First total synthesis of two new amide alkaloids from Piper boehmeriaefolium

Article abstract of DOI:10.3184/174751912X13263881939640

3-(3,4,5-Trimethoxyphenyl)propanoylpyrrole and 3-(3,5-dimethoxy-4- hydroxyphenyl)propanoylpyrrole, two new amide alkaloids, were prepared from 3,4,5-trimethoxybenzaldehyde via 3,4,5-trimethoxycinnamic acid and the corresponding dihydroacid. This route is simple and the reaction conditions are mild.

Full text of DOI:10.3184/174751912X13263881939640

56 RESEARCH PAPER
JANUARY, 56–57
JOURNAL OF CHEMICAL RESEARCH 2012
First total synthesis of two new amide alkaloids from
Piper boehmeriaefolium
Shao-Jun Shan*, Hong Zhang and Xiao-Dan Wang
School of Pharmaceutical and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, P. R. China
3-(3,4,5-Trimethoxyphenyl)propanoylpyrrole and 3-(3,5-dimethoxy-4-hydroxyphenyl)propanoylpyrrole, two new
amide alkaloids, were prepared from 3,4,5-trimethoxybenzaldehyde via 3,4,5-trimethoxycinnamic acid and the
corresponding dihydroacid. This route is simple and the reaction conditions are mild.
Keywords: amide alkaloids, 3-(3,4,5-trimethoxyphenyl)propanoylpyrrole, 3-(3,5-dimethoxy-4-hydroxyphenyl)propanoylpyrrole
Phytochemical investigations of Piper species have revealed
the occurrence of amides which are reported to possess
various ACAT inhibitory,1 cytotoxic,2–3 antimycobacterial,4–5
insecticidal,6–7 antiprotozoan,8 analgesic,9 and antidepressant10
activities.
3-(3,4,5-Trimethoxyphenyl)propanoylpyrrole 1 and 3-(3,
5-dimethoxy-4-hydroxyphenyl)propanoylpyrrole 2, two new
amide alkaloids, were first isolated from Piper boehmeriaefo-
lium in 2011.11 The total synthesis of 1 and 2 has not only
theoretical importance but potential medical prospect. The
synthesis of 1 and 2 has not been reported so far. We report
here a facile approach (Scheme 1) as illustrated in the total
synthesis of 1 and 2.
1 and 2. This route is simple and the reaction conditions are
mild.
Experimental
Reagents and solvents were obtained from commercial suppliers.
Melting points were determined on a X-4 melting-point apparatus and
are uncorrected. NMR spectroscopy was performed on a BrukerAvance
400-MHz (1H, 400 MHz; 13C, 100 MHz) instrument. Mass spectra
(EI-MS) were determined on a Thermo Finnigan LCQ-Advantage.
3,4,5-Trimethoxycinnamic acid (4): Piperidine (3 mL) was added to
