Synthesis of New C-2 Triazole-Linked Analogs of Triterpenoid Pentacyclic Saponins

Article abstract of DOI:10.1007/s10600-018-2331-1

C-2 mono- and bis-1,2,3-triazole-linked analogs of lupane, ursane, and oleane triterpenoid saponins were synthesized for the first time using regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) of peracetylated sugar azides and C-2 propynyl derivatives of triterpene acids. Cytotoxic activity of the synthesized compounds was studied in vitro at the National Cancer Institute (USA). Several of the synthesized compounds exhibited weak cytotoxic activity.

Full text of DOI:10.1007/s10600-018-2331-1

DOI 10.1007/s10600-018-2331-1
Chemistry of Natural Compounds, Vol. 54, No. 2, March, 2018
SYNTHESIS OF NEW C-2 TRIAZOLE-LINKED ANALOGS
OF TRITERPENOID PENTACYCLIC SAPONINS
*
A. Yu. Spivak, Z. R. Galimshina,
D. A. Nedopekina, and V. N. Odinokov
C-2 mono- and bis-1,2,3-triazole-linked analogs of lupane, ursane, and oleane triterpenoid saponins were
synthesized for the first time using regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) of
peracetylated sugar azides and C-2 propynyl derivatives of triterpene acids. Cytotoxic activity of the
synthesized compounds was studied in vitro at the National Cancer Institute (USA). Several of the synthesized
compounds exhibited weak cytotoxic activity.
Keywords: triterpenoids, betulinic acid, ursolic acid, oleanolic acid, glycosides, 1,2,3-triazoles, 1,3-dipolar cycloaddition.
Saponins are a specific class of broadly distributed plant secondary metabolites, the molecules of which contain
a pentacyclic triterpenoid or steroid aglycon called a sapogenin and one or more sugar chains connected at various positions
through O-glycoside bonds to the hydrophobic polycyclic core. Triterpenoid saponins display a variety of structures and
exhibit broad spectra of biological and pharmacological activities such as hemolytic, cytotoxic, anti-inflammatory, antimicrobial,
and hypolipidemic [1, 2]. Many natural and synthetic O-glycosides of the lupane-, ursane-, and oleane-type have now been
synthesized using classical methods to form triterpene C-3 and/or C-28 glycoside bonds [3]. It is assumed that the water-
solubility and absorption would be improved; the pharmacological properties of the triterpenoids, enhanced, if hydrophilic
sugar residues were bonded to them. An analysis of the structure–activity relationship of many libraries of obtained compounds
revealed changes of biological activity even if the chemical structure was slightly altered and a dependence on the types of
aglycon, sugar, number of sugar residues in the chains, and positions at which the sugar was bound to the aglycon [3].
Conjugates of pentacyclic triterpenoids and sugars linked through 1H-1,2,3-triazole rings were investigated several times
[4–6]. Therefore, it seemed interesting to determine how replacing the traditional O-glycoside bond by an artificial biologically
active 1,2,3-triazole linker would affect the biological activity of the triazole-containing triterpene saponin analogs.
Herein, syntheses of previously unknown 1,2,3-triazole conjugates of lupane, ursane, and oleane triterpenoids with
mono- and disaccharides based on Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides to acetylenes (CuAAC) are reported.
The CuAAC reaction has been widely employed in the last decade in medicinal and biological chemistry [7, 8]. Although
triazole bridges are unknown in natural products, they possess several attractive properties such as high metabolic stability,
water solubility, and the ability to form H-bonds with many enzymes.
C-2 propynyl derivatives of betulinic, ursolic, and oleanolic acids 1–3 were used to prepare triazolylglycopyranosides
of triterpenoids 8a–d, 9, 10, 11a–d, 12, and 13 (Scheme 1). These starting substrates with a terminal acetylene became
available as a result of our development of ꢀ-alkylation by propargyl bromide of potassium enoxytriethylborates obtained
from 3-ketotriterpenoids [9].
The sugar components, glycosylazides 4–7, were prepared by reacting per-O-acetylated ꢁ-D-glucose, ꢁ-D-galactose,
ꢀ-D-mannose, and ꢁ-D-lactose with trimethylsilylazide in the presence of SnCl . The spectral data of the obtained sugars
4
agreed with the literature [10, 11].
The CuAAC between triterpenoids 1–3 and sugar azides 4–7 was carried out under conditions optimized by us earlier
during studies of the conjugation of ꢁ-D-glucopyranose azide 4 with propynyl derivatives of betulinic (1) and ursolic acids (2)
(Cu, CuSO 45H O, t-BuOH, 40°C) [9] (Scheme 1).
4
2
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prosp. Oktyabrya, Ufa, 450075,
fax: (347) 284 27 50, e-mail: spivak.ink@gmail.com. Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April,
2018, pp. 265–272. Original article submitted September 11, 2017.
©
0009-3130/18/5402-0315 2018 Springer Science+Business Media, LLC
315

30
30
30 29
29
29
20
19
19
12
26
13
25
5
25
25
13 17
26
26
17
CO H
2
CO H
2
CO H
2
1
1
1
4
28
28
28
10
15
3
7
27
27
27
5
HO
HO
HO
24
24
23
24 23
23
1
2
3
+
4 - 7
a
CuAAC
N
N
N
R
R
R
N
N
N
N
N
N
HO
HO
HO
b
b
b
8a-d
11a-d
9
12
10
13
8a,9,10: R = per-O-Ac-ꢁ-D-Glc; 8b: R = per-O-Ac-ꢁ-D-Gal; 8c: R = per-O-Ac-ꢀ-D-Man; 8d: R = per-O-Ac-Galꢁ(1ꢂ4)Glc;
11a,12,13: R = ꢁ-D-Glc; 11b: R = ꢁ-D-Gal; 11c: R = ꢀ-D-Man; 11d: R = Galꢁ(1ꢂ4)Glc
a. Cu powder, CuSO 45H O, t-BuOH, 40ꢃC; b. Et N, MeOH, H O, 20ꢃC
4
2
3
2
Scheme 1
OAc
OAc
OAc
OAc
OAc
AcO
AcO
AcO
AcO
OAc
O
O
O
O
O
N
N
3
N
O
3
3
AcO
AcO
AcO
AcO
AcO
OAc
OAc
OAc
OAc
N
3
4
6
7
5
The type of triterpenoid aglycon (betulinic, ursolic, and oleanolic acids) was varied for future pharmacological studies
of the structure–activity (cytotoxic) relationship of 8a, 9, and 10. The triterpenoid aglycon (betulinic acid) in 8a–d was linked
through a 1,2,3-triazole ring to various sugars. The transformation terminated with de-O-acetylation of 8a–d, 9, and 10 using
Et N in MeOH [12] to produce high yields of series of bioconjugates 11a–d, 12, and 13 with free hydroxyls in the sugars.
