A Modular Synthesis of the Lamellarins: Total Synthesis of Lamellarin G Trimethyl Ether

Article abstract of DOI:10.1021/jo0352833

A modular synthesis of the lamellarin family of natural products has been developed that is based on the application of three iterative halogenation/cross-coupling reaction sequences. The ability to halogenate the pyrrole core in a regioselective fashion, even in the presence of highly electron-rich aryl substituents, has been established. The compatibility of Suzuki coupling conditions with free alcohols and phenols in the boronic acids has been employed to reduce the number of protection/deprotection steps. Indeed, the presence of a free phenol on boronic acid 3 has been determined to be critical for the successful final coupling in route to lamellarin G trimethyl ether, since protected versions fail to undergo coupling.

Full text of DOI:10.1021/jo0352833

A Mod u la r Syn th esis of th e La m ella r in s: Tota l Syn th esis of
La m ella r in G Tr im eth yl Eth er
Scott T. Handy,* Yanan Zhang, and Howard Bregman
Department of Chemistry, State University of New York at Binghamton, Binghamton, New York 13902
shandy@binghamton.edu
Received September 2, 2003
A modular synthesis of the lamellarin family of natural products has been developed that is based
on the application of three iterative halogenation/cross-coupling reaction sequences. The ability to
halogenate the pyrrole core in a regioselective fashion, even in the presence of highly electron-rich
aryl substituents, has been established. The compatibility of Suzuki coupling conditions with free
alcohols and phenols in the boronic acids has been employed to reduce the number of protection/
deprotection steps. Indeed, the presence of a free phenol on boronic acid 3 has been determined to
be critical for the successful final coupling in route to lamellarin G trimethyl ether, since protected
versions fail to undergo coupling.
In tr od u ction
The lamellarins are a growing family of at least 35
related marine natural products,1 the first members of
which were isolated in 1985 by Faulkner and co-workers
(Figure 1).2 In addition to their interesting structure,
members of the lamellarin family have been reported as
exhibiting a number of potentially valuable biological
activities. For example, virtually all of the lamellarins
have been found to be cytotoxic to a wide range of cancer
cell lines. The most potent of these compounds (lamel-
larin D, K, and M) exhibit cytotoxicity values in the mid-
to-high nanomolar range (38-110 nM).3a Interestingly,
multidrug-resistant cell lines are also affected by the
lamellarins, which appear to be not only cytotoxic agents
but also single-digit micromolar inhibitors of the p-
glycoprotein responsible for the MDR effect.3 Lamellarin
K and L have also been observed to have immunomodu-
latory effects in the micromolar range.4 More recently,
Faulkner and co-workers reported that lamellarin R-20
sulfate is a selective inhibitor of HIV integrase both in
vitro and in vivo.5 Unlike most other natural product
integrase inhibitors, inhibition was not completely regu-
lated by the core domain but also partially by the N- and/
or C-terminal domains (IC50 for disintegration for the
F IGURE 1. Members of the lamellarin family of natural
products.
catalytic core 64 µM, for the intact enzyme 7 µM)
indicating that some form of unique multisite binding
might be responsible for this inhibition.
In light of these interesting biological activities and the
difficulty in obtaining large quantities of the lamellarins
from their natural source, they have garnered a consider-
able amount of synthetic interest. A number of elegant
strategies have been employed in which highly function-
alized precursors are assembled into the pyrrole core by
means of an intramolecular ylide cycloaddition,6 an
(1) Carroll, A. R.; Bowden, B. F.; Coll, J . C. Aust. J . Chem. 1993,
46, 489-501. Rami Reddy, M. V.; Faulkner, D. J .; Venkateswarlu, Y.;
Rama Rao, M. Tetrahedron 1997, 53, 3457-3466. Urban, S.; Capon,
R. J . Aust. J . Chem. 1996, 49, 711-713. Urban, S.; Butler, M. S.;
Capon, R. J . Aust. J . Chem. 1994, 47, 1919-1924. Urban, S.; Hobbs,
L.; Hooper, J . N. A.; Capon, R. J . Aust. J . Chem. 1995, 48, 1491-1494.
Davis, R. A.; Carroll, A. R.; Piersens, G. K.; Quinn, R. J . J . Nat. Prod.
