One-pot reductive-cyclization as key step for the synthesis of rutaecarpine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2007.11.094

The quinazolinocarboline alkaloids including rutaecarpine (1a), euxylophoricine A (1b), and euxylophoricine C (1c) have been synthesized efficiently from the ring opened β-carboline derivative as key intermediate by a one-pot reductive-cyclization reaction. The key intermediate was prepared from tryptamine (6) following Bischler-Napieralski cyclization, benzoylation, and oxidative cleavage of the exocyclic double bond.

Full text of DOI:10.1016/j.tetlet.2007.11.094

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 481–484
One-pot reductive-cyclization as key step for the synthesis
of rutaecarpine alkaloids
*
Chih-Shone Lee , Cheng-Kuo Liu, Yuen-Lin Chiang, Yen-Yao Cheng
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, ROC
Received 10 October 2007; revised 13 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
The quinazolinocarboline alkaloids including rutaecarpine (1a), euxylophoricine A (1b), and euxylophoricine C (1c) have been syn-
thesized efficiently from the ring opened b-carboline derivative as key intermediate by a one-pot reductive-cyclization reaction. The key
intermediate was prepared from tryptamine (6) following Bischler–Napieralski cyclization, benzoylation, and oxidative cleavage of the
exocyclic double bond.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Alkaloids; Rutaecarpine; One-pot reductive-cyclization
Rutaecarpine (1a)1 isolated from the dried fruits of Evo-
dia rutaecarpa and callus tissue cultured from the stem of
Phellodendron amurense2–5 has been used in China and
Japan as traditional medicine for remedy such as headache,
dysentery, cholera, worm infections, and postpartum.6
Rutaecarpine (1a) and its analogues, euxylophoricine A
(1b), euxylophoricine C (1c), and dehydroevodiamine (2)
(Fig. 1) were also found to possess anti-stomachic, anti-
emetic, anti-nociceptive, anti-inflammatory, anti-pyretic,
analgesic, astringent, anti-hypertensive, uterotonic, cyclox-
ygenase (COX-2) inhibitory, and agonist TCDD-receptor
activities.7 Furthermore, rutaecarpine (1a) can also sup-
press platelet plug formation in mesenteric venules and
increase intracellular Ca2+ in endothelial cells.8
Recently, Don et al.9 reported that rutaecarpine deriva-
tives selectively inhibited human CYP1A1, CYP1A2, and
CYP2B1. Robinson and co-workers10 reported the first
total synthesis of rutaecarpine and since then several routes
to it and its derivatives have been developed.11
The generalized approach toward the synthesis of ruta-
ecarpine (1a) and various analogues involved the late con-
struction of the indole skeleton (A, B rings) by the widely
used Fischer indole synthesis through an acid-catalyzed
or thermal sigmatropic rearrangement of an N-aryl hydra-
zone. On the other hand, the quinazolinocarboline back-
bone of dehydroevodiamine (2) has been reported to give
the ring opened b-carboline derivative 2a upon the addition
of water.12 Furthermore, the pseudobase has been pro-
A
B
N
H
C
N
D
O
N
O
N
N
N
E
R1
R3
R2
posed as
a likely but never isolated or observed
2 Dehydroevodiamine
1a : R1 = R2 = R3 = H , Rutaecarpine
intermediate.
1b : R1 = H ; R2 = R3 = OMe , Euxylophoricine A
1c : R1 = H ; R2 , R3 = -O-CH2-O- , Euxylophoricine C
N
O
Fig. 1. Rutaecarpine and its analogues.
N
H
O
N
*
H
Me
Corresponding author. Tel.: +886 7 525 3947; fax: +886 7 525 3908.
2a
E-mail address: shonle@faculty.nsysu.edu.tw (C.-S. Lee).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.094

482
C.-S. Lee et al. / Tetrahedron Letters 49 (2008) 481–484
Our synthetic strategy for rutaecarpine alkaloids 1a–c is
construction of a b-carboline C, D, E rings first, followed
by the construction of the quinazolinone ring has been
reported.
to construct an intermediate similar to b-carboline 2a. The
retrosynthetic analysis is shown in Scheme 1. We envisage
that the reverse cyclization to rutaecarpine alkaloids 1a–c
from the nitro-intermediate of the ring opened b-carboline
derivatives can be carried out in a one-pot reaction via
reductive-cyclization. Furthermore, the 2,3,4,9-tetrahy-
dro-b-carbolin-1-one 3a–c can be readily prepared from
1-methyl-4,9-dihydro-3H-b-carboline (5) in two steps that
involved the isomerization of the endocyclic double bond
to the exocyclic double bond,13 followed by an oxidative
cleavage of the double bond to give the requisite carbonyl
group.14 It is also of interest to investigate the biological
activities of these ring opened b-carboline derivatives syn-
thesized. To our knowledge, no approach involving the
The 1-methyl-4,9-dihydro-3H-b-carboline (5) can be
prepared from commercially available tryptamine (6).
