Synthesis of O-Vinyl Ethers of Pentacyclic Triterpene Alcohols and Lupane-Type Oximes

Article abstract of DOI:10.1007/s10600-020-03067-2

Vinylation by acetylene of lupane-type pentacyclic triterpene C-28- and C-3β-alcohols and C-20-oximes in superbase solutions synthesized the corresponding C-28- and C-3β-O-vinyl ethers and C-20-O-vinyloximes. The reaction of 3β,28-dimethoxy-29-norlupan-20

Full text of DOI:10.1007/s10600-020-03067-2

DOI 10.1007/s10600-020-03067-2
Chemistry of Natural Compounds, Vol. 56, No. 3, May, 2020
SYNTHESIS OF O-VINYL ETHERS OF PENTACYCLIC
TRITERPENE ALCOHOLS AND LUPANE-TYPE OXIMES
N. G. Komissarova,* A. V. Orlov, and O. V. Shitikova
Vinylation by acetylene of lupane-type pentacyclic triterpene C-28- and C-3β-alcohols and C-20-oximes in
superbase solutions synthesized the corresponding C-28- and C-3β-O-vinyl ethers and C-20-O-vinyloximes.
The reaction of 3β,28-dimethoxy-29-norlupan-20-one with acetylene in superbase KOH–DMSO produced
a derivative with an N-vinylpyrrole ring in the C-19 side chain.
Keywords: betulin, lupeol, 3β,28-dimethoxy-29-norlupan-20-one oxime, acetylene, superbase solution, O-vinyl ethers.
Vinyl ethers of alcohols and oximes [1–3] are valuable intermediates in the synthesis of polymers [4] and various
classes of heterocyclic compounds [1, 5]. The development of methods to prepare vinyl ethers of oxygenated compounds has
recently become very significant because they can resolve design issues for biodegradable polymers [6].
Direct vinylation by acetylene of hydroxyl-containing compounds in superbase solutions is a rational method for
preparing vinyl ethers [1–3]. The method is successfully used in the laboratory and industry, allows available reagents and
simple apparatuses to be used, and is environmentally benign.
Previously, vinylation by acetylene of betulin and allobetulin in KOH–DMSO superbase solution was used by us to
prepare betulin 28-O-vinyl and 3β,28-O,O-divinyl ethers [7] and allobetulin 3β-O-vinyl ether [8].
Herein, several lupane-type pentacyclic triterpenes (1–3) with C-3 or C-28 hydroxyls and 3β,28-dihydroxy- and
3β,28-dimethoxy-29-norlupan-20-ones (4 and 5) were used as examples to demonstrate the synthesis of new O-vinyl ethers of
triterpene alcohols and the first O-vinylketoximes, which are of interest as monomers for polymerization and starting compounds
for synthesizing heterocyclic derivatives.
OTr
R
28
a
b
HX
O
β
HA
HB
from 2
from 1
3
O
α
HO
7
8
1, 2
1: R = CH OTr; 2: R = CH
2
3
a. C H , KOH–DMSO, 130°C, 2 h; b. C H , NaOH–CsF–DMSO, 130°C, 2.5 h
2
2
2 2
Compound 1 was prepared by the literature method [9]. Lupeol (2) was isolated from birch bark as before [10].
Alcohol 3 was synthesized by treating 28-acetoxybetulin (6) with TsCl in Py first at room temperature and then under reflux to
give 28-acetoxylupa-2,20(29)-diene, which was hydrolyzed without isolation by KOH in MeOH. Vinylation of the C-28-OH
in betulin and 3β-OH in allobetulin to form the corresponding vinyl ethers was shown in our previous work to occur readily in
KOH–DMSO superbase solution at 80 and 110°C with triterpenoid–DMSO ratios of 1:100 (for betulin 28-O-vinyl ether) and
1:40 ratios (for allobetulin 3β-O-vinyl ether) [7, 8]. Attempts to produce ethers 7–9 under analogous conditions did not give
the desired results. Vinylation of the 3β-OH of C-28-O-trityl-substituted betulin derivative 1 formed ether 7 in KOH–DMSO
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, 71 Prosp. Oktyabrya, Ufa,
450054, Russia, e-mail: ngkom@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2020,
pp. 414–418. Original article submitted November 19, 2019.
©
0009-3130/20/5603-0481 2020 Springer Science+Business Media, LLC
481

superbase solution at 130°C for 2 h (1–DMSO, 1:40). Vinylation of lupeol (2) occurred at 130°C in the presence of
NaOH–CsF–DMSO (2–DMSO, 1:40, 2.5 h). Vinylation of C-28-alcohol 3 went smoothly in 20 min in KOH–DMSO superbase
solution at 130°C (3–DMSO, 1:100). The yields of 7, 8, and 9 after isolation of them by column chromatography (CC) over
silica gel or Al O were 52, 76, and 50%, respectively.
2
3
OH
O
OAc
a, b
c
HO
9
6
3
a. TsCl, Py, 25°C, 8 h, then reflux 16 h; b. KOH, MeOH, 3 h; c. C H , KOH–DMSO, 130°C, 20 min
2
2
The reaction of acetylene in superbase solution with ketoximes without an α-methylene was a general method for
synthesizing O-vinylketoximes, which were key intermediates in the Trofimov pyrrole synthesis [1, 2].
