Solid-phase synthesis of lamellarins Q and O

Article abstract of DOI:10.1016/j.tet.2004.05.110

An efficient solid phase synthesis of the pyrrole-based alkaloids lamellarins Q and O using Merrifield resin and N-protected methyl 3,4-dibromopyrrole-2-carboxylate as a scaffold is described.

Full text of DOI:10.1016/j.tet.2004.05.110

Tetrahedron 60 (2004) 8659–8668
Solid-phase synthesis of lamellarins Q and O
a,b
Marta Marfil,a,b Fernando Albericioa,c and Mercedes Alvarez
,
,
´
*
*
aBarcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, Josep Samitier 1, E-08028 Barcelona, Spain
bLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII s/n, E- 08028 Barcelona, Spain
´ ´
Department of Organic Chemistry, University of Barcelona, Martı i Franques 1, E-08028 Barcelona, Spain
c
Received 16 January 2004; accepted 4 May 2004
Available online 14 August 2004
Abstract—An efficient solid phase synthesis of the pyrrole-based alkaloids lamellarins Q and O using Merrifield resin and N-protected
methyl 3,4-dibromopyrrole-2-carboxylate as a scaffold is described.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
from human epidermatoid carcinoma,1c polycytone A
inhibits the growth of SV 40 transformed fibroblast3a at
concentrations of 10 mg ml21, lamellarins O and P demon-
strated antibiotic activity,1c lamellarins D and C caused
inhibition of cell division1a and lamellarin N tested by the
NCI in a 60 cell-line panel showed selectivity towards
melanoma cell lines.1f In addition, a select set of lamellarins
exhibit equally potent cytotoxic activity against multidrug-
resistant (MDR) cell lines arising over expression of
P-glycoprotein and/or reverse MDR at noncyctotoxic
concentrations, resensitising the resistant cell lines to
conventional therapeutic agents.4f
An important group of marine natural compounds including
lamellarins,1 lukianols, ningalins,2 and polycytones3 have a
pyrrole ring as a core component of their skeleton. These
compounds are important on the basis of their biological
activities and the novelty of their structures, which are
without precedent. Lamellarins and related compounds have
been isolated from invertebrates such as the prosobranch
mollusc Lamellaria sp., ascidians such as Didemnum
chartaceum and the sponge Dendrilla Cactos collected
from different sea areas. The structures of these natural
products are related because they probably have a common
biogenetic origin. The common structural feature is a
pyrrole ring substituted at positions 3 and 4 by polyhydroxy-
or methoxyphenyl groups. Lamellarins Q and O (1, 2) are
the simplest compounds in this family. The structure is
present in more complex molecules such as polycytone A
(3), which contains a symmetrically substituted pyrrole, and
lukianol A (4) and ningaline A (5), in which new rings
condensed to pyrrole are present due to lactonisation
processes. Lamellarin A (6) possesses the most complex
structure and is an example of a pentacyclic lamellarin that
is characterised by a lactone and an isoquinoline both
condensed to the pyrrole ring. This group of pentacyclic
compounds contains the largest number of related natural
products.
A number of synthetic routes have been described for
lamellarins,4 lukianols,4a,b,f,5 and ningalins4f,6 but only one
has been developed using the solid-phase approach.7 Solid-
phase combinatorial synthesis is one of the most useful
techniques for the preparation of small libraries. This
technique provides rapid access to larger collections of
products that can possess great diversity and may incorpor-
ate optimised physical and pharmacological properties
associated with certain structures.
Palladium-catalysed cross-coupling reactions are good
methods for the preparation of bisaryl or heteroaryl
derivatives. Our previous experience in Pd-catalysed
heteroaryl coupling reactions8 encouraged us to use this
methodology for the solid phase preparation of the
structurally least complex components of the group of
compounds under investigation, namely lamellarins Q and
O. The developed methodology will be used in the
preparation of compound libraries in which elements of
diversity would be introduced in the aromatic substituents at
positions 3 and 4 and on the nitrogen of the pyrrole ring. For
this reason it was important to develop a synthetic procedure
that would be compatible with the sequential introduction of
A considerable number of these natural products possess
important cytotoxic activities (Fig. 1). For example,
lukianol A exhibits activity against a cell line derived
Keywords: Solid-phase synthesis; Heteroaryl cross-coupling; Marine
natural products; Cytotoxicity.
*
Corresponding authors. Tel.: þ34-93-403-70-86; fax: þ34-93-403-71-26;
e-mail addresses: malvarez@pcb.ub.es; albericio@pcb.ub.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.110

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M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
Figure 1.
these aromatic rings into an appropriately functionalised
pyrrole ring.
the resin through the nitrogen to give 8. However, this
strategy was ruled out because it suffers from a serious
limitation in that it lacks the flexibility required for the
introduction of a nitrogen substituent and therefore loses
one avenue to introduce diversity.
We describe here a solid phase synthesis of lamellarins Q
and O using methyl N-(triisopropylsilyl)-3,4-dibromo-
pyrrole-2-carboxylate (7a) as a scaffold. Banwell et al.4b
used the dibromopyrrole 7a in an elegant convergent
synthesis of several compounds from this family of marine
alkaloids. As shown in Figure 2, compound 7 can be
attached to the resin at three different positions that
could be potentially useful for the preparation of related
libraries using coupling methodologies in solid-phase
synthesis.
The results obtained on linking compounds 9 and 10 to a
polystyrene (Merrifield) resin are now described. The
formation of an ester linkage between the acid 7b and
hydroxymethyl functionalized Merrifield resin, as in
compound 9 (strategy b), was tested for the sequential
introduction of three elements of diversity into the pyrrole.
Strategy c, on the other hand, involves compound 10 and
requires an appropriately substituted iodophenol to be
attached to a chloro-functionalised Merrifield resin. A
The first strategy (a) involved linking the dibromopyrrole to
Figure 2.

M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
8661
subsequent Pd-catalysed cross-coupling reaction with a
derivative of 7a would then be used to introduce the
scaffold.
conditions using the phenoxy anion, which displaces the
Cl of the resin.9 Treatment with NaOMe was also carried
out in order to cap any reactive residual chloromethyl
groups.
The methyl ester 7a10 was used for the chemoselective
halogen–metal interchange and preparation of zinc deriva-
tive 12. Compound 12 was obtained by selective ortho-
directed bromine/lithium interchange at position 3 by
treatment of 7a with n-BuLi at low temperature followed
by metal–metal interchange using zinc chloride. The
organometallic compound 12 was employed in a Pd(0)-
catalysed Negishi cross-coupling reaction with the resin-
bound iodophenol 11.
2. Results and discussion
The anchored pyrrole 9 was obtained by reaction of the acid
7b and hydroxy-functionalised Merrifield resin using
DIPCDI as an activating agent and DMF as the solvent.
Formation of 9 was confirmed by performing a cleavage
reaction and characterising the resulting methyl 3,4-
dibromopyrrole-2-carboxylate. Several experiments were
performed to assess the regioselective formation of a zinc
derivative of 9, using nBuLi and ZnCl2, followed by a
Pd-catalysed cross-coupling reaction with p-iodoanisole.
