Lewis acid-assisted olefin cross-metathesis reaction: An efficient approach for the synthesis of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin and evaluation of their antitumor activity

Article abstract of DOI:10.1016/j.tetlet.2012.01.001

A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a-g) were synthesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OⁱPr)₄ 30 mol % and 10 mol % of Grubb's second generation catalyst with good to excellent yields. Most of these compounds exhibited significant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e) showed potent cytotoxic activity.

Full text of DOI:10.1016/j.tetlet.2012.01.001

Tetrahedron Letters 53 (2012) 1287–1291
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis acid-assisted olefin cross-metathesis reaction: an efficient approach
for the synthesis of glycosidic-pyrroloquinolinone based novel building
blocks of camptothecin and evaluation of their antitumor activity
Lingaiah Nagarapu a, , Hanmant K. Gaikwad a, Rajashaker Bantu a, Sheeba Rani Manikonda a,
⇑
C. Ganesh Kumar b, Sujitha Pombala b
a Organic Chemistry Division-II, Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500607, India
b Chemical Biology Laboratory, Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of glycosidic-pyrroloquinolinone based novel building blocks of camptothecin (2a–g) were syn-
thesized via Lewis acid-assisted olefin cross-metathesis reaction using Ti(OiPr)4 30 mol % and 10 mol % of
Grubb’s second generation catalyst with good to excellent yields. Most of these compounds exhibited sig-
nificant growth inhibitory effects on all the tested cancer cell lines and three compounds (2c, 2d and 2e)
showed potent cytotoxic activity.
Received 1 November 2011
Revised 28 December 2011
Accepted 1 January 2012
Available online 8 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Camptothecin
Glycosidic-pyrroloquinolinone
Olefin cross-metathesis
Antitumor activity
Camptothecin (CPT, 1), an antitumor alkaloid was first isolated
by Wall and co-workers1 in 1966 from Camptotheca acuminate a
tree native to China, which showed potent inhibitory activity
against a broad spectrum of tumors.2 A key biochemical target
for CPT is the covalent binary complex formed between DNA and
topoisomerase I during DNA relaxation and stabilization of this
complex leads to cell death.3,4 CPT has limited clinical use in cancer
therapy because of its poor water solubility and its severe adverse
side effects including neutropenia, thrombocytopenia, hemor-
rhagic cystitis, and G.I. symptoms with significant diarrhea. In re-
cent years, studies have demonstrated the clinical use of CPT
analogs as antitumor agents which has prompted intensive efforts
to identify additional clinical candidates in this class.5–9 As a result,
three drugs, topotecan,5 irinotecan,6 and belotecan10,11 have been
approved for the treatment of human cancers.
There are obvious structural similarities between CPT (1) and
2a–g, notably in identical ring A–C (Fig. 1). The differences are in
rings D and E, which are known to be critical for CPT function as
topoisomerase I inhibitors and antineoplastic agents.12,13 Alter-
ation in the lactone ring renders CPT dysfunctional, although a
few exceptions have been reported.14,15 The attachment of glyco-
sidic olefins by olefin cross-metathesis reaction with N-allylpyrrol-
oquinolinone led to the discovery of a series of potent compounds,
which may provide insight leading to improved therapeutic agents.
This basis has led us to design a new class of glycosidic-pyrrolo-
quinolinone based building blocks of camptothecin.
In our on-going search to discover and develop potential new
anticancer agents, we have identified several classes of molecules
as novel tumor growth inhibitors.16–19 Herein, we report the Lewis
acid-assisted olefin cross-metathesis reaction, an efficient approach
for the synthesis of novel series of glycosidic-pyrroloquinolinone
based building blocks of camptothecin and evaluation of their pre-
liminary cytotoxicity against the human cancer cell lines in vitro.