This method has been used in the scientific literature to synthesize O-vinylketoximes of various structural types.
5
5
In particular, steroidal Δ -pregnen-3β-ol-20-one oxime was reacted with acetylene in KOH–DMSO to form Δ -pregnen-3β-
ol-20-one O-vinyloxime (10% yield) [11]. O-Vinyl derivatives of pentacyclic triterpenoid ketoximes have not been reported.
Triterpenoids 4 and 5 with free and protected C-3 and C-28 hydroxyls were used as examples to study reactions of
triterpene ketoximes with acetylene in superbase solution.
Ozonolysis of betulin diacetate 10 and 3β,28-dimethoxylup-20(29)-ene 11 produced the corresponding C-20-ketones
12 and 13, subsequent reaction of which with NH OH⋅HCl synthesized oximes 14 and 5. Hydrolysis of the acetates in 14 by
2
Ca(OH) in MeOH–CHCl gave 3β,28-dihydroxy-29-norlupan-20-one 4, O-vinylation of which by acetylene in KOH–DMSO
2
3
superbase solution under conditions analogous to those for preparing betulin 28-O-vinyl ether formed an unidentified product
mixture. A mixture of divinyl- (15) and trivinyloxy-derivatives (16) in a 9:1 ratio (according to PMR data) was isolated in
overall yield ~20% if the reaction was performed at 80°C under high-dilution conditions (oxime–DMSO, 1:330). However,
the reaction of 3β,28-O,O-dimethyl-substituted ketoxime 5 with acetylene in KOH–DMSO at 80°C with a 5–DMSO ratio of
1:100 gave after 15 min C-20-O-vinylketoxime 17 in 66% yield (after CC over Al O ). A difficultly identified mixture of
2
3
compounds including 18 (4% yield) with an N-vinylpyrrole ring in the C-19 side chain formed if the reaction of 5 with
acetylene was carried out at 110°C.
HO
NO
NH
O
O
OR
OR
OR
a
b
d
RO
RO
RO
15, 16
15 : 16 (9 : 1)
4, 5, 14
10, 11
12, 13
c
14
4
4, 15: R = H; 5, 11, 13: R = Me; 10, 12, 14: R = Ac; 16: R = CH=CH
2
a. O , CH Cl , –60°C, Me S; b. NH OH⋅HCl, Py, MeOH, reflux, 6 h; c. Ca(OH) , 70 h, 50°C; d. C H , KOH–DMSO, 80°C, 75 min
3
2
2
2
2
2
2
2
5'
1'
β
NO
N
α
2'
3'
19
OMe
OMe
a
b
5
MeO
MeO
17
18
a. C H , KOH–DMSO, 80°C, 15 min; b. C H , KOH–DMSO, 110°C, 40 min
2
2
2 2
482

The structures of the obtained compounds were established by NMR spectroscopy and mass spectrometry.
13
PMR and C NMR resonances for 5, 8, 15, 17, and 18 were fully assigned using 2D experiments on Bruker Avance III or
Bruker AM-300 instruments.
Thus, direct vinylation by acetylene in superbase solution of lupane-type pentacyclic triterpene alcohols and
C-20-ketoximes produced new O-vinyl triterpene alcohols and the first triterpene O-vinylketoximes.
EXPERIMENTAL
13
PMR and C NMR spectra were obtained on a Bruker Avance III pulsed spectrometer (Germany) at operating
1
13
frequency 500.13 MHz for H and 125.47 MHz for C or on a BrukerAM-300 spectrometer (Germany) at operating frequency
13
300.13 and 75.47 MHz, respectively. Chemical shifts in PMR and C NMR spectra were given in ppm vs. solvent resonances
(CDCl and CD OD) or TMS internal standard. SSCC ( H– H) were given in Hz. 2D spectra were recorded in standard
1
1
3
3
modes using multi-pulse sequences embedded in Bruker Avance III or Bruker AM-300 instrument software. Electron-impact
mass spectra were measured using direct sample introduction into the ion source of a Thermo Finnigan MAT95XP mass
spectrometer (temperature programmed from 50 to 270°C, ionizing potential 70 eV). Column chromatography used SiO
2
(L grade, 100/160 mesh, Russia) and Al O (L grade, 40/250 mesh, Czechoslovakia). TLC used Sorbfil plates (PTSKh-AF-A,
2
3
Imid Ltd., Krasnodar, Russia) with detection of chromatograms by anisaldehyde. Melting points were determined on a Kofler
apparatus.
