Total synthesis of the marine natural products lukianols A and B

Article abstract of DOI:10.1016/j.tet.2013.01.077

Total synthesis of the pyrrolic marine natural products lukianols A (1) and B (2) has been achieved using N-benzenesulfonyl-3,4-dibromopyrrole (3) as a common starting material. The key synthetic strategy developed is the combined bromine-directed lithiation and palladium-catalyzed cross-coupling of 3 to produce 3,4-diarylpyrrol-2-carboxylates. Regioselective iodination of the phenolic intermediate 24 was thoroughly investigated for the synthesis of lukianol B.

Full text of DOI:10.1016/j.tet.2013.01.077

Tetrahedron 69 (2013) 2782e2788
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Tetrahedron
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Total synthesis of the marine natural products lukianols A and B
Kaoru Takamura a, Hisami Matsuo a, Ayana Tanaka a, Junji Tanaka b, Tsutomu Fukuda a,
,
Fumito Ishibashi c, Masatomo Iwao a
*
a Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
b Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
c Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of the pyrrolic marine natural products lukianols A (1) and B (2) has been achieved using
N-benzenesulfonyl-3,4-dibromopyrrole (3) as a common starting material. The key synthetic strategy
developed is the combined bromine-directed lithiation and palladium-catalyzed cross-coupling of 3 to
produce 3,4-diarylpyrrol-2-carboxylates. Regioselective iodination of the phenolic intermediate 24 was
thoroughly investigated for the synthesis of lukianol B.
Received 14 January 2013
Accepted 26 January 2013
Available online 4 February 2013
Keywords:
Ó 2013 Published by Elsevier Ltd.
Lukianols A, B
Total synthesis
Pyrrole
Directed lithiation
Cross-coupling
1. Introduction
derived from a human epidermatoid carcinoma (KB), whereas
lukianol B was inactive. Recently, Fuente and co-workers screened
Lukianols A (1) and B (2) were isolated from a tunicate collected
in the lagoon of Palmyra atoll by Scheuer and co-workers (Fig. 1).1
Their unique 3,7,8-tris(4-hydroxyphenyl)-1H-pyrrolo[2,1-c][1,4]
oxazin-1-one structures were elucidated by spectral methods.
Lukianol A exhibited moderate cytotoxicity against a cell line
about two thousand marine natural products to find out structur-
ally novel human aldose reductase (h-ALR2) inhibitors.2 They re-
ported lukianol B (2) was the most potent one among the
compounds tested. Its h-ALR2 inhibitory activity (IC50¼0.6
mM) was
six-fold more potent than that of the known ALR inhibitor sorbinil.
The therapeutic effects of h-ALR2 inhibitors for some degenerative
complications of diabetes, such as neuropathy, nephropathy, and
retinopathy, are well recognized.3 Therefore, 2 can be regarded as
a new lead to develop therapeutic agents for treatment of these
disorders.
HO
HO
OH
OH
I
In spite of its impressive biological activity, total synthesis of
lukianol B (2) has not been achieved so far, though simpler lukianol
A (1) has been synthesized by several groups.4 Herein, we report
the total synthesis of both 1 and 2.
O
O
N
N
O
O
2. Results and discussion
OH
OH
The key strategy employed in our total synthesis is the com-
bined directed lithiation and palladium-catalyzed cross-coupling of
N-benzenesulfonyl-3,4-dibromopyrrole (3) to produce 3,4-
diarylpyrrole-2-carboxylates (Scheme 1). This method could pro-
vide not only 3,4-symmetrically substituted pyrrole-2-carboxylates
5, but also 3,4-unsymmetrically substitute ones 8 by means of
bromine-directed regioselective lithiation (6/7) developed in our
laboratories.5
lukianol A (1)
lukianol B (2)
Fig. 1. Structures of lukianols A and B.
* Corresponding author. Tel./fax: þ81 95 819 2681; e-mail address: iwao@na-
gasaki-u.ac.jp (M. Iwao).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.01.077

K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
2783
Ar1
i-PrO
Br
Oi-Pr
Br
Br
1st
cross-coupling
N
N
Br
Br
CO2Bn
SO2Ph
SO2Ph
a
b
3
CO2Bn
6
X
3
N
Y
N
SO2Ph
Br-directed lithiation–
functionalization
ref. 5
11 (Y=SO2Ph)
12 (Y=H)
9 (X=H)
10 (X=CO2Bn)
c
Ar1
Br
Br
Br
i-PrO
i-PrO
Oi-Pr
Oi-Pr
CO2R
CO2R
N
N
SO2Ph
4
SO2Ph
7
d
f
O
CO2R
N
N
double
cross-coupling
2nd
O
O
cross-coupling
Ar1
Ar2
Ar
Ar
CO2R
CO2R
OMe
OMe
13 (R=Bn)
14 (R=H)
N
N
15
SO2Ph
8
SO2Ph
5
e
R1O
OR1
O
lukianol A (1)
lukianol B (2)
N
g or h
O
Scheme 1. Key synthetic strategy.
16 (R1=H, R2=Me)
1 (R1=R2=H)
The synthesis of lukianol A (1) is shown in Scheme 2. A known
N-benzenesulfonyl-3,4-dibromopyrrole (3)6 was lithiated with
1.2 equiv of lithium diisopropylamide (LDA) in Et2O at ꢀ78 ꢁC for
1 h and the resulting lithio species was trapped with benzyl
chloroformate to give 2-benzyloxycarbonylpyrrole 9 in 62% yield as
a single product. When THF was used as a solvent, undesired 2,5-
diester 10 was formed as a by-product. The palladium-catalyzed
cross-coupling of 9 with 3.0 equiv of p-isopropoxyphenylboronic
acid in the presence of bulky 1,10-bis(di-tert-butylphosphino)fer-
rocene (dtbpf) ligand produced 3,4-diarylated pyrrole 11 in 93%
yield. The double cross-coupling in the presence of common
Pd(PPh3)4 was sluggish. The benzenesulfonyl protecting group was
then removed with tetrabutylammonium fluoride (TBAF). The
resulting pyrrole 12 was alkylated with p-methoxyphenacyl bro-
mide to give 13. Hydrogenolysis of the benzyl ester provided the
corresponding acid 14 in excellent yield.7 Dehydrative cyclization of
14 by heating in acetic anhydride gave the pyrrolooxazinone 15.4
The isopropyl groups of 15 were selectively removed by treat-
OR2
Scheme 2. Reagents and conditions: (a) (1) LDA (1.2 equiv), Et2O, e78 ꢁC, 1 h, (2)
ClCO2Bn (1.8 equiv), e78 ꢁC, 1
(62%). (b) p-(i-PrO)eC6H4eB(OH)2 (3.0 equiv),
h
Pd(dba)2 (5 mol %), dtbpf (5 mol %), Na2CO3 (6.6 equiv), aq THF, reflux, 14 h (93%). (c)
TBAF (1.5 equiv), THF, reflux, 2 h (92%). (d) p-(MeO)eC6H4eCOCH2Br (2.5 equiv), K2CO3
(3.0 equiv), DMF, 70 ꢁC, 3 h (81%). (e) H2, PdeC, EtOAc, rt, 4 h (98%). (f) Ac2O, NaOAc,
100 ꢁC, 1 h (84%). (g) BCl3 (6.0 equiv), CH2Cl2, e78 ꢁC, 0.5 h/0 ꢁC, 2.5 h (16: 99%). (h)
BBr3 (9.0 equiv), CH2Cl2, e78 ꢁC, 1 h/0 ꢁC, 3 h/rt, 0.5 h (1: quant).
converted to the pyrrolooxazinone 23 in essentially same manner as
described above without any complications. Selective deprotection
of the isopropyl group of 23 with BCl3 produced the phenol 24 in 99%
yield.
