Novel selenium-containing non-natural diamino acids

Article abstract of DOI:10.1016/j.tetlet.2006.12.096

The general synthesis of a new class of non-natural diamino acids, 2-amino-3-[(2′-aminoalkyl)seleno]propanoic acids, or Se-(aminoalkyl)selenocysteines, is reported. Under the conditions devised, enantiopure N-Boc-protected β-l-iodoamines, which are readil

Full text of DOI:10.1016/j.tetlet.2006.12.096

Tetrahedron Letters 48 (2007) 1425–1427
Novel selenium-containing non-natural diamino acidsI
Romualdo Caputo,* Stefania Capone, Marina Della Greca,
Luigi Longobardo and Gabriella Pinto
`
Dipartimento di Chimica Organica e Biochimica, Universita di Napoli Federico II, Via Cynthia 4, I-80126 Napoli, Italy
Received 21 November 2006; revised 12 December 2006; accepted 15 December 2006
Available online 20 December 2006
Abstract—The general synthesis of a new class of non-natural diamino acids, 2-amino-3-[(20-aminoalkyl)seleno]propanoic acids, or
Se-(aminoalkyl)selenocysteines, is reported. Under the conditions devised, enantiopure N-Boc-protected b-L-iodoamines, which are
readily generated from proteinogenic a-amino acids, were treated with the selenolate anion obtained from NaBH4 splitting of the
Se–Se bond in commercial L-selenocystine. The Se-alkylation products were enantiomerically pure and the reaction is high yielding
(92–98%), without any detectable traces of accompanying by-products.
Ó 2007 Elsevier Ltd. All rights reserved.
Selenium is an essential micronutrient for animals and
humans: to date, its bio-availability seems to depend
upon the naturally occurring selenium-containing amino
acids selenocysteine (Sec) and selenomethionine,
although other selenoamino acids, such as Se-methyl-
selenocysteine, selenohomocysteine and selenocystathio-
nine, are also involved in selenoamino acid metabolic
pathways.1
Exciting areas of research using chiral organoselenium
compounds also include catalytic asymmetric reactions
to provide enantiomerically enriched compounds, repre-
senting a new trend in this field of organometallic
chemistry. In this context, chiral selenide- and diselenide-
containing ligands have been employed as useful cata-
lysts in various asymmetric transformations including
enantioselective addition of diethylzinc to aldehydes,4,5
the 1,4-addition of Grignard reagents to enones,6 and
palladium-catalyzed asymmetric allylic substitution.7
In recent years, organoselenium chemistry has emerged
as an exceptional class of structures, due to its pivotal
role in the synthesis of a large number of biological com-
pounds and important therapeutic products ranging
from antiviral and anticancer agents to naturally occur-
ring food supplements.2
R
CO2H
HO2C
CO2H
NH2
Se
X
NH2
NH2
NH2
2
1
Simple organochalcogenide compounds have been
reported to display antioxidant activity in vitro and
in vivo. It has been suggested that the exploitation of
the redox activity of selenium, as in the case of tellu-
rium, could provide antioxidants of considerable
potency, which would be suitable tools in free radical
biology, as the scavengers of reactive oxidizing agents.3
a
, b
(X = S) (X = Se)
Here we report the synthesis of new enantiopure non-
natural diamino acids (1) containing selenium. They
represent a new family of chalcogenide diamino acids
paralleling their sulfurated analogues that we have
recently reported.8 The interest of both classes of such
novel non-natural diamino acids depends essentially
upon their structural similarities with natural meso-lan-
thionine (2a), key-residue of lanthibiotic peptides and
meso-selenolanthionine (2b), respectively. Even more
interesting is their inclusion in peptides8 that performs
formal ‘bioconjugation’ processes,9,10 mimicking the
results of the alkylation, by proteinogenic a-amino acid
moieties, at the chalcogen atom of selenocysteines
(Sec), or cysteines (Cys) already present in peptide
Keywords: Organoselenium; Selenolanthionine; Selenocystine; b-Iodo-
amines; Diamino acids.
q Chiral aminoalkyl cation equivalents, 2.
*
Corresponding author. Tel.: +39 081 674117; fax: +39 081 674
102; e-mail: rocaputo@unina.it
Present address: Laboratorium fur Organische Chemie, ETH Zurich,
¨
¨
HCI Ho¨nggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich,
¨
Switzerland.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.096

