New carborane-containing amino acids and their derivatives. Crystal structures of n-protected carboranylalaninates

Article abstract of DOI:10.1007/s11172-007-0118-9

New alanine derivatives containing both the carboranyl and trifluoromethyl groups were synthesized by the reaction of organometallic derivatives of o-carborane with methyl trifluoropyruvate imines. When using the 1R-(-)-menthoxycarbonyl protecting group at the nitrogen atom, one of diastereomers was isolated and characterized. Trifluoromethyl-carboranylalanine methyl esters containing different protecting groups at the nitrogen atom were studied by X-ray diffraction. Both complete and partial deprotection of the amino and carboxy groups was performed.

Full text of DOI:10.1007/s11172-007-0118-9

Russian Chemical Bulletin, International Edition, Vol. 56, No. 4, pp. 791—797, April, 2007
791
New carboraneꢀcontaining amino acids and their derivatives.
Crystal structures of Nꢀprotected carboranylalaninates
a
b
a
S. V. Timofeev,a V. I. Bregadze,a S. N. Osipov, I. D. Titanyuk, P. V. Petrovskii,
ꢀ
Z. A. Starikova,a I. V. Glukhov,a and I. P. Beletskayab
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: bre@ineos.ac.ru
bDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Eꢀmail: beletska@org.chem.msu.su
New alanine derivatives containing both the carboranyl and trifluoromethyl groups were
synthesized by the reaction of organometallic derivatives of оꢀcarborane with methyl
trifluoropyruvate imines. When using the 1Rꢀ(–)ꢀmenthoxycarbonyl protecting group at the
nitrogen atom, one of diastereomers was isolated and characterized. Trifluoromethylꢀ
carboranylalanine methyl esters containing different protecting groups at the nitrogen atom
were studied by Xꢀray diffraction. Both complete and partial deprotection of the amino and
carboxy groups was performed.
Key words: amino acids, alanine, organofluorine compounds, imines, carboranes, Xꢀray
diffraction study.
Boron neutron capture therapy (BNCT) of cancer
would be one of possible applications of carboraneꢀconꢀ
taining amino acids.1,2 This expectation is based on the
fact that pꢀdihydroxyborylphenylalanine (BPA) is used in
clinical practice as a reagent for BNCT. It should be
taken into account that normal cells fundamentally differ
from cancer cells in that the latter are characterized by
high growth and division rates, i.e., cancer cells absorb
much higher amounts of substances necessary for their
replication. Because of this, compounds serving as cell
building blocks (in particular, amino acids and peptides)
or their analogs should be absorbed predominantly by
cancer cells, which opens possibilities for selective delivꢀ
ery of 10B to tumors.
αꢀamino acid esters containing the trifluoromethyl group
by the reactions of organometallic derivatives of carboꢀ
ranes with highly electrophilic methyl trifluoropyruvate
imines6—8 (see the preliminary communication9).
Results and Discussion
The reaction of оꢀcarboranylmethylmagnesium broꢀ
mide with imines (CF3)(CO2Me)C=NR (R = SO2Ph,
COCF3, or CO2But) in diethyl ether at –78 °C proꢀ
duced βꢀcarboranylꢀαꢀtrifluoromethylꢀαꢀamino acid esꢀ
ters (1—3), in which the amino group is protected by the
benzenesulfonyl, trifluoroacetyl, or tertꢀbutoxycarbonyl
(Boc) group (Scheme 1).
It is also known that the introduction of fluorine and
fluoroalkyl substituents into amino acids sometimes leads
to an increase in their biological activity.3 In peptide and
amino acid chemistry, βꢀfluorineꢀsubstituted αꢀamino
acids are of particular interest because they serve as irreꢀ
versible enzyme inhibitors.4,5 These acids have a broad
spectrum of biological activities, including antiviral and
antitumor activities.3
In the present study, we synthesized amino acids and
their derivatives containing both the carboranyl group
and the trifluoromethyl fragment and established their
structures. We believe that this combination of fragments
imparts unusual biological properties to the resulting
compounds. We have synthesized αꢀ and βꢀcarboranylꢀ
Free amino acid was prepared by deprotection, which
was carried out for compound 3 in two steps. The
Boc group was removed by the reaction with trifluoroacetic
acid in dichloromethane at room temperature followed by
hydrolysis of the ester group. The intermediate solid comꢀ
pound (methyl ester 4) was refluxed in 6 M HCl until the
precipitate was completely dissolved (~8 h) to prepare
amino acid 5 as hydrochloride. Compound 5•HCl was
obtained as a waterꢀsoluble white crystalline compound.
