Synthesis of α,γ-peptide hybrids by selective conversion of glutamic acid units

Article abstract of DOI:10.1021/ol301552c

The site-selective modification of small peptides at a glutamate residue allows the ready preparation of α,γ-hybrids. In this way, a single peptide can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained.

Full text of DOI:10.1021/ol301552c

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3542–3545
Synthesis of r,γ-Peptide Hybrids
by Selective Conversion of Glutamic
Acid Units
ꢀ
Carlos J. Saavedra, Alicia Boto,* and Rosendo Hernandez*
´ ´
ꢀ
Instituto de Productos Naturales y Agrobiologıa CSIC, Avda. Astrofısico Fco. Sanchez
3, 38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
Received June 5, 2012
ABSTRACT
The site-selective modification of small peptides at a glutamate residue allows the ready preparation of R,γ-hybrids. In this way, a single peptide
can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained.
The synthesis of R,γ-peptide hybrids has recently elicited
much interest both from the synthetic and the pharmaceu-
tical fields. These peptides display promising antibiotic,
antiviral, antihypertensive, antimalaric, and anti-Alzheimer
properties.1 In addition, unlike natural peptides, they are
resistant to in vivo degradation.
Thus, pepstatin 1 (Figure 1) is a potent inhibitor of
aspartic acid protease and displays antibiotic activity,1b
while the cyclic peptide 2 acts as an antagonist of the
chemokine receptor at nanomolar concentrations and is a
promising drug lead for the prevention of tumor meta-
stasis.1c Other useful hybrid peptides or peptidomimetics
are the antitumorals dolastatin, tamandarin A, and hapa-
losin, the anti-HIV drug indinavir, etc.1a
Traditionally, to obtain collections of these hybrids, each
peptide is prepared de novo from the starting R- or γ-amino
acids.1,2 This method is time-consuming and also requires a
Figure 1. Bioactive R,γ-peptide hybrids.
supply of different and often expensive γ-amino acids.
An attractive alternative would start from a single R,
ꢀ~
(1) (a) Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18,
γ-hybrid that could be selectively modified at one residue,
converting it into a variety of unnatural γ-amino acids.
However, the site-selective modification of peptides is
usually very difficult3 because of the similar reactivity of
the amino acid units.4
3–99. (b) Pesenti, C.; Arnone, A.; Bellosta, S.; Bravo, P.; Canavesi, M.;
Corradi, E.; Frigerio, M.; Meille, S. V.; Monetti, M.; Panzeri, W.; Viani,
F.; Venturini, R.; Zanda, M. Tetrahedron 2001, 57, 6511–6522. (c)
Tamamura, H.; Araki, T.; Ueda, S.; Wang, Z.; Oishi, S.; Esaka, A.;
Trent, J. O.; Nakashima, H.; Yamamoto, N.; Peiper, S. C.; Otaka, A.;
Fujii, N. J. Med. Chem. 2005, 48, 3280–3289.
(2) (a) For two representative examples, see: Dai, C. F.; Cheng, F.;
Xu, H. C.; Ruan, Y. P.; Huang, P. Q. J. Comb. Chem. 2007, 9, 386–394.
(b) Wipf, P.; Wang, Z. Org. Lett. 2007, 9, 1605–1607.
In this work, we report an efficient method for the one-
pot conversion of peptides 3(Scheme 1) containing glutamic
r
10.1021/ol301552c
Published on Web 06/25/2012
2012 American Chemical Society

