Chiral seleno-amines from indium selenolates. A straightforward synthesis of selenocysteine derivatives

Article abstract of DOI:10.1021/jo060286b

A simple and efficient procedure for the synthesis of chiral β-seleno-amines derivatives from a one-pot indium(I) iodide-mediated aziridine ring opening with diorganoyl diselenides has been developed. As an application, the synthesis of selenocysteine and

Full text of DOI:10.1021/jo060286b

Chiral Seleno-Amines from Indium Selenolates.
A Straightforward Synthesis of Selenocysteine
Derivatives
SCHEME 1. Aziridine Ring Opening with Sodium
Selenolate Anions
‡
Antonio L. Braga,* Paulo H. Schneider, Marcio W. Paix a˜ o,
Anna M. Deobald, Clovis Peppe, and Diana P. Bottega
Departamento de Qu ´ı mica, UniVersidade Federal de Santa
Maria, Santa Maria, RS, 97105-900, Brazil
Reduction of Se-Se bonds, especially cleavage of diphenyl or
diaryl diselenides, has recently received much effort for the
preparation of unsymmetrical diorganyl selenides. Chemical
cleavage of Se-Se bonds in diaryl diselenides was realized with
reducing agents such as NaBH4, Na/NH3, Bu3SnH, and LiAlH4.5
In recent years, some protocols with indium(I) iodide-mediating
cleavage of diorganyl diselenides have been developed to
albraga@quimica.ufsm.br
ReceiVed February 10, 2006
6
7
prepare vinylic selenides, selenoesters, and â-hydroxy se-
8
lenides with special attention given to unsymmetrical diorganyl
9
selenides.
In this context, we recently reported the synthesis of a new
set of chiral R-seleno-amines in a straightforward manner
through the stereoselective aziridine ring opening with selenolate
anions (Scheme 1). In this work, the selenium nucleophile
required to open the aziridine ring was generated by reduction
of the diselenide with sodium borohydride in protic solvent.
However, this reaction failed to prepare selenocysteine deriva-
tives through the ring opening of functionalized aziridine.
A simple and efficient procedure for the synthesis of chiral
â-seleno-amines derivatives from a one-pot indium(I) iodide-
mediated aziridine ring opening with diorganoyl diselenides
has been developed. As an application, the synthesis of
selenocysteine and selenotreonine derivatives has been
accomplished.
1
0
Attempting to disclose further extension of this work, we
examine here the reaction between the indium(III)-chalcogeno-
lates, obtained from indium(I) iodide and diorganyl diselenides,
and several types of aziridines. The work resulted in an efficient
and mild synthesis of R-seleno-amines and selenocysteine
derivatives under mild and neutral conditions. It is well-known
that indium(I) compounds, through their oxidative insertion into
a suitable substrate, generate the corresponding indium(III)
derivative. Thus, the complex bis(organoylseleno)iodoindium-
(III), 1, is readily prepared by reacting equimolar amounts of
In recent years interest in selenocystein and its derivatives
has extremely increased as they are building blocks for the
synthesis of selenoproteins and due to their potential biological
1
activity. The biological and medicinal properties of selenium
and organoselenium compounds are increasingly appreciated,
mainly due to their antioxidant, antitumor, antimicrobial, and
2
antiviral properties. In addition, selenocysteine derivatives can
3
serve as convenient precursors to dehydroamino acids, which
are useful electrophilic handles for the chemoselective prepara-
tion of peptide conjugates.4
The development of new methods for the introduction of
selenium-containing groups into organic molecules, particularly
in a stereocontrolled manner, remains a significant challenge.
(
4) (a) Besse, D.; Siedler, F.; Diercks, T.; Kessler, H.; Moroder, L. Angew.
Chem., Int. Ed. Engl. 1997, 36, 883-885. (b) Besse, D.; Budisa, N.;
Karnbrock, W.; Minks, C.; Musiol, H.-J.; Pegoraro, S.; Siedler, F.; Weyher,
E.; Moroder, L. Biol. Chem. 1997, 378, 211-218. (c) Zhu, Y.; van der
Donk, W. A. Org. Lett. 2001, 3, 1189.
(
5) (a) Andreadou, I.; Menge, W. M. P. B.; Commandeur, J. N. M.;
*
Author to whom corresponding should be addressed. Phone: +55-55-3220-
Worthington, E. A.; Vermeulen, N. P. E. J. Med. Chem. 1996, 39, 2040.