However, all attempts in this direction were unsuccessful. In
all cases the same product, methyl 3,4-dibromopyrrole-2-
carboxylate, was obtained after cleavage of the crude
coupling reaction product. This result indicates that the
bromo-lithium interchange, which occurs prior to formation
of the zinc derivative, did not take place. It seems
reasonable that this failure is due to steric hindrance caused
by the resin being attached close to the reaction site.
Several experiments were carried out in order to find the
optimal conditions for obtaining 10 and the results of these
are shown in Table 1. In all the experiments Pd(PPh3)4 was
used as the catalyst and THF as the solvent. Two parameters
were changed in an attempt to improve the yield of the
coupling reaction; the relative proportion of the reagents
and the reaction time. Each reaction was assessed by
performing a cleavage reaction using ZnBr2 and acetyl
1
bromide in DCM and the H NMR spectra of the crude
product were evaluated. The cleavage using ZnBr2 and
AcBr produced several simultaneous reactions in addition to
the desired ether cleavage; O-acetylation of the resulting
phenol occurred along with N-desilylation of the pyrrole
and acylation at position 5 of the pyrrole. Thus, under
these cleavage conditions O-acetyl iodophenol
13a—corresponding to the unreacted starting resin—and
As an alternative, strategy c was investigated using
compound 10. The attachment of the p-iodophenol to the
chloro-functionalised Merrifield resin was achieved under
basic conditions (Scheme 1).
4-Iodophenol was attached to the resin under basic
Scheme 1. Reagents: (i) NaOMe, dry DMF, N2, 80 8C, 24 h; (ii) Pd(PPh3)4, dry THF, N2, rt, 24 h; (iii) aq. 2 M Na2CO3, Pd(PPh3)4, dioxane, reflux, 21–48 h;
(iv) NH4F, DCM/MeOH (1:1), reflux, 6 h; (v) NaH (or LDA), dry THF, N2, 278 8C, 24 h; or 18-crown-6 (2.5 M in DMF), microwave, 100 8C, 30–40 W,
2 min; (vi) AlCl3, dry DCM, rt, 3 h.

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M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
Table 1. Solid-phase cross-coupling reaction between the anchored iodophenol 11 and the zinc derivative 12
Cross-coupling conditions
Productsa
Entry
12/11 (equiv.)
Time (h)
13a/14a
1
2
3
4
5
2.5
3
5
10
10
21
18
18
18
24
33:66
50:50
50:50
15:85
0:100
Reagents: (i) 15 mol% Pd(PPh3)4, dry THF, rt; (ii) AcBr (40 equiv.), ZnBr2 (3.5 equiv.), dry DCM.
a
1
Proportion of unreacted iodine with respect to the cross-coupling product calculated from the H NMR spectra of the crude cleaved material.
the diacetylarylpyrrole 14a were obtained. The relative
integrations of the doublets at 6.86 and 7.17 ppm, due to the
aromatic protons ortho to the acetate groups in each
compound, indicate the proportion of compound 13a to
14a. The anchored arylpyrrole 1011 was obtained in
quantitative yield (entry 5, Table 1) by treatment of resin
11 with 10 equiv. of 12 at rt for 24 h.
entries 4–6, Table 2.15 Under the same reaction conditions
it was found that dioxane (entry 8) and dimethoxyethane
(DME) (entry 7) gave better yields of 18 than THF (entry 4)
as a solvent. Dioxane was the solvent of choice after
comparison of yields obtained with these two solvents.
AlCl3 in DCM was used as the cleavage reagent (entries
7–9) to avoid the formation of acylated products 14b and
18e, which would be produced with ZnBr2 and AcBr. Both
cleavage reagents (entries 6 and 7) afforded the same yield
but AlCl3 has the advantage of producing cleaner cleavage
products without side-reactions such as acetylation. Increas-
ing the amount of boronic acid with respect to resin 10
(entry 8) produced only a small change in the yield, but an
increase in the reaction time under these conditions to 21 h
improved the yield to 84% (entry 10).
It was envisaged that bisarylpyrrole 16a would be prepared
from 10 by a new Pd(0)-catalysed cross-coupling reaction.
Two different alternative procedures could be followed for
the formation of the second aryl–pyrrole bond. The first
would involve the preparation of the organometallic
compound on the resin through a halogen–metal inter-
change of the bromo-substituent at position 4 of 10 and the
second approach would employ an organometallic aryl
compound for the cross-coupling reaction with the bromo-
containing pyrrole 10 anchored on the resin.
The same reaction conditions were applied to the synthesis
of bisarylpyrroles 16b-16d16 using for the second cross-
coupling reaction the appropriate boronic acid 15b-d.
Preparation of lamellarins Q and O requires the use of a
p-hydroxyphenylboronic acid with a suitable hydroxy-
protecting group for the introduction of the second aryl
substituent. p-Isopropoxyphenylboronic acid was used for
the cross-coupling reaction with bromide 10 and similar
results were obtained as described above.17 GP 13C NMR
was used to assess the success of the cross-coupling
reaction, with the signals due to the isopropoxy group at
22.1 and 69.6 ppm (methyl and CH, respectively) confirm-
ing the formation of 16b.
Preparation of the zinc derivative of 10 by bromine/lithium
interchange with n-BuLi followed by treatment with ZnCl2
and a subsequent coupling reaction with 4-iodoanisole was
tried under different catalytic conditions (entries 1–3,
Table 2). Unfortunately, all the experiments with zinc
derivatives of 10 produced, after cleavage, a crude material
that was difficult to manipulate and did not contain either the
product corresponding to the coupling or the starting
material.12
The second option for aryl–pyrrole bond formation was
assessed and Suzuki13 conditions were tried with resin 10.14
The different conditions tested for the Suzuki cross-
coupling reaction between 10 and 4-methoxyphenylboronic
acid are shown in Table 2 (entries 4–10).
In the case of resin 16b, the best conditions found for the
cleavage of 16a were used. Cleavage with AlCl3 of a large
amount of resin 16 (1 g) afforded only traces of 18 and the
resin beads were found to break down under these
conditions.18 A reduction in the amount of AlCl3 and the
reaction time allowed the isolation of 18a in good yield
working on a 1 g scale of 16b. The same results were
obtained from the resins 16c and 16d, from which the
bisarylpyrroles 18c and 18d were isolated. As observed
previously, N-deprotection of pyrrole was concomitant
during the cleavage. In addition, the application of these
Formation of bisarylpyrrole 16a was confirmed by gel phase
nuclear magnetic resonance (GP 13C NMR). The signal of
the methoxy group at 67.0 ppm was indicative of the
introduction of the new phenyl ring into the system. The
amount of 16a produced was determined after cleavage
from the resin. Cleavage with ZnBr2 and AcBr was used in

M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
Table 2. Solid-phase preparation of bisarylpyrrole 16a and cleavage conditions
8663
Entry
Coupling conditionsa
Cat., Lig. (%)
Cleav. cond.b
Yieldc (%)
14d
Reag. A (equiv.)
Reag. B (equiv.)
