Stereoselective synthesis of Boc-protected L-seleno- and tellurolanthionine, L-seleno- and tellurocystine and derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.11.101

Optically active seleno- and telluro amino acids can be synthesized from serine via its β-lactone with selenides and tellurides under overall retention of the serine stereochemistry. Boc-protected l-selenolanthionine, l-tellurolanthionine, l-selenocystine

Full text of DOI:10.1016/j.tetlet.2005.11.101

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1019–1021
Stereoselective synthesis of Boc-protected L-seleno- and
tellurolanthionine, L-seleno- and tellurocystine and derivatives
a
b
c
b
´
Alex Schneider, Oscar E. D. Rodrigues, Marcio W. Paixao, Helmoz R. Appelt,
˜
Antonio L. Bragac and Ludger A. Wessjohanna,*
aLeibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
bCentro Universita´rio Franciscano—UNIFRA, 97010-032, Santa Maria, RS, Brazil
cDepartamento de Quı´mica, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
Received 14 October 2005; revised 17 November 2005; accepted 21 November 2005
Available online 20 December 2005
Abstract—Optically active seleno- and telluro amino acids can be synthesized from serine via its b-lactone with selenides and tellu-
rides under overall retention of the serine stereochemistry. Boc-protected L-selenolanthionine, L-tellurolanthionine, L-selenocystine,
L-tellurocystine and L-tellurocysteine derivatives can be obtained in good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In biochemistry, organochalcogenides gain increasing
interest beyond the obvious importance of the proteino-
genic sulfur amino acids cyst(e)ine and methionine, and
more recently selenocysteine.1,2 In recent years, it was
shown that various selenium and tellurium compounds
can function as antioxidants, chemoprotectors, apopto-
sis inducers, and effective chemopreventors in a variety
of organs, including brain, mammary gland, liver, skin,
colon, lung, and prostate.3–5 In comparison to sulfur
compounds, the corresponding selenium analogues were
more effective in cancer prevention.6,7 Tellurium com-
pounds were shown to be much more effective antioxi-
dants and chemoprotectors than their corresponding
selenium and sulfur analogues.5,8
1 with R = H), selenocystine, selenolanthionine (2),
and selenocysteine-Se-conjugates [(R)Sec, 1]; and the
analogous tellurium compounds (3 and 4). Especially,
the latter ones are almost unexplored with respect to
both synthesis and biological properties.
Selenocysteine (Sec) usually is considered the 21st natu-
ral amino acid. It is encoded in DNA and has a special
function in a number of naturally occurring proteins.2,9
Vermeulen and co-workers10 reported that tellurocys-
teine Te-conjugates in particular Te-Phenyl-L-tellurocys-
teine (cf. compound 8) might be an interesting prodrug
for the formation of biologically active tellurols.
Despite the increasing importance of selenium and tellu-
rium analogues of sulfur amino acids, very few methods
are available for their production. The synthesis is com-
plicated by facile decomposition, especially by oxidation
to form, for example, higher oligochalcogenides (e.g.,
The most important group of selenium and tellurium
compounds with interesting biological properties is
derived from the higher chalcogenide cysteine analogues
and derivatives (Fig. 1), such as selenocysteine (Sec, U,
Figure 1. Chemical structures of selenocysteine 1 (Sec, U; R = H), Sec-conjugates 1 (R 5 H), like Se-lanthionine 2, tellurocysteine 3 (Tec, R = H)
and Tec-conjugates 3 (R 5 H), like Te-lanthionine 4.
*
Corresponding author. Tel.: +49 345 5582 1301; fax: +49 345 5582 1309; e-mail: wessjohann@ipb-halle.de
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.101

