Isoselenocyanates derived from Boc/Z-amino acids: Synthesis, isolation, characterization, and application to the efficient synthesis of unsymmetrical selenoureas and selenoureidopeptidomimetics

Article abstract of DOI:10.1016/j.tet.2010.06.082

Isoselenocyanates derived from Boc/Z-amino acids are prepared by the reaction of the corresponding isonitriles with selenium powder in presence of triethylamine at reflux. The utility of these new classes of isoselenocyanates in the preparation of selenoureidodipeptidomimetics possessing both amino as well as carboxy termini has been accomplished. The ¹H NMR analysis confirmed that the protocol involving the conversion of isonitriles to isoselenocyanates and their use as coupling agents in assembling selenoureido derivatives is free from racemization.

Full text of DOI:10.1016/j.tet.2010.06.082

Tetrahedron 66 (2010) 6718e6724
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Isoselenocyanates derived from Boc/Z-amino acids: synthesis, isolation,
characterization, and application to the efficient synthesis of unsymmetrical
selenoureas and selenoureidopeptidomimetics
Gundala Chennakrishnareddy a, Govindappa Nagendra a, Hosahalli P. Hemantha a, Ushati Das b,
,
Tayur N. Guru Row b, Vommina V. Sureshbabu a
*
a Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, Bangalore 560 001, India
b Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2010
Received in revised form 22 June 2010
Accepted 29 June 2010
Available online 3 July 2010
Isoselenocyanates derived from Boc/Z-amino acids are prepared by the reaction of the corresponding
isonitriles with selenium powder in presence of triethylamine at reflux. The utility of these new classes of
isoselenocyanates in the preparation of selenoureidodipeptidomimetics possessing both amino as well as
carboxy termini has been accomplished. The 1H NMR analysis confirmed that the protocol involving the
conversion of isonitriles to isoselenocyanates and their use as coupling agents in assembling selenour-
eido derivatives is free from racemization.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Isoselenocyanates
Peptidomimetics
Selenoureas
Selenoureidopeptidomimetics
1. Introduction
selenazoles18 and selenohydantoins19 is well documented. Sele-
nosugars including glycosyl isoselenocyanates have been widely
Peptides and proteins, although, ubiquitous in living cells have
to be modified chemically to make them employable as drugs
and to prepare artificial enzymes.1e3 Ureidopeptides, peptidyl
used in carbohydrate chemistry for the preparation of di-
saccharides, C-glycosides, O-glycosides, and glycoconjugates.20
The synthesis of Se-containing compounds is of interest in
peptide science owing to the discovery of a number of seleno-
proteins.21a,22 Selenocysteine (Sec) is being viewed as 21st pro-
teinogenic amino acid because its insertion is genetically
controlled.21,23e26 Glutathione peroxidase (GPx),27 possessing Sec
in the active site, is an antioxidant enzyme, which protects various
organisms from oxidative damage.28 Selenocysteine mediated
chemo-selective ligation is useful in chemical synthesis and semi-
synthesis of large peptides and a range of proteins through native
chemical ligation.29 Despite the growing importance of seleno-
peptides/proteins, the insertion of Se into a peptide sequence is
mainly limited to the above-described studies.30
ureas, oligourea/peptide hybrids comprising either
b
a and/or
-amino acid residues have been prepared and studied.4 Another
new class of mimetics, thioureidopeptides was recently reported
by us.5
Interest in the use of organoselenium compounds (OrgSeCs)
in biochemistry is growing steadily6 due to (i) increase in the
availability of stable OrgSeCs and (ii) the beneficial effects asso-
ciated with them as antioxidants, enzyme inhibitors, cytokine
inducers, immunomodulators, antitumor, antihypertensive, anti-
viral, antibacterial, antifungal, and anti-infective agents.7 Hun-
dreds of OrgSeCs are being used as reagents and intermediates in
organic synthesis. Woollins’ reagent is regularly employed for
various selenation reactions.8 Various strategies and reagents for
the efficient incorporation of selenium functionality into molec-
ular architecture are being developed.9e17 Their utility in the
construction of several classes of heterocycles such as
Isoselenocyanates31 are easy to prepare and store, less toxic and
safe to handle. Along with other applications, their utility especially
in the synthesis of various selenium containing heterocycles is well
documented.32 Their preparation involves reaction of an isonitrile
with Se or direct conversion of formamides into isoselenocyanates
via the isonitrile intermediate.31a,33 Other important reports for
their synthesis include the reaction of phenylimidolyl chloride with
sodium selenide; isocyanates with phosphorous(V) selenide;
treatment of N-aryl-carbimidic dichlorides with sodium selenide;
* Corresponding author. Tel.: þ9180 22961339; e-mail addresses:
sureshbabuvommina@rediffmail.com, hariccb@gmail.com (V.V. Sureshbabu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.082

G. Chennakrishnareddy et al. / Tetrahedron 66 (2010) 6718e6724
6719
photochemical rearrangement of selenocyanates; cycloaddition of
2. Results and discussion
nitrile oxides with primary selenoamide and alkylation of seleno-
cyanate ion.34 An apparently convenient protocol would be the
treatment of an amine with carbon diselenide, which is in very
limited use due to the non availability of CSe2.35 There are few other
procedures available, which are yet to gain the merit of general
applicability.36
2.1. Synthesis of isoselenocyanates 3 from N-Boc-amino acids
The isonitriles precursors required for the preparation of re-
spective class of isoselenocyanates were obtained by LiAlH4 re-
duction of the corresponding nitriles of the N-Boc-amino acids
followed by the formylation of the amine group as formamides 6.43
In the literature, isocyanates37 and isothiocyanates38,39 (2a and
2b) derived from amino/peptide acid esters as well as N-protected
amino acids are known to be employed as key synthons in both de
novo design and for accessing biologically potent molecules4,40e42
(Fig. 1). Their utility as building blocks for the construction of
uriedo/thioureido peptidomimetics has been the focus of several
research publications37,38 (Figs. 1 and 2).
