Straightforward synthesis of non-natural chalcogen peptides via ring opening of aziridines

Article abstract of DOI:10.1016/j.tet.2012.08.082

The synthesis of new chiral non-natural seleno-, thio-, and telluro-peptides is described herein. These new compounds were prepared through simple and brief synthetic route, from inexpensive and commercially available amino acids. The products, possessing a highly modular character, were obtained in good to excellent yields (50-96%), via ring opening of aziridines with chalcogenolate anions, generated using indium(I) iodide as a reducing agent.

Full text of DOI:10.1016/j.tet.2012.08.082

Tetrahedron 68 (2012) 10449e10455
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Straightforward synthesis of non-natural chalcogen peptides via ring opening of
aziridines
*
*
Ricardo S. Schwab , Paulo H. Schneider
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, C.P. 15003, 91501-970 Porto Alegre-RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2012
Received in revised form 23 August 2012
Accepted 27 August 2012
Available online 6 September 2012
The synthesis of new chiral non-natural seleno-, thio-, and telluro-peptides is described herein. These
new compounds were prepared through simple and brief synthetic route, from inexpensive and com-
mercially available amino acids. The products, possessing a highly modular character, were obtained in
good to excellent yields (50e96%), via ring opening of aziridines with chalcogenolate anions, generated
using indium(I) iodide as a reducing agent.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Peptides
Organochalcogen
Indium(I) iodide
Aziridines
Ring opening
1. Introduction
a selenocysteine residue at the active site as a catalyst for various
redox reactions.11 Perhaps the most important and studied enzyme
The interest in synthesizing small molecules that mimic the
structures of bioactive peptides has become an important goal in
synthetic organic chemistry.1 A special emphasis has been given to
the replacement of natural amino acids in peptides for non-
proteinogenic derivatives in order to obtain drug-like target mol-
ecules.2 Moreover the interest in the biological and medicinal
properties of selenium and organoselenium compounds is also
increasingly appreciated, mainly due to their antioxidant, antitu-
mor, antimicrobial, and antiviral properties.3 This increasing in-
terest has attracted considerable attention in the development of
new organoselenium compounds. In this context, synthetic
methods for the preparation of selenocysteine,4 selenium based
peptides,5 selenoglycosides,6 selenonucleosides,7 seleno-carbohy-
drates,8 and other important natural coumpounds9 are currently an
area of intensive research.
is glutathione peroxidase (GPx), which protects the body against
the potentially damaging effects of reactive oxygen species formed
during aerobic metabolism.12 Several neurodegenerative diseases,
including Alzheimer’s, Parkinson’s and other physiological and in-
flammatory processes are associated with oxidative stress.13 Since
the discovery that selenium plays a pivotal role in GPx enzymes,
synthetic developments toward design of new chalcogen based
catalytic antioxidants have attracted considerable attention.3a,14 In
this context, novel compounds derived from amino acids contain-
ing chalcogen atom have arisen as excellent candidates for GPx
mimics.15
Chalcogen-containing peptides offer attractive and practical
potential toward the development of new ligands for asymmetric
transformations.16 Further, they are easily prepared from readily
available, modular chiral building blocks.
Among selenium and tellurium compounds, the chalcogen
amino acids have emerged as an exceptional class of structures in
recent years, due to their interesting biological properties, such as
selenocysteine, selenomethionine and the analogous tellurium
compounds, in which the amino acid side chain is isosteric with
On the other hand, chiral aziridines are one of the most versatile
three-membered ring systems in modern synthetic chemistry.17
They constitute a useful class of nitrogen-containing compounds
and are also key intermediates for the regiocontrolled introduction
of a chalcogen atom in the product. In this context different b-seleno
cysteine
or
methionine.10
Many
selenoenzymes
have
amines and selenocysteine derivatives have been prepared via ring
opening of aziridines with chalcogen nucleophiles, generated by
reducing agents, such as NaBH4, LiBHEt3, Zn, rongalite and KOH/
CuO.18 In recent years our groupdeveloped an indium (I) protocol for
the preparation of selenocysteine derivatives through the ring
opening of aziridine-2-carboxylate. By this method, a series of
* Corresponding authors. Tel.: þ55 51 3308 6293; fax: þ55 51 3308 7304 (R.S.S.);
tel.: þ55 51 3308 6286; fax: þ55 51 3308 7304 (P.H.S.); e-mail addresses:
rschwab28@gmail.com (R.S. Schwab), paulos@iq.ufrgs.br (P.H. Schneider).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.082

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R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
selenoamino acids could be synthesized in good to excellent
yields.19 In this work we discovered that when the selenolate anion
was generated using NaBH4/EtOH the reaction failed to prepare
selenocysteine derivatives. Notably, indium selenolate promoted
faster aziridine ring opening in the absence of a Lewis acid (Fig. 1).
With the (S)-1-tritylaziridine-2-carboxylic acid 4 in hand, we
turned your attention toward coupling with -amino esters 5. To
accomplish this transformation, we chose the mixed anhydride
method.23 Coupling conditions consisted of treatment of the (S)-1-
tritylaziridine-2-carboxylic acid 4 with N-methylmorpholine in
chloroform, followed by the addition of ethyl chloroformate to af-
L
ford the mixed anhydride in situ, which was then treated with L-
amino esters 5 and other equivalent of N-methylmorpholine to
form the amide bond (Scheme 3). A series of compounds was
synthesized through variation of the amino ester residues. Com-
pounds of type 3 were submitted to a short purification over silica
gel to remove the unreacted starting materials.
In order to facilitate an efficient ring opening of the aziridine, it
was necessary to replace the trityl group with an electron with-
drawing group, such as tert-butoxycarbonyl (Boc). Following the
protocol reported in the literature,24 the protecting group in-
terconversion 3/2 was achieved using a one-pot strategy in order
to avoid the isolation of the intermediate free aziridines. Hence,
removal of trityl group from 3 using trifluoroacetic acid, basification
with excess of triethylamine and in situ reprotection with Boc2O
gave the N-Boc aziridines 2aed in good yields (Scheme 3).
Fig. 1. Proposed mechanism for the aziridine ring opening.
