1,3-Cycloaddition synthesis of 1,2,3-triazole conjugates of betulonic acid with peptides

Article abstract of DOI:10.1007/s11172-011-0369-3

1,2,3-Triazole conjugates of betulonic acid with peptides were synthesized by 1,3-dipolar cycloaddition of azido peptides to N-(3-oxolup-20(29)-en-28-oyl)- 4-ethynylaniline.

Full text of DOI:10.1007/s11172-011-0369-3

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2401—2405, November, 2011
2401
1,3ꢀСycloaddition synthesis of 1,2,3ꢀtriazole conjugates of betulonic acid
with peptides*
A. I. Govdi,a S. F. Vasilevsky,a V. G. Nenajdenko,b N. V. Sokolova,b and G. A. Tolstikovc
aInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences,
3 ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 7350. Eꢀmail: vasilev@kinetics.nsc.ru
bDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 932 8846
cN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752
1,2,3ꢀTriazole conjugates of betulonic acid with peptides were synthesized by 1,3ꢀdipolar
cycloaddition of azido peptides to Nꢀ(3ꢀoxolupꢀ20(29)ꢀenꢀ28ꢀoyl)ꢀ4ꢀethynylaniline.
Key words: triterpenoids, betulonic acid, arylacetylenes, azides, peptides, 1,3ꢀdipolar
cycloaddition, 1,2,3ꢀtriazoles.
The most important trend of modern medicinal chemꢀ
istry is the modification of metabolites isolated from variꢀ
ous plants,1 molecules of which bear two or more strucꢀ
tural fragments of different type.2 Synthetic transformaꢀ
tions of metabolites into bioconjugates with various strucꢀ
tural moieties are of growing interest.3,4
Efficiency of this approach was demonstrated on the
example of triterpenoids by the introduction of 1,2,3ꢀtriꢀ
azole moieties in their structures. Among previously
synthesized 1,2,3ꢀtriazole derivatives of betulonic acid
amides,5 bioconjugates exhibiting strong antiꢀinflammaꢀ
tory and antioxidant properties were found. It is known6,7
that the 1,2,3ꢀtriazole fragment is bioisosteric to the amide
bond; this fact should be considered in the design of the
bioconjugates.
In the present work, we described the synthesis of
a new series of triterpene derivatives bearing fragments of
1,2,3ꢀtriazoleꢀsubstituted peptides (Scheme 1). Synthetic
strategy was based on the click chemistry concept. One of
most popular reaction within the click chemistry is the
CuI catalyzed 1,3ꢀdipolar cycloaddition of azides to
alkynes. The azide—alkyne assembling is very effective for
combining different building blocks, including biologically
active structural synthons. This reaction is simple and proꢀ
vides high yields, regioꢀ and stereoselectivity, provides high
atom economy, simple product isolation and can be perꢀ
formed under physiological conditions.8—10
The starting terminal acetylene 1 was synthesized earꢀ
lier.11 Peptides 2a—f with azido group were prepared by
the Ugi reaction (Scheme 2).
The Ugi fourꢀcomponent condensation12—14 on the
base of isonitriles is a versatile procedure towards the strucꢀ
tural amino acid fragments, peptides and peptidomiꢀ
metics.15—20 Peptide analogs bearing azido moieties were
prepared by the Ugi condensation using protected amino
acids and chiral azido isonitriles21 as the acid and isoꢀ
nitrile components, respectively.
The structures of the compounds synthesized were esꢀ
tablished on the base of analytical and spectral data (Table 1).
The structures of amides of betulonic acid 3a—f with
1,4ꢀdisubstututed 1,2,3ꢀtriazole fragments were confirmed
experimentally by stereospecific formation of only 4ꢀisoꢀ
mers (not 5ꢀ) of 1,2,3ꢀtriazolopeptides in the reaction of
azides with terminal alkynes in the presence of CuI.8 Moreꢀ
over, data obtained by us previously5 also unambiguꢀ
ously confirm selective formation of only 4ꢀsubstituted
1,2,3ꢀtriazoles in the reactions of alkyl and aryl azides
with terminal alkynes of the series of betulonic acid amides
in the presence of CuCl.
