Synthesis of lamellarin R, lukianol A, lamellarin O and their analogues

Article abstract of DOI:10.1039/d0ra09249e

Three lamellarin alkaloids type III (lamellarin R, lukianol A and lamellarin O) were synthesized using the Barton-Zard reaction as a key step to construct the central pyrrole core. Some of their corresponding 4-benzoyl and 5-phenyl substituted pyrrole ana

Full text of DOI:10.1039/d0ra09249e

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Synthesis of lamellarin R, lukianol A, lamellarin O
and their analogues†
Cite this: RSC Adv., 2020, 10, 43168
ab
c
Iddum Satyanarayana,a Ding-Yah Yang
*
*
and Teau-Jiuan Liou
Three lamellarin alkaloids type III (lamellarin R, lukianol A and lamellarin O) were synthesized using the
Barton–Zard reaction as a key step to construct the central pyrrole core. Some of their corresponding
4-benzoyl and 5-phenyl substituted pyrrole analogues were also prepared via an initial three-component
reaction of glycine methyl ester, benzaldehyde, and chalcone to generate the pyrrolidine scaffold, and
followed by DDQ oxidation and N-alkylation.
Received 30th October 2020
Accepted 22nd November 2020
DOI: 10.1039/d0ra09249e
rsc.li/rsc-advances
Okano's groups,9 whereas the latter is exemplied by Boger,10
1 Introduction
Vazquez,11 Furstner,12 Jia,13 Hwu,14 Iwao,15 and Yang's groups.16
}
While the total synthesis of lamellarin alkaloids type III has
been documented by the aforementioned researchers, the
development of more efficient and greener synthesis of these
natural products along with their analogues leaves more room
for improvement.
Lamellarins are a family of pyrrole-containing alkaloids isolated
from marine mollusks, ascidians, and sponges by Faulkner and
co-workers since 1985.1 Today, more than 70 different lamel-
larins have been identied and reported.2 They can be generally
classied into lamellarin alkaloids type I, II, and III, depending
upon their molecular structures. These lamellarin alkaloids
have been found to exhibit a variety of biological activities. For
instance, lamellarin I, a representative compound in lamellarin
alkaloids type I, reverses multidrug resistance by direct inhibi-
tion of P-glycoprotein-mediated drug efflux at noncytotoxic
doses.3 Lamellarin D, a leading pentacyclic compound in
lamellarin alkaloids type II, is a potent inhibitor of both nuclear
and mitochondrial topoisomerase I.4 The type III lamellarin
alkaloid lukianol A, exhibits signicant cytotoxicity against
human epidermatoid carcinoma cell lines.5 Fig. 1 depicts the
representative structures of lamellarin alkaloids type III,
including ningalins A, B, lamellarins Q, O, R and lukianol A.
In light of their intriguing biological properties along with
the difficulty in obtaining large quantities from natural sources,
the synthesis of the lamellarins has become an attractive goal
for organic chemists in the past two decades. A key feature in
the synthesis of lamellarin alkaloids type III is the construction
of the aryl-substituted pyrrole ring, which can be categorized
into two different synthetic approaches, that is, functionaliza-
tion of a simple pyrrole core and synthesis of the functionalized
pyrrole moiety from the appropriate precursors. The former is
represented by the works of Banwell,6 Iwao,7 Wong8 and
Recently, Samet and coworkers17 have reported a metal-free
synthesis of ethyl-3,4-diarylpyrrole-2-carboxylate (1) via Bar-
ton–Zard reaction18 of nitrostilbene (2) with ethyl iso-
cyanoacetate (Scheme 1), and subsequently applied it to the
synthesis of lamellarin Q. To further demonstrate the useful-
ness of this Barton–Zard reaction to the preparation of another
lamellarin type III alkaloids, here we report the modular
synthesis of lamellarin R, lukianol A and lamellarin O, utilizing
the Barton–Zard reaction to construct the pyrrole core. More-
over, some of lamellarin type III alkaloid analogues were also
prepared by employing a three-component reaction of glycine
methyl ester, benzaldehyde and chalcone to assemble the
highly substituted pyrrolidine ring.
aDepartment of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan. Boulevard,
Xitun District, Taichung 407224, Taiwan. E-mail: yang@thu.edu.tw
bGraduate Program for Biomedical and Materials Science, Tunghai University, No.
1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 407224, Taiwan
cDepartment of Applied English, Chaoyang University of Technology, No. 168, Jifeng E.
Rd., Wufeng District, Taichung 413310, Taiwan. E-mail: tjl@cyut.edu.tw
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra09249e
Fig. 1 Representative structures of lamellarin alkaloids type III.
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Scheme 1 Synthesis of ethyl-3,4-diarylpyrrole-2-carboxylate (1).
2 Results and discussion
Scheme 2 depicts the total synthesis of lamellarin R (3). It
started with the bromination of commercially available p-
methoxy-b-nitrostyrene (4) with Br2 in chloroform to give the
brominated compound 5. The subsequent Suzuki coupling of 5
with p-methoxybenzeneboronic acid under basic conditions
generated the nitrostilbene 6 in 68% yield. The key Barton–Zard
reaction was realized via reacting of nitrostilbene 6 with methyl
isocyanoacetate in the presence of three equivalents of K2CO3 as
a base in methanol to furnish the key intermediate methyl-3,4-
diarylpyrrole-2-carboxylate 7 in 76% yield. The routine Buch-
wald–Hartwig amination19 of pyrrole 7 with p-iodoanisole in
toluene at 110 ꢀC for 12 h gave the corresponding N-substituted
pyrrole 8 in 76% yield. Final exhaustive demethylation of
pyrrole 8 with an excess of BBr3 afforded the target lamellarin R
in 92% yield.
Scheme 3 outlines the preparation of lukianol A (9) from
intermediate 7. It began with N-alkylation of pyrrole 7 with 2-
bromo-1-(4-methoxyphenyl)ethan-1-one under basic conditions
in DMF to give the corresponding pyrrole 10 in 70% yield. The
subsequent LiOH-mediated hydrolysis of methyl ester 10
generated the carboxylic acid 11 which, without isolation, was
reacted with NaOAc in Ac2O under reux conditions for 1 h to
obtain the cyclized 12 in 52% yield. The nal exhaustive deme-
thylation of pyrrole 12 with an excess of BBr3 afforded the target
lukianol A (9) in 72% yield. Thus, natural product lukianol A was
successfully prepared in six steps from the commercially available
p-methoxy-b-nitrostyrene (4) in an overall yield of 9.8%.
Scheme 3 Synthesis of lukianol A (9) from 7.
moiety of 10 were able to be selectively demethylated. Unfor-
tunately, even though compound 10 was treated with different
demethylation agents such as BBr3, AlCl3 and LiCl under
various reaction conditions, all attempts failed to afford the
desired lamellarin O in acceptable yield. Thus, the protection of
the two hydroxyl groups on the pyrrole ring with a functional
group other than OMe seems inevitable for the preparation of
lamellarin O. Scheme 4 shows the synthesis of lamellarin O (13)
from the OBn protected (E)-1-(benzyloxy)-4-(2-nitrovinyl)benzene
(14). Similar to that of lamellarin R, the synthesis started with
bromination of 14 with Br2 to give the brominated 15.
Next, the palladium-catalyzed Suzuki coupling of 15 with (p-
(benzyloxy)phenyl)boronic acid generated the nitrostilbene 16
in 75% yield. Barton–Zard reaction between nitrostilbene 16
Ideally, lamellarin O can be obtained directly from pyrrole 10
if the two 4-methoxyphenyl groups substituted on pyrrole
Scheme 2 Synthesis of lamellarin R (3).
Scheme 4 Synthesis of lamellarin O (13) and 19.
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synthesis of lamellarin O, lamellarin R and lukianol A
analogues.
Unfortunately, the Buchwald–Hartwig coupling reaction
between pyrrole-2-carboxylate 24 and p-iodoanisole failed to
give the desired lamellarin R analogue 25 (Scheme 6), presum-
ably due to the steric hindrance induced by the nearby phenyl
and ester groups adjacent to the nitrogen atom.21 Nevertheless,
the N-alkylation of 24 with 2-bromo-1-(4-methoxyphenyl)ethan-
1-one in the presence of K2CO3 in DMF did afford the lamellarin
O analogue 26 in 84% yield. Saponication of the methyl ester
26 with LiOH in THF : H2O (1 : 1) furnished the crude oxo-acid
which, without isolation, was allowed to react with NaOAc in
Ac2O at 90 ꢀC for 1 h to obtain the corresponding lukianol A
analogue 27 in 58% yield.
Scheme 5 Preparation of lamellarin Q analogue 24.
and methyl isocyanoacetate in methanol gave the benzyl-3,4-
diarylpyrrole-2-carboxylate 17 in 78% yield. The intermediate
17 was then subjected to N-alkylation with 2-bromo-1-(4-
methoxyphenyl)ethan-1-one under basic conditions in DMF to
yield the corresponding pyrrole 18 in 81%. Final deprotection of
two OBn groups on the pyrrole moiety with hydrogen in the
presence of palladium hydroxide on carbon as a catalyst affor-
ded the target lamellarin O (13) in an overall yield of 37.5%. It is
worth mentioning that the reduced compound 19 was obtained
as an exclusive product when the palladium on carbon was used
as a catalyst for the debenzylation of 18.
Aer realizing the total synthesis of lamellarin O, lamellarin
R and lukianol A, we then shied our focus to the preparation of
their analogues. Scheme 5 outlines the two-step synthesis of the
4-benzoyl and 5-phenyl substituted lamellarin Q analogue 24. It
started with the Cs2CO3-mediated, three-component reaction of
chalcone 20, benzaldehyde (21), and glycine methyl ester (22) in
toluene at 90 ꢀC for 12 h to give the tetra-substituted pyrrolidine
23. The mechanism of this three-component reaction presum-
ably involved the [3+2] cycloaddition reaction between chalcone
20 and 1,3-dipolar N-benzylidene glycine methyl ester generated
in situ from benzaldehyde (21) and glycine methyl ester (22).20
The subsequent DDQ oxidation of pyrrolidine 23 afforded the
lamellarin Q analogue 24 in good yield. This lamellarin Q
analogue 24 then serves as a common precursor for the
We believe that the rapid synthesis of those potentially valuable
lamellarin type III analogues may facilitate the process for the
future development of novel lamellarin-derived antitumor drugs.
3 Conclusions
In summary, the natural products lamellarin R, lukianol A and
lamellarin O were synthesized from commercially available
nitrostilbenes in ve, six and ve steps with overall yields of
26.0, 9.8 and 37.5%, respectively. The common feature of the
syntheses involved the Barton–Zard reaction to construct the
pyrrole core structure. Besides, lamellarin Q, lukianol A and
lamellarin O analogues bearing 4-benzoyl and 5-phenyl groups
substituted on the pyrrole moiety were prepared in two to four
steps from a three-component reaction of glycine methyl ester,
benzaldehyde and chalcone to assemble the highly substituted
pyrrolidine ring, and followed by DDQ oxidation and N-alkyl-
ation. The biological activities of those prepared compounds
are currently under investigation.
4 Experimental
4.1 General
Melting points were determined on a Mel-Temp melting point
apparatus in open capillaries and were uncorrected. Infrared
(IR) spectra were recorded using 1725XFT-IR spectrophotom-
eter. High-resolution mass spectra (HRMS) were obtained on
a Thermo Fisher Scientic Finnigan MAT95XL spectrometer
using a magnetic sector analyzer. Peptide mass analysis was
obtained by MALDI TOF MS (Bruker), and peptide purity was
1
conrmed by RP-HPLC (Hitachi). H NMR (400 MHz) and 13C
NMR (100) spectra were recorded on a Bruker 400 spectrometer.
Chemical shis were reported in parts per million on the scale
relative to an internal standard (tetramethylsilane, or appro-
priate solvent peaks) with coupling constants given in hertz. 1H
NMR multiplicity data are denoted by s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet). Analytical thin-layer chro-
matography (TLC) was carried out on Merck silica gel 60G-254
plates (25 mm) and developed with the solvents mentioned.
Visualization was accomplished by using portable UV light, and
an iodine chamber. Flash chromatography was performed in
columns of various diameters with Merck silica gel (230–400
mesh ASTM 9385 Kieselgel 60H) by elution with the solvent
Scheme 6 Synthesis of lamellarin O and lukianol A analogues.
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systems. Solvents, unless otherwise specied, were reagent 638 mg. Yield 75%. Mp 240–242 ꢀC. 1H NMR (CDCl3, 400
grade and distilled once before use. All new compounds MHz): d 8.21 (s, 1H), 7.51–7.39 (m, 10H), 7.28 (d, J ¼ 8.8 Hz, 2H),
exhibited satisfactory spectroscopic and analytical data.
