First total synthesis of mariamide A

Article abstract of DOI:10.1177/1747519819890821

Mariamide A, a lignanamide isolated from the seeds of Silybum marianum, has demonstrated potential utility as an antioxidant and antidiabetic agent and possesses an 8-O-4′ neolignan skeleton. Herein, a first total synthesis of mariamide A is presented that proceeds in nine steps using vanillin as the starting material. The key steps for the preparation of mariamide A involve an I₂-catalyzed bromomethoxylation of an alkene group, a nucleophilic substitution followed by a sequential elimination and a monoacylation reaction.

Full text of DOI:10.1177/1747519819890821

890821CHL0010.1177/1747519819890821Journal of Chemical ResearchXia et al.
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Research Paper
Journal of Chemical Research
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First total synthesis of mariamide A
https://doi.org/10.1177/1747519819890821
DOI: 10.1177/1747519819890821
journals.sagepub.com/home/chl
Yamu Xia1, Chenglong Chen1 , Mengying Li1,
Weizeng Zhou1, Shuyu Sun1, Shanpeng Chu1
and Hui Wang2
Abstract
Mariamide A, a lignanamide isolated from the seeds of Silybum marianum, has demonstrated potential utility as an
antioxidant and antidiabetic agent and possesses an 8-O-4′ neolignan skeleton. Herein, a first total synthesis of mariamide
A is presented that proceeds in nine steps using vanillin as the starting material. The key steps for the preparation of
mariamide A involve an I2-catalyzed bromomethoxylation of an alkene group, a nucleophilic substitution followed by a
sequential elimination and a monoacylation reaction.
Keywords
8-O-4′ neolignans, I2-catalyzed bromomethoxylation, lignanamides, mariamide A, lignans
Date received: 9 July 2019; accepted: 24 October 2019
reticulum stress-induced cytotoxicity,13 and phytotoxicity
Introduction
role.7 Given their relative rarity in nature and the limited
Lignans are widely distributed in the plant kingdom and
number of biological studies concerning these compounds,
represent an enormous class of pharmacologically active
lignanamides are worthy of further investigation as desira-
secondary metabolites.1,2 These compounds are derived
ble synthetic targets. Several elegant reports on lignanamide
from the oxidative coupling of two phenylpropanoid units
synthesis have been reported.12,14,15 Motivated by these unu-
by a β,β′-linkage with a different degree of oxidation in the
side chain and a different substitution pattern on the aro-
sual structural features and significant biological activity,
our laboratory accomplished the first total synthesis of
matic moieties.3 Therefore, lignans exhibit an enormous
cannabisin F in 201416 and cannabisin B in 2015,17 both of
structural diversity originating from the various linking pat-
which belong to the lignanamides.
terns of these phenylpropanoid units.
A small but significant subgroup within the lignans, lig-
nanamides were first found in the roots of Capsicum ann-
uum var. grossum,4 and later were isolated from Mitrephora
thorelii,5 Cannabis sativa,6 Hyoscyamus niger,7 Solanum
melongena L,8 Lycium chinense,9,10 and so on. Lignanamides
possess significant pharmacological effects such as anti-
inflammatory,8,11 antihyperlipidemic,9 radical-scavenging
1College of Chemical Engineering, Qingdao University of Science and
Technology, Qingdao, P.R. China
2ShanDong Jincheng Kery Chemical Co., Ltd, Zibo, P.R. China
Corresponding author:
Yamu Xia, College of Chemical Engineering, Qingdao University of
Science and Technology, Qingdao 266042, P.R. China.
activity,10 antiproliferative,12 reduction of endoplasmic Email: xiayamu@126.com

2
Journal of Chemical Research 00(0)
Scheme 2. Synthesis of 8-O-4′ neolignan intermediate (7).
Scheme 1. Retrosynthetic analysis of mariamide A (1).
compound 5′, and a lower or higher reaction temperature
provided a low yield of compound 6. Dicarboxylic acid 7
could be prepared in 95% yield from compound 6.
Recently Qin et al.18 was the first to report the lignana-
mide, mariamide A (1) from the seeds of Silybum mari-
anum. Mariamide A (1) has demonstrated potential utility
as an antioxidant and an antidiabetic agent and possesses an
8-O-4′ neolignan skeleton structurally, which attracted our
interest. Based on our previous work, we set out to explore
a new methodology for the synthesis of mariamide A (1)
under more convenient and general conditions.
