Pyrrole-based scaffolds for turn mimics

Article abstract of DOI:10.1021/ol103022m

Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with an idealized type 1 β-turn and with an inverse γ-turn.(Figure Presented)

Full text of DOI:10.1021/ol103022m

ORGANIC
LETTERS
2011
Vol. 13, No. 5
980–983
Pyrrole-Based Scaffolds for Turn Mimics
Eunhwa Ko and Kevin Burgess*
Texas A & M University, Chemistry Department, P.O. Box 30012, College Station,
Texas 77842, United States
burgess@tamu.edu
Received December 13, 2010
ABSTRACT
Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates
into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with
an idealized type 1 β-turn and with an inverse γ-turn.
Placement of acarbonylgroup atthe 2-or 5-position of a
pyrrole arranges the CO and heterocyclic N- in a 1,3-
disposition, just like the main-chain CO and N of amino
acids. Several groups have seen this as an opportunity to
incorporate pyrrole 2-carboxylic acids into peptides as
amino acid surrogates.1 Simultaneously, others have used
amino acid starting materials for syntheses of pyrroles with
protein/peptide-like side chains.2 However, to the best of
our knowledge, none of these strategies have used two amino
acids to give pyrrole derivatives with two amino acid de-
rived side chains.
outlined above, to produce analogs of β-turns, specifically
compounds 1, that project two amino acid side chains in
orientations corresponding to i þ 1 and i þ 2 residues of a
type I β-turn. Moreover, it was anticipated that syntheses
of these molecules could be facilitated by numerous new
methods that have emerged recently for intramolecular
Our group is interested in molecules that resemble sec-
ondary structures by presenting pertinent amino acid side
chains, i.e. minimalist secondary structure mimics.3 We
saw the opportunity to build on the insights of others
(1) (a) Chakraborty, T. K.; Krishna Mohan, B.; Kiran Kumar, S.;
Kunwar, A. C. Tetrahedron Lett. 2002, 2589. (b) Alongi, M.; Minetto,
G.; Taddei, M. Tetrahedron Lett. 2005, 7069. (c) Bonauer, C.; Koenig, B.
Synthesis 2005, 2367. (d) Minchev, I.; Vladimirova, S.; Vezenkov, L.;
Bijev, A.; Moussis, V.; Nikolaeva-Glomb, L.; Tsikaris, V.; Czeuz, M.;
Galabov, A. Protein Pept. Lett. 2007, 917.
(2) (a) Yavari, I.; Kowsari, E. Synlett 2008, 897. (b) Zhang, Z.;
Zhang, J.; Tan, J.; Wang, Z. J. Org. Chem. 2008, 5180. (c) Gouault,
N.; Le Roch, M.; Cornee, C.; David, M.; Uriac, P. J. Org. Chem. 2009,
5614. (d) Alizadeh, A.; Hosseinpour, R.; Rostamnia, S. Synthesis 2008,
2462.
(3) (a) Angell, Y.; Chen, D.; Brahimi, F.; Saragovi, H. U.; Burgess, K.
J. Am. Chem. Soc. 2008, 556. (b) Ko, E.; Ling, J.; Perez, L. M.; Lu, G.;
Schaefer, A.; Burgess, K. J. Am. Chem. Soc. 2011, 133, 462–477.
Figure 1. Conceptual basis of 1H-pyrrolo[1,2-c]imidazol-3(2H)-
ones as β-turn mimics.
r
10.1021/ol103022m
Published on Web 01/26/2011
2011 American Chemical Society

Scheme 1. Syntheses of the Target Compounds 1
Scheme 2. Hydroamination/Cyclization
amination of alkynes to produce N-heterocycles via the
disconnections shown (Figure 1).4
Syntheses of the target compounds 1 began with
Weinreb amides5 of Boc-protected amino acids (Scheme 1).6
These were reduced to the corresponding aldehydes, which,
without isolation, were immediately reacted with dianio-
nic, Boc-protected alkynes derived from amino acids.7 Sev-
eral exploratory sets of conditions were employed to effect
this transformation, and an alternative route involving
formation of propargyl ketones was also investigated
(see Supporting Information). The conditions outlined in
Scheme 1 were the most effective overall. This is a difficult
reaction, because it involves combination of an anionic
electrophile with a nucleophile dianion.
Sarpong’s platinum (2þ) mediated cyclizations of pro-
pargylic (2-pyridyl)alcohols8 were used as an initial para-
digm for formation of pyrroles in this work (Scheme 2a).
Scheme 2b reiterates the mechanistic hypothesis outlined
by Sarpong et al. for their transformation. It soon became
evident that elimination of the NHBoc group on the newly
formed pyrrole side chain would be problematic. Conse-
quently, a series of microwave-mediated trial reactions were
run to optimize the conversion and 3:4 product ratio. At-
tempts to use other catalysts did not give better results.
Similarly, acidic or basic additives, or phosphine ligands,
gave no benefits (see Supporting Information). However,
changingthe solvent fromtolueneto1,4-dioxanemarkedly
increased the conversion but gave approximately the same
product selectivity (Table 1).
(4) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 3079.
(b) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
11260. (c) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 12050.
(d) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009,
4624. (e) Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 5002.
(5) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707.
(6) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. J. Med.
Chem. 1995, 3193.
(7) Ghosh, A. K.; Xi, K.; Ratia, K.; Santarsiero, B. D.; Fu, W.;
Harcourt, B. H.; Rota, P. A.; Baker, S. C.; Johnson, M. E.; Mesecar,
A. D. J. Med. Chem. 2005, 6767.
(8) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org.
Lett. 2007, 1169.
Figure 2. A possible mechanism for elimination of the NHBoc
group.
Scheme 2c shows the result of subjecting the isolated,
purified product 3 to the same reaction conditions used to
make it in Table 1, entry 2. Alkenyl pyrrole 4a was formed
in this experiment, but the 3a:4a product ratio favored 3a
Org. Lett., Vol. 13, No. 5, 2011
981

