Covalent and Ionic Conjugates of Trolox and α-Tocopherol with 1-Aminoadamantane

Article abstract of DOI:10.1007/s10600-017-2201-2

Covalent, ionic, and ionic-covalent conjugates of trolox and α-tocopherol with 1-aminoadamantane were synthesized. Their structures were elucidated using mass spectrometry and IR, PMR, and ¹³C NMR spectroscopy. The water solubility of the ionic trolox conjugates with 1-aminoadamantane increased by 2–24 times as compared with that of trolox whereas that of the α-tocopherol succinate conjugates remained the same as that of α-tocopherol.

Full text of DOI:10.1007/s10600-017-2201-2

DOI 10.1007/s10600-017-2201-2
Chemistry of Natural Compounds, Vol. 53, No. 6, November, 2017
COVALENT AND IONIC CONJUGATES OF TROLOX
AND ꢀ-TOCOPHEROL WITH 1-AMINOADAMANTANE
*
Yu. V. Yushkova, S. V. Morozov,
E. I. Chernyak, and I. A. Grigorꢁev
Covalent, ionic, and ionic-covalent conjugates of trolox and ꢀ-tocopherol with 1-aminoadamantane were
13
synthesized. Their structures were elucidated using mass spectrometry and IR, PMR, and C NMR
spectroscopy. The water solubility of the ionic trolox conjugates with 1-aminoadamantane increased by
2–24 times as compared with that of trolox whereas that of the ꢀ-tocopherol succinate conjugates remained
the same as that of ꢀ-tocopherol.
Keywords: trolox, ꢀ-tocopherol, 1-aminoadamantane, adamantane dimers, ionic conjugates, covalent conjugates,
water solubility.
Targeted modification of lead molecules with pronounced biological activity is one of the most promising thrusts of
synthetic organic and pharmaceutical chemistry for new drug development [1, 2]. Conjugation of two or more pharmacologically
active molecules with considerably different properties can be utilized to synthesize new biologically active compounds [3, 4].
Molecular hybridization of natural and synthetic medicinal and inactive compounds has been demonstrated in the last 20 years
to be effective for developing anticancer, antiviral, antifungal, antimalarial, antituberculosis, anti-inflammatory, and other
agents. In most instances, the hybrid molecules are less toxic than the individual starting compounds and exhibit synergism,
indicating that conjugates have greater pharmacological potential [5].
The platform molecules ꢀ-tocopherol and trolox were considered promising for synthesizing hybrid compounds
because they contain the chromane moiety, an important chemical synthon for constructing drugs to treat diseases associated
with oxidative stress. Several examples showed that compounds with chromane moieties exhibit broad spectra of biological
activity, e.g., antioxidant, neuroprotective, anticancer, etc. [6, 7].
The second pharmacophore consisted of adamantane derivatives, which exhibit broad spectra of biological activity
and can enhance the lipophilicity and stability of pharmacologically active compounds by improving their pharmacokinetics
and ability to penetrate the blood–brain barrier as compared with the unmodified analogs [8, 9]. Amine-derivatives of adamantane
such as amantadine, rimantadine, and trimantadine became famous for their activity against flu virus. However, amantadine is
a CNS-active compound, i.e., an NMDA-receptor antagonist, and is used for complex therapy of mid-stage Parkinson’s and
Alzheimer’s diseases. Currently, memantine is under scrutiny as a moderate non-competitive NMDA-receptor antagonist.
ꢀ-Tocopherol and trolox acted as platforms for preparing many hybrid compounds with various biological activities.
In most instances, trolox was modified at the chromane 2-carboxylic acid; ꢀ-tocopherol, at the phenolic 6-OH. ꢀ-Tocopherol
and trolox were chemically modified at three positions, i.e., the aromatic 5-Me, the phenolic 6-OH, and the trolox chromane
2-COOH, by selecting 1-aminoadamantane as the modifier and using both covalent and ionic bonding. The ionic hybridization
allowed the water solubility of the obtained conjugates to be increased, thereby expanding their possible applications [10].
The amide of trolox (3) was prepared by reacting 1-aminoadamantane with succinimide 2, which was synthesized
from 1 and N-hydroxysuccinimide in THF in the presence of carbonyldiimidazole (CDI). Ammonium salt 4 was prepared by
adding a solution of 1-aminoadamantane to a solution of trolox in THF in a 1:1 mole ratio at 20–25°C (Scheme 1).
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
9 Prosp. Akad. Lavrentꢁeva, Novosibirsk, 630090, e-mail: yushkova@nioch.nsc.ru. Translated from Khimiya Prirodnykh
Soedinenii, No. 6, November–December, 2017, pp. 900–906. Original article submitted January 27, 2017.
