Synthesis of novel carboranyl derivatives of α-amino acids

Article abstract of DOI:10.1007/s11172-010-0052-0

New routes to closo-carboranyl derivatives of L-lysine and L-glutamic acid with free α-NH₂ groups were proposed.

Full text of DOI:10.1007/s11172-010-0052-0

110
Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 110—115, January, 2010
Synthesis of novel carboranyl derivatives of αꢀamino acids
a
a
a
a
a
b
D. A. Gruzdev, G. L. Levit, I. V. Bazhov, A. M. Demin, L. Sh. Sadretdinova, V. A. Ol´shevskaya,
b
a
a
V. N. Kalinin, V. P. Krasnov, and O. N. Chupakhin
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
2
2/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Eꢀmail: ca@ios.uran.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
8 ul. Vavilova, 119991 Moscow, Russian Federation.
2
New routes to closoꢀcarboranyl derivatives of Lꢀlysine and Lꢀglutamic acid with free αꢀNH2
groups were proposed.
Key words: carboranes, amino acids, Cꢀ and Nꢀprotecting groups, amides.
Boron neutron capture therapy (BNCT) is a modern
The highest affinity for folate receptors is exhibited by
folic acid derivatives with the modified γꢀcarboxy group of
the Lꢀglutamic acid fragment and the free αꢀcarboxy
approach to cancer treatment that is under intensive deꢀ
velopment. This is based on capturing thermal neutrons
1
0
11
19—22
by B nuclei followed by fission of radioactive B isoꢀ
topes emitting α particles, which cause local damage to
the target cells. This results in selective death of cells conꢀ
taining boron compounds. Intensive relevant investigaꢀ
tions in the last decade were aimed at searching for new
BNCT agents.1 In this respect, dicarbaꢀclosoꢀdodecabꢀ
orane (carborane) derivatives are very promising. Essenꢀ
tial requirements to BNCT agents include selective delivꢀ
ery to tumor cells and the ability to be retained and accuꢀ
mulate in these cells. In previous attempts at designing
such agents, carboraneꢀcontaining derivatives of biomolꢀ
group.
Targeted introduction of carborane residues into amiꢀ
no acids containing additional functional groups (e.g.,
lysine or glutamic acid) can be an important step in the
preparation of promising BNCT agents and thus is of conꢀ
siderable interest.
—4
The goal of the present work was to develop methods
for the synthesis of carboraneꢀcontaining derivatives of
γ
Lꢀlysine and N ꢀ(1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ3ꢀyl)ꢀLꢀ
glutamic acid.
5
—7
8,9
10—12
ecules (nucleosides,
porphyrins, amino acids,
Results and Discussion
1
,2
etc. ) were used. Carborane derivatives containing amiꢀ
We used (1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetic
acid (3) and Nꢀprotected (3ꢀaminoꢀ1,2ꢀdicarbaꢀclosoꢀ
dodecaboranꢀ1ꢀyl)acetic acids 4 (see Ref. 14) and 5
no and/or carboxy groups, including 3ꢀaminoꢀ1,2ꢀdicarꢀ
baꢀclosoꢀdodecaborane (1)1 and 2ꢀ(3ꢀaminoꢀ1,2ꢀdicarꢀ
3
baꢀclosoꢀdodecaboranꢀ1ꢀyl)acetic acid (2)14 are promisꢀ
ing objects for the synthesis of novel BNCT agents
(
see Ref. 23) as the starting carboraneꢀcontaining reagents
for the preparation of carboranyl derivatives of Lꢀlysine
Scheme 1). The starting Lꢀlysine derivative used was
(
α
α
N ꢀTFAꢀLꢀlysine methyl ester (6), because the N ꢀTFA
and COOMe protecting groups can simultaneously be reꢀ
moved under mild conditions without destruction of the
closoꢀcarborane cage. Earlier, in the synthesis of Nꢀ[(3ꢀ
aminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetyl] derivꢀ
atives of amino acids, we have found that closoꢀcarboranes
2
3
withstand basic hydrolysis under mild conditions.
Coupling of carboranylacetic acids 3—5 with comꢀ
pound 6 at room temperature using N,N´ꢀdicyclohexylꢀ
carbodiimide (DCC) in the presence of 1ꢀhydroxybenzotꢀ
riazole (HOBt) in DMF gave compounds 7—9 in 60—80%
yields (see Scheme 1). Compounds 8 and 9 containing the
fragments of planarꢀchiral carboranes 4 and 5 were obꢀ
tained as mixtures of diastereomers.
Amino acids and peptides are essential components of
proliferating malignant cells. The mechanisms of active
transport are most efficient for Lꢀamino acid derivatives
containing free carboxy and αꢀamino groups.1
5,16
Recent investigations showed that tumor cells are charꢀ
17—19
acterized by increased and selective uptake of folic acid.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 110—115, January, 2010.
066ꢀ5285/10/5901ꢀ0110 © 2010 Springer Science+Business Media, Inc.