3
The 1,2,3-triazole ring and sugar in conjugates 8a–d, 9, 10, 11a–d, 12, and 13 were linked through an N-glycoside
bond. Compounds 17–19, in which a spacer between the triazole ring and the sugar was bonded through an O-glycoside bond,
were prepared in order to vary the sugar–triterpenoid bioconjugate structure. They were synthesized by reacting
azidoethylglycosides of galactose (14) and lactose peracetates (15) with a propynyl derivative of 1 or methyl betulinate (16).
Azides 14 and 15 were prepared using glycosylation of protected sugars by 2-bromoethanol in the presence of BF 4Et O in
3
2
CH Cl followed by reaction of the bromoethylglycosides with NaN in DMF [13] (Scheme 2).
2
2
3
OAc
OAc
AcO
AcO
OAc
AcO
N
N
3
O
3
O
O
O
O
O
AcO
15
AcO
OAc
OAc
OAc
14
+
CO R
2
HO
1 or 16
CuAAC
a
OAc
OAc
AcO
AcO
OAc
AcO
N
N
N
N
O
O
O
O
O
O
N
N
AcO
AcO
HO
HO
OAc
OAc
OAc
1,17,19: R = H; 16,18: R = Me
17
18, 19
a. Cu powder, CuSO 45H O, t-BuOH, 40ꢃC
Scheme22
4
316

13
TABLE 1. C NMR Spectral Data for 8a–d, 9, and 10 (ꢄ, ppm)
Atom or group
8a
8b
8c
8d
9
10
1
2
45.0
35.7
45.1
35.7
45.3
35.7
45.1
35.6
44.3
35.3
45.8
35.3
3
4
81.6
37.4
81.7
37.4
82.0
37.4
81.7
37.4
80.8
39.0
80.8
38.9
5
6
55.6
18.5
55.6
18.5
55.5
18.5
55.6
18.5
55.4
18.4
55.4
18.4
7
8
34.3
40.7
34.3
40.7
34.2
40.7
34.3
40.7
32.9
39.4
32.4
39.2
9
10
50.4
39.2
50.4
39.2
50.4
39.2
50.4
39.2
47.4
36.8
47.7
36.9
11
12
13
14
20.8
25.5
38.3
42.4
20.8
25.5
38.3
42.5
20.9
25.4
38.3
42.5
20.8
25.5
38.3
42.4
23.0
23.1
125.6
138.1
41.9
122.3
143.7
41.5
15
16
29.6
32.2
29.6
32.2
29.6
32.2
29.6
32.2
27.8
23.9
27.4
22.7
17
18
56.3
49.2
56.3
49.2
56.3
49.2
56.3
49.3
47.9
52.9
46.2
41.3
19
20
46.9
150.5
46.9
150.5
46.9
150.5
46.9
150.5
38.9
39.0
44.2
30.3
21
22
30.5
37.1
30.5
37.1
30.5
37.1
30.5
37.1
30.4
36.7
33.5
32.6
23
24
25
28.3
16.2
16.0
28.3
16.2
16.1
28.3
16.2
16.0
28.3
16.2
16.0
27.8
15.9
15.4
27.8
16.4
15.3
26
27
16.8
14.7
16.8
14.7
16.9
14.7
16.8
14.7
16.3
22.9
15.9
25.2
28
29
30
181.6
109.6
19.3
181.5
109.6
19.3
181.8
109.7
19.3
181.5
109.6
19.3
180.1
16.5
20.3
180.3
32.3
22.8
CH=C–N-
=C–CH2
CH=C–N–
COCH3
120.3
28.9
147.1
20.7, 20.6
20.5, 20.1
170.5, 169.9
169.4, 168.9
120.4
29.0
147.0
20.7, 20.6
20.5, 20.2
170.4, 170.0
169.8, 169.1
122.1
29.0
147.1
20.7, 20.6
20.5, 20.3
170.5, 170.0
169.7, 169.4
120.3
28.9
146.9
121.5
27.9
146.5
19.3, 19.2
19.1, 18.9
170.8, 170.1
169.8, 168.6
121.4
27.9
146.5
19.3, 19.2
19.1, 18.9
170.8, 170.1
169.8, 168.6
20.7, 20.6
20.5, 20.3
170.4, 170.3
170.2, 170.1
169.5, 169.1
85.5, 75.9
75.7, 72.5
70.9, 61.8
101.1, 70.8
70.6, 69.1
66.6, 60.8
COCH3
85.7, 75.1
72.6, 70.3
67.8, 61.6
86.2, 74.0
70.8, 67.9
66.9, 61.2
83.4, 72.1
68.9, 68.2
66.2, 61.5
85.4, 74.6
72.6, 70.8
67.9, 61.6
85.4, 74.5
72.5, 70.7
67.9, 61.6
1ꢅ–6ꢅ
1ꢅꢅ–6ꢅꢅ
A bis-triazole linker was constructed in the glycosylated triterpenoids using our previously developed methodology
for three-component cycloaddition of NaN and epichlorohydrin to propargylglycosides, which occurs with regioselective
3
opening of the oxirane ring of epichlorohydrin under CuAAC conditions [14]. 2,3,4,6-Tetra-O-acetyl-ꢁ-D-glucopyranose
ꢁ-propargylglycoside (20) was chosen as the starting sugar substrate. It was synthesized by reacting commercially available
ꢁ-D-glucopyranose pentaacetate with propargyl alcohol [15]. The one-pot condensation of 20 and excesses of epichlorohydrin
(2.0 eq) and NaN (4.0 eq) in the presence of CuSO 45H O and NaAsc in H O at room temperature gave triazolylazide alcohol
3
4
2
2
21 in acceptable (56%) yield. The last underwent Cu(I)-catalyzed conjugation with triterpenoids 1 and 16 (Scheme 3).
