One-pot multicomponent synthesis of diversely substituted 2-aminopyrroles. A short general synthesis of rigidins A, B, C, and D

Article abstract of DOI:10.1021/ol103149b

Privileged medicinal scaffolds based on the structures of tetra-and pentasubstituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkylsulfonamido)acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C, and D in overall yields of 61%, 58%, 60%, and 53%, respectively. Of these, rigidins B, C, and D were synthesized for the first time.(Figure Presented)

Full text of DOI:10.1021/ol103149b

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1118–1121
One-Pot Multicomponent Synthesis of
Diversely Substituted 2-Aminopyrroles.
A Short General Synthesis of Rigidins A,
B, C, and D†
Liliya V. Frolova,‡ Nikolai M. Evdokimov,‡ Kathryn Hayden,§ Indranil Malik,§
Snezna Rogelj,§ Alexander Kornienko,‡ and Igor V. Magedov*,‡
Departments of Chemistry and Biology, New Mexico Institute of Mining and
Technology, Socorro, New Mexico 87801, United States
imagedov@nmt.edu
Received December 27, 2010
ABSTRACT
Privileged medicinal scaffolds based on the structures of tetra- and pentasubstituted 2-aminopyrroles were prepared via one-pot multicomponent
reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkylsulfonamido)acetophenones with activated methylene compounds. This
methodology was used in a four-step synthesis of alkaloids rigidins A, B, C, and D in overall yields of 61%, 58%, 60%, and 53%, respectively. Of
these, rigidins B, C, and D were synthesized for the first time.
Polysubstituted pyrroles are an important class of het-
erocycles that display diverse pharmacological activities.1
Furthermore, they are useful building blocks in the synth-
esis of natural products and heterocyclic chemistry. Altho-
ugh a large number of new pyrrole syntheses,2 including
multicomponent reactions (MCRs),3 have been reported
in recent years, relatively few examples are known for
the preparation of polysubstituted 2-aminopyrroles.4
Aminopyrroles are not readily available through general
pyrrole ring-formation methods. At the same time the
2-aminopyrrole fragment is part of many different bioac-
tive compounds and it is recognized as a privileged med-
icinal structure. Known bioactivities for this class of
compounds include anti-inflammatory,5 anticancer,6 anti-
viral,7 antifungal,8 pesticidal,9 radioprotective,10 MEK
inhibitory,11 MK2 inhibitory,12 FAK, KDR and Tie2 inhib-
itory,13 PDE inhibitory,14 anti-interleukin-6,15 TNF-R
production inhibitory,16 and afferent pelvic nerve activity
† This paper is dedicated to Prof. Yuri I. Smushkevich on the occasion of
his 75th birthday.
(2) For selected examples, see: (a) Lu, Y.; Arndtsen, B. Org. Lett.
2009, 11, 1369–1372. (b) Blangetti, M.; Deagostino, A.; Prandi, C.;
Tabasso, S.; Venturello, P. Org. Lett. 2009, 11, 3914–3917. (c) Aponick,
A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624–4627.
(d) Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 11, 5002–5005.
(e) Satito, A.; Konishi, T.; Hanzawa, Y. Org. Lett. 2010, 12, 372–374.
(f) Wang, H.-Y.; Mueller, D. S.; Sachwani, R. M.; Londino, H. N.;
Anderson, L. L. Org. Lett. 2010, 12, 2290–2293 and references cited
therein.
‡ Department of Chemistry.
§ Department of Biology.
(1) For recent reviews, see: (a) Furstner, A. Angew. Chem., Int. Ed.
2003, 42, 3582–3603. (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F.
Chem. Rev. 2008, 108, 264–287. (c) Nakao, Y.; Fusetani, N. J. Nat. Prod.
2007, 70, 689–710. (d) Urban, S.; Hickkford, S. J. H.; Blunt, J. W.;
Munro, M. H. G. Curr. Org. Chem. 2000, 4, 765–807.
r
10.1021/ol103149b
Published on Web 01/26/2011
2011 American Chemical Society