©
0009-3130/17/5306-1059 2017 Springer Science+Business Media New York
1059

NH
2
OH
N
9'
O
O
10'
3'
7'
O
4
HO
6
O
HO
O
HO
O
5'
4a
8a
N
2
OH
O
N
H
CDI, THF
O
O
O
8
O
2
3
1
THF
HO
O
H N
2
_
+
3
O
H N
O
4
Scheme 1
Trolox and ꢀ-tocopherol derivatives modified at the phenolic 6-OH were prepared from trolox methyl ester 5 and
ꢀ-tocopherol 6 by reacting their succinyl derivatives 7 and 8 with a solution of 1-aminoadamantane in THF in a 1:1 mole ratio
to give the corresponding ammonium salts 9 and 10. Treatment of trolox and ꢀ-tocopherol succinyl derivatives 7 and 8 with
N-hydroxysuccinimide and 1-aminoadamantane gave their amide derivatives 13 and 14 (Scheme 2).
NH
2
O
O
O
O
O
_
O
+
NH
HO
O
O
HO
3
Y
Y
Y
a
O
O
O
O
O
5, 6
7, 8
9, 10
OH
N
O
O
NH
2
O
O
O
O
N
O
O
5, 7, 9, 11, 13: Y =
6, 8, 10, 12, 14: Y =
HN
O
O
Y
Y
O
O
O
O
O
3
11, 12
13, 14
a. DMAP, Et N, CH Cl
3
2
2
Scheme 2
IR spectra of covalent conjugates 3, 13, and 14 exhibited characteristic bands for amide stretching vibrations at
–1
1660–1678 cm ; ionic conjugates 4, 9, and 10, bands for asymmetric and symmetric carboxylate-anion stretching vibrations
–1
–1
at 1606–1637 and 1398–1408 cm , respectively; and bands for quaternary N bending vibrations (ꢂN–H) at 1552–1556 cm
[11, 12]. This argued in favor of ionic structures for 4, 9, and 10. Furthermore, IR spectra of 9, 10, 13, and 14 showed
–1
characteristic bands for ester C=O stretching vibrations at 1737–1755 cm .
13
PMR and C NMR spectra of 3, 4, 9, 10, 13, and 14 exhibited all characteristic resonances of trolox, ꢀ-tocopherol,
and 1-aminoadamantane moieties. The resonance of the carboxylate C atom of 4 (181.74 ppm) underwent a weak-field shift
of 5.44 ppm relative to that of the carboxylic C atom of trolox (176.30 ppm), which was characteristic for carboxylic C atoms
after forming salts [13].
Trolox and ꢀ-tocopherol conjugates with 1-aminoadamantane in the aromatic 5-position were prepared by synthesizing
their 5-bromomethyl derivatives 15 and 16 via bromination of trolox methyl ester 5 and ꢀ-tocopherol 6 followed by acylation
with acetic anhydride in CH Cl in the presence of AcOH and H SO [14, 15]. The reactions of 15 and 16 with
2
2
2
4
1-aminoadamantane in CH Cl followed by neutralization of the reaction mixture with KOH solution produced 5-aminomethyl
2
2
derivatives 17 and 18 (Scheme 3).
1060

NH
2
H
N
O
Br
O
15, 17:Y =
16, 18:Y =
O
O
Y
Y
CH Cl
O
O
2
2
O
3
O
15, 16
17, 18
Scheme 3
R
R
H N
HN
O
O
O
O
Y
Y
O
O
R = Adamantyl
Fig. 1. Formation of intramolecular H-bond in 17 and 18.
IR spectra of amines 17 and 18 contained characteristic bands for 6-C=O ester stretching vibrations as 1755–1759 cm
and bands at 1620 cm . The shift of characteristic bands at 1760–1730 to 1620 cm could have been due to the formation of
–1
–1
–1
an intramolecular H-bond of the C=O O atom and the NH H atom (Fig. 1). Trolox amine 17 showed ester 2-C=O stretching
–1
13
bands at 1738 cm . PMR and C NMR spectra of 17 and 18 had all characteristic resonances for the 1-aminoadamantane,
ꢀ-tocopherol, and trolox moieties.
Furthermore, dimers of 1-aminoadamantane in which its molecules were joined by covalent, ionic, and ionic-covalent
bonds using trolox succinate as a linker were also synthesized.
Ionic dimer 20 was synthesized by reacting trolox succinate 19 with 1-aminoadamantane in a 1:2 mole ratio in THF.
Compound 19 was produced via acylation of trolox by succinic anhydride in CH Cl in the presence of DMAP and Et N.
2
2
3
Reaction of 19 with N-hydroxysuccinimide in a 1:2 ratio in THF in the presence of CDI gave trolox succinate succinimide 21,
which reacted with 1-aminoadamantane in a 1:2 ratio in CH Cl to synthesize covalent dimer 22. Acylation of amide 3 by
2
2
succinic anhydride in CH Cl in the presence of DMAP and Et N synthesized succinate 23 that reacted further with
2
2
3
1-aminoadamantane in THF to afford ionic-covalent dimer 24 (Scheme 4).
