Fast and efficient microwave-assisted synthesis of functionalized peptoids via Ugi reactions

Article abstract of DOI:10.1039/c1ob05471f

A wide range of N-alkylglycines (peptoids) can be efficiently prepared via Ugi reactions using microwave irradiations. The results confirm the versatility and efficiency of the methodology for the preparation of functionalized peptoids. The products can be used in consecutive Ugi reactions to yield cyclic peptoids of potential biological interest. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05471f

View Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 5024
www.rsc.org/obc
COMMUNICATION
Fast and efficient microwave-assisted synthesis of functionalized peptoids via
Ugi reactions†‡
Ange´lica de Fa´tima S. Barreto,a Otilie E. Vercillo,a Mike A. Birkett,b John C. Caulfield,b
Ludger A. Wessjohannc and Carlos Kleber Z. Andrade*a
Received 24th March 2011, Accepted 16th May 2011
DOI: 10.1039/c1ob05471f
A wide range of N-alkylglycines (peptoids) can be efficiently
prepared via Ugi reactions using microwave irradiations.
The results confirm the versatility and efficiency of the
methodology for the preparation of functionalized peptoids.
The products can be used in consecutive Ugi reactions to yield
cyclic peptoids of potential biological interest.
building blocks in one step: an amine, a carboxylic acid, an
aldehyde or ketone, called oxo-component, and an isonitrile.
MCRs play a significant role on the development of atom-
economic and synthetically effective methodologies, which are
important goals of synthetic organic chemistry and some of the
keys of modern drug discovery.4,5
At the same time, the use of microwave (mw) energy to facilitate
chemical reactions often results in a dramatic acceleration of
reactions, resulting in cleaner outcomes and increased yields.6,7
Combining these two versatile tools is a particularly attractive
method in current organic synthesis.8
Recently, literature has provided many examples of microwave-
promoted Ugi reactions.9,10 Indeed, this reaction can benefit sig-
nificantly from mw irradiation since it proceeds via relatively polar
intermediates, which might interact with the microwaves. The solid
phase microwave-assisted synthesis of peptoids has already been
studied.11 However, except for a single first and specialized example
by one of us,10a the microwave-assisted synthesis of peptoids by Ugi
reactions is unexplored. Thus, as a continuation of our research on
MCRs,5a,b we decided to investigate the use of microwave heating
in these reactions for peptoid synthesis (Scheme 1).
Peptoids, oligomers of N-substituted alkyl glycines that mimic the
primary natural structure of peptides (Fig. 1),1–3 are attractive non-
natural molecules for drug discovery approaches due to their many
biological activities, their facile synthesis, proteolytic stability and
wide variety of non-native functionality that can be incorporated
into their amide side chains.1,2 These oligomers can increase
cellular permeabilities3a and are evaluated as tools to search for
biomolecular interactions.3b,c
Fig. 1 Generic structures of a peptide (a) and a peptoid (b).
Faster and more efficient methodologies for the synthesis of
peptoids need to be explored to improve studies of their biological
activities. The synthesis of peptide analogues is also essential to
enable a better understanding of structure–activity relationships.
Among several useful reactions, the Ugi four-component re-
action (U-4CR)4 is known to be one of the most versatile tools
for the construction of a peptoid backbone. This multicomponent
reaction (MCR) easily provides a di-amide by combining four
Scheme 1 Microwave-assisted Ugi reactions.
Methyl isocyanoacetate
2
(a glycine building block),
paraformaldehyde 1, Cbz-glycine 3, and several different amines
were put together on a microwave reactor (CEM Co., Discover)
at 45 ◦C, subjected to a potency of 150 W and monitored by
TLC. For a green, economic and facile synthesis, the use of eco-
friendly solvent or ideally solvent-free conditions can be combined
with energy-efficient microwave heating. Thus, two different sets of
conditions (with and without solvent) were investigated. Overall,
the solvent-free combination offered reaction times and yields
comparable to conditions using a solvent (Table 1).
To evaluate the efficiency of our method as compared to
the usual conditions, compounds 5b and 5h were prepared in
solution at 45 ◦C (oil bath), in the absence of mw irradiation
(method C). After 18 h, the yields of the products were 78% and
52%, respectively. Using the mw approach, the yields are higher
aLaborato´rio de Qu´ımica Metodolo´gica e Orgaˆnica Sinte´tica (LaQMOS),
Instituto de Qu´ımica, Universidade de Bras´ılia, C.P. 4478, 70910-970,
Bras´ılia, DF, Brasil. E-mail: ckleber@unb.br; Fax: +55(61) 32734149;
Tel: 31073861
bCentre for Sustainable Pest and Disease Management, Biological Chemistry
Department, Rothamsted Research, Harpenden, Hertfordshire, UK, AL5
2JQ
cDepartment of Bioorganic Chemistry, Leibniz Institute of Plant Biochem-
istry, Weinberg 3, D-06120, Halle, (Saale), Germany
† Dedicated to Prof. Peter Bakuzis (from University of Bras´ılia, Brazil) on
the occasion of his 70th Birthday.
‡ Electronic supplementary information (ESI) available: Experimental de-
tails and spectra of selected for compounds. See DOI: 10.1039/c1ob05471f
5024 | Org. Biomol. Chem., 2011, 9, 5024–5027
This journal is
The Royal Society of Chemistry 2011
©

View Online
Table 1 Microwave-assisted Ugi reactions
Table 2 Results of the microwave-assisted ester hydrolysis of some
peptoids
Entry Amine (R1)
Peptoid
Methodb/Time Yieldc
1a
A: 2 min
B: 4 min
80
77
2
3
A: 30 s
B: 1 min
C: 18 h
87
88
78
Entry
Reagent
Product
Time (min)
Yield (%)a
1
2
3
4
5
6
5a
5b
5e
5g
5h
5i
6a
6b
6e
6g
6h
6i
3
3
4
3
3
5
94
93
92
96
96
98
A: 3 min
B: 2 min
92
81
a Isolated yields of the chromatographically pure products.
4
5
A: 2 min
B: 4 min
79
74
Spectral analysis of 5a–i supported the success of the mw-
mediated quadruple one-pot condensation. The isolated products
were characterized on the basis of 1H and 13C NMR spectroscopy,
and high resolution mass spectra. The most important characteris-
tics of the 1H NMR spectra of these compounds are the NH peaks
between 5.5 and 7.1 ppm and the three methylene groups around
4.1–4.4 ppm. The 13C NMR spectra corroborated the analysis of
the compounds, showing four peaks corresponding to the carbonyl
groups (155–170 ppm).
To check the possibility to perform consecutive Ugi reactions
(as described by our research group in the synthesis of cyclic RGD
pentapeptoids),5a using microwave irradiation, we performed the
hydrolysis of some peptoids using lithium hydroxide in THF and
water. The hydrolysis mixture was irradiated for 3–4 min (150 W)
under magnetic stirring and the temperature raised to 60 ◦C. The
reaction conditions are specified in Table 2.
A: 2 min
B: 6 min
87
81
6
7
A: 1 min
B: 4 min
77
78
A: 3 min
B: 5 min
84
91
After hydrolysis of esters 5b, 5g and 5i, the resulting acids 6
were used in a subsequent Ugi reaction with paraformaldehyde,
a second amine and methyl isocyanoacetate to give esters 7 in
high yields after 3–5 min (45 ◦C, 150 W, method B) of microwave
irradiation (Table 3).
The precursor amino acid for the cyclization was obtained
after ester hydrolysis of 7b under our previously described
conditions, providing acid 8 in 90% yield (Scheme 2). The Cbz
protecting group was removed12 in the presence of 10% Pd–C and
ammonium formate in just 5 min (120 ◦C, 150 W), providing the
amino acid 9 in 88% yield, which was cyclized via Ugi reaction
with paraformaldehyde and t-butyl isocyanide under conditions
of pseudo-dilution, i.e. very slow addition of the bifunctional
building block 9, to prevent oligomerization. The resulting residue
was purified by reverse phase flash chromatography, furnishing the
cyclic peptoid 10 in 69% yield (Scheme 2).
8
9
A: 2 min
B: 3 min
C: 18 h
89
88
52
A: 2 min
B: 3 min
90
90
a 1 equivalent of Et3N was used (amine hydrochloride). b Method A: 0.5–
3 min, 150 W, 45 ◦C, MeOH as solvent; Method B: 1–6 min, 150 W, 45 ◦C,
solvent-free; Method C: 45 ◦C, 18 h, MeOH as solvent. c Isolated yields of
the chromatographically pure products.
