Straightforward method for the synthesis of selenocysteine and selenocystine derivatives from L-serine methyl ester

Article abstract of DOI:10.1055/s-0030-1258188

A set of selenoamino acids has been efficiently synthesized under smooth conditions by a simple, flexible and modular strategy. In this method, O-mesylated l-serine methyl ester is generated in situ and directly substituted with various selenolate anions

Full text of DOI:10.1055/s-0030-1258188

PAPER
3131
Straightforward Method for the Synthesis of Selenocysteine and Selenocystine
Derivatives from L-Serine Methyl Ester
S
elenocysteine and
n
Selenocysti
t
ne
D
er
o
ivatives from
n
L
-Serine Me
i
thyl
E
o
ste
r
L. Braga,*a Ludger A. Wessjohann,b Paulo S. Taube,a Fábio Z. Galetto,a,c Fabiano M. de Andradec
a
b
c
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-970, Brazil
Leibniz Institute of Plant Biochemistry, Bioorganic Chemistry, Weinberg 3, 06120 Halle, Germany
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Fax +55(48)37216850; E-mail: albraga@qmc.ufsc.br
Received 8 March 2010; revised 12 May 2010
gates.11 Due to the great importance of Sec and its
derivatives, many research groups have focused on their
synthesis. Initial attempts were of limited success. Most
strategies described involve the use of O-tosylated L-
Abstract: A set of selenoamino acids has been efficiently synthe-
sized under smooth conditions by a simple, flexible and modular
strategy. In this method, O-mesylated L-serine methyl ester is gen-
erated in situ and directly substituted with various selenolate anions
to afford selenocysteine, selenolanthionine, and selenocystine de- serine12 or b-halogenated alanine13 derivatives. Although
rivatives in good yields. Also, a tellurocysteine derivative can be
these compounds have been key intermediates for the as-
obtained by this method.
sembly of Sec derivatives, they also impose some prob-
Key words: organoselenium, selenoamino acids, selenocysteine,
selenocystine, tellurocysteine
lems, such as: (i) the O-tosylation of L-serine derivatives,
also required in several methods for the synthesis of b-ha-
logenated alanines, easily leads to the formation of dehy-
droalanine derivatives;13c and (ii) these reactive
Organoselenium compounds have been employed as very intermediates must be isolated before conversion into Sec
useful reagents in organic synthesis1 and as powerful derivatives.
ligands in asymmetric catalysis.2 The biological and me-
An alternative strategy to overcome this problem is the
dicinal role of selenium and organoselenium compounds
use of ring-opening reactions of different types of N- and/
or O-based heterocycle with selenolate anions. Several re-
has also been widely described.3
In this context, selenoamino acids are important due to ports describe the use of aziridines,14 b-lactones,10a,15 ox-
their potential biological activity, for example, in protect- azolines,16 and oxazolidinones.17 However, most of these
ing against neurodegenerative diseases, such as Parkin- approaches are not readily adapted to the preparation of
son’s and Alzheimer’s diseases.4 In recent years, interest orthogonally protected selenocysteine derivatives.18
in selenoamino acids, particularly selenocysteine (Sec or Therefore, it remains a challenge to develop novel syn-
U, 21st natural amino acid) and their derivatives has in- thetic methods that can permit the introduction of seleni-
creased considerably, due to a number of unique proper- um into optically active amino acids without racemization
ties exhibited by these compounds.5 Selenium’s or elimination, and with amino acid protective groups, for
biological effect is expressed by several selenoenzymes use as ready building blocks for the synthesis of sele-
including glutathione peroxidase (GPx),6 iodothyronine nopeptides and their derivatives.
deiodinase (ID),7 and thioredoxin reductase (TrxR).8
In the course of our increasing interest in the preparation
In terms of synthetic studies, selenoamino acids are build- of chiral organoselenium compounds and selenopeptides
ing blocks for the synthesis of selenium-containing pep- with potential biological activity,19 we have developed the
tides and proteins9 and serve as convenient precursors of straightforward method of synthesis described here. In
dehydroamino acids,10 which are useful electrophilic han- this approach (Scheme 1), the O-mesylated L-serine inter-
dles for the chemoselective preparation of peptide conju- mediate is generated in situ and directly substituted with
O
O
O
O
1) MsCl, Et3N
2) Li2Sen
1) MsCl, Et3N
HO
OMe
RY
OMe
MeO
Se
OMe
NHBoc
2) R2Y2, NaBH4
n
HN
HN
NHBoc
PG
PG
1a–c
4, n = 1, selenolanthionine 55%
5, n = 2, selenocystine 74%
2, Y = Se, 26–83%
3, Y = Te, 32%
PG = Boc, Cbz, Fmoc
Scheme 1 General method for the synthesis of Se- or Te-containing amino acids
SYNTHESIS 2010, No. 18, pp 3131–3137
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258188; Art ID: M01710SS
© Georg Thieme Verlag Stuttgart · New York

