The 1H-NMR, 13C-NMR and DEPT spectra of compounds 3a-3c showed the signals of 4
aromatic methine groups, 3 methylene groups including 1 group attached to nitrogen, 1 nitrogenattached methine group, 3 carbonyl groups and 2 sp2 carbons. Otherwise, 1H-NMR and 13CNMR spectra of compound 3a displayed the signals of one cyclohexane ring with 5 methylene
groups, one nitrogen-attached methylene group and one methine group. 1H-NMR and 13C-NMR
spectra of compound 3b consisted the signal of an additional benzyl ring with 5 aromatic
methine groups, 1 quarternary carbon and 1 nitrogen-attached methylene group. 1H-NMR and
13C-NMR spectra of 3c is similar to 3b, except the signals of 2 olefin methine groups in δH 4.28
(1H, dd, J = 6.5, 15.0 Hz); 4.09 (1H, dd, J = 6.5, 15.0 Hz) and δC 124.4, 133.9. The trans
conformation of these 2 protons has been confirmed by the large coupling constant (J = 15.0
Hz). The data on the spectrum allowed us to define the attachment of substituents
(methylcyclohexan, benzyl, cinnamyl) to the amino group on the δ-lactam ring. The mass
spectrum of the molecular ion displayed the peak at the mass of the expected formula.
Afterward, the removal of protection groups of 3a-3c by hydrazine gives N-alkyl amino lactam
4a-4c derivatives respectively. In comparision with 3a-3c compounds, 1H-NMR and 13C-NMR
spectra of compound 4a-4c lacks of the signals of two carbonyl groups, 4 A2B2-type aromatic
methine groups, and 2 quarternary carbons, which are the evidence of removal of protectingTổng hợp một số dẫn xuất n-alkyl amino lactam
297
groups and 4a-4c compound were N-alkyl amino lactam derivatives. Mass spectrometry of these
derivatives displayed the peak at the mass of the expected formula.
1
H-NMR, 13C-NMR and DEPT spectra of the seven-membered ring derivatives (7a-7c và
8a-7c) were similar to the 6 seven-membered ones (3a-3c và 4a-4c), except the signal of an
additional methylene of ε-lactam ring. Mass spectrometry of these derivatives displayed the peak
at the mass of the expected formula.
8 trang |
Chia sẻ: honghp95 | Lượt xem: 582 | Lượt tải: 0
Bạn đang xem nội dung tài liệu Synthesis of n-Alkyl amino lactam derivatives - Phi Thi Dao, để tải tài liệu về máy bạn click vào nút DOWNLOAD ở trên
Journal of Science and Technology 54 (2C) (2016) 291-298
SYNTHESIS OF N-ALKYL AMINO LACTAM DERIVATIVES
Phi Thi Dao1, Vu Van Loi1, Nguyen Thi Bich2, Doan Thi Mai Huong1, *,
Nguyen Hien2, Chau Van Minh1, Pham Van Cuong1
1Institute of Marine Biochemistry, Vietnam Academy of Science and Technology,
18 Hoang Quoc Viet, Hanoi
2Hanoi National University of Education, 136 Xuan Thuy, Cau Giay, Hanoi
*Email: doanhuong7@yahoo.com
Received: 15 May 2016; Accepted for publication: 15 October 2016
ABSTRACT
Bengamides are sponge-derived natural products of mixed biosynthesis (polyketides and
amino acids), the first two members, isolated from Jaspidae sponges in coral surrounding Fiji
islands, were reported in 1986. The main structural variation is located on the 3-
aminocaprolactam moiety, and displays a wide range of biological activities, including
antitumor, antibiotic, and anthelmintic properties. These interesting biological activities have
made bengamides popular targets for synthesis and biological studies. There have been some
reports on diverse modifications of the caprolactame unit, and indication that N-substitution on
caprolactam greatly influences the antitumor activity. In this paper, we reported the method for
synthesis of 6 amino lactams containing an additional N-alkyl group (4a-4c) and (8a-8c) for
further synthesis of new bengamide analogues. Their structures were established by MS and
NMR spectroscopies.
Keywords: bengamides, amino-lactams, cytotoxic activity.