Hydrolysis of the ester group without deprotection of
nitrogen was performed for compound 1 by the reaction
with lithium hydroxide in a water—THF system giving
rise to Nꢀprotected acid 6. This acid is potentially suitable
for peptide synthesis.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 761—767, April, 2007.
1066ꢀ5285/07/5604ꢀ0791 © 2007 Springer Science+Business Media, Inc.

792
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
Timofeev et al.
Scheme 1
R = SO2Ph (1), COCF3 (2), CO2But (3)
Compounds 1—6 were characterized by 1H NMR
spectroscopy and elemental analysis. The structures of
compounds 1 and 2 were established by Xꢀray diffraction.
The reaction of (methylꢀоꢀcarboranyl)lithium with
imine produces NꢀBocꢀprotected αꢀcarboranylꢀαꢀtriꢀ
fluoromethylꢀαꢀamino acid methyl ester 7 (Scheme 2).
The reaction affords the target product in virtually quanꢀ
titative yield already at –78 °C. The protecting group at
the nitrogen atom was removed by the reaction with
trifluoroacetic acid giving rise to the corresponding amino
acid methyl ester 8. Compounds 7 and 8 are colorless
crystals soluble in most of organic solvents. An attempt to
synthesize the corresponding free amino acid by acid
hydrolysis of the ester group with the use of hydrochloric
acid failed. Alkali hydrolysis leads to degradation of
the carborane cage and the formation of, apparently,
a nido structure.
With the aim of synthesizing optically active trifluoroꢀ
methylcarboranylalanine, we performed the reaction of
the lithium derivative of methylꢀоꢀcarborane with chiral
trifluoropyruvate imine containing the (1R)ꢀmenthoxyꢀ
carbonyl group at the nitrogen atom (Scheme 3).
Unfortunately, we failed to achieve the expected
stereoselectivity and obtained diastereomers 9a and 9b in
a ratio of ~1 : 1. Nevertheless, we succeeded in isolating
methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(1´ꢀmethylꢀоꢀcarboranyl)ꢀNꢀ
({[(1S,2R,5S)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexyl]oxy}carꢀ
bonyl)ꢀDꢀalaninate (9a) by crystallization from chloroꢀ
form. The structure of 9a was established by Xꢀray difꢀ
fraction.
Scheme 2
i. KOH or HCl.

New carboraneꢀcontaining amino acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
793
Scheme 3
Therefore, we developed a simple and efficient proceꢀ
dure for the synthesis of fluorineꢀcontaining carboranylꢀ
alaninates, which are potential reagents for BNCT. The
synthesis of optically active representatives of this class
and the peptide synthesis based on these compounds will
be the subject of further investigation.
The structures of 1 and 2 each contain two crystalloꢀ
graphically independent molecules. The structure of one
of two independent molecules 1 is shown in Fig. 1; one
independent molecule 2, in Fig. 2. In both crystal strucꢀ
tures, two independent molecules differ by a small rotaꢀ
tion of the {B9C2} cage about the C(1)—C(3) bond (the
C(2)—C(1)—C(3)—C(4) torsion angles in independent
molecules are 97.8(2) and 116.9(2)°) and in the orientaꢀ
tion of the Ph rings relative to the S(1)N(1)C(4) plane
(the corresponding dihedral angles are 68.5 and 76.0°). In
the crystal structure of 2, the rotation of the {B9C2} cage
about the C(1)—C(3) bond in two independent molecules
is characterized by the torsion angles of 160(1) and
169(1)°; the C(4)—N(1)—C(7)—C(8) torsion angles charꢀ
C(11)
F(5)
F(2)
F(1)
C(10)
C(12)
F(6)
O(3)
F(3)
C(9)
C(7)
C(9)
F(2)
C(8)
H(1A)
C(13)
C(5)
F(1)
C(4)
C(8)
F(3)
N(1)
C(5)
F(4)
H(1N)
O(1)
O(2)
O(2)
S(1)
C(6)
C(4)
O(1)
C(3)
C(7)
C(6)
N(1)
O(4)
O(3)
C(1)
C(2)
B(3)
C(3)
C(1)
C(2)
B(4)
B(9)
B(3)
B(5)
B(6)
B(4)
B(6)
B(11)
B(8)
B(5)
B(7)
B(8)
B(7)
B(11)
B(10)
B(10)
B(9)
B(12)
B(12)
Fig. 1. Molecular structure of 1.
