A facile one-pot synthesis of selenoureidopeptides employing lialhseh through staudinger aza-wittig-type reaction

Article abstract of DOI:10.1055/s-0034-1379638

A one-pot protocol for the synthesis of selenoureidopeptides employing lithium aluminum hydride hydroselenide (LiAlHSeH) as a selenating agent via a Staudinger aza-Wittig-type reaction is reported. The protocol involves the use of N^α-protected aminoalkyl azides and isothicyanato esters to afford the desired products in good yields. This protocol is a direct approach to the synthesis of selenourea compounds that avoids the synthesis of isoselenocyanates and does not require multistep synthesis.

Full text of DOI:10.1055/s-0034-1379638

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 801–806
paper
801
Basavaprabhu et al.
Paper
Synthesis
A Facile One-Pot Synthesis of Selenoureidopeptides Employing
LiAlHSeH through Staudinger Aza-Wittig-Type Reaction
Basavaprabhu
Ph3P
(i)
Kupendra M. Sharanabai
Girish Prabhu
R2
COOX
R1
R1
SCN
H
H
Veladi Panduranga
Vommina V. Sureshbabu*
N
N
COOX
N3
PGHN
PGHN
LiHAlSeH
(ii)
Se
R2
THF, 0 °C to r.t.
Peptide Research Laboratory, Department of Studies in Chemis-
try, Central College Campus, Dr. B. R. Ambedkar Veedhi, Banga-
lore University, Bangalore-560 001, India
hariccb@hotmail.com
one pot
sureshbabuvommina@rediffmail.com
ariccb@gmail.com
Received: 26.09.2014
Accepted after revision: 17.11.2014
Published online: 08.01.2015
chemoselective ligation is useful in the chemical synthesis
and semisynthesis of polypeptides and a range of proteins
through native chemical ligation.11 Despite the growing im-
portance of selenopeptides/proteins, the insertion of sele-
nium into a peptide sequence is mainly limited to the
above-described studies.
DOI: 10.1055/s-0034-1379638; Art ID: ss-2014-z0554-op
Abstract A one-pot protocol for the synthesis of selenoureidopeptides
employing lithium aluminum hydride hydroselenide (LiAlHSeH) as a
selenating agent via a Staudinger aza-Wittig-type reaction is reported.
The protocol involves the use of Nα-protected aminoalkyl azides and
isothicyanato esters to afford the desired products in good yields. This
protocol is a direct approach to the synthesis of selenourea compounds
that avoids the synthesis of isoselenocyanates and does not require
multistep synthesis.
The general route available for the synthesis of sele-
nourea molecules is by the reaction of an amine with an
isoselenocyanate.12 Ishihara and co-workers reported the
synthesis of selenoureas by the reaction of N,N′-dialkyl- or
N,N′-diarylcarbodiimides with lithium aluminum hydride
hydroselenide (LiAlHSeH).13 Selenoureas can also be ac-
cessed by treating a carbodiimide with hydrogen selenide,
which is highly toxic and air-sensitive.14 Only a few studies
of isoselenocyanates have been reported. The reported syn-
theses of isoselenocyanates include the reaction of isocya-
nides with selenium,12c phenylimidoyl chloride with sodi-
um selenide,15 isocyanate with phosphorus pentaselenide,16
and alkyl/aryl isoselenocyanates from N-monosubstituted
formamides.16b,c The preparation of isoselenocyanates in-
volves the reaction of N-protected aminoalkyl isocyanides
with selenium powder and also the synthesis of the isocya-
nide itself is a multistep protocol. Alternatively, the isosele-
nocyanate moiety can be inserted in place of an amino
group of an α-amino acid through N-formylation followed
by reaction with selenium.17 An apparently convenient pro-
tocol would be the treatment of an amine with carbon
diselenide, but this procedure is of very limited use due to
the use of carbon diselenide which is not commercially
available.18,19 Another report describes the synthesis of
isoselenocyanates via the cycloaddition reaction of a nitrile
oxide with a primary selenoamide20 (Scheme 1). Many of
the protocols are not general applicable, use unstable reac-
tants, and lack of broad functional group tolerance.
