Three-component synthesis of disubstituted 2H-pyrrol-2-ones: Preparation of the violacein scaffold

Article abstract of DOI:10.1016/j.tetlet.2014.02.111

An efficient, three-component, microwave-mediated cyclization to prepare the 3,5-disubstituted 2H-pyrrol-2-one core of the bis-indole alkaloid, violacein, is described. Preliminary results indicate an iterative, thermally driven, condensation of a γ-ketoe

Full text of DOI:10.1016/j.tetlet.2014.02.111

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component synthesis of disubstituted 2H-pyrrol-2-ones:
preparation of the violacein scaffold
⇑
Emily C. McLaughlin , Matthew W. Norman, Thant Ko Ko, Ingrid Stolt
Bard College, 30 Campus Road, Annandale-on-Hudson, NY 12504, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, three-component, microwave-mediated cyclization to prepare the 3,5-disubstituted
Received 20 February 2014
Revised 26 February 2014
Accepted 26 February 2014
Available online xxxx
2H-pyrrol-2-one core of the bis-indole alkaloid, violacein, is described. Preliminary results indicate an
iterative, thermally driven, condensation of a c-ketoester, ammonium acetate, and isatin in polyethylene
glycol. This methodology is an effective and environmentally benign route to prepare a series of violacein
analogs in good overall yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Violacein
Microwave synthesis
Polyethylene glycol
Indole alkaloids
Pyrrol-2-one
Three-component cyclization
The indole ring system is one of the most prevalent heterocyclic
scaffolds found in biologically active molecules.1 Biosynthetically
derived from tryptophan, indole natural product motifs are found
in a multitude of pharmacologically active substrates. More specif-
ically, the 5-hydroxy-indole subunit (an analog of the neurotrans-
mitter serotonin) accounts for an extensive number of these
relevant synthetic targets.2 Violacein (1) contains this 5-hydroxy-
indole moiety which is a bright purple microbial pigment3 and
possesses an arsenal of biological activity. It also has structural
analogy to the bis-indole alkaloids staurosporine and rebeccamy-
cin.4 Together with the two aforementioned natural products,
violacein has garnered much attention as an antimicrobial and
anticancer therapeutic and is most frequently obtained as a bio-
synthetic secondary metabolite from bacterial cell cultures.5
To date, only a handful of syntheses of violacein have been re-
ported in the chemical literature. Over fifty years ago, Ballantine
first prepared violacein by converting its furanone structural ana-
log to the pyrrolone core through treatment with ammonia and
heat.6 In 2001, Wille and Steglich delineated a 7-step synthetic
sequence wherein the three subunits (5-hydroxyindole, pyrroli-
din-2-one, and 2-oxoindole) were installed by step-wise nucleo-
philic additions.7 Most recently, Petersen and Nielsen developed
a tandem ring-closing metathesis/nucleophilic addition methodol-
ogy to prepare violacein in a 5-step approach.8
Based on the aromatic properties and highly stable nature of
this indole alkaloid,5c we envisioned the possibility of a more effi-
cient, thermally driven approach to the violacein heterocyclic scaf-
fold. This methodology involved the simple condensation of three
building blocks: ammonia, a
c-ketoacid (2), and isatin (3) to
assemble the pentacyclic core structure (Scheme 1). We based
our initial trials of this methodology on similar work wherein re-
flux of an aromatic ketoacid with ammonium acetate and isatin
in high-boiling solvents was utilized to create a 3,5-disubstituted
pyrrol-2-one ring system.9
To test our proposed methodology, we prepared the 3-indoyl
substrate 5 in two steps. First, indole was reacted under Friedel–
Crafts conditions to afford 4, which was hydrolyzed to 5 in good
yield (Scheme 2).10 Attempts to directly acylate indole with
succinic acid, succinic anhydride, or succinyl chloride (mediated
by Lewis acid) to afford 5 in one step were unsuccessful.11 Next,
⇑
Corresponding author. Tel.: +1 845 752 2355; fax: +1 845 752 2339.
E-mail address: mclaughl@bard.edu (E.C. McLaughlin).
Scheme 1. Retrosynthetic analysis.
http://dx.doi.org/10.1016/j.tetlet.2014.02.111
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: McLaughlin, E. C.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.02.111