Fig. 2. Molecular structure of 2.

794
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
Timofeev et al.
F(6)
C(8)
F(5)
F(4)
O(3)
C(7)
N(1)
H(1A)
O(1A)
C(4)
C(5)
O(2A)
C(4A)
C(5A)
H(1AA)
F(1A)
O(2)
O(1)
N(1A)
F(3A)
C(8A)
C(7A)
O(3A)
F(2A)
Fig. 3. Structure of the hydrogenꢀbonded dimer in the crystal structure of 2.
acterizing rotation of the NH—CO—CF3 fragment about
the N(1)—C(4) bond are 175(1) and 171(1)°.
The bond lengths and bond angles in molecules 1, 2,
and 9a have standard values.
The presence of different substituents R in similar
molecules 1 and 2 (SO2Ph and COCF3, respectively) reꢀ
sults in the different involvement of the NH group in
hydrogen binding. Only the intramolecular N—H...O(1)
hydrogen bond with one of the oxygen atoms of the SO2
group (H...O, 2.16 and 2.29 Å; N...O, 2.618(2) and
2.631(2) Å; N—H…... 113, 118°) is formed in molecules 1.
The IR spectrum of solid compound 1 shows νNH
absorption bands at 3300, 3288, and 3251 cm–1. In the
νCO region, the corresponding absorption bands are obꢀ
served at 1751 and 1765 cm–1. The IR spectrum of a
solution of compound 1 has a νNH band at 3319 cm–1 and
a νCO band at 1756 cm–1, which can be assigned to NH
and CO groups involved in intramolecular hydrogen
binding.
In the crystal structure of 2, the H(N) atoms are inꢀ
volved not only in intramolecular but also in intermoꢀ
lecular hydrogen bonds. Independent molecules are linked
C(17)
F(2)
F(1)
F(3)
C(16)
C(5)
O(1)
C(15)
B(11)
B(7)
B(12)
C(4)
B(6)
C(2)
C(14)
O(3)
O(4)
C(6)
C(8)
C(7)
B(10)
B(9)
C(13)
H(1N)
N(1)
O(2)
B(3)
C(1)
C(9)
C(12)
B(8)
B(5)
C(10)
B(4)
C(11)
C(18)
C(3)
Fig. 4. Molecular structure of 9a.

New carboraneꢀcontaining amino acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
795
imine (3.2 mmol) in diethyl ether (25 mL) was added dropwise
at –70 °C to an ethereal solution of the Grignard reagent, which
was prepared from bromomethylꢀоꢀcarborane (3 mmol) and
magnesium (4 mmol). The reaction mixture was stirred at –70 °C
for 1 h, slowly warmed to 20 °C, and stirred for 6 h. Then the
reaction mixture was treated with a saturated NH4Cl solution
and extracted with diethyl ether (2×20 mL). The combined etheꢀ
real extracts were dried with sodium sulfate, the solvent was
removed, and the product was finally purified on a silica gel
column using a hexane—ethyl acetate mixture as the eluent.
Methyl Nꢀ(phenylsulfonyl)ꢀαꢀ(trifluoromethyl)ꢀоꢀcarboranylꢀ
alaninate (1, R = SO2Ph), m.p. 94—95 °C, the yield was 75%.