Key words selenation, Staudinger aza-Wittig-type reaction, LiAlHSeH,
selenoureidopeptide mimics
Interest in the use of organoselenium compounds in
chemical biology1 is growing steadily due to (i) an increase
in the availability of stable organoselenium compounds and
(ii) the beneficial effects associated with them as antioxi-
dants, enzyme inhibitors, cytokine inducers, immunomod-
ulators, and antitumor, antihypertensive, antiviral, antibac-
terial, antifungal, and anti-infective agents.2 Woollins’ re-
agent is employed in various selenation protocols.3 Several
strategies and reagents for the efficient incorporation of se-
lenium functionality into molecular architecture are being
developed.4 Their utility in the construction of several
classes of heterocycles such as selenazoles5 and selenohy-
dantoins6 is well documented.
The synthesis of selenium-containing compounds is of
interest in peptide science owing to the discovery of a num-
ber of selenoproteins.7 Selenocysteine (Sec) is regarded as
21st proteinogenic amino acid because its insertion into
protein sequences is genetically controlled.8 Glutathione
peroxidase (GPx),9 possessing selenocysteine in the active
site, is an antioxidant enzyme that protects various organ-
isms from oxidative damage.10 Selenocysteine-mediated
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 801–806

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Basavaprabhu et al.
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Synthesis
H2Se or
LiAlHSeH
R1
N
C
N
R2
R1
N
N
C
C
O
H
H
N
N
R1 N3
SCN R2
Se
R1
R2
+
retro analysis
LiAlHSeH
Se
NH2
R1 NCSe
R1
R2
P2Se5
aza-Wittig type reaction
(one-pot)
Se
NH2
+
N
R1
C
O–
R
present method
reported routes
Scheme 1 Methods for the synthesis of selenoureas
Aza-Wittig reactions have undergone tremendous de-
velopment over the last three decades and they have now
become a powerful tool in organic synthesis for the con-
struction of acyclic and cyclic compounds, mainly because
the reaction is conducted in neutral solvents in the absence
of a catalyst and generally at low temperatures, and it usu-
ally proceeds in high yield.21
mixture was stirred for about three hours and the disap-
pearance of the isothiocyanato ester and the formation of a
complex (formed by the reaction of isothiocyanate, Ph3P,
and azide) was observed followed by the appearance of a
new spot in the TLC analysis. During the course of the reac-
tion, IR analysis of the reaction mixture revealed the pres-
ence of a strong absorption band in the region 2118 cm–1
corresponding to the N=C=N stretch of the carbodiimide
and thus clearly indicates the formation of a carbodiimide.
This was then treated with a suitable selenating agent. In
this step, various selenating agents viz, phosphorus pen-
taselenide, Woolins’ reagent, lithium aluminum hydride hy-
droselenide, and phosphorus pentachloride/selenium were
screened (Table 1). Among them, lithium aluminum hy-
dride hydroselenide afforded the corresponding selenourea
3a in good (86%) yield within 10 minutes. The selenating re-
agent lithium aluminum hydride hydroselenide, required
for the selenation of the in situ generated carbodiimide, was
prepared according to the method reported by Ishihara et
al.,4a which involves the treatment of lithium aluminum hy-
dride with selenium powder in anhydrous tetrahydrofuran
at room temperature.
Among various methods available for the construction
of the carbodiimide functionality,22 the intermolecular aza-
Wittig-type reaction of iminophosphoranes with heterocu-
mulenes, such as isocyanates/isothiocyanates, is a useful
protocol23 as it can be executed under neutral conditions.
Thus we augmented the aza-Wittig condensation of alkyl
azides with isothiocyanates to achieve our present objec-
tive. The proposed protocol is simple and involves the addi-
tion of lithium aluminum hydride hydroselenide to an in
situ generated carbodiimide to form selenoureidopeptides.
To address our synthetic objective, we designed an al-
ternative protocol involving Staudinger reaction followed
by aza-Wittig condensation employing an Nβ-urethane-pro-
tected aminoalkyl azide24 and an isothiocyanato ester25 as
precursor components. Thus the in situ generated carbo-
diimide served as the active intermediate, which further
participated in the subsequent step leading to the forma-
tion of selenoureidopeptides (Scheme 2).
