Synthesis of betulonic acid amides

Article abstract of DOI:10.1007/s10600-008-9054-7

Betulonic acid amides of interest as potential biologically active compounds were prepared.

Full text of DOI:10.1007/s10600-008-9054-7

Chemistry of Natural Compounds, Vol. 44, No. 3, 2008
SYNTHESIS OF BETULONIC ACID AMIDES
A. N. Antimonova, N. V. Uzenkova, N. I. Petrenko,*
UDC 547.597+547.233+
542.953+543.42
M. M. Shakirov, E. E. Shul ts, and G. A. Tolstikov
′
Betulonic acid amides of interest as potential biologically active compounds were prepared.
Key words:
betuloic acid, amides, NMR spectra.
Derivatives of betulonic acid containing various substituents on C-28 are known to possess various types of biological
activity [1, 2]. Thus, amides, peptides, and hydrazides of betulonic acid exhibit antiviral (including anti-HIV) [3-5],
immunostimulating [5], and antitumor activity [6]. It was demonstrated [7] that derivatives of betulonic acid containing
ω-amino acids are active indicators of apoptosis in leucocytes and hepatocarcinoma cells in vitro. Furthermore, amides
containing β-alanine exhibit antioxidant activity and can lower the toxicity of antitumor preparations [8]. In the search for
biologically active compounds, we synthesized new amides of betulonic acid for subsequent studies of their pharmacological
properties.
The reaction of betulonic acid chloride 1 with various amines produced compounds 2a-n with the corresponding
secondaryor tertiaryamine group on C-28 (Scheme 1). The reaction was carried out at room temperature in anhydrous CH Cl
2
2
in the presence of triethylamine. The yields of products were 70-89%. The isolated betulonic acid amides were
chromatographed over Al O in order to obtain analyticallypure samples. Amide 3 with the methyl ester of α-alanine on C-28,
2
3
alkaline hydrolysis of which smoothly gave amino-acid derivative 4, was synthesized analogously (Scheme 1).
29
20
19 21
30
26
13
27
11
O
O
25
17
15
C
C28
Amine
1
9
Cl
R
2a - n
, 70 - 89%
3
CH Cl , Et N, 20° C, 48 h
2
2
3
5
7
O
O
1
23
24
⋅
HCl NH CH(CH )COOCH
2
3
3
O
CH Cl , Et N, 20° C
2
2
3
C
O
O
4M NaOH
C
N
O
N
H
1'
4'
2'
THF + MeOH, 20°C
OH
H
1'
2'
OCH
3
O
3'CH
3
O
3'CH
3
4
, 98%
3
, 70%
7''
H CO
3
2''
3'
5'
1'
3'
1'
5'
3'
3'
5' N
1'
1'
NH
N
O
a:
b:
i:
j:
l:
R =
R =
R = NHCH CH CH CH
R =
R =
e:
f:
N
R =
2
2
2
3
1'
1'
N
9'
7'
5'
3'
5'
1'
N
N3'
N
1'O
NH
R =
R = NHCH CH CH
m:
2
2
2
3'
3'
3'
5'
5'
4'
1'
6'
2'
g:
h:
O
1'
R = NHCH
c:
R = NHCH CH Ph
2
2
2
1'
N
7'
7'
3'
1'
1'
5'
3'
3'
k:
R = NHCH
2
NH
n:
R =
CH Ph
d:
R =
R = NHCH Ph
2
2
5'
N 1'
Scheme 1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
630090, Novosibirsk, prosp. Akad. Lavrent′eva, 9, Russia, fax(383)3309752, e-mail:petrenko@nioch.nsc.ru. Translatedfrom
Khimiya Prirodnykh Soedinenii, No. 3, pp. 259-264, May-June, 2008. Original article submitted March 7, 2008.
0009-3130/08/4403-0327 ©2008 Springer Science+Business Media, Inc.