Having the 8-O-4′ neolignan intermediate 7 secured, the
total synthesis of mariamide A (1) was completed in a few
steps (Scheme 4; Figure 1). Thus, benzoic acid derivative 9,
which was obtained in two steps in 80% overall yield from
commercially available ethyl 4-hydroxybenzoate (8), was
coupled with 1,4-diaminobutane using Verma et al.’s21
method to generate monoacylated diamine unit 10. The
presence of 20% NaCl solution was necessary to obtain a
useful yield in the reaction, but the yield with further
increase in NaCl concentration did not show improvement.
Next, the dicarboxylic acid 7 was coupled with mono-
acylated diamine 10 to give the precursor 11. The desired
target 1 was obtained successfully by removal of the MOM
protecting groups in precursor 11.
The 1H NMR spectrum of synthetic 1 (Table 2) showed
the signals due to one E form 1,2-disubstituted and one
trisubstituted olefin moieties (δ 7.41 (1H, d, J=15.5Hz),
6.44 (1H, d, J=15.5Hz); 7.23 (1H, s)), two methoxys (δ
3.94, 3.68), and a series of methylenes, which is similar
with the isolated compound 1. The presence of an ether
bridge connecting between C-8′ and C-4‴ was supported
by the data C-7′ signal δ 125.1 and C-8′ signal δ 141.9, as
well as the H-7′ signal δ 7.23, which is similar with the
isolated compound 1.
Herein, we describe a first synthetic route to mariamide
A (1) in nine steps using vanillin as the starting material.
Results and discussion
Retrosynthetically, we envisaged that compound 1 could be
accessed from an amidation reaction between an 8-O-4′
neolignan skeleton and a monoacylated diamine unit
(Scheme 1). The 8-O-4′ skeleton intermediate could be
traced back to ethyl ferulate (3) that in turn could be
accessed from vanillin (2) via a Knoevenagel reaction.
As shown in Scheme 2, Knoevenagel reaction of vanil-
lin (2) with monoethyl malonate easily afforded ethyl feru-
late (3) in 98% yield. To obtain the desired 8-O-4′ neolignan
intermediate 6 efficiently, protection of the phenolic group
in 3 by using methoxymethyl chloride (MOM-Cl) to fur-
nish compound 4 was necessary. With compound 4 in hand,
our next task was to explore the bromomethoxylation of the
alkene group in 4. NBS is a common halogen source for
bromomethoxylation reaction. However, a longer reaction
time and low yield, especially with electron-deficient alk-
enes, are major drawbacks.19 Inspired by Lodh et al.’s20 and
Bar’s19 work, we anticipated that iodine might catalyze the
electrophilic halogen transfer from NBS to the olefin. An
initial experiment was performed at −10°C using 4 as the
substrate and iodine as the catalyst, which lead to the for-
mation of 5 as the sole reaction product in 98% isolated
yield. Further investigations revealed that a low reaction
temperature was necessary. With precursor 5 in hand, we
turn to the implementation of the coupling between 3 and 5
to form the crucial 8-O-4′ neolignan intermediate 6. After
screening various conditions (Table 1), compound 6 could
be obtained by using Cs2CO3 and KI in DMF at 100°C in
synthetically useful yields; no undesired compound 6′ was
Conclusion
In summary, the lignanamide mariamide A (1) has been syn-
thesized for the first time in nine steps from inexpensive com-
mercially available starting materials (vanillin) using a
concise I2-catalyzed bromomethoxylation reaction of an alk-
ene group, a nucleophilic substitution reaction followed by a
sequential elimination reaction and a monoacylation reaction
as key steps. The strategy may also be useful for the prepara-
tion of various 8-O-4′ neolignans or lignanamides and their
derivatives, while potentially contributing to an improved and
deeper understanding of bioactivities of related compounds.
Experimental
observed. We speculate that any compound 6′ formed in the All chemicals were purchased (Aladdin or Sinopharm
reaction was converted into compound 6 immediately via Chemical Reagent Co., Ltd) for the reactions are analytical
elimination of CH3OH (Scheme 3). Excess Cs2CO3, how- grade and were used without further purification. Solvents
ever, accelerated the elimination of HBr in 5 to form olefin were dried and stored using standard procedures. Highly

Xia et al.
3
Table 1. Comparison of different reaction condition for the synthesis of compound 6.
Entry
Condition
Base (equiv.)
Solvent
Yield of 5′ (%)
Yield of 6 (%)
1
2
3
4
5
6
7
8
9
KI, 10h, reflux
KI, 10h, reflux
KI, 10h, 100°C
KI, 10h, 100°C
KI, 10h, 100°C
KI, 10h, 60°C
KI, 10h, 60°C
KI, 10h, 100°C
KI, 10h, reflux
KI, 10h, 120°C
K2CO3 (1)
Cs2CO3 (1)
K2CO3 (1)
Cs2CO3 (1)
NaH (1)
K2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Acetone
Acetone
DMF
DMF
DMF
DMF
DMF
DMF
CH3OH
DMF
0
91
85
78
89
93
92
45
0
0
Trace
8
12
Trace
0
Trace
32
0
22
10
51
Figure 1. Mariamide A.18
Scheme 3. A plausible mechanism for the synthesis of
compound 6.
(E)-Ferulic acid ethyl ester (3)
To an oven-dried round-bottom flask (500mL) charged
with vanillin (2) (38.48g, 252.88mmol), monoethyl
malonate (50.11g, 379.32mmol) and piperidine (4.0g,
50.58mmol) was added pyridine (100mL) under air at
room temperature. The reaction solution was stirred for
24h at 100°C. The resulting solution was cooled to 0°C and
hydrochloric acid was added dropwise until pH was 1–2.
The mixture was allowed to stand for 24h at −10°C, and
then filtered and dried. The residue was purified by flash
column chromatography (petroleum/EtOAc=6/1) to afford
3: white solid: m.p. 60–61°C (Lit.22 59–61°C); yield:
1
55.08g (98%); H NMR (500MHz, CDCl3), δ 7.61 (d,
J=16Hz, 1H, ArCH=CH), 7.06 (dd, J=8Hz, 2Hz, 1H,
ArH), 7.03 (d, J=2Hz, 1H, ArH), 6.91 (d, J=8Hz, 1H,
ArH), 6.29 (d, J=16Hz, 1H, ArCH=CH), 5.92 (s, 1H,
ArOH), 4.25 (q, J=7Hz, 2H, CH2CH3), 3.92 (s, 3H, OCH3),
1.33 (t, J=7Hz, 3H, CH2CH3); 13C NMR (125MHz,
Scheme 4. Completion of the total synthesis of mariamide A (1).
moisture- or oxygen- sensitive reactions were performed CDCl3), δ 167.5 (C=O), 147.8, 146.7, 145.0, 127.5, 123.1,
under a nitrogen atmosphere. Melting points were taken on 115.8, 114.6, 109.5, 60.4, 55.8, 14.40. The spectral data are
a Gallenkamp melting point apparatus without calibration. consistent with the literature.23
Flash column chromatography and thin-layer chromatogra-
phy (TLC) inspections were performed on Aladdin silica
Ethyl (E)-3-(3-methoxy-4-(methoxymethoxy)
phenyl)acrylate (4)
gel (200–300 mesh) and silica gel plates (GF254), respec-
1
tively. The H NMR and 13C NMR spectra were recorded
on Bruker AM-500MHz, Bruker AM-600MHz spectrom- To an oven-dried round-bottom flask (250mL) charged
eters. high-resolution mass spectra (HRMS) were obtained with a solution of 3 (10g, 45.0mmol) in acetone (80mL)
on a Bruker APEXII47e spectrometer.
was added anhydrous K2CO3 (18.66g, 135.0mmol) under

4
Journal of Chemical Research 00(0)
Table 2. Comparison of the spectroscopic data for the isolated compound in CD3OD18 and the synthetic compound in CDCl3.