However, the olefin cross-metathesis reaction of N-allyl amines
and amides has not been carried out using metathesis reaction
conditions.20–24 There is a report on ring closing metathesis, how-
ever, no report exists on cross-metathesis reaction of N-allyl amide
substrates using Ru complexes. In this context, we have expanded
the scope of olefin cross-metathesis reaction by utilizing Lewis acid
in the synthesis and the investigation of these biologically active
new building blocks of 1, on reaction of furanoside olefins (6a–g)
O
A
B
N
N
D
N
C
O
N
R3
O
E
O
H
R1
R2
OH
O
2a-g
1
⇑
Corresponding author. Tel.: +91 40 27191509; fax: +91 40 27193382.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
Figure 1. Structure of camptothecin (1) and its novel building blocks (2a–g).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.001

1288
L. Nagarapu et al. / Tetrahedron Letters 53 (2012) 1287–1291
PCy3
Ru
i, ii
N
N
N
Mes
Ph
Mes
N
Ph
Cl
Cl
N
5
N
O
O
Cl
Cl
7 (>84%)
Ru
PCy3
PCy3
Scheme 2. Isomerization of N-allyl lactam. Reagents and conditions: (a) 5 mol % 3,
Toluene, 110 °C, 12 h. (b) 5 mol % 4, CH2Cl2, 70 °C, 12 h.
3
4
Figure 2. Ruthenium based Grubbs catalysts.
entry 2). We observed that olefin CM reaction worked very well
under the optimized conditions resulting in good to excellent
yields.
with N-allyl-1H-pyrrolo[3,4-b]quinolin-3(2H)-one (5) and allowing
the flexibility in the furanoside ring system with varying stereo-
centers using Grubbs25–30 catalyst 3 [(PCy3)2Cl2Ru@CHPh] and 4
[Cl2(Im)(PCy3)Ru@CHPh] (Fig. 2).
The synthesized compounds 2a–g were further evaluated for
their in vitro cytotoxic activity against human alveolar adenocarci-
noma (A549), breast adenocarcinoma (MDA-MB-231, MCF-7), cer-
vical cancer (HeLa), and neuroblastoma (IMR-32) cell lines using
the standard MTT assay.31 To obtain more meaningful comparison
of relative potencies, Camptothecin, Luotonin A, and Doxorubicin
were used as positive controls. The antitumor potency of the com-
pounds indicated by IC50 values (50% inhibitory concentration) was
calculated from the plotted absorbance data for the dose–response
Our experience indicated that the metathesis of N-allyl-1H-pyr-
rolo[3,4-b]quinolin-3(2H)-one (5) possess a basic or nucleophilic
nitrogen atom which could not be deactivated under harsh reac-
tion conditions,20 but this substrate has to be deactivated for the
ruthenium-catalyzed reactions. Initially the compound 6a was al-
lowed to react with 5 in the presence of Grubbs second generation
catalyst (10 mol %) to afford a mixture of compound 2a (31%) and 7
(27%) (Scheme 1). In the presence of catalysts 3 and 4 under harsh
conditions the isomerization of double bond is favored in N-allyl
lactam (Scheme 2).
In order to prevent the coordination of N-atom with the ruthe-
nium carbene intermediate, Lewis acid has been introduced and
we conducted a model reaction with compound 5 in the presence
of second generation Grubbs catalyst to afford 2a (Table 1) with
all the Lewis acids. When the amount of Ti(OiPr)4 is increased to
100 mol %, the yield slightly decreased from 86% to 72% (Table
1, entries 4–7). The yield could be improved to 86% when
30 mol % of Ti(OiPr)4 was used (Table 1, entry 6). Several other
Lewis acids have also been tested (Table 1, entries 1–3) and it
was found that AlCl3, TiCl4, and Sc(OTf)3 were too strong for the
reaction or were found to decompose the catalyst in a short time
(Table 1, entries 1–3). We chose the optimized conditions as in
curves. IC50 values (in
lM) are expressed as the average of two
independent experiments. From the data reported in Table 3, most
of the prepared compounds possessed significant growth inhibi-
tory effects on all the tested cell lines and potencies of some com-
pounds were better or comparable to the lead compound,
camptothecin. Among them, four compounds (2b, 2c, 2d, 2e)
showed potent inhibitory activity.