1. INTRODUCTION
Bengamides from natural marine products were first isolated from Jaspis sponges species
[1]. So far, 24 bengamide compounds have been isolated and structural elucidated [2 - 4]. Many
of these compounds show high bioactivity against several cancer cell lines. Intense cytotoxic
studies of the antitumor activities of the bengamides, together with the results provided by the
NCI-DTP database, has resulted in their identification as promising new anticancer agents. Thus,
IC50 values for natural bengamides A, E, O and Z (IC50 values of 1.0, 3.3, 0.29 and 2.9 nM
respectively) were determined against MDA-MB-435 human mammary carcinoma with the best
anti-proliferative in vitro activities observed for bengamides having a fatty acid attached to the
caprolactam ring [5]. Due to the difficulty in harvesting large quantity of sponge, full synthetic
compounds and analogs of bengamide class were much concerned by scientists all over the
world to obtain substances with larger quantity for the study of biological activities [6 - 8]. In a
recent research, Gang Liu and co-workers published some bengamide E analogs, containing N-
Phi Thi Dao, et al
292
alkyl lactam ring, which shows very strong activity against MDA-MB-435 breast cancer cell
lines with IC50 values from 0.017 to 1.28 µM [8]. Based on those bioactivities, we suggest the
synthetic procedure of new bengamid E analogs containing N-alkyl lactam ring and the study of
cytotoxic activity for these analogs on several cancer cell lines (Figure 1). In the framework of
this paper, we report the synthesis of 6 N-alkyl amino lactam derivatives (4a-4c and 8a-8c),
which are important intermediates in the synthesis of new N-alkyl lactam analogs.
Figure 1. Plan for synthesis of bengamide analogues.
2. MATERIALS AND METHODS
Nuclear magnetic resonance spectra were recorded on 500 MHz Bruker NMR Avance with
TMS as internal standard. Mass spectra were measured on liquid chromatography coupled with
mass spectrometry probe MSD (LC/MSD Agilent 1100 series), using ESI mode and DAD
detector. Pole of rotation was measured on Atago Polax-21. Thin layer chromatography (TLC)
was performed on Merck silica gel plate 60 F254. Chromatography was performed using 40-63
μm silica gel and Sephadex LH-20 (Aldrich). Reagents for organic synthesis were purchased
from Aldrich and Merck.
Synthesis of (S)-2-(2-oxopiperidin-3-yl)isoindoline-1,3-dione (2): Synthesis procedure was
reported in the article [9] with the overall yield of the two reactions from L-ornithine
monohydrochloride at 32 %. White solid; [α]D25 -45.6 (c, 1.1, CHCl3), mp. 233-234oC; 1H-NMR
(500 MHz, CDCl3) δH (ppm): 1.95 (1H, m); 2.10 (2H, m); 2.40 (1H, dq, J = 3.0; 12.5 Hz); 3.39
(1H, m); 3.52 (1H, td, J = 4.0; 12.0 Hz); 4.77 (1H, dd, J = 12.0; 6.5 Hz); 6.15 (1H, brs); 7.69-
7.72 (2H, m); 7.83-7.86 (2H, m). 13C-NMR (125 MHz, CDCl3) δC (ppm): 22.3 (CH2); 26.3
(CH2); 42.4 (CH2); 49.2 (CH); 123.4 (2 x CH); 132.1 (2 x C); 134.0 (2 x CH); 167.7 (C=O);
168.1 (2 x C=O).
General procedure for synthesis of 3a-3c: Compound 2 (0.8 g; 3.28 mmol) was dissolved in 8
ml of DMSO. The mixture was stirred under N2 and cooled to 0 οC. After 5 minutes, 0.905 g
K2CO3 (2eq) and 0.367 g of KOH (2eq) were added slowly into the reactor. The reaction mixture
was stirred for 10 minutes, then 3 eq of bromide reagents [bromomethyl cyclohexane (1.37 ml),
benzyl bromide (1.17 ml), or cinnamyl bromide (1.46 ml)] were added slowly. After 5 minutes,
0.544 g KI (1 eq) was added in the reaction mixture, the temperature of the reaction mixture was
gradually raised to room temperature in 30 minutes, then reached 50 - 60 oC by heating. The
reaction was monitored by thin layer chromatography. After 23 hours, the reaction mixture was
cooled to 0 °C, and neutralized to pH 6 using 1N HCl acid. The residue was partitioned with
EtOAc/water and chomatographed (n-hexane/EtOAc gradient) to obtain 501 mg of product 3a
(45 %); 460 mg of product 3b (42 %) and 590 mg of product 3c (50 %).