In this context, and as a part of our growing interest in chalcogen
compounds,20 we describe herein an easy, inexpensive and
straightforward synthetic route for the preparation of a series of
non-natural chalcogen peptides. Our approach to the preparation of
these new N-Boc chalcogen peptides took advantage of our pre-
vious protocol,19 and consisted of a ring opening reaction of azir-
idine by indium chalcogenolate anions as depicted in the proposed
retrosynthetic analysis (Scheme 1). For the preparation of the key
aziridines, we selected some procedures already described in the
literature, which explores the preparation of these aziridines
starting from common available amino acids.
Scheme 3. Synthetic strategies to prepare N-Boc aziridines 2aed. Reagents and con-
ditions: (i) NMM, ethyl chloroformate, NMM, CHCl3, 0 ꢀC, then 24 h rt; (ii) TFA, MeOH,
CH2Cl2, 0 ꢀC, 30 min (iii) Et3N, Boc2O, 0 ꢀC, then 15 h rt.
It is worth noting that we did not observe any epimerization at
the original chiral center from 4. This result was confirmed through
the synthesis of a racemic aziridine rac-4, which was coupling with
L-amino ester of alanine, followed by the removal of trityl group
and in situ reprotection with Boc2O to afford a mixture of di-
astereoisomers 2b. By the comparison of both spectra of 1H NMR,
we could then confirm the absence of epimerization, since only
a single set of signals was observed for an enantiomerically pure N-
Scheme 1. Retrosynthetic analysis for chalcogen peptides 1.
Boc aziridine 2b, when compared with
astereoisomers 2b (see Supplementary data).
a mixture of di-
With the N-Boc aziridines 2aed in hand, we promoted the in-
sertion of the organochalcogen moiety through the nucleophilic
ring opening with different selenium anions. To accomplish this
task the selenium nucleophile was generated by reduction of
diphenyl diselenide with sodium borohydride in a mixture of THF
and ethanol. However, under these conditions the ring opening of
aziridine 2a failed and the product was not obtained. This result is
in agreement with those previously reported in the literature for
a similar aziridine.19 Attempting to solve this problem we decided
to use our protocol, which employs indium (I) iodide to promote
the cleavage of diorganoyl diselenides.19 According to that, indium
(I) iodide undergoes an oxidative insertion into a suitable substrate,
generating the complex bis(organoylseleno)iodoindium (III). This
complex is readily prepared by reacting equimolar amounts of InI
and R1SeSeR1 in dichloromethane (Scheme 4).
2. Results and discussion
According to our objectives and as the starting point for the
synthesis of chalcogen peptides 1 we had to devise an efficient
method of preparation for chiral N-Boc-aziridines 2 in a short and
high yielding sequence. To accomplish this task we used method-
ologies already described in the literature.
Following the protocol previously reported, the (S)-methyl 1-
tritylaziridine-2-carboxylate 6 was prepared in high yields start-
ing from L
-serine.21 In the next step the hydrolysis of methyl ester
was achieved by reaction with 2 M lithium hydroxide in acetonitrile
affording (S)-1-tritylaziridine-2-carboxylic acid 4 in 91% yield
(Scheme 2).22
As outlined in the sequence below, the preparation of chalcogen
peptides proceeds through the regioselective nucleophilic attack of
the organoselenolate anion at the less hindered carbon of the
aziridine ring.
After optimization of the reaction conditions, several aziridines
and diorganoyl dichalcogenides were applied in order to check the
Scheme 2. Synthesis of (S)-1-tritylaziridine-2-carboxylic acid 4 from L-serine.

R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
10451
vs 8e11). We observed that steric effects exerted some influence
during the reaction and the substituents attached to the para po-
sition of diselenide furnished better yields (Table 1, Entries 6 and 8)
than those with the same substituents in the ortho position (Entries
7 and 9). Moreover, the introduction of aliphatic group (Bu, entry
12, 79% yield) was also achieved in very good yield. Due to the
success obtained with the preparation of the seleno-peptides, we
decided to extend our studies to sulfur and tellurium analogs. In
this way, the reduction of diphenyl disulfide with InI, under the
same conditions used for the diselenides, followed by the ring
opening of N-Boc aziridine 2a, afforded the corresponding thio-
peptide 1n in good yield (Table 1, Entry 13). For the preparation
of the telluro-peptides it was necessary to alter the procedure
somewhat, since it was observed that the organotellurolate anion
underwent decomposition under the reaction conditions. In this
Scheme 4. Indium (I) iodide-mediated N-Boc aziridine ring opening with diorganoyl
diselenides.
versatility of the protocol, and the results are summarized in Table 1.
In general, all reactions proceeded smoothly and the target com-
pounds 1aep were obtained in good to excellent yields, ranging
from 50 to 96 %. Changing the amino acid residue did not produce
a pronounced effect on the yield of the products (Table 1, Entries
2e4).
We found that electronic effects had no significant influence on
the reactivity of the process, as the products were obtained without
meaningful change on the reaction yield (Table 1 Entries 1 and 5e7
Table 1
Synthesis of N-Boc chalcogen peptides 1aep
Entry
1
R
Product
Yield (%)a
77
Entry
9
R
Product
Yield (%)a
86
Bn
1a
1b
1c
1d
Bn
1i
1j
2
3
4
Me
iPr
86
86
83
10
11
12
Bn
Bn
Bn
71
82
79
1l
iBu
1m
5
6
7
Bn
Bn
Bn
Bn
1e
1f
77
85
80
96
13
14
15
Bn
Bn
Bn
1n
1o
1p
86
80
50
1g
1h
8
a
Yields of isolated materials.

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R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
case diphenyl ditelluride or di-(p-methoxyphenyl) ditelluride were
added to a solution of N-Boc aziridine 2a followed by InI and
allowed to react for 2 h, affording the telluro-peptides in good and
moderate yields (Table 1, Entries 14 and 15).
thickness. For visualization, TLC plates were either placed under
ultraviolet light, or stained with iodine vapor, or acidic vanillin. The
yields of the products included in all tables refer to isolated yields.
The following solvents were dried and purified by distillation from
the reagents indicated: THF from sodium with benzophenone in-
dicator, EtOH from magnesium/iodine, CH2Cl2 from phosphorus
pentoxide and DMF from magnesium sulfate. All other solvents
were ACS or HPLC grade unless otherwise noted. The chalcogenides
were conveniently prepared from classical procedures.25,26 (S)-1-
tritylaziridine-2-carboxylic acid 4 was prepared according the
procedures described in literature.21,22 All others reagents and
solvents were purchased from commercial suppliers. Air- and
moisture-sensitive reactions were conducted in flame-dried or
oven dried glassware equipped with tightly fitted rubber septa and
under a positive atmosphere of dry nitrogen. Reagents and solvents
were handled using standard syringe techniques.