1999, 62, 419-424. Kang, H.; Fenical, W. J . Org. Chem. 1997, 62,
3254-3262. Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J .
J . Org. Chem. 1988, 53, 4570-4574.
(2) Andersen, R. J .; Faulkner, D. J .; Cun-heng, H.; Van Duyne, G.
D.; Clardy, J . J . Am. Chem. Soc. 1985, 107, 5492-5495.
(3) (a) Quesada, A. R.; Gravalos, M. D. G.; Puentes, J . L. F. Brit. J .
Cancer 1996, 74, 677-682. (b) Boger, D. L.; Boyce, C. W.; Labroli, M.
A.; Sehon, C. A.; J in, Q. J . Am. Chem. Soc. 1999, 121, 54-62.
(4) Carroll, A. R.; Bowden, B. F.; Coll, J . C. Aust. J . Chem. 1993,
46, 489-501.
(5) 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, 1901-1907. Ridley, C. P.; Reddy, M. V. R.; Rocha, G.;
Bushman, F. D.; Faulkner, D. J . Bioorg. Med. Chem. 2002, 10, 3285-
3290.
(6) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001, 42, 1205-
1208. Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53,
5951-5962. Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun.
1997, 2259-2260. Ploypradith, P.; J inaglueng, W.; Pavaro, C.; Ruchira-
wat, S. Tetrahedron Lett. 2003, 44, 1363-1366. Cironi, P.; Manzanares,
I.; Albericio, F.; Alvarez, M. Org. Lett. 2003, 5, 2959-2962.
10.1021/jo0352833 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
2362
J . Org. Chem. 2004, 69, 2362-2366

Synthesis of Lamellarin G Trimethyl Ether
SCHEME 1. Ba n w ell Ap p r oa ch to th e La m ella r in
Sk eleton
SCHEME 3. Bor on ic Acid Su bu n it Syn th eses
SCHEME 2. Retr osyn th esis for th e Mod u la r
Ap p r oa ch to th e La m ella r in s
In this manner, the complete regiocontrol required for
the preparation of differentially substituted triaryl pyr-
role esters (as found in the more complex members of
the lamellarin family) can be obtained. At the same time,
the use of a robust cross-coupling method ensures the
maximum amount of flexibility and functional group
tolerance.
Such an approach raises three main questions. The
first question is simply whether the pyrrole ester nucleus
can be halogenated in a regiocontrolled manner. The
literature contains remarkably few examples of the
selective halogenation of pyrrole esters, beyond the
selective preparation of 4-halopyrrole carboxylates.12
Indeed, only a single report exists indicating that
4-arylpyrrole-2-carboxylates can be halogenated selec-
tively at the C5 position (pyrrole numbering).13 The
second question is whether halogenation will occur
selectively on the pyrrole ring of the mono- and diarylated
intermediates as opposed to the electron-rich aryl sub-
stituents. The final question is whether boronic acids
such as 2 and 3, with free hydroxyl groups, can be
successfully employed in the necessary Suzuki couplings,
thereby avoiding additional protection/deprotection se-
quences throughout the synthesis.
With these questions in mind, the first stage in the
synthesis of the lamellarins was the preparation of the
necessary aryl subunits 1, 2, and 3 (Scheme 3). Boronic
acid 1 is commercially available. Boronic acid 2 was
prepared starting with commercially available alcohol 5
via bromination at C6. Protection of the alcohol as a THP
ether set the stage for the standard preparation of boronic
acids from aryl halides: halogen-metal exchange, quench-
ing with tri(isopropyl)borate, and hydrolysis of the bo-
ronic ester with aqueous hydrochloric acid. This final
hydrolysis also served to cleave the THP ether, affording
boronic acid 2 in sufficient purity to be directly used in
the subsequent coupling reactions without further puri-
fication, although 2 could also be further purified by
recrystalization.
azadiene Diels-Alder cycloaddition,3b or an oxidative
dimerization.7 One unifying feature of all of these syn-
theses is that they form the pyrrole core late in the
synthesis,8 doubtless due to the difficulty in functional-
izing pyrrole in a regiocontrolled fashion. At the same
time, there are potential advantages, particularly from
the standpoint of analogue preparation, to starting with
an intact pyrrole core.
