Synthesis, Structure, and Properties of New Lupinine O-Acyl Derivatives

Article abstract of DOI:10.1007/s10600-019-02726-3

Acylation of the alkaloid lupinine produced O-cinnamoyllupinine and O-lipoyllupinine. The structure of O-cinnamoyllupinine was established by an X-ray crystal structure analysis.

Full text of DOI:10.1007/s10600-019-02726-3

DOI 10.1007/s10600-019-02726-3
Chemistry of Natural Compounds, Vol. 55, No. 3, May, 2019
SYNTHESIS, STRUCTURE, AND PROPERTIES OF NEW
LUPININE O-ACYL DERIVATIVES
O. A. Nurkenov,1 Zh. S. Nurmaganbetov, S. D. Fazylov,
*
1,2
1
1
,3
3
4
Zh. B. Satpaeva, K. M. Turdybekov, T. M. Seilkhanov,
5
and S. A. Talipov
Acylation of the alkaloid lupinine produced O-cinnamoyllupinine and O-lipoyllupinine. The structure
of O-cinnamoyllupinine was established by an X-ray crystal structure analysis.
Keywords: alkaloid lupinine, cinnamoyl chloride, lipoic acid, O-cinnamoyllupinine, O-lipoyllupinine.
The possibility of discovering highly efficacious, selective, and stereospecific biologically active compounds can be
greatly improved by modifying quinolizidine alkaloids. The simple quinolizidine alkaloid lupinine is a convenient and available
synthetic starting material with a tertiary base and primary alcohol. Lupinine has a trans-quinolizidine ring and an axial
hydroxymethyl group and changes configuration from trans- to cis-fusion of the quinolizidine ring with conversion of the
axial hydroxymethyl to equatorial with a change of sign of the torsion angle after protonation (iodomethylation) [1, 2]. Reactions
of fatty-acid and benzoic-acid chlorides with lupinine produced esters with steric structures that might not correspond to the
conformation of lupinine because of the lability of the quinolizidine fragment in solution [3]. These features of lupinine are
very important for studying the structure–bioactivity relationship.
In continuation of research on lupinine transformations, new acyl derivatives were synthesized by us using reactions
with 3-phenylacrylic (cinnamoyl) and 5-[(3R)-dithiolan-3-yl]pentanoic (lipoic) acid chlorides. Many cinnamoyl derivatives
are recommended as promising drugs for treating and/or preventing arterial and/or venous thrombosis, acute coronary syndrome,
restenosis, stable angina, arrhythmia, myocardial infarct, hypertension, cardiac failure, and stroke [4]. Lipoic acid (lipoate,
vitamin N) is a very important antioxidant and acts as a coenzyme in oxygen metabolism, especially in the pyruvate
dehydrogenase complex. The R-enantiomer has biological significance [5].
Lupinine was acylated by the aforementioned acid chlorides in anhydrous C H in the presence of Et N.
6
6
3
The reaction occurred smoothly and produced O-acyl lupinines in 82.3% (1) and 82.0% yields (2), respectively.
1
1
12
14
CH O
C
CH CH 15
18
2
7
O
5
Cl(O)C-CH=CH-C6H5
Cl(O)CCH (CH ) CH
2
N
3
CH2OH
1
1
1
0
1
1
12
C
16
1
7
20
CH2O
C13H2(CH2)2CH2
2
2 2
N
7
S
S
S
S
O
4
18
N
9
2
2
1) Institute of Organic Synthesis and Carbon Chemistry of the Republic of Kazakhstan, 1 Alikhanova St., Karaganda,
100008, Kazakhstan, e-mail: nurkenov_oral@mail.ru; 2) Karaganda State Medical University, 40 Gogolya St., Kazakhstan;
e-mail: nzhangeldy@yandex.ru; 3) E. A. Buketov Karaganda State University of the Republic of Kazakhstan, 28 Universitetskaya
St., Karaganda, 100028, Kazakhstan, e-mail: satpaeva_zh@mail.ru; 4) Sh. Ualikhanov Kokshetau State University, 76 Abaya St.,
Kokshetau, 020000, Kazakhstan, e-mail: tseilkhanov@mail.ru; 5) A. S. Sadykov Institute of Bioorganic Chemistry, Academy of
Sciences of the Republic of Kazakhstan, 83 Kh. Abdullaeva St., Tashkent, Uzbekistan; e-mail: samat_talipov@yahoo.com. Translated
from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2019, pp. 434–436. Original article submitted September 28, 2018.
