Synthesis of ortho-carboranyl derivatives of (S)-asparagine and (S)-glutamine

Article abstract of DOI:10.1134/S1070428017050190

(S)-Asparagine and (S)-glutamine ortho-carboranyl derivatives with free amino and carboxy groups in the α-position were synthesized. By an example of N^γ-(1,2-dicarba-closo-dodecarboran-3-yl)-(S)-glutamine it was demonstrated that the developed synthetic approach carboranyl derivatives of amino acids allowed the preparation of optically pure isomers.

Full text of DOI:10.1134/S1070428017050190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 769–776. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © D.А. Gruzdev, G.L. Levit, V.А. Olshevskaya, V.P. Krasnov, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 5,
pp. 756–762.
Synthesis of ortho-Carboranyl Derivatives of (S)-Asparagine
and (S)-Glutamine
a
a
b
a
D. А. Gruzdev ,* G. L. Levit , V. А. Olshevskaya , and V. P. Krasnov
a
Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990 Russia
*
e-mail: gruzdev-da@ios.uran.ru
b
Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
Received February 25, 2017
Abstract—(S)-Asparagine and (S)-glutamine ortho-carboranyl derivatives with free amino and carboxy groups
γ
in the α-position were synthesized. By an example of N -(1,2-dicarba-closo-dodecarboran-3-yl)-(S)-glutamine
it was demonstrated that the developed synthetic approach carboranyl derivatives of amino acids allowed the
preparation of optically pure isomers.
DOI: 10.1134/S1070428017050190
γ
Dicarba-closo-dodecarboranes (carboranes) are
molecules of icosahedral structure including ten boron
atoms and two carbon atoms. Introduction of different
substituents at carbon atoms or boron atoms opens a
synthetic route to compounds of various structures [1,
composition and optical purity. N -Carboranylglutami-
ne was previously obtained as salt of trifluoracetic acid
[14], however the free amino acid was not isolated from
salt and its enantiomeric purity was not determined.
O
2
]. Carborane moieties are used as building blocks in
HN
designing the molecular devices, liquid crystals, and
nanomaterials [3–6]. The introduction of carborane
fragments in the structures of biomolecules [7–10],
including natural amino acids [11–14], is an important
way to novel bioactive compounds, as well as reagents
for boron neutron capture therapy of cancer.
i-Pr
CO Bu-t
2
NHAc
1
Hereinafter: ○ are BH groups and B atoms, ● are CH
groups and C atom.
Derivatives of polyfunctional amino acids with free
α-amino and α-carboxy groups are especially promising
for creation of new pharmaceuticals (pharmaceutical
agents) [15–18]. Compounds capable to self-
organization into ordered nanostructures exhibiting
piezoelectric properties were found among amino acids
and their derivatives. Amide 1 obtained from [3-
The most convenient precursors for N-carbonyl
amino acids 2 and 3 are α-tert-butyl amino esters 4 and
5. To obtain esters 4 and 5 with protected α-functional
groups we carried out esterification of readily available
monomethyl esters of (S)-aspartic acid (6) or (S)-
(
acetylamino)-о-carboran-1-yl]acetic acid and natural
amino acid valine has piezoelectric coefficient
exceeding that of classic inorganic piezoelectrics [19].
Scheme 1.
We have obtained derivatives of (S)-asparagine 2
and (S)-glutamine 3 with a fragment of о-carborane
and free α-amino acid groups, which allows using these
compounds as analogs of α-amino acids (Scheme 1).
BocHN
CO Bu-t
2
O
NH2
( )
n
HO C
2
N
H
( )n
2, 3
CO H
2
Biological and physical properties of chiral
compounds significantly depend on stereoisomeric
4, 5
n = 1 (2, 4), 2 (3, 5).
7
69

7
70
GRUZDEV et al.
Scheme 2.
_
Cl
o
1
2
. t-BuOAc, HClO (cat.), 20 C
H N
3
CO H
4
H N
2
CO Bu-t
BocHN
CO Bu-t
2
2
2
_
. Na CO , H O Et O
Boc O, Et N
2 3
2
3
2
2
o
(
)n
( )n
DMF, 20 C
( )n
MeO C
MeO C
MeO C
2
2
2
6
, 7
8, 9
10, 11
LiOH,
_
THF H O,
2
_
_
o
5
20 C
4
, 5
BocHN
CO Bu-t
o
2
1
2
. Boc O, Et N, DMF, 20 C
2 3
o
. Boc O, DMAP, t-BuOH, 40 C
2
7
CO Me
2
1
1, ee 86%
n = 1 (6, 8, 10), 2 (7, 9, 11).
