A convergent total synthesis of the marine sponge alkaloid ageladine A via a strategic 6π-2-azatriene electrocyclization

Article abstract of DOI:10.1016/j.tet.2007.06.089

A second generation total synthesis of the marine sponge metabolite ageladine A utilizing a biogenetically inspired 6π-2-azaelectrocyclization of triene 34 as the key step is performed to construct the imidazopyridine core of the metabolite.

Full text of DOI:10.1016/j.tet.2007.06.089

Tetrahedron 63 (2007) 9112–9119
A convergent total synthesis of the marine sponge alkaloid
ageladine A via a strategic 6p-2-azatriene electrocyclization
*
Matthew L. Meketa and Steven M. Weinreb
Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA
Received 19 April 2007; revised 22 June 2007; accepted 25 June 2007
Available online 4 July 2007
Abstract—A second generation total synthesis of the marine sponge metabolite ageladine A utilizing a biogenetically inspired 6p-2-aza-
electrocyclization of triene 34 as the key step is performed to construct the imidazopyridine core of the metabolite.
Ó 2007 Elsevier Ltd. All rights reserved.
N
1. Introduction
N
NH2
NH2
N
N
H
HN
N
H
N
H
In 2003, Fusetani and co-workers reported the isolation of
ageladine A (1) from the hydrophilic extract of the marine
sponge Agelas nakamurai Hoshino, which was collected
off the coast of Kuchinoerabu-jima Island in Southern Japan
(Fig. 1).1 The structure of this fluorescent marine alkaloid
was elucidated using a series of NMR studies, including
HMBC data for various N-methylated derivatives. Interest-
ingly, ageladine A (1) is the first and, to date, only isolated
metabolite of this family to possess a 2-aminoimidazopyr-
idine core.
H
HN
Br
Br
Br
Br
2
ageladine A (1)
H
N
H
N
Br
Br
O
CO2H
N
NH2
4
6
N
N
H
HN
Ageladine A (1) displays inhibitory activity against matrix
metalloproteinases (MMPs), particularly MMP-2 at micro-
molar levels. MMPs are a family of over two dozen zinc-
dependent enzymes that regulate multiple steps of tumor
angiogenesis.2 One role of MMPs is to mediate the break-
down of connective tissue, allowing tumor growth. In addi-
tion to being involved in angiogenesis, MMP-2 is known to
complex with other MMPs at the tumor migration front.1,3
Thus, MMP-2 inhibitors are presumed to be both antiangio-
genic and antimetastatic, making them potential cancer
chemotherapeutic agents.
N
N
NH
NH
Br
Br
3
CO2H
H2N
H2N
5
7
Figure 1. Postulated biosynthesis of ageladine A.
to have an atypical and as yet unknown mode of MMP
inhibition.
We reported the first total synthesis of ageladine A in 2006,
which featured a 6p-1-azatriene electrocyclization and a
Suzuki–Miyaura coupling of a 2-chloropyridine derivative
as key steps.3 Shengule and Karuso later described a second
synthesis of the marine metabolite in which an efficient
Pictet–Spengler reaction, followed by an oxidation, fur-
nished the natural product.4 Earlier this year we described
a biogenetically inspired total synthesis highlighted by
a 6p-2-azatriene electrocyclization to construct the imidazo-
pyridine skeleton of ageladine A.5,6 Herein, we provide a
detailed account of our second generation total synthesis
of ageladine A (1).
MMP inhibitors usually act by chelation of the catalytic
zinc(II) ion within the active site of the enzymes. Interestingly,
studies have shown that ageladine A (1) is not capable of
zinc(II) binding and that the inhibition of MMP-2 is not com-
petitive by kinetic analysis.1 Thus, ageladine A is believed
Keywords: Ageladine A; Electrocyclization; Natural product; Imidazole;
Pyrrole.
* Corresponding author. Tel.: +1 (814) 863 0189; fax: +1 (814) 863 8403;
e-mail: smw@chem.psu.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.089

M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
9113
2. Synthetic plan
introduced a thiomethyl moiety. Without workup, addition
of another equivalent n-butyllithium to the reaction mixture
metallated C(5) and subsequent protonation of the lithiated
species using isopropanol gave 4-bromoimidazole 14
(Scheme 1). Metallation of crude 4-bromoimidazole 14,
followed by addition of DMF gave the desired imidazole
aldehyde 15 in 31% overall yield, along with 4-bromo-5-
carboxaldehyde imidazole 16 and 4,5-unsubstituted imid-
azole 17 as significant by-products. Due to the formation
of these unwanted compounds in the formylation of 14, an
alternative more efficient route to aldehyde 15 was devised.
Marine sponges of the genus Agelas have been reported to
contain numerous bioactive pyrrole–imidazole alkaloids,
with most being derivatives of the oroidin class of natural
products.7 Kerr and co-workers have demonstrated through
feeding studies of radio-labeled amino acids that the bio-
genetic precursors of one such metabolite, stevensine, are
proline and histidine.8,9 Based on these experimental results,
Fusetani and co-workers proposed a biosynthesis for agela-
dine A (1) involving either an intramolecular 6p-2-azatriene
electrocyclization of N-vinyl imine 3 or a Mannich-like ring
closure of this same intermediate, followed by dehydrogena-
tion of the resulting dihydropyridine 2 (Fig. 1). Formation of
imine 3 could be envisioned from the precursors dibromo-
pyrrole aldehyde 4 and histamine (5), which could be de-
rived from proline (6) and histidine (7), respectively.1
Br
H
4
Br
Br
4
5
i) n-BuLi, Me2S2
THF, - 78 °C
ii) n-BuLi, i-PrOH
-78 °C
3
N
N
N
N
BOM
13
2
n-BuLi, DMF
THF, -78 °C
SMe
Br
BOM
14
Br
H
H
N
N
N
N
O
We decided to explore a 6p-1-azatriene cyclization to pro-
duce the pyridine core and thus required a key 2-azatriene
like 9 (Fig. 2). This intermediate is similar to that proposed
by Fusetani, except that 9 is in a higher oxidation state than
imine 3 (cf. Fig. 1). As a result, the cyclized product 8 could
provide the fully aromatic imidazopyridine core of agela-
dine A simply via loss of H–X. Imidate derivative 9 should
be available from the corresponding enamide 10, which
would be obtained from the coupling of (Z)-vinyl iodide
11 and dibromopyrrole amide 12. We also planned to incor-
porate the pyrrole bromine atoms into intermediate 10,
which would avoid the inefficient late stage pyrrole haloge-
nation step that was used in our first generation total synthe-
sis of ageladine A.3
SMe
SMe
SMe
O
N
N
BOM
17
H
BOM
15
(31% from 8)
BOM
16
(29%)
(22%)
Scheme 1.