A few examples employing the functionalization of an
intact pyrrole core have appeared. Of particular note is
the approach of Banwell and co-workers. They have used
a simple pyrrole ester as their starting point and then
functionalized this core using an unusual tandem in-
tramolecular Heck reaction (Scheme 1).9 Although the
yield of the tandem Heck reaction was quite modest
(16%), it is an interesting alternative approach to the
traditional methods for pyrrole synthesis. Simpler mem-
bers of the lamellarins (O and P) have also been prepared
independently by Banwell and Wong using Stille and
Suzuki cross-coupling methods.10 More recently, lamel-
larin G trimethyl ether has been prepared by Iwao and
co-workers.11 Starting from a symmetric bis-trifloxy
pyrrole, two sequential Suzuki coupling reactions were
employed to desymmetrize the molecule and eventually
lead to the intact lamellarin framework.
Resu lts a n d Discu ssion
Our approach to the synthesis of the lamellarin skel-
eton likewise chooses to elaborate on a preexisting pyrrole
core. As seen in Scheme 2, this strategy focuses on the
use of sequential halogenation/cross-coupling reactions.
The preparation of boronic acid 3 was more problem-
atic. We wished to prepare this compound with the
unprotected o-phenol since it was suspected that a
protecting group on the oxygen adjacent to the boronic
acid might seriously impede the final Suzuki coupling
for steric reasons. Further, couplings of simple 2-hydroxy-
phenylboronic acid have been reported in the literature
(7) (a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed.
Engl. 1997, 36, 155-156. (b) Peschko, C.; Winklhofer, C.; Steglich, W.
Chem. Eur. J . 2000, 6, 1147-1152.
(8) This same feature is true of synthetic approaches that do not
fall into the previous three categories. See: Gupton, J . T.; Clough, S.
C.; Miller, R. B.; Lukens, J . R.; Henry, C. A.; Knaters, R. P. F.; Sikorski,
J . A. Tetrahedron 2003, 59, 207-215.
(9) Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R.; Longmore, R.
W.; Rae, A. D. Aust. J . Chem. 1998, 52, 755-765.
(10) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R.
Chem. Commun. 1997, 207-208. Liu, J .-H.; Yang, Q.-C.; Mak, T. C.
W.; Wong, H. N. C. J . Org.Chem. 2000, 65, 3587-3595.
(11) Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi,
F. Tetrahedron Lett. 2003, 44, 4443-4446.
(12) Belanger, P. Tetrahedron Lett. 1979, 27, 2505-2508.
(13) Balsamini, C.; Bedini, A.; Diamantini, G.; Spadoni, G.; Tontini,
A.; Tarzia, G.; Di Fabio, R.; Feriani, A.; Reggiani, A.; Tedesco, G.; Valigi,
R. J . Med. Chem. 1998, 41, 808-820.
J . Org. Chem, Vol. 69, No. 7, 2004 2363

Handy et al.
SCHEME 4. P r ep a r a tion of th e Key Tr icyclic In ter m ed ia te
SCHEME 5. Cou p lin gs w ith Br om id e 16 Lea d in g
to La m ella r in G Tr im eth yl Eth er
and proceed well.14 To that end, THP-protected bromide
9 was the target, since we had already established that
these ethers were cleaved under the conditions required
for the hydrolysis of the boronic ester. Unfortunately, all
attempts to protect 2-bromo-3,4-dimethoxyphenol were
unsuccessful as even mildly acidic conditions resulted in
extensive decomposition. Fortunately, protection of the
phenol prior to bromination avoided this acid-catalyzed
decomposition. Thus, THP ether 8 could be readily
prepared using normal conditions and then carefully
brominated in the presence of sodium carbonate to afford
bromide 9 in roughly 80% yield overall. The sodium
carbonate was required, since bromination in the absence
of any base, or even in the presence of a milder base such
as sodium bicarbonate, resulted in nearly complete
cleavage of the THP ether. With bromide 9 in hand,
standard conditions for the preparation of boronic acids
afforded highly sensitive boronic acid 3.
With the necessary subunits in hand, the synthesis
itself began with known bromopyrrole ester 10 (prepared
in three steps from pyrrole)12 (Scheme 4). Previous
studies indicated that the nitrogen of this pyrrole must
be protected prior to the first coupling event to avoid
extensive dehalogenation.15 To that end, bromopyrrole
ester 10 was protected as the corresponding tert-butyl
carbamate to afford 11 in nearly quantitative yield.
