Synthesis of meta-Carboranyl-(S)-homocysteine Sulfoxide

Article abstract of DOI:10.1134/S1070428018100251

New (S)-homocysteine derivatives containing a meta-carborane fragment were synthesized. m-Carboranyl-(S)-homocysteine sulfoxide was obtained as a mixture of diastereoisomers. The reduction of the side-chain carboxy group of N-tert-butoxycarbonyl-(S)-aspartic acid α-tert-butyl ester with sodium tetrahydridoborate was not accompanied by racemization.

Full text of DOI:10.1134/S1070428018100251

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 10, pp. 1579–1582. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © D.A. Gruzdev, V.O. Ustinova, G.L. Levit, V.A. Ol’shevskaya, V.P. Krasnov, 2018, published in Zhurnal Organicheskoi Khimii, 2018,
Vol. 54, No. 10, pp. 1564–1567.
SHORT
COMMUNICATIONS
Synthesis of meta-Carboranyl-(S)-homocysteine Sulfoxide
D. A. Gruzdeva,* V. O. Ustinovaa, G. L. Levita, V. A. Ol’shevskayab, and V. P. Krasnova
a Postovskii 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,
ul. Vavilova 28, Moscow, 119991 Russia
Received April 9, 2018
Abstract—New (S)-homocysteine derivatives containing a meta-carborane fragment were synthesized.
m-Carboranyl-(S)-homocysteine sulfoxide was obtained as a mixture of diastereoisomers. The reduction of the
side-chain carboxy group of N-tert-butoxycarbonyl-(S)-aspartic acid α-tert-butyl ester with sodium tetra-
hydridoborate was not accompanied by racemization.
DOI: 10.1134/S1070428018100251
Amino acid derivatives containing polyhedral
dicarba-closo-dodecaborane (carborane) fragments in
the side chain and unsubstituted functional groups in
the α-position are promising agents for boron neutron
capture therapy (BNCT) of cancer. Amino acid
derivatives are efficiently transported to tumor cells
[1–4], and boron-containing amino acid and peptide
derivatives are capable of selectively accumulating in
tumors [5–8].
activity of Mycobacterium tuberculosis, so that it is the
target of tuberculostatic agents [13, 14]. We believe
that compound 1 could be used as a BNCT agent and
also as a potential mycobacterial glutamine synthetase
inhibitor.
By analogy with the previously reported procedure
[15], the reduction of N-Boc-(S)-aspartic acid α-tert-
butyl ester (S)-2 afforded Boc-(S)-homoserine tert-
butyl ester (S)-3 without loss of enantiomeric purity
(Scheme 1). According to the HPLC data (chiral
stationary phase), the ee value of (S)-3 was 98% [in
comparison to racemate (RS)-3]. Protected homoserine
(RS)-3 was prepared starting from racemic aspartic
acid methyl ester through the same reaction sequence
as in the synthesis of (S)-3 [10, 15] (Scheme 2).
We previously synthesized a series of lysine, gluta-
mine, and asparagine derivatives containing an o-car-
borane fragment in the side chain and free carboxy and
amino groups in the α-position [9, 10]. In this work we
were the first to synthesize S-(m-carboran-9-yl)-(S)-
homocysteine sulfoxide [1, (2S)-2-amino-4-(1,7-di-
carba-closo-dodecaboran-9-yl)sulfinylbutanoic acid] as
a mixture of diastereoisomers.
Sulfonylation of (S)-3 and subsequent nucleophilic
substitution gave m-carboranylhomocysteine deriva-
tive 5 in an overall yield of 47% (Scheme 1). Analo-
gous approach to homocysteine derivatives was de-
scribed in [16, 17]. By oxidation of 5 with hydrogen
peroxide in acetic acid at 20°C we obtained sulfoxide
6, and deprotection of the latter by the action of tri-
fluoroacetic acid afforded m-carboranyl-(S)-homo-
cysteine sulfoxide 1 which was isolated in a moderate
yield after purification by preparative reversed-phase
chromatography. Some signals in the NMR spectra of
Boc-amino acid tert-butyl esters were doubled due to
the presence of stable conformers. Compounds 1 and 6
possess an asymmetric sulfur atom, and they were iso-
Sulfur-substituted homocysteine and methionine
derivatives are potent glutamine synthetase inhibitors
[11, 12]. This enzyme is very important for the vital
H2N
COOH
S
O
1
Hereinafter, light circles denote BH groups and boron atoms,
and dark circles denote CH groups.
1579