Solvent
THFf
Temperature
Time (h)
21
18e
1
2
nBuLi (10),
ZnCl2 (16)
Pd2dba3,
AsPh3
(15, 40)
37 8C
ZnBr2
AcBr
(10)
Crude material
difficult to
manipulate
nBuLi (10),
ZnCl2 (16)
PdCl2(PPh3)2,
PPh3
(25, 20)
THFf
rt
21
ZnBr2
AcBr
(10)
(10)
3
4
nBuLi (10),
ZnCl2 (16)
Pd(PPh3)4
(15)
THFf
THF
rt
21
19
ZnBr2
AcBr
—
—
—
—
—
—
—
Pd(PPh3)4,
2 N Na2CO3
(10, 5)
Reflux
ZnBr2
AcBr
a (30)
b (16)
e (20)
(4)
5
Pd(PPh3)4,
2 N Na2CO3
(10, 5)
DME
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
19
19
19
19
19
21
ZnBr2
AcBr
b (28)
e (15)
f (16)
(4)
6
Pd(PPh3)4,
2 N Na2CO3
(10, 5)
Dioxane
DME
ZNBR2
AcBr
a (13)
b (18)
e (22)
f (10)
(4)
7
Pd(PPh3)4,
2 N Na2CO3
(10, 5)
AlCl3
AlCl3
AlCl3
AlCl3
c (46)
c (32)
c (15)
(0)
a (27)
a (34)
a (37)
a (84)
(4)
8
Pd(PPh3)4,
2 N Na2CO3
(10, 5)
Dioxane
Dioxane
Dioxane
(4)
9
Pd(PPh3)4,
2 N Na2CO3
(10, 10)
(10)
(10)
10
Pd(PPh3)4,
2 N Na2CO3
(20, 10)
a
30–60 mg of 10 were used.
Dry THF was used.
All cleavage reactions were carried out in dry DCM at rt.
Calculated from the HPLC of the crude cleavage product.
tr 14a 9.52 min, MS (380, 378); tr 14b 7.90 min, MS (338, 336); tr 14c 7.82 min, MS (298, 296).
tr 18a 8.74 min, MS (325); tr 18e 10.12 min, MS (408); 18f 8.82 min, MS (366).
b
c
d
e
f
cleavage conditions to resin 16b also led to deprotection of
the O-isopropoxy group to give lamellarin Q (1). Other
Lewis acids, such as SnCl4, reacted with 16b to produce
cleavage from the resin and N-deprotection but not the
desired O-isopropoxy deprotection. This is a new example
of how the choice of the appropriate cleavage reaction
conditions allows different substituted derivatives to be
obtained.19
N-Deprotection of 16a and 16b by treatment with NH4F in
DCM produced the anchored bisarylpyrroles 19a and 19b,
respectively. The absence in the GP 13C NMR of

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M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
characteristic signals for isopropylsilyl groups provided
evidence that N-desilylation had occurred.
column (3.9£150 mm, 5 mm), Waters 2487 Dual Absorb-
ance Detector and H2O (0.1% formic acid) and AcCN
(0.07% formic acid) as eluents. Purification by HPLC was
carried out with Waters 2487 Dual Absorbance Detector,
Waters 600 Controller and Waters Fraction Collector II
using a SYMMETRY C18 (30£100 mm, 5 mm) column and
H2O (0.1% TFA) and AcCN (0.05% TFA) as eluents. Solid-
phase reactions were shaken in a Vibromatic SELECTA.
Microwave reactions were carried out in a DISCOVER
(CEM).
N-Alkylation of 19a with p-methoxybromoacetylbenzene
(17a) was investigated under different experimental con-
ditions.20 The use of excess NaH or LDA as a base21 in dry
THF under reflux gave, after cleavage with AlCl3, moderate
yields of the N-alkyl derivative 21a.22 Similar N-alkylation
results were obtained starting with the O-isopropoxy-
protected derivatives 19b and 17a.23 Cleavage of the
alkylation product 20b with AlCl3 afforded mixtures of 1
and 2, as determined by HPLC and HPLC-MS.22 The
dimethylacetal of p-methoxybromoacetylbenzene24 was
prepared to avoid the possibility of enolate formation
under the basic alkylation conditions but the N-alkylation
process was not improved by this change.
3.1.1. 3,4-Dibromo-1-(triisopropylsilyl)pyrrole-2-car-
boxylic acid 7b.4b nBuLi (1.36 ml, 2.17 mmol, 1.6 M)
was added dropwise to a cooled (278 8C) solution of 2,3,4-
tribromo-1-trimethylsilanylpyrrole (1 g, 2.17 mmol) in dry
THF (15 ml) under N2 and the mixture was stirred for
15 min at that temperature. Dry CO2 was bubbled through
the mixture at that temperature and the cooling bath was
removed. The reaction mixture was stirred at rt for 20 min.
The solution was diluted with H2O, acidified to pH 1 with
1 N HCl and extracted with EtOAc. The organic layer was
dried and evaporated under vacuum. The crude product was
purified by flash chromatography. Elution with hexane/
DCM (8:2) gave 7b as a white solid (425 mg, 46%). mp
142.3–143.3 8C (hexane/EtOAc). IR (KBr) n 3272, 1653,
1460, 825; 1H NMR (CDCl3, 300 MHz) d 1.14 (d,
J¼7.7 Hz, 18H, CH3), 1.41 [m, 1H, CH(CH3)2], 6.98 (d,
J¼3.3 Hz, 1H, H5), 9.65 (bs, 1H, CO2H); 13C NMR
(CDCl3, 75 MHz) d 12.3 [q, (CH3)2], 17.8 [d, CH(CH3)2],
102.7 (s, C4), 106.3 (s, C3), 121.8 (s, C2), 122.5 (d, C5),
159.4 (s, CvO); MS (EI) m/z 428 (2 81BrMþ, 19), 426
(81BrMþ, 79BrMþ, 34), 424 (2 79BrMþ, 18), 384 (2 81BrMþ,
54), 382 (81BrMþ, 79BrMþ, 100), 380 (2 79BrMþ, 50);
HRMS (EI) m/z calculated for C13H24NO2Br2Si: 426.9956;
found: 426.9940.
Finally, other alkylating agents—MeI and the tosylate of
2-(2-bromophenyl)ethanol25—afforded resins 20d and
20e26 which, after cleavage with AlCl3 and purification by
HPLC, produced N-methyllamellarin Q (21c) in moderate
yield. However, 21d proved impossible to isolate by HPLC.
An efficient solid-phase strategy has been devised for the
preparation of the pyrrole-containing alkaloids, lamellarins
Q and O. The process involves the incorporation of the
appropriately substituted pyrrole ring onto a p-alkoxy
iodophenyl resin through a Negishi cross-coupling reaction.
This step is followed by a Suzuki cross-coupling reaction to
introduce the second substituted phenyl ring and N-alkyl-
ation of the pyrrole. Final cleavage was achieved using a
Lewis acid to give the desired product. Diversity can be
introduced in each step of the synthetic process as well as
during the final cleavage by using the appropriate Lewis
acid conditions. GP 13C NMR has proven to be a good
method to follow the different steps in the process.