With the phenol 24 in hand, we examined the iodination of this
compound. The results are summarized in Table 1. A reaction with
N-iodosuccinimide (NIS) in DMF resulted in recovery of the starting
material 24 (entry 1). Treatment with more electrophilic N-iodo-
saccharin (NISac)9 or iodine monochloride (ICl) produced un-
expected compound 25 in which the central pyrrolooxazinone core
was iodinated at C6 (entries 2, 3). The position of the iodo group in
25 was confirmed by the X-ray crystallographic analysis (Fig. 2). On
the other hand, reaction with 1.0 equiv of iodine in the presence of
ammonia10 gave the desired iodide 26 in 20% yield accompanied by
a small amount of diiodide 27 (entry 4). Use of 2.0 equiv of iodine
under similar conditions afforded 27 selectively albeit in low yield
(entry 5). Use of NISac instead of iodine improved the yields of the
products 26 and 27 (entries 6e8). Although diiodide 27 was ob-
tained selectively in good yield using 2.0 equiv of NISac (entry 8),
the monoiodide 26 was hardly produced in acceptable yields even
if lower amount of NISac was employed (entries 6, 7). Fortunately,
however, 26 was produced from 27 by reductive elimination of an
iodo group with ZneCu couple11 (Scheme 4).
8
ment with BCl3 in 99% yield to give 40-O-methyllukianol A (16).
Treatment of 15 with BBr3 removed all of the isopropyl and the
methyl groups to furnish lukianol A (1) in quantitative yield.
Next, we turned our attention to the synthesis of lukianol B (2).
We planned to introduce the pivotal iodo group at the late stage of
the synthesis by a regioselective iodination of the key phenol in-
termediate 24. The synthesis of 24 is shown in Scheme 3. Cross-
coupling of 3 with 2.0 equiv of p-isopropoxyphenylboronic acid in
the presence of Pd(PPh3)4 gave the mono-coupling product 17 in
57% yield accompanied by a small amount the di-coupling product6
(15%). Bromine-directed lithiation5 of 17 with LDA in THF followed
by a reaction with benzyl chloroformate afforded 18 in 75% yield as
a single regioisomer. The regioselectivity of this reaction was con-
firmed at the later stage by the X-ray crystallographic analysis of the
compound 25 (vide infra). Second cross-coupling of 18 with p-
methoxyphenylboronic acid produced the key 3,4-unsymmetrically
arylated pyrrol-2-carboxylate 19 in good yield. This compound was
Finally the iodide 26 was converted to lukianol B (2) by deme-
thylation with BBr3 in excellent yield (Scheme 4). In a similar
manner, diiodide 27 was also deprotected to provide diiodolukianol

2784
K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
i-PrO
i-PrO
OMe
Br
a
c
3
X
CO2Bn
N
N
Y
SO2Ph
17 (X=H)
18 (X=CO2Bn)
19 (Y=SO2Ph)
20 (Y=H)
b
d
i-PrO
RO
OMe
OMe
e
g
Fig. 2. X-ray crystal structure of 25.
O
CO2R
N
N
O
O
I
HO
HO
OH
OH
I
I
O
O
OMe
OMe
21 (R=Bn)
22 (R=H)
N
N
c
a
b
27
26
O
O
23 (R=i-Pr)
24 (R=H)
f
h
Scheme 3. Reagents and conditions: (a) p-(i-PrO)eC6H4eB(OH)2 (2.0 equiv), Pd(PPh3)4
(10 mol %), Na2CO3 (6.6 equiv), aq THF, reflux, 14.5 h (57%). (b) (1) LDA (1.2 equiv),
THF, e78 ꢁC, 1 h, (2) ClCO2Bn (1.8 equiv), e78 ꢁC, 1 h (75%). (c) p-(MeO)eC6H4eB(OH)2
(1.8 equiv), Pd(PPh3)4 (10 mol %), Na2CO3 (6.6 equiv), aq DME, reflux, 15 h (88%).
(d) TBAF (1.5 equiv), THF, reflux 2 h (96%). (e) p-(MeO)eC6H4eCOCH2Br (2.5 equiv),
K2CO3 (3.0 equiv), DMF, 70 ꢁC, 3 h (79%). (f) H2, PdeC, EtOAc, rt, 7 h (85%). (g) Ac2O,
NaOAc, 100 ꢁC, 1.5 h (93%). (h) BCl3 (3.0 equiv), CH2Cl2, e78 ꢁC, 0.5 h/0 ꢁC, 1.5 h (99%).
OH
OH
28
2
Scheme 4. Reagents and conditions: (a) ZneCu, DMA, rt, 1.5
h (68%). (b) BBr3
(7.0 equiv), CH2Cl2, e78 ꢁC, 0.5 h/rt, 0.5 h/reflux, 3 h (95%). (c) BBr3 (7.0 equiv),
CH2Cl2, e78 ꢁC, 0.5 h/0 ꢁC, 2.5 h/rt, 6.5 h/reflux, 3 h (74%).
Table 1
Iodination of the phenol 24
for structureeactivity relationship studies to develop effective h-
ALR2 inhibitors. The studies along this line are in progress in our
laboratories.
I
HO
HO
HO
OMe
OMe
OMe
I
I
4. Experimental
4.1. General
O
O
O
I
6
N
N
N
Conditions
O
O
O
24
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a JEOL JNM-AL400 spectrometers at 400 and 100 MHz,
respectively, using TMS as an internal standard. IR spectra were
recorded on a Nicolet Nexus 670 FT-IR spectrometer. High-
resolution mass spectra were recorded on a JEOL JMS-700N spec-
trometer. Elemental analyses were performed using a Perkin Elmer
2400II instrument. Gravity column chromatography was conducted
OMe
25
OMe
26
OMe
27
Entrya Conditions
Yield (%)b
24 25 26 27
1
2
3
4
5
6
7
8
NISc (1.05 equiv), DMF, 0 ꢁC, 1 h
NISacd (1.0 equiv), DMF, 0 ꢁC, 2 h
ICI (2.3 equiv), CH2Cl2, DMF, MeOH, 0 ꢁC, 2.5 h 15 49
I2 (1.0 equiv), NH3, EtOH, DMF, 0 ꢁC, 2 h
I2 (2.0 equiv), NH3, EtOH, DMF, 0 ꢁC, 8.5 h
NISac (1.0 equiv), NH3, EtOH, DMF, 0 ꢁC, 2 h
NISac (1.5 equiv), NH3, EtOH, DMF, 0 ꢁC, 2 h
NISac (2.0 equiv), NH3, EtOH, DMF, 0 ꢁC, 2 h
85
40 13
0
0
0
0
0
0
0
6
32
using spherical silica gel 60N, 63e210
Flash column chromatography was conducted using spherical silica
gel 60N, 40e50 m (Kanto Chemical Co. Inc.).
mm (Kanto Chemical Co. Inc.).
26
10
40
23
6
0
0
0
0
0
20
0
20 17
27 50
m
4.2. Synthesis of lukianol A (1)
6
78
a
b
c
4.2.1. Benzyl N-benzenesulfonyl-3,4-dibromopyrrole-2-carboxylate
(9). A LDA solution was prepared by dropwise addition of 1.48 M
hexane solution of BuLi (4.86 mL, 7.20 mmol) to a stirred solution of
diisopropylamine (1.26 mL, 9.00 mmol) in dry Et2O (31 mL) at
ꢀ78 ꢁC under Ar atmosphere followed by warming up to 0 ꢁC over
ca. 5 min. The solution was cooled again to ꢀ78 ꢁC and a solution of
3 (2.19 g, 6.00 mmol) in dry Et2O (45 mL) was added dropwise. After
stirring for 1 h, benzyl chloroformate (1.54 mL, 10.8 mmol) dis-
solved in dry Et2O (21 mL) was added dropwise. The reaction
mixture was stirred for 1 h before being quenched with a saturated
solution of NH4Cl. The whole was extracted three times with Et2O
and the extracts were combined, washed successively with water
and brine, dried over Na2SO4, and concentrated. The crude product
was chromatographed on silica gel (188 mL) using toluene/hexane
(1:1) as an eluent to give 9 (1.846 g, 62%) as white solid along with
All reactions were carried out using 30 mg of 24.
Isolated yield.