The formation of significant amounts of the undesired re-
gioisomeric aldehyde 16 can be rationalized by invoking
the well documented adjacent lone pair effect (ALP ef-
fect),11 where the carbanion resulting from halogen–metal
exchange of imidazole 14 at C(4) is destabilized by the
lone pair on the N(3) nitrogen. However, we believed that
placing a C(5) protecting group on the imidazole should
obviate this problem. Thus, tribromoimidazole 13 was selec-
tively metallated, followed by addition of dimethyl disulfide
to afford sulfide 18 (Scheme 2). In a one-pot process based
upon the methodology of Begtrup and co-workers,12 dibro-
moimidazole 18 was then lithiated at C(5) and subsequent
addition of trimethylsilyl chloride resulted in the 4-bromo-
5-silylimidazole 19. Without isolation, this compound
was immediately metallated and formylated with DMF
to yield the functionalized aldehyde 20. Without purifica-
tion, TMS-imidazole 20 was desilylated using potassium
N
N
NH2
NH2
N
X
N
N
X
N
P
N
P
H
1
P
P
N
Br
Br
Br
Br
9
8
N
N
NH2
I
NH2
N
P
HN
O
11
N
P
P
N
Br
Br
n-BuLi
n-BuLi
TMS-Cl
N
P
N
O
Me2S2
SMe
13
Br
Br
Br
Br
Figure 2. Retrosynthesis of ageladine A.
N
BOM
18
THF
- 78 °C
THF
- 78 °C
10
NH2
12
Br
TMS
N
N
N
n-BuLi
O
SMe
SMe
DMF
N
BOM
TMS
- 78 °C
BOM
19
3. Results and discussion
20
Our initial synthetic efforts focused on a model study of the
pivotal 6p-2-azatriene electrocyclization where the dibro-
mopyrrole fragment of the natural product was replaced by
a phenyl group. The synthesis began with BOM-protected
tribromoimidazole (13), which can be sequentially and pre-
dictably metallated.10 Thus, in a one-pot procedure, tribro-
moimidazole 13 was first metallated with n-butyllithium
at C(2), and subsequent addition of dimethyl disulfide
K2CO3
CH2Cl2
MeOH
I
N
N
N
BOM
21
I
O
SMe
SMe
Ph3P
I
N
BOM
H
KOt-Bu
THF, - 78 °C
93%
rt
15
85% from 13
Scheme 2.

9114
M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
carbonate in methanol to afford the desired imidazole alde-
hyde 15 in 85% overall yield from tribromoimidazole 13.
Utilizing the procedure of Stork and Zhao,13 aldehyde 15
was then smoothly converted to the requisite (Z)-vinyl iodide
21 using (iodomethyl)triphenylphosphonium iodide14 and
potassium tert-butoxide.
utilized to convert the nitrile functionality of pyrrole 29 to
the corresponding amide 30.20 Fortunately, bromination of
pyrrole amide 30 with NBS gave the required 4,5-dibromo-
pyrrole amide 31 in high yield. X-ray crystallography was
used to confirm that the pyrrole had the desired bromine
regiochemistry required for the natural product.
Continuing with the model study, an imidate substrate for the
6p-2-azatriene electrocyclization was fashioned.15 Thus,
the procedure of Buchwald and co-workers was used to cou-
ple (Z)-vinyl iodide 21 with benzamide to afford enamide 22
in high yield and with complete retention of the olefin geo-
metry (Scheme 3).16 Unfortunately, enamide 22 could not be
directly converted to an imidate under a variety of condi-
tions, including Meerwein’s salt, triflic anhydride, trifluoro-
acetic anhydride, and several different silylating/base
combinations. In all cases only starting imidate 22 was re-
covered. However, it was finally found that treatment of 22
with Lawesson’s reagent gave the corresponding thioen-
amide 23 in 95% yield. Conversion of thioenamide 23 to
the desired thioimidate 24 proceeded smoothly using methyl
triflate.17 We were pleased to find that subjecting a dilute so-
lution of thioimidate 24 in p-xylene to microwave irradiation
at 160 ꢀC gave the desired imidazopyridine 26 as a separable
mixture of BOM-regioisomers in 73% combined yield.18
Heating enamide 24 as a dilute solution in refluxing xylene
produced cyclization products 26 in significantly lower
yield. Refluxing a solution of BOM-protected imidazopyr-
idine regioisomers 26 in 6 N HCl in ethanol produced N–H
imidazopyridine 27. It might be noted that facile BOM
migration has been noted in other imidazole systems.19
Bu NHSO4
4
50% H2O2
20% NaOH
BOMCl
NaH
BOM
N
H
N
CN
O
CN
THF, rt
99%
CH2Cl2, rt
91%
28
29
BOM
N
BOM
NBS
O
N
THF
Br
Br
NH2
NH2
(X-ray)
rt, 94%
30
31
Scheme 4.
With both necessary substrates in hand, (Z)-vinyl iodide 21
and dibromopyrrole amide 31 were coupled using the Buch-
wald conditions to give (Z)-enamide 32 stereoselectively in
92% yield (Scheme 5). In addition, the copper-catalyzed
coupling reaction was completely chemoselective, with the
pyrrole bromine atoms being unaffected.21 Following the
protocol developed in the above model study, enamide 32
was first converted to the corresponding thioenamide 33
using Lawesson’s reagent and treatment with methyl triflate
then produced thioimidate 34 in good overall yield. How-
ever, attempts at the 6p-2-azatriene electrocyclization of
thiomethyl imidate 34 in p-xylene using microwave irradia-
tion at 160 ꢀC gave complex mixtures of starting (Z)-vinyl
thioimidate 34, isomerized (E)-vinyl imidate 36, and both
BOM-regioisomers of imidazopyridine 35. On the other
hand, when the cyclization was performed by heating a dilute
solution of 34 in mesitylene at 145 ꢀC, BOM-regioisomer 29
was produced in 44% isolated yield (51% based on recov-
ered starting material). The major byproduct in this 6p-2-
azaelectrocyclization was the isomerized (E)-vinyl imidate
36 (27%). A range of reaction temperatures and solvent
With the model system successfully tested, we addressed the
synthesis of ageladine A by preparing the requisite dibromo-
pyrrole amide substrate. Thus, commercially available 2-
cyanopyrrole (28) was first BOM-protected to afford 29 in
high yield (Scheme 4). Initial bromination attempts with
unprotected nitrile 28 or BOM-protected nitrile 29 using
a variety of brominating reagents led to complex mixtures
of starting pyrrole, as well as mono-, di-, and tribrominated
products in poor yields. Thus, basic hydrogen peroxide was
benzamide
10 mol % CuI
Cs2CO3, THF
70 °C, 99%
N
N
Lawesson's
SMe
S
SMe
O
NH
NH
reagent
N
BOM
N
BOM
21
PhMe, 100 °C
95%
Ph
Ph
MeHN
NHMe
22
23
MeOTf
CH2Cl2
N
N
p-xylene
SMe
BOM
SMe
N
N
N
rt, 97%
N
MW
160 °C
MeS
N
H
MeS
Ph BOM
24
Ph
25
N
N
6N HCl
EtOH
SMe
BOM
SMe
N
-MeSH
N
N
H
100 °C
50%
Ph
Ph
26
27
73% combined yield
of BOM-regioisomers
Scheme 3.