7.12 (d, J ¼ 8.8 Hz, 2H), 7.11 (d, J ¼ 8.8 Hz, 2H), 6.86 (d, J ¼
8.8 Hz, 2H), 5.16 (s, 2H), 5.07 (s, 2H). 13C NMR (CDCl3, 100
MHz): d 160.9, 159.9, 147.5, 136.5, 136.2, 134.7, 133.2, 132.1,
129.8, 128.7, 128.3, 127.7, 127.5, 124.1, 123.3, 115.7, 115.4,
115.2, 70.2, 70.1. IR nmax (neat) 2944, 2839, 1642, 1588, 1508,
1425, 848, 744 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C28H23NO4,
437.1627; found, 437.1625.
4.2 General procedure for the synthesis of 5 and 15
To a solution of b-nitrostyrene (5.58 mmol) in CHCl3 (25 mL)
was added Br2 (5.58 mmol, 1.0 equiv.) at room temperature
within 5 min. The reaction mixture was reuxed for 20 min.
Upon complete consumption of the starting material, the
reaction mixture was cooled to 8 ꢀC and the solution of Et3N
(8.37 mmol, 1.5 equiv.) was added dropwise within 20 min. The
4.4 General procedure for the synthesis of 7 and 17
mixture was maintained for 30 min and then poured into To a stirred solution of 6 or 16 (1.75 mmol, 1.0 equiv.) and
a mixture of EtOAc : H2O (1 : 1). The organic layer was washed K2CO3 (5.26 mmol, 3.0 equiv.) in MeOH (10 mL) was added
with H2O (200 mL), brine (2 ꢁ 150 mL), dried with Na2SO4 and methyl isocyanoacetate (2.10 mmol, 1.2 equiv.) at room
concentrated in vacuo. The crude residue was puried by ash temperature. The yellow solution was stirred at that tempera-
column chromatography to give the title compound.
ture for 12 h. The reaction mixture was diluted with water (30
4.2.1 (Z)-1-(2-Bromo-2-nitrovinyl)-4-methoxybenzene (5). mL), neutralized with HCl and extracted with ethyl acetate (3 ꢁ
Yellow solid. Rf ¼ 0.5 (10% EtOAc/hexanes). Light yellow solid, 5 mL). The solvent was concentrated in vacuo and the crude
1.04 g. Yield 72%. Mp 66–68 ꢀC (lit. (ref. 22) 67–68 ꢀC). 1H NMR residue was puried by ash column chromatography (10%
(CDCl3, 400 MHz): d 8.66 (s, 1H), 7.95 (d, J ¼ 8.8 Hz, 2H), 7.03 (d, EtOAc in hexanes) to give the title compound.
J ¼ 9.2 Hz, 2H), 3.91 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 162.8,
4.4.1 Methyl-3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-
136.4, 133.5, 125.4, 122.4, 114.6, 55.6. IR nmax (neat) 2988, 1639, carboxylate (7). Brown solid. Rf ¼ 0.5 (50% EtOAc/hexanes).
1612, 1418, 1125, 819 cmꢂ1. HRMS (EI) m/z: [M+] calcd for 460 mg. Yield 76%. Mp 176–178 C (lit. (ref. 15) 176–177 C). H
1
ꢀ
ꢀ
C9H8BrNO3, 256.9688; found, 256.9682.
NMR (CDCl3, 400 MHz): d 9.20 (s, 1H), 7.21 (d, J ¼ 8.8 Hz, 2H),
4.2.2 (Z)-1-(Benzyloxy)-4-(2-bromo-2-nitrovinyl)benzene
7.045 (d, J ¼ 8.8 Hz, 2H), 7.051 (s, 1H), 6.87 (d, J ¼ 8.8 Hz, 2H), 6.77
(15). Yellow solid. Rf ¼ 0.5 (10% EtOAc/hexanes). 1.63 g. Yield (d, J ¼ 8.8 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H). 13C NMR
87%. Mp 166–168 ꢀC. 1H NMR (CDCl3, 400 MHz): d 8.66 (s, 1H), (CDCl3, 100 MHz): d 161.7, 158.5, 158.0, 131.9, 129.5, 129.1, 127.1,
7.95 (d, J ¼ 8.8 Hz, 2H), 7.48–7.39 (m, 5H), 7.10 (d, J ¼ 8.8 Hz, 126.5, 120.2, 119.3, 113.7, 113.1, 55.18, 55.16, 51.3. IR nmax (neat)
2H), 5.18 (s, 2H). 13C NMR (CDCl3, 100 MHz): d 161.9, 136.3, 3424, 3277, 3042, 2949, 1705, 1466, 1299, 1244 cmꢂ1. HRMS (EI) m/
136.0, 133.5, 128.8, 128.4, 127.5, 125.6, 122.7, 115.4, 70.3. IR z: [M+] calcd for C20H19NO4, 337.1314; found, 337.1319.
nmax (neat) 3011, 1644, 1612, 1572, 1414, 965, 879 cmꢂ1. HRMS
4.4.2 Methyl-3,4-bis(4-(benzyloxy)phenyl)-1H-pyrrole-2-
(EI) m/z: [M+] calcd for C15H12BrNO3, 333.0001; found, 333.0005. carboxylate (17). Brown solid. Rf ¼ 0.5 (50% EtOAc/hexanes).
ꢀ
ꢀ
670 mg. Yield 78%. Mp 166–168 C (lit. (ref. 19c) 166–168 C).
1H NMR (CDCl3, 400 MHz): d 9.22 (s, 1H), 7.50–7.35 (m, 10H),
7.23 (d, J ¼ 8.4 Hz, 2H), 7.06 (d, J ¼ 8.4 Hz, 2H), 7.05 (s, 1H), 6.96
(d, J ¼ 8.8 Hz, 2H), 6.86 (d, J ¼ 8.8 Hz, 2H), 5.10 (s, 2H), 5.04 (s,
2H), 3.76 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 161.5, 157.9,
157.3, 137.13, 137.08, 131.9, 129.5, 129.0, 128.6, 127.9, 127.7,
127.5, 127.3, 126.7, 126.5, 120.1, 119.4, 114.6, 114.0, 70.0, 51.3.
IR nmax (neat) 3310, 2999, 2948, 2836, 1715, 1646, 1254,
975 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C32H27NO4, 489.1940;
found, 489.1936.