327

TABLE 1. 13C NMR Spectra of Amides 2a-n, 3, 4 (δ, ppm)
C atom
2a
2b
2c
2d
2e
2f
2g
2h
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
39.46 t
33.93 t
217.74 d
47.10 s
54.85 d
19.46 t
33.57 t
40.56 s
39.47
33.92
217.76
47.08
54.90
19.46
33.51
40.41
39.43
33.95
217.98
47.12
54.81
19.44
33.47
40.47
39.42
33.85
217.56
47.01
54.85
19.42
33.46
40.37
39.43
33.88
217.70
47.05
54.85
19.47
33.48
40.39
39.44
33.91
217.61
47.07
54.86
19.47
33.57
40.54
39.38
33.89
217.98
47.06
54.71
19.40
33.47
40.41
40.43
49.73
49.75
36.65
21.21
21.24
25.36
25.38
37.50
37.53
42.28
42.37
29.11
29.17
33.40
55.37
55.47
49.71
49.87
46.40
46.49
150.67
30.58
30.62
38.16
38.20
26.36
20.76
15.72
15.74
15.61
15.69
14.30
14.31
175.94
175.97
109.13
19.22
39.40
33.86
217.75
47.03
54.75
19.43
33.38a
40.46
C-9
49.83 d
50.05
49.78
50.01
49.97
49.85
49.78
C-10
C-11
36.74 s
21.32 t
36.74
21.52
36.71
21.23
36.69
21.47
36.70
21.44
36.74
21.31
36.66
21.25
C-12
C-13
C-14
C-15
25.48 t
37.69 d
42.33 s
29.19 t
25.52
36.80
41.74
29.66
25.39
37.53
42.30
29.15
25.47
36.75
42.75
29.61
25.43
36.75
41.71
29.54
25.46
37.51
42.32
29.25
25.44
37.48
42.28
29.17
C-16
C-17
33.57 t
55.22 s
33.51
54.44
33.47
55.42
33.46
54.40
33.48
54.24
33.57
55.29
33.49a
55.35
C-18
C-19
49.96 d
46.67 d
52.59
45.49
49.78
46.49
52.52
45.44
52.36
45.37
49.97
46.44
49.92
46.35
C-20
C-21
150.76 s
30.75 t
151.24
31.22
150.64
30.60
151.11
31.18
150.84
31.06
150.71
30.72
150.62
30.64
C-22
38.27 t
35.72
38.12
35.68
35.60
38.22
38.13
C-23
C-24
C-25
26.44 q
20.81 q
15.80a q
26.42
20.79
15.76a
26.40
20.83
15.78a
26.40
20.75
15.72
26.39
20.77
15.73a
26.44
20.81
15.71
26.41
20.77
15.70
C-26
C-27
C-28
15.74a q
14.38 q
174.90 t
15.71a
15.74a
14.32
15.66
14.35
15.67a
14.35
15.86
14.35
15.70
14.31
14.39
172.97
175.88
172.98
173.39
175.95
175.70
C-29
C-30
C-1′
C-2′
109.09 t
19.33 q
47.52 d
32.76b t
108.79
19.51
109.21
19.26
35.66
40.11
108.81
19.48
109.03
19.49
109.10
19.30
109.12
19.28
42.96
44.45a
32.05b
32.25
26.02
24.56
26.02
66.71
32.14
66.63
53.68
77.77
77.90
28.22
28.29
25.63
25.69
67.84
67.89
C-3′
C-4′
C-5′
24.73c t
25.48 t
24.80c t
38.16
32.36b
44.85a
32.14
53.68
328

TABLE 1. (continued)
C atom
2a
2b
2c
2d
2e
2f
2g
2h
C-6′
C-7′
C-8′
C-9′
Ar
33.08b t
32.25
42.75
66.71
66.63
57.78
25.03
38.80
42.25
126.28
128.43
128.51
138.92
125.72
127.98
128.78
139.76
126.94
127.40
128.30
139.05