3132
A. L. Braga et al.
PAPER
various selenolate anions, providing a small library of reactions using Se-potassium 4-methylselenobenzoic acid
structurally diverse Sec derivatives. Prior to this report, salt were carried out: one under the standard conditions
Salvatore and co-workers described the use of the same and the other with the addition of one equivalent of 18-
intermediate in the synthesis of Se-phenyl-L-selenocys- crown-6 ether, affording the desired product in 54% and
teine.20 However, in this case the O-mesylated L-serine 67% yields, respectively (entry 7). A flexible synthetic
methyl ester needed to be isolated before use and cesium route should also allow different N-protecting groups in
bases were required.
the L-serine methyl ester. This flexibility was shown by
synthesizing N-Cbz-Se-phenyl-L-selenocysteine 2h and
N-Fmoc-Se-phenyl-L-selenocysteine 2i in 50% and 35%
yields, respectively (entries 8 and 9).
To allow direct comparison with the previous study, the
best conditions were examined for the synthesis of pro-
tected Se-Ph-Sec 2a (Table 1). The best manner to gener-
ate the selenium nucleophile and the most appropriate Additionally, the synthesis of a tellurocysteine derivative
solvent, base, and amount of base were evaluated. After 3 was achieved. Although compound 3 was obtained in a
selection of the best conditions (entry 3) the method was quite modest yield (entry 10), it is important to emphasize
applied to a broader range of diselenides and N-protected the instability of these compounds. Considering this, the
L-serine methyl ester derivatives 1, in order to evaluate the route constitutes an attractive option for the preparation of
scope and limitations of the reaction procedure (Table 2). further tellurocysteine derivatives in the future in only one
step.
A series of Sec derivatives could be synthesized in a
straightforward manner allowing some interesting struc- For comparison, reactions starting from the isolated O-
tural diversity. To examine the influence of different elec- mesylated L-serines were also performed. The overall
tronic properties on the selenolate anions, some yields for these transformations are given in Table 2. No-
substituted diaryl diselenides were used and the results tably, in all cases, better yields were observed when the
were very encouraging with good yields being obtained in new one-pot process was employed (cf. entries 1–10).
all cases (entries 2 and 3).
Table 1 Optimization of Reaction Conditions for the Synthesis of
Sec Derivative 3a
Table 2 Synthesis of Sec Derivatives 2a–i and Tellurocysteine De-
rivative 3
O
O
O
O
1) MsCl, base, solvent
0 °C, 20 min
1) MsCl, Et3N, THF
0 °C, 20 min
HO
OMe
RY
OMe
PhSe
OMe
Boc
HO
OMe
Boc
2) RYYR, NaBH4
THF–EtOH (3:1)
2) PhSe–, 12 h, r.t.
HN
HN
HN
HN
PG
PG
1a–c
2a–i, 3
1a
2a
Entry PhSe–
Base
(equiv)
Solvent Isolated
yield (%)
Entry RY
Cpd 1, PG Product Yield (%)
One-pota Two-stepb
a
1
2
(PhSe)2, NaBH4
pyridine (1.2)
THF
28
35
80
44
1
2
3
4
5
6
7
PhSe
1a, Boc
1a, Boc
1a, Boc
1a, Boc
1a, Boc
2a
2b
2c
2d
2e
2f
80
76
83
55
73
50
68
64
70
48
62
43
a
a
a
a
a
a
(PhSe)2, NaBH4
(PhSe)2, NaBH4
(PhSe)2, NaBH4
(PhSe)2, NaBH4
(PhSe)2, NaBH4
(PhSe)2, NaBH4
i-Pr2NEt (1.2) THF
4-MeC6H4Se
4-ClC6H4Se
EtSe
3
Et3N (1.2)
Et3N (2.4)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
THF
THF
4
5
CH2Cl2 48
BnSe
6
Et2O
DMF
THF
THF
THF
53
12
29
36
15
4-MeOC6H4CH2Se 1a, Boc
4-MeC6H4COSe
1a, Boc
2g
45, (54)c, 33
[67]d
7
8
(PhSe)2, LiBEt3H
(PhSe)2, BuLi
(PhSe)2, Na
8
9
PhSe
PhSe
PhTe
1b, Cbz
2h
50
35
32
41
26
27
9
1c, Fmoc 2i
1a, Boc
10
10
3
a In THF–EtOH (3:1).
a Isolated yield of the corresponding product following the one-pot
procedure.
The reaction also was performed with dialkyl diselenides
as the selenide source, furnishing the products 2d–g in
moderate to good yields (entries 4–7).
b Yields corresponding to the two-step procedure with isolated O-me-
sylated L-serine derivatives.
c Yield obtained when 4-MeC6H4COSeK was used as a nucleophilic
source of selenium, NaBH4 was omitted.