Treatment of tryptamine (6) with acetic anhydride gave
the N-acetylated product 8 and subsequent Bischler–Napi-
eralski cyclization in POCl3 to give compound 5 in good
yield. The reaction of compound 5 with various benzoly
chloride derivatives, prepared from the corresponding ben-
zoic acid derivatives 7a–c with SOCl2, afforded the requisite
intermediates 4a–c for the synthesis of rutaecarpine alka-
loids (Scheme 2).
We first attempted to oxidatively cleave the exocyclic
double bond of 4a–c under ozonolysis condition, but was
N
O
N
O
N
O
N
H
N
H
N
H
O
N
NO2
R1
NO2
R1
N
NH2
N
H
N
H
R1
R3
R3
R3
R2
R2
R2
1a-c
3a-c
4a-c
5
6
COOH
NO2
R3
R1
7a : R1 = R2 = R3 = H
R2
7b : R1 = H; R2 = R3 = OMe
7c : R1 = H; R2, R3 = -O-CH2-O-
7a-c
Scheme 1. Retrosynthetic analysis of 1a–c.
COCl
R2
COOH
NO2
NO2
R1
SOCl2
DCM
R3
R3
R1
R2
N
O
N
H
7a-c
NO2
R1
7a : R1 = R2 = R3 = H
7b : R1 = H ; R2 = R3 = OMe
7c : R1 = H ; R2 , R3 = -O-CH2-O-
R3
R2
4a-c
4a : R1 = R2 = R3 = H ; 88%
4b : R1 = H ; R2 = R3 = OMe ; 88%
4c : R1 = H ; R2 , R3 = -O-CH2-O- ; 82%
Ac2O
DCM
POCl3
NH2
N
HN
CH3CN
N
H
N
H
5
N
H
O
8
6
KMnO4
dry acetone
N
O
N
O
N
O
SnCl2
NH2
N
H
N
H
N
H
O
O
NO2
R1
N
Sn
NaOH , Et3N
DCM
HCl / MeOH
R3
R1
R3
R1
R3
R2
R2
R2
3a-c
1a-c
3a : R1 = R2 = R3 = H ; 32%
3b : R1 = H ; R2 = R3 = OMe ; 35%
3c : R1 = H ; R2 , R3 = -O-CH2-O- ; 32%
1a : R1 = R2 = R3 = H ; 94%
1b : R1 = H ; R2 = R3 = OMe ; 90%
1c : R1 = H ; R2 , R3 = -O-CH2-O- ; 91%
Scheme 2. Total synthesis of 1a–c.

C.-S. Lee et al. / Tetrahedron Letters 49 (2008) 481–484
483
Loc, C. V.; Higa, T.; Koizumi, M.; Ihara, M.; Fukumoto, K. J. Am.
Chem. Soc. 1977, 99, 2306; (c) Danieli, B.; Palmisano, G. Heterocycles
unsuccessful. The use of potassium permanganate for the
oxidative cleavage of the exocyclic double bond success-
fully gave the desired 2,3,4,9-tetrahydro-b-carbolin-1-one
derivatives 3a–c.15
´
´ ´
1978, 9, 803; (d) Ko¨ko¨si, J.; Hermecz, I.; Szasz, G.; Meszaros, Z.
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We have obtained the ring open b-carboline intermedi-
ates 3a–c in three steps from tryptamine (6). A one-pot
reaction was sorted for the formation of the quinazolinone
ring. This involved the reduction of the nitro- to the amino-
group, followed by an in situ condensation of the free
amino group with the ring amide to form the quinazoli-
none ring. It was found that the treatment of 3a–c with
tin in HCl/MeOH followed by basic workup can afford
rutaecarpine analogue alkaloids 1a–c16 in a one-pot
reaction.