(S)-2-(1-(cyclohexylmethyl)-2-oxopiperidin-3-yl) isoindoline-1,3-dione (3a): White solid;
[α]D25 -62.6 (c, 0.5, CHCl3). mp. 157-160oC; ESI-MS: m/z 341 [M+H]+ (C20H25N2O3);1H-NMR
(500 MHz, CDCl3) δH (ppm): 7.82-7.84 (2H, m); 7.68-7.70 (2H, m); 4.76 (1H, dd, J = 6.0; 12.0
Hz); 3.54 (1H, dt, J = 4.0; 12.0 Hz); 3.19-3.32 (3H, m); 2.44 (1H, dq, J = 3.0; 12.0 Hz); 2.07
(2H, m); 1.98 (1H, m); 1.13-1.26 (3H, m); 0.95 (2H, m). 13C-NMR (125 MHz; CDCl3) δC (ppm):
Synthesis of n-alkyl amino lactam derivatives
293
22.3 (CH2); 25.8 (CH2); 25.9 (CH2); 26.4 (CH2); 26.5 (CH2); 30.6 (CH2); 31.0 (CH2); 35.8 (CH);
48.8 (CH2); 49.9 (CH); 54.1 (CH2); 123.4 (2 x CH); 132.2 (2 x C); 133.9 (2 x CH); 166.1 (C=O);
167.9 (2 x C=O).
(S)-2-(1-benzyl-2-oxopiperidin-3-yl)isoindoline-1,3-dione (3b): White solid; [α]D25 -59.9 (c,
0.6, CHCl3). mp. 146 – 147 oC; ESI-MS: m/z 335 [M+H]+ (C20H19N2O3); 1H-NMR (500 MHz,
CDCl3) δH (ppm): 7.85-7.87 (2H, m); 7.70-7.73 (2H, m); 7.26-7.37 (5H, m); 4.85 (1H, dd, J =
6.5; 12.0 Hz); 4.73 (1H, d, J = 15.0 Hz); 4.56 (1H, d, J = 15.0 Hz); 3.42 (1H, dt, J = 4.5; 12.0
Hz); 3.26 (1H, m); 2.48 (1H, dq, J = 3.5; 12.0 Hz); 2.11 (1H, m); 1.92-2.05 (2H, m). 13C-NMR
(125 MHz; CDCl3) δC (ppm): 23.5 (CH2); 27.9 (CH2); 48.6 (CH2); 51.4 (CH); 52.2 (CH2); 124.8
(2 x CH); 128.8 (CH); 129.5 (2 x CH); 130.1 (2 x CH); 133.6 (2 x C); 135.4 (2 x CH); 138.1
(C); 167.8 (C=O); 169.3 (2 x C=O).
(S,E)-2-(1-cinnamyl-2-oxopiperidin-3-yl)isoindoline-1,3-dione (3c): White solid; [α]D25 -62.6
(c, 0.5, CHCl3). mp. 135-134oC; ESI-MS: m/z 361 [M+H]+ (C22H21N2O3); 1H-NMR (500 MHz,
CDCl3) δH (ppm): 7.88 (2H, m); 7.74 (2H, m); 7.43 (2H, d, J = 7.0 Hz); 7.36 (2H, t, J = 7.0 Hz);
7.28 (1H, t, J = 8.0 Hz); 6.60 (1H, d, J = 16.0 Hz); 6.20 (1H, dt, J = 6.5; 16.0 Hz; 1H); 4.85
(1H, dd, J = 6.0; 12.0 Hz); 4.23 (2H, m); 3.57 (1H, dt, J = 4.5; 12.0 Hz); 3.38 (1H, m); 2.50
(1H, m); 2.15 (2H, m); 2.03 (1H, m). 13C-NMR (125 MHz; CDCl3) δC (ppm): 22.1 (CH2); 26.5
(CH2); 47.3 (CH2); 49.5 (CH2); 49.9 (CH); 123.4 (2 x CH); 123.9 (CH); 126.5 (2 x CH); 127.7
(CH); 128.6 (2 x CH); 132.2 (2 x C); 133.1 (CH); 134.0 (2 x CH); 136.6 (C); 166.1 (C=O);
167.9 (2 x C=O).
General procedure for synthesis of 4a-4c: To a stirred solution of compounds 3a-3c (500 mg)
in CH3CN (4 mL), hydrazin 35 % solution (10 eq) was added. The reaction was stirred for 2 h at
room temperature. The solvent was evaporated under reduced pressure, water was then added,
and the mixture was extracted with ethyl acetate. The organic phase was evaporated under
reduced pressure. The residue was purified by chromatography, eluting with a CH2Cl2/MeOH
97/3 to give 278 mg of product 4a (90 %), 213 mg of product 4b (70 %), 230 mg of product 4c
(72 %).