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A. Schneider et al. / Tetrahedron Letters 47 (2006) 1019–1021
R-(Se)n-R) and Se- or Te-cystine. This constitutes prob-
lems if the unprotected form is required for further syn-
thesis, for example, of peptides. We wanted to develop
short syntheses of optically active N-t-Boc-protected L-
Se- and L-Te-cystine as ready precursors to the reduced
forms Sec and Tec, respectively, to Se- and Te-lanthio-
nine, and to Sec- and Tec-conjugates, which can be
deprotected on demand.
dures produce N-(t-Boc)-b-lactone in high yield—84%
from N-(t-Boc)-D-serine and 72% from N-(t-Boc)-L-
serine 5—and can be ring opened by nucleophiles to
form b-substituted a-amino acids.
In order to demonstrate the wider scope of this ring
opening reaction, we investigated the possibility of
transforming a serine b-lactone18 with several selenium
and tellurium anions to the corresponding seleno- and
tellurocysteine derivatives (Scheme 1). L-Selenolanthio-
nine 7a and L-tellurolanthionine 7b are readily pre-
pared using dilithium chalcogenides (Li2Se and Li2Te)
available from the reaction of elemental selenium or
tellurium with lithium triethyl-borohydride (super
hydride).19 Furthermore, using dilithium dichalcoge-
nides (Li2Se2 and Li2Te2), L-selenocystine 9a and L-tell-
urocystine 9b are obtained in good yields (Scheme 1).
For the preparation of tellurocysteine conjugates, for
example, 8, the monoaryl- and monoalkyl telluride
anions, produced by the reduction of the corresponding
ditellurides with sodium borohydride, can be employed
as nucleophiles. However, non-aromatic (R)-Tec-com-
pounds are very sensitive, especially Te-cystine and
Tec itself.
Previously reported syntheses of L-Se-cystine and
-lanthionine describe an overall yield of 55% and 41%,
respectively.11 Apart from the moderate yields, the use
of an excess of hydrogen selenide for the preparation
of one of the starting materials (sodium hydrogen sele-
nide) is highly impractical for labeling purposes and
with respect to safety. Another synthesis of selenocys-
teine and tellurocysteine is based on suitably protected
aziridine carboxylates,12 or b-haloalanines.13 For exam-
ple, for the latter approach Boc-protected serine methyl
ester was converted into iodoalanine methyl ester via its
tosylate and reacted with lithium diselenide or lithium
ditelluride to afford the protected selenocystine or tell-
urocystine derivatives, respectively. The overall yields
of deprotected L-selenocystine and L-tellurocystine from
Boc-protected serine methyl ester were 47% and 14%.
Unfortunately, the yields of this multistep synthesis do
not transfer to scale-up procedures. Van der Donk
and co-workers14 reported an alternative synthetic
route to selenocystine and Fmoc-Se-phenylselenocys-
teine with three orthogonal protecting groups for the
amino, carboxylate, and selenol function. The four-step
sequence provided doubly protected Sec in 61% yield
and N-protected (Ph)Sec in 37% overall yield on a 15 g
scale.
Thus, the most difficult task in the whole procedure is
the purification. Selenium compounds tend to contain
elemental selenium or mono-, di-, or oligoselenide
impurities. The non-aromatic Te compounds are air,
light, base, and electrophile sensitive and decompose
on prolonged exposure to silica. They can be cleaned
to some extent on RP-18 or similar material. Eventu-
ally, direct crystallization of the alkaline metal salts of
the telluro- and selenocysteine derivatives 7 and 9
proved best with respect to purity, at the same time
giving acceptable yields. Ph-Tec-compound 8 also can
be crystallized, but shows co-crystallization of di-
phenylditelluride. Free acids 7–9 (R = H) can be obtained
by acidification with hydrochloric acid and rapid
extraction.20
As part of our study program of higher organochalco-
genides,15 we decided to improve the synthetic route
to selenocysteine Se-conjugates and tellurocysteine Te-
conjugates with respect to the number of steps and
scale-up. Our synthetic strategy is based on a previously
reported similar method for the generation of the
unnatural amino acid (Se-phenyl)selenocysteine [(Ph)Sec]
by ring opening of Boc-L-serine b-lactone 6.16 Vederas
and co-workers reported an efficient synthesis of b-
lactones under Mitsunobu conditions.17 Both proce-
In summary, we have developed an efficient and versatile
synthesis of optically active seleno- and telluro-deriva-
tives of cysteine, cystine, and lanthionine from serine,
using simple reactions with good yields.
Scheme 1. Yields are for crystallized compounds (M = Li or Na). Acidification to pH ꢀ 2 with HCl provides free acids (R = H, limited stability).