In conclusion, a simple procedure for the preparation of
rutaecarpine analogue alkaloids 1a–c and their ring opened
b-carboline derivatives has been reported. The one-pot
reductive-cyclization reaction for the construction of the
quinazolinone ring is noteworthy.
´
´ ´
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Acknowledgment
We thank National Science Council, R.O.C. for finan-
cial support (NSC82-0208-M110-066).
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Supplementary data
The 1H NMR spectra of 1a–c. Supplementary data asso-
ciated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.11.094.
14. Yamada, F.; Yoshihiro, S.; Somei, M. Heterocycles 1968, 2619.
15. N-(2-Nitrobenzoyl)-1-oxo-1,2,3,4-tetrahydro-b-carboline (3a): mp
109–111 °C (MeOH/CH2Cl2); IR (CHCl3, cmÀ1) 3457 (NH), 1684
(C@O), 1680 (C@O), 1530 (NO2), 1347 (NO2); 1H NMR (300 MHz,
CDCl3) d 3.21 (t, J = 6.0 Hz, 2H), 4.56 (br, 2H), 7.16–7.21 (m, 1H),
7.25–7.27 (m, 1H), 7.33–7.39 (m, 2H), 7.49–7.55 (m, 1H), 7.71–7.83
(m, 2H), 8.19 (dd, J = 1.2, 8.4 Hz, 1H), 8.76 (br s, 1H, NH); 13C
NMR (75 MHz, CDCl3) d 20.51, 44.01, 112.58, 120.93, 120.98,
123.99, 124.67 (2C), 125.16, 126.83, 126.88, 129.12, 134.09, 135.29,
138.62, 144.60, 160.03, 168.22; LRMS m/z (%) 335 (M+, 35.6%), 289
(M+À46, 91.6%), 185 (M+À150, 51.9%), 184 (M+À151, 45.8%), 56
(M+À179, 67.3%), 150 (M+À85, 50.4%), 129 (M+À206, 100%), 128
(M+À207, 85.5%); HRMS m/z (%) 335.0893 (M+, 65.5%), calcd for
C18H13N3O4 335.0890. N-(4,5-Dimethoxy-2-nitrobenzoyl)-1-oxo-
1,2,3,4-tetrahydro-b-carboline (3b): mp 117–119 °C (MeOH/CH2Cl2);
IR (CHCl3, cmÀ1) 3456 (NH), 1704 (C@O), 1684 (C@O), 1518 (NO2),
1333 (NO2); 1H NMR (300 MHz, CDCl3) d 3.22 (t, J = 6.3 Hz, 2H),
3.94 (s, 3H), 3.95 (s, 3H), 4.57 (t, J = 6.3 Hz, 2H), 6.87 (s, 1H), 7.18 (t,
J = 6.9 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 6.9 Hz, 1H),
7.64 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 8.81 (br s, 1H, NH); 13C NMR
(75 MHz, CDCl3) d 20.53, 44.11, 56.36, 56.54, 106.73, 108.55, 112.49,
121.00, 121.04, 124.70, 124.76, 125.32, 126.95, 129.65, 137.60, 138.58,
148.74, 154.02, 160.05, 168.10; LRMS m/z (%) 395 (M+, 0.1%), 350
(M+À45, 2.37%), 349 (M+À46, 100%), 136 (M+À259, 39.1%), 129
(M+À266, 32.6%), 128 (M+À267, 26.7%), 93 (M+À302, 25.3%);
HRMS m/z (%) 395.1124 (M+, 10.6%), calcd for C20H17N3O6
References and notes
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395.1126.
N-(4,5-Dimethylenedioxy-2-nitrobenzoyl)-1-oxo-1,2,3,4-
tetrahydro-b-carboline (3c): mp 111–113 °C (MeOH/CH2Cl2); IR
(CHCl3, cmÀ1) 3464 (NH), 1674(C@O), 1669 (C@O), 1552 (NO2),
1340 (NO2); 1H NMR (300 MHz, CDCl3) d 3.22 (t, J = 6.3 Hz, 2H),
4.57 (t, J = 6.3 Hz, 2H), 6.14 (s, 2H), 6.75 (s, 1H), 7.19–7.21 (m, 1H),
7.30–7.40 (m, 2H), 7.64 (s, 1H), 7.65 (d, J = 3.6 Hz, 1H), 8.68 (br s,
1H, NH); 13C NMR (75 MHz, CDCl3) d 20.57, 44.10, 103.46, 104.81,
106.16, 112.46, 121.12, 121.17, 124.73, 124.86, 125.31, 127.09, 131.98,
138.52, 139.26, 148.11, 152.71, 159.98, 167.62; LRMS m/z (%) 379
9. Don, M. J.; Lewis, D. F. V.; Wang, S. Y.; Tsai, M. W.; Ueng, Y. F.
Bioorg. Med. Chem. Lett. 2003, 2535.
