Synthesis of Aminoalkylated Aziridines from (+)-3-Carene

Article abstract of DOI:10.1007/s10600-019-02664-0

Aminoalkylated carane-type aziridines were synthesized via epoxidation of (+)-3-carene by H₂O₂ solution (7%) in EtOAc catalyzed by α-Al₂O₃ nanoparticles, opening of the epoxide by NaN₃, and cyclization of the azidoalcohol by Ph₃P followed by condensation of the resulting aziridines with formalin and secondary amines. The cytotoxicity of the aminoalkylated aziridines with heteroorganic substituents increased on going from a five-membered pyrrolidine ring substituent to a six-membered piperidine ring and decreased sharply upon replacing a piperidine by a morpholine ring or increased on going to a piperazine ring. The structures of products were established using IR and NMR spectroscopy and an X-ray crystal structure analysis.

Full text of DOI:10.1007/s10600-019-02664-0

DOI 10.1007/s10600-019-02664-0
Chemistry of Natural Compounds, Vol. 55, No. 2, March, 2019
SYNTHESIS OF AMINOALKYLATED AZIRIDINES
FROM (+)-3-CARENE
1
1
1
S. N. Curlat, A. N. Barba, V. V. Boldescu,
2
1*
K. Panekok, and F. Z. Macaev
Aminoalkylated carane-type aziridines were synthesized via epoxidation of (+)-3-carene by H O solution
2
2
(7%) in EtOAc catalyzed by α-Al O nanoparticles, opening of the epoxide by NaN , and cyclization of the
2
3
3
azidoalcohol by Ph P followed by condensation of the resulting aziridines with formalin and secondary
3
amines. The cytotoxicity of the aminoalkylated aziridines with heteroorganic substituents increased on
going from a five-membered pyrrolidine ring substituent to a six-membered piperidine ring and decreased
sharply upon replacing a piperidine by a morpholine ring or increased on going to a piperazine ring. The
structures of products were established using IR and NMR spectroscopy and an X-ray crystal structure
analysis.
Keywords: (+)-3-carene, aziridines, aminoalkylation, cytotoxicity.
(+)-3-Carene (1) fostered a positive outcome on osteoporosis due to increased mineralization of bone tissue [1].
Also, acetylcholine esterase inhibitor and monoterpene 1 was proposed for treatingAlzheimer’s disease [2, 3]. Transformation
of plant metabolites to enhance or diminish their native properties is a promising direction for designing active ingredients of
medicinal formulations [4–7]. Transformations of bicyclic olefine 1 into optically active compounds are also known [8–11].
Several carane-type aziridines were reported [12–15], although their aminoalkylated derivatives were not synthesized for
biological studies.
This issue was resolved by selecting aziridine 2 [13], which was synthesized according to Scheme 1, including initial
preparation of epoxide 3 using H O solution (7%) in EtOAc in the presence of α-Al O nanoparticles [16].
2
2
2 3
10
R
1
R
2
O
NH
R
3
3
[5, 16]
[16]
[13]
1
65%
97%
49-92%
6
9
8
1
3
4a,b
4a: R = N , R = Me, R = OH
2
1
3
2
3
4b: R = Me, R = OH, R = N
1
2
3
3
Scheme 1
Known methods for preparing azides 4a,b include opening of epoxide 3 by NaN in the presence of NH Cl in
3
4
refluxing alcohols or stirring with NaN in aqueous AcOH at 30°C [13, 14]. The researchers noted that, in the first instance,
3
an equal mixture of azides 4a,b (49% overall yield) formed whereas, in the second, compound 4a (65% yield) formed
regiospecifically. This contradicted the literature [15] reporting a mixture of isomeric (86:14) 4a,b in 92% overall yield.
Under these conditions, we isolated predominantly (74% yield) 4a with mp 32°C instead of a product with mp 35°C [15].
The sample PMR spectrum (ppm) featured 3H singlets for gem-dimethyls (0.97 and 1.02) and 10-Me (1.35) and four
1H doublets of doublets for H-2 and H-5 (1.3, 2.11 and 1.7, 2.09, respectively). A doublet for the OH proton appeared at
medium field (1.96 ppm). Resonances of H-1, H-4, and H-6 differed from those in the literature [15].
