Utility of polymer-supported reagents in the total synthesis of lamellarins

Article abstract of DOI:10.1021/jo050388m

Four solid-supported reagents have been utilized in the multistep synthesis of lamellarins. The use of Amberlyst A-26 Br₃^- and polymer bound pyridine hydrobromide perbromide (PVPHP) for keto α-bromination of the less studied ortho-su

Full text of DOI:10.1021/jo050388m

Utility of Polymer-Supported Reagents in the Total Synthesis of
Lamellarins
Poonsakdi Ploypradith,*,† Rachel Kirk Kagan,‡ and Somsak Ruchirawat*,†,§
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vipavadee-Rangsit
Highway, Bangkok 10210, Thailand, Department of Chemistry, California State University,
Chico, California 95929-0210, and Program on Research and Development of Synthetic Drugs,
Institute of Science and Technology for Research and Development, Mahidol University,
Salaya Campus, Nakhon Pathom, Thailand
poonsakdi@tubtim.cri.or.th; somsak@tubtim.cri.or.th
Received March 2, 2005
Four solid-supported reagents have been utilized in the multistep synthesis of lamellarins. The
-
use of Amberlyst A-26 Br3 and polymer bound pyridine hydrobromide perbromide (PVPHP) for
keto R-bromination of the less studied ortho-substituted acetophenone derivatives selectively
furnished the corresponding monobromination products (phenacyl bromide derivatives), which were
used directly in condensation reactions with benzyldihydroisoquinoline mediated by Amberlyst A-26
NaCO3-. The 2H-pyrrole carbonates subsequently underwent intramolecular Friedel-Crafts
transacylation followed by lactonization to provide the lamellarin skeleton. Alternatively, Amberlyst
A-26 NaCO3- effectively served as base in condensation reaction of benzyldihydroisoquinoline with
R-nitrocinnamate derivatives to provide the corresponding 2-ethoxycarbonyl pyrroles, which
smoothly underwent O-debenzylation reaction followed by lactonization to furnish the lamellarin
skeleton. The novel Amberlyst-15 mediated lactonization reactions effectively combined the
otherwise two separate steps into a single transformation.
Introduction
of marine natural products are nontoxic inhibitors of the
p-glycoprotein possibly responsible for acquired multi-
drug-resistance (MDR) in various cancer cell lines.4 In
addition, lamellarins K and L exhibit immunomodulatory
effects.5 More recently, there have been reports of lamel-
larin R-20 sulfate as a selective inhibitor of HIV-1
integrase both in vitro and in vivo.6 Other modes of action
of lamellarins, as well as the development of lamellarin
As part of our research program on the synthesis of
bioactive natural alkaloids, we have been involved with
the synthesis of lamellarins (1), a group of marine natural
products, which have been found to exhibit a wide array
of interesting biological activities. Since the first isolation
in 1985 by Faulkner,1 more than 35 structurally related
lamellarins have been reported.2 A number of lamellarins
have been found to be cytotoxic to a wide range of cancer
cell lines.3 More importantly, some members of this class
(3) Urban, S.; Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G. Curr.
Org. Chem. 2000, 4, 765-807.
(4) Quesada, A. R.; Gravalos, M. D. G.; Puentes, J. L. F. Br. J.
Cancer 1996, 74, 677-682. (b) Vanhuyse, M.; Kluza, J.; Tardy, C.;
Otero, G.; Cuevas, C.; Bailly, C.; Lansiaux, A. Clin. Cancer Res. 2003,
9, 6109S.
(5) Cironi, P.; Albericio, F.; AÄ lvarez, M. In Lamellarins: Isolation,
activity and synthesis in Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Elsevier: New York, 2004; Vol. 16,
Chapter 1.
(6) (a) 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. (b) Ridley, C. P.; Reddy, M. V. R.; Rocha,
G.; Bushman, F. D.; Faulkner, D. J. Bioorg. Med. Chem. 2002, 10,
3285-3290.
† Chulabhorn Research Institute.
‡ California State University.
§ Mahidol University.
(1) Andersen, R. J.; Faulkner, D. J.; He, C.-H.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492-5495.
(2) (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771-1791. (b) Bowden,
B. F. Stud. Nat. Prod. Chem. Part D 2000, 23, 233-283. (c) Ham, J.;
Kang, H. Bull. Korean Chem. Soc. 2002, 23, 163-166. (d) Krishnaiah,
P.; Reddy, V. L. N.; Venkataramana, G.; Ravinder, K.; Srinivasulu,
M.; Raju, T. V.; Ravikumar, K.; Chandrasekar, D.; Ramakrishna, S.;
Venkateswarlu, Y. J. Nat. Prod. 2004, 67, 1168-1171.
10.1021/jo050388m CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/27/2005
J. Org. Chem. 2005, 70, 5119-5125
5119

Ploypradith et al.
SCHEME 1. Retrosynthetic Analysis of
Lamellarin Skeleton 1
D as a novel potent inhibitor of topoisomerase I are under
extensive investigation.7
To establish a more comprehensive structure-activity
relationship (SAR) and to investigate further the mech-
anism(s) of action, relatively large quantities of lamel-
larins are required. However, because the natural sources
of lamellarins, some species of ascidians, sponges, and
molluscs, provide these compounds in only minute quan-
tities, total synthesis is a vital alternative in providing
these compounds for detailed biological evaluations. A
number of research groups worldwide have reported
elegant strategies for total syntheses of lamellarins over
the past 8 years.5,8 Recently, our research group has
reported some developments of their synthesis either via
(1) lithium-bromine exchange/intramolecular lactoniza-
tion of the 2-bromopyrrole carbonate intermediate de-
rived from the condensation of benzyldihydroisoquinoline
2 with phenacyl bromide carbonate 3 (pathway A in
Scheme 1) or (2) Michael addition/ring closure (Mi-RC)
reaction between 2 and the R-nitrocinnamate derivative
4 (pathway B) as the key step.9 The basic units for both
approaches are the simple and easily prepared benzade-
hyde derivatives (5-7) and acetophenone 8.