506
0009-3130/19/5503-0506 ©2019 Springer Science+Business Media, LLC

C3
C2
C1
C19
C18
C17
C4
C5
C9
C10 O1
C13
C14
C11
O2
C12
C15
N1
C6
C8
C16
C7
Fig. 1. Molecular structure of O-cinnamoyllupinine (1).
Synthesized compounds 1 and 2 were a crystalline solid and oil, respectively, that were very soluble in most organic
1
13
solvents. The structures of 1 and 2 were confirmed using PMR spectra and two-dimensional HMQC ( H– C) NMR
spectroscopy.
The molecular structure of 1 was established by an X-ray crystal structure analysis and is shown in Fig. 1.
The configurations of chiral centers C1 and C9 were the same as in the crystal structure of lupinine hydrochloride [6].
The geometry of 1 was analyzed and showed that the phenyl bond lengths were slightly less than the standard value
°
(
1.384 A ) [7] because of large thermal vibrations of the ring atoms. The adjusted isotropic thermal vibration constants U
eq
°
2
° 2
were 0.096–0.125 A . The large thermal vibrations of O1, O2, and C11–C13 (U 0.123–0.156 A ), which linked the lupinine
eq
framework and the phenyl ring, caused the bond lengths to deviate significantly from the standard values (given in parentheses):
°
O1–C11 1.363 (1.332), C11–C12 1.642 (1.340), C12–C13 1.063 (1.340), and C13–C14 1.759 (1.488 A). The disordering of
the atoms was dynamic rather than static. The electron-density peaks of these atoms were slightly broadened in space but did
not separate into individual peaks. The low melting point even for molecular crystals (77–78°C) indicated that the binding
energy between molecules in the crystal of 1 was rather low.
The conformations of six-membered rings C1–C2…N1(A) and C1…C9(B) were similar to the corresponding ones in
2
3,4
the crystal structure of lupinine [8] and formed an almost ideal chair (ΔC = 0.9° and ΔC2 = 0.7° for the former and
ΔCS = 0.3° and ΔC2 = 1.5° for the latter).
S
8
7,8
EXPERIMENTAL
PMR spectra of 1 and 2 were recorded in DMSO-d on a JNM-ECA 400 spectrometer (JEOL) at frequencies 400 and
6
1
13
13
1
00 MHz for H and C, respectively. Chemical shifts were measured relative to resonances of residual protons and
C
atoms in DMSO-d . Melting points were determined on a Boetius apparatus. TLC used Silufol UV-254 plates and solvent
6
systems i-PrOH–NH OH–H O (7:2:1) and EtOH–CHCl (1:4) with detection by I vapor. Reaction products were isolated by
4
2
3
2
column chromatography over Al O .