Lupa-2,20(29)-dien-28-ol (3). Asolution of 6 (2.0 g, 4.126 mmol) [12] and TsCl (7.55 g, 39.610 mmol) in anhydrous
Py (48 mL) was stirred for 8 h at room temperature, refluxed for 16 h, cooled, treated with HCl solution (10%) to pH ~2, and
extracted with CHCl . The organic layer was separated, washed with H O, dried over Na SO , and evaporated. The resulting
3
2
2
4
solid was dissolved in MeOH (250 mL), treated with KOH (10.10 g, 0.18 mol), stirred for 3 h, treated with HCl solution (5%),
and filtered. The filtrate was concentrated and extracted with CHCl . The organic layer was separated, washed with H O,
3
2
dried over Na SO , and evaporated. The solid was chromatographed over SiO (eluents hexane and hexane–EtOAc, 5:1) to
2
4
2
1
afford 3 (1.12 g, 75%). Amorphous compound. Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.86, 0.87, 0.94, 0.99,
3
1.05, 1.67 (3H each, s, CH -25, 24, 23, 27, 26, 30), 2.41 (1H, m, H-19), 3.34, 3.81 (1H each, d, J = 11.0, H-28), 4.59, 4.69 (1H
3
13
each, s, H-29), 5.36 (1H, d, J = 10.0, H-3), 5.40 (1H, dd, J = 10.0, 5.0, H-2). C NMR spectrum (75 MHz, CDCl , δ, ppm): 14.70
3
(ÑH -27), 15.64 (CH -26), 16.36 (CH -25), 19.10 (CH -30), 19.35 (C-6), 21.20 (C-11), 22.53 (CH -24), 25.33 (C-12), 27.00
3
3
3
3
3
(C-15), 29.87 (C-16, 21), 31.72 (C-23), 33.29 (C-7), 34.67 (C-4), 34.72 (C-22), 36.35 (C-10), 37.39 (C-13), 40.95 (C-8),
41.17 (C-1), 42.69 (C-14), 47.06 (C-17), 47.80 (C-19), 48.80 (C-18), 48.93 (C-9), 52.04 (C-5), 60.54 (C-28), 109.44 (C-29),
121.58 (C-2), 137.94 (C-3), 150.70 (C-20).
Preparation of O-Vinyl Ethers 7, 9, and 17 and N-Vinylpyrrole 18. A mixture of 1, 3, or 5 (0.52 g, 0.759 mmol)
and KOH⋅0.5H O (0.25 g, 3.91 mmol) in DMSO [ratios of alcohol or oxime (g) to DMSO (mL), 1:40 for 7, 1:100 for 9, 17,
2
and 18] was heated and purged with acetylene until the starting compound disappeared according to TLC (130°C and 2 h for
7, 130°C and 20 min for 9, 80°C and 15 min for 17, 110°C and 40 min for 18). The mixture was cooled, diluted with ice H O,
2
and extracted with methyl-t-butyl ether (MTBE). The organic layer was separated, washed with H O, dried over Na SO , and
2
2
4
evaporated. The resulting solid was stirred with pentane. The insoluble part was filtered off. The filtrate was evaporated. The
solid was chromatographed. Compounds 7 and 9 were isolated over SiO and worked up with Et N [hexane eluent and
2
3
hexane–EtOAc (10:1 and 5:1) for 7; hexane and hexane–EtOAc (9:1) for 9]. Compounds 17 and 18 were chromatographed
over Al O (eluent benzene for 17; hexane for 18).
2
3
1
28-Triphenylmethoxylup-20(29)-en-3β-ol O-Vinyl Ether (7). Yield 52%, Amorphous compound. Í NMR spectrum
(300 MHz, CDCl , δ, ppm, J/Hz): 0.50 (3H, s, CH -25), 0.64 (1H, d, J = 10.0, H-5), 0.76, 0.79, 0.88, 0.91, 1.64 (3H each, s,
3
3
CH -27, 24, 26, 23, 30), 2.15 (3H, m, H -16, 22, H-19), 2.90, 3.21 (1H each, d, J = 8.8, H -28), 3.23 (1H, dd, J = 11.2, 4.0,
3
a
H-3), 3.90 (1Í, dd, J = 6.5, 1.2, vinyl: H ), 4.25 (1H, dd, J = 14.1, 1.2, vinyl: Í ), 4.50, 4.57 (1H each, d, J = 1.5, H-29), 6.30 (1H,
A
B
13
dd, J = 14.1, 6.5, vinyl: Í ), 7.10–7.40 (9Í, m, Ph), 7.50 (6H, d, J = 7.2, Ph). C NMR spectrum (75 MHz, CDCl , δ, ppm):
X
3
14.81 (C-26), 15.95 (C-25), 16.18 (Ñ-27), 16.43 (C-24), 19.22 (C-6, 30), 20.82 (C-11), 23.70 (C-12), 25.23 (C-15), 26.98 (C-2),
28.05 (C-23), 29.97 (C-21), 30.23 (C-16), 35.33 (C-7, 22), 37.31 (C-10, 13), 38.69 (C-1, 4), 40.70 (C-8), 42.55 (C-14), 47.65
(C-17), 47.82 (C-19), 48.96 (C-18), 50.34 (C-9), 55.73 (C-5), 59.57 (C-28), 85.90 (OCPh ), 87.23 (C-β), 87.42 (C-3), 109.50
3
(C-29), 126.90, 127.80, 128.84, 144.54 (Ph), 150.83 (C-20), 152.32 (C-α).