Coupling with boronic acid 1 proceeded cleanly to afford
monoaryl compound 12 in 70% yield. It is worth noting
that a modest excess (2-3 equiv) of the boronic acid was
required. The use of only 1.2 equiv of the boronic acid
afforded 50-60% yields of compound 12 along with some
homocoupling of bromide 11.
a
51% of 15 was also recovered.
equimolar amount of N-bromosuccinimide led cleanly to
selective halogenation at the C5 position. At this point,
the second coupling with boronic acid 2 was then carried
out under standard Suzuki coupling conditions. A poten-
tial concern with this coupling was the possibility that,
given the proximity of the alcohol to the boronic acid, it
could hinder either the initial oxidative insertion or, by
stabilization, further steps along the catalytic pathway.
Fortunately, the coupling proceeded as planned to afford
adduct 14 and avoided the need to protect the free
hydroxyl group. At this point, the dihydroisoquinoline
ring was closed in a two step procedure: formation of
the tosylate followed by intramolecular alkylation of the
pyrrole nitrogen. The yield over these two steps was 61%.
As expected on the basis of the previous halogenation
result, the final halogenation also proceeded cleanly at
C3 to afford bromide 16 (Scheme 5). Initial efforts at
coupling with boronic acid 3 were only slightly encourag-
ing. Trace amounts of lamellarin G trimethyl ether were
observed indicating that both the desired coupling as well
as lactonization could occur in the same reaction pot.
Nevertheless, the yield of this coupling (8%) was too low
for any practical applications of this method. The most
significant problem appeared to be the thermal sensitiv-
ity of boronic acid 3. Storage at room temperature for a
With compound 12 in hand, the first significant ques-
tions regarding the regioselectivity of halogenation could
be addressed. Gratifyingly, treatment of 12 with an
(14) For an example, see: Ito, K.; Kashiwagi, R.; Iwasaki, K.;
Katsuki, T. Synlett 1999, 1563-1566.
(15) Handy, S. T.; Bregman, H.; Lewis, J .; Zhang, X.; Zhang, Y.
Tetrahedron Lett. 2003, 44, 427-430.
2364 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of Lamellarin G Trimethyl Ether
and regioselective halogenation/coupling events. This
route accesses the complete structure of lamellarin G
trimethyl ether in 11 steps and 9% overall yield. Future
efforts will focus on improving the yield of the final
coupling step and in exploring regioselective couplings
on polyhalogenated pyrrole esters. These efforts will be
reported in due course.
F IGURE 2. Protected versions of boronic acid 3.
few days was sufficient to cause nearly complete decom-
position. Given the high temperatures required for the
Suzuki coupling, it seemed likely that even more rapid
decomposition of the boronic acid might be responsible
for the very modest yield of this reaction. In an effort to
confirm this suspicion, couplings were undertaken with
both phenyl boronic acid and boronic acid 1 under
identical conditions. Interestingly, in both cases the
anticipated Suzuki-coupling product was the major prod-
uct (82% and 56% with phenyl boronic acid and boronic
acid 1, respectively). The hypothesis that decomposition
of boronic acid 3 was the limiting factor in the final
coupling was further supported by the observation that
the use of a larger excess of the boronic acid (8 equiv)
led to the isolation of lamellarin G trimethyl ether in 20%
yield.
At this point, there were two further alternatives for
increasing the yield of this final coupling. The first
approach was to see if a protecting group on the phenol
would serve to stabilize the boronic acid and yet at the
same time not impede the coupling by increasing the
steric hindrance. In light of the synthetic manipulations
required for the preparation of boronic acids such as 3,
ether protecting groups appeared to be the most promis-
ing. Both the benzyl and BOM-protected versions of 3
were prepared (Figure 2). They did indeed exhibit much
greater thermal and acid stability. Unfortunately, at-
tempts at coupling these boronic acids with bromide 16
or the corresponding iodide resulted only in dehalogena-
tion of 16 and the nearly quantitative recovery of
compound 15. As a result, the steric hindrance of these
protected boronic acids appears to be too great for
effective coupling to occur without extensive optimization
of the reaction conditions.
