Synthesis of 2,3-seco-triterpene hydrazonohydrazides of the lupane and 19β,28-epoxy-18α-oleanane types

Article abstract of DOI:10.1007/s10600-012-0161-0

Hydrazonohydrazides were synthesized by acid-catalyzed condensation of 2,3-seco-triterpene 1-cyano-3hydrazides with aldehydes. The antiviral action of the hydrazonohydrazides was studied against vesicular stomatitis Indiana virus.

Full text of DOI:10.1007/s10600-012-0161-0

Chemistry of Natural Compounds, Vol. 48, No. 1, March, 2012 [Russian original No. 1, January-February, 2012]
SYNTHESIS OF 2,3-seco-TRITERPENE HYDRAZONOHYDRAZIDES
OF THE LUPANE AND 19ꢀ,28-EPOXY-18ꢁ-OLEANANE TYPES
1
1
N. V. Galaiko, I. A. Tolmacheva,
UDC 547.556.93:547,298.61:
547.288.3+578.242:578.824.21
2
1*
L. V. Volkova, and V. V. Grishko
Hydrazonohydrazides were synthesized by acid-catalyzed condensation of 2,3-seco-triterpene 1-cyano-3-
hydrazides with aldehydes. The antiviral action of the hydrazonohydrazides was studied against vesicular
stomatitis Indiana virus.
Keywords: A-seco-triterpenoids, betulin, betulinic acid, allobetulone, hydrazides, hydrazones, vesicular stomatitis
virus.
Betulin is a polycyclic triterpenoid that is readily available and exhibits a broad spectrum of biological activity. Its
derivatives betulonic acid and allobetulone are promising starting materials for chemical transformations [1, 2]. The
transformation pathways of these triterpenoids into N-containing biologically active derivatives include the formation of C-3
and C-28 amides or imines in the triterpene backbone. It was shown that additional modification of the triterpenoid carbon
framework by cleavage of the C2–C3 bond of ringAhelps in particular to increase the antiviral activity of the basic triterpenoids
[3, 4]. We recently synthesized 2,3-seco-triterpene hydrazones with high levels of therapeutic and preventative activity against
enveloped vesicular stomatitis Indiana virus (VSIV) by the reaction of lupane and 19ꢀ,28-epoxy-18ꢁ-oleanane 2,3-seco-
aldehydonitriles with substituted hydrazines [5–7]. The search for new anti-VSIV derivatives and reports of the antiviral
properties of triterpene hydrazides of betulinic and betulonic acids against enveloped Group A and Herpes Simplex Type I
viruses [8] prompted us to prepare 2,3-seco-hydrazonohydrazides of the lupane and 19ꢀ,28-epoxy-18ꢁ-oleanane types.
A-seco-Triterpene hydrazonohydrazides 7a–c and 8a–c were prepared from C3-carboxy derivatives 1 and 2 [9]
through the corresponding acid chlorides 3 and 4 that were used directly without purification in the hydrazinolysis reaction
with subsequent acid-catalyzed condensation of the resulting 1-cyano-3-hydrazides 5 and 6 with aldehydes.
1
R
R
R
NC
H NNHOC
2
NC
R
NC
NC
ClOC
c
a
b
R CH=NNHOC
1
HOOC
3
3, 4
1, 2
5, 6
7a - c, 8à - c
29
30
20
19
19
O
COOCH
3
28
28
1, 3, 5, 7:R =
2, 4, 6, 8:R =
7a, 8a: R = (CH ) CH-; 7b, 8b: R = (CH ) C-; 7c, 8c: R = Ñ Í -
1
3 2
1
3 3
1
6 5
a. (COCl) /CH Cl ; b. NH NH 4H O/CH Cl ; c. R CHO/C H OH/CH COOH
2
2
2
2
2
2
2
2
1
2
5
3
1) Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences, 614013, Perm, Ul. Akad. Koroleva,
3, Russia, e-mail: grishko@aport.ru; 2) Filial Mikrogen, RF Ministry of Health, Perm Biomed, 614089, Perm, Ul. Bratskaya,
177. Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2012, pp. 68–70. Original article submitted
June 10, 2011.
©
72
0009-3130/12/4801-0072 2012 Springer Science+Business Media, Inc.

