Extending pummerer reaction chemistry: Application to the assembly of the pentacyclic core of dibromopalau'amine

Article abstract of DOI:10.1021/ol1018322

A pentacyclic model system featuring the trans azabicyclo[3.3.0]octane unit of dibromopalau'amine was prepared with complete diastereoselectivity in the polycyclic core from a tricyclic precursor. The key transformations of this sequence include (a) a Pum

Full text of DOI:10.1021/ol1018322

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4532-4535
Extending Pummerer Reaction
Chemistry: Application to the Assembly
of the Pentacyclic Core of
Dibromopalau’amine
Ken S. Feldman* and Ahmed Yimam Nuriye
Chemistry Department, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
ksf@chem.psu.edu
Received August 5, 2010
ABSTRACT
A pentacyclic model system featuring the trans azabicyclo[3.3.0]octane unit of dibromopalau’amine was prepared with complete diastereoselectivity
in the polycyclic core from a tricyclic precursor. The key transformations of this sequence include (a) a Pummerer reaction-mediated oxidative
bicyclization, and (b) a Wolff rearrangement-based ring contraction to deliver the strained azabicyclo[3.3.0]octane core.
Palau’amine1 and its monobromo- and dibromo- conge-
ners2 have been the focus of numerous structural3 and
synthesis3d,4 studies since the original disclosure by Scheuer
and Kinnel, and for a long time these species stood at the
pinnacle of structural complexity among the pyrrole-imida-
zole alkaloids. More recently, a structural revision (reversed
stereochemistry at C(11) and C(17)) revealed palau’amine
to possess a highly strained trans azabicyclo[3.3.0]octane core
instead of the originally assigned cis fused configuration
(Figure 1).3 This revision derailed several ongoing ap-
proaches to the synthesis of the palau’amine skeleton and
reset the synthesis clock. The synthesis challenges inherent
Figure 1. (Revised) structure of dibromopalau’amine.
in the revised palua’amine architecture recently were met
by Baran et al., who described an elegant solution to the
preparation of the trans azabicyclo[3.3.0]octane moiety en
route to a concise assembly of the natural product target.5
Speculation about the biosynthesis of the palau’amine
system has run in several directions,2,3c,4g,6 but one line of
thinking suggests that 1 may owe its origins to the simple
precursor oroidin.6 Oroidin also has been invoked as a
(1) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376–3377.
(2) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.; Skoropowski, G.; Scheuer,
P. J. J. Org. Chem. 1998, 63, 3281–3286.
(3) (a) Grube, A.; Ko¨ck, M. Angew. Chem., Int. Ed. 2007, 46, 2320–
2324. (b) Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett.
2007, 48, 4573–4574. (c) Ko¨ck, M.; Grube, A.; Seiple, I. B.; Baran, P. S.
Angew. Chem., Int. Ed. 2007, 46, 6586–6594. (d) Lanman, B. A.; Overman,
L. E.; Paulini, R.; White, N. S. J. Am. Chem. Soc. 2007, 129, 12896–12900.
10.1021/ol1018322  2010 American Chemical Society
Published on Web 09/14/2010

