Six new benzopyran derivatives were synthesized by reduction reaction and Michael reaction from malloapelta B. Their structures were determined as 8-(1’-oxo-butyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (2), 8-(1’-oxo-3’(R)-methyl-4’-acetyl-5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (3), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-(methyl fomiate)-5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (4,4’), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-(ethyl formiate)-5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (5,5’) by spectroscopic data, including two-dimensional NMR techniques and ESI spectrum.Keywords: Malloapelta B; Michael reaction; reduction reaction; 5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran

Kiem, Phan Van

Minh, Chau Van

Nam, Nguyen Hoai

Nhiem, Nguyen Xuan

Tung, Nguyen Huu

Vietnam Academy of Science and Technology: Journals Online

250
Journal of Chemistry, Vol. 45 (2), P. 250 - 254, 2007 
Study on the synthesis of some new Derivatives of 
malloapelta B isolated from Mallotus apelta 
Received 6 June 2006 
Nguyen Hoai Nam, Nguyen Huu Tung, Nguyen Xuan Nhiem,  
Chau Van Minh, Phan Van Kiem 
Institute of Natural Products Chemistry, Vietnamese Academy of Science and Technology 
 
summary 
Six new benzopyran derivatives were synthesized by reduction reaction and Michael reaction 
from malloapelta B. Their structures were determined as 8-(1’-oxo-butyl)-5,7-dimethoxy-2,2-
dimethyl-2H-1-benzopyran (2), 8-(1’-oxo-3’(R)-methyl-4’-acetyl-5’-oxo-hexyl)-5,7-dimethoxy-
2,2-dimethyl-2H-1-benzopyran (3), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-(methyl fomiate)-5’-oxo-
hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (4,4’), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-(ethyl 
formiate)-5’-oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran (5,5’) by spectroscopic 
data, including two-dimensional NMR techniques and ESI spectrum. 
Keywords: Malloapelta B; Michael reaction; reduction reaction; 5,7-dimethoxy-2,2-dimethyl-
2H-1-benzopyran. 
I - introduction 
Malloapelta B (1), a new benzopyran 
derivative was isolated from the Vietnamese 
traditional medicinal plant Mallotus apelta 
(Lour.) Muell.-Arg. [1]. It shows strong 
cytotoxic effect as well as strong activity against 
NF-B activation with IC50 value 0.54±0.05 µM. 
This compound is continued studying further for 
cancer treatment [2, 3]. To investigate the 
relations between the structures and their 
bioactivities as well as probably find new 
derivatives having stronger bioactivities, we 
have synthesized a series of its derivatives.  
As a part of our research, we report herein 
six new derivatives synthesized by reduction 
reaction and Michael reaction. Their structures  
were determined as 8-(1’-oxo-butyl)-5,7-
dimethoxy-2,2-dimethyl-2H-1-benzopyran (2), 
8-(1’-oxo-3’(R)-methyl-4’-acetyl-5’-oxo-
hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran (3), 8-(1’-oxo-3’(R)-methyl-4’(S/R)-
(methyl formiate)-5’-oxo-hexyl)-5,7-dimethoxy 
-2,2-dimethyl-2H-1-benzopyran (4, 4’), 8-(1’-
oxo-3’(R)-methyl-4’(S/R)-(ethyl formiate)-5’-
oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran (5, 5’) by the NMR and MS spectra. 