(S)-3-amino-1-(cyclohexylmethyl)piperidin-2-one (4a): Pale yellow oil; [α]D25 -61.2 (c, 0.5,
CHCl3); ESI-MS: m/z 211 [M+H]+ (C12H23N2O);1H-NMR (500 MHz, CDCl3) δH (ppm): 3,.25-
3.34 (4H, m); 3.60 (1H, dd, J = 7.0; 13.0 Hz); 2.18 (1H, m); 1.91 (1H, m); 1.85 (1H, m); 1.71
(2H, m); 1.60 (4H, m); 1.12-1.24 (4H, m); 0.94 (2H, m). 13C-NMR (125MHz; CDCl3): see Table
1.
(S)-3-amino-1-benzylpiperidin-2-one (4b): Pale yellow oil; [α]D25 -65.6 (c, 0.6, CHCl3); ESI-
MS: m/z 205 [M+H]+ (C12H17N2O); 1H-NMR: (500 MHz; CDCl3) δ (ppm): 7.23-7.33 (5H, m);
4.68 (1H, d, J = 14.5 Hz); 4.47 (1H, d, J = 14.5 Hz); 3.43 (1H, m); 3.22 (1H, m); 2.20 (1H, m);
1.87 (1H, m); 1.81 (1H, m); 1.62 (1H, m). 13C-NMR (125 MHz; CDCl3): see Table 1.
(S)-3-amino-1-cinnamylpiperidin-2-one (4c): Pale yellow oil; [α]D25 -62.6 (c, 0.5, CHCl3; ESI-
MS: m/z 231 [M+H]+ (C14H19N2O); 1H-NMR (500 MHz, CDCl3) δH (ppm): 7.37 (2H, d, J = 7.5
Hz); 7.31 (2H, d, J = 7.5 Hz); 7.24 (1H, m); 6.52 (1H, d, J = 15.5 Hz); 6.15 (1H, dt, J = 6.5;
15.5 Hz); 4.21 (1H, ddd, J = 1.0; 6.5; 14.5 Hz); 4.07 (1H, dd, J = 1.0; 6.5; 14.5 Hz); 3.37 (1H,
dd, J = 6.0; 11.0 Hz); 3.30 (2H, m); 2.20 (1H, m); 1.80-1.93 (2H, m); 1.63 (1H, m). 13C-NMR
(125MHz; CDCl3): see Table 1.
Synthesis of (S)-2-(2-oxoazepan-3-yl)isoindoline-1,3-dione (6): Synthesis procedure was
reported in the article [9] with the overall yield of the two reactions from L-lysine was 45,6 %.
White solid [α]D25 -67.9 (c, 0.52, CHCl3), mp. 265 – 267 oC; 1H-NMR (500 MHz, DMSO-d6) δH
(ppm): 1.32 (1H, m); 1.65 (1H, m); 1.81 (1H, m); 2.01 (2H, m); 2.41 (1H, m); 3.12 (1H, m);
Phi Thi Dao, et al
294
3.22 (1H, m); 4.83 (1H, d, J = 11.0 Hz); 7.87 (4H, m). 13C-NMR (125 MHz, DMSO) δC (ppm):
28.3 (CH2); 28.6 (CH2); 28.8 (CH2); 41.0 (CH2); 54.2 (CH); 123.1 (2 x CH); 131.5 (2 x C);
134.5 (2 x CH); 167.7 (C=O); 171.5 (C=O).
General procedure for synthesis of 7a-7c: Compound 6 (0.8 g, 3.1 mmol) was dissolved in 8
ml of DMSO in the round-bottom flask. The mixture was stirred under N2 and cooled to 0 οC.
After 5 minutes, 0.855 g K2CO3 (2 eq) and 0.347 g of KOH (2 eq) were added slowly into the
reactor. The reaction mixture was stirred for 10 minutes, then 3eq of bromide reagents
[(bromomethyl) cyclohexane (1.3 ml), benzyl bromide (1.1 ml), or cinnamyl bromide (1.38 ml)]
were added slowly. After 5 minutes, 0.514 g KI (1 eq) was added into the reaction mixture, the
temperature of the reaction mixture was gradually raised to room temperature in 30 minutes,
then reached 50 – 60 oC by heating. After 23 hours, the reaction mixture was cooled to 0 °C, and
neutralized to pH 6 using 1N HCl acid. The residue was partitioned with EtOAc/water and
chomatographed (n-hexane/EtOAc gradient) to obtain 505 mg of product 7a (46 %); 593 mg of
product 7b (55 %) and 580 mg of product 7c (50 %).