1

Carboranyl derivatives of amino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
111
Scheme 1
oranꢀ1ꢀyl)acetylꢀLꢀlysine trifluoroacetate (13) (Scheme 2),
which is highly hygroscopic and unstable on storage. When
stored at room temperature for a week, compound 13 unꢀ
derwent partial decomposition (TLC) into unidentified
products.
Scheme 2
ε
For the synthesis of free N ꢀ(3ꢀaminoꢀ1,2ꢀdicarbaꢀ
closoꢀdodecaboranꢀ1ꢀyl)acetylꢀLꢀlysine, we developed an
alternative approach (Scheme 3). Coupling of racemic
α
NꢀBocꢀamino acid 5 with N ꢀbenzyloxycarbonyl(Z)ꢀLꢀ
lysine methyl ester (14) in the presence of DCC and HOBt
gave amide 15 as a mixture of diastereomers (HPLC on
silica gel).
Compound
R
3, 7, 10
4, 8, 11
NHAc
5, 9, 12
NHBoc
H
Reagents and conditions: i. DCC, HOBt, NEt , DMF;
3
+
Reflux of compound 15 in TFA resulted in simultaꢀ
neous removal of the protecting NꢀBoc and NꢀZ groups
from the aminocarborane and lysine fragments, respecꢀ
tively. Elimination of the NꢀZ group under the action of
ii. 1) KOH/H O—acetone, 0 °C; 2) H .
2
Treatment of derivatives 7—9 with KOH in aqueous
acetone at 0 °C smoothly afforded the corresponding comꢀ
pounds 10—12 in 83—90% yields. According to H NMR
data, the protecting groups were completely removed
from the lysine residue and no deboronation products
nidoꢀderivatives) were formed: the spectra of the comꢀ
2
5—27
TFA has been described earlier.
This method is preꢀ
1
ferred for the synthesis of methyl ester 16 from compound
15. Hydrolysis of the NꢀZ group with TFA at room temꢀ
perature was incomplete (60% conversion upon treatment
1
(
for 1 day, H NMR), while reflux in TFA for 40 min gave
pounds showed no signal at δ –2.3—2.5 characteristic of
the bridging B—H—B proton in nidoꢀcarboranes.
product 16 free of the starting compound and deboroꢀ
nation products ( H NMR). Subsequent routine hydrolyꢀ
2
4
1
Introduction of closoꢀcarborane fragments is known to
sis of the ester group afforded target compound 17 in
95% yield.
make biomolecules substantially more lipophilic and less
soluble in water.1
,2,7
That is why the synthesis of carboraꢀ
LꢀGlutamic acid γꢀamide with 3ꢀaminoꢀ1,2ꢀdicarbaꢀ
closoꢀdodecaborane (1) was synthesized from accessible
nyl derivatives with the maximum number of polar groups
is of particular interest, e.g., compounds containing amiꢀ
no acid 2 with a free amino group in position 3 of the
carborane cage.
α
γꢀmethyl Lꢀglutamate (18). First, the Nꢀ and C ꢀprotectꢀ
ing groups (NꢀBoc and tertꢀbutyl ester) were successively
introduced into compound 18; they can simultaneously be
removed under mild conditions. The NꢀBoc group was
Treatment of compound 12 with trifluoroacetic acid
(
TFA) at room temperature according to a standard proꢀ
introduced into compound 18 under the action of Boc O
in the presence of triethylamine in DMF (Scheme 4).
2
ε
cedure afforded N ꢀ(3ꢀaminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecabꢀ

112
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Gruzdev et al.
Scheme 3
Scheme 4
Reagents and conditions: i. Boc O, NEt , DMF; ii. Boc O,
2
3
2
t
Py/DMAP, Bu OH; iii. NaOH/H O—acetone.
2
the carbodiimide method. The best results (50% yield)
were obtained using DCC and HOBt in DMF (Scheme 5).
The Nꢀ and Cꢀprotecting groups were removed by treating
amide 22 with TFA at room temperature for 5 h. No deboꢀ
ronation of the closoꢀcarborane fragment with the formaꢀ
tion of nidoꢀderivatives occurred under these conditions
1
γ
(
H NMR). The yield of compound 23 was 77%. N ꢀ(1,2ꢀ
dicarbaꢀclosoꢀdodecaboranꢀ3ꢀyl)ꢀLꢀglutamine (23) can be
used as starting material for the synthesis of the correꢀ
sponding folic acid γꢀamide.
Scheme 5
Reagents and conditions: i. DCC, HOBt, NEt , DMF;
3
+
ii. 1) KOH/H O—acetone, 0 °C; 2) H .
2
tertꢀButyl ester 20 was obtained by activation of the carꢀ
boxy group of the amino acid followed by a reaction with
t
28
Bu OH. With Boc O as an activating agent, the yield of
2
compound 20 was 60%, while the use of DCC was less
efficient: the target product was isolated by flash chromꢀ
atography in ~40% yield.
