Domino coupling relay approach to polycyclic pyrrole-2-carboxylates

Article abstract of DOI:10.1021/ja053408a

CuBr₂-catalyzed three-component coupling of N-benzylallylamine, ethyl glyoxalate, and terminal alkynes afforded glycine-tethered 1,6-enynes, which were further transformed into polycyclic pyrrole-2-carboxylates via novel cycloisomerization/Diel

Full text of DOI:10.1021/ja053408a

Published on Web 07/19/2005
Domino Coupling Relay Approach to Polycyclic Pyrrole-2-carboxylates
Yoshihiko Yamamoto,* Hiroki Hayashi, Tomoaki Saigoku, and Hisao Nishiyama
Department of Applied Chemistry, Graduate School of Engineering, Nagoya UniVersity, Chikusa,
Nagoya 464-8603, Japan
Received May 25, 2005; E-mail: yamamoto@apchem.nagoya-u.ac.jp
Pyrroles represent an important class of nitrogen heterocycles,
which are found in various biologically active natural compounds.1
Specifically, pyrrole-2-carboxylate is an interesting cyclic amino
acid motif, which is found in natural and artificial functional
Figure 1. Glycinate-tethered R,ω-ethynes.
molecules such as bioactive natural products,2 selective DNA-
binding ligands,3 and conformationally constrained peptides.4 The
construction of multiply substituted pyrrole rings is, however, still
relying largely on the classical condensation methods such as Paal-
Knorr synthesis,1 although catalytic multicomponent coupling
approaches have attracted recent attention as environmentally benign
alternatives.5 The convergent synthesis of highly valuable polycyclic
analogues along this line has also remained to be developed. In
this context, we explored a novel four-component coupling strategy
to synthesize polycyclic pyrrole-2-carboxylates. Complexity-
generating domino multicomponent coupling processes have be-
come increasingly important in terms of the diversity-oriented
synthesis toward the construction of small molecular libraries.6,7
Our approach comprises the relay process of the following two
catalytic domino reactions: (1) the Cu-catalyzed three-component
condensation giving rise to glycinate-tethered 1,6-enynes and (2)
the subsequent Ir-catalyzed cycloisomerization/Diels-Alder cy-
cloaddition/dehydrogenative aromatization.
Scheme 1
Scheme 2
Glycinate-tethered R,ω-enynes are fascinating precursors for the
synthesis of constrained cyclic R-amino acids (Figure 1).8 The
preparation of 1,6-enynes A, however, has not been reported to
date, while similar 1,7-enynes B were synthesized from a protected
glycine through four-step operations.8b To realize a single-step
assembly of the enyne A, we first developed the Cu-catalyzed
Mannich condensation route to alkynylglycinate (Scheme 1).9,10
According to the recent report of Knochel et al.,11 several copper
salts were examined as catalysts toward the reaction of 1 equiv
each of ethyl glyoxalate, dibenzylamine, and phenylacetylene in
toluene containing molecular sieve 4A at room temperature. The
reaction proceeded in the presence of 10 mol % CuBr, and the
formation of the desired alkynylglycinate 1a (R ) Ph) was
confirmed by the 1H NMR measurement of the crude product.
Purification with column chromatography on silica gel or alumina,
however, led to the decomposition of 1a to ketoester 2a and
dibenzylamine. To avoid the decomposition, the crude materials
were rapidly purified by the short column chromatography on
Florisil. As a result, 1a was obtained in 89% yield. In a similar
manner, CuBr2 and CuCl2 gave 1a in 85 and 79% yields,
respectively. In contrast, Cu(OAc)2 and CuI proved to be ineffective.
On the basis of these results, further explorations were carried out
with CuBr2, which is cheaper and more robust than CuBr. Under
the optimal reaction conditions, 1-hexyne and trimethylsilylacety-
cycloisomerization (Scheme 2). The cycloisomerization of enynes
is known as a powerful method to obtain exocyclic 1,3-dienes,
which can be utilized as diene components of Diels-Alder
reaction.12 Toward this end, we carried out the reaction of 1 equiv
each of N-benzylallylamine, ethyl glyoxalate, and 1-hexyne to obtain
the desired enyne 3b. After filtration to remove MS 4A, the crude
enyne 3b was submitted to the reported palladium-catalyzed
cycloisomerization conditions (5 mol % Pd2(dba)3, 10 mol % PPh3,
10 mol % AcOH, toluene reflux, 24 h)12c to result in the formation
of an intractable product mixture. Thus, we turned our attention to
the recently developed iridium catalyst system of Chatani, Murai,
and co-workers.13 According to their report, crude 3b was treated
with 3 mol % [IrCl(cod)]2 and 12 mol % AcOH in refluxing toluene
for 24 h. As a result, the iridium-catalyzed conditions proved to be
viable for the cycloisomerization of 3b, but the obtained product
was unexpected pyrrole-2-carboxylate 5, which was probably
formed by the iridium-catalyzed isomerization of exocyclic diene
4.
n
lene similarly gave rise to 1b (R ) Bu) or 1c (R ) TMS). The
former was isolated in 81% yield, but the latter was decomposed
during the Florisil chromatography.
As the next step, we attempted the Cu-catalyzed three-component
coupling synthesis of glycinate-tethered 1,6-enynes 3 and its
To trap putative intermediate 4 with Diels-Alder reaction, we
further carried out the cycloisomerization of 3b in the presence of
1.1 equiv of N-phenylmaleimide.14 Gratifyingly, a 1:1 cycloadduct
9
10804
J. AM. CHEM. SOC. 2005, 127, 10804-10805
10.1021/ja053408a CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Fused Pyrrolecarboxylates 7
Ethynylferrocene was employed as a teminal alkyne component to
afford 7ga in 52% yield (run 7), and its structure was unambigu-
ously established by X-ray crystallographic analysis (see Supporting
Information). In addition to N-phenylmaleimide, maleic anhydride
can be used as a dienophile in the second step to afford 7bb in
52% yield (run 8). On the other hand, the use of 1,4-naphthoquinone
led to the formation of 7fc possessing both pyrrole and naphtho-
quinone rings albeit in lower yield of 35% (run 9). The formation
of 7fc can be considered as a result of the double dehydrogenation
under the influence of the iridium species.
In conclusion, we successfully established the novel domino-
coupling relay approach to polycyclic pyrrole-2-carboxylates
through the Cu-catalyzed Mannich condensation of N-benzylally-
lamine, ethyl glyoxalate, and terminal alkynes, and the Ir-catalyzed
cycloisomerization/Diels-Alder reaction/dehydrogenative aroma-
tization of the resultant glycinate-tethered 1,6-enynes.
Acknowledgment. This research was partially supported by the
MEXT, Grant-in-Aid for Young Scientists (A) (17685008), and
Scientific Research on Priority Area “Creation of Biologically
Functional Molecules” (17035038). We gratefully acknowledge
financial support from the Tokuyama Science Foundation.
Supporting Information Available: Experimental procedure and
analytical data for products (CIF, PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
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