Solid-phase chemistry has played a major role in
revolutionizing different areas of chemistry, especially
combinatorial synthesis. While solid-phase synthesis has
proved efficient for building up compound libraries,
monitoring the reaction progress and determining the
compound loading on the polymer still requires some
specialized analytical equipment and techniques, such as
single-bead IR, solid-state NMR, or cleavage of the
compound from the polymer. Thus, the use of polymer-
supported materials as reagents, instead of as anchors
for substrates, is an attractive alternative and has been
developed to circumvent those limitations encountered
in “traditional” solid-phase synthesis. This line of chem-
istry has resulted in the development of a number of
useful polymer-supported reagents which are finding
increasing utility in organic synthesis.10 Recently, the
solid-phase synthesis of lamellarins has been reported.11
We have now applied four polymer-supported reagents
(bromine on polymer support (Amberlyst A-26 Br3--form
and PVPHP), carbonate on polymer support (Amberlyst
A-26 NaCO3--form), and Amberlyst 15) for both synthetic
pathways A and B shown in Scheme 1.
Results and Discussion
As shown in Scheme 1, both approaches share a
common intermediate in benzyldihydroisoquinoline (2)
whose synthesis is well documented.12 We first investi-
gated the polymer-supported bromination of ortho-
substituted acetophenones 9a and 9b to the correspond-
ing phenacyl bromides 10a and 10b (Scheme 2). Some
examples of R-bromination of acetophenone derivatives
using polymer support have been reported.13 However,
in those cases, the substrates usually contained substit-
uents on the aromatic at positions other than at the
ortho-position. Compounds 9a and 9b which carry a
carbonate group at the ortho position of acetophenone
ring system appeared more prone to the undesired R,R-
(7) (a) Fu¨rstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58,
6373-6380. (b) Bailly, C.; Facompre, M.; Tardy, C.; Mahieu, C.; Perez,
C.; Manzanares, I.; Cuevas, C. Clin. Cancer Res. 2003, 9, 6112S-
6113S. (c) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez,
C.; Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392-
7399. (d) Tardy, C.; Facompre, M. L.; Laine, W.; Baldeyrou, B.; Garcia-
Gravalos, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jimenez, J. A.;
Manzanares, I.; Cuevas, C.; Bailly, C. Bioorg. Med. Chem. 2004, 12,
1697-1712.
(8) (a) Diaz, M.; Guitian, E.; Castedo, L. Synlett 2001, 7, 1164-1165.
(b) Barun, O.; Chakrabarti, S.; Ila, H.; Junjappa, H. J. Org. Chem.
2001, 66, 4457-4461. (c) Kim, S.; Son, S.; Kang, H. Bull. Korean Chem.
Soc. 2001, 22, 1403-1406. (d) Peshko, C.; Winklhofer, C.; Steglich,
W. Chem.-Eur. J. 2000, 6, 1147-1152. (e) Heim, A.; Terpin, A.;
Steglich, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 155-156. (f)
Banwell, M. G.; Flynn, B.; Hockless, D. C. R. Chem. Commun. 1997,
2259-2260. (g) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D.
C. R. Chem. Commun. 1997, 207-208. (h) Banwell, M. G.; Flynn, B.
L.; Hockless, D. C. R.; Longmore, R. W.; Rae, A. D. Aust. J. Chem.
1999, 52, 755-765. (i) Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron
1997, 53, 5951-5962. (j) Ishibashi, F.; Tanabe, S.; Oda, T.; Iwao, M.
J. Nat. Prod. 2001, 65, 500-504. (k) Boger, D. L.; Boyce, C. W.; Labroli,
M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54-62. (l)
Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69, 2362-
2366.
(10) For a review of polymer-supported reagents, see: Ley, S. V.;
Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbot-
tom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem.
Soc., Perkin Trans. 1 (special review issue) 2000, 3815-4195.
(11) For solid-phase synthesis of lamellarins, see: (a) Cironi, P.;
Manzanares, I.; Albericio, F.; AÄ lvarez, M. Org. Lett. 2003, 5, 2959-
2962. (b) Marfil, M.; Albericio, F.; AÄ lvarez, M. Tetrahedron 2004, 60,
8659-8668.
(12) Tietze, L. F.; Eicher, T. Reactions and Synthesis in the Organic
Chemistry Laboratory; University Science Books: Mill Valley, CA,
1989; pp 177-178.
(13) (a) Cacchi, S.; Caglioti, L. Synthesis 1979, 64-66. (b) Bongini,
A.; Cainelli, G.; Contento, M.; Manescalchi, F. Synthesis 1980, 143-
146. (c) Hassanein, M.; Akelah, A.; Selim, A.; Hamshary, H. E. Eur.
Polym. J. 1989, 25, 1083-1085. (d) Sˇket, B.; Zupan, M. Synth.
Commun. 1989, 19, 2481-2487. (e) Babadjamian, A.; Kessat, A. Synth.
Commun. 1995, 25, 2203-2209. (f) Habermann, J.; Ley, S. V.; Scott,
J. S. J. Chem. Soc., Perkin Trans. 1 1998, 3127-3130. (g) Habermann,
J.; Ley, S. V.; Smits, R. J. Chem. Soc., Perkin Trans. 1 1999, 2421-
2423. (h) Habermann, J.; Ley, S. V.; Scicinski, J. J.; Scott, J. S.; Smits,
R.; Thomas, A. W. J. Chem. Soc., Perkin Trans. 1 1999, 2425-2427.
(9) (a) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001, 42,
1205-1208. (b) Ploypradith, P.; Jinagleung, W.; Pavaro, C.; Ruchira-
wat, S. Tetrahedron Lett. 2003, 44, 1363-1366. (c) Ploypradith, P.;
Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S. Angew.
Chem., Int. Ed. 2004, 43, 866-868.
5120 J. Org. Chem., Vol. 70, No. 13, 2005

Total Synthesis of Lamellarins
TABLE 2. Base-Mediated Condensationa of 11 with 10a
and 10b
SCHEME 2. Polymer-Supported Synthesis of
Lamellarins 13a and 13ba
time
(h)
yieldc
(%)
entry
R
baseb
equivalent
1
2
3
4
5
6
7
H
A
1.2
1.2
2.4
6.0
1.1
1.2
1.1
18
48
48
18
24
18
20
72
Trace
0
H
B
H
B
H
C
0
H
Cd
A
49
60
60
OMe
OMe
Cd
a Unless otherwise noted, the reactions were performed in
refluxing CH3CN. b A ) NaHCO3; B ) Ambersep 900 OH; C )
-
Amberlyst A-26 NaCO3
.
c Isolated yields of the desired pyrrole
carbonate 12a and 12b over two steps after subjecting the crude
material to the carbonation reaction using Et3N, EtOCOCl, and
DMAP in DCM. d The material was dried under vacuum for 6 h
prior to use.
supported brominating agents gave the best selectivity
for monobromination product when toluene was used as
the solvent and the reaction was performed at low
temperature with slow warming to room temperature.