10. Asahina, Y.; Manske, R. H. F.; Robinson, R. J. Chem. Soc. 1927,
1708.
11. (a) Kametani, T.; Higa, T.; Loc, C. V.; Ihara, M.; Koizumi, M.;
Fukumoto, K. J. Am. Chem. Soc. 1976, 98, 6186; (b) Kametani, T.;

484
C.-S. Lee et al. / Tetrahedron Letters 49 (2008) 481–484
(M+, 80.4%), 129 (M+À250, 63.59%), 120 (M+À259, 71%), 55
1H), 7.66 (s, 1H), 9.22 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) d
19.69, 41.10, 56.22, 56.35, 106.41, 107.12, 111.97, 114.50, 117.64,
119.99, 120.62, 125.36, 125.73, 127.35, 138.13, 143.68, 143.99, 148.76,
154.98, 160.90; LRMS m/z (%) 347 (M+, 100%), 332 (M+À25, 22.7%),
128 (M+À219, 13.4%), 55 (M+À292, 48.6%), 43 (M+À304, 74.6%);
HRMS m/z (%) 347.1265 (M+, 100%), calcd for C20H17N3O3
347.1264. Euxylophoricine C (1c): mp 307–308 °C (MeOH/CH2Cl2);
IR (CHCl3, cmÀ1) 3469 (NH), 1663 (C@O); 1H NMR (300 MHz,
CDCl3) d 3.27 (t, J = 6.9 Hz, 2H), 4.57 (t, J = 6.9 Hz, 2H), 6.10 (s,
2H), 7.03 (s, 1H), 7.18 (t, J = 6.9 Hz, 1H), 7.36 (t, J = 6.9 Hz, 1H),
7.44 (d, J = 6.9 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.64 (s, 1H), 9.07
(br s, 1H, NH); 13C NMR (75 MHz, CDCl3) d 19.88, 41.89, 102.53,
104.29, 105.96, 111.97, 116.10, 117.64, 120.00, 120.60, 125.38, 125.70,
127.24, 138.11, 143.81, 143.58, 147.10, 153.42,160.87; LRMS m/z (%)
331 (M+, 100%), 330 (M+À1, 94%); HRMS m/z (%) 331.0957 (M+,
37.1%), calcd for C19H13N3O3 331.0957.
(M+À324, 98.9%), 44 (M+À335, 100%); HRMS m/z (%) 379.0788
(M+, 16.3%), calcd for C19H13N3O6 379.0784.
16. Rutaecarpine (1a): mp 254–255 °C (MeOH/CH2Cl2); IR (CHCl3,
cmÀ1) 3463 (NH), 1676 (C@O); 1H NMR (300 MHz, CDCl3) d 3.24
(t, J = 6.9 Hz, 2H), 4.59 (t, J = 6.9 Hz, 2H), 7.19 (t, J = 8.4 Hz, 1H),
7.34 (dt, J = 1.2, 6.8 Hz, 1H), 7.41–7.67 (m, 2H), 7.63–7.73 (m, 3H),
8.32 (dd, J = 1.2, 7.8 Hz, 1H), 9.27 (br s, 1H,NH); 13C NMR
(75 MHz, CDCl3) d 19.68, 41.12, 112.07, 118.33, 120.08, 120.62,
121.37, 125.58, 125.64, 126.19, 126.61, 127.23, 134.32 (2C), 138.27,
144.95, 147.52, 161.59; LRMS m/z (%) 287 (M+, 79.2%), 286 (M+À1,
100%); HRMS m/z (%) 287.1055 (M+, 38.9%), calcd for C18H13N3O
287.1054. Euxylophoricine A (1b): mp 293–295 °C (MeOH/CH2Cl2);
IR (CHCl3, cmÀ1) 3461 (NH), 1663 (C@O); 1H NMR (300 MHz,
CDCl3) d 3.23 (t, J = 7.0 Hz, 2H), 3.98 (s, 3H), 4.01 (s, 3H), 4.59 (t,
J = 7.0 Hz, 2H), 7.06 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.33 (dd,
J = 7.8, 8.1 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz,