Amides of N-Deacetyllappaconitine and Amino Acids

Article abstract of DOI:10.1007/s10600-018-2519-4

Amides were prepared from N-deacetyllappaconitine and the amino acids glycine, taurine, and γ-aminobutyric acid.

Full text of DOI:10.1007/s10600-018-2519-4

DOI 10.1007/s10600-018-2519-4
Chemistry of Natural Compounds, Vol. 54, No. 5, September, 2018
AMIDES OF N-DEACETYLLAPPACONITINE
AND AMINO ACIDS
*
T. M. Gabbasov, E. M. Tsyrlina,
L. V. Spirikhin, and M. S. Yunusov
Amides were prepared from N-deacetyllappaconitine and the amino acids glycine, taurine, and γ-aminobutyric
acid.
Keywords: diterpene alkaloids, N-deacetyllappaconitine, glycine, taurine, γ-aminobutyric acid.
Several N-deacetyllappaconitines with various substituents on the aromatic N atom have been reported. In particular,
the reaction of N-deacetyllappaconitine with benzoic, methacrylic, crotonic, cinnamic, chloroacetic, and methanesulfonic
acids in anhydrous CH Cl in the presence of Py produced the corresponding N-substituted deacetyllappaconitines in 72–86%
2
2
yield. N-Chloroacetyl-N′-deacetyllappaconitine reacted with secondary amines (diethylamine, morpholine, N-methylpiperazine)
to give the corresponding N-substituted glycyl amides [1].
Stressful situations are known to be one reason for the growth in the incidence of ischemic cardiac disease and the
occurrence of myocardial infarct. Neutral amino acids γ-aminobutyric acid, glycine, β-alanine, and taurine are so-called
inhibitory mediators that regulate excitation in vivo.
In continuation of studies of the modification of N-deacetyllappaconitine (1), several derivatives containing amino-
acid residues were synthesized.
Amino acids were introduced into 1 by using known methods to synthesize N-phthalimidoacids of glycine,
γ-aminobutyric acid [2], and taurine [3], which were converted to the corresponding acid chlorides 2 and 3 and sulfonyl
chloride 4. Compound 1 was acylated by heating in CH Cl in the presence of Et N. Resulting derivatives 5–7 were purified
2
2
3
by column chromatography (CC). The yields of acylated products were 79–89%.
The structures of 5–7 were confirmed by IR spectroscopy and mass spectrometry. A series of 2D NMR spectral
13
experiments allowed complete assignment of resonances for C-atoms and H atoms bonded to them in PMR and C NMR
spectra. Table 1 confirmed that the synthesized compounds contained phthalimido groups with resonances for aromatic
C atoms (δ 123–134 ppm) and additional resonances for three CO groups bonded to a N atom (δ 164–167 ppm).
C
C
OCH
OCH
3
3
13
14
H CO
3
H CO
3
16
17
OCH
OH
OCH
3
3
10
1
OH
O
15
N
N
8
O
3
OH
OH
5
NR
+
19
6
O
O
N
O
5 - 7, 10: R =
O
2
O
1'
NH
NHR
1
2
O
2'
8, 9, 11: R = NH
2
2
1
2 - 4
5'
5 - 11
R = CH COCl (2); CH CH CH COCl (3); R = CH CH SO Cl (4)
2
2
2
2
2
2
2
R = COCH R (5,8); R = COCH CH CH R (6); SO CH CH R (7,9); COCH NHSO CH CH R (10,11)
1
2
2
1
2
2
2
2
2
2
2
2
2
2
2
2 2
Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, 71 Prosp. Oktyabrya, Ufa,
450054, Russian Federation, e-mail: tsirlina@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 5,
September–October, 2018, pp. 806–809. Original article submitted March 23, 2018.