(S)-2-(1-(cyclohexylmethyl)-2-oxoazepan-3-yl)isoindoline-1,3-dione (7a): White solid; [α]D25
-63.8 (c, 0.58, CHCl3), mp. 115 – 117 oC; ESI-MS: m/z 355 [M+H]+ (C21H27N2O); 1H-NMR
(500 MHz, CDCl3) δH (ppm): 7.81 - 7.84 (2H, m); 7.67 - 7.69 (2H, m); 5.03 (1H, d, J = 11.5
Hz); 3.60 (1H, dd, J = 11.5; 15.0 Hz); 3.40 (1H, dd, J = 12.0; 13.5 Hz); 3.29 (1H, dd; J = 5.5;
15.5 Hz); 3.05 (1H, dd, J = 7.5; 13.5 Hz); 2.66 (1H, m); 2.24 (1H, m); 2.12 (2H, m); 1.89 (1H,
m); 1.53-1.74 (6H, m); 1.17 (4H, m); 0.92 (2H, m). 13C-NMR (125 MHz, CDCl3) δC (ppm): 25.5
(CH2); 25.9 (CH2); 26.4 (CH2); 27.7 (CH2); 28.7 (CH2); 29.4 (CH2); 30.8 (CH2); 31.0 (CH2);
36.7 (CH); 49.7 (CH2); 54.5 (CH); 55.8 (CH2); 123.3 (2 x CH); 132.2 (2 x C); 133.8 (2 x CH);
168.4 (C=O); 170.3 (2 x C=O).
(S)-2-(1-benzyl-2-oxoazepan-3-yl)isoindoline-1,3-dione (7b): White solid; [α]D25 -62.9 (c, 0.5,
CHCl3), mp. 137 - 140 oC; ESI-MS: m/z 349 [M+H]+ (C21H21N2O3); 1H-NMR (500MHz, CDCl3)
δC (ppm): 7.90 - 7.93 (2H, m); 7.75-7.78 (2H, m); 7.30-7.39 (5H, m); 5.15 (1H, d, J = 11.5 Hz);
4.84 (1H, d, J = 15.0 Hz); 4.49 (1H, d, J = 15.0 Hz); 3.56 (1H, dd, J = 12.0; 15.5 Hz); 3.37 (1H,
dd, J = 5.5; 15.5 Hz); 2.77 (1H, m); 2.31 (1H, m); 2.15 (1H, m); 1.83 (1H, m); 1.71 (1H, m);
1.45 (1H, m). 13C-NMR (125 MHz, CDCl3) δC (ppm): 27.4 (CH2); 28.7 (CH2); 29.4 (CH2); 48.2
(CH2); 52.1 (CH); 54.5 (CH2); 123.4 (2 x CH); 127.5 (CH); 128.3 (2 x CH); 128.6 (2 x CH);
132.2 (2 x C); 133.9 (2 x CH); 137.2 (C); 168.4 (C=O); 170.5 (2 x C=O).
(S,E)-2-(1-cinnamyl-2-oxoazepan-3-yl)isoindoline-1,3-dione (7c): White solid; [α]D25 -61.7 (c,
0.59, CHCl3), mp. 130 - 132 oC; ESI-MS: m/z 375 [M+H]+ (C23H23N2O3); 1H-NMR (500 MHz,
CDCl3) δC (ppm): 1H-NMR (500 MHz, CDCl3) δC (ppm): 7.84-7.86 (2H, m); 7.69-7.72 (2H, m);
7.35 (1H, d, J = 7.5 Hz); 7.31 (1H, t, J = 7.5 Hz); 7.24 (1H, m); 6.51 (1H, d, J = 16.0 Hz); 6.14
(1H, td, J = 6.5; 16.0 Hz); 5.07 (1H, d, J = 11.0 Hz); 4.28 (1H, dd, J = 6.5; 15.0 Hz); 4.10 (1H,
dd, J = 6.5; 15.0 Hz); 3.55 (1H, dd, J = 12.0; 15.5 Hz); 3.37 (1H, dd, J = 5.0; 15.5 Hz); 2.68
(1H, m); 2.10 (2H, m); 1.89 (1H, m); 1.71 (1H, m); 1.54 (1H, m). 13C-NMR (125 MHz, CDCl3)
δC (ppm): 27.8 (CH2); 28.7 (CH2); 29.5 (CH2); 47.9 (CH2); 50.9 (CH2); 54.5 (CH); 123.4 (2 x
CH); 124.5 (CH); 126.5 (2 x CH); 127.8 (C); 128.6 (2 x CH); 132.2 (2 x C); 133.4 (CH); 133.9
(2 x CH); 136.5 (C); 168.4 (C=O); 170.2 (2 x C=O).