Found (%): B, 23.84. C13H22B10F3NO4S. Calculated (%):
B, 23.84. 1H NMR (CDCl3), δ: 7.80 (m, 5 H, Ph); 6.24 (s, 1 H,
NH); 4.37 (s, 1 H, CHcarb); 3.95 (s, 3 H, OMe); 3.72 (d, 1 H,
CH2, J = 16.0 Hz); 3.22 (d, 1 H, CH2, J = 16.0 Hz); 3.10—1.00
(br.s, 10 H, BH). 19F NMR (CDCl3, CF3COOH as the stanꢀ
dard), δ: 5.33 (s, 3 F, CF3). IR (KBr pellets), ν/cm–1: 3300,
by the latter bonds to form isolated hydrogenꢀbonded
dimers (Fig. 3). The hydrogen bond parameters are as
follows: N(1)...O(1), 2.61(1) Å; N(1)...O(1A), 3.08(1) Å;
N(1A)...O(1), 3.12(1) Å; N(1A)...O(1A), 2.66(1) Å;
H(1A)...O(1), 2.17 Å; H(1A)...O(1A), 2.32 Å;
H(1AA)...O(1), 2.33 Å; H(1AA)...O(1A), 2.13 Å;
N(1)—H(1A)...O(1), 112°; N(1)—H(1A)...O(1A), 148°;
N(1A)—H(1AA)...O(1A), 118°; N(1A)—H(1AA)...O(1),
153°. In addition, the H(N) atoms in all molecules form
short intramolecular contacts with the fluorine atoms
(H(1A)...F(4), 2.46 Å; H(1AA)...F(3A), 2.24 Å). These
contacts are indicative of the presence of specific directed
interactions;10 all other H...F contacts are substantially
longer (2.66—2.95 Å).
The IR spectrum of a solid sample of compound 2
shows bands at 3337 and 3309 cm–1 assigned to
bonded NH groups. In the νCO region, there are bands at
1738 cm–1 (belonging to stretching vibrations of the
hydrogenꢀbonded C=O group) and 1762 cm–1 (the free
C=O group). In the spectrum of a solution of compound 2,
the position of the highꢀfrequency band νCO remains unꢀ
changed, whereas the band of the bonded C=O group
(1738 cm–1) is shifted to higher frequencies, which may
be indicative of the cleavage of the intermolecular hydroꢀ
gen bond. In the νNH region, weak bands are observed at
3314 and 3362 cm–1, which can be assigned to the
NH group involved in an intramolecular hydrogen bond.
An interesting feature of the structure of 9a (Fig. 4) is
the presence of shortened intramolecular F...H—B conꢀ
tacts (F(1)...H(7)—B(7) and F(3)...H(11)—B(11); the
F(1)...H(7) and the F(3)...H(11) distances are 2.43 Å).
However, these contacts are apparently forced because
the rather strong intramolecular C(3)—H(3c)...N(1)
hydrogen bond (the C(3)...N(1) and H(3c)...N(1) disꢀ
tances are 3.002 and 2.24 Å, respectively, and the
C(3)—H(3c)...N(1) angle is 136°) fixes the orientation of
the N substituent and, as a consequence, the orientations
of other substituents.
3288, 3251 (N—H); 1751, 1765 (C=O). IR (CH2Cl2), ν/cm–1
:
3319 (N—H); 1756 (C=O).
Methyl Nꢀ(trifluoroacetyl)ꢀαꢀ(trifluoromethyl)ꢀоꢀcarboranylꢀ
alaninate (2, R = COCF3), m.p. 81—82 °C, the yield was 76%.
Found (%): C, 24.35; H, 4.30. C8H17B10F6NO3. Calculated (%):
C, 24.18; H, 4.31. 1H NMR (CDCl3), δ: 7.59 (s, 1 H, NH); 4.11
(d, 1 H, CH2, J = 16.0 Hz); 4.04 (s, 3 H, OMe); 3.70 (s, 1 H,
CHcarb); 3.35 (s, 1 H, CH2, J = 16.0 Hz); 3.00—1.50 (br.s, 10 H,
BH). 19F NMR (CDCl3, CF3COOH as the standard), δ: 3.60 (s,
3 F, CF3); 1.62 (s, 3 F, CF3). IR (sol.), ν/cm–1: 3337, 3309
(N—H); 1738, 1762 (C=O). IR (CH2Cl2), ν/cm–1: 3414, 3362,
3292 (N—H); 1747, 1763 (C=O).
Methyl Nꢀ(tertꢀbutoxycarbonyl)ꢀαꢀ(trifluoromethyl)ꢀоꢀcarꢀ
boranylalaninate (3, R = Boc), m.p. 164—165 °C, the yield
was 72%. Found (%): C, 34.89; H, 6.33; B, 26.42.
