Heterocyclic α-alkylidene cyclopentenones obtained via a Pauson-Khand reaction of amino acid derived allenynes. A scope and limitation study directed toward the preparation of a tricyclic pyrrole library

Article abstract of DOI:10.1021/jo0481607

(Chemical Equation Presented) The synthesis of a novel class of tricyclic pyrroles has been accomplished by using a Pauson-Khand/Stetter/Paal-Knorr reaction sequence. Full details of the Pauson-Khand reaction of amino acid tethered allenynes 4a-e and 9a-d

Full text of DOI:10.1021/jo0481607

Heterocyclic r-Alkylidene Cyclopentenones Obtained via a
Pauson-Khand Reaction of Amino Acid Derived Allenynes. A
Scope and Limitation Study Directed toward the Preparation of a
Tricyclic Pyrrole Library
Kay M. Brummond,* Dennis P. Curran, Branko Mitasev, and Stefan Fischer
University of Pittsburgh, Department of Chemistry, Pittsburgh, Pennsylvania 15260
kbrummon@pitt.edu
Received October 18, 2004
The synthesis of a novel class of tricyclic pyrroles has been accomplished by using a Pauson-
Khand/Stetter/Paal-Knorr reaction sequence. Full details of the Pauson-Khand reaction of amino
acid tethered allenynes 4a-e and 9a-d are disclosed. The study of this reaction led to the discovery
of an unprecedented substituent effect on the diastereoselectivity of the Mo(CO)6 mediated allenic
Pauson-Khand reaction. It was found that amino acid tethered allenynes with aromatic side chains
afford R-alkylidene cyclopentenones with the opposite diastereoselectivity compared to those with
aliphatic side chains. This effect has been attributed to complexation of the metal mediator to the
aromatic ring in the substrate. Furthermore, an isomerization of one of the diastereomers of the
R-alkylidene cyclopentenones was encountered, leading to eventual decomposition. The stable
diastereomers were found to react well in the Stetter reaction leading to 1,4-diketones that were
converted to pyrroles. The observation that the first generation of 2-alkyl-substituted pyrroles was
unstable led to a second generation of 2-carboxamide pyrroles with sufficient stability for biological
tests which are in progress.
Introduction
fication strategies, since seemingly small changes in the
reaction conditions or catalyst can lead to remarkable
changes in the bonds formed and broken during the
synthetic transformation.
Diversity oriented synthesis (DOS) constitutes a pow-
erful concept for synthesizing collections of small mol-
ecules that will impact research, either as biological tools
or pharmacological agents.1 The DOS approach used most
frequently involves sequential reactions whereby sub-
structures are incorporated into scaffolds of growing
complexity, thereby creating diversity. An alternative and
less common approach involves the construction of a
pivotal compound that, when subjected to the appropriate
reagents or catalysts, can give new, structurally distinct
products. Nature has made extensive use of this latter
diversification strategy, for example, by enzyme-catalyzed
construction of the various sesquiterpene carbon skel-
etons of secondary metabolites from one common precur-
sor, farnesyl pyrophosphate. Transition metal catalyzed
processes are ideal for these reagent-controlled diversi-
Recently we have communicated our results pertaining
to the scope and limitations of converting a common
intermediate A to three heterocyclic scaffolds B, C, and
D by changing only the transition metal catalyst (Scheme
1).2 In short, 15 common intermediates were synthesized
in an effort to establish the effect of the substrate
specificity on the course of the transition metal catalyzed
reactions. The results were very encouraging with most
common intermediates affording good yields of the cross-
conjugated triene B,3 4-alkylidene cyclopentenone C,4 or
R-alkylidene cyclopentenone D.5 While the compounds
generated thus far are novel and will be tested for
biological activity, it is the unique reactivity profile of
(2) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
(3) Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc.
2002, 124, 15186.
(4) Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.;
Rickards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 11, 1931
* Address correspondence to this author. Phone: (412) 624-1955.
Fax: (412) 624-8611.
(1) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46.
10.1021/jo0481607 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/05/2005
J. Org. Chem. 2005, 70, 1745-1753
1745

Brummond et al.
SCHEME 1. Diversification of Allenyne A by
Changing Only the Catalyst
FIGURE 1. Amino acid-derived allenynes 4a-e.
SCHEME 2. Diversification Potential of
1,4-Dicarbonyl Compounds Derived from D
each scaffold (cross-conjugated triene, 4-alkylidene cy-
clopentenone, R-alkylidene cyclopentenone) and its po-
tential to be differentially functionalized that is deemed
the most valuable feature of this approach. The subse-
quent diversification of each scaffold enhances the size
and the diversity of the small molecule libraries that can
be synthesized, and the approach therefore follows the
“libraries from libraries” principle originally introduced
by Houghten et al. and used by others.6
In this report, results obtained during our efforts to
diversify scaffold D, the R-alkylidene cyclopentenone, are
discussed. Moreover, complete details describing the
conversion of the common intermediate A to R-alkylidene
cyclopentenones are presented. The most enticing char-
acteristic of scaffold D is the exocyclic double bond of the
cross-conjugated enone, which can be used in various
Michael-type additions. Specifically, umpolung addition
of an aldehyde to D via a Stetter7 reaction would yield a
1,4-diketone moiety E. This 1,4-dicarbonyl moiety can be
transformed to furan F or pyrrole G via a Paal-Knorr
synthesis or enone H depending on the reaction condi-
tions used (Scheme 2). We were motivated to first
examine the formation of pyrrole G for three reasons: (1)
multicomponent processes involving a Stetter/Paal-
Knorr reaction sequence have been utilized previously
for the synthesis of functionalized pyrroles;8 (2) an
additional diversification site could be easily introduced
by the preparation of pyrrole G by using a variety of
amines (R3-NH2); and (3) a plethora of biologically
interesting compounds possess pyrroles as part of their
substructure.9 Thus, these compounds are likely to be
useful as biological probes.