inhibitory.17 Moreover, 2-aminopyrroles are precursors
for the synthesis of purine analogues ;pyrrolopyrimidines,
pyrrolotriazines, and pyrrolopyridines.18-24 These
pyrrole-containing heterocycles are widely investigated for
their multiple bioactivities, which, among many others, are
known to include anti-inflammatory,18 anticancer,19 antiv-
iral,20 antifungal,21 adenosine A1 receptor inhibitory,22
adenosine kinase,23 and dihydrofolate reductase24 inhibi-
tory. The pyrrolo[2,3-d]pyrimidine ring system is also a
common motif in several natural products, such as nucleo-
side antibiotics tubercidin, toyocamycin, sangivamycin,25
and marine alkaloids rigidins A, B, C, D, and E.26
Previously, we described a novel method for the synth-
esis of multisubstituted pyrrolines using a multicomponent
reaction of various N-(aryl- and alkylsulfonamido)aceto-
phenones with aldehydes and malononitrile (see Table 1
graphic).27 While the reaction is regioselective, it is not
stereoselective and gives mixtures of cis- and trans-2-
pyrrolines, which are not easily separable. Utilizing this
methodology as a starting point, we developed a new multi-
component one-pot method for the synthesis of diversely
tetra- and pentasubstituted 2-aminopyrroles. In addition,
we utilized the new method for a short total synthesis of
alkaloids rigidins A, B, C, and D.
Pentasubstituted 2-aminopyrroles A1-17 were prepared
by a multicomponent reaction of N-(aryl-, hetaryl-, and
alkylsulfonamido)acetophenones, aldehydes, and cyano-
acetic acidderivatives in acetonitrile, followed by oxidation
withDDQ inone pot (Table1). Thisthree-componentpro-
cess works well for any tested combination of aliphatic,
aromatic (including sterically hindered or heteroaromatic)
aldehydes and malononitrile, cyanoacetamide, or ethyl
cyanoacetate. Because of the lower reactivity of the inter-
mediate Knoevenagel products of cyanoacetamide or ethyl
cyanoacetate, the reactions were sluggish in acetonitrile
(A16 and A17). In these cases the pyrrolines were obtained
in ethanol, the solvent was then evaporated, and the crude
material was redissolved in acetonitrile for the subsequent
oxidation with DDQ. When phenylsulfonyl- or 4-methox-
ybenzoylacetonitriles were used in this reaction, a mixture
of pyrrolines was obtained, which did not undergo oxida-
tion to the corresponding pyrroles.
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Org. Lett., Vol. 13, No. 5, 2011
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Table 1. Synthesis of Pentasubstituted Pyrroles A
Table 2. Synthesis of Tetrasubstituted Pyrroles B
Table 3. Synthesis of Tetrasubstituted Pyrroles B
pyrrole
Ar
R2
E
yield, %
B5
Ph
Ph
Ph
3,4,5-MeO-Ph
2-Cl-6-F-Ph
4-MeO-Ph
3,4,5-MeO-Ph
4-Br-Ph
CN
CN
CN
CN
CN
80
76
55
85
73
48
28
40
52
57
48
93
89
B6
B7
B8
4-MeO-Ph
a The intermediate pyrrolines were obtained in EtOH.
B9
Ph
B10
B11
B12
B13
B14
B15
B16
B17
4-MeO-Ph
4-MeO-Ph
4-O2N-Ph
4-MeO-Bz
SO2Ph
Ph
NH-pyrroles B1-5 (Table 2). We found that 4-MeO-
PhSO2- and MeSO2- leaving groups are the best for this
reaction, but it is necessary to change the solvent from
acetonitrile to DMF. Furthermore, after the experimenta-
tion with different solvents, bases, and reaction tempera-
tures we found that simply refluxing a solution of the three
reactants containing 0.6 equiv of K2CO3 in ethanol results
in pyrroles B5-17 (Table 3).29
The reaction scope encompasses the use of aliphatic,
aromatic, and heterocyclic aldehydes as well as diverse
activated methylene compounds including cyano, acyl,
sulfono, alkoxycarbono, and carbamido acetonitriles.
Tetrasubstituted 2-aminopyrroles, containing a 3-car-
bamido-group, are a structural unit of marine alkaloids
Ph
4-Br-Ph
SO2Ph
Ph
3,4,5-MeO-Ph
3,4,5-MeO-Ph
2,6-Cl-Ph
SO2Ph
Ph
COOEt
CONH2
CONH2
CONH2
Ph
Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
rigidins(Figure 1). These alkaloids havebeenisolated from
tunicates obtained near Okinawa and New Guinea and
have been shown to possess calmodulin antagonistic and
cytotoxic activities.26 Several syntheses of rigidins A and E
have been reported.30 Using our methodology for the
synthesis of tetrasubstituted pyrroles, we developed the
(30) (a) Edstrom, E. D.; Wei, Y. J. Org. Chem. 1993, 58, 403–407.
(b) Sakamoto, T.; Kondo, Y.; Sato, S.; Yamanaka, H. J. Chem. Soc.,
Perkin Trans. I 1996, 459–464. (c) Gupton, J. T.; Banner, E. J.; Scharf,
A. B.; Norwood, B. K.; Kanters, R. P. F.; Dominey, R. N.; Hempel,
J. E.; Kharlamova, A.; Bluhn-Chertudi, I.; Hickenboth, C. R.; Little,
B. A.; Sartin, M. D.; Coppock, M. B.; Krumpe, K. E.; Burnham, B. S.;
Holt, H.; Du, K. X.; Keertikar, K. M.; Diebes, A.; Ghassemi, S.;
Sikorski, J. A. Tetrahedron 2006, 62, 8243–8255.
(29) As our work was in progress (Frolova, L. V.; Magedov, I. V.;
Kornienko, A. Abstracts of Papers, 239th National Meeting of the
American Chemical Society, San Francisco, CA; American Chemical
Society: Washington, DC, 2010; ORGN-1069) a report of a similar
synthesis of tetrasubstituted pyrroles appeared, see: Wang, K.; Domling, A.
Chem. Biol. Drug Des. 2010, 75, 277–283.
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Org. Lett., Vol. 13, No. 5, 2011