C atom
2i
2j
2k
2l
2m
2n
3
4
C-1
C-2
C-3
C-4
C-5
C-6
C-7
39.38
33.83
217.63
46.99
54.76
19.40
33.48
39.47
33.92
217.67
47.08
54.85
19.46
33.57
39.38
33.86
217.85
47.02
54.72
19.39
33.28a
39.44
33.88
217.67
47.05
54.87
19.42
33.49
39.36
33.80
217.51
47.01
54.69
19.30
33.27
39.49
34.00
217.77
47.17
54.86
19.47
33.54a
39.15
33.66
217.51
46.83
54.49
19.15
33.07
39.38
33.86
218.86
47.11
54.71
19.40
33.38
33.42
40.47
49.72
36.66
21.22
25.38
37.54
37.59
42.26
42.32
29.08
29.13
33.26
33.32
55.39
49.66
49.78
46.38
150.37
150.43
30.49
30.55
37.85
38.17
26.41
20.78
15.71
15.51
15.59
14.30
14.33
C-8
C-9
C-10
C-11
C-12
C-13
40.45
49.77
36.65
21.24
25.41
37.50
40.56
49.86
36.74
21.32
25.50
37.58
40.44
49.74
36.65
21.23
25.40
37.47
40.41
50.01
36.71
20.77
25.48
36.77
40.33
49.74
36.63
21.23
25.20
36.76
40.56
49.84
36.76
21.31
25.47
37.65
40.21
49.49
36.42
20.96
25.12
37.18
37.28
41.99
42.06
28.78
28.88
33.13
33.19
55.05
49.44
49.55
46.13
150.30
150.36
30.26
30.32
37.58
37.90
26.13
20.53
15.48
15.28
15.39
14.04
14.09
C-14
C-15
C-16
42.25
29.15
33.48
42.34
29.48
33.57
42.25
29.15
33.44a
41.73
29.58
33.49
41.89
29.42
32.82
42.35
29.19
33.68a
C-17
C-18
55.27
49.90
55.27
50.00
55.37
49.87
54.36
52.47
57.37
51.13
55.19
49.93
C-19
C-20
46.42
150.67
46.53
150.76
46.30
150.46
45.42
150.99
44.93
149.40
46.64
150.84
C-21
C-22
30.64
38.17
30.74
38.28
30.60
38.04
31.13
35.75
30.37
36.63
30.75
38.16
C-23
C-24
C-25
C-26
26.39
20.72
15.66
15.66
26.45
20.80
15.75
15.75
26.40
20.74
26.40
21.48
15.73
15.73
26.30
20.72
15.71
15.48
26.44
20.86
15.70b
15.58b
15.76b
15.79b
C-27
14.28
14.36
14.28
14.38
14.33
14.41
329

TABLE 1. (continued)
C atom
C-28
2i
2j
2k
2l
2m
2n
3
4
175.69
175.07
176.13
173.25
172.61
175.5
175.28
175.49
108.88
108.97
18.98
19.03
47.34
176.21
176.51
109.24
109.32
19.22
C-29
C-30
C-1′
C-2′
C-3′
C-4′
108.99
19.25
38.63
31.67
19.87
13.49
109.06
19.35
109.18
19.26
108.93
19.49
109.93
19.15
109.16
19.35
19.25
20.15
20.45
45.80
45.82
29.16
29.24
10.31
39.49
47.70
47.60
32.30
50.75
137.24
32.73c
23.59d
23.62d
33.09c
173.40
173.42
17.51
17.83
51.87
51.91
176.81
176.85
17.49
17.83
129.56
117.32
C-5′
C-6′
C-7′
C-7′′
Ar
50.75
32.30
40.44
55.19
111.28
118.08
120.82
123.14
140.53
152.05
123.26
134.93
135.44
148.18
148.72
______
a,b,c,dChemical shifts denoted with the same letters could possibly be switched within the same column.