The best ratio for monobromination product 10a was 33:1
with the use of PVPHP when performed in toluene for 3
days (entry 9). For the more activated acetophenone
derivative 9b, which is expected to be more prone to
dibromination, the best ratio of 7:1 was obtained when
PVPHP was employed in toluene under similar reaction
conditions (entry 14). We reasoned that toluene, a
relatively nonpolar solvent, would provide better selectiv-
ity for monobromination due to less effective enolization
of the monobromination product.13f-h
With the phenacyl bromide derivatives in hand, we
then focused on the subsequent base-mediated formation
of the pyrroles by coupling of 11 with phenacyl bromides
10a and 10b. Our previously reported conditions for this
coupling reaction employed sodium bicarbonate as base
and provided the desired pyrrole carbonate 12a in 72%
yield and 12b in 60% yield (entries 1 and 6, Table 2).9b
Two polymer-supported bases were explored for this
coupling reaction, and the results are summarized in
Table 2.
When 1.2 equiv of Ambersep 900 OH was employed,
only a trace amount of the desired product, along with
some phenacyl bromide carbonate 10a, could be isolated.
A larger excess of Ambersep 900 OH resulted in complete
consumption of starting phenacyl bromide carbonate but
gave none of the desired product. We then turned to
Amberlyst A-26 NaCO3--form.15 After some experimenta-
tion, we found that drying the reagent under vacuum was
critical. With dried reagent, the desired products 12a and
12b were isolated, after column chromatography, in 49%
and 60% yields, respectively (entries 5 and 7). When
compared with NaHCO3 (method A), the use of Amberlyst
a Reagents and conditions: (a) Amberlyst A-26 Br3--form and
PVPHP, Table 1 (see also Supporting Information); (b) Amberlyst
A-26 NaCO3--form, Table 2; (c) Amberlyst 15, Table 3.
TABLE 1. Keto r-Brominationa of Acetophenone
Carbonate Derivatives (9a and 9b)
brominating
agentb
time
(h)
ratio
yield
entry
R
solventc
(mono:di) (%)d
1
H
A
B
B
B
B
B
C
C
C
C
A
B
C
C
DCM
18
18
18
18
18
18
18
18
72
120
18
18
18
72
14:1
5:1
3.5:1
2:1
8:1
100:0
6.5:1
96
83
85
66
92
2
H
DCM
3
H
CH3CN
hexane
toluene
THF
4
H
5
H
6e
7f
8g
9
H
H
DCM
87
0
H
toluene
toluene
toluene
DCM
H
33:1
25:1
10:1
5:1
4.6:1
7:1
98
97
90
85
86
88
10
11
12
13
14
H
OMe
OMe
OMe
OMe
toluene
DCM
toluene
a Unless otherwise noted, the reactions were performed at 0 °C
-
to room temperature. b A ) BnNMe3Br3; B ) Amberlyst A-26 Br3
-
form; C ) PVPHP. c DCM ) dichloromethane; THF ) tetrahy-
drofuran. d Yield of monobromination was determined by 1H NMR
of the crude material. Isolated and estimated yields (1H NMR)
were comparable. The crude mixture contained only monobromi-
nation and dibromination products and could be used in the
subsequent step without further purification. e There were some
unidentifiable inseparable contaminants with the monobromina-
tion product. f The reaction was performed at room temperature.
g The reaction was not complete; virtually only starting material
was observed by 1H NMR.
dibromination when performed in solution phase.9b Thus,
use of appropriate brominating agents and reaction
conditions for selective R-monobromination of ortho-
substituted acetophenones 9a and 9b was required.
When BnNMe3Br3 was employed as the brominating
agent in dichloromethane (DCM), slow addition and a low
effective concentration of bromine at low-temperature
played an important role in minimizing the amount of
dibromination. As shown in Table 1, the best ratio14
achieved for 10a was 14:1 (entry 1) and for 10b was 10:1
(entry 11) with complete conversion.
We then explored the use of polymer-bound brominat-
ing agent, Amberlyst A-26 Br3--form and PVPHP. After
some experimentation, we found that both polymer-
(14) Only reactions in DCM were attempted because BnNMe3Br3
is not completely soluble in other solvents. Partial optimization was
performed for methods of addition (which affect the effective concentra-
tion of bromine) and temperatures. Addition of BnNMe3Br3 either (1)
as a solid in batches at 0 °C with slow warming up of the resulting
reaction mixture to room temperature following the addition or (2) as
a solution in DCM dropwise at room temperature resulted in less
selectivity for monobromination product. Between these two sets of
reaction conditions, the latter gave slightly better selectivity, providing
10a and 10b in about 7:1 and 4:1 ratios, respectively.
(15) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. Synthesis 1981,
793-794.
J. Org. Chem, Vol. 70, No. 13, 2005 5121

Ploypradith et al.
FIGURE 2. Structure of 2-ethoxycarbonyl pyrrole intermedi-
ate 15.
FIGURE 1. Structure of 2-formylpyrrole 14a and 2-bromopy-
rrole 14b.
SCHEME 3. Polymer-Supported Synthesis of
Lamellarins 18a and 13b via Mi-RCa
TABLE 3. Acid-Mediated Friedel-Crafts Reactiona of
12a and 12b
entry
1
R
acidb equivalent solvent T (°C) yieldc (%)
H
AlCl3
A
1.2
DCM
d
110
110
110
105
105
105
110
105
catalytic
PhMee
PhMee
THF
86f
90
0g
2
3
4
5
6
7
8
H
A
0.5
1.1
1.5
3
H
B
h
H
B
PhMe
PhMe
PhMe
PhMef
PhMe
-
H
B
98
95
91
94
H
B
5
0.5
3
OMe
OMe
A
B
a Unless otherwise noted, the reactions were performed for 18
h. b A ) p-TsOH; B ) Amberlyst-15. c Isolated yields after recrys-
tallization from MeOH/hexane. d 0 °C to room temperature. e The
reactions were performed in refluxing toluene for 1.5 h. f Overall
yield. g All starting material was recovered. h A 1:1 mixture of
starting material 12a and the desired product (13a) was obtained.