Results and Discussion
We therefore set out to examine the scope and limita-
tions of this diversification strategy for the preparation
of a collection of pyrroles. Initially, allenynes of three
different amino acids were prepared (Figure 1): one
containing an aromatic residue in the side chain (phen-
ylalanine 4a and 4b) and two containing an aliphatic side
chain (alanine 4c and 4d and leucine 4e). Alanine- and
phenylalanine-derived allenynes were prepared either
with a terminal alkyne (4b, 4d) or a methyl-substituted
alkyne (4a, 4c). The syntheses of all compounds but 4e
have been reported previously, and 4e was synthesized
in an analogous manner.2
Pauson-Khand Reaction. With these allenynes in
hand, we next examined the Pauson-Khand reaction to
effect formation of the R-alkylidene cyclopentenones. We
were interested in both the regioselectivity and diaste-
reoselectivity of this transformation under the standard
Mo(CO)6 conditions used by our group for effecting allenic
Pauson-Khand reactions. When phenylalanine-derived
allenynes were submitted to the standard Pauson-
Khand conditions, the reaction proceeded in high yield
to give a mixture of products whose composition could
be easily determined by integration of the olefinic reso-
(5) (a) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett.
1995, 36, 2407. (b) Brummond, K. M.; Wan, H. Tetrahedron Lett. 1998,
39, 931. (c) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998,
63, 6535. (d) Brummond, K. M. In Advances in Cycloaddition; Harmata,
M., Ed.; JAI Press Inc: Stamford, CT, 1999; Vol. 6, p 211. (e)
Brummond, K. M.; Lu, J. J. Am. Chem. Soc. 1999, 121, 5087. (f)
Brummond, K. M.; Lu, J.; Petersen, J. L. J. Am. Chem. Soc. 2000,
122, 4915. Brummond, K. M.; Sill, P.; Rickards, B.; Geib, S. J.
Tetrahedron Lett. 2002, 43, 3735.
(6) (a) Ostresh, J. M.; Husar, G. M.; Blondelle, S. E.; Do¨rner, B.;
Weber, P. A.; Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91,
11138. (b) Nefzi, A.; Ostresh, J. M.; Yu, J.; Houghten, R. A. J. Org.
Chem. 2004, 69, 3603. (c) Nicolaou, K. C.; Pfefferkorn, J. A.; Barluenga,
S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000,
122, 9968.
(7) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl.
1973, 12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
639. (c) Stetter, H.; Kuhlman, H. In Org. React. 1991, 40, 408. (d)
Stetter, H.; Haese, W. Chem. Ber. 1984, 117, 682.
(8) (a) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. (b)
Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. Org. Lett. 2001, 3, 3297.
1
nances in the H NMR spectrum of the crude reaction
(9) (a) Gossauer, A. Die Chemie der Pyrrole; Springer-Verlag: Berlin,
Germany, 1974. (b) Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R.; Rees, C. W.; Scriven, E. F., Eds.; Pergamon Press: Oxford,
UK, 1996; Vol. 2, p 207. (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (e) Lindquist,
N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Org. Chem. 1988, 53,
4570. (f) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin,
Q. J. Am. Chem. Soc. 1999, 121, 54. (g) Cozzi, P.; Mongelli, N. Curr.
Pharm. Des. 1998, 4, 181. (h) Huffman, J. W. Curr. Med. Chem. 1999,
6, 705.
1746 J. Org. Chem., Vol. 70, No. 5, 2005

Heterocyclic R-Alkylidene Cyclopentenones
TABLE 1. Pauson-Khand Reaction of Phenylalanine-Derived Allenynes 4a and 4b
a Ratios determined by integration of the olefinic resonances in the 1H NMR spectrum.
TABLE 2. Pauson-Khand Reaction of Alanine- and Leucine-Derived Allenynes
a Ratios determined by integration of the olefinic resonances in the 1H NMR spectra.
SCHEME 3. Stereochemical Assignment of the
Pauson-Khand Products from Table 2
mixture. In both reactions, the major diastereomers 5a
and 5b could be easily separated by column chromatog-
raphy from the remaining two components (the minor
diastereomers 6a and 6b and the [6-5] products 7a and
7b, respectively) that coeluted.
The relative configuration of the major diastereomer
5b was determined by X-ray crystallography, showing the
benzyl group and Ha to reside in a syn orientation. On
the basis of an X-ray crystal structure of compound 15
(vide infra) this is also the configuration of the major
diastereomer in the reaction of 4a.
Next, we examined the Pauson-Khand reaction of the
three allenynes possessing aliphatic side chains. A dra-
matic increase in the regioselectivity was observed show-
ing a preference for reaction at the internal double bond
(12-14:1 versus 5-6:1; compare Tables 1 and 2). More-
over, the diastereoselectivities were substantially higher
especially for substrates 4c and 4d (compared to 4a and
4b).
When the products from the Pauson-Khand reaction
of 4d and 4e were applied to silica gel, a new compound
was isolated and determined to be 8d and 8e based on
1H NMR, 13C NMR, dept, and MS (eq 1). Further studies
revealed that 8d and 8e resulted from isomerization of
5d and 5e, respectively.10 Unfortunately, compounds 8d
and 8e were unstable and decomposed upon storage in
solution.
alkyl-derived substrates may be affording opposite dia-
stereoselectivity. NOESY study of the two diastereomers
in the leucine case (5e and 6e) revealed this to be true
(Scheme 3). The major diastereomer (5e) of this reaction
is the one where the ester functionality and the ring
fusion hydrogen Hb are on the same side of the ring.