(b) Sakakibara, M.; Katsumata, K.; Watanabe, Y.; Toru, T.; Ueno, Y.
Synthesis 1992, 377. (c) Bhasin, K. K.; Singh, N.; Kumar, R.; Deepali, D.
G.; Mehta, S. K.; Klapoetke, T. M.; Crawford, M. J. J. Organomet. Chem.
2004, 689, 3327. (d) Crich, D.; Grant, D. J. Org. Chem. 2005, 70, 2384.
(6) do Rego Barros, O. S.; Lang, E. S.; de Oliveira, C. A. F.; Peppe, C.;
Zeni, G. Tetrahedron Lett. 2003, 43, 7921.
(7) Ranu, B. C.; Das, A. AdV. Synth. Catal. 2005, 347, 712.
(8) do Rego Barros, O. S.; de Carvalho, A. B.; Lang, E. S.; Peppe, C.
Lett. Org. Chem. 2004, 1, 43.
8
781. Fax +55-55-3220-8998.
‡
Universidade Federal do Rio Grande do Sul.
(
1) (a) Moroder, R. J. Peptide Sci. 2005, 11, 187-214. (b) Pegoraro, S.;
Fiori, S.; Cramer, J.; Rudolph-B o¨ hner, S.; Moroder, L. Protein Sci. 1999,
8
, 1605-1613. (c) Fiori, S.; Pegoraro, S.; Rudolph-B o¨ hner, S.; Cramer, J.;
Moroder, L. Biopolymers 2000, 53, 550-654. (d) Stadman, T. C. Annu.
ReV. Biochem. 1996, 65, 83.
(2) (a) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. ReV. 2001, 101,
2
125. (b) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2003, 125, 13455. (c)
Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. ReV. 2004, 104, 6255.
3) (a) Okeley, N. M.; Zhu, Y.; van der Donk, W. A. Org. Lett. 2000, 2,
603. (b) Hashimoto, K.; Sakai, M.; Okuno, T.; Shirahama, H. Chem.
(9) (a) Ranu, B. C.; Mandal, T.; Samanta, S. Org. Lett. 2003, 5, 1439.
(b) Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69, 5793. (c) Ranu, B. C.
Eur. J. Org. Chem. 2000, 2343.
(
3
Commun. 1996, 1139. For an application see: (c) Nicolaou, K. C.; Safina,
B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.; Bella, M.; Estrada, A. A.; Funke,
C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127, 11159. (d) Nicolaou,
K. C.; Safina, B. S.; Zak, M.; Nevalainen, M.; Bella, M.; Estrada, A. A. J.
Am. Chem. Soc. 2005, 127, 11176.
(10) (a) Braga, A. L.; L u¨ dtke, D. S.; Paix a˜ o, M. W.; Rodrigues, O. E.
D.; Org Lett. 2003, 5, 2635. (b) Braga, A. L.; Paix a˜ o, M. W.; Marin, G.
Synlett 2005, 11, 1675. (c) For the preparation of â-seleno-amines through
stereoselective oxazoline ring opening see: Braga, A. L.; Vargas, F.;
Senhem, J. A.; Braga, R. C.;J. Org. Chem. 2005, 70, 9021.
1
0.1021/jo060286b CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/22/2006
J. Org. Chem. 2006, 71, 4305-4307
4305

SCHEME 2. Indium(I) Iodide-Mediated Aziridine Ring Opening with Diorganoyl Diselenides
TABLE 1. Ring-Opening Reaction of Aziridine
TABLE 2. Synthesis of Selenocysteine Derivatives
isolated
yield (%)
entry
R1
R
product
time (h)
1
2
3
4
5
6
H
H
H
H
Me
Me
H
Ph
5a
5b
5c
5d
5e
5f
6
12
6
24
28
16
24
85
98
60
64
80
96
isolated
p-ClPh
p-MePh
p-MeOBn
Ph
p-ClPh
Ph
entry
R1
R
product
solvent
yield (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
i-Pr
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
3a
3a
3a
3a
3b
3c
3d
3e
3f
THF
EtOH
CH CN
3
DCM
DCM
DCM
DCM
DCM
DCM
65
56
87
94
77
85
90
68
82
a
7
5g
a
Trityl was used as a protecting group of the nitrogen.
p-MePh
p-ClPh
Bn
Et
InI and RSeSeR in dichloromethane (Scheme 2).9a,11 As outlined
in the sequence below, the preparation of â-seleno-amines
proceeds through the regioselective nucleophilic attack of the
organoyl selenide anion at the less hindered position of the
aziridine ring.