The other main possibility was to add an excess of
boronic acid 3 slowly over time. In this way, any potential
thermal decomposition of 3 at the high temperatures
required for the coupling could be largely mitigated. In
the event, three equivalents of boronic acid 3 were added
immediately to the reaction mixture, followed by the slow
addition of an additional five equivalents of 3 over the
span of 2.5 h. In this way, lamellarin G trimethyl ether
was obtained in 46% yield along with 51% of compound
15. The spectral data and melting point were consistent
with that reported in the literature.7a Although further
optimization is clearly required to make this coupling
more efficient, it does support our hypothesis that boronic
acid stability is the limiting factor. By applying a greater
excess of the boronic acid and more active catalysts
(which in turn should enable the use of lower reaction
temperatures), the yield of this coupling should be
improved even more.
Exp er im en ta l Section
4-Br om op yr r ole-1,2-d ica r boxylic Acid 1-ter t-Bu tyl Es-
ter 2-Eth yl Ester (11). To a solution of 2.81 g (13.1 mmol) of
4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester in 25 mL of
anhydrous acetonitrile was successively added 160 mg (1.31
mmol) of DMAP and 3.71 g (17.0 mmol) of di-tert-butyl
dicarbonate. The reaction was stirred at room temperature for
1 h. To the mixture was added 80 mL of diethyl ether and 40
mL of 1 M aqueous KHSO4. The organic layer was separated
and washed sequentially with aqueous KHSO4, water, satu-
rated aqueous NaHCO3, and brine and then dried with
anhydrous magnesium sulfate. The solvent was removed in
vacuo. The resulting residue was purified by chromatography
on silica gel, using 20:80 EtOAc-hexane, to afford 3.87 g
(93.0%) of 11 as a yellow oil: 1H NMR (360 MHz, CDCl3) δ
7.28 (s, 1H), 6.76 (s, 1H), 4.28 (q, 2H, J ) 7.2), 1.55 (s, 9H),
1.32 (t, 3H, J ) 7.2); 13C NMR (90 MHz, CDCl3) δ 159.8, 147.1,
125.9, 125.3, 121.9, 98.7, 85.5, 61.2, 27.7, 14.1; IR (neat) 3440
(w, br), 3139 (w), 2982 (m), 1757 (s), 1729 (s), 1458 (w), 1397
(m), 1371 (m), 1304 (s), 1153 (s), 1072 (m), 922 (w), 845 (w),
774 (w) cm-1; HRMS (electrospray) calcd for C12H16BrNO4
Na 340.0160, found 340.0158.
+
4-(3,4-Dim eth oxyp h en yl)-1H-p yr r ole-2-ca r boxylic Acid
Eth yl Ester (12). To a solution of 187.4 mg (0.60 mmol) of
11, 328 mg (1.80 mmol) of 3,4-dimethoxyphenyl boronic acid
(1), and 34.7 mg (0.03 mmol) of tetrakis(triphenylphosphine)-
palladium(0) in 10 mL of DMF was added 3.0 mL of 2 M
aqueous Na2CO3. The reaction mixture was stirred at 110 °C
for 15 h. The reaction was quenched with 20 mL of water and
extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with water and brine and dried with
anhydrous magnesium sulfate. The solvent was removed in
vacuo. The resulting residue was chromatographed on silica
gel, using 10:90 acetone-benzene, to afford 116 mg (70.0%) of
1
12 as a white solid: mp 136.3-137.5 °C; H NMR (360 MHz,
CDCl3) δ 9.13 (br s, 1H), 7.14 (m, 2H), 7.05 (m, 2H), 6.87 (d,
1H, J ) 8.3 Hz), 4.34 (q, 2H, J ) 7.1 Hz), 3.94 (s, 3H), 3.92 (s,
3H), 1.38 (t, 3H, J ) 7.1); 13C NMR (90 MHz, CDCl3) δ 161.2,
149.1, 147.7, 127.7, 126.7, 123.5, 119.0, 117.5, 112.2, 111.5,
108.9, 60.5, 55.9, 55.8, 14.4; IR (neat) 3281 (s), 2989 (w), 1682
(s), 1487 (m), 1405 (m), 1294 (m), 1253 (m), 1230 (s), 1213 (s),
1180 (m), 1136 (m), 1022 (m), 833 (w), 765 (m); HRMS
(electrospray) calcd for C15H17NO4 + Na 298.1055, found
298.1059.