317

13
TABLE 2. C NMR Spectral Data for 11b–d, 13, and 17–19 (ꢄ, ppm)
Atom or group
11b
11c
11d
13
17
18
19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
44.9
35.9
81.5
37.0
55.6
18.3
34.2
40.6
50.5
39.0
20.7
25.5
38.2
42.2
29.4
32.0
56.1
49.0
47.1
150.6
30.3
36.8
27.7
15.6
15.3
16.1
13.8
178.8
108.8
18.2
121.5
28.4
146.3
–
44.9
35.9
81.5
37.0
55.6
18.3
34.2
40.6
50.6
39.0
20.7
25.5
38.2
42.3
29.5
32.3
56.2
49.1
47.2
150.8
30.4
37.0
27.7
15.7
15.4
16.1
13.8
–
46.4
37.4
83.0
38.5
57.1
19.8
35.7
42.1
52.1
40.5
22.2
27.0
39.8
43.7
30.9
33.5
57.6
50.6
48.6
152.1
31.8
38.3
29.2
17.1
16.8
17.6
15.3
180.4
110.3
19.7
123.7
29.9
–
46.0
35.6
81.6
38.9
55.5
18.4
32.5
39.2
47.8
36.9
23.1
122.1
143.9
41.6
27.5
22.7
46.3
41.4
44.6
30.3
33.6
32.6
27.8
16.5
15.3
15.9
25.1
181.4
32.3
22.7
122.1
28.3
146.1
–
45.2
35.7
81.7
38.3
55.6
18.5
34.3
40.7
50.4
39.2
20.8
25.5
38.3
42.4
29.6
32.2
56.3
49.3
46.9
150.5
30.5
37.1
28.4
16.2
16.1
16.9
14.7
181.6
109.7
19.3
123.3
28.4
146.1
67.8
50.0
45.3
35.6
81.7
37.4
55.6
18.5
34.2
40.7
50.4
39.1
20.8
25.5
38.2
42.4
29.6
32.1
56.5
49.4
47.0
150.5
30.5
36.9
28.3
16.2
15.9
16.8
14.7
176.6
109.6
19.3
123.0
29.2
146.1
67.9
50.0
46.3
37.4
83.1
38.5
57.1
19.8
35.7
42.1
52.0
40.5
22.3
27.0
39.7
43.7
31.0
33.7
57.8
50.6
49.2
152.3
31.9
38.5
29.2
17.2
16.9
17.7
15.4
181.6
110.3
19.8
124.8
29.9
147.6
69.0
51.3
108.7
18.2
121.7
28.4
146.3
–
30
CH=C–N–
=C–CH2
CH=C–N–
CH2–O
CH2–N
COCH3
–
–
–
–
–
–
–
–
–
20.7, 20.6
20.5, 20.4
170.4, 170.2
170.0, 169.6
20.7, 20.6
20.5, 20.3
170.3, 170.1
170.0, 169.7
169.6, 169.0
51.2
100.3, 76.1
72.8, 72.4
71.4, 61.7
101.0, 70.9
70.7, 69.1
66.6, 60.8
21.0, 20.9
20.8, 20.7
172.4, 172.0
171.7, 171.5
171.2, 171.1
–
100.2, 77.8
74.3, 74.2
72.9, 63.6
100.6, 72.5
71.9, 70.8
68.7, 62.4
COCH3
–
–
–
–
CO2Me
1ꢅ–6ꢅ
1ꢅꢅ–6ꢅꢅ
–
–
–
–
–
88.7, 78.6
74.0, 69.9
69.0, 61.1
88.6, 78.4
74.0, 69.9
69.1, 61.1
89.3, 79.8
79.7, 77.3
77.1, 62.7
105.2, 74.9
73.7, 72.7
70.5, 61.7
88.0, 79.7
77.2, 72.6
69.5, 61.0
100.9, 70.9
70.6, 68.5
66.9, 61.2
Conjugation between alkyne 16 and triazolylazide 21 in the presence of Cu powder and CuSO 45H O in t-BuOH at
4
2
40°C gave bioconjugate 22 in yields <20%. An attempt to produce 22 using CuI in the presence of diisopropylethylamine in
refluxing THF was unsuccessful, probably because of the low reactivity of triazolylazide 21. Target product 22 was obtained
in 62% yield via CuI-catalyzed reaction of 21 with 16 in t-BuOH under Ar for 23 h at 70°C. Under these conditions, the
reaction afforded conjugate 23 in 53% yield. Conjugates 22 and 23 were chromatographically inseparable mixtures (1:1,
PMR data) of the R/S-diastereomers relative to the CH–OH C atom in the bis-triazole linker.
318

OAc
N
O
OAc
Cl
N
N
N
3
O
O
O
O
AcO
AcO
AcO
AcO
a
OH
OAc
OAc
20
21
b
CO R
2
N
OAc
N
N
N
O
O
AcO
AcO
N
N
OH
HO
22: R = Me; 23: R = H
OAc
22, 23
a. NaN , H O, CuSO 45H O, NaAsc; b. 1 or 16, CuI, t-BuOH, 70ꢃC, 23 h
3
2
4
2
Scheme 3
13
The structures of all synthesized compounds were confirmed by 1D (PMR, C NMR, APT) and 2D homo- (COSY,
NOESY) and heteronuclear experiments (HSQC, HMBC). Chemical shifts of terpene skeleton atoms were determined by
a comparison with the literature [9]. The appearance in PMR spectra of 8a–d, 9, 10, 11a–d, 12, 13, and 17–19 of characteristic
13
resonances for CH=C–N at ꢄ 7.33–8.04 was consistent with formation of triazole rings. C NMR spectra showed resonances
of [1,5]-triazole C atoms CH=C–N and CH=C–N at 120.3–124.8 and 146.3–147.9 ppm, respectively (Tables 1 and 2).
–1
Strong absorption in the IR spectrum of 21 at 2106 cm was consistent with an azide. PMR spectra exhibited
13
a resonance for the triazole-ring proton at ꢄ 7.69. A comparison of PMR and C NMR spectra of 22 and 23 with those of 21
confirmed that they had formed. Thus, the protons of both triazole rings resonated as four singlets at ꢄ 7.48, 7.50, 7.75, and
7.76 in the PMR spectrum of the diastereomeric mixture of 22. C atoms of triazole rings bound to sugars CH=C–N and
CH=C–N resonated at ꢄ 125.0 and 143.8. Resonances of [1,5]-triazole C atoms of the second triazole ring were found
at ꢄ 123.9, 123.8 and 146.3, 146.4. Anomeric sugar proton H-1ꢅ appeared as a doublet at ꢄ 4.71 with SSCC J = 8.0 Hz, typical
for a ꢁ-glycoside bond.
Cytotoxic activity of the synthesized glycoside triterpenoid derivatives was studied using standard procedures at the
National Cancer Institute (NCI, USA) on panels consisting of 60 human tumor cell lines (leukemia, melanoma and cancer of
the lung, colon, kidneys, ovaries, breasts, prostate, and CNS) (http://dtp.cancer.gov/btp/ivclsp.html). All compounds at the
–5
single concentration 10 M exhibited weak cytotoxic activity that did not meet selection criteria for second stage testing at
five different doses.
Thus, Cu(I)-catalyzed 1,3-dipolar cycloaddition of alkynes and azides synthesized series of new C-2 glycoconjugates
of lupane-, ursane-, and oleane-type triterpenoids in which the sugar moiety and triterpene core are linked through biologically
active mono- or bis-1H-1,2,3-triazole rings. Considering the broad spectra of biological activities found for natural triterpene
saponins, we plan further biological studies of this new family of glycosylated triterpene-acid derivatives.