1) Institute of Chemistry, 3 Akademicheskaya St., MD-2028, Kishinev, Moldova, e-mail: flmacaev@gmail.com;
2) Rega Institute, Herestraat 49, Box 1030, 3000 Leuven, Belgium. Translated from Khimiya Prirodnykh Soedinenii, No. 2,
March–April, 2019, pp. 232–236. Original article submitted September 27, 2018.
©
0009-3130/19/5502-0269 2019 Springer Science+Business Media, LLC
269

b
c
N
3
Me
H
OH
H
H
H
H
H
Me
H
Me
4a
Fig. 1. NOESY correlations in 4a.
Fig. 2. Homomolecular structure of azidoalcohol 4a.
Protons H-1 and H-6 were attributed before to a multiplet at 0.69–0.80 ppm whereas they resonated in the studied
sample as two separate resonances, i.e., a triplet of doublets at 0.74 ppm and a triplet at 0.78 ppm. Also, the multiplicities of
H-4 differed. In our instance, it was found as a doublet of doublets of doublets. A NOESY correlation was observed between
H-5α and H-6 and the 10-Me group. The Me-8 protons coupled with H-2α, H-4, and H-5β, respectively (Fig. 1).
–1
–1
The IR spectrum of 4a had azide bands at 2099 cm and characteristic OH bands at 3440 cm . Also, a maximum at
–1
1381 cm confirmed that the gem-dimethyl group was present. The structure of 4a was confirmed by an X-ray crystal
structure analysis (XSA).
A crystal of C H ON was monoclinic with homomolecular contacts in a structure stabilized by H-bonds (Fig. 2).
10 17
3
Aziridine 2 that was required for studying aminoalkylation was prepared by reacting azidoalcohol 4a with Ph P (65%
3
yield). However, azidoalcohol 4b did not give the corresponding aziridine [13].
Next, the course of the Mannich reaction was studied as a function of the secondary amine using Scheme 2.
12'
12
11
11'
11
10
N
N
10'
N
NR R
NH
N
1
2
HN
NH
N
13 13'
a
(CHO)n
5 - 7
2
10
b
(CHO)n
(CHO)n
N
H
HN
R
OH OH
11
12
11
12
18
N
N
15
17
13
N
N
11
N
N
13
13'
OH
13
R
12
12'
OH OH
12'
13'
11 - 14
5: R = R = Et; 6: R = Ph, R = Et; 7: R = R = CH CH OH; 11: R = N-Me; 12: R = N-Ph; 13: R = CH ; 14: R = O
8
9
1
2
1
2
1
2
2
2
2
a. HN-R R , (CHO) ; b. N-methyl-D-glucamine, (CHO)
1
2
n
n
Scheme 2
Reaction of amine 2 with formalin and diethylamine formed 5 in 87% yield. Its PMR spectrum (ppm) contained two
3H singlets for the gem-dimethyl group (at 0.87 and 0.98), a 6H triplet for two methyls at 1.06, a 4H quartet for ethyl methylenes
at 2.54–2.66, and two doublets (3.03, 3.53) for protons of the methylene linking the diethylamino and aziridine fragments, in
contrast with the spectrum of aziridine 2.
The yield of phenylethylamine 6 decreased by 10% as compared with diethylamine derivative 5. The yield increased
insignificantly to 89% for diethanolamine derivative 7.
270

Aminosugar derivative 8 was prepared by reacting aziridine 2 with formaldehyde and N-methyl-D-glucamine. The
reaction with pyrrolidine proceeded in high yield to give diamine 9. The reaction of piperazine with two equivalents of
aziridine 2 and formaldehyde produced symmetric bis-amine 10 (95% yield); with N-methylpiperazine, phenylpiperazine, and
piperidine, high yields of corresponding products 11–13, respectively. The reaction of aziridine 2 and formaldehyde with
morpholine gave the best aminoalkylation yield to form 14.
The synthesized compounds were tested for inhibition of HIV-1 (strain III ) and HIV-2 (strain ROD) replication in
B
acutely infected MT-4 cells with parallel determination of their cytotoxicity in these same cells. None of the tested compounds
affected replication of the viruses at concentrations lower than the cytotoxic ones (CC from 0.04 to 0.74 mM). Thus,
50
regioisomers 4a and 4b exhibited different cytotoxicities with CC values of 0.56 0.05 and 0.36 mM, respectively. Aziridine
50
2 was prepared from azide 4a and showed the lowest cytotoxicity of all studied compounds with CC = 0.74 0.06 mM. The
50
cytotoxicity of diethylamino derivative 5 was 2.5 times greater than that of starting 2. Replacing ethyl by phenyl increased the
cytotoxicity even more for 6, i.e., ~15 times greater than that of 2.
Compound 7 had cytotoxicity that was comparable with that of 6, was a diethanolamine derivative, and had the
highest cytotoxicity (CC = 0.04 0.01 mM) of the whole spectrum of compounds analyzed by us. Adding a pyrrolidine
50
substituent in 9 produced cytotoxicity comparable to that of 5. Piperazine derivatives 10, 11, and 12 had cytotoxicities inferior
to and significantly less than that of the pyrrolidine derivative. The toxicity of piperidine derivative 13 was comparable to that
of 10. The cytotoxicity of morpholine derivative 14 was only slightly greater than that of 2 and comparable to that of azide 4a.
Thus, the cytotoxicity of the aminoalkylated aziridines derived from (+)-3-carene with heteroorganic substituents increased on
going from a five-membered pyrrolidine ring to a six-membered piperidine ring and decreased sharply on replacing piperidine
by morpholine and increased on going to piperazine. Starting aziridine 2 and azide 4a had the lowest cytotoxicities.
EXPERIMENTAL
13
IR spectra were recorded on a PerkinElmer Spectrum 100 FTIR spectrometer. PMR and C NMR spectra were
taken from solutions (2–3%) with TMS internal standard on a Bruker Avance III spectrometer (400.13 and 100.61 MHz).
Specific rotation was measured on a Jacso-2000 automated polarimeter. Elemental analyses of the synthesized compounds
were recorded on an Elementar Vario LIII instrument. Column chromatography used silica gel (SiO , 40/63 μ, Fluka); preparative
2
TLC, Silpearl silica gel with UV indicator UV-254; and TLC, Silica gel F plates (Merck). Compounds were detected by
254
aqueous Ce [P(Mo O )] solution (5%).
3
12 40 4
Preparative TLC used Silpearl silica gel with UV indicator UV-254.
20
20
(+)-3-Carene (1), [α] +17.0° (neat); N-methyl-D-glucamine, [α] –16.5° (c 2, H O); and α-Al O (4–5 nm) were
D
D
2
2 3
purchased (Aldrich). Petroleum ether fraction 35–45°C was used.
XSA. Crystallographic structural data and experimental conditions given in the work were deposited in the Cambridge
Crystallographic Database (deposit@ccdc.cam.ac.uk) as a supplement (CCDC-1861493). The XSA was performed at 296 K
on a Stoe IPDS II diffractometer with monochromatic MoKα-radiation. The structure was solved by direct methods and
refined by anisotropic full-matrix least squares methods using the SHELXL-2014/6 program.
3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-azatricyclo[5.1.0 ]octane (2) was synthesized in 65% yield by the literature
method [13].
3.5
(1S,3S,5R,7R)-3,8,8-Trimethyl-4-oxatricyclo[5.1.0 ]octane (3) was synthesized in 97% yield by the literature
method [16].
(1R,3R,4R,6S)-4-Azido-4,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (4a) was synthesized in 74% yield by the literature
methods [15, 16].
(1S,3S,4S,6R)-4-Azido-3,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (4b) was synthesized in 30% yield by the literature
method [15].
General Aminoalkylation Method. A mixture of aziridine 2 (1.51 g, 10 mmol) in aqueous formalin (40%, 750 mg,
10 mmol) was stirred at room temperature, treated with secondary amine, stirred for 8 h, treated with benzene (50 mL), and
evaporated. The procedure was repeated four times. The resulting precipitate with R 0.3–0.4 (CH Cl –MeOH, 9:1) was
f
2
2
chromatographed on a flat glass plate (20 × 30 cm) with unattached Silpearl sorbent (2-mm layer) using various solvents as
mobile phases. The plate was eluted twice with CH Cl –MeOH (9:1). The sample was extracted by placing scraped sorbent
2
2
into a Schott glass filter, treating with MeOH, and removing the solvent to afford the sample for the studies.
271

3.5
N-Ethyl-N-{[(1S,3R,5S,7R)-3,8,8-trimethyl-4-azatricyclo[5.1.0.0 ]octan-4-yl]methyl}ethaneamine (5). Yield
20
–1
87%, yellow oil, [α] –7.80° (c 0.01, MeOH). IR spectrum (ν, cm ): 1065, 1100, 1207 (C-N), 1379 (Ìå Ñ), 2928 (N-CH -N).
D
2
2
1
Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.48–0.72 (2H, m, Í-1, 6), 0.56 (2H, m, Íα-2, Hβ-5), 0.87 (3H, s,
3
Í-8), 0.98 (3H, s, Í-9), 1.06 (6H, t, J = 7.0, Í-13, 13′), 1.21 (3H, s, Í-10), 1.29–1.35 (1H, m, Í-4), 1.87 (1H, dd, J = 15.3, 9.0,
13
Íα-5), 2.6 (4H, m, Í-12, 12′), 2.65–2.75 (1H, m, Hβ-2), 3.03 (1H, d, J = 11.7, Í-11), 3.53 (1H, d, J = 11.7, Í-11). C NMR
spectrum (100 MHz, CDCl , δ, ppm): 70.5 (ÑÍ , Ñ-11), 45.7 (ÑÍ , Ñ-12, 12′), 44.8 (ÑÍ, Ñ-4), 37.4 (Ñ, Ñ-3), 28.8 (ÑÍ ,
3
2
2
3
Ñ-9), 28.2 (ÑÍ , Ñ-2), 20.0 (ÑÍ , Ñ-5), 19.7 (ÑÍ, Ñ-1), 19.4 (ÑÍ, Ñ-6), 18.7 (Ñ, Ñ-7), 18.5 (ÑÍ , Ñ-10), 15.0 (ÑÍ , Ñ-8),
2
2
3
3
12.6 (2 ÑÍ , Ñ-13, 13′). C H N .
3
15 28 2
3.5
N-Ethyl-N-{[(1S,3R,5S,7R)-3,8,8-trimethyl-4-azatricyclo[5.1.0.0 ]octan-4-yl]methyl}aniline (6). Yield 78%,
20
–1
yellow oil, [α] +5.42° (c 0.01, MeOH). IR spectrum (ν, cm ): 1193, 1255 (C-N), 1374 (Ìå Ñ), 1504, 1598 (arom), 2928,
D
2
1
2926 (N-CH -N). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.58 (2H, m, Í-1, 6), 0.72 (2H, m, Íα-2, Hβ-5), 0.82
2
3
(3H, s, Í-8), 0.97 (3H, s, Í-9), 1.01 (3H, s, Í-10), 1.16 (3H, t, J = 7.0, Í-13), 1.91 (1H, dd, J = 15.0, 8.5, Íα-5), 2.19–2.37 (1H,
m, Íβ-2), 3.16 (2H, q, J = 7.1, Í-12), 3.73 (1H, d, J = 12.5, Í-11), 4.07 (1H, d, J = 12.5, Í-11), 6.60 (2H, d, J = 7.8, Í-15, 15′),
13
6.69 (1H, t, J = 7.3, Í-17), 6.87 (2H, m, Í-16, 16′). C NMR spectrum (100 MHz, CDCl , δ, ppm): 148.4 (Ñ, Ñ-14), 129.2
3
(ÑÍ, Ñ-16, 16′), 129.2 (CH, C-16,16′, 128.4 (CH, C-17), 112.8 (CH, Ñ-15, 15′), 77.2 (ÑÍ , Ñ-11), 44.7 (ÑÍ, Ñ-4), 44.3 (ÑÍ ,
2
2
Ñ-12), 38.4 (Ñ, Ñ-3), 28.7 (ÑÍ , Ñ-2), 20.4 (ÑÍ , Ñ-5), 20.1 (ÑÍ, Ñ-6), 19.9 (ÑÍ, Ñ-1), 19.1 (Ñ, Ñ-7), 18.4 (ÑÍ , Ñ-10), 14.9 (ÑÍ ,
2
2
3
3
Ñ-8), 12.7 (ÑÍ , Ñ-13). C H N .