4.3 General procedure for the synthesis of 6 and 16
To a stirred solution of 5 or 15 (1.94 mmol, 1.0 equiv.) and (4-
methoxyphenyl)boronic acid (2.91 mmol, 1.5 equiv.) in THF (10
mL) was added Pd(PPh3)4 (0.01 equiv.) and Na2CO3 (4.85 mmol,
2.5 equiv. in 5 mL of H2O) at room temperature. The resulting
light yellow solution was stirred at room temperature for 30 min
and then heated to reux in an oil bath for 6 h. Aer cooled
down to room temperature, the mixture was ltered through
Celite with the aid of ethyl acetate and concentrated in vacuo.
The crude residue was puried by ash column chromatog-
raphy (5% EtOAc in hexanes) to give the title compound.
4.3.1 (E)-4,40-(1-Nitroethene-1,2-diyl)bis(methoxybenzene)
4.5 Procedure for the synthesis of 8
To a suspension of 1-iodo-4-methoxybenzene (0.29 mmol, 1.1
˚
(6). Yellow solid. Rf ¼ 0.5 (5% EtOAc/hexanes). 378 mg. Yield equiv.) and powdered molecular sieves 4 A in toluene (5.0 mL)
68%. Mp 140–142 ꢀC (lit. (ref. 23) 140–141 ꢀC). 1H NMR (CDCl3, was successively added 7 (0.27 mmol, 1.0 equiv.), ethylene
400 MHz): d 8.21 (s, 1H), 7.28 (d, J ¼ 8.4 Hz, 2H), 7.11 (d, J ¼ diamine (0.026 mmol, 0.1 equiv.) and CuI (0.013 mmol, 0.05
8.8 Hz, 2H), 7.04 (d, J ¼ 8.8 Hz, 2H), 6.78 (d, J ¼ 8.8 Hz, 2H), 3.91 equiv.) under N2 at rooꢀm temperature. The resulting mixture
(s, 3H), 3.81 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 161.7, 160.7, was then heated at 120 C in an oil bath for 12 h. Aer cooled
147.5, 134.7, 133.2, 132.1, 123.9, 123.0, 114.8, 114.3, 55.37, down to room temperature, the mixture was passed through
55.36. IR nmax (neat) 2944, 2839, 1642, 1588, 1508, 1425, 848, a pad of Celite and the ltrate was concentrated under reduced
744 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C16H15NO4, 285.1001; pressure. The crude residue was puried by ash column
found, 285.1006.
chromatography to give the title compound.
4.3.2 (E/Z)-4,40-(1-Nitroethene-1,2-diyl)bis((benzyloxy)
4.5.1 Methyl-1,3,4-tris(4-methoxyphenyl)-1H-pyrrole-2-
benzene) (16). Yellow solid. Rf ¼ 0.5 (5% EtOAc/hexanes). carboxylate (8). White solid. Rf ¼ 0.5 (20% EtOAc/hexanes).
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98 mg. Yield 76%. Mp 42–44 ꢀC (lit. (ref. 17c) 42–44 ꢀC). 1H NMR
(CDCl3, 400 MHz): d 7.34 (d, J ¼ 8.8 Hz, 2H), 7.25 (d, J ¼ 8.8 Hz,
2H), 7.04 (s, 1H), 7.07 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.8 Hz, 2H),
6.90 (d, J ¼ 8.8 Hz, 2H), 6.78 (d, J ¼ 8.8 Hz, 2H), 3.89 (s, 3H), 3.86 (s,
3H), 3.79 (s, 3H), 3.50 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 161.7,
158.9, 158.5, 158.0, 134.1, 131.8, 131.0, 129.4, 127.3, 127.1, 126.8,
126.5, 125.0, 121.3, 113.9, 113.7, 113.1, 55.5, 55.2, 50.9. IR nmax
(neat) 2948, 1708, 1644, 1514, 1256, 845 cmꢂ1. HRMS (EI) m/z: [M+]
calcd for C27H25NO5, 443.1733; found, 443.1729.
4.8 General procedure for the synthesis of 10, 18 and 26
A mixture of 7, 17 or 24 (0.74 mmol, 1.0 equiv.), anhydrous
potassium carbonate (4.44 mmol, 6.0 equiv.) and 2-bromo-1-(4-
methoxyphenyl)ethan-1-one (1.11 mmol, 1.5 equiv.) in DMF (10
mL) was heated at 70 ꢀC in oil bath for 4 h. Aer cooled to room
temperature, the solvent was evaporated, dried over Na2SO4 and
concentrated in vacuum. The crude residue was puried by ash
column chromatography to give the title compound.
4.8.1 Methyl-3,4-bis(4-methoxyphenyl)-1-(2-(4-methox-
yphenyl)-2-oxoethyl)-1H-pyrrole-2-carboxylate (10). Yellow solid.
Rf ¼ 0.5 (50% EtOAc/hexanes). 250 mg. Yield 70%. Mp 68–70 ꢀC
(lit. (ref. 11) 68–72 ꢀC). 1H NMR (CDCl3, 400 MHz): d 8.05 (d, J ¼
8.8 Hz, 2H), 7.18 (d, J ¼ 8.8 Hz, 2H), 7.03–7.01 (m, 4H), 6.95 (s,
1H), 6.85 (d, J ¼ 8.8 Hz, 2H), 6.74 (d, J ¼ 8.8 Hz, 2H), 5.76 (s, 2H),
3.92 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.49 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d 191.9, 164.0, 162.3, 158.3, 157.9, 131.9,
131.1, 130.3, 129.4, 128.2, 127.9, 127.2, 127.0, 124.7, 119.8,
114.1, 113.5, 112.9, 55.63, 55.55, 55.1, 50.8. IR nmax (neat) 3008,
2938, 2844, 2041, 1722, 1688, 1568, 1172 cmꢂ1. HRMS (EI) m/z:
[M+] calcd for C29H27NO6, 485.1838; found, 485.1844.
4.6 Procedure for the synthesis of lamellarin R (3)
To a stirred solution of 8 (0.23 mmol, 1.0 equiv.) in DCM (30 mL)
was added BBr3 (3.0 equiv. in 30 mL of DCM) at ꢂ78 ꢀC under N2
ꢀ
atmosphere. The mixture was allowed to stir at 0 C in an ice
bath for 12 h. Aer diluted with MeOH (5 mL), the solvent was
removed under reduced pressure. The residue was dissolved in
H2O and extracted with EtOAc (2 ꢁ 30 mL). The combined
organic phase was dried over Na2SO4 and concentrated in
vacuum. The crude residue was puried by ash column chro-
matography to give the title compound.