glutamic acid (7) followed by introduction of N-Boc
groups with subsequent selective hydrolysis of methyl
esters 10 and 11. Amino diesters 8 and 9 were obtained
from compounds 6 and 7 by treating with tert-butyl
compound 4 starting from protected puroglutamic acid
was also described [29]. The comparison of values of
specific rotation and melting points of compounds 4
and 5 and intermediate compounds 10 and 11 with the
published data indicates that the synthesis of
selectively protected amino acids 4 and 5 according to
Scheme 2 was not accompanied by racemization.
acetate in the presence of HClO . Compounds 8 and 9
4
are unstable in a free state, so in following
transformations they were used directly after their
isolation and purification. The introduction of Boc
group into amino esters 8 and 9 and the hydrolysis of
methyl esters 10 and 11 under mild alkaline conditions
resulted in selectively protected amino acids 4 and 5 in
An alternative sequence of protective groups
introduction (first of Boc group followed by
esterification with tert-butyl alcohol in the presence of
DCC or Boc O/DMAP [27–31]) resulted in partial
2
2
9 and 33% overall yield, respectively (Scheme 2).
racemization of protected glutamic acid 9 (86% ee by
polarimetry). Evidently, the partial racemization
occured at the stage of tert-butyl ester formation from
the Boc-amino acid [32].
Hardly available tert-butyl methyl N-Cbz-amino
diesters were selected as the starting compounds in the
published approach to the synthesis of compounds 4
and 5 [20]. Other synthetic routes to compounds 4 and
Coupling of о-carboran-3-amine 12 [33] and acids
4 and 5 by the method of mixed anhydrides resulted in
tert-butyl esters 13 and 14 (77 and 69% yield
respectively). After the removal of protecting groups in
5
were also described; they distinguished by the nature
of applied protecting groups and by the sequence of
their introduction and removal [21–28]; the synthesis of
Scheme 3.
_
o
O
NHBoc
( )
CO Bu-t
n
1. EtOCOCl, MeN(CH CH ) O, THF, 15 C
2 2 2
_
_
o
2
. Et N, THF, 15 20 C
3
+
O
NHBoc
CO Bu-t
HO
2
NH2
N
H
( )
13, 14
, 3
n
2
4
, 5
12
o
1
2
. TFA, CH Cl , 20 C
2 2
. NaOH, AcOH, H O
2
2
n = 1 (13), 2 (14).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

SYNTHESIS OF ortho-CARBORANYL DERIVATIVES OF (S)-ASPARAGINE AND
771
Scheme 4.
o
1
2
. 6N HCl, PhOH, 110 C, 24 h
_
_
o
. SOCl , MeOH, 10 20 C
2
_
o
O
3. BzCl, Et N, CH Cl , 0 20 C
MeO C
CO Me
2
3
2
2
2
CO H
2
N
H
NHBz
NH2
3
15
HO C
CO H
2
2
1
5
NH2
S)-Glu
(
the amino acid fragment by treating with TFA followed
by neutralization with equimolar amount of NaOH we
EXPERIMENTAL
β
1
13
smoothly obtained N -(о-carboranyl)-(S)-asparagine 2
H and C NMR spectra were registered on Bruker
DRX-400 (400 and 100 MHz respectively) and Bruker
Avance 500 (500 and 125 MHz respectively) spec-
trometers, TMS as an internal reference. Melting
points were measured on a Stuart SMP3 apparatus
γ
and N -(о-carboranyl)-(S)-glutamine 3. Compounds 2
and 3 are poorly soluble in water and precipitated from
aqueous solutions at pH 5–6 as hydrates (according to
the elemental analysis data) (Scheme 3).
(
Barloworld Scientific, Great Britain). Specific
To confirm the optical purity of (S)-glutamine
derivative 3 we converted it into dimethyl N-benzoyl-
rotation, deg·mL/(g·dm), was determined on a Perkin
Elmer Model 341 polarimeter, solution concentration
g/100 mL. Elemental analysis was carried out on a
Perkin Elmer 2400 II CHNS automatic analyzer. High
resolution mass spectra were registered on a Bruker
maXis impact HD instrument, electrospray ionization
(
S)-glutamate 15 that was analyzed by HPLC on a
chiral stationary phase. Dimethyl ester 15 was obtained
as a result of acidic hydrolysis of compound (S)-3 [34]
and subsequent treatment of the formed (S)-glutamic
acid with thionyl chloride in methanol and benzoyl
chloride in methylene chloride. Reference compounds
for HPLC analysis of amino acids (S)-15 and (RS)-15
were specially synthesized from an enantiomerically
pure (S)-glutamic acid and a racemate (Scheme 4).