The reaction was initially conducted with the aziridine 2a
and the phenyl selenolate anion, prepared through the reaction
between PhSeSePh and InI in four different solvents (Table 1
entries 1-4). Product 3a was obtained in dichloromethane with
a yield higher than that observed when coordinating solvents
were used (compare entries 1-4, Table 1). We attribute that
oxygen-donnor solvents and acetonitrile are capable of coor-
dination to the hard metallic center of the indium selenolate 1,
forming stable compexes,12 competing with the required coor-
dination of the aziridine for the ring-opening reaction. Aceto-
nitrile promotes significative improvement on the reaction yield
FIGURE 1. Proposed mechanism for the aziridine ring-opening
reaction.
generality of the present method. As described in Table 1, all
the â-seleno-amines were obtained in good to excellent yields
for all the aziridines studied. Concerning the R group, the
presence of an electron-donating group, such as methyl, or an
electron-withdrawing group, such as chloro, in the aromatic rings
of the diselenides has no significant influence on the reactivity
of the process, since the products were obtained with a slight
decrease in the reaction yield (entries 6 and 7). The reaction
was performed also with dialkyl diselenides as the nucleophilic
source of selenium, furnishing the products 3e and 3f in good
yields (entries 8 and 9).
(entry 3), but the best yield was obtained when the reaction
was performed with the noncoordinating solvent dichlo-
romethane (entry 4).
Due to the potential biological activity of selenocysteine and
their derivatives, some recent and classical successful approaches
aiming at their synthesis have been documented in recent years.13
In this context, a formidable challenge still remains to develop
novel synthetic methods that can permit the introduction of
selenium into optically active amino acids, which could be
widely explored as building blocks for the synthesis of seleno
peptides and derivatives. Thus, we also turned our attention
to use this method to synthesize selenocysteine and selenotreo-
nine derivatives, employing the aziridine-2-carboxylate 4 as the
starting material (Table 2).
Notably, the indium selenolate 1 promotes faster aziridine
ring-opening reaction (4 h) than the selenolate anion generated
with NaBH4/EtOH (48 h).1 We envisage that this fact is
probably due to coordination of the indium(III) complex through
the oxygen of the N-Boc group at the initial aziridine (Figure
0b
1
4
1
). This fact could be supported by the experiment carried out
when a trityl group was used as the protecting group of the
nitrogen (Table 2, entry 7). In this case no reaction was observed
and the starting material could be recovered.
The mild reaction conditions, its speed, and the excellent
yields obtained encouraged us to examine the scope and
(
12) Some stable solid species are: InX3‚2THF (X ) Cl, Br), symmetry
D3h by X-ray crystallography, see the following references: (a) Evans, C.
A.; Taylor, M. J. J. Chem. Soc. A 1969, 9, 1343. (b) Self, M. F.; McPhail,
A. T.; Wells, R. L. Polyhedron 1993, 12, 455. InX3‚2CH3CN (X ) Cl, Br,
I), symmetry D3h by vibrational spectroscopy, see: Habeeb, J. J.; Said, F.
F.; Tuck, P. G. J. Chem. Soc., Dalton Trans. Inorg. Chem. 1980, 7, 1261.
(11) (a) Peppe, C.; Tuck, D. G. Can. J. Chem. 1984, 62, 2798. (b) do
Rego Barros, O. S.; Lang, E. S.; de Oliveira, C. A.; Peppe, C.; Zeni, G.
Tetrahedron Lett. 2002, 43, 7921.
4
306 J. Org. Chem., Vol. 71, No. 11, 2006

As we can see in Table 2, a series of selenoamino acids could
be synthesized in a straightforward manner allowing some
interesting structural diversity. To examine the influence of
different electronic properties on the selenolate anions, some
substituted aryl diselenides were used, and to our delight, good
yields were obtained (Table 2, entries 1-4). Also the reaction
could be carried out, with high yields, when aziridines with more
steric hindrance at the 3-position were used furnishing the
selenotreonine derivatives (Table 2, entries 5 and 6). It is
especially noteworthy that all products were obtained without
derivatives,17 whereas 5a is used for the mild oxidative
introduction of dehydroalanines.