4.8.2 Methyl-3,4-bis(4-(benzyloxy)phenyl)-1-(2-(4-methox-
yphenyl)-2-oxoethyl)-1H-pyrrole-2-carboxylate (18). Yellow solid.
Rf ¼ 0.5 (50% EtOAc/hexanes). 382 mg. Yield 81%. Mp 120–
122 ꢀC (lit,11 120–122 ꢀC). 1H NMR (CDCl3, 400 MHz): d 8.06 (d, J
¼ 8.8 Hz, 2H), 7.51–7.35 (m, 10H), 7.22 (d, J ¼ 8.4 Hz, 2H), 7.06
(d, J ¼ 8.8 Hz, 2H), 7.02 (d, J ¼ 8.8 Hz, 2H), 6.97–6.95 (m, 3H),
6.84 (d, J ¼ 8.4 Hz, 2H), 5.74 (s, 2H), 5.10 (s, 2H), 5.02 (s, 2H),
3.91 (s, 3H), 3.50 (s, 3H). 13C NMR (CDCl3, 100 MHz): d 191.8,
164.0, 162.3, 157.6, 157.2, 137.2, 137.1, 131.9, 131.1, 130.4,
129.4, 128.6, 128.2, 127.9, 127.7, 127.5, 127.3, 127.2, 124.6,
119.8, 114.5, 114.1, 113.9, 70.0, 55.6, 55.5, 50.8. IR nmax (neat)
3028, 2931, 1716, 1678, 1608, 1544, 1248, 1072 cmꢂ1. HRMS (EI)
m/z: [M+] calcd for C41H35NO6, 637.2464; found, 637.2457.
4.8.3 Methyl-4-benzoyl-1-(2-(4-methoxyphenyl)-2-oxoethyl)-
3,5-diphenyl-1H-pyrrole-2-carboxylate (26). Yellow solid. Rf ¼
4.6.1 Methyl-1,3,4-tris(4-hydroxyphenyl)-1H-pyrrole-2-
carboxylate (3). White solid. Rf ¼ 0.5 (30% EtOAc/hexanes).
85 mg. Yield 92%. Mp 142–144 ꢀC. 1H NMR (acetone-d6, 400
MHz): d 8.76 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.24 (d, J ¼ 8.4 Hz,
2H), 7.13 (s, 1H), 7.08 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.4 Hz, 2H),
6.93 (d, J ¼ 8.8 Hz, 2H), 6.79 (d, J ¼ 8.4 Hz, 2H), 6.68 (d, J ¼
8.8 Hz, 2H), 3.42 (s, 3H). 13C NMR (acetone-d6, 100 MHz):
d 161.2, 156.8, 156.3, 155.8, 133.1, 131.8, 130.3, 129.3, 126.6,
126.2, 125.9, 125.7, 124.9, 121.5, 115.2, 114.9, 114.4, 50.0. IR
nmax (neat) 3364, 1694, 1624, 1442, 1133, 846 cmꢂ1. HRMS (EI)
m/z: [M+] calcd for C24H19NO5, 401.1263; found, 401.1269.
ꢀ
0.5 (10% EtOAc/hexanes). 330 mg. Yield 84%. Mp 152–154 C.
4.7 Procedure for the synthesis of lukianol A (9)
1H NMR (CDCl3, 400 MHz): d 7.99 (d, J ¼ 8.8 Hz, 2H), 7.61 (d, J ¼
7.2 Hz, 2H), 7.32 (d, J ¼ 7.2 Hz, 4H), 7.25–7.10 (m, 9H), 6.98 (d, J
¼ 8.8 Hz, 2H), 5.64 (s, 2H), 3.88 (s, 3H), 3.49 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d 193.5, 192.1, 164.1, 162.2, 141.4, 138.5,
134.5, 133.6, 132.1, 130.5, 130.4, 130.3, 129.8, 129.6, 129.1,
128.4, 127.8, 127.6, 127.1, 126.8, 124.1, 119.5, 114.1, 55.6, 53.0,
51.0. IR nmax (neat) 3022, 2913, 2837, 1729, 1689, 1665, 1629,
1519, 915 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C34H27NO5,
529.1889; found, 529.1891.
To a stirred solution of 12 (0.22 mmol, 1.0 equiv.) in DCM (30
mL) at ꢂ78 ꢀC was added BBr3 (3.0 equiv. in 30 mL of DCM) over
ꢀ
a period of 20 min. The solution was stirred at ꢂ78 C for 1 h
and then at room temperature for 12 h. The solution was diluted
with Et2O (25 mL) and EtOAc (5 mL) and washed aqueous
NaHCO3 (5 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The crude residue was puried by ash
column chromatography to give the title compound.
4.7.1 3,7,8-Tris(4-hydroxyphenyl)-1H-pyrrolo[2,1-c][1,4]
oxazin-1-one (9). White solid. Rf ¼ 0.5 (60% EtOAc/hexanes).
4.9 General procedure for the synthesis of 12 and 27
1H NMR (acetone-d6, 400 MHz): d 9.89 (s, 1H), 9.47 (s, 1H), 9.43 To a stirred solution of 10 or 26 (0.41 mmol, 1.0 equiv.) and
ꢀ
ꢀ
65 mg. Yield 72%. Mp 262–264 C (lit. (ref. 10a) 264–266 C).