Table 4. Biological Activities of Pyrroles A and B
IC50, μM
(HeLa)
MIC, μM
(S. epi)
IC50, μM
(HeLa)
MIC, μM
(S. epi)
A2
12.5
17
>200
>200
>200
>200
>200
>200
>200
25
B2
B3
B4
B5
B6
B8
B10
37.5
>100
3.1
>200
30
A3
A6
20
>200
>200
25
A7
6.2
75
A8
50
>100
37.5
20
A13
A14
A15
75
>200
50
25
>100
activity was assessed by using the cancer cell line, HeLa,
as a model for human cervical adenocarcinoma, through
the measurements of mitochondrial dehydrogenase activities
using the MTT method.31 In addition, pyrroles A and B
were tested against Staphylococcus epidermidis (ATCC
75984), where Minimum Inhibitory Concentrations (MICs)
were determined by the broth microdilution method.32 We
foundthat selectedsynthesizedpyrrolesexhibitactivitiesin
these assays (Table 4), supporting the idea that diverse
biological activities are likely to be found within the
libraries of privileged medicinal structures such as 2-ami-
nopyrroles. More detailed biological evaluation will be
published elsewhere later.
In summary, a one-pot, multicomponent reaction of
structurally diverse aldehydes, N-(aryl-, hetaryl-, and alkyl-
sulfonamido)acetophenones, with activated methylene
compounds results in the formation of tetra- and penta-
substituted 2-aminopyrroles. This methodology was used
for a four-step total synthesis of natural products rigidins
A, B, C, and D. This synthesis is flexible and can be adap-
ted to the preparation of a library of rigidin analogues.
Figure 1. Total synthesis of rigidins A, B, C, and D.
shortest general approach to obtain these alkaloids. More-
over, rigidinsB, C, and D weresynthesizedforthefirst time
(Figure 1). Commercially available aminoacetophenones
were converted to N-(methanesulfonamido)acetophenones
1 and 2 in almost quantitative yields and the latter were used
in the three-component reaction to obtain 2-aminopyrroles
B18-B21. Carbonylation was achieved with oxalyl chloride
in diglyme to give pyrimidinediones C1-C4, which were
subjected to hydrogenolysis to yield the desired rigidins with
overall yields of 61% for A, 58% forB, 60% for C, and 53%
for D. Our synthesis compares favorably with the published
approaches for rigidin A (7-9 steps and 26-40% overall
yields).30 The spectral data are consistent with those pub-
lished for the natural products.26 At the present time, we
are preparing a library of rigidin analogues for biological
testing.
Acknowledgment. This work is supported by the U.S.
National Institutes of Health (grants RR-16480 and CA-
135579) under the BRIN/INBRE and AREA programs.
Collaboration with the Mass Spectroscopy Facility at the
University of New Mexico is acknowledged.
We performed a preliminary biological evaluation of the
synthesized tetra- and pentasubstituted pyrroles for antic-
ancer and antibacterial activities. The antiproliferative
Supporting Information Available. Experimental pro-
cedures and characterization of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(31) Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.
(32) LaPlante, K. L.; Rybak, M. J. Antimicrob. Agents Chemother.
2004, 48, 4665–4672.
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