3
19 28 2
3.5
2,2′-{[(1S,3R,5S,7R)-3,8,8-Trimethyl-4-azatricyclo[5.1.0.0 ]octan-4-yl]methyl}azanediyl)di(ethan-1-ol) (7).
20
–1
Yield 89%, yellow oil, [α] –7.58° (c 0.01, MeOH). IR spectrum (ν, cm ): 1042, 1160 (C-N), 1376 (Ìå Ñ), 2933 (N-CH -N),
D
2
2
1
3363 (ÎÍ). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.62 (2H, m, Í-1, 6), 0.74 (2H, m, Íβ-2, 5), 0.84 (3H, s,
3
Í-8), 0.99 (3H, s, Í-9), 1.32 (3H, s, Í-10), 1.94 (1H, dd, J = 7.7, 4.5, Í-4), 2.01 (1H, dd, J = 14.7, 7.6, Íα-5), 2.30 (1H, dt,
J = 18.3, 9.1, Íα-2), 2.69–2.75 (2H, m, Í-12, 12′), 2.98 (2H, dt, J = 6.8, 1.2, Í-12, 12′), 3.59–3.65 (2H, m, Í-13, 13′), 3.76 (2H, dt,
13
J = 6.5, 0.6, Í-13, 13′), 4.30 (2H, m, Í-11). C NMR spectrum (100 MHz, CDCl , δ, ppm): 86.9 (ÑÍ , Ñ-11), 63.2 (ÑÍ , Ñ-12),
3
2
2
60.5 (ÑÍ , Ñ-13′), 56.3 (ÑÍ , Ñ-13), 52.1 (ÑÍ , Ñ-12′), 38.0 (ÑÍ, Ñ-4), 35.7 (Ñ, Ñ-3), 28.5 (ÑÍ , Ñ-9), 27.1 (ÑÍ , Ñ-2), 26.4 (ÑÍ ,
2
2
2
3
2
3
Ñ-10), 21.7 (ÑÍ , Ñ-5), 21.2 (ÑÍ, Ñ-6), 20.9 (ÑÍ, Ñ-1), 19.8 (Ñ, Ñ-7), 14.7 (ÑÍ , Ñ-8). C H N O .
2
3
15 28 2 2
N-Methyl-N-(1S,3R,5S,7R)-3,8,8-trimethyl-4-{[(2S,3R,4R,5R)-aminoheptane-1,2,3,4,5-pentaol]
3.5
20
–1
methyl}azatricyclo [5.1.0.0 ]octane (8). Yield 74%, yellow oil, [α] +2.93° (c 0.01, MeOH). IR spectrum (ν, cm ): 1076,
D
1
1145,1197 (C-N), 1378 (Ìå Ñ), 2926 (N-CH -N), 3354 (ÎÍ). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.46–0.73
2
2
3
(2H, m, Í-1, 6), 0.82 (3H, s, Í-8), 0.96 (3H, s, Í-9), 1.06–1.24 (2H, m, Íβ-2, 5), 1.28 (3H, s, Í-10), 1.52 (1H, dd, J = 7.7, 4.3,
H-4), 2.24 (3H, s, Í-12), 2.27 (1H, d, J = 12.0, Íα-5), 2.34–2.48 (1H, m, Íα-2), 2.96 (1H, d, J = 12.0, Í-11), 3.47–4.07 (8H,
13
m, Í-13, 14, 15, 16, 17, 18), 4.13–4.67 (6H, m, H-11, 5-OH). C NMR spectrum (100 MHz, CDCl , δ, ppm): 86.5 (ÑÍ ,
3
2
Ñ-11), 77.2 (ÑÍ, Ñ-17), 73.4 (ÑÍ, Ñ-16), 70.7 (ÑÍ, Ñ-15), 67.1 (ÑÍ, Ñ-14), 63.3 (ÑÍ , Ñ-18), 59.2 (ÑÍ , Ñ-13), 40.4 (ÑÍ ,
2
2
3
Ñ-12), 38.2 (ÑÍ, Ñ-4), 35.9 (Ñ, Ñ-3), 28.5 (ÑÍ , Ñ-9), 27.0 (ÑÍ , Ñ-10), 26.2 (ÑÍ , Ñ-2), 21.6 (ÑÍ , Ñ-5), 21.2 (ÑÍ, Ñ-6),
3
3
2
2
20.9 (ÑÍ, Ñ-1), 20.0, 19.9 (Ñ, Ñ-7), 14.5 (ÑÍ , Ñ-8). C H N O .