M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
9115
1) n-BuLi, Me2S2
THF, - 78 °C
94%
systems were examined for the electrocyclization, as well as
the addition of various Lewis acids and buffers. However, the
partial (E)/(Z) isomerization of the vinyl thioimidate could
not be suppressed. Interestingly, this thermal (E)/(Z) isomer-
ization was not observed in the model system 24. Unfortu-
nately, (E)-isomer 36 did not undergo cyclization either
thermally or via microwave irradiation to give the desired
imidazopyridine 35. It should also be noted that attempts
to photochemically effect the cyclization of thioenamide
33 or thioimidate 34 failed to give any pyridine products,
with only starting material or isomerized (E)-vinyl imidate
36 being recovered.22
BOM
N
BOM
N
I
I
O
Ph3P
SMe
2) LDA, DMF
THF, - 78 °C
93%
KOt-Bu
THF
-78 °C
N
37
N
38
H
BOM
N
31, Cs2CO3
10 mol % CuI
THF, 70 °C
BOM
N
SMe
O
NH
SMe
I
N
N
MeHN
NHMe
BOM
N
(a) (b)
39
(a) (b)
40
Z
: E
Z
: E
Br
Br
66% 27%
16% 68%
10 mol % CuI
Cs2CO3, THF
70 °C, 92%
N
Scheme 6.
Lawesson's
reagent
SMe
O
N
NH
Br
N
BOM
21
31
BOM
PhMe, 100 °C
82%
MeHN
NHMe
ageladine A (1). Initial attempts to oxidize sulfide 35 using
Oxone in a methanol/H2O solvent system gave an insepara-
ble 1:2 mixture of sulfoxide 41 and the corresponding 2-
imidazolone derivative, respectively (Scheme 7). The use
of hydrogen peroxide with a variety of molybdenum and va-
nadium catalysts to oxidize sulfide 35 produced a complex
mixture of products. However, we were pleased to find that
treatment of sulfide 35 with m-CPBA produced mainly
sulfoxide 41 (76%) along with a small amount of the corre-
sponding sulfone 42 (10%). The reaction temperature in this
step had to be carefully controlled to optimize the sulfoxide/
sulfone yield. This sulfoxide/sulfone mixture was subse-
quently treated with sodium azide in DMSO at rt to provide
2-azidoimidazopyridine 43 in 87% yield. When DMF was
used as the solvent in this displacement as was done in our
previous synthesis,3 the reaction time was significantly lon-
ger and a substantial decrease in product yield was observed.
The azide functionality was then reduced to amine 44 in high
yield using Lindlar catalyst. It should be noted that attempts
at direct displacement of sulfone 42 with methanolic ammo-
nia did not afford the desired amine 44, but rather gave
a complex mixture of products.25
32
Br
3
N
N
2
MeOTf
CH2Cl2
SMe
SMe
S
N
NH
Br
N
N
BOM
N
1
BOM
MeS
BOM
BOM
rt, 93%
N
33
34
Br
Br
Br
N
N
SMe
MeS
BOM
N
mesitylene
145 °C
N
N
N
SMe
BOM
N
BOM
N
BOM
Br
Br
36 (27%)
Br
Br
35 (44%, 51% brsm)
Scheme 5.
At this point, we decided to examine an alternative system
to possibly improve the yield of the 6p-2-azaelectrocycli-
zation product 35. We chose to examine the imidazole
N(3) BOM-regioisomer of 34 where the protecting group
is adjacent to the vinyl substituent, perhaps relieving steric
strain during the 6p-2-azaelectrocyclization. Thus, BOM-
protected imidazole (37)23 was selectively metallated at
C(2) using n-butyllithium and converted to the correspond-
ing sulfide with dimethyl disulfide. The 2-methylthioimid-
azole was then selectively metallated at C(5) with lithium
diisopropylamide and the resulting carbanion was formyl-
ated to afford aldehyde imidazole 38 in high yield
(Scheme 6). Stork–Zhao Wittig reaction of aldehyde 38
was found to be non-stereoselective giving a separable
mixture of (Z)- and (E)-vinyl iodides 39a and 39b in
66% and 27% yields, respectively.24 Interestingly, the un-
desired (E)-vinyl iodide 39b had not been observed in
the other BOM-regioisomeric series (cf. Scheme 2).
When (Z)-vinyl iodide 39a and pyrrole amide 31 were sub-
jected to the Buchwald copper-catalyzed coupling condi-
tions, the reaction produced (E)-enamide 40b as the
major product (68%) and the requisite (Z)-enamide 40a
in only 16% yield. Due to the poor overall yield of the
(Z)-enamide 40a, this route was abandoned.
N
N
m-CPBA
CH2Cl2
NaN3
DMSO
S(O)nMe
N3
N
N
N
N
N
BOM
N
BOM
35
-78 °C - rt
86%
rt, 87%
BOM
BOM
41 n = 1
42 n = 2
43
Br
Br
Br
Br
N
N
NH
AlCl3
CH2Cl2
NH2
2
Lindlar cat.
N
N
N
N
BOM
N
H
MeOH, THF
rt, 63%
rt, 94%
BOM
HN
Br
Br
Br
Br
44
ageladine A (1)
Scheme 7.
To complete the synthesis, both BOM protecting groups
needed to be removed from tricycle 44. Initial experimenta-
tion using refluxing 8 N HCl in ethanol led to complex mix-
tures that could not be separated. Attempts at using boron
tribromide to partially cleave the BOM groups to the
Continuing the synthesis from sulfide imidazopyridine 35, it
was necessary at this point to install the 2-amino moiety of

9116
M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
corresponding hydroxymethyl compounds, followed by
treatment with aqueous potassium carbonate, failed to give
the desired deprotected compound. However, it was finally
found that subjecting 44 to anhydrous aluminum chloride26
in methylene chloride at rt provided ageladine A (1) in 63%
yield. This material was identical to the alkaloid that we pre-
viously synthesized via our first-generation route.3
The crude mixture was dissolved in THF (100 mL) and
n-BuLi in hexanes (2.5 M, 6.73 mL, 16.83 mmol) was added
at ꢂ78 ꢀC. After the mixture was stirred for 10 min at
ꢂ78 ꢀC, TMSCl (1.83 g, 16.83 mmol) was added slowly.