(
ESI) in positive ions mode, carrier gas (nitrogen) flow
rate 4 L/min, pressure in nebulizer 0.4 bar, pin voltage
.5 kV.
4
Enantiomeric composition of compound 15 was
determined by the chiral HPLC on a Knauer Smart-line
1100 instrument (Knauer Wissen-schaftliche Geräte,
Enantiomeric excess (ee) of compound 15 obtained
from carborane 3 was 97.6% (according to HPLC data
on a chiral stationary phase). The treatment of
enantiomerically pure (S)-glutamic acid similarly to
compound 3 also resulted in diester 15, 97.6% ee.
-
Germany), Chiralcel OD-H column, 5 µm (Daicel
Corp., Japan), detection at 230 nm, mobile phase
hexane–MeOH–i-PrOH, 10 : 0.8 : 0.2, elution rate 1.0
mL/min. For flash column chromatography Silica gel
Thus, for the first time we synthesized (1,2-dicarba-
closo-dodecarboran-3-yl) derivatives of (S)-as-
paragine and (S)-glutamine. The applied approach to
the synthesis of asparagine and glutamine derivatives
with free α-amino and α-carboxy groups allows the
preparation of enantiomerically pure derivatives of
amino acids with an ortho-carboranyl substitutent in
the side chain. The obtained carboranyl derivatives of
amino acids may be applied to the production of
piezoelectric materials, and also as potential reagents
for boron neutron capture therapy of cancer.
6
0 0.063–0.040 mm (Alfa Aesar, Great Britain) was
used; for TLC, Sorbfil plates (Imid, Russia). TLC
detection of compounds 2–5 and 8–11 was performed
with 0.2% ninhydrin in acetone; of compounds 13 and
1
4, with Denigés’ reagent; of compound 15, with UV
irradiation.
β-Methyl (S)-asparagine hydrochloride [35], γ-
methyl (S)-glutamate hydrochloride [36], and dimethyl
(S)-glutamate hydrochloride [37] were obtained by
known methods.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
72
GRUZDEV et al.
13
Diesters 8 and 9. General procedure. tert-Butyl
5.43 d (1H, NH, J 7.4 Hz). C NMR spectrum (125 МHz,
acetate (82 mL) was added to a solution of
CDCl , 25°C), δ, ppm: 27.87 (3C), 28.30 (3C), 36.98,
3
hydrochloride of methyl ester 6 or 7 (12.2 mmol) in
50.56, 51.79, 79.86, 82.31, 155.41, 169.95, 171.33.
2
.45 mL of 58% HClO at vigorous stirring. The
Found, %: C 55.46; H 8.48; N 4.46. С Н NО .
4
14 25
6
mixture was stirred at room temperature for 72 h, then
poured into cooled (5°C) mixture of 270 mL of 10%
Na CO solution and 40 mL of Et O. The organic layer
Calculated, %: C 55.43; H 8.31; N 4.62.
α-tert-Butyl γ-methyl N-tert-butoxycarbonyl-(S)-
glutamate (11). Yield 2.21 g (86%). Colorless powder, mp
2
3
2
was separated, the reaction products were extracted
20
6
3.5–65.0°C (62–63.5°C [20], 65–67°C [39]), [α]D –28.5
from the aqueous layer with Et O (2 × 70 mL).
25
2
(c 1.1, MeOH) {[α]D –25.0 (c 1.0, MeOH) [20]; –28.2 (c
Combined organic layers were washed with 10%
solution of Na CO (2 × 100 mL), dried over Na SO ,
1
1
.52, MeOH) [40]}. H NMR spectrum (400 MHz,
2
3
2
4
CDCl , 25°C), δ, ppm: 1.44 s (9H, t-Bu), 1.47 s (9H, t-
3
and evaporated. The residue was purified by flash
chromatography (eluent CH Cl –MeOH, 98 : 2).
3B
3A
Bu), 1.87–1.96 m (1H, H ), 2.11–2.20 m (1H, H ),
.32–2.47 m (2H, H ), 3.68 s (3H, CO Me), 4.18–4.23
m (1H, H ), 5.07 d (1H, NH, J 7.5 Hz). C NMR
spectrum (125 МHz, CDCl , 25°C), δ, ppm: 27.97
4
2
2
2
2
2
13
α-tert-Butyl β-methyl (S)-aspartate (8). Yield 1.29 g
1
(
52%). Colorless oily substance. H NMR spectrum
3
(
3C), 28.11, 28.30 (3C), 30.11, 51.71, 53.40, 79.75,
(
400 MHz, CDCl , 25°C), δ, ppm: 1.46 s (9H, t-Bu),
3
3
B
3A
8
8
8
2.17, 155.36, 171.29, 173.30. Found, %: C 56.92; H
.78; N 4.34. С Н NО . Calculated, %: C 56.77; H
.57; N 4.41.