The dehydration of these formamides 6 afforded N-b-Boc-amino
alkyl isonitriles 7 in good yields. These novel classes of isonitriles
could also be useful as precursors for well known multi-component
reactions as well.43
As Sonoda et al. have reported that effective conversion of
aliphatic isocyanides to corresponding isoselenocyanates re-
quires an organic base such as TEA,31 we conceived the idea that
the reaction of N-
would offer new class of isoselenocyanates. In this context,
a mixture of 1 mmol each of Nb-BoceVale
[CH2NC] 7a and Se
b-Boc-amino alkyl isonitriles 7 with Se powder
R
R
J
N=C=X
Y
PgHN
X=C=N
n
powder in THF in presence of 0.7 mmol of TEA was refluxed. The
reaction was complete in 5e6 h as analyzed by TLC. The corre-
sponding isoselenocyanate 3a was isolated in 90% yield. With
this result, a series of isoselenocyanates (3aej) derived from
corresponding Boc-amino acids were synthesized (Scheme 1),
which could be stored for several weeks at subzero temperature
without any decomposition. The IR spectrum of these iso-
selenocyanates exhibited a sharp peak at 2148 cmꢀ1 character-
istic of eNCSe group. While 13C NMR spectrum showed
O
1
2
1a. Isocyanates: X = O; n = 0 or 1
Pg = Fmoc, Boc or Z group.
2a. Isocyanates: X = O;
Y = OMe, OEt or OBzl group.
2b. Isothiocyanates: X = S;
Y = OMe, OEt or OBzl group.
1b. Isothiocyanates: X = S; n = 1
Pg = Fmoc, Boc or Z group.
R
N=C=Se
Boc/Z-HN
3 or 4
N-protected isoselenocyanates
characteristic signal at around
carbonyl carbon while 77Se NMR spectrum possesses a signal at
around
ꢀ350.
d 125 corresponding to seleno-
Figure 1. Structures of isocyanates, isothiocyanates, and isoselenocyanates derived
from amino acids.
d
R1
O
R3
2.2. N-Z-Amino alkyl isoselenocyanates 4
H
N
OH
R1
H2N
N
H
O
R2
O
Efficacy of the protocol for the synthesis of Boc-amino alkyl
isoselenocyanates 3 prompted us to extend the study to the iso-
nitrile derivatives of Z-amino acids 10, which were obtained
through the dehydration of corresponding formamides 9, prepared
by the formolysis of their isocyanates 8 by following our reported
procedure.43,44 In the final step, the selenation of the isonitriles 10
n
Native Peptide
R1
X
R2
O
H
N
H
N
N
H
N
H
PgHN
OH
n
O
O
X
R2
was undertaken to afford Nb-ZeXaae
J[CH2NCSe]s 4 in satisfactory
X = O/S/Se
Ureido/thio/selenoureido peptidomimetics
Ureido/thioureido peptides with N and C-termini
yield (Scheme 2).
with two carboxyl termini
Further, for the insertion of isoselenocyanate moiety in the side
chain of an amino acid, the -carboxyl group of Glu was converted
to the corresponding isonitrile using oxazolidinone as bidentate
protection for
-amino and carboxy groups.45 Na-ZeGlueOH de-
rived oxazolidinone was prepared employing microwave assisted
transformation of
-carboxyl group of Na-ZeGlueOH to formamide
via formylation of corresponding isocyanate. It was dehydrated and
converted to corresponding isoselenocyanate 11 as described
before (Fig. 3).
g
Figure 2. General structures of peptide and peptidylurea analogs.
a
In continuation of our interest in such mimetics, we now pres-
ent our works on the syntheses of isoselenocyanates 3 and 11 de-
rived from N-Boc/Z-amino acids, hitherto unreported class of
OrgSeCs and demonstrate their utility for the synthesis of sele-
noureido derivatives (Scheme 1).
g
Sl.
Amino
Yield (%)
R
R
HCOOH,
DCC
No. acid
H
N
6
7
3
NH2
H
BocHN
BocHN
1
2
3
4
5
6
7
8
Val
Leu
Ile
Phe
Phg
Pro
Met
Cys(Bzl) 87
Ser(Bzl) 82
Aib
89
88
89
91
92
80
88
89
92
90
95
93
88
93
91
90
90
90
95
92
96
89
85
88
80
86
92
O
R
5
6
R
burgess
reagent
Se powder
NCSe
NC
BocHN
BocHN
TEA, THF
Reflux
9
10
3
82
7
Scheme 1. Preparation of isoselenocyanates 3 derived from Boc-amino acids and the respective yields.

6720
G. Chennakrishnareddy et al. / Tetrahedron 66 (2010) 6718e6724
R
R
Sl.
No.
Amino
acid
Yield (%)
HCOOH,
DMAP
H
N
NCO
H
9
10
82
92
85
89
93
80
83
79
81
74
4
ZNH
ZNH
1
2
3
4
5
6
7
8
9
10
Ala
Val
Leu
Ile
Phe
Pro
Met
Cys(Bzl) 79
Ser(Bzl) 76
Lys(Boc) 75
82
87
85
82
90
75
86
91
84
83
88
90
77
88
75
76
79
O
8
9
R
burgess
reagent
R
Se powder
TEA, THF
NCSe
NC
ZNH
ZNH
Reflux
4
10
Scheme 2. Preparation of isoselenocyanates 4 derived from Z-amino acids.
[eNHeCXeNHe, X¼O or S] in place of peptide bond. In this di-
rection, we have now prepared six selenoureidodipeptides 13aef. It
has been found that the reaction of 3 or 4 with an amino acid ester
was clean and complete within 30 min at room temperature
(Scheme 3). After regular workup, the selenoureido products 13aef
were obtained in about 90% yield (Table 1).
NCSe
2
O
ZN
O
11
Figure 3. Structure of isoselenocyanate derived from ZeGlue5-oxazolidinone.
2.3. Synthesis of unsymmetrical selenoureas 12aee and
selenoureidopeptides 13aef
2.4. Tests for racemization
Racemization while formation of the isoselenocyanates and
during the coupling with amines as well as amino acid esters
was expected to be unlikely considering the mild conditions
chosen for the functional group transformations. However, as the
penultimate part of this study, we undertook the synthesis of
In general, selenoureas are prepared by the reaction of an iso-
selenocyanate with an amino component.9a,46 In order to demon-
strate the synthetic utility of the isoselenocyanates 3 and 4, five
unsymmetrical selenoureas were prepared. In the first set of ex-
periments 3a, 3b, 3d, 4d, 11e were made to react with five different
aromatic amines (Scheme 3, Table 1). All the selenoureas 12aee
were obtained in good yield after column chromatographic purifi-
cation using ethyl acetate/hexane (9:1). However, the reaction of 3
with aromatic amines possessing electron-withdrawing groups
attached to the aromatic nucleus failed to form corresponding
selenoureas. Among the various spectral data recorded for these
selenoureas, the chemical shifts of compounds 12 and 13 in 77Se
three sets of epimeric selenoureas. In the first two sets, Boce
L-
Phee [CH2NCSe] 3d, and Ze -Phee [CH2NCSe] 4e were cou-
J
L
J
pled with (R)-, (S)- and a racemic mixture of 1-phenylethylamine
in parallel experiments and six selenoureas 14aec and 15aec
were isolated (Fig. 4). In each set, 1H NMR of the particular
epimers contained a single distinct methyl group doublet. Ob-
served
d values for the eCH3 group of the compounds are as
follows: 14a: 1.34, 1.32 and 14b: 1.26, 1.24; 15a: 1.50, 1.48 and
15b: 1.56, 1.54. Further, the compounds 14c and 15c, prepared by
coupling the corresponding isoselenocyanates with racemic 1-
phenylethylamine showed two distinct doublets in each case
NMR were observed approximately at
d 280.
Our long-term interest in the area of peptidomimetics has
resulted in the design and insertion of ureido/thioureido moiety
H2N
COOY
R1
O
R1
R1
H
N
H
N
R3-NH2
CH2Cl2, rt,
0.5 h
R2
H
N
H
N
NCSe
PgHN
OY
PgHN
R3
PgHN
CH2Cl2, rt,
0.5 h
Se R2
Se
3: Pg= Boc
4: Pg= Z
12a-e
13a-f
Scheme 3. Synthesis of selenoureas 12 and selenoureidopeptides 13.
Table 1
List of selenoureas 12 and selenoureidodipeptides 13 synthesized
Entry
Pg
R1
R3
Yield (%)
94
Entry
Pg
R1
R2
CH(CH3)2
Y
Yield (%)
95
Cl
12a
Boc
CH(CH3)2
13a
Boc
CH2C6H5
Me
12b
12c
12d
Boc
Boc
Z
CH2C6H5
98
98
98
13b
13c
13d
Boc
Boc
Z
CH(CH3)2
CH2CH(CH3)2
Me
Me
Me
92
98
95
CH2CH(CH3)2
CH2C6H5
CH2CH(CH3)2
(CH2)2SCH3
H
CH3
12e
Z
CH(CH3)(C2H5)
98
13e
13f
Z
Z
CH(CH3)2
CH(CH3)(C2H5)
CH(CH3)2
Bzl
Me
90
92
Br
CH2CH(CH3)2

G. Chennakrishnareddy et al. / Tetrahedron 66 (2010) 6718e6724
6721
hydrogen bonds in the ac plane, wherein the nitrogen atom of
the amino group acts as a donor to the hydrogen bond acceptor,
oxygen of the carbonyl moiety. The NeH/O interactions are
H
N
H
N
H
N
H
N
∗
∗
ZHN
BocHN
further supplemented with CeH/
p
weak interactions along the
Se
Se
a axis.
15a: R at *; 15b: S at *; 15c: R and S at *
14a: R at *; 14b S at *; 14c: R and S at *
BoceValeJ[CH2NCSe] 3a and BocePheeJ[CH2NCSe] 3d crys-
tallize in the orthorhombic crystal system in the non-centrosym-
metric space group P212121 with Z0¼1 and in the asymmetric unit,
the N]C]Se bond is nearly linear with an angle of 177.79ꢁ and
Figure 4. Epimeric diselenoureidopeptides synthesized for racemization studies.
suggesting the presence of two isomers, which confirms the
absence of racemization.
178.59ꢁ, respectively. The ZeLeue
J[CH2NCSe] 4c crystallize in the
monoclinic crystal system in the non-centrosymmetric space group
P21, with Z0¼1 with N]C]Se bond almost linear at an angle of
178.68ꢁ (Fig. 6). The selected bond lengths, crystal data and struc-
ture refinement parameters, selected torsion angles, and hydrogen
bonding geometry of the above crystals have been furnished in
Supplementary data.
2.5. Crystal structures of BocePhee
J
[CH2NC] 7d, BoceVale
J
[CH2NCSe] 3a, BocePhee
J[CH2NCSe] 3d, and ZeLeue
J
[CH2NCSe] 4c
It is important to mention that not many N-protected amino acid
derived synthons have been crystallized although a small portion of
conformationally restricted amino acid derivatives are studied
through X-ray crystallography. Recently, we had reported the crystal
structure of novel N-Boc-amino alkyl isothiocyanates obtained from
Gly and Phe.21 Guichard’s group reported the crystal structures of
succinimidyl carbamates of BoceProeOH and BoceProeValeOH,
which were derived from their corresponding isocyanates.41c In the
3. Summary
In summary, we have delineated a simple protocol for the
preparation of new classes of isoselenocyanates derived from Boc
as well as Z-protected amino acids. These two classes of chiral
OrgSeCs were isolated in good yields and fully characterized. The
isoselenocyanates 3 and 4 are storable at 0 ꢁC. Three samples of
N-Boc/Z-amino acid derived isoselenocyanates were obtained as
single crystals and their structure was confirmed through X-ray
crystallography. Straightforward reaction of isoselenocyanates 3
present work, three isoselenocyanates namely, BoceVale
[CH2NCSe] 3a, BocePhee [CH2NCSe] 3d, ZeLeue [CH2NCSe] 4c,
and an isonitrile BocePhee [CH2NC] 7d have been isolated as
J
J
J
J
crystals and their structures have been determined. To the best of
our knowledge, this is the first report on the crystal structure anal-
ysis of amino acid derivatives containing an isocyano group or iso-
selenocyanato group.
and
4
with amino components has yielded selenour-
eidopeptidomimetics and unsymmetrical selenoureas.
4. Experimental
4.1. General
BocePheeJ[CH2NC] 7d crystallizes in the orthorhombic
crystal system in the non-centrosymmetric space group P212121
with Z0¼1. Compound 7d (Fig. 5) shows the asymmetric unit and
the atom-numbering scheme (see Supplementary data). In the
asymmetric unit, the plane of the phenyl ring is tilted from the
rest of the molecule at a dihedral angle C5eC6eC11eC15 of
74.91ꢁ. As expected, the CeNþ^C bond is nearly linear, with
a C10eN2eC14 angle of 178.33ꢁ. The molecular assembly is
chiefly stabilized by an extensive network of NeH/O strong
All amino acids were used as obtained from SigmaeAldrich
Company, USA. Unless or otherwise mentioned, all amino acids
used were of L-configuration. All the solvents were dried and pu-
rified using recommended procedures in the literature whenever
necessary. High resolution mass spectra were recorded on
a Micromass Q-TOF micromass spectrometer using electron spray
ionization mode, elemental analyses were carried out using Carlo
Erba 1106 CHN analyzer, 1H NMR and 13C NMR spectra were
recorded on a Bruker AMX 300 MHz and 100 MHz spectrometer,
respectively, at the Indian Institute of Science, Bangalore. IR spectra
were recorded on a Schimadzu model FT-IR spectrometer at Ban-
galore University, Bangalore. Melting points were determined in an
open capillary and are uncorrected. TLC experiments were done
using MERCK TLC aluminum sheets (silica gel 60 F254) and
chromatograms were visualized by exposing in iodine chamber,
UV-lamp or spraying with KMnO4, and heating. Column chroma-
tography was performed on silica gel (100e200 mesh) using ethyl
acetate and hexane mixtures as eluent.
4.2. Typical procedure for formamides derived from Boc-
amino acids 6
To the CH2Cl2 solution of N-Boc-b-amino alkyl amine (10.0 mmol
5) at 0 ꢁC were added ethyl-3-(3-dimethylaminopropyl)carbodi-
imide (EDC) (2.1 g, 11.0 mmol) and 98% of formic acid (0.42 mL,
11.0 mmol). After stirring the mixture for 3 h, the reaction mixture
was filtered and the filtrate was evaporated under reduced pressure.
The crude mixturewas diluted with CH2Cl2 (20 mL) and was washed
with 5% Na2CO3, water, and brine, dried over anhydrous sodium
sulfate, and the solvent was removed in vacuo. The crude was sub-
jected to column purification (Silicagel 100e200 mesh, 20% EtOAc/
hexane).
Figure 5. Crystal structure of BocePheeJ[CH2NC] 7d showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms
have been omitted for the sake of clarity.

6722
G. Chennakrishnareddy et al. / Tetrahedron 66 (2010) 6718e6724
Figure 6. The molecular structures of A. BoceValeJ[CH2NCSe] 3a; B. BocePheeJ[CH2NCSe] 3d and C. ZeLeueJ[CH2NCSe] 4c showing the atom-labeling scheme. Displacement
ellipsoids are drawn at the 50% probability level and H atoms have been omitted for the sake of clarity.
4.2.1. (S)-tert-Butyl 1-formamido-3-methylbutan-2-ylcarbamate
(BoceVale [CH2NHCHO]) (6a). Compound 6a was prepared by the
crude was subjected to column purification (Silicagel 100e200 mesh,
20% EtOAc/n-hexane).
J
above method and purified by column chromatography using 5:1
hexanes/EtOAc to afford 6a (89%) as a white solid: mp 74e76 ꢁC; Rf
4.3.1. (S)-Benzyl 1-formamido-4-(methylthio)butan-2-ylcarba-
mate (ZeMeteJ[CH2NHCHO]) (9g). Compound 9a was prepared
25
value 0.24 (n-hexane/EtOAc 1:1); [
a
]
ꢀ4.1 (c 1.0, CHCl3); IR (KBr)
n
D
1654,1710; 1H NMR (300 MHz, DMSO-d6)
d
0.95 (6H, d, J¼6.7 Hz, eCH
by the above method and purified by column chromatography
using 5:1 hexanes/EtOAc to afford 9a (86%) as a white solid: mp
(CH3)2), 1.42 (9H, s, eC(CH3)3), 1.65e1.88 (1H, m, eCH(CH3)2),
3.25e3.37 (2H, m, eCH2eNHCHO), 4.08 (1H, m, eCHeCH2e), 6.62 (1H,
124e126 ꢁC; Rf value 0.22 (n-hexane/EtOAc 1:1); [
a]
25 ꢀ20.3 (c 1.0,
D
m, NH), 8.05 (1H, m, eNHCHO); 13C NMR (100 MHz, DMSO-d6)
d
18.5,
CHCl3); IR (KBr)
n
1666, 1703; 1H NMR (300 MHz, CDCl3)
d
1.61e1.72
19.3, 28.3, 29.1, 44.1, 54.2, 79.7, 155.4, 162.3; MS (ESI-HR) m/z calcd for
(2H, m, CH3eSeCH2CH2e), 2.04 (3H, s, CH3eSe), 2.47e2.58 (2H, m,
CH3eSeCH2e), 3.27e3.45 (2H, m, eCH2eNHCHO), 3.82 (1H, m,
eCHeCH2e), 5.02 (2H, s, AreCH2), 6.30 (1H, br, NH), 7.12e7.32 (5H,
C11H22N2NaO3 253.1528 (MþNaþ), found 253.1525 (MþNaþ).
m, ArH), 8.20 (1H, s, eNHCHO); 13C NMR (100 MHz, CDCl3)
d 16.0,
4.3. Typical procedure for formamides derived from Z-amino
acids 9
29.6, 31.8, 43.4, 54.1, 66.2, 127.3, 128.0, 128.7, 136.1, 156.4, 162.6; MS
(ESI-HR) m/z calcd for C14H20N2NaO3S 319.1092 (MþNaþ), found
319.1096 (MþNaþ).
To a THF solution of N-Z-
b
-amino acid (10.0 mmol) at ꢀ20 ꢁC were
added N-methylmorpholine (1.21 mL, 11.0 mmol) and ethyl chloro-
formate (1.05 mL,11.0 mmol). Afterstirring the mixture for 10 min, aq
sodium azide (975 mg, 15 mmol) was added and the stirring was
continued until completion of the reaction (TLC analysis). The re-
action mixture was concentrated under vacuum and the residue was
dissolved in 30.0 mL of CH2Cl2. The organic layer was washed with
20 mL each of 5% Na2CO3, 10% citric acid, water, and brine, dried over
anhydrous sodium sulfate, and evaporated under reduced pressure.
The resulting residue was dissolved in 15.0 mL of toluene and heated
at 65 ꢁC for 30 min under argon. Upon complete formation of the
isocyanate (strong IR peak at 2220 cmꢀ1 and absence of azide peak at
2100 cmꢀ1), toluene was removed in vacuo. The isocyanates obtained
were dissolved in 15 mL of dry CH2Cl2 and the solution was stirred at
ꢀ15 ꢁC with the addition of 98% formic acid (0.77 mL, 20 mmol) and
DMAP (36 mg, 0.3 mmol), till the end of the reaction. The reaction
mixture was diluted with CH2Cl2 and washed with 20 mL each of 10%
citric acid, 5% Na2CO3, water, and brine solution and dried over an-
hydrous Na2SO4 and the solvent was evaporated under vaccum. The
4.4. General procedure for the preparation N-Boc/Z-amino
acid derived isonitriles 7 and 10
Burgess reagent (3.57 g, 15.0 mmol) was added to a solution of
formamide 6aej or 9aej (10.0 mmol) in dry CH2Cl2 (20 mL) and the
resulting solution was refluxed till completion of the reaction (TLC).
It was diluted with CH2Cl2 (10 mL) and washed with water
(2ꢂ10 mL), brine (10 mL), dried over anhydrous sodium sulfate and
was concentrated in vacuo to obtain the crude product that was
purified by column chromatography (100e200 mesh silica gel)
using 10% ethyl acetate in hexane. Alternatively, the reaction mix-
ture was concentrated in vacuo and the crude compound was pu-
rified by column chromatography to obtain pure isonitrile.
4.4.1. (S)-tert-Butyl 1-isocyano-4-methylpentan-2-ylcarbamate
(BoceLeueJ[CH2NC]) (7b). Compound 7b was prepared by the
above method and purified by column chromatography using 9:1

G. Chennakrishnareddy et al. / Tetrahedron 66 (2010) 6718e6724
6723
hexanes/EtOAc to afford 7b (92%) as a white solid: mp 55e57 ꢁC; Rf
equimolar quantity of NMM in CH2Cl2) or an organic amine was
added and the reaction mixture was stirred at room temperature
for about 30 min. After the completion of reaction as monitored by
TLC, it was diluted with CH2Cl2 (10 mL), 10% citric acid solution
(10 mL) was added and the layers were separated. The organic layer
was subsequently washed with water, brine and finally dried over
anhydrous sodium sulfate. It was concentrated in vacuo to afford
the title compounds as pure solids.
value 0.47 (n-hexane/EtOAc 4:1); [
a
]
25 ꢀ22.4 (c 1.0, CHCl3); IR (KBr)
n
D
1687, 2146; 1H NMR (300 MHz, CDCl3)
d
1.01 (6H, d, J¼5.6 Hz, eCH
(CH3)2), 1.48 (9H, s, eC(CH3)3), 1.72e1.80 (2H, m, eCH2eCH(CH3)2),
1.88 (1H, m, eCH(CH3)2), 3.43e3.64 (2H, m, eCHeCH2e), 4.11 (1H, m,
eCHeCH2e), 5.28(1H, br, NH); 13C NMR (100 MHz, CDCl3)
d 22.0, 23.9,
24.1, 28.2, 40.7, 47.4, 49.4, 80.1, 154.3,156.2; MS (ESI-HR) m/z calcd for
C12H22N2NaO2 m/z 249.1579 (MþNaþ), found 249.1575 (MþNaþ).
4.4.2. (S)-Benzyl 1-isocyano-3-phenylpropan-2-ylcarbamate (ZePhee
J
4.6.1. (S)-tert-Butyl 1-(3-(3-chlorophenyl)selenoureido)-3-methylbutan-
[CH2NC]) (10e). Compound 10e was obtained as a white solid (93%):
2-ylcarbamate (BoceValeJ[CH2NHCSeNH]em-Cl-C6H4) (12a). Com-
mp 130e132 ꢁC; Rf value 0.45 (n-hexane/EtOAc 4:1); [
1.0, CHCl3); IR (KBr)
a]
25 ꢀ16.0 (c
pound 12a was prepared by the above method and purified by
column chromatography using 7:3 hexanes/EtOAc to afford 12a
(88%) as a white solid: mp 139e141 ꢁC; Rf value 0.40 (n-hexane/
D
n
1697, 2148; 1H NMR (300 MHz, CDCl3)
d
2.34e2.48 (2H, m, eCHeCH2eAr), 3.36e3.51 (2H, m, eCH2eNC),
3.92 (1H, m, eCHeCH2eNC), 5.12 (2H, s, AreCH2), 5.68 (1H, br, NH),
7.13e7.46 (10H, m, ArH); 13C NMR (100 MHz, CDCl3)
39.8, 42.4,
EtOAc 1:1); IR (neat) n d 0.95
1546, 1693; 1H NMR (300 MHz, CDCl3)
d
(6H, d, J¼5.6 Hz, eCH(CH3)2), 1.32 (9H, s, eC(CH3)3), 1.82 (1H, m,
eCH(CH3)2), 3.59 (1H, m, eCHeCH2eNHe), 3.65e3.80 (2H, m,
eCHeCH2eNHe), 4.72 (1H, br, NH), 7.19e7.55 (4H, m, ArH), 8.67
52.9, 67.3, 127.5, 128.4, 128.4, 128.9, 129.2, 130.1, 136.8, 137.9, 157.7,
163.0; MS (ESI-HR) m/z calcd for C18H18N2NaO2 317.1266 (MþNaþ),
found 317.1256 (MþNaþ).
(1H, br, NH); 13C NMR (100 MHz, CDCl3)
d
18.1, 28.1, 30.7, 52.7, 55.4,
79.9, 123.2, 125.2, 127.2, 130.8, 135.4, 137.2, 157.0, 179.1; 77Se NMR
4.5. General procedure for the synthesis of isoselenocyanates
3 and 4
(CDCl3) d 261.1; MS (ESI) m/z calcd for C17H26ClN3O2Se 442.1
(MþNaþ), found 442.2 (MþNaþ). Anal. Calcd for C17H26ClN3O2Se: C,
48.75; H, 6.26; N, 10.03. Found: C, 48.77; H, 6.29; N, 10.04.
To a solution of N-Boc/Z-amino acid derived isonitriles 7 or 10
(1 mmol) in dry THF (12 mL), TEA (0.97 mL, 0.7 mmol) and sele-
nium powder (2.37 g, 3 mmol) were added. It was refluxed for
a minimum of 5 h. After the completion of reaction (TLC), it was
allowed to cool to room temperature and was passed through a pad
of Celite. The filtrate was diluted with ethyl acetate (15 mL) and
washed with dilute citric acid (10 mLꢂ2), water (10 mLꢂ2), and
brine (10 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated. The crude was purified by column chro-
matography (silica gel 100e200 mesh, 10% ethyl acetate in hexane)
to afford the product as crystalline solid.