A-26 NaCO3--form (method C) as base in the pyrrole
formation step could provide the desired pyrrole carbon-
ate products, albeit in slightly lower yields.
a Reagents and conditions: (a) 11, NaHCO3 (1.2 equiv), CH3CN,
reflux, 50% (17a), 60% (17b); (b) 11, Amberlyst A-26 NaCO3- (1.1
equiv; dried), CH3CN, reflux, 44% (17a); (c) Amberlyst-15, toluene,
105 °C, 63% (18a), 90% (13b).
The remaining step for the synthesis of lamellarin
involves transacylation from the carbonate to the 2-posi-
tion of 2H-pyrrole followed by lactonization. Previously,
we reported an anionic approach involving the generation
of a carbanion at the 2-position of the pyrrole via either
directed remote metalation (DreM) of 12a and 12b or
lithium-bromine exchange of the corresponding 2-bro-
mopyrrrole carbonate.9b In both approaches, the carbon-
ate serves a dual role as the phenoxy protecting group
and a masked carbonyl equivalent. With DreM, we
encountered some problems of reproducibility, while the
bromide route requires an additional step. After careful
examination, we noted that the 2-position of the 2H-
pyrrole appears susceptible to electrophilic attack by
Vilsmeier species generating 2-formylpyrrole 14a9a and
by N-bromosuccinimide yielding 2-bromopyrrole 14b9b as
shown in Figure 1.
Thus, the 2-position is sufficiently nucleophilic for an
intramolecular electrophilic attack from the acyl group
of the carbonate moiety with appropriate acid activation.
In other words, the direct acid-mediated intramolecular
Friedel-Crafts transacylation from the carbonate car-
bonyl group to the 2-position of pyrrole and subsequent
lactonization of the resulting intermediate could lead to
the desired lamellarin skeleton (13a and 13b) in one step.
Results of this Friedel-Crafts transacylation/lactoniza-
tion are summarized in Table 3.
2H-pyrrole starting material could directly undergo the
Friedel-Crafts transacylation/lactonization to the de-
sired lamellarin when treated with p-TsOH. When the
reaction was performed using 0.5 equiv of p-TsOH in
refluxing toluene for 1.5 h, 13a was obtained in 90% yield
(entry 2).
Amberlyst-15 was chosen as a polymer-supported acid
to mediate the novel Friedel-Crafts transacylation/
lactonization reaction on the basis of its sulfonic acid
functionality, analogous to that in p-TsOH. When 1.1
equiv of this reagent was employed in refluxing THF,
only starting material was recovered. When the reaction
was performed in toluene at 105 °C16 using 1.5 equiv of
the polymer-supported acid, a ca. 1:1 mixture of starting
material and the desired lamellarin was obtained (entry
4). The reaction went to completion when 3-5 equiv of
the acid were employed under similar reaction conditions
(entries 5 and 6), providing the desired lamellarin 13a
or 13b in excellent yields (94-98%).
An alternative route to the lamellarin skeleton involves
the base-mediated Michael addition/ring closure (Mi-RC)
between 11 and R-nitrocinnamate 16a or 16b (Scheme
3).9c Similar to the base-mediated pyrrole formation of
11 and 10a or 10b, we found that Amberlyst A-26
NaCO3--form could serve as the base to mediate Mi-RC
when 1.1 equiv of the dried reagent was employed in
refluxing acetonitrile. The reaction provided the desired
2-ethoxycarbonyl pyrrole intermediate 17a in 44% yield,
Our initial attempt employed AlCl3 as a Lewis acid in
DCM to yield a 1:1 mixture of the starting material and
the corresponding 2-ethoxycarbonyl pyrrole intermediate
15 (Figure 2). Treatment of such mixture with p-TsOH
in toluene gave cleanly the desired lamellarin skeleton
13a in 86% yield (entry 1). The result suggested that the
(16) The temperature was arbitrarily chosen not to exceed 120 °C
at which, according to the supplier (Fluka), Amberlyst-15 decomposes.
5122 J. Org. Chem., Vol. 70, No. 13, 2005

Total Synthesis of Lamellarins
mination product and purified (see Table 1 for yields). It should
be noted that 10a was recrystallized from MeOH/hexanes to
give a 12:1 mixture of mono- and dibromination product while
column chromatography on silica gave 10a as a mixture with
hydrolyzed product. 10b was purified by column chromatog-
raphy on silica.
which is comparable to the 50% yield obtained when the
reaction was performed in the presence of NaHCO3.
With the observation that Amberlyst-15 could mediate
O-debenzylation,17 we now envisioned that the lamellarin
skeleton could be obtained directly in one step via a novel
O-debenzylation/lactonization reaction from a substrate
containing an ethoxycarbonyl functionality at the pyrrole
C-2 and an ortho-benzyloxyaryl substituent at the pyrrole
C-3 (17a or 17b). In fact, when compounds 17a and 17b
were heated with 3 equiv of Amberlyst-15 in toluene at
105 °C, the corresponding lamellarins 18a and 13b were
obtained in 63%18 and 90% yields, respectively.
2-(2-Bromoacetyl)phenyl Ethyl Carbonate (10a) (as a
12:1 inseparable mixture of monobromination and di-
1
bromination product). H NMR (200 MHz, CDCl3): δ 1.41
(t, 3H, J ) 7.0 Hz), 4.35 (q, 2H, J ) 7.0 Hz), 4.46 (s, 2H), 6.80
(s, 1H, dibromination product, COCHBr2), 7.31 (d, 1H, J )
8.0 Hz), 7.39 (t, 1H, J ) 8.0 Hz), 7.61 (t, 1H, J ) 8.0 Hz), 7.86
(d, 1H, J ) 8.0 Hz), 7.95 (d, 1H, J ) 7.2 Hz, dibromination
product). 13C NMR (50 MHz, CDCl3): δ 14.1, 34.1, 42.0
(dibromination product), 65.4, 65.6 (dibromination product),
123.3, 123.4 (dibromination product), 126.3, 126.4 (dibromi-
nation product), 127.7, 130.6, 131.1 (dibromination product),
134.1, 134.3 (dibromination product), 134.5 (dibromination
product), 149.6, 152.7, 190.7.
