Extending pummerer reaction chemistry. Synthesis of (±)- dibromophakellstatin by oxidative cyclization of an imidazole derivative

Article abstract of DOI:10.1021/ol0500113

(Chemical Equation Presented) The diastereoselective oxidative cyclization of a dihydrooroidin derivative is reported. The thioimidate product formed by application of a new variant of the Pummerer reaction serves as a precursor to dibromophakellstatin.

Full text of DOI:10.1021/ol0500113

ORGANIC
LETTERS
2005
Vol. 7, No. 5
929-931
Extending Pummerer Reaction
Chemistry. Synthesis of
(±)-Dibromophakellstatin by Oxidative
Cyclization of an Imidazole Derivative
Ken S. Feldman* and Amanda P. Skoumbourdis
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
ksf@chem.psu.edu
Received January 4, 2005
ABSTRACT
The diastereoselective oxidative cyclization of a dihydrooroidin derivative is reported. The thioimidate product formed by application of a new
variant of the Pummerer reaction serves as a precursor to dibromophakellstatin.
Oxidation of 2-aminoimidazole systems with concomitant
cyclization of a tethered nucleophile has been postulated to
underlie the biosynthesis of many polycyclic marine alka-
loids,1 and the mimicry of this process has fueled several
concise synthesis strategies for these species,2 inter alia.
However, not all heterocycle-based oxidative cyclization
biosynthesis blueprints translate readily to the laboratory, as
complications due to overoxidation and/or lack of regiocon-
trol upon nucleophile attack can compromise these ap-
proaches.3 Recently, a new approach for avoiding these issues
in indole oxidative cyclizations at C(3), which relies on a
variant of the Pummerer reaction,4 was reported.5 Extension
of this process to the imidazole nucleus would enable facile
access to spirocyclic 4,4-disubstituted imidazolines, a mo-
lecular framework that defines many biologically active
sponge metabolites.1a,6 Seminal work in this area by Bu¨chi
(Br2 as oxidant),2a with recent improvements by Horne (NBS
as oxidant),2f illustrate the value of this strategy for rapid
access to the relatively simple targets dibromophakellstatin
(1)6a and dibromophakellin (2).6b However, the use of the
Pummerer process described below, with its well-defined and
unambiguous site of oxidative initiation, may hold some
value in oxidative cyclization attempts directed toward the
more structurally complex and functionally rich members
(3) (a) 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. (b)
Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada, K.; Yamada,
F. Heterocycles 2000, 53, 7-10. (c) Wang, H.; Ganesan, A. J. Org. Chem.
2000, 65, 4685-4693. (d) Irikawa, H.; Mutoh, S.; Uehara, M.; Okumura,
Y. Bull. Chem. Soc. Jpn. 1989, 62, 3031-3033. (e) Gu¨ller, Borschberg,
H.-J. HelV. Chim. Acta 1993, 76, 1847-1862.
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10.1021/ol0500113 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/05/2005

Scheme 2. Oxidative Cyclization of Pummerer Precursor,
with Mechanistic Speculation and Conversion of Cyclization
Product to Dibromophakellstatin
Figure 1. Two dihydrooroidin-derived sponge metabolites.
of this family, such as palau’amine6c or styloguanine.6d As
a stepping stone toward those goals, the synthesis of 1 was
pursued in order to establish the feasibility of the Pummerer-
based strategy in imidazole oxidative cyclization chemistry.
The key cyclization substrate 7 was prepared to test this
premise (Scheme 1). The imidazole C(2)/C(5) functional-
ization procedure described by Vollinga7 was employed to
generate the chloride 4 from imidazole (3). This species was
then converted to the amine 5 through straightforward
chemistry. Dibromoacylpyrrole attachment to the primary
amine of 5 afforded the polyfunctional dihydrooroidin
derivative 7, ready for the oxidative cyclization sequence.
Scheme 1. Synthesis of Pummerer Oxidative Cyclization
Precursor
encompass the structures 8-12. Initial formation of the
activated sulfur intermediate 8 sets up a mechanistic di-
chotomy involving either a Vinylogous Pummerer pathway9
or an alternative additiVe Pummerer sequence.10 The viny-
logous path bears some resemblance to SN1 chemistry in that
initial ionization of the nucleofuge precedes nucleophile
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J. P.; Ferna´ndez de la Pradilla, R.; Laborde, E. Synthesis 1987, 1088-
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Treatment of sulfide 7 with Stang’s reagent,8 PhI(CN)-
OTf, in the presence of diisopropylethylamine initiated the
oxidative cyclization sequence that delivered the tetracyclic
material 13 (Scheme 2). A putative mechanistic course might
(6) (a) 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) Fedoreev, S. A.; Utkina, N. K.; Il’in, S. G.; Reshetnyak, M.
V.; Maksimov, O. B. Tetrahedron Lett. 1986, 27, 3177-3180. (c) Kinnel,
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Tetrahedron Lett. 1995, 36, 2133-2136. Other approaches/syntheses to 1
include: (e) Jacquot, D. E. N.; Hoffmann, H.; Polborn, K.; Lindel, T.
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930
Org. Lett., Vol. 7, No. 5, 2005

addition, whereas the additive path is more closely aligned
with SN2′-type chemistry in that nucleophilic addition and
iodine departure are concerted. At present, there is no
evidence in hand that permits discrimination between these
two hypotheses. The intermediacy of the tricyclic species
10/12 remains a matter of speculation as well, as only
tetracyclic product is observed even under short reaction
times. Regioselectivity upon cyclization appears to be
complete. No product of C-N bond formation between
N(14) and C(6) was detected (cf. 9), nor was there any
evidence for C(3)-to-C(6) cyclization (cf. 10). Control
experiments demonstrated that product 13 (1) is only very
slightly degraded (<10%) upon exposure to Stang’s reagent
under long reaction times and (2) survives chromatographic
purification without decomposition.
thioimidate 13 furnished the urea-containing species (()-
dibromophakellstatin (1). No disruption of either aminal
function is seen during this transformation.
The successful acquisition of this marine alkaloid il-
lustrates the role that Pummerer oxidative cyclization
chemistry can play in the synthesis of dihydrooroidin-derived
natural products. The transformation proceeds without
interference byproduct overoxidation or regiochemical com-
plexities upon nucleophile addition, and these attributes may
find value upon application of this chemistry to more
complex members of this class.
Acknowledgment. The authors thank the National Sci-
ence Foundation (CHE 04-14877) for financial support of
this work.
The thioimidate moiety within 13 serves as a convenient
precursor to the sponge metabolite 1 through further func-
tional group interchange. Oxidative hydrolysis11 of the
Supporting Information Available: Spectral data in-
cluding 1H NMR, 13C NMR, IR, and MS for 1, 4, 5, 7, and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) Ho, T.-L.; Ho, H. C.; Wong, C. M. J. Chem. Soc., Chem. Commun.
1972, 791.
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