One of the major advantages of this strategy is its modular
construction, where modifications in the structure of the products
can be easily introduced. In this way and as a further extension of
the present methodology we attempted the synthesis of the dis-
elenide 1r (Scheme 5). To accomplish this task, we took advantage
of our previous strategy for the synthesis of telluro-peptides, which
employs a nucleophilic ring opening of N-Boc aziridine 2a. In this
way the treatment of N-Boc aziridine 2a with di-(4-methylbenzoyl)
diselenide and InI afforded after 7 h the key intermediate 1q in 50%
yield. The selenoester group was then removed from seleno-
peptide 1q through the reaction with piperazine in dry N,N-dime-
thylformamide, furnishing diselenide 1r after air oxidation in 43%
yield.25
4.2. General procedure for the synthesis of N-Boc aziridines
(2)
Under a nitrogen atmosphere, N-methylmorpholine (0.303 g,
3.0 mmol) was added to a solution of (S)-1-tritylaziridine-2-
carboxylic acid 4 (0.987 g, 3.0 mmol) in CHCl3 (20 mL) at 0 ꢀC. Af-
ter stirring for 15 min at this temperature, ethyl chloroformate
(0.324 g, 3.0 mmol) was added dropwise and stirring was pro-
longed for additional 30 min at 0 ꢀC. After this time the appropriate
amino ester (3.0 mmol) was added, followed by 1 equiv of N-
methylmorpholine and the resulting solution was stirred at 0 ꢀC for
additional 1 h and then at room temperature for 24 h. After this
time the solution was diluted with 30 mL of CHCl3, washed with
saturated NaHCO3 (2ꢁ20 mL), 10% aqueous citric acid (2ꢁ20 mL),
and brine (20 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated. The resulting products were
purified through a short column and were used in the next step.
Trifluoroacetic acid (0.48 mL, 6.25 mmol) was added dropwise over
1 min to a stirred solution of the appropriate N-Trt aziridine 3
(2.5 mmol) in dichloromethane (20 mL) and methanol (0.1 ml,
2.5 mmol) at 0 ꢀC under an atmosphere of nitrogen. The solution
was stirred at 0 ꢀC for 30 min and then triethylamine (2.17 mL,
15.62 mmol) was added dropwise over 2 min. The mixture was
stirred at 0 ꢀC for an additional 10 min, and then di-tert-butyl
dicarbonate (0.60 g, 2.75 mmol) in dichloromethane (5 mL) was
added over 5 min. The solution was warmed to room temperature,
stirred for 15 h and then washed with 10% aqueous citric acid so-
lution (3ꢁ10 ml) and water (2ꢁ10 mL). The combined organic ex-
tracts were dried with Na2SO4 and the solvent concentrated under
vacuum to afford the crude products, which were purified by
chromatography on silica gel using 7:3 hexane:ethyl acetate.
Scheme 5. Synthesis of diselenide 1r.
3. Conclusion
In summary, we have described herein a novel synthetic entry
into selenium-, thio- and teluro-peptides systems. These com-
pounds were prepared in a concise and flexible route in good to
excellent yields, which permitted the synthesis of a wide range of
compounds with a highly modular character. Additionally, the
method was easily adapted for the synthesis of diselenide species.
We also believe that this modular approach may have significant
importance for biological screenings. Further research efforts are
currently underway in our laboratories to investigate the influence
of amino acid sequence and the chalcogen identity toward bi-
ological activity of this class of compounds.
4. Experimental
4.1. General information
Hydrogen nuclear magnetic resonance spectra (1H NMR) were
obtained, on a Varian INOVA, 300 MHz spectrometer and on
a Bruker AVANCE III 400 MHz spectrometer. Spectra were recorded
in CDCl3 solutions. Chemical shifts are reported in parts per million,
referenced to the solvent peak of TMS. Data are reported as follows:
4.2.1. (S)-tert-Butyl 2-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)
carbamoyl)aziridine-1-carboxy-late 2a. Colorless oil. Yield: 78%;
20
[a
]
¼þ15.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
¼7.29e7.19
d
D
(m, 3H), 7.08e7.06 (m, 2H), 6.72 (d, J¼7.8 Hz, 1H), 4.83 (q,
J1¼14.1 Hz, J2¼6.6 Hz, 1H), 3.72 (s, 3H), 3.17 (dd, J1¼13.9 Hz,
J2¼5.6 Hz, 1H), 3.01 (dd, J1¼13.9 Hz, J2¼6.6 Hz, 1H), 2.94e2.91 (m,
1H), 2.36 (d, J¼6.3 Hz, 1H), 2.02 (d, J¼3.4 Hz, 1H), 1.44 (s, 9H) ppm
chemical shift (
d
), multiplicity (br¼broad, s¼singlet, d¼doublet,
dd¼double doublet, t¼triplet, q¼quartet, m¼multiplet), and cou-
pling constant (J) in Hertz and integrated intensity. Carbon-13 nu-
clear magnetic resonance spectra (13C NMR) were obtained either
at 75 MHz and 100 MHz. Spectra were recorded in CDCl3 solutions.
Chemical shifts are reported in ppm, referenced to the solvent peak
of CDCl3. High-resolution mass spectra (ESI) were measured at the
13C NMR (100 MHz, CDCl3):
d¼171.29, 167.14, 159.94, 135.59, 129.05,
128.36, 126.98, 82.19, 52.58, 52.19, 37.62, 36.65, 31.69, 27.66 ppm
HRMS (ESI) calcd for C18H24N2O5 [MþNaþ]: 371.1583 m/z; ob-
served: 371.1572 m/z.