©
0009-3130/18/5405-0951 2018 Springer Science+Business Media, LLC
951

13
TABLE 1. C NMR Spectra of N-Acyl and N-Sulfonamide Derivatives of N-Deacetyllappaconitine (1) (CDCl , δ, ppm)
3
C atom
5
6
7
8
9
10
11
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
84.2
26.7
31.4
84.7
48.7
24.0
47.5
75.6
78.5
49.7
50.8
26.2
36.2
90.1
44.8
82.9
61.5
55.1
48.9
13.7
56.7
57.9
56.1
167.6
115.8
140.8
120.0
134.6
122.9
130.9
41.7
84.2
26.8
31.8
84.6
48.6
24.1
47.6
75.6
78.6
49.8
50.9
26.2
36.3
90.1
44.8
82.9
61.5
55.4
49.0
13.6
56.6
57.9
56.1
167.3
115.8
141.5
120.2
134.3
122.3
131.0
84.0
26.7
31.7
85.2
48.5
24.1
47.6
75.6
78.6
49.8
50.9
26.2
36.3
90.1
44.8
82.8
61.5
55.3
48.9
13.5
56.5
57.9
56.1
167.1
116.4
140.3
117.7
134.6
122.8
131.7
84.2
26.8
31.8
84.4
48.6
24.2
47.5
75.6
78.6
49.8
50.9
26.2
36.2
90.2
44.8
82.9
61.5
55.5
49.0
13.6
56.6
57.9
56.2
166.9
116.8
140.7
120.5
134.2
122.6
131.2
46.4
84.0
26.7
31.8
85.3
48.3
24.1
47.6
75.6
78.6
49.9
51.0
26.2
36.2
90.1
44.7
82.8
61.5
55.4
49.0
13.5
56.6
57.9
56.2
167.2
116.4
140.6
118.0
134.7
122.8
131.8
84.1
26.7
31.8
85.1
48.5
24.1
47.5
75.6
78.6
49.8
50.9
26.2
36.2
90.1
44.8
82.8
61.5
55.4
49.0
13.5
56.6
57.9
56.1
167.4
116.2
140.6
120.3
134.4
123.1
131.2
46.8
84.1
26.7
31.8
85.1
48.4
24.2
47.6
75.6
78.6
49.9
50.9
26.2
36.2
90.1
44.8
82.8
61.5
55.5
49.0
13.5
56.5
57.9
56.1
167.4
116.4
140.5
120.4
134.4
123.2
131.2
46.5
19
NCH2CH3
NCH2CH3
1-ÎÑÍ3
14-ÎÑÍ3
16-ÎÑÍ3
ÎCO
′
1
2′
′
3
4′
′
5
6′
COCH2
COCH2ÑÍ2ÑÍ2
COCH2ÑÍ2ÑÍ2
COCH2ÑÍ2ÑÍ2
NHCO
N(ÑÎ)2
1′′, 6′′
2′′, 5′′
3′′, 4′′
SO2ÑÍ2ÑÍ2
SO2ÑÍ2ÑÍ2
35.6
24.2
37.4
170.7
168.4
132.1
133.9
123.2
164.8
167.6
132.3
134.1
123.6
172.3
167.1
168.4
131.9
134.2
123.5
50.5
167.2
167.4
132.0
134.6
123.4
49.2
54.7
36.8
54.6
36.9
32.4
32.8
The protection in 5 and 7 was removed by refluxing in EtOH with 85% hydrazine hydrate without purifying
the amides obtained beforehand from the acylation step. The standard work up and purification by CC over SiO produced 8
2
and 9 and 67 and 71% yields (total for two steps). The protection could not be removed from 6 because it hydrolyzed to
N-deacetyllappaconitine and lappaconine.
Repeated acylation of 8 by phthalimidoethanesulfonyl chloride (4) analogously as above produced 10 and 11 after
removal of the protection in 70% yield (total for two steps).
13
Based on 1D and 2D NMR experiments (DEPT, COSY, HSQC, and HMBC), resonances in PMR and C NMR
spectra of the synthesized compounds were fully assigned (Table 1).
952

EXPERIMENTAL
General comments were published [4].
General Method for Preparing Phthalimidoacids. A mixture of amino acid (0.01 mol) and thoroughly ground
phthalic anhydride (0.01 mol) was heated for 30 min at 145–150°C on an oil bath [2] and cooled. The solid reaction product
was dissolved in hot MeOH (10 mL), filtered, and diluted with H O (10 mL). The phthalimidoacids precipitated during slow
2
cooling.
Phthalimidoacetic Acid. C H O N. Yield 86%, mp 191–192°C. High-resolution mass spectrum, m/z 204.1701
10
7 4
–
[M – H] . Calcd 204.1707.