3
18 34 2 5
3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-[(pyrrolidin-1-yl)methyl]-4-azatricyclo[5.1.0.0 ]octane (9). Yield 92%, yellow
20
–1
1
oil, [α] –16.50° (c 0.01, MeOH). IR spectrum (ν, cm ): (1098, 1145 (C-N), 1374 (Ñ(Ìå) ), 2927 (N-CH -N). Í NMR
D
2
2
spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.54 (2H, m, Í-1, 6), 0.83 (3H, s, Í-8), 0.84 (2H, m, Íβ-2, 5), 0.95 (3H, s, Í-9),
3
1.21 (3H, s, Í-10), 1.34 (1H, dd, J = 7.6, 4.3, Í-4), 1.69–1.78 (4H, m, Í-13, 13′), 1.87 (1H, dd, J = 15.0, 8.5, Íα-2), 2.21 (1H,
13
dt, J = 7.9, 5.0, Íα-5), 2.51–2.69 (4H, m, Í-12, 12′), 2.91, 3.51 (1H each, d, J = 10.0, Í-11). C NMR spectrum (100 MHz,
CDCl , δ, ppm): 73.2 (ÑÍ , Ñ-11), 51.1 (2 ÑÍ , Ñ-12, 12′), 45.0 (CH, Ñ-4), 38.4 (C, Ñ-3), 28.9 (CH , Ñ-2), 28.7 (CH , Ñ-9),
3
2
2
2
3
23.5 (2CH , Ñ-13, 13′), 20.4 (ÑÍ , Ñ-5), 20.0 (ÑÍ, Ñ-6), 19.9 (ÑÍ, Ñ-1), 19.1 (Ñ, Ñ-7), 18.1 (ÑÍ , Ñ-10), 15.0 (ÑÍ , Ñ-8).
2
2
3
3
C H N .
15 26
2
3,5
1,4-Bis{[(1S,3R,5S,7R)-3,8,8-trimethyl-4-azatricyclo[5.1.0 ]octan-4-yl]methyl}piperazine (10). Yield 95%,
whitish-yellow powder, mp 83–84°Ñ (hexane–Et O), [α] –12.71° (c 0.01, MeOH). IR spectrum (ν, cm ): 1096, 1153, 1164
(C-N), 1375 (Ìå Ñ), 2926 (N-CH -N). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.55 (4H, m, Í-1, 6, 1′, 6′), 0.78
20
–1
2
D
1
2
2
3
(4H, m, Íβ-2, 5, 2′, 5′), 0.83 (6H, s, Í-8, 8′), 0.96 (6H, s, Í-9, 9′), 1.21 (6H, s, Í-10, 10′), 1.34 (2H, dd, J = 7.6, 4.4, Í-4, 4′),
1.87 (2H, dd, J = 15.0, 8.4, Íα-2, 2′), 2.22 (2H, dt, J = 16.9, 8.1, Íα-5, 5′), 2.55 (8H, m, Í-12, 12′, 13, 13′), 2.85 (2H, d,
13
J = 10.6, Í-11, 11′), 3.42 (2H, d, J = 10.5, Í-11, 11′). C NMR spectrum (100 MHz, CDCl , δ, ppm): 76.5 (2 ÑÍ , Ñ-11, 11′),
3
2
50.9 (4 ÑÍ , Ñ-12, 12′, 13, 13′), 45.4 (2ÑÍ, Ñ-4, 4′), 38.4 (2 Ñ, Ñ-3, 3′), 29.0 (2 ÑÍ , Ñ-2, 2′), 28.6 (2 ÑÍ , Ñ-9, 9′), 20.5
2
2
3
(2 ÑÍ , Ñ-5, 5′), 20.1 (2 ÑÍ, Ñ-6, 6′), 20.0 (2ÑÍ, Ñ-1, 1′), 19.2 (2 Ñ, Ñ-7, 7′), 18.0 (2 ÑÍ , Ñ-10, 10′), 15.0 (2 ÑÍ , Ñ-8, 8′).