~
Universidade de Sao Paulo with a LC-MS Bruker Daltronics Micro-
4.2.2. (S)-tert-Butyl 2-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)
20
TOF in ESI mode. Optical rotations were carried out on a Perkin
Elmer Polarimeter 341. Column chromatography was performed
using Merck Silica Gel (70e230 mesh). Thin layer chromatography
(TLC) was performed using Merck Silica Gel GF254, 0.25 mm
aziridine-1-carboxylate 2b. Colorless oil. Yield: 66%; [
a
]
¼ꢂ59.0
D
(c¼1, EtOAc); 1H NMR (300 MHz, CDCl3):
¼7.00 (d, J¼7.0 Hz, 1H),
d
4.53e4.43 (m, 1H), 3.68 (s, 3H), 2.97e2.94 (m, 1H), 2.37 (d, J¼6.4 Hz,
1H), 2.27 (d, J¼2.9 Hz,1H),1.38 (s, 9H),1.32 (d, J¼7.6 Hz, 3H) ppm 13C

R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
10453
NMR (75 MHz, CDCl3):
d
¼172.60, 166.94, 159.88, 81.97, 52.19, 47.59,
133.03, 129.20, 127.37, 80.37, 57.16, 54.37, 52.07, 31.23, 29.38, 28.16,
18.84, 17.64 ppm HRMS (ESI) calcd for C20H30N2O5Se [MþNaþ]:
481.1218 m/z; observed: 481.1218 m/z.
36.38, 31.47, 27.55, 17.83 ppm HRMS (ESI) calcd for C12H20N2O5
[MþNaþ]: 295.1269 m/z; observed: 295.1259 m/z.
4.2.3. (S)-tert-Butyl 2-(((S)-1-methoxy-3-methyl-1-oxobutan-2-yl)
4.3.4. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(phenyl-
carbamoyl)aziridine-1-carboxylate 2c. Colorless oil. Yield: 71%;
selanyl)propanamido)-3-methylbutanoate 1d. Pale yellow solid.
20
20
[
a
]
¼ꢂ24.0 (c¼1, EtOAc); 1H NMR (300 MHz, CDCl3):
d
¼6.93 (d,
Yield: 83%; [
a
]
D
¼ꢂ55.0 (c¼1, EtOAc); 1H NMR (300 MHz, CDCl3):
D
J¼8.8 Hz,1H), 4.47e4.42 (m,1H), 3.67 (s, 3H), 3.01e2.98 (m,1H), 2.38
d
¼7.84e7.46 (m, 2H), 7.20e7.18 (m, 3H), 6.62 (br s, 1H), 5.22 (br s,
(d, J¼6.4 Hz,1H), 2.26 (d, J¼3.5 Hz,1H), 2.13e2.02 (m,1H),1.38 (s, 9H)
1H), 4.52e4.25 (m, 1H), 4.27 (br s, 1H), 3.64 (s, 3H), 3.22e3.10 (m,
2H), 1.58e1.40 (m, 3H), 1.34 (s, 9H), 0.84 (d, J¼5.2 Hz, 6H) ppm 13C
ppm 13C NMR (75 MHz, CDCl3):
d
¼171.59,167.27,159.79, 81.86, 56.53,
51.82, 36.48, 31.52, 30.90, 27.47,18.58,17.46 ppm HRMS (ESI) calcd for
NMR (75 MHz, CDCl3):
d¼172.83, 170.23, 155.30, 133.03, 129.21,
C14H24N2O5 [MþNaþ]: 323.1583 m/z; observed: 323.1575 m/z.
127.39, 80.41, 54.23, 52.24, 50.77, 41.42, 29.52, 28.14, 24.67, 22.72,
21.83 ppm HRMS (ESI) calcd for C21H32N2O5Se [MþNaþ]: 495.1374
m/z; observed: 495.1378 m/z.
4.2.4. (S)-tert-Butyl 2-(((S)-1-methoxy-4-methyl-1-oxopentan-2-yl)
carbamoyl)aziridine-1-carboxylate 2d. Colorless oil. Yield: 60%;
20
[
a
]
¼ꢂ36.0 (c¼1, EtOAc); 1H NMR (300 MHz, CDCl3):
d¼6.88 (d,
4.3.5. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(p-tol-
ylselanyl)propanamido)-3-phenyl-propanoate 1e. Pale yellow solid.
D
J¼8.8 Hz,1H), 4.57e4.49 (m, 1H), 3.66 (s, 3H), 2.99e2.96 (m,1H), 2.37
(d, J¼5.8 Hz,1H), 2.25 (d, J¼2.3 Hz,1H),1.59e1.45 (m, 3H),1.38 (s, 9H)
20
Yield: 77%; [
d
a
]
¼ꢂ13.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
D
ppm 13C NMR (75 MHz, CDCl3):
d¼172.60, 167.15, 159.82, 81.91, 51.99,
¼7.40 (d, J¼7.8 Hz, 2H), 7.29e7.21 (m, 3H), 7.10e7.05 (m, 4H), 6.68
50.12, 41.02, 36.41, 31.46, 27.49, 24.45, 22.46, 21.51 ppm HRMS (ESI)
(d, J¼7.0 Hz, 1H), 5.14 (br s, 1H), 4.75 (q, J1¼13.4 Hz, J2¼6.1 Hz, 1H),
calcd for C15H26N2O5 [MþNaþ]: 337.1739 m/z; observed: 337.1736 m/z.
4.27 (br s, 1H), 3.69 (s, 3H), 3.18e3.02 (m, 4H), 2.30 (s, 3H), 1.40 (s,
9H) ppm 13C NMR (100 MHz, CDCl3):
d¼171.38, 170.11, 155.14, 137.57,
4.3. General procedure for the synthesis of selenium- and
sulfur-peptides (1)
135.71, 133.56, 130.06, 129.28, 128.51, 127.09, 125.26, 80.35, 54.48,
53.33, 52.22, 37.87, 29.98, 29.63, 28.17, 21.02 ppm HRMS (ESI) calcd
for C25H32N2O5Se [MþNaþ]: 543.1374 m/z; observed: 543.1376 m/z.
To a 25 mL round-bottomed flask, under a nitrogen atmosphere,
InI (0.121 g, 0.5 mmol) was added to a solution of the appropriate
diorganyl diselenide (0.5 mmol) in dry CH2Cl2 (5 mL). The mixture
was allowed to stir until all InI was dissolved (1 h). Following this,
the appropriate protected N-Boc aziridine (0.5 mmol) was added
and the reaction was stirred at room temperature for 2 h. The
mixture was quenched with H2O, extracted with CH2Cl2 (3ꢁ15 mL)
and the combined organic fractions were dried over Na2SO4 and
filtered. The solvent was then removed under vacuum yielding the
crude products, which were purified by column chromatography
on silica gel (8:2 hexane:ethyl acetate).
