To a solution of 12 (10.0 g, 21.55 mmol, 1.0 equiv)
in CH2Cl2 (60 mL) was added TFA (30 mL) dropwise at room
temperature. The resulting solution was stirred for 2 h under a N2
atmosphere. After completion of the starting material, monitored by
TLC, the reaction was quenched by adding H2O (100 mL). The
mixture was extracted with CH2Cl2 (2 × 100 mL), and the combined
organic extracts were dried over Na2SO4 and concentrated to give a
crude. The crude was purified by column chromatography (hexane/EA,
1:2), which afforded 13 (7.56 g, 86% yield) as a pale yellow oil: Rf = 0.3
1
(hexane/EtOAc 1:1); H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H),
6.80−6.70 (m, 2H), 6.56 (d, J = 2.6 Hz, 1H), 5.43 (s, 1H), 5.18 (s, 1H),
4.14−4.05 (m, 2H), 4.02 (td, J = 6.6, 2.0 Hz, 2H), 3.71 (s, 3H), 3.67 (s,
3H), 2.99 (d, J = 16.7 Hz, 1H), 2.66 (d, J = 16.7 Hz, 1H), 2.14−1.97 (m,
5H), 1.83 (tdd, J = 10.9, 6.4, 4.3 Hz, 1H), 1.59−1.47 (m, 1H), 1.19 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.3, 173.8,
171.4, 153.1, 150.8, 145.9, 130.7, 118.9, 117.4, 113.3, 111.5, 64.8, 61.2,
55.8, 55.7, 52.5, 37.9, 30.0, 23.8, 21.0, 13.9; IR (neat) γmax 3020, 1715,
1495, 1416, 1214, 1045, 922, 742, 667 cm−1; HRMS (ESI) m/z [M +
H]+ calcd for C21H29O8 409.1862, found 409.1855.
Ethyl 2-(3-Acetoxypropyl)-5,8-dimethoxy-1-methylene-4-oxo-
1,2,3,4-tetrahydronaphthalene-2-carboxylate (14). To a solution of
13 (4 g, 9.80 mmol, 1.0 equiv) in CH2Cl2 (40 mL) was added oxalyl
chloride (0.92 mL, 10.78 mmol, 1.1 equiv) dropwise at 0 °C. The
resulting solution was stirred at the same temperature for 5 min, and
then a catalytic amount of DMF (2 drops) was added with stirring
under a N2 atmosphere. After stirring for 1 h, AlCl3 (1.43 g, 10.78 mmol,
1.1 equiv) was added portionwise at 0 °C. The reaction mixture was
stirred for 30 min at the same temperature, and the completion of the
reaction was monitored by TLC. The reaction was quenched by adding
excess water dropwise at 0 °C, and the mixture was extracted with
CH2Cl2 (2 × 30 mL). The combined organic extracts were dried over
Na2SO4 and concentrated to give a crude, which when purified by
column chromatography (hexane/EA, 1:1) afforded 14 (2.29 g, 60%
Ethyl 8,11-Dimethoxy-7-oxo-4,5,6,7-tetrahydro-1H-3,11b-
epoxynaphtho[1,2-c]-oxepine-5a(3H)-carboxylate (16). To a sol-
ution of 8 (0.5 g, 1.44 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added
m-CPBA (0.4 g (77%), 1.80 mmol, 1.25 equiv) at 0 °C. The reaction
mixture was stirred at 0 °C for 4 h. Then p-TSA (0.24 g, 1.44 mmol, 1.0
equiv) was added portionwise over 15 min under a nitrogen
atmosphere. After 2 h, the reaction was quenched with saturated
aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (2 × 10 mL).
The combined organic extracts were dried over Na2SO4 and
concentrated to give a crude. [Note that, during the epoxidation with
m-CPBA, acetal 16 was also observed along with ∼1:1 ratio of both
epoxide isomers (monitored by TLC).]