A feature of the synthesized conjugates is the formaꢀ
tion of stable hydrates, which was confirmed by elemental
analysis. Earlier,22 the similar property, namely, the forꢀ
mation of stable hydrates by hydrogen bonding between
the nitrogen atoms and the oxygen atoms of the water
molecules. Thus, according to the microanalysis data,
compound 3d is monohydrate (see Table 1), while for
the sample dried in vacuo (2 Torr, 80 °C) over KOH
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2354—2358, November, 2011.
1066ꢀ5285/11/6011ꢀ2401 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Govdi et al.
Scheme 1
Scheme 2
2
a
b
c
R1
Me
Me
Bn
R2
H
Bn
R3
DMB
DMB
PMB
R4
H
Me
Me
R5
H
Me
Me
2
d
e
R1
Bn
R2
Pri
Pri
R3
PMB
PMB
R4
Me
Me
R5
Me
Me
Butꢀ2(R)ꢀyl
Butꢀ2(R)ꢀyl
DMB — 2,4ꢀdimethoxybenzyl, PMB — 4ꢀmethoxybenzyl

Betulonic acid peptide conjugates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2403
Table 1. Yields, melting points, elemental analysis data and IR spectra of triazole derivatives of betulonic acid 3a—f
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
IRꢀspectra
(CHCl3), ν/cm–1
(%)
C
H
N
3a
3b
3c
3d
46
45
49
48
125—127
115—117
140—143
138—140
68.80
68.38
69.86
69.65
72.00
72.07
71.92
71.90
72.91
73.05
70.86
70.87
70.79
70.92
8.27
8.27
8.16
8.34
8.33
8.55
8.69
8.48
8.48
8.44
8.85
8.92
8.05
8.37
8.63
9.46
7.90
8.36
8.14
8.40
7.96
8.51
8.36
8.64
8.77
8.23
7.95
8.39
C59H83N7O8•H2O
C68H93N7O8•2H2O
C70H97N7O7•H2O
C69H95N7O7•H2O
C69H95N7O7
1701 (С=О),
3438 (NH)
1710 (С=О),
3434 (NH)*
1708 (С=О),
3439 (NH)*
1701 (С=О),
3440 (NH)
3e
3f
57
46
133—135
139—141
C66H97N7O7•H2O
C69H93N7O7•2H2O
1706 (С=О),
3438 (NH)
1672 (С=О),
3442 (NH)
* In KBr pellets.
temperature for 24 h. The solvent was removed in vacuo, column
chromatography of the residue (elution with hexane—ethyl acetꢀ
ate, 2 : 1) afforded the mixture of rotamers (3 : 1) in a yield of
the elemental analysis data confirm the loss of the water
molecule.
In summary, in the present work, the versatile synthetꢀ
ic procedure towards novel betulonic acid derivatives bearꢀ
ing 1,2,3ꢀtriazolylpeptide fragments were developed. The
compounds synthesized currently tested for pharmacoꢀ
logical activity.