O
_
O
NH
+
O
O
2
NH
3
_
O
+
H N
3
O
O
O
THF
20
O
O
O
O
HO
O
O
O
HO
O
HO
OH
O
OH
CH Cl
N
2
2
O
O
O
O
H
3
1
19
OH
N
O
O
O
O
O
O
a
b
O
O
O
O
O
O
O
N
O
HO
O
N
O
N
H
O
O
23
O
21
NH
2
NH
2
THF
CH Cl
2
2
O
O
_
O
+
NH
O
O
O
O
3
N
H
O
N
H
O
N
H
O
O
24
22
a. CH Cl , DMAP, Et N; b. CDI, THF
2
2
3
Scheme 4
1061

–1
IR spectra of 20 and 22–24 exhibited characteristic bands for ester C=O stretching vibrations at 1743–1757 cm and
–1
–1
for amides at 1645–1679 cm . Compound 23 also showed a carboxylic C=O stretching band at 1715 cm . IR spectra of 20
–1
and 24 contained bands for asymmetric and symmetric carboxylate-anion stretching vibrations at 1626, 1627 and 1389,1392 cm ,
respectively, and bands for quaternary N bending vibrations (ꢂN–H) at 1560 cm [10, 11], indicating that these conjugates
–1
had ionic bonds.
13
PMR and C NMR spectra of 20 and 22–24 exhibited all characteristic resonances for succinyl, trolox, and
1-aminoadamantane moieties. The C NMR spectrum of 20 showed characteristic weak-field shifts of 3.92 and 4.13 ppm for
the carboxylate C atoms relative to those of carboxylic C atoms of trolox succinate 19 [13]. PMR and C NMR spectra of
13
13
ionic-covalent conjugate 24 contained two sets of resonances in a 2:1 ratio. This may have been due to the presence of
the asymmetric C atom and hindered rotation around the C–N amide bond.
Thus, spectral results confirmed the structures of the ionic, covalent, and ionic-covalent conjugates of trolox
and ꢀ-tocopherol.
Water solubilities of ionic conjugates 4, 9, 10, 20, and 24 were determined by the literature method [16]. The results
are given below:
Compound
Water solubility, g/L
Compound
Water solubility, g/L
0.1
< 0.1
1
< 0.1
2.4
0.2
1
6
4
9
10
20
24
0.3
The water solubility of trolox conjugates with 1-adamantane 4, 9, 20, and 24 increased by 2–24 times as compared
with trolox (1). This allowed these conjugates to be given the pharmacopoeial classifications [17] very slightly (VSS) and
slightly soluble (SS), respectively. However, the solubility of ionic conjugate 10 turned out to be the same as that of
ꢀ-tocopherol 6. This may have been due to the high lipophilicity of the 2-alkyl group of ꢀ-tocopherol. Ionic conjugate 10,
like 6, had the pharmacopoeial classification insoluble in water (PI).
Thus, covalent, ionic, and ionic-covalent conjugates were synthesized from trolox and ꢀ-tocopherol and 1-adamantane.
13
Their compositions and structures were confirmed by elemental analyses, mass spectrometry, and IR, PMR, and C NMR
spectroscopy. The obtained conjugates were variously soluble in water and, obviously, had different lipophilicities and
bioavailabilities. This provided an opportunity to construct new drug prototypes from them.
EXPERIMENTAL
NMR spectra of compounds in CD OD and CDCl solutions were recorded on Bruker AV-300, AV-400, and
3
3
DRX-500 spectrometers. IR spectra were recorded from KBr pellets on a Vector-22 instrument. Elemental analyses used
a Euro EA3000 CHN Elemental Analyzer and agreed with those calculated for 4, 10, 18, and 20. Melting points were
measured on a Mettler Toledo FP 90 Central Processor apparatus at heating rate 5°C/min in the range 50–300°C with an
uncertainty of ꢃ0.3°C. Mass spectrometry was performed on an Agilent 1200 liquid chromatograph with a micrOTOF-Q
hybrid quadrupole–time-of-flight mass spectrometer (Bruker) using direct sample introduction, mass detection with electrospray
at atmospheric pressure (API-ES), scanning of positive and negative ions in the range m/z 80–3000, capillary potential (V
)
cap
4500 V, sprayer pressure 1.6 bar, drying-gas (N ) temperature 230°C at flow rate 8 L/min.
2
Trolox, CDI, and 1-aminoadamantane hydrochloride (Acros Organics); D,L-ꢀ-tocopherol (Alfa Aesar), and
N-hydroxysuccinimide (Aldrich) were purchased.
Trolox succinimide (2) was prepared by reacting trolox (1) with N-hydroxysuccinimide in THF in the presence of
CDI [18]. Trolox methyl ester (5) was prepared by methylating 1 with diazomethane in MeOH–CH Cl in a 1:1 ratio and was
2
2
recrystallized from this mixture [19]. Succinyl derivatives 7 and 8 were synthesized from 5 and 6 according to the literature
[20]. 5-Bromomethyl derivatives of trolox and ꢀ-tocopherol (15 and 16) were synthesized as before [14, 15] via bromination
of 5 and 6 followed by acylation by acetic anhydride in CH Cl in the presence of AcOH and H SO . Trolox succinate 19 was
2
2
2
4
prepared by reacting trolox with succinic anhydride in CH Cl in the presence of Et N and DMAP [20]. Trolox succinate
2
2
3
succinimide 21 was obtained from the reaction of 19 with N-hydroxysuccinimide in a 1:2 ratio in THF in the presence of CDI
[18]. 1-Aminoadamantane was obtained by extraction with Et O from an alkaline aqueous solution of 1-aminoadamantane
2
hydrochloride.