Table 1 Screening of Selenating Agentsa
Entry
Selenating agent
Yieldb (%) of 3a
(i)
Ph3P
R2
1
2
3
4
P2Se5
36
48
86
32
R1
R1
Woolins’ reagent
LiAlHSeH
PCl5/Se
SCN
COOX
H
H
2
N
N
COOX
N3
PGHN
PGHN
LiHAlHSeH
THF, 0 °C to r.t.
(ii)
Se
3a–k
R2
1
a Reaction condition: Cbz-Phe-CH2N3 (1.0 mmol), Ph3P (1.2 mmol), THF,
0 °C, 10–15 min, then addition of isothiocyanatoalaninate (1.3 mmol) fol-
lowed by selenating agent (1.2 mmol) at 0 °C–r.t., 3 h.
b Isolated yield.
one pot
Scheme 2 One-pot synthesis of selenoureidopeptides
A Cbz-Phe-OH derived aminoalkyl azide was chosen as a
model substrate; it reacted with triphenylphosphine in an-
hydrous tetrahydrofuran at 0 °C to room temperature and
the disappearance of the starting azide was observed by
TLC analysis. This was then followed by the addition of the
isothiocyanato ester of an amino acid, alanine. The reaction
The first step of the reaction involves the formation of a
carbodiimide (vide infra). The general mechanism of the
carbodiimide synthesis by aza-Wittig condensation pro-
ceeds through the reaction of an alkyl azide 1 with isothio-
cyanate 2 to form phosphinimine intermediate 5 that un-
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Basavaprabhu et al.
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Synthesis
R2
COOX
R2
COOX
R2
R1
S
C
R1
N
COOX
N
R1
N
R1
C
S
N
C
S
N
Ph3P
2
N3
PGHN
PGHN
PPh3
N
PGHN
PGHN
PPh3
5
Ph3P
6
1
4
Ph3P
S
R1
COOX
R2
R1
COOX
R2
R1
COOX
R2
C
N
N
LiAlHSeH
H
C
N
H
N
PGHN
C
N
PGHN
N
Se
PGHN
H
Se
8
7
3
SeH
Scheme 3 Possible mechanism for the formation of selenoureidopeptides
dergoes the desired transformation through intermediate 6
to form carbodiimide 7 with loss of triphenylphosphine sul-
fide. In the next step, the in situ generated carbodiimide 7
reacts with lithium aluminum hydride hydroselenide to
produce the carbodiimidoyl selenol species 8, which then
rearranges further to form the desired selenoureidopep-
tides 3 (Scheme 3).
avoids the synthesis of isoselenocyanates, and thus the syn-
thesis of Nα-protected aminoalkyl isocyanides, which pre-
cludes multistep synthesis.
Table 2 Selenoureidopeptides Synthesizeda
Entry
1
Product
Yieldb
(%)
With the reaction conditions established, a variety of
amino acids 1 were employed and the corresponding sele-
noureidopeptides 3a–k were obtained in good yields (Table
2). Urethane protecting groups, such as Cbz, Fmoc, and Boc,
also worked well in affording the desired products in good
yields. All the products were purified by column chroma-
H
N
H
N
COOMe
COOMe
3a
86
84
FmocHN
FmocHN
Se
Se
H
N
H
N
1
tography and characterized by mass spectrometry, H, 13C,
and 77Se NMR analyses.
2
3
3b
3c
The optical purity of the N-protected guanidinopeptide
mimic was evaluated by an 1H NMR study of the model
compound prepared via the present protocol. The diaste-
reomeric selenoureidopeptide mimics 3j and 3k were syn-
thesized by coupling Fmoc-Phg-ψ[CH2N3] with L- and D-
Ala-OMe, respectively, in presence of lithium aluminum hy-
dride hydroselenide in separate experiments. 1H NMR of 3j
and 3k showed a single distinct methyl group doublet at 3j:
δ = 1.17, 1.18 and 3k: δ = 1.24, 1.25. Furthermore, the mix-
ture prepared by coupling Fmoc-Phg-ψ[CH2N3] with race-
mic L,D-Ala-OMe showed methyl groups as two doublets
with at δ = 1.15, 1.16 and 1.23, 1.24 indicating the presence
of two isomers and confirming that the protocol is free
from epimerization.