Similar observations were made in the alanine case
5d, so it is predicted based upon these examples that all
aliphatic amino acids will give product 5 as the major
diastereomer and 6 as the minor diastereomer.11 The
facile isomerization of diastereomers 5d, 5e and 6b may
result from the methyl ester carbonyl functionality
serving as an internal Lewis base assisting in the
deprotonation of the ring fusion proton. Compounds 5c
and 6c, where R2 ) Me, did not isomerize under any of
these conditions. In the case of 5c and 6c the double bond
is already tetrasubstituted, which may account for this
(10) Isomerization of the enones was prevented by using 1% acetic
acid in the eluting solvent during column chromatography on silica
gel. In this way pure enones were obtained and then re-adsorbed onto
silica gel. Diastereomers 5d and 5e isomerized completely within 1 h
and diastereomers 6d and 6e did not isomerize. Exposure of 5d, 6d,
5e, and 6e to triethylamine led to rapid isomerization of 5d and 5e,
but negligible isomerization of 6d and 6e. For similar base-promoted
isomerizations see: Areces, P.; Duran, A. M.; Plumet, J.; Hursthouse,
M. B.; Light, M. E. J. Org. Chem. 2002, 67, 3506.
Since the phenylalanine-derived Pauson-Khand prod-
uct 5b (Table 1) did not isomerize under basic or silica
gel conditions, we became suspicious that the aryl- and
(11) Another substrate derived from norvaline (R1 ) n-Bu) was
shown to give the same diastereoselectivity as alanine and leucine
(communication from Stefan Fischer, Curran group).
J. Org. Chem, Vol. 70, No. 5, 2005 1747

Brummond et al.
SCHEME 4. Ab Initio Energy Calculations of the
r-Methylene Cyclopentenones
observation. The phenylalanine-derived cyclopentenones
5a and 6a did not isomerize.
Ab initio calculations were performed to compare the
energy differences between the diastereomeric R-meth-
ylene cyclopentenones and the new dienones 8. It was
found that the transformations of both 5e to 8e and 6b
to 8b are energetically favorable. However, when com-
paring the energies of 6e to 8e and 5b to 8b, these are
nearly isoenergetic (Scheme 4).12 These calculations are
consistent with the observed results.
To determine whether the diastereoselectivity of the
Pauson-Khand reaction could be increased, other aro-
matic amino acid-derived substrates were synthesized
bearing a p-OMe-phenyl, p-F-phenyl, 2-thienyl, and 3-N-
Boc-indolyl moieties. These aromatic groups were chosen
to provide an electron-donating group, an electron-
withdrawing group, and two heterocyclic aromatic groups,
respectively (9a-d).
FIGURE 2. Arene complexation model explaining the dia-
stereoselectivity in the Pauson-Khand reaction.
metal as shown in 4b, Figure 2. Whereas in the case of
the aliphatic side chain, the aliphatic group resides
preferentially in the pseudoequatorial position (4d, Fig-
ure 2).
Stetter Reaction. Next, conversion of the R-methyl-
ene cyclopentenones to 1,4-dicarbonyl compounds was
examined by using a Stetter reaction protocol reported
by Tius.13 Diversifications were performed only with
phenylalanine-derived R-methylene cyclopentenones 5a
and 5b since the major diastereomers 5d and 5e (from
the alanine- and leucine-derived substrates, respectively)
isomerized under basic conditions needed for the Stetter
reaction.14 Exposure of 5a to butyraldehyde, Et3N, and
thiazolium salt 13 in 1,4-dioxane for 6 h at 70 °C resulted
in the Stetter product 11 in 73% yield as a 4:1 mixture
of diastereomers (eq 3).15 The relative configuration of
11a was subsequently assigned by X-ray crystallography
of the reduced product (15, eq 5). The major diastereomer
is depicted in eq 3. Cyclopentenone 5b was also submitted
to the same reaction conditions to give a 66% yield of
product 12 with the same diastereoselectivity.
Interestingly, the Pauson-Khand reaction of all four
substrates (9a-d) gave nearly the same diastereomeric
ratios as the phenylalanine case (4b) (eq 2). Again,
isomerization of the major diastereomers was not ob-
served, whereas the minor diastereomers isomerized
upon standing neat at room temperature.
Thus, for the aromatic amino acids the opposite
isomers are favored for the Pauson-Khand reaction,
giving diastereomeric ratios in the range of 2-3:1 com-
pared to the aliphatic amino acids which give dr values
of 1:5-11. We speculate that this interesting reversal in
diastereoselectivity can be attributed to complexation of
the aromatic ring from the side chain with the transition
A single attempt to convert 11a to a pyrrole by using
a Paal-Knorr protocol was unsuccessful (eq 4).16 The
reversibility of the pyrrole forming reaction and the
(13) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123,
8509.
(14) Treatment of 5e and 5d to the Stetter reaction conditions
resulted mainly in decomposition and very low yields of 1,4-diketone.
(15) This ratio was confirmed to be kinetic by an experiment where
a 3:1.7 mixture of starting material and minor diastereomer 11b was
submitted to the reaction conditions. The observed diastereomeric ratio
after the reaction was approximately 1:1. The ratio expected based on
a complete conversion of the starting material to products and no
decomposition would also be 1:1.
(12) Calculations were performed with MacSpartan Pro 1.0.4. First,
a conformational search with MMFF94 calculation was performed,
followed by a geometry optimization with a semiempirical program
RHF/AM1.
1748 J. Org. Chem., Vol. 70, No. 5, 2005

Heterocyclic R-Alkylidene Cyclopentenones
TABLE 3. Preparation of Tricyclic Pyrroles from 16
strained nature of product 14 was deemed problematic,
so reduction of the double bond in 11a was effected to
alleviate strain. Reduction of cyclopentenones 11a and
12a gave single diastereomers of cyclopentanones 15 and
16 (eq 5). The structure and relative stereochemistry of
15 was confirmed by X-ray crystallography.
a R2NH2 (5 equiv), AcOH (5 equiv). b R2NH2 (10 equiv), AcOH
(8 equiv).