5-Br om o-4-(3,4-d im et h oxyp h en yl)-1H -p yr r ole-2-ca r -
boxylic Acid Eth yl Ester (13). A solution of 170 mg (0.616
mmol) of 12 in 5 mL of DMF was chilled to 0 °C. To this
solution was added portionwise 110 mg (0.616 mmol) of NBS.
The reaction was allowed to warm to room temperature
overnight. The reaction was quenched with 20 mL of water
and extracted with EtOAc (3 × 15 mL). The combined organic
layers were separated, washed sequentially with saturated
aqueous Na2S2O3, water, and brine, and concentrated in vacuo
to afford 218 mg (100%) of 13 as a white solid: mp (Et2O)
1
123.4-125.0 °C; H NMR (360 Hz, CDCl3) δ 9.20 (br s, 1H),
7.11 (m, 2H), 7.02 (s, 1H), 6.90 (d, 1H, J ) 8.6), 4.38 (q, 2H, J
) 8.6), 3.89 (s, 3H), 3.86 (s, 3H), 1.36 (t, 3H, J ) 8.8); 13C NMR
(360 Hz, CDCl3) δ 160.9, 148.7, 148.0, 126.5, 125.2, 123.5,
120.0, 115.3, 111.1, 111.0, 103.2, 60.9, 55.8, 55.7, 14.4; IR (neat)
3248 (s), 2930 (w), 1708 (s), 1524 (m), 1477 (m), 1433 (m), 1381
(m), 1246 (s), 1204 (m), 1140 (m), 1026 (m), 764 (m); HRMS
(electrospray) calcd for C15H16BrNO4 + Na 376.0160, found
376.0179.
Con clu sion
In short, we have completed a modular synthesis of
the lamellarin skeleton that employs three sequential
J . Org. Chem, Vol. 69, No. 7, 2004 2365

Handy et al.
4-(3,4-Dim e t h oxyp h e n yl)-5-[2-(2-h yd r oxye t h yl)-4,5-
d im et h oxyp h en yl]-1H-p yr r ole-2-ca r b oxylic Acid E t h yl
Ester (14). To a solution of 57 mg (0.16 mmol) of 13, 43.6 mg
(0.19 mmol) of 2, and 9.2 mg (0.08 mmol) of tetrakis-
(triphenylphosphine)palladium(0) in 20 mL of DMF was added
0.7 mL of 2 M aqueous Na2CO3. The reaction mixture was
stirred at 110 °C for 15 h. After being cooled to room
temperature, the reaction was quenched with 10 mL of water
and extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with water and brine, dried with magne-
sium sulfate, and concentrated in vacuo. The resulting residue
was chromatographed on silica gel using 40:60 EtOAc-hexane
to give 39.6 mg (54.4%) of 14 as a white solid: mp 171.3-
(m), 1435 (m), 1244 (s), 1212 (m), 1142 (m), 1061 (w), 1026
(w), 860 (w), 762 (w), 668 (w); HRMS (electrospray) calcd for
C25H27NO6 + Na 460.1736, found 460.1746.
