Synthesis of polycitrin A and 3,4-bis(4-hydroxyphenyl)pyrrole derivatives related to polycitone A

Article abstract of DOI:10.1055/s-2006-950190

The oxidative condensation of 3-arylpyruvic acids with arylethylamines to give 3,4-diarylpyrrole-2,5-dicarboxylic acids was used for an efficient synthesis of polycitrin A (4). Investigation of the bromine-mediated degradation of acid 2b to maleimide 3b s

Full text of DOI:10.1055/s-2006-950190

PAPER
3043
Synthesis of Polycitrin A and 3,4-Bis(4-hydroxyphenyl)pyrrole Derivatives
Related to Polycitone A
S
ynthesis of Poly
h
citrin A
a
nd
r
Polycito
i
ne
A
D
s
erivativestian Winklhofer, Andreas Terpin, Christian Peschko, Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13 (F), 81377 München, Germany
Fax +49(89)218077756; E-mail: wolfgang.steglich@cup.uni-muenchen.de
Received 22 May 2006
Dedicated to Professor Siegfried Hünig on the occasion of his 85th birthday
MeO
R
R
OMe
R
Abstract: The oxidative condensation of 3-arylpyruvic acids with
arylethylamines to give 3,4-diarylpyrrole-2,5-dicarboxylic acids
was used for an efficient synthesis of polycitrin A (4). Investigation
of the bromine-mediated degradation of acid 2b to maleimide 3b
suggested that 2,5-dibromopyrrole (5) and 5,5-dimethoxy-3-pyrro-
line-2-one (6) are intermediates in this process. The debromo ana-
logue of polycitone A (10) was prepared in two steps from pyrrole
dicarboxylic acid diester 7.
R
OMe
R
O
R
HO2C
CO2H
N
b
a
79%
Key words: biomimetic synthesis, bromination, marine alkaloids,
pyrroles, polycitrins, polycitones
CO2H
OMe
2a, R = Br (79%)
2b, R = H (67%)
1a, R = Br
1b, R = H
Polycitrins and polycitones constitute a group of highly
brominated marine alkaloids that have been isolated by
Kashman et al.1,2 from ascidians of the genus Polycitor.
Polycitone A is a potent general inhibitor of retroviral
transcriptase and cellular DNA polymerases,3 and its pen-
tamethyl ether inhibits the growth of SV40 transformed fi-
broblast cells.1
MeO
Br
Br Br
OMe
Br
HO
Br Br
OH
Br
Br
c
O
O
In our previous synthesis, polycitrin A (4) was obtained
from 3-(4-methoxyphenyl)pyruvic acid in six steps and
26% overall yield.4 Key steps were the oxidative degrada-
tion of a pyrrole-2,5-dicarboxylic acid with sodium hy-
pochlorite and the conversion of the resulting maleimide
into the corresponding anhydride (prepolycitrin A), fol-
lowed by reaction of the latter with tyramine. A maleic an-
hydride intermediate was also used by Becalli5 in his
convergent synthesis of polycitrin B.
O
O
N
N
66%
OMe
OH
3a
4
Scheme 1 Reagents and conditions: (a) NaH (or n-BuLi, 2 equiv),
THF, then I2 (0.5 equiv), 4-MeOC6H4CH2CH2NH2, 4 Å MS; (b) Br2,
MeOH-H2O, reflux; (c) BBr3.
In this publication we describe a considerably shorter
route to polycitrin A (4) (Scheme 1). It starts from 3-(3,4-
dibromo-4-methoxyphenyl)pyruvic acid (1a), which can
be prepared from 3,4-dibromo-4-methoxybenzaldehyde
and N-acetylglycine under standard Erlenmeyer condi-
tions.6 Oxidative dimerization of the sodium enolate of
arylpyruvate 1a with 0.5 equivalent iodine and subsequent
one-pot pyrrole formation4 with 2-(4-methoxyphenyl)eth-
ylamine afforded pyrrole dicarboxylic acid 2a in 79%
yield. Treatment of the latter with bromine in refluxing
aqueous MeOH yielded the desired maleimide 3a. After
removal of the O-methyl groups with BBr3, polycitrin A
(4) was obtained from keto acid 1a in three steps and in
43% overall yield, thus representing a considerable im-
provement over our earlier synthesis.
