Synthesis of glycyrrhizic acid conjugates containing L-lysine

Article abstract of DOI:10.1007/s10600-006-0210-7

Activated esters and N-hydroxybenzotriazole-N,N′- dicyclohexylcarbodiimide (DCC) or N-hydroxysuccinimide-DCC were used to synthesize conjugates of glycyrrhizic acid (GA) with N^ε- carbobenzyloxy-L-lysine [Lys(Z)-OH] and its esters containing two

Full text of DOI:10.1007/s10600-006-0210-7

Chemistry of Natural Compounds, Vol. 42, No. 5, 2006
SYNTHESIS OF GLYCYRRHIZIC ACID CONJUGATES
CONTAINING L-LYSINE
L. A. Baltina, Jr.,1,2 R. M. Kondratenko,1 L. A. Baltina,1,2
O. A. Plyasunova,3 F. Z. Galin,2 and G. A. Tolstikov4
UDC 547.598.458.22
N
N,N′
N
Activated esters and -hydroxybenzotriazole-
-dicyclohexylcarbodiimide (DCC) or -hydroxy-
Nε
succinimide-DCC were used to synthesize conjugates of glycyrrhizic acid (GA) with -carbobenzyloxy-L-
Z
lysine [Lys( )-OH] and its esters containing two or three amino components. It was shown that the conjugate
Z
of GA 30-methyl ester with Lys( )-OH possessed anti-HIV-1 activity.
Key words: glycyrrhizic acid, L-lysine.
Chemical modification of glycyrrhizic acid (GA, 1), the principal triterpene glycoside in the extract of licorice root
(
L. and
Fisher), is a promising method for preparing new medically valuable and biologically
G. uralensis
Glycyrrhiza glabra
active anti-inflammatory, antiulcer, immunomodulating, and antiviral compounds [1, 2].
We have previouslysynthesized glucopeptide conjugates (GC) with various amino acids and dipeptides, among which
were found stimulators of the primary immune response [3-5] and anti-inflammatory, antiulcer, and anti-HIV agents [6-8].
In continuation of our research on the synthesis of new biologically active GA derivatives, we synthesized new
conjugates (2-8) with an amide bond formed through the α-NH group of Nε-carbobenzyloxy-L-lysine or its esters containing
2
two or three amino components.
COR
O
1:
2:
3:
4:
5:
6:
7:
8:
R = R1 = OH
R = R1 = Lyz(Z)-OMe
R = OH, R1 = Lys(Z)-OMe
COR
OH
1
O
t
O
R = OH, R1 = Lys(Z)-OBu
R = OMe, R1 = Lys(Z)-OMe
t
HO
COR
R = OMe, R1 = Lys(Z)OBu
O
R = OH, R1 = Lys(Z)-OH
1
R = OMe, R1 = Lys(Z)-OH,
O
Lys(Z)-OH = C6H5CH2OCONH5CH2 CH2 CH2 CH2 CH(COOH)NH-
4
3
2
1
OH
HO
OH
1 - 8
ε
2
Conjugate was synthesized by condensation of GA with the trifluoroacetate of N -carbobenzyloxy-L-lysine methyl
ester [Lys(Z)-OMe·CF COOH] using N-hydroxybenzotriazole (HOBt)-N,N′-dicyclohexylcarbodiimide (DCC) in the presence
3
2
of triethyloamine (Et N) as described previously [9]. The yield of after purification by column chromatography (CC) over
3
silica gel (SG) was 52%.
1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya,
71, e-mail: baltina@anrb.ru; 2) Bashkir State Medical University, 450000, Ufa, ul. Lenina, 3; 3) Vector State Scientific Center
of Virology and Biotechnology, 633159, Novosibirsk Dist., Kol′tsovo; 4) Novosibirsk Institute of Organic Chemistry, Siberian
Division, Russian Academy of Sciences, 630090, Novosibirsk, pr. Lavrent′eva, 9. Translated from Khimiya Prirodnykh
Soedinenii, No. 5, pp. 437-441, September-October, 2006. Original article submitted July 26, 2006.
0009-3130/06/4205-0543 ©2006 Springer Science+Business Media, Inc.