NIS: N-iodosuccinimide.
d
NISac: N-iodosaccharin.
A (28) in good yield. The 1H and 13C NMR data of the synthetic
lukianol B (2) were found to be identical with those of the natural
product.1 The first total synthesis of lukianol B (2) was thus
completed.
3. Conclusion
In summary, we have achieved the total synthesis of lukianols A
(1) and B (2) using a new method to produce 3,4-diarylpyrrole-2-
carboxylates. The synthesis described herein can be applied to
provide a wide range of lukianol analogues, which may be utilized

K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
2785
recovered 3 (0.551 g, 25%). Recrystallization of 9 from Et2Oehexane
gave colorless needles, mp 97e97.5 ꢁC. IR (KBr): 1720, 1449, 1379,
1128 cmꢀ1
.
1H NMR (CDCl3):
d
1.30 (d, J¼6.0 Hz, 6H), 1.34 (d,
J¼6.0 Hz, 6H), 4.47 (sep, J¼6.0 Hz, 1H), 4.52 (sep, J¼6.0 Hz, 1H), 5.19
(s, 2H), 6.71 (d, J¼8.8 Hz, 2H), 6.77 (d, J¼8.8 Hz, 2H), 6.98e7.01 (m,
3H), 7.12e7.17 (m, 4H), 7.24e7.29 (m, 3H), 9.27 (br s, 1H). 13C NMR
1172, 1086 cmꢀ1. 1H NMR (CDCl3):
d 5.30 (s, 2H), 7.34e7.40 (m, 5H),
7.50 (dd, J¼8.4, 7.6 Hz, 2H), 7.62e7.66 (m, 1H), 7.65 (s, 1H), 7.93 (dd,
J¼8.4, 1.2 Hz, 2H). 13C NMR (CDCl3):
d
67.7, 104.7, 112.1, 123.7, 125.3,
(CDCl3): d 22.1, 22.2, 65.8, 69.7,115.0,115.5,119.4,120.2,126.4, 126.6,
128.1, 128.5, 128.5, 128.6, 129.1, 134.4, 134.7, 138.0, 158.3. Anal. Calcd
for C18H13Br2NO4S: C, 43.31; H, 2.62; N, 2.81. Found: C, 43.22; H,
2.40; N, 2.80.
126.8, 127.9, 127.9, 128.3, 129.3, 131.9, 135.9, 156.3, 156.9, 161.1. Anal.
Calcd for C30H31NO4: C, 76.73; H, 6.65; N, 2.98. Found: C, 76.82; H,
6.75; N, 2.95.
4.2.2. Benzyl N-benzenesulfonyl-3,4-dibromopyrrole-2,5-dicarboxylate
(10). A LDA solution was prepared in a similar manner as described
4.2.5. Benzyl 3,4-bis(4-isopropoxyphenyl)-1-[2-(4-methoxyphenyl)-
2-oxoethyl]pyrrole-2-carboxylate (13). A mixture of 12 (1.19 g,
2.52 mmol), p-methoxyphenacyl bromide (1.45 g, 6.31 mmol),
K2CO3 (1.05 g, 7.57 mmol) in DMF (59.6 mL) was stirred at 70 ꢁC for
3 h under Ar atmosphere. After cooling the reaction mixture was
diluted with AcOEt, washed successively with water (four times)
and brine (once), dried over Na2SO4, and concentrated under re-
duced pressure. The crude product was purified by a flash chro-
matography on silica gel (141 mL) using toluene/AcOEt (30:1) as an
eluent to give 13 (1.26 g, 81%) as white solid along with recovered
12 (169 mg, 14%). Recrystallization of 13 from Et2Oehexane gave
colorless granules, mp 131e133 ꢁC. IR (KBr): 1686, 1598, 1241, 1172,
above using BuLi (1.47 M hexane solution, 814
mL, 1.2 mmol),
diisopropylamine (210 L, 1.5 mmol), and dry THF (5.2 mL). To
m
this solution was added dropwise a solution of 3 (365 mg,1.00 mmol)
in dry THF (3.5 mL). After stirring for 1 h at ꢀ78 ꢁC, a solution of
benzyl chloroformate (257 mL, 1.8 mmol) in dry THF (3.5 mL) was
added. The mixture was stirred for 1 h at the same temperature
and quenched with saturated aqueous NH4Cl. The products were
extracted with Et2O as described above and purified by a column
chromatography (toluene/hexane 2:1) to give 10 (190 mg, 30%) as
white solid along with 9 (63 mg, 13%) and the starting material 3
(159 mg, 44%). Recrystallization of 10 from Et2Oehexane gave
colorless needles, mp 95.5e96 ꢁC. IR (KBr): 1739, 1717, 1202, 725,
1100 cmꢀ1
.
1H NMR (CDCl3):
d
1.28 (d, J¼6.0 Hz, 6H), 1.33 (d,
J¼6.0 Hz, 6H), 3.88 (s, 3H), 4.47 (sep, J¼6.0 Hz, 2H), 4.97 (s, 2H), 5.73
(s, 2H), 6.68 (d, J¼8.7 Hz, 2H), 6.72 (d, J¼8.7 Hz, 2H), 6.82e6.83 (m,
2H), 6.92 (s, 1H), 6.97 (d, J¼8.7 Hz, 2H), 6.97 (d, J¼8.9 Hz, 2H), 7.12
(d, J¼8.7 Hz, 2H), 7.14e7.17 (m, 3H), 7.99 (d, J¼8.9 Hz, 2H). 13C NMR
602 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 5.34 (s, 4H), 7.33e7.39
(m, 10H), 7.42 (dd, J¼8.4, 7.6 Hz, 2H), 7.60 (tt, J¼7.6, 1.3 Hz,
1H), 8.16 (dd, J¼8.4, 1.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 68.4,
110.1, 128.3, 128.6, 128.6, 128.6, 128.7, 128.8, 134.4, 134.5, 138.1,
159.0; HRFABMS m/z calcd for C26H20Br2NO6S (MþH)þ 631.9378,
found 631.9425.
(CDCl3): d 22.1, 22.2, 55.5, 65.5, 69.62, 69.65,114.1,114.9,115.3,119.8,
124.8, 126.7, 127.2, 127.5, 127.6, 127.87, 127.93, 128.0, 129.3, 130.3,
131.4, 131.9, 135.6, 156.1, 156.7, 161.7, 164.0, 191.8. Anal. Calcd for
C39H39NO6: C, 75.83; H, 6.36; N, 2.27. Found: C, 75.81; H, 6.15; N,
2.27.
4.2.3. Benzyl
N-benzenesulfonyl-3,4-bis(4-isopropoxyphenyl)pyr-
role-2-carboxylate (11). A mixture of 9 (100 mg, 0.200 mmol), 4-
isopropoxyphenylboronic acid (108 mg, 0.602 mmol), Pd(dba)2
(5.8 mg, 0.01 mmol), dtbpf (4.8 mg, 0.01 mmol), Na2CO3 (140 mg,
1.32 mmol), dry THF (2.5 mL), and degassed water (0.5 mL) was
stirred at refluxing temperature for 14 h under Ar atmosphere.
