Extending pummerer reaction chemistry. Synthesis studies in the phakellin alkaloid area

Article abstract of DOI:10.1021/jo701487j

(Chemical Equation Presented) The syntheses of (±)- dibromophakellstatin and, from this species, (±)-dibromophakellin are described. Oxidative cyclization of a phenylthiolated dihydrooroidin derivative triggered by a Pummerer reaction constitutes the key

Full text of DOI:10.1021/jo701487j

Extending Pummerer Reaction Chemistry. Synthesis Studies in the
Phakellin Alkaloid Area
Ken S. Feldman,* Amanda P. Skoumbourdis, and Matthew D. Fodor
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
ksf@chem.psu.edu
ReceiVed July 17, 2007
The syntheses of (()-dibromophakellstatin and, from this species, (()-dibromophakellin are described.
Oxidative cyclization of a phenylthiolated dihydrooroidin derivative triggered by a Pummerer reaction
constitutes the key step in this biomimetic approach to this family of marine alkaloids.
Introduction
ization of the problem as an oxidative cyclization of a dihy-
drooroidin derivative opened up the possibility of extending the
recently developed Pummerer reaction-based indole oxidative
cyclization transform4 to imidazole substrates. The ultimate goal
is to expand the utility of this methodology for achieving aro-
matic heterocycle oxidative cyclization. The full details of the
development of this transform on an imidazole platform, in the
context of (()-dibromophakellstatin (1) synthesis, is described
below.2f Subsequent conversion of this natural product to the
related species (()-dibromophakellin (2a) is documented as
well.
The family of tetracyclic (and larger) sponge alkaloids
presumably derived from oroidin (11) presents some significant
challenges to organic synthesis from the standpoint of complex-
ity, condensed functionality, and stereochemistry; see Figure
1.1 Several different strategies have been pursued in synthesis
projects targeting members of this class,2 including approaches
patterned on the bond formations implied in an oroidin-based
biosynthesis.3 Although the implementation of a biomimetic
approach can take several forms (vide infra), the conceptual-
(1) (a) For dibromophakellstatin, see: Pettit, G. R.; McNulty, J.; Herald,
D. L.; Doubek, D. L.; Chapuis, J.-C.; Schmidt, J. M.; Tackett, L. P.; Boyd,
M. R. J. Nat. Prod. 1997, 60, 180-183. (b) For dibromophakellin and
monobromophakellin, see: Sharma, G.; Magdoff-Fairchild, B. J. Org. Chem.
1977, 42, 4118-4124. (c) For 7-N-methyldibromophakellin and 7-N-
monobromophakellin, see: Gautschi, J. T.; Whitman, S.; Holman, T. R.;
Crews, P. J. Nat. Prod. 2004, 67, 1256-1261. (d) For dibromoisophakellin,
see: Fedoreev, S. A.; Utkina, N. K.; Il´ıin, S. G.; Reshetnyak, M. V.;
Maksimov, O. B. Tetrahedron Lett. 1986, 27, 3177-3180. (e) For
monobromoisophakellin, see: Assmann, M.; Ko¨ck, M. Z. Naturforsch. 2002,
57, 153-156. (f) For 1-N-methyldibromoisophakellin, see: Assmann, M.;
van Soest, R. W. M.; Ko¨ck, M. J. Nat. Prod. 2001, 64, 1354-1347. (g)
For 12-chloro-11-hydroxydibromoisophakellin, see: Kitagawa, I.; Koba-
yashi, M.; Kitanaka, K.; Kido, M.; Kyogoku, Y. Chem. Pharm. Bull. 1983,
31, 2321-2328. (h) For palau’amine, monobromopalau’amine, and
dibromopalau’amine, see: Kinnel, R. B.; Gehrken, H.-P.; Swali, R.;
Skoropowski, G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281-3286. (i)
For konbu’acidin A, see: Koybashi, J.; Suzuki, M.; Tsuda, M. Tetrahedron
1997, 53, 15681-15684. (j) For styloguanidine, monobromostyloguanidine,
and dibromostyloguanidine, see: Kato, T.; Shizuri, Y.; Izumida, H.;
Yokoyama, A.; Endo, M. Tetrahedron Lett. 1995, 36, 2133-2136. (k) For
structural/stereochemical revisions, see: Grube, A.; Ko¨ck, M. Angew. Chem.,
Int. Ed. 2007, 46, 2320-2324. (l) Buchanan, M. S.; Carroll, A. R.; Quinn,
R. J. Tetrahedron Lett. 2007, 48, 4573-4574.
(2) For a general review, see: (a) Hoffmann, H.; Lindel, T. Synthesis
2003, 1753-1783. For dibromophakellstatin, see: (b) Wiese, K. J.;
Yakushijin, K.; Horne, D. A. Tetrahedron Lett. 2002, 43, 5135-5136. (c)
Poullennec, K. G.; Romo, D. J. Am. Chem. Soc. 2003, 125, 6344-6345.
(d) Chung, R.; Yu, E.; Incarvito, C. D.; Austin, D. J. Org. Lett. 2004, 6,
3881-3884. (e) Jacquot, D. E. N.; Zo¨llinger, M.; Lindel, T. Angew. Chem.,
Int. Ed. 2005, 44, 2295-2298. (f) Feldman, K. S.; Skoumbourdis, A. P.
Org. Lett. 2005, 7, 929-931. (g) Lu, J.; Tan, X.; Chen, C. J. Am. Chem.
Soc. 2007, 129, 7768-7769. For dibromophakellin, see: (h) Bu¨chi, G.;
Foley, L. H. J. Am. Chem. Soc. 1982, 104, 1776-1777. (i) See ref 2b. (j)
Travert, N.; Martin, M.-T.; Bourguet-Kondracki, M.-L.; Al Mourabit, A.
Tetrahedron Lett. 2005, 46, 249-252. For palau’amine, see: (k) Overman,
L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997,
119, 7159-7160. (l) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535-
1538. (m) Be´langer, G.; Hong, F.-T.; Overman, L. E.; Rogers, B. N.; Tellew,
J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67, 7880-7883. (n) Koenig, S.
G.; Miller, S. M.; Leonard, K. A.; Lo¨we, R. S.; Chen, B. C.; Austin, D. J.
Org. Lett. 2003, 5, 2203-2206. (o) Lovely, C. J.; Du, H.; He, Y.; Rasika
Dias, H. V. Org. Lett. 2004, 6, 735-738. (p) Garrido-Hernandez, H.;
Nakadai, M.; Vimolratana, M.; Li, Q.; Doundoulakis, T.; Harran, P. G.
Angew. Chem., Int. Ed. 2005, 44, 765-769.
(3) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
(4) Feldman, K. S.; Boneva Vidulova, D.; Karatjas, A. G. J. Org. Chem.
2005, 70, 6429-6440.
10.1021/jo701487j CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/13/2007
8076
J. Org. Chem. 2007, 72, 8076-8086

Synthesis Studies in the Phakellin Alkaloid Area
SCHEME 1. Speculative Biosynthesis/Biomimetic
Chemistry of Dibromophakellin
cyclization reaction by the expedient of using NBS in CF3CO2H
to generate dibromophakellin in a remarkable 90% yield.2b As
a counterpoint to this dihydrooroidin oxidative cyclization
strategy, Al Mourabit and Potier favor a biosynthesis route for
2a that features only proton-mediated isomerization of oroidin
itself; see Scheme 1, 11 f 12 f 2a.3 A significant point of
distinction between the two hypotheses lies in the regiochemistry
of the first-formed N-C bond, as the Al Mourabit/Potier scheme
proceeds through initial N(1)-C(6) bond formation to furnish
a nine-membered lactam 12. No experimental test of this
hypothesis has appeared. The dihydrooroidin brominative cy-
clization approach has the appeal of simplicity and the benefit
of successful implementation, but the extension of this experi-
mental protocol (NBS in CF3CO2H) to some of the more
complex and/or sensitive targets in Figure 1 raises concerns
about compatibility/stability. From this perspective, the develop-
ment of milder/more selective oxidative cyclization procedures
may impact favorably on the larger question of total synthesis
projects within the phakellin family.
The oxidative cyclization chemistry of aromatic heterocycles
has been thoroughly explored with indole systems, but oc-
casional problems of product overoxidation and/or unpredictable
nucleophile addition regiochemistry have hampered the devel-
opment of general protocols.5 One approach to this transforma-
tion that avoids these issues by deliberate design involves the
use of Pummerer chemistry to trigger the sequence; see Scheme
2, 13 f 15. In this process, oxidation is confined to the reactive
sulfur atom in the substrate, and the regiochemistry of nucleo-
philic addition (i.e., C(3)) is secured by the energy gain
accompanying rearomatization from 14 to 15 in a vinylogous
mechanism or, equivalently, by avoiding any disruption of the
aryl ring in 13 via an additive mechanism.6 A distinction
between these two mechanistic paths has not yet been made.
The extension of this chemistry to the imidazole nucleus is
exemplified by the conversion of 17 into 18, a spirocyclic
species that bears some resemblance to the spirocyclic inter-
FIGURE 1. Members of the phakellin family of marine alkaloids.