GRUZDEV et al.
1580
Scheme 1.
(1) EtOC(O)Cl, NEt3
THF, –10°C
(2) NaBH4, THF–H2O
MsCl, (i-Pr)2NEt
CH2Cl2, 0°C
O
NHBoc
O
NHBoc
NHBoc
O
–10 to 20°C
OBu-t
OBu-t
OBu-t
HO
HO
MsO
O
(S)-2
(S)-3
(S)-4
BocNH
BocNH
O
O
(1) KOH, MeOH, 20°C
(2) (S)-4, MeOH–PhH, 20°C
OBu-t
OBu-t
H2O2, AcOH, 20°C
SH
S
S
O
5
6
(1) CF3COOH, CH2Cl2, 20°C
(2) NaOH (1 equiv), H2O
1
Scheme 2.
O
NH2·HCl
NHBoc
i–iii
OH
OBu-t
MeO
HO
O
O
(RS)-3
Reagents and conditions: i: (1) t-BuOAc, HClO4, 20°C; (2) Boc2O, NEt3, DMF, 20°C; ii: LiOH, THF–H2O, 0–20°C;
iii: (1) EtOCOCl, NEt3, THF, –10°C; (2) NaBH4, THF–H2O, –10 to 20°C.
lated as mixtures of diastereoisomers distinguishable
by NMR and HPLC.
N-tert-Butoxycarbonyl-(RS)-aspartic acid α-tert-
butyl ester (RS)-2 was synthesized as described in
[10] for (S)-2 [10] from (RS)-aspartic acid β-methyl
tert-Butyl (2S)-2-(tert-butoxycarbonylamino)-
4-hydroxybutanoate (S)-3. A solution of 0.65 g
(2.25 mmol) of N-Boc-(S)-aspartic acid α-tert-butyl
ester [10] in 5 mL of THF was cooled to –10°C,
0.24 mL of ethyl chloroformate and 0.35 mL of tri-
ethylamine were added, and the mixture was stirred for
30 min at –10°C. The precipitate was filtered off, a
solution of 0.18 g (4.73 mmol) of sodium tetrahydrido-
borate in 5 mL of water was added to the filtrate, and
the mixture was stirred for 22 h at 20°C. The mixture
was then acidified with 1 M aqueous HCl to pH 3 and
extracted with ethyl acetate (3×10 mL). The combined
extracts were washed with 5% aqueous sodium hydro-
gen carbonate (2×15 mL) and brine (2×15 mL), dried
over Na2SO4, and evaporated, and the residue was
purified by flash chromatography using hexane–ethyl
acetate (85:15 to 70:30) as eluent. Yield 0.46 g (70%),
colorless oily material, [α]D20 = –14.7° (c = 0.63,
EtOH); published data: [α]D25 = –39.9° (c = 1.0, EtOH)
[18], –37.5° (c = 1, EtOH) [15]; ee 98%. HPLC
(Chiralcel OD-H, hexane–i-PrOH–CF3CO2H,
10:1:0.02), τ = 8.4 min. The 1H and 13C NMR spectra
of (S)-3 were identical to those reported in [18].
1
ester [19]. White powder, mp 111°C. The H and 13C
NMR spectra were identical to those of (S)-2 [10].
tert-Butyl (2RS)-2-(tert-butoxycarbonylamino)-
4-hydroxybutanoate (RS)-3 was synthesized as
described above for (S)-3 from 0.32 g (1.11 mmol) of
(RS)-2. Yield 0.21 g (70%), colorless oily material.
HPLC (Chiralcel OD-H, hexane–i-PrOH–CF3CO21H,
10:1:0.02): τ(R)-3 = 7.3 min, τ(S)-3 = 8.4 min. The H
and 13C NMR spectra were identical to those of (S)-3.
tert-Butyl (2S)-2-(tert-butoxycarbonylamino)-
4-(methanesulfonyloxy)butanoate (S)-4. A solution
of 0.4 g (1.38 mmol) of (S)-3 in 10 mL of methylene
chloride was cooled to 0°C, 0.12 mL (1.53 mmol) of
methanesulfonyl chloride and 0.72 mL (4.15 mmol) of
ethyl(diisopropyl)amine were added, and the mixture
was stirred for 2 h at 0°C. The mixture was washed
with a 10% solution of citric acid (3×10 mL) and
water (2×10 mL), the organic phase was dried over
Na2SO4 and evaporated, and the residue was purified
by flash chromatography using hexane–ethyl acetate
(6:4 to 1:1) as eluent. Yield 0.44 g (89%), white
powder, mp 87–90°C, [α]D20 = +12.0° (c = 0.51,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