In addition, the selenoester 2g could be prepared using the
corresponding selenoacid potassium salt21 instead of di-
selenide, omitting the reducing agent. In this context, two
d 4-MeC6H4COSeK was used as a nucleophilic source of selenium in
the presence of 18-crown-6 ether (1 equiv), NaBH4 was omitted.
Synthesis 2010, No. 18, 3131–3137 © Thieme Stuttgart · New York

PAPER
Selenocysteine and Selenocystine Derivatives from L-Serine Methyl Ester
3133
O
O
O
L-serine intermediate was reacted with lithium selenide or
lithium diselenide as nucleophiles, which are readily ac-
cessible by addition of the appropriate amounts of Super
Hydride (1 M soln in THF) to gray, powdered selenium.23
The selenolanthionine derivative 4 was formed in satis-
factory yield (55%), whereas the selenocystine derivative
5 was obtained in quite good yield (74%).
1) MsCl, Et3N
HO
HN
OMe
MeO
Se
OMe
Boc
2) Se0/LiEt3BH (1:2)
THF
HN
HN
Boc
Boc
4 55%
1a
1) MsCl, Et3N
2) Se0/LiEt3BH (1:1)
THF
In a further extension, the Sec derivatives 2a and 2f were
employed as building blocks for the synthesis of the sele-
nopeptides 6a–c (Scheme 3). By the use of appropriate
conditions, compound 2a could be deprotected selective-
ly, allowing the peptide coupling to its amino or carboxy-
lic acid moiety. Peptide 6c was prepared by the coupling
between the Sec derivative 2f and N-Boc-proline. This
compound is a key intermediate in the synthesis of an or-
ganocatalyst developed in our group.24
Boc
NH
O
Se
Se
OMe
MeO
HN
O
Boc
5 74%
Scheme 2 One-pot synthesis of selenolanthionine 4 and seleno-
cystine 5 derivatives from L-serine methyl ester
Selenoester 2g can also serve as a precursor for the syn-
thesis of selenolanthionine 4 and selenocystine 5. As de-
picted in Scheme 4, the 4-methylbenzoyl-selenium
protecting group21 can be removed with cesium carbonate
and piperazine in dry N,N-dimethylformamide, with the
generation of nucleophilic selenium species. As shown in
path I, nucleophilic attack onto an appropriate electro-
phile, like O-mesylated L-serine, is an option. Another al-
ternative is the oxidation of intermediate A (path II) to
form 5, a possibility that also can be applied to crosslink
or macrocyclize peptides via internal Se or Se-Se bridges.
In general, 2g can constitute an interesting building block
for the synthesis of selenocysteine containing peptides.9c
It is worth noting that all products were obtained without
loss of optical purity. This was established by comparison
of the optical rotation analytical data obtained for the
compounds with data reported in the literature.14b
In contrast to the tellurocysteine, all Sec derivatives syn-
thesized by this route have high stability. Some of them
are obtained orthogonally protected18 and can be used di-
rectly for the synthesis of a variety of selenopeptides. As
an example, N-Boc-Se-phenylselenocysteine derivative
2a (Table 2, entry 1) and the Se-4-methoxybenzyl-pro-
tected amino acid derivative 2f (entry 6) have been used
as precursors for solid-phase peptide synthesis (SPPS) of
selenocysteine-containing peptides.10b Compound 2f al-
lows the incorporation of free selenocysteine into pep-
tides,22 whereas 2a is used for the mild oxidative
formation of dehydroalanines.10
In summary, a simple efficient and broadly applicable
general method for the preparation of Sec derivatives
from readily available and inexpensive starting materials
is reported. Features of the present method include the fol-
lowing: (i) selenoamino acids were obtained in a one-pot
process using easily accessible starting materials and
smooth conditions; (ii) the handling of O-activated L-
serine intermediates is avoided; (iii) a great improvement
Additionally, selenolanthionine 4 and selenocystine 5 de-
rivatives were synthesized (Scheme 2). The O-mesylated
SePh
O
1) TFA, CH2Cl2
O
O
2) NMM, ClCO2Et
O
PhSe
OMe
Boc
BnO
N
O
O
H
HN
NHBoc
OMe
BnO
OH
2a
6a 83%
NHBoc
O
O
1) LiOH, H2O
2) NMM, ClCO2Et
OMe
PhSe
OMe
NHBoc
PhSe
N
H
O
HN
O
Boc
6b 89%
SeBn
HCl⋅H2N
OMe
2a
O
O
1) TFA, CH2Cl2
2) NMM, ClCO2Et
O
N
BnSe
OMe
Boc
H
O
N
OMe
HN
Boc
OH
2f
N
6c 79%
Boc
Scheme 3 Application of Sec derivatives 2a and 2f as building blocks in the synthesis of selenium-containing peptides
Synthesis 2010, No. 18, 3131–3137 © Thieme Stuttgart · New York