The basic structural motif of the phakellin class of marine
alkaloids is embodied in the inaugural member of this family,
dibromophakellin (2a). Structural diversity is introduced by (a)
variation of the number of bromines (e.g., 2b and 4b), (b)
methylating a core nitrogen (3a, 3b, and 5), (c) incorporating
higher oxidation (6), and finally, by (d) switching the N(1) f
C(6) pyrrole attachment to a C(3) f C(6) connection (4, 5, 6,
and 8). The hexacyclic relatives pala’uamines (7a-7c),
konbu’acidin A (7d), and styloguanidines (8a-8c) are formal
oroidin dimers wherein one of the oroidin modules constitutes
the phakellin (or isophakellin)-type tetracyclic core, and the
second oroidin unit is appended to the pyrrolidine ring. As a
bookkeeping mnemonic, the structural features of these species
that distinguish them from the “parent” dibromophakellin are
highlighted in red in Figure 1.
The recognition that the remarkable structural diversity of
this collection of secondary metabolites all stems from the single
simple precursor oroidin has fueled attempts to develop a
biomimetic strategy for total synthesis of the representative
member dibromophakellin (2a). The seminal work by Bu¨chi
(Scheme 1, 11 f 9 f 10 f 2a) revealed that brominative
activation of dihydrooroidin (9) is sufficient to promote the
required oxidative cyclization and deliver the key spirocycle
10.2g The ensuing base-mediated closure then delivered the intact
tetracycle 2a. Horne subsequently improved on this oxidative
(5) (a) Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada,
K.; Yamada, F. Heterocycles 2000, 53, 7-10. (b) Wang, H.; Ganesan, A.
J. Org. Chem. 2000, 65, 4685-4693. (c) Irikawa, H.; Mutoh, S.; Uehara,
M.; Okumura, Y. Bull. Chem. Soc. Jpn. 1989, 62, 3031-3033. (d) Gu¨ller,
R.; Borschberg, H.-J. HelV. Chim. Acta 1993, 76, 847-862. (e) Braun, N.
A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini,
M. A. J. Org. Chem. 2000, 65, 4397-4408.
(6) Feldman, K. S. Tetrahedron 2006, 62, 5003-5034.
J. Org. Chem, Vol. 72, No. 21, 2007 8077

Feldman et al.
SCHEME 4. Pummerer-Mediated Oxidative Cyclization
SCHEME 2. Pummerer-Chemistry-Initiated Oxidative
Cyclization of Indoles and Imidazoles
Attempt of an Imidazole 2-Sulfoxide
SCHEME 3. Synthesis of a Thiophenyl Dihydrooroidin
Oxidative Cyclization Precursor
lithiation/thiolation (alkylation), leading to the C(2),C(5)-
disubstituted intermediate 21, with no evidence for regioisomer
formation. Simple functional group manipulation of the imida-
zole chloride 21 furnished the requisite sulfide 24a. The direct
oxidation of 24a into sulfoxide 24b was capricious, and so, an
alternative procedure featuring the earlier oxidation of the
protected imidazole sulfide 22a into the corresponding sulfoxide
22b was pursued. In a manner identical to the 22a f 24a
conversion, 22b was processed into the requisite imidazole
sulfoxide 24b. The imidazole rings in 24 and other related
structures in this paper are depicted as the 5-tautomer by analogy
1
with the H NMR-based assignment made for oroidin (11) by
Lindel (HMBC correlation between 15N(15) and H(10), oroidin
numbering; see Scheme 1).8 It is likely that the 4- and
5-imidazole tautomers interconvert under the (protic) oxidative
cyclization conditions.
mediate 10 in the Bu¨chi/Horne work. Thus, by appropriate
choice of the nucleophile and tether, this reaction can be mapped
into the dihydrooroidin-type oxidative cyclizations that already
have documented utility in dibromophakellin synthesis. Suc-
cessful demonstration of this proof-of-principle with the rela-
tively well-explored dibromophakellin system can then lay the
groundwork for future studies directed toward the more complex
members of the phakellin family.
Initial oxidative cyclization experiments with the sulfoxides
24b were anticipated to follow the successful indole sulfoxides
chemistry, 13a f 15, but that expectation was not born out in
practice. A limited survey of Pummerer initiation conditions,
utilizing various activators (TFAA, Tf2O) and bases (2,6-
lutidine, i-Pr2NEt), did not lead to the discovery of any protocols
that favored formation of oxidative cyclization products of the
type 18. In almost all cases, starting sulfoxide 24b was
consumed without generation of any isolable/characterizable
products. Eventually, a triflic anhydride-mediated procedure,
which did furnish a small amount of a discrete reaction product
27 (Scheme 4), was identified. The spectroscopic data were
consistent with the assigned structure 27 shown. Particularly,
diagnostic information was provided by HMBC/HMQC spectra,
with key correlations indicated on the structure (cf. Scheme 4).
The conjecture that the imidazole N-H is adjacent to the triflate
(imidazole-5-triflate) rather than adjacent to the alkyl chain
(imidazole-4-triflate) is based upon lack of a three-bond
correlation between this N-H and C(11) (phakellin numbering),
and this tautomer assignment should be considered tentative.
Results and Discussion
Exploration of the Pummerer-initiated oxidative cyclization
chemistry of imidazoles required access to appropriate C(2)-
sulfide and C(2)-sulfoxide imidazole substrates bearing a
tethered nucleophile. The dihydrooroidin-based test substrates
sulfide 24a and sulfoxide 24b were chosen as initial targets,
given their relevance to the synthesis objectives in the phakellin
area. Both species were prepared by straightforward imidazole
lithiation chemistry as described by Vollinga,7 Scheme 3. The
differential kinetic acidity of the C(2) versus the C(5) proton
of 19 could be exploited to permit sequential and regioselective
(7) Vollinga, R. C.; Menge, W. M. P. B.; Timmerman, H. Recl. TraV.
Pays-Bas 1993, 112, 123-125.
(8) Ko¨ck, M.; Junker, J.; Lindel, T. Org. Lett. 1999, 1, 2041-2044.
8078 J. Org. Chem., Vol. 72, No. 21, 2007

Synthesis Studies in the Phakellin Alkaloid Area
TABLE 1. Tetracyclization of 24a via Stang’s Reagent,
PhI(CN)OTf
Thus, in stark contrast to the previously studied indole series,
a reactive, electrophilic intermediate 25 generated from classical
Pummerer activation of sulfoxides 24b did not trap the proximal
nucleophilic nitrogen. Rather, the triflate counterion, in a rare
display of nucleophilicity, apparently outcompeted this amide
unit (attack at C(11), oroidin numbering) for the activated and
electrophilic imidazole ring (attack at C(12)). Attack of triflate
via an SN1-like vinylogous Pummerer mechanism (25a f 25b
f 26b) or the SN2′-like additive alternative (25a f 25c f 26a)
cannot be distinguished at this point. However, the additive
channel does require a tautomerization of the imidazole ring
prior to triflate attack. This point is significant because it raises
the requirement that once N(15) is deprotonated (as per the
vinylogous mechanism), the resultant anion must reprotonate
at N(13) faster than it expels triflate for the additive mechanism
to compete with the vinylogous alternative. Whatever the
mechanistic subtleties, this result indicates that successful
cyclization of an oroidin derivative into the phakellin skeleton
via Pummerer methodology would require generating an elec-
trophilic intermediate of the types 25a or 25b in the presence
of a counterion even less nucleophilic than triflate.
conc
(mM)
temp
yield
(%)b
entry
solvent
toluene
base
(°C)a
1
2
10
10
10
100
10
10
10
5
5
5
5
10
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
-78
-78
-45
0
6
7
8
CH2Cl2
3
4
5
6
7
8
9
10
11
12
CH3CN
CF3CH2OH
CH3CN
CH2Cl2
CH2Cl2
27
22
27
42
48
60-73
56
48
40
0
5
10
25
25
40
40
45
CH2Cl2
CH2Cl2/CH3OHc
CH2Cl2
CH2Cl2/CH3OHc
CH3CN
i-Pr2NEt
In order to achieve this goal, attention was turned to a
contemporary variant of Pummerer initiator, PhI(CN)OTf, as
the discouraging results with sulfoxide 24b and sulfonoylative
initiators became apparent. This hypervalent iodine reagent was
first introduced by Stang and Zhdankin as an effective iodonium
transfer reagent useful for alkynyliodonium salt synthesis.9 It
appeared to be both a milder and a “softer” iodonium species
than the more commonly used hypervalent reagents PhI(OAc)2
or PhI(OTFA)2, and as such, a preference for reaction with the
“soft” sulfide’s sulfur atom in 24a over other electron-rich sites
was anticipated. More importantly, previous use of this reagent
in the context of alkynyliodonium salt/alkylidenecarbene chem-
istry did not reveal any instance of either triflate or cyanide
acting as a nucleophile, even in the presence of highly reactive
alkylidenecarbenes.10 Initial trials with the other aforementioned
hypervalent iodine reagents, which themselves were documented
Pummerer triggers, did not lead to productive reaction. In
contrast, the Stang reagent uniquely did promote tetracyclization
of 24a (Table 1) and, for the first time, did provide entry into
the phakellin structural series. Optimization studies were
pursued, and some trends can be discerned from the representa-
tive data presented in Table 1. The yield of tetracycle was not
particularly sensitive to solvent, as yields in CH2Cl2 and toluene
(-78 °C) or in CH3CN and CF3CH2OH (0 °C) did not vary
much. However, the incorporation of a small amount of
methanol in CH2Cl2 did lead to consistently higher yields
compared with pure CH2Cl2 (entry 9 vs 8). Temperature was a
more important variable, as the product yield maximized at 25
°C, with notable yield dropoffs upon initiating the reaction
sequence at temperatures g40 °C or dropping it to subzero
regimes. Concentration appeared to be another contributor to
success, as yields improved slightly at 5 mM compared with
more concentrated solutions. A final critical component for
achieving high-yielding tetracyclization was the portionwise
addition of excess iodonium reagent as the reaction progressed.