25
0.35 g (61%), white solid, m.p. 77—78 °C, [α]D –16.9 (c 1.0,
MeOH). 1H NMR, δ: 1.42, 1.47 (s, 9 H, Boc); 1.49 (s, 3 H,
H(50)); 1.52 (s, 3 H, H(51)); 1.70—1.78 (m, 1 H, H(62));
1.86—1.97 (m, 2 H, H(61), H(62)); 2.01—2.10 (m, 1 H, H(61));
2.69—2.75, 2.82—2.87 (m, 1 H, H(41)); 2.99—3.09 (m, 1 H,
H(41)); 3.28—3.45 (m, 3 H, H(63), H(39)); 3.51—3.60 (m, 1 H,
H(39)); 3.83 (s, 3 H, OMe); 4.16—4.24, 4.26—4.34 (m, 1 H,
Experimental
H(60)); 4.37—4.45 (m, 1 H, H(40)); 4.59 (d, 1 H, H(52), JAA´
=
Melting points were determined on a Kofler apparatus. IR
spectra were recorded on a Vector 22 spectrometer in the KBr
pellets or in the CHCl3 solutions. High resolution mass spectra
(70 eV) were run on a DFS instrument (Thermo Electron Corꢀ
poration). Elemental analyses were carried out on a CHNꢀanaꢀ
lyzer (model 1106, Carlo Erba, Italy). NMR spectra were run on
a Bruker AVꢀ400 spectrometer (400.13 (1H) and 100.61 MHz
= 18.2 Hz); 4.70, 4.95 (d, 1 H, H(52), JAA´ = 18.2 Hz); 5.75, 6.30
(d, 1 H, NH, J = 8.2 Hz); 6.93—6.97 (m, 2 H, H(55), H(57));
7.19—7.33 (m, 5 H, H(43)—H(47)); 7.38—7.44 (m, 2 H, H(54),
H(58)). 13C NMR, δ: 24.02 (C(50)); 24.40 (C(51)); 24.50 (C(62));
28.55 (3 CH3, Boc); 30.42 (C(61)); 37.60 (C(41)); 47.29 (C(52));
47.58 (C(63)); 51.03 (C(40)); 52.39 (C(39)); 55.27 (OMe); 57.30
(C(60)); 63.54 (C(49)); 79.50 (C(65)); 114.18, 114.31, 126.40,
127.27, 127.41, 128.45, 128.59, 129.29, 129.38, 130.78, 137.82
(C(42)—C(47), C(53)—C(55), C(57), C(58)); 154.65 (C(64));
158.85 (C(56)); 174.34 (C(59)); 174.59, 174.64 (C(48)). Found (%):
C, 64.21; H, 7.54; N, 14.33. C31H42N6O5. Calculated (%):
C, 64.34; H, 7.32; N, 14.52.
Reaction of compound 1 with azides 2a—f (general proceꢀ
dure). A mixture of acetylene 1 (0.17 mmol), azide 2a—f
(0.17 mmol), CuCl (2 mg) in butanꢀ1ꢀol (3—4 mL) was stirred at
110—115 °C for 4—9 h. After completion of the reaction, the
mixture was diluted with toluene (10 mL) and washed with aqueꢀ
ous ammonia. The organic layer was dried with Na2SO4, filtered
through the SiO2 pad (1×1.5 cm). The solvent was removed
in vacuo, the residue was triturated with hexane. The precipitate
that formed was filtered off to give compounds 3a—f.
(
13C)) in CDCl3. Chemical shifts are given in the δ scale relative
to the solvent residual signal (δ 7.24 and δ 76.90). In the
H
C
13C NMR spectra, signal multiplicities were determined using
Jꢀmodulations of spin echoes (JMOD). Signals of the polycyclic
framework in the 1H and 13C NMR spectra of compounds 3a—f
were assigned by the comparison with the corresponding signals
of betulonic acid as the reference compound.23 Only characterꢀ
istic signals of the compounds in the 1H NMR are given due
to difficulties in attributing of all signals. The main part of the
signals of the triterpenoid framework resonate in the region of
δ 2.7—0.8.
Silica gel Kieselgel 60 (70—230 mesh) were used for the
column chromatography.