Isolated compound 1
δH (400MHz)
Synthetic compound 1
δH (500MHz)
δC (100MHz)
δC (500MHz)
1
126.5
130.2
116.1
161.9
170.0
125.5
113.7
148.9
149.5
116.2
126.2
125.1
141.8
165.7
40.3
126.6
130.3
116.2
161.9
170.0
125.5
113.7
148.9
149.6
116.2
126.3
125.1
141.9
165.7
40.32
27.80
27.83
40.4
126.5
130.2
116.1
162.1
170.1
132.0
112.3
150.6
147.8
115.3
122.2
141.2
121.1
168.7
40.29
27.9
2,6
3,5
4
7
1′
2′
3′
4′
5′
6′
7′
8′
9′
10′
11′
12′
13′
1″
2″, 6″
3″, 5″
4″
7.65, d (7.8)
6.80, d (7.8)
7.66 d (8.0)
6.81–6.79, m
7.30, s
7.30, s
6.71, d (8.7)
7.03, d (8.7)
7.22, br s
6.70, d (8.5)
7.05, d (8.5)
7.23, s
3.28, m
1.50, m
1.50, m
3.28, m
3.27–3.24, m
1.49–1.40, m
1.49–1.40, m
3.27–3.24, m
27.8
27.9
40.4
126.5
130.2
116.0
162.0
170.1
131.9
112.3
150.5
147.7
115.3
122.2
141.0
121.0
168.7
40.3
7.68, d (7.8)
6.80, d (7.8)
7.68, d (8.0)
6.81–6.79, m
7″
1‴
2‴
3‴
4‴
5‴
6‴
7‴
7.22, br s
7.23, s
6.76, d (8.7)
6.98, d (8.7)
7.40, d (15.2)
6.45, d (15.2)
6.75, d (8.5)
6.96, d (8.5)
7.41, d (15.5)
6.44, d (15.5)
8‴
9‴
10‴
11‴
12‴
13‴
3′-OCH3
3‴-OCH3
3.35, m
1.63, m
1.63, m
3.36, m
3.66, s
3.95, s
3.34–3.30, m
1.63–1.57, m
1.63–1.57, m
3.40–3.36, m
3.68, s
27.8
28.0
40.5
56.0
28.0
40.5
56.0
56.5
56.4
3.94, s
air at room temperature. The reaction mixture was stirred 60.4, 56.3, 55.9, 14.3. HRMS (ESI): M/Z [M]+ calcd for
for 1h at room temperature and MOM-Cl (5.43g, C14H18O5: 266.1154; found: 266.1159.
67.49mmol) was added dropwise at 0°C. After stirring for
6h, the reaction was quenched with water and the aqueous
Ethyl 2-bromo-3-methoxy-3-(3-methoxy-4-
layer was extracted with ethyl acetate (3×20mL). The
(methoxymethoxy)phenyl)propanoate (5)
combined organic extracts were washed with water
(3×10mL) and brine (3×10mL), and dried (MgSO4), and To an oven-dried round-bottom flask (100mL) charged
the solvent was removed in vacuo. The crude product was with a well-stirred solution of 4 (2.0g, 7.51mmol) in dry
purified by flash chromatography (petroleum/EtOAc=6/1) methanol (20mL) was added NBS (1.47g, 8.26mmol) and
to give 4: white solid; m.p. 50–53°C; yield 11.74g (98 %); iodine (0.19g, 0.75mmol) at −10°C under a nitrogen
1H NMR (500MHz, CDCl3), δ 7.62 (d, J=16Hz, 1H, atmosphere. After stirring for 10h, the resulting solution
ArCH=CH), 7.14 (d, J=8Hz, 1H, ArH), 7.08–7.06 (m, 2H, was quenched with saturated NaHSO3 solution and
ArH), 6.32 (d, J=16Hz, 1H, ArCH=CH), 5.26 (s, 2H, extracted with EtOAc (3×20mL). The combined organic
CH3OCH2O), 4.25 (q, J=7Hz, 2H, CH2CH3), 3.91 (s, 3H, extracts were washed with saturated NaHCO3 solution
OCH3), 3.51 (s, 3H, CH3OCH2O), 1.33 (t, J=7Hz, 3H, (3×20mL) and brine (3×20mL), and dried (MgSO4), and
CH2CH3); 13C NMR (125MHz, CDCl3), δ 167.2 (C=O), the solvent was removed in vacuo. The crude product was
150.0, 148.4, 144.4, 128.8, 122.2, 116.5, 115.8, 110.2, 95.1, purified by flash chromatography (petroleum/EtOAc=3/1)

Xia et al.
5
1
to yield 5: yellowish oil; yield 2.77g (98%); H NMR ArCH=CH), 5.23 (s, 2H, CH3OCH2O), 4.26–4.22 (m, 4H,
(500MHz, CDCl3), δ 6.96 (d, J=8Hz, 1H, ArH), 6.76–6.72 2×CH3CH2), 3.98 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
(m, 2H, ArH), 5.05 (s, 2H, CH3OCH2O), 4.32 (d, J=10Hz, 3.48 (s, 3H, CH3OCH2O), 1.33 (t, J=7.2Hz, 3H, CH2CH3),
1H, CHBr), 4.10 (q, J=7Hz, 2H, CH2CH3), 4.05 (d, 1.22 (t, J=7.2Hz, 3H, CH2CH3); 13C NMR (150MHz,
J=10Hz, 1H, ArCH), 3.70 (s, 3H, OCH3), 3.32 (s, 3H, CDCl3), δ 167.1 (C=O), 164.4 (C=O), 161.8, 149.6, 149.4,
CH3OCH2O), 3.03 (s, 3H, ArCHOCH3), 1.34 (t, J=7Hz, 148.9, 148.2, 144.2, 129.6, 127.5, 121.9, 120.4, 116.9,
3H, CH2CH3); 13C NMR (125MHz, CDCl3), δ 168.5 116.2, 115.6, 111.0, 109.9, 105.2, 95.1, 60.5, 60.2, 56.4,
(C=O), 149.7, 146.8, 130.8, 121.0, 115.6, 110.5, 95.2, 83.8, 56.1, 55.9, 14.3, 14.2; HRMS (ESI): M/Z [M]+ calcd for
61.7, 57.2, 55.9, 55.6, 47.4, 13.8; HRMS (ESI) calcd for C26H30O9: 486.1890; found: 486.1898.