Table 1. Pt(II)-Catalyzed Pyrrole Formation through Hydro-
amination (Solvent Effect)
Table 2. Pt(II)-Catalyed Pyrrole Formation through Hydroa-
mination
conversion
entry
solvent
benzene
3a:4a
yield (%)
1
2
3
4
5
6
4.0:1.0
4.3:1.0
2.4:1.0
2.1:1.0
4.8:1.0
1.1:1.0
85
80
61
50
46
21
1,4-dioxane
THF
1,2-dichloroethane
toluene
EtOH
much more than in the synthesis of this material. This
observation indicates some, but not all, of the elimination
product 4 is derived from 3 via the process outlined in
Figure 2. This competing mechanism could involve elim-
ination of the NHBoc group to give an eneyne before
pyrrole formation.
Table 2 shows data for a series of substrates 3 with the
various amino acid side chains used. The methodology
was therefore validated using Ile, Leu, Val, Tyr(Bn), Met,
and Thr(Bn). An adjustment had to be made for the
glycine-containing substrate 2f, because very little product
was formed in this situation. Product was formed when the
bis-Boc protected substrate 2f0 was used instead, but still
the product yield was low.
Removal of the pyrrole-N protecting group under
basic conditions led to simultaneous cyclization to the 1H-
pyrrolo[1,2-c]imidazol-3(2H)-one scaffolds 1 as in Scheme 3a.
Removal of both Boc-protecting groups without cycliza-
tion was also of interest, because the diamines correspond-
ing to 3 can be regarded as β-turn mimics, though less
rigid than the target compounds 1. It proved difficult to
do this; in the event, we only succeeded in removing the
Boc-protection from the sidechain in3aunderthebuffered
conditions indicated.9 In fact, even this reaction was hard
to control and reproduce.
Scheme 3. Cyclization to the β-Turn Mimics
1H-Pyrrolo[1,2-c]imidazol-3(2H)-ones of different kinds
have been associated with various types of characteris-
tics in medicinal chemistry. These include molluscicidal,10
antidiabetic,11 and 5HT3 antagonist12 activities. This in-
dicates the scaffold itself is amenable to interactions in bio-
logical systems.
As turn mimics, compounds 1 are compact and overlay
well with the class of β-turns most frequently encountered
(9) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 870.
(10) Mishriky, N.; Asaad, F. M.; Ibrahim, Y. A.; Girgis, A. S.
Pharmazie 1998, 607.
(11) Yamawaki, I.; Matsushita, Y.; Asaka, N.; Ohmori, K.; Nomura,
N.; Ogawa, K. Eur. J. Med. Chem. 1993, 481.
(12) Varasi, M.; Heidempergher, F.; Caccia, C.; Salvati, P. Imidazo-
lylalkyl derivatives of imidazo[1,5-a]indol-3-one and their use as ther-
apeutic CNS agents. US 5874457, May 2, 1995.
982
Org. Lett., Vol. 13, No. 5, 2011

Hamilton14 and Hirschmann/Smith,15 for instance, em-
ployed a similar concept before us. However, we have
recently noted3b that scaffolds described as minimalist
tend to be superimposable on other elements of secondary
structure; i.e. they tend to be promiscuous. In fact, this is
true of compounds 1. Figure 3 illustrates how scaffold 1
can be overlaid with the i þ 1 and i þ 2 side chains of an
ideal type I β-turn and with i þ 1 and i þ 2 of an inverse
γ-turn.
Peptidomimetic scaffolds that overlap more than one
secondary structure may appear to be vulnerable to non-
selective binding. This is not so, however, because proteins
are targeted by proteins/peptides by choosing the corre-
sponding side chains.16 Thus duality, or even multiplicity,
of fit increases the value of scaffolds for secondary struc-
ture mimics because they can be applied more widely, par-
ticularly in libraries designed for high throughput screening
against many diverse targets.3b In our opinion, this is a
concept that should become more widely applied in pepti-
domimetic design.
Acknowledgment. Financial support for this project was
provided by the National Institutes of Health (MH070040,
GM076261) and the Robert A. Welch Foundation (A-
1121). TAMU/LBMS-Applications Laboratory provided
mass spectrometric support. The NMR instrumentation at
Texas A&M University was supported by a grant from the
National Science Foundation (DBI-9970232) and the Texas
A&M University System.
Figure 3. Overlay with the i þ 1 and i þ 2 side chains of an ideal
type I β-turn (a) and with the i þ 1 and i þ 2 side chains of an
inverse γ-turn (b).
in protein and peptide conformations, i.e. type I.13 In our
group, we refer to compounds like this, ones that achieve
mimicry using only appropriately projected side chains, as
minimalist mimics.3a Though they did not use this term,
(13) Rose, G. D.; Gierasch, L. M.; Smith, J. A. Turns in Peptides and
Proteins; Academic Press, Inc.: 1985; Vol. 37, p 1.
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
reported. This material is available free of charge via the
Internet at http://pubs.acs.org.
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