1062

6-Hydroxy-N-(1-adamantanamine)-2,5,7,8-tetramethylchromane-2-carboxamide (3). A solution of trolox
succinimide (2, 36 mg, 0.1 mmol) in CH Cl (0.5 mL) at 20–25°C was stirred, treated with 1-aminoadamantane (17.3 mg,
2
2
0.11 mmol) in CH Cl (1 mL), stirred for 16–20 h at 20–25°C, washed with H O, dried over Na SO , and evaporated. Yield
2
2
2
2
4
–1
83%, viscous light-yellow liquid. IR spectrum (KBr, ꢄ, cm ): 1661 (CONH). Mass spectrum: found m/z 384.255
[M + Í] , calcd for C H NO , 384.253. Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 1.45, 2.08, 2.14, 2.17 (each
+
1
24 34
3
3
3Í, s, ÑÍ ), 2.18–2.27 (1Í, m, Íà-3), 2.50–2.63 (2Í, m, ÑÍ -4), 1.62 (6Í, t, J = 3.0, Í-4ꢁ, 6ꢁ, 10ꢁ), 1.86–1.88 (6Í, m, Í-2ꢁ,
3
2
13
8ꢁ, 9ꢁ), 1.98–2.05 (4Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ, Hb-3). C NMR spectrum (100 MHz, CDCl , ꢂ, ppm): 11.36, 11.91, 12.29 (ÑÍ -5, 7, 8),
3
3
20.47, 24.05, 29.39 (Ñ-3, 4, ÑÍ -2), 29.36, 36.29, 41.34 (ÑÍ -4ꢁ, 6ꢁ, 10ꢁ, 2ꢁ, 8ꢁ, 9ꢁ, ÑÍ-3ꢁ, 5ꢁ, 7ꢁ), 51.23 (Ñ-1ꢁ), 78.12 (Ñ-2),
3
2
118.08, 118.96, 121.33, 121.74 (Ñ-5, 7, 8, 4à), 144.27, 145.46 (Ñ-6, 8à), 173.40 (C=O).
1-Adamantylammonium 6-Hydroxy-2,5,7,8-tetramethylchromane-2-carboxylate (4). Trolox (21 mg, ~0.08 mmol)
in THF (0.5 mL) was treated with 1-aminoadamantane (12.6 mg, 0.08 mmol) in THF (0.3 mL), held for 16–20 h at 20–25°C,
and evaporated. The viscous residue was triturated with Et O until the formation of a powder that was filtered off, rinsed with
2
–1
EtOAc, and dried to constant weight. Yield 72%, white powder, mp 247.9–249.4°C. C H NO . IR spectrum (KBr, ꢄ, cm ):
1398 and 1606 (COÎ ), 1554 (ꢂN-H). Í NMR spectrum (400 MHz, CD OD, ꢂ, ppm): 1.52, 2.07, 2.15, 2.17 (each 3Í, s,
24 35
4
–
1
3
ÑÍ ), 1.66–1.85 (13Í, m, Í-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, Íb-3), 2.13–2.18 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ), 2.39–2.45 (1Í, m, Ía-3), 2.55–2.69
3
13
(2Í, m, Í-4). C NMR spectrum (125 MHz, CDCl , ꢂ, ppm) 11.84, 12.34, 12.80 (Ñ-5, 7, 8), 22.60, 25.73, 32.35 (Ñ-3, 4, 2),
3
30.41, 36.46, 41.50 (Ñ-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, 3ꢁ, 5ꢁ, 7ꢁ), 52.58 (Ñ-1ꢁ), 79.55 (Ñ-2), 118.65, 121.69, 123.02, 124.05 (Ñ-5, 7, 8, 4à),
145.89, 147.96 (Ñ-6, 8à), 181.74 (Ñ=Î).
1-Adamantanylammonium 4-[2-(Methoxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy]-4-oxobutanoate (9).
Succinate 7 (16.2 mg, ~0.04 mmol) in THF (0.5 mL) was treated with 1-aminoadamantane (6.7 mg, 0.04 mmol) in THF
(0.3 mL), held for 16–20 h at 20–25°C, and evaporated. The viscous residue was triturated with Et O until the formation of
2
a powder that was filtered off, rinsed with EtOAc, and dried to constant weight. Yield 85%, white powder, mp 141.5–142.4°C.
–1
–
IR spectrum (KBr, ꢄ, cm ): 1408 and 1625 (COÎ ), 1556 (ꢂN-H), 1737, 1753 (ester COO). Mass spectrum: found
+
1
m/z 516.292 [M + Í] , calcd for C H NO , 516.296. Í NMR spectrum (400 MHz, CD OD, ꢂ, ppm, J/Hz): 1.60, 1.95, 2.03,
29 42
7
3
2.14 (each 3Í, s, ÑÍ ), 1.66–1.90 (14Í, m, Í-3, 2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ), 2.15–2.19 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ), 2.40–2.50 (2Í, m, Í-4),
3
2.56 (2Í, t, J = 7.0), 2.88 (2Í, t, J = 7.0) – succinyl CH ; 3.67 (3Í, s, COOCH ).