For a rapid extension and in an attempt to modify peptoids and
synthesize new, crosslinked peptide analogues, we decided to join
two peptoid backbones by a click reaction incorporating a triazole
moiety.
The synthesis of modified peptoids by click chemistry has
already been demonstrated, but the peptoids were synthesized
by the standard submonomer-approach on solid phase.13 For
our purpose, linear peptoids were synthesized which possess
and – most important – the reaction times are much shorter (Table
1, entries 2 and 8, respectively).
Aromatic amines substituted either with electron withdrawing
or electron donating groups, such as aniline (5 min, 72%), m-
anisidine (5 min, 70%), and p-nitroaniline (6 min, 51%), also
reacted in short reaction times and furnished the products in
moderate to good yields using method B.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5024–5027 | 5025
©

View Online
Table 3 Results of consecutive Ugi reactions
Scheme 3 Peptoid crosslinking by microwave-assisted “click chemistry”.
can be further functionalized at the N-Cbz moiety as some of
us have shown previously.5a Moreover, some peptoids but surely
the method itself may prove to be of interest for biological
applications.
Entry
Acid
Amine
Product
Time (min)
Yield (%)a
1
2
3
4
6b
6g
6b
6i
4c
4g
4i
7a
7b
7c
7d
3
5
4
4
86
81
92
89
4b
Acknowledgements
a Isolated yields of the chromatographically pure products.
We thank the Instituto de Qu´ımica, Universidade de Bras´ılia,
FINEP-CT INFRA n◦ 970/01, CAPES, CNPq, and DAAD for
financial support. We also thank Denio Souza Costa for ESI-MS
spectra.
References
1 (a) B. Yoo and K. Kirshenbaum, Curr. Opin. Chem. Biol., 2008, 12,
714; (b) S. A. Fowler and H. E. Blackwell, Org. Biomol. Chem., 2009,
7, 1508.
2 (a) L. A. Wessjohann, C. K. Z. Andrade, O. E. Vercillo and D. G. Rivera,
Target in Heterocyclic Systems, 2006, 10, 24; (b) L. A. Wessjohann, C.
R. B. Rhoden, D. G. Rivera and O. E. Vercillo, Top. Heterocycl. Chem.,
2010, 23, 199; (c) R. N. Zuckermann, E. J. Matin, D. C. Spellmeyer, G.
B. Stauber, K. R. Shoemaker, J. M. Kerr, G. M. Figliozzi, D. A. Goff,
M. A. Siani, R. J. Simon, S. C. Banville, E. G. Brown, L. S. Richter and
W. H. Moss, J. Med. Chem., 1994, 37, 2678; (d) S. M. Miller, R. J. Simon,
S. Ng, R. N. Zuckermann, J. M. Kerr and W. H. Moss, Bioorg. Med.
Chem. Lett., 1994, 4, 2657; (e) J. Messeguer, I. Masip, M. Montolio,
J. A. Rio, E. Soriano and A. Messeguer, Tetrahedron, 2010, 66,
2444.
Scheme 2 Synthesis of cyclopeptoid 10.
3 (a) Y.-U. Kwon and T. Kodadek, J. Am. Chem. Soc., 2007, 129, 1508;
(b) X. S. Xiao, P. Yu, H.-S. Lim, D. Sikder and T. Kodadek, J. Comb.
Chem., 2007, 9, 592; (c) D. G. Udugamasooriya, S. P. Dineen, R. A.
Brekken and T. J. Kodadek, J. Am. Chem. Soc., 2008, 130, 5744.
4 (a) A. Do¨mling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168;
(b) A. Do¨mling, Chem. Rev., 2006, 106, 17.
5 (a) O. E. Vercillo, C. K. Z. Andrade and L. A. Wessjohann, Org. Lett.,
2008, 10, 205; (b) A. F. S. Barreto, O. E. Vercillo and C. K. Z. Andrade,
J. Braz. Chem. Soc., 2011, 22, 462; (c) L. A. Wessjohann, D. G. Rivera
and O. E. Vercillo, Chem. Rev., 2009, 109, 796; (d) D. G. Rivera and L. A.
Wessjohann, J. Am. Chem. Soc., 2006, 128, 7122; (e) L. A. Wessjohann,
T. T. Phuong Thao, B. Westermann, DE 10 2006 039 615.4, Germany
(24.08.2006). EP 07 786 713.3.