The relationships between their structures and 
cytotoxicities will be reported elsewhere. 
II - Experimental 
Materials and methods 
Material 
Malloapelta B was isolated from Mallotus 
apelta (Lour.) Muell.-Arg.. The reagents were 
purchased of Aldrich Co. Solvents were distilled 
prior to use. 
General Experimental Procedures 
The Electronspray Ionization (ESI) mass 
spectrum was obtained by using an AGILENT 
1100 LC-MSD Trap spectrometer. The 1H-NMR 
(500 MHz) and 13C-NMR (125 MHz) spectra 
251
were recorded on a Bruker AM500 FT-NMR 
spectrometer using TMS as the internal 
standard. Column chromatography (CC) was 
performed on silica gel (Kieselgel 60, 70-230 
mesh and 230-400 mesh, Merck). TLC was 
performed with Thin layer Art 5562 DC-
Alurolle Kieselgel made by Merck Co.   
The synthesis of  8-(1’- oxo-butyl)-5,7-dime-
thoxy-2,2-dimethyl-2H-1-benzopyran (2) 
20 mg (0.62 mmol) NaBH4 was added 
slowly to a solution of 150 mg (0.52 mmol) 
malloapelta B with 15 ml MeOH in a 40 ml 
round-flask placed on a magnetic stirrer. The 
reaction was kept at room temperature for 4 h. 
The reaction mixture was extracted with mixture 
CHCl3/H2O. The CHCl3 extract was separated 
by column chromatography over silica gel 
eluted with n-hexane-acetone (10:1) to afford 
128 mg of the reduced product 2, yield 85%. 
1H-NMR (500 MHz, MeOD),  (ppm): 5.44 
(1H, d, J = 10.5 Hz, H-3), 6.56 (1H, d, J = 10.5 
Hz, H-4), 6.00 (1H, s,  H-6), 2.72 (2H, m, H-2’), 
1.70 (2H, m, H-3’), 0.95 (3H, t, J = 6.5 Hz, H-
4’), 3.70 (3H, 7-OCH3), 3.83 (3H, 5-OCH3), 
1.39 (6H, s, H-11, H-12). 
13C-NMR (125 MHz, MeOD),  (ppm): 76.7 
(s, C-2), 126.6 (d, C-3), 116.4 (d, C-4), 157.6 (s, 
C-5), 87.8 (d, C-6), 156.5 (s, C-7), 113.6 (s, C-
8), 151.5 (s, C-9), 104.2 (s, C-10), 27.7 (q, C-11, 
C-12), 204.2 (s, C-1’), 47.0 (t, C-2’), 17.6 (t, C-
3’), 13.9 (q, C-4’), 55.7 (q, 7-OCH3), 55.8 (q, 5-
OCH3). 
ESI m/z: 291 [M+H]+ (C17H23O4). 
The synthesis of 8-(1’-oxo-3’(R)-methyl-4’-
acetyl-5’-oxo-hexyl)-5,7-dimethoxy-2,2-
dimethyl-2H-1-benzopyran (3) 
A mixture of 150 mg (0.52 mmol) 
malloapelta B and acetylacetone in 15ml MeOH 
added 200 µL NaOH20% was placed on a 
magnetic stirrer in a 40 ml round-flask. The 
mixture was maintained at room temperature in 
12h. Removal of the solvent afforded a residue 
that was purified by column chromatography 
over silica gel eluted with n-hexane-acetone 
(6:1) to give 138 mg product 3, yield 68%. 
1H-NMR (500 MHz, MeOD),  (ppm): 5.44 
(1H, d, J = 10.5 Hz, H-3), 6.55 (1H, d, J = 10.5 
Hz, H-4), 5.99 (1H, s, H-6), 1.39 (3H, s, H-11), 
1.37 (3H, s, H-12), 2.71 (1H, dd,  J = 17.0, 8.5 
Hz, Ha-2’), 2.74 (1H, dd, J = 17.0, 4.0 Hz, Hb-
2’), 2.80 (1H, m, H-3’), 3.84 (1H d, J = 9.0 Hz, 
H-4’), 1.01 (3H, d, J = 6.5 Hz, H-5’), 2.18 (3H, 
s, H-7’), 2.19 (3H, s, H-9’), 3.83 (3H, s, 7-
OCH3), 3.78 (3H, s, 5-OCH3). 
13C-NMR (125 MHz, MeOD),  (ppm): 76.8 
(s, C-2), 126.7 (d, C-3), 116.3 (d, C-4), 156.7 (s, 
C-5), 87.8 (d, C-6), 157.6 (s, C-7), 113.2 (s, C-
8), 151.5 (s, C-9), 104.3 (s, C-10), 27.7 (q, C-11, 
C-12), 202.0 (s, C-1’), 48.7 (t, C-2’), 30.2 (d, C-
3’), 73. (d, C-4’), 17.7 (q, C-5’), 204.6 (s, C-6’), 
29.7 (q, C-7’), 204.6 (s, C-8’), 29.9 (q, C-9’), 
55.7 (q,  7-OCH3) and 55.7 (q, 5-OCH3). 
ESI m/z: 389 [M+H]+ (C22H29O6). 