Decomposition of the PhI(CN)OTf appeared to compete with
productive oxidation at sulfur, and continual replenishment of
a Temperature of mixing; in all cases, the reaction solution was then
slowly brought to room temperature. b Yield of chromatographically pure
product. c 1.5% by volume of CH3OH added.
the oxidant proved essential to drive the process to completion.
Product overoxidation did not present a problem (resubmission
experiments). Neither the desbromo- nor the C(4) monobromo
analogues of 24a provided characterizable compounds upon
exposure to Stang’s reagent under optimized conditions. In both
instances, the starting material was rapidly consumed, suggesting
that both of the bromide substituents were necessary to protect
the pyrrole ring from undesired oxidation by the iodonium
reagent.
The stereochemistry of tetracycle formation was suggested
by comparison of 28’s spectral data with that recorded for
dibromophakellstatin itself, and it was later confirmed by
conversion of 28 into 1, eq 1. This transformation formally
amounted to no more than a hydrolysis of the thioamidine
function within 28, but it was accomplished with the greatest
facility via the agency of the potent oxidant ceric ammonium
nitrate (CAN). The thioamidine of 28 was immune to further
oxidation by PhI(CN)OTf, a result readily rationalized by noting
the resonance stabilization for sulfur’s lone pair provided by
the imine function in comparison to the lack of same in the
starting thioimidazole in 24a. However, the stronger oxidant
CAN sufficed to generate a labile intermediate susceptible to
hydrolysis by the H2O present. Thus, the racemic natural product
(()-dibromophakellstatin (1) was available from imidazole
dimethylsulfonamide (19) in eight steps, with an overall yield
of 16%.
(9) Zhdankin, V. V.; Crittell, C. M.; Stang, P. J.; Zefirov, N. S.
Tetrahedron Lett. 1990, 31, 4821-4824.
(10) (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-
2584. (b) Stang, P. J. J. Org. Chem. 2003, 68, 2997-3008. (c) Knorr, R.
Chem. ReV. 2004, 104, 3795-3850.
The mechanistic course of this tetracyclization remains
unsettled (Scheme 5). Within the working hypothesis that a
J. Org. Chem, Vol. 72, No. 21, 2007 8079

Feldman et al.
TABLE 2. Cyclization Substrates Explored in This Study
SCHEME 5. Mechanistic Speculation Governing the
PhI(CN)OTf-Mediated Tetracyclization of 24a
entry
R
X
Y
36 (%)
37 (%)
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
Br
Br
Br
H
H
H
H
Br
Br
Br
Br
Br
53
62
64
82
67
79
44
44
80
72
71
88
76
67
56
85
83
63
MOM
SEM
CH3
H
CH3
MOM
SEM
CH3
chemistry for guanidine formation from ureas.13a Treatment of
the synthesized natural product dibromophakellstatin (1) with
Meerwein’s salt furnished the 8-ethoxyamidine 33 as an isolable
and completely stable (to alumina) white solid. Following a
procedure developed by Jacobi,13b heating a mixture of 33 and
ammonium propionate to 135 °C without solvent led to
formation of the guanidine-containing product dibromophakellin
(2a) in moderate yield. Pure product was isolated from the crude
reaction mixture via Sephadex G-10 chromatography, and the
spectral data for the synthesized 2a (optical rotation excepted)
matched those reported for the natural isolate in all respects
(see Supporting Information). Attempts to apply this procedure
to the thiophenyl substrate 28 did not meet with success; only
decomposition of the starting material was observed. The success
of these seemingly harsh reaction conditions on a demonstrably
delicate substrate points to the possible utility of this transform
in the synthesis of the more complex members of the oroidin
family.
Pummerer transformation is operational, two distinct bond
formation schemes can be envisioned, termed the additive
Pummerer (path a) and the vinylogous Pummerer (path b). The
latter sequence features elimination of the leaving group (29 f
31, - H-OTf) prior to N-C bond formation (31 f 32) and
passes through the neutral imine electrophile 32 en route to the
final N(1) f C(6) closure. The alternative additive pathway
proceeds through direct SN2′-like -OTf displacement within
29 prior to N-H proton loss, and this cyclization furnishes a
presumably more electrophilic thionium ion-bearing imine 30
as a partner for the pyrrole’s N(1). At present, there is no basis
for distinguishing between these mechanistic options. In the
related indole series, circumstantial evidence that is consistent
with the additive sequence and not the vinylogous alternative
has been recorded.
Much effort was expended in attempts to convert the
thioamidine function of tetracycle 28 into the guanidine moiety
of dibromophakellin (2a). Several different reagent protocols
have been developed to facilitate this transformation, but none
of these approaches proved effective with 28. Thus, all
procedures that featured either (a) direct displacement of the
- 11
PhS unit of 28 with a nitrogen nucleophile (NH3, BnNH2, N3
)
or (b) oxidation of the sulfide to a sulfoxide or sulfone, followed
by nitrogen nucleophile displacement,12 led to one of two results,
recovered 28 or complete destruction of the starting material
without formation of any isolable compound(s). These failures
led to a redirection of strategy that relied on much older
Several other cyclization substrates, 37, all bearing differing
bromide and/or nitrogen substituents on the pyrrole ring, were
examined in the Stang’s reagent-mediated polycyclization
cascade. These species were conveniently synthesized from
primary amine 34 and the various pyrroles 35, as indicated in
Table 2. For example, an attempt was made to access the
isophakellin skeleton (cf. 4a/4b, 5) by forcing pyrrole C(3)
participation upon bond formation to the electrophilic carbon
C(6). This redirection of the cascade sequence away from N(1)
was probed with substrates 37g-37i, all bearing a non-hydrogen
substituent at the N(1) of the pyrrole. The substrates 37g-37i
feature pyrrole units with the full complement of bromides, but
the monobromo species 37e and 37f were examined as well in
the hopes that removing electron-withdrawing bromides might
(11) (a) Blythin, D. J.; Kaminski, J. J.; Domalski, M. S.; Spitler, J.;
Solomon, D. M.; Conn, D. J.; Wong, S.; Verbiar, L. L.; Bober, L. A. J.
Med. Chem. 1986, 29, 1099-1113. (b) Beljean-Leymarie, M.; Pays, M.;
Richer, J. Can. J. Chem. 1983, 61, 2563-2566. (c) Flaherty, D.; Balse, P.;
Li, K.; Moore, B. M.; Doughty, M. B. Nucleosides Nucleotides 1995, 14,
65-76. (d) Matsumoto, K.; Inoue, T.; Yoshioka, K.; Iio, H.; Tanaka, T.
Bioorg. Med. Chem. Lett. 2006, 16, 1553-1556. (e) Posteri, H.; Borghi,
D.; Varasi, M. Org. Lett. 2005, 7, 5641-5644. (f) Reddick, R. E.; Kenyon,
G. L. J. Am. Chem. Soc. 1987, 109, 4380-4387.
(12) (a) Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443-1446.
(b) Chauviere, G.; Bouteille, B.; Enanga, B.; de Albuquerque, C.; Croft, S.
L.; Dumas, M.; Perie, J. J. Med. Chem. 2003, 46, 427-440. (c) Bierer, D.
E.; O’Connell, J. F.; Parquette, F. R.; Thompson, C. M.; Rapoport, H. J.
Org. Chem. 1992, 57, 1390. (d) Zani, F.; Mazza, P.; Benvenuti, S.; Severi,
F.; Malmusi, L.; Vampa, G.; Antolini, L. E. J. Med. Chem. 1995, 30, 729-
740. (e) Ronne, E.; Grivas, S.; Olsson, K. Acta Chem. Scand. 1994, 48,
823-830.
(13) (a) Tanino, H.; Nakata, T.; Kaneka, T.; Kishi, Y. J. Am. Chem.
Soc. 1977, 99, 2818-2819. (b) Jacobi, P. A.; Martinelli, M. J.; Slovenko,
P. J. Am. Chem. Soc. 1984, 106, 5594-5595.
8080 J. Org. Chem., Vol. 72, No. 21, 2007

Synthesis Studies in the Phakellin Alkaloid Area
render the C(3) of the pyrrole ring correspondingly more
nucleophilic. The end result, in all cases, was the same: no
formation of tetracyclic material was evident. Uncharacterizable
decomposition products accompanied all attempts at executing
a Stang-reagent-mediated Pummerer oxidative cyclization with
all of the sulfide substrates indicated in Table 2. Thus, it appears
that the PhI(CN)OTf-mediated cyclization of thiophenylimida-
zole dihydrooriodin derivatives has a rather narrow scope but
nevertheless works well for those species that bear tolerated
substituents on the pyrrole ring.
In summary, the tetracyclic skeleton of the phakellins was
readily prepared by Pummerer-mediated oxidative cyclization
of a dihydrooriodin derivative featuring a phenylthio moiety at
C(2) of the imidazole ring. Conversion of this cyclization
product into (()-dibromophakellstatin was straightforward (eight
steps in total from protected imidazole 19, 16% overall yield),
and subsequent synthesis of (()-dibromophakellin from dibro-
mophakellstatin proceeded in two additional steps. Further
attempts to fashion the isophakellin structure via oxidative
cyclization of pyrrole-N-protected oroidin derivatives were not
rewarded.