General procedure for synthesis of 8a–8c: To a stirred solution of compounds 7a-7c (0,2 g) in
DMSO (8 mL), hydrazin 35 % solution (10 eq) was added. The reaction was stirred for 2 h at
room temperature. The solvent was evaporated under reduced pressure, water was then added,
and the mixture was extracted with ethyl acetate. The organic phase was evaporated under
reduced pressure. The residue was purified on Sephadex column chromatography with MeOH as
Synthesis of n-alkyl amino lactam derivatives
295
solvent to obtain 116 mg of product 8a (92 %), 101 mg of product 8b (81 %), 107 mg of product
8c (82 %).
(S)-3-amino-1-(cyclohexylmethyl)azepan-2-one (8a): White solid; [α]D25 -63.7 (c, 0,5, CHCl3);
ESI-MS: m/z 225 [M+H]+ (C13H25N2O); 1H-NMR (500 MHz, CDCl3) δH (ppm): 3.66 (1H, d, J =
11.0 Hz); 3.45 (1H, dd, J = 11.0; 15.0 Hz); 3.38 (1H, dd, J = 5.5; 13.5 Hz); 3.17 (1H, dd, J = 5.5;
15.0 Hz); 3.09 (1H, dd, J = 8.0; 13.5 Hz); 1.95 (1H, m); 1.86 (1H, m); 1.78 (1H, m); 1.72 (2H,
m); 1.65 (4H, m); 1.53 (2H, m); 1.35 (1H, m); 1.16 (3H, m); 0.97 (2H, m). 13C-NMR (125 MHz;
CDCl3): see Table 1.
(S)-3-amino-1-benzylazepan-2-one (8b): Pale yellow oil; [α]D25 -65.6 (c, 0.49, CHCl3); ESI-
MS: m/z 219 [M+H]+ (C13H19N2O); 1H-NMR (500 MHz, CDCl3) δH (ppm): 7.25-7.33 (5H, m);
4.76 (1H, d, J = 14.5 Hz); 4.48 (1H, d, J = 14.5 Hz); 3.70 (1H, d, J = 11.0 Hz); 3.39 (1H, d, J =
11.0; 15.0 Hz); 3.20 (1H, d, J = 5.5; 15.0 Hz); 1.85 (2H, m); 1.65 (2H, m); 1.55 (1H, m); 1.20
(1H, m). 13C-NMR (125 MHz; CDCl3): see Table 1.
(S)-3-amino-1-cinnamylazepan-2-one (8c): Pale yellow oil; [α]D25 -62.6 (c, 0.5, CHCl3); ESI-
MS: m/z 245 [M+H]+ (C15H21N2O); 1H-NMR (500MHz, CDCl3) δC (ppm): 7.36 (2H, d, J = 7.0
Hz); 7.30 (2H, t, J = 7.5 Hz); 7.24 (1H, m); 6.50 (1H, d, J = 16.0 Hz); 6.13 (1H, dt, J = 6.5;
16.0 Hz); 4.31 (1H, ddd, J = 1.0; 6.5; 15.0 Hz); 4.10 (1H, ddd, J = 1.0; 6.5; 15.0 Hz); 3.67 (1H,
d, J = 10.5 Hz); 3.42 (1H, d, J = 11.5; 15.0 Hz); 3.26 (1H, dd, J = 5.0; 15.0 Hz); 1.95 (1H, m);
1.85 (1H, m); 1.77 (1H, m); 1.67 (1H, m); 1.53 (1H, m); 13C-NMR (125 MHz; CDCl3): see
Table 1.