After cooling, the solvent was removed under reduced pressure and
the residue was extracted three times with Et2O. The combined
extracts were washed successively with water and brine, dried over
Na2SO4, and concentrated. The crude product was chromato-
graphed on silica gel (47 mL) using toluene as an eluent to give 11
(113 mg, 93%) as white solid. Recrystallization from Et2Oehexane
gave colorless granules, mp 155.5e156 ꢁC. IR (KBr): 1718, 1373,
4.2.6. 3,4-Bis(4-isopropoxyphenyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]
pyrrole-2-carboxylic acid (14). A mixture of 13 (46.5 mg,
0.0753 mmol) and 20% w/w Pd/C (9.3 mg) in AcOEt (5 mL) was
vigorously stirred under hydrogen atmosphere (balloon) at room
temperature for 4 h. The mixture was diluted with CH2Cl2 and fil-
tered through a pad of Celite. Concentration of the filtrate gave
practically pure 14 (41.0 mg, 98%). Recrystallization from
CH2Cl2ehexane gave white powder, mp 192e193 ꢁC. IR (KBr): 1686,
1652, 1598, 1456, 1242 cmꢀ1 1H NMR (DMSO-d6):
. d 1.20 (d,
J¼6.0 Hz, 6H),1.25 (d, J¼6.0 Hz, 6H), 3.85 (s, 3H), 4.49 (sep, J¼6.0 Hz,
1H), 4.56 (sep, J¼6.0 Hz,1H), 5.82 (s, 2H), 6.70 (d, J¼8.9 Hz, 2H), 6.80
(d, J¼8.7 Hz, 2H), 6.91 (d, J¼8.9 Hz, 2H), 7.04 (d, J¼8.7 Hz, 2H), 7.10
(d, J¼8.9 Hz, 2H), 7.21 (s, 1H), 8.02 (d, J¼8.9 Hz, 2H). 13C NMR
1243, 1183, 1135 cmꢀ1. 1H NMR (CDCl3):
d
1.30 (d, J¼6.1 Hz, 6H), 1.32
(d, J¼6.1 Hz, 6H), 4.48 (sep, J¼6.1 Hz, 1H), 4.48 (sep, J¼6.1 Hz, 1H),
5.08 (s, 2H), 6.69 (d, J¼8.7 Hz, 2H), 6.72 (d, J¼8.7 Hz, 2H), 6.94e7.01
(m, 6H), 7.18e7.25 (m, 3H), 7.51 (dd, J¼8.0, 7.5 Hz, 2H), 7.56 (s, 1H),
7.62 (tt, J¼7.5, 1.4 Hz, 1H), 8.04 (dd, J¼8.0, 1.4 Hz, 2H). 13C NMR
(DMSO-d6):
d 22.7, 22.7, 56.4, 69.8, 69.8, 114.9, 115.3, 116.0, 120.9,
123.8, 127.3, 127.5, 128.5, 128.6, 129.6, 130.2, 131.0, 132.5, 156.3,
156.8, 163.2, 164.3, 193.3. Anal. Calcd for C32H33NO6: C, 72.85; H,
6.30; N, 2.65. Found: C, 73.06; H, 6.52; N, 2.64.
(CDCl3):
d 22.0, 22.1, 67.1, 69.6, 69.7, 115.1, 115.5, 122.5, 122.8, 124.6,
124.7, 127.4, 127.9, 128.0, 128.1, 128.2, 129.0,129.5, 131.2, 133.1, 133.8,
135.0, 139.0, 157.1, 157.4, 160.9. Anal. Calcd for C36H35NO6S: C, 70.91;
H, 5.79; N, 2.30. Found: C, 71.00; H, 5.72; N, 2.26.
4.2.7. 7,8-Bis(4-isopropoxyphenyl)-3-(4-methoxyphenyl)-1H-pyr-
rolo[2,1-c][1,4]oxazin-1-one (15). A solution of 14 (971 mg,
1.75 mmol) and dehydrated AcONa (2.59 g, 31.6 mmol) in Ac2O
(130 mL) was heated at 100 ꢁC for 1 h. After cooling to room tem-
perature, the Ac2O was removed azeotropically with toluene under
reduced pressure. The oily residue was dissolved in Et2O and the
solution was washed three times with a saturated solution of
NaHCO3, dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by a column chromatography on silica gel
(163 mL) using hexane/AcOEt (3:1) as an eluent to give 15 (790 mg,
84%) as white solid. Recrystallization from Et2Oehexane gave col-
orless granules, mp 131.5e132.5 ꢁC. IR (KBr): 1733, 1248, 1178, 1118,
4.2.4. Benzyl 3,4-bis(4-isopropoxyphenyl)-1H-pyrrole-2-carboxylate
(12). To a solution of 11 (100 mg, 0.164 mmol) in dry THF
(7.8 mL) was added dropwise a 1.0 M THF solution of TBAF (245 mL,
0.245 mmol) at room temperature. The whole was heated at reflux
for 2 h and, after cooling to room temperature, the mixture was
quenched with water. The solvent was removed under reduced
pressure and the residue was extracted three times with CH2Cl2.
The combined extracts were washed successively with water and
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The oily residue was chromatographed on silica gel (31 mL)
using toluene/EtOAc (30:1) as an eluent to give 12 (70.7 mg, 92%) as
white solid. Recrystallization from Et2Oehexane afforded colorless
needles, mp 128e128.5 ꢁC. IR (KBr): 3299, 1678, 1398, 1241,
1027 cmꢀ1
.
1H NMR (CDCl3):
d
1.32 (d, J¼6.0 Hz, 6H), 1.35 (d,
J¼6.0 Hz, 6H), 3.83 (s, 3H), 4.51 (sep, J¼6.0 Hz, 1H), 4.55 (sep,
J¼6.0 Hz, 1H), 6.77 (d, J¼8.8 Hz, 2H), 6.83 (d, J¼8.8 Hz, 2H), 6.93 (d,
J¼8.9 Hz, 2H), 7.06 (d, J¼8.8 Hz, 2H), 7.17 (s, 1H), 7.27 (d, J¼8.8 Hz,

2786
K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
2H), 7.30 (s,1H), 7.63 (d, J¼8.9 Hz, 2H). 13C NMR (CDCl3):
d
22.1, 22.2,
138.5, 157.7. HRFABMS m/z calcd for C19H18BrNO3S (Mþ) 419.0191,
found 419.0216.
55.4, 69.7, 69.8, 102.7, 112.8, 114.2, 115.0, 115.6, 119.0, 123.1, 124.4,
125.6, 125.8, 128.2, 129.78, 129.81, 132.1, 141.8, 154.3, 156.9, 157.3,
160.4. Anal. Calcd for C32H31NO5: C, 75.42; H, 6.13; N, 2.75. Found: C,
75.44; H, 5.96; N, 2.66.
4.3.2. Benzyl
pyrrole-2-carboxylate (18). To a solution of LDA prepared from
diisopropylamine (565 L, 4.03 mmol) and BuLi (1.51 M in hexane,
N-benzenesulfonyl-3-bromo-4-(4-isopropoxyphenyl)
m
4.2.8. 7,8-Bis(4-hydroxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrolo
[2,1-c][1,4]oxazin-1-one (16). Boron trichloride (1 M heptane solu-
tion,1.18 mL,1.18 mmol) was added dropwise to a stirred solution of
15 (100 mg, 0.196 mmol) in dry CH2Cl2 (6 mL) at ꢀ78 ꢁC under Ar
atmosphere. The mixture was stirred for 0.5 h at ꢀ78 ꢁC and for
2.5 h at 0 ꢁC, and quenched with saturated aqueous NaHCO3. To the
mixture was added AcOEt and the whole was stirred at room
temperature for 50 min and evaporated. The residue was washed
with water and filtered to give practically pure 16 (82.9 mg, 99%) as
white powder, mp>300 ꢁC (sealed capillary). IR (KBr): 3446, 3234,
2.14 mL, 3.23 mmol) in dry THF (14 mL), was added dropwise
a solution of 17 (1.13 g, 2.69 mmol) in THF (5 mL) at ꢀ78 ꢁC under Ar
atmosphere. After 1 h, benzyl chloroformate (691 mL, 4.84 mmol)
dissolved in THF (5 mL) was added dropwise. After 1 h, the reaction
mixture was quenched by adding a saturated aqueous NH4Cl and
the solvent was evaporated in vacuo. The residue was extracted
three times with Et2O and the extracts were combined, washed
successively with water and brine, dried over Na2SO4, and con-
centrated in vacuo. The crude product was purified by column
chromatography on silica gel (251 mL) using hexane/toluene (1:2)
as an eluent to give 18 (1.12 g, 75%) as pale yellow solid. Re-
crystallization from Et2Oehexane gave pale yellow powder, mp
136.5e137.5 ꢁC. IR (KBr): 1725, 1375, 1234, 1187, 1120 cmꢀ1. 1H NMR
1690, 1610, 1515 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 3.81 (s, 3H),
6.67 (d, J¼8.6 Hz, 2H), 6.72 (d, J¼8.6 Hz, 2H), 6.97 (d, J¼8.6 Hz, 2H),
7.05 (d, J¼8.9 Hz, 2H), 7.07 (d, J¼8.6 Hz, 2H), 7.59 (s, 1H), 7.67 (d,
J¼8.9 Hz, 2H), 8.14 (s, 1H), 9.45 (br s, 2H); 13C NMR (100 MHz,
(CDCl3):
d
1.35 (d, J¼6.1 Hz, 6H), 4.57 (sep, J¼6.1 Hz, 1H), 5.32 (s,
DMSO-d6):
d
55.3, 103.7, 112.0, 114.5, 114.6, 115.3, 120.1, 122.9, 123.2,
2H), 6.92 (d, J¼8.8 Hz, 2H), 7.33e7.42 (m, 7H), 7.47 (dd, J¼7.5, 8.5 Hz,
2H), 7.55 (s, 1H), 7.61 (tt, J¼7.5, 1.0 Hz, 1H), 7.94 (dd, J¼8.5, 1.0 Hz,
124.0, 125.4, 127.5, 129.0, 129.5, 131.8, 140.4, 153.6, 156.4, 156.7,
160.0. HRFABMS m/z calcd for C26H19NO5 (Mþ) 425.1263, found
425.1127.