C12H26B10F3NO4. Calculated (%): C, 34.86; H, 6.34; B, 26.15.
1H NMR (CDCl3), δ: 5.91 (s, 1 H, NH); 4.92 (s, 1 H, CHcarb);
4.06 (d, 1 H, CH2, J = 20.0 Hz); 3.95 (s, 3 H, OMe); 3.23 (d,
1 H, CH2, J = 20.0 Hz); 3.10—1.30 (br.s, 10 H, BH); 1.48 (s,
9 H, But). 19F NMR (CDCl3, CF3COOH as the standard), δ:
2.39 (s, 3 F, CF3).
Methyl αꢀ(trifluoromethyl)ꢀоꢀcarboranylalaninate (4). Comꢀ
pound 3 (0.2 g, 0.48 mmol) was dissolved in trifluoroacetic acid
(5 mL) at ~20 °C and the mixture was stirred until gas evolution
ceased (~3 h). Then the reaction mixture was concentrated, and
compound 4 was obtained in a yield of 0.15 g. Found (%):
Experimental
1
B, 34.39. C7H18B10F3NO2. Calculated (%): B, 34.50. H NMR
(CDCl3), δ: 4.67 (s, 1 H, CHcarb); 4.91 (s, 3 H, NH3); 3.40 (s,
3 H, OMe); 3.20 (s, CH2, J = 16 Hz); 2.68 (d, CH2, J =
16.0 Hz); 2.60—1.40 (br.s, 10 H, BH). 19F NMR (CDCl3, CFCl3
as the standard), δ: –79.43 (s, 3 F, CF3).
Starting methyl trifluoropyruvate imines were synthesized
according to procedures described earlier.6,7
The 1H and 19F NMR spectra were measured on Brukerꢀ
Avanceꢀ400 (400.13 MHz for 1H) and BrukerꢀAvanceꢀ300
(282.4 MHz for 19F) spectrometers. The chemical shifts (δ) for
1H are given relative to Me4Si. The IR spectra were recorded on
an Infralyum FTꢀ801 Fourierꢀtransform spectrometer in diꢀ
chloromethane in CaF2 cells (d = 0.04—0.22 cm). The mass
spectra were obtained on a Finnigan Polaris instrument
(EI, 70 eV). The elemental analysis was carried out in the
Laboratory of Microanalysis of A. N. Nesmeyanov Institute
of Organoelement Compounds of the Russian Academy of
Sciences.
αꢀ(Trifluoromethyl)ꢀоꢀcarboranylalanine hydrochloride (5).
Compound 4 (0.15 g, 0.47 mmol) was refluxed in 12 M HCl
(8 mL) until complete dissolution (~8 h). Then the reaction
mixture was concentrated, and compound 5 was obtained in a
1
yield of 0.1 g. H NMR (acetoneꢀd6), δ: 5.14 (s, 1 H, CHcarb);
2.93 (d, CH2, J = 16.0 Hz)*. 19F NMR (CDCl3, CFCl3 as the
standard), δ: 79.39 (s, 3 F, CF3). MS (EI, 70 eV), m/z (Irel (%)):
298 [M]+ (1.7).
Reactions of imines with оꢀcarboranylmethylmagnesium broꢀ
mide. A solution of the corresponding methyl trifluoropyruvate
* The second doublet of CH2 overlaps with a signal of water
present in acetone.

796
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
Timofeev et al.
Nꢀ(Phenylsulfonyl)ꢀαꢀ(trifluoromethyl)ꢀоꢀcarboranylalanine
eluent. The yield of compound 7 was 89%. Found (%): C, 34.89;
H, 6.33; B, 25.42; N, 3.19. C12H26B10F3NO4. Calculated (%):
C, 34.85; H, 6.29; B, 25.10; N, 3.38. 1H NMR (CDCl3), δ: 5.27
(s, 1 H, NH); 3.89 (s, 3 H, OMe); 3.50—1.30 (br.s, 10 H, BH);
2.26 (s, 3 H, Me); 1.42 (s, 9 H, But). 19F NMR (CDCl3,
CF3COOH as the standard), δ: 9.02 (s, 3 F, CF3).