(s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.57 (d, J ¼ 8.8 Hz, 2H), 7.06 (d, LiOH (0.82 mmol, 2.0 equiv.) in 1 : 1 THF–H2O (10 mL) was
ꢀ
J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼ 8.4 Hz, 2H), 6.88 (d, J ¼ 8.8 Hz, 2H), heated to 50 C in oil bath for 6 h. Aer cooled down to room
6.71 (d, J ¼ 8.4 Hz, 2H), 6.66 (d, J ¼ 8.8 Hz, 2H). 13C NMR temperature, the solution was concentrated in vacuo, the
(acetone-d6, 100 MHz): d 158.9, 157.1, 156.8, 154.1, 141.3, 132.2, residue was diluted with 10% aqueous KOH (15 mL) and
129.9, 129.2, 127.8, 126.0, 124.4, 123.6, 121.7, 120.4, 116.3, extracted with EtOAc (20 mL). The aqueous phase was acidied
115.7, 115.1, 112.4, 103.5. IR nmax (neat) 3412, 1696, 1618, 1422, with 1 N HCl (pH ¼ 1), extracted with CH2Cl2, dried with Na2SO4
1268, 9983 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C25H17NO5, and concentrated under reduced pressure. The remaining
411.1107; found, 411.1121.
residue was suspended in Ac2O (20 mL) and was added NaOAc
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(0.82 mmol, 2.0 equiv.). The resulting mixture was reuxed in for 1 h. Aer that, the mixture was ltered through Celite and
oil bath for 1 h. The excess Ac2O was removed by co-evaporation the solvent was evaporated under reduced pressure. The
with toluene in vacuo. The crude product was taken up in Et2O resulting crude residue was puried by ash column chroma-
(50 mL) and washed with aqueous NaHCO3. The organic layer tography (60% EtOAc in hexanes) to afford the desired product
was dried over Na2SO4 and concentrated in vacuo. The crude 19 as a colorless solid.
residue was puried by ash column chromatography to give
the title compound.
4.11.1 Methyl-3,4-bis(4-hydroxyphenyl)-1-(4-methox-
yphenethyl)-1H-pyrrole-2-carboxylate (19). White solid. Rf ¼ 0.5
1
ꢀ
4.9.1 3,7,8-Tris(4-methoxyphenyl)-1H-pyrrolo[2,1-c][1,4]
(40% EtOAc/hexanes). 30.2 mg. Yield 87%. Mp 174–176 C. H
oxazin-1-one (12). Brown solid. Rf ¼ 0.5 (40% EtOAc/hexanes). NMR (acetone-d6, 400 MHz): d 8.32 (s, 1H), 8.24 (s, 1H), 7.17 (d, J
97 mg. Yield 52%. Mp 206–208 ꢀC (lit. (ref. 12) 206–208 ꢀC). ¼ 8.4 Hz, 2H), 7.03 (s, 1H), 7.00 (d, J ¼ 8.4 Hz, 2H), 6.88 (d, J ¼
1H NMR (CDCl3, 400 MHz): d 7.69 (d, J ¼ 8.8 Hz, 2H), 7.36 (s, 8.8 Hz, 4H), 6.78 (d, J ¼ 8.4 Hz, 2H), 6.65 (d, J ¼ 8.8 Hz, 2H), 4.54
1H), 7.31 (d, J ¼ 8.8 Hz, 2H), 7.24 (s, 1H), 7.11 (d, J ¼ 8.8 Hz, 2H), (t, J ¼ 7.2 Hz, 2H), 3.78 (s, 3H), 3.56 (s, 3H), 3.05 (t, J ¼ 7.2 Hz, 2H).
6.99 (d, J ¼ 8.8 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H), 6.83 (d, J ¼ 13C{1H} NMR (acetone-d6, 100 MHz): d 161.9, 158.5, 156.0, 155.6,
8.8 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H). 13C NMR 131.7, 130.7, 130.6, 129.9, 129.2, 127.3, 126.3, 126.2, 123.9, 119.1,
(CDCl3, 100 MHz): d 160.5, 159.0, 158.6, 154.4, 142.0, 132.1, 114.8, 114.2, 113.8, 54.6, 51.1, 49.9, 37.3. IR nmax (neat) 3382, 3154,
129.8, 129.2, 128.2, 125.9, 124.7, 123.1, 119.0, 114.7, 114.3, 3021, 2932, 2831, 1741, 1614, 1544, 1216 cmꢂ1. HRMS (EI) m/z:
113.9, 113.4, 113.0, 102.7, 55.4, 55.22, 55.16. IR nmax (neat) 3112, [M+] calcd for C27H25NO5, 443.1733; found, 443.1729.
3038, 2948, 1745, 1614, 1422, 1188 cmꢂ1. HRMS (EI) m/z: [M+]
calcd for C28H23NO5, 453.1576; found, 453.1582.
4.12 Procedure for the synthesis of 23
4.9.2 7-Benzoyl-3-(4-methoxyphenyl)-6,8-diphenyl-1H-pyr-
rolo[2,1-c][1,4]oxazin-1-one (27). Brown solid. Rf ¼ 0.5 (20%
A mixture of chalcone 20 (0.48 mmol, 1.0 equiv.), amine 22 (1.2
equiv.) and aldehyde 21 (1.2 equiv.) in toluene was stirred at
90 ꢀC in an oil bath for 12 h. Aer cooled to room temperature,
the reaction was quenched with water (30 mL). The mixture was
extracted with ethyl acetate (3 ꢁ 10 mL) and concentrated under
reduced pressure to give the crude product 23 which was further
puried by ash column chromatography (10% EtOAc in
hexanes) to give the title compound.
1
ꢀ
EtOAc/hexanes). 119 mg. Yield 58%. Mp 224–226 C. H NMR
(CDCl3, 400 MHz): d 7.62–7.59 (m, 4H), 7.45–7.41 (m, 7H), 7.33
(s, 1H), 7.31 (t, J ¼ 7.2 Hz, 1H), 7.22–7.19 (m, 3H), 7.16 (t, J ¼
7.6 Hz, 2H), 6.93 (d, J ¼ 8.8 Hz, 2H), 3.84 (s, 3H). 13C{1H} NMR
(CDCl3, 100 MHz): d 192.8, 160.8, 154.3, 143.1, 137.6, 133.9, 132.8,
131.4, 130.5, 130.3, 129.7, 129.0, 128.1, 128.0, 127.9, 127.7, 126.3,
126.2, 122.8, 114.3, 111.9, 100.2, 55.4. IR nmax (neat) 3222, 3016,
2955, 1733, 1688, 1635, 1624, 1522, 976 cmꢂ1. HRMS (EI) m/z: [M+]
calcd for C33H23NO4, 497.1627; found, 497.1623.