plausible precursor to simpler pyrrole-imidazole alkaloids
of the phakellin family,6 and several synthesis strategies
directed toward these sponge alkaloids that were based upon
this model have come to fruition.7 In our laboratories, a
possibly biomimetic oxidative cyclization of sulfur-contain-
ing dihydrooroidin derivatives has been developed for the
construction of this phakellin-type structure, and this chem-
istry has been featured in total syntheses of the simple
pyrrole-imidazole alkaloids dibromophakellstatin, dibro-
mophakellin, and dibromoagelaspongin.7c,d,f,g The pivotal
transform in this chemistry is a Pummerer reaction, which
is utilized to transfer a unit of “oxidation” from sulfur to
the imidazole nucleus, thus activating it for nucleophilic
capture by the tethered nitrogens.8
“X+” to initiate the Pummerer cyclization cascade. Note that
for simplicity of presentation, only the vinylogous Pummerer
intermediate 4 (diazacyclopentadiene thionium ion) is il-
lustrated; the additive mechanism may be operational as
well.8 The anticipated outcome of this process is the
pentacyclic product 6, which bears a greater or lesser
resemblence to the palau’amine skeleton, depending upon
the exact nature/stereochemistry of the appended ring.
The initial foray into this chemistry involved the synthesis
of a Pummerer cyclization substrate 2 featuring the requisite
trans cyclopentane ring in place of the dotted lines. Unfor-
tunately, all attempts at achieving this cyclization met with
failure.9 These frustrated Pummerer bicyclization attempts
led to a reevaluation of the synthesis plan, and as a result
recourse was made to an alternative and indirect strategy
for trans cyclopentane introduction. Specifically, the use of
a less torsionally demanding cyclohexene ring with trans
disposed substituents might both enable the Pummerer
chemistry and provide a handle for the later ring contraction
that ultimately is necessary to provide the requisite trans
azabicyclo[3.3.0]octane moiety of the palau’amine structure.
This hypothesis was tested by first preparing a cyclohexene
ring featuring vicinal and trans disposed imidazole and pyrrole
moieties through Diels-Alder chemistry. The dienophile for
this Diels-Alder reaction was prepared from imidazole in 4
steps as illustrated in Scheme 2. Standard functionalization
The extension of this chemistry to the more demanding
palau’amine system is illustrated in conceptual form in
Scheme 1, where now a thiophenylated dihydrooroidin
Scheme 1. Pummerer-Reaction-Based Approach to the
Pentacyclic Core of the Dibromopalau’amine Skeleton
Scheme 2
.
Synthesis of the Imidazole-Based Diels-Alder
Dienophile 10
derivative 2 bearing a third ring of undefined dimensions
(dotted line) can be activated by a sulfur-specific electrophile
(4) (a) Overman, L. E.; Rodgers, B. N.; Tellew, J. E.; Trenkle, W. C.
J. Am. Chem. Soc. 1997, 119, 7159–7160. (b) Dilley, A. S.; Romo, D. Org.
Lett. 2001, 3, 1535–1538. (c) 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. (d) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559–9568.
(e) Lovely, C. J.; Du, H.; He, Y.; Rasika Das, H. V. Org. Lett. 2004, 6,
735–738. (f) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li,
Q.; Doundoulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765–
769. (g) Dransfield, P. J.; Dilley, A. S.; Wang, S.; Romo, D. Tetrahedron
2006, 62, 5223–5247. (h) Tan, X.; Chen, C. Angew. Chem., Int. Ed. 2006,
45, 4345–4348. (i) Lanman, B. A.; Overman, L. E. Heterocycles 2006, 70,
557–570. (j) Bultman, M. S.; Ma, J.; Gin., D. Y. Angew. Chem., Int. Ed.
2008, 47, 6821–6824. (k) Zancanella, M. A.; Romo, D. Org. Lett. 2008,
10, 3685–3688. (l) Hudon, J.; Cernak, T. A.; Ashenhurst, J. A.; Gleason,
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procedures utilizing imidazole metalation chemistry10 furnished
the aldehyde 9, which was converted to the unsaturated primary
amide 10 through Emmons-Horner chemistry.
Acquisition of dienophile 10 set the stage for the key
Diels-Alder reaction,11 which proceeded smoothly with
butadiene at high temperature to afford the trans-substituted
cyclohexene-containing product 11 in moderate yield, Scheme
3. The simple butadiene adduct 11 was an adequate starting
point to test the further chemistry, and so the amide function
(5) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.;
Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095–1098.
(6) (a) Al-Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237–243.
(7) (a) Bu¨chi, G.; Foley, L. H. J. Am. Chem. Soc. 1982, 104, 1776–
1777. (b) Wiese, K. J.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett.
2002, 43, 5135–5136. (c) Feldman, K. S.; Skoumbourdis, A. P. Org. Lett.
2005, 7, 929–931. (d) Feldman, K. S.; Skoumbourdis, A. P.; Fodor, M. D.
J. Org. Chem. 2007, 72, 8076–8086. (e) Lu, J.; Tan, X.; Chen, C. J. Am.
Chem. Soc. 2007, 129, 7768–7769. (f) Feldman, K. S.; Fodor, M. D. J. Am.
Chem. Soc. 2008, 130, 14964–14965. (g) Feldman, K. S.; Fodor, M. D. J.
Org. Chem. 2009, 74, 3449–3461.
(8) (a) Feldman, K. S. Tetrahedron 2006, 62, 5003–5034. (b) Feldman,
K. S.; Fodor, M. D.; Skoumbourdis, A. P. Synthesis 2009, 3162–3173.
(9) Li, J. M. S. Thesis, Pennsylvania State University, 2009.
(10) Vollinga, R. C.; Menge, W. M. P. B.; Timmerman, H. Recl. TraV.
Pays-Bas 1993, 112, 123–125.
(11) For a related Diels-Alder reaction of a ꢀ-imidazole unsaturated
ester, see: Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta,
S. Tetrahedron 2006, 62, 10182–10192.
Org. Lett., Vol. 12, No. 20, 2010
4533