The success of this reduction was highly dependent on
the purity of the starting enone; presumably sulfur-
containing impurities from the Stetter reaction can
poison the palladium catalyst. When 16 was treated with
benzylamine and AcOH in methanol in the presence of
molecular sieves at 70 °C, it afforded tricyclic N-benzyl
pyrrole 17 in 90% yield (eq 6).
strates for the pyrrole formation since substitution next
to the amine results in complete recovery of the starting
material. Of the two aromatic amines tested, electron-
rich p-anisidine was an excellent substrate for the pyrrole
formation and 2-aminopyridine was unreactive, which
can be attributed to the presence of a second basic
nitrogen in the molecule proximal to the reactive primary
amine.
Reaction of a single diastereomer of the methyl-
substituted diketone 15 with furfurylamine gave pyrrole
19 in 75% yield, unfortunately as a mixture of two
diastereomers in 2:1 ratio (eq 7). The diastereomers
resulted from epimerization of the stereocenter bearing
the methyl group.
Other amines were tested in this pyrrole-forming
reaction to determine its scope, and the results are shown
in Table 3. We first attempted the reaction with an amino
acid derivative, since incorporation of a second amino acid
would be an interesting diversification feature. The
soluble glycine-methyl ester hydrochloride participated
in the reaction and gave pyrrole 18a in 70% yield (Table
3, entry 1) but the more sterically hindered valine methyl
ester failed to participate under the same reaction
conditions (Table 3, entry 2). Next the aromatic amine
anisidine was used (Table 3, entry 3) and the reaction
proceeded to give 18c in 85% yield. Similarly, ethanol-
amine gave 18d in 76% yield (Table 3, entry 4). Finally,
2-aminopyridine gave none of the desired product (Table
3, entry 5). Based upon this small sampling of amines,
aliphatic amines of type H2N-CH2-R are the best sub-
Based upon these exploratory studies, a protocol was
developed to form a small library of pyrroles from a single
diastereomer of 1,4-diketone 20. Heating 20 to 140 °C in
toluene, in the presence of amine and excess acetic acid,
afforded the desired pyrroles (Table 4). Upon completion
of the reaction, the excess amine was scavenged from the
reaction mixture with polymer-bound sulfonic acid resin,17
and the crude reaction mixtures were purified by semi-
preparative HPLC. As expected all compounds were
obtained as mixtures of diastereomers due to epimeriza-
tion of the methyl-bearing stereocenter.
(16) 11a was treated with AcOH (excess) and 3 equiv of benzylamine
in refluxing methanol in the presence of molecular sieves. After 12 h,
the reaction afforded a mixture of unidentifiable compounds with
mostly recovered starting material (eq 4).
(17) Resin was purchased from Novabiochem. Smith, R. A.; Bhar-
gava, A.; Browe, C.; Chen, J.; Dumas, J.; Hatoum-Mokdad, H.; Romero,
R. Bioorg. Med. Chem. Lett. 2001, 11, 2951.
J. Org. Chem, Vol. 70, No. 5, 2005 1749

Brummond et al.
SCHEME 5. Addition of Glyoxylamides to 5b and Reduction of the Double Bond
TABLE 4. Preparation of a Collection of Pyrroles from
20 with Use of an Amine Scavenger Protocol
tively. A slightly modified protocol for pyrrole formation
was developed with use of 3 equiv of the amine, excess
acetic acid, and EtOH as solvent. Heating at 50 °C for
2-3 h generally gave complete conversion to pyrroles 28,
which were isolated following an acidic workup and short
column chromatography purification (Table 5). To our
knowledge, the resulting pyrrole-2-carboxamide moiety
has not been previously synthesized directly via a Paal-
Knorr synthesis.22
Two pyrroles were also prepared from diketone 26 by
using the same conditions (eq 8).
Unfortunately, compounds 18a,c,d and 21a-j decom-
posed when stored neat or open to the atmosphere,
rendering them undesirable for biological assays. Stabi-
lizing the pyrrole moiety with an acyl substituent had
potential since this group could be introduced via the
Stetter reaction by 1,4-addition of a glyoxylamide.18 Two
glyoxylamides, dimethylamine (22) and pyrrolidine (23),
were prepared.19 These highly electrophilic aldehydes
both participated in the Stetter reaction under the same
conditions affording the products in 10 min as single
diastereomers (Scheme 5). After Stetter’s original report
in 1987, there are no examples in the literature utilizing
this 1,4-addition of glyoxylamides. This reaction is a
viable entry into the R-keto-amide moiety that is both
synthetically useful20 and present in biologically active
molecules.21
The most suitable aliphatic amines for the Paal-Knorr
reaction do not have branching at the position R to the
amine since cyclohexylamine failed to give any product.
When 2,2,2-trifluoroethylamine and isobutylamine were
used, the reaction rate was significantly retarded, and
in both cases the reaction failed to go to completion.
(20) (a) Aoyama, H.; Hasegawa, T.; Watanabe, M.; Shiraishi, H.;
Omote, Y. J. Org. Chem. 1978, 43, 419. (b) Hashizume, D.; Kogo, H.;
Sekine, A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem. Soc., Perkin
Trans. 2 1996, 61. (c) Youn, S. W.; Kim, Y. H.; Hwang, J.-W.; Do, Y.
Chem. Commun. 2001, 996.
(21) (a) Wada, C. K.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Garland, R.
B.; Holms, J. H.; Li, J.; Pease, L. J.; Guo, J.; Glaser, K. B.; Marcotte,
P. A.; Richardson, P. L.; Murphy, S. S.; Bouska, J. J.; Tapang, P.;
Magoc, T. J.; Albert, D. H.; Davidsen, S. K.; Michaelides, M. R. Bioorg.
Med. Chem. Lett. 2003, 13, 3331. (b) Wasserman, H. H.; Petersen, A.
K.; Xia, M. Tetrahedron 2003, 59, 6771. (c) Otto, H. H.; Schirmeister,
T. Chem. Rev. 1997, 97, 133. (d) Han, W.; Hu, Z.; Jiang, X.; Decicco,
C. P. Bioorg. Med. Chem. Lett. 2000, 10, 711.
Next, the double bonds of enones 24 and 25 were
reduced giving 26 and 27 in 81% and 74% yield, respec-
(22) (a) Meth-Cohn, O.; Wang, M.-X. Tetrahedron Lett. 1995, 36,
9561. (b) Jousseaume, B.; Kwon, H.; Verlhac, J.-B.; Denat, F.; Dubac,
J. Synlett 1993, 117. (c) Martyn, D. C.; Vernall, A. J.; Clark, B. M.;
Abell, A. D. Org. Biomol. Chem. 2003, 1, 2103.
(18) Stetter, H.; Skobel, H. Chem. Ber. 1987, 120, 643.
(19) Suzuki, M.; Kimura, Y.; Terashima, S. Bull. Chem. Soc. Jpn.
1986, 59, 3559.
1750 J. Org. Chem., Vol. 70, No. 5, 2005

Heterocyclic R-Alkylidene Cyclopentenones
TABLE 5. Preparation of a Small Library of Acyl Pyrroles from 27a
a Conditions: R-NH2 (3 equiv), AcOH (excess).
Increased heating drives the reaction further but results
in the formation of impurities (eq 9).
versification elements (amino acid, aldehyde, amine) were
easily incorporated into the reaction sequence. Interest-
ingly, the amino acid diversification element led to an
unprecedented substituent effect on the diastereoselec-
tivity of the Pauson-Khand reaction. Glyoxylamides
participate in the Stetter reaction with R-methylene
cyclopentenones to provide R-keto amides stereoselec-
tively, which are converted into pyrrole-2-carboxamides.
This reaction sequence provides a direct route to a novel
class of pyrroles. Finally, the protocols used to synthesize
these pyrroles are currently in the hands of the staff
within the University of Pittsburgh Chemical Methodolo-
gies and Library Development Center (UPCMLD). The
robustness of the chemistry is highlighted by the Center’s
preparation of 179 unique acyl pyrroles (∼20 mg each)
in less than 10 weeks.23 The compounds are currently
being evaluated for biological activity.
To determine whether the newly formed acyl pyrroles
28a-n are more stable than the alkyl pyrroles as
postulated, we performed an NMR experiment where an
alkyl and acyl pyrrole of benzylamine were placed in an
NMR tube together with a standard (p-phthalic acid ethyl
ester) in d6-DMSO. The sample was kept at room tem-
Experimental Section
1
perature in a sealed NMR tube. Monitoring of the H
NMR of the sample over a period of 60 days revealed that
the alkyl pyrrole had been reduced to half of its initial
amount, whereas the acyl pyrrole remained virtually
unchanged.
Mo(CO)6-Mediated Pauson-Khand Reaction (General
Procedure D). To a solution of the allenyne (0.3 mmol) in
toluene (3 mL) in a 10-mL round-bottomed flask was added
DMSO (1.5-3.0 mmol)24 followed by Mo(CO)6 (0.37 mmol) at
room temperature under N2 atmosphere. The flask was
equipped with a reflux condenser and heated slowly to 80-90
°C in an oil bath. Stirring was continued at this temperature
until TLC analysis showed the absence of starting material.
Upon completion of the reaction, the volume of the mixture
Conclusions
We have developed a concise route to novel tricyclic
pyrroles using a Pauson-Khand, Stetter, Paal-Knorr
reaction sequence. The final compounds are obtained as
single diastereomers by chromatographic separation of
the diastereomeric Pauson-Khand adducts. Three di-
(23) Werner, S.; Coleman, C. M.; Fodor, M. D.; Iyer, P. S.; Mitasev,
B.; Twining, L. A.; Brummond, K. M. Manuscript in preparation.
(24) See individual compounds for details.
J. Org. Chem, Vol. 70, No. 5, 2005 1751

Brummond et al.
was reduced to 1 mL under vacuum and the brown liquid
mixture directly applied to a silica gel column pretreated with
a solvent system hexanes-EtOAc 20:1 v/v (1% AcOH) and
purified with gradient elution (hexanes-EtOAc 20:1 to 1:1 v/v
(1% AcOH)). Product ratios were determined by integration
of the olefinic peaks in the 1H NMR taken after complete
removal of all volatiles from a small reaction sample.
Pauson-Khand Reaction of 4b. General procedure D
was followed for the molybdenum-mediated allenic Pauson-
Khand reaction with 2-(benzoylprop-2-ynylamino)-2-benzyl-
hexa-3,4-dienoic acid methyl ester 4b (360 mg, 1.0 mmol),
DMSO (355 µL, 5.0 mmol), and Mo(CO)6 (330 mg, 1.25 mmol).
The reaction was heated to 90 °C for 20 min and the crude
mixture was purified by flash chromatography (gradient
elution, hexanes-EtOAc, 19:1 to 1:1, v/v (1% AcOH)). The yield
of crude mixture was 365 mg (94%) consisting of 5b (57%), 6b
(19%), and 7b (15%). Due to isomerization of 6b to 8b, only
8b was characterized.
chromatography (gradient elution, hexanes-EtOAc 3:1 to 0:1
v/v) to afford the product as a single diastereomer (NMR).