In conclusion, herein we have described a one-pot pro-
tocol for the synthesis of selenoureidopeptides employing
lithium aluminum hydride hydroselenide as the selenating
agent via a Staudinger aza-Wittig-type reaction. The proto-
col involves the use of Nα-protected aminoalkyl azides and
isothiocyanato esters. The present protocol affords the de-
sired products in good yields and can be extended to simple
as well as bifunctional amino acids. This protocol is a direct
approach to the synthesis of selenourea compounds and
H
N
H
N
83
89
FmocHN
COOMe
Se
4
3d
H
H
N
N
COOMe
COOMe
CbzHN
CbzHN
Se
Se
H
N
H
N
5
6
3e
3f
81
78
H
N
H
N
COOBn
CbzHN
Se
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Synthesis
Table 2 (continued)
Lithium Aluminum Hydride Hydroselenide (LiAlHSeH)
To a solution of Se powder (0.08 g, 1.0 mmol) in anhydrous THF (10
mL) was added LiAlH4 (0.038 g, 1.0 mmol) at 0 °C under an argon
atmosphere. The mixture was stirred for 20–30 min. The reagent
LiAlHSeH was formed in situ, and the gray solution was used directly.
Entry
Product
Yieldb
(%)
Note: The reagent should be prepared prior to use.
7
3g
82
H
H
N
N
COOMe
COOMe
Isothiocyanato Esters 2;25d,e General Procedure
BocHN
BocHN
To a solution of amino acid ester salt (10 mmol) in CH2Cl2 was added
CS2 (11 mmol) followed by Et3N (40 mmol) at 0 °C; the mixture was
stirred at this temperature for 30 min and then at r.t. for 30 min. The
mixture was cooled to 0 °C and TsCl (13 mmol) was added. Stirring
was continued for 3 h or until completion of the reaction (TLC analy-
sis). Excess CH2Cl2 (2 × 5 mL) was added and the organic layer was
washed with 10% citric acid solution (2 × 15 mL), water (2 × 10 mL),
and brine (2 × 10 mL). It was then dried (anhyd Na2SO4) and concen-
trated under reduced pressure. The resulting crude product was sub-
jected to column chromatography (10% EtOAc–hexane) to afford the
pure product.
Se
Se
H
H
N
N
8
9
3h
3i
78
80
H
N
H
N
COOMe
BocHN
Selenoureidopeptides 3a–k; General Procedure
Se
To a solution of N-protected aminoalkyl azide 1 (1.0 mmol) in anhyd
THF (8 mL) at 0 °C was added Ph3P (1.2 mmol) and the mixture was
stirred for 10–15 min. Isothiocyanato ester (1.3 mmol) was added to
the mixture and it was stirred for ca. 2 h; freshly prepared LiAlHSeH
(1.2 mmol) in anhyd THF (4 mL) was added portionwise to the mix-
ture and it was then stirred until completion of the reaction (TLC
monitoring). The organic layer was then evaporated in vacuo to afford
the crude product which was purified by column chromatography
(EtOAc–n-hexane, 30:70).
10
11
3j
80
82
H
H
N
N
COOMe
COOMe
FmocHN
FmocHN
Se
Se
3k
H
N
H
N
Fmoc-Val-ψ[CH2NHC(Se)NH]-Ala-OMe (3a)
White solid; yield: 444.18 mg (86%); mp 171–173 °C.
IR (neat): 1512, 1693, 1740 cm–1
.
a Reaction conditions: Nα-protected aminoalkyl azide 1 (1.0 mmol), Ph3P
(1.2 mmol), THF, 0 °C, 10–15 min, then addition of isothiocyanato ester 2
(1.3 mmol) followed by LiAlHSeH (1.2 mmol), anhydrous THF, 0 °C–r.t., 3 h.
b Isolated yield.
1H NMR (400 MHz, CDCl3): δ = 0.97 (dd, J = 7.1 Hz, 6 H), 1.40 (d, J = 7.2
Hz, 3 H), 2.05–2.20 (m, 1 H), 3.12 (m, 2 H), 3.73 (s, 3 H), 4.00–4.10 (m,
1 H), 4.21 (t, J = 7.0 Hz, 1 H), 4.25–4.50 (m, 2 H), 4.50–4.65 (m, 1 H),
5.43 (br s, 1 H), 5.56 (d, J = 8.8 Hz, 1 H), 6.56 (br s, 1 H), 7.30 (m, 2 H),
7.39 (t, J = 7.5 Hz, 2 H), 7.59 (d, J = 7.1 Hz, 2 H), 7.76 (d, J = 7.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.80, 21.6, 29.8, 44.2, 46.8, 52.4, 59.6,
63.2, 65.8, 126.7, 127.2, 127.9, 128.4, 141.1, 142.8, 154.1, 170.4, 183.5.