The formation of substituted hydrazides 7a–c and 8a–c was confirmed by IR and NMR spectroscopy. IR spectra of
–1
7a–c and 8a–c showed absorption bands in the range 1652–1658 (C=N), 2237–2241 (CꢂN), and 3230–3250 (NH) cm .
PMR spectra of 7a–c and 8a–c contained resonances for protons characteristic of the triterpene moiety and for imine and
13
amide protons at 7.27–8.12 and 8.36–8.86 ppm, respectively. C NMR spectra had a resonance characteristic of C-3 (174.12–
175.07 ppm).
The synthesized compounds (7a–c and 8a–c) did not exhibit inhibition against VSIV upon addition to a cell suspension
before introducing the virus [6]. This indicated that the 2,3-seco-triterpene hydrazonohydrazides did not exhibit preventative
VSIV-inhibiting activity.
EXPERIMENTAL
–1
IR spectra (ꢃ, cm ) were taken in mineral oil mulls on an IFS 66/S IR-Fourier spectrometer (Bruker). PMR and
13
C NMR spectra (ꢄ, ppm, J/Hz) were recorded in CDCl solution on a Mercury+ spectrometer (Varian, USA) at operating
3
frequency 300 or 75.5 MHz. Melting points were determined on an OptiMelt MPA100 instrument (USA). TLC was performed
on Sorbfil plates (Russia) using hexane:EtOAc (7:3). Compounds were detected by treatment with H SO (5%) with subsequent
2
4
heating of the plate at 95–100°C. Column chromatography used Merck silica gel (60–200 ꢅm) with an ~1:20 compound:sorbent
ratio and elution by hexane:EtOAc (7:1).
General Method for Preparing N -Substituted Hydrazides (7a–c, 8a–c). A solution of acid (1 or 2, 0.54 mmol) in
anhydrous CH Cl (12 mL) under Ar was treated with oxalylchloride (1.1 mmol) and stirred at room temperature for 6 h. The
2
2
solvent was distilled in vacuo (water aspirator) to dryness on a water bath (30°C). The solid was treated with anhydrous
CH Cl (10 mL). The solvent was evaporated. The procedure was repeated three times. The resulting acid chloride in
2
2
CH Cl was stirred, cooled to 0 5°C, and treated dropwise with hydrazine hydrate (36 mmol, 98%). The solvent was
2
2
evaporated. The hydrazide-containing solid was dissolved in EtOH (20 mL), treated with aldehyde (0.54 mmol) and glacial
acetic acid (2 drops), and left at room temperature for 7 h. The reaction was monitored by TLC. The solvent was evaporated.
The solid was purified by column chromatography.
28-Methoxy-28-oxo-1-cyano-2,3-seco-lup-20(29)-en-3-oicAcid N -(2-Methylpropylidene)hydrazide (7a). Yield
20
0.07 g (23%), R 0.2 (hexane:EtOAc, 7:3), mp 113.5°C (hexane:EtOAc, 5:1), [ꢁ] –6.4° (c 0.5, CHCl ). IR spectrum
f
D
3
–1
(ꢃ, cm ): 1653 (C=N), 1724 (COOCH ), 2241 (CꢂN), 3243 (NH).
3
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.93, 0.98, 1.30 (9H, 3s, 3CH ), 1.00 (6H, s, 2CH ), 1.11 and 1.23
3
3
3
[6H, 2d, J = 6.9, CH(CH ) ], 1.66 (3H, s, 3H-30), 2.41 and 2.50 (2H, 2d, J = 18.7, AB-system, 2H-1), 2.67 [1H, sept, J = 6.9,
3 2
AB
CH(CH ) ], 2.91–3.02 (1H, m, H-19), 3.65 (3H, s, COOCH ), 4.59 and 4.71 (2H, 2s, 2H-29), 7.27 (1H, d, J = 7.8, CH=N),
3 2
8.46 (1H, s, NH).
13
3
C NMR spectrum (75.5 MHz, CDCl , ꢄ, ppm): 14.55, 15.68, 17.56, 19.17, 19.83 (2C), 20.12, 21.18, 21.75, 25.45,
3
28.23, 29.24, 29.56, 30.40, 31.53, 31.87, 33.24, 36.80, 38.18, 40.57, 42.59, 42.79, 44.76, 44.86, 46.82, 49.14, 51.27, 52.58,
56.45, 109.84 (C-29), 119.35 (C-2), 150.14 (C-20), 157.04, 174.12 (C-3), 176.54 (C-28).