For MDA-MB-231 and MCF-7 cell lines, compounds (2c, 2d and
2e) showed higher inhibitory activity with IC50 values ranging from
6.0–19.3 lM against alveolar and breast cancer cells. For A549 and
HeLa cell lines, all the compounds showed significant activity,
while IMR-32 cell line exhibited moderate cytotoxic activity. It
has been observed from Table 3, that the compound with methoxy
and acetate moieties on furanoside ring had higher cytotoxicity as
compared to acetonide. For example, compounds 2c, 2d bearing
methoxy and acetate substituents showed most potent cytotoxic-
ity in human alveolar and breast adenocarcinoma cell lines, the
entry
6 of Table 1 for further investigation. Compound 2a
was characterized by its 1H NMR spectrum which showed a char-
acteristic olefinic multiplet at d 5.70–5.90 and the 13C NMR spec-
trum showed olefinic carbons at d 108.42, 111.26, which was
further characterized by HR-MS having a mass m/z = 397.1756
[M+H]+.32
IC50 values ranged from 6.0–11.8 lM. These results indicated that
the attachment of furanoside ring with the N-allyl-1H-pyrrol-
o[3,4-b]quinolin-3(2H)-one facilitated the increase of their antitu-
mor activities.
In summary, we have developed a Lewis acid-assisted olefin
cross-metathesis as a new strategy for the synthesis of glyco-
sidic-pyrroloquinolinone based novel building blocks (2a–g) of
camptothecin and evaluated their antitumor activities against five
human cancer cell lines (A549, MDA-MB-231, MCF-7, HeLa, and
IMR-32). Most of the prepared compounds indicated significant
growth inhibitory effects and compounds 2c, 2d, 2e were more po-
tent against alveolar and breast adenocarcinoma cell lines. The
attachment of furanoside ring with N-allyl-1H-pyrrolo[3,4-b]quin-
olin-3(2H)-one (5) is associated with a distinct tendency to in-
crease the in vitro antitumor potency. This study may provide
valuable information for further designing and developing more
potent anticancer agents.
With the optimized protocol extended, the scope of these ole-
finic cross-metathesis reactions was then studied for the synthesis
of glycosidic-pyrroloquinolinone based building blocks of CPT (1).
As revealed in Table 2, a series of furanoside olefins (6a–g) with
N-allyl-1H-pyrrolo[3,4-b]quinolin-3(2H)-one (5) were found suit-
able for such a transformation (Table 2, entries 1–7). The reaction
of furanoside olefin containing acetonide, methoxy group with 5
afforded 81% to 86% yields (Table 2, entries 1, 3 and 6), whereas
reaction of furanoside olefin containing acetate group with 5 affor-
ded slightly decreased yields ranging from 86% to 72% (Table 2, en-
tries 4 and 7) and without any substitution on furanoside olefin
was also carried out successfully with a moderate yield (Table 2,
O
N
N
OCH3
+
i
+
N
O
N
OCH3
N
H
O
O
O
H
O
O
O
O
2a ( 31 %)
7 (27 %)
5
6a
Scheme 1. Olefin cross-metathesis reaction. Reagent and conditions: (i) Cat. 4, 10 mol %, CH2Cl2, 40 °C, 18 h.

L. Nagarapu et al. / Tetrahedron Letters 53 (2012) 1287–1291
1289
Table 1
Synthesis of 2a by olefin cross-metathesis reaction of 5 and 6a in presence of Lewis acidsa
O
OCH3
4
Cat. , 10 mol %,
N
N
+
H
O
N
N
Lewis acids, CH2Cl2,
40 oC, 86 %.