Hydrolysis of γꢀmethyl ester 20 with NaOH in aqueꢀ
ous acetone at reduced temperature was accompanied
R =
by partial (7—15%) hydrolysis of the tertꢀbutyl ester
1
(
H NMR). Compound 21 was isolated by flash chromaꢀ
Thus, we obtained for the first time closoꢀcarboranyl
derivatives of natural Lꢀamino acids with free αꢀfunctionꢀ
al groups and developed methods for the targeted syntheꢀ
tography on silica gel in 60% yield.
Amide 22 was obtained by coupling of 3ꢀaminocarboꢀ
rane 1 with αꢀtertꢀbutyl NꢀBocꢀLꢀglutamate (21) using
γ
sis of N ꢀ(1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ3ꢀyl)ꢀLꢀglutꢀ

Carboranyl derivatives of amino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
113
ε
amine, N ꢀ(3ꢀacetylaminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboꢀ
J = 14.5 Hz); 1.97 (s, 3 H, COMe); 1.77 (m, 2 H, C(5)H2); 1.4
(
m, 2 H, C(3)H ); 1.3 (m, 2 H, C(4)H ); 1.4—2.8 (m, 9 H,
2 2
BH). MS (ESI), m/z (Irel (%)): 497 [M – H] (100); 533
ranꢀ1ꢀyl)acetylꢀLꢀlysine, and a compound with an addiꢀ
tional free amino group at the B(3) atom of the carborane
cage. The structures of all the products were confirmed by
H NMR and GCꢀMS data. The compounds obtained are
promising BNCT agents and can serve as precursors for
more complex carboraneꢀcontaining molecules.
–
9
[
M + Cl]– (43); 498 [M + H]+ (57); 519 [M + Na]+ (75).
Calculated for C H B F N O : M = 497.53.
1
15 30 10
3
3
5
ε
N ꢀ{[3ꢀ(tertꢀButoxycarbonylamino)ꢀ1,2ꢀdicarbaꢀclosoꢀdodeꢀ
α
caboranꢀ1ꢀyl]acetyl}ꢀN ꢀtrifluoroacetylꢀLꢀlysine methyl ester (9).
1
Yield 80%, colorless crystals, m.p. 59—62 °C. H NMR, δ: 9.82
α
ε
(
(
(
d, 1 H, N H, J = 7.4 Hz); 8.24 (t, 1 H, N H, J = 5.4 Hz); 7.53
s, 1 H, NH—carborane); 5.05 (s, 1 H, CH of carborane); 4.31
ddd, 1 H, C(2)H, J = 9.6 Hz, J = 7.3 Hz, J = 5.0 Hz); 3.67 (s, 3 H,
Experimental
COOMe); 3.02 (m, 2 H, C(6)H ); 2.98 (d, 1 H, CO—CH —
2
A
The starting compounds 3ꢀaminoꢀ1,2ꢀdicarbaꢀclosoꢀdodeꢀ
caborane (1) and (1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetic
acids 3—5 were prepared according to known procedures.
—carborane, J = 14.5 Hz); 2.85 (d, 1 H, CO—CH —carborane,
B
J = 14.5 Hz); 1.77 (m, 2 H, C(5)H ); 1.40 (m, 2 H, C(3)H );
2
2
1
3,14,23
1.40 (s, 9 H, COOCMe ); 1.3 (m, 2 H, C(4)H ); 1.4—2.5 (m, 9 H,
3 2
t
–
Other reagents are commercially available. Melting points were
determined on a Boetius instrument; optical rotation was meaꢀ
9 BH). MS (ESI), m/z (I (%)): 480 [M – Bu OH – H] (100);
rel
t
+
+
456 [M – Bu – CO + 2H] (100); 579 [M + Na] (97). Calcuꢀ
2
1
sured on a PerkinꢀElmer M 341 polarimeter. H NMR spectra
lated for C H B F N O : M = 555.61.
18
36 10
3
3
6
ε
were recorded on a Bruker DRXꢀ400 instrument (400 MHz) in
DMSOꢀd6 with SiMe4 as the internal standard. Mass spectra
were recorded on a Shimadzu LCMSꢀ2010 instrument fitted
with a quadrupole analyzer for positive or negative ions (APCI
or ESI, acetonitrile—water as a mobile phase). HPLC analysis
was carried out on a MerckꢀHitachi chromatograph on a Hibar
N ꢀ[(3ꢀRꢀ1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetyl]ꢀLꢀ
lysine (10—12) (general procedure). A 1 M solution of KOH
(1.2 mL) was added dropwise at 0 °C to a stirred solution of
compound 7, 8, or 9 (0.5 mmol) in acetone (4 mL). The reaction
mixture was stirred at 10 °C for 16 h, diluted with water (5 mL),
and washed with Et O. The aqueous layer was separated and
2
preꢀpacked RT250ꢀ4 LiChrosorb Siꢀ60 column (4×250 mm,
acidified with 1 M HCl to pH 5.5. The product was extracted
i
5
1
μm) with hexane—Pr OH (10 : 1) as an eluent (elution rate
mL min , Lꢀ4000A Intelligent Pump instrument, UV detecꢀ
with AcOEt. The organic layer was dried with MgSO and conꢀ
4
–
1
centrated. The residue was dissolved in EtOH, the solution was
filtered, and the filtrate was concentrated to dryness.
tion at λ = 220 nm, an Lꢀ4000A UV detector, a Dꢀ2500A Chroꢀ
ε
matoꢀIntegrator).