2-Benzoyl-1-benzyl-4-methyl-5-oxo-6-(2-oxopentyl)-1,-
2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-1-carboxylic
Acid Methyl Ester (11). 11 was prepared by following
general procedure E with 5a (163 mg, 0.403 mmol), Et3N (42
µL, 0.30 mmol), butyraldehyde (184 µL, 2.03 mmol), 3-benzyl-
5-(2-hydroxyethyl)-4-methylthiazolium chloride (22 mg, 0.080
mmol), and 1,4-dioxane (2 mL). Isolated: 11a (121 mg, 63%)
and 11b (19 mg, 10%). 11a (major diastereomer, eluting
slower, hexanes-EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.55-
7.44 (m, 5H), 7.33-7.27 (m, 3H), 7.17-7.14 (m, 2H), 4.17 (d,
J ) 15.0 Hz, 1H), 4.10 (d, J ) 14.2 Hz, 1H), 3.99 (d, J ) 15.1
Hz, 1H), 3.75 (s, 3H), 3.44-3.39 (m, 1H), 3.28 (d, J ) 14.2 Hz,
1H), 3.03 (dd, J ) 18.4, 5.1 Hz, 1H), 2.86 (dd, J ) 18.4, 3.9
Hz, 1H), 2.50 (t, J ) 7.2 Hz, 2H), 2.13 (dd, J ) 8.5, 4.1 Hz,
1H), 1.66 (sex, J ) 7.4 Hz, 2H), 1.62 (s, 3H), 0.99 (t, J ) 7.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.4, 207.8, 171.6,
171.3, 166.0, 136.1, 136.0, 131.8, 131.2, 131.0, 128.6, 128.4,
128.3, 127.4, 127.2, 71.7, 52.4, 51.7, 50.8, 45.4, 44.5, 40.9, 37.7,
17.1, 13.7, 8.8; IR (thin film) 2953, 1740, 1719, 1687, 1638,
1390 cm-1; MS m/z (%) 473 (7), 441 (8), 414 (17), 382 (20), 350
(18), 105 (100); EI HRMS calcd for C29H31NO5 m/z [M+]
473.2202, found 473.2181. 11b (minor diastereomer, eluting
faster, hexanes-EtOAc): 1H NMR (300 MHz, CDCl3) δ 7.55-
7.29 (m, 10H), 4.21 (d, J ) 14.8, 1H), 4.03-3.94 (m, 2H), 3.71
(s, 3H), 3.68 (br s, 1H), 3.34-3.27 (m, 1H or ddd, J ) 10.8,
7.0, 3.4), 3.11 (d, J ) 14.1 Hz, 1H), 2.91 (dd, J ) 19.2, 3.5 Hz,
1H), 2.52 (t, J ) 7.4 Hz, 2H), 2.43 (dd, J ) 19.2, 11.3 Hz, 1H),
1.73 (sex, J ) 7.4 Hz, 2H), 1.62 (s, 3H), 1.00 (t, J ) 7.4 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 209.0, 208.9, 172.6, 171.6,
168.2, 136.5, 135.8, 131.6, 131.4, 131.2, 128.7, 128.2, 127.6,
127.0, 69.7, 52.4, 50.7, 49.0, 44.1, 42.0, 39.4, 36.3, 17.2, 13.8,
8.5.
2-Benzoyl-1-benzyl-6-(2,3-dioxo-3-pyrrolidin-1-yl-pro-
pyl)-5-oxo-1,2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-1-
carboxylic Acid Methyl Ester (25). 25 was prepared by
following general procedure E with 5b (840 mg, 2.17 mmol),
Et3N (905 µL, 6.51 mmol), oxo-pyrrolidin-1-yl-acetaldehyde
(1.38 g, 11.8 mmol), and 1,4-dioxane (20 mL). 25: yield 1.17
g, >95%; 1H NMR (300 MHz, CDCl3) δ 7.54-7.42 (m, 5H),
7.36-7.29 (m, 3H), 7.23-7.20 (m, 2H), 5.91 (s, 1H), 4.27 (d,
J ) 15.7 Hz, 1H), 4.17 (d, J ) 14.3 Hz, 1H), 4.07 (d, J ) 15.7
Hz, 1H), 3.82 (s, 3H), 3.66 (t, J ) 6.4 Hz, 2H), 3.58 (t, J ) 6.4
Hz, 2H), 3.52-3.44 (m, 2H), 3.33 (dd, J ) 18.7, 5.3 Hz, 1H),
3.23 (d, J ) 14.3 Hz, 1H), 2.47 (q, J ) 4.7 Hz, 1H), 1.99-1.90
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 207.4, 198.2, 174.1, 171.2,
161.9, 135.6, 131.2, 131.0, 128.6, 128.4, 127.2, 123.4, 71.5, 53.2,
52.6, 51.7, 47.3, 46.4, 46.0, 37.6, 37.1, 26.3, 23.6; IR (thin film)
2952, 1716, 1638, 11447, 1384 cm-1; MS m/z (%) 514 (13), 455
(6), 416 (17), 105 (100); EI-HRMS calcd for C30H30N2O6 m/z
[M+] 514.2104, found 514.2115.
2-Benzoyl-1-benzyl-6-methylene-5-oxo-1,2,3,5,6,6a-hexa-
hydrocyclopenta[c]pyrrole-1-carboxylic acid methyl es-
1
ter (5b): 224 mg, 57%; H NMR (300 MHz, CDCl3) δ 7.52-
7.27 (m, 10H), 6.19 (s, 1H), 6.07 (s, 1H), 5.63 (s, 1H), 4.24 (1/2
AB, J ) 14.9 Hz, 1H), 4.23 (1/2 AB, J ) 14.2 Hz, 1H), 4.03
(1/2 AB, J ) 15.0 Hz, 1H), 3.98 (s, 1H), 3.62 (s, 3H), 3.39 (1/2
AB, J ) 14.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 195.2,
170.9, 170.2, 170.1, 140.6, 135.7, 135.5, 131.1, 128.6, 128.5,
127.3, 126.2, 118.0, 70.8, 52.3, 51.5, 50.9, 37.7; IR (thin film)
3027, 1741, 1710, 1641, 1383 cm-1; MS m/z (%) 387 (15), 328
(10), 282 (22), 105 (100); EI-HRMS calcd for C24H21NO4 m/z
[M+] 387.1471, found 387.1470.