4.3.6. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((4-
methoxyphenyl)selanyl)propanamido)-3-phenylpropanoate
20
1f. Yellow solid. Yield: 85%; [
(400 MHz, CDCl3):
a
]
D
¼ꢂ29.0 (c¼1, EtOAc); 1H NMR
d
¼7.45 (d, J¼8.7 Hz, 2H), 7.28e7.20 (m, 3H), 7.10
(d, J¼6.4 Hz, 2H), 6.79 (d, J¼8.7 Hz, 2H), 6.70 (d, J¼7.3 Hz, 1H), 5.17
(m, 1H), 4.76 (q, J1¼13.7 Hz, J2¼6.1 Hz, 1H), 4.25 (br s, 1H), 3.77 (s,
3H), 3.68 (s, 3H), 3.15e3.02 (m, 4H), 1.40 (s, 9H) ppm 13C NMR
(100 MHz, CDCl3):
d
¼171.36, 170.11, 159.62, 155.13, 135.85, 135.68,
129.24, 128.47, 127.05, 118.87, 114.96, 80.30, 55.17, 54.41, 53.27,
52.18, 37.84, 30.58, 28.16 ppm HRMS (ESI) calcd for C25H32N2O6Se
[MþNaþ]: 559.1323 m/z; observed: 559.1320 m/z.
4.3.1. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(phenyl-
selanyl)propanamido)-3-phenyl-propanoate 1a. Pale yellow solid.
4.3.7. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((2-
20
Yield: 77%; [
a
]
D
¼ꢂ16.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
methoxyphenyl)selanyl)propanamido)-3-phenylpropanoate 1g. Pale
20
d
¼7.50e7.48 (m, 2H), 7.27e7.18 (m, 6H), 7.10e7.08 (m, 2H), 6.78 (d,
yellow solid. Yield: 80%; [
(400 MHz, CDCl3):
a]
¼ꢂ14.0 (c¼1, EtOAc); 1H NMR
D
J¼7.5 Hz, 1H), 5.29 (d, J¼8.0 Hz, 1H), 4.75 (q, J1¼13.7 Hz, J2¼5.8 Hz,
1H), 4.33 (br s, 1H), 3.66 (s, 1H), 3.20e3.15 (m, 2H), 3.11 (dd,
J1¼13.9 Hz, J2¼5.8 Hz, 1H), 3.03 (dd, J1¼13.9 Hz, J2¼6.1 Hz, 1H), 1.39
d
¼7.52e7.50 (m, 1H), 7.29e7.20 (m, 4H), 7.12 (d,
J¼6,4 Hz, 2H), 6.90e6.84 (m, 3H), 5.64 (br s, 1H), 4.78 (q, J1¼13.1 Hz,
J2¼5.8 Hz, 1H), 4.34 (br s, 1H), 3.87 (s, 1H), 3.68 (s, 1H), 3.33 (br s,
1H), 3.16e3.00 (m, 3H),1.39 (s, 9H) ppm 13C NMR (100 MHz, CDCl3):
(s, 9H) ppm 13C NMR (100 MHz, CDCl3):
d
¼171.23, 170.01, 154.96,
135.57, 132.83, 129.10, 129.03, 128.33, 127.18, 126.89, 80.11, 54.23,
53.19, 52.05, 37.66, 29.59, 28.03 ppm HRMS (ESI) calcd for
C24H30N2O5Se [MþNaþ]: 529.1218 m/z; observed: 529.1212 m/z.
d
¼171.34, 170.34, 158.39, 155.41, 135.73, 134.63, 129.30, 128.45,
126.98, 121.48,118.22, 110.70, 80.20, 55.74, 54.16, 53.34, 52.17, 37.28,
28.29, 28.17 ppm HRMS (ESI) calcd for C25H32N2O6Se [MþNaþ]:
559.1323 m/z; observed: 559.1322 m/z.
4.3.2. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-
(phenylselanyl)propanamido)propanoate 1b. Pale yellow solid.
4.3.8. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((4-
20
Yield: 86%; [
a
]
¼ꢂ16.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
chlorophenyl)selanyl)propanamido)-3-phenylpropanoate
1h. Pale
D
20
d
¼7.46e7.44 (m, 2H), 7.18e7.15 (m, 3H), 6,91 (br s, 1H), 5.40 (d,
yellow solid. Yield: 96%; [
a
]
D
¼ꢂ17.0 (c¼1, EtOAc); 1H NMR
J¼8.0 Hz, 1H), 4.42e4.35 (m, 1H), 4.32 (br s, 1H), 3.22e3.16 (m, 2H),
(400 MHz, CDCl3):
d
¼7.44 (d, J¼8.1 Hz, 2H), 7.29e7.20 (m, 5H), 7.08
1.34 (s, 9H), 1.27 (d, J¼7.3 Hz, 3H) ppm 13C NMR (75 MHz, CDCl3):
(d, J¼6.7 Hz, 2H), 5.18 (br s, 1H), 4.75 (q, J1¼13.4 Hz, J2¼6.1 Hz, 1H),
d
¼172.64, 169.99, 155.10, 132.68, 128.91, 127.02, 79.92, 53.95, 52.17,
4.31 (br s, 1H), 3.70 (s, 3H), 3.24e3.03 (m, 4H), 1.41 (s, 9H) ppm 13C
47.87, 29.70, 27.97, 17.84 ppm HRMS (ESI) calcd for C18H26N2O5Se
NMR (100 MHz, CDCl3):
d
¼171.32, 169.82, 155.05, 135.55, 134.41,
[MþNaþ]: 453.0905 m/z; observed: 453.0901 m/z.
133.69, 129.33, 129.22, 128.52, 127.36, 127.12, 80.44, 54.24, 53.26,
52.29, 37.77, 30.07, 28.16 ppm HRMS (ESI) calcd for C24H29ClN2O5Se
[MþNaþ]: 563.0828 m/z; observed: 563.0826 m/z.
4.3.3. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(phenyl-
selanyl)propanamido)-3-methylbutanoate 1c. Pale yellow solid.