3. RESULTS AND DISCUSSION
Our synthesis of N-alkyl amino lactam derivatives is described in Figure 2. Compound 2
was synthesized via 2 steps from L-ornithine monohydrochloride under microwave irradiation
with the overall performance of 32 % [9]. Six-membered N-alkyl amino lactam derivatives were
synthesized from compound 2 by 2 step procedure. The first was the alkylation of compound 2
with R-Br agent to obtain 3a-3c. Then the protection group was removed by hydrazine to obtain
N-alkyl amino lactam derivatives 4a-4c respectively. Similarly, compound 6 was synthesized via
two steps from L-lysine under microwave irradiation with the overall performance of 45.6 % [9],
then the alkylation of compound 6 by R-Br agent to achieve 7a-7c. Finally, the protection group
was removed by hydrazine to obtain N-alkyl amino lactam derivatives 8a-8c respectively.
Figure 2. Synthetic procedure of 4a-4c and 8a-8c.
Phi Thi Dao, et al
296
The structures of all compounds were confirmed by MS and NMR spectroscopies (Details
are presented in the experimental section and Table 1).
Table 1. 13C-NMR spectrum data for compounds 4a-4c and 8a-8c.
C
4a
(δC) ppm
4b
(δC) ppm
4c
(δC) ppm
8a
(δC) ppm
8b
(δC) ppm
8c
(δC) ppm
2 172.8 172.7 172.5 176.2 176.7 176.4
3 51.9 52.1 52.1 53.9 54.0 54.0
4 29.8 29.7 29.9 33.7 33.9 33.9
5 21.4 21.3 21.3 27.2 27.3 27.7
6 48.8 47.4 49.2 28.1 28.1 28.1
7 49.1 51.8 47.5
1’ 53.5 50.4 47.5 55.3 47.7 50.5
2’ 35.9 137.0 133.2 36.8 137.6 132.9
3’ 31.8 128.1 124.1 31.0 128.2 124.8
4’ 25.9 128.7 136.5 25.9 128.6 136.6
5’ 26.4 127.5 126.4 26.4 127.5 126.4
6’ 25.9 128.7 128.6 25.9 128.6 128.4
7’ 31.9 128.1 127.8 30.9 128.2 127.7
8’ 128.6 128.4
9’ 126.4 126.4
The 1H-NMR, 13C-NMR and DEPT spectra of compounds 3a-3c showed the signals of 4
aromatic methine groups, 3 methylene groups including 1 group attached to nitrogen, 1 nitrogen-
attached methine group, 3 carbonyl groups and 2 sp2 carbons. Otherwise, 1H-NMR and 13C-
NMR spectra of compound 3a displayed the signals of one cyclohexane ring with 5 methylene
groups, one nitrogen-attached methylene group and one methine group. 1H-NMR and 13C-NMR
spectra of compound 3b consisted the signal of an additional benzyl ring with 5 aromatic
methine groups, 1 quarternary carbon and 1 nitrogen-attached methylene group. 1H-NMR and
13C-NMR spectra of 3c is similar to 3b, except the signals of 2 olefin methine groups in δH 4.28
(1H, dd, J = 6.5, 15.0 Hz); 4.09 (1H, dd, J = 6.5, 15.0 Hz) and δC 124.4, 133.9. The trans
conformation of these 2 protons has been confirmed by the large coupling constant (J = 15.0
Hz). The data on the spectrum allowed us to define the attachment of substituents
(methylcyclohexan, benzyl, cinnamyl) to the amino group on the δ-lactam ring. The mass
spectrum of the molecular ion displayed the peak at the mass of the expected formula.
Afterward, the removal of protection groups of 3a-3c by hydrazine gives N-alkyl amino lactam
4a-4c derivatives respectively. In comparision with 3a-3c compounds, 1H-NMR and 13C-NMR
spectra of compound 4a-4c lacks of the signals of two carbonyl groups, 4 A2B2-type aromatic
methine groups, and 2 quarternary carbons, which are the evidence of removal of protecting
Tổng hợp một số dẫn xuất n-alkyl amino lactam
297
groups and 4a-4c compound were N-alkyl amino lactam derivatives. Mass spectrometry of these
derivatives displayed the peak at the mass of the expected formula.
1H-NMR, 13C-NMR and DEPT spectra of the seven-membered ring derivatives (7a-7c và
8a-7c) were similar to the 6 seven-membered ones (3a-3c và 4a-4c), except the signal of an
additional methylene of ε-lactam ring. Mass spectrometry of these derivatives displayed the peak
at the mass of the expected formula.