C15H2179BrO6: 376.0522; found: 376.0535. The NMR data
are similar with that reported in Bar’s19 work.
2-[4-(2-Carboxyeth-1-en-1-yl)-2-
methoxyphenoxy]-3-[3-methoxy-4-
Ethyl (Z)-3-methoxy-3-(3-methoxy-4-
(methoxymethoxy)phenyl)acrylate (5′)
(methoxymethoxy)phenyl]prop-2-enoic acid
(7)
To an oven-dried round-bottom flask (100mL) charged To an oven-dried round-bottom flask (50mL) charged with
with 3 (888.96mg, 4.0mmol) in dry DMF (3mL) was a solution of ester 6 (50.0mg, 0.103mmol) in EtOH (1mL)
added Cs2CO3 (1.30g, 4.0mmol) under a nitrogen atmos- was added 3M aqueous solution of NaOH (3mL). The mix-
phere at room temperature. After stirring for 1h, catalytic ture was stirred and reflux for 6h. After cooling and con-
amounts of KI (10%) was added and a solution of 5 centration, diethyl ether (10mL) and 3.0M aqueous acetic
(754.46mg, 2.0mmol) in dry DMF (2mL) was added drop- acid (6mL) were added at 0°C. The organic phase was
wise at 40°C. The reaction mixture was stirred for 6h at separated and the aqueous phase was extracted with diethyl
40°C under a nitrogen atmosphere. The resulting mixture ether (3×10mL). The combined organic layers were
was treated with water (20mL) and extracted with EtOAc washed with water (3×20mL) and brine (3×20mL), and
(3×50mL). The combined organic layer was washed with dried (MgSO4), and the solvent was removed in vacuo. The
water (3×20mL) and brine (3×20mL), and dried crude product was purified by recrystallization (EtOAc/
(MgSO4), and the solvent was removed in vacuo. The crude petroleum ether=3/1) to yield 7: white solid; m.p. 187–
product was purified by flash chromatography (petroleum/ 189°C; yield 42mg (95%); 1H NMR (500MHz, DMSO-d6),
EtOAc=10/1) to yield 5′: colorless oil; yield 533.35mg δ 7.51 (d, J=16Hz, 1H, ArCH=CH), 7.49 (s, 1H, ArH),
1
(90%); H NMR (500MHz, CDCl3), δ 7.16–7.11 (m, 2H, 7.43 (s, 1H, ArH), 7.38 (s, 1H, ArCH=C), 7.23 (d, J=8Hz,
ArH), 7.06 (s, 1H, ArH), 5.52 (s, 1H, CHC=O), 5.26 (s, 2H, 1H, ArH), 7.12 (d, J=8Hz, 1H, ArH), 7.03 (d, J=8Hz, 1H,
CH3OCH2O), 4.20 (q, J=7Hz, 2H, CH2CH3), 3.90 (s, 3H, ArH), 6.68 (d, J=8Hz, 1H, ArH), 6.47 (d, J=16Hz, 1H,
OCH3), 3.85 (s, 3H, ArCOCH3), 3.52 (s, 3H, CH3OCH2), ArCH=CH), 5.16 (s, 2H, CH3OCH2O), 3.91 (s, 3H, OCH3),
1.31 (t, J=7Hz 3H, CH2CH3). HRMS (ESI): M/Z [M]+ 3.65 (s, 3H, OCH3), 3.34 (s, 3H, CH3OCH2O); 13C NMR
calcd for C15H20O6: 296.1260; found: 296.1268.
(125MHz, DMSO-d6), δ 173.0 (C=O), 169.3 (C=O), 154.6,
153.9, 152.4, 152.1, 148.9, 143.8, 134.1, 131.6, 131.4,
128.9, 127.3, 122.9, 121.2, 118.6, 118.3, 116.8, 99.7, 61.1,
61.0, 60.4; HRMS (ESI): M/Z [M]+ calcd for C22H22O9:
430.1264; found: 430.1255.