20
Yield: 86%; [
d
a]
¼ꢂ33.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
4.3.9. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((2-
D
¼7.47e7.46 (m, 2H), 7.20e7.18 (m, 3H), 6.79 (br s, 1H), 5.30 (d,
chlorophenyl)selanyl)propanamido)-3-phenylpropanoate 1i. White
20
J¼7.8 Hz, 1H), 4.42e4.39 (m, 1H), 4.29 (br s, 1H), 3.65 (s, 3H),
3.23e3.15 (m, 2H) 2.11e2.01 (m, 1H), 1.35 (s, 9H), 0.83 (t, J¼8.3 Hz,
solid. Yield: 86%; [
CDCl3):
a
]
D
¼ꢂ27.0 (c¼1, EtOAc); 1H NMR (400 MHz,
d
¼7.44e7.42 (m, 1H), 7.30e7.26 (m, 1H), 7.23e7.16 (m, 4H),
6H) ppm 13C NMR (75 MHz, CDCl3):
d¼171.78, 170.44, 155.34,
7.12e7.09 (m, 2H), 7.03e7.00 (m, 2H), 6.66e6.64 (m, 1H), 5.17 (br s,

10454
R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
1H), 4.70 (q, J1¼13.5 Hz, J2¼6.0 Hz, 1H), 4.32 (br s, 1H), 3.63 (s, 3H),
3.29e3.26 (m, 1H), 3.16e3.11 (m, 1H), 3.06 (dd, J1¼13.8 Hz,
J2¼5.8 Hz, 1H), 2.99 (dd, J1¼13.8 Hz, J2¼6.0 Hz, 1H), 1.33 (s, 9H) ppm
room temperature for 2 h. The mixture was quenched with H2O,
extracted with CH2Cl2 (3ꢁ15 mL) and the combined organic frac-
tions were dried over Na2SO4 and filtered. The solvent was then
removed under vacuum yielding the crude products, which were
purified by column chromatography on silica gel (8:2 hexane:ethyl
acetate).
13C NMR (100 MHz, CDCl3):
d
¼171.26, 169.92, 155.11, 135.79, 135.59,
132.33, 130.01, 129.60, 129.24, 128.53, 128.08, 127.40, 127.11, 80.49,
54.02, 53.39, 52.26, 37.80, 28.49, 28.16 ppm HRMS (ESI) calcd for
C24H29ClN2O5Se [MþNaþ]: 563.0828 m/z; observed: 563.0827 m/z.
4.4.1. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(phenyl-
4.3.10. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((4-
tellanyl)propanamido)-3-phenylpropanoate 1o. Orange oil. Yield:
20
fluorophenyl)selanyl)propanamido)-3-phenylpropanoate 1j. Yellow
80%; [
a]
¼ꢂ18.0 (c¼1, EtOAc); 1H NMR (300 MHz, CDCl3):
D
20
solid. Yield: 71%; [
CDCl3):
a
]
D
¼ꢂ20.0 (c¼1, EtOAc); 1H NMR (400 MHz,
d
¼7.65e7.62 (m, 2H), 7.21e7.01 (m, 8H), 6.72 (d, J¼7.0 Hz, 1H), 5.21
d
¼7.51e7.47 (m, 2H), 7.28e7.20 (m, 3H), 7.09 (d, J¼6.7 Hz,
(d, J¼8.2 Hz, 1H), 4.67 (q, J1¼14.0 Hz, J2¼6.4 Hz, 1H), 4.39 (br s, 1H),
2H), 6.94 (t, J¼8.7 Hz, 2H), 6.72 (d, J¼7.6, 1H), 5.26 (d, J¼7.8 Hz, 1H),
4.76 (q, J1¼13.4 Hz, J2¼6.1 Hz, 1H), 4.30 (br s, 1H), 3.68 (s, 3H),
3.15e3.06 (m, 4H), 1.41 (s, 9H) ppm 13C NMR (100 MHz, CDCl3):
3.60 (s, 3H), 3.16e2.93 (m, 4H), 1.32 (s, 9H) ppm 13C NMR (75 MHz,
CDCl3):
d
¼171.25, 170.62, 155.10, 138.35, 135.52, 129.14, 128.39,
127.71, 126.97, 112.16, 80.19, 54.51, 53.19, 52.17, 37.64, 28.07,
10.82 ppm HRMS (ESI) calcd for C24H30N2O5Te [MþNaþ]:
579.1115 m/z; observed: 579.1109 m/z.
d
¼171.32, 169.93, 163.70, 161.23, 155.04, 135.69, 135.61, 135.56,
129.17, 128.44, 127.02, 123.53, 116.40, 116.18, 80.27, 54.21, 53.21,
52.18, 37.74, 30.48, 28.11 ppm HRMS (ESI) calcd for C24H29FN2O5Se
[MþNaþ]: 547.1123 m/z; observed: 547.1122 m/z.
4.4.2. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((4-
methoxyphenyl)tellanyl)propanamido)-3-phenylpropanoate
¼ꢂ16.0 (c¼1, EtOAc); 1H NMR
20
4.3.11. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-((3-
(trifluoromethyl)phenyl)selanyl)pro-panamido)-3-phenylpropanoate
1p. Orange oil. Yield: 50%; [
a
]
D
(400 MHz, CDCl3):
d
¼7.61 (d, J¼8.5 Hz, 1H), 7.23e7.14 (m, 4H), 7.03
1l. Yellow oil. Yield: 82%; [
a
]
¼ꢂ9.0 (c¼1, EtOAc); 1H NMR
(d, J¼8.3 Hz, 2H), 6.67 (d, J¼8.8 Hz, 2H), 6.62 (br s, 1H), 5.11 (br s,
1H), 4.68 (q, J1¼13.6 Hz, J2¼6.0 Hz, 1H), 4.32 (br s, 1H), 3.71 (s, 3H),
3.62 (s, 3H), 3.09e2.90 (m, 4H), 1.33 (s, 9H) ppm 13C NMR (75 MHz,
20
D
(400 MHz, CDCl3):
d
¼7.75 (s, 1H), 7.67 (d, J¼7.8 Hz, 1H), 7.47 (d,
J¼7.6 Hz, 1H), 7.35 (t, J¼7.8 Hz, 1H), 7.27e7.19 (m, 3H), 7.09 (d,
J¼6.7 Hz, 2H), 6.85 (d, J¼7,3 Hz, 1H), 5.39 (d, J¼7,8 Hz, 1H), 4.78 (q,
J1¼13.7 Hz, J2¼6.1 Hz,1H), 4.41 (br s,1H), 3.67 (s, 3H), 3.25e3.28 (m,
2H), 3.12 (dd, J1¼13.7 Hz, J2¼5.8 Hz, 1H), 3.05 (dd, J1¼13.7 Hz,
CDCl3):
d
¼171.37, 170.70, 159.88, 155.19, 141.10, 135.64, 129.24,
128.51, 127.08, 115.28, 100.97, 80.36, 55.09, 54.73, 53.29, 52.27,
37.81, 28.19, 11.06 ppm HRMS (ESI) calcd for C25H32N2O6Te
[MþNaþ]: 609.1220 m/z; observed: 609.1217 m/z.