Afterwards, the reaction mixture was stirred at ꢂ78 ꢀC for
an additional 20 min, before n-BuLi in hexanes (2.5 M,
6.73 mL, 16.83 mmol) was added slowly. After the mixture
was stirred for 10 min at ꢂ78 ꢀC, DMF (3.69 g, 3.92 mL,
50.49 mmol) was added slowly. The reaction mixture was
stirred at ꢂ78 ꢀC for 1 h and then warmed to rt. The mixture
was diluted with H2O (50 mL) and was extracted with
CH2Cl2 (3ꢁ10 mL).
4. Conclusion
In conclusion, we have completed a convergent total synthe-
sis of ageladine A (1) from commercially available tribro-
moimidazole and 2-cyanopyrrole in 12.5% overall yield
for the longest linear sequence (11 operations). This second
generation synthesis incorporates a novel 6p-2-azatriene
electrocyclization to furnish the imidazopyridine core of
the marine metabolite. Furthermore, synthetic structural
analogues of ageladine A for biological testing should be
available via this approach.
MeOH (20 mL) and K2CO3 (4.65 g, 33.66 mmol) were
added to the combined organic extracts, and the reaction
mixture was stirred at rt for 3 h. The mixture was diluted
with H2O (100 mL) and was extracted with CH2Cl2 (3ꢁ
30 mL). The combined organic extracts were dried (MgSO4)
and concentrated. Purification of the residue by column
chromatography (hexanes/EtOAc 3:1) afforded aldehyde
1
15 (3.79 g, 85%) as a yellow solid. H NMR (400 MHz,
CDCl3) d 9.49 (s, 1H), 7.45 (s, 1H), 7.00–7.45 (m, 5H),
5.04 (s, 2H), 4.23 (s, 2H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 185.1, 148.6, 142.7, 136.7, 129.4, 129.2, 129.1,
128.7, 75.9, 71.6, 16.2; ESI (+): [M+H]+ calcd for
C13H15N2O2S, 263.0854; found 263.0863.
5. Experimental
5.1. General methods
All non-aqueous reactions were carried out under a positive
atmosphere of nitrogen in flame-dried glassware unless
otherwise noted. Air and moisture sensitive liquid reagents
were added via a dry syringe. Anhydrous THF, CH2Cl2, and
toluene were obtained from a solvent dispensing system.
All other solvents and reagents were used as obtained from
commercial sources without further purification unless
noted. Microwave irradiation reactions were performed on
a CEM Discover microwave reactor. 1H and 13C NMR
spectra were recorded on Bruker DPX-300, CDPX-300, or
5.1.2. 1-Benzyloxymethyl-4-(2-iodovinyl)-2-methylsul-
fanylimidazole (21). To a solution of Ph3PCH2I2 (8.08 g,
15.25 mmol) in THF (50 mL) was added t-BuOK (1.71 g,
15.25 mmol). The reaction mixture was stirred at rt for
5 min and cooled to ꢂ78 ꢀC before a solution of aldehyde
15 (2.00 g, 7.62 mmol) in THF (10 mL) was added slowly.
The reaction mixture was stirred at ꢂ78 ꢀC for 30 min and
then warmed to rt. The mixture was diluted with H2O
(30 mL) and was extracted with CH2Cl2 (3ꢁ20 mL). The
combined organic extracts were dried (MgSO4) and concen-
trated. Purification of the residue by column chromatography
(hexanes/EtOAc 3:1) afforded vinylimidazole 21 (2.74 g,
1
DRX-400 MHz spectrometers. Chemical shifts of H and
13C NMR spectra were referenced to the solvent peaks: dH
3.30 and dC 49.0 for CD3OD. Flash chromatography was
performed using Sorbent Technologies silica gel 60 (230–
400 mesh). Purification by preparative reverse phase
HPLC employed an Agilent 1100 preparative pump/gradient
extension instrument equipped with a Hamilton PRP-1
(polystyrene–divinylbenzene) reverse phase column (7 mm
particle size, 21.5 mmꢁ25 cm). The following two solvent
systems were used: solvent system A (99.9% double
deionized H2O and 0.1% TFA) and solvent system B
(99.9% acetonitrile and 0.1% TFA). The HPLC gradient
for the purification of ageladine A (20 mL/min flow rate)
was as follows: 99–70% A from 0 to 5 min and 70–60% A
from 5 to 25 min; retention time of 1 was 10.2 min.
1
93%) as a yellow oil. H NMR (300 MHz, CDCl3) d 7.88
(s, 1H), 7.31 (d, J¼8.7 Hz, 1H), 7.18–7.22 (m, 5H), 6.26
(d, J¼8.7 Hz, 1H), 5.18 (s, 2H), 4.37 (s, 2H), 2.48 (s, 3H);
13C NMR (75 MHz, CDCl3) d 144.1, 140.0, 136.7, 133.3,
129.0, 128.7, 128.5, 120.5, 76.7, 75.1, 70.8, 16.7; ESI (+):
[M+H]+ calcd for C14H16N2OSI, 387.0028; found 387.0023.
5.1.3. N-[2-(1-Benzyloxymethyl-2-methylsulfanylimid-
azol-4-yl)vinyl]benzamide (22). In an oven-dried Schlenk
tube was placed (Z)-vinyliodide 21 (250 mg, 0.65 mmol),
benzamide (94 mg, 0.78 mmol), CuI (12 mg, 0.07 mmol),
Cs2CO3 (422 mg, 1.29 mmol), N,N0-dimethylethylenedi-
amine (11 mg, 0.13 mmol), and THF (4 mL). The tube was
flushed with nitrogen, sealed, and heated at 70 ꢀC for 15 h.
The reaction mixture was then cooled to rt and filtered
through a Celite pad, which was washed with EtOAc. The
filtrate was concentrated and the residue was purified by col-
umn chromatography (hexanes/EtOAc 2:1) affording the
coupled (Z)-enamide 22 (243 mg, 99%) as a white solid.