N ꢀ[(1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetyl]ꢀLꢀlysine
ε
α
N ꢀ[(3ꢀRꢀ1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetyl]ꢀN ꢀ
(10). Yield 90%, colorless crystals, m.p. 184—185 °C (decomp.),
[α]D20 +2.10 (c 1, MeOH). H NMR, δ: 8.46 (t, 1 H, N H,
1
ε
trifluoroacetylꢀLꢀlysine methyl ester (7—9) (general procedure).
α
+
Compound 6 (0.205 g, 0.7 mmol), NEt (0.098 mL, 0.7 mmol),
J = 5.3 Hz); 7.3—8.0 (br.s, 3 H, N H3 ); 5.23 (s, 1 H, CH of
3
HOBt (0.109 g, 0.7 mmol), and DCC (0.145 g, 0.7 mmol) were
carborane); 4.56 (m, 1 H, C(2)H); 3.23 (t, 2 H, C(6)H , J = 5.5
2
added to a solution of 3ꢀRꢀ2ꢀ(1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ
Hz); 3.13 (s, 2 H, CO—CH —carborane); 3.02 (m, 2 H, C(3)H );
2
2
1
ꢀyl)acetic acid (3, 4, or 5) (0.7 mmol) in DMF (7 mL). The
1.7 (m, 2 H, C(5)H ); 1.4 (m, 2 H, C(4)H ); 1.2—2.8 (m, 10 H,
2 2
–
–
reaction mixture was stirred at room temperature for 24 h and
poured into water (25 mL). The product was extracted with
10 BH). MS (ESI), m/z(I (%)): 330 [M – H] (100); 320 [M – B]
rel
+
(40); 331 [M + H] (100). Calculated for C H B N O :
1
0
26 10
2
3
AcOEt. The organic layer was dried with MgSO and concenꢀ
M = 330.44.
4
ε
trated to dryness. The residue was treated with acetone (4 mL);
the precipitate of N,N´ꢀdicyclohexylurea was filtered off and the
filtrate was concentrated to dryness. The residue was purified by
flash chromatography on silica gel in benzene—AcOEt.
N ꢀ[(3ꢀAcetylaminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)ꢀ
acetyl]ꢀLꢀlysine (11). Yield 90%, colorless crystals, m.p.
149—152 °C. H NMR, δ: 8.56, 8.53 (both s, 1 H, NH—carboꢀ
rane); 8.44 (t, 1 H, N H, J = 4.8 Hz); 5.24 (s, 1 H, CH of
carborane); 3.48 (m, 1 H, C(2)H); 3.01 (m, 2 H, C(6)H ); 2.90
1
ε
ε
α
N ꢀ[(1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)acetyl]ꢀN ꢀtrifluꢀ
oroacetylꢀLꢀlysine methyl ester (7). Yield 60%, colorless crystals,
2
(d, 1 H, CO—CH —carborane, J = 14.5 Hz); 3.00 (d, 1 H,
A
2
0
1
m.p. 138—140 °C, [α]D –12.8 (c 1, MeOH). H NMR, δ: 9.81
d, 1 H, N H, J = 7.4 Hz); 8.23 (t, 1 H, N H, J = 5.5 Hz); 5.11
s, 1 H, CH of carborane); 4.31 (ddd, 1 H, C(2)H, J = 9.5 Hz,
CO—CH —carborane, J = 14.5 Hz); 1.98 (s, 3 H, COMe); 1.73
B
α
ε
(
(
(m, 2 H, C(3)H ); 1.25—1.45 (m, 4 H, (CH ) ); 1.2—2.6 (m, 9 H,
2
2 2
–
9 BH). MS (APCI), m/z (I (%)): 386 [M – H] (100); 388
rel
+
J = 7.4 Hz, J = 5.1 Hz); 3.67 (s, 3 H, COOMe); 3.09 (s, 2 H,
[M + H] (100). Calculated for C H B N O : M = 387.49.
12
29 10
3
4
ε
CO—CH —carborane); 3.03 (m, 2 H, C(6)H ); 1.8 (m, 2 H,
N ꢀ{[3ꢀ(tertꢀButoxycarbonylamino)ꢀ1,2ꢀdicarbaꢀclosoꢀdodeꢀ
caboranꢀ1ꢀyl]acetyl}ꢀLꢀlysine (12). Yield 83%, colorless crystals,
2
2
C(5)H ); 1.4 (m, 2 H, C(3)H ); 1.3 (m, 2 H, C(4)H ); 1.2—2.8
2
2
2
–
1
ε
(
4
m, 10 H, 10 BH). MS (ESI), m/z (I (%)): 440 [M – H] (100);
75 [M + Cl] (26); 460 [M + H O + H] (100); 442 [M + H]
m.p. 163—165 °C. H NMR, δ: 8.44 (m, 1 H, N H); 7.2—8.3
(br.s, 3 H, N H3 ); 7.56 (s, 1 H, NH—carborane); 5.09 (s, 1 H,
rel
–
+
+
α
+
2
(
7). Calculated for C H B F N O : M = 440.48.