2H). 13C NMR (CDCl3):
d 22.1, 67.6, 69.9, 109.3, 115.7, 122.9, 123.5,
124.0, 127.9, 128.4, 128.5, 128.6, 129.1, 130.0, 134.1, 135.0, 138.5,
157.9,159.4. Anal. Calcd for C27H24BrNO5S: C, 58.49; H, 4.36; N, 2.53.
Found: C, 58.75; H, 4.15; N, 2.47.
4.2.9. Lukianol A (1). Boron tribromide (1 M CH2Cl2 solution,
883 mL, 0.883 mmol) was added dropwise to a stirred solution of 15
(50.0 mg, 0.0981 mmol) in dry CH2Cl2 (5 mL) at ꢀ78 ꢁC. The mix-
ture was stirred at ꢀ78 ꢁC (1 h), 0 ꢁC (3 h) and then room tem-
perature (30 min), before being quenched with saturated aqueous
NaHCO3. To the mixture was added AcOEt and the whole was
stirred at room temperature for 30 min and evaporated. The residue
was washed with water and filtered. The crude product was dis-
solved in acetone and filtered through a short column on silica gel
(4 mL) using AcOEt as an eluent to give 1 (41.8 mg, quant). Re-
crystallization from ethanol gave white powder, mp 220e300 ꢁC
4.3.3. Benzyl N-benzenesulfonyl-4-(4-isopropoxyphenyl)-3-(4-
methoxyphenyl)pyrrole-2-carboxylate (19). A mixture of 18
(692 mg, 1.25 mmol), 4-methoxyphenylboronic acid (338 mg,
2.22 mmol), Pd(PPh3)4 (144 mg, 0.125 mmol), Na2CO3 (872 mg,
8.22 mmol), DME (18 mL), and degassed water (3.72 mL) was stirred
at 85 ꢁC for 15 h. After cooling to room temperature, the solvent was
evaporated in vacuo and the residue was extracted three times with
Et2O. The combined extracts were washed successively with water
and brine, dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by a column chromatography on silica gel
(188 mL) using toluene/AcOEt (30:1) as an eluent to give 19 (638 mg,
88%) as white solid. Recrystallization from Et2Oehexane gave color-
less granules, mp 120e122 ꢁC. IR (KBr): 1713, 1367, 1247, 1174,
(dec) (sealed capillary). IR (KBr): 3338, 1693, 1420, 1244, 1207 cmꢀ1
1H NMR (DMSO-d6):
.
d
6.67 (d, J¼8.6 Hz, 2H), 6.72 (d, J¼8.6 Hz, 2H),
6.89 (d, J¼8.8 Hz, 2H), 6.97 (d, J¼8.6 Hz, 2H), 7.07 (d, J¼8.6 Hz, 2H),
7.56 (d, J¼8.8 Hz, 2H), 7.59 (s, 1H), 8.06 (s, 1H) 9.20e9.95 (br s, 3H).
13C NMR (DMSO-d6):
d
102.6, 111.5, 114.2, 114.8, 115.4, 119.5, 120.8,
837 cmꢀ1. 1H NMR (CDCl3):
d
1.29 (d, J¼6.1 Hz, 6H), 3.76 (s, 3H), 4.48
122.8, 123.5, 125.1, 127.0, 128.4, 129.0, 131.3, 140.5, 153.2, 155.9,
156.2, 158.1. HRFABMS m/z calcd for C25H17NO5 (Mþ) 411.1107,
found 411.1107.
(sep, J¼6.1Hz,1H), 5.07(s, 2H), 6.69(d, J¼8.9Hz, 2H), 6.71 (d,J¼8.9 Hz,
2H), 6.93e6.98 (m, 4H), 7.01 (d, J¼8.9 Hz, 2H), 7.18e7.25 (m, 3H), 7.51
(dd, J¼8.5, 7.4 Hz, 2H), 7.57 (s,1H), 7.62 (tt, J¼7.4,1.0 Hz,1H), 8.04 (dd,
J¼8.5,1.0 Hz, 2H). 13C NMR (CDCl3):
d 22.0, 55.1, 67.1, 69.8,113.4,115.6,
4.3. Synthesis of the phenol 24
122.6, 122.9, 124.7, 125.0, 127.4, 127.9, 128.0, 128.2, 129.0, 129.5, 131.2,
133.1, 133.8, 135.0, 139.1, 157.1, 159.0, 160.8. Anal. Calcd for
C34H31NO6S: C, 70.20; H, 5.37; N, 2.41. Found: C, 70.31; H, 5.14; N, 2.43.
4.3.1. N-Benzenesulfonyl-3-bromo-4-(4-isopropoxyphenyl)pyrrole
(17). A mixture of 3 (365 mg,1.00 mmol), 4-isopropoxyphenylboronic
acid (304 mg, 2.00 mmol), Pd(PPh3)4 (116 mg, 0.100 mmol), Na2CO3
(700 mg, 6.60 mmol), THF (10 mL), and degassed water (2 mL) was
stirred at refluxing temperature for 14.5 h under Ar atmosphere. After
cooling to room temperature, the solvent was evaporated under re-
duced pressure and the residue was extracted three times with Et2O.
The combined extracts were washed successively with water and
brine, dried over Na2SO4, and concentrated in vacuo. The crude
product was purified by a column chromatography on silica gel
(94 mL) using hexane/toluene (1:1 to 1:2) as an eluent to give 17
(241 mg, 57%) as pale yellow gum, along with 3,4-diarylated product
(known compound. See, Ref. 6) (75 mg, 15%) and recovered 3 (82 mg,
22%). The spectroscopic data of 17 are as follows. IR (KBr): 1375, 1247,
4.3.4. Benzyl 4-(4-isopropoxyphenyl)-3-(4-methoxyphenyl)-1H-pyr-
role-2-carboxylate (20). To a solution of 19 (1.13 g,1.94 mmol) in dry
THF (92 mL), was added dropwise a 1 M THF solution of TBAF
(2.90 mL, 2.90 mmol) at room temperature. After refluxing for 2 h,
the mixture was cooled to room temperature and quenched by
addition of water. The solvent was evaporated in vacuo and the
residue was extracted three times with CH2Cl2. The extracts were
combined, washed successively with water and brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by a column chromatography on silica gel (251 mL) using toluene/
AcOEt (30:1) as an eluent to give 20 (822 mg, 96%) as white solid.
Recrystallization from Et2Oehexane gave colorless needles, mp
1186, 1135, 1057 cmꢀ1. 1H NMR (CDCl3):
d
1.34 (d, J¼6.0 Hz, 6H), 4.56
128.5e129.5 ꢁC. IR (KBr): 3308, 1678, 1288, 1240, 1180 cmꢀ1
.