(1ꢀtertꢀButoxycarbonylꢀLꢀprolyl)ꢀN1ꢀ[(2S)ꢀ1ꢀazidoꢀ3ꢀphenylꢀ
propꢀ2ꢀyl]ꢀN2ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀmethylalanineamide (2f). To
a solution of acetone (0.058 g, 1 mmol) and 4ꢀmethoxybenzylꢀ
amine (0.137 g, 1 mmol) in MeOH (5 mL), NꢀBocꢀLꢀproline
(0.216 g, 1 mmol) and 1ꢀ((S)ꢀ3ꢀazidoꢀ2ꢀisocyanopropyl)benzene
(0.172 g, 1 mmol) were added. The solution was kept at ambient
(NꢀtertꢀButoxycarbonylglycyl)ꢀN2ꢀ(2,4ꢀdimethoxybenzyl)ꢀ
N1ꢀ((1S)ꢀ2ꢀ{4ꢀ[4ꢀ(3,28ꢀdioxolupꢀ20(29)ꢀenꢀ28ꢀylamino)phenyl]ꢀ
1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ1ꢀmethylethyl)glycineamide (3a). 1H NMR,
δ: 0.85—1.03 (m, 18 H, C(23)H3—C(27)H3, C(41)H3); 1.42 (s, 9 H,
Boc); 1.68 (s, 3 H, C(30)H3); 3.17 (m, 1 H, H(19)); 3.75 (s, 6 H,

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Govdi et al.
2 OMe); 4.07—4.48 (m, 9 H, 2 H(39), H(40), 2 H(43), 2 H(44),
2 H(52)); 4.59, 4.74 (both s, 1 H each, H(29)); 5.50—5.52 (m, 1 H,
NH); 6.30 (d, 1 H, NH, J = 7.5 Hz); 6.37—6.39 (m, 2 H, H(47),
H(49)); 6.97 (d, 1 H, H(50), J = 8.3 Hz); 7.33 (br.s, 1 H, NH);
7.54 (d, 2 H, H(32), H(36), J = 8.5 Hz); 7.81 (d, 2 H, H(33),
H(35), J = 8.5 Hz); 7.87 (s, 1 H, H(38)). 13C NMR, δ: 14.14
(C(27)); 16.40 (C(26)); 16.65 (C(25)); 19.24 (C(6)); 19.56
(C(30)); 20.89 (C(24)); 22.66 (C(11)); 25.48 (C(12)); 27.08
(C(23)); 28.41 (3 CH3, Boc); 29.84 (C(21)); 30.47 (C(15)); 33.70
(C(16)); 34.03 (C(7)); 34.48 (C(2)); 36.95 (C(22)); 37.79 (C(13));
38.19 (C(10)); 40.72 (C(1)); 41.65 (C(8)); 42.30 (C(14)); 17.54,
42.69, 43.74, 45.33, 53.53 (C(41), C(40), C(52), C(44), C(43));
46.61 (C(19)); 47.72 (C(4)); 50.37 (C(18)); 50.74 (C(9)); 55.37
(C(5)); 55.45 (2 OMe); 56.54 (C(17)); 62.04, 79.65, 98.89,
104.13, 115.13 (C(39), C(54), C(47), C(49), C(45)); 109.57
(C(29)); 120.19 (C(32), C(36)); 120.60 (C(38)); 126.31 (C(33),
C(35), C(50)); 130.66 (C(34)); 138.22 (C(31)); 147.39 (C(37));
150.73 (C(20)); 156.09, 158.62, 161.30, 168.58, 170.35 (C(46),
C(48), C(53), C(51), C(42)); 176.97 (C(28)); 218.20 (C(3)).
(NꢀtertꢀButoxycarbonylꢀLꢀphenylalanyl)ꢀN2ꢀ(2,4ꢀdimethoxyꢀ
benzyl)ꢀN1ꢀ((1S)ꢀ2ꢀ{4ꢀ[4ꢀ(3,28ꢀdioxolupꢀ20(29)ꢀenꢀ28ꢀylꢀ
amino)phenyl]ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ1ꢀmethylethyl)ꢀ2ꢀmethylꢀ
alanineamide (3b). 1H NMR, δ: 0.91—1.03 (m, 15 H, C(23)H3—
C(27)H3); 1.35 (s, 15 H, Boc, C(44)H3, C(45)H3); 1.68 (s, 3 H,
C(30)H3); 3.13—3.17 (m, 1 H, H(19)); 3.76 (s, 6 H, 2 OMe);
4.08—4.61 (m, 8 H, H(29), 2 H(39), H(40), H(54), H(46),
2 H(55)); 4.76 (s, 1 H, H(29)); 5.11 (d, 1 H, NH, J = 9.9 Hz);
5.82 (d, 1 H, NH, J = 8.5 Hz); 6.40—6.43 (m, 2 H, H(49),
H(51)); 7.04—7.09 (m, 2 H, H(52), NH); 7.23—7.24 (m, 4 H,
H(57), H(58), H(60), H(61)); 7.30—7.32 (m, 1 H, H(59)); 7.56
(d, 2 H, H(32), H(36), J = 8.5 Hz); 7.82 (d, 2 H, H(33), H(35),
J = 8.5 Hz); 8.18 (s, 1 H, H(38)). 13C NMR, δ: 13.66, 17.42
(C(41), C(44), C(45)); 14.64 (C(27)); 15.85 (C(26)); 16.51
(C(25)); 19.16 (C(30)); 19.43 (C(6)); 20.77 (C(24)); 23.46
(C(11)); 25.32 (C(12)); 26.94 (C(23)); 28.15 (3 CH3, Boc); 29.70
(C(21)); 30.41 (C(15)); 30.69 (C(16)); 33.93 (C(7)); 34.33 (C(2));
36.55 (C(22)); 37.66 (C(13)); 38.07 (C(10)); 39.90 (C(1)); 41.51
(C(8)); 42.55 (C(14)); 46.48 (C(19)); 48.34 (C(4)); 50.23 (C(18));
50.58 (C(9)); 43.60, 45.78, 52.93, 53.55 (C(46), C(40), C(55),
C(54)); 55.14 (C(5)); 55.22 (2 OMe); 56.46 (C(17)); 62.71, 65.30,
79.53, 98.43, 104.12, 118.04 (C(43), C(39), C(63), C(49), C(51),
C(47)); 109.42 (C(29)); 120.09 (C(32), C(36)); 121.02 (C(38));
126.09 (C(33), C(35)); 126.39 (C(34)); 126.72, 128.34, 129.49,
136.45 (C(59), C(58), C(60), C(57), C(61), C(56)); 137.95
(C(31)); 147.04 (C(37)); 150.59 (C(20)); 154.70, 156.94, 160.10,
172.99, 174.25 (C(62), C(48), C(50), C(53), C(42)); 176.84
(C(28)); 217.71 (C(3)).
(C(11)); 25.49 (C(12)); 26.43 (C(23)); 28.16 (3 CH3, Boc); 29.47
(C(21)); 30.41 (C(15)); 30.66, 38.32 (C(62), C(61)); 33.56
(C(16)); 33.77 (C(7)); 34.05 (C(2)); 37.11 (C(22)); 37.53 (C(13));
38.05 (C(10)); 39.53 (C(1)); 40.58 (C(8)); 42.50 (C(14)); 46.36
(C(19)); 47.24 (C(4)); 49.90 (C(18)); 50.08 (C(9)); 46.81, 48.33,
50.87, 54.91 (C(42), C(52), C(40), C(60)); 55.15 (OMe); 55.47
(C(5)); 56.46 (C(17)); 62.73, 65.30, 79.50, 114.09 (C(49), C(39),
C(66), C(55), C(57)); 109.50 (C(29)); 120.11 (C(32), C(36));
121.33 (C(38)); 126.09 (C(33), C(35)); 126.29 (C(34)); 126.86,
127.53, 128.66, 129.21, 129.83, 136.74 (C(45), C(43), C(47),
C(54), C(58), C(46), C(48), C(53), C(42)); 137.99 (C(31));
147.01 (C(37)); 150.51 (C(20)); 155.29, 158.81, 173.42, 174.31
(C(65), C(56), C(59), C(48)); 176.83 (C(28)); 218.08 (C(3)).
(NꢀtertꢀButoxycarbonylꢀLꢀvalyl)ꢀN1ꢀ((2S)ꢀ1ꢀ{4ꢀ[4ꢀ(3,28ꢀ
dioxolupꢀ20(29)ꢀenꢀ28ꢀylamino)phenyl]ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ
3ꢀphenylpropꢀ2ꢀyl)ꢀN 2ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀmethylalanineꢀ
amide (3d). 1H NMR, δ: 0.90 (s, 3 H, C(25)H3); 0.96 (s, 3 H,
C(24)H3); 0.98 (s, 6 H, C(26)H3, C(27)H3); 1.03 (s, 3 H,
C(23)H3); 1.38 (s, 9 H, Boc); 1.68 (s, 3 H, C(30)H3); 3.17 (dt, 1 H,
H(19), J1 = 4.0 Hz, J2 = 11.0 Hz); 3.76 (s, 3 H, OMe); 4.31—4.35
(m, 1 H, H(39)); 4.47—4.56 (m, 3 H, H(39), H(40), H(60));
4.59 (br.s, 3 H, H(29), 2 H(52)); 4.74 (s, 1 H, H(29)); 5.03 (d, 1 H,
NH, J = 9.7 Hz); 5.88 (d, 1 H, NH, J = 6.8 Hz); 6.85 (d, 2 H,
H(55), H(57), J = 8.3 Hz); 7.22—7.33 (m, 7 H, H(43)—H(47),
H(54), H(58)); 7.54 (d, 2 H, H(32), H(36), J = 8.6 Hz); 7.78
(d, 2 H, H(33), H(35), J = 8.6 Hz); 8.08 (s, 1 H, H(38)). 13C NMR,
δ: 14.46 (C(27)); 15.82 (C(26)); 15.88 (C(25)); 17.11, 23.68
(C(62), C(63), C(50), C(51)); 19.39 (C(30)); 19.49 (C(6)); 20.91
(C(24)); 21.32 (C(11)); 25.48 (C(12)); 26.43 (C(23)); 28.17
(3 CH3, Boc); 29.47 (C(21)); 30.66 (C(15)); 33.56 (C(16)); 33.77
(C(7)); 34.05 (C(2)); 31.86, 36.81 (C(41), C(61)); 37.11 (C(22));
37.53 (C(13)); 38.05 (C(10)); 39.53 (C(1)); 40.58 (C(8)); 42.50
(C(14)); 46.36 (C(19)); 47.24 (C(4)); 49.90 (C(18)); 50.08 (C(9));
46.78, 50.80, 51.26 (C(52), C(40), C(49)); 54.92 (C(5)); 55.15
(OMe); 56.46 (C(17)); 56.06, 62.72, 79.50, 114.13 (C(60), C(39),
C(65), C(55), C(57)); 109.50 (C(29)); 120.11 (C(32), C(36));
121.33 (C(38)); 126.09 (C(33), C(35)); 126.29 (C(34)); 126.86,
127.53, 128.66, 129.21, 129.67, 136.69 (C(45), C(43), C(47),
C(54), C(58), C(44), C(46), C(53), C(42)); 137.99 (C(31));
147.01 (C(37)); 150.51 (C(20)); 155.41, 158.85, 173.21 (C(64),
C(56), C(48)); 174.33 (C(28)); 218.07 (C(3)).
(NꢀtertꢀButoxycarbonylꢀLꢀvalyl)ꢀN1ꢀ((2S,3S)ꢀ1ꢀ{4ꢀ[4ꢀ(3,28ꢀ
dioxolupꢀ20(29)ꢀenꢀ28ꢀylamino)phenyl]ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ
3ꢀmethylpentꢀ2ꢀyl)ꢀN2ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀmethylalanineamide
(3e). 1H NMR, δ: 0.90—1.03 (m, 27 H, C(23)H3—C(27)H3,
C(51)H3, C(52)H3, C(64)H3, C(65)H3); 1.39 (s, 9 H, Boc); 1.67
(s, 3 H, C(30)H3); 3.16—3.19 (m, 1 H, H(19)); 3.75 (s, 3 H,
OMe); 4.06—4.18 (m, 1 H, H(40)); 4.48—4.59 (m, 6 H, H(29),
2 H(39), 2 H(51), H(57)); 4.74 (s, 1 H, H(29)); 5.10 (d, 1 H,
NH, J = 9.8 Hz); 5.66 (d, 1 H, NH, J = 7.7 Hz); 6.85 (d, 2 H,
H(52), H(54), J = 8.1 Hz); 7.26 (d, 2 H, H(51), H(55), J = 8.1 Hz);
7.34 (s, 1 H, NH); 7.51 (d, 2 H, H(32), H(36), J = 7.9 Hz); 7.72
(d, 2 H, H(33), H(35), J = 7.9 Hz); 8.01 (s, 1 H, H(38)).
13C NMR, δ: 10.83, 15.51, 17.11, 24.14, 24.93, 32.09, 35.61
(C(43), C(44), C(59), C(60), C(47), C(48), C(42), C(58), C(41));
13.61 (C(27)); 16.26 (C(26)); 16.52 (C(25)); 19.15 (C(6)); 19.45
(C(30)); 23.47 (C(11)); 23.76 (C(24)); 25.33 (C(12)); 26.94
(C(23)); 28.16 (3 CH3, Boc); 29.65 (C(21)); 30.43 (C(15)); 30.70
(C(16)); 33.89 (C(7)); 34.34 (C(2)); 36.55 (C(22)); 37.68 (C(13));
38.14 (C(10)); 41.51 (C(1)); 42.55 (C(8)); 43.59 (C(14)); 46.48
(C(19)); 46.82 (C(4)); 50.22 (C(18)); 50.59 (C(9)); 48.33, 50.72,
(NꢀtertꢀButoxycarbonylꢀLꢀisoleucyl)ꢀN1ꢀ((2S)ꢀ1ꢀ{4ꢀ[4ꢀ(3,28ꢀ
dioxolupꢀ20(29)ꢀenꢀ28ꢀylamino)phenyl]ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ
3ꢀphenylpropꢀ2ꢀyl)ꢀN2ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀmethylalanineamide
(3c). 1H NMR, δ: 0.90—1.03 (m, 27 H, C(23)H3—C(27)H3,
C(50)H3, C(51)H3, C(63)H3, C(64)H3); 1.38 (s, 9 H, Boc); 1.68
(s, 3 H, C(30)H3); 3.16—3.19 (m, 1 H, H(19)); 3.76 (s, 3 H,
OMe); 4.48—4.59 (m, 6 H, H(29), H(39), 2 H(52), H(60),
H(40)); 4.74 (s, 1 H, H(29)); 4.98 (d, 1 H, NH, J = 9.2 Hz); 5.89
(d, 1 H, NH, J = 7.0 Hz); 6.85 (d, 2 H, H(55), H(57), J = 8.4 Hz);
7.20—7.32 (m, 7 H, H(43)—H(47), H(54), H(58)); 7.54 (d, 2 H,
H(32), H(36), J = 8.6 Hz); 7.78 (d, 2 H, H(33), H(35), J = 8.6 Hz);
8.07 (s, 1 H, H(38)). 13C NMR, δ: 11.08, 15.52, 23.97 (C(63),
C(64), C(50), C(51)); 13.62 (C(27)); 14.45 (C(26)); 14.65
(C(25)); 19.15 (C(6)); 19.38 (C(30)); 23.71 (C(24)); 23.71

Betulonic acid peptide conjugates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2405
53.26 (C(49), C(40), C(57)); 55.16 (OMe); 55.94 (C(5)); 56.47
(C(17)); 61.89, 62.86, 79.39, 114.22 (C(46), C(39), C(62), C(52),
C(54)); 109.42 (C(29)); 120.08 (C(32), C(36)); 120.50 (C(38));
126.05 (C(33), C(35)); 126.27 (C(34)); 127.57, 129.83 (C(51),
C(55), C(50)); 137.97 (C(31)); 147.09 (C(37)); 150.58 (C(20));
155.27, 158.91, 173.01, 174.30 (C(61), C(53), C(56), C(45));
176.83 (C(28)); 217.48 (C(3)).
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(1ꢀtertꢀButoxycarbonylꢀLꢀprolyl)ꢀN1ꢀ((2S)ꢀ1ꢀ{4ꢀ[4ꢀ(3,28ꢀ
dioxolupꢀ20(29)ꢀenꢀ28ꢀylamino)phenyl]ꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl}ꢀ
3ꢀphenylpropꢀ2ꢀyl)ꢀN2ꢀ(4ꢀmethoxybenzyl)ꢀ2ꢀmethylalanineamꢀ
ide (3f). 1H NMR, δ: 0.83—1.01 (m, 21 H, C(23)H3—C(27)H3,
C(50)H3, C(51)H3); 1.40 (s, 9 H, Boc); 1.68 (s, 3 H, C(30)H3);
3.11—3.41 (m, 6 H, H(19), 2 H(63), 2 H(41), H(61)); 3.76 (s, 3 H,
OMe); 3.79 (s, 2 H, H(52)); 4.48—4.59 (m, 6 H, H(29), 2 H(39),
H(49), H(61), H(40)); 4.74 (s, 1 H, H(29)); 6.63 (d, 1 H, NH,
J = 8.4 Hz); 6.85 (d, 2 H, H(55), H(57), J = 8.6 Hz); 7.25—7.33
(m, 7 H, H(43)—H(47), H(54), H(58)); 7.51 (d, 2 H, H(32),
H(36), J = 8.5 Hz); 7.74 (d, 2 H, H(33), H(35), J = 8.5 Hz); 7.89
(s, 1 H, H(38)). 13C NMR, δ: 13.66 (C(27)); 14.01 (C(26));
14.64 (C(25)); 19.15 (C(6)); 19.42 (C(30)); 20.76, 22.53, 30.57
(C(50), C(51), C(62), C(61)); 24.10 (C(24)); 24.40 (C(11)); 25.34
(C(12)); 26.94 (C(23)); 28.16 (3 CH3, Boc); 29.69 (C(21)); 30.41
(C(15)); 30.71 (C(16)); 31.46 (C(7)); 31.56 (C(2)); 33.90 (C(22));
34.34 (C(13)); 38.08 (C(10)); 41.52 (C(1)); 42.55 (C(8)); 43.60
(C(14)); 46.49 (C(19)); 47.20 (C(4)); 47.66, 48.33, 51.24, 51.75
(C(41), C(52), C(63), C(40)); 50.23 (C(18)); 50.60 (C(9)); 55.18
(OMe); 56.47 (C(17)); 57.23 (C(5)); 61.91, 63.47, 65.29, 79.60,
114.18 (C(60), C(39), C(49), C(65), C(55), C(57)); 109.42
(C(29)); 120.04 (C(32), C(36)); 120.69 (C(38)); 126.15 (C(33),
C(35)); 126.39 (C(34)); 126.64, 127.00, 128.55, 129.23, 130.49,
137.98 (C(45), C(43), C(47), C(53), C(54), C(58), C(44), C(46),
C(42)); 137.25 (C(31)); 146.96 (C(37)); 150.60 (C(20)); 154.66,
158.69, 174.72, 174.94 (C(64), C(56), C(59), C(48)); 176.84
(C(28)); 217.56 (C(3)).
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This work was financially supported by the Siberian
Branch of the Russian Academy of Sciences (Integration
Grant 93), the Russian Academy of Sciences (Grant 5.9.3),
the Russian Foundation for Basic Research (Project
No. 10ꢀ03ꢀ00257ꢀa), and the Chemical Service Center of
the SB RAS.
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Received May 20, 2011