1H NMR (300 MHz, CDCl3) d 11.88 (d, J¼10.1 Hz, 1H),
7.91–7.94 (m, 2H), 7.34–7.44 (m, 3H), 7.19–7.28 (m, 5H),
7.07–7.16 (m, 1H), 6.86 (s, 1H), 5.49 (d, J¼8.9 Hz, 1H),
5.18 (s, 2H), 4.39 (s, 2H), 2.59 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 163.2, 142.9, 139.5, 135.2, 133.2,
5.1.1. 1-Benzyloxymethyl-2-methylsulfanylimidazole-4-
carbaldehyde (15). To a solution of BOM-protected 2,4,5-
tribromoimidazole 13 (7.15 g, 16.83 mmol) in THF
(100 mL) was added n-BuLi in hexanes (2.5 M, 6.73 mL,
16.83 mmol) at ꢂ78 ꢀC and the reaction mixture was stirred
for 10 min. Dimethyl disulfide (1.59 g, 16.83 mmol) was
then added dropwise at ꢂ78 ꢀC. The reaction mixture was
stirred at ꢂ78 ꢀC for 15 min and then warmed to rt. The
mixture was diluted with H2O (100 mL) and was extracted
with CH2Cl2 (3ꢁ30 mL). The combined organic extracts
were dried (MgSO4) and concentrated.

M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
9117
1
130.7, 127.6, 127.5, 127.2, 126.9, 126.4, 121.4, 117.2, 99.2,
73.5, 69.4, 14.8; ESI (+): [M+H]+ calcd for C21H22N3O2S,
380.1433; found 380.1425.
imidazopyridine 27 (1.5 mg, 50%) as a clear oil. H NMR
(300 MHz, MeOD) d 8.23 (d, J¼5.7 Hz, 1H), 8.18–8.21
(m, 2H), 7.46–7.55 (m, 3H), 7.42 (d, J¼5.7 Hz, 1H), 2.78
(s, 3H); ESI (+): [M+H]+ calcd for C13H12N3S, 242.0752;
found 242.0738.
5.1.4. N-[2-(1-Benzyloxymethyl-2-methylsulfanylimid-
azol-4-yl)-vinyl]thiobenzamide (23). To a solution of en-
amide 22 (0.20 g, 0.53 mmol) in PhMe (20 mL) was added
Lawesson’s reagent (0.13 g, 0.32 mmol). The reaction mix-
ture was heated at 100 ꢀC for 3.5 h and then concentrated.
Purification of the residue by column chromatography (hex-
anes/EtOAc 1:1) afforded thioenamide 23 (0.20 g, 95%) as
5.1.8. 1-Benzyloxymethylpyrrole-2-carboxylic acid
amide (30). To a solution of nitrile 29 (1.00 g, 4.71 mmol)
and Bu4NHSO4 (1.60 g, 4.71 mmol) in CH2Cl2 (15 mL)
was added 50% H2O2 (3 mL), followed by 20% aq NaOH
(3 mL). The reaction mixture was stirred at rt for 3 h, diluted
with H2O (100 mL), and was extracted with CH2Cl2. The
combined organic extracts were dried (MgSO4) and concen-
trated. Purification of the residue by column chromato-
graphy (hexanes/EtOAc 3:1) afforded amide 30 (0.99 g,
91%) as a white solid. 1H NMR (300 MHz, CDCl3) d
7.17–7.23 (m, 5H), 6.84 (dd, J¼2.8, 1.7 Hz, 1H), 6.66 (dd,
J¼3.8, 1.7 Hz, 1H), 6.19 (br s, 2H), 6.07 (dd, J¼3.8, 2.8 Hz,
1H), 5.64 (s, 2H), 4.42 (s, 2H); 13C NMR (75 MHz, CDCl3)
d 165.6, 139.1, 130.5, 129.9, 129.6, 127.6, 117.4, 110.6,
78.5, 72.1; ESI (+): [M+H]+ calcd for C13H15N2O2,
231.1134; found 231.1120.
1
a yellow solid. H NMR (300 MHz, CDCl3) d 13.19 (d,
J¼9.6 Hz, 1H), 7.92–7.95 (m, 2H), 7.61–7.68 (m, 1H),
7.17–7.42 (m, 8H), 6.95 (s, 1H), 5.77 (d, J¼8.9 Hz, 1H),
5.18 (s, 2H), 4.40 (s, 2H), 2.46 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 192.7, 144.0, 140.7, 138.7, 135.1, 130.2,
127.6, 127.3, 126.9, 126.4, 124.8, 118.4, 104.2, 73.5, 69.5,
14.6; ESI (+): [M+H]+ calcd for C21H22N3OS2, 396.1204;
found 396.1198.
5.1.5. N-[2-(1-Benzyloxymethyl-2-methylsulfanylimid-
azol-4-yl)-vinyl]thiobenzimidic acid methyl ester (24). To
a solution of thioenamide 23 (150 mg, 0.38 mmol) in
CH2Cl2 (15 mL) was added MeOTf (68 mg, 0.42 mmol).
The reaction mixture was stirred at rt for 45 min and then
concentrated. The crude reaction mixture was partitioned
between CH2Cl2 (15 mL) and NaOH (1 N, 20 mL), and
the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4) and concentrated. The
reaction cleanly afforded thioimidate 24 (151 mg, 97%) as
5.1.9. 1-Benzyloxymethyl-4,5-dibromopyrrole-2-carb-
oxylic acid amide (31). To a solution of pyrrole amide 30
(1.00 g, 4.34 mmol) in THF (50 mL) was added NBS
(1.62 g, 9.12 mmol). The reaction mixture was stirred at rt
for 30 min and then concentrated. Purification of the residue
by column chromatography (hexanes/EtOAc 2:1) afforded
dibromopyrrole 31 (1.58 g, 94%) as a white solid. X-ray
crystal structure analysis27 confirmed the assignment of di-
bromopyrrole 31 (recrystallized from CH2Cl2). Mp 129–
1
a yellow oil. H NMR (300 MHz, CDCl3) d 7.75 (br s,
1H), 7.19–7.50 (m, 10H), 6.64 (br s, 1H), 6.03 (br s, 1H),
5.29 (s, 2H), 4.44 (s, 2H), 2.55 (s, 3H), 2.47 (br s, 3H); ESI
(+): [M+H]+ calcd for C22H24N3OS2, 410.1361; found
410.1365.
1
130 ꢀC; H NMR (300 MHz, CDCl3) d 7.19–7.25 (m, 5H),
6.71 (s, 1H), 5.82 (s, 2H), 4.54 (s, 2H); 13C NMR
(75 MHz, CDCl3) d 160.5, 135.9, 127.4, 126.9, 126.6,
126.5, 116.2, 111.0, 99.3, 74.5, 69.7; ESI (+): [M+H]+ calcd
for C13H13N2O279Br2, 386.9344; found 386.9381.