1H
(sep, J¼6.0 Hz,1H), 6.89 (d, J¼8.9 Hz, 2H), 7.17 (d, J¼2.6 Hz,1H), 7.26 (d,
J¼2.6 Hz,1H), 7.39 (d, J¼8.9 Hz, 2H), 7.53 (dd, J¼8.3, 7.3 Hz, 2H), 7.63 (tt,
NMR (CDCl3):
d
1.29 (d, J¼6.0 Hz, 6H), 3.80 (s, 3H), 4.46 (sep,
J¼6.0 Hz, 1H), 5.18 (s, 2H), 6.71 (d, J¼8.8 Hz, 2H), 6.79 (d, J¼8.8 Hz,
2H), 6.98e7.02 (m, 3H), 7.10e7.13 (m, 2H), 7.17 (d, J¼8.8 Hz, 2H),
J¼7.3, 1.4 Hz, 1H), 7.90 (dd, J¼8.3, 1.3 Hz, 2H). 13C NMR (CDCl3):
d 22.1,
69.9, 102.8, 115.7, 117.4, 120.7, 124.1, 127.1, 129.0, 129.4, 129.6, 134.3,
7.24e7.28 (m, 3H), 9.25 (br s,1H). 13C NMR (CDCl3):
d 22.1, 55.1, 65.9,

K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
2787
69.8, 113.2, 115.6, 119.5, 120.2, 126.6, 126.7, 126.8, 127.9, 128.3, 129.3,
131.9, 135.9, 156.4, 158.6, 161.0. Anal. Calcd for C28H27NO4: C, 76.17;
H, 6.16; N, 3.17. Found: C, 76.17; H, 6.10; N, 3.13.
(10.9 mL, 10.9 mmol) was added dropwise to a cooled (ꢀ78 ꢁC) and
stirred solution of 23 (1.75 g, 3.63 mmol) in dry CH2Cl2 (187 mL).
After 30 min at ꢀ78 ꢁC, the reaction mixture was warmed up to 0 ꢁC
and stirred for an additional 1.5 h before being quenched with
saturated aqueous NaHCO3. AcOEt was added to the mixture and
stirred at room temperature, during which time white crystals
appeared. The whole was evaporated in vacuo and the residual
solid was washed with water and collected by filtration to give 24
(1.59 g, 99%) as white solid. Recrystallization from acetone gave
colorless granules, mp>300 ꢁC (dec) (sealed capillary). IR (KBr):
4.3.5. Benzyl 4-(4-isopropoxyphenyl)-3-(4-methoxyphenyl)-1-[2-(4-
methoxyphenyl)-2-oxoethyl]pyrrole-2-carboxylate (21). A mixture
of 20 (210 mg, 0.475 mmol), p-methoxyphenacyl bromide (272 mg,
1.19 mmol), and K2CO3 (197 mg, 1.43 mmol) in DMF (11 mL) was
stirred at 70 ꢁC for 3 h. The mixture was then cooled to room tem-
perature, diluted with water, and extracted with AcOEt. The organic
layer was washed successively with water (four times) and brine
(once), dried over Na2SO4, and concentrated in vacuo. The crude
product was purified bya chromatographyon silica gel (141 mL) using
hexane/AcOEt (3:1) as an eluent to give 21 (221 mg, 79%) as white
solid along with recovered of 20 (38.8 mg,18%). Recrystallization of 21
from AcOEtehexane gave colorless needles, mp 142e144 ꢁC. IR (KBr):
3331, 1700, 1428, 1255, 1177 cmꢀ1 1H NMR (DMSO-d6):
. d 3.75 (s,
3H), 3.78 (s, 3H), 6.65 (d, J¼8.6 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 6.91
(d, J¼8.6 Hz, 2H), 7.04 (d, J¼8.9 Hz, 2H), 7.16 (d, J¼8.8 Hz, 2H), 7.62
(s, 1H), 7.65 (d, J¼8.9 Hz, 2H), 8.11 (s, 1H), 9.53 (br s, 1H). 13C NMR
(DMSO-d6): d 55.2, 55.5, 103.8, 112.2, 113.3, 114.6, 115.5, 120.4, 123.0,
124.0, 125.0, 125.6, 127.8, 128.6, 129.7, 132.0, 140.7, 153.8, 156.5,
158.6, 160.1. Anal. Calcd for C27H21NO5: C, 73.79; H, 4.82; N, 3.19.
Found: C, 73.51; H, 4.79; N, 3.11.
1701,1686,1229,1177,1096 cmꢀ1.1H NMR (CDCl3):
d
1.28 (d, J¼6.0 Hz,
6H), 3.77 (s, 3H), 3.89 (s, 3H), 4.45 (sep, J¼6.0 Hz,1H), 4.96 (s, 2H), 5.74
(s, 2H), 6.68 (d, J¼8.8 Hz, 2H), 6.72 (d, J¼8.7 Hz, 2H), 6.81 (dd, J¼8.0,
1.4 Hz, 2H), 6.93 (s,1H), 6.972 (d, J¼8.8 Hz, 2H), 6.976 (d, J¼8.7 Hz, 2H),
4.4. Selective iodination of the phenol 24
7.11e7.20 (m, 5H), 7.99 (d, J¼8.8 Hz, 2H).13C NMR (CDCl3):
d 22.1, 55.0,
55.5, 65.6, 69.7,113.0,114.1,115.4,119.8,124.8,126.7,127.2,127.5,127.7,
127.9, 128.0, 128.1, 129.2, 130.3, 131.4, 131.8, 135.5, 156.2, 158.3, 161.7,
164.0, 191.8. Anal. Calcd for C37H35NO6: C, 75.36; H, 5.98; N, 2.38.
Found: C, 75.20; H, 5.95; N, 2.37.
4.4.1. 7-(4-Hydroxyphenyl)-6-iodo-3,8-bis(4-methoxyphenyl)-1H-
pyrrolo[2,1-c][1,4]oxazin-1-one (25). Compound 24 (30.0 mg,
0.0683 mmol) was dissolved in DMF (2 mL) and MeOH (1 mL) was
added slowly. The solution was cooled to 0 ꢁC and ICl (1.0 M in
CH2Cl2, 157
mL, 0.157 mmol) was added dropwise. After stirring
4.3.6. 4-(4-Isopropoxyphenyl)-3-(4-methoxyphenyl)-1-[2-(4-methox-
yphenyl)-2-oxoethyl]pyrrole-2-carboxylic acid (22). A suspension of
21 (350 mg, 0.593 mmol) and 20% w/w PdeC (70 mg) in AcOEt
(70 mL) was vigorously stirred at room temperature under hydrogen
atmosphere (balloon) for 7 h. The mixture was diluted with CH2Cl2
and filtered through a pad of Celite. Concentration of the filtrate in
vacuo gave practically pure 22 (300 mg, 85%) as white solid. Re-
crystallization from CH2Cl2ehexane gave colorless needles, mp
2.5 h at 0 ꢁC, MeOH was evaporated and the residue was diluted
with AcOEt. The solution was washed successively with water
(three times) and brine (once), dried over Na2SO4, and concentrated
in vacuo. The crude product was applied on a column of silica gel
(12 mL) and eluted successively with hexane/AcOEt (1:1), hexane/
AcOEt (1:2), AcOEt, and acetone to give 25 (18.8 mg, 49%) as white
solid along with the starting material 24 (4.4 mg, 15%). Re-
crystallization of 25 from CH2Cl2eEt2O gave colorless powder, mp
186e187 ꢁC. IR (KBr): 1681, 1647, 1536, 1457, 1237 cmꢀ1
(DMSO-d6):
.