(6). Compound 1 (0.3 g, 0.66 mmol) was added to a solution of
lithium hydroxide (0.07 g, 2.29 mmol) in a mixture of THF
(12 mL) and water (6 mL). The reaction mixture was stirred at
20 °C for 4 days and extracted with benzene (2×20 mL). Then
1 M HCl (4 mL) was added to the aqueous layer. The precipitate
that formed was extracted with diethyl ether and dried with
anhydrous sodium sulfate. After removal of the solvent, comꢀ
pound 6 was obtained in a yield of 0.17 g. 1H NMR (DMSOꢀd6),
δ: 7.52 (m, 5 H, Ph); 5.29 (s, 1 H, NH); 4.92 (s, 1 H, CHcarb).
MS (EI, 70 eV), m/z (Irel (%)): 375 [M]+ (2.3).
Methyl Nꢀ(tertꢀbutoxycarbonyl)ꢀ3,3,3ꢀtrifluoroꢀ2ꢀ(2ꢀmethylꢀ
оꢀcarboranyl)alaninate (7). A 1.6 M butyllithium solution in
hexane (3.95 mL) was added dropwise to a solution of methylꢀоꢀ
carborane (1.0 g, 6.3 mmol) in diethyl ether (30 mL) at 0 °C.
The temperature of the reaction mixture was slowly raised
to ~20 °C. Then the mixture was refluxed for 30 min and cooled
to –78 °C. A solution of the corresponding imine (1.6 g,
6.3 mmol) in diethyl ether (5 mL) was added. The temperature
of the reaction mixture was slowly raised to ~20 °C, and the
mixture was kept at this temperature for 16 h. Then the reaction
mixture was treated with 1 M HCl (50 mL). The organic layer
was separated and dried with magnesium sulfate. After drying,
the solvent was removed, and the residue was finally purified on
a silica gel column using a hexane—ethyl acetate mixture as the
Methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(2ꢀmethylꢀоꢀcarboranyl)alaninate
(8). Trifluoroacetic acid (10 mL) was added to a solution of
compound 7 (1.0 g) in dichloromethane (20 mL). The reaction
mixture was stirred at room temperature for 6 h and concenꢀ
trated. The residue (oil) was dissolved in ethyl acetate and treated
with a saturated Na2CO3 solution (20 mL). The organic layer
was separated, the aqueous layer was extracted with ethyl aceꢀ
tate (2×30 mL), the combined extracts were dried with magneꢀ
sium sulfate, the solvent was removed, and the residue was puriꢀ
fied on a silica gel column using a hexane—ethyl acetate mixture
as the eluent. The yield of compound 8 was 82%. Found (%):
C, 25.94; H, 5.76; B, 35.39; N, 4.17. C7H18B10F3NO2. Calcuꢀ
lated (%): C, 25.36; H, 5.43; B, 34.50; N, 4.22. 1H NMR
(CDCl3), δ: 3.92 (s, 3 H, OMe); 3.10—1.25 (br.s, 10 H, BH);
2.37 (br.s, 2 H, NH2); 2.29 (s, 3 H, CH3). 19F NMR (CDCl3,
CF3COOH as the standard), δ: 7.65 (br.s, 3 F, CF3).
Methyl 3,3,3ꢀtrifluoroꢀNꢀmenthoxycarbonylꢀ2ꢀ(2´ꢀmethylꢀ
оꢀcarboranyl)alaninate (9). A 2.5 M butyllithium solution in hexꢀ
ane (1.83 mL) was added dropwise to a solution of methylꢀоꢀ
Table 1. Xꢀray data collection and refinement statistics for compounds 1, 2, and 9a
Parameter
1
2
9a
Molecular formula
Molecular weight
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
C13H22B10F3NO4S
453.48
C9H17B10F3NO3
C18H36B10F3NO4
495.58
409.34
C2/c
P–1
11.420(4)
11.986(4)
15.406(5)
95.66(2)
107.27(2)
104.17(2)
1919(1)
P21
24.197(4)
13.754(2)
27.524(4)
90.0
110.032(6)
90.0
8606(2)
16
1.400
6.786(2)
17.501(4)
11.342(2)
90.0
96.342(2)
90.0
1337.6(5)
2
1.230
γ/deg
V/Å3
Z
4
dcalc/g cm–3
1.417
Crystal color and shape
Crystal dimensions/mm
Radiation
Colorless prism
0.50×0.35×0.30
Colorless plate
0.35×0.25×0.20
MoꢀKα (λ = 0.71073 Å)
1.26
Colorless plate
0.55×0.35×0.25
µ/cm–1
1.98
SADABS
0.604/0.802
φ/ω
0.90
—
—
Absorption correction
Tmin/Tmax
Scan mode
—
—
θ/2θ
2θmax/deg
Total number of reflections
56.0
12586
42.0
4163
56.0
3586
Number of independent reflections (Rint
)
10240 (0.0579)
3930 (0.1081)
0.1397 (2381 refl.)