1
1684 cm-1; H NMR (360 MHz, CDCl3) δ 7.56 (s, 1H), 5.81 (s,
2H), 3.55 (t, J ) 8.3 Hz, 2H), 0.85 (t, J ) 8.3 Hz, 2H), -0.09 (s,
9H); 13C NMR (90 MHz, CDCl3) δ 171.4, 125.8, 123.3, 119.3,
101.5, 95.2, 76.0, 66.4, 17.7, -1.4; LRMS (ESI) m/z (relative
intensity) 514.9 (85% M + NH4+); HRMS (ESI) m/z calcd for
[C12H20N2Br2O2Cl3Si]+, 514.8726; found, 514.8737.
2-Benzenesulfinyl-5-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-
propyl]imidazole-1-sulfonic Acid Dimethylamide (22b). A stir-
ring solution of phthalimidosulfide 22a (21.8 g, 46.3 mmol) in 250
mL of CH2Cl2 was cooled to 0 °C and treated with mCPBA (8.00
g, 46.3 mmol). After 60 min, the reaction solution was warmed to
room temperature and poured into aqueous NaHCO3 (200 mL).
The resulting solution was partitioned between CH2Cl2 and H2O,
and the aqueous layer was extracted with CH2Cl2 (2 × 100 mL).
The organic fractions were combined, dried with Na2SO4, and
concentrated to give a yellow oil. Purification of this oil by flash
column chromatography (gradient 50-90% EtOAc/hexanes) af-
forded 22.8 g (98%) of phthalimidosulfoxide 22b as a white solid:
Experimental Section
mp 45-47 °C; IR (thin film) 1713 cm-1; H NMR (300 MHz,
1
CDCl3) δ 7.74-7.67 (m, 4H), 7.62-7.57 (m, 2H), 7.38-7.32 (m,
3H), 6.94 (s, 1H), 3.65 (t, J ) 6.8 Hz, 2H), 2.80 (s, 6H), 2.76-
2.57 (m, 2H), 1.95 (quint, J ) 7.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 167.8, 150.7, 142.8, 135.1, 133.7, 131.4, 131.3, 128.7,
128.5, 125.9, 122.8, 37.5, 36.8, 26.4, 22.6; LRMS (ESI) m/z (relative
intensity) 487.1 (100% M + H+); HRMS (ESI) m/z calcd for
[C22H23N4O5S2]+, 487.1112; found, 487.1110.
2,2,2-Trichloro-1-(4,5-dibromo-1-methoxymethyl-1H-pyrrol-
2-yl)ethanone (35g). Following General Procedure D (Supporting
Information), acyl pyrrole 23 (1.0 g, 2.7 mmol) in 10 mL of DMF
was treated with NaH (0.119 g, 2.97 mmol) followed by MOM-
Cl (0.250 mL, 3.24 mmol) to give 0.882 g (79%) of protected
pyrrole 35g as a colorless oil: IR (thin film) 1684 cm-1; 1H NMR
(360 MHz, CDCl3) δ 7.64 (s, 1H), 5.82 (s, 2H), 3.36 (s, 3H); 13C
NMR (90 MHz, CDCl3) δ 171.5, 126.0, 123.3, 119.4, 101.7, 95.1,
78.1, 56.4; LRMS (ESI) m/z (relative intensity) 411.8 (35% M +
H+); HRMS (ESI) m/z calcd for [C8H7NO2Br2Cl3]+, 411.7909;
found, 411.7911.
5-(3-Aminopropyl)-2-phenylsulfanylimidazole-1-sulfonic Acid
Dimethylamide (34). Following General Procedure A (Supporting
Information), phthalimidosulfide 22a (4.28 g, 9.09 mmol) in 90
mL of EtOH was heated to reflux and treated with hydrazine (5.7
mL, 180 mmol) to give 2.67 g (86%) of aminosulfide 34 as a white
1
solid: mp 42-43 °C; IR (thin film) 3364 cm-1; H NMR (400
MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.39-7.34 (m, 3H), 6.65 (app
d, J ) 1.0 Hz, 1H), 2.99 (s, 6H), 2.80 (t, J ) 7.6 Hz, 4H), 1.79
(quint, J ) 7.5 Hz, 2H), 1.27 (br s, 2H); 13C NMR (75 MHz, CDCl3)
δ 143.2, 135.8, 132.5, 131.0, 129.0, 128.3, 127.7, 41.4, 38.1, 32.0,
23.8; LRMS (ESI) m/z (relative intensity) 341.1 (100% M + H+);
HRMS (ESI) m/z calcd for [C14H21N4O2S2]+, 341.1106; found,
341.1103.
2,2,2-Trichloro-1-[1-(2-trimethylsilanylethoxymethyl)-1H-
pyrrol-2-yl]ethanone (35c). Following General Procedure D (Sup-
porting Information), acyl pyrrole 35a (1.0 g, 4.7 mmol) in 10 mL
of DMF was treated with NaH (0.207 g, 5.17 mmol) followed by
SEM-Cl (0.917 mL, 5.18 mmol) to give 0.663 g (39%) of protected
1
pyrrole 35c as a yellow oil: IR (thin film) 1664 cm-1; H NMR
(360 MHz, CDCl3) δ 7.57 (dd, J ) 4.3, 1.4 Hz, 1H), 7.22 (dd, J )
2.5, 1.8 Hz, 1H), 6.30 (dd, J ) 4.3, 2.5 Hz, 1H), 5.71 (s, 2H), 3.57
(t, J ) 8.3 Hz, 2H), 0.92 (t, J ) 8.3 Hz, 2H), -0.03 (s, 9H); 13C
NMR (90 MHz, CDCl3) δ 172.8, 132.4, 125.2, 121.5, 109.6, 96.2,
78.2, 66.5, 17.8, -1.5; LRMS (ESI) m/z (relative intensity) 364.0
(100% M + Na+); HRMS (ESI) m/z calcd for [C12H18NO2Cl3-
SiNa]+, 364.0070; found, 364.0065.
2,2,2-Trichloro-1-[4,5-dibromo-1-(2-trimethylsilanylethoxy-
methyl)-1H-pyrrol-2-yl]ethanone (35h). Following General Pro-
cedure D (Supporting Information), acyl pyrrole 23 (1.0 g, 2.7
mmol) in 10 mL of DMF was treated with NaH (0.119 g, 2.97
mmol) followed by SEM-Cl (0.478 mL, 3.34 mmol) to give 1.02
g (75%) of protected pyrrole 35h as a yellow oil: IR (thin film)
5-(3-Aminopropyl)-2-benzenesulfinylimidazole-1-sulfonic Acid
Dimethylamide. Following General Procedure A (Supporting
Information), phthalimidosulfoxide 22b (22.0 g, 45.2 mmol) in 500
mL of EtOH was heated to reflux and treated with hydrazine (31.2
mL, 937 mmol) to give 11.4 g (71%) of the aminosulfoxide product
1
as an unstable colorless oil: IR (thin film) 3442 cm-1; H NMR
(300 MHz, CDCl3) δ 7.80-7.74 (m, 2H), 7.48-7.33 (m, 3H), 6.91
(s, 1H), 2.87 (s, 6H), 2.67 (m, 4H), 1.71 (quint, J ) 7.4 Hz, 2H),
J. Org. Chem, Vol. 72, No. 21, 2007 8081

Feldman et al.
1.51 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 150.6, 142.9, 136.3,
131.5, 128.9, 128.7, 126.0, 41.1, 37.8, 31.2, 22.6; LRMS (ESI) m/z
(relative intensity) 357.1 (100% M + H+); HRMS (ESI) m/z calcd
for [C14H21N4O3S2]+, 357.1055; found, 357.1071.
(100% M + H+); HRMS (ESI) m/z calcd for [C19H22Br2N5O3S2]+,
589.9531; found, 589.9510.
4,5-Dibromo-1H-pyrrole-2-carboxylic Acid [3-(2-Benzene-
sulfinyl-3-dimethylsulfamoyl-3H-imidazol-4-yl)propyl]amide. Fol-
lowing General Procedure B (Supporting Information), 5-(3-
aminopropyl)-2-benzenesulfinylimidazole-1-sulfonic acid dimethyl-
amide (2.49 g, 6.98 mmol) in 20 mL of MeCN was treated
consecutively with Na2CO3 (0.658 g, 6.98 mmol) followed by acyl
pyrrole 23 (2.59 g, 6.98 mmol) to give 1.95 g (46%) of amidosul-
foxide product as an off-white solid: mp 172-174 °C; IR (thin
1H-Pyrrole-2-carboxylic Acid [3-(3-Dimethylsulfamoyl-2-phe-
nylsulfanyl-3H-imidazol-4-yl)propyl]amide (36a). Following Gen-
eral Procedure B (Supporting Information), amine 34 (0.150 g,
0.441 mmol) in 5 mL of MeCN was treated consecutively with
Na2CO3 (0.046 g, 0.43 mmol) followed by acyl pyrrole 35a (0.094
g, 0.44 mmol) to give 0.102 g (53%) of amidosulfide 36a as a
colorless oil: IR (thin film) 3250, 1627 cm-1; 1H NMR (300 MHz,
CDCl3) δ 9.53 (br s, 1H), 7.61-7.48 (m, 2H), 7.41-7.34 (m, 3H),
6.90 (dt, J ) 2.6, 1.2 Hz, 1H), 6.77 (s, 1H), 6.58 (ddd, J ) 3.6,
2.4, 1.5 Hz, 1H), 6.22 (app dt, J ) 3.6, 2.6 Hz, 1H), 6.19 (t, J )
5.6 Hz, 1H), 3.48 (q, J ) 6.3 Hz, 2H), 2.97 (s, 6H), 2.82 (t, J )
7.5 Hz, 2H), 1.92 (quint, J ) 6.7 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 161.5, 143.7, 135.3, 132.7, 130.8, 129.1, 128.5, 128.0,
125.7, 121.6, 109.33, 109.26, 38.6, 38.1, 28.7, 23.8; LRMS (ESI)
m/z (relative intensity) 434.1(100% M + H+); HRMS (ESI) m/z
calcd for [C19H24N5O3S2]+, 434.1321; found, 434.1333.