1426
R. Caputo et al. / Tetrahedron Letters 48 (2007) 1425–1427
chains. An illustrative example of the use of N(Boc)-b-
iodoamines, obtained from aspartic and glutamic acids,
to alkylate a pre-existing cysteine in a solid-phase grow-
ing peptide was already reported.11
ily [as well as ‘CyX’ family for the sulfur-containing
terms].
The stereochemical integrity of the final products
1
was assessed by RP-HPLC, H and 13C NMR.
The synthesis of compounds 4a–c (Scheme 1) was
accomplished in a very simple, clean and high yielding
synthetic route starting from commercial L-selenocystine
and N(Boc)-b-L-iodoamines as Se-alkylation species.
The procedure reported for the synthesis of their sul-
fur-containing analogues8 could not be adapted, due
to the high tendency of L-selenocysteine to undergo oxi-
dation. Hence, L-selenocystine was refluxed with NaBH4
in dry EtOH, under argon atmosphere, to produce
in situ (R)-2-amino-2-carboxyethaneselenolate anion.
The formation of the latter could be observed by the dis-
appearance of the initial intense yellow colour of seleno-
cystine ethanolic solution.12 The corresponding13,14
N(Boc)-b-L-iodoamine 3a–c (obtained from Phe, Pro
and Val, respectively) was then added to the solution
to alkylate the anion and after refluxing the reaction
mixture for a few more minutes, the Boc mono-
protected selenodiamino acids 4a–c were observed as
sole products (TLC, LC–MS). Attempts to use cystine
under the same conditions to prepare sulfur analogues
of 4a–c were disappointing, due to the poorest reaction
yields.
Selenium nucleophiles have been reported16 to react
with aziridines that act as chiral aminoalkyl cation
equivalents. In our experience, chiral b-iodoamines ap-
pear to be strongly competitive with aziridines: as an
illustrative example, we obtained almost quantitative
formation of (S)-tert-butyl 1-phenyl-3-(phenylselen-
yl)propan-2-ylcarbamate (7), in only a few minutes
using the protected b-iodoamine 3a, from N(Boc)-L-
phenylalanine, and benzeneselenolate anion generated
in situ from diphenyl diselenide and NaBH4 in refluxing
EtOH. The same product had been reported17 to be
formed in 24 h, 72% yield, using the same benzeneselen-
olate anion and N(Boc)-aziridine from N(Boc)-L-
phenylalanine.
PhSeSePh
NaBH4
Ph
I
Ph
SePh
EtOH, THF
15 min, 94%
NH-Boc
NH-Boc
3a
7
Diamino acids 4a–c were not isolated as such,15 but were
converted into N,N-protected compounds, ready for
peptide coupling, bearing either a second Boc group
(5a–c) or orthogonal Boc/Fmoc (6a–c) protection
(Scheme 1).
In conclusion, these new, non-natural selenylated diami-
no acids can be obtained enantiopure, in good yields
and if required, in orthogonally protected forms ready
for insertion into peptide sequences. The synthesis is
very simple and the starting materials are generally inex-
pensive and easily accessible as well. All the mentioned
observations highlight the synthetic value of the enantio-
merically pure N(Boc)-b-iodoamines as aminoalkyl
cation equivalents.
We propose for any of these new chalcogen-containing
diamino acids an acronym to avoid cumbersome system-
atic names in the current laboratory practice and in
order to readily recognize their presence in peptide
sequences as well. The proposed acronym is composed
of ‘Se’ (from ‘Sec’) [as well as ‘Cy’ (from ‘Cys’) for the
terms containing the sulfur atom] and the italicized
‘one-letter code’ denoting the a-amino acid whose side
chain (R in formula 3 and others therefrom) is present
in it. Accordingly, the selenodiamino acids reported in
this Letter are shown in Table 1 with their acronyms
and the whole family should be referred to as ‘SeX ’ fam-
It is also worth noting that the lysine-like configuration
of our diamino acids, associated with a proteinogenic
side chain, prompts their exploitation as branching dia-
mino acids to build up chalcogen-containing peptide-
bond based new dendrimeric structures. Work is already
in progress in our lab to produce enzyme-mimicking
dendrimeric scaffolds including proteinogenic a-amino
R
I
CO2H
3
NH-Boc
HO2C
Se
R
CO2H
NH2
Se
NH2
Se
NH-Boc
NaBH4 in EtOH
reflux, 5 min
NH2
4
FmocOSu
Boc2O
a
: R = CH2C6H5
(Phe)
b
: R = CH2CH2CH2N (Pro)
c
R
CO2H
: R = CH(CH3)2
(Val)
R
CO2H
Se
Se
NH-Boc
NH-Boc
NH-Boc
NH-Fmoc
5
6
Scheme 1. Synthesis of N,N-protected SeX diamino acids from L-selenocystine and b-L-iodoamines.