TABLE 2. Physical Chemical Properties and Yields of 2a-n, 3, 4
M+
Compound
Yield, %
[α], deg, (c)
Empirical formula
found
calc.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
3
74
84
72
87
73
75
86
80
70
85
83
77
89
78
70
+22 (3.6)
+21 (5.2)
+31 (5.3)
+8 (3.6)
+23 (4.2)
+26 (3.6)
+33 (4.5)
+43 (4.8)
+29 (4.1)
+29 (3.5)
+26 (4.3)
+21 (3.4)
+7 (4.5)
C36H57NO2
C35H55NO2
C38H55NO2
C42H61NO2
C34H53NO3
C37H60N2O3
C35H55NO3
C37H53NO2
C34H55NO2
C34H55NO2
C36H52N2O2
C41H60N2O3
C33H48N2O2
C35H55NO2
C34H53NO4
C33H51NO4
535.43718
521.42281
557.42227
611.46932
523.40126
580.46206
537.42134
543.40625
509.42338
509.42404
544.40151
628.45614
409.34248*
521.42281
539.39779
525.38163
535.43890
521.42326
557.42326
611.47020
523.40252
580.46037
537.41817
543.40761
509.42326
509.42326
544.40286
628.46037
409.34702*
521.42326
539.39743
525.38178
+30 (5.1)
+30 (4.4)
+36 (3.7)
4
98
2C8
O
*Fragment ion M −
N
N
330

The compositions and structures of 2a-n, 3, and 4 were confirmed by elemental analysis and mass, IR, and NMR
spectra. Thus, IR spectra of the synthesized compounds lacked an absorption band at 1804 cm−1 corresponding to carbonyl
stretching vibrations ofCOCl and contained bands for stretching vibrations ofCONHin the range 1625-1644 cm−1 (amide band
13
I) and 3346-3489 cm−1 (trans-associated NH). PMR and C NMR spectra of 2a-n, 3, and 4 agreed completely with their
structures. Resonances of H and C atoms in NMR spectra of 2a-n, 3, and 4 were assigned based on two-dimensional NMR
spectra of 2d, f, g, i, m, and 4 using literature data for betulonic acid and its amino-acid derivatives [9, 10]. We verified the
resonances for H-2′ (8.23 ppm) and H-4′ (7.00 ppm) (protons of the imidazole ring) of 2m, for which chemical shifts at 7.01
and 8.25 ppm, respectively, were assigned [11]. Resonances of certain atoms in the NMR spectra of 2g, j, 3, and 4 were doubled
because we used the corresponding amines, including the methyl ester of α-alanine, as a mixture of optical isomers (D and L).
13
Table 1 lists the C NMR spectra of 2a-n.
EXPERIMENTAL
NMR spectra in CDCl were recorded on Bruker AC-200 and AM-400 instruments at operating frequencies 200.13
3
1
13
13
and 400.13 MHz for H and 50.32 and 100.61 MHz for C. The multiplicity of signals in C NMR spectra was determined
by standard procedures for recording spectra with J-modulation (JMOD) and with off-resonance proton decoupling. 2D NMR
1
1
13
1
H— H (COSY) and C— H (COSY 125 Hz, COLOC 7 Hz) spectra of 2d, e, g, h, j, and n in CDCl were recorded on a
3
1
13
Bruker DRX-500 instrument at operating frequency 500.13 MHz for H and 125.76 MHz for C using standard Bruker
programs. The internal standards were resonances of CDCl solvent (δ 76.90) and residual protons (δ 7.24 ppm). Mass
3
C
H
spectra were obtained in a Finnigan MAT 8200 high-resolution mass spectrometer at ionizing potential 70 eV. Specific rotation
([α] ) was measured on a Polamat A polarimeter in CHCl at room (20-25°C) temperature. Elemental analyses were
580
3
performed on a Carlo Erba 1106 CHN-analyzer.
The course ofreactions and purityofproducts were monitored using TLC on Silufol UV-254 plates and CHCl :CH CN
3
3
(30:1) for 2a-c, d, g, h-i, m, n, 3, and 4; CHCl :CH OH (20:1), 2e-f and j-l. Spots were developed by spraying with H SO
3
3
2
4
(20%) followed by heating to 100°C.