4.12.1 Methyl-4-benzoyl-3,5-diphenylpyrrolidine-2-
carboxylate (23). Rf ¼ 0.5 (20% EtOAc/hexanes). 141 mg. Yield
76%. 1H NMR (CDCl3, 400 MHz): d 7.57–7.55 (m, 2H), 7.42–7.40
(m 2H), 7.36 (t, J ¼ 7.6 Hz, 2H), 7.28–7.25 (m, 4H), 7.15–7.09 (m,
5H), 5.02 (d, J ¼ 8.4 Hz, 1H), 4.54 (t, J ¼ 7.6 Hz, 1H), 4.22–4.13 (m,
4.10 Procedure for the synthesis of lamellarin O (13)
A mixture of 18 (0.078 mmol, 1.0 equiv.) and Pd(OH)2/C 2H), 3.77 (s, 3H). 13C{1H} NMR (CDCl3,100 MHz): d 198.7, 173.4,
(10 mol%) in MeOH was stirred under H2 atmosphere at room 140.8, 139.0, 137.5, 132.8, 128.8, 128.2, 128.13, 128.06, 127.7, 127.6,
temperature for 1 h. Aer that, the mixture was ltered through 127.4, 127.1, 67.7, 66.7, 60.6, 52.8, 52.3. IR nmax (neat) 3029, 2988,
Celite and the solvent was evaporated under reduced pressure. 1721, 1675, 1600, 1344, 1160, 1098, 784 cmꢂ1. HRMS (EI) m/z: [M+]
The resulting crude residue was then puried by ash column calcd for C25H23NO3, 385.1678; found, 385.1672.
chromatography (80% EtOAc in hexanes) to afford the desired
product 13 as a colorless solid.
4.13 Procedure for the synthesis of 24
4.10.1 Methyl-3,4-bis(4-hydroxyphenyl)-1-(2-(4-methox-
yphenyl)-2-oxoethyl)-1H-pyrrole-2-carboxylate (13). White solid.
Rf ¼ 0.5 (50% EtOAc/hexanes). 32.5 mg. Yield 91%. Mp 258–
260 ꢀC (lit. (ref. 11) 258–260 ꢀC). 1H NMR (acetone-d6, 400 MHz):
d 8.35 (s, 1H), 8.27 (s, 1H), 8.09 (d, J ¼ 8.8 Hz, 2H), 7.20 (s, 1H),
7.11 (d, J ¼ 8.8 Hz, 2H), 7.04 (d, J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼
8.8 Hz, 2H), 6.79 (d, J ¼ 8.4 Hz, 2H), 6.67 (d, J ¼ 8.4 Hz, 2H), 5.91
(s, 2H), 3.93 (s, 3H), 3.41 (s, 3H). 13C NMR (acetone-d6, 100
MHz): d 191.8, 164.0, 161.9, 156.1, 155.6, 131.8, 130.6, 130.1,
129.2, 128.3, 127.4, 127.1, 126.2, 124.2, 119.8, 114.9, 114.3,
114.0, 55.5, 55.1, 49.8. IR nmax (neat) 3379, 3148, 3019, 2928,
2835, 1752, 1668, 1156 cmꢂ1. HRMS (EI) m/z: [M+] calcd for
A mixture of 23 (0.52 mmol, 1.0 equiv.) and DDQ (3.0 equiv.) in
toluene was reuxed in an oil bath for 2 h. Aer cooled down to
room temperature, the resulting mixture was ltered through
Celite and the solvent was evaporated under reduced pressure.
The crude residue was puried by ash column chromatog-
raphy (30% EtOAc in hexanes) to afford the desired product 24
as a colorless solid.
4.13.1 Methyl-4-benzoyl-3,5-diphenyl-1H-pyrrole-2-
carboxylate (24). White solid. Rf ¼ 0.5 (10% EtOAc/hexanes).
1
ꢀ
177 mg. Yield 89%. Mp 88–90 C. H NMR (CDCl3, 400 MHz):
d 9.41 (s, 1H), 7.68–7.66 (m, 2H), 7.48–7.46 (m, 2H), 7.33–7.30
(m, 6H), 7.23–7.16 (m, 5H), 3.78 (s, 3H). 13C NMR (CDCl3, 100
MHz): d 194.0, 161.8, 138.2, 137.02, 137.00, 133.2, 133.0, 132.6,
130.5, 130.3, 129.8, 128.7, 128.1, 127.9, 127.4, 127.3, 123.3,
118.7, 51.7. IR nmax (neat) 3308, 2831, 1741, 1681, 1621, 1444,
C
27H23NO6, 457.1525; found, 457.1529.
4.11 Procedure for the synthesis of 19
A mixture of 18 (0.078 mmol, 1.0 equiv.) and Pd/C (10 mol%) in 854 cmꢂ1. HRMS (EI) m/z: [M+] calcd for C25H19NO3, 381.1365;
MeOH was stirred under H2 atmosphere at room temperature found, 381.1362.
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F. Ishibashi and M. Iwao, Tetrahedron, 2006, 62, 594; (c)
M. Komatsubara, T. Umeki, T. Fukuda and M. Iwao, J. Org.
Chem., 2014, 79, 529; (d) T. Fukuda, E. I. Sudo,
K. Shimokawa and M. Iwao, Tetrahedron, 2008, 64, 328.
8 J. H. Liu, Q. C. Yang, T. C. W. Mak and H. N. C. Wong, J. Org.
Chem., 2000, 65, 3587.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the Ministry of Science and Technology of the
Republic of China, Taiwan, for nancially supporting this
research under Contract No. MOST 108-2113-M-029-001 and
109-2113-M-029-010-MY3.
9 D. Morikawa, K. Morii, Y. Yasuda, A. Mori and K. Okano, J.
Org. Chem., 2020, 85, 8603.
10 (a) D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon and
Q. Jin, J. Am. Chem. Soc., 1999, 121, 54; (b) D. L. Boger,
D. R. Soenen, C. W. Boyce, M. P. Hedrick and Q. Jin, J. Org.
Chem., 2000, 65, 2479.
11 A. Ramirez-Rodriguez, J. M. Mendez, C. C. Jimenez, F. Leon
and A. Vazquez, Synthesis, 2012, 44, 3321.
12 A. Fuerstner, H. Weintritt and A. Hupperts, J. Org. Chem.,
1995, 60, 6637.
Notes and references
1 R. J. Andersen, D. J. Faulkner, C. H. He, G. D. V. Duyne and
J. Clardy, J. Am. Chem. Soc., 1985, 107, 5492.
2 (a) N. Lindquist, W. Fenical, G. D. V. Duyne and J. Clardy, J.