A. Schneider et al. / Tetrahedron Letters 47 (2006) 1019–1021
1021
(100 mL) under argon, dimethylazodicarboxylate (3.57 g,
24.4 mmol) is added dropwise over 10 min. A solution of
N-(tert-butoxycarbonyl)-L-serine (5.0 g, 24.4 mmol) in
THF (100 mL) is added dropwise over 30 min. The
mixture is stirred at À78 ꢁC for 20 min before it is slowly
warmed to room temperature within 2.5 h. The solvent is
removed in vacuo, and the residual pale yellow syrup is
purified by flash column chromatography on silica
(hexane/ethyl acetate, 4:1) to give N-(tert-butoxycar-
bonyl)-L-serine b-lactone (2.02 g, 44%), a white solid after
recrystallization from (CH3OH/hexane): [a]D À24.7 (22 ꢁC,
c 0.5, CH3CN); 1H NMR (CDCl3, 399.9 MHz, ppm) d
1.46 (s, 3 · CH3), 4.38–4.50 (m, CHAHB), 5.11 (br m, CH),
5.25 (br m, NH); HRMS (ESI, MNa+) calcd for
C8H13NO4Na+ 210.0737, found 210.0738.
Acknowledgements
The authors thank CAPES and DAAD (German
Academic Exchange Service) for travel grants as part
of PROBRAL, DFG (We 1467.4-2), CNPq and
FAPERGS for financial support. Dr. J. Schmidt
and Dr. A. Porzel provided valuable help for the
characterization.
References and notes
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´
19. General procedure for t-Boc-protected L-seleno- and
tellurocystine 9a,9b (a), L-seleno- and tellurolanthionine
7a,7b (b), and phenyltellurocysteine 8 (c) salts. (a, b):
To a suspension of elemental selenium or tellurium
(a—1.1 mmol, b—0.55 mmol) in freshly distilled THF
(3 mL), under argon Super-hydride (1.1 mmol) is added.
(c): Diphenyl ditelluride (0.55 mmol) is dissolved in 3 mL
ethanol. To this NaBH4 (1.38 mmol) is added. (a–c): The
resulting solution is heated to reflux and stirred for 15 min
under argon. At room temperature, 6 mL of dry and
degassed THF solution of N-(t-Boc)-L-serine b-lactone
(1 mmol) is added dropwise over 10 min and stirred
overnight to ensure that the reaction is complete. The
solution can be filtered through a pad of reverse phase
silica gel (RP-18) in order to remove rests of elemental
selenium or tellurium. The product is crystallized from
chloroform/hexane. 7a: 1H NMR (CD3OD, 399.9 MHz,
ppm) d 1.45 (s, 3 · CH3), 2.93 (dd, J = 8.1, 12.7 Hz,
CHAHB), 3.07 (dd, J = 4.3, 12.7 Hz, CHACHB), 4.35 (br
m, CH); 13C NMR (CD3OD, 100.6 MHz, ppm) d 27.0,
28.7, 55.6, 80.7, 157.8, 174.4; HRMS (ESI, MÀLiÀ) m/z
calcd 455.0938, found 455.0940; 7b: HRMS (ESI, MÀLiÀ)
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1
m/z calcd 505.0835, found 505.0844; 8: H NMR (CDCl3,
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399.9 MHz, ppm) d 1.42 (s, 3 · CH3), 3.26 (dd, J = 5.8,
12.6 Hz, CHAHB), 3.34 (dd, J = 5.1, 12.6 Hz, CHACHB),
4.71 (br m, CH), 5.27 (d, J = 7.3, NH), 7.25 (br m, 3H, m,
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(CD3OD, 399.9 MHz, ppm) d 1.45 (s, 3 · CH3), 3.20
(dd, J = 9.1, 12.6 Hz, CHAHB), 3.44 (dd, J = 4.8, 12.6 Hz,
CHACHB), 4.40 (br m, CH); HRMS (ESI, MÀLiÀ) m/z
calcd 535.0103, found 535.0110; 9b: HRMS (ESI, MÀLiÀ)
m/z calcd 632.9880, found 632.9881.
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1
rapidly and strictly under argon. 7b: H NMR (pyridine-
d5, 499.8 MHz, ppm) d 1.51 (s, 3 · CH3), 3.54 (dd, J = 7.9,
12.0 Hz, CHAHB), 3.72 (dd, J = 5.6, 12.0 Hz, CHACHB),
5.21 (br m, CH), 8.22 (d, J = 8.2, NH); 9b: 1H
NMR (pyridine-d5, 499.8 MHz, ppm) d 1.53 (s, 3 · CH3),
3.98 (dd, J = 8.5, 11.4 Hz, CHAHB), 4.27 (dd, J = 6.1,
11.4 Hz, CHACHB), 5.12 (br m, CH), 8.31 (d, J = 7.6,
NH).
18. Preparation of N-(tert-butoxycarbonyl)-L-serine b-lactone
(6): To triphenylphosphine (6.40 g, 24.4 mmol), dried in
vacuo for 72 h over P2O5, at À78 ꢁC in anhydrous THF