4. CONCLUSION
In conclusion, we have synthesized 6 N-alkyl amino lactam compounds from the
corresponding amino acids with the highest overall performance of 20.3%. Synthetic procedure
was simple and efficient. Especially, we have applied the microwave irradiation on the synthesis
of some compounds, thus, shortened the reaction time and increased reaction efficiency. The N-
alkyl amino lactams compounds should be used for further synthesis of bioactive compounds
having an N-alkyl amino-lactam substructures such as for synthesis of bengamide analogues
(Figure 1).
Acknowledgement. This work was carried out within the framework of application-oriented basic research
project. Project code: NCCB-ĐHƯD.2012-G/05.
REFERENCES
1. Quinoa E., Adamczeski M., Crews P. - Bengamides, heterocyclic anthelminthics from a
jaspidae marine sponge, J. Org. Chem. 51 (1986) 4497–4498.
2. Madeline A., Emilio Q., Philippes C. - Novel sponge-derived amino acid. 5. Structure,
Stereochemistry and Synthesis of several new heterocycles, J. Am. Chem. Soc 111 (1989)
647-654.
3. Valeria D. A. M., Clelia G., Liugi M., Angela Z., Cécile D. and Maryvonne F. -
Bengamides and Related New Amino acid Derivatives from the New Caledonian Marine
Sponge Japis carteri, J. Nat. Prod 60 (1997) 814-816.
4. Rogelio F., Michel D., Yes L., Mohamed N., Jean F. V. and Jean F. B. - Antifugal
Metabolites from the Marine Sponge Pachastrissa sp., J. Nat. Prod. 62 (1999) 678-680.
5. Boeckman R. K. J., Clark T. J., Shook B. C. - A Practical Enantioselective Total Synthesis
of the Bengamides B, E, and Z, Org. Lett. 4 (2002) 2109-2112.
6. Martin G. B. and Kenneth J. M. - A Chemoenzymatic Total Synthesis of ent-Bengamide
E, J. Org. Chem. 66 (2001) 6768–6774.
7. Zia T., Frederick R. K., Kenneth W. B., John B., Ania M. C., Richard W. V., Penny E. P.,
Miranda L. S., Sompong W., and Phillip C. - Bengamides Revisited: New Structures and
Antitumor Studies, J. Org. Chem. 66 (2001) 1733–1741.
8. Wenming Li., Joanna M. S., Liladhar W., Oljan R. and Thomas J. B. - Total Synthesis of
Bengamide E, Tetrahedron Letters 43 (8) (2002) 1373-1375.
9. Phí T. Đ., Đoàn T. M. H., Vũ V. L., Châu V. M., Phạm V. C. - Microwave-assisted
synthesis of lactams from amino acids, Vietnam Journal of Chemistry 53 (2e) (2015)
198-201.
Phi Thi Dao, et al
298
TÓM TẮT
TỔNG HỢP MỘT SỐ DẪN XUẤT N-ALKYL AMINO LACTAM
Phí Thị Đào1, Vũ Văn Lợi1, Nguyễn Thị Bích2, Đoàn Thị Mai Hương1, *, Nguyễn Hiển2,
Châu Văn Minh1, Phạm Văn Cường1, *
1Viện Hóa sinh biển, Viện Hàn lâm KH&CNVN, 18 Hoàng Quốc Việt, Cầu Giấy, Hà Nội
2Trường Đại học Sư phạm Hà Nội, 136 Xuân Thủy, Cầu Giấy, Hà Nội
*Email: doanhuong7@yahoo.com
Các hợp chất bengamide có nguồn gốc thiên nhiên biển được Crews và cộng sự phân lập
lần đầu tiên từ các loài hải miên Jaspis vào năm 1986. Cho tới nay, đã có nhiều hợp chất
bengamide thể hiện hoạt tính chống ung thư rất tốt như một số analog chứa nhóm N-alkyl trên
vòng lactam của bengamide E. Trong khuôn khổ bài báo này, chúng tôi trình bày quy trình tổng
hợp 6 dẫn xuất N-alkyl amino lactam (4a-4c và 8a-8c), đây là các hợp chất trung gian quan trọng
trong quá trình tổng hợp các analog mới chứa nhóm N-alkyl trên vòng lactam.
Từ khóa: bengamides, amino-lactams, hoạt tính gây độc tế bào.
Các file đính kèm theo tài liệu này:
- 11849_103810382134_1_sm_7498_2061493.pdf