EXPERIMENTAL
13
IR spectra were taken from thin layers or CHCl solutions on a Bruker Vertex 70 V spectrometer. PMR and C NMR
3
spectra were recorded in CDCl or CD OD with TMS internal standard on a Bruker Avance-500 (operating frequency
3
3
1
13
500.13 MHz for H and 125.78 MHz for C) or Bruker Avance-400 instrument (operating frequency 400.13 and 100.62 MHz,
respectively). MALDI TOF mass spectra were recorded in positive-ion mode using 2,5-dihydroxybenzoic and ꢀ-cyano-4-
hydroxycinnamic acids as matrices on a BrukerAutoflex III spectrometer. Optical rotation was determined on a PerkinElmer-141
–1
–1
polarimeter where [ꢀ] is the specific rotation [deg4mL4(g4dm) ]; c, solution concentration [g4(100 mL) ]. Elemental analyses
D
were measured on a Carlo Erba 1106 analyzer. TLC used Sorbfil plates (Sorbpolimer, Krasnodar, Russia) and hexane–EtOAc
or CHCl –MeOH (4:1) with anisaldehyde detector. Column chromatography was performed over silica gel L (50–160 ꢆm,
3
KSKG grade). SnCl (1 M in CH Cl ), CH COCl, TMSiN , Et N, BF 4Et O, 2-bromoethanol, CeCl 47H O, NaBH , LiI,
4
2
2
3
3
3
3
2
3
2
4
DMF, t-BuOH, Cu powder, NaN , sodium ascorbate, epichlorohydrin, betulinic acid, ursolic acid, oleanolic acid, KN(SiMe )
3
3 2
(1 M in THF), BEt (95%), propargyl bromide, and propargyl alcohol were purchased (Aldrich). Solvents were prepared as
3
usual. All reactions were conducted underAr. Triterpenoids 1–3 and 16 were prepared as before [9]. Spectral data for 11a and
319

12 agreed with the literature [9]. Elemental analyses of all new compounds agreed with those calculated. Tables 1 and 2
13
present C NMR spectral data for 8a–d, 9, 10, 11b–d, 13, and 17–19.
Reaction of 1–3 and 16 with Glycosylazides 4–7, 14, and 15. General Method. A solution of 1, 2, 3, or 16
(0.4 mmol) in t-BuOH (6 mL) was treated in turn with glycosylazide 4–7, 14, or 15 (0.5 mmol), Cu powder (0.014 g,
0.22 mmol), and CuSO ·5H O solution (0.08 mL, 1 M, 0.08 mmol); heated for 20–24 h at 40°C (TLC monitoring); cooled;
4
2
filtered over a column with a thin layer of silica gel to remove Cu powder; poured into H O; and extracted with CH Cl
2
2
2
(30 mL). The organic layer was washed with H O (30 mL) and dried (MgSO ). The products were purified by column
2
4
chromatography over silica gel [n-hexane–EtOAc (1:1) or CHCl –MeOH eluent (4:1)] to afford 8a–d, 9, 10, 17, 18, or 19.
3
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-
22
–1
en-28-oic Acid (8a). C H N O . Yield 89%, mp 164–168ꢃÑ, [ꢀ] –11ꢃ (c 1.2, CHCl ). IR spectrum (CHCl , ꢇ, cm ):
47 69
1
3
12
D
3
3
1757 (C=O), 3471 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.78, 0.80, 0.90, 0.93, 0.96 (3H each, s, CÍ -23–27), 1.67 (3H, s,
3
CÍ -30), 0.62–2.27 (23H, m, CH, CH in pentacyclic skeleton), 1.84, 2.03, 2.07, 2.08 (3H each, s, COCH ), 2.68 (1H, dd,
3
2
3
J = 14.0, 7.0, H -CH ), 2.78 (1H, d, J = 10.5, H-3), 2.97–3.02 (2H, m, H-19, H -CH ), 3.99–4.03 (1H, m, H-5ꢅ), 4.15 (1Í, d,
a
2
b
2
J = 12.5, H -6ꢅ), 4.31 (1H, dd, J = 12.5, 5.0, H -6ꢅ), 4.59, 4.71 (1H each, br.s, H-29), 5.24 (1H, t, J = 9.5, H-4ꢅ), 5.40–5.46 (2H,
a
b
+
m, H-3ꢅ, 2ꢅ), 5.83 (1H, d, J = 9.0, H-1ꢅ), 7.59 (1H, s, ÑÍ=C–N). MS m/z 890.5 [M + Na] (calcd for C H N O , 867.5).
47 69
3 12
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-galactopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-
18
20(29)-en-28-oic Acid (8b). C H N O . Yield 92%, mp 136–138ꢃÑ, [ꢀ] –2ꢃ (c 0.9, CHCl ). IR spectrum (CHCl , ꢇ,
47 69
1
3
12
D
3
3
–1
cm ): 1756 (C=O), 3474 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.80, 0.82, 0.92, 0.95, 0.97 (3H each, s, CÍ -23–27), 1.68
3
(3H, s, CÍ -30), 0.66–2.28 (23H, m, CH, CH in pentacyclic skeleton), 1.87, 2.02, 2.05, 2.23 (3H each, s, COCH ), 2.73 (1H,
3
2
3
dd, J = 14.0, 7.0, H -CH ), 2.80 (1H, d, J = 11.0, H-3), 2.98–3.03 (2H, m, H-19, H -CH ), 4.12–4.24 (3H, m, H-5ꢅ, H -6ꢅ),
a
2
b
2
ab
4.59, 4.72 (1H each, br.s, H-29), 5.26 (1H, dd, J = 11.0, 3.5, H-3ꢅ), 5.53–5.57 (2H, m, H-2ꢅ, 4ꢅ), 5.83 (1H, d, J = 10.0, H-1ꢅ),
+
7.63 (1H, s, ÑÍ=C–N). MS m/z 890.5 [M+Na] (calcd for C H N O , 867.5).
47 69
3 12
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢀ-D-mannopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-
18
20(29)-en-28-oic Acid (8c). C H N O . Yield 87%, mp 156–158ꢃÑ, [ꢀ] +18.5ꢃ (c 0.8, CHCl ). IR spectrum (CHCl , ꢇ,
47 69
1
3
12
D
3
3
–1
cm ): 1754 (C=O), 3448 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.80, 0.83, 0.91, 0.96, 0.98 (3H each, s, CÍ -23–27), 1.68
3
(3H, s, H-30), 2.05, 2.07, 2.09, 2.17 (3H each, s, COCH ), 0.64–2.26 (23H, m, CH, CH in pentacyclic skeleton), 2.69–2.73
3
2
(1H, m, H -CH ), 2.84 (1H, d, J = 11.0, H-3), 3.00–3.06 (2H, m, H-19, H -CH ), 3.87–3.89 (1H, m, H-5ꢅ), 4.05 (1H, d,
a
2
b
2
J = 12.5, H -6ꢅ), 4.38 (1H, dd, J = 12.5, 5.5, H -6ꢅ), 4.59, 4.72 (1H each, br.s, H-29), 5.36 (1H, t, J = 10.0, H-4ꢅ), 5.90–5.92
a
b
+
(2H, m, H-2ꢅ, 3ꢅ), 5.98 (1H, d, J = 11.5, H-1ꢅ), 7.52 (1H, s, ÑÍ=C–N). MS m/z 890.3 [M + Na] (calcd for C H N O , 867.5).