543

TABLE 1. 13C NMR Spectra of the Aglycon of Conjugates 2-8 (75.5 MHz, δ, ppm, 25°C)
2
3
4
5
6
7
8
C atom
(CD3OD)
(CD3OD)
(CD3OD)
(CD3OD+CDCl3)
(acetone-d6)
(DMF-d7)
(acetone-d6)
1
2
3
4
5
6
7
8
40.6
27.4
90.9
40.9
56.7
18.8
34.0
47.0
63.4
38.1
202.8
129.2
171.7
44.9
27.6
27.9
33.2
-
41.8
44.9
32.8
38.4
28.7
17.4
17.7
19.7
23.9
29.1
29.5
174.0
-
40.2
27.1
90.8
40.7
56.4
18.6
33.8
46.8
63.1
38.1
202.7
128.5
171.3
44.7
27.5
27.9
33.0
-
42.5
44.5
32.5
39.0
28.5
17.1
17.4
19.4
23.4
28.8
29.3
180.5
-
39.8
26.8
88.7
40.7
54.5
16.6
31.2
46.2
61.2
38.6
200.7
127.7
171.3
43.2
26.9
27.4
32.0
-
42.7
44.9
31.1
38.9
26.9
15.5
15.7
17.8
22.4
27.6
28.7
179.1
-
38.7
27.4
90.6
39.0
56.4
18.5
33.8
46.7
63.1
38.1
202.5
129.5
171.4
44.6
27.4
27.6
33.0
-
42.5
44.9
32.5
38.1
28.8
17.1
17.4
19.4
24.1
28.5
29.2
176.3
51.2
39.9
25.8
88.3
40.6
54.5
16.9
32.1
-
61.2
37.3
198.4
129.9
170.1
44.8
26.9
26.9
31.5
47.8
42.4
43.4
31.3
38.6
-
40.1
26.3
88.9
40.2
56.4
17.7
31.7
44.8
61.0
36.9
199.0
128.1
169.3
43.5
27.6
27.8
-
48.1
42.8
43.5
31.2
38.9
-
15.7
16.9
17.9
22.5
-
39.3
26.2
88.5
40.3
54.6
17.1
32.4
45.1
61.5
37.5
199.3
128.9
170.5
43.0
27.3
27.9
31.5
48.2
43.1
43.9
31.3
38.8
-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
15.6
16.0
17.7
22.6
-
29.4
175.9
50.9
15.9
16.2
18.2
-
-
-
25.5
180.0
-
176.3
51.0
TABLE 2. 13C NMR Spectra of the Carbohydrate Part of Conjugates 2-8 (75.5 MHz, δ, ppm, 25°C)
C atom
2
3
4
5
6
7
8
1′
2′
3′
4′
5′
105.2
81.4
76.2
73.6
78.0
171.6
105.3
76.1
76.5
73.8
77.5
171.7
104.9
81.6
76.4
73.1
77.7
171.3
105.3
76.1
76.5
73.6
77.4
171.6
102.9
81.7
73.7
71.6
75.7
169.4
103.0
73.3
73.9
71.8
75.1
169.6
105.0
81.8
76.3
73.3
77.8
171.3
105.2
76.0
76.4
73.5
77.3
171.4
103.1
81.2
74.2
72.1
75.7
168.6
103.2
73.0
73.5
72.1
75.3
169.5
106.4
79.9
75.9
72.0
76.6
168.8
108.7
75.0
75.9
72.0
76.2
169.0
103.2
81.2
74.6
72.2
76.0
169.6
103.7
73.1
74.3
72.2
75.5
169.5
6′
1′′
2′′
3′′
4′′
5′′
6′′
Compounds 3 and 4 with two Lys(Z)-OMe or Lys(Z)-O-t-Bu units only in the carbohydrate part of the molecule were
preparedbyactivation oftheGAcarboxylswith N-hydroxysuccinimide(HOSu)-DCCata moleratioGA:HOSu:DCC:Lys(Z)-OR
1:4:2.3-2.5:3 mmol in dioxane. The free COOH group in the aglycon part of 3 and 4 was confirmed byretention ofthe chemical
13
shift (CS) of C-30 at about 180 ppm in C NMR spectra of these compounds, like in the spectrum of GA [10, 11].