2
3
Synthesis of O-Cinnamoyllupinine (1). A solution of lupinine (3 g, 17.75 mmol) in C H (50 mL) was stirred,
6
6
treated with Et N (2.47 mL, 17.75 mmol) and a solution of 3-phenylacrylic acid chloride (2.95 g, 17.75 mmol) in C H
3
6 6
(
20 mL), and stirred for 4 h at room temperature as a precipitate formed. The precipitate of Et NHCl was filtered off. The
3
filtrate was evaporated. The residue was chromatographed over Al O (petroleum ether–C H eluent) to afford 1 (2.47 g,
2
3
6 6
1
8
2.3%) as yellow crystals with mp 77–78°C. The elemental analysis agreed with that calculated for C H NO . Í NMR
19 25 2
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.09–1.15 (1Í, m, Í-8àõ), 1.31–1.35 (5Í, m, Í-3àõ, 4àõ, 7, 9àõ), 1.43–1.46
6
(
(
1H, m, Í-9eq), 1.52–1.55 (1H, m, Í-3eq), 1.61–1.64 (1Í, m, H-8eq), 1.74–1.89 (5Í, m, H-4eq, 5, 6, 2ax, 10ax), 2.66–2.69
2Í, m, H-2eq, 10eq), 4.22–4.35 (2Í, m, Í-11), 6.58 (1Í, d, J = 16.0, Í-13), 7.60 (1Í, d, J = 18.3, Í-14), 7.37–7.38 (3Í, m,
Í-16, 18, 20), 7.66 (2Í, br.s, Í-17, 19). C NMR spectrum (100 MHz, DMSO-d , δ, ppm): 21.12 (Ñ-3), 25.14 (Ñ-8), 25.74
1
3
6
(
1
(
Í
Ñ-9), 27.23 (Ñ-4), 29.81 (Ñ-7), 37.81 (Ñ-5), 57.42 (Ñ-2, 10), 63.57 (Ñ-11), 64.34 (Ñ-6), 118.67 (Ñ-13), 128.88 (Ñ-17, 19),
1
13
4ax
4
29.43 (Ñ-16, 20), 130.96 (Ñ-18), 134.54 (Ñ-15), 144.92 (Ñ-14), 166.80 (Ñ-12). HMQC NMR spectrum ( H– C): Í –Ñ
4
eq
4
3ax
3
3eq
3
7
7
5
5
1.30, 27.26), Í –Ñ (1.78, 27.20), Í –Ñ (1.20, 27.26), Í –Ñ (1.52, 27.26), Í –Ñ (1.40, 29.65), Í –Ñ (1.87, 37.78),
2
ax,10ax 2,10
2eq,10eq 2,10
13 13
18 18
16 16
–Ñ
(1.77, 57.13), Í
–Ñ
(2.66, 57.17), Í –Ñ (6.60, 118.64), Í –Ñ (7.36, 130.98), Í –Ñ (7.37,
1
7
17
14 14
1
29.42), Í –Ñ (7.67, 128.92) and Í –Ñ (7.62, 144.93).
Synthesis of O-Lipoyllupinine (2). Lipoic acid (1.5 g, 7.317 mmol) was dissolved in C H (25 mL), stirred, treated
6
6
dropwise with thionylchloride (0.64 mL, 4.387 mmol), and stirred for 3 h at room temperature to afford lipoylchloride
1.46 g). A solution of lupinine (1.5 g, 8.862 mmol) in C H (50 mL) was stirred, treated with Et N (1.22 mL, 8.783 mmol)
(
6
6
3
507

and lipoylchloride (1.46 g, 6.465 mmol) dissolved in C H (25 mL), and stirred for 5 h at room temperature as a precipitate
6
6
formed. The precipitate was filtered off. The filtrate was evaporated. The residue was chromatographed over Al O
2
3
1
(
C H –CHCl eluent) to afford 2 (1.23 g, 82.0%) as a yellowish-green thick oil. Í NMR spectrum (400 MHz, DMSO-d , δ,
6
6
3
6
ppm): 1.13–1.25 (2Í, m, Í-15), 1.31–1.96 (14Í, m, 2Í-14, 3, 4, 8, 9, Í-5, 6, 21ax, 7ax), 2.25–2.29 (3Í, m, Í-13, 13, 7eq),
.40–2.44 (1Í, m, Í-21eq), 2.72–2.79 (4Í, m, Í-2, 10), 3.04–3.16 (2Í, m, Í-20), 3.49–3.56 (1Í, m, Í-17), 4.14–4.19 (1Í,
2
1
3
m, Í-11ax), 4.31–4.35 (1Í, m, Í-11eq). C NMR spectrum (100 MHz, DMSO-d , δ, ppm): 21.22 (Ñ-2), 24.80 (Ñ-9), 25.07
6
(
(
Ñ-8), 27.05 (Ñ-14), 28.88 (Ñ-4), 29.69 (Ñ-15), 34.28 (Ñ-13, 7), 34.70 (Ñ-16), 37.96 (Ñ-5), 38.58 (Ñ-20), 40.29 (Ñ-21), 56.43
Ñ-17), 57.39 (Ñ-2, 10), 63.64 (Ñ-11), 64.43 (Ñ-6), 173.56 (Ñ-12). HMQC NMR spectrum ( H– C): Í –Ñ (1.23, 24.89),
1
13
8
8
1
5
15
14àõ 14
4
4
3eq
3
8
8
14eq 14
Í –Ñ (1.21, 29.81), Í
–Ñ (1.36, 27.06), Í –Ñ (1.43, 29.15), Í –Ñ (1.67, 21.36), Í –Ñ (1.71, 25.06), Í
–Ñ
1
6
16
5
5
21àõ 21
21eq 21
2àõ,10àõ 2,10
(
(
(
1.78, 26.96), Í –Ñ (1.66, 34.57), Í –Ñ (1.84, 37.98), Í
–Ñ (1.90, 40.12), Í
–Ñ (2.41, 40.42), Í
–Ñ
1.92, 57.05), Í2
4.16, 63.64), Í11eq–Ñ11 (4.30, 63.76).