3134
A. L. Braga et al.
PAPER
intermediate A
O
O
O
Boc
O
NH
air, 3 h, [O]
path II
Cs2CO3, piperazine
DMF
Se
OMe
Se
OMe
Boc
Se
OMe
MeO
Se
HN
HN
2g
Boc
HN
O
Boc
5 38%
O
MsO
OMe
Boc
path I
HN
O
O
MeO
Se
OMe
Boc
HN
HN
Boc
4 45%
Scheme 4 Application of compound 2g as precursor for the synthesis of higher selenoamino acids
THF (1.5 mL) and EtOH (0.5 mL) and transferred to flask 1 contain-
ing the O-mesyl-L-serine methyl ester intermediate. The resulting
soln was stirred at r.t. for 12 h. The mixture was quenched with sat.
aq NH4Cl soln and extracted with CH2Cl2 (3 × 30 mL). The com-
bined organic fractions were collected, dried (MgSO4), and filtered.
The solvent was removed in vacuo yielding the crude products
2a–i and 3, which were purified by flash column chromatography.
in the overall yields is achieved compared to the nondirect
processes; and (iv) orthogonally protected, enantiopure
Sec derivatives are obtained. Additionally, the method
was easily adapted for the synthesis of a tellurocysteine
derivative, albeit in lower yield forming an unstable prod-
uct. Further improvements and extensions of the present
method that allow better synthesis of convenient Se-pro-
tected Sec derivatives (such as 2g), and their application
in the synthesis of non-natural selenium containing pep-
tides, are currently in progress in our laboratories.
Selenolanthionine Derivative 4; Typical Procedure
In a 25-mL round-bottomed flask (flask 1), under an argon atmo-
sphere, a soln of N-Boc-L-serine methyl ester 1a (438 mg, 2.0
mmol) and Et3N (207 mg, 2.4 mmol) in THF (5 mL) was cooled to
0 °C. Then, MsCl (229 mg, 2.0 mmol) was added dropwise. The
mixture was stirred at 0 °C for 20 min. Li2Se was generated (flask
2) by reaction of gray, powdered Se (79 mg, 1 mmol) with 1 M
LiBEt3H in THF (2.1 mL, 2.1 mmol) in anhyd THF (5 mL). The
suspension was heated to reflux and stirred for at least 20 min and
then transferred via canula to flask 1. The resulting soln was stirred
at r.t. for 12 h. The mixture was quenched with sat. aq NH4Cl soln
and extracted with CH2Cl2 (3 × 30 mL). The combined organic frac-
tions were collected, dried (MgSO4), and filtered. The solvent was
removed in vacuo yielding crude product 4, which was purified by
flash column chromatography.
IR spectra (range 4000–600 cm–1, KBr or neat oils) were recorded
1
using a Nicolet Magna 550 spectrophotometer. H NMR were ob-
tained at 400 MHz on a Bruker DPX-400 NMR spectrometer;
CDCl3 solns referenced to the solvent peak. 13C NMR was obtained
at 100 MHz in CDCl3 solns referenced to the solvent peak. HRMS
(ESI) were measured at the Institut of Plant Biochemistry, Halle-
Saale, Germany, with a Bruker BioApex 70e FT-ICR (Bruker Dal-
tonics, Billerica, USA) instrument in ESI mode. Melting points
were measured on digital equipment MQ APF–302. Column chro-
matography was performed (Merck Silica Gel, 230–400 mesh) fol-
lowing the methods described by Still.25 TLC was performed using
Merck Silica Gel GF254 (0.25 mm) visualized with UV light or
stained with I2 vapor or acidic vanillin. Most reactions were moni-
tored by TLC for disappearance of starting material. Common sol-
vents were purified as follows: CH2Cl2 (refluxed under P2O5 and
distillation), THF (reflux under KOH and distilled under Na/ben-
zophenone), and EtOH (distilled under Mg/I2). The diselenides
were conveniently prepared from classical procedures.26 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 argon. Reagents and solvents were
handled using standard syringe techniques. Temperature at 0 °C
was maintained by use of an ice bath.
Selenocystine Derivative 5
Following in principle the procedure for compound 4, in this case,
Li2Se2 was generated (flask 2) by reaction of gray, powdered Se (79
mg, 1 mmol) with 1 M LiBEt3H in THF (1.0 mL, 1.0 mmol) in an-
hyd THF (5 mL).
Methyl N-(tert-Butoxycarbonyl)-Se-phenyl-L-selenocysteinate
(2a)
Yellow oil.
[a]D20 +67 (c 1, CH2Cl2).