Ethyl (Z)-2-(4-((E)-3-ethoxy-3-oxoprop-1-en-
1-yl)-2-methoxyphenoxy)-3-(3-methoxy-4-
(methoxymethoxy)phenyl)acrylate (6)
To an oven-dried round-bottom flask (100mL) charged
with 3 (888.96mg, 4.0mmol) in dry DMF (3mL) was
Ethyl 4-(methoxymethoxy)benzoate (9)
added Cs2CO3 (651.64mg, 2.0mol) under nitrogen atmos- To an oven-dried round-bottom flask (100mL) charged
phere at room temperature. After stirring for 1h, a catalytic with a solution of 8 (3.32g, 20mmol) in acetone (20mL)
amount of KI of catalytic amounts (10%) was added and was added anhydrous K2CO3 (8.30g, 60mmol) at room
the solution of 5 (754.46mg, 2.0mmol) in dry DMF (2mL) temperature. The reaction mixture was stirred for 1h at
was added dropwise at 100°C. The reaction mixture was room temperature and MOM-Cl (3.22g, 40mmol) was
stirred for 10h at 100°C under a nitrogen atmosphere. The added dropwise at 0°C. After stirring for 6h, the reaction
resulting mixture was added water (20mL) and extracted was quenched with water and the aqueous layer was
with EtOAc (3×50mL). The combined organic layer was extracted with ethyl acetate (3×20mL). The combined
washed with water (3×20mL) and brine (3×20mL), and organic layers were washed with water (3×10mL) and
dried (MgSO4), and the solvent was removed in vacuo. The brine, and dried (MgSO4), and the solvent was removed in
crude product was purified by flash chromatography (petro- vacuo to give the corresponding protected ester.
leum/EtOAc=20/1) to yield 6: white solid; m.p. 91–93°C;
To an oven-dried round-bottom flask (50mL) charged
1
yield 311.36mg (32%); H NMR (600MHz, CDCl3), δ with a solution of the protected ester in EtOH (20mL) was
7.60 (d, J=16.2Hz, 1H, ArCH=CH), 7.42 (d, J=1.8Hz, added a 3.0M aqueous solution of KOH (10mL). The mix-
1H, ArH), 7.36 (s, 1H, ArCH=C), 7.18 (dd, J=8.4Hz, ture was stirred at refluxed for 4h. After cooling and con-
1.8Hz, 1H, ArH), 7.13 (d, J=1.8Hz, 1H, ArH), 7.09 (d, centration, 3.0M aqueous acetic acid (25mL) was added at
J=8.4Hz, 1H, ArH), 6.98 (dd, J=8.4Hz, 1.8Hz, 1H, ArH), 0°C. The crude white product was precipitated, filtered and
6.76 (d, J=8.4Hz, 1H, ArH), 6.31 (d, J=16.2Hz, 1H, washed with water, dried and recrystallized from ethanol to

6
Journal of Chemical Research 00(0)
yield compound 9: white powder; m.p. 123–124°C (Lit.24 purified by flash chromatography (dichloromethane/meth-
125–126°C); yield 2.91g (80%); 1H NMR (500MHz, anol=3/0.1) to yield 11: colorless oil; yield 47.62mg
CDCl3), δ 8.09 (d, J=8.7Hz, 2H, ArH), 7.11 (d, J=8.7Hz, (57%); 1H NMR (500MHz, CDCl3), δ 7.47 (d, J=15.5Hz,
2H, ArH), 5.24 (s, 2H, OCH2OCH3), 3.49 (s, 3H, 1H, ArCH=CH), 7.36 (s, 1H, ArCH=C), 7.16 (d, J=8.5Hz,
OCH2OCH3); 13C NMR (125MHz, CDCl3), δ 170.2 (C=O), 1H, ArH), 7.07–7.02 (m, 7H, ArH), 6.92 (d, J=8.5Hz, 1H,
161.3, 132.0, 122.7, 116.0, 94.2, 56.9.