483

Lup-20(29)-en-3β-ol O-Vinyl Ether (8). A mixture of lupeol (2, 1.84 g, 4.312 mmol), NaOH (0.86 g, 21.560 mmol),
and CsF (3.28 g, 21.560 mmol) in DMSO (74 mL) at atmospheric pressure and 130°C was purged with acetylene for 2.5 h
(TLC monitoring), cooled, diluted with ice H O (50 mL), and extracted with MTBE (5 × 30 mL). The combined organic
2
extracts were washed with H O, dried over Na SO , and evaporated. The solid was chromatographed over SiO and worked
2
2
4
2
up with Et N (eluents hexane and hexane–EtOAc, 30:1) to afford 2 (0.33 g) and 8 (1.48 g) (76% yield, 81% conversion of 2).
3
1
Amorphous compound. Í NMR spectrum (500 MHz, CDCl , δ, ppm, J/Hz): 0.71 (1H, d, J = 9.1, H-5), 0.79, 0.82, 0.85, 0.94,
3
0.95 (3H each, s, CH -28, 24, 25, 23, 27), 0.88 (1H, td, J = 13.7, 4.1, H -1), 1.03 (4H, s, H -15, CH -26), 1.06 (1H, m, H -12),
3
a
a
3
a
1.20 (1H, m, H -22), 1.26 (2H, m, H-9, H -11), 1.29 (1H, m, H -21), 1.36 (2H, m, H -16, H-18), 1.39 (5H, m, H -6, H-7, H -11,
a
a
a
a
a
b
22), 1.48 (1H, m, H -16), 1.52 (1H, m, H -6), 1.58 (1H, m, H -2), 1.66 (1H, m, H -1), 1.68 (4H, m, H -2, 12, 15, H-13; 3H, s,
b
b
a
b
b
CH -30), 1.92 (1H, tt, J = 11.0, 10.3, H -21), 2.39 (1H, td, J = 11.0, 5.2, H-19), 3.48 (1H, dd, J = 11.8, 4.1, H-3), 3.92 (1H, d,
3
b
J = 6.3, vinyl: H ), 4.02 (1H, d, J = 14.0, vinyl: H ), 4.57, 4.69 (1H each, s, H-29), 6.03 (1H, dd, J = 14.0, 6.3, vinyl: H ).
A
B
X
13
C NMR spectrum (125 MHz, CDCl , δ, ppm): 14.51 (C-27), 15.96 (C-24), 16.12 (C-26), 16.32 (C-25), 17.98 (C-28), 18.15
3
(C-6), 19.30 (C-30), 20.94 (C-11), 23.57 (C-2), 25.10 (C-12), 27.41 (C-15), 27.95 (C-23), 29.84 (C-21), 34.24 (C-7), 35.56
(C-16), 37.13 (C-10), 38.00 (C-13), 38.46 (C-1), 38.60 (C-4), 39.98 (C-22), 40.84 (C-8), 42.80 (C-14), 42.98 (C-17), 47.95
(C-19), 48.27 (C-18), 50.40 (C-9), 55.69 (C-5), 87.10 (C-β), 87.39 (C-3), 109.34 (C-29), 150.90 (C-20), 152.28 (C-α).
1
Lupa-2,20(29)-dien-28-ol O-Vinyl Ether (9). Yield 50%, Amorphous compound. Í NMR spectrum (500 MHz,
CDCl , δ, ppm, J/Hz): 0.81, 0.86, 0.93, 0.98, 1.04, 1.68 (3H each, s, CH -25, 24, 23, 27, 26, 30), 1.95 (3H, m, H -16, 21, 22),
3
3
b
2.43 (1H, td, J = 11.0, 5.0, H-19), 3.37, 3.82 (1H each, d, J = 9.2, H-28), 3.96 (1H, dd, J = 6.7, 1.8, vinyl: H ), 4.20 (1H, d,
A
J = 14.3, 1.8, vinyl: H ), 4.59, 4.69 (1H each, s, H-29), 5.36 (1H, dd, J = 10.0, 2.0, H-3), 5.40 (1H, ddd, J = 10.0, 5.5, 1.3,
B
13
H-2), 6.54 (1H, dd, J = 14.3, 6.7, vinyl: H ). C NMR spectrum (125 MHz, CDCl , δ, ppm): 14.77 (C-27), 15.67 (C-26),
X
3
16.38 (C-25), 19.13 (C-30), 19.48 (C-6), 21.22 (C-11), 22.62 (C-24), 25.30 (C-12), 27.12 (C-15), 29.79 (C-16, 21), 31.74
(C-23), 33.34 (C-7), 34.59 (C-22), 34.67 (C-4), 36.38 (C-10), 37.73 (C-13), 40.99 (C-8), 41.24 (C-1), 42.69 (C-14), 46.75
(C-17), 47.94 (C-19), 48.78 (C-18), 49.03 (C-9), 52.10 (C-5), 66.16 (C-28), 85.54 (C-β), 109.57 (C-29), 121.58 (C-2), 137.96
(C-3), 150.51 (C-20), 152.84 (C-α).
General Method for Preparing Ketones 12 and 13. A solution of 10 [12] or 11 [13] (1.90 mmol) in anhydrous
CH Cl (90 mL) at –60°C was purged with an O /O mixture (ozonator output 45 mmol/min) until the solution became deep
2
2
3
2
blue, purged with Ar, treated with Me S (6 mL), and stirred for 1 h at 10°C and for 12 h at room temperature. The solvent was
2
evaporated. The solid was chromatographed over SiO [eluents hexane and hexane–EtOAc (10:1 and 5:1) for 12; dichloroethane
2
for 13].
3β,28-Diacetoxy-29-norlupan-20-one (12). Yield 86%, mp 187–188°Ñ (lit.: 186.5–189.5°C [14], 185–187°C [15],
1
190–191°C [16]). Í NMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.80 (1H, d, J = 10.2, H-5), 0.83, 0.95, 1.02, 2.16 (3H
3
each, s, CH -24, 25, 26, 30), 0.85 (6H, s, CH -23, 27), 2.03, 2.08 (3H each, s, 28, 3-OAc), 2.65 (1H, td, J = 11.3, 5.8, H-19), 3.79,
3
3
13
4.20 (1H each, d, J = 11.0, H-28), 4.48 (1H, dd, J = 10.6, 4.4, H-3). The C NMR spectrum agreed with the literature [15, 16].
1
3β,28-Dimethoxy-29-norlupan-20-one (13). Yield 40%, mp 171–173°C (Et O) (lit.: 170–173°Ñ [13]). Í NMR
2
spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.64 (1H, d, J = 9.0, H-5), 0.73, 0.81, 0.94, 0.98, 1.00, 2.14 (3Í each, s, ÑH -24, 25,
3
3
13
27, 23, 26, 30), 2.63 (2H, m, H-3, 19), 2.97, 3.42 (1H each, d, J = 9.3, H-28), 3.34, 3.36 (3H each, s, 28, 3-OCH ). C NMR
3
spectrum (75 MHz, CDCl , δ, ppm): 14.72 (Ñ-27), 15.95 (Ñ-24), 16.05 (Ñ-25), 16.14 (Ñ-26), 18.19 (Ñ-6), 20.89 (Ñ-11), 22.21
3
(Ñ-2), 27.29 (Ñ-12, 15), 27.95 (Ñ-21), 28.01 (Ñ-23), 29.31 (Ñ-30), 29.80 (Ñ-16), 34.19 (Ñ-7), 34.79 (Ñ-22), 36.42 (Ñ-13), 37.21
(Ñ-10), 38.57 (Ñ-1), 38.81 (Ñ-4), 40.87 (Ñ-8), 42.55 (Ñ-14), 47.23 (Ñ-17), 49.68 (Ñ-18), 50.28 (Ñ-9), 52.34 (Ñ-19), 55.82 (Ñ-5),
+
57.50 (3-ÎCH ), 59.65 (28-ÎCH ), 71.62 (C-28), 88.55 (C-3), 212.28 (C-20). EI-MS, m/z 472 [M] (calcd for Ñ Í O 472).
3
3
31 52 3
General Method for Preparing Ketoximes 5 and 14. Asuspension of ketone 13 or 12 (1.10 mmol) and NH OH⋅HCl
2
(10.99 mmol) in anhydrous MeOH (12 mL) and Py (4 mL) was refluxed for 6 h and evaporated to dryness. The resulting solid
(5) was chromatographed over SiO (eluent dichloroethane) or (14) over Al O (eluents benzene and benzene–MTBE, 8:1).
2
2 3
1
3β,28-Dimethoxy-28-norlupan-20-one (E)-Oxime (5). Yield 63%, mp 143–144°Ñ (lit.: 148–151°Ñ [17]). Í NMR
spectrum (500 MHz, CDCl , δ, ppm, J/Hz): 0.67 (1H, d, J = 9.3, H-5), 0.75 (3Í, s, ÑH -24), 0.81 (1H, m, H -1), 0.82, 0.92,
3
3
a
0.95 (3Í each, s, CH -25, 27, 23), 0.95 (1H, m, H -15), 1.01 (3Í, s, ÑÍ -26), 1.05 (1H, m, H -12), 1.07 (1H, m, H -22), 1.20
3
a
3
a
a
(1H, m, H -16), 1.22 (1H, m, H -11), 1.25 (1H, m, H-9), 1.38 (3H, m, H -6, H-7), 1.42 (2H, m, H -2, H -11), 1.47 (1H, m,
a
a
a
a
b
H -21), 1.50 (1H, m, H -6), 1.52 (1H, m, H -15), 1.57 (1H, m, H-18), 1.68 (2H, m, H -1, 12), 1.70 (1H, m, H-13), 1.78 (1H,
a
b
b
b
m, H -2), 1.81 (3H, s, CH -30), 1.97 (3H, m, H -16, 21, 22), 2.60 (1H, td, J = 10.5, 6.3, H-19), 2.63 (1H, dd, J = 11.5, 4.0,
b
3
b
13
H-3), 3.02, 3.45 (1H each, d, J = 9.0, H-28), 3.34, 3.35 (3H each, s, 28, 3-OCH ), 9.04 (1H, br.s, NOH). C NMR spectrum
3
(125 MHz, CDCl , δ, ppm): 10.59 (C-30), 14.50 (C-27), 16.05 (C-24), 16.06 (C-25), 16.07 (C-26), 18.09 (C-6), 20.65 (C-11),
3
484

22.13 (C-2), 25.20 (C-15), 26.97 (C-12), 27.50 (C-21), 27.92 (C-23), 29.83 (Ñ-16), 34.09 (C-7), 34.71 (C-22), 36.70 (C-13),
37.09 (C-10), 38.52 (C-1), 38.72 (C-4), 40.81 (C-8), 42.48 (C-14), 45.34 (C-19), 46.91 (C-17), 49.30 (C-18), 50.15 (C-9),
+
55.78 (C-5), 57.60 (3-OCH ), 59.73 (28-OCH ), 71.19 (C-28), 88.57 (C-3), 162.81 (C-20). EI-MS, m/z 487 [M] (calcd for
3
3
Ñ Í NO 487).