0.2628
3290 (0.0226)
0.443 (2172 refl.)
0.0863
R1 (based on F 2 for reflections with I > 2σ(I )) 0.0525 (6561 refl.)
wR2 (based on F 2 for all reflections)
0.1136
Number of parameters in refinement
Weighting scheme
579
w
523
325
)
2
2
–1 = σ (Fo2) + (aP)2 + bP, где P = 1/3(Fo2 + 2Fc
a
b
0.0357
10.950
1.015
3712
0.0050
20.602
1.140
824
0.0103
—
0.994
520
GOOF
F(000)

New carboraneꢀcontaining amino acids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 4, April, 2007
797
carborane (0.72 g, 4.64 mmol) in diethyl ether (30 mL) at –10 °C.
The temperature of the reaction mixture was slowly raised to
room temperature, and the mixture was refluxed for 30 min.
After cooling to –78 °C, a solution of the corresponding imine
(1.54 g, 4.54 mmol) in diethyl ether (5 mL) was added. The
temperature of the reaction mixture was slowly raised to ~20 °C,
and the mixture was kept at this temperature for 16 h. Then the
mixture was treated with a solution of ammonium chloride (6 g)
in water (10 mL). The organic layer was separated. The aqueous
layer was extracted with diethyl ether (2×10) and dried with
magnesium sulfate. After removal of the solvent, a mixture of
diastereomers was obtained in a yield of 1.5 g (66%). Crystalliꢀ
zation of this mixture from chloroform afforded 3,3,3ꢀtrifluoroꢀ
2ꢀ(1ꢀmethylꢀоꢀcarboranyl)ꢀNꢀ({[(1S,2R,5S)ꢀ2ꢀisopropylꢀ5ꢀ
methylcyclohexyl]oxy}carbonyl)ꢀDꢀalanine methyl ester (9a).
1H NMR of a mixture of diastereomers (CDCl3), δ: 5.37 (s, 1 H,
NH); 4.54 (m, 1 H, OCH); 3.9 (s, 3 H, OMe); 2.28 (s, 3 H,
MeCcarb); 1.93 (m, 2 H, OCCH2CHMe); 1.81 (m, 1 H,
MeCHMe); 1.67 (m, 2 H, CHCHCH2CH2); 1.54, (m, 2 H,
CHCH2CH2CH); 0.89 (m, 9 H, CH3CHCH3, CHCH3).
19F NMR (CDCl3, CFCl3 as the standard), δ: 67.28 (s, 3 F, CF3).
Xꢀray diffraction study. Single crystals of 1, 2, and 9a were
grown by crystallization from a dichloromethane—hexane
mixture.
Xꢀray diffraction data sets were collected on a Bruker
SMART CCD area detector diffractometer at 120 K (1) and a
Syntex P21 diffractometer at 183 K (2) and 193 K (9a). The
Xꢀray reflections were processed using the SAINTPlus11 and
SADABS programs12 for 1 and the P3 and XDISK programs13
for 2 and 9a.
The structures were solved by direct methods. All nonꢀ
hydrogen atoms were located in difference electron density maps
and refined anisotropically based on F 2hkl. The hydrogen atoms
of the carborane fragments and the NH groups were located in
difference electron density maps and refined isotropically using
a riding model. Other hydrogen atoms were positioned geoꢀ
metrically and refined using a riding model with U(H) = nU(C),
where U(C) are the equivalent thermal parameters of the carbon
atoms to which the corresponding H atoms are attached, n = 1.2
(for CH2 and CH groups) and n = 1.5 for Me groups.
ited with the Cambridge Structural Database (CCDC 231182,
231183, and 601913).