1
film) 3331, 1634 cm-1; H NMR (400 MHz, CDCl3) δ 8.11 (t, J
) 5.5 Hz, 1H), 7.74-7.72 (m, 2H), 7.56-7.54 (m, 3H), 7.13 (s,
1H), 6.83 (s, 1H), 3.29 (q, J ) 6.2 Hz, 2H), 2.91 (s, 6H), 2.74 (t,
J ) 7.4 Hz, 2H), 1.84 (quint, J ) 6.5 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 160.0, 150.3, 143.0, 136.1, 131.1, 129.3, 128.7, 128.1,
125.6, 112.2, 105.7, 96.1, 37.7, 37.3, 27.4, 22.2; LRMS (ESI) m/z
(relative intensity) 605.9 (100% M + H+); HRMS (ESI) m/z calcd
for [C19H22Br2N5O4S2]+, 605.9480; found, 605.9593.
1-Methyl-1H-pyrrole-2-carboxylic Acid [3-(3-Dimethylsulfa-
moyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]amide (36d). Fol-
lowing General Procedure B (Supporting Information), amine 34
(0.150 g, 0.441 mmol) in 5 mL of MeCN was treated consecutively
with Na2CO3 (0.046 g, 0.43 mmol) followed by acyl pyrrole 35d
(0.100 g, 0.441 mmol) to give 0.162 g (82%) of amidosulfide 36d
as a colorless oil: IR (thin film) 3326, 1634 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.47-7.42 (m, 2H), 7.35-7.32 (m, 3H), 6.73 (s,
1H), 6.66 (app t, J ) 1.6 Hz, 1H), 6.54 (dd, J ) 3.9, 1.6 Hz, 1H),
6.36 (t, J ) 5.6 Hz, 1H), 6.02 (dt, J ) 2.6, 1.2 Hz, 1H), 3.89 (s,
3H), 3.63 (q, J ) 6.6 Hz, 2H), 2.93 (s, 6H), 2.82 (t, J ) 7.6 Hz,
2H), 1.87 (quint, J ) 6.9 Hz, 2H); 13C NMR (90 MHz, CDCl3) δ
161.9, 143.4, 135.3, 132.6, 130.8, 129.0, 128.4, 127.9, 127.5, 125.4,
111.3, 106.9, 38.3, 38.0, 36.4, 28.7, 23.8; LRMS (ESI) m/z (relative
intensity) 448.1 (100% M + H+); HRMS (ESI) m/z calcd for
[C20H26N5O3S2]+, 448.1477; found, 448.1475.
4-Bromo-1H-pyrrole-2-carboxylic Acid [3-(3-Dimethylsulfa-
moyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]amide (36e). Fol-
lowing General Procedure B (Supporting Information), amine 34
(0.150 g, 0.441 mmol) in 5 mL of MeCN was treated consecutively
with Na2CO3 (0.046 g, 0.43 mmol) followed by acyl pyrrole 35e
(0.128 g, 0.441 mmol) to give 0.174 g (67%) of amidosulfide 36e
as a white solid: mp 146-148 °C; IR (thin film) 3215, 1629 cm-1
;
1H NMR (400 MHz, CDCl3) δ 9.94 (br s, 1H), 7.50-7.47 (m, 2H),
7.38-7.34 (m, 3H), 6.88 (dd, J ) 2.2, 1.1 Hz, 1H), 6.77 (s, 1H),
6.56 (dd, J ) 2.0, 1.1 Hz, 1H), 6.17 (t, J ) 5.1 Hz, 1H), 3.45 (q,
J ) 6.5 Hz, 2H), 2.98 (s, 6H), 2.85 (t, J ) 7.2 Hz, 2H), 1.91 (quint,
J ) 6.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 160.4, 144.1, 135.3,
133.1, 130.7, 129.30, 128.8, 128.3, 126.1, 121.4, 111.0, 96.9, 38.8,
38.4, 29.0, 23.9; LRMS (ESI) m/z (relative intensity) 512.1 (100%
M + H+); HRMS (ESI) m/z calcd for [C19H23BrN5O3S2]+,
512.0426; found, 512.0443.
4-Bromo-1-methyl-1H-pyrrole-2-carboxylic Acid [3-(3-Di-
methylsulfamoyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]amide
(36f). Following General Procedure B (Supporting Information),
amine 34 (0.150 g, 0.441 mmol) in 5 mL of MeCN was treated
consecutively with Na2CO3 (0.046 g, 0.43 mmol) followed by acyl
pyrrole 35f (0.135 g, 0.441 mmol) to give 0.184 g (79%) of
amidosulfide 36f as a white solid: mp 144-145 °C; IR (thin film)
4,5-Dibromo-1H-pyrrole-2-carboxylic Acid [3-(3-Dimethyl-
sulfamoyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]amide. Fol-
lowing General Procedure B (Supporting Information), amine 34
(0.203 g, 0.548 mmol) in 5 mL of MeCN was treated consecutively
with Na2CO3 (0.058 g, 0.55 mmol) followed by acyl pyrrole 23
(0.187 g, 0.548 mmol) to give 0.282 g (87%) of amidosulfide
product as a white solid: mp 123-124 °C; IR (thin film) 3117,
1643 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (br s, 1H), 7.46-
7.44 (m, 2H), 7.42-7.35 (m, 3H), 6.87 (s, 1H), 6.53 (s, 1H), 3.23
(q, J ) 6.5 Hz, 2H), 2.93 (s, 6H), 2.72 (t, J ) 7.4 Hz, 2H), 1.75
(quint, J ) 7.1 Hz, 2H); 13C NMR (90 MHz, CDCl3) δ 161.7, 142.2,
135.6, 132.6, 131.3, 130.9, 129.2, 128.4, 127.7, 112.2, 108.5, 94.7,
37.9, 37.8, 28.0, 23.5; LRMS (ESI) m/z (relative intensity) 589.9
1
3307, 1644 cm-1; H NMR (300 MHz, CDCl3) δ 7.48-7.45 (m,
2H), 7.38-7.32 (m, 3H), 6.74 (s, 1H), 6.66 (d, J ) 1.8 Hz, 1H),
6.52 (d, J ) 1.8 Hz, 1H), 6.25 (t, J ) 5.5 Hz, 1H), 3.87 (s, 3H),
3.38 (q, J ) 6.6 Hz, 2H), 2.98 (s, 6H), 2.83 (t, J ) 7.4 Hz, 2H),
1.88 (quint, J ) 6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 161.0,
143.7, 135.3, 132.8, 130.8, 129.2, 128.6, 128.1, 127.0, 126.2, 113.2,
94.2, 38.6, 38.3, 36.7, 28.8, 24.0; LRMS (ESI) m/z (relative
intensity) 526.0 (100% M + H+); HRMS (ESI) m/z calcd for
[C20H25BrN5O3S2]+, 526.0589; found, 526.0585.
8082 J. Org. Chem., Vol. 72, No. 21, 2007

Synthesis Studies in the Phakellin Alkaloid Area
4,5-Dibromo-1-methyl-1H-pyrrole-2-carboxylic Acid [3-(3-
Dimethylsulfamoyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]-
amide (36i). Following General Procedure B (Supporting Infor-
mation), amine 34 (0.150 g, 0.441 mmol) in 5 mL of MeCN was
treated consecutively with Na2CO3 (0.046 g, 0.43 mmol) followed
by acyl pyrrole 35i (0.170 g, 0.441 mmol) to give 0.214 g (80%)
of amidosulfide 36i as a white solid: mp 68-70 °C; IR (thin film)
1-(2-Trimethylsilanylethoxymethyl)-1H-pyrrole-2-carboxyl-
ic Acid [3-(3-Dimethylsulfamoyl-2-phenylsulfanyl-3H-imidazol-
4-yl)propyl]amide (36c). Following General Procedure B (Sup-
porting Information), amine 34 (0.317 g, 0.923 mmol) in 5 mL of
MeCN was treated consecutively with Na2CO3 (0.098 g, 0.92 mmol)
followed by acyl pyrrole 35c (0.314 g, 0.923 mmol) to give 0.334
g (64%) of amidosulfide 36c as a colorless oil: IR (thin film) 3331,
1
3317, 1644 cm-1; H NMR (300 MHz, CDCl3) δ 7.49-7.46 (m,
1
1641 cm-1; H NMR (360 MHz, CDCl3) δ 7.49-7.46 (m, 2H),
2H), 7.37-7.35 (m, 3H), 6.76 (s, 1H), 6.23 (s, 1H), 6.14 (t, J )
6.6 Hz, 1H), 3.93 (s, 3H), 3.40 (q, J ) 6.5 Hz, 2H), 2.99 (s, 6H),
2.82 (t, J ) 7.5 Hz, 2H), 1.91 (quint, J ) 6.8 Hz, 2H); 13C NMR
(90 MHz, CDCl3) δ 160.5, 144.0, 135.3, 133.0, 130.8, 129.30,
128.7, 128.3, 127.6, 111.5, 109.5, 97.8, 38.7, 38.4, 35.6, 29.0,
24.0; LRMS (ESI) m/z (relative intensity) 604.0 (100% M + H+);
HRMS (ESI) m/z calcd for [C20H23Br2N5O3S2]+, 603.9687; found,
603.9691.