77Se NMR (CDCl3): δ = 288.6.
HRMS: m/z [M + Na]+ calcd for C25H31N3O4Se: 540.0785; found:
540.0781.
All amino acids were used as obtained from Sigma-Aldrich Company,
USA. Unless otherwise mentioned, all amino acids used were of L-
configuration. All the solvents were dried and purified using recom-
mended literature procedures whenever necessary. High-resolution
mass spectra were recorded on a Micromass Q-TOF mass spectrome-
ter using electrospray ionization mode. 1H NMR and 13C NMR spectra
were recorded on a Bruker AMX 400 MHz and 100 MHz spectrometer,
respectively, at the Indian Institute of Science, Bangalore. IR spectra
were recorded on a Shimadzu model FT-IR spectrophotometer at Ban-
galore University, Bangalore. Melting points were determined in an
open capillary and are uncorrected. TLC experiments were carried
out on Merck aluminum TLC sheets (silica gel 60 F254) and chromato-
grams were visualized by exposing in an iodine chamber or with a UV
lamp, or by spraying with KMnO4 followed by heating. Column chro-
matography was performed on neutralized silica gel (100–200 mesh)
using mixtures of ethyl acetate and hexane as eluents.
Fmoc-Gly-ψ[CH2NHC(Se)NH]-Phe-OMe (3b)
White solid; yield: 463.42 mg (84%); mp 182–184 °C.
IR (neat): 1515, 1691, 1742 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.12–3.24 (m, 4 H), 3.67 (s, 3 H), 3.77–
3.82 (m, 1 H), 4.12–4.28 (m, 3 H), 4.66 (d, J = 5.6 Hz, 2 H), 5.17 (br s, 1
H), 6.45 (br s, 2 H), 7.15–7.41 (m, 9 H), 7.53 (d, J = 7.2 Hz, 2 H), 7.68 (d,
J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 37.6, 39.8, 41.2, 47.6, 56.9, 60.7, 67.3,
120.4, 125.1, 125.6, 127.5, 128.1, 129.4, 129.8, 134.9, 141.7, 144.3,
156.1, 173.8, 183.1.
N-Protected aminoalkyl azides 124 and isothiocyanato esters225d,e are
known compounds.
77Se NMR (CDCl3): δ = 290.4.
HRMS: m/z [M + Na]+ calcd for C28H29N3O4Se: 574.1221; found:
574.1224.
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Synthesis
Fmoc-Leu-ψ[CH2NHC(Se)NH]-β-Ala-OMe (3c)
Boc-Phe-ψ[CH2NHC(Se)NH]-Val-OMe (3g)
White solid; yield: 440.33 mg (83%); mp 173–174 °C.
White solid; yield: 385.77 mg (82%); mp 165–166 °C.
IR (neat): 1518, 1696, 1742 cm–1
.
IR (neat): 1520, 1697, 1740 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.92 (d, J = 6.8 Hz, 6 H), 1.37 (m, 2 H),
1.66 (m, 1 H), 2.58 (m, 2 H), 3.58 (s, 3 H), 3.65–3.80 (m, 4 H), 4.02 (m,
1 H), 4.19 (t, J = 6.8 Hz, 1 H), 4.35 (m, 2 H), 5.21 (br, 1 H), 6.96 (br, 2 H),
7.22–7.76 (m, 8 H).
1H NMR (400 MHz, CDCl3): δ = 0.87 (d, J = 6.4 Hz, 3 H), 0.93 (d, J = 6.8
Hz, 3 H), 1.45 (s, 9 H), 2.00–2.20 (m, 1 H), 3.05–3.20 (m, 4 H), 3.71 (s, 3
H), 3.85–4.00 (m, 1 H), 4.80–4.95 (m, 1 H), 5.04 (d, J = 7.7 Hz, 1 H),
6.37 (br s, 2 H), 7.05–7.15 (m, 2 H), 7.25–7.35 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 22.4, 23.5, 25.29, 34.0, 42.3, 47.6, 52.3,
54.0, 64.3, 67.3, 120.4, 125.6, 127.6, 128.2, 141.7, 144.1, 157.7, 173.4,
183.8.