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The crude was purified by flash chromatography (hexane/EtOAc
1:1), which afforded 16 (0.31 g, 60% yield) as a pale yellow solid (mp
101−104 °C): Rf = 0.5 (hexane/EtOAc 1:1); H NMR (500 MHz,
Notes
The authors declare no competing financial interest.
1
CDCl3) δ 7.03 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 5.51 (s,
1H), 4.89 (d, J = 8.9 Hz, 1H), 4.80 (d, J = 8.9 Hz, 1H), 3.97 (qd, J = 7.1,
2.6 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.15 (d, J = 17.4 Hz, 1H), 2.83
(d, J = 17.4 Hz, 1H), 2.48−2.36 (m, 1H), 1.91 (td, J = 13.1, 5.6 Hz, 1H),
1.72−1.64 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 195.2, 173.7, 152.0, 150.1, 127.4, 125.3, 117.8, 114.4, 101.1,
81.5, 68.8, 61.3, 56.9, 56.6, 50.1, 45.0, 27.1, 26.4, 13.9; IR (neat) γmax
3498, 3375, 1680, 1580, 1461, 1274, 1190, 1145, 1074, 819 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C19H23O7 363.1444, found
363.1436.
8,11-Dimethoxy-7-oxo-4,5,6,7-tetrahydro-1H-3,11b-
epoxynaphtho[1,2-c]oxepine-5a(3H)-carboxylic acid (2). To a
solution of 16 (50 mg, 0.13 mmol, 1.0 equiv) in THF (5 mL), H2O
(2.5 mL), and MeOH (2.5 mL) was added LiOH·H2O (57 mg, 1.38
mmol, 10.0 equiv) at room temperature. The reaction mixture was
stirred for 12 h at room temperature. The reaction was quenched and
neutralized with 1 N HCl (15 mL) and extracted with CH2Cl2 (2 × 10
mL). The combined organic extracts were dried over Na2SO4 and
concentrated to give a crude. The crude was purified by flash
chromatography (MeOH/CH2Cl 1:15, which afforded 2 (39 mg,
85% yield) as a white solid (mp 116−118 °C): Rf = 0.4 (MeOH/
CH2Cl2 1:15); 1H NMR (500 MHz, DMSO) δ 7.32 (d, J = 9.3 Hz, 1H),
7.19 (d, J = 9.3 Hz, 1H), 5.53 (s, 1H), 4.82 (s, 2H), 3.80 (s, 3H), 3.79 (s,
3H), 3.05 (d, J = 17.4 Hz, 1H), 2.71 (d, J = 17.3 Hz, 1H), 2.32 (td, J =
13.1, 5.7 Hz, 1H), 1.91−1.79 (m, 1H), 1.65 (dd, J = 13.6, 5.2 Hz, 2H);
13C{1H} NMR (100 MHz, DMSO) δ 194.3, 175.0, 151.3, 149.9, 127.0,
ACKNOWLEDGMENTS
■
Authors thank the Council of Scientific and Industrial Research
(CSIR), Ministry of Science and Technology, Government of
India, for research facilities. T.V. thanks the CSIR, New Delhi,
for a research fellowship. S.C. thanks the SERB for the J. C. Bose
fellowship (SB/S2/JCB-002/2015), communication no. IICT/
Pubs./2020/356.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00205.
1
Copies of H and 13C spectra for all new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Srivari Chandrasekhar − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology (CSIR-IICT), Hyderabad 500007, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0003-3695-
4343; Email: srivaric@iict.res.in
Authors
Telugu Venkatesh − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology (CSIR-IICT), Hyderabad 500007, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India
Prathama S. Mainkar − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology (CSIR-IICT), Hyderabad 500007, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India
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Falguieres, A. Regioselective ring opening of epoxides with lithium
azide. Synthesis 1992, 9, 821−822.
(12) Kende, A. S.; Kawamura, K.; DeVita, R. J. Enantioselective total
synthesis of neooxazolomycin. J. Am. Chem. Soc. 1990, 112, 4070−
4072.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00205
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https://doi.org/10.1021/acs.joc.1c00205
J. Org. Chem. 2021, 86, 5412−5416