1
γ-Phthalimidobutyric Acid. Yield 90%, mp 108–111°Ñ. Í NMR spectrum (500 MHz, DMSO-d , δ, ppm, J/Hz):
6
13
1.76–1.90 (2Í, m), 2.29 (2Í, t, J = 7.2), 3.62 (2Í, t, J = 6.8), 7.75–7.92 (4Í, m, Ar), 12.10 (1Í, s). C NMR spectrum
(125 MHz, DMSO-d , δ, ppm): 173.8, 167.9, 134.2, 137.6, 122.9, 36.8, 30.9, 23.3.
6
General Method for Preparing Phthalimidoacid Chlorides. A mixture of amino-acid phthalyl derivative
(0.001 mol) and thionylchloride (6 mL) was refluxed for 3 h at 50°C. The excess of thionylchloride was vacuum distilled.
Anhydrous toluene was added to the reaction flask and distilled off in vacuo three times for complete removal of thionylchloride.
Then, obtained chlorides 2 and 3 were used for acylation.
Phthalimidoethanesulfonyl Chloride (4). According to the literature method [3], phthalic anhydride (0.072 mol)
was treated with a suspension of taurine (0.068 mol) and KOAc (0.072 mol) in glacial AcOH (24 mL), refluxed for 2 h until
completely dissolved, cooled to 5°C, and filtered to remove the precipitate of potassium 2-phthalimidoethanesulfonate, which
was rinsed with AcOH and MeOH and dried in air and in vacuo. Yield 76%, mp >300°C. PMR spectrum (500 MHz, D O, δ,
2
ppm, J/Hz): 7.85 (4H, m), 4.05 (3H, t, J = 8), 3.25 (2H, t, J = 8).
The obtained salt (0.017 mol) in C H (50 mL) was treated with PCl (0.012 mol), refluxed for 1 h, treated again with
6
6
5
PCl (0.012 mol), refluxed for 1.5 h, and evaporated. The residue was mixed with powdered ice (30 g). Solid 4 was filtered
5
off, rinsed with ice water, and dried in air. Yield 61%, mp 158–159°C.
General Method for Acylating N-deacetyllappaconitine with Phthalimidoacid Chlorides. The obtained
phthalimidoacid chloride was treated with a solution of 1 (1.1 mmol) in CH Cl (15 mL) and Et N (0.45 mL). The mixture
2
2
3
was stirred at 40°C for 4 h, made basic with soda to pH 9, and extracted with CHCl (3 × 15 mL). The extract was dried over
3
anhydrous Na SO . The solvent was distilled off. The product was either used without isolation for removal of the phthalimide
2
4
protection or purified by CC over SiO using CHCl –MeOH (99:1).
2
3
N-[2-(1,3-Dioxoisoindolin-2-yl)acetyl]-N-deacetyllappaconitine (5). Yield 81%. High-resolution mass spectrum,
–
+
+
m/z 728.3173 [M – Í] , calcd 728.3178. Mass spectrum (EI, 70 eV), m/z (I , %): 728 ((M – 1) , 0.5), 714 ((M – 15) , 0.8), 698
rel
+
–1
((M – 31) , 5). IR spectrum (ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1777 (ΖÑÎ), 1715 (N–ÑÎ), 1680 (NHÑO), 1130–1080 (Ñ–Î).
Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz): 1.07 (3Í, t, J = 7.1, ÑÍ ÑÍ N), 1.50 (1Í, m, Í -6), 1.55 (1Í, m, Í -3),
1
3
3
2
a
a
1.97 (1Í, m, Í -12), 2.00 (1Í, m, Í -15), 2.02 (1Í, m, Í -2), 2.04 (1Í, m, Í-10), 2.05 (1Í, m, Í -2), 2.10 (1Í, m, Í-7), 2.19
a
a
a
b
(1Í, m, Í-5), 2.24 (1Í, m, Í -3), 2.32 (1Í, d, J = 11.8, Í -19), 2.34 (1Í, m, Í-13), 2.35 (1Í, m, Í -15), 2.40 (1Í, m,
b
a
b
ÑÍ ÑÍ N), 2.48 (1Í, m, Í -12), 2.52 (1Í, m, ÑÍ ÑÍ N), 2.68 (1Í, dd, J = 15.1, 7.4, Í -6), 2.94 (1Í, s, Í-17), 3.10 (1Í, m,
3
à
b
3
b
b
Í-1), 3.11 (1Í, d, J = 11.8, Í -19), 3.28 (1Í, m, Í-16), 3.29 (3Í, s, 1-ÎÑÍ ), 3.30 (3Í, s, 16-ÎÑÍ ), 3.39 (3Í, s, 14-ÎÑÍ ),
b
3
3
3
3.43 (1Í, d, J = 4.8, Í-14), 4.51 (1Í, d, J = 16.9, ÑÎÑÍ ), 4.60 (1Í, d, J = 16.9, ÑÎÑÍ ), 7.03 (1Í, t, J = 7.7, Í-5′), 7.48 (1Í, t,
à
b
J = 7.5, 8.2, Í-4′), 7.77 (2Í, m, Í-2′′, 5′′), 7.84 (1Í, d, J = 8.0, Í-6′), 7.92 (2Í, m, Í-3′′, 4′′), 8.62 (1Í, d, J = 8.4, Í-3′), 11.65 (1Í,
s, NÍ).