2-Br om o-1-(3,4-d im et h oxyp h en yl)-8,9-d im et h oxy-5,6-
dih ydr opyr r olo[2,1-a ]isoqu in olin e-3-car boxylic Acid Eth -
yl Ester (16). A solution of 189 mg (0.43 mmol) of 15 in 5 mL
of DMF was chilled to 0 °C. To this solution was added in
portions 86 mg (0.48 mmol) of NBS. The reaction was allowed
to warm to room temperature overnight. The reaction was
poured into 10 mL of water and extracted with ethyl acetate
(3 × 15 mL). The combined organic layers were washed with
saturated aqueous sodium bicarbonate, water, and brine and
then dried with anhydrous magnesium sulfate. The solvent
was removed in vacuo to afford 221 mg (99.6%) of 16 as a
brown solid: mp (toluene) 166.7-168.3 °C; 1H NMR (360 MHz,
CDCl3) δ 6.93 (m, 2H), 6.88 (s, 1H), 6.69 (s, 1H), 6.56 (s, 1H),
4.60 (t, 2H, J ) 7.1), 4.38 (q, 2H, J ) 7.2), 3.91 (s, 3H), 3.86 (s,
3H), 3.63 (s, 3H), 3.33 (s, 3H), 3.01 (t, 3H, J ) 6.8), 1.41 (t,
3H, J ) 7.2); 13C NMR (90 MHz, CDCl3) δ 160.9, 148.9, 148.4,
148.3, 147.2, 131.7, 127.2, 125.7, 123.4, 122.3, 119.9, 114.0,
111.2, 110.6, 108.5, 107.6, 107.5, 60.4, 55.9, 55.8, 55.8, 55.2,
43.3, 28.7, 14.3; IR (neat) 3400 (w, br), 2930 (w), 1698 (s), 1522
(m), 1466 (s), 1438 (m), 1381 (w), 1243 (s), 1207 (m), 1142 (m),
1027 (m), 860 (w), 767 (w); HRMS (electrospray) calcd for
1
172.4 °C; H NMR (360 MHz, CDCl3) δ 11.1 (br, s, 1H), 7.06
(s, 1H), 6.76-6.70 (m, 4H), 6.61 (s, 1H), 4.25 (q, 2H, J ) 7.2),
3.87 (m, 5H), 3.79 (s, 3H), 3.64 (s, 3H), 3.52 (s, 3H), 2.77 (t,
2H, J ) 7.2), 1.31 (t, 3H, J ) 7.2); 13C NMR (90 MHz, CDCl3)
δ 161.6, 149.0, 148.4, 147.1, 147.0, 132.2, 130.4, 128.2, 124.7,
123.7, 121.5, 120.0, 114.6, 114.1, 112.2, 111.1, 111.0, 63.6, 60.2,
55.8, 55.7, 55.6, 55.5, 35.0, 14.4; IR (neat) 3500 (w, br), 3273
(w), 2930 (w), 1702 (s), 1523 (s), 1467 (s), 1440 (m), 1243 (s),
1210 (s), 1140 (m), 1027 (m), 857 (w), 764 (w); HRMS
(electrospray) calcd for C25H29NO7 + Na 478.1842, found
478.1837.
1-(3,4-Dim et h oxyp h en yl)-8,9-d im et h oxy-5,6-d ih yd r o-
p yr r olo[2,1-a ]isoqu in olin e-3-ca r boxylic Acid Eth yl Ester
(15). A solution of 260 mg (0.57 mmol) of 14 in 2 mL of
chloroform was chilled to 0 °C. To this solution was added 0.14
mL (1.71 mmol) of pyridine. After 10 min, 218 mg (1.14 mmol)
of p-toluenesulfonyl chloride was added in portions over 30
min. The reaction was allowed to warm to room temperature
overnight. To the reaction mixture was added 30 mL of diethyl
ether, and the resulting mixture was washed with 1 N HCl
and water and dried with magnesium sulfate. The solvent was
removed in vacuo, and the residue was chromatographed on
silica gel using 40:60 EtOAc-hexane to give 215.2 mg (62.0%)
of the tosylate as a white solid: 1H NMR (360 MHz, CDCl3) δ
9.19 (br s, 1H), 7.52 (d, 2H, J ) 8.4), 7.22 (m, 3H), 7.08 (d, 1H,
J ) 2.8), 6.76 (s, 1H), 6.66 (m, 3H), 4.29 (q, 2H, J ) 7.2), 3.82
(m, 11H), 3.58 (s, 3H), 2.61 (t, 2H, J ) 7.2), 2.40 (s, 3H), 1.35
(t, 3H, J ) 7.2); 13C NMR (90 MHz, CDCl3) δ 161.1, 149.2,
148.5, 147.8, 147.3, 144.5, 132.7, 131.4, 129.6 (2 carbons),
128.6, 127.6 (2 carbons), 124.4, 123.8, 122.1, 118.9, 114.1,
113.6, 112.8, 111.1, 110.0, 70.0, 60.4, 55.9, 55.8, 55.7, 55.3, 32.3,
21.5, 14.4 (one aromatic 13C signal unresolved for two carbons);
IR (neat) 3290 (m), 2914 (w), 1654 (s), 1522 (s), 1466 (s), 1407
(m), 1315 (m), 1243 (s), 1180 (s), 1016 (m), 952 (m), 764 (w),
713 (w); HRMS (electrospray) calcd for C32H35NO9S + Na
632.1930, found 632.1938. To a solution of 270 mg (0.44 mmol)
of the tosylate in 8 mL of DMSO was added 44 mg (1.10 mmol)
of sodium hydride (60% in mineral oil) in portions. The solution
was stirred for 2 h before 80 mL of ethyl acetate was added,
and then the solution was washed with water and brine and
dried with magnesium sulfate. The solvent was removed in
vacuo and the residue chromatographed on silica gel (40%
ethyl acetate/hexanes) to afford 189.0 mg (98.3%) of 15 as a
C
25H26BrNO6 + Na 538.0841, found 538.0828.