ArH), 6.82 (d, J=8.5Hz, 1H, ArH), 6.77–6.40 (m, 4H,
ArH), 6.33 (d, J=15.5Hz, 1H, ArCH=CH), 5.21 (s, 2H,
CH3OCH2O), 5.20 (s, 2H, CH3OCH2O), 5.19 (s, 2H,
CH3OCH2O), 3.95 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
3.48–3.44 (m, 9H, 3×CH3OCH2O) 3.48–3.44 (m, 2H,
N-(4-Aminobutyl)-4-(methoxymethoxy)
benzamide (10)
To an oven-dried round-bottom flask (50mL) was added 9 CONHCH2), 3.42–3.38 (m, 2H, CONHCH2), 3.34–3.31
(182.18mg, 1mmol) and CDI (178.35mg, 1.1mmol), and (m, 4H, 2×CONHCH2), 1.70–1.60 (m, 4H, CH2CH2),
the reaction mixture was mixed with a spatula to start the 1.52–1.39 (m, 4H, CH2CH2); 13C NMR (125MHz, CDCl3),
reaction. The reaction mixture was left at room temperature δ 167.3, 167.1, 166.1, 163.3, 159.8, 149.5, 149.0, 147.6,
for 10min until the solid reaction mixture turned to a pale 145.7, 141.7, 139.6, 131.1, 128.7, 127.9, 126.7, 124.2,
yellow liquid. To separate round-bottom flask charged with 124.1, 121.3, 120.8, 115.9, 115.7, 115.6, 113.1, 111.2, 95.2,
a stirred solution of 1,4-diaminobutane (440.75mg, 94.2, 56.3, 56.2, 56.0, 55.6, 39.6, 39.3, 39.1, 27.2, 27.1,
5.0mmol) in deionized water (20mL) was added 1,4-diam- 26.8, 26.5; HRMS (ESI) calcd for C48H58N4O13: 898.4000;
inobutane dihydrochloride (805.35mg, 5.0mmol), and found: 898.4007.
after stirring for 20min, NaCl (4.0g, 68.446mmol) was
added. This brine solution was added to the flask contain-
ing the acyl imidazole and the mixture was stirred for 1h at
Mariamide A (1)
room temperature. The aqueous layer was washed with To an oven-dried round-bottom flask (50mL) charged with a
ethyl acetate to remove the diacylated product. Next 10mL solution of compound 11 (40.0mg, 0.045mmol) in dry
of a saturated solution of NaOH was added to the aqueous CH2Cl2 (2mL) was added TFA (0.11mL, 1.35mmol) at
layer which was then extracted with ethyl acetate room temperature. After stirring for 8h, the solvent was
(3×20mL). The organic layer was washed with water removed in vacuo. The crude product was purified by flash
(3×10mL) and brine (3×20mL), and dried (MgSO4), and chromatography (dichloromethane/methanol=3/0.1) to
the solvent was removed in vacuo. The crude product was yield 1: white amorphous powder; yield 22.86mg (67%) 1H
purified by flash chromatography (dichloromethane/meth- NMR (500MHz, CD3OD), δ 7.68 (d, J=8Hz, 2H, ArH),
anol=3/0.1) to yield 10: yellowish oil; yield 174.08mg 7.66 (d, J=8Hz, 2H, ArH), 7.41 (d, J=15.5Hz, 1H,
1
(69%); H NMR (500MHz, CDCl3), δ 7.72 (d, J=8.5Hz, ArCH=CH), 7.30 (s, 1H, ArH), 7.23 (s, 1H, ArCH=C), 7.23
2H, ArH), 6.94 (d, J=8.5Hz, 2H, ArH), 5.11 (s, 2H, (s, 1H,ArH), 7.05 (d, J=8.5Hz, 1H,ArH), 6.96 (d, J=8.5Hz,
CH3OCH2O), 3.39 (s, 3H, CH3OCH2O), 3.37–3.29 (m, 2H, 1H, ArH), 6.81–6.79 (m, 4H, ArH), 6.75 (d, J=8.5Hz, 1H,
CONHCH2), 2.76–2.62 (m, 2H, CH2NH2), 1.65–1.42 (m, ArH), 6.70 (d, J=8.5Hz, 1H, ArH), 6.44 (d, J=15.5Hz, 1H,
4H, CH2CH2); 13C NMR (125MHz, CDCl3), δ 167.3 ArCH=CH), 3.94 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.40–
(C=O), 159.6, 128.8, 128.0, 115.7, 94.1, 56.1, 41.0, 39.7, 3.36 (m, 2H, CONHCH2), 3.34–3.30 (m, 2H, CONHCH2),
29.3, 26.9; HRMS (ESI): M/Z [M]+ calcd for C13H20N2O3: 3.27–3.24 (m, 4H, 2×CONHCH2), 1.63–1.57 (m, 4H,
252.1470; found: 252.1469.