47 69
3 12
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-galactopyranosyl)-(1ꢂ4)-(2,3,6-tri-O-acetyl-ꢁ-D-glucopyranos-
1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-en-28-oic Acid (8d). C H N O . Yield 86%, mp 166–168ꢃÑ,
59 85
3 20
21
–1
1
[ꢀ] –14.4ꢃ (c 0.7, CH ÎÍ). IR spectrum (CH ÎÍ, ꢇ, cm ): 1753 (C=O), 3444 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz):
D
3
3
0.79, 0.83, 0.89, 0.93, 0.95 (3H each, s, CÍ -23–27), 1.67 (3H, s, H-30), 1.84, 1.97, 2.05, 2.06, 2.08, 2.10, 2.16 (3H each, s,
3
COCH ), 0.64–2.26 (23H, m, CH, CH in pentacyclic skeleton), 2.69–2.78 (1H, m, H -CH ), 2.76 (1H, d, J = 10.0, H-3),
3
2
a
2
2.97–2.99 (2H, m, H-19, H -CH ), 3.91–3.99, 4.11–4.17 (6H, 2 m, H -6ꢅ, H -6ꢅꢅ, H-4ꢅ, 5ꢅ, 5ꢅꢅ), 4.49 (1H, d, J = 10.0, H -6ꢅ),
b
2
a
ab
b
4.53 (1H, d, J = 8.0, H-1ꢅꢅ), 4.58, 4.71 (1H each, br.s, H-29), 4.98 (1H, dd, J = 10.5, 3.5, H-3ꢅꢅ), 5.13 (1H, t, J = 8.0, H-2ꢅ),
+
5.37–5.43 (3H, m, H-2ꢅꢅ, 3ꢅ, 4ꢅꢅ), 5.80 (1H, d, J = 10.0, H-1ꢅ), 7.50 (1H, s, ÑÍ=C–N). MS m/z 1178.7 [M + Na] (calcd for
C H N O , 1155.6).
59 85
3 20
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxyurs-12-en-
22
–1
28-oic Acid (9). C H N O . Yield 89%, mp 152–154ꢃÑ, [ꢀ] +10ꢃ (c 1.1, CHCl ). IR spectrum (CHCl , ꢇ, cm ): 1757
(C=O), 3474 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.88 (3Í, d, J = 6.5, H-29), 0.94 (3H, s, H-30), 0.84, 0.85, 0.98, 1.04,
47 69
1
3
12
D
3
3
1.10 (3H each, s, CÍ -23–27), 0.60–2.26 (22H, m, CH, CH in pentacyclic skeleton), 1.85, 2.03, 2.07, 2.08 (3H each, s, COCH ),
3
2
3
2.62 (1H, dd, J = 13.5, 8.5, H -CH ), 2.86 (1H, d, J = 10.5, H-3), 3.10 (1H, d, J = 13.5, H -CH ), 4.20 (1Í, d, J = 12.5, H -6ꢅ),
a
2
b
2
a
4.25–4.28 (1H, m, H-5ꢅ), 4.36 (1H, dd, J = 12.5, 5.0, H -6ꢅ), 5.22 (1H, s, H-12), 5.28–5.34 (1H, m, H-2ꢅ), 5.53–5.59 (2H, m,
b
+
H-4ꢅ, 3ꢅ), 6.11 (1H, d, J = 8.5, H-1ꢅ), 8.04 (1H, s, ÑÍ=C–N). MS m/z 890.4 [M + Na] (calcd for C H N O , 867.5).
47 69
3 12
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxyolean-12-en-
21
–1
28-oic Acid (10). C H N O . Yield 88%, mp 168–170ꢃÑ, [ꢀ] +17.9ꢃ (c 0.9, CHCl ). IR spectrum (CHCl , ꢇ, cm ): 1757
47 69
3
12
D
3
3
1
(C=O), 2946 (C=C), 3476 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.81, 0.85, 0.91, 0.92, 0.96, 1.03, 1.14 (3H each, s,
CÍ -23–27, 29, 30), 1.22–2.02 (21H, m, CH, CH in pentacyclic skeleton), 1.85, 2.03, 2.06, 2.08 (3H each, s, COCH ), 2.62
3
2
3
(1H, dd, J = 14.0, 8.5, H -CH ), 2.83–2.87 (2H, m, H-3, 18), 3.11 (1H, d, J = 14.0, H -CH ), 4.19–4.28 (2H, m, H-5ꢅ, H -6ꢅ), 4.36
a
2
b
2
a
320

(1H, dd, J = 13.0, 5.0, H -6ꢅ), 5.23 (1Í, s, Í-12), 5.30 (1H, t, J = 9.5, H-4ꢅ), 5.53–5.59 (2H, m, H-2ꢅ, 3ꢅ), 6.12 (1H, d, J = 8.5,
b
+
H-1ꢅ), 8.02 (1H, s, ÑÍ=C–N). MS m/z 890.6 [M + Na] (calcd for C H N O , 867.5).
47 69
3 12
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-galactopyranos-1-yl)-ethylene-1H-1,2,3-triazol-4-yl]-3ꢁ-
18
hydroxylup-20(29)-en-28-oic Acid (17). C H N O . Yield 85%, mp 152–154ꢃÑ, [ꢀ] –17ꢃ (c 0.8, CHCl ). IR spectrum
49 73
3
13
D
3
–1
1
(CHCl , ꢇ, cm ): 1752 (C=O), 3467 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.80, 0.83, 0.91, 0.94, 0.97 (3H each, s, CÍ -23–27),
3
3
1.68 (3H, s, CÍ -30), 0.59–2.26 (23H, m, CH, CH in pentacyclic skeleton), 1.94, 1.98, 2.05, 2.17 (3H each, s, COCH ),
3
2
3
2.79–2.91 (3H, m, Í-3, CH ), 3.00–3.04 (1H, m, Í-19), 3.88–3.93, 4.11–4.17, 4.25–4.26, 4.51–4.53, 4.57–4.63 (7H, 5 m, H-5ꢅ,
2
H -6ꢅ, CH -Î, CH -N), 4.44 (1H, d, J = 10.0, H-1ꢅ), 4.59, 4.72 (1H each, br.s, H-29), 4.98 (1H, dd, J = 10.0, 3.5, H-3ꢅ),
ab
2
2
+
5.17–5.21 (1H, m, H-2ꢅ), 5.39 (1H, s, H-4ꢅ), 7.39 (1H, s, ÑÍ=C–N). MS m/z 934.3 [M + Na] (calcd for C H N O , 911.5).