28-Methoxy-28-oxo-1-cyano-2,3-seco-lup-20(29)-en-3-oic Acid N -(2,2-Dimethylpropylidene)hydrazide (7b).
20
Yield 0.02 g (7%), R 0.3 (hexane:EtOAc, 7:3), mp 109.5°C (hexane:EtOAc, 5:1), [ꢁ] 0° (c 0.5, CHCl ). IR spectrum
f
D
3
–1
(ꢃ, cm ): 1653 (C=N), 1723 (COOCH ), 2241 (CꢂN), 3247 (NH).
3
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.93, 0.98, 1.01, 1.22, 1.30 (15H, 5s, 5CH ), 1.14 (9H, s, 3CH ),
3
3
3
1.66 (3H, s, 3H-30), 2.42 and 2.50 (2H, J = 18.8, AB-system, 2H-1), 2.93–3.03 (1H, m, CH-19), 3.66 (3H, s, COOCH ),
AB
3
4.59 and 4.71 (2H, 2s, 2H-29), 7.34 (1H, s, CH=N), 8.36 (1H, s, NH).
28-Methoxy-28-oxo-1-cyano-2,3-seco-lup-20(29)-en-3-oicAcid N -(Benzylidene)hydrazide (7c). Yield 0.1 g (33%),
20
–1
R 0.3 (CHCl :EtOAc, 10:1), mp 119°C (hexane:EtOAc, 7:1), [ꢁ] 0° (c 0.5, CHCl ). IR spectrum (ꢃ, cm ): 1658 (C=N),
f
3
D
3
1724 (COOCH ), 2239 (CꢂN), 3250 (NH).
3
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.94, 1.28, 1.37 (9H, 3s, 3CH ), 1.01 (6H, s, 2CH ), 1.66 (3H, s,
3
3
3
3H-30), 2.44 and 2.53 (2H, 2d, J = 18.6, AB-system, 2H-1), 2.96 (1H, td, J = 10.2, 6.0, H-19), 3.66 (3H, s, COOCH ), 4.59
AB
3
and 4.71 (2H, 2s, 2H-29), 7.37 (3H, t, J = 2.9, arom.), 7.73 (2H, t, J = 3.5, arom.), 8.11 (1H, s, CH=N), 8.86 (1H, s, NH).
13
C NMR spectrum (75.5 MHz, CDCl , ꢄ, ppm): 14.59, 15.72, 17.60, 19.21, 20.33, 21.70, 21.82, 22.91, 25.48,
3
28.52, 28.94, 29.59, 30.44, 31.88, 33.23, 36.81, 38.19, 40.60, 42.66, 42.80, 44.77, 45.31, 46.84, 49.16, 51.29, 52.42, 56.48,
109.86 (C-29), 119.40 (C-2), 127.81 (2C), 128.57 (2C), 130.37, 147.97, 150.17 (C-20), 175.07 (C-3), 176.55 (C-28).
73

1-Cyano-19ꢀ,28-epoxy-2,3-seco-18ꢁ-olean-3-oicAcid N -(2-Methylpropylidene)hydrazide (8a). Yield 0.1 g (40%),
20
–1
R 0.3 (CHCl :MeOH, 20:1), mp 143.2°C (hexane:EtOAc, 5:1), [ꢁ] –17.2° (c 0.5, CHCl ). IR spectrum (ꢃ, cm ): 1653
f
3
D
3
(C=N), 2240 (CꢂN), 3238 (NH).
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.78, 0.92, 0.96, 0.99, 1.01, 1.23, 1.32 (21H, 7s, 7CH ), 1.11 and
3
3
1.12 [6H, 2d, J = 6.6, CH(CH ) ], 2.45 and 2.53 (2H, 2d, J = 18.6, AB-system, 2H-1), 2.66 [1H, sept, J = 6.6, CH(CH ) ],
3 2
AB
3 2
3.44 and 3.75 (2H, 2d, J = 7.7, AB-system, 2H-28), 3.51 (1H, s, H-19), 7.29 (1H, d, J = 6.6, CH=N), 8.45 (1H, s, NH).