5.1.6. 3-Benzyloxymethyl-2-methylsulfanyl-4-phenylimid-
azopyridine (26). A solution of thioimidate 24 (55 mg,
0.13 mmol) in p-xylene (2.5 mL) was subjected to micro-
wave irradiation at 160 ꢀC for 1 h and then concentrated. Pu-
rification of the residue by preparative TLC (hexanes/EtOAc
1:1) afforded imidazopyridine 26a (19 mg, 40%) and BOM-
regioisomeric imidazopyridine 26b (16 mg, 33%) as clear
oils. Imidazopyridine 26a: 1H NMR (400 MHz, CDCl3)
d 8.60 (d, J¼7.4 Hz, 2H), 8.39 (d, J¼5.4 Hz, 1H), 7.43–
7.47 (m, 2H), 7.36–7.38 (m, 1H), 7.18–7.28 (m, 5H), 7.14
(d, J¼5.4 Hz, 1H), 5.46 (s, 2H), 4.45 (s, 2H), 2.81 (s, 3H);
13C NMR (75 MHz, CDCl3) d 155.9, 147.3, 143.3, 141.7,
138.6, 137.5, 136.6, 129.7, 129.6, 129.0, 128.8, 128.7,
5.1.10. 1-Benzyloxymethyl-4,5-dibromopyrrole-2-carb-
oxylic acid [2-(1-benzyloxymethyl-2-methylsulfanyl-
imidazol-4-yl)-vinyl]amide (32). In an oven-dried Schlenk
tube was placed imidazole vinyliodide 21 (0.50 g,
1.29 mmol), pyrrole amide 31 (0.55 g, 1.42 mmol), CuI
(25 mg, 0.13 mmol), Cs2CO3 (0.84 g, 2.59 mmol), N,N0-di-
methylethylenediamine (23 mg, 0.26 mmol), and THF
(6 mL). The tube was flushed with nitrogen, sealed, and
heated at 70 ꢀC for 17 h. The reaction mixture was then
cooled to rt and filtered through a Celite pad, which was
washed with EtOAc. The filtrate was concentrated and the
residue was purified by column chromatography (hexanes/
EtOAc 4:1) affording the coupled (Z)-enamide 32 (0.77 g,
92%) as a white solid. 1H NMR (400 MHz, CDCl3)
d 11.63 (d, J¼10.2 Hz, 1H), 7.11–7.23 (m, 10H), 6.93 (dd,
J¼10.2, 9.0 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 5.91 (s,
2H), 5.43 (d, J¼8.9 Hz, 1H), 5.13 (s, 2H), 4.51 (s, 2H),
4.35 (s, 2H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 157.1, 144.5, 140.8, 137.9, 136.6, 129.1, 128.8, 128.7,
128.6, 128.4, 128.1, 128.0, 121.9, 118.8, 116.3, 112.5,
100.7, 100.6, 75.9, 75.0, 71.2, 70.9, 16.4; ESI (+): [M+H]+
calcd for C27H27N4O3S79Br2, 645.0171; found 645.0167.
1
128.3, 104.3, 73.1, 71.3, 15.3. Imidazopyridine 26b: H
NMR (400 MHz, CDCl3) d 8.40 (d, J¼5.5 Hz, 1H), 7.53–
7.55 (m, 2H), 7.49 (d, J¼5.5 Hz, 1H), 7.40–7.42 (m, 3H),
7.18–7.21 (m, 3H), 7.04–7.07 (m, 2H), 5.09 (s, 2H), 4.09
(s, 2H), 2.75 (s, 3H); 13C NMR (75 MHz, CDCl3) d 160.3,
150.3, 144.2, 142.3, 138.4, 136.9, 131.8, 129.6, 129.4,
129.0, 128.8, 128.4, 127.8, 112.6, 73.6, 71.0, 15.1; ESI (+):
[M+H]+ calcd for C21H20N3OS, 362.1327; found 362.1310.
5.1.7. 2-Methylsulfanyl-4-phenylimidazopyridine (27). A
solution of BOM-protected imidazopyridine 26 (5 mg,
0.01 mmol) in EtOH (2 mL) and 6 N HCl (1.5 mL) was
heated at 100 ꢀC for 1 h and then concentrated. Purification
of the residue by preparative TLC (EtOAc) afforded N–H
5.1.11. 1-Benzyloxymethyl-4,5-dibromopyrrole-2-carbo-
thioic acid [2-(1-benzyloxymethyl-2-methylsulfanylimid-

9118
M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
azol-4-yl)-vinyl]amide (33). To a solution of enamide 32
(0.60 g, 0.93 mmol) in PhMe (30 mL) was added Lawes-
son’s reagent (0.56 g, 1.39 mmol). The reaction mixture
was heated at 100 ꢀC for 2 h and then concentrated. Purifica-
tion of the residue by column chromatography (hexanes/
EtOAc 4:1) afforded thioenamide 33 (0.51 g, 82%) as a yel-
low oil. 1H NMR (400 MHz, CDCl3) d 13.00 (d, J¼9.8 Hz,
1H), 7.49 (t, J¼9.7 Hz, 1H), 7.18–7.26 (m, 5H), 7.08–7.11
(m, 5H), 6.90 (s, 1H), 6.64 (s, 1H), 6.13 (s, 2H), 5.71 (d,
J¼8.8 Hz, 1H), 5.13 (s, 2H), 4.41 (s, 2H), 4.37 (s, 2H),
2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) d 180.1, 145.8,
140.0, 137.6, 137.5, 136.6, 129.1, 128.8, 128.4, 128.2, 128.0,
124.8, 120.0, 114.5, 113.3, 105.7, 101.0, 75.5, 75.0, 71.2,
71.1, 16.0; ESI (+): [M+H]+ calcd for C27H27N4O2S279Br2,
660.9942; found 660.9994.
of the residue by column chromatography (hexanes/EtOAc
1:1) afforded sulfoxide 41 (31 mg, 76%) as a clear oil, along
with the corresponding sulfone 42 (4 mg, 10%). Sulfoxide
41: 1H NMR (300 MHz, CDCl3) d 8.47 (d, J¼5.5 Hz, 1H),
7.66 (d, J¼5.5 Hz, 1H), 7.22–7.25 (m, 3H), 7.14–7.19 (m,
2H), 7.09–7.11 (m, 3H), 6.84–6.87 (m, 2H), 6.58 (s, 1H),
5.46–5.58 (m, 2H), 5.36–5.37 (m, 2H), 4.35 (s, 2H), 4.24
(s, 2H), 3.12 (s, 3H); 13C NMR (75 MHz, CDCl3) d 158.9,
148.7, 142.7, 137.0, 136.6, 136.3, 132.7, 129.8, 129.0,
128.7, 128.3, 128.2, 127.8, 127.7, 115.9, 115.6, 108.0,
100.6, 75.4, 73.4, 71.8, 70.8, 40.8; ESI (+): [M+H]+ calcd
for C27H25N4O3S79Br2, 643.0014; found 642.9984. Sulfone
42: 1H NMR (400 MHz, CDCl3) d 8.50 (d, J¼5.2 Hz, 1H),
7.68 (d, J¼5.3 Hz, 1H), 7.17–7.26 (m, 5H), 7.09–7.11 (m,
3H), 6.85–6.87 (m, 2H), 6.60 (s, 1H), 5.57 (s, 2H), 5.32 (s,
2H), 4.38 (s, 2H), 4.25 (s, 2H), 3.43 (s, 3H).