3.1.2. 3,4-Dibromo-1-triisopropylsilylpyrrole-2-car-
boxylate resin 9. Merrifield-OH resin (1 g, loading
0.68 mmol/g) was swelled in dry DMF and 7b (289 mg,
1 equiv.) and DMAP (41 mg, 0.5 equiv.) in DMF (0.5 ml)
and DIPCDI (106 ml, 1 equiv.) were added. The reaction
mixture was stirred at rt for 3 h. The resin was washed with
DMF and a second treatment with the same quantities of
7b, DMAP and DIPCDI was carried out. The reaction
mixture was stirred for 3 h at rt. Finally, the resin was
washed with DMF, DCM, MeOH and Et2O and dried under
vacuum.
3. Experimental
3.1. General
Melting points were determined in capillary tubes and are
uncorrected. TLC was carried out on SiO2 (silica Gel 60
F254, Merck) and spots were located with UV light. Column
chromatography was carried out on SiO2 (silica Gel 60 SDS
0.035–0.070 mm). Organic extracts were dried over
anhydrous Na2SO4 and solutions were evaporated under
reduced pressure with a rotatory evaporator. IR spectra were
obtained using a Thermo Nicolet Nexus spectrophotometer.
NMR spectra were acquired with Varian Gemini-200
(200 MHz), Varian Gemini-300 (300 MHz), Mercury-400
(400 MHz) and Varian VXR-500 (500 MHz) spectrometers;
data are given on the d scale referenced to TMS. Mass
spectra were measured in the electron impact (EI) mode
with a Hewlett–Packard model 5989A spectrometer. High
resolution mass spectra were performed on an Auto-
3.1.3. Methyl 3,4-dibromopyrrole-2-carboxylate 7c.
Resin 9 (100 mg) was swelled in DCM (5 ml) and LiOH
(32.5 mg, 20 equiv.) in MeOH (5 ml) was added. The
reaction mixture was shaken at reflux temperature for 2 h.
The resin was washed with DCM and the organic layer was
evaporated. The crude product was diluted in H2O, acidified
to pH 2 with 1 N HCl and extracted with EtOAc. The
organic layer was dried and evaporated under vacuum to
give the title compound (3.5 mg of crude material). The
spectroscopic data of the product are the same as described
´
Spec/VG by Unidad de Espectrometrıa de Masas de
1
previously.4b IR (NaCl) n 3359,31, 1728, 1368; H NMR
Santiago de Compostela. HPLC was carried out using a
Waters 996 Photodiode Array Detector, a SYMMETRY C18
column (4.6£150 mm, 5 mm) and H2O (0.045% TFA) and
AcCN (0.036% TFA) as eluents. HPLC-MS was carried out
on a Waters micromass ZQ using a SYMMETRY C18
(CDCl3, 200 MHz) d 3.91 (s, 3H, CO2CH3), 7.00 (d,
J¼2.8 Hz, 1H, H5); MS (EI) m/z 285 (2 81BrMþ, 31), 283
(81BrMþ, 79BrMþ, 63), 281 (2 79BrMþ, 33), 253 (2 81BrMþ,
50), 251 (81BrMþ, 79BrMþ, 100), 249 (2 79BrMþ, 51).

M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
8665
3.1.4. 4-(4-Bromo-2-methoxycarbonyl-1-triisopropyl-
silylpyrrol-3-yl)phenoxy resin 10. n-BuLi (8.13 ml,
10 equiv., 1.6 M) was added dropwise to a cooled
(278 8C) solution of methyl 3,4-dibromo-1-trimethyl-
silanylpyrrole-2-carboxylate (5.71 g, 10 equiv.) in dry
THF (35 ml) under N2 and the mixture was stirred for
15 min at 278 8C. A solution of ZnCl2 (2.84 g, 16 equiv.) in
dry THF (8 ml) was added and the reaction mixture was
stirred for 5 min at 278 8C and 25 min at rt. The reaction
mixture was transferred using N2 to a mixture of the swelled
resin 11 (2.82 g) with dry THF (15 ml) and Pd(PPh3)4
(225 mg, 0.15 equiv.). The reaction mixture was shaken for
24 h at rt and, after this time, was washed with THF, DCM,
MeOH, Et2O (3£10 ml, each) and finally was dried in a
vacuum oven at 40 8C. IR (KBr) n 1697 (CvO), 1600, 741,
Na2CO3 (10 equiv.), boronic acid 15 (10 equiv.) and
Pd(PPh3)4 (0.2 equiv.) were added and the reaction mixture
was shaken under reflux between 21 and 48 h. Resin 16 was
washed with dioxane, DCM, MeOH, Et2O (3£4 ml, each)
and was dried under vacuum.
3.3.1. 4-[2-Methoxycarbonyl-4-(4-methoxyphenyl)-1-
triisopropylsilylpyrrol-3-yl]phenoxy resin 16a. The
general diaryl synthesis procedure, with resin 10 (1 g) and
4-methoxyphenylboronic acid, gave resin 16a after a
reaction time of 19 h. IR (KBr) n 1691 (CvO), 1600, 1450,
746. 13C NMR (CDCl3, Gel Phase, 75 MHz) d 13.6
[CH(CH3)2], 18.6 [CH(CH3)2], 53.4 (CO2CH3), 67.0 (OCH3).
3.3.2. 4-[2-Methoxycarbonyl-4-(4-isopropoxyphenyl)-1-
triisopropylsilylpyrrol-3-yl]-phenoxy resin 16b. The
general diaryl synthesis procedure, with resin 10 (1 g) and
4-isopropoxyphenylboronic acid,16 gave resin 16b after a
reaction time of 48 h. IR (KBr) n 1695 (CvO), 1600, 744.
13C NMR (CDCl3, Gel Phase, 75 MHz) d 13.6 [CH(CH3)2],
18.6 [CH(CH3)2], 22.1 [OCH(CH3)2], 53.4 (CO2CH3), 69.6
[OCH(CH3)2].
700; 13C MAS NMR (CDCl3, 125 MHz)
[CH(CH3)2], 18.3 (CHCH3), 50.9 (CO2CH3).
d 13.4
3.1.5. 4-Iodophenoxy-resin 11.27 Merrifield-Cl resin (4 g,
loading 0.5 mmol/g) was swelled in dry DMF (60 ml) for
30 min and 4-iodophenol (2.20 g, 5 equiv.) and NaOMe
(22.3 ml, 5 equiv., 4.4 M) in dry DMF were added. The
reaction mixture was warmed at 80 8C and shaken for 24 h.
The resin was washed with DCM, DMF/DCM (1:1), DMF,
DCM, MeOH, Et2O (3£3 ml, each) and was dried under
vacuum. The resin was swelled in dry DMF (60 ml) for
15 min, NaOMe (1.2 ml, 4 equiv., 4.4 M) was added and the
mixture was shaken for 3 h at 80 8C. The resin was washed
with DMF, DCM, MeOH and Et2O (3£10 ml) and dried under
vacuum. IR (KBr) n 1943, 1872, 1803, 1599, 743, 698.