OCH3
O
O
O
O
H
O
O
6a
2a
5
Entry
Lewis acids
Amount (mol %)
Time (h)
Yield (%)
1
2
3
4
5
6
7
AlCl3
100
100
100
100
50
2
4
2
12
16
18
24
0b
0b
0b
72
78
86
81
Sc(OTf)3
TiCl4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
30
10
a
Reaction and conditions: 4 (1 mmol), 5a (2 mmol), 3 (10 mol %), Lewis acids (10–100 mol %), 40 °C, CH2Cl2 (20 mL).
Catalyst decomposed.
b
Table 2
Formation of olefins 2a–g by reaction of 5 with 6a–ga
R
N
N
O
b
Entry
Entry
6a-g
N
N
2a-gb
R
O
5
O
O
OCH3
OCH3
a
H
1
5
a (86)
O
O
b
2
3
5
5
b (78)
c (81)
H
HO OH
O
OCH3
c
d
H
H3CO OCH3
O
OCH3
4
5
6
7
5
5
5
5
d (73)
e (79)
f (83)
g (75)
H
OCOCH3
H3COCO
O
O
O
e
O
O
H
HO
f
O
O
H
H3CO
g
O
O
H
H3COCO
a
Cat. 3, 10 mol %, 30 mol % Ti(OiPr)4, CH2Cl2, 40 °C, 18 h.
Isolated % yield in parentheses.
b

1290
L. Nagarapu et al. / Tetrahedron Letters 53 (2012) 1287–1291
19. Nagarapu, L.; Paparaju, V.; Satyender, A. Bioorg. Med. Chem. Lett. 2008, 18,
Table 3
2351.
Antitumor activity of the novel building blocks of Camptothecin
20. Dieltiens, N.; Stevens, C. V.; Vos, D. D.; Allaert, B.; Drozdzak, R.; Verpoort, F.
Tetrahedron Lett. 2004, 45, 8995.
a
Compounds
IC50
(
lM)
21. Clercq, B. D.; Verpoort, F. Tetrahedron Lett. 2001, 42, 8959.
22. Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000,
2, 1517.
23. Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204.
24. Yang, Q.; Xiao, W. –J.; Yu, Z. Org. Lett. 2005, 7, 871.
25. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 413.
26. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
27. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
28. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
29. Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH: Weinheim, 2003; Vol. 2,
30. Ung, T.; Hejl, A.; Grubbs, R. H.; Schrodi, Y. Organometallics 2004, 23, 5399.
31. Mosmann, T. J. Immunol. Meth. 1983, 65, 55.
A549
MDA-MB-231
MCF-7
HeLa
IMR-32
2a
2b
2c
2d
2e
2f
11.95
57.77
7.32
8.49
11.68
11.99
—
31.6
13.7
11.8
9.7
6.1
—
—
—
7.6
9.8
< 1
73.2
15.5
7.2
14.5
17.8
26.1
6.6
45.1
31.7
—
—
8.5
7.2
< 1
-
7.4
10.3
57.7
35.0
27.5
6.9
—
6.9
6.7
1.2
6.0
19.3
68.3
22.2
—
6.1
7.8
2g
5
—
LAb
CPTc
Doxd
5.81
6.41
1.00
1.0
32. Typical procedure for olefin cross-metathesis: The N-allyl-1H-pyrrolo[3,4-
b]quinolin-3(2H)-one (5, 50 mg, 0.223 mmol) and furanoside olefin (6a,
90 mg, 0.446 mmol) was dissolved in freshly distilled and degassed
dichloromethane (3 mL) under nitrogen atmosphere. Then Ti(OiPr)4 (0.02 mL,
0.067 mmol) dissolved in dichloromethane was added by syringe. After stirring
for 1.0 h at room temperature, ruthenium catalyst 4 (18 mg, 0.0223 mmol)
dissolved in dichloromethane was added by syringe. After 24 h at 40 °C, the
reaction was complete as indicated by TLC. Then saturated sodium bicarbonate