2
3
3
C H N .
26 44
4
272

3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-[(4-methylpiperazin-1-yl)methyl]-4-azatricyclo[5.1.0.0 ]octane (11). Yield
20
–1
88%, yellow oil, [α] –9.96° (c 0.02, MeOH). IR spectrum (ν, cm ): 1099, 1157, 1170 (C-N), 1375 (Ìå Ñ), 2926 (N-CH -N).
D
2
2
1
Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.52 (2H, m, Í-1, 6), 0.76 (2H, m, Íβ-2, 5), 0.78 (3H, s, Í-8), 0.91 (3H,
3
s, Í-9), 1.16 (3H, s, Í-10), 1.27 (1H, dd, J = 7.6, 4.2, Í-4), 1.82 (1H, dd, J = 15.1, 8.5, Íα-2), 2.15 (1H, dd, J = 15.3, 8.1,
Íα-5), 2.22 (3H, s, Ìå-14), 2.37 (4H, m, Í-13, 13′), 2.56 (4H, m, Í-12, 12′), 2.82, 3.37 (1H each, d, J = 10.5, Í-11).
13
C NMR spectrum (100 MHz, CDCl , δ, ppm): 76.26 (ÑÍ , Ñ-11), 54.96 (2 ÑÍ , Ñ-12, 12′), 50.43 (2 ÑÍ , Ñ-13, 13′), 46.02
3
2
2
2
(ÑÍ , Ñ-14), 45.29 (ÑÍ , Ñ-4), 38.25 (Ñ, Ñ-3), 28.91 (ÑÍ , Ñ-2), 28.62 (ÑÍ , Ñ-9), 20.37 (ÑÍ , Ñ-5), 20.01 (ÑÍ, Ñ-6),
3
2
2
3
2
19.96 (ÑÍ, Ñ-1), 19.12 (Ñ, Ñ-7), 18.02 (ÑÍ , Ñ-10), 14.94 (ÑÍ , Ñ-8). C H N .
3
3
16 29 3
3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-[(4-phenylpiperazin-1-yl)methyl]-4-azatricyclo[5.1.0.0 ]octane (12). Yield
20
–1
86%, yellow oil, [α] –10.83° (c 0.01, MeOH). IR spectrum (ν, cm ): 1128, 1141, 1234 (C-N), 1379 (Ìå Ñ), 1452, 1509,
D
2
1
1600 (arom.), 2922 (N-CH -N). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.50–0.73 (2H, m, Í-1, 6), 0.87 (3H, s,
2
3
Í-8), 0.88 (2H, m, Íβ-2, 5), 0.99 (3H, s, Í-9), 1.26 (3H, s, Í-10), 1.40 (1H, dd, J = 7.6, 4.4, Í-4), 1.92 (1H, dd, J = 15.0, 8.5,
Íα-2), 2.25 (1H, dt, J = 15.9, 8.0, Íα-5), 2.65–2.82 (4H, m, Í-13, 13′), 2.95 (1H, d, J = 10.6, Í-11), 3.23 (4H, m, Í-12, 12′),
3.49 (1H, d, J = 10.6, Í-11), 6.84 (1H, t, J = 7.2, Í-17), 6.94 (2H, d, J = 8.2, Í-15, 15′), 7.26 (2H, t, J = 7.2, Í-16, 16′).
13
C NMR spectrum (100 MHz, CDCl , δ, ppm): 151.5 (Ñ, Ñ-14), 129.0 (2 ÑÍ, Ñ-15, 15′), 119.4 (ÑÍ, Ñ-17), 116.0 (2 ÑÍ,
3
Ñ-16, 16′), 76.4 (ÑÍ , Ñ-11), 50.7 (2 ÑÍ, Ñ-13, 13′), 49.1 (2 ÑÍ , Ñ-12, 12′), 45.3 (ÑÍ, Ñ-4), 38.4 (Ñ, Ñ-3), 28.9 (ÑÍ , Ñ-2),
2
2
2
28.7 (ÑÍ , Ñ-9), 20.4 (ÑÍ , Ñ-5), 20.0 (ÑÍ, Ñ-6), 19.9 (ÑÍ, Ñ-1), 19.1 (Ñ, Ñ-7), 18.1 (ÑÍ , Ñ-10), 15.0 (ÑÍ , Ñ-8). C H N .
3
2
3
3
21 31 3
3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-[(piperidin-1-yl)methyl]-4-azatricyclo[5.1.0.0 ]octane (13). Yield 91%, yellow
20
–1
1
oil, [α] –8.60° (c 0.01, MeOH). IR spectrum (ν, cm ): 1093, 1120 (C-N), 1377 (Ìå Ñ), 2929 (N-CH -N). Í NMR
D
2
2
spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 0.6 (2H, m, Í-1, 6), 0.84 (3H, s, Í-8), 0.85 (2H, m, Íβ-2, 5), 0.95 (3H, s, Í-9),
3
1.17 (3H, s, Í-10), 1.38 (2H, m, Í-4, 14), 1.55 (4H, m, Í-13, 13′), 1.84 (1H, dd, J = 15.0, 8.5, Íα-2), 2.18 (1H, td, J = 12.4,
13
9.9, Íα-5), 2.40–2.58 (4H, m, Í-12, 12′), 2.82, 3.38 (1H each, d, J = 10.8, Í-11). C NMR spectrum (100 MHz, CDCl , δ,
3
ppm): 77.0 (ÑÍ , Ñ-11), 51.8 (2 ÑÍ , Ñ-12, 12′), 45.3 (ÑÍ, Ñ-4), 38.0 (Ñ, Ñ-3), 28.7 (ÑÍ , Ñ-2), 28.5 (ÑÍ , Ñ-9), 25.8
2
2
2
3
(2 ÑÍ , Ñ-13, 13′), 24.3 (ÑÍ , Ñ-5), 20.3 (ÑÍ , Ñ-14), 19.8 (ÑÍ, Ñ-6), 19.9 (ÑÍ, Ñ-1), 19.1 (Ñ, Ñ-7), 15.0 (ÑÍ , Ñ-8). C H N .
2
2
2
3
16 28 2
3.5
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-[(morpholin-1-yl)methyl]-4-azatricyclo[5.1.0.0 ]octane (14). Yield 94%, yellow
20
–1
1
oil, [α] –8.46° (c 0.01, MeOH). IR spectrum (ν, cm ): 1071, 1115 (C-N), 1375 (Ìå Ñ), 2926 (N-CH -N). Í NMR spectrum
D
2
2
(400 MHz, CDCl , δ, ppm, J/Hz): 0.44–0.68 (2H, m, Í-1, 6), 0.82 (3H, s, Í-8), 0.84 (2H, m, Íβ-2, 5), 0.96 (3H, s, Í-9), 1.19
3
(3H, s, Í-10), 1.34 (1H, dd, J = 7.5, 4.1, Í-4), 1.86 (1H, dd, J = 15.0, 8.5, Íα-2), 2.20 (1H, dt, J = 15.8, 7.9, Íα-5), 2.41–2.63
13
(4H, m, Í-12, 12′), 2.83, 3.37 (1H each, d, J = 10.3, Í-11), 3.69 (4H, t, J = 4.6, Í-13, 13′). C NMR spectrum (100 MHz,
CDCl , δ, ppm): 76.7 (ÑÍ , Ñ-11), 66.9 (2 ÑÍ , Ñ-13, 13′), 51.1 (ÑÍ , Ñ-12, 12′), 45.3 (ÑÍ, Ñ-4), 38.3 (Ñ, Ñ-3), 28.8 (ÑÍ ,
3
2
2
2
2
Ñ-2), 28.6 (ÑÍ , Ñ-9), 20.3 (ÑÍ , Ñ-5), 19.9 (ÑÍ, Ñ-1), 19.9 (ÑÍ, Ñ-6), 19.1 (Ñ, Ñ-7), 15.0 (ÑÍ , Ñ-8). C H N O.
3
2
3
15 26 2
ACKNOWLEDGMENT
We thank the Science and Technology Center of Ukraine (STCU) and the National Agency for Research and
Development (ANCD) of the Republic of Moldova for financial support under Project 17.80013.8007.10/6245STCU.
We thank Dr. Denis Prodius for performing the XSA and Kristen Ervin for carrying out the biotesting.
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