N-[4-(1,3-Dioxoisoindolin-2-yl)butanoyl]-N-deacetyllappaconitine (6). Yield 89%. High-resolution mass spectrum,
–
+
+
m/z 756.3497 [M – Í] , calcd 756.3491. Mass spectrum (EI, 70 eV), m/z (I , %): 756 ((M – 1) , 0.1), 742 ((M – 15) , 0.2), 726
rel
+
–1
((M – 31) , 0.9). IR spectrum (ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1772 (ΖÑÎ), 1710 (N–ÑÎ), 1673 (NHÑO), 1130–1080
(Ñ–Î). Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz): 1.11 (3Í, t, J = 7.2, ÑÍ ÑÍ N), 1.58 (1Í, dd, J = 15.0, 8.3,
1
3
3
2
Í -6), 1.78 (1Í, m, Í -3), 1.97 (1Í, m, Í -12), 2.01 (1Í, dd, J = 14.8, 7.6, Í -15), 2.07 (1Í, m, Í-10), 2.12 (2Í, m,
à
à
à
à
COCH ÑÍ ÑÍ ), 2.14 (1Í, m, Í-7), 2.17 (1Í, m, Í -2), 2.27 (1Í, m, Í -2), 2.36 (2Í, m, Í-5, 13), 2.39 (1Í, m, Í -15),
2
2
2
à
b
b
2.49 (1Í, m, Í -12; 2Í, m, COCH ÑÍ ÑÍ ), 2.50 (1Í, m, ÑÍ ÑÍ N), 2.54 (1Í, d, J = 11.4, Í -19), 2.55 (1Í, m, ÑÍ ÑÍ N),
b
2
2
2
3
à
à
3
â
2.66 (1Í, m, Í -3), 2.68 (1Í, m, Í -6), 3.00 (1Í, s, Í-17), 3.18 (1Í, m, Í-1), 3.29 (3Í, s, 1-ÎÑÍ ), 3.30 (3Í, s, 16-ÎÑÍ ;
b
b
3
3
1Í, m, Í-16), 3.39 (3Í, s, 14-ÎÑÍ ), 3.43 (1Í, d, J = 4.6, Í-14), 3.58 (1Í, d, J = 11.4, Í -19), 3.80 (2Í, t, J = 6.8, COCH ÑÍ ÑÍ ),
3
b
2
2
2
6.98 (1Í, t, J = 7.6, Í-5′), 7.42 (1Í, t, J = 7.9, Í-4′), 7.66 (2Í, m, Í-2′′, 5′′), 7.79 (2Í, m, Í-3′′, 4′′), 7.89 (1Í, d, J = 8.0,
Í-6′), 8.57 (1Í, d, J = 8.2, Í-3′), 11.03 (1Í, s, NÍ).
953

N-[2-(1,3-Dioxoisoindolin-2-yl)ethanesulfonyl]-N-deacetyllappaconitine (7). Asolution of 1 (0.2 mmol) in CH Cl
2
2
(4 mL) was treated with 2-phthalimidoethanesulfonyl chloride (4, 0.3 mmol) and Et N (0.1 mL). The mixture was stirred at
3
room temperature for 4 h. The product was purified by CC over SiO using CHCl –MeOH (98.5:1.5). Yield 79%.
2
3
+
+
High-resolution mass spectrum, m/z 779.3086 [M] , calcd 779.3082. Mass spectrum (EI, 70 eV), m/z (I , %): 779 (M , 0.5),
764 ((M – 15) , 0.5), 748 ((M – 31) , 5). IR spectrum (ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1682 (NHSO), 1130–1080 (Ñ–Î).
Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz): 1.14 (3Í, t, J = 7.1, ÑÍ ÑÍ N), 1.59 (1Í, m, J = 15.1, 8.2, Í -6), 1.78
rel
+
+
–1
1
3
3
2
à
(1Í, m, Í -3), 2.00 (1Í, m, Í -12), 2.03 (1Í, m, Í -15), 2.11 (1Í, m, Í-10), 2.15 (1Í, m, Í-7), 2.17 (1Í, m, Í -2), 2.31
à
à
à
à
(1Í, m, Í -2), 2.37 (1Í, m, Í-5), 2.38 (2Í, m, Í-13, Í -15); 2.50 (1Í, m, Í -12); 2.51 (1Í, m, ÑÍ ÑÍ N); 2.55 (1Í, d,
b
b
b
3
à
J = 11.5, Í -19); 2.57 (1Í, m, ÑÍ ÑÍ N); 2.70 (1Í, m, Í -3; 1Í, dd, Í -6), 3.01 (1Í, s, Í-17), 3.19 (1Í, m, Í-1), 3.30 (3Í,
à
3
b
b
b
s, 1-ÎÑÍ ), 3.31 (1Í, m, Í-16), 3.32 (3Í, s, 16-ÎÑÍ ), 3.41 (3Í, s, 14-ÎÑÍ ), 3.44 (1Í, d, J = 4.6, Í-14), 3.57 (2Í, m,
3
3
3
J = 13.9, 7.1, SO ÑÍ ÑÍ ), 3.62 (1Í, d, J = 11.5, Í -19), 4.14 (2Í, m, J = 13.8, 6.9, SO ÑÍ ÑÍ ), 7.02 (1Í, t, J = 8.1, Í-5′),
2
2
2
b
2
2
2
7.47 (1Í, t, J = 15.9, 7.0, Í-4′), 7.62 (1Í, d, J = 8.3, Í-3′), 7.70 (2Í, m, Í-2′′, 5′′), 7.80 (2Í, m, Í-3′′, 4′′), 7.88 (1Í, d, J = 8.0,
Í-6′), 10.67 (1Í, s, NÍ).
General Method for Removing Phthalyl Protection. A solution of amide 5, 7, or 10 in EtOH (4 mL) was treated
with hydrazine hydrate (85%, 0.4 mL), refluxed for 1 h, and evaporated. The residue was treated with water and acidified with
HCl solution (1 N). The phthalyl hydrazide was filtered off. The eluate was evaporated to dryness. The products were
purified by CC over SiO using CHCl –MeOH (99:1).
2
3
–
N-Glycyl-N-deacetyllappaconitine (8). Yield 69%. High-resolution mass spectrum, m/z 598.3127 [M – Í] , calcd
598.3123. Mass spectrum (EI, 70 eV), m/z (I , %): 598 ((M – 1) , 0.8), 584 ((M – 15) , 0.6), 568 ((M – 31) , 4.5). IR spectrum
(ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1740 (ΖÑÎ), 1673 (NHÑO), 1130–1080 (Ñ–Î). Í NMR spectrum (500 MHz, ÑDCl , δ,
+
+
+
rel
–1
1
3
ppm, J/Hz): 1.11 (3Í, t, J = 7.1, ÑÍ ÑÍ N), 1.60 (1Í, m, J = 15.0, 8.2, Í -6), 1.80 (1Í, m, Í -3), 1.96 (1Í, m, Í -12), 2.01
3
2
à
à
à
(1Í, m, Í -15), 2.08 (1Í, m, Í-10), 2.15 (2Í, m, Í -2, Í-7), 2.28 (1Í, m, Í -2), 2.36 (1Í, m, Í-13), 2.39 (1Í, m, Í -15),
à
à
b
b
2.41 (1Í, m, Í-5), 2.49 (1Í, m, ÑÍ ÑÍ N), 2.50 (1Í, m, Í -12), 2.54 (1Í, m, ÑÍ ÑÍ N), 2.55 (1Í, d, J = 11.3, Í -19), 2.67
3
à
b
3
b
à
(1Í, m, Í -3), 2.68 (1Í, dd, J = 15.0, 7.4, Í -6), 2.99 (1Í, s, Í-17), 3.18 (1Í, m, Í-1), 3.28 (3Í, s, 1-ÎÑÍ ), 3.30 (1Í, m,
b
b
3
Í-16; 3Í, s, 16-ÎÑÍ ), 3.40 (3Í, s, 14-ÎÑÍ ), 3.43 (1Í, d, J = 4.5, Í-14), 3.54 (2Í, s, ÑÎÑÍ ), 3.60 (1Í, d, J = 11.3,
3
3
2
Í -19), 7.04 (1Í, t, J = 7.6, Í-5′), 7.49 (1Í, t, J = 7.5, 15.1, Í-4′), 7.92 (1Í, d, J = 7.7, Í-6′), 8.71 (1Í, d, J = 8.4, Í-3′), 11.75
b
(1Í, s, NÍ).