31 53
3
1
3β,28-Diacetoxy-29-norlupan-20-one (E)-Oxime (14). Yield 55%, mp 193–195°Ñ (lit.: 197–198°Ñ [17]). Í NMR
spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.79 (1H, d, J = 9.0, H-5), 0.84, 0.95, 1.03, 1.82 (3H each, s, CH -24, 25, 26, 30),
3
3
0.85 (6H, s, CH -23, 27), 2.05, 2.07 (3H each, s, 28, 3-OAc), 2.60 (1H, td, J = 11.3, 5.8, H-19), 3.80, 4.28 (1H each, d, J = 11.0,
3
H-28), 4.48 (1H, dd, J = 10.5, 4.5, H-3).
3β,28-Dihydroxy-29-norlupan-20-one (E)-Oxime (4). A suspension of 14 (0.44 g, 0.81 mmol) and Ca(OH)
2
(1.90 g, 25.67 mmol) in MeOH–CHCl (15 mL, 1:1) was stirred vigorously for 70 h at 50°C. The precipitate was filtered off.
3
The solvent was evaporated. The solid was chromatographed over Al O (eluent hexane–MeOH, 5:1) to afford 4 (0.20 g,
2
3
1
54%), mp 178–179°C. Í NMR spectrum (300 MHz, CD OD, δ, ppm, J/Hz): 0.67 (1H, d, J = 9.2, H-5), 0.75, 0.81, 0.95, 0.96,
3
1.00, 1.80 (3H each, s, CH -24, 25, 27, 23, 26, 30), 1.95 (3H, m, H -16, 21, 22), 2.60 (1H, m, H-19), 3.18 (1H, dd, J = 11.0, 5.5,
3
b
13
H-3), 3.30, 3.80 (1H each, d, J = 10.0, H-28). C NMR spectrum (75 MHz, CD OD, δ, ppm): 10.86 (C-30), 15.18 (C-27),
3
16.16 (C-25), 16.52 (C-26), 16.73 (C-24), 19.43 (C-6), 21.86 (C-11), 26.47 (C-2), 28.00 (C-15, 21), 28.24 (C-12), 28.66
(C-23), 30.19 (C-16), 35.01 (C-7), 35.40 (C-22), 38.00 (C-13), 38.21 (C-10), 39.92 (C-4, 8), 40.01 (C-1), 42.05 (C-14), 43.70
(C-17), 46.45 (C-19), 50.26 (C-18), 51.64 (C-9), 56.76 (C-5), 60.29 (C-28), 79.54 (C-3), 163.49 (C-20).
Vinylation of Ketoxime 4. A mixture of 4 (0.10 g, 0.22 mmol) and KOH⋅0.5H O (0.07 g, 1.09 mmol) in DMSO (33 mL)
2
was purged with acetylene at 80°C for 1 h 15 min (TLC monitoring), cooled, diluted with ice H O (50 mL), and extracted with
2
EtOAc (5 × 20 mL). The organic layer was washed with H O, dried over Na SO , and evaporated. The solid was extracted
2
2
4
with pentane. The solution was decanted and evaporated to afford a mixture (0.02 g) of 15 and 16 in a 9:1 ratio (PMR).
1
3β-Hydroxy-28-O-vinyl-29-norlupan-20-one (E)-O-Vinyloxime (15). Í NMR spectrum (300 MHz, ÑDCl , δ,
3
ppm, J/Hz): 0.70 (1Í, d, J = 8.7, Í-5), 0.74, 0.81, 0.95, 0.96, 1.00, 1.84 (3H each, s, CH -24, 25, 27, 23, 26, 30), 1.95 (3H, m,
3
H -16, 21, 22), 2.63 (1H, m, H-19), 3.20 (1H, dd, J = 11.5, 4.8, H-3), 3.35, 3.77 (1H each, d, J = 9.5, H-28), 3.97 (1Í, dd,
b
J = 6.8, 2.0, vinyl: Í ), 4.07 (1Í, dd, J = 6.8, 1.5, vinyloxime: Í ), 4.19 (1Í, dd, J = 14.4, 2.0, vinyl: Í ), 4.55 (1H, dd, J = 14.3,
A
A
B
13
1.4, vinyloxime: Í ), 6.53 (1H, dd, J = 14.4, 6.8, vinyl: Í ), 6.87 (1H, dd, J = 14.3, 6.8, vinyloxime: Í ). C NMR spectrum
(75 MHz, ÑDCl , δ, ppm): 11.96 (C-30), 14.63 (Ñ-27), 15.33 (Ñ-24), 15.88 (Ñ-26), 16.03 (Ñ-25), 18.26 (Ñ-6), 20.68 (Ñ-11),
B
X
X
3
22.66 (Ñ-2), 25.43 (Ñ-15), 26.99 (Ñ-12), 27.37 (Ñ-21), 27.96 (Ñ-23), 31.90 (Ñ-16), 34.14 (Ñ-7), 34.60 (Ñ-22), 36.94 (Ñ-13),
37.15 (Ñ-10), 38.70 (Ñ-1), 38.84 (Ñ-4), 40.84 (Ñ-8), 42.58 (Ñ-14), 45.18 (Ñ-19), 46.56 (Ñ-17), 49.10 (Ñ-18), 50.23 (Ñ-9),
55.29 (Ñ-5), 65.99 (C-28), 78.93 (C-3), 85.76 (vinyl: C-β), 87.11 (vinyloxime: C-β), 152.59 (vinyl, vinyloxime: C-α), 164.80
(C-20).