AB
13
C NMR spectrum (75.5 MHz, CDCl , ꢄ, ppm): 13.41, 15.59, 17.82, 19.83, 19.85, 20.08, 21.16, 21.83, 24.48,
3
26.10, 26.31, 26.37, 28.37, 28.72, 29.30, 31.53, 32.64, 32.77, 34.24, 36.22, 36.61, 40.48, 41.12, 41.42, 42.66, 44.85, 45.23,
46.54, 52.71, 71.21 (C-28), 87.78 (C-19), 119.31 (C-2), 157.02, 174.86 (C-3).
1-Cyano-19ꢀ,28-epoxy-2,3-seco-18ꢁ-olean-3-oic Acid N -(2,2-Dimethylpropylidene)hydrazide (8b). Yield
20
0.1 g (43%), R 0.3 (hexane:EtOAc, 7:3), mp 112.9°C (hexane:EtOAc, 7:1), [ꢁ] –24.0° (c 0.5, CHCl ). IR spectrum (ꢃ,
f
D
3
–1
cm ): 1652 (C=N), 2241 (CꢂN), 3230 (NH).
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.78, 0.92, 0.96, 0.99, 1.01, 1.23, 1.32 (21H, 7s, 7CH ), 1.15 (9H,
3
3
s, 3CH ), 2.45 and 2.53 (2H, 2d, J = 17.4, AB-system, 2H-1), 3.44 and 3.75 (2H, 2d, J = 7.7, AB-system, 2H-28), 3.52
3
AB
AB
(1H, s, CH-19), 7.36 (1H, s, CH=N), 8.42 (1H, s, NH).
13
C NMR spectrum (75.5 MHz, CDCl , ꢄ, ppm): 13.42, 15.61, 17.85, 20.09, 21.12, 21.84, 24.48, 26.12, 26.32,
3
26.39, 27.28 (2C), 28.31, 28.74, 29.32, 29.67, 32.65, 32.79, 34.25, 34.99, 36.24, 36.61, 40.49, 41.14, 41.44, 42.67, 44.89,
45.24, 46.55, 52.72, 71.22 (C-28), 87.80 (C-19), 119.33 (C-2), 159.60, 174.78 (C-3).
1-Cyano-19ꢀ,28-epoxy-2,3-seco-18ꢁ-olean-3-oic Acid N -(Benzylidene)hydrazide (8c). Yield 0.2 g (34%), R 0.3
f
20
–1
(CHCl :EtOAc, 10:1), mp 203.4°C (hexane:EtOAc, 7:1), [ꢁ] 0° (c 0.5, CHCl ). IR spectrum (ꢃ, cm ): 1655 (C=N), 2237
3
D
3
(CꢂN), 3249 (NH).
PMR spectrum (300 MHz, CDCl , ꢄ, ppm, J/Hz): 0.78, 0.92, 0.97, 1.00, 1.03, 1.29, 1.39 (21H, 7s, 7CH ), 2.47 and
3
3
2.57 (2H, 2d, J = 18.6, AB-system, 2H-1), 3.44 and 3.75 (2H, 2d, J = 8.0, AB-system, 2H-28), 3.51 (1H, s, H-19), 7.37
AB
AB
(3H, t, J = 3.0, arom.), 7.73 (2H, t, J = 3.8, arom.), 8.12 (1H, s, CH=N), 8.86 (1H, s, NH).
13
C NMR spectrum (75.5 MHz, CDCl , ꢄ, ppm): 13.46, 15.62, 17.86, 20.27, 21.60, 21.87, 24.50, 26.12, 26.33,
3
26.40, 28.74, 29.02, 32.65, 32.78, 34.26, 36.24 (2C), 36.61, 40.51, 41.13, 41.44 (2C), 42.72, 45.26, 46.56, 52.58, 71.22
(C-28), 87.80 (C-19), 119.39 (C-2), 127.81 (2C), 128.57 (2C), 130.38, 133.55, 147.99, 175.04 (C-3).
ACKNOWLEDGMENT
The work was supported by the Targeted Program of Interdisciplinary Projects in collaboration with scientists of the
Ural and Siberian Branches, RAS, and the Federal Targeted Program “Research and Development in Priority Areas for
Development of the Russian Science and Technology Complex for 2007–2013” (State Contract No. 11.519.11.2033).
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