2×CH2CH2), 1.49–1.40 (m, 4H, 2×CH2CH2); 13C NMR
(125MHz, CD3OD), δ 170.1 (C=O), 170.0 (C=O), 168.7
(C=O), 165.7 (C=O), 162.1, 161.9, 150.6, 149.6, 148.9,
147.8, 141.9, 141.2, 132.0, 130.3, 130.2, 126.6, 126.5, 126.3,
125.5, 125.1, 122.2, 121.1, 116.21, 116.19, 116.1, 115.3,
113.7, 112.3, 56.5, 56.0, 40.5, 40.4, 40.32, 40.29, 28.0, 27.9,
27.83, 27.80;HRMS(ESI):M/Z[M]+ calcdforC42H46N4O10:
766.3214; found: 766.3219.
N-(4-((E)-3-(3-methoxy-4-(((Z)-1-(3-
methoxy-4-(methoxymethoxy)phenyl)-3-
((4-(4-(methoxymethoxy)benzamido)butyl)
amino)-3-oxoprop-1-en-2-yl)oxy)phenyl)
acrylamido)butyl)-4-(methoxymethoxy)
benzamide (11)
To an oven-dried round-bottom flask (50mL) charged with Declaration of conflicting interests
a solution of dicarboxylic acid intermediate 7 (40.0mg,
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
0.093mmol) in dry CH2Cl2 (5mL) was added CDI
(37.67mg, 0.232mmol) under a nitrogen atmosphere at
room temperature. After stirring for 2h, a solution of 10
(58.62mg, 0.232mmol) and DMAP (1.14mg, 0.929%
mmol) in dry CH2Cl2 (5mL) was added dropwise to the
reaction mixture. The mixture was stirred under a nitrogen
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
atmosphere at room temperature for 6h. Water (5mL) was project was supported by the National Natural Science Foundation
of China (No. 21472105).
added and the mixture was extracted with CH2Cl2
(3×20mL). The organic layer was washed with water
(3×10mL) and brine (3×20mL), and dried (MgSO4), and
ORCID iD
the solvent was removed in vacuo. The crude product was Chenglong Chen
https://orcid.org/0000-0002-3210-7000

Xia et al.
7
11. Chen F, Huang XJ, Liang QP, et al. Nat Prod Res 2018: 1.
12. Cardullo N, Pulvirenti L, Spatafora C, et al. J Nat Prod 2016;
79: 2122.
Supplemental material
Supplemental material for this article is available online.
13. Zhu GY, Yang J, Yao XJ, et al. J Org Chem 2018; 83: 2376.
14. Li D, Li W, Wang Q, et al. Bioorg Med Chem Lett 2010; 20:
5095.
15. Magoulas GE, Rigopoulos A, Piperigkou Z, et al. Bioorg
Chem 2016; 66: 132.
16. Xia Y-M, Xia J and Chai C. Chemical Papers 2014; 68.
17. Xia Y, Zhang H, Li C, et al. J Chem Res 2015; 39: 606.
18. Qin NB, Jia CC, Xu J, et al. Fitoterapia 2017; 119: 83.
19. Bar S. Can J Chem 2010; 88: 605.
References
1. Pan JY, Chen SL, Yang MH, et al. Nat Prod Rep 2009;
26: 1251.
2. Zhang J, Chen J, Liang Z, et al. Chem Biodivers 2014; 11: 1.
3. Teponno RB, Kusari S and Spiteller M. Nat Prod Rep 2016;
33: 1044.
4. Yoshihara T, Yamaguchi K, Takamatsu S, et al. Agr Biol
Chem Tokyo 1981; 45: 2593.
5. Ge F, Tang CP and Ye Y. Helv Chim Acta 2008; 91: 1023.
6. Sakakibara I, Ikeya Y, Hayashi K, et al. Phytochemistry
1995; 38: 1003.
7. Zhang WN, Luo JG and Kong LY. J Agric Food Chem 2012;
60: 1682.
8. Sun J, Gu YF, Su XQ, et al. Fitoterapia 2014; 98: 110.
9. Chen H, Li YJ, Sun YJ, et al. Fitoterapia 2017; 122: 119.
10. Zhang JX, Guan SH, Feng RH, et al. J Nat Prod 2013;
76: 51.
20. Lodh RS, Borah AJ and Phukan P. Indian J Chem 2014;
53B: 1425.
21. Verma SK, Ghorpade R, Pratap A, et al. Green Chem 2012;
14: 326.
22. Singh R, Tønnesen HH, Vogensen SB, et al. Inclusion
Phenomea Macrocyclic Chem 2010; 66: 335.
23. Vafiadi C, Topakas E, Wong KK, et al. Tetrahedron:
Asymmetry 2005; 16: 373.
24. Xia Y, Mo Z, Sun L, et al. J Chem Res 2017; 41: 296.