Synthesis of 2,7-naphthyridine-containing analogues of luotonin A

Article abstract of DOI:10.1055/s-0028-1087299

A series of luotonin A analogues 7a-d with the N-14 atom moved to position 18 was prepared using an intramolecular aza-hetero-Diels-Alder reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087299

LETTER
2989
Synthesis of 2,7-Naphthyridine-Containing Analogues of Luotonin A
S
ynthesis of 2,7-N
i
aphthyr
a
idine-Cont
n
aining
A
nalo
g
gues of Luot
q
onin A ian Dai,a Chen Cheng,a Chunyong Ding,b Qizheng Yao,b Ao Zhang*a
a
Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, P. R. of China
Fax +86(21)50806035; E-mail: aozhang@mail.shcnc.ac.cn
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. of China
b
Received 26 June 2008
O
Abstract: A series of luotonin A analogues 7a–d with the N-14
atom moved to position 18 was prepared using an intramolecular
aza-hetero-Diels–Alder reaction.
5
7
5
N
7
O
O
C
2
D
N
E
20
21
3
20
B
2
3
N
14
O
Key words: luotonin A, 2,7-naththyridine, anticancer, intramolec-
ular aza-hetero-Diels–Alder reaction
N1
A
N
18
15
11 X
16
17
camptothecin (1) X = CH
camptothecin (2) X = N
Ar
O
luotonin A (3)
Camptothecin (1), a natural product isolated from Chinese
tree Camptotheca acuminate in 1966,1 is one of the lead
molecules for the development of clinically effective an-
ticancer drugs. It exerts its biological effects by stabilizing
the covalent binary complex formed between DNA and
topoisomerase I during DNA relaxations.2 It has been
long accepted that the E-lactone ring, although not physi-
cochemically stable, is a key structural determinant for
camptothecin’s topoisomerase I inhibition and its antineo-
plastic properties. In this regard, the majority of the struc-
ture–activity relationship studies of 1 have been focused
on the optimization of rings A–C in the last two decades,3–
5 leading to two drugs (topotecan6 and irinotecan7) which
have reached the market and with dozens still remain in
clinical trials.8–10 Such strategy has changed since another
natural product, luotonin A (3)11–13 with an aromatic E-
ring, was identified and possessed a similar cellular
activity14 by interacting with DNA and topoisomerase I.
Although slightly lower than 1 in activity, luotonin A (3)
opens a new avenue for the development of clinically ef-
fective, chemically stable anticancer drugs.15
N
NH
O
N
4
O
R1
N
N
N
N
X
N
R2
5 X = OH, Y = H
6 X = H, Y = Et
Y
7
Figure 1 Camptothecin, luotonin A, and their analogues
O
O
N
O
N
HN
N
9
8
7
O
O
N
In our recent studies, we have successfully established a
method16 for the construction of the 2,7-naphthyridine
scaffold and synthesized several 2,7-naphthyridine-con-
taining natural products, for example, lophocladine A (4)
which was reported to possess anticancer activities.17 As a
continuation of this study, we decided to develop hybrid-
ized compounds by incorporation of the 2,7-naphthyri-
dine core into luotonin A, resulting in a class of new
analogues 7 (Figure 1). Such a design strategy can be
viewed as a N-walking approach through which the N-14
atom moves to C-18 in luotonin A.
N
N
HN
O
H
N
R2
EtOOC
10
11
Scheme 1 Retrosynthesis of naphthyridine analogues 7
A search of the literature disclosed that two compounds
(5,18 619) have been reported as camptothecin analogues
with a 2,7-naphthyridine fragment. Although no biologi-
cal data have been reported for these E-ring-modified
compounds of luotonin A, a 1,7-naphthyridine analogue
(2) has been described with slightly higher activity than 1
in the topoisomerase I cleavable complex assay.20 In addi-
tion, the reported synthesis of the 2,7-naphthyridine ana-
logues (5, 6) was primarily based on the key intermediate
naphthyridine-fused 3-pyrrolidinone 8 (Scheme 1, path
a), which was highly unstable.18,19 Therefore, it would be
SYNLETT 2008, No. 19, pp 2989–2992
x
x
.x
x
.2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1087299; Art ID: W10208ST
© Georg Thieme Verlag Stuttgart · New York