1
3β,28-Dimethoxy-29-norlupan-20-one (E)-O-Vinyloxime (17). Yield 66%, Amorphous compound. Í NMR
spectrum (500 MHz, CDCl , δ, ppm, J/Hz): 0.68 (1H, d, J = 9.5, H-5), 0.74, 0.82, 0.94, 0.95, 1.02 (3Í each, s, ÑH -24, 25, 26,
3
3
23, 27), 1.05 (1H, m, H -12), 1.08 (1H, m, H -22), 1.20 (1H, m, H -16), 1.25 (2H, m, H-9, H -11), 1.38 (2H, m, H-7), 1.39 (1H,
a
a
a
a
m, H -6), 1.40 (1H, m, H -2), 1.42 (1H, m, H -11), 1.47 (1H, m, H -21), 1.51 (1H, m, H -6), 1.52 (1H, m, H -15), 1.63 (1H,
a
a
b
a
b
a
m, H-18), 1.67 (1H, m, H -12), 1.68 (1H, m, H -1), 1.72 (1H, m, H-13), 1.79 (1H, m, H -2), 1.82 (3Í, s, ÑÍ -30), 1.92 (1H,
b
b
b
3
m, H -15), 1.97 (3H, m, H -16, 21, 22), 2.63 (2H, m, H-3, 19), 3.05, 3.48 (1H each, d, J = 9.0, H-28), 3.34, 3.36 (3H each, s,
b
b
28, 3-OCH ), 4.05 (1Í, dd, J = 6.8, 1.5, vinyloxime: Í ), 4.52 (1Í, dd, J = 14.2, 1.5, vinyloxime: H ), 6.85 (1H, dd, J = 14.2,
3
A
B
13
6.8, vinyloxime: H ). C NMR spectrum (125 MHz, CDCl , δ, ppm): 11.89 (Ñ-30), 14.56 (Ñ-27), 15.89 (Ñ-25), 15.90
X
3
(Ñ-26), 16.10 (Ñ-24), 18.12 (Ñ-6), 20.69 (Ñ-11), 22.13 (Ñ-2), 25.38 (Ñ-15), 27.03 (Ñ-12), 27.71 (Ñ-21), 27.96 (Ñ-23), 29.98
(Ñ-16), 34.11 (Ñ-7), 34.73 (Ñ-22), 36.74 (Ñ-13), 37.12 (C-10), 38.52 (Ñ-1), 38.74 (Ñ-4), 40.83 (Ñ-8), 42.51 (Ñ-14), 45.09
(Ñ-19), 46.98 (Ñ-17), 49.14 (Ñ-18), 50.18 (Ñ-9), 55.76 (Ñ-5), 57.43 (3-ÎÑÍ ), 59.69 (28-OÑÍ ), 71.25 (C-28), 86.97 (Ñ-β),
3
3
+
88.51 (Ñ-3), 152.54 (Ñ-α), 165.03 (Ñ-20). EI-MS, m/z 513 [M] (calcd for Ñ Í O N 513).