1H NMR
221.5e227 C (dec) (sealed capillary). IR (KBr): 3442, 1711, 1511,
ꢁ
d
1.21 (d, J¼6.0 Hz, 6H), 3.75 (s, 3H), 3.87 (s, 3H), 4.52
1253, 1173 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
3.72 (s, 3H), 3.80
(sep, J¼6.0 Hz, 1H), 5.86 (s, 2H), 6.72 (d, J¼8.8 Hz, 2H), 6.85 (d,
J¼8.8 Hz, 2H), 6.92 (d, J¼8.8 Hz, 2H), 7.08 (d, J¼8.8 Hz, 2H), 7.11 (d,
J¼8.9 Hz, 2H), 7.25 (s, 1H), 8.04 (d, J¼8.9 Hz, 2H), 11.84 (br s, 1H). 13C
(s, 3H), 6.69 (d, J¼8.6 Hz, 2H), 6.80 (d, J¼8.9 Hz, 2H), 6.90 (d,
J¼8.6 Hz, 2H), 7.04 (d, J¼9.0 Hz, 2H), 7.09 (d, J¼8.9 Hz, 2H), 7.73 (s,
1H), 7.75 (d, J¼9.0 Hz, 2H), 9.50 (br s, 1H); 13C NMR (100 MHz,
NMR (DMSO-d6):
d
21.8, 54.8, 55.5, 55.6, 68.8, 112.8, 114.0, 115.1,
DMSO-d6): d 54.9, 55.3, 82.3, 104.2, 112.7, 114.3, 114.9, 115.2, 122.5,
120.0, 122.8, 126.6, 127.1, 127.7, 128.0, 128.6, 129.1, 130.1, 131.5, 155.4,
157.7,162.3,163.3,192.3. Anal. Calcd for C30H29NO6: C, 72.13; H, 5.85;
N, 2.80. Found: C, 71.88; H, 6.07; N, 2.78.
124.0, 124.1, 125.9, 130.4, 131.5, 131.7, 133.6, 141.1, 152.9, 156.6, 158.3,
160.1. Anal. Calcd for C27H20INO5: C, 57.36; H, 3.57; N, 2.48. Found:
C, 57.25; H, 3.28; N, 2.47.
4.3.7. 7-(4-Isopropoxyphenyl)-3,8-bis(4-methoxyphenyl)-1H-pyrrolo
[2,1-c][1,4]oxazin-1-one (23). A mixture of 22 (91.0 mg,
0.182 mmol) and dehydrated AcONa (270 mg, 3.30 mmol) in Ac2O
(15 mL) was stirred at 100 ꢁC for 1.5 h. The Ac2O was azeotropically
removed in vacuo using toluene. The residue was dissolved in Et2O,
washed three times with saturated aqueous NaHCO3, dried over
Na2SO4, and concentrated in vacuo. The crude product was purified
by a column chromatography on silica gel (12 mL) using hexane/
AcOEt (2:1) as an eluent to give 23 (81.6 mg, 93%) as white solid.
Recrystallization from AcOEtehexane gave colorless needles, mp
193.5e195 ꢁC. IR (KBr): 1731, 1430, 1248, 1179, 1038 cmꢀ1. 1H NMR
4.4.2. 7-(4-Hydroxy-3-iodophenyl)-3,8-bis(4-methoxyphenyl)-1H-
pyrrolo[2,1-c][1,4]oxazin-1-one (26) and 7-(4-hydroxy-3,5-
diiodophenyl)-3,8-bis(4-methoxyphenyl)-1H-pyrrolo[2,1-c][1,4]ox-
azin-1-one (27). To a cooled (0 ꢁC) and stirred solution of 24
(30.1 mg, 0.0683 mmol) in a mixture of 2 M ethanolic ammonia
(1 mL) and DMF (2 mL), was added dropwise a solution of N-
iodosaccharin (31.7 mg, 0.102 mmol) in EtOH (1 mL). After 2 h, EtOH
was removed in vacuo and the residue was diluted with AcOEt,
washed successively with water (four times) and brine (once),
dried over Na2SO4, and concentrated in vacuo. The crude product
was applied on a column of silica gel (16 mL) and eluted succes-
sively with toluene/AcOEt (5:1), AcOEt, and AcOEt/MeOH (3:1) to
give monoiodide 26 (10.4 mg, 27%), diiodide 27 (23.4 mg, 50%) and
the starting material 24 (6.9 mg, 23%).
(CDCl3):
d
1.32 (d, J¼6.0 Hz, 6H), 3.82 (s, 3H), 3.84 (s, 3H), 4.51 (sep,
J¼6.0 Hz, 1H), 6.77 (d, J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 6.94 (d,
J¼8.8 Hz, 2H), 7.05 (d, J¼8.7 Hz, 2H), 7.19 (s, 1H), 7.29 (d, J¼8.7 Hz,
2H), 7.31 (s, 1H), 7.64 (d, J¼8.8 Hz, 2H). 13C NMR (CDCl3):
d
22.1, 55.1,
Compound 26: pale yellow powder, mp 286.5e287.5 ꢁC (sealed
55.4, 69.8, 102.7, 112.9, 113.3, 114.3, 115.7, 119.0, 123.1, 124.7, 125.5,
125.8, 128.2, 129.7, 129.8, 132.1, 141.9, 154.3, 156.9, 158.9, 160.5. Anal.
Calcd for C30H27NO5: C, 74.83; H, 5.65; N, 2.91. Found: C, 74.88; H,
5.63; N, 2.87.
capillary) (acetone). IR (KBr): 3398, 1696, 1518, 1248, 1180 cmꢀ1. 1H
NMR (acetone-d6):
d
3.83 (s, 3H), 3.87 (s, 3H), 6.83 (d, J¼8.4 Hz, 1H),
6.91 (d, J¼8.9 Hz, 2H), 7.00 (dd, J¼8.4, 2.1 Hz, 1H), 7.07 (d, J¼9.0 Hz,
2H), 7.27 (d, J¼8.9 Hz, 2H), 7.62 (d, J¼2.1 Hz,1H), 7.64 (s,1H), 7.74 (d,
J¼9.0 Hz, 2H), 8.00 (s, 1H), 9.08e9.25 (br s, 1H). 13C NMR (acetone-
4.3.8. 7-(4-Hydroxyphenyl)-3,8-bis(4-methoxyphenyl)-1H-pyrrolo
d6): d 55.5, 55.8, 84.3, 104.2, 114.0, 115.2, 115.6, 120.9, 124.2, 125.8,
[2,1-c][1,4]oxazin-1-one (24). A 1 M solution of BCl3 in heptane
126.5,127.3,128.1,130.1,130.8,132.9,140.0,142.5,154.3,156.5,160.1,

2788
K. Takamura et al. / Tetrahedron 69 (2013) 2782e2788
161.5. Anal. Calcd for C27H20INO5: C, 57.36; H, 3.57; N, 2.48. Found:
C, 57.09; H, 3.27; N, 2.55.
4.7. X-ray crystallographic analysis of 25
Compound 27: pale yellow powder, mp 159e161 ꢁC (sealed
capillary) (benzeneehexane). IR (KBr): 3473, 1718, 1515, 1409,
Results are as follows: compound formula
C
27H20INO5,
ꢀ
ꢀ
Mw¼565.36, orthorhombic, P212121, a¼6.8237(13) A, b¼15.066(3) A,
1248 cmꢀ1. 1H NMR (acetone-d6):
d 2.66e3.10 (br s,1H), 3.85 (s, 3H),
c¼22.218(5) A, V¼2284.2(8) A , Z¼4, Dcalcd¼1.644 g/cm3, mono-
3
ꢀ
ꢀ
¼1.443 mmꢀ1
,
ꢀ
3.87 (s, 3H), 6.95 (d, J¼8.9 Hz, 2H), 7.07 (d, J¼9.0 Hz, 2H), 7.28 (d,
chromatized radiation
l
(Mo
K
a
)¼0.71075 A,
m
J¼8.9 Hz, 2H), 7.59 (s, 2H), 7.72 (s, 1H), 7.74 (d, J¼9.0 Hz, 2H), 8.00 (s,
F(000)¼1128.00, T¼123 K. Data were collected on a Rigaku Sat-
1H). 13C NMR (acetone-d6):
d
55.6, 55.8, 84.2, 104.1, 113.8, 114.1,
urn724 CCD to a
q
limit of 27.41ꢁ, which yielded 22,261 reflections.
level.