Conclusion
We have significantly improved the total synthesis of
the lamellarin skeleton with the use of polymer-sup-
ported reagents in the selective monobromination of
ortho-substituted acetophenones by the use of Amberlyst
A-26 Br3--form and PVPHP, the base-mediated pyrrole
formation from the condensation of benzyldihydroiso-
quinoline with either phenacyl bromide or R-nitrocin-
namate by Amberlyst A-26 NaCO3--form, and the novel
acid-mediated lactone formation either via Friedel-
Crafts transacylation/lactonization or via O-debenzyla-
tion/lactonization by Amberlyst-15. The use of polymer-
supported reagents facilitates the synthesis by minimizing
both the workup procedure and column chromatography,
rendering synthetic approaches more practical. In addi-
tion, the use of polymer-supported reagents requires only
conventional means for monitoring reaction progress
(thin-layer chromatography) and assessing product yields.
Lamellarin skeletons such as 13a could be obtained from
acetophenone carbonate derivative 9a using three polymer-
supported reagents in 47% overall yield over three steps
as compared to 33% yield over five steps previously
reported.9b A more structurally complex unnatural lamel-
larin such as 18a could be obtained in a similar fashion
from R-nitrocinnamate 16a in 28% yield over two steps.
2-(2-Bromoacetyl)-4,5-dimethoxyphenyl Ethyl Carbon-
ate (10b). IR (KBr): νmax 3014, 2959, 1759, 1685, 1605, 1521,
1466, 1426, 1404, 1364, 1249, 1131, 1056, 1029 cm-1. 1H NMR
(200 MHz, CDCl3): δ 1.39 (t, 3H, J ) 7.0 Hz), 3.90 (s, 3H),
3.91 (s, 3H), 4.34 (q, 2H, J ) 7.0 Hz), 4.41 (s, 2H), 6.74 (s,
1H), 7.37 (s, 1H). 13C NMR (50 MHz, CDCl3): δ 14.2, 34.7,
56.2, 56.4, 65.4, 106.1, 111.8, 118.9, 145.2, 146.8, 152.8, 153.8,
188.8. LRMS (EI) m/z (rel intensity) 348 (M+ + 2, 9), 346 (M+,
9), 304 (4), 302 (4), 277 (4), 276 (33), 275 (4), 274 (34), 209
(17), 195 (7), 194 (8), 182 (14), 181 (100), 125 (10). FAB-HRMS
calcd for C13H16BrO6 (M + H+) 347.0130, found 347.0126.
B. General Procedure for Pyrrole Formation from 11
with Phenacyl Bromide Carbonates. To a stirred solution
of 11 (1.2 equiv) in acetonitrile (10 mL/mmol of 11) at room
temperature was added the base (equivalent as indicated in
Table 2) and phenacyl bromide carbonate (10a or 10b; 1 equiv).
The resulting mixture was heated at reflux for the amount of
time indicated in Table 2. At that time, if polymer-supported
reagent was employed, the reaction was filtered, the polymer
washed with DCM and EtOAc, and the resulting mixture
concentrated under reduced pressure. If NaHCO3 was used,
water was added and the two phases were separated. The
organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue
(from either polymer-supported reaction or NaHCO3 reaction)
was dissolved in DCM, and to the mixture were added Et3N,
ethyl chloroformate (1.2 equiv each based on the amount of
10a or 10b), and DMAP (ca. 0.1 equiv) at room temperature
for 18 h. The residue was purified by column chromatography
to furnish the desired product 12a or 12b (see Table 2 for
yields).
2-[1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihy-
dropyrrolo[2,1-a]isoquinolin-2-yl]phenyl Ethyl Carbon-
ate (12a). mp (MeOH) 174-175 °C. IR (Nujol): νmax 2924,
2855, 1761, 1464, 1329, 1251, 1224 cm-1. 1H NMR (300 MHz,
CDCl3): δ 1.25 (t, 3H, J ) 7.0 Hz), 3.03 (apparent t, 2H, J )
6.4 Hz), 3.41 (s, 3H), 3.64 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H),
4.07 (apparent t, 2H, J ) 6.4 Hz), 4.18 (q, 2H, J ) 7.0 Hz),
6.70 (s, 1H), 6.80 (s, 1H), 6.80 (d, 1H, J ) 8.0 Hz), 6.84 (s,
2H), 6.90 (dd, 1H, J ) 8.1, 1.8 Hz), 6.96 (dd, 1H, J ) 8.1, 1.8
Hz), 7.00 (ddd, 1H, J ) 8.1, 8.1, 1.8 Hz), 7.13 (dd, 1H, J ) 8.1,
1.8 Hz), 7.15 (ddd, 1H, J ) 8.1, 8.1, 1.8 Hz). 13C NMR (75 MHz,
CDCl3): δ 14.1, 29.4, 44.7, 55.2, 55.6, 55.75, 55.79, 64.3, 107.5,
110.9, 111.1, 114.3, 118.1, 119.5, 119.7, 121.6, 122.2, 122.9,
123.9, 125.4, 125.6, 126.7, 128.6, 128.7, 132.1, 146.8, 147.27,
147.34, 148.5, 148.7, 153.2. LRMS (EI) m/z (rel intensity) 530
(M + H+, 25), 529 (M+, 100), 514 (14), 483 (11), 456 (6), 350
(3), 213 (4), 133 (5). FAB-HRMS calcd for C31H32NO7 (M + H+)
530.2179, found 530.2178. Anal. Calcd for C31H31NO7: C,
70.30; H, 5.90; N, 2.64. Found: C, 70.21; H, 5.88; N, 2.94.