We thank V. N. Tsupreva for recording and interpretꢀ
ing IR spectra.
This study was financially supported by the Presidium
of the Russian Academy of Sciences (Program "Fundaꢀ
mental Sciences for Medicine"), the Russian Foundation
for Basic Research (Project Nos 05ꢀ03ꢀ32359, 04ꢀ03ꢀ
32644, and 03ꢀ03ꢀ32214), and the Council on Grants of
the President of the Russian Federation (Program for
State Support of Young Doctors, Grant MKꢀ9349.2006.3).
References
1. M. F. Hawthorne, Angew. Chem., Int. Ed. Engl., 1993,
32, 950.
2. A. H. Soloway, W. Tjarks, B. A. Barnum, F.ꢀG. Rong, R. F.
Barth, I. M. Codogni, and J. G. Wilson, Chem. Rev., 1998,
98, 1515.
3. N. Sewald and K. Burger, in Fluorineꢀcontaining Amino Acids:
Synthesis and Properties, Eds V. P. Kukhar´ and V. A.
Soloshonok, J. Wiley and Sons, Chichester, 1995, 139.
4. D. Schirlin, F. Gerhard, J. M. Hornsperger, M. Hamon,
J. Wagner, and M. J. Yung, J. Med. Chem., 1988, 31, 30.
5. D. E. Zembower, J. A. Gilbert, and M. M. Ames, J. Med.
Chem., 1993, 36, 305.
6. S. N. Osipov, N. D. Chkanikov, A. F. Kolomiets, and A. V.
Fokin, Izv. Akad. Nauk SSSR, Ser. Khim., 1986, 1384 [Bull.
Acad. Sci. USSR, Div. Chem. Sci., 1986, 35, 1256 (Engl.
Transl.)].
7. S. N. Osipov, A. S. Golubev, N. Sewald, T. Michel, A. F.
Kolomiets, A. V. Fokin, and K. Burger, J. Org. Chem., 1996,
61, 7521.
8. S. N. Osipov, A. F. Kolomiets, and A. V. Fokin, Usp. Khim.,
1992, 61, 1457 [Russ. Chem. Rev., 1995, 61, 798 (Engl.
Transl.)].
9. I. P. Beletskaya, V. I. Bregadze, S. N. Osipov, P. V.
Petrovskii, Z. A. Starikova, and S. V. Timofeev, Synlett,
2004, 1247.
10. Yu. V. Zefirov and P. M. Zorkii, Usp. Khim., 1995, 64, 446
[Russ. Chem. Rev., 1995, 64, 415 (Engl. Transl.)].
11. SAINTPlus. Data Reduction and Correction Program, V. 6.01,
Bruker AXS, Madison (Wisconsin, USA), 1998.
12. G. M. Sheldrick, SADABS, V. 2.01, Bruker/Siemens Area
Detector Absorption Correction Program, Bruker AXS, Madiꢀ
son (Wisconsin, USA), 1998.
Crystals of compound 2, which were grown after numerous
attempts to perform crystallization from different solvents, were
twins and had a very weak reflection ability. Xꢀray diffraction
data were collected from a small chip in the 2θ angle range < 42°.
The Xꢀray data set contained an admixture of a twin compoꢀ
nent, which is responsible for high values of R1 and wR2. Neverꢀ
theless, the established molecular structure of compound 2 is
reliable, although high errors in bond lengths (0.01—0.02 Å)
and bond angles (0.8—1°) did not allow us to perform a correct
comparative analysis.
13. P3 and XDISK. Release 4.1, Siemens AXS, Madison (Wisꢀ
consin, USA), 1989.
14. SHELXTL V. 5.10, Structure Determination Software Suite,
Bruker AXS, Madison (Wisconsin, USA), 1998.
All calculations were carried our using the SHELXTL
PLUS 5 program package.14 The Xꢀray data collection and reꢀ
finement statistics are given in Table 1. The atomic coordinates,
thermal parameters, and geometric characteristics were deposꢀ
Received December 11, 2006;
in revised form April 4, 2007