thionium ion moiety then leads to the observed product,
pentacycle 18. The structure and stereochemistry of 18 was
suggested by comparison of spectroscopic data (1H NMR
singlet at 5.37 ppm for H(6); 13C NMR 71.8 ppm C(6), 92.6
ppm C(10)) with a related but simplier system7c and
confirmed by single crystal X-ray analysis.13 Cyclization
product 18 was isolated as a single diastereomer whose
relative stereochemistry can be rationalized by citing reaction
through the conformer 16. This conformation should mini-
mize A1,3 strain along the imidazole-cyclohexene ring bond
compared to the diasatereomeric alternative (not shown) in
which the diazacyclopentadiene unit is rotated by 180° (i.e.,
)S+Ph pointing “up”). There are several interrelated bio-
synthesis proposals for palau’amine currently in play, and
the conformational preference f desired stereochemical
outcome implied in 16 is relevant to some of them.3c,6
Contracting the cyclohexene ring of the trans fused system
18 to a cyclopentane ring represents the final challenge to
completing this model dibromopalau’amine system. The
Wolff rearrangement of R-diazoketones seemed like a
reasonable starting point for developing a ring contraction
strategy, since (a) it has a long history of application to the
formation of small strained rings, and (b) it does not involve
a ring-opening/acyclic closure sequence.14 The synthesis of
an appropriate R-diazoketone from 18 commenced with an
oxymercuration/oxidation sequence to introduce the ketone
part, in this case as an inconsequential ∼3:1 mixture of
Scheme 3. Preparation of the Pummerer Reaction Substrate 14
was reduced to the amine in 12 via an intermediate nitrile
(direct reduction of 11 was capricious and low-yielding), and
that amine was acylated with the dibromopyrrole 13 to
deliver the Pummerer cyclization precursor 14 in good yield.
Treatment of sulfide 14 with PhI(CN)OTf (Stang’s re-
agent9) followed procedures developed earlier for the
synthesis of the simplier pyrrole-imidazole alkaloids,7c,d,12
Scheme 4. Mechanistic speculation for this cyclization
Scheme 4. Pummerer-Type Oxidative Cyclization of 14, with
Mechanistic Speculation, and Structural Characterization of the
Pentacyclic Product 18
Scheme 5
.
Formation of the Trifluoromethylacetyl Ketones
20a/b
extends to initial sulfur activation by the iodonium reagent
to give 15, which expels the elements of HCN and PhI to
deliver the presumed key electrophilic intermediate 16 (or
the additive Pumerer equivalent). Successive trapping of the
two electrophilic sites within the diazacyclopentadiene
regioisomers 19a/19b, Scheme 5. This mixture was processed
on to the R-trifluoromethylacetyl ketones 20a/20b, isolated
4534
Org. Lett., Vol. 12, No. 20, 2010

as enols, by the method of Danheiser15 to set up diazo
introduction. The regiochemical assigment of the isolable
major isomer 20a rests on the HMBC signals shown; three
other regioisomers were isolated as a mixture, and the most
prevalent of these three is assigned the regiochemistry shown
as 20b based upon mechanistic reasoning.
Purified major isomer 20a was treated with mesyl azide
to furnish the diazoketone 21, but that species proved too
reactive for isolation and purification, Scheme 6. Conse-
Figure 2. Key HMBC signals for the structural assignment of
pentacycle 23.
Scheme 6. Synthesis of the Pentacyclic Framework of
Dibromopalau’amine via Wolff Rearrangement
Thus, the highly strained trans-fused azabicyclo[3.3.0]octane-
bearing pentacyclic skeleton of dibromopalau’amine has been
prepared in a diastereoselective fashion in 15 overall steps
from imidazole. The use of the Pummerer-initiated bicy-
clization reaction to assemble the target’s framework extends
this methodology to a more demanding context, and, when
coupled to the Wolff ring contraction sequence, defines a
new approach to the palau’amine system.
Acknowledgment. Support from the National Science
Foundation via CHE 0808983 and CHE 0131112 (X-ray
Crystallographic facility) is gratefully acknowledged. This
paper is dedicated to my colleague and friend, Dr. Raymond
Funk, on the occasion of his 60th birthday.
Supporting Information Available: Experimental pro-
1
cedures, full spectral data and copies of H NMR and 13C
quently, it was used crude in the Wolff rearrangement
reaction. Irradiation of a sample of 21 prepared in this manner
at 300 nm in methanol led to a single cyclopentane-
containing regisomer as a mixture of epimers at C(17),
pentacycle 23. In a subsequent experiment, the mixture of
all 4 regioisomers of the trifluoromethylacetyl ketones 20
was subjected to both diazo introduction and Wolff rear-
rangement, and the same mixture of diastereomeric cyclo-
pentane methyl esters 23 as the major products resulted.
The structural assigment of 23 stems from analysis of its
HMBC signals, the most informative of which are shown in
Figure 2. The critical coupling constant between H(11) and
H(12) is 13.3 Hz for both diastereomers, similar to that
reported for palau’amine itself (14.4 Hz).
NMR spectra for 8, 9, 10, 11, 12, 14, 18, 19a, 20a, and 23;
X-ray crystallographic data in CIF format for 18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1018322
(12) Zhdankin, V. V.; Crittell, C. M.; Stang, P. J.; Zefirov, N. S.
Tetrahedron Lett. 1990, 31, 4821–4824.
(13) Cambridge Crystallographic Data Centre deposition number: CCDC
782151. The data can be obtained free from Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
(14) Kirmse, W. Carbene Chemistry; Academic Press: New York, NY,
1971; pp 484-487.
(15) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org.
Chem. 1990, 55, 1959–1964.
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