Betulonic acid chloride (1) was prepared by the literature method [9]. Table 2 lists the physical chemical properties
of 2a-n, 3, and 4 (yields, constants, mass spectra). The compounds were obtained as amorphous powders. Elemental analyses
of 2a-n, 3, and 4 agreed with those calculated.
General Method for Synthesizing Amides 2a-n, 3. A solution of betulonic acid chloride (1, 1 g, 2.12 mmol) in dry
CH Cl (60 mL) was treated with amine (4.24 mmol) and distilled triethylamine (8.48 mmol, 1.19 mL). The mixture was stored
2
2
at room temperature for 48 h, periodically stirred, washed with HCl (10%) and water, dried over anhydrous MgSO , and
4
evaporated. The resulting compound was chromatographed over Al O (activity II) using CH Cl and dried over P O .
2
3
2
2
2 5
N-[3-Oxolup-20(29)-en-28-oyl]cyclohexylamine (2a). PMR spectrum (δ, ppm, J/Hz): 0.86 (3H, s, Me), 0.91 (3H, s,
Me), 0.92 (3H, s, Me), 0.95 (3H, s, Me), 1.00 (3H, s, Me), 1.61 (3H, s, Me-30), 3.10 (1H, td, J = 11.2, J = 3.8, H-19), 3.69
1
2
(1H, m, H-1′), 4.52 and 4.67 (2H, both br.s, H-29), 5.43 (1H, d, J = 8.3, CONH) (only characteristic proton resonances are
given).
N-[3-Oxolup-20(29)-en-28-oyl]piperidine (2b). PMR spectrum (δ, ppm): 0.85 (3H, s, Me), 0.90 (3H, s, Me), 0.91
(3H, s, Me), 0.94 (3H, s, Me), 0.99 (3H, s, Me), 1.61 (3H, s, Me-30), 2.91 (2H, m, H-13,19), 3.45 (4H, m, H-2′,2′,6′,6′), 4.50
and 4.65 (2H, both br.s, H-29) (only characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]-2-phenylethylamine (2c). IRspectrum (KBr, ν, cm−1): 1639 (CONH), 1704 (C=O),
3392 (CONH). PMR spectrum (δ, ppm, J/Hz): 0.88 (3H, s, Me), 0.91 (6H, s, 2Me), 0.98 (3H, s, Me), 1.02 (3H, s, Me), 1.63
(3H, s, Me-30), 2.40 (3H, m, H-2,1′,1′), 2.78 (2H, m, H-2,13), 3.20 (1H, td, J = 11.9, J = 4.8, H-19), 3.48 (2H, m, H-2′,2′),
1
2
4.54 and 4.68 (2H, both br.s, H-29), 5.66 (1H, t, J = 5.3, CONH), 7.15-7.29 (5H, m, Ph) (only characteristic proton resonances
are given).
N-[3-Oxolup-20(29)-en-28-oyl]-4-benzylpiperidine (2d). PMR spectrum (δ, ppm, J/Hz): 0.89 (3H, s, Me-25), 0.91
(1H, m, H-12), 0.93 (3H, s, Me-27), 0.95 (3H, s, Me-26), 0.99 (3H, s, Me-24), 1.03 (3H, s, Me-23), 1.07 (2H, m, H-3′,5′), 1.13
(1H, m, H-15), 1.24-1.46 (12H, m, H-1,5,6,6,7,7,9,11,11,15,21,22), 1.46 (1H, m, H-16), 1.52 (1H, t, J = 11.2, H-18), 1.60-1.76
(4H, m, H-12,3′,4′,5′), 1.65 (3H, s, Me-30), 1.85 (2H, m, H-1,21), 1.92 (1H, m, H-22), 2.07 (1H, dt, J = 13.3, J = 3.4, H-16),
1
2
2.36 (1H, m, H-2), 2.43 (1H, m, H-2), 2.51 (2H, d, J = 7.2, H-7′), 2.64 (2H, m, H-2′,6′), 2.92 (1H, ddd, J = 13.1, J = 11.4,
1
2
331

J = 3.6, H-13), 2.97 (1H, td, J = 11.0, J = 3.9, H-19), 4.32 (2H, m, H-2′,6′), 4.54 and 4.69 (2H, both br.s, H-29), 7.09 (2H,
3
1
2
m, 2H ), 7.15 (1H, m, H ), 7.23 (2H, m, 2H ).