CH of carborane); 3.26 (m, 1 H, C(2)H); 3.01 (m, 2 H, C(6)H );
13
27 10
3
2
4
2
ε
N ꢀ[(3ꢀAcetylaminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl)ꢀ
3.02 (d, 1 H, CO—CH —carborane, J = 14.6 Hz); 2.91 (d, 1 H,
A
α
acetyl]ꢀN ꢀtrifluoroacetylꢀLꢀlysine methyl ester (8). Yield 69%,
colorless crystals, m.p. 66—68 °C. H NMR, δ: 9.81 (d, 1 H,
N H, J = 7.3 Hz); 8.37 (s, 1 H, NH—carborane); 8.21 (t, 1 H,
N H, J = 5.3 Hz); 5.24 (s, 1 H, CH of carborane); 4.31 (ddd,
CO—CH —carborane, J = 14.6 Hz); 1.6—1.7 (m, 2 H, C(3)H );
B
2
1
1.40 (s, 9 H, COOCMe ); 1.25—1.4 (m, 4 H, (CH ) ); 1.2—2.6
3 2 2
α
–
(m, 9 H, 9 BH). MS (APCI), m/z (I (%)): 444 [M – H]
rel
ε
+
(100); 446 [M + H] (100). Calculated for C H B N O :
15
35 10
3
5
1
H, C(2)H, J = 9.4 Hz, J = 7.3 Hz, J = 5.1 Hz); 3.67 (s, 3 H,
M = 445.57.
ε
COOMe); 3.04 (m, 2 H, C(6)H ); 2.14 (d, 1 H, CO—CH —
—
N ꢀ{[3ꢀAminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl]acetyl}ꢀ
Lꢀlysine bis(trifluoroacetate) (13). A solution of compound 12
2
A
carborane, J = 14.5 Hz); 2.84 (d, 1 H, CO—CH —carborane,
B

114
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Gruzdev et al.
(
125 mg, 0.28 mmol) in TFA (2.5 mL) was stirred at room
N H3+); 4.46 (s, 1 H, CH of carborane); 3.88 (m, 1 H, C(2)H);
α
temperature for 19 h. The reaction mixture was concentrated
to dryness and the residue was triturated with hexane. The yield
of compound 13 was 0.137 g (89%), colorless crystals, m.p.
2.95—3.09 (m, 2 H, C(6)H ); 3.08 (d, 1 H, CO—CH —carboꢀ
2
A
rane, J = 14.5 Hz); 2.97 (d, 1 H, CO—CH —carborane,
B
J = 14.5 Hz); 1.76 (m, 2 H, C(3)H ); 1.3—1.4 (m, 4 H, (CH ) );
2
2 2
1
ε
–
1
8
3
28—132 °C (decomp.). H NMR, δ: 8.27 (m, 1 H, N H);
.16—8.30 (m, 3 H, N H3 ); 4.45 (s, 1 H, CH of carborane);
1.0—2.6 (m, 9 H, 9 BH). MS (ESI), m/z (I (%)): 335 [M – B]
(100); 345 [M – H]– (53); 347 [M + H] (100). Calculated for
rel
+
α
+
.87 (m, 1 H, C(2)H); 3.03 (m, 2 H, C(6)H ); 3.08 (d, 1 H,
C H B N O : M = 345.45.
2
10 27 10
3
3
CO—CH —carborane, J = 14.6 Hz); 2.97 (d, 1 H, CO—CH —
γꢀMethyl NꢀBocꢀLꢀglutamate (19). Triethylamine (11.3 mL,
81.0 mmol) was added to a solution of γꢀmethyl Lꢀglutamate
hydrochloride (18) (8 g, 40.5 mmol) in DMF (20 mL). The
A
B
—
carborane, J = 14.6 Hz); 1.7—1.8 (m, 2 H, C(3)H ); 1.3—1.4
2
(
(
(
m, 4 H, (CH ) ); 1.0—2.6 (m, 9 H, 9 BH). MS (ESI), m/z
2 2
–
–
Irel (%)): 335 [M – B] (71), 447 [M + CF COOH – B]
precipitate that formed was filtered off. A solution of Boc O
3
2
62); 346 [M + H]+ (100). Calculated for C H B N O :
(17.7 g, 81.0 mmol) in Pr OH (15 mL) was added to the filtrate
i
1
0
27 10
3
3
M = 345.45.