acid residues into R,γ-peptides 4 with unnatural
γ-aminoacids. In this transformation, the R-carboxyl group
from the glutamic residue is replaced by different alkyl
chains. Since the starting peptides 3 are readily available
and cheaper than the R,γ-hybrid derivatives 4, this method
allows the preparation of high-value products that can be
used as drug leads.
Scheme 1
The transformation is achieved using a sequential radi-
cal decarboxylationꢀoxidationꢀalkylation process.5 The
radical decarboxylation is induced by treatment of the acid
3 (Scheme 1) with (diacetoxyiodo)benzene (DIB) and
iodine, in the presence of visible light (sunlight or 80 W
tungsten-filament lamps). The initial carboxyl radical un-
dergoes scission to give a C-radical 5. Under the reaction
conditions, this radical is oxidized to an acyliminium ion
6,6,7 which can be trapped by carbon nucleophiles,8 form-
ing the R,γ-hybrids 4.
The scissionꢀalkylation process was studied first using
simple glutamic acid derivatives 79a and 89b,c (Table 1).
Different reaction conditions were tried, and the best
results were obtained when the scission step proceeded at
room temperature, using a ratio substrate/DIB/I2 of 1/1.5/
0.3, while the addition of the nucleophile was carried out at
0 °C, using BF3 OEt2 as the Lewis acid. The process took
3
place in good yields, affording products 9ꢀ14, which
present a variety of alkyl chains. Noteworthy, the mild reac-
tion conditions were compatible with acid-labile groups,
such as Boc.
(3) (a) For reviews on the subject, see: Ebran, J. P.; Jensen, C. M.;
Johannesen, S. A.; Karaffa, J.; Lindsay, K. B.; Taaning, R.; Skrydstrup,
T. Org. Biomol. Chem. 2006, 4, 3553–3564. (b) Antos, J. M.; Francis,
M. B. Curr. Opin. Chem. Biol. 2006, 10, 253–262. (c) Qi, D.; Tann, C. M.;
Distefano, M. D. Chem. Rev. 2001, 101, 3081–3112. (d) Seebach, D.;
Bech, A. K.; Studer, A. Modern Synthetic Methods; Ernst, B., Leumann,
C., Eds.; VCH: Weinheim, 1995; Vol. 7.
(4) (a) The site-selective modification is particularly difficult when
several units of the “convertible” amino acid (glycine, dehydro amino
acids, etc.) are present in the peptide. For other approaches to this
subject, see: Datta, S.; Kazmaier, U. Org. Biomol. Chem. 2011, 9, 872–
880. (b) Franz, N.; Menin, L.; Klok, H. A. Org. Biomol. Chem. 2009,
7, 5207–5218. (c) Chapman, C. J.; Hargrave, J. D.; Bish, G.; Frost,
C. G. Tetrahedron 2008, 64, 9528–9539. (d) Wan, Q.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2007, 46, 9248–9252. (e) Dialer, H.;
Steglich, W.; Beck, W. Tetrahedron 2001, 57, 4855–4861. (f) Ricci, M.;
Madariaga, L.; Skrydstrup, T. Angew. Chem., Int. Ed. 2000, 39,
242–245.
The process was then tried with the known dipeptide
1510 (Scheme 2), which presents an N-terminal gluta-
mate residue. Although side-reactions (such as chain
scission) could take place in peptides, the process
proceeded in good yield, generating the R,γ-hybrid
peptides 16 and 17. The modified residue is an aspartate
analogue and can be used to extend the peptide chain in
other direction.
The configuration of dipeptides 16 (S) and 17 (R) was
assigned by chemical correlation to related compounds, as
commented later.
Since the reacting position is away from stereogenic
centers, a 1:1 mixture of the two possible diastereomers
16 and 17 was formed. The stereoselectivity should im-
prove when the glutamic residue is placed at other posi-
tions in the peptide. For instance, in the dipeptide 18
(Scheme 3), the glutamate amino group is attached to a
phenylalanine unit, which could act as a chiral auxiliary
during the addition step.
In effect, when the decarboxylationꢀalkylation was car-
ried out, the diastereomeric R,γ-dipeptides 19 and 20 were
obtained (dr 2:1, 71% yield).11 Their configuration was
determined as commented later.
(5) (a) For related works from our group, see: Boto, A.; Romero-
Estudillo, I. Org. Lett. 2011, 13, 3426–3429. (b) Saavedra, C.;
Hernandez, R.; Boto, A.; Alvarez, E. J. Org. Chem. 2009, 74, 4655–
4665 and references cited therein.
(6) (a) For a discussion of the sequential process mechanism, see:
ꢀ
ꢀ
Boto, A.; Hernandez, R.; Leon, Y.; Murguıa, J. R.; Rodrıguez-Afonso,
´ ´
A. Eur. J. Org. Chem. 2005, 673–682. (b) For a review on the modifica-
tion of amino acids through radical chemistry, see: Hansen, S. G.;
Skrydstrup, T. Top. Curr. Chem. 2006, 264, 135–162. (c) For a review
covering radical chemistry with hypervalent iodine reagents, see: Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358.
(7) (a) The decarboxylation of amino acids can also be induced
electrochemically. For reviews on the subject, see: Utley, J. Chem. Soc.
Rev. 1997, 26, 157–167. (b) Moeller, K. D. Tetrahedron 2000, 56, 9527–
9554. (c) See also: Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1986, 25, 843–844. (d) Papadoulos, A.; Lewall, B.; Steckhan, E.; Ginzel,
K.-D.; Knoch, F.; Nieger, M. Tetrahedron 1991, 47, 563–572. (e) Matsumura,
Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.; Maki, T.;
Onomura, O. Org. Lett. 2000, 2, 1689–1691.
(8) (a) Yazici, A.; Pyne, S. G. Synthesis 2009, 339–368 (part 1). (b)
Yazici, A.; Pyne, S. G. Synthesis 2009, 513–541 (part 2). (c) Ferraris, D.
Tetrahedron 2007, 63, 9581–9597. (d) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541–2569. (e) Schaus, S. E.; Ting, A. Eur. J. Org.
Chem. 2007, 5797–5815. (f) Petrini, M.; Torregiani, E. Synthesis 2007,
159–186 and references cited therein.
(9) (a) Trotter, N. S.; Brimble, M. A.; Harris, P. W. R.; Callis, D. J.;
Sieg, F. Bioorg. Med. Chem. 2005, 13, 501–518. (b) Feng, X.; Edstrom,
E. D. Tetrahedron: Asymmetry 1999, 10, 99–106. (c) Bavetsias, V.;
Jackman, A. L.; Kimbell, R.; Gibson, W.; Boyle, F. T.; Bisset,
G. M. F. J. Med. Chem. 1996, 39, 73–85.
The introduction of other alkyl chains also took place
satisfactorily (Scheme 4). Using 1-phenyl-1-(trimethylsiloxy)-
ethene as the nucleophile, the diastereomeric peptide hybrids
21 and 22 were obtained in 2:1 ratio (75% global yield).
(10) (a) Ranganathan, D.; Singh, G. P. J. Chem. Soc., Chem. Commun.
1990, 142–143. (b) Ranganathan, D.; Ranganathan, S.; Singh, G. P.; Patel,
B. K. Tetrahedron Lett. 1993, 34, 525–528.
(11) (a) For related compounds with known stereochemistry, see:
Subasinghe, N.; Schulte, M.; Chan, M. Y. M.; Roon, R. J.; Koerner,
J. F.; Johnson, R. L. J. Med. Chem. 1990, 33, 2734–2744. (b) Manesis,
N. J.; Goodman, M. J. Org. Chem. 1987, 52, 5342–5349.
Org. Lett., Vol. 14, No. 13, 2012
3543