3.3.3. 4-[2-Methoxycarbonyl-4-(3,4-dimethoxyphenyl)-
1-triisopropylsilylpyrrol-3-yl]phenoxy resin 16c. The
general diaryl synthesis procedure, with resin 10 (1 g) and
3,4-dimethoxyphenylboronic acid, gave resin 16c after a
reaction time of 48 h. IR (KBr) n 1694 (CvO), 1600, 1492,
744. 13C NMR (CDCl3, Gel Phase, 75 MHz) d 13.6
[CH(CH3)2], 18.6 [CH(CH3)2], 55.2 (–OCH3), 55.7
(–OCH3).
3.2. General procedure for cleavage with ZnBr2/AcBr
3.3.4. 4-[2-Methoxycarbonyl-4-(2-naphthyl)-1-triiso-
propylsilylpyrrol-3-yl]-phenoxy resin 16d. The general
diaryl synthesis procedure, with resin 10 (1 g) and
2-naphthaleneboronic acid, gave resin 16d after a reaction
time of 48 h. IR(KBr) n1694 (CvO), 1600. 13CNMR (CDCl3,
Gel Phase, 75 MHz) d 13.6 [CH(CH3)2], 18.6 [CH(CH3)2].
ZnBr2 (3.5 equiv.) and AcBr (40 equiv.) were added to the
swelled resin in DCM under N2 and the reaction mixture was
shakenfor 24 hatrt. The resinwasfilteredoffandwashedwith
DCM. The organic solution was washed with 5% aq.
NaHCO3, 5% aq. HCl, saturated NaCl, dried and evaporated.
3.2.1. 4-Iodophenol acetate 13a. The general procedure for
cleavage with ZnBr2/AcBr on resin 11 (40 mg) gave 13a
(2.5 mg, 50%). 1H NMR (CDCl3, 200 MHz)28 d 2.29 (s, 3H,
CH3), 6.86 (d, J¼8.8 Hz, 2H, H2, H6), 7.68 (d, J¼8.8 Hz,
2H, H3, H5).
3.4. General procedure for cleavage with AlCl3
AlCl3 (3 equiv.) was added to the swelled resin 16 in dry
DCM under N2. The reaction mixture was shaken for 3 h at
rt. The resin was washed with DCM. The organic layer was
washed with 10% aq. HCl, dried and evaporated to give 18.
The crude material was analysed by HPLC-MS.
3.2.2. Methyl 3-(4-acetoxyphenyl)-5-acetyl-4-bromo-
pyrrole-2-carboxylate 14a. The general procedure for
cleavage with ZnBr2/AcBr on resin 10 (110 mg) gave 14a
(17 mg). HPLC (35–50% ACN in 15 min; tr 12.28 min,
3.4.1. Methyl 3-(4-hydroxyphenyl)-4-(4-methoxy-
phenyl)pyrrole-2-carboxylate 18a. Resin 16a (600 mg)
gave 18a by following the general procedure for cleavage
with AlCl3 (15 equiv.). The crude material was analysed by
HPLC-MS (gradient 30–70% ACN in 15 min), 18a (tr
5.67 min, MS 324, Mþ1). Purification by HPLC (gradient
20–65% AcCN in 40 min) gave 18a (1 mg, 2%) as a pale-
1
83% purity). H NMR (CDCl3, 200 MHz) d 2.33 (s, 3H,
COCH3), 2.72 (s, 3H, OCOCH3), 3.75 (s, 3H, CO2CH3),
7.107 (d, J¼8.6 Hz, 2H, H30, H50), 7.35 (d, J¼8.6 Hz, 2H,
H2 , H60); 13C NMR (CDCl3, 50 MHz) d 17.7 (q, CH3), 21.3
(q, CH3), 52.2 (q, CH3), 104.9 (s), 120.8 (d), 122.2 (s), 129.4
(s), 130.6 (s), 130.9 (s), 131.6 (d), 150.4 (s), 165.1 (s), 169.2
(s), 188.2 (s). MS(EI) m/z 381 (81BrMþ, 11), 379 (79BrMþ,
11), 337 (74), 339 (72), 307 (74), 305 (74), 292 (40), 290
(40). HRMS (EI) m/z calculated for C16H14NO5Br:
379.0055; found: 379.0066.
1
yellow solid. H NMR (CDCl3, 500 MHz) d 3.73 (s, 3H,
CO2CH3), 3.76 (s, 3H, OCH3), 6.76 (bt, J¼8.7 Hz, 4H, H30,
H50, H300, H500), 7.00–7.06 (m, 3H, H20, H60, H5), 7.14 (d,
J¼8.5 Hz, 2H, H200, H600), 9.12 (bs, NH/OH). 13C NMR
(CDCl3, 125 MH0z0 ) d 51.4 (s, CO2CH3), 55.2 (s, OCH3),
113.8 (d, C300, C500), 114.8 (d, C30, C50), 129.6 (d, C20, C60),
132.2 (d, C200, C6 ). MS (EI) m/z 324 (Mþ1, 12), 323 (Mþ,
9), 292 (18). HRMS (EI) m/z calculated for C19H17NO4:
323.1157; found: 323.1157.
3.3. General procedure for the preparation of 16
Resin 10 was swelled with dioxane for 15 min. 2 M aq.

8666
M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
3.4.2. Methyl 3,4-bis(4-hydroxyphenyl)pyrrole-2-car-
boxylate 1: lamellarin Q. Resin 16b (500 mg), gave 1 by
following the general procedure for cleavage with AlCl3.
The crude product was analysed by HPLC-MS (gradient
20–40% ACN in 15 min) and 1 (tr 6.92 min, MS 310,
Mþ1). Purification by HPLC (gradient 20–40% ACN in
20 min) gave 1 (5 mg, 13%) as a pale-yellow gum. 1H NMR
(Acetone-d6, 400 MHz) d 3.64 (s, 3H, CO2CH3), 6.66 (d,
J¼8.4 Hz, 2H, H30, H50), 6.070 6 (d, J¼8.4 Hz, 2H, H300, H500),
6.9050 (d, 0J0 ¼8.4 Hz, 2H, H2 , H600), 7.05 (d, J¼8.4 Hz, 2H,
H2 , H6 ), 7.13 (bs, 1H, H5), 8.25 (bs, 2H, OH), 10.91 (bs,
2H, NH). 13C NMR (Acetone-d6, 100 MHz) d 50.3 (q,
CO2CH3), 114.4 (d, C300, C500), 115.0 (d, C30, C50), 120.5 (d,
C5), 120.7 (s, C2), 126.1 (s, C4), 126.2 (s, C3), 126.7 (s,
C100), 129.0 (s, C1), 129.5 (d, C20, C60), 132.1 (d, C200, C600),
155.8 (s, C400), 156.3 (s, C400), 161.2 (s, CvO). MS(EI) m/z
310 (Mþ1, 25), 309 (Mþ, 22), 278 (100); HRMS (EI) m/z
calculated for C18H15NO4: 309.1001; found: 309.1012.
3.4.5. Methyl 3-(4-hydroxyphenyl)-4-(2-naphthyl)-
pyrrole-2-carboxylate 18d. Resin 16d (700 mg) gave 18d
by following the general procedure for cleavage with AlCl3.