2990
X. Dai et al.
LETTER
Nagarajan's approach
NH2
Cl
Cl
Cl
H
La(OTf)3
N
N
CHO +
N
N
N
R
R
R
Fortunak and Yao's approach
R1
R1
R1
O
O
N
N
O
N
N
O
N
H
N
R2
OX
R2
R2
Scheme 2 Nagarajan’s and Fortunak’s intramolecular hetero-Diels–Alder reactions
7
O
O
6
O
4
N
v
R
ii–iv
N
N
N
N
N
3
H
1
N
EtO2C
N
Ar
14
O
12
13
i
i
11
O
O
O
N
v
R
ii–iv
N
N
N
N
N
H
N
EtO2C
N
Ar
O
15
16
7a, R = H, 78%
7b, R = 10–MeO, 64%
7c, R = 10–COOMe, 45%
Scheme 3 Reagents and conditions: i) allyl bromide for compound 12, propargyl bromide for compound 15, K2CO3, 90%; ii) LiOH, THF–
H2O, reflux; iii) oxalic chloride, CH2Cl2, 0 °C; iv) aniline, CH2Cl2, 50–60% for step ii–iv; v) Ph3PO (3.0 equiv), Tf2O (1.5 equiv), r.t.
of great importance to develop a versatile methodology to yield. However, the proposed intramolecular aza-DA cy-
efficiently construct such N-walking analogues 7 of clization of 13a (Ar = Ph) did not occur by using Nagara-
luotonin A.
jan’s catalytic conditions [La(OTf)3, dioxane, 140 °C].21
Extending the reaction time, elevating the temperature, or
increasing catalyst loading of Lewis acid [La(OTf)3] did
not trigger this reaction. Fortunately, after several trials,
we found that bis(triphenyl)oxodiphosphonium trifluo-
romethanesulfonate, formed in situ from Ph3PO and Tf2O
(reported by Yao),23 could readily initiate this reaction at
0 °C and yielded a major product in 78% yield. However,
the spectroscopic data24 of this cycloadduct did not sup-
port the structure of 14a (R = H), instead the 6,7-dehydro
product – quinoline 7a – was obtained. The formation of
compound 7a can be rationalized by the stability of aro-
matic system of 7a, which was driven by the acidity of the
catalytic system. Similarly, cyclization of compound 13b
under the same catalytic conditions gave compound 7b in
64% yield.24,25
Our synthesis was based on a modified intramolecular
imino hetero-Diels–Alder (DA) reaction (Scheme 1, path
b) which was validated recently by Nagarajan21 on the
synthesis of indolopyrroloquinolines. This approach is
also similar to the intramolecular aza-DA reaction initial-
ly developed by Fortunak22a and Batey,22b and further im-
proved by Yao23 recently in the synthesis of 1 and 3
(Scheme 2). In this regard, the key step in our synthesis is
to prepare the intermediate 10 where the allyl moiety acts
as the dienophile, and the N-aryl-amido moiety serves as
the diene.
To validate the proposed intramolecular aza-hetero-DA
reaction on the 2,7-naphthyridine model, we synthesized
3-ethoxycarbonyl-2,7-naphthyridin-1-one (11) from 4-
methyl-3-cyanopyridine by using a similar procedure to
the one we reported recently.16 N-Allylation of 11 with
allyl bromide and K2CO3 yielded naphthyridone 12 in
90% yield (Scheme 3). Saponification with LiOH fol-
lowed by treating with oxalyl chloride and then an appro-
priate aniline gave the key precursor 13 in 50–60% overall
It is of interest to note that using the same catalytic condi-
tions, cyclization of N-propargyl-2,7-naphthyridines
gave the same products. Thus, cyclization of 16
(Ar = 4-MeO2CC6H4) provided 7c in 45% yield. Similar
yield of 7a was obtained for cyclization of 16 (Ar = Ph).