544

TABLE 3. Chemical Shifts of Amino Acids [Lys(Z)-] in 13C NMR Spectra of Conjugates 2-8 (75.5 MHz, δ, ppm, 25°C)
Compound
C-1
C-2
C-3
C-4
C-5
2
174.0
173.3
173.2
174.7
172.9
170.9
170.4
174.7
173.9
171.0
170.2
176.4
173.4
172.8
172.6
53.8
53.5
53.2
53.6
53.0
52.0
51.9
53.8
53.5
52.3
51.9
52.0
51.0
51.6
51.4
30.8
30.5
29.5
32.1
30.6
30.4
30.5
32.7
32.3
30.9
30.3
31.9
31.4
30.9
30.5
24.3
24.1
23.9
24.1
23.9
22.2
21.7
24.3
23.9
22.2
21.9
22.2
21.8
22.8
22.2
68.8
67.7
67.0
68.6
67.4
65.7
65.5
64.7
64.3
65.1
65.1
65.0
65.0
65.7
65.7
3
4
5
6
7
8
______
Other signals for 2: 138.6, 138.1, 129.9, 129.7, 129.5, 129.0, 128.9, 128.2 (C6H5), 53.0, 53.2 (COOCH ).
3
3: 129.7, 129.5, 129.3, 128.8, 128.7, 128.0 (C6H5), 52.8, 52.7 (COOCH3).
4: 137.2, 127.9, 127.6, 127.3 (C6H5), 27.9, 26.9 (t-Bu).
5: 138.6, 138.0, 129.8, 129.7, 129.5, 129.2, 129.0, 128.9 (C6H5), 53.2, 53.0 (COOCH3).
6: 156.0, 137.2, 127.9, 127.6, 127.3 (C6H5), 27.93, 26.93 (t-Bu).
7: 139.7, 134.0, 131.9, 129.2, 128.1, 127.5, 113.3 (C6H5).
8: 158.4, 156.7, 137.2, 127.9, 127.8, 117.4 (C6H5).
30-Methyl esters 5 and 6 were prepared bytreating 3 and 4 with an ether solution of diazomethane in MeOH. The C-30
13
signal in the C NMR spectrum of 5 shifted to 177.3 ppm, like in the spectrum of methylglycyrrhetate [12].
The t-butyl esters in 4 and 6 were removed with CF COOH in CH Cl to produce 7 and 8, respectively, in 79-81%
3
2
2
13
yields. The structures ofthe newGA derivatives were confirmed byelemental analyses and IR, UV, PMR, and C NMR spectra
(Tables 1-3). Signals of C atoms in the C NMR spectra of 2-7 were assigned using literature data for analogous GA
13
derivatives [4, 9-12].
13
Introducing Lys(Z)-OH or its esters causes the appearance in the C NMR spectra of additional signals at 171-
174 ppm (COOH); 52-54 and 64-68 ppm (Lys); and aromatic C atoms of the C H group.
6
5
The cytotoxicity and anti-HIV-1 activities of 8 were studied using a model for primary infection of HIV-1 in MT-4
lymphoid cells and were compared with GA as described before [7, 8]. Inhibition of HIV-1 reproduction in the cells was
determined from the decrease in accumulation ofviralantigen p24(byimmunoenzymeanalysis)in culturemediumon the fourth
dayof cultivation bycomparison with a control (without added preparation). It was found that 8 possessed moderate anti-HIV-1
activity in MT-4 cell culture. The 50% inhibition dose (ID ) was 200 µg/mL; 50% toxic dose (CD ) causing 50% cell death,
50
50
2000 µg/mL; index of selectivity (IS) (ratio of CD to ID ) for p24 inhibition, 10. Thus, 8 exhibited 50% inhibition of HIV-1
50
50
at a lower concentration [ID GA (97%) = 250 µM]. The IS was comparable with that of GA (IS GA = 9.6) [13]. It is also
50
important to note that 8 exhibited no noticeable protective effect against the cytopathogenic activity of the virus.
EXPERIMENTAL
Column chromatographywasperformedover silica gel L(Chemapol, Czech Rep.)using CHCl :CH OH:H O mixtures
3
3
2
(300:10:1, 200:10:1, 100:10:1, v/v, stepwise gradient). TLC used Silufol plates (Chemapol, Czech Rep.) and
CHCl :CH OH:H O (45:10:1). Spots were developed using phosphotungstic acid solution (20%) in ethanol (96%) and heating
3
3
2
to100-120°C for 2-3 min. Optical activitywas measured on a Perkin—Elmer 241 MC polarimeter in a 1-dm tube with CH OH.
3
545

IR spectra were recorded on a Specord M80 spectrophotometer in mineral-oil mulls; UV spectra, on a Shimadzu UV-
13
365 spectrophotometer in CH OH; PMR and C NMR, on a Bruker AM-300 spectrometer at 300 and 75.5 MHz working
3
frequency in CD OD, CDCl +CD OD, or DMF-d with TMS internal standard.