33 55
3
1
3β,28-Dimethoxy-19-(1-vinyl-1H-pyrrol-2-yl)-20,29,30-trinorlupane (18). Yield 4%, mp 89°Ñ. Í NMR spectrum
(500 MHz, CDCl , δ, ppm, J/Hz): 0.62 (1H, d, J = 8.8, H-5), 0.73 (3Í, s, ÑH -24), 0.75 (1H, m, H -1), 0.80 (3Í, s, CH -25),
3
3
a
3
0.88 (1H, m, H -12), 0.95 (1H, m, H -15), 0.96, 1.01, 1.05 (3Í each, s, ÑÍ -23, 27, 26), 1.07 (1H, m, H -12), 1.12 (1H, m,
a
a
3
b
H -11), 1.20 (1H, m, H -9), 1.21 (1H, m, H -22), 1.25 (1H, m, H -16), 1.35 (1H, m, H -11), 1.40 (4H, m, H -2, 6, H-7), 1.46
a
a
a
a
b
a
(1H, m, H -21), 1.50 (1H, m, H -6), 1.65 (1H, m, H -1), 1.67 (1H, ddd, J = 11.5, 11.5, 4.5, H-13), 1.72 (2H, m, H -2, 15), 1.88
a
b
b
b
(1H, t, J = 12.0, H-18), 1.92 (1H, ddd, J = 11.0, 11.0, 3.5, H -22), 1.96 (1H, ddd, J = 10.5, 5.0, 2.0, H -16), 2.23 (1Í, dq,
b
b
J = 11.0, 7.0, Í -21), 2.62 (1Í, dd, J = 11.7, 4.4, Í-3), 2.80 (1Í, ddd, J = 11.0, 6.0, 5.0, H-19), 3.11, 3.53 (1H each, d, J = 9.0,
b
H-28), 3.34, 3.38 (3H each, s, 28, 3-OCH ), 4.62 (1H, d, J = 8.7, vinyl: H ), 5.07 (1H, d, J = 15.6, vinyl: H ), 5.87 (1H, dd,
3
A
B
13
J = 3.2, 1.7, H-4′), 6.10 (1H, t, J = 3.2, H-3′), 6.85 (1H, dd, J = 3.2, 1.7, H-5′), 6.92 (1H, dd, J = 15.6, 8.7, vinyl: H ). C NMR
X
485

spectrum (125 MHz, CDCl , δ, ppm, J/Hz): 14.76 (C-27), 16.03 (C-25), 16.06 (C-26), 16.14 (C-24), 18.17 (C-6), 21.05 (C-11),
3
22.19 (C-2), 27.24 (C-12), 27.28 (C-21), 27.99 (C-23), 30.10 (C-16), 32.98 (C-15), 34.18 (C-22), 34.27 (C-7), 35.67 (C-18),
37.12 (C-13), 37.15 (C-10), 38.52 (C-1), 38.77 (C-4), 41.00 (C-8), 42.67 (C-14), 47.02 (C-17), 50.24 (C-9), 52.08 (C-19), 55.77
(C-5), 57.53 (3-OCH ), 59.74 (28-OCH ), 71.29 (C-28), 88.62 (C-3), 98.25 (Ñ-β), 104.63 (C-4′), 108.97 (Ñ-3′), 115.38 (C-5′),
3
3
+
130.54 (Ñ-α), 140.02 (Ñ-2′). EI-MS, m/z 521 [M] (calcd for Ñ Í O N 521).
35 55
2
ACKNOWLEDGMENT
The work was performed on a State Task Topic for UfIC, UFRC, RAS (No. AAAA-A17-117011910025-6). The
spectral part of the study used equipment at the Khimiya CUC, UfIC, RAS and Agidel RCUC, UfIC, RAS.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
B. A. Trofimov and N. K. Gusarova, Russ. Chem. Rev., 76 (6), 507 (2007).
V. V. Voronin, M. S. Ledovskaya, A. S. Bogachenkov, K. S. Rodygin, and V. P. Ananikov, Molecules, 23, 2442 (2018).
M. S. Ledovskaya, V. V. Voronin, and K. S. Rodygin, Russ. Chem. Rev., 87 (2), 167 (2018).
S. Sugihara, Y. Kawamoto, Y. Maeda, Macromolecules, 49 (5), 1563 (2016).
B. A. Trofimov and E. Yu. Schmidt, Acc. Chem. Res., 51, 1117 (2018).
S. Samanta, D. R. Bogdanowicz, H. H. Lu, and J. T. Koberstein, Macromolecules, 49 (5), 1858 (2016).
A. V. Orlov, N. G. Komissarova, and O. V. Shitikova, Chem. Sustainable Develop., 2, 213 (2011).
A. V. Orlov, N. G. Komissarova, O. V. Shitikova, L. V. Spirikhin, and M. S. Yunusov, Russ. Chem. Bull.,
62 (3), 687 (2013).
9.
10.
11.
K. Hata, K. Hori, and S. Takahashi, J. Nat. Prod., 65, 645 (2002).
M. S. Yunusov, N. G. Komissarova, and N. G. Belenkova, RU Pat. 2,270,202, Feb. 20, 2006, Byull., No. 5, 2006.
A. M. Vasil′tsov, E. Yu. Schmidt, A. I. Mikhaleva, A. V. Afonin, and A. B. Zaitsev, Chem. Heterocycl. Compd.,
37 (12), 1488 (2001).
12.
13.
14.
15.
K. Hiroya, T. Takahashi, N. Miura, A. Naganuma, and T. Sakamoto, Bioorg. Med. Chem., 10, 3229 (2002).
V. Pouzar and A. Vystrcil, Collect. Czech. Chem. Commun., 41, 3452 (1976).
J. Kunot, N. Hovorkova, and A. Vystrcil, Collect. Czech. Chem. Commun., 35, 1105 (1970).
M. Kahnt, L. Heller, A. Al-Harrasi, R. Schafer, R. Kluge, C. Wagner, C. Otgonbayar, and R. Csuk, Med. Chem. Res.,
27, 1757 (2018).
16.
17.
O. B. Flekhter, G. V. Giniyatullina, F. Z. Galin, N. Zh. Baschenko, N. S. Makara, F. S. Zarudii, E. I. Boreko,
O. V. Savinova, N. I. Pavlova, Z. A. Starikova, and G. A. Tolstikov, Chem. Nat. Compd., 41, 706 (2005).
A. Vystrcil, V. Krecek, M. Budesinsky, and J. Protiva, Collect. Czech. Chem. Commun., 51, 581 (1986).
486