was added to quench the reaction, the organic layer was separated and the
aqueous layer was extracted with dichloromethane. The combined organic
layers were dried over anhydrous sodium sulfate and concentrated under
reduced pressure, and then the residue obtained was purified by flash column
chromatography. Spectral data: Compound 2a: Yield 86%, mp 152–154 °C, IR (v
cmÀ1): 2918, 2873, 1687, 1542, 1486, 1374, 1246, 1164, 1083, 836, 788, 683;
1NMR (300 MHz, DMSO-d6): d 1.26 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.26 (s, 3H,
OCH3), 4.31 (s, 2H, CH2), 4.51–4.66 (m, 5H, 1 Â CH2, 3 Â CH), 4.86–4.92 (m, 1H,
CH), 5.70–5.90 (m, 2H, 2 Â @CH), 7.67 (t, 1H, Ar-H), 7.81 (t, 1H, Ar-H), 8.02 (d,
1H, Ar-H), 8.23 (d, 1H, Ar-H), 8.45 (s, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): d
24.68, 26.02, 43.49, 46.44, 53.72, 83.60, 84.66, 86.03, 95.40, 108.42, 111.26,
126.90, 127.35, 127.94, 129.48, 129.58,130.76, 132.81, 147.98, 150.87, 164.65;
HR-MS (ESI+): m/z calcd for C22H24N2O5 [M+Na]+: 419.1582; found: 419.1586;
Compound 2b: Yield 78%, mp 203–205 °C, IR (v cmÀ1): 3424, 2989, 2878, 1689,
1562, 1489, 1416, 1247, 1089, 869, 776, 658; 1NMR (300 MHz, DMSO-d6): d
3.24 (s, 3H, OCH3), 4.18–4.32 (m, 3H, 1 Â CH, 1 Â CH2), 4.62 (s, 2H, CH2), 4.77–
4.86 (dd, J = 5.28, 6.42 Hz, 1H, CH), 4.98–5.04 (d, J = 6.98 hz, 1H, CH), 5.07–5.17
(dd, J = 6.23, 4.34 Hz, 1H, CH), 5.67–5.85 (m, 2H, 2 Â =CH), 7.73 (t, J = 7.54 Hz,
1H Ar-H), 7.87 (t, J = 7.07 Hz, 1H, Ar-H), 8.13 (d, J = 7.93 Hz, 1H, Ar-H), 8.21 (d,
J = 8.49 Hz, 1H, Ar-H), 8.61 (s, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): d 46.56,
54.29, 72.09, 72.79, 74.16, 74.98, 81.80, 102.80, 107.98, 125.83, 127.83, 128.16,
128.35, 129.73, 129.93, 130.87, 131.25, 133.77, 147.95, 151.80, 164.88; HR-MS
(ESI+): m/z calcd for C19H20N2O5 [M+Na]+: 379.1270; found: 379.1269;
Compound 2c: Yield 81%, mp 162–165 °C, IR (v cmÀ1): 2938, 2876, 1695,
1565, 1468, 1389, 1242, 1198, 1078, 1059, 878. 792 628; 1NMR (300 MHz,
CDCl3)): d 3.35 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.62–3.73
(m, 2H, CH2), 4.32–4.45 (m, 3H, 3 Â CH), 4.52 (s, 2H, CH2), 4.79–4.89 (m, 1H,
CH), 5.71–5.94 (m, 2H, 2 Â @CH), 7.62 (t, J = 7.17 Hz, 1H, Ar-H), 7.78 (t,
J = 6.96 Hz, 1H, Ar-H), 7.85 (d, J = 8.12 Hz, Ar-H), 8.18 (s, 1H, Ar-H), 8.38 (d,
J = 8.30 Hz, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): d 29.78, 44.60, 47.01, 55.27,
58.35, 71.65, 80.58, 82.08, 84.19, 96.22, 105.52, 105.52, 126.81, 127.70, 127.97,
128.85, 129.99, 130.74, 131.05, 134.43, 149.06, 165.56;HH HR-MS (ESI+): m/z
calcd for C21H24N2O5 [M+Na]+: 407.1582; found: 407.1601; Compound 2d:
Yield 73%, mp 137–140 °C, IR (v cmÀ1): 2986, 2864, 1742, 1736, 1686, 1552,