Synlett 2008, No. 19, 2989–2992 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,7-Naphthyridine-Containing Analogues of Luotonin A
2991
O
O
O
ii–iv
i
N
N
N
HN
N
N
O
a
a
H
N
EtC2O
EtO2C
b
O
OH
O
b
17
18
19
a
b
v
v
O
O
N
N
N
N
N
N
O
O
20
7d
Scheme 4 Reagents and conditions: i) allyl bromide, K2CO3, 45%; ii) LiOH, THF–H2O, reflux; iii) oxalic chloride, CH2Cl2, 0 °C; iv) anilin
CH2Cl2, 20% step ii–iv; v) Ph3PO (3.0 equiv), Tf2O (1.5 equiv), r.t.
This result was in complete agreement with Yao’s report
on isoquinolin-1-one.23 The somewhat lower yields of the
cycloadducts 7a–c were probably due to the lower reactiv-
ity of the 2,7-naphthyridine core compared to that of iso-
quinolin-1-ones.
References and Notes
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To examine the selectivity of the intramolecular aza-DA
reaction, we prepared compound 18 using a similar proce-
dure,16 and then converted it to the cyclization precursor
19 in 20% overall yield. The low yield of this conversion
may be ascribed to the contamination of bis-O-alkylation
product. Since both N- or O-propargyl moiety in 19 can
serve as the dienophile, two cycloadducts 7d and 20 could
be produced through intramolecular aza-DA reaction
(path a or path b) as described in Scheme 4. However, us-
ing the catalyst formed in situ from Ph3PO and Tf2O, only
one compound 7d26 was isolated in 30% yield, and com-
pound 20 was not observed. The production of compound
7d may be due to the less ring strain in forming the five-
membered C-ring in 7d than that in forming six-mem-
bered pyran ring in 20.
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In summary, we have demonstrated a procedure of in-
tramolecular aza-hetero-Diels–Alder reaction on the
3-(N-aryl-amido)-2-allyl-2,7-naphthyridin-1-ones as the
substrate, by combining Nagarajan’s and Yao’s reaction
conditions. A small series of luotonin A analogues 7a–d,
where the N-14 atom walked to position 18, was prepared
in moderate yields.
2203.
(14) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by a Hundred Talent Project of the Chine-
se Academy of Sciences, and grants from Chinese National Science
Foundation (30672517, 30772625), Shanghai Commission of Sci-
ence and Technology (06ZR14102, 07pj14104), and grants from
Shanghai Institute of Materia Medica.
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2007, 9, 916.
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Ballantine, D. L.; Murray, T. F.; Valeriote, F. A.; Gerwick,
W. H. J. Nat. Prod. 2006, 69, 640.
Synlett 2008, No. 19, 2989–2992 © Thieme Stuttgart · New York

2992
X. Dai et al.
LETTER
(18) Shamma, M.; Novak, L. Tetrahedron 1969, 25, 2275.
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J. Am. Chem. Soc. 1967, 89, 6741.
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CD3OD): d = 5.17 (br s, 2 H), 7.47 (m, 3 H), 7.63 (m, 1 H),
7.75 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 8.27 (s,
1 H), 8.51 (d, J = 5.4 Hz, 1 H), 9.37 (s, 1 H). HRMS: m/z
calcd for C18H11ON3: 285.0902; found: 285.0890.
Compound 7b (45%): slightly yellow solid, mp >200 °C.
MS (EI): m/z (%) = 343(100) [M+]. 1H NMR (300 MHz,
CDCl3–CD3OD): d = 3.81 (s, 3 H), 5.21 (br s, 2 H), 7.46 (s,
1 H), 7.52 (d, J = 5.4 Hz, 1 H), 8.03 (d, J = 9.0 Hz, 1 H), 8.16
(d, J = 8.4 Hz, 1H), 8.39 (s, 1 H), 8.48 (s, 1 H), 8.54 (d, J =
5.4 Hz, 1 H), 9.39 (s, 1 H). HRMS: m/z calcd for
C20H13O3N3: 343.0957; found: 343.0959.