2
1
4
.66 d.d (1H, H , J 16.2, 7.2 Hz), 2.76 d.d (1H, H , J
2
6.2, 4.9 Hz), 3.70 s (3H, CO Me), 3.71 d.d (1H, H , J 7.2,
15 27
6
2
1
3
.9 Hz). C NMR spectrum (125 МHz, CDCl , 25°C),
3
δ, ppm: 27.91 (3C), 39.03, 51.74, 51.83, 81.56, 171.74,
Compound (11). Scalemic sample. Boc O (5.70 g,
6.11 mmol) was added to a solution of 4.30 g
(21.76 mmol) of γ-methyl (S)-glutamate hydrochloride
2
+
1
73.34. Mass spectrum: m/z 204.1233 [M + H] .
2
C H NO . M 204.1230.
9
18
4
calc
and 4.57 g (54.40 mmol) of NaHCO in a mixture of
3
α-tert-Butyl γ-methyl (S)-glutamate (9). Yield
.35 g (51%). Colorless oily substance. H NMR spectrum
1
22 mL of H O and 44 mL of 1,4-dioxane at 0°C. The
2
1
(
1
(
reaction mixture was stirred at 0°C for 15 min, then at
20°C for 20 h and evaporated to half a volume. The
mixture was diluted with 50 mL of 5% aqueous NaHCO3
400 MHz, CDCl , 25°C), δ, ppm: 1.47 s (9H, t-Bu),
3
3
B
3A
.77–1.88 m (1H, H ), 2.00–2.09 m (1H, H ), 2.47 t
2H, H , J 7.6 Hz), 3.35 dd (1H, H , J 8.2, 5.2 Hz),
.68 s (3H, CO Me). C NMR spectrum (125 МHz,
4
2
1
3
and washed with Et O (3 × 25 mL). The aqueous
2
3
2
solution was acidified with citric acid to pH 3–4, the
reaction products were extracted with EtOAc (3 × 50 mL).
Organic layers were washed with brine (2 × 100 mL),
dried over Na SO , evaporated. The obtained γ-methyl
CDCl , 25°C), δ, ppm: 28.01 (3C), 29.82, 30.48,
3
5
1.62, 54.32, 81.22, 173.71, 174.87. Mass spectrum:
+
m/z 218.1384 [M + H] . C H NO . M 218.1387.
1
0
20
4
calc
2
4
Diesters 10 and 11. General procedure. Boc O
N-Boc-(S)-glutamate (4.21 g, 16.1 mmol) and 0.20 g
(0.16 mmol) of 4-(dimethylamino)pyridine were
dissolved in 22 mL of tert-butyl alcohol and a solution
2
(
1.94 g, 8.9 mmol) was added to a solution of 8.1 mmol
of diester 8 or 9 and 1.13 mL (8.1 mmol) of Et N in
3
1
3 mL of DMF. The mixture was stirred at room
of 4.19 g (19.3 mmol) of Boc O in 12 mL of tert-butyl
2
temperature for 20 h, then 40 mL of EtOAc was added.
The solution was washed with 10% solution of citric
acid (3 × 30 mL) and over brine (2 × 30 mL), dried with
Na SO , evaporated. The residue was purified by flash
alcohol was added. The reaction mixture was stirred
for 3 h at 40°C. A dark solution was evaporated, the
residue was purified by flash chromatography (eluent
hexane–EtOAc, from 95 : 5 to 80 : 20). Yield 2.71 g
(41%). Colorless oily substance, solidifying at storage,
2
4
chromatography (eluent hexane–EtOAc, 85 : 15).
2
0
8
5
6% еe, [α]D –24.6 (c 1.0, MeOH). Found, %: C
6.97; H 8.80; N 4.44. С Н NO . Calculated, %: C
α-tert-Butyl β-methyl N-tert-butoxycarbonyl-(S)-
aspartate (10). Yield 1.82 g (74%). Colorless powder,
1
5
27
6
2
0
56.77; H 8.57; N 4.41.