49 73
3 13
Methyl 2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-galactopyranosyl)-(1ꢂ4)-(2,3,6-tri-O-acetyl-ꢁ-D-
glucopyranos-1-yl)-ethylene-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-en-28-oate (18). C H N O . Yield 89%, mp
62 91
3 21
21
–1
1
142–144ꢃÑ, [ꢀ] –18.3ꢃ (c 0.9, CHCl ). IR spectrum (CHCl , ꢇ, cm ): 1753 (C=O). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.78,
D
3
3
0.80, 0.87, 0.91, 0.95 (3H each, s, CÍ -23–27), 1.66 (3H, s, H-30), 1.93, 1.94, 2.02, 2.03, 2.04, 2.10, 2.13 (3H each, s,
3
COCH ), 0.57–2.26 (23H, m, CH, CH in pentacyclic skeleton), 2.73 (1H, dd, J = 15.0, 7.0, H -CH ), 2.79 (1H, d, J = 10.0,
3
2
a
2
H-3), 2.83–2.87 (1H, m, H -CH ), 2.95–2.99 (1H, m, H-19), 3.57–3.60 (1H, m, H-5ꢅ), 3.64 (3H, s, OCH ), 3.75–3.78,
b
2
3
3.83–3.89, 4.04–4.18 (7H, 3 m, H -6ꢅ, H -6ꢅꢅ, H-4ꢅ, 5ꢅꢅ, CH -Î), 4.42–4.50, 4.54–4.56 (5H, 2m, H -6ꢅ, H-1ꢅꢅ, 1ꢅ, CH -N), 4.57,
a
ab
2
b
2
4.70 (1H each, br.s, H-29), 4.87 (1H, t, J = 8.0, H-2ꢅ), 4.95 (1H, dd, J = 10.5, 3.5, H-3ꢅꢅ), 5.08 (1H, dd, J = 10.0, 8.0, H-2ꢅꢅ), 5.15
+
(1H, t, J = 10.0, H-3ꢅ), 5.33 (1H, d, J = 3.0, H-4ꢅꢅ), 7.33 (1H, s, ÑÍ=C–N). MS m/z 1236.9 [M + Na] (calcd for C H N O ,
62 91
3 21
1213.6).
2ꢀ-Methylene-[1N(2,3,4,6-tetra-O-acetyl-ꢁ-D-galactopyranosyl)-(1ꢂ4)-(2,3,6-tri-O-acetyl-ꢁ-D-glucopyranos-
1-yl)-ethylene-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-en-28-oicAcid (19). C H N O . Yield 90%, mp 168–170ꢃÑ,
61 89
3 21
21
–1
1
[ꢀ] –20.5ꢃ (c 0.7, CH ÎÍ). IR spectrum (CH ÎÍ, ꢇ, cm ): 1753 (C=O), 3469 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz):
D
3
3
0.79, 0.82, 0.83, 0.97, 1.00 (3H each, s, CÍ -23–27), 1.70 (3H, s, H-30), 1.95, 1.97, 2.05, 2.06, 2.07, 2.13, 2.15 (3H each, s,
3
COCH ), 0.60–2.26 (23H, m, CH, CH in pentacyclic skeleton), 2.46–2.52 (1H, m, H -CH ), 2.83 (1H, d, J = 10.0, H-3),
3
2
a
2
3.03–3.10, 3.17–3.19 (2H, 2m, H -CH , H-19), 3.76–3.79, 3.83–3.87, 3.98–4.02, 4.10–4.17 (8H, 4 m, H -6ꢅ, H -6ꢅꢅ, H-4ꢅ, 5ꢅꢅ,
b
2
a
ab
CH -Î, H-5ꢅ), 4.54–4.56, 4.66–4.68 (5H, 2m, H -6ꢅ, H-1ꢅꢅ, 1ꢅ, CH -N), 4.59, 4.72 (1H each, br.s, H-29), 4.83 (1H, t, J = 8.0,
2
b
2
H-2ꢅ), 5.03 (1H, dd, J = 10.5, 3.5, H-3ꢅꢅ), 5.13–5.21 (2H, m, H-2ꢅꢅ, 3ꢅ), 5.38 (1H, d, J = 3.0, H-4ꢅꢅ), 7.69 (1H, s, ÑÍ=C–N).
+
MS m/z 1222.6 [M + Na] (calcd for C H N O , 1199.6).
61 89
3 21
Synthesis of 11a–d, 12, and 13. General Method. A solution of 8a–d, 9, or 10 (0.1 mmol) in MeOH (2 mL) and
H O (0.2 mL) was treated with Et N (0.5 mmol), stirred for 3–4 h at room temperature (TLC monitoring), and evaporated.
2
3
The products were purified by column chromatography over silica gel [n-hexane–EtOAc (1:1) or CHCl –MeOH eluent (4:1)]
3
13
to afford 11a–d, 12, or 13. PMR and C NMR spectra and physicochemical constants of 11a and 12 were published before [9].
2ꢀ-Methylene-[1N(ꢁ-D-galactopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-en-28-oicAcid (11b).
18
–1
C H N O . Yield 90%, mp 220–222ꢃÑ, [ꢀ] –24ꢃ (c 0.8, CH ÎÍ). IR spectrum (CHCl , ꢇ, cm ): 1697 (C=O), 3437
39 61
3
8
D
3
3
1
(OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.82, 0.83, 0.96, 0.99, 1.01 (3H each, s, CÍ -23–27), 1.71 (3H, s, CÍ -30),
3
3
0.63–2.32 (23H, m, CH, CH in pentacyclic skeleton), 2.54 (1H, dd, J = 14.5, 9.0, H -CH ), 2.83 (1H, d, J = 11.0, H-3),
2
a
2
3.00–3.05 (1H, m, H-19), 3.18 (1H, d, J = 14.5, H -CH ), 3.70–3.89 (4H, m, H-5ꢅ, H -6ꢅ, Í-3ꢅ), 4.00 (1H, br.s, H-4ꢅ), 4.19
b
2
ab
(1H, t, J = 9.0, H-2ꢅ), 4.61, 4.72 (1H each, br.s, H-29), 5.55 (1H, d, J = 9.5, H-1ꢅ), 7.97 (1H, s, ÑÍ=C–N). MS m/z 722.4
+
[M + Na] (calcd for C H N O , 699.5).
39 61
3 8
2ꢀ-Methylene-[1N(ꢀ-D-mannopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxylup-20(29)-en-28-oicAcid (11c).
21
–1
C H N O . Yield 70%, mp 256–258ꢃÑ, [ꢀ] –18ꢃ (c 0.7, CH ÎÍ). IR spectrum (CHCl , ꢇ, cm ): 1725 (C=O), 3442
39 61
3
8
D
3
3
1
(OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.82, 0.83, 0.97, 0.99, 1.00 (3H each, s, CÍ -23–27), 1.70 (3H, s, CÍ -30),
3
3
0.63–2.36 (23H, m, CH, CH in pentacyclic skeleton), 2.53–2.57 (1H, m, H -CH ), 2.84 (1H, d, J = 11.0, H-3), 3.07–3.09 (1H,
2
a
2
m, H-19), 3.18 (1H, d, J = 14.0, H -CH ), 3.73–3.87 (4H, m, H-5ꢅ, H -6ꢅ, Í-3ꢅ), 4.03 (1H, br.s, H-4ꢅ), 4.19 (1H, t, J = 9.0,
b
2
ab
+
H-2ꢅ), 4.59, 4.70 (1H each, br.s, H-29), 5.56 (1H, d, J = 9.0, H-1ꢅ), 7.99 (1H, s, ÑÍ=C–N). MS m/z 722.4 [M + Na] (calcd for
C H N O , 699.5).