3
3
3
7
Et N, DMF, and dioxane were purified by literature methods [14]. Solvents were evaporated in vacuo at 45-50°C.
3
We used GA (92 ± 2%) prepared as before [15], DCC (Ferak, Germany), Nα-Boc-Nε-Z-L-Lys and Nε-Z-L-Lys-O-t-Bu·HCl
(Reanal, Hungary).
Nα-t-Butyloxycarbonyl-Nε-carbobenzyloxy-L-lysine Methyl Ester. A solution of Nα-Boc-Nε-Z-Lys (13.4 g,
74 mmol) in CH OH (180 mL) was cooled on an ice bath, treated with an ether solution of diazomethane until a yellow color
3
was stable, stirred for 15-20 min, treated with glacial acetic acid (2 drops) to decompose the excess of diazomethane, and
evaporated in vacuo. The solid was dissolved in ethylacetate (150 mL) and washed with NaHCO solution (1 N) and water.
3
The organic phase was dried over MgSO and evaporated. The dry solid was recrystallized from ethylacetate:hexane. Yield
4
20
20
10.0 g (72%), R 0.71 (benzene:alcohol, 10:1), mp 115-118°C, [α]
(2%, CH OH); lit. [17] mp 115.5-116.56°C, [α]
+13° (c 0.02, EtOH); lit. [16] mp 117°C, [α]
16.7°C
f
D
D
20
+12.2° (2%, 0.1 N HCl).
3
D
3-O-{2-O-[N-(β-D-Glucopyranosyluronoyl)-Nε-(Z)-L-lysinemethylester]-N-(β-D-glucopyranosyluronoyl-Nε-(Z)-
L-lysine methyl ester}-(3β,20β)-11-oxo-30-(N-carbonyl-Nε-(Z)-L-lysine methyl ester)-olean-12-en (2).
1. Nε-Carbobenzyloxy-L-lysine methyl ester trifluoracetate. Nα-Boc-Lys(Z)-OMe (10 g) was dissolved in CF COOH
3
(20 mL), held for 30 min at 20-22°C, diluted with dry CH Cl (20 mL), and evaporated in vacuo. The solid was dried with dry
2
2
benzene (3 × 15 mL) to produce Lys-(Z)-OMe·CF COOH (5.8 g) that was reprecipitated from ethylacetate with hexane and
3
condensed with GA without further purification. C H N O F .
17 23
6 6 3
2. A solution of GA (0.82 g, 1 mmol) in dioxane (20 mL) at 0-5°C was treated with HOBt (0.47 g, 3.5 mmol) and DCC
(0.72 g, 3.5 mmol), stirred with cooling for 1 h and at 20-22°C for 6 h, left overnight in a refrigerator, and filtered to remove
solid N,N′-dicyclohexylurea. The filtrate was treated with Lys-(Z)-OMe·CF COOH (1.86 g, 4 mmol), DMF (10 mL), and Et N
3
3
(0.7 mL, 5.1 mmol). The mixture was periodically stirred at 20-22°C for 24 h, diluted with cold water, and acidified with citric
acid until the pH was about 3. The solid was filtered off, washed with water, and dried to produce 2 (1.04 g) that was
chromatographed over a column of SG (100/160 µm) with elution by CHCl :CH OH:H O (300:10:1, 200:10:1, 100:10:1,
3
3
2
50:10:1, v/v). The 100:10:1 mixture eluted 2 (0.86 g, 52%) that was homogeneous byTLC as an amorphous yellow compound,
20
-1
R 0.58, [α]
+35° (c 0.03). IR spectrum ( , cm ): 3600-3200 (OH, NH); 1730 (COOR); 1660 (C11=O); 1540 (CONH); 1520
f
D
(C H ). UV spectrum (λ , nm): 249 (log ε 4.38). C H N O .
6
5
87 122 6 25
max
PMR spectrum (300 MHz, CD OD, δ, ppm): 0.80, 0.82, 1.05, 1.10, 1.14, 1.24, 1.28 (21H, all s, 7CH ), 2.85 (1H, s,
3
3
13
H-9), 3.70, 3.72 (9H, s, 3COOCH ), 5.05 (4NH), 5.56 (1H, s, H-12), 7.34 (C H ). Tables 1-3 give the C NMR spectra.