J2¼6.1 Hz, 1H), 1.40 (s, 9H) ppm 13C NMR (100 MHz, CDCl3):
2
d
¼171.26, 169.87, 155.03,135.66, 135.50, 131.21 (q, JCF¼32.2 Hz),
1
129.32, 129.09, 126.96, 123.80, 123.48 (q, JCF¼272.9 Hz), 80.24,
54.05, 53.22, 52.12, 37.61, 29.87, 27.99 ppm HRMS (ESI) calcd for
C25H29F3N2O5Se [MþNaþ]: 597.1091 m/z; observed: 597.1088 m/z.
4.5. Procedure for the synthesis (S)-methyl 2-((R)-2-((tert-
butoxycarbonyl)amino)-3-((4-methylbenzoyl)selanyl)prop-
anamido)-3-phenylpropanoate 1q
4.3.12. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(bu-
tylselanyl)propanamido)-3-phenylpropanoate 1m. Pale yellow solid.
To a 25 mL round-bottomed flask, under a nitrogen atmosphere,
di-(4-methylbenzoyl) diselenide (0.198 g, 0.5 mmol) was added to
a solution of the N-Boc aziridine 2a (0.174 g, 0.5 mmol) in dry CH2Cl2
(5 mL), followed by InI (0.121 g, 0.5 mmol). The mixture was allowed
to stir at room temperature for 7 h. The mixture was quenched with
H2O, extracted with CH2Cl2 (3ꢁ15 mL) and the combined organic
fractions were collected, dried over Na2SO4, and filtered. The solvent
was then removed under vacuum yielding the crude products, which
were purified by column chromatography on silica gel (8:2 hex-
ane:ethyl acetate). The chalcogen peptide 1q was used in the next
20
Yield: 79%; [
d
a
]
¼ꢂ3.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
D
¼7.22e7.13 (m, 3H), 7.06e7.03 (m, 2H), 6.83 (d, J¼7.3 Hz,1H), 5.34 (d,
J¼7.0 Hz,1H), 4.76 (q, J1¼13.8 Hz, J2¼6.0 Hz,1H), 4.23 (br s,1H), 3.61 (s,
3H), 3.06 (dd, J1¼13.8 Hz, J2¼5.8 Hz, 1H), 3.01 (dd, J1¼13.8 Hz,
J2¼6.0 Hz,1H), 2.87e2.82 (m,1H), 2.72 (dd, J1¼12.8 Hz, J2¼6.2 Hz,1H),
2.50 (t, J¼7.3 Hz, 2H), 1.57e1.49 (m, 2H),1.36(s, 9H),1.32e1.25(m, 2H),
0.82 (t, J¼7.3 Hz, 3H) ppm 13C NMR (75 MHz, CDCl3):
¼171.28,170.29,
d
155.04, 135.55,129.11, 128.36, 126.93, 80.08, 54.08, 53.22, 52.11, 37.69,
32.33, 28.09, 25.57, 24.70, 22.69, 13.39 ppm HRMS (ESI) calcd for
C22H34N2O5Se [MþNaþ]: 509.1531 m/z; observed: 509.1534 m/z.
step. Pale yellow solid; Yield: 50%; 1H NMR (300 MHz, CDCl3):
d¼7.72
(d, J¼8.2 Hz, 2H), 7.20e7.14 (m, 5H), 7.06 (d, J¼7.6 Hz, 2H), 6.80 (br s,
1H), 5.22e5.20 (m, 1H), 4.76 (q, J1¼12.3 Hz, J2¼5.2 Hz, 1H), 4.36 (br s,
1H), 3.60 (s, 3H), 3.41e3.21 (m, 2H), 3.13 (dd, J1¼14.0 Hz, J2¼5.8 Hz,
1H), 3.01 (dd, J1¼14.0 Hz, J2¼6.4 Hz,1H), 2.33 (s, 3H),1.32 (s, 9H) ppm
4.3.13. (S)-Methyl 2-((R)-2-((tert-butoxycarbonyl) amino)-3-(phe-
nylthio)propanamido)-3-phenylpropanoate 1n. White solid. Yield:
20
86%; [
a]
¼ꢂ14.0 (c¼1, EtOAc); 1H NMR (400 MHz, CDCl3):
d
¼7.30
13C NMR (75 MHz, CDCl3):
d
¼194.59, 171.37, 170.33, 164.94, 145.10,
D
(d, J¼7.3 Hz, 2H), 7.22e7.11 (m, 6H), 7.01 (d, J¼7.8 Hz, 2H), 6.70 (d,
J¼7.3 Hz, 1H), 5.18 (d, J¼7.0 Hz, 1H), 4.69 (q, J1¼12.8 Hz, J2¼5.7 Hz,
1H), 4.17 (br s, 1H), 3.61 (s, 3H), 3.18 (br s, 1H), 3.04 (dd, J1¼13.8 Hz,
J2¼5.7 Hz, 1H), 2.97 (dd, J1¼13.8 Hz, J2¼5.7 Hz, 1H), 1.34 (s, 9H) ppm
135.84, 135.66, 129.48, 129.27, 128.53, 127.45, 127.07, 80.36, 55.12,
53.39, 52.27, 37.93, 28.16, 26.61, 21.73 ppm HRMS (ESI) calcd for
C26H32N2O6Se [MþNaþ]: 571.1323 m/z; observed: 571.1302 m/z.
13C NMR (75 MHz, CDCl3):
d¼171.28, 169.84, 155.09, 135.56, 134.50,
4.6. Procedurefor the synthesis(2S,20S)-dimethyl2,20-(((2R,20R)-
3,30-diselanediylbis(2-((tert butoxycarbonyl)amino)propanoyl))
bis(azanediyl))bis(3-phenylpropanoate) 1r
130.04, 129.18, 129.03, 128.45, 127.02, 126.74, 80.36, 53.83, 53.28,
52.25, 37.72, 35.99, 28.11 ppm HRMS (ESI) calcd for C24H30N2O5S
[MþNaþ]: 481.1773 m/z; observed: 481.1768 m/z.