IR: 3360, 2973, 1709, 1494, 1153 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56–7.50 (m, 2 H, Ph), 7.26–7.21
(m, 3 H, Ph), 5.40 (br s, 1 H, NH), 4.72–4.55 (m, 1 H, CH), 3.50 (s,
3 H, OCH3), 3.36–3.27 (m, 2 H, CH2), 1.41 (s, 9 H, CMe3).
Selenocysteine Derivatives 2a–i and Tellurocysteine Derivative
3; General Procedure
In a 25-mL round-bottomed flask (flask 1), under an argon atmo-
sphere, a soln of N-protected L-serine methyl ester 1a–c (2.0 mmol)
and Et3N (207 mg, 2.4 mmol) in THF (5 mL) was cooled to 0 °C.
Then MsCl (229 mg, 2.0 mmol) was added dropwise. The mixture
was stirred at 0 °C for 20 min. The chalcogenide anion was gener-
ated in flask 2 by reaction of the corresponding diorganyl dichalco-
genide (1.0 mmol) with NaBH4 (95 mg, 2.5 mmol) in a mixture of
13C NMR (100 MHz, CDCl3): d = 170.93 (CO2), 154.80 (HNCO),
135.67 (CPh), 133.55 (m-CPh), 128.97 (o-CPh), 127.37 (p-CPh), 79.85
(C), 53.22 (CH), 52.05 (OCH3), 30.41 (CH2), 28.11 (CMe3).
HRMS (EI): m/z [M + Na]+ calcd for C15H21NNaO4Se: 382.0528;
found: 382.0527.
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Selenocysteine and Selenocystine Derivatives from L-Serine Methyl Ester
3135
Methyl N-(tert-Butoxycarbonyl)-Se-(4-methylphenyl)-L-seleno-
cysteinate (2b)
Methyl N-(tert-Butoxycarbonyl)-Se-(4-methoxybenzyl)-L-sele-
nocysteinate (2f)
Yellow oil.
Yellow oil.
[a]D20 +44 (c 1, CH2Cl2).
IR: 3368, 2977, 1712, 1490, 159 cm–1.
[a]D20 +21 (c 1, CH2Cl2).
IR: 3366, 2977, 1712, 1510, 1158 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.43 (d, J = 8.0 Hz, 2 H, Ph), 7.06
(d, J = 8.0 Hz, 2 H, Ph), 5.35 (br s, 1 H, NH), 4.68–4.58 (m, 1 H,
CH), 3.52 (s, 3 H, OCH3), 3.31–3.21 (m, 2 H, CH2), 2.30 (s, 3 H,
C6H4CH3), 1.41 (s, 9 H, CMe3).
1H NMR (400 MHz, CDCl3): d = 7.23 (d, J = 8.5 Hz, 2 H, Ph), 6.82
(d, J = 8.5 Hz, 2 H, Ph), 5.32 (br s, 1 H, NH), 4.65–4.55 (m, 1 H,
CH), 3.78 (s, 3 H, C6H4OCH3), 3.76 (s, 2 H, CH2Ph), 3.74 (s, 3 H,
OCH3), 2.96–2.82 (m, 2 H, CH2Se), 1.45 (s, 9 H, CMe3).
13C NMR (100 MHz, CDCl3): d = 171.05 (CO2), 154.83 (HNCO),
138.99 (p-CPh), 136.11 (CPh), 134.03 (o-CPh), 129.88 (m-CPh), 79.82
(C), 53.29 (CH), 52.08 (OCH3), 30.67 (CH2), 28.15 (CMe3), 20.94
(CH3Ph).
13C NMR (100 MHz, CDCl3): d = 171.56 (CO2), 158.52 (p-CPh),
155.01 (HNCO), 130.54 (CPh), 129.89 (o-CPh), 113.94 (m-CPh),
80.00 (C), 55.15 (C6H4OCH3), 53.37 (CH), 52.37 (OCH3), 28.01
(CMe3), 27.78 (CH2Se), 27.31 (CH2Ph).
HRMS (EI): m/z [M + Na]+ for C16H23NNaO4Se: 396.0684; found:
HRMS (EI): m/z [M + Na]+ for C17H25NNaO5Se: 426.0790; found:
396. 0682.
426.0791.
Methyl N-(tert-Butoxycarbonyl)-Se-(4-chlorophenyl)-L-seleno-
cysteinate (2c)
Yellow solid; mp 64.2–66.6 °C.
Methyl N-(tert-Butoxycarbonyl)-Se-(4-methylbenzoyl)-L-sele-
nocysteinate (2g)
Yellow solid; mp 98–99 °C.
[a]D20 +46 (c 1, CH2Cl2).
IR: 3365, 2981, 1704, 1499, 1162 cm–1.
[a]D20 +26 (c 1, CH2Cl2).