5.1.12. 1-Benzyloxymethyl-N-[2-(1-benzyloxymethyl-2-
methylsulfanylimidazol-4-yl)-vinyl]4,5-dibromopyrrole-
2-carboximidothioic acid methyl ester (34). To a solution
of thioenamide 33 (100 mg, 0.15 mmol) in CH2Cl2 (15 mL)
was added MeOTf (27 mg, 0.17 mmol). The reaction mix-
ture was stirred at rt for 2 h and concentrated. The crude re-
action mixture was partitioned between CH2Cl2 (5 mL) and
NaOH (1 N, 10 mL), and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were dried
(MgSO4) and concentrated. Purification of the residue by
column chromatography (hexanes/EtOAc 3:1) afforded thio-
imidate 34 (95 mg, 93%) as a yellow oil. 1H NMR
(300 MHz, CDCl3) d 7.42 (br s, 1H), 7.14–7.23 (m, 11H),
6.49 (br s, 1H), 6.16 (br s, 1H), 5.21–5.70 (m, 4H), 4.39
(br s, 2H), 4.30 (s, 2H), 2.56 (s, 3H), 2.43 (br s, 3H); 13C
NMR (75 MHz, CDCl3) d 143.5, 138.9, 137.2, 136.8, 133.0,
129.0, 128.8, 128.6, 128.3, 128.0, 123.1, 118.3, 101.3, 76.0,
75.0, 70.9, 70.7, 17.0; ESI (+): [M+H]+ calcd for
C28H29N4O2S279Br2, 675.0099; found 675.0141.
5.1.15. 2-Azido-3-benzyloxymethyl-4-(1-benzyloxy-
methyl-4,5-dibromopyrrol-2-yl)imidazopyridine (43).
To a mixture of sulfoxide 41 (22 mg, 0.02 mmol) and sul-
fone 42 (3 mg, 3.0 mmol) in DMSO (0.5 mL) was added so-
dium azide (13 mg, 0.19 mmol). The reaction mixture was
stirred at rt for 6 h, then directly purified by column chroma-
tography (hexanes/EtOAc 1:1) to afford amide 43 (21 mg,
87%) as a clear oil. 1H NMR (300 MHz, CDCl3) d 8.41 (d,
J¼5.5 Hz, 1H), 7.50 (d, J¼5.5 Hz, 1H), 7.19–7.25 (m,
3H), 7.09–7.15 (m, 5H), 6.82–6.85 (m, 2H), 6.58 (s, 1H),
5.34 (s, 2H), 4.97 (s, 2H), 4.31 (s, 2H), 4.20 (s, 2H); 13C
NMR (75 MHz, CDCl3) d 153.0, 149.1, 142.8, 137.2, 136.7,
134.7, 131.5, 129.9, 129.0, 128.7, 128.6, 128.2, 127.9, 127.7,
115.3, 113.6, 107.4, 100.3, 75.5, 72.3, 71.7, 70.5; ESI (+):
[M+H]+ calcd for C26H22N7O279Br2, 622.0202; found
622.0239.
5.1.16. 3-Benzyloxymethyl-4-(1-benzyloxymethyl-4,5-di-
bromopyrrol-2-yl)imidazopyridin-2-ylamine (44). A so-
lution of azide 43 (17 mg, 0.03 mmol) in MeOH (1 mL)
and THF (1 mL) was reduced with Lindlar catalyst (4 mg)
at rt under one atmosphere of H2 for 17 h. The mixture
was then filtered through a Celite pad, which was washed
with MeOH. The filtrate was concentrated to afford amine
44 (16 mg, 94%) as a yellow solid sufficiently pure for use
5.1.13. 3-Benzyloxymethyl-4-(1-benzyloxymethyl-4,5-di-
bromopyrrol-2-yl)-2-methylsulfanyl-imidazopyridine
(35). A solution of thioimidate 34 (75 mg, 0.11 mmol) in
mesitylene (30 mL) was heated at 145 ꢀC for 16 h and
then concentrated. Purification of the residue by column
chromatography (hexanes/EtOAc 2:1) afforded pyridine 35
(31 mg, 44%, 51% brsm) as a clear oil, along with starting
thioimidate 34 (9 mg, 12%) and isomerized (E)-thioimidate
1
in the next step. H NMR (300 MHz, CD3OD) d 8.16 (d,
J¼5.5 Hz, 1H), 7.23–7.28 (m, 4H), 7.17–7.21 (m, 2H),
7.13–7.15 (m, 3H), 6.85–6.88 (m, 2H), 6.55 (s, 1H), 5.14
(s, 2H), 5.00 (s, 2H), 4.30 (s, 2H), 4.21 (s, 2H); 13C NMR
(75 MHz, CD3OD) d 159.1, 150.7, 141.9, 137.2, 131.6,
131.2, 130.7, 128.5, 128.3, 128.0, 127.8, 127.4, 114.4,
110.9, 106.1, 99.7, 75.0, 72.2, 70.5, 70.2; ESI (+): [M+H]+
calcd for C26H24N5O279Br2, 596.0297; found 596.0313.
1
36 (20 mg, 27%). H NMR (300 MHz, CDCl3) d 8.45 (d,
J¼5.4 Hz, 1H), 7.61 (d, J¼5.4 Hz, 1H), 7.27–7.37 (m,
5H), 7.19–7.21 (m, 3H), 6.92–6.96 (m, 2H), 6.65 (s, 1H),
5.41 (s, 2H), 5.14 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 2.86
(s, 3H); 13C NMR (75 MHz, CDCl3) d 160.8, 150.5, 142.3,
137.2, 136.7, 133.9, 133.5, 130.5, 129.0, 128.7, 128.6, 128.2,
128.1, 127.7, 115.1, 113.6, 107.1, 100.4, 75.5, 73.3, 71.5,
70.6, 15.1; ESI (+): [M+H]+ calcd for C27H25N4O2S79Br2,
627.0065; found 627.0047.
5.1.17. Ageladine A (1). To a solution of BOM-protected tri-
cyclic compound 44 (15.1 mg, 25.2 mmol) in CH2Cl2 (6 mL)
was added AlCl3 (33.7 mg, 0.25 mmol) in CH2Cl2 (2 mL).