with stirring. The reaction mixture was kept for 24 h and diluted
with water (150 mL). The solution was acidified with citric acid
to pH ≈ 4. The product was extracted from the resulting oily
liquid with AcOEt (4×45 mL). The extract was washed with
α
ε
N ꢀBenzyloxycarbonylꢀN ꢀ{[3ꢀ(tertꢀbutoxycarbonylamino)ꢀ
,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl]acetyl}ꢀLꢀlysine methyl esꢀ
1
ter (15). Compound 14 (0.232 g, 0.7 mmol), NEt (0.098 mL,
3
0
0
0
.7 mmol), HOBt (0.109 g, 0.7 mmol), and DCC (0.145 g,
.7 mmol) were added to a solution of compound 5 (0.222 g,
.7 mmol) in DMF (7 mL). The reaction mixture was stirred at
water, dried with MgSO , and concentrated under reduced presꢀ
4
sure. The yield of compound 19 was 8.46 g (80%), yellow oil.
1
H NMR, δ: 7.06 (d, 1 H, NH, J = 8.3 Hz); 3.7 (m, 1 H, C(2)H);
room temperature for two days. The precipitate of N,N´ꢀdicycloꢀ
3.59 (s, 3 H, COOMe); 2.38 (m, 2 H, C(4)H ); 1.98 (m, 1 H,
2
hexylurea was filtered off, the filtrate was poured into water
C(3)H ); 1.79 (m, 1 H, C(3)H ); 1.39 (s, 9 H, COOCMe ). MS
(ESI), m/z (Irel (%)): 262 [M + H] (100). Calculated for
A
B
3
+
(
35 mL), and the product was extracted with AcOEt. The organꢀ
ic layer was dried with MgSO and concentrated to dryness. The
C H NO : M = 261.04.
4
11 19
6
residue was dissolved in AcOEt (5 mL), the solution was filtered
through a short column of silica gel, and the eluate was concenꢀ
trated to dryness. The yield of compound 15 was 0.334 g (80%),
αꢀtertꢀButyl γꢀmethyl NꢀBocꢀLꢀglutamate (20). Pyridine
(4.88 mL, 60.0 mmol), a solution of Boc O (19.6 g, 90.0 mmol)
2
t
in Bu OH (45 mL), and DMAP (0.73 mg, 6.0 mmol) were added
to a solution of compound 19 (15.7 g, 60.0 mmol) in Bu OH
1
t
oil. HPLC data: τ = 8.28 min, τR2 = 10.26 min. H NMR, δ:
R1
ε
α
8
7
.22 (t, 1 H, N H, J = 5.6 Hz); 7.72 (d, 1 H, N H, J = 7.8 Hz);
(30 mL). The reaction mixture was stirred for 24 h and diluted
with water (200 mL). The product was extracted from the resultꢀ
ing oil with AcOEt (4×50 mL). The extract was washed with
10% NaHCO and water and dried with MgSO . The solvent
.52 (br.s, 1 H, NHꢀcarborane); 7.3—7.4 (m, 5 H, Ph); 5.05
(
br.s, 1 H, CH of carborane); 5.03 (s, 2 H, PhCH O); 4.00 (m, 1 H,
2
C(2)H); 3.63 (s, 3 H, COOMe); 2.92—3.09 (m, 2 H, C(6)H );
2
3
4
3
.00 (d, 1 H, CO—CH —carborane, J = 14.5 Hz); 2.85 (d, 1 H,
was removed under reduced pressure. The yield of compound 20
was 11.41 g (60%), yellow oil. H NMR, δ: 7.15 (d, 1 H, NH,
A
1
CO—CH —carborane, J = 14.5 Hz); 1.63 (m, 2 H, C(3)H );
B
2
1
.40 (s, 9 H, COOCMe ); 1.2—1.4 (m, 4 H, (CH ) ); 1.4—2.5
J = 7.8 Hz); 3.84 (ddd, 1 H, C(2)H, J = 9.0 Hz, J = 7.8 Hz,
3
2 2
–
(
m, 9 H, 9 BH). MS (ESI), m/z (I (%)): 630 [M + Cl] (100);
J = 5.2 Hz); 3.59 (s, 3 H, Me); 2.36 (m, 2 H, C(4)H ); 1.92 (m, 1 H,
rel
2
–
+
t
5
+
84 [M – B] (23); 616 [M + Na] (100); 495 [M – Bu – CO +
C(3)H ); 1.75 (m, 1 H, C(3)H ); 1.39 (s, 9 H, CMe —Boc);
2
A
B
3
+
t
2 H] (23). Calculated for C H B N O : M = 593.73.
1.38 (s, 9 H, CMe —OBu ). MS (ESI), m/z (I (%)): 318
3 rel
[M + H] (100). Calculated for C H NO : M = 317.39.