The synthesis of 8-(1’-oxo-3’(R)-methyl-4’-
(S/R)-(methyl formiate)-5’-oxo-hexyl)-5,7-di-
methoxy-2,2-dimethyl-2H-1-benzopyran (4,4’)
A mixture of 150 mg (0.52 mmol) 
malloapelta B and acetoacetate methyl ester in 
15 ml MeOH added 20 mg CH3ONa was placed 
on a magnetic stirrer in a 40 ml round-flask. The 
mixture was maintained at room temperature 
overnight. Removal of the solvent afforded a 
residue that was purified by column 
chromatography over silica gel eluted with        
n-hexane-acetone (4:1) to give 148 mg the 
mixture of two optical isomers 4 and 4’, yield 
71%. 
1H-NMR (500 MHz, MeOD),  (ppm): 5.43 
(d, J = 10.5 Hz, H-3), 6.55 (d, J = 10.5 Hz, H-4), 
5.99 (s, H-6), 1.38 (s, H-11), 1.38 (s, H-12), 
2.82 - 2.92 (m, H-2’), 2.74 (m, H-3’), 3.56 (d, J
= 7.5 Hz, H-4’)/3.65 (d, J = 7.5 Hz, H-4’), 1.05 
(3H, s, H-5’)/1.06 (3H, s, H-5’), 2.46 (s, H-7’), 
3.71 (s, H-9’), 3.78 (s, OCH3), 3.83 (s, OCH3). 
13C-NMR (125 MHz, MeOD),  (ppm): 
76.88/76.91 (s, C-2), 126.69/126.69 (d, C-3), 
116.30/116.31 (d, C-4), 156.65/156.68 (s, C-5), 
87.80/87.86 (d, C-6), 157.60/157.60 (s, C-7), 
113.21/113.28 (s, C-8), 151.54/151.54 (s, C-9), 
104.24/104.24 (s, C-10), 27.65/27.65 (q, C-11), 
27.70/27.70 (q, C-12), 202.06/202.17 (s, C-1’), 
252
48.71/48.96 (t, C-2’), 29.38/29.44 (d, C-3’), 
64.25/63.97 (d, C-4’), 17.28/17.84 (q, C-5’), 
29.64/29.44 (q, C-7’), 52.07/52.12 (q, C-9’), 
55.68/5.68 (q, 7-OCH3), 55.80/55.80 (q, 5-
OCH3). 
ESI m/z: 405 [M+H]+ (C22H29O7). 
The synthesis of 8-(1’-oxo-3’(R)-methyl-4’
(S/R)-(ethylformiate)-5’-oxo-hexyl)-5,7-dime-
thoxy-2,2-dimethyl-2H-1-benzopyran (5,5’)
A mixture of 150 mg (0.52 mmol) 
malloapelta B and acetoacetate ethyl ester in 15 
ml C2H5OH added 200 µL NaOH 20% was 
placed on a magnetic stirrer in a 40 ml round-
flask. The mixture was maintained at room 
temperature in 14 h. Removal of the solvent 
afforded a residue that was purified by column 
chromatography over silica gel eluted with n-
hexane-acetone (4:1) to give 152 mg the 
mixture of two optical isomers 5 and 5’, yield 
70%. 
1H-NMR (500 MHz, MeOD),  (ppm): 5.45 
(d, J = 10.5 Hz, H-3), 6.56 (d, J = 10.5 Hz, H-
4), 5.99 (s, H-6), 2.83 - 2.92 (m, H-2’), 2.74 (m, 
H-3’), 3.52 (d, J = 7.5 Hz, H-4’)/3.60 (d, J = 7.5 
H-4’), 1.05 (d, J = 6.5 Hz, H-5’)/1.06 (d, J =
6.5 Hz, H-5’), 2.24 (s, H = 7’), 4.17 (q, J = 6.5 
Hz, H-9’), 1.26 (t, J = 6.5 Hz, H-10’), 3.77 (s, 
7-OCH3), 3.83 (s, 5-OCH3). 
13C-NMR (125 MHz, MeOD),  (ppm): 
76.81/76.82 (s, C-2), 126.69/126.69 (d, C-3), 
116.30/116.80 (d, C-4), 156.63/156.67 (s, C-5), 
87.80/87.80 (d, C-6), 157.09/157.09 (s, C-7), 
113.26/113.34 (s, C-8), 151.51/151.51 (s, C-9), 
104.24/104.24 (s, C-10), 27.65/27.65 (q, C-11), 
27.70/27.70 (q, C-12), 202.13/202.21 (s, C-1’), 
48.77/48.99 (t, C-2’), 29.40/29.57 (d, C-3’), 
64.30/64.48 (d, C-4’), 17.35/17.80 (q, C-5’), 
203.36/203.38 (s, C-6’), 29.30/29.34 (q, C-7’), 
169.10/169.16 (s, C-8’), 61.10/61.09 (t, C-9’), 
14.12/14.13 (q, C-10’), 55.79/55.79 (q, OCH3), 
56.00/56.00 (s, OCH3). 
ESI m/z: 419 [M+H]+ (C23H31O7). 
III - RESULTS AND DISCUSSION 
Compound 2 was obtained as white crystals 
from the reduction reaction after being purified 
by column chromatography over silica gel. The 
synthetic process [4, 5] was illustrated as 
scheme 1. 
 