6 (a) R. S. Varma, Pure Appl. Chem., 2001, 73, 193; (b) R. S. Varma,
Indian J. Chem., Sec. B, 2006, 45B, 2305; (c) P. Lidstro¨m, J. Tierney, B.
Wathey and J. Westman, Tetrahedron, 2001, 57, 9225; (d) B. Jiang, F.
Shi and S. J. Tu, Curr. Org. Chem., 2010, 14, 357; (e) Y. G. Zhu, C. W.
Zhai and W. H. Hu, Prog. Chem., 2010, 22, 1380.
7 C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250.
8 For a review on microwave-mediated multicomponent reactions, see:
H. M. Hu¨gel, Molecules, 2009, 14, 4936.
Huisgen-Click reactive groups at specific side chain positions
that in principle are easily addressable by Ugi reactions using
the appropriate building block. The azide or alkyne functional
groups were incorporated as shown in Scheme 1, using 1-azido-3-
aminopropane 4c or propargylamine 4f as amino components.
The linear peptoids 5c and 5f obtained were submitted to
Cu(I)-catalyzed azide-alkyne [3 + 2] cycloaddition reaction.14
For a complete reaction only 1 min of microwave irradiation
(50 ◦C, 150 W) was sufficient in the presence of copper sulfate
pentahydrate, sodium ascorbate, and water in dichloromethane as
solvent. Product 11 was obtained in 73% isolated yield (Scheme
3). For comparison, the reaction was also conducted without mw
at room temperature, stirring for 18 h and the yield decreased to
63%.
We have demonstrated a rapid and direct method to produce
functionalized peptoids in good to excellent yields by a simple
and efficient route using a one-pot, four-component Ugi synthesis
with microwave heating. The procedure offers several advantages
including freedom from solvent requirement for the main reaction,
operational simplicity, and increased safety for small-scale high-
speed synthesis. All this makes the process useful and attractive.
Compounds 5a–i are versatile multifunctional intermediates that
9 (a) S. Santra and P. R. Andreana, Org. Lett., 2007, 9, 5035; (b) R. A.
De Silva, S. Santra and P. R. Andreana, Org. Lett., 2008, 10, 4541;
(c) E. F. DiMauro and J. M. Kennedy, J. Org. Chem., 2007, 72, 1013;
(d) X. Xing, J. Wu, G. Feng and W.-M. Dai, Tetrahedron, 2006, 62,
6774; (e) C. Hulme, S. Chappeta, C. Griffith, Y.-S. Lee and J. Dietrich,
Tetrahedron Lett., 2009, 50, 1939; (f) C. Hulme, S. Chappeta and J.
Dietrich, Tetrahedron Lett., 2009, 50, 4054.
5026 | Org. Biomol. Chem., 2011, 9, 5024–5027
This journal is
The Royal Society of Chemistry 2011
©

View Online
10 (a) M. Abbas, J. Bethke and L. A. Wessjohann, Chem. Commun., 2006,
541; (b) C. R. B Rhoden, B. Westermann and L. A. Wessjohann,
Synthesis, 2008, 13, 2077.
11 (a) H. J. Olivos, P. G. Alluri, M. M. Reddy, D. Salony and T. Kodadek,
Org. Lett., 2002, 4, 4057; (b) B. C. Gorske, S. A. Jewell, E. J. Guerard
and H. E. Blackwell, Org. Lett., 2005, 7, 1521.
12 (a) M. C. Daga, M. Taddei and G. Varchi, Tetrahedron Lett., 2001, 42,
5191; (b) G. Minetto, L. F. Raveglia, A. Sega and M. Taddei, Eur. J.
Org. Chem., 2005, 37, 5277.
13 (a) H. Jang, A. Fafarman, J. M. Holub and K. Kirshenbaum,
Org. Lett., 2005, 7, 1951; (b) J. M. Holub, H. Jang and K.
Kirshenbaum, Org. Biomol. Chem., 2006, 4, 1497; (c) J. M.
Holub, H. Jang and K. Kirshenbaum, Org. Lett., 2007, 9,
3275.
14 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., Int. Ed., 2001, 40, 2004; (b) A. Barge, S. Tagliapietra,
A. Binello and G. Cravotto, Curr. Org. Chem., 2011, 15,
189.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5024–5027 | 5027
©