o
p
m
N-[3-Oxolup-20(29)-en-28-oyl]morpholine (2e). PMR spectrum (δ, ppm): 0.85 (3H, s, Me), 0.91 (6H, s, 2Me), 0.96
(3H, s, Me), 0.99 (3H, s, Me), 1.61 (3H, s, Me-30), 2.88 (2H, m, H-13,19), 3.55 (8H, m, H-2′,2′,3′,3′,5′,5′,6′,6′), 4.51 and 4.65
(2H, both br.s, H-29) (only characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]-3-morpholinopropylamine (2f). IR spectrum (KBr, ν, cm−1): 1638 (CONH),
1699 (C=O), 3357, 3489 (CONH). PMR spectrum (δ, ppm, J/Hz): 0.83 (3H, s, Me-25), 0.89 (6H, s, Me-26,27), 0.91 (1H,
m, H-12), 0.93 (3H, s, Me-24), 0.98 (3H, s, Me-23), 1.07 (1H, dt, J = 13.2, J = 3.2, H-15), 1.15-1.52 (14H, m,
1
2
H-1,5,6,6,7,7,9,11,11,15,16,18,21,22), 1.59 (3H, s, Me-30), 1.60-1.68 (4H, m, H-12,22,8′,8′), 1.82 (1H, m, H-1), 1.87 (1H, m,
H-21), 1.90 (1H, m, H-16), 2.31 (1H, m, H-2), 2.35-2.43 (7H, m, H-2,3′,3′,5′,5′,7′,7′), 2.46 (1H, ddd, J = 13.0, J = 11.5,
1
2
J = 3.8, H-13), 3.07 (1H, td, J = 11.2, J = 4.5, H-19), 3.24 (2H, td, J = 6.4, J = 5.1, H-9′,9′), 3.64 (4H, t, J = 4.7,
3
1
2
1
2
H-2′,2′,6′,6′), 4.50 and 4.65 (2H, both br.s, H-29), 6.76 (1H, t, J = 5.1, CONH).
N-[3-Oxolup-20(29)-en-28-oyl]tetrahydrofurfurylamine (2g). PMR spectrum (δ, ppm, J/Hz): 0.86 (3H, s, Me-25),
0.91 (6H, s, Me-26,27), 0.93 (1H, m, H-12), 0.95 (3H, s, Me-24), 1.00 (3H, s, Me-23), 1.11 (1H, m, H-15), 1.18-1.55 (15H, m,
H-1,5,6,6,7,7,9,11,11,15,16,18,21,22,3′), 1.62(3H, s, Me-30), 1.63-1.75(2H,m,H-12,22),1.79-1.95(6H, m, H-1,16,21,4′,4′,3′),
2.33 (1H, m, H-2), 2.42 (2H, m, H-2,13), 3.07 (1H, m, H-19), 3.07, 3.17, 3.45, 3.53 (2H, m, H-6′,6′), 3.69 and 3.79 (2H, m,
H-5′,5′), 3.89 (1H, m, H-2′), 4.52 and 4.67 (2H, both br.s, H-29), 5.92 and 5.95 (1H, t, J = 7.1, CONH).