Table 1. One-Pot ScissionꢀAlkylationa
Scheme 3
Scheme 4
a DIB (1.5 equiv), I2 (0.3 equiv), hν, 25 °C, 3 h; then 0 °C, BF3 OEt2
3
(2 equiv), nucleophile (3 equiv), 0 f 25 °C, 3 h. b Yields for products
purified by chromatography.
In order to determine the configuration of the scissionꢀ
addition products, the solid compounds 21 and 22 were
crystallized, but the crystals proved unsuitable for X-ray
analysis. Therefore, a chemical correlation with related
R,γ-hybrids was explored. Thus, compound 7 underwent
the ArndtꢀEistert homologation12 to give compound 25,
which was transformed in four steps into the R,γ-dipeptide
26 (Scheme 5). The [R]D of this compound ([R]D = ꢀ48)
was very similar to the optical rotation of compound 16
([R]D = ꢀ40) but quite different than that of compound 17
([R]D = þ37). The other spectroscopic data were also very
similar for 26 and 16. Therefore, we propose the (S) con-
figuration for compound 16.
Scheme 2
In a similar way, compound 25 was transformed into
compound 27, precursor of the R,γ-dipeptide 28, whose
optical rotation ([R]D = ꢀ11) matches that of compound
When the reaction was carried out with 1-tert-butyl-
1-(trimethylsiloxy)ethene as the nucleophile, a separable
mixture of dipeptides 23 and 24 was formed (67% overall
yield, dr 6:5).
The formation of both diastereomers could be useful in
medicinal chemistry studies to determine structureꢀactivity
relationships. Therefore, it was necessary to confirm the
stereochemistry of both isomers.
(12) (a) Wipf, P.; Wang, Z. Org. Lett. 2007, 9, 1605–1607. (b)
Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913–941.
(c) Belsito, E.; Gioia, M. L.; Greco, A.; Leggio, A.; Liguori, A.; Perri,
F.; Siciliano, C.; Viscomi, M. C. J. Org. Chem. 2007, 72, 4798–4802.
€
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Org. Lett., Vol. 14, No. 13, 2012