2-Benzoyl-3-benzyl-6-oxo-2,3,5,6-tetrahydro-1H-[2]pyr-
indine-3-carboxylic acid methyl ester (7b): 58 mg, 15%;
1H NMR (300 MHz, CDCl3) δ 7.49-7.41 (m, 3H), 7.34-7.27
(m, 5H), 7.21-7.17 (m, 2H), 5.90 (s, 1H), 5.70 (s, 1H), 4.39 (1/2
AB, J ) 18.1 Hz, 1H), 4.15 (1/2 AB, J ) 13.8 Hz, 1H), 3.81 (s,
3H), 3.38 (1/2 AB, J ) 13.8 Hz, 1H), 3.05 (s, 2H), 3.01 (1/2 AB,
J ) 18.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 202.9, 171.3,
171.1, 161.1, 135.8, 135.4, 135.2, 130.3, 129.9, 128.7, 128.3,
127.4, 127.2, 126.3, 123.5, 65.9, 53.0, 45.1, 39.6, 37.7; IR (thin
film) 2950, 1740, 1710, 1643, 1391 cm-1; MS m/z (%) 387 (47),
356 (15), 328 (12), 296 (30), 105 (100); EI-HRMS calcd for
C24H21NO4 m/z [M+] 387.1471, found 387.1489.
2-Benzoyl-1-benzyl-6-methylene-5-oxo-1,2,3,4,5,6-hexa-
hydrocyclopenta[c]pyrrole-1-carboxylic acid methyl es-
ter (8b): 1H NMR (300 MHz, CDCl3) δ 7.46-7.35 (m, 5H),
7.27-7.25 (m, 3H), 7.11-7.08 (m, 2H), 5.94 (s, 1H), 5.58 (s,
1H), 4.08 (d, J ) 15.7 Hz, 1H), 4.04 (d, J ) 13.8 Hz, 1H), 3.84
(s, 3H), 3.56-3.52 (m, 2H), 2.85 (d, J ) 22.5 Hz, 1H), 2.70 (d,
J ) 22.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 201.5, 170.1,
169.2, 145.2, 142.5, 138.5, 136.2, 136.1, 130.1, 128.5, 127.9,
127.0, 126.4, 112.6, 74.3, 55.1, 52.9, 38.4, 36.2; IR (thin film)
2950, 1743, 1631, 1405, 1253 cm-1; ESI-HRMS calcd for C24H21-
NO4Na m/z [M + 23+] 410.1368, found 410.1375.
Preparation of Compounds 11, 12, 24, and 25 (General
Procedure E for the Stetter Reaction). To a solution of
cyclopentenone (0.3 mmol) in 1,4-dioxane (2 mL) was added
Et3N (0.9 mmol), aldehyde (1.5 mmol), and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride (0.06 mmol). The
reaction vessel was sealed with a rubber septum and heated
to 70 °C (6 h for compounds 11 and 12; 10 min for compounds
24 and 25). The reaction mixture was then poured into water
(50 mL), and the aqueous layer was extracted with Et2O (3 ×
25 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, and concentrated under vacuum.
Purification procedure for compounds 11 and 12: Hexanes (5
mL) was added and a white precipitate formed. The precipitate
was collected by decantation and purified by flash chroma-
tography (gradient elution; hexanes-EtOAc, 9:1 to 2:1, v/v)
to afford the major diastereomer. The minor diastereomer
remained in the decanted liquid, which could be purified by
flash chromatography. Purification procedure for compounds
24 and 25: The crude yellow oil was purified by flash
Preparation of Compounds 15, 16, 26, and 27 (General
Procedure F for Reduction of Enones). To a solution of
the enone (2.0 mmol) in methanol (50 mL) was added Pd (10
wt % on activated carbon) (170 mg) at room temperature. The
reaction was carried out in a low-pressure catalytic hydroge-
nation apparatus in a Pyrex centrifuge bottle. The bottle was
connected to a low-pressure hydrogen tank and alternatively
evacuated and filled with hydrogen three times. Hydrogen was
then admitted into the system until pressure reached the
designated level (1-3 atm) and the bottle was shaken for 4 h.
The bottle was then evacuated and air admitted. The mixture
was then filtered on a Bu¨chner funnel through a plug of Celite,
and the clear liquid was concentrated in vacuo. Purification
by flash chromatography (gradient elution, hexanes-EtOAc
3:1 to 1:3 v/v) afforded the desired compound.
2-Benzoyl-1-benzyl-6-(2,3-dioxo-3-pyrrolidin-1-yl-pro-
pyl)-5-oxo-octahydrocyclopenta[c]pyrrole-1-carboxylic
Acid Methyl Ester (27). 27 was prepared by following
general procedure F with 25 (1.17 g, 2.27 mmol), Pd (10 wt %
on activated carbon) (200 mg), H2 (1 atm). 27: yield 841 mg,
1752 J. Org. Chem., Vol. 70, No. 5, 2005

Heterocyclic R-Alkylidene Cyclopentenones
1
74%; H NMR (300 MHz, CDCl3) δ 7.50-7.24 (m, 10H), 4.18
extracted with EtOAc (3 × 20 mL) and the organic layers were
then combined and washed again with 1 M HCl (20 mL). After
drying over MgSO4 and removal of the solvent in vacuo, the
pale yellow residue was purified by flash chromatography
(gradient elution, hexanes-EtOAc, v/v) to afford the pyrrole
in high yields and purity (NMR).
(d, J ) 13.8 Hz, 1H), 3.86 (s, 3H), 3.65 (t, J ) 6.7, 2H), 3.53 (t,
J ) 6.7 Hz, 2H), 3.30-3.17 (m, 3H), 3.11-3.08 (m, 2H), 2.89-
2.87 (m, 2H), 2.22 (dd, J ) 19.3, 8.5 Hz, 1H), 2.08-1.80 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 216.6, 198.1, 171.5, 169.6,
161.9, 136.9, 136.7, 130.6, 129.9, 128.5, 127.1, 126.3, 72.8, 55.4,
52.7, 52.1, 47.3, 46.5, 45.6, 39.3, 38.7, 36.1, 26.3, 23.6; IR (thin
film) 2950, 1737, 1636, 1404 cm-1; MS m/z (%) 516 (8), 485
(7), 457 (36), 425 (51), 105 (100); EI-HRMS calcd for C30H32N2O6
m/z [M+] 516.2260, found 516.2255.
