Three-step total synthesis of pyrroloquinazolinoquinoline alkaloid, Luotonin A, by intramolecular hetero diels-alder reaction

Article abstract of DOI:10.3987/com-01-s(k)49

Total synthesis of luotonin A (1) was accomplished, starting from 3-aminomethyl-2-bromoquinoline (4) in three steps via intramolecular hetero Diels-Alder reaction.

Full text of DOI:10.3987/com-01-s(k)49

HETEROCYCLES, Vol. 56, 2002, pp. 101-103, Received, 12th June, 2001
THREE-STEP TOTAL SYNTHESIS OF PYRROLOQUINAZOLINO-
QUINOLINE ALKALOID, LUOTONIN A, BY INTRAMOLECULAR
HETERO DIELS-ALDER REACTION#
Masahiro Toyota*, Chiyo Komori, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, Japan
Abstract - Total synthesis of luotonin A (1) was accomplished, starting from 3-
aminomethyl-2-bromoquinoline (4) in three steps via intramolecular hetero
Diels–Alder reaction.
We have been exploring intramolecular hetero Diels–Alder reactions of 1-azadienynes for the
construction of biologically active heterocycles such as nothapodytine B.1 In order to demonstrate the
flexibility of our protocol, we envisioned a novel one-pot generation of quinazolinone ring systems by
using cyano group as a Diels-Alder dienophile.2 Since luotonins A (1) and B (2) possess quinazolinone
framework as their partial structures, luotonin A (1) was adopted as our present target molecule.
Luotonins A (1) and B (2) were originally isolated by Nomura and his coworkers in 1997 from the aerial
parts of Peganum nigellastrum (Figure 1).3 Because these alkaloids have unique
pyrroloquinazolinoquinoline ring system and luotonin A (1) shows cytotoxic activity against mouse
leukemia P-388 cells, luotonin A (1) has attracted significant attention in recent years.4 In this
communication, we report a three-step synthesis of luotonin A (1) employing intramolecular hetero
Diels–Alder reaction.
Figure
1
R
O
N
N
N
Luotonin A (1): R=H
Luotonin B (2): R=OH

The requisite substrate (6)5 for the pivotal hetero cycloaddition was easily prepared in two steps as
depicted in Scheme 1. Condensation of 2-methoxybenzoic acid (3) with 3-aminomethyl-2-
bromoquinoline (4)6 in the presence of BOP and Et3N provided the amide (5) in 91% yield. To introduce
cyano group into the C-2 position of 5, palladium-catalyzed coupling reaction of 5 with CuCN was
investigated.7 As a result, the reaction proceeded smoothly in the presence of 4 mol % of Pd2(dba)3, 16
mol % of DPPF and stoichiometric amounts of Et4NCN, giving the cyanide (6) in 84% yield.
With the efficient synthesis of 6 established, the compound (6) was next subjected to intramolecular
hetero Diels–Alder reaction. Heating of 6 with TMSCl and Et3N at 150 °C in the presence of ZnCl2
produced luotonin A (1) in 46% yield. The synthetic 1 thus obtained was spectroscopically identical with
that reported.3
Scheme
1
BOP
Et3N
O
OMe
CO2H
OMe
NH2
N
+
H
CH2Cl2
(91%)
N
Br
N
Br
4
5
3
Pd2(dba)3, DPPF
CuCN, Et4NCN
TMSCl, ZnCl2, Et3N
toluene, 150 °C
O
OMe
N
H
in sealed tube
(46%)
1,4-dioxane, reflux
(84%)
N
CN
6
OTMS
O
N
N
OMe
N
N
N
N
7
Luotonin A (1)

REFERENCES AND NOTES
# Dedicated to Professor James P. Kutney on the occasion of his 70th birthday.
1. (a) M. Toyota, C. Komori, and M. Ihara, J. Org. Chem., 2000, 65, 7110. (b) M. Toyota, C.
Komori, and M. Ihara, Heterocycles, 2000, 5 2, 591.
2. Although the ability of a nitrile to act as a heterodienophile has been known, the requirement of very
high reaction temperature has made nitrile unattractive as a heterodienophile. D. L. Boger and S. M.
Weinreb, Hetero Diels–Alder Methodology in Organic Synthesis, Academic Press, Inc., New York,
1987.
3 . Z.-Z. Ma, Y. Hano, T. Nomura, and Y.-J. Chen, Heterocycles, 1997, 4 6, 541.
4. (a) P. Molina, A. Tarraga, and A. Gonzalez-Tejero, Synthesis, 2000, 1523. (b) T. R. Kelly, S.
Chamberland, and R. A. Silva, Tetrahedron Lett., 1999, 40, 2723. (c) Z.-Z. Ma, Y. Hano, T.
Nomura, and Y.-J. Chen, Heterocycles, 1999, 51, 1593. (d) H. Wang and A. Ganesen,
Tetrahedron Lett., 1998, 3 9, 9097.
5. The intramolecular hetero Diels–Alder reaction of 8 afforded neither the corresponding cycloadduct
nor luotonin A (1).
O
N
H
N
CN
8
6 . K. Mekouar, Y. Ganisson, S. Leue, and A. G. Greene, J. Org. Chem., 2000, 65, 5212.
7 . T. Sakamoto and K. Ohsawa, J. Chem. Soc., Perkin Trans. 1, 1999, 2323.