15 27 6
2
4
43 10
3
7
ε
+
N ꢀ{[3ꢀAminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl]acetyl}ꢀ
Lꢀlysine methyl ester bis(trifluoroacetate) (16). A solution of comꢀ
pound 15 (0.300 g, 0.50 mmol) in TFA (5 mL) was refluxed for
αꢀtertꢀButyl NꢀBocꢀLꢀglutamate (21). A solution of comꢀ
pound 20 (1.3 g, 4.1 mmol) in acetone (15 mL) was cooled to
–2 °C. A solution of NaOH (0.49 g, 12.3 mmol) in water (2 mL)
was added. The reaction mixture was stirred at –2 °C for 1.5 h,
diluted with water (70 mL), and washed with benzene. The aqueꢀ
ous layer was acidified with citric acid to pH ≈ 4 and the product
was extracted with AcOEt (4×25 mL). The extract was washed
4
0 min. The reaction mixture was concentrated to dryness and
the residue was triturated with hexane and dried. The yield of
1
compound 16 was 0.282 g (96%), oil. H NMR, δ: 8.37 (br.s,
α
+
ε
3
H, N H3 ); 8.29 (t, 1 H, N H, J = 5.4 Hz); 4.52 (s, 1 H, CH of
carborane); 4.03 (m, 1 H, C(2)H); 3.76 (s, 3 H, COOMe);
.98—3.08 (m, 2 H, C(6)H ); 3.09 (d, 1 H, CO—CH —carboꢀ
2
with water, dried with MgSO , and concentrated under reduced
2
A
4
rane, J = 14.9 Hz); 3.00 (d, 1 H, CO—CH —carborane,
pressure. The residue was purified by flash chromatography on
silica gel in chloroform—MeOH. The yield of compound 21 was
0.75 g (60%), colorless needleꢀlike crystals, m.p. 154—156 °C.
B
J = 14.9 Hz); 1.77 (m, 2 H, C(3)H ); 1.20—1.45 (m, 4 H,
2
(
[
CH ) ); 1.0—2.6 (m, 9 H, 9 BH). MS (ESI), m/z (I (%)): 360
2 2 rel
+
1
M + H] (100). Calculated for C H B N O : M = 359.48.
H NMR, δ: 7.13 (d, 1 H, NH, J = 7.9 Hz); 3.82 (m, 1 H,
1
1
29 10
3
3
ε
N ꢀ{[3ꢀAminoꢀ1,2ꢀdicarbaꢀclosoꢀdodecaboranꢀ1ꢀyl]acetyl}ꢀ
C(2)H); 2.27 (m, 2 H, C(4)H ); 1.86 (m, 1 H, C(3)H ); 1.72
2
A
Lꢀlysine (17). A 1 M solution of KOH (1.7 mL) was added dropꢀ
wise at 0 °C to a stirred solution of compound 16 (0.280 g,
(m, 1 H, C(3)H ); 1.39 (s, 9 H, CMe —Boc); 1.38 (s, 9 H,
B 3
t
+
CMe —OBu ). MS (ESI), m/z (I (%)): 304 [M + H] (100);
3
rel
–
0
.48 mmol) in acetone (4.5 mL). The reaction mixture was stirred
302 [M – H] (100). Calculated for C H NO : M = 303.36.
14 25 6
α
γ
at 10 °C for 16 h, diluted with water (5 mL), and washed with
tertꢀButyl N ꢀ(tertꢀbutoxycarbonyl)ꢀN ꢀ(1,2ꢀdicarbaꢀclosoꢀ
dodecaboranꢀ3ꢀyl)ꢀLꢀglutamate (22). A solution of DCC (1.26 g,
6.09 mmol) in DMF (10 mL) was added to a solution of
3ꢀaminocarborane (1) (0.97 g, 6.09 mmol), HOBt (0.82 g, 6.09
mmol), and compound 21 (1.85 g, 6.09 mmol) in DMF (20 mL).
The reaction mixture was stirred at room temperature for 48 h
and diluted with water (140 mL). The product was extracted
Et O. The aqueous layer was separated and acidified with 1 M
2
HCl to pH 4.0. The product was extracted with AcOEt. The
organic layer was dried with MgSO and concentrated. The resꢀ
4
idue was triturated with acetone. The yield of compound 17 was
0
.158 g (95%), pale orange crystals, m.p. 72—74 °C (decomp.).
1
ε
H NMR, δ: 8.28 (t, 1 H, N H, J = 5.5 Hz); 8.24 (br.s, 3 H,

Carboranyl derivatives of amino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
115
from the resulting oil with AcOEt (4×30 mL). The extract was
8. M. Miura, P. L. Micca, C. D. Fisher, C. R. Gordon, J. C.
Heinrichs, D. N. Slatkin, Br. J. Radiol., 1998, 71, 773.
9. J. C. Clark, F. R. Fronczek, M. G. H. Vicente, Tetrahedron
Lett., 2005, 46, 2365.
10. I. M. Wyzlic, A. H. Soloway, Tetrahedron Lett., 1992,
33, 7489.
washed with 10% NaHCO and water and dried with MgSO .