To a solution of 1q (100 mg, 0.18 mmol in DMF 2.0 mL) in
a 25 mL round-bottomed under a nitrogen atmosphere, piperazine
(20 mg, 0.24 mmol) was added and the mixture was stirred at room
temperature for 2 h (TLC monitoring; 7:3 hexane:ethyl acetate). The
reaction mixture was extracted with EtOAc (2ꢁ15 mL), the com-
bined organic layer was washed with 2 M HCl, saturated NaHCO3
and brine, dried over Na2SO4, and concentrated under vacuum
yielding the crude product, which was purified by column
4.4. General procedure for the synthesis of telluro-peptides
(1)
To a 25 mL round-bottomed flask, under a nitrogen atmosphere,
diorganyl ditelluride (0.5 mmol) was added to a solution of the
N-Boc aziridine 2a (0.174 g, 0.5 mmol) in dry CH2Cl2 (5 mL), fol-
lowed by InI (0.121 g, 0.5 mmol). The mixture was allowed to stir at

R.S. Schwab, P.H. Schneider / Tetrahedron 68 (2012) 10449e10455
10455
9. (a) Caputo, R.; Capone, S.; Greca, M. D.; Longobardo, L.; Pinto, G. Tetrahedron
Lett. 2007, 48, 1425e1427; (b) Abdo, M.; Knapp, S. J. Am. Chem. Soc. 2008, 130,
9234e9235; (c) Sculaccio, S. A.; Rodrigues, E. M.; Cordeiro, A. T.; Magalhaes, A.;
Braga, A. L.; Alberto, E. E.; Thiemann, O. H. Mol. Biochem. Parasitol. 2008, 162,
165e171.
10. Moroder, L. J. Peptide Sci. 2005, 11, 187e214.
chromatography on silica gel (7:3 hexane:ethyl acetate). Yellow
20
solid. Yield: 43%; [
CDCl3):
a
]
¼ꢂ7.0 (c¼1, EtOAc); 1H NMR (300 MHz,
D
~
d
¼7.62 (d, J¼7.6 Hz, 1H), 7.19e7.08 (m, 5H), 5.41 (d,
J¼9.4 Hz,1H), 4.77 (q, J1¼14.3 Hz, J2¼8.2 Hz,1H), 4.62 (br s,1H), 3.59
(s, 3H), 3.21e3.11 (m, 3H), 2.97 (dd, J1¼14.0 Hz, J2¼8.2 Hz, 1H), 1.36
11. (a) Stadtman, T. C. Annu. Rev. Biochem. 1996, 65, 83e100; (b) Stadtman, T. C. Ann.
(s, 9H) ppm 13C NMR (75 MHz, CDCl3):
d
¼171.53, 170.38, 155.42,
ꢀ
N.Y. Acad. Sci. 2000, 899, 399e402; (c) Johansson, L.; Gafvelin, G.; Arner, E. S. J.
Biochim. Biophys. Acta 2005, 1726, 1e13.
136.20, 129.05, 128.48, 126.93, 80.08, 54.79, 53.91, 52.22, 37.70,
36.02, 28.30 ppm HRMS (ESI) calcd for C36H50N4O10Se2 [MþNaþ]:
881.1755 m/z; observed: 881.1759 m/z.
12. (a) Sies, H. Oxidative Stress: Introductory Remarks; Academic: London, 1985; (b)
Sies, H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1058e1071.
13. Flohe, L.; Pryor, W. A. Free Radicals in Biology; Academic: New York, NY, 1982.
€
14. (a) Muller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem. Pharmacol. 1984, 33,
3235e3239; (b) Wendel, A.; Fausel, M.; Safayhi, H.; Tiegs, G.; Otter, R. Bio-
chem. Pharmacol. 1984, 33, 3241e3245; (c) Press, D. J.; Mercier, E. A.; Kuzma,
D.; Back, T. G. J. Org. Chem. 2008, 73, 4252e4255; (d) Bhabak, K. P.; Mugesh,
G. Chem.dEur. J. 2009, 15, 9846e9854; (e) Nascimento, V.; Alberto, E. E.;
Tondo, D. W.; Dambrowski, D.; Detty, M. R.; Nome, F.; Braga, A. L. J. Am.
Chem. Soc. 2012, 134, 138e141; (f) Prestes, A. de S.; Stefanello, S. T.; Salman,
S. M.; Pazini, A. M.; Schwab, R. S.; Braga, A. L.; Barbosa, N. B. de V.; Rocha, J.
B. T. Mol. Cell. Biochem. 2012, 365, 85e92.
Acknowledgements
We are grateful to the CAPES, CNPq, INCT-CMN and FAPERGS for
financial support. CAPES is also acknowledged for post-doc fel-
lowship for R.S.S.
15. (a) Alberto, E. E.; Soares, L. C.; Sudati, J. H.; Borges, A. C. A.; Rocha, J. B. T.; Braga,
A. L. Eur. J. Org. Chem. 2009, 4211e4214; (b) Braga, A. L.; Alberto, E. E.; Soares, L.
C.; Rocha, J. B. T.; Sudati, J. H.; Roos, D. H. Org. Biomol. Chem. 2009, 7, 43e45.
16. (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481e2495; (b) Sprout, C. M.;
Richmond, M. L.; Seto, C. T. J. Org. Chem. 2005, 70, 7408e7417; (c) Davie, E. A. C.;
Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759e5812; (d) Schwab,
Supplementary data
Electronic Supplementary data (ESI) available: experimental
procedures, details 1H and 13C NMR spectra and high resolution MS.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.08.082.
€
~
R. S.; Galetto, F. Z.; Azeredo, J. B.; Braga, A. L.; Ludtke, D. S.; Paixao, M. W. Tet-
rahedron Lett. 2008, 49, 5094e5097; (e) Rambo, R. S.; Schneider, P. H. Tetra-
hedron: Asymmetry 2010, 21, 2254e2257; (f) Schwab, R. S.; Soares, L. C.;
~
Dornelles, L.; Rodrigues, O. E. D.; Paixao, M. W.; Godoi, M.; Braga, A. L. Eur. J. Org.
Chem. 2010, 3574e3578.
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