SYNTHESIS OF meta-CARBORANYL-(S)-HOMOCYSTEINE SULFOXIDE
1581
CHCl3); published data [20]: mp 85–87°C, [α]D20
=
the residue was purified by flash chromatography
using benzene–ethyl acetate (9:1 to 7:3) as eluent.
Yield 0.215 g (65%), colorless amorphous powder.
HPLC (Chiralcel OD-H, hexane–i-PrOH, 40:1),
+11.6° (c = 1.03, CHCl3). 1H NMR spectrum (CDCl3),
δ, ppm: 1.45 s (9H, t-Bu), 1.48 s (9H, t-Bu), 2.00–
2.10 m and 2.25–2.38 m (1H each, 3-H), 3.03 s (3H,
MeSO2), 4.25–4.36 m (2H, 4-H), 5.16 d (1H, NH, J =
6.7 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 27.94
(3C), 28.27 (3C), 32.21, 37.28, 50.90, 66.13, 80.11,
82.77, 155.35, 170.77. Found, %: C 47.72; H 7.83;
N 4.12; S 9.31. C14H27NO7S. Calculated, %: C 47.58;
H 7.70; N 3.96; S 9.07.
1
τ1 = 13.6 min, τ2 = 16.0 min. H NMR spectrum
(DMSO-d6), δ, ppm (a mixture of diastereoisomers A
and B at a ratio of 85:15): 1.36 s (1.35H, t-Bu, B),
1.38 s (7.65H, t-Bu, A), 1.40 s (7.65H, t-Bu, A), 1.42 s
(1.35H, t-Bu, B), 1.95–2.20 m (2H, 3-H), 1.50–3.20 m
(9H, BH), 2.58–2.87 m (2H, 4-H), 3.93–4.03 m (1H,
2-H), 4.32 br.s (2H, CH, carborane), 6.95 br.s (0.15H,
tert-Butyl (2S)-2-(tert-butoxycarbonylamino)-
4-[(1,7-dicarba-closo-dodecaboran-9-yl)sulfanyl]-
butanoate (5). 1,7-Dicarba-closo-dodecaborane-9-
thiol, 0.243 g (1.38 mmol), was added to a solution of
0.079 g (1.38 mmol) of potassium hydroxide in 3 mL
of methanol, and the mixture was stirred under argon
until it became homogeneous. A solution of 0.400 g
(1.1 mmol) of (S)-4 in 3 mL of benzene was then
added, and the mixture was stirred for 1.5 h at 20°C.
Ethyl acetate, 20 mL, was added, and the mixture was
washed with a 5% solution of NaHCO3 (3×15 mL),
water (15 mL), and brine (15 mL), dried over Na2SO4,
and evaporated. The residue was purified by flash
chromatography using hexane–ethyl acetate (90:10 to
80:20) as eluent. Yield 0.317 g (53%), colorless oily
13
NH, B), 7.28–7.36 m (0.85H, NH, A). C NMR spec-
trum (DMSO-d6), δC, ppm (a mixture of diastereoiso-
mers A and B): 25.81 (A), 26.43 (B), 27.56 (3C, A, B),
28.09 (3C, A, B), 48.13 (A), 48.32 (B), 52.96 (A),
53.56 (B), 56.53 (2C, A, B), 78.12 (A), 78.15 (B),
80.57 (A, B), 155.39 (A), 155.41 (B), 170.84 (A),
170.89 (B). Mass spectrum: m/z 456.3396 [M + Li]+.
11
C15H3510B2 B8LiNO5S. Calculated: M + Li 456.3394.
(2S)-2-Amino-4-[(1,7-dicarba-closo-dodecaboran-
9-yl)sulfinyl]butanoic acid (1, mixture of diastereo-
isomers). Trifluoroacetic acid, 1.5 mL, was added to
a solution of 0.195 g (0.42 mmol) of compound 6 in
1.5 mL of methylene chloride, and the mixture was
stirred for 4 h at 20°C. The mixture was evaporated,
the residue was dissolved in 2 mL of methanol, a 2 N
solution of NaOH was added to pH 6–7, the resulting
solution was evaporated, and the residue was purified
first by flash chromatography using chloroform–
methanol (9:1 to 7:3) as eluent and then by prepa-
rative HPLC. Yield 0.072 g (55%), colorless powder,