mp 51.5–53.5°C (52–54°C [38], 56–58°C [20]), [α]
D
2
0
+
[
17.0 (c 1.0, CHCl ) {[α] +16.7 (c 0.026, CHCl3)
38]}. H NMR spectrum (400 МHz, CDCl , 25°C), δ,
Esters 4 and 5 (general procedure). 0.2 N solution
of LiOH (38 mL, 7.6 mmol) was added to a solution of
6.9 mmol of N-Boc-diester 10 or 11 in 38 mL of THF
cooled to 0°C. The mixture was stirred at 0°C for 30 min,
then for 20 h at room temperature. The solution was
3
D
1
3
ppm: 1.45 s (9H, t-Bu), 1.46 s (9H, t-Bu), 2.77 d.d
3
B
3A
(
4
1H, H , J 16.6, 5.0 Hz), 2.95 d.d (1H, H , J 16.6,
2
.4 Hz), 3.69 s (3H, CO Me), 4.43–4.47 m (1H, H ),
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

SYNTHESIS OF ortho-CARBORANYL DERIVATIVES OF (S)-ASPARAGINE AND
773
evaporated by half, 20 mL of 5% aqueous solution of
1.00 mmol) was added to solution of 1.00 mmol of
protected amino acid 4 or 5 and 0.11 mL (1.00 mmol)
of 4-methylmorpholine in 9 mL of THF cooled to –15°C.
The mixture was stirred for 25 min at –15÷–10°C, then
a solution of 0.23 mL (1.67 mmol) of triethyl-amine in
7.5 mL of THF and 0.13 g (0.83 mmol) of 3-amino-1,2-
dicarba-closo-dodecarborane 12 were added. The
reaction mixture was stirred for 20 h at 20°C, then
evaporated. The residue was purified by flash
chromatography (eluent benzene–EtOAc).
NaHCO was added, the mixture was washed with
3
Et O (2 × 15 mL). Aqueous layer was acidified with
2
citric acid to pH 3–4, the reaction products were
extracted with Et O (4 × 20 mL). The organic layer
2
was washed with brine (50 mL), dried over Na SO ,
2
4
evaporated. The residue was recrystallized from a
hexane–EtOAc, 85 : 15 mixture.
(
S)-4-tert-Butoxy-3-(tert-butoxycarbonylamino)-
-oxobutanoic acid (4). Yield 1.52 g (76%). Colorless
powder, mp 109.0°C (hexane–EtOAc) (97–98°C [21],
8–100°C [24], 97–99°C [28], 99–100°C [23], 104.8°C
4
tert-Butyl (S)-2-(tert-butoxycarbonylamino)-4-
[(1,2-dicarba-closo-dodecarboran-3-yl)-amino]-4-
oxobutanoate (13). Yield 0.28 g (77%). Colorless
9
2
D
0
[25], 105–106°C [41], 106°C [20]), [α] –23.9 (c 1.0,
2
3.5
1
20
MeOH) {[α]D –23.6 (c 1.5, MeOH) [28]}. H NMR
powder, mp 167.5–168.5°C (hexane–CH Cl ), [α]
2
2
D
1
spectrum (400 MHz, CDCl , 25°C), δ, ppm (confor-
+18.2 (c 0.7, CH Cl ). H NMR spectrum (400 MHz,
3
2 2
mers A and B, 8 : 2): 1.45 s (9H, t-Bu), 1.46 s (9H, t-
DMSO-d , 100°C), δ, ppm: 1.39 s (9H, t-Bu), 1.40 s
6
3
B
3B
Bu), 2.83 d.d (1H, H , J 17.1, 4.1 Hz), 3.01 d.d (1H,
(9H, t-Bu), 2.58 d.d (1H, H , J 15.8, 6.9 Hz), 2.66 d.d
3
A
2
3A
H , J 17.1, 4.2 Hz), 4.30 br.s [0.2H, H (B)], 4.43–4.48
(1H, H , J 15.8, 5.7 Hz), 1.40–3.20 br.s (9H, BH),
2
2
m [0.8H, H (A)], 5.45 d [0.8H, NH (A), J 7.5 Hz],
.93 br.s [0.2H, NH (B)]. C NMR spectrum (125 МHz,
4.20–4.34 m (1H, H ), 4.83 s (2H, CHcarborane), 6.46 br.s
1
3
13
5
(1H, NHBoc), 8.00 s (1H, BNH). C NMR spectrum
CDCl , 25°C), d, ppm (conformers A and B): 27.83
(125 MHz, DMSO-d , 25°C), δ, ppm: 27.54 (3C),
3
6
(
5
3C, A and B), 28.29 (3C, A and B), 36.85 (A and B),
0.36 (A), 51.73 (B), 80.11 (A), 81.33 (B), 82.56 (A
and B), 155.51 (A), 155.84 (B), 169.58 (B), 169.78
A), 174.74 (B), 176.25 (A). Found, %: C 53.76; H
28.11 (3C), 38.33, 50.62, 56.98, 57.27, 78.15, 80.48,
155.13, 170.65, 173.52. Found, %: C 42.06; H 8.15; N
6.44. C H B N O . Calculated, %: C 41.84; H 7.96;
15
34 10
2
5
(
N 6.51.