A closer inspection of the bromine-mediated oxidative
degradation of pyrrole-2,5-dicarboxylic acids to maleim-
ides revealed the sequence of reactions depicted in
Scheme 2. Thus, if a solution of dicarboxylic acid 2b in
refluxing MeOH is slowly treated with bromine, the first
species detectable by TLC is the 2,5-dibromopyrrole 5. It
could be isolated in 72% yield if three equivalents of bro-
mine were employed. Compounds of type 5 are unknown
and offer interesting synthetic possibilities as reactants in
Pd-catalyzed cross-coupling reactions.7 The isolation of a
second intermediate 6 required the addition of sodium
methoxide to the reaction mixture in order to avoid acid-
catalyzed hydrolysis by liberated HBr. The pyrrolinone 6
SYNTHESIS 2006, No. 18, pp 3043–3047
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950190; Art ID: Z10306SS
© Georg Thieme Verlag Stuttgart · New York

3044
C. Winklhofer et al.
PAPER
MeO
OMe
MeO
OMe
could thus be obtained in 40% yield. 5,5-Dimethoxy-3-
pyrrolin-2-ones have been prepared before by electro-
chemical methoxylation of N-alkylpyrroles8 or rearrange-
ment of chlorinated 3-pyrrolin-2-ones.9 Treatment of acid
2b with excess bromine afforded maleimide 3b in quanti-
tative yield.
RO
OR
MeO2C
CO2Me
N
N
O
O
a
MeO
OMe
MeO
OMe
OMe
OMe
HO2C
CO2H
7
8a, R = Me (66%)
8b, R = MEM (52%)
N
Br
Br
Br2
N
MeOH, reflux
HO
OH
4"'
3"'
2"'
1"'
RO
OR
OMe
4"
OMe
4
5
3
3"
2b
8
5
1"
2"
2
N
b
O
O
MeO
OMe
MeO
OMe
6
7
1'
2'
3'
OMe
OMe
4'
OH
O
O
O
N
N
9, R = Me (71%)
10, R = H (92%)
Scheme 3 Synthesis of polydebromopolycitone A (10). Reagents
and conditions: (a) 1. 4-MeOC6H4MgBr (20 equiv), THF for 8a; 2. 4-
MEMOC6H4MgBr (20 equiv), THF for 8b; (b) BBr3, CH2Cl2.
OMe
OMe
3b
6
In conclusion, the biomimetic condensation of 3-aryl-
pyruvic acids with primary amines to give 3,4-diarylpyr-
role-2,5-dicarboxylic acids not only offers easy access to
pyrrole alkaloids of the polycitrin and polycitone series,
but also to 3,4-disubstituted 2,5-dibromopyrroles and 5,5-
dimethoxy-3-pyrrol-2-ones.
Scheme 2 Bromination of pyrrole dicarboxylic acid 2b.
Pyrrole dicarboxylic acid 2b could also be used for the
synthesis of polydebromopolycitone A (10) (Scheme 3).10
Thus reaction of 2b with methyl iodide and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) yielded the corresponding
dimethyl ester 7 which, upon treatment with a large excess
of 4-methoxyphenylmagnesium bromide, afforded dike-
tone 8a in 66% yield. The use of lesser amounts of the
Grignard reagent led to incomplete reaction. Treatment of
the permethyl ether 8a with an excess of BBr3 yielded
dimethyl ether 9 still containing the two O-methyl groups
at the 4-methoxybenzoyl residues. To avoid this problem,
we prepared the 2-methoxyethoxymethyl (MEM) ana-
logue 8b in the same manner as described for the methyl
derivative 8a. In this case, all of the O-protecting groups
were smoothly removed with BBr3 and the previously un-
reported polydebromo analogue of polycitone A (10) was
obtained in 92% yield. Based on diacid 2b, the total yield
of 10 was 45%. Attempts to brominate compound 10 so as
to generate polycitone A only led to complex mixtures of
bromo derivatives.
Melting points (uncorrected): Büchi SMP 535 apparatus. IR spec-
tra: PerkinElmer FT-IR Spectrum 1000. Abbreviations: s, strong;
m, medium; w, weak; br, broad. Mass spectra (EI, 70 eV): Finnigan
MAT 90 and Finnigan MAT 95Q. High-resolution mass spectra (EI,
70 eV): Finnigan MAT 95Q. NMR spectra: Bruker ARX 300 and
Bruker AMX 600. Spectra were recorded in CDCl3, DMSO-d6 or
acetone-d6 using the residual solvent peak as an internal standard
(CDCl3, dH = 7.26 and dC = 77.10; DMSO-d6, dH = 2.49 and
dC = 39.5; acetone-d6, dH = 2.04 and dC = 29.80). In the case of
compound 9, the assignment of the NMR signals was established by
2D NMR experiments (COSY, HMQC, HMBC). Elemental analy-
ses were carried out by the Microanalytical Laboratory of the De-
partment of Chemistry, University of Munich. Flash
chromatography (FC): Merck Kieselgel 60 (0.040–0.063 mm).
TLC: Aluminum-backed silica gel 60 F254 (Merck). Solvents for
flash chromatography (FC) were distilled before use. THF was dis-
tilled under argon from Na/benzophenone. CH2Cl2 was distilled un-
der argon from Sicapent (Merck). Anhyd DMF was purchased from
Fluka.
Synthesis 2006, No. 18, 3043–3047 © Thieme Stuttgart · New York

PAPER
Synthesis of Polycitrin A and Polycitone A Derivatives
3045
3-(3,5-Dibromo-4-methoxyphenyl)pyruvic Acid (1a)
trated under reduced pressure. FC (hexanes–EtOAc, 2:1) afforded
3a as a light yellow powder (144 mg, 79%); mp 61–63 °C.