a mixture of 3 ( 9.8 g, 0.05 mol) and malonic acid (7.8 g, 0.075 mol)
in pyridine (100 mL). The mixture was stirred at 80 °C until the reac-
tion was completed using TLC to monitor the reaction. The reaction
mixture was concentrated under vacuum to afford a residue, which
was dissolved in EtOAc (100 mL) and washed with 5% HCl (30 mL ×
2) and distilled water (30 mL × 2) respectively. It was dried over
anhydrous Na2SO4 and then concentrated under reduced pressure.
The residue was recrystallised from CH3OH–H2O to give 4 (10.59 g,
89%) as colourless crystals; m.p. 125–126 °C (lit.13 126–127 °C); 1H
NMR (CDCl3) δ: 12.10 (s, 1H), 7.62 (d, J = 15.9 Hz, 1H), 6.78 (s,
2H), 6.36 (d, J = 15.9 Hz, 1H), 3.89 (s, 6H), 3.88 (s, 3H); 13C NMR
(CDCl3) δ: 171.5, 153.6, 148.7, 139.7, 130.9, 116.5, 105.8, 60.3, 56.1;
EI-MS (m/z, %): 238 ([M] +, 100), 223 (46), 181 (11), 163 (25).
3,4,5-Trimethoxyhydrocinnamic acid (5):A suspension of 4 (4.76 g,
0.02 mol) and 0.3 g 5% Pd/C in 50 mL THF was hydrogenated at
room temperature and 30 psi. Uptake ceased after 3 h. After filtering,
the filtrate was rotary evaporated to produce a residue that was
recrystallised from water to give 5 (4.51 g, 94%) as white crystals;
m.p. 103–104 °C (lit.14 104–105 °C); 1H NMR (CDCl3) ; 8.65 (s, 1H),
6. 44 ( s, 2H), 3. 87 ( s, 6H), 3. 85 ( s, 3H), 2.80 (t, J = 7.4 Hz, 2H),
Results and discussion
Our synthetic approach, depicted in Scheme 1, began with
3,4,5-trimethoxybenzaldehyde 3. 3,4,5-Trimethoxycinnamic
acid 4 was prepared in 89% yield using Knoevenagel–Doebner
reaction conditions starting from 3 and malonic acid and pyri-
dine in the presence of Piperidine as a catalyst. Subsequent
catalytic hydrogenation of 4 in tetrahydrofuran gave 3,4,5-
trimethoxyhydrocinnamic acid 5 in 94% yield. In the next step,
the direct N-acylation of pyrrole with the carboxylic acid 5
afforded the title compound 1 in 82% yield. The second title
compound 2 was prepared in 53% yield by the monodemethyl-
ation of 1 using a standard literature procedure using AlCl3.12
In summary, we have developed a concise and efficient
synthetic method for preparation of two new amide alkaloids
Scheme 1 a, Malonic acid, pyridine, piperidine, 80 °C, 89%; b, H2, 5% Pd/C, THF, 94%; c, DCC, DMAP, DCM, 82%;
d, AlCl3, CH2Cl2, 53%.
* Correspondent. E-mail: gongke1122@hotmail.com