8
8
.14; N 4.78. С Н NO . Calculated, %: C 53.97; H
13 23 6
tert-Butyl (S)-2-(tert-butoxycarbonylamino)-5-
(1,2-dicarba-closo-dodecarboran-3-yl)amino]-5-oxo-
.01; N 4.84.
S)-5-α-tert-Butoxy-4-(tert-butoxycarbonyl-
[
(
pentanoate (14). Yield 0.25 g (69%). Colorless powder,
2
0
1
amino)-5-oxopentanoic acid (5). Yield 1.57 g (75%).
mp 76–79°C, [α]D –14.1 (c 0.74, MeOH). H NMR
Colorless powder, mp 111–114°C (hexane–EtOAc)
spectrum (400 MHz, DMSO-d , 100°C), δ, ppm: 1.39
6
3
B
(
1
103.5–105.5°C [29], 102–105°C [22], 108–111°C [24],
10–114°C [20]), [α]D –30.6 (c 1.0, MeOH) {[α]D
s (9H, t-Bu), 1.41 s (9H, t-Bu), 1.74–1.82 m (1H, H ),
2
0
20
3A
4
1.90–1.97 m (1H, H ), 2.28 t (2H, H , J 7.6 Hz), 1.40–
2
–
27.5 (c 0.6, MeOH) [24]; –30.2 (c 1.0, MeOH) [20]}.
3.10 br.s (9H, BH), 3.84 d.d.d (1H, H , J 8.4, 8.3, 5.4
1
H NMR spectrum (400 MHz, CDCl , 25°C), δ, ppm
Hz), 4.86 s (2H, CH
7.90 s (1H, BNH). C NMR spectrum (125 MHz,
), 6.49 br.s (1H, NHBoc),
3
carborane
1
3
(
(
conformers A and B, 8 : 2): 1.45 s (9H, t-Bu), 1.47 s
3
B
9H, t-Bu), 1.86–1.94 m (1H, H ), 2.13–2.22 m (1H,
DMSO-d , 25°C), δ, ppm: 26.04, 27.60 (3C), 28.11
6
3
A
4
2
H ), 2.37–2.52 m (2H, H ), 4.01–4.11 m [0.2H, H
(
(
(3C), 32.84, 53.72, 57.04, 57.13, 78.01, 80.24, 155.45,
171.51, 175.64. Found, %: C 43.23; H 8.42; B 24.50;
N 6.05. C H B N O . Calculated, %: C 43.23; H
2
B)], 4.20–4.25 m [0.8H, H (A)], 5.16 d [0.8H, NH
1
3
A), J 7.4 Hz], 5.60 br.s [0.2H, NH (B)]. C NMR
1
6
36 10
2
5
spectrum (125 МHz, CDCl , 25°C), δ, ppm (confor-
8.16; B 24.32; N 6.30.
3
mers A and B): 27.40 (B), 27.99 (3C, A and B), 28.12
Compounds 2 and 3 (general procedure). A
solution of 0.30 mmol of protected derivative 13 or 14
in 2 mL of a mixture CH Cl –CF CO H, 1 : 1,
was stirred for 4 h at 20°C, then evaporated. The
residue was dried in a vacuum. The reaction
product as a salt of trifluoroacetic acid was
dissolved in 0.5 mL of MeOH, and a solution of
(
A), 28.30 (3C, A and B), 30.15 (A and B), 53.30 (A),
5
1
1
4
4
4.77 (B), 80.05 (A), 81.09 (B), 82.20 (B), 82.42 (A),
55.62 (A), 155.98 (B), 170.99 (B), 171.28 (A),
77.46 (B), 177.80 (A). Found, %: C 55.27; H 8.43; N
.54. С Н NO . Calculated, %: C 55.43; H 8.31; N
.62.
N-(ortho-Carboran-3-yl)amides 13 and 14
general procedure). Ethyl chloroformate (0.096 mL,
2
2
3
2
14
25
6
0.024 g (0.60 mmol) NaOH in 2.0 mL of H O was
2
(
added. Acetic acid (17 µL, 0.3 mmol) was added to the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

7
74
GRUZDEV et al.
obtained solution. The residue was filtered, dried in a
vacuum over P O .
residue was purified by flash chromatography on silica
gel (eluent hexane–EtOAc, 7 : 3).