39 61
3 8
2ꢀ-Methylene-[1N(ꢁ-D-galactopyranosyl)-(1ꢂ4)-( ꢁ-D-glucopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-
21
hydroxylup-20(29)-en-28-oicAcid (11d). C H N O . Yield 84%, mp 236–238ꢃÑ, [ꢀ] –22ꢃ (c 0.8, CH ÎÍ). IR spectrum
45 71
1
3
12
D
3
–1
(CH ÎÍ, ꢇ, cm ): 1683 (C=O), 3452 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.82, 0.83, 0.96, 0.99, 1.00 (3H each, s,
3
CÍ -23–27), 1.71 (3H, s, H-30), 0.62–2.32 (23H, m, CH, CH in pentacyclic skeleton), 2.51–2.56 (1H, m, H -CH ), 2.82 (1H,
3
2
a
2
d, J = 10.0, H-3), 3.00–3.05 (1H, m, H-19), 3.16–3.20 (1H, m, H -CH ), 3.50–3.66, 3.73–3.95, 4.00–4.04 (12H, 3m, CH-OH,
b
2
321

CH OH in disaccharide), 4.44 (1H, d, J = 8.0, H-1ꢅꢅ), 4.61, 4.72 (1H each, br.s, H-29), 5.62 (1H, d, J = 10.0, H-1ꢅ), 7.94 (1H,
2
+
s, ÑÍ=C-N). MS m/z 884.3 [M + Na] (calcd for C H N O , 861.5).
45 71
3 12
2ꢀ-Methylene-[1N(ꢁ-D-glucopyranos-1-yl)-1H-1,2,3-triazol-4-yl]-3ꢁ-hydroxyolean-12-en-28-oic Acid (13).
18
–1
C H N O . Yield 93%, mp 220–222ꢃÑ, [ꢀ] –1ꢃ (c 0.8, CH ÎÍ). IR spectrum (CH ÎÍ, ꢇ, cm ): 1695 (C=O), 2944
39 61
3
8
D
3
3
1
(C=C), 3383 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.78, 0.81, 0.88, 0.89, 0.92, 0.98, 1.13 (3H each, s, CÍ -23–27, 29, 30),
3
0.64–1.99 (21H, m, CH, CH in pentacyclic skeleton), 2.51 (1H, dd, J = 14.5, 9, H -CH ), 2.81–2.83 (2H, m, H-3, 18), 3.14
2
a
2
(1H, d, J = 14.5, H -CH ), 3.47–3.58 (3H, m, H-3ꢅ, 4ꢅ, 5ꢅ), 3.69–3.72 (1H, m, H -6ꢅ), 3.86–3.91 (2H, m, H-2ꢅ, H -6ꢅ), 5.19 (1Í,
b
2
a
b
+
s, Í-12), 5.55 (1H, d, J = 9.0, H-1ꢅ), 7.91 (1H, s, ÑÍ=C-N). MS m/z 722.5 [M + Na] (calcd for C H N O , 699.5).
39 61
3 8
Reactions of Triterpenoids 1 and 16 with Triazolylazide 21. General Method. A solution of triterpenoid 1 or 16
(0.2 mmol) in t-BuOH (3 mL) was treated in turn with triazolylazide 21 (0.3 mmol) and CuI (0.008 g, 0.04 mmol), stirred for
23 h at 70°C (TLC monitoring), cooled, treated with H O (6 mL), and extracted (4 ꢈ 10 mL) with EtOAc. The organic layer
2
was washed with H O (40 mL) and dried (MgSO ). The products were purified by column chromatography over silica gel
2
4
(CHCl –MeOH eluent, 15:1) to afford 22 or 23.
3
3-Azido-[1-(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-methylene-1H-1,2,3-triazol-4-yl]propan-2-ol (21) was
25
prepared by the literature method [14]. C H N O . Yield 56%, amorphous compound, [ꢀ] –18.6ꢃ (c 0.6, CHCl ).
IR spectrum (CHCl , ꢇ, cm ): 2106 (N ). Í NMR spectrum (ꢄ, ppm, J/Hz): 1.98, 1.99, 2.02, 2.08 (3H each, s, COCH ),
20 28
6
11
D
3
–1
1
3
3
3
3.54–3.61 (2H, m, ÑÍ -N ), 3.72–3.75 (1H, m, H-5), 4.15 (1H, d, J = 12.5, H -6), 4.26 (1H, dd, J = 12.5, 4.0, H -6), 4.28–4.33
2
3
a
b
(1H, m, ÑÍ-ÎÍ), 4.60–4.65 (2Í, m, CH -Î), 4.68 (1Í, d, J = 8.0, Í-1), 4.78 (1Í, dd, J = 13.0, = 4.0, H -CH N), 4.88 (1Í, d,
2
a
2
J = 13.0, H -CH N), 4.95–4.99 (1H, m, Í-2), 5.08 (1Í, t, J = 10.0, H-4), 5.20 (1H, t, J =10.0, H-3), 7.69 (1H, s, ÑÍ=C-N).
b
2
13
C NMR spectrum (ꢄ, ppm, J/Hz): 20.8 (COCH ), 45.9 (ÑÍ -N ), 53.1 (CH -Î), 61.8 (C-6), 62.9 (CH -N), 68.3 (C-4), 69.9
3
2
3
2
2
(CH-OH), 71.3 (C-2), 71.9 (C-5), 72.7 (C-3), 100.0 (C-1), 124.6, 124.7 (ÑÍ=C-N), 144.0 (ÑÍ=C-N), 169.4, 169.5, 170.2,
+
170.8 (COCH ). MS m/z 567.1 [M + K] (calcd for C H N O , 528.2).