A mixture of 3,5-dibromo-4-methoxybenzaldehyde (18.0 g, 61
mmol), N-acetylglycine (8.60 g, 73 mmol), and NaOAc (6.54 g, 80
mmol) in Ac2O (150 mL) was heated for 7 h at 90 °C. The ensuing
mixture was cooled to 0 °C and quenched with H2O. The crude
azlactone was collected by filtration, washed with ice-water (3 ×),
and poured into refluxing 5% aq NaOH. The resulting dark-brown
solution was cooled to 0 °C and adjusted to pH 2 with concd HCl.
The resulting precipitate was recrystallized from MeOH to yield a-
acetamino-3,5-dibromo-4-methoxycinnamic acid (5.08 g, 21%) as
a colorless solid.
1H NMR (300 MHz, CDCl3): d = 2.91 (t, J = 7.5 Hz, 2 H), 3.80 (s,
3 H), 3.84 (t, J = 7.5 Hz, 2 H), 3.94 (s, 6 H), 6.85, 7.14 (d each,
J = 8.7 Hz, 2 H), 7.62 (s, 4 H).
13C NMR (75 MHz, CDCl3): d = 34.0 (CH2), 40.5 (CH2), 55.8
(CH3), 61.2 (CH3), 114.6 (CH), 119.1, 126.6, 130.0, 130.2 (CH),
133.9, 134.2 (CH), 156.3, 158.9, 169.7.
EI-MS: m/z (%) = 763 (1, [M(81Br4)]+), 761 (5), 759 (7,
[M(79Br281Br2)]+), 757 (5), 755 (1, [M(79Br4)]+), 135 (10), 134 (100),
121 (47).
a-Acetamino-3,5-dibromo-4-methoxycinnamic Acid
Mp 242 °C.
HRMS: m/z calcd for C27H2179Br281Br2NO5: 754.8153; found:
754.8124.
Anal. Calcd for C12H11Br2NO4: C, 36.67; H, 2.82; N, 3.56. Found:
C, 36.65; H, 2.48; N, 3.53.
Polycitrin A (4)
BBr3 (0.06 mL, 0.66 mmol) was added to maleimide 3a (50 mg,
0.066 mmol) in anhyd CH2Cl2 (10 mL) at –78 °C. The violet reac-
tion mixture was warmed to r.t. and stirred for 18 h. Aq 2 N NaOH
(1 mL) was then added dropwise, and, after a short period of stir-
ring, the solution was acidified with 2 N HCl (5 mL). After addition
of EtOAc (30 mL), the organic phase was washed with 1 M aq
KHSO4, H2O, brine, and dried (MgSO4). FC (CHCl3–MeOH, 10:1)
afforded polycitrin A (4) as an orange solid (33 mg, 70%); mp 180–
182 °C. The spectral data for synthetic 4 agreed with those reported
for the natural product.1
The above cinnamic acid was dissolved in 40% aq NaOH (30 mL)
and the resulting solution heated under reflux. TLC was used to
monitor the reaction. Once the reaction was complete, the mixture
was cooled to 0 °C and adjusted to pH 3 with concd HCl. Extraction
of the solution with EtOAc (3 × 100 mL), concentration of the com-
bined extracts under vacuum and purification by FC (CH2Cl2–ace-
tone–HCO2H, 50:5:1) yielded 1a (1.04 g, 78%) as a colorless solid,
mp 163–164 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.78 (s, 3 H), 6.34 (s, 1 H),
8.04 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 60.7 (CH3), 106.3 (CH), 117.5,
133.1 (CH), 134.7, 143.5, 152.0, 165.9.
3,4-Bis(4-methoxyphenyl)-1-[2-(4-methoxyphenyl)ethyl]pyr-
role-2,5-dicarboxylic Acid (1b)
A solution of 3-(4-methoxyphenyl)pyruvic acid11 (4.86 g, 25 mmol)
in anhyd THF (400 mL) was treated with a 2.5 M solution of n-BuLi
in hexane (20 mL, 50 mmol) at –78 °C. The mixture was stirred for
20 min at –78 °C and then treated dropwise with a solution of I2
(3.17 g, 12.5 mmol) in anhyd THF (50 mL). After completion of the
addition, the cold-bath was removed and the mixture stirred for 1 h
at r.t. 2-(4-Methoxyphenyl)ethylamine (11.34 g, 75 mmol) and 4 Å
molecular sieves (5 g) were then added, and the stirring was contin-
ued for 18 h. The mixture was filtered, the filtrate acidified with aq
1 M KHSO4, and extracted with EtOAc (3 × 200 mL). The com-
bined extracts were washed with H2O (300 mL) and brine (300 mL),
then dried (Na2SO4), and concentrated under reduced pressure. Re-
crystallization of the residue from MeOH yielded 1b (4.23 g, 67%)
as a colorless powder; mp 223–224 °C; Rf 0.54 (benzene–HCO2Et–
HCO2H, 5:4:1).