X-ray Crystal Structure Analysis (XSA) of 1. Cell constants and intensities of 3296 reflections (2509 independent,
eq,10eq 2,10
–Ñ
(2.78, 57.42), Í –Ñ (1.98, 64.33), Í13,7–Ñ
6
6
13,7
(2.27, 34.30), Í –Ñ (3.55, 56.40), Í
17 17
11àõ
–Ñ11
Rint = 0.0309) were measured on an Xcalibur Ruby diffractometer (Oxford Diffraction) (Cu Kα-radiation, graphite
monochromator, ω-scanning, 3.86° ≤ θ ≤ 76.02°) at 293 K. The crystals were monoclinic, a = 8.4783(5), b = 8.7702(6),
°
° 3
3
c = 11.9317(7) A , β = 106.471(6)°, V = 850.80(9) A , Z = 2 (C H NO ), space group P2 , d = 1.557 g/cm ,
calcd
μ = 0.124 mm .
1
9
25
2
1
–
1
The structure of 1 was solved by direct methods. Positions of nonhydrogen atoms were refined using anisotropic
full-matrix least-squares methods. H atoms were positioned geometrically and refined isotropically with fixed positional and
thermal parameters (rider model). The calculations used 1477 independent reflections with I ≥ 2σ(I). The number of refined
parameters was 200. The final agreement parameters were R = 0.0673, wR = 0.1606 ([reflections with I ≥ 2σ(I)], and
1
2
R = 0.1100, wR = 0.1950 (all reflections), GooF = 1.057. The structure was solved and refined using SHELXS-97 [9] and
1
2
SHELXL-97 programs [10]. XSA data were deposited as a CIF file in the Cambridge Crystallographic Data Centre
CCDC 1869785).
(
REFERENCES
1.
R. T. Tlegenov, D. N. Dalimov, Kh. Kh. Khaitbaev, A. A. Abduvakhabov, and K. U. Uteniyazov, Chem. Nat. Compd.,
6, 434 (1990).
2
2.
A. A. Abduvakhabov, R. Tlegenov, Kh. Kh. Khaitbaev, G. I. Vaizburg, D. N. Dalimov, and K. U. Uteniyazov,
Chem. Nat. Compd., 26, 60 (1990).
3.
A. A. Abduvakhabov, K. Toremuratov, Kh. A. Aslanov, V. B. Leont′ev, S. I. Mukhamedkhanova, and A. S. Sadykov,
Izv. Akad. Nauk SSSR, Ser. Khim., 1, 219 (1973).
4.
M. Peres, M. Lamot, et al., RU Pat. No. 2,440,997, “Cinnamoyl-piperazine derivatives and their application as PAR-1
antagonists,” Jul. 27, 2012; Byull., No. 3.
5.
A. A. Savchenko, E. N. Anisimova, A. G. Borisov, and A. E. Kondakov, Vitamins as a Basis for Immunometabolic
Therapy [in Russian], KrasGMU, Krasnoyarsk, 2011, 213 pp.
6.
A. E. Koziol, M. Gdaniec, and Z. Kosturkiewicz, Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem.,
3
6, 980 (1980).
F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans.
, 19 (1987).
A. E. Koziol, Z. Kosturkiewicz, and H. Podkowinska, Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem.,
4, 3491 (1978).
7.
2
8.
3
9
.
G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr. (Suppl.), 64, 112 (2008).
G. M. Sheldrick, SHELXL-97, Program for the Refinement of Crystal Structures, University of Goettingen,
Germany, 1997.
10.
508