13C NMR (100 MHz, CDCl3): δ = 16.9, 19.2, 21.4, 29.6, 30.22, 43.66,
48.24, 53.44, 65.23, 82.35, 127.2, 127.7, 128.2, 128.6, 128.8, 135.1,
138.3, 158.0, 172.9, 184.2.
77Se NMR (CDCl3): δ = 288.2.
77Se NMR (CDCl3): δ = 290.6.
HRMS: m/z [M + Na]+ calcd for C26H33N3O4Se: 554.1534; found:
HRMS: m/z [M + Na]+ calcd for C21H33N3O4Se: 494.0785; found:
554.1535.
494.0781.
Cbz-Phe-ψ[CH2NHC(Se)NH]-Ala-OMe (3d)
Boc-Val-ψ[CH2NHCSeNH]-Leu-OMe (3h)
White solid; yield: 424.02 mg (89%); mp 166–167 °C.
White solid; yield: 340.43 mg (78%); mp 169–170 °C.
IR (neat): 1510, 1690, 1746 cm–1
.
IR (neat): 1515, 1694, 1744 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.36 (d, J = 7.1 Hz, 3 H), 3.08 (m, 4 H),
3.72 (s, 3 H), 4.30–4.45 (m, 1 H), 4.45–4.60 (m, 1 H), 5.00 (s, 2 H), 5.45
(br s, 1 H), 6.81 (br, 2 H), 7.15–7.35 (m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 16.9, 33.6, 38.6, 47.3, 53.3, 60.7, 66.6,
126.6, 127.6, 127.9, 128.3, 128.5, 129.0, 136.14, 136.9, 156.7, 172.5,
182.6.
1H NMR (400 MHz, CDCl3): δ = 0.84–1.00 (m, 12 H), 1.36 (s, 9 H),
1.62–1.66 (m, 2 H), 1.81–1.85 (m, 1 H), 2.25–2.29 (m, 1 H), 3.27–3.31
(m, 1 H), 3.46–3.51 (m, 1 H), 3.64–4.05 (m, 4 H), 4.30–4.34 (m, 1 H),
4.71–4.74 (m, 1 H), 5.18 (br s, 1 H), 6.28 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.2, 22.9, 25.6, 26.2, 26.6, 28.2, 31.2,
42.3, 47.5, 49.5, 52.3, 55.8, 80.1, 155.4, 170.6, 185.2.
77Se NMR (CDCl3): δ = 290.1.
77Se NMR (CDCl3): δ = 239.9.
HRMS: m/z [M + Na]+ calcd for C22H27N3O4Se: 500.1064; found:
HRMS: m/z [M + Na]+ calcd for C18H35N3O4Se: 460.1690; found:
500.1060.
460.1685.
Cbz-Val-ψ[CH2NHC(Se)NH]-Leu-OMe (3e)
Boc-Leu-ψ[CH2NHCSeNH]-Gly-OMe (3i)
White solid; yield: 381.07 mg (81%); mp 169–170 °C.
Gummy; yield: 315.49 mg (80%).
IR (neat): 1517, 1689, 1745 cm–1
.
IR (neat): 1509, 1687, 1741 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.91 (d, J = 5.9 Hz, 6 H), 0.93 (dd, J = 6.8,
12.6 Hz, 6 H), 1.45–1.75 (m, 3 H), 2.00–2.20 (m, 1 H), 3.71 (s, 3 H),
3.89 (m, 1 H), 4.55–4.65 (m, 1 H), 5.02 (s, 2 H), 5.51 (br s, 1 H), 6.70 (br
s, 2 H), 7.05–7.32 (m, 5 H).
1H NMR (400 MHz, CDCl3): δ = 0.96 (d, J = 5.7 Hz, 6 H), 1.37 (s, 9 H),
1.50–1.55 (m, 2 H), 1.76–1.79 (m, 1 H), 2.64–2.88 (m, 2 H), 3.50–3.53
(m, 2 H), 3.63 (s, 3 H), 3.93 (m, 1 H), 5.60 (br s, 1 H), 6.68 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 23.6, 28.1, 43.8, 44.8, 50.1, 53.8,
58.7, 78.8, 155.9, 174.6, 184.1.