1H NMR (300 MHz, DMSO-d6): d = 2.97 (t, J = 7.2 Hz, 2 H), 3.66
(s, 6 H), 3.71 (s, 3 H), 4.74 (t, J = 7.2 Hz, 2 H), 6.70 (d, J = 8.8 Hz,
4 H), 6.86 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 4 H), 7.10 (d,
J = 8.8 Hz, 2 H), 12.61 (br, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 37.1 (CH2), 48.2 (CH2), 55.0
(CH3), 55.2 (CH3), 112.8 (CH), 114.1 (CH), 124.5, 127.0, 129.5,
129.7 (CH), 130.4, 131.6 (CH), 157.8, 158.1, 162.7.
HRMS: m/z calcd for C10H879Br2O4: 349.8789; found: 349.8773.
3,4-Bis(3,5-dibromo-4-methoxyphenyl)-1-[2-(4-methoxyphen-
yl)ethyl]pyrrole-2,5-dicarboxylic Acid (2a)
NaH (53 mg, 2.2 mmol) was added to a solution of keto acid 1a (352
mg) in anhyd THF (15 mL) at 0 °C. After H2 evolution had ceased,
a solution of I2 (127 mg, 0.5 mmol) in anhyd THF (5 mL) was added
dropwise, and the mixture was stirred for 1 h at r.t. 2-(4-Methoxy-
phenyl)ethylamine (352 mg, 1.00 mmol) and portions of 4 Å molec-
ular sieves were then added and the stirring continued for 18 h.
After removal of the molecular sieves by filtration, the filtrate was
diluted with EtOAc (50 mL) and washed several times with 1 M aq
KHSO4, H2O and brine. The organic layer was dried (MgSO4), con-
centrated, and purified by FC (toluene–HCO2Et–HCO2H, 5:4:1) to
yield 2a (325 mg, 79%) as a colorless powder, mp 218–219 °C.
IR (KBr): 3435 (s, br), 2924 (s), 2854 (m), 1701 (m), 1638 (w),
1512 (m), 1459 (w), 1415 (m), 1376 (w), 1249 (w), 1200 (w), 1170
(w), 1068 (w), 1000 (w), 892 (w), 784 (w), 743 (w), 571 (w) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.98 (t, J = 7.6 Hz, 2 H), 3.72
(s, 3 H), 3.75 (s, 6 H), 4.87 (t, J = 7.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz,
2 H), 7.08 (d, J = 8.6 Hz, 2 H), 7.31 (s, 4 H).
13C NMR (75 MHz, DMSO-d6): d = 36.9 (CH2), 48.3 (CH2), 55.2
(CH3), 60.5 (CH3), 114.1 (CH), 116.1, 124.8, 126.8, 129.9 (CH),
130.1, 133.6, 134.9 (CH), 152.1, 158.2, 161.8.
FAB-MS (mNBA): m/z (%) = 822 (17), 821 (31, [M(81Br4)]+), 820
(75), 819 (75), 818 (93), 817 (100, [M(79Br281Br2)]+), 816 (66), 815
(58), 814 (23), 813 (16, [M(79Br4)]+), 805 (11), 804 (11), 803 (10),
802 (32), 801 (16), 800 (27), 799 (10), 798 (23), 796 (9), 776 (16),
754 (10), 744 (9), 707 (23), 705 (19).
EI-MS: m/z (%) = 501 (5, [M]+), 457 (10, [M – CO2]+), 413 (94, [M
– 2 × CO2]+), 292 (100, [M – 2 × CO2 – CH2C6H4OCH3]+), 279 (11,
[M – 2 × CO2 – C2H3C6H4OCH3]+), 121 (14, [CH2C6H4OCH3]+).
HRMS: m/z calcd for C29H27NO7: 501.1788; found: 501.1796.
Anal. Calcd for C29H27NO7: C, 69.45; H, 5.43; N, 2.79. Found: C,
69.45; H, 5.54; N, 2.70.
2,5-Dibromo-3,4-bis(4-methoxyphenyl)-1-[2-(4-methoxyphen-
yl)ethyl]pyrrole (5)
Polycitrin A Trimethyl Ether (3a)
A solution of Br2 (0.04 mL, 0.72 mmol) in MeOH (5 mL) was added
at 0 °C to a solution of 2a (195 mg, 0.24 mmol) in MeOH–H2O (10
mL, 20:1). The resulting mixture was stirred for 18 h at r.t. and then
treated with EtOAc (30 mL). The organic phase was washed with
sat. aq NaHCO3, H2O, and brine, then dried (MgSO4) and concen-
A solution of Br2 (0.2 mL, 0.64 g, 2 equiv) in anhyd MeOH (20 mL)
was added dropwise to a refluxing solution of dicarboxylic acid 2b
in anhyd MeOH (100 mL). The mixture was cooled to r.t. and par-
titioned between H2O (350 mL) and EtOAc (200 mL). The aq phase
was extracted with EtOAc (2 × 100 mL), and the combined organic
Synthesis 2006, No. 18, 3043–3047 © Thieme Stuttgart · New York

3046
C. Winklhofer et al.
PAPER
phases were dried (MgSO4) and concentrated under reduced pres-
sure. FC (Et2O–hexanes, 1:1) yielded 5 (0.41 g, 36%) as a colorless
solid together with varying amounts of pyrrolinone 6 and maleimide
3b; mp 158–160 °C. Compound 5 decomposes at r.t. within a few
days and must be kept in a refrigerator.