Org. Chem., 1988, 53, 4570; (b) A. R. Carroll, B. F. Bowden and
J. C. Coll, Aust. J. Chem., 1993, 46, 489; (c) S. Urban,
M. S. Butler and R. J. Capon, Aust. J. Chem., 1994, 47, 1919;
(d) S. Urban, L. Hobbs, J. N. A. Hooper and R. J. Capon,
Aust. J. Chem., 1995, 48, 1491; (e) S. Urban and R. J. Capon,
Aust. J. Chem., 1996, 49, 711; (f) M. V. R. Reddy,
D. J. Faulkner, Y. Venkateswarlu and M. R. Rao,
Tetrahedron, 1997, 53, 3457; (g) C. L. Cantrell, A. Groweiss,
K. R. Gustafson and M. R. Boyd, Nat. Prod. Lett., 1999, 14,
39; (h) R. A. Davis, A. R. Carroll, G. K. Pierens and
R. J. Quinn, J. Nat. Prod., 1999, 62, 419; (i) M. V. R. Reddy,
M. R. Rao, D. Rhodes, M. S. T. Hansen, K. Rubins,
F. D. Bushman, Y. Venkateswarlu and D. J. Faulkner, J.
Med. Chem., 1999, 42, 1901; (j) J. Ham and H. Kang, Bull.
Korean Chem. Soc., 2002, 23, 163; (k) P. Krishnaiah,
V. L. N. Reddy, G. Venkataramana, K. Ravinder,
M. Srinivasulu, T. V. Raju, K. Ravikumar, D. Chandrasekar,
S. Ramakrishna and Y. Venkateswarlu, J. Nat. Prod., 2004,
67, 1168; (l) S. M. Reddy, M. Srinivasulu, N. Satyanarayana,
A. K. Kondapi and Y. Venkateswarlu, Tetrahedron, 2005, 61,
9242; (m) F. Plisson, X. C. Huang, H. Zhang, Z. Khalil and
R. J. Capon, Chem.–Asian J., 2012, 7, 1616.
13 Q. Li, J. Jiang, A. Fan, Y. Cui and Y. Jia, Org. Lett., 2011, 13,
312.
14 J. R. Hwu, A. Roy, A. Panja, W. C. Huang, Y. C. Hu, K. T. Tan,
C. C. Lin, K. C. Hwang, M. H. Hsu and S. C. Tsay, J. Org.
Chem., 2020, 85, 9835.
15 K. Takamura, H. Matsuo, A. Tanaka, J. Tanaka, T. Fukuda,
F. Ishibashi and M. Iwao, Tetrahedron, 2013, 69, 2782.
16 (a) K. B. Manjappa, J. R. Syu and D. Y. Yang, Org. Lett., 2016,
18, 332; (b) K. B. Manjappa, J. M. Lin and D. Y. Yang, J. Org.
Chem., 2017, 82, 7648; (c) S. Vyasamudri and D. Y. Yang, J.
Org. Chem., 2019, 84, 3662.
17 E. A. Silyanova, A. V. Samet, L. K. Salamandra,
V. N. Khrustalev and V. V. Semenov, Eur. J. Org. Chem.,
2020, 2093.
18 (a) D. H. R. Barton and S. Z. A. Zard, J. Chem. Soc., Chem.
Commun., 1985, 1098; (b) D. H. R. Barton, J. Kervagoret
and S. Z. A. Zard, Tetrahedron, 1990, 46, 7587; (c)
G. W. Gribble, Names Reactions in Heterocyclic Chemistry,
2005, p. 70; (d) N. Ono, Heterocycles, 2008, 75, 243; (e)
S. C. Zheng, Q. Wang and J. Zhu, Angew. Chem., Int. Ed.,
2019, 58, 9215.
19 (a) A. S. Guram, R. A. Rennels and S. L. A. Buchwald, Angew.
Chem., Int. Ed. Engl., 1995, 34, 1348; (b) J. Louie and
J. F. Hartwig, Tetrahedron Lett., 1995, 36, 3609; (c)
´
3 A. R. Quesada, M. D. G. Gravalos and J. L. F. Puentes, Br. J.
Cancer, 1996, 74, 677.
´
4 (a) M. Facompre, C. Tardy, C. Bal-Mahieu, P. Colson,
´
´
´
´
H. Zavala-Gomez, A. Ramırez-Rodrıguez and A. Vazquez, J.
Chem. Res., 2017, 41, 677; (d) S. V. Ley and A. W. Thomas,
Angew. Chem., Int. Ed., 2003, 42, 5400.
C. Perez, I. Manzanares, C. Cuevas and C. Bailly, Cancer
Res., 2003, 63, 7392; (b) E. Marco, W. Laine, C. Tardy,
A. Lansiaux, M. Iwao, F. Ishibashi, C. Bailly and F. Gago, J.
Med. Chem., 2005, 48, 3796.
5 (a) J. Kluza, M. A. Gallego, A. Loyens, J. C. Beauvillain,
J. M. F. Sousa-Faro, C. Cuevas, P. Marchetti and C. Bailly,
Cancer Res., 2006, 66, 3177; (b) C. Ballot, J. Kluza, S. Lancel,
A. Martoriati, S. M. Hassoun, L. Mortier, J. C. Vienne,
20 (a) S. K. Ray, R. G. Biswas, A. Suneja, M. M. Sadhu and
V. K. Singh, J. Org. Chem., 2018, 83, 2293; (b) Z. Zhu,
H. S. Chandak and D. Seidel, Org. Lett., 2018, 20, 4090; (c)
L. Zhu, X. Ren, Z. Liao, J. Pan, C. Jiang and T. Wang, Org.
Lett., 2019, 21, 8667.
21 J. C. Antilla, J. M. Baskin, T. E. Barder and S. L. Buchwald, J.
Org. Chem., 2004, 69, 5578.
´
G. Briand, P. Formstecher, C. Bailly, R. Neviere and
P. Marchetti, Apoptosis, 2010, 15, 769.
6 K. Hasse, A. C. Willis and M. G. Banwell, Eur. J. Org. Chem.,
2011, 88.
7 (a) M. Iwao, T. Takeuchi, N. Fujikawa, T. Fukuda and
F. Ishibashi, Tetrahedron Lett., 2003, 44, 4443; (b)
N. Fujikawa, T. Ohta, T. Yamaguchi, T. Fukuda,
22 L. V. Romashov, Y. A. Khomutova, V. M. Danilenko,
S. L. Ioffe and A. V. Lesiv, Synthesis, 2010, 407.
23 J. G. Greger, S. J. P. Yoon-Miller, N. R. Bechtold,
S. A. Flewelling, J. P. MacDonald, C. R. Downer,
E. A. Cohen and E. T. Pelkey, J. Org. Chem., 2011, 76, 8203.
43174 | RSC Adv., 2020, 10, 43168–43174
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