Experimental Section
A. General Procedure for Keto r-Bromination of
Acetophenone Carbonates. To a stirred solution of ac-
etophenone carbonate derivatives (9a or 9b; 1 equiv) in solvent
(10 mL/mmol) and at the temperature indicated in Table 1
was added the brominating agent (1.05 equiv of A, B, or C as
indicated in Table 1). In case of BnNMe3Br3 (brominating
agent A), its solution in DCM was added very slowly via a
dropping funnel to the reaction mixture at 0 °C. The mixture
was allowed to stir at the given temperature for, typically, 18
h (or otherwise as noted in Table 1). At that time, if polymer-
supported reagent was employed, the reaction was filtered,
the polymer washed with DCM and EtOAc, and the resulting
mixture concentrated under reduced pressure. The mixture
was then analyzed for the ratio of monobromination product
to dibromination product and used in the next step without
further purification. If BnNMe3Br3 was used, after 18 h, water
was added and the two phases were separated. The organic
layers were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
analyzed for the ratio of monobromination product to dibro-
(17) Amberlyst-15 mediated debenzylation is currently under in-
vestigation in our laboratory, and the results will be reported in due
course.
(18) Some product of benzylation of the aromatic ring ortho to the
hydroxy group was formed in 10% yield.
2-[1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihy-
dropyrrolo[2,1-a]isoquinolin-2-yl]-4,5-dimethoxyphe-
nyl Ethyl Carbonate (12b). IR (CHCl3): νmax 3014, 2830,
J. Org. Chem, Vol. 70, No. 13, 2005 5123

Ploypradith et al.
1748, 1696, 1615, 1522, 1035 cm-1
.
1H NMR (200 MHz,
recrystallized from MeOH to furnish the desired product 16a
(67%) or 16b (55%) as yellow-orange solids.
CDCl3): δ 1.27 (t, 3H, J ) 7.0 Hz), 3.05 (apparent t, 2H, J )
6.4 Hz), 3.40 (s, 3H), 3.42 (s, 3H), 3.69 (s, 3H), 3.84 (s, 3H),
3.86 (s, 3H), 3.87 (s, 3H), 4.08 (apparent t, 2H, J ) 6.4 Hz),
4.21 (q, 2H, J ) 7.0 Hz), 6.43 (s, 1H), 6.67 (s, 1H), 6.70 (s,
1H), 6.77 (s, 1H), 6.85 (d, 1H, J ) 1.2 Hz), 6.86 (s, 1H), 6.87-
6.91 (m, 2H). 13C NMR (50 MHz, CDCl3): δ 14.2, 29.4, 44.7,
55.2, 55.5, 55.8 (2 carbons), 55.85, 55.91, 64.4, 105.4, 107.4,
111.0, 111.2, 111.8, 113.9, 114.2, 118.0, 119.4, 120.1, 122.1,
123.2, 123.9, 125.5, 129.0, 141.7, 146.1, 146.7, 147.0, 147.3,
147.4, 148.7, 153.6. LRMS (EI) m/z (rel intensity) 590 (M +
H+, 34), 589 (M+, 100), 543 (61), 529 (14), 516 (19), 500 (13),
485 (12), 338 (10), 181 (19), 165 (15). FAB-HRMS calcd for
C33H36NO9 (M + H+) 590.2390, found 590.2387.
Ethyl 3-(2,4-Bisbenzyloxy-5-methoxyphenyl)-2-nitro-
acrylate (16a). mp (MeOH) 103-104 °C (lit.9c mp 104-105
°C). IR (KBr): νmax 2938, 1754, 1714, 1608, 1573, 1522, 1268,
1225 cm-1. 1H NMR (200 MHz, CDCl3): δ 1.34 (t, 3H, J ) 7.2
Hz), 3.79 (s, 3H), 4.34 (q, 2H, J ) 7.2 Hz), 5.00 (s, 2H), 5.12 (s,
2H), 6.50 (s, 1H), 6.83 (s, 1H), 7.27-7.36 (m, 10 H), 7.99 (s,
1H). 13C NMR (50 MHz, CDCl3): δ 14.0, 56.2, 62.5, 70.9, 71.6,
100.4, 110.3, 110.5, 127.1 (2 carbons), 127.4, 128.2, 128.66,
128.70 (2 carbons), 135.8, 136.0, 137.9, 144.2, 152.9, 153.8,
159.9. LRMS (EI) m/z (rel intensity) 464 (M + H+, 7), 463 (M+,
40), 326 (28), 236 (29), 181 (36), 91 (100). HR-MS (FAB) calcd
for C26H26NO7 (M + H+) 464.1709, found 464.1699. Anal. Calcd
for C26H25NO7: C, 67.38; H, 5.44; N, 3.02. Found: C, 67.51;
H, 5.62; N, 2.98. These spectroscopic data are identical to those
reported previously.9c
Ethyl 3-(2-Benzyloxy-4,5-dimethoxyphenyl)-2-nitroacry-
late (16b). mp (MeOH) 132-133 °C. IR (KBr): νmax 2924,
1733, 1707, 1609, 1576, 1524, 1466, 1440, 1275, 1226, 1044
cm-1. 1H NMR (200 MHz, CDCl3): δ 1.35 (t, 3H, J ) 7.0 Hz),
3.78 (s, 3H), 3.86 (s, 3H), 4.35 (q, 2H, J ) 7.0 Hz), 5.15 (s,
2H), 6.52 (s, 1H), 6.82 (s, 1H), 7.41 (m, 5H), 8.03 (s, 1H). 13C
NMR (50 MHz, CDCl3): δ 14.0, 56.0, 56.1, 62.5, 71.7, 98.2,
109.8, 109.9, 127.2, 127.4, 128.2, 128.7, 136.0, 137.8, 143.7,
153.9, 154.1, 159.9. LRMS (EI) m/z (rel intensity) 388 (M +
H+, 2), 387 (M+, 9), 251 (12), 250 (74), 222 (16), 91 (100), 65
(11). FAB-HRMS calcd for C20H22NO7 (M + H+) 388.1397,
found 388.1396. Anal. Calcd for C20H21NO7: C, 62.01; H, 5.46;
N, 3.62. Found: C, 61.98; H, 5.41; N, 3.72.