2
5
β
N -(1,2-Dicarba-closo-dodecarboran-3-yl)-(S)-
asparagine (2). Yield 0.056 g (68%). Colorless
Dimethyl N-benzoyl-(S)-glutamate [(S)-15]. Yield
0.37 g (91%). Colorless powder, mp 81–83°C (79–80°C
2
0
20
powder, mp 168–169°C, [α] –21.1 (c 0.5, MeOH).
H NMR spectrum (400 MHz, DMSO-d , 25°C), δ,
ppm: 2.82–2.88 m (1H, H ), 3.46 br.s (2H, H ), 1.30–
.90 br.s (9H, BH), 5.04 s (2H, CHcarborane), 6.20–8.60
br.s (3H, NH and CO H), 8.98 s (1H, BNH).
NMR spectrum (125 МHz, DMSO-d , 25°C), δ, ppm:
[43]), [α]D +21.0 (c 0.97, CHCl ), 99.6% еe. HPLC:
D
3
1
1
τ(R)-15 16.8 min (0.2%), τ(S)-15 24.8 min (99.8%). H
6
2
3
NMR spectrum (500 MHz, DMSO-d , 25°C), δ, ppm:
6
3
B
3A
3
2.12–2.20 m (1H, H ), 2.30–2.37 m (1H, H ), 2.42–
2.56 m (2H, H ), 3.66 s (3H, OMe), 3.79 s (3H, OMe),
4.81–4.85 m (1H, H ), 7.02 d (1H, NH, J 6.9 Hz), 7.44–
1
3
4
C
2
2
2
6
3
8.11, 50.46, 57.23, 57.55, 169.20, 174.60. Found, %:
7.47 m (2H, Ph), 7.51–7.54 m (1H, Ph), 7.82–7.83 m
(2H, Ph). Found, %: C 60.30; H 6.07; N 4.75.
C H NO . Calculated, %: C 60.21; H 6.14; N 5.02.
C 25.10; H 7.00; N 9.35. C H B N O ·H O.
Calculated, %: C 24.65; H 6.90; N 9.58.
6
18 10
2
3
2
1
4
17
5
γ
N -(1,2-Dicarba-closo-dodecarboran-3-yl)-(S)-
glutamine (3). Yield 0.074 g (81%). Colorless powder,
Dimethyl N-benzoyl-(RS)-glutamate [(RS)-15].
Yield 0.38 g (92%). Colorless oily substance solidi-
fying at storage, mp 64–66°C. HPLC: τ 16.8 min
2
0
mp 164–166°C (decomp) (EtOH–H O), [α] –6.4 (c
.44, MeOH). H NMR spectrum (400 MHz, DMSO-d ,
5°C), δ, ppm: 1.78–1.93 m (2H, H ), 2.34–2.40 m
2H, H ), 3.20 t (1H, H , J 6.3 Hz), 1.50–2.70 br.m
9H, BH), 5.11 s (2H, CHcarborane), 7.60 br.s (3H, NH
and CO H), 8.67 s (1H, BNH). C NMR spectrum
125 MHz, DMSO-d , 25°C), δ, ppm: 26.71, 33.15,
3.39, 57.35, 169.96, 176.22. Found, %: C 27.62; H
.22; B 35.03; N 8.85. C H B N O ·H O. Calculated,
: C 27.44; H 7.24; B 35.29; N 9.14.
Dimethyl (RS)-glutamate hydrochloride. SOCl2
0.65 mL, 8.87 mmol) was added to 5.5 mL of
methanol cooled to –10°C. The mixture was stirred for
5 min at –10°C, then 0.37 g (2.22 mmol) of (RS)-
glutamic acid monohydrate was added. The reaction
mixture was stirred at room temperature for 17 h. The
solution was evaporated, the residue was treated with
2
D
(R)-15
1
1
0
2
(
(
(50%), τ(S)-15 24.8 min (50%). H NMR spectrum was
identical to that of compound (S)-15. Found, %: C
60.42; H 5.98; N 4.78. C H NO . Calculated, %: C
6
3
4
2
1
4
17
5
2
60.21; H 6.14; N 5.02.
1
3
2
Hydrolysis of compound 3. A solution of 0.064 g
0.21 mmol) of compound 3 in 15.3 mL of 6 N HCl,
(
6
(
5
containing 0.1% of phenol was incubated for 24 h in a
sealed flask at 110–115°C. The solution was evapo-
rated, the residue was dried in a vacuum over P O and
7
7
20 10
2
3
2
%
2
5
KOH. The hydrolyzate was dissolved in 3.0 mL of
MeOH, and 155 µL (2.09 mmol, 10 equiv) of SOCl2
was added at –5–0°С. The mixture was stirred for
15 min at –5–0°C and for 18 h at room temperature,
then evaporated and dried in a vacuum over P O and
(
1
2
5
KOH. The obtained residue was dissolved in 4.0 mL of
CH Cl , 310 µL (2.20 mmol, 10.5 equiv) of Et N and
2
2
3
1
2 mL of Et O. The precipitate was filtered off, dried
97 µL (0.84 mmol, 4 equiv) of benzoyl chloride was
added to this solution at 0°C. The mixture was stirred
at room temperature for 2 h. CH Cl (10 mL) was
added to the solution and the mixture was washed
successively with 1 N HCl (3 × 8 mL), brine (2 × 8 mL),
2
in a vacuum over P O and KOH. Yield 0.46 g (99%).