of the product. After completion of the Br2 addition, the solvent was
removed under reduced pressure to yield 3b (1.73 g, ca. 100%) as
yellow crystals; mp 120–124 °C.
IR (KBr): 2865 (w), 2819 (w), 1765 (w), 1697 (s), 1602 (s), 1513
(s), 1454 (w), 1442 (w), 1408 (m), 1352 (w), 1296 (m), 1252 (s),
1177 (s), 1117 (w), 1035 (m), 1023 (m), 845 (m), 835 (m), 789 (m),
532 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.90 (t, J = 7.8 Hz, 2 H), 3.76 (s,
3 H), 3.80 (t, J = 7.8 Hz, 2 H), 3.81 (s, 6 H), 6.83 (d, J = 8.2 Hz, 2
H), 6.86 (d, J = 8.7 Hz, 4 H), 7.17 (d, J = 8.2 Hz, 2 H), 7.44 (d,
J = 8.7 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 33.8 (CH2), 40.0 (CH2), 55.2
(CH3), 55.3 (CH3), 113.9 (CH), 114.0 (CH), 121.3, 129.8 (CH),
130.2, 131.4 (CH), 134.0, 158.3, 160, 171.1.
EI-MS: m/z (%) = 444 (16), 443 (61, [M]+), 322 (11), 310 (16), 309
(100), 223 (11), 134 (17), 133 (14), 121 (27).
IR (KBr): 3436 (m, br), 2953 (w), 2832 (w), 1612 (m), 1575 (w),
1536 (s), 1512 (s), 1500 (m), 1466 (w), 1453 (w), 1377 (w), 1350
(m), 1287 (w), 1248 (s), 1176 (m), 1108 (w), 1034 (s), 836 (m), 794
(w), 740 (w), 608 (w), 526 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.00 (t, J = 8.1 Hz, 2 H), 3.78 (s,
6 H), 3.82 (s, 3 H), 4.28 (t, J = 8.1 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 4
H), 6.87 (d, J = 8.6 Hz, 2 H), 7.07 (d, J = 8.6 Hz, 2 H), 7.18 (d,
J = 8.7 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 36.2 (CH2), 50.0 (CH2), 55.5
(CH3), 55.7 (CH3), 101.8, 113.8 (CH), 114.5 (CH), 124.6, 126.8,
130.2, 130.4 (CH), 131.7 (CH), 158.6, 159.9.
EI-MS: m/z (%) = 574 (14), 573 (52, [M(81Br2)]+), 572 (29), 571
(100, [M(79Br81Br)]+), 570 (15), 569 (50, [M(79Br2)]+), 493 (11), 492
(38), 491 (18), 490 (37), 489 (6), 412 (21), 411 (68), 371 (15), 369
(15), 135 (39).
UV (MeOH): lmax (e) = 206 (22134), 228 (23819), 268 (123081),
364 (3880), 406 nm (5180).
HRMS: m/z calcd for C27H25NO5: 443.1724; found: 443.1734.
HRMS: m/z calcd for C27H2579Br2NO5: 569.0201; found: 569.0174;
m/z calcd for C27H2579Br81BrNO5: 571.0181; found: 571.0153; m/z
calcd for C27H2581Br2NO5: 573.0160; found: 573.0157.
3,4-Bis(4-methoxyphenyl)-1-[2-(4-methoxyphenyl)ethyl]pyr-
role-2,5-dicarboxylic Acid Dimethyl Ester (7)
A solution of 2b (1.50 g, 3.0 mmol) in anhyd DMF (50 mL) was
treated with DBU (0.99 mL, 6.57 mmol) at 0 °C. The mixture was
maintained for 10 min at 0 °C, then treated with MeI (1.89 mL, 29.9
mmol), and stirred for 18 h at r.t. After the addition of H2O, the mix-
ture was carefully extracted with Et2O. For removal of the DMF, the
organic phases were washed several times with 1 M aq KHSO4,
H2O, 1 N aq NaOH, and brine. Evaporation of the dried (MgSO4)
Et2O solution yielded 7 (1.49 g, 94%); mp 185–187 °C.