2
3
1-Adamantanylammonium 4-Oxo-4-[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-
yloxy]butanoate (10). Succinate 7 (13.3 mg, ~0.025 mmol) in THF (0.5 mL) was treated with 1-aminoadamantane (3.8 mg,
0.025 mmol) in THF (0.3 mL), held for 16–20 h at 20–25°C, and evaporated. The residue was triturated with Et O until the
2
formation of a viscous precipitate that was filtered off, rinsed with EtOAc, and dried to constant weight. Yield 96%, white
–1
–
viscous liquid. C H NO . IR spectrum (KBr, ꢄ, cm ): 1408 and 1637 (ꢄCOÎ ), 1552 (ꢂN-H), 1755 (ester ꢄCOO).
43 71
5
1
Í NMR spectrum (400 MHz, CD OD, ꢂ, ppm, J/Hz): 0.87–0.93 (12H, m, alkyl side-chain CH ), 1.07–1.64 (21Í, m, alkyl
3
3
side-chain CH and CH), 1.27, 2.00, 2.03, 2.10 (each 3Í, s, ÑÍ ), 2.60–2.67 (4Í, m) and 2.91 (2Í, t, J = 7.0) succinyl
2
3
CH -4 and CH ; 1.69–1.91 (14Í, m, Í-3, 2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ), 2.15–2.22 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ).
2
2
Methyl-6-[4-(1-aminoadamantane)-4-oxobutanoyloxy]-2,5,7,8-tetramethylchromane-2-carboxylate (13).
Succinimide 11 was prepared by reacting succinate 7 with N-hydroxysuccinimide in a 1:1 ratio [17] and used without further
purification. Succinimide 11 (22.4 mg, 0.048 mmol) in CH Cl (0.2 mL) was treated with 1-aminoadamantane (7.4 mg,
2
2
0.048 mmol) in CH Cl (0.4 mL), held for 16–20 h at 20–25°C, washed with H O, dried over MgSO , and evaporated. Yield
2
2
2
4
–1
70%, viscous light-yellow liquid. IR spectrum (ꢄ, cm ): 1660 (CONH), 1737, 1751 (ester COO). Mass spectrum: found
m/z 498.283 [M + Í] , calcd for C H NO , 498.285. Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm): 1.57 (s) and 1.58 (s)
+
1
29 40
6
3
(3Í, ÑÍ ), 1.95 (s) and 1.96 (s) (3Í, ÑÍ ), 1.99 (3Í, s, ÑÍ ), 2.12 (s) and 2.13 (s) (3Í, ÑÍ ), 1.66–1.90 (14Í, m, Í-3, 2ꢁ, 4ꢁ,
3
3
3
3
6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ), 2.15–2.19 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ), 2.34–2.66 (4Í, m) and 2.81–2.96 (2Í, m) succinyl CH -4 and CH ; 3.65 (s) and
2
2
3.66 (s) (3Í, COO-CH ).
3
2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl 1-Aminoadamantane-4-oxobutanoate (14).
1-Aminoadamantane (5.7 mg, 0.04 mmol) in CH Cl (0.7 mL) was treated dropwise with a solution of succinimide 12
2
2
(21.6 mg, 0.03 mmol) in CH Cl (0.4 mL), held for 16–20 h at 20–25°C, washed with H O, dried over MgSO , and evaporated.
2
2
2
4
Succinimide 12 was prepared by reacting succinate 8 with N-hydroxysuccinimide in a 1:1 ratio [17] and used without further
–1
purification. Yield 86%, viscous light-yellow liquid. IR spectrum (KBr, ꢄ, cm ): 1678 (CONH), 1747 (ester COO). Mass
+
1
spectrum: found m/z 664.527 [M + Í] , calcd for C H NO , 664.530. Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz):
43 70
4
3
0.80–0.86 (12H, m, alkyl side-chain CH ; 0.96–1.56 (21Í, m, alkyl side-chain CH and CH), 1.93, 1.98, 2.06 (each 3Í, s,
3
2
1063

ÑÍ ), 2.49 (2Í, t, J = 6.7), 2.52–2.59 (2Í, m), 2.93 (2Í, t, J = 6.7) succinyl CH -4 and CH ; 1.70–1.81 (2Í, m, Í-3),
3
2
2
1.62–1.66 (6Í, m) and 1.94–1.97 (6Í, m) adamantane CH ÑÍ -2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, 2.01–2.05 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ).