The crude material was analysed by HPLC-MS (gradient
30–70% ACN in 15 min), 18d (tr 8.6 min, MS 344, Mþ1).
Purification by HPLC (gradient 35–65% AcCN in 30 min)
gave 18d (1 mg, 2%) as a white solid. 1H NMR (Acetone-d6,
500 MHz) d 3.67 (s, 3H, CO2CH3), 6.76 (d, J¼9 Hz, 2H,
H30, H50), 7.1000(d, J¼9 Hz, 2H, H20, 00H60), 7.24 (dd, J¼8,
1.500Hz, 1H, H3 ), 7.4 (m, 3H, H050 , H5 , H800), 7.67 (m, 3H,
H1 , H600, H700), 7.79 (m, 1H, H4 ). MS (EI) m/z 344 (Mþ1,
19), 343 (Mþ, 59). HRMS (EI) m/z calculated for
C22H17NO3: 343.1208; found: 343.1193.
3.5. General procedure for N-desilylation
Resin 16 was swelled in DCM for 10 min and a solution of
NH4F (7 equiv.) in MeOH was added. The mixture was
shaken under reflux for 6 h. The resin was washed with
DCM and MeOH (5£4 ml, each) and dried.
3.4.3. Methyl 3-(4-hydroxyphenyl)-4-(4-isopropoxy-
phenyl)pyrrole-2-carboxylate 18b. Resin 16b (100 mg)
was swelled in DCM for 10 min, SnCl4 (10 equiv.) was
added and the mixture was shaken at rt for 12 h. The resin
was washed with DCM and the organic layer was washed
with 10% aq. HCl, dried and evaporated. The crude material
was analysed by HPLC-MS (gradient 20–40% ACN in
15 min) and 18b (tr 10.09 min, MS 352) was obtained.
Purification by HPLC (gradient 50–70% ACN in 20 min)
gave 18b (1 mg, 11%) as a white solid. 1H NMR (Acetone-
d6, 500 MHz) d 1.27 [d, J¼6 Hz, 6H, (CH3)2], 3.65 (s, 3H,
CO2CH3), 4.55 [h, J¼6 Hz, 1H, CH(CH3)2], 6.73 (d,
J¼8.7 Hz, 2H, H30, H50), 6.760 (d, J¼8.7 Hz, 2H, H300,
H500), 7.03 (d,00J¼8.7 Hz, 2H, H2 , H60), 7.06 (d, J¼8.7 Hz,
2H, H200, H6 ), 7.17 (d, J¼3 Hz, 1H, H5). 13C NMR
(Acetone-d6, 100 MHz) d 22.1 [q, (CH3)2], 50.3 (q,
CO2CH3), 69.4 [d, CH(CH3)2], 114.5 (d, C300, C500), 115.5
(d,0 C30, C50), 120.8 (d, C5), 125.8 (s, C100), 125.9 (s,
C1 ),1020 8.8 0(0s, C3), 129.4 (d, C20, C60), 131.8 (s, C4), 132.1
(d, C2 , C6 ), 156.1 (s, C40), 156.3 (s, C400), 162.6 (s, CvO).
MS (EI) m/z 352 (Mþ1, 15), 351 (Mþ, 11), 320 (38). HRMS
(EI) m/z calculated for C21H21NO4: 351.1470; found:
351.1465.
3.5.1. 4-[2-Methoxycarbonyl-4-(4-methoxyphenyl)-
pyrrol-3-yl]phenoxy resin 19a. Resin 16a (2 g) gave
resin 19a by following the general procedure for desilyl-
ation. IR (KBr) n 3414, 3286, 1690, 1600, 1451, 756, 695.
13C NMR (CDCl3, Gel Phase, 75 MHz) d 53.4 (CO2CH3),
69.8 (OCH3).
3.5.2. 4-[2-Methoxycarbonyl-4-(4-isopropoxyphenyl)-
pyrrol-3-yl phenoxy resin 19b. Resin 16b (370 mg) gave
resin 19b by following the general procedure for desilyl-
ation. IR (KBr) n 3430, 3287, 1690 (CvO), 1600, 755. 13
C
NMR (CDCl3, Gel Phase, 75 MHz) d 22.0 [OCH(CH3)2],
53.3 (CO2CH3), 69.6 [OCH(CH3)2].
3.5.3. 4-{2-Methoxycarbonyl-4-(4-methoxyphenyl)-1-[2-
(4-methoxyphenyl)-2-oxoethyl]pyrrol-3-yl}-phenoxy-
resin 20a. LDA (150 ml, 2 equiv.) was added dropwise to
swelled resin 19a (370 mg) in dry THF (10 ml) under N2 at
278 8C. The resin was shaken for 1 h at this temperature.
2-Bromo-40-methoxyacetophenone (172 mg, 5 equiv.) was
added. The cooling bath was removed and the crude mixture
was shaken in a vibromatic at 86 8C for 24 h. After this time
the resin was washed with THF, DCM, MeOH and Et2O
(3£5 ml, each) and dried under vacuum. IR (KBr) n 3400,
2920, 1691, 1600. 13C NMR (CDCl3, 75 MHz) d 55.2
(CO2CH3), 69.9 (OCH3).
3.4.4. Methyl 3-(4-hydroxyphenyl)-4-(3,4-dimethoxy-
phenyl)pyrrole-2-carboxylate 18c. Resin 16c (820 mg)
gave 18c by following the general procedure for cleavage
with AlCl3. The crude material was analysed by HPLC-MS
(gradient 20–40% ACN in 15 min), 18c (tr 10.09 min, MS
354, Mþ1). Purification by HPLC (gradient 25–40% ACN
in 30 min) gave 18c (10 mg, 14%) as a white solid. 1H NMR
(Acetone-d6, 500 MHz) d 2.98 (bs, 1H, OH/NH), 3.52 0(0 s,
3H, C400 –OCH3), 3.65 (s, 3H, CO2CH3), 3.75 (s, 3H, C3 –
OCH3), 6.63 (d, J¼2 Hz, 1H, H200), 6.77–6.81 (m, 3H, H50,
H30, H600), 7.07 (d, J¼8.5 Hz, 2H, H60, H20), 7.23 (d,
J¼3.5 Hz, 1H, H5), 10.96 (bs, 1H, NH/OH). 13C NMR
(Acetone-d6, 100 MHz) d 50.3 (q, CO2CH3), 54.9 (q,
OCH3), 55.4 (q, OCH3), 112.0 (d, C600), 112.6 (d, C200),
114.5 (d, C50, C30), 119.4 (s, C2), 120.2 (d, C500), 120.6 (d,
C5), 120.8 (s, C4), 126.4 (s, C100), 128.3 (s, C3), 129.1 (s,
C10), 132.1 (s, C60, C20), 147.9 (s, C300), 149.1 (s, C400), 156.4
(s, C40), 161.2 (s, CvO). MS (EI) m/z 354 (Mþ1, 39), 353
(Mþ, 31), 322 (100). HRMS (EI) m/z calculated for
C20H19NO5: 353.1263; found: 353.1261.