2
E. C. McLaughlin et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
Preparation of violacein analogs
Entry
R1
R2
Product
Yielda (%)
1
2
3
4
5
6
7
8
H
H
H
Br
Bn
PMB
H
H
PMB
Bn
6
7
8
53
42
62
49
57
33
59
76
Scheme 2. Synthesis of benzyldeoxyviolacein 6.
9
Br
10
11
12
13
pyrrolone cyclization of 5 with ammonium acetate and benzyl isat-
in12 (3a) in refluxing xylenes over 24 h provided a 35% yield of a
bright purple solid, benzyl deoxyviolacein (6).13
OBn
OCH3
OiPr
Bn
PMB
Optimization of this one-pot, three-component methodology
commenced with the investigation of the ammonia equivalent
(NH4OAc, NH4Cl, and NH4HCO2), solvent, temperature, reaction
time, and heating methods (Table 1). Trials with ammonium ace-
tate proved to be the most successful; however, ammonium for-
mate also resulted in product formation as observed by LCMS.
Additionally, the ratios of the 3-acyl indole, benzyl isatin, and
ammonium acetate were varied. We found the best conversions
with a 1:1.2:4 ratio of the three components, respectively.14 In a
solvent screen, we found that higher boiling traditional organic
solvents (Table 1, entries 1–4) and relatively high temperatures
(140–200 °C) were required for complete cyclization of benzyl
deoxyviolacein (6). Moreover, the use of microwave irradiation sig-
nificantly shortened the reaction time compared to conventional
reflux (entries 2–4). An attempt to employ polar, lower boiling sol-
vents with milder conditions showed decomposition of starting
materials and no desired product (entries 5 and 6).
Ultimately, we were pleased to find polyethylene glycol (PEG)
to be an advantageous solvent for our methodology (Table 1, en-
tries 7–9).15 The use of PEG is beneficial in that it is an environ-
mentally benign and low-cost solvent16 that also withstands high
reaction temperatures and it is favorable for microwave mediated
processes.17 Accordingly, we found that PEG improved the effi-
ciency of this reaction, reducing heating times to one hour at
a
Isolated yields.
200 °C. Finally, we were able to demonstrate that the cyclization
is also effective when starting with -ketoester 4, conserving one
c
synthetic step in the overall sequence (entries 8 and 9) by elimi-
nating the need for ester hydrolysis (Scheme 2). Consequently,
we are now able to prepare the deoxyviolacein heterocyclic scaf-
fold in only two synthetic steps starting from indole and benzyl isat-
in 3a.
We proceeded to investigate the versatility of this approach
through preparation of a variety of violacein structural analogs (Ta-
ble 2). Benzyl (3a), p-methoxybenzyl (3b) N-protected isatin, as
well as unprotected isatin (3) were compatible with the optimized
reaction conditions (entries 1–3, 42–62% yields). In earlier trials we
discovered that the attenuated solubility of isatin (3) in organic
solvents such as xylenes and chlorobenzene resulted in insufficient
yields (<10%) of the product. We did not observe this problem with
the use of PEG (entries 3 and 4).
Subsequent modification of the indole 5-position also proved to
be effective. Acyl indole analogs 4a–4d (Table 2) were prepared in
the same manner as 4 (Scheme 2) from the corresponding 5-substi-
10a
tuted indole.
Bromo-, methoxy-, and isopropoxy- substituents
afforded good yields (49–76%) of dark purple solids (entries 4, 5,
Table 1
Optimization of pyrrolone formation
Entry
R
Heating methoda
Reflux
Solvent
Temp (°C)
Timeb (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
Et
Et
Xylenes
Xylenes
Toluene
PhCl
1,2-DCE
THF
PEG
PEG
PEG
150
24
5
7
7
7
7
3
3
1
35
30
<10
<10
No product
No product
42
23
53
l
l
l
l
l
l
l
l
wave
wave
wave
wave
wave
wave
wave
wave
150–165
150–165
150–165
80–120
100–120
150
150
200
a
b
c
Conventional heating at reflux was performed in a temperature-regulated oil bath. See the associated supporting information for details on microwave heating.
Reactions were monitored in 1–2 h increments by TLC and/or LCMS and then determined to be complete by full consumption of the acyl indole 5 or 4.
Isolated yields.
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E. C. McLaughlin et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
References and notes
1. For selected reviews on the bioactivity and synthesis of indoles, see: (a) Taber,
D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195–7210; (b) Ertl, P.; Jelfs, S.;
Mühlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med. Chem. 2006, 49, 4568–4573.
2. (a) Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma, A.; Choi, E.
Molecules 2013, 18, 6620–6662; (b) Buemi, M. R.; De Luca, L.; Chimirri, A.;
Ferro, S.; Gitto, R.; Alvarez-Builla, J.; Alajarin, R. Bioorg. Med. Chem. 2013, 21,
4575–4580; (c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489–4497.
3. Volacein was first isolated and described by: Strong, F. M. Science 1944, 100,
287.
4. Ryan, K. S.; Drennan, C. L. Chem. Biol. 2009, 16, 351–364.
5. (a) Sánchez, C.; Braña, A. F.; Méndez, C.; Salas, J. A. ChemBioChem. 2006, 7,
1231–1240; (b) Balibar, C. J.; Walsh, C. T. Biochemistry 2006, 45, 15444–15457;
(c) Durán, N.; Justo, G. Z.; Ferreira, C. V.; Melo, P. S.; Cordi, L.; Martins, D.
Biotechnol. Appl. Biochem. 2007, 48, 127; (d) Durán, M.; Ponezi, A. N.; Faljoni-
Alario, A.; Teixeira, M. F.; Justo, G. Z.; Durán, N. Med. Chem. Res. 2012, 21, 1524–
1532.
Scheme 3. Proposed reaction pathway.
7, and 8); however, the lability of the benzyloxy group on 11 was
problematic, furnishing a more modest product yield.
6. (a) Ballantine, J. A.; Barrett, C. B.; Beer, R. J. S.; Eardley, S.; Robertson, A.; Shaw,
B. L.; Simpson, T. H. J. Chem. Soc. 1958, 755–760; (b) Ballantine, J. A.; Beer, R. J.
S.; Crutchley, D. J.; Dodd, G. M.; Palmer, D. R. J. Chem. Soc. 1960, 2292–2299.
7. Wille, G.; Steglich, W. Synthesis 2001, 759–762.
8. Petersen, M. T.; Nielsen, T. E. Org. Lett. 2013, 15, 1986–1989.
9. Abd Alla, M. M.; Soliman, E. A.; Hamed, A. A.; Osman, M. W. Rev. Roum. Chim.
1980, 25, 1549–1560. In their manuscript ‘Some reactions of b-3,4-
dicholorobenzoyl propionic acid’, Abd Alla and co-workers report numerous
The probable mechanistic pathway for the three-component
cyclization is outlined in Scheme 3. First, ketoacid (or ester) 5 con-
denses with ammonia to generate 2-hydroxy pyrrole 14,18 which
then attacks the more electrophilic carbonyl at the 3-position of
isatin. Ensuing dehydration of 15 affords the violacein skeleton.
During our optimization studies, we confirmed the presence of
15 in our crude reaction mixtures through NMR and LCMS.19
A
condensations of the above-named c-ketoacid with a variety of electrophiles
for the preparation of furanone derivatives. They also claim to prepare
pyrrolone analogs using the same methods. Their methodology includes the
scheme below, key precedent for our work.
more complete conversion of 15 to 6 was found by increasing
the reaction temperature and by utilizing molecular sieves as a
dehydrating agent (Table 2).
In conclusion, we have developed a green methodology for the
preparation of the bis-indole violacein scaffold. Through a micro-
wave-mediated three-component reaction, we are now able to rap-
idly prepare a variety of violacein analogs ranging from 2 to 4
synthetic steps in moderate to good yields. Studies are underway
to expand the scope of this methodology to a broader range of
ketoesters and suitable electrophiles.
10. (a) Wynne, J. H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.; Stalick, W. M. Synthesis
2004, 2277–2282; (b) Thompson, M. J.; Louth, J. C.; Ferrara, S.; Sorrell, F. J.;
Irving, B. J.; Cochrane, E. J.; Meijer, A. J. H. M.; Chen, B. ChemMedChem. 2010, 6,
115–130.
Acknowledgments
11. Ottoni, O.; de Neder, A. V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett.
2001, 3, 1005–1007.
12. Cassani, C.; Melchiorre, P. Org. Lett. 2012, 14, 5590–5593.
13. All new compounds were characterized by full spectroscopic (1H and 13C NMR,
IR, HRMS) data. Yields refer to spectroscopically and chromatographically
homogeneous (>95%) materials.
14. In general, the cyclization was performed using 1 equiv of acyl indole, 1.2 equiv
of benzyl isatin, and 4 equiv of ammonium acetate in a selected solvent
concentration of about 0.2 M.
15. Rao, H. S. P.; Senthilkumar, S. P. J. Chem. Sci. 2004, 116, 163–168.
16. For an overview of green chemistry principles, see: (a) Anastas, P. T.; Kirchhoff,
M. M. Acc. Chem. Res. 2002, 35, 686–694; For examples of PEG as a sustainable
solvent, see: (b) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green
Chem. 2005, 7, 64–82.
The authors acknowledge financial support from the American
Chemical Society’s Petroleum Research Fund (ACS-PRF, #49471-
UNI1) and as well as Research Corporation for Scientific Advance-
ment (RCSA #20215), Bard College, and the Bard College Summer
Research Institute (BSRI). Mass spectrometry was performed using
instrumentation supported by funding from a National Science
Foundation MRI Grant (#1039659, Teresa A. Garrett, P. I.).
Supplementary data
17. Zhou, T.; Xiao, X.; Li, G.; Cai, Z.-W. J. Chromatogr., A 2011, 1218, 3608–3615.
18. Aginagalde, M.; Bello, T.; Masdeu, C.; Vara, Y.; Arrieta, A.; Cossío, F. P. J. Org.
Chem. 2010, 75, 7435–7438.
Supplementary data (experimental and spectral data for com-
pounds 4a, 4c, 4d, and 6–13) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.02.111.
19. Compound 15 was identified in a crude mixture with 6 (LCMS m/z: 435.16; 13
C
NMR signal at 66.4 ppm, C–OH).
Please cite this article in press as: McLaughlin, E. C.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.02.111