7.39-7.33 (m, 3H), 6.89 (dd, J ) 2.5, 1.4 Hz, 1H), 6.76 (s, 1H),
6.67 (dd, J ) 3.6, 1.4 Hz, 1H), 6.55 (t, J ) 7.6, 1H), 6.13 (dd, J
) 4.0, 2.8 Hz, 1H), 5.63 (s, 2H), 3.54 (t, J ) 8.3 Hz, 2H), 3.44 (q,
J ) 6.5 Hz, 2H), 2.97 (s, 6H), 2.83 (t, J ) 7.2 Hz, 2H), 1.91 (quint,
J ) 6.8 Hz, 2H), 0.90 (t, J ) 8.3 Hz, 2H), -0.04 (s, 9H); 13C
NMR (90 MHz, CDCl3) δ 161.6, 143.6, 135.3, 132.8, 130.9, 129.2,
128.6, 128.1, 126.5, 126.4, 113.6, 108.1, 76.6, 65.8, 38.6, 38.2,
28.8, 24.0, 17.6, -1.57; LRMS (ESI) m/z (relative intensity) 564.2
(100% M + H+); HRMS (ESI) m/z calcd for [C25H38N5O4S2Si]+,
564.2143; found, 564.2141.
1-Methoxymethyl-1H-pyrrole-2-carboxylic Acid [3-(3-Di-
methylsulfamoyl-2-phenylsulfanyl-3H-imidazol-4-yl)propyl]amide
(36b). Following General Procedure B (Supporting Information),
amine 34 (0.226 g, 0.881 mmol) in 5 mL of MeCN was treated
consecutively with Na2CO3 (0.094 g, 0.88 mmol) followed by acyl
pyrrole 35b (0.300 g, 0.881 mmol) to give 0.260 g (62%) of
4,5-Dibromo-1-(2-trimethylsilanylethoxymethyl)-1H-pyrrole-
2-carboxylic Acid [3-(3-Dimethylsulfamoyl-2-phenylsulfanyl-3H-
imidazol-4-yl)propyl]amide (36h). Following General Procedure
B (Supporting Information), amine 34 (0.300 g, 0.881 mmol) in 5
mL of MeCN was treated consecutively with Na2CO3 (0.093 g,
0.97 mmol) followed by acyl pyrrole 35h (0.485 g, 0.969 mmol)
to give 0.282 g (44%) of amidosulfide 36h as a colorless oil: IR
(thin film) 3326, 1651 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.50-
7.47 (m, 2H), 7.39-7.34 (m, 3H), 6.76 (s, 2H), 6.60 (t, J ) 5.4
Hz, 1H), 5.74 (s, 2H), 3.61 (dt, J ) 8.3, 2.9 Hz, 2H), 3.41 (q, J )
6.5 Hz, 2H), 2.99 (s, 6H), 2.83 (t, J ) 7.2 Hz, 2H), 1.91 (quint, J
amidosulfide 36b as a colorless oil: IR (thin film) 3331, 1641 cm-1
;
1H NMR (360 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.39-7.33 (m,
3H), 6.90 (dd, J ) 2.9, 1.8 Hz, 1H), 6.76 (s, 1H), 6.67 (dd, J )
4.0, 1.8 Hz, 1H), 6.44 (t, J ) 5.8 Hz, 1H), 6.14 (dd, J ) 3.6, 2.5
Hz, 1H), 5.61 (s, 2H), 3.43 (q, J ) 6.8 Hz, 2H), 3.30 (s, 3H), 2.97
(s, 6H), 2.82 (t, J ) 6.8 Hz, 2H), 1.91 (quint, J ) 6.5 Hz, 2H); 13
C
NMR (90 MHz, CDCl3) δ 161.6, 143.7, 135.3, 132.8, 130.8, 129.2,
128.6, 128.1, 126.8, 126.2, 113.5, 108.1, 78.5, 55.9, 38.6, 38.3,
28.8, 24.0; LRMS (ESI) m/z (relative intensity) 478.1 (100% M +
H+); HRMS (ESI) m/z calcd for [C21H28N5O4S2]+, 478.1583; found,
478.1584.
) 6.8 Hz, 2H), 0.91 (dt, J ) 8.3, 2.9 Hz, 2H), -0.03 (s, 9H); 13
C
NMR (90 MHz, CDCl3) δ 160.1, 143.9, 135.3, 132.9, 130.8, 129.3,
128.9, 128.8, 128.3, 115.8, 110.7, 99.9, 75.1, 66.2, 39.0, 38.4, 28.9,
24.1, 17.8, -1.46; LRMS (ESI) m/z (relative intensity) 720.1 (100%
M + H+); HRMS (ESI) m/z calcd for [C25H36Br2N5O4S2Si]+,
720.0345; found, 720.0362.
4,5-Dibromo-1-methoxymethyl-1H-pyrrole-2-carboxylic Acid
[3-(3-Dimethylsulfamoyl-2-phenylsulfanyl-3H-imidazol-4-yl)pro-
pyl]amide (36g). Following General Procedure B (Supporting
Information), amine 34 (0.300 g, 0.881 mmol) in 5 mL of MeCN
was treated consecutively with Na2CO3 (0.093 g, 0.97 mmol)
followed by acyl pyrrole 35g (0.402 g, 0.969 mmol) to give 0.246
g (44%) of amidosulfide 36g as a white oil: IR (thin film) 3310,
1H-Pyrrole-2-carboxylic Acid [3-(2-Phenylsulfanyl-3H-imi-
dazol-4-yl)propyl]amide (37a). Following General Procedure C
(Supporting Information), amide 36a (0.084 g, 0.19 mmol) in 3
mL of THF was heated to reflux and treated with 0.516 mL of a
1.5 M HCl solution to give 0.054 g (85%) of the deprotection
product 37a as a colorless oil: IR (thin film) 3212, 1613 cm-1; 1H
NMR (400 MHz, d4-MeOH) δ 7.26-7.22 (m, 2H), 7.18-7.14 (m,
3H), 6.94 (s, 1H), 6.88 (dd, J ) 2.2, 1.1 Hz, 1H), 6.76 (dd, J )
3.6, 1.0 Hz, 1H), 6.14 (app t, J ) 2.5 Hz, 1H), 3.35 (t, J ) 6.8 Hz,
2H), 2.64 (t, J ) 7.6 Hz, 2H), 1.81 (quint, J ) 7.1 Hz, 2H); 13C
NMR (90 MHz, DMSO-d6) δ 162.3, 137.3, 136.8, 132.4, 131.2,
130.5, 130.2, 126.3, 122.9, 119.5, 111.7, 110.0, 38.6, 28.7, 22.6;
LRMS (ESI) m/z (relative intensity) 327.1 (100% M + H+); HRMS
(ESI) m/z calcd for [C17H19N4OS]+, 327.1280; found, 327.1284.
1
1651 cm-1; H NMR (360 MHz, CDCl3) δ 7.48-7.46 (m, 2H),
7.39-7.33 (m, 3H), 6.75 (s, 1H), 6.74 (s, 1H), 6.54 (t, J ) 5.0 Hz,
1H), 5.74 (s, 2H), 3.41 (q, J ) 6.5 Hz, 2H), 3.35 (s, 3H), 2.98 (s,
6H), 2.81 (t, J ) 7.6 Hz, 2H), 1.89 (quint, J ) 6.8 Hz, 2H); 13C
NMR (90 MHz, CDCl3) δ 160.0, 144.0, 135.3, 133.0, 130.8, 129.4,
128.8, 128.7, 128.4, 115.6, 111.0, 100.6, 77.8, 56.3, 38.9, 38.4,
29.0, 24.1; LRMS (ESI) m/z (relative intensity) 634.0 (100% M +
H+); HRMS (ESI) m/z calcd for [C21H26Br2N5O4S2]+, 633.9814;
found, 633.9805.
J. Org. Chem, Vol. 72, No. 21, 2007 8083

Feldman et al.
1633 cm-1; H NMR (360 MHz, CDCl3) δ 7.21-7.13 (m, 5H),
6.86 (br s, 1H), 6.82 (s, 1H), 6.65 (d, J ) 1.5 Hz, 1H), 6.60 (d, J
) 1.4 Hz, 1H), 3.82 (s, 3H), 3.38 (q, J ) 6.1 Hz, 2H), 2.63 (t, J
) 6.5 Hz, 2H), 1.82 (quint, J ) 6.1 Hz, 2H); 13C NMR (90 MHz,
DMSO-d6) δ 161.2, 137.0, 136.1, 131.8, 130.8, 130.2, 130.0, 127.7,
126.7, 119.4, 114.3, 93.7, 38.1, 36.9, 28.3, 22.3; LRMS (ESI) m/z
(relative intensity) 419.0 (100% M + H+); HRMS (ESI) m/z calcd
for [C18H20BrN4OS]+, 419.0541; found, 419.0562.