3
6 5
3-O-{2-O-[N-(β-D-Glucopyranosyluronoyl)-Nε-(Z)-L-lysine methyl ester]-N-(β-D-glucopyranosyluronoyl)-Nε-(Z)-
L-lysine methyl ester}-(3β,20β)-11-oxo-olean-12-en-30-oic Acid (3). A solution of GA (0.82 g, 1 mmol) in dioxane (15 mL)
at 0-5°C was treated with HOSu (0.46 g, 4 mmol) and DCC (0.55 g, 2.5 mmol), stirred at this temperature for 2 h, stored in
a refrigerator overnight, and filtered to remove solid N,N′-dicyclohexylurea. The filtrate was cooled to 0-5°C; treated with
CF COOH·Lys-(Z)-OMe (1.39 g, 3 mmol), DMF (10 mL), and Et N (0.7 mL, 5.1 mmol); held at 20-22°C with periodic stirring
3
3
for 24 h, diluted with cold water, and acidified with citric acid until the pH was about 3. The solid was filtered off, washed with
water, and dried to produce crude product (1.0 g) that was chromatographed over a column of SG as described above. Yield
20
-1
0.62 g (45%), R 0.6, [α]
+60° (c 0.02). IR spectrum ( , cm ): 3600-3200 (OH, NH); 1740 (COOR); 1665 (C =O); 1540
11
f
D
(CONH). UV spectrum (λ , nm): 248 (log ε 4.22). C H O N .
72 102 22
4
max
PMRspectrum (300 MHz, CD OD, δ, ppm): 0.80, 1.04, 1.08, 1.10, 1.14, 1.16, 1.40 (21H, all s, 7CH ), 3.30, 3.35 (6H,
3
3
13
both s, 2COOCH ), 5.56 (1H, s, H-12), 7.34 (2C H ). Tables 1-3 give the C NMR spectra.
3
6 5
Conjugate 2 (10%) and starting GA (20%) were isolated from the reaction products as impurities and were identified
by TLC with markers.
3-O-{2-O-[N-(β-D-Glucopyranosyluronoyl)-Nε-(Z)-L-lysine-t-butyl ester]-N-(β-D-glucopyranosyluronoyl)-Nε-(Z)-
L-lysine-t-butyl ester}-(3β,20β)-11-oxo-olean-12-en-30-carboxylic Acid (4). A solution of GA (0.82 g, 1 mmol) in
dioxane (30 mL) at 0-5°C was treated with HOSu (0.6 g, 5.2 mmol) and DCC (0.65 g, 3 mmol), stirred and cooled for 2 h, and
stored in a refrigerator overnight. Solid N,N′-dicyclohexylurea was filtered off. The filtrate was cooled in an ice bath, treated
with Lys-(Z)-O-t-Bu·HCl (1.12 g, 1 mmol) and Et N (0.6 mL, 4 mmol), held at 20-22°C with periodic stirring for 24 h, diluted
3
with cold water, and acidified with citric acid until the pH was about 3. The solid was filtered off, washed with water and dried.
The resulting product (1.07 g) was reprecipitated from CHCl :CH OH with ether and chromatographed over a column of SG
3
3
546

20
-1
as described above. Yield 0.68 g (48%), R 0.50, [α]
+55° (c 0.02). IR spectrum ( , cm ): 3600-3200 (OH, NH); 1740
f
D
(COOR); 1660 (C11=O); 1540 (CONH). UV spectrum (λ , nm): 248.8 (log ε 4.20). C H O N .
76 114 22
4
max
PMR spectrum (300 MHz, CD OD, δ, ppm, J/Hz): 0.74, 0.86, 0.90, 0.97, 1.04, 1.07, 1.14, 1.30, 1.37, 1.39 (39H, all
3
s, 13CH ), 2.58 (1H, s, H-9), 3.05 (1H, d, J = 6.0, H-3), 4.30 (1H, d, J = 6.9, H-5′), 4.48 (1H, d, J = 7.0, H-1′), 4.98 (4H, s, NH),
3
13
5.54 (1H, s, H-12), 6.24, 7.25 (2C H ). Tables 1-3 give the C NMR spectra.
6
5
General Method for Methylating 3 and 4. A solution of 3 or 4 (0.5 g) in CH OH (20 mL) at 0-5°C was treated with
3
an ether solution of diazomethane until the yellow color was stable. The solutions were filtered and evaporated. The solid was
chromatographed over a column of SG as described above.