Colorless powder, mp 156–157°C (149°C [42]). H
and C NMR spectra are similar to the spectra of (S)-
enantiomer [37]. Found, %: C 39.60; H 6.52; Cl 16.68;
N 6.50. C H ClNO . Calculated, %: C 39.72; H 6.67;
2
5
1
2
2
13
5% solution of NaHCO (2 × 8 mL), water (2 × 8 mL).
7
14
4
3
Cl 16.75; N 6.62.
The organic layer was dried over MgSO
The residue was purified by flash chromatography
eluent hexane–EtOAc, 7 : 3). Yield 0.058 g (99%).
Yellowish oily substance, 97.6% еe. HPLC: τ(R)-15
4
, evaporated.
Esters 15 (general procedure). Benzoyl chloride
0.26 mL, 2.20 mmol) was added to a mixture of 0.31 g
1.46 mmol) of dimethyl glutamate hydrochloride, 6 mL
(
(
(
1
6.8 min (1.2%), τ(S)-15 24.8 min (98.8%).
of CH Cl , and 0.82 mL (5.86 mmol) of Et N, cooled
2
2
3
to 0°C, the mixture was stirred for 2 h at room tempe-
rature, then 15 mL of CH Cl was added and the
Control experiment was performed similarly using
0.088 g (0.59 mmol) of (S)-glutamic acid (ee ≥ 99.6%),
2
2
reaction mixture was washed successively with 1N
HCl (3 × 12 mL), brine (2 × 12 mL), 5% solution of
44 mL of 6N HCl with 0.1% of phenol, 8.1 mL of
MeOH, 0.43 mL (5.95 mmol) of SOCl , 10.5 mL of
2
NaHCO (2 × 12 mL), and water (2 × 12 mL). The
CH Cl , 0.87 mL (6.24 mmol) of Et N, 0.28 mL
3
2
2
3
organic layer was dried over MgSO , evaporated. The
(2.38 mmol) of benzoyl chloride. Yield 0.16 g (99%).
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

SYNTHESIS OF ortho-CARBORANYL DERIVATIVES OF (S)-ASPARAGINE AND
775
Yellowish oily substance, 97.6% еe. HPLC: τ(R)-15
Krasnov, V.P., and Chupakhin, O.N., Russ. Chem. Bull.,
2
010, vol. 59, p. 110. doi 10.1007/s11172-010-0052-0
1
6.8 min (1.2%), τ(S)-15 24.8 min (98.8%).
1
1
5. Walker, I., Nicholls, D., Irwin, W.J., and Freeman, S.,
ACKNOWLEDGMENTS
Int. J. Pharm., 1994, vol. 104, p. 157.
6. Bonina, F.P., Arenare, L., Palagiano, F., Saija, A.,
Nava, F., Trombetta, D., and de Caprariis, P., J. Pharm.
Sci., 1999, vol. 88, p. 561.
Authors are grateful to M.A. Ezhikova and
Candidate of Chemical Sciences М.I. Kodess for
registering the NMR spectra, to Candidate of Chemical
Sciences I.N. Ganebnykh for registering mass spectra,
to L.Sh. Sadretdinova for performing HPLC analysis.
17. Peura, L., Malmioja, K., Huttunen, K., Leppänen, J.,
Hämäläinen, M., Forsberg, M.M., Rautio, J., and Laine, K.,
Pharm. Res., 2013, vol. 30, p. 2523. doi 10.1007/
s11095-012-0966-3
The study was financially supported by the Russian
Foundation for Basic Research (grant no. 16-33-
1
8. Singh, V.K. and Subudhi, B.B., Med. Chem. Res., 2015,
vol. 24, p. 624.
6
0122).
1
9. Nuraeva, A.S., Vasileva, D.S., Vasilev, S.G., Zelenov-
skiy, P.S., Gruzdev, D.A., Krasnov, V.P., Olshevs
kaya, V.A., Kalinin, V.N., and Shur, V.Ya.,
Ferroelectrics, 2016, vol. 496, p. 1. doi 10.1080/
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