Preparation of Compounds 17, 18, and 19 (General
Procedure G). To a solution of 1,4-dione (0.03 mmol) in
methanol (0.6 mL) was added amine (0.15-0.3 mmol), AcOH
(0.15-0.3 mmol), and 4 Å molecular sieves (30 mg) activated
by flame drying under vacuum. The reaction mixture was
stirred at 70 °C for 1 to 4 h. Upon completion, the reaction
mixture was diluted with EtOAc (50 mL) and washed with 1
M HCl (2 × 20 mL). The organic layer was then dried over
MgSO4, and the solvents were removed in vacuo. The crude
material was purified by flash chromatography (gradient
elution; hexanes-EtOAc, 19:1 to 3:1, v/v) to afford the desired
pyrrole.
5-Benzoyl-4-benzyl-1-(3-methylbutyl)-2-(pyrrolidine-1-
carbonyl)-3b,4,5,6,6a,7-hexahydro-1H-1,5-diaza-cyclopen-
ta[a]pentalene-4-carboxylic Acid Methyl Ester (28m).
28m was prepared by following general procedure I with 27
(35 mg, 0.068 mmol), 3-methylbutylamine (21 µL, 0.20 mmol),
and AcOH (90 µL). 28m: yield 36 mg, 95%; 1H NMR (300 MHz,
CDCl3) δ 7.48-7.27 (m, 10H), 4.23 (d, J ) 13.5 Hz, 1H), 4.17-
4.10 (m, 1H), 3.98-3.85 (m, 2H), 3.74-3.55 (m, 7H), 3.40 (d,
J ) 13.7 Hz, 1H), 3.37-3.30 (m, 1H), 3.21-3.15 (m, 1H), 2.53
(dd, J ) 15.1, 6.9 Hz, 1H), 2.36-2.25 (m, 1H), 2.21 (d, J )
16.1 Hz, 1H), 2.01-1.85 (m, 4H), 1.50-1.45 (m, 3H), 0.85 (d,
J ) 5.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 172.2, 169.7,
162.0, 140.3, 137.6, 137.1, 130.9, 130.6, 129.5, 129.2, 128.5,
128.3, 128.1, 126.7, 126.2, 122.1, 72.9, 56.3, 52.0, 45.4, 45.2,
40.3, 39.2, 28.5, 25.7, 22.5, 22.4; IR (thin film) 2951, 1735, 1639,
1611, 1446, 1399 cm-1; MS m/z (%) 567 (32), 476 (41), 405 (24),
301 (61), 91 (100); EI-HRMS calcd for C35H41N3O4 m/z [M+]
567.3097, found 567.3114.
5-Benzoyl-1,4-dibenzyl-2-propyl-3b,4,5,6,6a,7-hexahy-
dro-1H-1,5-diaza-cyclopenta[a]pentalene-4-carboxylic
Acid Methyl Ester (17). 17 was prepared by following
general procedure G with 16 (10 mg, 0.021 mmol), benzylamine
(23 µL, 0.21 mmol), AcOH (12 µL, 0.21 mmol), and methanol
(0.5 mL). 17: yield 10 mg, 90%; 1H NMR (300 MHz, CDCl3) δ
7.43-7.22 (m, 13H), 6.87 (d, J ) 7.0 Hz, 2H), 5.70 (s, 1H),
4.85 (s, 2H), 4.24 (d, J ) 13.6 Hz, 1H), 3.91 (d, J ) 7.2 Hz,
1H), 3.71 (s, 3H), 3.37 (d, J ) 13.6 Hz, 1H), 3.36-3.30 (m,
1H), 3.20-3.14 (m, 1H), 2.39 (t, J ) 7.6 Hz, 2H), 2.39-2.31
(m, 1H), 2.22 (quin, J ) 7.6 Hz, 1H), 2.01 (d, J ) 14.5 Hz,
1H), 1.55 (sex, J ) 7.6 Hz, 2H), 0.93 (t, J ) 7.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 172.4, 169.9, 138.5, 138.0, 137.6,
137.5, 134.9, 131.2, 129.6, 128.7, 128.4, 128.2, 127.3, 126.7,
126.4, 126.1, 122.4, 73.1, 56.8, 52.9, 52.1, 48.3, 45.5, 39.4, 29.1,
Acknowledgment. We gratefully acknowledge
the financial support provided by the National In-
stitutes of Health (P50 GM067982), the University
of Pittsburgh, and the Center for Chemical Method-
ologies and Library Development (UPCMLD, http://
ccc.chem.pitt.edu). S.F. acknowledges the Postdoc-Pro-
gramme of the German Academic Exchange Service
(DAAD) for fellowship support and we would also like
to thank Dr. Gary Bolton for helpful discussions.
Supporting Information Available: Compounds 4a-d
have been prepared previously in our laboratories2 and the
corresponding procedures and characterization for compounds
4e and 9a-d prepared in an analogous manner from the
corresponding amino acids are given; the Pauson-Khand
reactions of 4a, 4b, 4c, and 4d have been reported previously2
and the procedures for the preparation and characterization
data (not including spectra) for compounds 21a-j are given.
This material is available free of charge via the Internet at
http://pubs.acs.org.
28.8, 22.4, 14.1; IR (thin film) 2950, 1734, 1642, 1402 cm-1
;
MS m/z (%) 532 (24), 441 (16), 250 (20), 105 (100); EI-HRMS
calcd for C35H36N2O3 m/z [M+] 532.2726, found 532.2724.
Preparation of Compounds 28a-n (General Proce-
dure I). To a solution of the 1,4-dione (0.07 mmol, 1 equiv) in
EtOH (0.9 mL) in a test tube was added amine (0.21 mmol, 3
equiv) followed by glacial acetic acid (90 µL) at room temper-
ature. The test tube was then heated to 50 °C in an oil bath
for 2 h when the reaction was complete (as observed by TLC).
The light yellow solution was then diluted with EtOAc (20 mL)
and poured into 1 M HCl (30 mL). The aqueous layer was
JO0481607
J. Org. Chem, Vol. 70, No. 5, 2005 1753