2
2
Methyl-6-acetoxy-5-[(1-adamantaneamino)methyl]-2,7,8-trimethylchromane-2-carboxylate (17). Asolution of
1-adamantane (11.8 mg, 0.08 mmol) in CH Cl (0.1 mL) at 20–25°C was stirred, treated with a solution of trolox methyl ester
2
2
5-bromomethyl derivative 15 (12 mg, 0.03 mmol), stirred for 16–20 h at 20–25°C, treated with aqueous KOH solution (10%),
stirred for 30 min, washed with H O, dried over MgSO , and purified by column chromatography over silica gel using
2
4
–1
CHCl –MeOH (10:0.5). Yield 81%, viscous light-orange liquid. IR spectrum (KBr, ꢄ, cm ): 1738, 1755 (ester COO). Mass
spectrum: found m/z 456.274 [M + Í] , calcd for C H NO , 456.274. Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm): 1.64,
3
+
1
27 38
5
3
2.05, 2.20 (each 3Í, s, ÑÍ ), 1.60–1.76 (12Í, m, Í-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ), 1.85–1.97 (2Í, m, Í-3), 2.07–2.14 (3Í, m, Í-3ꢁ, 5ꢁ,
3
7ꢁ), 2.37 (3Í, s, acetate CH ), 2.39–2.48 (1Í, m, Ía-4), 2.59–2.76 (1Í, m, Íb-4), 3.40–3.64 (2Í, m, Í-5), 3.72 (3Í, s,
3
13
COO-CH ). C NMR spectrum (100 MHz, CDCl , ꢂ, ppm): 12.09, 13.01 phenol CH ; 19.50 (ÑÍ -2), 20.78, 52.47 (acetate
3
3
3
3
CH , COO-CH ); 30.13, 36.27 (Ñ-3, 4), 41.83 (ÑÍ -5), 77.49 (Ñ-2), 117.98, 124.95, 127.49 (Ñ-5, 7, 8, 4à), 141.61, 149.60
3
3
2
(Ñ-6, 8à), 170.39, 174.44 – carbonyl C atoms; 29.61, 36.76, 42.40 (Ñ-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, 3ꢁ, 5ꢁ, 7ꢁ), 50.75 (Ñ-1ꢁ).
5-[(1-Adamantanamino)methyl]-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl Acetate (18).
A solution of 1-aminoadamantane (26.4 mg, 0.17 mmol) in CH Cl (0.1 mL) at 20–25°C was stirred, treated with a solution of
2
2
ꢀ-tocopherol 5-bromomethyl derivative 16 (48 mg, 0.09 mmol), stirred for 16–20 h at 20–25°C, treated with aqueous KOH
(10%), stirred for 30 min, washed with H O, dried over MgSO , and purified by column chromatography over silica gel using
2
4
–1
1
EtOAc. Yield 45%, viscous yellow liquid. C H NO . IR spectrum (KBr, ꢄ, cm ): 1620, 1759 (ester COO). Í NMR
41 67
3
spectrum (400 MHz, CDCl , ꢂ, ppm): 0.79–0.86 (12H, m, alkyl side-chain CH ); 0.98–1.79 (23Í, m, ÑÍ -3, alkyl side-chain
3
3
2
CH and CH), 1.20, 2.06, 2.07 (each 3Í, s, ÑÍ ), 2.12 (3Í, s, acetate CH ), 1.56–1.75 (12Í, m, Í-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ), 2.04–
2
3
3
2.10 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ), 2.57–2.66 (2Í, m, Í-4), 3.89 (2Í, s, Í-5à).
1-Adamantaneammonium 6-(3-Carboxylatopropanoyloxy)-2,5,7,8-tetramethylchromane-2-carboxylate (20).
Trolox succinate 19 (14.1 mg, ~0.04 mmol) in THF (0.5 mL) was treated with 1-aminoadamantane (12.2 mg, 0.08 mmol) in
THF (0.3 mL), held for 16–20 h at 20–25°C, and evaporated. The viscous precipitate was triturated with Et O until the
2
formation of a powder that was filtered off, washed with EtOAc, and dried to constant weight. Yield 85%, white powder, mp
–1
–
1
179.6°C (dec.). C H N O . IR spectrum (KBr, ꢄ, cm ): 1389 and 1626 (COÎ ), 1560 (ꢂN-H), 1757 (ester COO). Í NMR
38 56
2 7
spectrum (300 MHz, CD OD, ꢂ, ppm, J/Hz): 1.56, 1.96, 2.03, 2.19 (each 3Í, s, ÑÍ ), 2.41–2.49 (1Í, m, Ía-3), 2.56–2.66
3
3
(4Í, m) and 2.89 (2Í, t, J = 7.1) succinyl CH -4 and CH ; 1.70–1.88 (25Í, m, Í-2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, 2ꢁꢁ, 4ꢁꢁ, 6ꢁꢁ, 8ꢁꢁ, 9ꢁꢁ, 10ꢁꢁ,
2
2
13
Íb-3), 2.14–2.19 (6Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ,3ꢁꢁ, 5ꢁꢁ, 7ꢁꢁ). C NMR spectrum (75 MHz, CD OD, ꢂ, ppm): 12.27, 13.19 (ÑH -5, 7, 8), 22.50,
3
3
25.89, 31.51, 32.03, 33.28 (Ñ-3, 4, succinyl CH -2 and CH ), 30.41, 36.45, 41.52 (Ñ-4ꢁ, 6ꢁ, 10ꢁ, 2ꢁ, 8ꢁ, 9ꢁ, 3ꢁ, 5ꢁ, 7ꢁ), 52.66 (Ñ-1ꢁ),
3
2
80.16 (Ñ-2), 119.30, 123.76, 126.02, 127.63 (Ñ-5, 7, 8, 4à), 141.93, 151.67 (Ñ-6, 8à), 174.17 – carbonyl C atom; 179.64,
181.15 – carboxylate C atoms.
2,5,7,8-Tetramethyl-2-(1-adamantanecarbamoyl)chroman-6-yl 4-Oxo-4-(1-adamantaneamino)butanoate (22).