IR: 3343, 2981, 1741, 1690, 1607, 1529, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.48 (d, J = 8.2 Hz, 2 H, Ph), 7.25
(d, J = 8.2 Hz, 2 H, Ph), 5.39 (br s, 1 H, NH), 4.69–4.58 (m, 1 H,
CH), 3.56 (s, 3 H, OCH3), 3.38–3.21 (m, 2 H, CH2), 1.41 (s, 9 H,
CMe3).
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 8.2 Hz, 2 H, Ph), 7.25
(d, J = 8.2 Hz, 2 H, Ph), 5.34 (d, J = 7.6 Hz, 1 H, NH), 4.77–4.51
(m, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.60–3.36 (m, 2 H, CH2), 2.40
(s, 3 H, CH3Ph), 1.43 (s, 9 H, CMe3).
13C NMR (100 MHz, CDCl3): d = 170.81 (CO2), 154.67 (HNCO),
137.00 (p-CPh), 134.93 (o-CPh), 133.66 (CPh), 129.21 (m-CPh), 79.89
(C), 53.31 (CH), 52.15 (OCH3), 30.71 (CH2), 28.08 (CMe3).
HRMS (EI): m/z [M + Na]+ for C15H20ClNNaO4Se: 416.0138;
found: 416.0133.
13C NMR (100 MHz, CDCl3): d = 192.75 (COPh), 171.36 (CO2),
155.11 (HNC=O), 144.97 (CPh), 135.83 (CPh), 129.46 (o-CPhCO),
127.41 (m-CPhCO), 80.04 (C), 53.51 (OCH3), 52.56 (CH), 28.21
(CMe3), 27.15 (C6H4CH3), 21.67 (CH2).
HRMS (EI): m/z [M + Na]+ for C17H23NNaO5Se: 424.0639; found:
424.0634.
Methyl N-(tert-Butoxycarbonyl)-Se-ethyl-L-selenocysteinate
(2d)
Methyl N-(Benzyloxycarbonyl)-Se-phenyl-L-selenocysteinate
Yellow oil.
(2h)
Yellow oil.
[a]D20 +49 (c 1, CH2Cl2).
IR: 3340, 3033, 1705, 1506, 1207 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54–7.46 (m, 2 H, Ph), 7.38–7.20
(m, 8 H, Ph), 5.66 (br s, 1 H, NH), 5.09 (s, 2 H, CH2Cbz), 4.76–4.65
(m, 1 H, CH), 3.49 (s, 3 H, OCH3), 3.40–3.25 (m, 2 H, CH2).
[a]D20 +31 (c 1, CH2Cl2).
IR: 3369, 2977, 1712, 1499, 1159 cm–1.
1H NRM (400 MHz, CDCl3): d = 5.40 (br s, 1 H, NH), 4.64–4.56
(m, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.04–2.95 (m, 2 H, CH2), 2.59
(q, J = 7.6 Hz, 2 H, CH2CH3), 1.45 (s, 9 H, CMe3), 1.38 (t, J = 7.6
Hz, 3 H, CH3CH2).
13C NMR (100 MHz, CDCl3): d = 171.52 (CO2), 154.97 (HNCO),
79.91 (C), 53.38 (CH), 52.30 (OCH3), 28.18 (CMe3), 25.24 (CH2),
18.10 (CH2CH3), 15.50 (CH3CH2).
HRMS (EI): m/z [M + Na]+ for C11H21NNaO4Se: 334.0528; found:
334.0533.
13C NMR (100 MHz, CDCl3): d = 170.61 (CO2), 155.41 (HNCO),
136.05 (CPh), 133.61 (o-CPh), 129.00 (CPh), 128.60 (p-CPh), 128.02
(p-CPh), 127.96 (m-CPh), 127.91 (m-CPh), 127.47 (o-CPh), 67.13
(CH2Ph), 53.64 (CH), 52.20 (OCH3), 30.16 (CH2).
HRMS (EI): m/z [M + Na]+ for C18H19NNaO4Se: 416.0371; found:
416.0369.
Methyl Se-Benzyl-N-(tert-butoxycarbonyl)-L-selenocysteinate
(2e)
Methyl N-(Fluoren-9-ylmethoxycarbonyl)-Se-phenyl-L-seleno-
Yellow oil.
cysteinate (2i)
Yellow oil.
[a]D20 +19 (c 1, CH2Cl2).
IR: 3392, 3065, 1705, 1437, 1206 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 7.5 Hz, 2 H, Ph), 7.63–
7.50 (m, 5 H, Ph), 7.42–7.20 (m, 6 H, Ph), 5.65 (br s, 1 H, NH),
4.75–4.65 (m, 1 H, CH), 4.32 (d, J = 6.8 Hz, 1 H, CH2-Fmoc), 4.17
(t, J = 6.8 Hz, 1 H, CH2-Fmoc), 4.08 (t, J = 6.2 Hz, 1 H, CH-Fmoc),
3.50 (s, 3 H, OCH3), 3.41–3.25 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 170.69 (CO2), 155.47 (HNCO),
143.64 (Ph), 141.19 (Ph), 133.67 (o-CPh), 128.64 (CPh), 127.63 (m-
CPh), 127.42 (Ph), 126.98 (p-CPh), 126.93 (Ph), 125.04 (Ph), 119.90
[a]D20 +13 (c 1, CH2Cl2).