13C NMR (100 MHz, CDCl3): δ = 19.1, 34.0, 40.2, 47.5, 47.9, 51.1, 52.3,
67.4, 120.4, 125.5, 127.5, 128.2, 141.7, 144.1, 157.4, 173.4, 183.2.
77Se NMR (CDCl3): δ = 286.0.
HRMS: m/z [M + Na]+ calcd for C21H33N3O4Se: 494.1534; found:
77Se NMR (CDCl3): δ = 239.9.
HRMS: m/z [M + Na]+ calcd C15H29N3O4Se: 418.1221; found: 418.1214.
494.1532.
Fmoc-Phg-ψ[CH2-NHC(Se)NH]-(S)-Ala-OMe (3j)
White solid; yield: 446.40 mg (80%); mp 171–173 °C.
Cbz-Val-ψ[CH2NHC(Se)NH]-Ile-OBn (3f)
IR (neat): 1518, 1693, 1743 cm–1
.
White solid; yield: 426.31 mg (78%); mp 173–174 °C.
1H NMR (400 MHz, CDCl3): δ = 1.17–1.18 (d, J = 4.0 Hz, 3 H), 3.21–3.57
(m, 2 H), 3.72 (s, 3 H), 4.13–4.20 (m, 3 H), 4.32 (d, J = 8.0 Hz, 2 H), 5.24
(br s, 1 H), 6.10 (br s, 1 H), 7.28–7.48 (m, 8 H), 7.56 (d, J = 4.0 Hz, 2 H),
7.74 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 17.1, 43.9, 46.3, 53.9, 58.2, 67.1, 120.0,
125.0, 127.0, 127.7, 128.3, 128.4, 128.6, 135.5, 141.3, 143.7, 155.1,
171.1, 182.6.
IR (neat): 1511, 1689, 1739 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.61–1.11 (m, 12 H), 1.16–1.35 (m, 2
H), 1.64–1.92 (m, 2 H), 3.36–3.53 (m, 1 H), 3.71–4.00 (m, 2 H), 4.10–
4.22 (m, 1 H), 5.22 (s, 4 H), 5.51 (br s, 1 H), 6.89 (br s, 1 H), 7.18–7.38
(m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 12.1, 15.6, 18.1, 26.3, 33.8, 38.5, 48.6,
54.3, 55.6, 67.3, 68.8, 127.2, 127.7, 128.2, 128.6, 128.8, 135.1, 136.3,
157.4, 171.2, 179.8.
77Se NMR (CDCl3): δ = 270.1.
HRMS: m/z [M + Na]+ calcd C28H29N3O4Se: 574.1221; found: 574.1220.
77Se NMR (CDCl3): δ = 290.5.
MS (ES): m/z [M + Na]+ calcd for C27H37N3O4Se: 570.18; found: 570.20.
Fmoc-Phg-ψ[CH2-NHC(Se)NH]-(R)-Ala-OMe (3k)
White solid; yield: 451.41 mg (82%); mp 171–173 °C.
IR (neat): 1514, 1688, 1745 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 801–806

806
Basavaprabhu et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.24–1.25 (d, J = 4.0 Hz, 3 H), 3.20–3.51
(m, 2 H), 3.74 (s, 3 H), 4.10–4.19 (m, 3 H), 4.32 (d, J = 8.0 Hz, 2 H), 5.23
(br s, 1 H), 6.07 (br s, 1 H), 7.25–7.49 (m, 8 H), 7.54 (d, J = 4.0 Hz, 2 H),
7.77 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 17.2, 43.8, 46.2, 53.7, 58.4, 67.1, 120.1,
125.2, 127.3, 127.7, 128.4, 128.5, 128.6, 135.4, 141.2, 143.6, 155.2,
171.4, 182.3.
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HRMS: m/z [M + Na]+ calcd for C28H29N3O4Se: 574.1221; found:
574.1222.
Acknowledgement
We sincerely thank Department of Science and Technology (DST) for
financial assistance. B.P. thanks CSIR for an SRF.
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