7
6
5
10
9
8
4
3
2O
1'
O 2'
3'
H3CO
OCH3
1
NaBH4/MeOH
O
3'
O 2'
H3CO
OCH3
2
Scheme 1 
 
The NMR spectra of 2 were similar to those 
of 1, except for the absence of the double bond 
signals at C-2’ and C-3’, and the additional of 
two methylene signals at C 47.0/17.6 and H
2.72 (m)/1.70 (m) in the NMR spectra of 2.
These changes were further confirmed by 
analysis of the proton-coupling constants and by 
the appearance of a quasi ion peak at m/z 291 
[M+H] (C17H22O4 + H) in the positive ESI 
spectrum of 2. Consequently, the structure of 2
was 8-(1’-oxo-butyl)-5,7-dimethoxy-2,2-
dimethyl-2H-1-benzopyran. 
Compounds 3, 4/4’, 5/5’ were obtained as 
white crystals by Michael reaction with 
acetylacetone, acetoacetate methyl ester, and 
acetoacetate ethyl ester as agents of the 
reactions, respectively. The synthetic process of 
these compounds [4, 5] was illustrated as 
scheme 2. 
 
253
O
O
CH 3
CH 3
CH 3
CH 3O
OCH 3
O
O
R
CH 3
CH 3
H 3C O
OCH 3
H 3C
CH 3COCH 2R
HC
O
O
CH 3
CH 3
HC
O
O
CH 3
OCH 3
HC
O
O
CH 3
OCH 2CH 3
R =
1
(M ichael reaction)
; ;
3 4,4' 5,5 '
5
7
8
1' 2 '
3 '
4 '
2
5
7
8
1 ' 2 '
3 '
4 '
11
12
11
12
5 '
6 ' 7 '
8 ' 9 '
5 '
6 ' 7 '
8 ' 9 '
5 '
6 ' 7 '
8 ' 9 ' 10'
 
Scheme 2 
 
The 1H-NMR of 3 exhibited two doublets at 
 5.44 and 6.55 (J = 10.5 Hz), which were 
assigned to H-3 and H-4, respectively. A singlet 
of H-6 was at  5.99, two quaternary methyl 
groups at  1.37 and 1.39 as the singles, two 
methoxyl groups were at 3.78 and 3.83. The 
acetoacetyl group was determined to connect at 
C-3’ from the appearance of two methyl groups 
at  2.18 and 2.19, and a methine proton at 
3.84 (d, J = 9.0 Hz). In addition, the methyl 
group at  1.01 as a doublet (J = 6.5 Hz) also 
confirmed the acetoacetyl group attached to C-
3’. The 13C-NMR and DEPT spectra of 3
showed signals of 22 carbons. The two acetyl 
groups were confirmed at  204.6, 29.7/29.9. 
The methylene and methine carbons at  48.7
and 30.2, respectively evidenced the absence of 
the double bond. Furthermore, the ESI exhibited 
a quasi ion peak at m/z 389 [M+H], correspond 
to the molecular formula of C22H28O6. From the 
above data, compound 3 was determined to be 
8-(1’-oxo-3’(R)-methyl-4’-acetyl-5’-oxo-
hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran. 
Compounds 4/4’ and 5/5’ were obtained as 
two racemics, which were confirmed by the 
analysis of NMR data. All the NMR spectra of 
4/4’ and 5/5’ were similar to those of 3, except 
for the more appearance of the methoxy group 
(C 52.12/52.07 and H 3.71) instead of the 
methyl carbon at C 29.9/H 2.19). The 
stereochemistry at C-3’ of  4/4’ and 5/5’ were 
suggested to be (R) by comparing the chemical 
shifts and proton coupling constants of  4/4’ and 
5/5’ with those of 6-(methyl 1-oxo-3-hydroxy-
butyl ether)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran and 6-(1-oxo-3-hydroxy-butyl)-
5,7-dimethoxy-2,2-dimethyl-2H-1-benzopyran 
[6], and with the similar structure reported in the 
literature [7]. In addition, the ESI spectra of 4/4’
and 5/5’ showed the ion peaks at m/z 405
[M+H]+ and 419 [M+H]+ corresponding to the 
molecular formula of C22H28O7 and C23H30O7,
respectively. Thus, compound 4/4’was 
determined to be a racemic of 8-(1’-oxo-3’(R)-
methyl-4’(S/R)-(methyl formiate)-5’-oxo-
hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran and  5/5’ was a racemic of 8-(1’-
oxo-3’(R)-methyl-4’(S/R)-(ethyl formiate)-5’-
oxo-hexyl)-5,7-dimethoxy-2,2-dimethyl-2H-1-
benzopyran.  
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Study on synthesis of some new derivatives of Malloapelta B isolated from Mallotus apelta

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Study on synthesis of some new derivatives of Malloapelta B isolated from Mallotus apelta

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