3
20 28 6 11
Methyl 2ꢀ-Methylene-{1N-1H-1,2,3-triazol-4-yl-[3-(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-methylene-
1H-1,2,3-triazol-4-ylpropan-2-ol]}-3ꢁ-hydroxylup-20(29)-en-28-oate (22). C H N O . Yield 62%, mp 128–130ꢃÑ,
54 80
1
6 14
25
–1
[ꢀ] –19.1ꢃ (c 0.7, CHCl ). IR spectrum (CHCl , ꢇ, cm ): 1757 (C=O), 3444 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.79,
D
3
3
0.81, 0.90, 0.94, 0.96 (3H each, s, CÍ -23–27), 1.68 (3H, s, CÍ -30), 0.59–2.25 (23H, m, CH, CH in pentacyclic skeleton),
3
3
2
2.01, 2.04, 2.09, 2.10 (3H each, s, COCH ), 2.59–2.65 (1H, m, H -CH ), 2.82–2.90 (2H, m, H-3, H -CH ), 2.99–3.02 (1H, m,
3
a
2
b
2
H-19), 3.67 (3H, s, CO Me), 3.74–3.78 (1H, m, H-5ꢅ), 4.17–4.19 (1Í, m, H -6ꢅ), 4.25–4.45 (3H, m, H -6ꢅ, CH N), 4.50–4.59
2
a
b
2
(4H, m, H-29, ÑÍ-ÎÍ, CH -Î), 4.70 (1Í, d, J = 8.0, Í-1ꢅ), 4.73 (1H, s, Í-29), 4.81 (1Í, dd, J = 12.5, 2.5, H -CH N), 4.92
2
a
2
(1Í, dd, J = 12.5, 6.0, H -CH N), 4.97–5.01 (1H, m, Í-2ꢅ), 5.10 (1Í, dt, J = 10.0, 2.5, H-4ꢅ), 5.22 (1H, t, J = 10, H-3ꢅ), 7.48,
b
2
13
7.50, 7.75, 7.76 (2H, 4 s, ÑÍ=C-N). C NMR spectrum (ꢄ, ppm, J/Hz): 14.7 (Ñ-27), 15.9 (Ñ-25), 16.3 (Ñ-24), 16.9 (Ñ-26),
18.5 (Ñ-6), 19.4 (Ñ-30), 20.5, 20.6, 20.7, 20.8 (ÑÎÑÍ ), 20.9 (Ñ-11), 25.5 (Ñ-12), 28.4 (Ñ-23), 29.2 (=C-CH ), 29.6 (C-15),
3
2
30.6 (C-21), 32.2 (C-16), 34.2 (C-7), 35.7 (C-2), 36.9 (C-22), 37.4 (C-4), 38.2 (C-13), 39.2 (C-10), 40.7 (C-8), 42.4 (C-14), 45.4
(C-1), 47.0 (C-19), 49.5 (C-18), 50.4 (C-9), 51.3 (CO Me), 53.2 (CH -N), 55.5 (C-5), 56.5 (C-17, CH -O), 61.8 (C-6ꢅ), 62.9
2
2
2
(CH -N), 68.3 (C-4ꢅ), 68.7 (CH-OH), 71.3 (C-2ꢅ), 71.9 (C-5ꢅ), 72.7 (C-3ꢅ), 82.2 (C-3), 99.9 (C-1ꢅ), 109.6 (C-29), 123.8, 123.9,
2
125.0 (ÑÍ=C-N), 143.8, 146.3, 146.4 (ÑÍ=C-N), 150.6 (Ñ-20), 169.5, 169.6, 170.2, 170.8 (COCH ), 176.7 (Ñ-28).
3
+
MS m/z 1059.6 [M + Na] (calcd for C H N O , 1036.6).
54 80
6 14
2ꢀ-Methylene-{1N-1H-1,2,3-triazol-4-yl-[3-(2,3,4,6-tetra-O-acetyl-ꢁ-D-glucopyranos-1-yl)-methylene-1H-1,2,3-
triazol-4-ylpropan-2-ol]}-3ꢁ-hydroxylup-20(29)-en-28-oic Acid (23). C H N O . Yield 53%, mp 144–146ꢃÑ,
53 78
1
6 14
21
–1
[ꢀ] –17.4ꢃ (c 0.8, CHCl ). IR spectrum (CHCl , ꢇ, cm ): 1756 (C=O), 3446 (OH). Í NMR spectrum (ꢄ, ppm, J/Hz): 0.79,
D
3
3
0.80, 0.91, 0.95, 0.97 (3H each, s, CÍ -23–27), 1.68 (3H, s, CÍ -30), 0.58–2.28 (23H, m, CH, CH in pentacyclic skeleton),
3
3
2
2.01, 2.04, 2.09, 2.10 (3H each, s, COCH ), 2.54–2.65 (1H, m, H -CH ), 2.84–3.02 (3H, m, H-3, H -CH , H-19), 3.75–3.77
3
a
2
b
2
(1H, m, H-5ꢅ), 4.12–4.19 (1Í, m, H -6ꢅ), 4.25–4.44 (3H, m, H -6ꢅ, CH N), 4.50–4.59 (4H, m, H-29, ÑÍ-ÎÍ, CH -Î), 4.70 (1Í,
a
b
2
2
d, J = 8.5, Í-1ꢅ), 4.72 (1H, s, Í-29), 4.80 (1Í, d, J = 12.5, H -CH N), 4.92 (1Í, dd, J = 12.5, 1.5, H -CH N), 4.97–5.01 (1H,
a
2
b
2
13
m, Í-2ꢅ), 5.10 (1Í, dt, J = 10.0, 1.5, H-4ꢅ), 5.22 (1H, t, J = 10, H-3ꢅ), 7.52, 7.76, 7.77 (2H, 3 s, ÑÍ=C-N). C NMR spectrum
(ꢄ, ppm, J/Hz): 14.7 (Ñ-27), 16.0 (Ñ-25), 16.3 (Ñ-24), 16.9 (Ñ-26), 18.5 (Ñ-6), 19.3 (Ñ-30), 20.5, 20.6, 20.7, 20.8 (ÑÎÑÍ ),
3
20.9 (Ñ-11), 25.4 (Ñ-12), 28.4 (Ñ-23), 29.2 (=C-CH ), 29.6 (C-15), 30.6 (C-21), 32.2 (C-16), 34.2 (C-7), 35.7 (C-2), 37.0
2
(C-22), 37.4 (C-4), 38.4 (C-13), 39.3 (C-10), 40.7 (C-8), 42.5 (C-14), 45.4 (C-1), 47.0 (C-19), 49.3 (C-18), 50.4 (C-9), 53.2
(CH -N), 55.5 (C-5), 56.3 (C-17, CH -O), 61.8 (C-6ꢅ), 62.8 (CH -N), 68.3 (C-4ꢅ), 68.7 (CH-OH), 71.3 (C-2ꢅ), 71.9 (C-5ꢅ), 72.7
2
2
2
(C-3ꢅ), 82.2 (C-3), 99.9 (C-1ꢅ), 109.6 (C-29), 123.8, 124.0, 125.0 (ÑÍ=C-N), 143.9, 146.3, 146.4 (ÑÍ=C-N), 150.5 (Ñ-20),
+
169.5, 169.7, 170.3, 170.9 (COCH ), 181.1 (Ñ-28). MS m/z 1045.5 [M + Na] (calcd for C H N O , 1022.6).
3
53 78 6 14
322

ACKNOWLEDGMENT
The work was financially supported by the Russian Science Foundation (Grant No. 16-13-10051). Bis-triazole
derivatives 22 and 23 were synthesized by D. A. Nedopekina with financial support from the Russian Foundation for Basic
Research (Grant No. mol_a 16-33-00044). We thank the National Cancer Institute (NCI) for in vitro tests for antitumor
activity of the synthesized compounds.
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