A solution of trolox succinate succinimide 21 (20 mg, 0.036 mmol) in CH Cl (0.4 mL) at 20–25°C was stirred, treated with
2
2
1-aminoadamantane (11.1 mg, 0.07 mmol) in CH Cl (0.8 mL), stirred for 48 h at 20–25°C, washed with H O, dried over
2
2
2
–1
Na SO , and evaporated. Yield 54%, viscous light-yellow liquid. IR spectrum (KBr, ꢄ, cm ): 1662 (CONH), 1743 (ester
2
4
+
1
COO). Mass spectrum: found m/z 617.386 [M + Í] , calcd for C H N O , 617.395. Í NMR spectrum (400 MHz, CDCl ,
38 53
2
5
3
ꢂ, ppm): 1.42–1.48 (3Í, s, ÑÍ -2), 1.94, 2.01, 2.12 (each 3Í, s, ÑÍ ), 2.45–2.51 (2Í, m), 2.52–2.62 (2Í, m) and 2.86–2.95
3
3
(2Í, m) succinyl CH -4 and CH ; 1.56–1.67 (13Í, m), 1.86–1.98 (4Í, m), 1.92–1.97 (12Í, m), 2.02–2.06 (3Í, m) Í-2ꢁ, 4ꢁ, 6ꢁ,
2
2
8ꢁ, 9ꢁ, 10ꢁ, 2ꢁꢁ, 4ꢁꢁ, 6ꢁꢁ, 8ꢁꢁ, 9ꢁꢁ, 10ꢁꢁ, Ía-3ꢁ, 5ꢁ, 7ꢁ, 3ꢁꢁ, 5ꢁꢁ, 7ꢁꢁ, 3.
4-[2-(1-Adamantanecarbamoyl)-2,5,7,8-tetramethylchroman-6-yloxy]-4-oxobutanoic Acid (23). A solution of
trolox amide 3 (27.3 mg, 0.07 mmol) in CH Cl (0.3 mL) at 20–25°C was stirred; treated with succinic anhydride (21.3 mg,
2
2
0.21 mmol), DMAP (4 mg), and Et N (11 ꢅL); stirred for 48 h at 20–25°C; washed with HCl solution (5%); dried over
3
–1
Na SO ; and evaporated. Yield 79%, viscous light-yellow liquid. IR spectrum (KBr, ꢄ, cm ): 1645 (CONH), 1714 (COÎH),
1747 (ester COO). Mass spectrum: found m/z 482.265 [M + Í] , calcd for C H NO , 482.255. Í NMR spectrum
2
4
+
1
28 36
6
(300 MHz, CDCl , ꢂ, ppm): 1.45, 1.94, 2.02, 2.12 (each 3Í, s, ÑÍ ), 2.50–2.62 (2Í, m, Í-4), 2.77–2.83 (2Í, m) and 2.88–2.94
3
3
(2Í, m) succinyl CH ; 1.58–1.66 (7Í, m), 1.83–1.93 (7Í, m) – Í-4ꢁ, 6ꢁ, 10ꢁ, 2ꢁ, 8ꢁ, 9ꢁ and 3; 2.00–2.05 (3Í, m, Í-3ꢁ, 5ꢁ, 7ꢁ).
2
13
C NMR spectrum (75 MHz, CDCl , ꢂ, ppm): 11.81, 11.95, 12.82 (ÑÍ -5, 7, 8), 20.14, 24.18, 28.23, 28.45, 28.72 (Ñ-3, 4,
3
3
ÑÍ -2, succinyl CH ); 29.22, 36.11, 41.21 (ÑÍ -2ꢁ, 4ꢁ, 6ꢁ, 8ꢁ, 9ꢁ, 10ꢁ, ÑÍ-3ꢁ, 5ꢁ, 7ꢁ), 51.20 (Ñ-1ꢁ), 78.35 (Ñ-2), 118.16, 122.11,
3
2
2
125.53, 127.10 (Ñ-5, 7, 8, 4à), 141.24, 147.95 (Ñ-6, 8à), 170.62, 173.12, 177.11 – carbonyl, carboxylic, and carboxamide
C atoms.