E. General Procedure for Pyrrole Formation from 11
with r-Nitrocinnamates (Mi-RC). To a stirred solution of
11 (1.2 equiv) in acetonitrile (10 mL/mmol of 11) at room
temperature was added the base (1.1 equiv) and R-nitrocin-
namate (16a or 16b; 1 equiv). The resulting mixture was
heated to reflux for 18 h. At that time, if polymer-supported
reagent was employed, the reaction was filtered, the polymer
washed with DCM and EtOAc, and the resulting mixture
concentrated under reduced pressure. If NaHCO3 was used,
water was added and the two phases were separated. The
organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography to furnish the desired
product 17a (50%, using NaHCO3; 44%, using Amberlyst A-26
NaCO3-) or 17b (60%).
C. General Procedure for the Acid-Mediated Friedel-
Crafts Transacylation/Lactonization. 2H-Pyrrole carbon-
ate (12a or 12b; 1 equiv) was dissolved in solvent (40
mL/mmol) as indicated in Table 3, at room temperature. An
acid (equiv as indicated in Table 3) was then added, and the
resulting mixture was stirred at temperature and for the
amount of time indicated in Table 3. If polymer-supported
reagent was employed, the reaction was filtered, the polymer
washed with DCM and EtOAc, and the crude concentrated
under reduced pressure. If p-TsOH was used, the reaction was
neutralized by Et3N. The resulting mixture was concentrated
under reduced pressure. The crude material was purified by
recrystallization from MeOH/hexanes to furnish the desired
lamellarins 13a or 13b (see Table 3 for yields).
14-(3,4-Dimethoxyphenyl)-11,12-dimethoxy-8,9-dihydro-
6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one
(13a). mp (MeOH) 244-245 °C. IR (Nujol): νmax 3028, 1696,
1
1515, 1485, 1432, 1339 cm-1. H NMR (200 MHz, CDCl3): δ
3.12 (apparent t, 2H, J ) 7.0 Hz), 3.37 (s, 3H), 3.86 (s, 3H),
3.89 (s, 3H), 3.99 (s, 3H), 4.82 (apparent t, 2H, J ) 7.0 Hz),
6.65 (s, 1H), 6.76 (s, 1H), 6.97-7.07 (m, 4H), 7.22-7.39 (m,
3H). 13C NMR (50 MHz, CDCl3): δ 28.7, 42.5, 55.2, 55.9, 56.1
(two carbons), 108.8, 110.0, 112.1, 113.9, 114.5, 115.8, 117.1,
118.3, 120.0, 123.4, 123.7, 126.6, 127.3, 127.5, 127.9, 136.1,
147.5, 149.0, 149.9, 151.3, 155.2. LRMS (EI) m/z (rel intensity)
484 (M + H+, 30), 483 (M+, 100), 469 (4), 468 (13), 226 (19),
189 (10), 141 (3), 139 (12). FAB-HRMS calcd for C27H26NO5
(M + H+) 484.1760, found 484.1760. Anal. Calcd for C27H25-
NO5: C, 72.02; H, 5.21; N, 2.90. Found: C, 71.60; H, 5.23; N,
2.71.
14-(3,4-Dimethoxyphenyl)-2,3,11,12-tetramethoxy-8,9-
dihydro-6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-
6-one (13b; Lamellarin G Trimethyl Ether). mp (MeOH)
245-246 °C (lit.8e mp 235 °C (no range given), lit.8l mp 239.1-
240.7 °C). IR (Nujol): νmax 3025, 1699, 1522, 1485, 1444, 1425,
1342, 1250 cm-1. 1H NMR (200 MHz, CDCl3): δ 3.09 (apparent
t, 2H, J ) 6.6 Hz), 3.35 (s, 3H), 3.45 (s, 3H), 3.82 (s, 3H), 3.86
(s, 6H), 3.94 (s, 3H), 4.75 (apparent t, 2H, J ) 6.6 Hz), 6.64 (s,
1H), 6.69 (s, 1H), 6.74 (s, 1H), 6.84 (s, 1H), 7.05-7.15 (m, 3H).
13C NMR (50 MHz, CDCl3): δ 28.6, 42.3, 55.1, 55.4, 55.85,
55.88, 56.09, 56.13, 100.3, 104.3, 108.5, 110.1, 110.8, 111.7,
113.6, 113.8, 114.7, 119.9, 123.5, 126.6, 127.9, 128.0, 135.8,
145.3, 145.9, 147.3, 148.6, 148.7, 148.8, 149.6, 155.4. LRMS
(EI) m/ z (rel intensity) 543 (M+, 100), 528 (6), 496 (7), 470 (3),
454 (4), 440 (3), 271 (20), 248 (6), 227 (11). These spectroscopic
data are identical to those reported previously.8e,f
D. General Procedure for the Knoevenagel Reaction.
A round-bottomed flask equipped with a Dean-Stark ap-
paratus was charged with the appropriately substituted al-
dehyde (1 equiv), Et2NH‚HCl (1.5 equiv), ethyl nitroacetate
(1.25 equiv), and toluene (12 mL/mmol of aldehyde) at room
temperature. The mixture was refluxed under argon for 48 h.
Toluene was removed, and water and CH2Cl2 were added. Two
phases were separated, and the aqueous phase was extracted
with CH2Cl2 (3×). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure to give the crude product, which was
Ethyl 1-(3,4-Dimethoxyphenyl)-2-(2,4-dibenzyloxy-5-
methoxy)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinoline-3-carboxylate (17a). mp (EtOAc/hexanes) 165-
166 °C. IR (CHCl3): νmax 3018, 2935, 1686, 1610, 1482, 1422,
1398, 1335, 1255, 1214, 1176, 1130, 1064, 1027 cm-1. 1H NMR
(200 MHz, CDCl3): δ 0.84 (t, 3H, J ) 7.0 Hz), 3.07 (apparent
t, 2H, J ) 6.6 Hz), 3.36 (s, 3H), 3.53 (s, 3H), 3.65 (s, 3H), 3.83
(s, 3H), 3.88 (s, 3H), 4.00 (q, 2H, J ) 7.0 Hz), 4.64 (br m, 2H),
4.75 (s, 2H), 5.03 (s, 2H), 6.43 (s, 1H), 6.60 (s, 1H), 6.68 (s,
1H), 6.73 (m, 4H), 7.05-7.15 (m, 2H), 7.20-7.38 (m, 8H). 13C
NMR (50 MHz, CDCl3): δ 13.7, 29.1, 42.7, 55.2, 55.6, 55.8 (2
carbons), 56.4, 59.5, 71.1, 71.6, 102.9, 108.6, 110.5, 110.7,
113.9, 116.0, 118.7, 119.1, 121.0, 121.6, 123.0, 125.8, 126.7,
127.2, 127.3, 127.7, 128.1, 128.2, 128.4, 130.8, 137.0, 137.8,
143.4, 146.9, 147.1, 147.4, 147.8, 148.3, 150.5, 162.0. LRMS
(EI) m/z (rel intensity) 756 (M + H+, 4), 755 (M+, 12), 679 (6),
664 (8), 588 (10), 500 (8), 91 (100), 65 (25). FAB-HRMS calcd
for C46H46NO9 (M + H+) 756.3172, found 756.3177. Anal. Calcd
for C46H45NO9: C, 73.10; H, 6.00; N, 1.85. Found: C, 73.31;
H, 6.02; N, 1.94.