20
-1
30-Methyl Ester of 5. Yield 82%, [α]
+35° (c 0.02). IR spectrum ( , cm ): 3600-3200 (OH, NH); 1750-1730
D
(COOMe); 1600 (C11=O); 1540 (CONH). UV spectrum (λ , nm): 249 (log ε 4.10). C H O N . Tables 1-3 give the
73 104 22
4
max
13
C NMR spectra.
30-Methyl Ester of 6. Yield 0.43 g (86%), [α]
20
-1
+35° (c 0.02). IR spectrum ( , cm ): 3600-3200 (OH, NH); 1740
D
(COOR); 1660 (C11=O); 1540 (CONH). UV spectrum (λ , nm): 247 (log ε 4.31). C H O N .
76 117 22
4
max
PMR spectrum (300 MHz, acetone-d , δ, ppm, J/Hz): 0.78, 0.86, 1.10, 1.14, 1.44, 1.50 (42H, all s, 14CH ), 2.65 (1H,
3
6
s, H-9), 3.14 (1H, d, J = 5.4, H-3), 3.65 (3H, s, COOCH ), 4.40 (1H, d, J = 7.5, H′), 4.75 (1H, d, J = 7.5, H′′), 4.90 (1H, H-2′),
3
5.10 (4H, s, NH), 5.55 (1H, s, H-12), 7.30, 7.35 (2C H ).
6
5
General Method for Deblocking 4 and 6. Conjugate 4 or 6 (0.5 g) was dissolved in a mixture of CF COOH (5 mL)
3
and CH Cl (5 mL) and held at 20-22°C for 1 h. Solvent and CF COOH were evaporated with drybenzene (3 × 5 mL) in vacuo
2
2
3
at about 50°C. The solid was chromatographed over SG with elution byCHCl :CH OH:H O(200:10:1, 100:10:1, 50:10:1, v/v).
3
3
2
Fractions that were homogeneous by TLC were combined and evaporated.
3-O-{2-O-[N-(β-D-glucopyranosyluronoyl)-Nε-(Z)-L-lysine]-N-(β-D-glucopyranosyluronoyl)-Nε-(Z)-L-lysine}-
20
-1
(3β,20β)-11-oxo-olean-12-en-30-oic Acid (7). Yield 0.38 g (80.8%), R 0.4, [α]
+55°(c 0.02). IRspectrum ( , cm ): 3600-
f
D
3200 (OH, NH); 1670 (C=O); 1530 (CONH); 1450 (C H ). UV spectrum (λ , nm): 248 (log ε 4.2). C H O N .
6
5
70 98 22 4
max
PMRspectrum (300 MHz, DMF-d , δ, ppm): 0.50, 0.70, 0.75, 0.82, 0.86, 1.00, 1.20 (21H, all s, 7CH ), 4.80 (4H, NH),
3
7
13
5.25 (1H, s, H-12), 7.10, 7.25 (2C H ). Tables 1-3 give the C NMR spectra.
6
5
Methyl Ester of3-O-{2-O-[N-(β-D-Glucopyranosyluronoyl)-Nε-(Z)-L-lysine]-N-(β-D-glucopyranosyluronoyl)-Nε-
20
(Z)-L-lysine}-(3β,20β)-11-oxo-olean-12-en-30-oic Acid (8). Yield 0.37 g (78.7%), R 0.45, [α]
+25° (c 0.02). IRspectrum
f
D
-1
( , cm ): 3600-3200 (OH, NH); 1740 (COOMe); 1700 (COOH); 1660 (C11=O); 1540 (CONH). UV spectrum (λ , nm): 248
max
(log ε 4.1). C H O N .
70 98 22
4
PMR spectrum (300 MHz, acetone-d , δ, ppm, J/Hz): 0.80, 0.86, 0.94, 1.10, 1.40 (21H, all s, 7CH ), 3.64 (3H, s,
3
6
COOCH ), 4.54 (1H, d, J = 7.5, H-1′′), 5.05 (1H, d, J = 7.0, H-1′), 5.56 (1H, s, H-12), 6.50 (4H, NH), 7.65 (C H ). Tables 1-3
3
6 5
13
give the C NMR spectra.
ACKNOWLEDGMENT
The work was supported financially by Rosnauki (No. 2005-RI-12.0/004/088) and State Contract 02.434.11.7060.
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