Finally, compounds 21 and 23 were also assigned the S
configuration because of the optical and spectroscopical
similarities with respect to isomers 19 and 28.
Scheme 5
It should be pointed out that the ArndtꢀEistert homo-
logation allows the generation of R-unsubstituted or
R-monosubstituted amino esters but not R,R-disubstituted
derivatives. In those cases, the present methodology is a
useful alternative to the ArndtꢀEistert homologation. More-
over, as shown by compounds 21ꢀ24, a variety of other alkyl
chains can be introduced in a straightforward way.
In summary, the one-pot decarboxylationꢀalkylation pro-
cess allows the efficient conversion of peptides with glutamic
acid residues into R,γ-peptide hybrids with unnatural
γ-amino acids. The process takes place under mild conditions
in good yields. From a single peptide a collection of R,
γ-peptide hybrids can be obtained in good global yield.
Although epimer mixtures are generated, the isomers can
be readily separated, which is quite useful to study structureꢀ
activity relationships. The dr could also be improved by using
chiral catalysts, as will be reported in due course.
Nevertheless, this is the first reported site-selective peptide
modification that allows the preparation of R,γ-hybrids. The
use of the glutamate unit to generate diversity is particularly
interesting. Since the carboxyl group of the glutamic units can
be protected with different orthogonal groups, the starting
peptide could contain several glutamic residues, but only the
unprotected one(s) would be modified. For further modifica-
tions, the orthogonal protecting groups could be sequentially
removed. The application of this methodology to the synthesis
of bioactive or catalytic R,γ-hybrids is very promising.
Acknowledgment. This work was supported by the
Research Program CTQ2009-07109 of the Plan Nacional
ꢀ
de Investigacion Cientıfica, Desarrollo e Innovacion
Tecnologica, Ministerio de Ciencia e Innovacion/ Economıa
´
ꢀ
´
ꢀ
ꢀ
y Competitividad, Spain. We also acknowledge finan-
cial support from FEDER funds. C.J.S. thanks ACIISI
(Gobierno de Canarias) for a predoctoral fellowship.
Supporting Information Available. Procedures for the
synthesis of compounds 9ꢀ14, 16ꢀ28, the precursors of
1
the scission substrates 30 and 31, and their H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
19 ([R]D = ꢀ12) but differs from the one of isomer 20
([R]D = þ26). Compounds 19 and 20 were then assigned
the S and R configurations, respectively.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3545