material, [α]D20 = +17.0° (c = 0.49, CHCl3). H NMR
1
spectrum (DMSO-d6), δ, ppm (a mixture of conformers
A and B at a ratio of 8:2): 1.36 s (1.8H, t-Bu, B),
1.38 s (7.2H, t-Bu, A), 1.39 s (7.2H, t-Bu, A), 1.41 s
(1.8H, t-Bu, B), 1.76–1.92 m (2H, 3-H), 1.00–3.20 m
(9H, BH), 3.30–3.39 m (2H, 4-H), 3.83–3.90 m (0.2H,
2-H, B), 3.88–3.94 m (0.8H, 2-H, A), 4.09 br.s (2H,
CH, carborane), 6.80 d (0.2H, NH, B, J = 7.5 Hz),
7.15 d (0.8H, NH, A, J = 7.9 Hz). 13C NMR spectrum
(DMSO-d6), δC, ppm: 27.57 (3C), 28.12 (3C), 28.61,
32.66, 53.31, 55.38 (2C), 77.98, 80.25, 155.44, 171.38.
Found, %: C 41.42; H 8.32; N 3.23. C15H35B10NO4S.
Calculated, %: C 41.55; H 8.14; N 3.23.
1
mp 260°C (decomp.). H NMR spectrum (D2O+DCl),
δ, ppm (a mixture of diastereoisomers A and B): 1.70–
3.40 m (9H, BH), 2.02–2.10 m (0.5H, 3-H, A), 2.11–
2.17 m (1H; 3-H, A; 3-H, B), 2.20–2.27 m (0.5H, 3-H,
B), 2.76–2.82 m (0.5H, 4-H, A), 2.84–2.92 m (1H;
4-H, A; 4-H, B), 2.93–3.01 m (0.5H, 4-H, B), 3.29–
3.36 m (1H, 2-H, A, B), 4.32 br.s (2H, CH, carborane),
7.74 br.s (3H, NH2, COOH). 13C NMR spectrum
(DMSO-d6), δC, ppm (A/B): 26.65 (A), 27.06 (B),
48.23 (A), 48.48 (B), 52.86 (A), 53.22 (B), 56.54 (2C,
A, B), 168.88 (A), 169.05 (B). Found, %: C 24.60;
H 6.38; N 4.57. C6H19B10NO3S. Calculated, %:
C 24.56; H 6.53; N 4.77.
tert-Butyl (2S)-2-(tert-butoxycarbonylamino)-
4-[(1,7-dicarba-closo-dodecaboran-9-yl)sulfinyl]-
butanoate (6, mixture of diastereoisomers). Com-
pound 5, 0.300 g (0.69 mmol), was dissolved in
1.3 mL of acetic acid, 0.26 mL of 30% hydrogen
peroxide was added, and the mixture was stirred for
30 min at 20°C. The mixture was treated with 10 mL
of methylene chloride, the organic layer was separated,
and the aqueous layer was adjusted to pH 8 by adding
NaHCO3 and extracted with methylene chloride
(3×10 mL). The combined extracts were washed with
a 5% solution of NaHCO3 (3×15 mL) and water
(2×15 mL), dried over Na2SO4, and evaporated, and
1
The H and 13C NMR spectra were recorded at
25°C on a Bruker Avance 500 spectrometer (500 and
125 MHz, respectively) using tetramethylsilane as
internal standard. The melting points were measured
on a Stuart SMP3 melting point apparatus (Barloworld
Scientific, UK). The optical rotations were determined
with a Perkin Elmer Model 341 polarimeter. The
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

GRUZDEV et al.
1582
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performed on a Shimadzu LC-20 Prominence instru-
ment (Japan) using a Chiralcel OD-H column, 250×
4.6 mm, grain size 5 μm (Daicel, Japan); detection at
λ 220 nm; eluent flow rate 1.0 mL/min. Compound 1
was purified by preparative HPLC on a Reprosil-Pur
C18-AQ column, 250×20 mm, 10 μm (Dr. Maisch,
Germany); detection at λ 210 nm; eluent acetonitrile–
water, 9:1, flow rate 10 mL/min. Silica gel 60 (0.063–
0.040 mm, Alfa Aesar, UK) was used for column flash
chromatography.
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