The reaction mixture was stirred at rt for 30 min. The mix-
ture was diluted with H2O (15 mL) and extracted with
CH2Cl2 (3ꢁ5 mL). The aqueous layer was concentrated
and purification of the residue by reverse phase HPLC af-
forded ageladine A (1, 5.7 mg, 63%) as a yellow solid, which
was identical to previously prepared material.3 1H NMR
(400 MHz, CD3OD) d 8.05 (d, J¼6.4 Hz, 1H), 7.42 (d,
J¼6.4 Hz, 1H), 7.17 (s, 1H); ESI (+): [M+H]+ calcd for
C10H8N579Br2, 355.9146; found 355.9146.
5.1.14. 3-Benzyloxymethyl-4-(1-benzyloxymethyl-4,5-di-
bromopyrrol-2-yl)-2-methanesulfinyl-imidazopyridine
(41). To a solution of sulfide 35 (40 mg, 0.06 mmol) in
CH2Cl2 (4 mL) was added m-CPBA (29 mg, 0.13 mmol, dis-
solved in 1 mL of CH2Cl2) at ꢂ78 ꢀC. The reaction mixture
was stirred at ꢂ78 ꢀC for 15 min, 0 ꢀC for 1 h, and then at rt
for 20 min. The reaction mixture was diluted with saturated
Na2SO3 and extracted with CH2Cl2. The combined organic
extracts were dried (MgSO4) and concentrated. Purification

M. L. Meketa, S. M. Weinreb / Tetrahedron 63 (2007) 9112–9119
9119
14. Seyferth, D.; Heeren, J. K.; Singh, G.; Grim, S. O.; Hughes,
W. B. J. Organomet. Chem. 1966, 5, 267.
Acknowledgements
15. For a generalreview of triene electrocyclizations, see:Okamura,
W. H.; de Lera, A. R. 1,3-Cyclohexadiene Formation Reactions.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 699–750.
16. Jieng, L.; Job, G. E.; Klapers, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667.
17. Interestingly, the NMR spectra of thioimidate 24 exhibited
broad peaks (cf. Section 5) which might be due to rapid inver-
sion of the amine nitrogen.
We gratefully acknowledge financial support from the
National Science Foundation (CHE-0404792). We also
wish to thank Dr. H. Yennawar (Penn State Small Molecule
X-ray Cystallographic Facility) for the X-ray determination
of dibromopyrrole 31, as well as Professor Blake Peterson
and Jocelyn Edathil for assistance with reverse phase
HPLC analysis.
18. Cf. (a) Biere, H.; Russe, R.; Seelen, W. Liebigs Ann. Chem.
1986, 1749; (b) Qiang, L. G.; Baine, N. H. Tetrahedron Lett.
1988, 29, 3517; (c) Palacios, F.; Gil, M. J.; Martinez de
Marigorta, E.; Rodriguez, M. Tetrahedron 2000, 56, 6319.
19. (a) Kukla, M. J.; Fortunato, J. M. J. Org. Chem. 1984, 49, 5003;
(b) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71,
3159 and references cited therein; (c) Sun, C. Ph.D. Thesis,
The Pennsylvania State University, 2005.
References and notes
1. (a) Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.;
Yamashita, J.; van Soest, R. W. M.; Fusetani, N. J. Am.
Chem. Soc. 2003, 125, 15700; (b) Nakao, Y.; Fusetani, N.
J. Nat. Prod. 2007, 70, 689.
2. (a) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H.
Chem. Rev. 1999, 99, 2735; (b) Matter, A. Drug Discov.
Today 2001, 6, 1005.
20. Zlatopolskiy, B. D.; Kroll, H.-P.; Melotto, E.; de Meijere, A.
Eur. J. Org. Chem. 2004, 4492.
3. (a) Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443; (b)
Meketa, M. L.; Weinreb, S. M.; Nakao, Y.; Fusetani, N. J. Org.
Chem. 2007, 72, 4892.
4. Shengule, S. R.; Karuso, P. Org. Lett. 2006, 8, 4083.
5. Meketa, M. L.; Weinreb, S. M. Org. Lett. 2007, 9, 853.
6. For a brief review of the three ageladine A total syntheses, see:
Weinreb, S. M. Nat. Prod. Rep., in press.
7. Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
8. Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G.
Tetrahedron Lett. 1999, 40, 4775.
9. For other biosynthetic studies on pyrrole-imidazole alkaloids,
see: Vergne, C.; Boury-Esnault, N.; Perez, T.; Martin, M.-T.;
Adeline, M.-T.; Dau, E. T. H.; Al Mourabit, A. Org. Lett.
2006, 8, 2421.
21. For a related halogen-selective coupling, see: Sun, C.; Camp,
J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779.
22. (a) de Mayo, P.; Sydnes, L. K.; Wenska, G. J. Chem. Soc., Chem.
Commun. 1979, 499; (b) de Mayo, P.; Sydnes, L. K.; Wenska, G.
J. Org. Chem. 1980, 45, 1549; (c) Armesto, D.; Horspool,
W. M.; Langa, F.; Ortiz, M. J.; Perez-Osorio, R.; Romano, S.
Tetrahedron Lett. 1985, 26, 5213; (d) Campos, P. J.; Caro, M.;
Rodriguez, M. A. Tetrahedron Lett. 2001, 42, 3575.
23. Ngochindo, R. I. J. Chem. Res., Synop. 1990, 2, 58.
24. For other examples of formation of (Z)- and (E)-vinyl iodide
mixtures using this Wittig chemistry, see: (a) Bestmann,
H. J.; Rippel, H. C.; Dostalek, R. Tetrahedron Lett. 1989, 30,
5261; (b) de Lera, A. R.; Torrado, A.; Iglesias, B.; Lopez, S.
Tetrahedron Lett. 1992, 33, 6205; (c) Paquette, L. A.; Bailey,
S. J. Org. Chem. 1995, 60, 7849.
10. Preparation of 13 from commercially available 2,4,5-tribromo-
imidazole: Schumacher, R. W.; Davidson, B. S. Tetrahedron
1999, 55, 935.
25. Chauviꢀere, G.; Bouteille, B.; Enanga, B.; de Albuquerque, C.;
ꢁ
Croft, S. L.; Dumas, M.; Perie, J. J. Med. Chem. 2003, 46, 427.
11. (a) Takeuchi, Y.; Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A. J. Org.
Chem. 1978, 43, 3565; (b) Takeuchi, Y.; Kirk, K. L.; Cohen,
L. A. J. Org. Chem. 1978, 43, 3570.
12. Eriksen, B. L.; Vedso, P.; Begtrup, M. J. Org. Chem. 2001,
66, 8344.
13. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
26. Groves, J. K.; Cundasawmy, N. E.; Anderson, H. J. Can. J.
Chem. 1973, 51, 1089.
27. CCDC 644278 contains the supplementary crystallographic
data which can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.