1
4-Bromo-1H-pyrrole-2-carboxylic Acid [3-(2-Phenylsulfanyl-
3H-imidazol-4-yl)propyl]amide (37e). Following General Proce-
dure C (Supporting Information), amide 36e (0.161 g, 0.314 mmol)
in 3 mL of THF was heated to reflux and treated with 0.837 mL of
a 1.5 M HCl solution to give 0.085 g (67%) of the deprotection
product 37e as a colorless oil: IR (thin film) 3183, 1622 cm-1; 1H
NMR (300 MHz, d4-MeOH) δ 7.26-7.22 (m, 2H), 7.18-7.14 (m,
3H), 6.95 (br s, 1H), 6.88 (d, J ) 1.5 Hz, 1H), 6.77 (d, J ) 1.5 Hz,
1H), 3.33 (t, J ) 6.9 Hz, 2H), 2.63 (t, J ) 7.5 Hz, 2H), 1.85 (quint,
J ) 7.0 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 161.0, 137.1,
137.0, 132.4, 131.1, 130.4, 130.0, 127.1, 122.5, 119.4, 112.8, 96.2,
38.6, 28.5, 22.6; LRMS (ESI) m/z (relative intensity) 405.0 (100%
M + H+); HRMS (ESI) m/z calcd for [C17H18BrN4OS]+, 405.0388;
found, 405.0359.
4,5-Dibromo-1-methyl-1H-pyrrole-2-carboxylic Acid [3-(2-
Phenylsulfanyl-3H-imidazol-4-yl)propyl]amide (37i). Following
General Procedure C (Supporting Information), amide 36i (0.150
g, 0.248 mmol) in 3 mL of THF was heated to reflux and treated
with 0.660 mL of a 1.5 M HCl solution to give 0.073 g (63%) of
the deprotection product 37i as a colorless oil: IR (thin film) 3154,
1
1632 cm-1; H NMR (300 MHz, CDCl3) δ 7.20-7.11 (m, 5H),
6.80 (s, 1H), 6.70 (s, 1H), 3.84 (s, 3H), 3.35 (q, J ) 5.9 Hz, 2H),
2.62 (t, J ) 6.4 Hz, 2H), 1.81 (quint, J ) 6.2 Hz, 2H); 13C NMR
(90 MHz, DMSO-d6) δ 161.4, 137.2, 136.9, 132.5, 131.2, 130.6,
130.1, 128.5, 119.5, 115.1, 111.9, 98.1, 36.4, 36.4, 28.4, 22.7;
LRMS (ESI) m/z (relative intensity) 496.9 (100% M + H+);
HRMS (ESI) m/z calcd for [C18H19N4OS Br2]+, 496.9646; found,
496.9651.
4,5-Dibromo-1H-pyrrole-2-carboxylic Acid [3-(2-Phenylsul-
fanyl-3H-imidazol-4-yl)propyl]amide (24a). Following General
Procedure C (Supporting Information), 4,5-dibromo-1H-pyrrole-
2-carboxylic acid [3-(3-dimethylsulfamoyl-2-phenylsulfanyl-
3H-imidazol-4-yl)propyl]amide (0.310 g, 0.524 mmol) in 2 mL of
THF was heated to reflux and treated with 2.80 mL of a 1.5 M
HCl solution to give 0.240 g (95%) of the deprotection product
24a as a white solid previously described by Feldman and
Skoumbourdis.2f
1-Methoxymethyl-1H-pyrrole-2-carboxylic Acid [3-(2-Phe-
nylsulfanyl-3H-imidazol-4-yl)propyl]amide (37b). Following Gen-
eral Procedure C (Supporting Information), amide 36b (0.300 g,
0.881 mmol) in 3 mL of THF was heated to reflux and treated
with 2.35 mL of a 1.5 M HCl solution to give 0.213 g (71%) of
the deprotection product 37b as a colorless oil: IR (thin film) 3180,
1
1629 cm-1; H NMR (400 MHz, CDCl3) δ 7.16-7.04 (m, 5H),
1-Methyl-1H-pyrrole-2-carboxylic Acid [3-(2-Phenylsulfanyl-
3H-imidazol-4-yl)propyl]amide (37d). Following General Proce-
dure C (Supporting Information), amide 36d (0.125 g, 0.279 mmol)
in 3 mL of THF was heated to reflux and treated with 0.774 mL of
a 1.5 M HCl solution to give 0.072 g (76%) of the deprotection
product 37d as a colorless oil: IR (thin film) 3059, 1631 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.15-7.09 (m, 5H), 6.95 (br s, 1H),
6.78 (s, 1H), 6.73 (br t, J ) 6.0 Hz, 1H), 6.65 (app t, J ) 1.8 Hz,
1H), 6.57 (dd, J ) 3.9, 1.6 Hz, 1H), 6.00 (dd, J ) 3.9, 2.6 Hz,
1H), 3.83 (s, 3H), 3.33 (t, J ) 6.3 Hz, 2H), 2.59 (t, J ) 6.8 Hz,
2H), 1.73 (quint, J ) 6.6 Hz, 2H); 13C NMR (90 MHz, DMSO-d6)
δ 163.6, 137.53, 137.46, 132.9, 131.5, 130.9, 130.1, 129.7, 126.0,
119.5, 114.1, 108.4, 37.30, 37.26, 28.8, 22.9; LRMS (ESI) m/z
(relative intensity) 341.1 (100% M + H+); HRMS (ESI) m/z calcd
for [C18H21N4OS]+, 341.1436; found, 341.1438.
6.83 (t, J ) 1.4 Hz, 1H), 6.76 (s, 1H), 6.69 (dd, J ) 3.7, 1.5 Hz,
1H), 6.05 (dd, J ) 3.7, 2.7 Hz, 1H), 5.52 (s, 2H), 3.43 (q, J ) 6.0
Hz, 2H), 3.20 (s, 3H), 2.56 (t, J ) 6.8 Hz, 2H), 1.76 (quint, J )
6.6 Hz, 2H); 13C NMR (90 MHz, DMSO-d6) δ 162.7, 137.5, 136.7,
132.1, 131.0, 130.6, 130.2, 128.8, 126.0, 119.7, 115.1, 108.6, 78.6,
56.2, 38.6, 28.7, 22.7; LRMS (ESI) m/z (relative intensity) 371.1
(100% M + H+); HRMS (ESI) m/z calcd for [C19H23N4O2S]+,
371.1542; found, 371.1560.
4,5-Dibromo-1-methoxymethyl-1H-pyrrole-2-carboxylic Acid
[3-(2-Phenylsulfanyl-3H-imidazol-4-yl)propyl]amide (37g). Fol-
lowing General Procedure C (Supporting Information), amide 36g
(0.067 g, 0.11 mmol) in 3 mL of THF was heated to reflux and
treated with 0.084 mL of a 1.5 M HCl solution to give 0.040 g
(72%) of the deprotection product 37g as a colorless oil: IR (thin
film) 3180, 1629 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52 (br s,
1H), 7.21-7.13 (m, 5H), 6.83 (s, 1H), 6.81 (br s, 1H), 5.70 (s,
2H), 3.37 (q, J ) 5.8 Hz, 2H), 3.27 (s, 3H), 2.62 (t, J ) 6.2 Hz,
2H), 1.82 (quint, J ) 5.9 Hz, 2H); 13C NMR (90 MHz, DMSO-d6)
δ 160.8, 137.1, 136.7, 132.2, 131.1, 130.4, 130.1, 129.1, 119.5,
116.1, 111.6, 99.9, 77.0, 56.4, 38.6, 28.3, 22.5; LRMS (ESI) m/z
4-Bromo-1-methyl-1H-pyrrole-2-carboxylic Acid [3-(2-Phe-
nylsulfanyl-3H-imidazol-4-yl)propyl]amide (37f). Following Gen-
eral Procedure C (Supporting Information), amide 36f (0.149 g,
0.283 mmol) in 3 mL of THF was heated to reflux and treated
with 0.750 mL of a 1.5 M HCl solution to give 0.067 g (56%) of
the deprotection product 37f as a colorless oil: IR (thin film) 3119,
8084 J. Org. Chem., Vol. 72, No. 21, 2007

Synthesis Studies in the Phakellin Alkaloid Area
(relative intensity) 527.0 (100% M + H+); HRMS (ESI) m/z calcd
for [C19H21 Br2N4O2S]+, 526.9752; found, 526.9766.
Trifluoromethanesulfonic Acid 5-{3-[(4,5-Dibromo-1H-pyr-
role-2-carbonyl)amino]propyl}-2-phenylsulfanyl-3H-imidazol-
4-yl Ester (27). A stirring solution of amidosulfoxide 24b (0.092
g, 0.18 mmol) in 3.5 mL of CH2Cl2 was cooled to -78 °C and
treated with i-Pr2NEt (61 µL, 0.37 mmol). After 5 min, Tf2O (169
µL, 0.552 mmol) was added, and the reaction solution changed
from colorless to red. The reaction mixture was held at -78 °C
for 30 min and was then warmed to room temperature over 10 min
and poured into H2O (5 mL). The resulting solution was partitioned
between CH2Cl2 and H2O, and the aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). The combined organic fractions were
dried with Na2SO4 and concentrated to give a yellow oil. Purifica-
tion of this oil by flash column chromatography (1:1 EtOAc/
hexanes) gave 0.010 g (9%) of the triflate 27 as an unstable yellow
oil: IR (thin film) 3129, 1618 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 13.3 (br s, 1H), 12.7 (br s, 1H), 8.16 (t, J ) 5.6 Hz, 1H),
7.37-7.15 (m, 5H), 6.89 (d, J ) 2.4 Hz, 1H), 3.20 (q, J ) 6.5 Hz,
2H), 2.58 (t, J ) 7.4 Hz, 2H), 1.78 (quint, J ) 7.5 Hz, 2H); 13C
NMR (75 MHz, DMSO-d6) δ 158.9, 140.6, 134.4, 130.4, 129.5,
128.1, 127.6, 127.0, 122.8, 112.4, 104.5, 97.7, 37.9, 28.3, 20.2;
LRMS (ESI) m/z (relative intensity) 630.8 (100% M + H+); HRMS
(ESI) m/z calcd for [C18H16N4O4F3S2Br2]+, 630.8967; found,
630.8932. Carbon-fluorine coupling was not observed due to a
paucity of material and the instability of 27, which experienced
decomposition even after short NMR acquisition times.