Compound 7c (64%): slightly yellow solid, mp >210 °C.
MS (EI): m/z (%) = 315(100) [M+]. 1H NMR (300 MHz,
CDCl3–CD3OD): d = 3.94 (s, 3 H), 5.31 (s, 2 H), 7.19 (s,
1 H), 7.45 (m, 1 H), 7.51 (s, 1 H), 7.58 (d, 1 H, J = 7.6 Hz),
8.06 (d, J = 12.4 Hz, 1 H), 8.25 (s, 1 H), 8.69 (s, 1 H), 9.60
(s, 1 H). HRMS: m/z calcd for C19H13O2N3: 315.1008; found:
315.1017.
(24) General Procedure for the Intramolecular Aza-Diels–
Alder Cyclization
To a solution of Ph3PO (837 mg, 2.98 mmol) in anhyd
CH2Cl2 (20 mL) at 0 °C was added dropwise a solution of
Tf2O (0.25 mL, 1.5 mmol) in CH2Cl2 (2 mL). After the
mixture was stirred for 15 min at 0 °C, a solution of 2-allyl-
1-oxo-N-aryl-2,7-naphthyridin-3-carboxamide (13, 1.0
mmol) or 2-propargyl-1-oxo-N-aryl-2,7-naphthyridin-3-
carboxamide (16, 1.0 mmol) in CH2Cl2 (20 mL) was
dropped slowly. The reaction mixture was stirred at 0 °C for
0.5 h, and then at r.t. for 1–5 h. The completion of the
reaction was detected by disappearance of the carboxamide
substrate 13. A solution of aq Na2CO3 (10%, 10 mL) was
added to quench the reaction. The mixture was extracted
with CHCl3 (3 × 30 mL). The organic phases were
combined, washed with brine, and dried over anhyd Na2SO4.
After filtration, the solvent was removed, and the residue
was subjected to column chromatography (CH2Cl2–MeOH,
10:1). The cyclization products 7a–c were obtained.
Compound 7a (78%): white solid, mp >210 °C. MS (EI):
m/z (%) =285(100) [M+]. 1H NMR (300 MHz, CDCl3–
(25) The cycloadducts 7a–c showed extremely poor solubility in
regular deuterated solvents (CDCl3, CD3OD, CD3SOCD3,
D2O). Their purity (>95%) was further confirmed by HPLC
analysis on an Agilent 1100 series LC system (Agilent
ChemStation Rev.A.10.02; ZORBAX Eclipse XDB-C8,
4.8 mm × 150 mm, 5 mM, 1.0 mL/min, UV: l = 254 nm, r.t.)
with two solvent systems (MeCN–H2O, and MeOH–H2O).
(26) Compound 7d (30%): yellow solid, mp 202–204 °C. MS
(EI): m/z = 341 [M+]. 1H NMR (300 MHz, CDCl3–CD3OD):
d = 4.90 (d, J = 6.0 Hz, 1 H), 5.35 (s, 2 H), 5.36 (d, J = 6.6
Hz, 1 H), 5.50 (dd, J = 1.2, 17.1 Hz, 1 H), 6.37 (m, 1 H), 7.62
(t, J = 7.2 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.86 (m, 2 H),
8.23 (d, J = 8.7 Hz, 1 H), 8.28 (s, 1 H), 8.85 (d, J = 5.7 Hz,
1 H), 9.68 (s, 1 H). 13C NMR (75 MHz, CDCl3–CD3OD):
d = 49.7, 76.0, 115.4, 118.9, 119.6, 127.0, 127.6, 127.8,
128.4, 129.8, 130.2, 133.3, 134.2, 134.9, 140.7, 148.8,
150.4, 150.5, 151.7, 158.6. HRMS: m/z calcd for
C21H15O2N3: 341.1164; found: 341.1160.
Synlett 2008, No. 19, 2989–2992 © Thieme Stuttgart · New York