Ethyl 1-(3,4-Dimethoxyphenyl)-2-(2-benzyloxy-4,5-di
methoxy)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinoline-3-carboxylate (17b). IR (CHCl3): νmax 3019, 2937,
2837, 1684, 1610, 1583, 1500, 1335, 1215, 1130, 1064, 1026
cm-1. 1H NMR (200 MHz, CDCl3): δ 0.93 (t, 3H, J ) 7.0 Hz),
3.08 (apparent t, 2H, J ) 6.6 Hz), 3.35 (s, 3H), 3.56 (s, 3H),
3.66 (s, 3H), 3.76 (s, 3H), 3.83 (s, 3H), 3.90 (s, 3H), 4.06 (q,
5124 J. Org. Chem., Vol. 70, No. 13, 2005

Total Synthesis of Lamellarins
2H, J ) 7.0 Hz), 4.65 (apparent t, 2H, J ) 6.6 Hz), 4.84 (s,
2H), 6.45 (s, 1H), 6.61 (s, 1H), 6.72 (apparent s, 2H), 6.74
(apparent s, 3H), 7.13-7.25 (m, 5H). 13C NMR (50 MHz,
CDCl3): δ 13.8, 29.1, 42.8, 55.2, 55.7, 55.85 (2 carbons), 55.94,
56.3, 59.5, 72.1, 100.8, 108.8, 110.8, 111.0, 114.2, 115.8, 118.3,
119.2, 121.1, 121.8, 123.2, 125.8, 126.8, 127.4, 128.2, 128.3,
128.6, 130.8, 137.9, 143.0, 147.3, 147.6, 148.0, 148.3, 148.5,
150.8, 161.9. LRMS (EI) m/z (rel intensity) 680 (M + H+, 40),
679 (M+, 95), 590 (10), 589 (45), 588 (87), 544 (20), 543 (69),
542 (77), 527 (20), 511 (45), 500 (31), 484 (20), 468 (12), 452
(12), 440 (12), 424 (9), 178 (8), 165 (13), 91 (100), 65 (15). FAB-
HRMS calcd for C40H42NO9 (M + H+) 680.2860, found 680.2862.
F. General Procedure for O-Debenzylation/Lacton-
ization. 2-Carboethoxy pyrrole (17a or 17b; 1 equiv) was
dissolved in toluene (40 mL/mmol) at room temperature.
Amberlyst-15 (3 equiv) was then added, and the resulting
mixture was stirred at 105 °C for 18 h. The reaction was
filtered, the polymer washed with DCM and EtOAc, and the
crude concentrated under reduced pressure. The crude mate-
rial was purified by recrystallization from MeOH/hexanes to
furnish the desired lamellarins 18a (63%) or 13b (90%).
14-(3,4-Dimethoxyphenyl)-3-hydroxy-2,11,12-tri-
methoxy-8,9-dihydro-6H-chromeno[4′,3′:4,5]pyrrolo[2,1-
a]isoquinolin-6-one (18a). mp (MeOH/hexanes) 240-241 °C.
IR (KBr): νmax 3396 (br), 3000, 2936, 2834, 1676, 1610, 1519,
1485, 1438, 1415, 1339, 1320, 1252, 1246, 1216, 1165, 1045,
862 cm-1. 1H NMR (200 MHz, CDCl3): δ 3.12 (apparent t, 2H,
J ) 7.0 Hz), 3.37 (s, 3H), 3.49 (s, 3H), 3.88 (s, 3H), 3.90 (s,
3H), 3.97 (s, 3H), 4.74-4.84 (m, 2H), 5.90 (br s, 1H), 6.63 (s,
1H), 6.70 (s, 1H), 6.76 (s, 1H), 6.95 (s, 1H), 7.06-7.10 (m, 3H).
13C NMR (50 MHz, CDCl3): δ 28.6, 42.3, 55.1, 55.5, 55.9, 56.1,
56.2, 103.3, 103.9, 108.5, 110.1, 110.9, 111.7, 113.6, 113.9,
114.5, 119.9, 123.6, 126.6, 128.0, 128.2, 135.8, 143.3, 145.4,
146.3, 147.3, 148.7, 148.9, 149.6, 155.6. LRMS (EI) m/z (rel
intensity) 530 (M + H+, 34), 529 (M+, 100), 515 (11), 514 (14),
454 (14), 233 (7), 218 (8), 189 (6), 183 (6), 56 (12). FAB-HRMS
calcd for C30H28NO8 (M + H+) 530.1815, found 530.1819. Anal.
Calcd for C30H27NO8: C, 68.04; H, 5.14; N, 2.65. Found: C,
67.82; H, 5.29; N, 2.69.
Acknowledgment. This work is dedicated to Pro-
fessor Steven V. Ley on his 60th birthday. Financial
support from the Thailand Research Fund (RTA/07/2544
and Senior Research Scholar for S.R. and DBG4780006
for P.P.), from the Thailand Toray Science Foundation
(TTSF) for P.P., and from the NSF-REU (INT-0123857)
for R.K.K. is gratefully acknowledged.
Supporting Information Available: 1H and 13C NMR of
10a, 10b, 12a, 12b, 13a, 16b, 17a, 17b, and 18a and an
extensive table of the R-keto bromination reaction. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050388M
J. Org. Chem, Vol. 70, No. 13, 2005 5125