4.6.2. (S)-Methyl 2-(3-((S)-2-(benzyloxycarbonyl)-4-(methylthio)bu-
tyl)selenoureido) propanoate (ZeMeteJ[CH2NHCSeNH]eAlaeOMe)
(13d). Compound 13b was prepared by the above method and
purified by column chromatography using 5:1 hexanes/EtOAc to
afford 13b (95%) as gum; Rf value 0.35 (n-hexane/EtOAc 1:1); IR
(neat)
n d 1.10e1.45
1512, 1693, 1740; 1H NMR (300 MHz, CDCl3)
(3H, d, J¼5.7 Hz, eCHeCH3), 1.81e2.00 (2H, m, eCH2eCH2eSe),
2.05 (3H, s, eSeCH3), 2.55 (2H, m, eCH2eCH2eSe), 3.48e3.56 (2H,
m, eCHeCH2eNHe), 3.68 (3H, s, eCOOCH3), 3.82 (1H, m,
eCHeCH2eNe), 3.89 (1H, m, eNHeCHe), 5.31 (2H, s, AreCH2e),
7.14e7.48 (5H, m, ArH); 13C NMR (100 MHz, CDCl3,)
d
17.5, 17.9, 29.9,
4.5.1. (S)-tert-Butyl 1-isoselenocyanato-4-methylpentan-2-ylcarba-
31.9, 48.2, 49.5, 53.4, 56.2, 67.2,127.1,127.3,127.6,128.3,128.6,137.2,
mate (BoceLeue
J[CH2NCSe]) (3b). Compound 3b was prepared by
155.4,172.6,183.2; 77Se NMR (CDCl3)
d 262.2; MS (ESI-HR) m/z calcd
the above method and purified by column chromatography using
for C18H27N3O4SSe 484.0785 (MþNaþ), found 484.0781 (MþNaþ).
9:1 hexanes/EtOAc to afford 3b (95%) as a white solid: mp
25
89e91 ꢁC; Rf value 0.51 (n-hexane/EtOAc 4:1); [
a
]
ꢀ122.4 (c 1.0,
D
Acknowledgements
CHCl3); IR (KBr) n d 0.95 (6H,
1697, 2148; 1H NMR (300 MHz, CDCl3)
d, J¼5.2 Hz, eCH(CH3)2), 1.45 (9H, s, eC(CH3)3), 1.47e1.70 (3H, m,
eCH2eCH(CH3)2), 3.55e3.77 (2H, m, eCH2eNCSe), 4.61 (1H, m,
eCHeCH2eNCSe), 5.48 (1H, br, NH); 13C NMR (100 MHz, CDCl3)
Financial supports from the Department of Science and Technol-
ogy (grant no. SR/S1/OC-26/2008) and Council of Scientific and
Industrial Research (grant no. 01(2323)/09/EMR-II), Govt. of India are
gratefully acknowledged. We thank Bangalore University, Bangalore
for partial financial support. C.K. thanks CSIR, Govt. of India for Senior
Research Fellowship. We also acknowledge the Departments of
Organic Chemistry, Inorganic & Physical Chemistry and Sophisticated
Instrument Facility, Indian Institute of Science, Bangalore for re-
cording NMR and mass spectra. We thank Prof. K.M. Sivanandaiah for
hissupportand useful discussions and Dr. H.N. Gopi, IISER, Pune, India
for the needful assistance.
d
22.1, 24.8, 28.4, 40.8, 48.3, 49.8, 58.9, 80.2, 124.5, 155.1; 77Se NMR
(CDCl3)
d
ꢀ357.6; MS (ESI-HR) m/z calcd for C12H23N2NaO2Se
329.0744 (MþNaþ), found 329.0739 (MþNaþ).
4.5.2. (S)-Benzyl 1-isoselenocyanatopropan-2-ylcarbamate (ZeAlae
J
[CH2NCSe]) (4a). Compound 4a was prepared by the above method
and purified bycolumn chromatography using 5:1 hexanes/EtOAc to
25
afford 4a (91%) as gum. Rf value 0.49 (n-hexane/EtOAc 4:1); [
ꢀ11.6 (c 1.0, CHCl3); IR (neat)
1.25 (3H, d, J¼4.9 Hz, eCHeCH3), 3.35e3.55 (2H, m, CH2eNCSe),
4.20 (1H, m, eCHeCH2eNCSe), 5.10 (2H, s, AreCH2e), 7.23e7.48 (5H,
m, ArH); 13C NMR (100 MHz, CDCl3)
20.6, 53.4, 62.2, 69.0, 128.1,
a]
D
n
1714, 2148; 1H NMR (300 MHz, CDCl3)
d
Supplementary data
d
General remarks and product characterization data for all the
new compounds along with selected copies of IR, 1H NMR, 13C NMR,
77Se NMR, and HRMS spectra and crystal structure details and CIFs
of the compounds 7d, 3a, 3d, and 4c are provided. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2010.06.082.
128.5,128.7,128.9,134.6,155.1; 77Se NMR (CDCl3)
d
ꢀ356.6; MS (ESI)
m/z calcd for C12H14N2O2Se 321.0 (MþNaþ), found 321.0 (MþNaþ).
4.6. General procedure for the synthesis of Nb-Boc/Z-
protected unsymmetrical selenoureas 12 and
selenoureidopeptides 13
References and notes
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