1516, 1453, 1318, 1248, 1189, 1079, 1028, 896, 798, 653; 1NMR (500 MHz,
CDCl3)): d 2.00 (s, 3H, CH3), 2.09 (s, 3H, CH3), 3.38 (s, 3H, OCH3), 4.35 (d,
J = 6.38 Hz, 2H, CH2), 4.41–4.50 (m, 3H, 1 Â CH, 1 Â CH2), 4.83 (s, 1H, CH), 5.08–
5.13 (m, 1H, CH), 5.16–5.21 (m, 1H, CH), 5.74–5.87 (m, 2H, 2 Â @CH), 7.58 (t,
J = 7.29 Hz, 1H, Ar-H), 7.75 (t, J = 7.29 Hz, 1H, Ar-H), 7.81(d, J = 8.20 Hz, 1H, Ar-
H), 8.15 (s, 1H, Ar-H), 8.34 (d, J = 8.20 Hz, 1H, Ar-H); HR-MS (ESI+): m/z calcd for
a
b
c
Data presented is the mean value of two independent determinations.
Luotonin A.
Camptothecin.
Doxorubicin are positive controls.
d
Acknowledgments
Authors are grateful to the Director and Head, Organic Chemis-
try Division-II, IICT for their support. Hanmant K. Gaikwad is
thankful to the University Grant Commission (UGC), New Delhi
for a research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.001.
References and notes
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C
23H24N2O7 [M+Na]+: 463.1481; found: 463.1485; Compound 2e: Yield 79%,
mp 216–217 °C, IR (v cmÀ1): 3352, 2924, 2886, 1693, 1503, 1474, 1415, 1319,
1238, 1081, 1019, 768, 577; 1NMR (300 MHz, DMSO-d6): d 1.26 (s, 3H, CH3),
1.43 (s, 3H, CH3), 392.3.98 (m, 1H, CH), 4.24–4.35 (m, 1H, CH), 4.37–4.44 (m,
2H, CH2), 4.50–4.55 (m, 1H, CH), 4.61 (s, 2H, CH2), 4.95–5.02 (m, 1H, CH), 5.77–
5.81 (m, 1H, @CH), 5.83–5.90 (m, 1H, @CH), 7.65 (t, J = 7.38 Hz, 1H, Ar-H), 7.79
(t, J = 8.17 Hz, 1H, Ar-H), 7.97 (d, J = 7.17 Hz, 1H, Ar-H), 8.25 (d, J = 8.49 Hz, 1H,
Ar-H), 8.38 (s, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): d 25.83, 26.41, 43.75,
46.28, 75.23, 80.29, 84.94, 95.44, 103.95, 110.20, 127.27, 127.56, 127.85,
128.64, 129.40, 129.60, 130.30, 130.65, 147.99, 164.69; HR-MS (ESI+): m/z
calcd for C21H22N2O5 [M+Na]+: 405.1426; found: 405.1420; Compound 2f:
Yield 83%, mp 150–154 °C, IR (v cmÀ1): 2774, 2916, 1682, 1562, 1503, 1379,
1218, 1052, 1018, 768, 689; 1NMR (300 MHz, CDCl3)): d 1.29 (s, 3H, CH3), 1.48
(s, 3H, CH3), 3.39 (s, 3H, OCH3), 3.60 (d, J = 2.64 Hz, 1H, CH), 4.16–4.29 (dd,
J = 6.42, 6.23 Hz, 1H, CH), 4.43–4.54 (m, 4H, 1 Â CH2, 2 Â CH), 4.56–4.65 (m, 2H,
CH2), 5.76–5.99 (m, 2H, 2 Â @CH), 7.60 (t, J = 7.09 Hz, 1H, Ar-H), 7.77 (t,
J = 7.03 Hz, 1H, Ar-H), 7.84 (d, J = 8.12 Hz, 1H, Ar-H), 8.16 (s, 1H, Ar-H), 8.37 (d,
J = 8.49 Hz, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): d 19.79, 26.12, 29.86, 44.02,
46.71, 55.38, 81.12, 82.46, 83.98, 96.12, 105.41, 126.78, 127.69, 127.98, 128.83,
129.68, 130.46, 131.41, 134.78, 149.84, 165.62; HR-MS (ESI+): m/z calcd for
11. Lee, H. S.; Park, H. J.; Lee, J. H.; Hwang, I. C.; Lee, H. W.; Kim, J. K.; Ahn, S. K.;
Hong, C. I. Proc. Am. Assoc. Cancer Res. 2003, 44, 347.