1-(2-Trimethylsilanylethoxymethyl)-1H-pyrrole-2-carboxyl-
ic Acid [3-(2-Phenylsulfanyl-3H-imidazol-4-yl)propyl]amide (37c).
Following General Procedure C (Supporting Information), amide
36c (0.315 g, 0.559 mmol) in 3 mL of THF was heated to reflux
and treated with 1.49 mL of a 1.5 M HCl solution to give 0.224 g
(88%) of the deprotection product 37c as a colorless oil: IR (thin
film) 3182, 1634 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14-7.06
(m, 5H), 6.85 (br d, J ) 3.2 Hz, 1H), 6.77 (s, 1H), 6.68 (dd, J )
3.7, 1.6 Hz, 1H), 6.07 (t, J ) 3.6 Hz, 1H), 5.58 (s, 2H), 3.49 (t, J
) 8.6 Hz, 2H), 3.32 (q, J ) 6.1 Hz, 2H), 2.58 (t, J ) 6.2 Hz, 2H),
1.78 (quint, J ) 6.5 Hz, 2H), 0.84 (t, J ) 8.6 Hz, 2H), -0.08 (s,
9H); 13C NMR (90 MHz, DMSO-d6) δ 162.8, 137.2, 136.8, 132.5,
131.1, 130.5, 130.0, 128.5, 126.2, 119.4, 114.8, 108.6, 76.7, 65.8,
38.4, 28.8, 22.5, 18.0, -0.8; LRMS (ESI) m/z (relative intensity)
457.2 (100% M + H+); HRMS (ESI) m/z calcd for [C23H33 N4O2-
SSi]+, 457.2094; found, 457.2106.
4,5-Dibromo-1-(2-trimethylsilanylethoxymethyl)-1H-pyrrole-
2-carboxylic Acid [3-(2-Phenylsulfanyl-3H-imidazol-4-yl)propyl]-
amide (37h). Following General Procedure C (Supporting Infor-
mation), amide 36h (0.243 g, 0.367 mmol) in 3 mL of THF was
heated to reflux and treated with 0.979 mL of a 1.5 M HCl solution
to give 0.187 g (83%) of the deprotection product 37h as a color-
less oil: IR (thin film) 3143, 1634 cm-1; H NMR (400 MHz,
1
Ethylated Isourea (33). A stirring solution of dibromophakell-
statin 1 (0.107 g, 0.274 mmol) in 10 mL of CH2Cl2 was treated
with NaHCO3 (0.460 g, 5.48 mmol). After 5 min, Et3O+BF4- (0.260
g, 1.37 mmol) was added, and the reaction mixture was held at
room temperature for 2 h and then poured into 10 mL of ice-cold
aqueous NaHCO3. The resulting solution was partitioned between
CH2Cl2 and H2O, and the aqueous layer was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic fractions were dried with
Na2SO4 and concentrated to give a yellow oil. Purification of this
oil by flash column chromatography (alumina, gradient 70-100%
EtOAc/hexanes) gave 0.051 g (45%) of the ethyl derivative 33 as
a white solid: mp 208-210 °C (dec); IR (thin film) 3230, 1621
cm-1; 1H NMR (360 MHz, d4-MeOH) δ 6.89 (s, 1H), 5.88 (s, 1H),
4.27-4.13 (m, 2H), 3.79 (br m, 1H), 3.69-3.61 (m, 1H), 2.25-
2.07 (m, 4H), 1.28 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 161.1, 154.8, 125.8, 114.9, 104.0, 102.4, 88.2, 72.5, 65.8, 44.2,
40.7, 20.2, 14.2; LRMS (ESI) m/z (relative intensity) 438.9 (100%
M + Na+); HRMS (ESI) m/z calcd for [C13H14N4O2Br2Na]+,
438.9381; found, 438.9405.
CDCl3) δ 7.50 (br s, 1H), 7.19-7.09 (m, 5H), 6.81 (s, 1H), 6.79
(s, 1H), 5.70 (s, 2H), 3.49 (t, J ) 8.5 Hz, 2H), 3.32 (q, J ) 5.8 Hz,
2H), 2.60 (t, J ) 6.4 Hz, 2H), 1.81 (quint, J ) 6.2 Hz, 2H), 0.85
(t, J ) 8.5 Hz, 2H), -0.07 (s, 9H); 13C NMR (90 MHz, DMSO-
d6) δ 161.0, 137.1, 136.8, 132.5, 131.1, 130.5, 130.0, 129.1, 119.5,
116.1, 111.5, 99.8, 75.3, 66.2, 38.7, 28.5, 22.5, 18.0, -0.8;
LRMS (ESI) m/z (relative intensity) 613.0 (100% M + H+);
HRMS (ESI) m/z calcd for [C23H31Br2N4O2SSi]+, 613.0303; found,
613.0327
4,5-Dibromo-1H-pyrrole-2-carboxylic Acid [3-(2-Benzene-
sulfinyl-3H-imidazol-4-yl)propyl]amide (24b). Following General
Procedure C (Supporting Information), 4,5-dibromo-1H-pyrrole-
2-carboxylic acid [3-(2-benzenesulfinyl-3-dimethylsulfamoyl-3H-
imidazol-4-yl)propyl]amide (0.500 g, 0.823 mmol) in 4 mL of THF
was heated to reflux and treated with 2.20 mL of a 1.5 M HCl
solution to give 0.186 g (45%) of the deprotection product 24b as
a white solid: mp 200-202 °C (dec); IR (thin film) 3043, 1629
1
cm-1; H NMR (300 MHz, DMSO-d6, 80 °C) δ 7.79-7.76 (m,
2H), 7.61-7.59 (m, 3H), 7.31 (s, 1H), 6.86 (s, 1H), 3.20 (t, J )
6.7 Hz, 2H), 2.63 (t, J ) 7.4 Hz, 2H), 1.78 (quint, J ) 6.9 Hz,
2H); 13C NMR (90 MHz, DMSO-d6) δ 159.6, 146.0, 141.2, 137.8,
133.4, 130.6, 128.4, 125.6, 120.2, 113.5, 105.0, 98.5, 38.2, 28.5,
22.6; LRMS (ESI) m/z (relative intensity) 498.9 (70% M + H+);
HRMS (ESI) m/z calcd for [C17H17Br2N4O2S]+, 498.9431; found,
494.9435.
Dibromophakellin Hydrochloride (2a)•HCl. A neat mixture
+
of isourea 33 (0.020 g, 0.048 mmol) and EtCO2-NH4 (1.0 g, 11
mmol) was heated to 135 °C and held at this temperature for 30
min. The resulting dark-yellow solution was allowed to cool to room
temperature, and the excess propionate salt was removed by
J. Org. Chem, Vol. 72, No. 21, 2007 8085

Feldman et al.
sublimation under vacuum at 80 °C to leave a brown oil.
Purification of this oil by gravity column chromatography (Sepha-
dex G-10, H2O then MeOH) gave a white gum that was dissolved
in 100 mL of CH2Cl2, and HCl (g) was bubbled through the solution
for 10 min. The reaction mixture was then concentrated to give
0.012 g (59%) of dibromophakellin hydrochloride (2a)•HCl as a
white solid: mp 218-220 °C (dec); IR (thin film) 3411, 1679,
Acknowledgment. Funding from the National Science
Foundation (CHE 04-14877) is gratefully acknowledged.
Supporting Information Available: General experimental
procedures; copies of 1H NMR and 13C NMR spectra for 2a, 22b,
24b, 27, 33, 34, 35c, 35g, 35h, 36a-i, 37a-i, 5-(3-Aminopropyl)-
2-benzenesulfinylimidazole-1-sulfonic acid dimethylamide, 4,5-
dibromo-1H-pyrrole-2-carboxylic acid [3-(3-dimethylsulfamoyl-2-
phenylsulfanyl-3H-imidazol-4-yl)propyl]amide, and 4,5-dibromo-
1H-pyrrole-2-carboxylic acid [3-(2-benzenesulfinyl-3-dimethylsulfa-
moyl-3H-imidazol-4-yl)propyl]amide. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
1637 cm-1; H NMR (360 MHz, d4-MeOH) δ 7.01 (s, 1H), 6.24
(s, 1H), 3.83 (ddd, J ) 11.7, 8.4, 3.3 Hz, 1H), 3.68-3.60 (m, 1H),
2.46-2.42 (m, 2H), 2.25-2.13 (m, 2H); 13C NMR (75 MHz, d4-
MeOH) δ 158.0, 156.5, 126.0, 117.1, 107.7, 104.1, 84.2, 70.2, 46.2,
40.1, 20.5; LRMS (ESI) m/z (relative intensity) 387.9 (70% M+);
HRMS (ESI) m/z calcd for [C11H12N5OBr2]+, 387.9409; found,
387.9392.
JO701487J
8086 J. Org. Chem., Vol. 72, No. 21, 2007