1H NMR (300 MHz, CDCl3): d = 3.09 (t, J = 7.7 Hz, 2 H), 3.58 (s,
6 H, CO2CH3), 3.76 (s, 6 H, OCH3), 3.79 (s, 3 H, OCH3), 4.84 (t,
J = 7.7 Hz, 2 H), 6.71 (d, J = 8.9 Hz, 4 H), 6.85 (d. J = 8.6 Hz, 2 H),
6.92 (d, J = 8.9 Hz, 4 H), 7.19 (d, J = 8.6 Hz, 2 H).
5,5-Dimethoxy-3,4-bis(4-methoxyphenyl)-1-[2-(4-methoxyphe-
nyl)ethyl]-1,5-dihydropyrrol-2-one (6)
NaOMe [2 g, 30% solution (w/w) in MeOH] was added to 2b (1 g,
1.98 mmol) in anhyd MeOH (100 mL). The mixture was heated at
reflux and a solution of Br2 (0.31 mL, 0.96 g, 3 equiv) in anhyd
MeOH (20 mL) was then added dropwise. The Br2 was immediately
decolorized, and the solution slowly developed a blue-green fluo-
rescence. After completion of the Br2 addition, the mixture was
cooled to r.t. and partitioned between H2O (350 mL) and EtOAc
(200 mL). The aqueous layer was extracted with EtOAc (2 × 100
mL), and the combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. FC (Et2O–hexanes, 1:1) af-
forded 6 (0.39 g, 40%) as a colorless solid exhibiting a greenish flu-
orescence.
13C NMR (75 MHz, CDCl3): d = 37.5 (CH2), 48.8 (CH2), 51.4
(CH3), 55.1 (CH3), 55.3 (CH3), 112.7 (CH), 113.9 (CH), 124.1,
126.9, 130.1, 130.6 (CH), 130.7, 131.5 (CH), 158.1, 158.4, 162.1.
EI-MS: m/z (%) = 530 (31, [M + H]+), 529 (100, [M]+), 408 (78),
407 (19), 395 (14), 363 (20), 121 (14).
IR (KBr): 3435 (s, br), 2998 (w), 2935 (w), 2837 (w), 1702 (s), 1606
(s), 1571 (w), 1514 (s), 1462 (w), 1442 (w), 1421 (m), 1399 (m),
1299 (m), 1249 (s), 1180 (m), 1125 (m), 1111 (m), 1072 (w), 1043
(m), 1031 (m), 984 (w), 838 (m), 786 (w), 601 (w), 576 (w), 536
(w), 412 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.01 (m, 2 H), 3.11 (s, 6 H), 3.50
(m, 2 H), 3.79, 3.81, 3.84 (s each, 3 H), 6.81, 6.86, 6.91, 7.24, 7.43,
7.60 (d each, J = 8.8 Hz, 2 H); the d at d = 7.24 overlapped with the
CDCl3 signal.
13C NMR (75 MHz, CDCl3): d = 34.2 (CH2), 40.5 (CH2), 51.5
[C(OCH3)2], 55.7 (CH3), 113.5, 114.4 (3 × CH), 123.1, 123.5, 130.3
(CH), 130.6 (CH), 131.5 (CH), 133.1, 142.4 [C(OCH3)2], 158.6,
160.4, 160.9, 169.6. One signal was obscured.
EI-MS: m/z (%) = 490 (32), 489 (95, [M]+), 459 (15), 458 (45, [M –
OCH3]+), 369 (16), 368 (72), 356 (22), 355 (100, [M –
CHCH2C6H4OCH3]+), 338 (24), 336 (14), 324 (24), 323 (16), 309
(15), 308 (14), 208 (48), 135 (48), 134 (16), 121 (18), 116 (20).
HRMS: m/z calcd for C31H31NO7: 529.2101; found: 529.2112.
Anal. Calcd for C31H31NO7: C, 70.31; H, 5.90; N, 2.64. Found: C,
70.33; H, 5.86; N, 2.64.
{5-(4-Methoxybenzoyl)-3,4-bis(4-methoxyphenyl)-1-[2-(4-
methoxyphenyl)ethyl]-1H-pyrrol-2-yl}-(4-methoxyphen-
yl)]methanone (8a); Typical Procedure
A solution of diester 7 (0.53 g, 1.00 mmol) in anhyd THF (30 mL)
was treated, dropwise at 0 °C, with the Grignard reagent freshly pre-
pared from Mg (0.61 g, 25 mmol) and 4-bromoanisole (2.50 mL, 20
mmol) in anhyd THF (25 mL). The mixture was warmed to r.t.,
stirred for 18 h at r.t. and then quenched with H2O (3 mL). After ad-
dition of EtOAc (100 mL), the solution was washed with 1 M aq
KHSO4, H2O, and brine, dried (MgSO4), and concentrated. Purifi-
cation of the residue by FC (Et2O–hexanes, 1:1) yielded 8a (0.45 g,
66%) as a beige powder; mp 72–73 °C.