JOURNAL OF CHEMICAL RESEARCH 2012 57
2.63 (t, J = 7.4 Hz, 2H); 13C NMR (CDCl3) δ: 174.2, 153.5, 135.8,
135.7, 105.3, 61.4, 56.1, 34.3, 30.5; EI-MS (m/z, %): 240 ([M]+, 100),
225 (42), 181 (83), 151 (19), 137 (27).
Received 16 December 2011; accepted 8 January 2012
Paper 1101044 doi: 10.3184/174751912X13263881939640
Published online: 31 January 2012
3-(3,4,5-Trimethoxyphenyl)propanoylpyrrole (1): A stirred solution
of DCC (2.06 g, 0.01 mol) in CH2Cl2 (20 mL) was added to a solution
of pyrrole (1.34 g, 0.02 mol), DMAP (1.22 g, 0.01 mol) and carboxy-
lic acid 5 (2.4 g, 0.01 mol) in CH2Cl2 (50 mL) at 0 °C under a nitrogen
atmosphere were added The solution was warmed to rt and stirred for
6 h, then the mixture was filtered. The solvent was distilled off
and the residue was purified by silica gel chromatography on silica
gel to give 1 (2.37 g, 82%) as a white solid; m.p. 51–53 °C (lit.11 52–
References
1
M.C. Rho, S.W. Lee, H.R. Park, J.H. Choi, J.Y. Kang, K. Kim, H.S. Lee
and Y.K. Kim, Phytochemistry, 2007, 68, 899.
2
3
C.Y. Duh, Y.C. Wu and S.K. Wang, J. Nat. Prod., 1990, 53, 1575.
I.L. Tsai, F.P. Lee, C.C. Wu, C.Y. Duh, T. Ishikawa, J.J. Chen, Y.C. Chen,
H. Seki and I.S. Chen, Planta Med., 2005, 71, 535.
1
53 °C); H NMR (CDCl3) δ: 7.30 (s, 2H), 6.43 (s, 2H), 6.28 (t,
4
5
6
7
8
9
A.C. Ale´cio, V. da S. Bolzani, M.C.M. Young, M.J. Kato and M. Furlan,
J. Nat. Prod., 1998, 61, 637.
S.V. Reddy, P.V. Srinivas, B. Praveen, K.H. Kishore, B.C. Raju, U.S.
Murthy and J.M. Rao, Phytomedicine, 2004, 11, 697.
I.K. Park, S.G. Lee, S.C. Shin, J.D., Park and Y.J. Ahn, J. Agric. Food
Chem., 2002, 50, 1866.
Y.C. Yang, S.G., Lee, H.K. Lee, M.K. Kim, S.H. Lee and H.S. Lee,
J. Agric. Food Chem., 2002, 50, 3765.
H.S. Bodiwala, G. Singh, R. Singh, C.S. Dey, S.S. Sharma, K.K. Bhutani
and I.P. Singh, J. Nat. Med., 2007, 61, 418.
J = 2.4 Hz, 2H), 3.85 (s, 6H), 3.82 (s, 3H), 3.13 (m, 2H), 3.06 (m, 2H);
13C NMR (CDCl3) δ: 169.1, 152.4, 135.7, 135.5, 118.1, 112.7, 60.1,
53.8, 35.9, 30.2; EI-MS (m/z, %): 289 ([M]+, 83), 222 (11), 194 (21),
181 (100).
3-(3,5-Dimethoxy-4-hydroxyphenyl) propanoylpyrrole (2): Anhy-
drous aluminium chloride (2.66 g, 20 mmol) was added to a solution
of 1 (1.45 g, 5 mmol) in dry CH2Cl2 (20 mL) was added. The mixture
was sonicated for 20 min, quenched with sat. NH4Cl, and then washed
with water and brine. The aqueous solution was extracted with CH2Cl2.
The organic phase was dried and concentrated. The residue was
purified by silica gel chromatography on silica gel to give 2 (0.73 g,
53%) as white solid; m.p. 88–90 °C (lit.11 89–90 °C); 1H NMR
(CDCl3) δ: 7.25 (s, 2H), 6.42 (s, 2H), 6.20 (t, J = 2.2 Hz, 2H), 5.63 (s,
1H), 3.78 (s, 6H), 3.06 (t, J = 7.5 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H); 13C
NMR (CDCl3) δ: 168.9, 146.1, 132.8, 130.5, 118.2, 112.3, 54.4, 36.1,
29.8; EI-MS (m/z, %): 275 ([M]+, 100), 208 (21), 180 (36), 167 (86).
E.B. Lee, K.H. Shin and W.S. Woo, Arch. Pharm. Res., 1984, 7, 127.
10 C.Y.Yao, J. Wang, D. Dong, F.G. Qian, J. Xie and S.L. Pan, Phytomedicine,
2009, 16, 823.
11 G.H. Tang, D.M. Chen, B.Y. Qiu, L. Sheng, Y.H. Wang, G.W. Hu, F.W.
Zhao, L.J. Ma, H. Wang, Q.Q Huang, J.J. Xu, C.L. Long and J. Li, J. Nat.
Prod., 2011, 74, 45.
12 D. Pla, A. Marchal, C.A. Olsen, A. Francesch, C. Cuevas, F. Albericio and
M.A. lvarez, J. Med. Chem., 2006, 49, 3257.
13 H. Rapoport and J. Campion, J. Am. Chem. Soc., 1951, 73, 2239.
14 H.R. Frank, P.E. Fanta and D.S. Tarbell, J. Am. Chem. Soc., 1948, 70,
2314.
We thank the National Natural Science Foundation of China
(grant No. 21104097) for financial support of this research.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.