3.5.4. 4-{2-Methoxycarbonyl-4-(4-isopropoxyphenyl)-1-
[2-(4-methoxyphenyl)-2-oxoethyl]pyrrol-3-yl}phenoxy-
resin 20b. Resin 19b (500 mg) was swelled in a solution of
18-crown-6 in DMF (2.5 M, 25 ml) for 10 min. K2CO3
(6 equiv.) and 2-bromo-40-methoxyacetophenone (6 equiv.)
were added. The reaction mixture was heated in a
microwave oven at 100 8C and 30–40 W during 2 min.
The resin was washed with DMF, DMF/H2O (1:1), DCM,
MeOH and Et2O (3£5 ml, each) and dried under vacuum.
20b was obtained. IR (KBr) n 3417, 1724(CvO), 1690
(CvO), 1600. 13C NMR (CDCl3, 75 MHz) d 22.1
[OCH(CH3)2], 59.8 (CO2CH3), 69.6 [OCH(CH3)2].
3.5.5. 4-[2-Methoxycarbonyl-4-(4-isopropoxyphenyl)-1-
methylpyrrol-3-yl]phenoxy resin 20d. Resin 19b

M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
8667
(300 mg) was swelled in a solution of 18-crown-6 in DMF
(2.5 M) for 10 min and K2CO3 (15 equiv.) and MeI
(6 equiv.) were added. The reaction mixture was shaken at
rt for 24 h. The resin was washed with DMF, DMF/H2O
(1:1), DCM, MeOH and Et2O (3£5 ml, each) and dried
under vacuum. 20d was obtained. IR (KBr) n 1693, 1600,
1492, 743. 13C NMR (CDCl3, Gel Phase, 75 MHz) d 22.1
[OCH(CH3)2], 69.6 [OCH(CH3)2].
3.5.10. Methyl 3,4-bis-(4-hydroxyphenyl)-1-[2-(4-meth-
oxyphenyl)-2-oxoethyl]pyrrole-2-carboxylate 2: lamel-
larin O. Resin 20b (500 mg) gave 2 by following
the general procedure for cleavage with AlCl3. The
crude product was analysed by HPLC-MS (gradient
40–80% ACN in 15 min): 2 [tr 11.94 min, MS 458 (Mþ1)].
Acknowledgements
3.5.6. 4-{2-Methoxycarbonyl-4-(4-isopropoxyphenyl)-1-
[2-(2-bromophenethyl)]pyrrol-3-yl}-phenoxy-resin 20e.
Resin 19b (500 mg) was swelled in a solution of 18-
crown-6 in DMF (2.5 M, 25 ml) for 10 min and K2CO3
(4 equiv.) and 2-bromophenethyl tosylate (4 equiv.) were
added. The reaction mixture was shaken at 80 8C for 24 h.
After this time, the resin was washed with DMF, DMF/H2O
(1:1), DCM, MeOH and Et2O (3£5 ml, each) and dried
This work was partially supported by CICYT (PBQU2000-
0235) and Pharma Mar (Madrid). The authors thank Dr.
Carmen Cuevas for support.
References and notes
under vacuum. 20e was obtained. IR (KBr) n 1642, 610. 13
C
NMR (CDCl3, 75 MHz) d 22.1 [OCH(CH3)2], 69.6
[OCH(CH3)2].
1. (a) Andersen, R. J.; Faulkner, D. J.; Chun-heng, H.; Van
Duyne, D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492.
(b) Lindquist, N.; Fenical, W. J. Org. Chem. 1988, 53, 4570.
(c) Urban, S.; Butlet, M. S.; Capon, R. J. Aust. J. Chem. 1994,
47, 1919. (d) Urban, S.; Hobbs, L.; Hooper, J. N. A.; Capon,
R. J. Aust. J. Chem. 1995, 48, 1491. (e) Urban, S.; Capon, R. J.
Aust. J. Chem. 1996, 49, 711. (f) Reddy, M. V. R.; Faulkner,
D. J. Tetrahedron 1997, 53, 3457. (g) Davis, R. A.; Carroll,
A. R.; Pierens, G. K.; Quinn, R. J. J. Nat. Prod. 1999, 62, 419.
(h) Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S.
T.; Rubins, K.; Bushman, F. D.; Venkateswarlu, Y.; Faulkner,
D. J. J. Med. Chem. 1999, 42, 1901.
3.5.7. Methyl 3-(4-hydroxyphenyl)-4-(4-methoxy-
phenyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl] pyrrole-2-
carboxylate 21a. Resin 20a (300 mg) gave 21a by
following the general procedure for cleavage with AlCl3
(15 equiv.) for 6 h. The crude product was analysed by
HPLC-MS (gradient 35–50% ACN in 15 min): 21a [tr
12.89 min, MS (472, Mþ1)]. Purification by HPLC
(gradient 30–60% ACN in 30 min) gave 21a (1.0 mg,
2%) as a yellow solid.1H NMR (CDCl3, 600 MHz) d 3.45
(s, 3H, CO2Me), 3.81 (s, 3H, OMe), 3.86 (s, 3H, OMe), 5.72
(s, 2H, CH2), 6.89 (d, 2H, J¼9 Hz, H300, H500), 7.00 (s, 1H,
H5), 7.05 (d, 2H, J¼8.4 Hz, H3000, H5000), 7.08 (0d, 2H,
J¼7.6 Hz, H30, H50), 7.16 (d, 2H, J¼7.6 Hz, H20, H6 ), 7.44
(d, 0020 H, J¼8.4 Hz, H200, H600), 8.03 (d, 2H, J¼9 Hz, H2000,
H6 ).
2. Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254.
3. (a) Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.;
Schleyer, M.; Kashman, Y. J. Org. Chem. 1994, 59, 999.
(b) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J.
1999, 344, 85. (c) Rudi, A.; Evan, T.; Aknin, M.; Kashman, Y.
J. Nat. Prod. 2000, 63, 832. (d) Kreipl, A. T.; Reid, C.;
Steglich, W. Org. Lett. 2002, 4, 3287.
3.5.8. Methyl 3,4-bis(4-hydroxyphenyl)-1-methyl-
pyrrole-2-carboxylate 21c. Resin 20d (500 mg) gave 21c
by following the general procedure for cleavage with AlCl3.
The crude product was analysed by HPLC-MS (gradient
30–70% ACN in 15 min): 21c (tr 5.67 min, MS 324,
Mþ1). Purification by HPLC (gradient 20–70% ACN in
(Acetone-d6, 500 MHz) d 2.92 (bs, OH), 3.53 (s, 3H,
CO2CH3), 3.95 (s, 3H, N–CH3), 6.64 (d, J¼8.5 Hz, 2H,
H30, H50), 6.75 (d, J¼8.5 Hz, 2H, H300, H500), 6.91 (d,
J¼8.5 Hz, 2H, H20, H60), 6.97 (d, J¼8.5 Hz, 2H, H200, H600),
7.10 (s, 1H, H5). 13C NMR (Acetone-d6, 100 MHz) d 36.9
(q, CH3), 50.0 (q, CO2CH3), 112.4 (d, C300, C500), 115.0 (d,
C30, C50), 120.6 (s, C2), 124.1 (s, C4)0, 126.6 (s, C10), 127.0
(d, C5), 1270.04 (s,00C100), 129.4 (d, C2 , C50), 13000 .6 (s, C3),
131.9 (d, C2 , C5 ), 155.8 (s, C40), 156.3 (s, C4 ), 162.6 (s,
CvO). MS(EI) m/z 324 (Mþ1, 14), 323 (Mþ, 23), 292 (58).