1064

1-Adamantaneammonium 4-[2-(1-Adamantanecarbamoyl)-2,5,7,8-tetramethylchroman-6-yloxy]-4-
oxobutanoate (24). A solution of succinate 23 (19.1 mg, 0.04 mmol) in THF (0.3 mL) at 20–25°C was treated with
1-aminoadamantane (5.99 mg, 0.04 mmol) in THF (0.3 mL), held for 16–20 h at 20–25°C, and evaporated. The residue was
triturated with Et O until the formation of a viscous precipitate that was filtered off, washed with EtOAc, and dried to constant
2
–1
–
weight. Yield 71%, light-yellow liquid. IR spectrum (KBr, ꢄ, cm ): 1392 è 1628 (COÎ ), 1560 (ꢂN-H), 1657 (CONH), 1757
(ester COO). Mass spectrum: found m/z 635.405 [M + Í] , calcd for C H N O , 635.406. Í NMR spectrum (400 MHz,
+
1
38 55
2 6
CD OD, ꢂ, ppm): 1.49 (1H, s) and 1.52 (2H, s) ÑÍ ; 2.08 (2H, s) and 2.10 (1H, s) ÑÍ ; 2.16–2.22 (6H, m, ÑÍ ), 1.67–1.93
3
3
3
3
(28Í, m) and 1.98–2.07 (4Í, m) ÑÍ -3, adamantane CH and CH; 2.44–2.68 (5Í, m) and 2.91 (1Í, t, J = 6.9) succinyl
2
2
13
CH -4 and CH . C NMR spectrum (100 MHz, CDCl , ꢂ, ppm): 10.45, 10.58, 10.64, 10.90, 11.39, 11.80 (ÑÍ -5, 7, 8),
2
2
3
3
19.95, 20.18, 23.47, 23.69, 29.32, 29.40, 29.42, 29.52, 31.28, 31.75 (Ñ-3, 4, succinyl CH -2 and CH ); 29.00, 29.82, 35.06,
3
2
36.13, 40.13, 40.79 (ÑÍ -4ꢁ, 6ꢁ, 10ꢁ, 2ꢁ, 8ꢁ, 9ꢁ, ÑÍ-3ꢁ, 5ꢁ, 7ꢁ), 50.61, 51.30 (Ñ-1ꢁ); 77.87, 78.34 (Ñ-2), 117.49, 118.10, 120.96,
2
121.07, 121.81, 123.40, 125.80, 127.43 (Ñ-5, 7, 8, 4à), 141.76, 144.04, 145.93, 147.74 (Ñ-6, 8à); 173.81, 174.09, 174.27,
177.74, 178.03, 178.14 – carbonyl, carboxylic, and carboxamide C atoms.
Determination of the Solubility of 1, 4, 6, 9, 10, 20, and 24 [16]. Weighed portions of 1, 4, 6, 9, 10, 20, and 24
(0.5–1 mg) were treated with distilled H O (0.1–0.5 mL) and shaken for 10 min. The addition of H O was repeated until the
2
2
compounds were completely dissolved or a solubility of <0.1 g/L was reached. The transparency was determined visually by
comparing the test solution with the solvent.
ACKNOWLEDGMENT
The work was supported financially by RFBR Grant No. 16-34-00465.
REFERENCES
1.
2.
J. A. M. Christiaans and H. Timmerman, Eur. J. Pharm. Sci., 4, 1 (1996).
J. Sebestik, S. M. Marques, P. L. Fale, S. Santos, D. M. Arduino, S. M. Cardoso, C. R. Oliveira, M. L. M. Serralheiro,
and M. A. Santos, J. Enzyme Inhib. Med. Chem., 26, 485 (2011).
3.
D. Hadjipavlou-Litina, G. E. Magoulas, S. E. Bariamis, D. Drainas, K. Avgoustakis, and D. Papaioannou, Bioorg. Med.
Chem., 18, 8204 (2010).
4.
5.
6.
V. Anbharasi, N. Cao, and S.-S. Feng, J. Biomed. Mater. Res. Part A, 94, 730 (2010).
Shaveta, S. Mishra, and P. Singh, Eur. J. Med. Chem., 124, 500 (2016).
M. Koufaki, Expert Opin. Ther. Pat., 26, 1 (2015).
7.
P. Rawat and S. M. Verma, Drug Des., Dev. Ther., 10, 2779 (2016).
8.
L. Wanka, K. Iqbal, and P. R. Schreiner, Chem. Rev., 113, 3516 (2013).
9.
G. Lamoureux and G. Artavia, Curr. Med. Chem., 17, 2967 (2010).
10.
11.
12.
13.
Y. Kawabata, K. Wada, M. Nakatani, S. Yamada, and S. Onoue, Int. J. Pharm., 420, 1 (2011).
E. A. Dikusar, V. I. Potkin, N. G. Kozlov, D. A. Rudakov, and S. G. Stepin, Vestn. Farm., 4, 99 (2013).
G. Socrales, Infrared Characteristic Group Frequencies: Tables and Charts, 2 Ed., Wiley, New York, 1994, p. 249.
H. Gunther, NMR Spectroscopy: Basic Principles, Concepts and Applications in Chemistry, 3rd Ed., 2013,
ISBN: 978-3-527-33004-1, p. 734.
nd
14.
15.
16.
17.
18.
J. A. Hyatt, Synth. Commun., 38, 8 (2008).
F. Mazzini, T. Netscher, and P. Salvadori, Tetrahedron, 61, 813 (2005).
State Pharmacopoeia of the RF, XII, Moscow, 2007, p. 92.
S. Stegemann, F. Leveiller, D. Franchi, H. de Jong, and H. Linden, Eur. J. Pharm. Sci., 31, 249 (2007).
H. Fonge, S. K. Chitneni, J. Lixin, K. Vunckx, K. Prinsen, J. Nuyts, L. Mortelmans, G. Bormans, Y. Ni,
and A. Verbruggen, Bioconjugate Chem., 18, 1924 (2007).
19.
20.
A. Demirbas, Fuel, 90, 2273 (2011).
F. Mazzini, M. Betti, B. Canonico, T. Netscher, F. Luchetti, S. Papa, and F. Galli, ChemMedChem, 5, 540 (2010).
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