12. Hutchinson, C. R. Tetrahedron 1981, 37, 1047.
13. Hertzberg, R. P.; Caranfa, M. J.; Holden, K. G.; Jakas, D. R.; Gallagher, G.;
Mattern, M. R.; Mong, S.-M.; Bartus, J. O.; Johnson, R. K.; Kingsbury, W. D. J.
Med. Chem. 1989, 32, 715.
14. Lavergne, O.; Lesueaur-Ginot, L.; Pla Rodas, F.; Kasprzyk, P. G.; Pommier, J.;
Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.-M.;
Harnett, J.; Pons, D.; Camara, J.; Bigg, D. C. H. J. Med. Chem. 1998, 41, 5410.
15. Lesueur-Ginot, L.; Demarquay, D.; Kiss, R.; Kasprzyk, P. G.; Dassonneville, L.;
Bailly, C.; Camara, J.; Lavergne, O.; Bigg, D. C. H. Cancer Res. 1999, 59,
2939.
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K. M.; Kalvendi, S. V. Eur. J. Med. Chem. 2010, 45, 4720.
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L. Nagarapu et al. / Tetrahedron Letters 53 (2012) 1287–1291
1291
C22H24N2O5 [M+Na]+: 419.1582; found: 419.1597; Compound 2g: Yield 75%,
mp 136–138 °C, IR (v cmÀ1): 2988, 2921, 1738, 1690, 1575, 1470, 1379, 1248,
1070, 1020, 770, 633; 1NMR (300 MHz, DMSO-d6)): d 1.28 (s, 3H, CH3), 1.46 (s,
3H, CH3), 2.02 (s, 3H, CH3), 4.31 (d, J = 5.85 Hz, 2H, CH2), 4.48–4.62 (m, 4H,
1 Â CH2, 2 Â CH), 4.68–4.74 (m, 1H, CH), 5.04–5.09 (m, 1H, CH), 5.80–6.01 (m,
2H, 2 Â @CH), 7.66 (t, J = 7.45 Hz, 1H, Ar-H), 7.80 (t, J = 7.60 Hz, 1H, Ar-H), 8.00
(d, J = 8.30 Hz, 1H, Ar-H), 8.23 (d, J = 8.49 Hz, 1H, Ar-H), 8.43 (s, 1H, Ar-H); 13C
NMR (75 MHz, DMSO-d6): d 20.07, 26.11, 25.67, 43.56, 46.39, 76.62, 82.72,
95.44, 103.71, 110.87, 126.26, 127.20, 127.66, 127.92, 128.29, 129.26, 129.65,
130.46, 148.05, 164.65,168.51; HR-MS (ESI+): m/z calcd for C23H24N2O6
[M+Na]+: 447.1532; found: 447.1543.