HRMS (EI) m/z calculated for C19H17NO4: 323.1158; found
323.1149.
4. (a) Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem.
1995, 60, 6637. (b) Banwell, M. G.; Flynn, B. L.; Hamel, E.;
Hockless, D. C. R. J. Chem. Soc., Chem. Commun. 1997, 207.
(c) Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun.
1997, 2259. (d) Ishibashi, F.; Miyazaki, Y.; Iwao, M.
Tetrahedron 1997, 53, 5951. (e) Heim, A.; Terpin, A.;
Sterlich, W. Angew. Chem., Int. Ed. 1997, 36, 155. (f) Boger,
D. L.; Boyce, C. W.; Labrodi, M. A.; Sehon, A. A.; Jin, Q.
J. Am. Chem. Soc. 1999, 121, 54. (g) Banwell, M. G.; Flynn,
B. L. WO 99/67250.. (h) Peschko, C.; Winklhofer, C.;
1
50 min) gave 21c (1.7 mg, 6%) as a brown solid. H NMR
´
Steglich, W. Chem. Eur. J. 2000, 6, 1147. (i) Dıaz, M.;
´
Guitian, E.; Castedo, L. Synlett 2001, 1164. (j) Ruchirawat, S.;
Mutarapat, T. Tetrahedron Lett. 2001, 42, 1205.
5. (a) Gupton, J. T.; Krumpe, K. E.; Burnham, B. S.; Webb, T. M.;
Shuford, J. S.; Sikorski, J. A. Tetrahedron 1999, 55, 14515.
(b) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C.
J. Org. Chem. 2000, 65, 3587.
6. (a) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.;
Jin, Q. J. Org. Chem. 2000, 65, 2479. (b) Namsaaid, A.;
Ruchirawat, S. Org. Lett. 2002, 4, 2633. (c) Boger, D. L. WO
0164635 A1, 2001. (d) Peschko, C.; Steglich, W. Tetrahedron
Lett. 2000, 41, 9477.
3.5.9. Methyl 3,4-bis(4-hydroxyphenyl)-1-[2-(2-bromo-
phenyl)ethyl]pyrrole-2-carboxylate 21d. Resin 20c
(500 mg) gave 21d by following the general procedure for
cleavage with AlCl3. The crude product was analysed by
HPLC-MS (gradient 30–70% ACN in 15 min): 21d [tr
12.64 min, MS (492, Mþ1)].
7. Cironi, P. G.; Albericio, F.; Alvarez, M. Org. Lett. 2003, 5,
2959.
´
8. (a) Alvarez, M.; Feliu, L.; Ajana, W.; Joule, J. A. Tetrahedron
´
2000, 56, 3703. (b) Alvarez, M.; Fernandez, D.; Joule, J. A.
´

8668
M. Marfil et al. / Tetrahedron 60 (2004) 8659–8668
described in Chaumeil, H.; Signorella, S.; Le Drian, C.
Tetrahedron Lett. 2001, 42, 315. (c) Ahaidar, A.;
´ ´
Fernandez, D.; Danelon, G.; Cuevas, C.; Manzanares, I.;
Tetrahedron 2000, 56, 9655.
´
Albericio, F.; Joule, J. A.; Alvarez, M. J. Org. Chem. 2003, 68,
10020.
18. The stability of chloro-Merrifield resin under the same
reaction conditions, i.e. large excess of AlCl3 in DCM at rt
during 3 h, was tested and the result was the total breakdown
of the resin beads. Less harsh conditions involving an excess
of 3 equiv. of AlCl3 over the resin during 3 h allowed total
recovery of the resin beads.
9. Li, W.-R.; Yo, Y.-C. Tetrahedron Lett. 1999, 40, 9085.
10. Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell,
T. T.; Artis, D. R.; Muchoswski, J. M. J. Org. Chem. 1990, 55,
6317.
11. Formation of 10 was investigated by 13C MAS NMR and
corroborated by characterisation of the diacetyl derivative 14a
obtained by the cleavage reaction of 10 with ZnBr2 and AcBr.
12. The crude cleavage material was analysed by HPLC and
HPLC-MS.
19. Cironi, P.; Cuevas, C.; Albericio, F.; Alvarez, M. Tetrahedron
2004, 60, 8669.
´
20. K2CO3 as base and TBAF in THF or DMF, as described in
solution in Ref. 6b, proved ineffective.
21. 15 equiv. of NaH or 2 equiv. of LDA in dry THF at reflux for
24 h afforded, after cleavage, mixtures of 18a and 21a in
which the alkylation product was obtained in 25% (NaH) and
30% (LDA) yield (HPLC-MS). Increasing the amount of LDA
or the use of other bases did not improve the yield of 21a.
22. The compound was not isolated after trying different
purification procedures on the crude cleavage material by
semipreparative HPLC. The loss of material, probably by
decomposition in the column.
13. Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., de Meijere, A., Eds.; Willey-
Interscience: New York, 2002; Vol. 1, p 493.
14. Commercial 3-methoxyphenylboronic acid was used to find
the best reaction conditions to be applied to the synthesis of
lamellarins and derivatives.
15. Mixtures of 18e and 18f, as well as of 14a and 14b, in different
proportions were produced during the cleavage with ZnBr2 in
AcBr due to electrophilic acetylation on the pyrrole.
Compound 18f was not isolated but detected by HPLC-MS
and its structure postulated on the basis of the 1H NMR
spectrum of the crude mixture by the singlet at 7.29 ppm due
to the pyrrole proton 5.
23. The best results were obtained using an excess of K2CO3
and 18-crown-6 as base in DMF in a microwave at 100 8C and
30–40 W during 2 min.
24. Tanaka, R.; Rodgers, M.; Simonaitis, R.; Miller, S. I.
Tetrahedron 1971, 27, 2651.
16. GP 13C NMR of bisarylpyrroles 16b-16d were used to
corroborate the introduction of the new aromatic ring.
17. The 4-isoproxoxyphenylboronic acid 15b was not commercial
when we started this project. It was prepared from the
p-iodophenol by protection with 2-iodopropane followed by
boronic acid formation via halogen–metal interchange using
nBuLi followed by reaction with trimethylboronate as
25. Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R.; Longmore,
R. W.; Rae, A. D. Aust. J. Chem. 1998, 52, 755.
26. The N-alkylation was performed using K2CO3 and 18-crown-6
in DMF.
27. Ma, S.; Duan, D.; Shi, Z. Org. Lett. 2000, 2, 1419.
28. 1H NMR data were identical to those described in Menger,
F. M. Chem. Soc. Rev. 1972, 1, 229.