1H NMR (300 MHz, CDCl3): d = 3.01 (t, J = 7.8 Hz, 2 H), 3.64 (s,
6 H), 3.69 (s, 3 H), 3.74 (s, 6 H), 4.49 (t, J = 7.8 Hz, 2 H), 6.48 (d,
J = 8.8 Hz, 4 H), 6.61 (d, J = 9.0 Hz, 4 H), 6.70 (d, J = 8.6 Hz, 2 H),
6.79 (d, J = 8.8 Hz, 4 H), 7.10 (d, J = 8.6 Hz, 2 H), 7.61 (d, J = 9.0
Hz, 4 H).
HRMS: m/z calcd for C29H31NO6: 489.2160; found: 489.2156.
3,4-Bis(4-methoxyphenyl)-1-[2-(4-methoxyphenyl)ethyl]pyr-
role-2,5-dione (3b)
A solution of Br2 (0.62 mL, 1.92 g, 3 equiv) in anhyd MeOH (30
mL) was added dropwise to a refluxing solution of 2b (2 g, 3.99
mmol) in anhyd MeOH (200 mL). The progress of the reaction
could be followed by the development of the intense yellow color
13C NMR (75 MHz, CDCl3): d = 38.3 (CH2), 48.1 (CH2), 55.4
(CH3), 55.5 (CH3), 55.7 (CH3), 113.46 (CH), 113.54 (CH), 114.2
Synthesis 2006, No. 18, 3043–3047 © Thieme Stuttgart · New York

PAPER
Synthesis of Polycitrin A and Polycitone A Derivatives
3047
(CH), 126.5, 127.6, 130.4 (CH), 130.7, 131.2, 131.8 (CH), 132.3,
132.8 (CH), 158.3, 158.6, 163.6, 189.5.
3,4-Bis(4-hydroxyphenyl)-2,5-bis(4-hydroxybenzoyl)-1-[2-(4-
hydroxyphenyl)ethyl]pyrrole (10)
From 8b (0.22 g, 0.27 mmol) and BBr3 (0.30 mL, 3.22 mmol) as de-
scribed for polycitrin (3). FC (toluene–HCO2Et–HCO2H, 5:4:1) af-
forded diketone 10 (0.15 g, 92%) as a solid; mp 143–144 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.73 (t, J = 7.6 Hz, 2 H), 4.22
(t, J = 7.6 Hz, 2 H), 6.37 (d, J = 8.6 Hz, 4 H), 6.58 (d, J = 8.7 Hz, 4
H), 6.59 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 8.6 Hz, 4 H), 6.78 (d,
J = 8.6 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 4 H).
EI-MS: m/z (%) = 682 (15, [M + H]+), 681 (31, [M]+), 560 (11), 548
(37), 547 (100, [M + H – COC6H4OCH3]+), 135 (59), 121 (68).
UV (MeOH): lmax (e) = 228 (41869), 284 nm (25928).
HRMS: m/z calcd for C43H39NO7: 681.2727; found: 681.2692.
Anal. Calcd for C43H39NO7: C, 75.75; H, 5.77; N, 2.05. Found: C,
75.43; H, 5.88; N, 2.02.
13C NMR (75 MHz, DMSO-d6): d = 37.3 (CH2), 47.2 (CH2), 114.6
(CH), 115.1 (CH), 115.5 (CH), 124.3, 126.6, 127.9, 128.7, 129.4
(CH), 131.0, 131.6 (CH), 132.5 (CH), 155.8, 156.2, 162.7, 188.2.
EI-MS: m/z (%) = 612 (12, [M + H]+), 611 (24, [M]+), 504 (15), 492
(36), 491 (100, [M – C8H8O]+), 490 (15), 384 (11), 372 (17), 371
(65), 370 (16), 265 (10), 264 (59), 121 (70), 120 (11), 107 (44), 94
(23), 93 (10), 77 (10), 65 (11), 46 (29), 45 (26).
{5-[4-(2-Methoxyethoxymethoxy)benzoyl]-3,4-bis(4-methox-
yphenyl)-1-[2-(4-methoxyphenyl)ethyl]-1H-pyrrol-2-yl}-[4-(2-
methoxyethoxymethoxy)phenyl]methanone (8b)
From diester 7 (0.40 g, 0.76 mmol) and the Grignard reagent pre-
pared from 4-(2-methoxyethoxymethoxy)-1-bromobenzene as de-
scribed above; yield: 0.34 g (52%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 3.01 (t, J = 7.6 Hz, 2 H), 3.34 (s,
6 H), 3.48 (m, 4 H), 3.59 (s, 6 H), 3.66 (s, 3 H), 3.78 (m, 4 H), 4.52
(t, J = 7.6 Hz, 2 H), 5.17 (s, 4 H), 6.46 (d, J = 8.7 Hz, 4 H), 6.70 (d,
J = 8.5 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 4 H), 6.77 (d, J = 8.9 Hz, 4 H),
7.10 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.9 Hz, 4 H).
HRMS: m/z calcd for C38H29NO7: 611.1944; found: 611.1973.
Acknowledgment
The authors thank the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie for financial support of this work
and Prof. M. G. Banwell (ANU, Canberra) for improvements in the
manuscript.
13C NMR (75 MHz, CDCl3): d = 37.8 (CH2), 47.5 (CH2), 54.8
(CH3), 54.9 (CH3), 58.8 (CH3), 67.6 (CH2), 71.3 (CH2), 92.9 (CH2),
112.9 (CH), 113.7 (CH), 115.0 (CH), 125.9, 127.4, 129.8 (CH),
130.1, 131.3, 131.6, 131.7 (CH), 132.1 (CH), 157.8, 158.1, 160.6,
189.9.
EI-MS: m/z (%) = 830 (26, [M + H]+), 829 (48, [M]+), 696 (23), 695
References
(51, [M – C9H10O]+), 135 (31), 121 (26), 89 (52), 59 (100).
(1) Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.;
Schleyer, M.; Kashman, Y. J. Org. Chem. 1994, 59, 999.
(2) Rudi, A.; Evan, T.; Aknin, M.; Kashman, Y. J. Nat. Prod.
2000, 63, 832.
HRMS: m/z calcd for C49H51NO11: 829.3462; found: 829.3465.
3,4-Bis(4-hydroxyphenyl)-1-[2-(4-hydroxyphenyl)ethyl]-2,5-
bis(4-methoxybenzoyl)pyrrole (9)
From 8a (100 mg, 0.15 mmol) and BBr3 (0.21 mL, 2.20 mmol) as
described for polycitrin (3). FC (toluene–HCO2Et–HCO2H, 5:4:1)
afforded dimethyl ether 9 (67 mg, 71%) as a solid; mp 102–103 °C.
(3) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J. 1999,
344, 85.
(4) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51,
9941.
1H NMR (600 MHz, acetone-d6): d = 2.92 (t, J = 8.0 Hz, 2 H, 7-H),
3.78 (s, 6 H, 4¢¢-OCH3), 4.44 (t, J = 8.0 Hz, 2 H, 6-H), 6.47 (d,
J = 8.6 Hz, 4 H, 3¢¢¢/5¢¢¢-H), 6.69 (d, J = 8.6 Hz, 4 H, 3¢/5¢-H), 6.76
(d, J = 9.0 Hz, 4 H, 3¢¢/5¢¢-H), 6.77 (d, J = 8.8 Hz, 4 H, 2¢¢¢/6¢¢¢-H),
6.96 (d, J = 8.6 Hz, 2 H, 2¢/6¢-H), 7.65 (d, J = 9.0 Hz, 4 H, 2¢¢/6¢¢-H).
13C NMR (150 MHz, acetone-d6): d = 38.5 (C-7), 48.3 (C-6), 55.8
(4¢¢-OCH3), 114.1 (C-3¢¢/5¢¢), 115.3 (C-3¢¢¢/5¢¢¢), 116.1 (C-3¢/5¢),
126.0 (C-1¢¢¢), 128.0 (C-2/5), 129.8 (C-2¢/6¢), 130.5 (C-1¢), 131.8
(C-3/4), 132.1 (C-1¢¢), 132.7 (C-2¢¢¢/6¢¢¢), 133.0 (C-2¢¢/6¢¢), 156.7 (C-
4¢¢¢), 156.9 (C-4¢), 164.2 (C-4¢¢), 189.3 (C-8).
(5) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron
2000, 56, 2699.
(6) Reviews: (a) Carter, H. Org. React. 1946, 3, 198.
(b) Steglich, W. Fortschr. Chem. Forsch. 1969, 12, 77.
(7) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.; Wong,
D. J. Eur. J. Org. Chem. 2006, 3043.
(8) (a) Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31,
4054. (b) Tedjar, F.; Ymmel, S.; Janda, M.; Duchek, P.;
Holy, P.; Stibor, I. Collect. Czech. Chem. Commun. 1989,
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(9) Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron
2003, 59, 1147.
EI-MS: m/z (%) = 640 (18, [M + H]+), 639 (42, [M]+), 532 (20), 520
(39), 519 (100, [M – C8H8O]+), 518 (12), 135 (70), 121 (79), 120
(10), 107 (11), 77 (14).
(10) Syntheses of polycitone A: (a) Kreipl, A. T.; Reid, C.;
Steglich, W. Org. Lett. 2002, 4, 3287. (b) Gupton, J. T.;
Miller, R. B.; Krumpe, K. E.; Clough, S. C.; Banner, E. J.;
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E.; Solano, J. M.; Adams, B. R.; Callahan, D. W.; Little, B.
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HRMS: m/z calcd for C40H33NO7: 639.2257; found: 639.2239.
Anal. Calcd for C43H39NO7·1.5 H2O: C, 72.06; H, 5.44; N, 2.10.
Found: C, 72.48; H, 5.30; N, 2.10.
(11) Niederl, J. B.; Ziering, A. J. Am. Chem. Soc. 1942, 64, 885.
Synthesis 2006, No. 18, 3043–3047 © Thieme Stuttgart · New York