–
N-Tauryl-N-deacetyllappaconitine (9). Yield 71%. High-resolution mass spectrum, m/z 648.2953 [M – Í] , calcd
+
+
+
648.2949. Mass spectrum (EI, 70 eV), m/z (I , %): 648 ((M – 1) , 0.3), 634 ((M – 15) , 0.2), 618 ((M – 31) , 6). IR spectrum
rel
–1
1
(ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1674 (NHSO), 1130–1080 (Ñ–Î). Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz):
3
1.10 (3Í, t, J = 7.2, ÑÍ ÑÍ N), 1.56 (1Í, m, J = 14.9, 8.3, Í -6), 1.83 (1Í, m, Í -3), 1.97 (1Í, m, Í -12), 2.01 (1Í, m,
3
2
à
à
à
J = 15.0, 7.4, Í -15), 2.10 (1Í, m, J = 4.5, Í-10), 2.16 (1Í, m, Í-7), 2.19 (1Í, m, Í -2), 2.28 (1Í, m, Í -2), 2.39 (1Í, m,
à
à
b
Í-13), 2.39 (1Í, m, Í -15), 2.42 (1Í, m, Í-5), 2.50 (1Í, m, Í -12), 2.52 (1Í, m, ÑÍ ÑÍ N), 2.53 (1Í, d, J = 11.3, Í -19),
b
b
3
à
à
2.58 (1Í, m, ÑÍ ÑÍ N), 2.62 (1Í, m, Í -3), 2.68 (1Í, dd, J = 14.9, 7.4, Í -6), 3.00 (1Í, s, Í-17), 3.19 (1Í, m, Í-1), 3.21
3
b
b
b
(2Í, m, SO ÑÍ ÑÍ ), 3.28 (3Í, s, 1-ÎÑÍ ), 3.29 (2Í, m, SO ÑÍ ÑÍ ), 3.30 (1Í, m, Í-16), 3.31 (3Í, s, 16-ÎÑÍ ), 3.41
2
2
2
3
2
2
2
3
(3Í, s, 14-ÎÑÍ ), 3.44 (1Í, d, J = 4.5, Í-14), 3.56 (1Í, d, J = 11.3, Í -19), 7.07 (1Í, t, J = 7.4, Í-5′), 7.50 (1Í, t, J = 7.0,
3
b
Í-4′), 7.69 (1Í, d, J = 8.3, Í-3′), 7.93 (1Í, d, J = 6.7, Í-6′).
N-{2-[2-(1,3-Dioxoisoindolin-2-yl)ethylsulfamido]acetyl}-N-deacetyllappaconitine (10). Asolution of 8 (0.3 mmol)
in CH Cl (10 mL) was treated with 2-phthalylethanesulfonyl chloride (4, 0.3 mmol) and Et N (0.05 mL), stirred, and refluxed
2
2
3
for 2 h. The product 10 was purified by CC over SiO using CHCl –MeOH (99:1). Yield 65%. High-resolution mass
2
3
+
+
+
spectrum, m/z 836.3223 [M] . Calcd 836.3226. Mass spectrum (EI, 70 eV), m/z (I , %): 836 (M , 0.1), 821 ((M – 15) , 0.1),
805 ((M – 31) , 0.2). IR spectrum (ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1684 (NHCO), 1130–1080 (Ñ–Î). Í NMR spectrum
rel
+
–1
1
(500 MHz, ÑDCl , δ, ppm, J/Hz): 1.12 (3Í, t, J = 7.1, ÑÍ ÑÍ N), 1.57 (1Í, dd, J = 14.8, 8.3, Í -6), 1.80 (1Í, m, Í -3), 2.00
3
3
2
à
à
(1Í, m, Í -12), 2.01 (1Í, m, Í -15), 2.09 (1Í, m, Í-10), 2.16 (1Í, m, Í-7), 2.18 (1Í, m, Í -2), 2.29 (1Í, m, Í -2), 2.37 (1Í,