IR: 3370, 2977, 1709, 1494, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.18 (m, 5 H, Ph), 5.30 (br
s, 1 H, NH), 4.66–4.54 (m, 1 H, CH), 3.79 (s, 2 H, CH2Ph), 3.73 (s,
3 H, OCH3), 2.97–2.82 (m, 2 H, CH2Se), 1.45 (s, 9 H, CMe3).
13C NMR (100 MHz, CDCl3): d = 171.53 (CO2), 155.01 (HNCO),
138.64 (CPh), 128.80 (o-CPh), 128.49 (m-CPh), 126.85 (p-CPh), 80.03
(C), 53.37 (CH), 52.39 (OCH3), 28.23 (CMe3), 27.80 (CH2Ph),
25.81 (CH2).
HRMS (EI): m/z [M + Na]+ for C16H23NNaO4Se: 396.0684; found:
396. 0686.
Synthesis 2010, No. 18, 3131–3137 © Thieme Stuttgart · New York

3136
A. L. Braga et al.
PAPER
Methyl [N-(tert-Butoxycarbonyl)-Se-phenyl-L-selenocys-
(Ph), 67.10 (CH2-Fmoc), 65.03 (CH), 53.74 (CH-Fmoc), 47.00
(OCH3), 30.17 (CH2).
teinyl]glycinate (6b)
Yield: 89%.
HRMS (EI): m/z [M + Na]+ for C25H23NNaO4Se: 504.0684; found:
504.0684.
1H NMR (400 MHz, CDCl3): d = 7.73–7.26 (m, 5 H), 4.67–4.56 (s,
1 H), 4.13 (s, 2 H), 3.76 (s, 3 H), 2.12–1.87 (m, 2 H), 1.26 (s, 9 H).
Methyl N-(tert-Butoxycarbonyl)-Te-phenyl-L-tellurocysteinate
(3)
Methyl N-[N-(tert-Butoxycarbonyl)-l-prolyl]-Se-benzyl-L-sele-
Yellow oil.
nocysteinate (6c)
Yield: 79%.
[a]D20 +19 (c 1, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.29–7.19 (m, 5 H), 4.87–4.78 (m,
1 H), 4.33–4.24 (m, 1 H), 3.79–3.77 (m, 2 H), 3.72 (s, 3 H), 3.45–
3.36 (m, 2 H), 3.00–2.81 (m, 2 H), 2.30–1.85 (m, 4 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.00, 170.86, 155.01, 138.66,
128.78, 128.40, 126.76, 80.38, 61.46, 52.18, 51.99, 46.93, 29.22,
28.28, 27.72, 25.71, 24.02.
IR: 3418, 2985, 1712, 1508, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.88–7.34 (m, 2 H, Ph), 7.38–7.15
(m, 3 H, Ph), 5.37 (br s, 1 H, NH), 4.80–4.65 (m, 1 H, CH), 3.51 (s,
3 H, OCH3), 3.33–3.23 (m, 2 H, CH2), 1.41 (s, 9 H, CMe3).
13C NMR (100 MHz, CDCl3): d = 171.53 (CO2), 152.45 (HNCO),
137.54 (o-CPh), 129.18 (m-CPh), 127.98 (p-CPh), 110.83 (CPh), 80.59
(C), 52.71 (CH), 52.19 (OCH3), 28.15 (CH2), 11.48 (CMe3).
Methyl Se-Phenyl-L-cysteinate
Yellow solid; yield: 100%; mp 58–59.5 °C.
HRMS (EI): m/z [M + Na]+ for C15H21NNaO4Te: 432.0397; found:
[a]D20 –4 (c 1, CH2Cl2).
432.0425.
IR: 3442, 2360, 1670, 1570, 1211 cm–1.
Dimethyl N,N¢-Bis(tert-butoxycarbonyl)selenolanthionine (4)
Yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.56–7.53 (m, 2 H), 7.27–7.24 (m,
3 H), 3.72–3.69 (m, 1 H), 3.57 (s, 3 H), 3.27 (dd, J1 = 12.4 Hz, J2 =
6.8Hz, 1 H), 3.17 (dd, J1 = 12.4 Hz, J2 = 6.8 Hz, 1 H), 1.83 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 173.96, 133.12, 128.88, 128.86,
127.15, 53.82, 51.81, 32.96.