R. Caputo et al. / Tetrahedron Letters 48 (2007) 1425–1427
Table 1. New N,N-protected SeX diamino acids
1427
25
N(Boc)-b-L-Iodoamine
SeX diamino acid
Yielda (%)
Mp (°C)
½aꢀD ðCHCl3Þ
3a
3a
3b
3b
3c
3c
Boc–SeF(Boc)–OH
(5a)
(6a)
(5b)
(6b)
(5c)
(6c)
98
95
92
94
97
95
132–133
138–139
Foam
97–98
Foam
45.1
40.2
23.8
31.3
35.7
38.5
Fmoc–SeF(Boc)–OH
Boc–SeP(Boc)–OH
Fmoc–SeP(Boc)–OH
Boc–SeV(Boc)–OH
Fmoc–SeV(Boc)–OH
88–89
a Yield of diprotected selenodiamino acid, referred to the starting b-iodoamine.
(4 mL) was then added. After 10 min under reflux, the
reaction mixture was cooled to room temperature and split
in two portions. The first one, after evaporation of the
solvents under vacuum, was redissolved in THF (10 mL)
and treated with FmocOSu (0.3 g, 1 mmol) under standard
conditions to afford eventually (R)-2-{[(9H-fluoren-9-yl)-
methoxy]carbonylamino}-3-[(S)-2-(tert-butoxycarbon-
ylamino)-3-methylbutylselenyl]propanoic acid, Fmoc–
SeV(Boc)–OH (6c), (96%). An analytical sample: mp 88–
acids, such as Ser, His and Asp, that are commonly
involved in the enzymatic active sites.18
References and notes
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89 °C (from CH2Cl2–hexane), ½aꢀD +38.5 (c 1.0, CHCl3).
1H NMR (500 MHz, CD3OD, J in Hz): d = 0.87 (d, 3H,
J = 6.8), 0.90 (d, 3H, J = 6.8), 1.44, (s, 9H), 1.77 (dq, 1H,
J = 6.8), 2.67 (dd, 1H, J = 9.3 and 12.2), 2.82 (dd, 1H,
J = 4.4 and 12.2), 2.97 (dd, 1H, J = 7.8 and 12.7), 3.03
(dd, 1H, J = 4.9 and 12.7), 3.50 (m, 1H), 4.25 (t, 1H,
J = 6.8), 4.34 (m, 2H), 4.44 (m, 1H), 7.31 (t, 2H, J = 7.8),
7.39 (t, 2H, J = 7.8), 7.69 (d, 2H, J = 7.8), 7.79 (d, 2H,
J = 7.8); 13C NMR (125 MHz, CD3OD): d = 18.8, 20.5,
27.0, 29.3, 29.9, 33.9, 48.7, 56.3, 58.0, 68.7, 80.4, 121.4,
126.8, 128.6, 129.3, 142.9, 145.6, 158.8, 174.6. HR-MS
(EI): calcd for C28H36N2O6Se [M+H+] 576.5626, found
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under vacuum, was also redissolved in THF (10 mL) and
treated with Boc2O (0.2 g, 1 mmol) under standard con-
ditions to afford (R)-2-(tert-butoxycarbonylamino)-3-[(S)-
2-(tert-butoxycarbonylamino)-3-methylbutylselenyl]prop-
anoic acid, Boc–SeV(Boc)–OH (5c) (97%). An analytical
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25
sample: foam, ½aꢀD +35.7 (c 1.6, CHCl3). 1H NMR
(500 MHz, CD3OD, J in Hz): d = 0.89 (d, 3H, J = 6.8),
0.92 (d, 3H, J = 6.8), 1.45 (s, 18H), 1.78 (dq, 1H, J = 6.8),
2.65 (dd, 1H, J = 12.7 and 8.9), 2.83 (dd, 1H, J = 12.7 and
3.9), 2.93 (dd, 1H, J = 12.7 and 6.8), 3.0 (dd, 1H, J = 12.7
and 4.9), 3.50 (m, 1H), 4.37 (br t, 1H); 13C NMR
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pended in anhydrous EtOH (10 mL) under argon atmo-
sphere. Solid NaBH4 (0.2 g, 5 mmol) was added in one
portion and the mixture refluxed for 5 min, until clear and
colourless. tert-Butyl (S)-1-iodo-3-methylbutan-2-ylcarba-
mate 3c (0.6 g, 2 mmol) dissolved in anhydrous THF
25
17. Mp 81–82 °C (from Et2O–hexane), ½aꢀD 15.5 (c 1.0,
CH2Cl2); lit.16 1H NMR spectrum consistent with
25
the structure; mp 80.7–81.3 °C, ½aꢀD 14.
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