à
à
à
b
m, Í-13), 2.39 (2Í, m, Í-5, Í -15), 2.50 (2Í, m, Í -12, ÑÍ ÑÍ N), 2.56 (1Í, m, ÑÍ ÑÍ N), 2.59 (1Í, d, J = 10.6, Í -19),
b
b
3
à
3
b
à
2.64 (1Í, m, Í -3), 2.69 (1Í, m, Í -6), 3.00 (1Í, s, Í-17), 3.18 (1Í, m, Í-1), 3.29 (3Í, s, 1-ÎÑÍ ), 3.31 (1Í, m, Í-16; 3Í,
b
b
3
s, 16-ÎÑÍ ), 3.40 (3Í, s, 14-ÎÑÍ ), 3.43 (1Í, d, J = 4.6, Í-14), 3.50 (2Í, m, SO ÑÍ ÑÍ ), 3.58 (1Í, d, J = 10.6, Í -19),
3
3
2
2
2
b
4.13 (2Í, s, J = 3.1, ÑÎÑÍ ), 4.36 (2Í, m, SO ÑÍ ÑÍ ), 7.03 (1Í, t, J = 7.7, Í-5′), 7.48 (1Í, t, J = 7.8, Í-4′), 7.63 (1Í, d,
2
2
2
2
J = 7.9, Í-3′), 7.70 (2Í, m, Í-2′′, 5′′), 7.80 (2Í, m, Í-3′′, 4′′), 7.89 (1Í, d, J = 8.0, Í-6′), 10.67 (1Í, s, NÍ).
N-[2-(2-Aminoethylsulfamido)acetyl]-N-deacetyllappaconitine (11). Yield 70% (total for two steps).
–
High-resolution mass spectrum, m/z 705.1184 [M – Í] , calcd 705.1179. Mass spectrum (EI, 70 eV), m/z (I , %):
rel
954

+
+
+
–1
705 ((M – 1) , 0.3), 691 ((M – 15) , 0.2), 675 ((M – 31) , 0.7). IR spectrum (ÊÂr, ν, cm ): 3600–3200 (ÎÍ), 1684 (NHCO),
1
1130–1080 (Ñ–Î). Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz): 1.13 (3Í, t, J = 7.1, ÑÍ ÑÍ N), 1.57 (1Í, dd,
3
3
2
J = 14.9, 8.3, Í -6), 1.85 (1Í, m, Í -3), 1.98 (1Í, m, Í -12), 2.04 (1Í, m, Í -15), 2.09 (1Í, m, Í-10), 2.17 (1Í, m, Í-7), 2.19
à
à
à
à
(1Í, m, Í -2), 2.28 (1Í, m, Í -2), 2.37 (1Í, m, Í-13), 2.40 (1Í, m, Í -15), 2.43 (1Í, m, Í-5), 2.50 (2Í, m, Í -12, ÑÍ ÑÍ N),
à
b
b
b
3
à
2.56 (1Í, m, ÑÍ ÑÍ N), 2.57 (1Í, d, J = 11.3, Í -19), 2.62 (1Í, m, Í -3), 2.69 (1Í, m, J = 14.9, 7.3, Í -6), 3.01 (1Í, s,
3
b
à
b
b
Í-17), 3.19 (1Í, m, Í-1), 3.30 (3Í, s, 1-ÎÑÍ ), 3.32 (1Í, m, Í-16; 3Í, s, 16-ÎÑÍ ; 2Í each, m, SO ÑÍ ÑÍ , SO ÑÍ ÑÍ ),
3
3
2
2
2
2
2
2
3.41 (3Í, s, 14-ÎÑÍ ), 3.44 (1Í, d, J = 4.6, Í-14), 3.57 (1Í, d, J = 11.3, Í -19), 4.07 (2Í, s, ÑÎÑÍ ), 7.10 (1Í, t, J = 15.2,
3
b
2
7.6, Í-5′), 7.51 (1Í, t, J = 14.9, 7.4, Í-4′), 7.69 (1Í, d, J = 8.3, Í-3′), 7.90 (1Í, d, J = 7.6, Í-6′), 11.43 (1Í, s, NÍ).
ACKNOWLEDGMENT
The work was performed on state task topic No. AAAA-A-17-117011910025-6.
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4.
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