115.2, 121.0, 124.1, 125.35, 125.38, 126.5, 130.1, 130.8, 132.9, 140.3,
142.6, 154.2, 154.9, 160.2, 161.5. HRFABMS m/z calcd for C27H19I2NO5
(Mþ) 690.9353, found 690.9340.
There are 5187 unique reflections with 4897 observed at the 2
s
The structure was solved by direct methods (SIR92)12 and refined
using full-matrix least-squares on F2 (SHELXL97).13 The final model
was refined using 310 parameters and all 5187 data. All non-
hydrogen atoms were refined with isotropic thermal displace-
ments. The final agreement statistics are as follows: R¼0.0476
4.5. Conversion of diiodide 27 to monoiodide 26
(based on 4897 reflections with I>2
s
(I)), wR¼0.0926, S¼1.097. The
3
ꢀ
A mixture of 27 (42.6 mg, 0.0616 mmol) and ZneCu couple
(7.4 mg) in DMA (3 mL) was stirred at room temperature for 1.5 h.
Silica gel (306 mg) was added and DMA was evaporated at 26 ꢁC/
190 Pa. The residue was charged on a silica gel column (16 mL) and
eluted with tolueneeAcOEt (5:1) to give 26 (23.5 mg, 68%) and the
starting material 27 (4.5 mg, 11%).
maximum peak height in a final difference Fourier map is 0.88 e A ,
and this peak is without chemical significance. CCDC 918506 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
4.6. Synthesis of lukianol B (2) and diiodolukianol A (28)
This work was performed under the Cooperative Research
Program of ‘Network Joint Research Center for Materials and De-
vices’ (Institute for Materials Chemistry and Engineering, Kyushu
University).
4.6.1. Lukianol B (2). A 1 M solution of BBr3 in CH2Cl2 (362
mL,
0.362 mmol) was added dropwise to a cooled (ꢀ78 ꢁC) and stirred
solution of 26 (29.2 mg, 0.0516 mmol) in dry CH2Cl2 (10 mL) under
Ar atmosphere. After 30 min, the mixture was gradually warmed up
to room temperature and stirred for 0.5 h and heated at reflux for
3 h. After cooling to room temperature, the reaction was quenched
by addition of saturated aqueous NaHCO3 and stirred until white
crystals appeared. The whole was evaporated in vacuo and the
residue was washed with water and filtered to give 2 (26.4 mg, 95%)
as white solid. Recrystallization from acetoneehexane gave white
powder, mp 278e300 ꢁC (dec) (sealed capillary). IR (KBr): 1698,
Supplementary data
Supplementary data (1H and 13C NMR spectra of all compounds
synthesized in this work) associated with this article can be found,
in the online version. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2013.01.077.
1518, 1406, 1243, 1209 cmꢀ1 1H NMR (acetone-d6):
. d 6.82 (d,
J¼8.7 Hz, 2H), 6.84 (d, J¼8.4 Hz, 1H), 6.96 (d, J¼8.8 Hz, 2H), 7.00 (dd,
J¼8.4, 2.1 Hz, 1H), 7.18 (d, J¼8.7 Hz, 2H), 7.61 (s, 1H), 7.63 (d,
J¼2.1 Hz, 1H), 7.65 (d, J¼8.8 Hz, 2H), 7.93 (s, 1H), 8.30e9.15 (br s,
References and notes
1. Yoshida, W. Y.; Lee, K. K.; Carrol, A. R.; Scheuer, P. J. Helv. Chim. Acta 1992, 75,
1721e1725.
1H). 13C NMR (acetone-d6):
d 84.3, 103.7, 113.7, 115.5, 115.6, 116.6,
ꢁ
ꢁ
2. Manzanaro, S.; Salva, J.; de la Fuente, J. A. J. Nat. Prod. 2006, 69, 1485e1487.
3. Aldose Reductase Inhibition: An Approach to Prevention of Diabetic Complications;
Porte, D., Ed.; McGrwaw-Hill: New York, 1987.
120.7, 123.2, 124.7, 126.7, 127.1, 128.3, 130.3, 130.8, 133.0, 139.9,
142.8, 154.4, 156.4, 157.7, 159.4. HRFABMS m/z calcd for C25H16INO5
(Mþ) 537.0073, found 537.0061.
€
4. (a) Furstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60, 6637e6641;
(b) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R. Chem. Commun.
1997, 207e208; (c) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J.
Am. Chem. Soc. 1999, 121, 54e62; (d) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong,
H. N. C. J. Org. Chem. 2000, 65, 3587e3595; (e) Kim, S.; Son, S.; Kang, H. Bull.
Korean Chem. Soc. 2001, 22, 1403e1406; (f) Hinze, C.; Kreipl, A.; Terpin, A.;
Steglich, W. Synthesis 2007, 608e612; (g) Lu, Y.; Arndtsen, B. A. Org. Lett. 2009,
11, 1369e1372.
5. (a) Fukuda, T.; Ohta, T.; Sudo, E.; Iwao, M. Org. Lett. 2010, 12, 2734e2737; (b)
Fukuda, T.; Iwao, M. Heterocycles 2012, 86, 1261e1273; (c) Ohta, T.; Fukuda, T.;
Ishibashi, F.; Iwao, M. J. Org. Chem. 2009, 74, 8143e8153.
6. Fukuda, T.; Sudo, E.; Shimokawa, K.; Iwao, M. Tetrahedron 2008, 64, 328e338.
7. Alkaline hydrolysis of the corresponding methyl ester under the literature
conditions (Ref. 4) produced 14 in low yield. A major by-product was N-deal-
kylated pyrrole 12.
8. (a) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 2593e2598; (b)
Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetra-
hedron 2006, 62, 594e604.
4.6.2. Diiodolukianol A (28). A 1 M solution of BBr3 in CH2Cl2
(368
m
L, 0.368 mmol) was added dropwise to a cooled (ꢀ78 ꢁC) and
stirred solution of 27 (36.3 mg, 0.0525 mmol) in CH2Cl2 (10 mL)
under Ar atmosphere. The mixture was stirred at ꢀ78 ꢁC (30 min),
0
ꢁC (2.5 h), room temperature (6.5 h), and then refluxing tem-
perature (3 h). The mixture was cooed to room temperature,
quenched by addition of saturated aqueous NaHCO3 and stirred
until white crystals appeared. The whole was evaporated in vacuo
and the residue was washed with water and filtered to give 28
(25.6 mg, 74%). Recrystallization from acetoneehexane gave pale
brown powder, mp 286e300 ꢁC (dec) (sealed capillary) (aceto-
neehexane). IR (KBr): 1699, 1518, 1413, 1242, 1209 cmꢀ1. 1H NMR
9. Dolenc, D. Synlett 2000, 544e546.
(acetone-d6):
J¼8.9 Hz, 2H), 7.19 (d, J¼8.7 Hz, 2H), 7.60 (s, 2H), 7.65 (d, J¼8.9 Hz,
2H), 7.68 (s, 1H), 7.92 (s, 1H). 13C NMR (acetone-d6):
84.3, 103.7,
d
3.64e3.96 (br, 1H), 6.85 (d, J¼8.7 Hz, 2H), 6.96 (d,
€
10. Holtke, C.; Law, M. P.; Wagner, S.; Breyholz, H.-J.; Kopka, K.; Bremer, C.; Levkau,
€
B.; Schober, O.; Schafers, M. Bioorg. Med. Chem. 2006, 14, 1910e1917.
11. Smith, R. D.; Simmons, H. E. Organic Syntheses; 1973; Collect. Vol. No. 5, pp
d
855e858.
115.5,115.6,116.6,121.0,123.1,124.3,125.3, 126.7, 130.4, 130.9, 132.9,
140.3, 142.9, 154.3, 154.9, 157.9, 159.5. HRFABMS m/z calcd for
C25H15I2NO5 (Mþ) 662.9040, found 662.9044.
12. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435e436.
13. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.