HRMS (EI): m/z [M + H]+ for C10H14NO2Se: 260.0184; found:
260.020.
[a]D20 +19 (c 1, CH2Cl2).
IR: 3366, 2977, 2931, 1715, 1512, 1166 cm–1.
1H NRM (400 MHz, CDCl3): d = 5.47 (d, 2 H, NH), 4.63–4.62 (m,
2 H, CH), 3.77 (s, 6 H, OCH3), 3.44–3.29 (m, 4 H, CH2), 1.45 (s, 18
H, CMe3).
13C NMR (100 MHz, CDCl3): d = 171.72 (CO2), 155.47 (HNCO),
80.69 (C), 54.13 (OCH3), 52.97 (CH), 32.66 (CH2), 28.68 (CMe3).
HRMS (EI): m/z [M + Na]+ for C18H32N2NaO8Se: 507.1216; found:
N-(tert-Butoxycarbonyl)-Se-phenyl-L-cysteine
Yellow solid; yield: 100%; mp 68–69 °C.
[a]D20 +3 (c 1, CH2Cl2).
507.1200.
IR: 3445, 3314, 2925, 2854, 1732, 1655, 1578, 1166 cm–1.
Dimethyl N,N¢-Bis(tert-butoxycarbonyl)-L-selenocystine (5)
Yellow solid; mp 36–38 °C.
1H NMR (400 MHz, CDCl3): d = 8.37 (s, 1 H), 7.56–7.53 (m, 2 H),
7.28–7.24 (m, 3 H), 5.35 (d, J = 6.8 Hz, 1 H), 4.66–4.65 (m, 1 H),
3.41–3.30 (m, 2 H), 1.40 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 174.65, 155.14, 133.55, 132.88,
131.44, 129.11, 80.24, 53.42, 30.19, 28.16.
HRMS (EI): m/z [M + Na]+ for C14H19NNaO4Se: 368.0372; found:
368.0369.
[a]D20 +15 (c 1, CH2Cl2).
IR: 3365, 2978, 1739, 1688, 1515, 1160 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.41 (s, 2 H, NH), 4.73–4.68 (m,
2 H, CH), 3.77 (s, 6 H, OCH3), 3.61–3.30 (m, 4 H, CH2), 1.46 (s, 18
H, CMe3).
13C NMR (100 MHz, CDCl3): d = 171.27 (CO2), 155.03 (HNCO),
80.30 (C), 53.71 (OMe), 52.59 (CH), 28.32 (CCH3), 25.27 (CH2).
Methyl Se-Benzyl-L-cysteinate
Yellow solid; yield: 90%; mp 72–74 °C.
HRMS (EI): m/z [M + Na]+ for C18H32N2NaO8Se2: 587.0387; found:
[a]D20 +10 (c 1, CH2Cl2).
587.0380.
IR: 3336, 3025, 1738, 1493, 1453, 1175 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.29–7.17 (m, 5 H), 3.78 (s, 2 H),
3.69 (s, 3 H), 3.64–3.58 (m, 1 H), 2.89–2.65 (m, 2 H), 1.77 (s, 2 H).
Methyl N-[O1-Benzyl-N-(tert-butoxycarbonyl)-L-glutam-5-yl]-
Se-phenyl-L-selenocysteinate (6a)
Yield: 83%.
IR: 3360, 2976, 2947, 2855, 1792, 1746, 1717, 1518, 1176, 1157
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56–7.22 (m, 10 H), 5.20 (s, 2 H),
4.39–4.03 (m, 2 H), 3.51 (s, 3 H), 2.64–2.19 (m, 4 H), 2.08–1.97 (m,
2 H), 1.43 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 175.95, 173.53, 171.38, 155.89,
149.44, 135.26, 134.00, 129.35, 128.92, 128.75, 127.82, 83.87,
67.58, 59.16, 52.57, 32.16, 30.68, 29.92, 28.01, 22.93, 21.75.
13C NMR (100 MHz, CDCl3): d = 173.84, 138.48, 128.30, 127.89,
126.83, 53.90, 51.50, 28.30, 27.09, HRMS (EI): m/z [M + H]+ for
C11H16NO2Se: 274.0341; found: 274.0343.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
HRMS (EI): m/z [M + Na]+ for C27H34N2NaO7Se: 601.14234;
found: 601.1428.
The authors gratefully acknowledge CNPq for financial support and
a fellowship to P. S. Taube. A. L. Braga, L. A. Wessjohann, F. Z.
Galetto also acknowledge CAPES and DAAD for travel grants as
part of a PROBRAL project.
Synthesis 2010, No. 18, 3131–3137 © Thieme Stuttgart · New York

PAPER
Selenocysteine and Selenocystine Derivatives from L-Serine Methyl Ester
3137
C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127,
11159.
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Synthesis 2010, No. 18, 3131–3137 © Thieme Stuttgart · New York