N-[3-Oxolup-20(29)-en-28-oyl]benzylamine (2h). PMR spectrum (δ, ppm, J/Hz): 0.86 (3H, s, Me), 0.88 (3H, s, Me),
0.92 (3H, s, Me), 0.96 (3H, s, Me), 1.01 (3H, s, Me), 1.64 (3H, s, Me-30), 3.13 (1H, td, J = 11.2, J = 3.5, H-19), 4.35 (2H,
1
2
ABX, J = 15.1, J = 5.8, H-1′,1′), 4.54 and 4.68 (2H, both br.s, H-29), 6.19 (1H, t, J = 4.6, CONH), 7.23 (5H, m, Ph) (only
1
2
characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]-n-butylamine (2i). PMR spectrum (δ, ppm, J/Hz): 0.84 (3H, s, Me-25), 0.85 (3H,
t, J = 10.3, Me-4′), 0.90 (6H, s, Me-26,27), 0.92 (1H, m, H-12), 0.94 (3H, s, Me-24), 0.99 (3H, s, Me-23), 1.09 (1H, m, H-15),
1.15-1.45 (17H, m, H-1,5,6,6,7,7,9,11,11,15,16,21,22,2′,2′,3′,3′), 1.49 (1H, m, H-18), 1.60 (3H, s, Me-30), 1.66 (2H, m,
H-12,22), 1.82 (1H, m, H-1), 1.88 (2H, m, H-16,21), 2.32 (1H, m, H-2), 2.42 (2H, m, H-2,13), 3.08 (2H, m, H-19,1′), 3.22 (1H,
m, H-1′), 4.51 and 4.65 (2H, both br.s, H-29), 5.73 (1H, t, J = 5.3, CONH).
N-[3-Oxolup-20(29)-en-28-oyl]-sec-butylamine (2j). IRspectrum (KBr, ν, cm−1): 1625 (CONH), 1709 (C=O), 3346
(CONH). PMR spectrum (δ, ppm, J/Hz): 0.85 (3H, s, Me), 0.91 (3H, s, Me), 0.92 (3H, s, Me), 0.95 (3H, s, Me), 0.99 (3H, s,
Me), 1.61 (3H, s, Me-30), 3.09 (1H, td, J = 12.1, J = 3.8, H-19), 3.83 (1H, m, H-2′), 4.51 and 4.65 (2H, both br.s, H-29), 5.34
1
2
(1H, d, J = 8.1, CONH) (only characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]pyridin-3-yl-methylamine (2k). PMRspectrum (δ, ppm, J/Hz): 0.79(3H, s, Me), 0.81
(3H, s, Me), 0.88 (3H, s, Me), 0.92 (3H, s, Me), 0.96 (3H, s, Me), 1.59 (3H, s, Me-30), 3.06 (1H, td, J = 12.2, J = 3.8, H-19),
1
2
4.33 (2H, ABX, J = 15.5, J = 5.6, H-7′,7′), 4.51 and 4.65 (2H, both br.s, H-29), 6.55 (1H, t, J = 4.6, CONH), 7.16, 7.58, 8.41
1
2
(1H, 1H, 2H, heterocycle) (only characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]-4-(2-methoxyphenyl)piperazine (2l). PMR spectrum (δ, ppm, J/Hz): 0.87 (3H, s,
Me), 0.93 (3H, s, Me), 0.94 (3H, s, Me), 0.96 (3H, s, Me), 1.01 (3H, s, Me), 1.64 (3H, s, Me-30), 2.96 (6H, m,
H-13,19,3′,3′,5′,5′), 3.73 (4H, m, H-2′,2′,6′,6′), 3.81 (3H, s, H-7′′), 4.53 and 4.68 (2H, both br.s, H-29), 6.77-7.02 (4H, m, Ar)
(only characteristic proton resonances are given).
N-[3-Oxolup-20(29)-en-28-oyl]-1-imidazole (2m). PMR spectrum (δ, ppm, J/Hz): 0.85 (3H, s, Me-25), 0.87 (3H, s,
Me-26), 0.93 (6H, s, Me-24,27), 0.94 (1H, m, H-12), 0.97 (3H, s, Me-23), 1.09-1.45 (12H, m, H-1,5,6,6,7,7,9,11,11,15,15,21),
1.62 (3H, s, Me-30), 1.65 (1H, m, H-22), 1.69 (1H, m, H-18), 1.71 (1H, m, H-12), 1.74 (1H, m, H-16), 1.78 (1H, m, H-21), 1.82
(1H, m, H-1), 2.22 (1H, m, H-22), 2.32 (1H, m, H-2), 2.37 (1H, m, H-16), 2.40 (1H, m, H-2), 2.65 (1H, ddd, J = 13.0, J = 11.7,
1
2
J = 3.6, H-13), 2.88 (1H, td, J = 11.2, J = 4.8, H-19), 4.56 and 4.68 (2H, both br.s, H-29), 7.00 (1H, br.s, H-4′), 7.49 (1H,
3
1
2
br.s, H-5′), 8.23 (1H, br.s, H-2′).
N-[3-Oxolup-20(29)-en-28-oyl]cyclopentylamine (2n). PMR spectrum (δ, ppm, J/Hz): 0.89 (3H, s, Me), 0.94 (3H,
s, Me), 0.95 (3H, s, Me), 0.98 (3H, s, Me), 1.03 (3H, s, Me), 1.65 (3H, s, Me-30), 3.13 (1H, td, J = 11.2, J = 4.2, H-19), 4.14
1
2
(1H, m, H-1′), 4.55 and 4.70 (2H, both br.s, H-29), 5.44 (1H, d, J = 7.0, CONH) (only characteristic proton resonances are
given).
Methyl EsterofN-[3-Oxolup-20(29)-en-28-oyl]-D,L-α-aminopropionic Acid(3). IRspectrum (KBr, ν, cm−1): 1644
(CONH), 1704 (C=O), 1744 (COOCH ), 3395 (CONH). PMR spectrum (δ, ppm, J/Hz): 0.85 (3H, s, Me), 0.90 (3H, s, Me),
3
332

0.94 (6H, s, 2Me), 0.99 (3H, s, Me), 1.61 (3H, s, Me-30), 3.04 (1H, td, J = 11.1, J = 4.0, H-19), 3.68 (3H, s, Me-4′), 4.46 (1H,
1
2
m, H-1′), 4.52 and 4.66 (2H, both br.s, H-29), 6.06 and 6.12 (1H, both d, J = 7.1, CONH) (onlycharacteristic proton resonances
1
are given).
N-[3-Oxolup-20(29)-en-28-oyl]-D,L-α-aminopropionic Acid (4). A solution of 3 (0.54 g, 1 mmol) in CH OH
3
(10 mL) and THF (5 mL) under Ar at 0°C was treated with NaOH solution (2 mL, 8 mmol, 4 M), stored at room temperature
for 1 d, and poured into ice mixed with HCl. The resulting precipitate was filtered off, washed with water, and dried over P O
2
5
to afford 4 (0.52 g, 98%) as an amorphous powder. IR spectrum (KBr, ν, cm−1): 1641 (CONH), 1706 (C=O), 3430 (CONH).
PMR spectrum (δ, ppm, J/Hz): 0.89 and 0.90 (3H, s, Me-25), 0.94 and 0.95 (3H, s, Me-26), 0.96 (3H, s, Me-27), 0.97 (1H, m,
H-12), 1.00 (3H, s, Me-24), 1.04 (3H, s, Me-23), 1.14-1.41 (12H, m, H-1,5,6,6,7,7,9,11,11,15,21,22), 1.43 and 1.45 (3H, d,
J = 7.0, H-3′), 1.47-1.62 (3H, m, H-15,16,18), 1.66 (3H, s, Me-30), 1.67-2.01 (5H, m, H-1,12,16,21,22), 2.33-2.52 (3H, m,
H-2,2,13), 3.07 (1H, td, J = 11.2, J = 4.0, H-19), 4.51 (1H, m, H-1′), 4.58 and 4.71 (2H, both br.s, H-29), 6.05 and 6.11 (1H,
1
2
both d, J = 7.0, CONH), 8.84 (1H, broad, COOH).
1
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