3
c,13c,16
In summary, the present procedure with indium(I) iodide
provides a practical and concise synthesis of a wide range of
chiral â-seleno-amines and their derivative in an easy, straight-
forward, and flexible synthetic route, starting from the easily
1
8
achieved chiral aziridines. This method offers significant
improvements with regards to operational simplicity, reaction
time, reaction conditions (room temperature and neutral me-
dium), and high isolated yields of products. More importantly,
with the complexes bis(organoylseleno)iodoindium(III), 1, we
could also achieve an efficient and general procedure for the
synthesis of selenocysteine and selenotreonine derivatives.
1
loss of optical purity. This was established by H NMR
experiments, where single sets of signals for compounds 5e-f
were observed and compared to the analytical data obtained
for the compounds with the data reported in the litera-
3
a,15
ture.
Experimental Section
It is worth mentioning that all products have high stability.
Besides, some of them are obtained orthogonally protected and
can be used directly for the synthesis of a variety of selenopep-
tides. For example, N-Boc-Se-phenylselenocysteine derivatives
General Procedure for the Synthesis of Protected Selenocys-
teines 5. In a 25-mL round-bottomed flask, under an argon
atmosphere, InI (powder, 121 mg, 0.5 mmol) was added to a
solution of the appropriate diorganyl diselenide (0.5 mmol) in dry
CH Cl (5 mL). The mixture was allowed to stir until all the InI
5
a (Table 2, entry 1) and the Se-p-methoxibenzyl-protected
2
2
amino acid derivatives 5d (Table 2, entry 4) have been used as
precurors for solid-phase peptide synthesis (SPPS) of seleno-
cysteine-containing peptides.16 Compound 5d allows the incor-
poration of free selenocysteine into peptides or the selenocystine
(15-45 min) was dissolved, then the appropriate protected aziridine
0.5 mmol) was added and the reaction was monitored by TLC.
The mixture was quenched with H O and extracted with CH Cl
(
2
2
2
and the combined organic fractions were collected, dried over
MgSO , and filtered; the solvent was then removed in vacuo
4
(
13) For the synthesis of selenocysteine and their analogues, see: (a)
Reich, H. J.; Jasperse, C. P.; Renga, J. M. J. Org. Chem. 1986, 51, 2981.
b) Stocking, E. M.; Schwarz, J. N.; Seen, H.; Salzmann, M.; Silks, L. A.
yielding the crude products which were purified by flash chroma-
tography on silica gel (9:1 hexane:ethyl acetate).
(
J. Chem. Soc., Perkin Trans. 1 1997, 2243. (c) Okeley, N. M.; Zhu, Y.;
van der Donk, W. A. Org. Lett. 2000, 2, 3603. (d) Hashimoto, K.; Sakai,
M.; Okuno, T.; Shirahama, H. Chem. Commun. 1996, 1139. (e) Gielsman,
M. D.; Xie, L.; van der Donk, W. A. Org Lett. 2001, 3, 1331. (f) Bhat, R.
G.; Porhiel, E.; Saravanan, V.; Chandrasekaran, S. Tetrahedron Lett. 2003,
Acknowledgment. The authors gratefully acknowledge
CAPES, CNPq, FAPERGS, and DAAD for financial support.
M.W.P. also acknowledge DAAD for travel grants as part of a
PROBAL project.
4
4, 5251. (g) Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur.
J. Org. Chem. 2004, 2905.
14) (a) Gieselman, M. D.; Zhu, Y.; Zhou, H.; Galonic, D.; van der Donk,
Supporting Information Available: Text and figures giving
full experimental procedures and characterization data for the
compounds discussed in this paper. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
W. A. ChemBioChem 2002, 3, 709. (b) Braga, A. L.; L u¨ dtke, D. S.; Paix a˜ o,
M. W.; Alberto, E. E.; Stefani, H. A.; Juliano, L. Eur. J. Org. Chem. 2005,
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260. (c) Schneider, A.; Rodrigues, O. E. D.; Paix a˜ o, M. W.; Appelt, H.
R.; Braga, A. L.; Wessjohann, L. A. Tetrahedron Lett. 2006, 47, 1019. (d)
Abbas, M.; Bethke, J.; Wessjohann, L. A. Chem. Commun. 2006, 541.
JO060286B
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4
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(
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