3
4
The solvent was removed under reduced pressure. The residue
was purified by flash chromatography on silica gel in chloroꢀ
form—MeOH. The yield of compound 22 was 1.36 g (50%),
1
colorless needleꢀlike crystals, m.p. 167—169 °C. H NMR, δ:
8
5
3
.27 (s, 1 H, NH—carborane); 7.10 (d, 1 H, NH, J = 7.8 Hz);
.06 (br.s, 2 H, 2 CH of carborane); 3.80 (m, 1 H, C(2)H);
11. J. K. Prashar, D. Lama, D. E. Moore, Tetrahedron Lett.,
1993, 34, 6799.
12. P. A. Radel, S. B. Kahl, J. Org. Chem., 1996, 61, 4582.
13. L. I. Zakharkin, V. N. Kalinin, Izv. Akad. Nauk SSSR,
Ser. Khim., 1967, 11, 2585 [Bull. Acad. Sci. USSR, Div. Chem.
Sci. (Engl. Transl.), 1967, 11, 2471].
14. V. A. Ol´shevskaya, R. Ayuob, Z. G. Brechko, P. V. Petroꢀ
vskii, E. G. Kononova, G. L. Levit, V. P. Krasnov, V. N.
Charushin, O. N. Chupakhin, V. N. Kalinin, J. Organomet.
Chem., 2005, 690, 2761.
.0—1.3 (m, 10 H, 9 BH); 2.27 (m, 2 H, C(4)H ); 1.88 (m, 1 H,
2
C(3)H ); 1.70 (m, 1 H, C(3)H ); 1.40 (s, 9 H, CMe ); 1.38 (s, 9 H,
CMe ). MS (ESI), m/z (I (%)): 445 [M + H] (100). Calcuꢀ
lated for C H B N O : M = 444.58.
A
B
3
+
3
rel
16
36 10
2
5
γ
N ꢀ(1,2ꢀDicarbaꢀclosoꢀdodecaboranꢀ3ꢀyl)ꢀLꢀglutamine bisꢀ
trifluoroacetate) (23). A solution of compound 22 (1.36 g,
(
3
5
.06 mmol) in TFA (5 mL) was stirred at room temperature for
h. The excess of TFA was removed under reduced pressure and
the residue was triturated with hexane. The yield of compound
15. G. K. Grimble, in Proteins, Peptides, and Amino Acids
in Enteral Nutrition, Eds P. Fürst, V. Young, A. G. Basel,
2000, pp. 63—88.
16. H. Daniel, B. Spanier, G. Kottra, D. Weitz, Physiology, 2006,
21, 93.
2
0
2
3 was 1.12 g (71%), yellow oil, [α]D –3.96 (c 1, acetone).
1
H NMR, δ: 8.41 (s, 1 H, NH—carborane); 8.29 (br.s, 3 H,
NH3 ); 5.05 (br.s, 2 H, 2 CH of carborane); 3.94 (m, 1 H,
+
C(2)H); 3.0—1.3 (m, 9 H, 9 BH); 2.40 (m, 2 H, C(4)H ); 2.00
2
(
m, 2 H, C(3)H ). Found (%): C, 25.98; H, 4.46; N, 4.96;
17. S. D. Weitman, R. H. Lark, L. R. Coney, D. W. Fort,
V. Frasca, V. R. Zurawski, Jr., B. A. Kamen, Cancer Res.,
1992, 52, 3396.
2
F, 21.55. C H B N O F . Calculated (%): C, 25.58; H, 4.29;
N, 5.42; F, 22.07.
1
1
22 10
2
7 6
1
8. J. F. Ross, P. K. Chaundhuri, M. Ratnam, Cancer, 1994,
73, 2432.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00684)
and the State Program for Support of Leading Scientific
Schools (Grant NSh 3758.2008.3).
19. P. S. Low, W. A. Henne, D. D. Doorneweerd, Acc. Chem.
Res., 2008, 41, 120.
2
2
2
2
0. J. Luo, M. D. Smith, D. A. Lantrip, S. Wang, P. L. Fuchs,
J. Am. Chem. Soc., 1997, 119, 10004.
1. M. Nomura, S. Shuto, A. Matsuda, J. Org. Chem., 2000,
65, 5016.
2. C. Lainé, C. Mocquet, L. Lemiègre, T. Benvegnu, Tetraheꢀ
dron, 2009, 65, 1455.
3. G. L. Levit, V. P. Krasnov, D. A. Gruzdev, A. M. Demin,
I. V. Bazhov, L. Sh. Sadretdinova, V. A. Olshevskaya, V. N.
Kalinin, C. S. Cheong, O. N. Chupakhin, V. N. Charushin,
Collect. Czech. Chem. Commun., 2007, 72, 1697.
4. G. L. Levit, A. M. Demin, M. I. Kodess, M. A. Ezhikova,
L. Sh. Sadretdinova, V. A. Ol´shevskaya, V. N. Kalinin, V. P.
Krasnov, V. N. Charushin, J. Organomet. Chem., 2005,
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Received March 25, 2009;
in revised form July 3, 2009