14-(3,4-Dim eth oxyp h en yl)-2,3,11,12-tetr a m eth oxy-8,9-
d ih yd r o-6H-ch r om en o[4′,3′:4,5]p yr r olo[2,1-a ]isoqu in olin -
6-on e (La m ella r in G Tr im eth yl Eth er ). A solution of 51.6
mg (0.1 mmol) of 16 in 2 mL of DMF was degassed with argon.
To this solution was successively added 54.9 mg (0.3 mmol) of
3, 11.6 mg (0.01 mmol) of tetrakis(triphenylphosphine)-
palladium(0), and 95.4 mg (0.9 mmol) of sodium carbonate in
0.5 mL of water. The reaction was heated to 110 °C. To the
reaction was added slowly 99.0 mg (0.5 mmol) of 3 in 1 mL of
DMF via syringe pump over 2.5 h. The reaction was stopped
after 5 h and was poured into 5 mL of water and extracted
with ethyl acetate (3 × 5 mL). The combined organic layers
were dried over anhydrous magnesium sulfate. The solvent
was removed in vacuo. The resulting residue was chromato-
graphed in EtOAc-hexane (50:50) to afford 25.0 mg (46.0%)
of lamellarin G trimethyl ether as a white solid and 22.4 mg
(51.3%) of 15: mp 239.1-240.7 °C (lit.7a mp 235 °C, no range
given); 1H NMR (360 MHz, CDCl3) δ 7.08 (m, 3H), 6.88 (s, 1H),
6.74 (s, 1H), 6.69 (s, 1H), 6.64 (s, 1H), 4.77 (m, 2H), 3.93 (s,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.44 (s, 3H), 3.34
(s, 3H), 3.10 (t, 2H, J ) 6.5); 13C NMR (90 MHz, CDCl3) δ 155.4,
149.7, 148.9, 148.8, 148.6, 147.4, 146.0, 145.4, 135.8, 128.0,
127.9, 126.6, 123.6, 120.0, 114.7, 113.9, 113.6, 111.8, 110.9,
110.2, 108.6, 104.4, 100.3, 56.2, 56.1, 55.9, 55.8, 55.4, 55.1, 42.3,
28.6; IR (neat) 3420 (w, br), 2936 (w), 1703 (s), 1513 (m), 1486
(m), 1463 (m), 1438 (m), 1415 (s), 1270 (s), 1241 (s), 1214 (s),
1166 (s), 1041 (m), 758 (w).
Ack n ow led gm en t. We thank the State University
of New York and the Research Foundation for support
of this project.
1
white solid: mp 147.2-149.0 °C; H NMR (360 MHz, CDCl3)
δ 6.94 (m, 3H), 6.85 (m, 2H), 6.68 (s, 1H), 4.56 (t, 2H, J ) 6.5),
4.25 (q, 2H, J ) 7.2), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H),
3.39 (s, 3H), 2.97 (t, 2H, J ) 6.9), 1.31 (t, 3H, J ) 7.7); 13C
NMR (90 MHz, CDCl3) δ 161.2, 148.7, 148.1, 147.8, 147.1,
131.3, 129.2, 125.8, 121.5, 121.4, 120.9, 120.4, 119.0, 112.5,
111.1, 110.7, 108.5, 59.7, 55.9, 55.8, 55.8, 55.3, 42.4, 29.0, 14.4;
IR (neat) 3400 (w), 2930 (w), 1690 (s), 1549 (w), 1518 (w), 1464
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the preparation of boronic acids 2 and 3. H and
13C spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0352833
2366 J . Org. Chem., Vol. 69, No. 7, 2004