Synthesis of new lavendamycin analogues

Article abstract of DOI:10.1016/j.tet.2007.12.016

Friedl?nder reaction between methyl acetoacetate and 2,4-diaminobenzaldehyde provided quinoline 11. Subsequent tosylation, reduction, silylation, and then oxidation led to aldehyde 15. The latter was subjected to a Pictet-Spengler reaction with tryptophan

Full text of DOI:10.1016/j.tet.2007.12.016

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2241e2250
www.elsevier.com/locate/tet
Synthesis of new lavendamycin analogues
*
Arnaud Nourry, Stephanie Legoupy , Franc¸ois Huet
*
´
Laboratoire de Synthe`se Organique, UCO2M, UMR CNRS 6011, Faculte´ des Sciences et Techniques, Universite´ du Maine,
Avenue Olivier Messiaen, F-72085 Le Mans cedex 9, France
Received 12 October 2007; received in revised form 5 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
Friedlander reaction between methyl acetoacetate and 2,4-diaminobenzaldehyde provided quinoline 11. Subsequent tosylation, reduction,
¨
silylation, and then oxidation led to aldehyde 15. The latter was subjected to a PicteteSpengler reaction with tryptophan methyl ester that
yielded product 16, and then desilylation gave the lavendamycin analogue 17. This compound was oxidized by DesseMartin periodinane,
and the cyclized derivative 18 was obtained via a hemiaminal intermediate. The same sequence from 2,4-diamino-5-methoxybenzaldehyde
or from (2,4-diaminophenyl)propan-3-one led to compounds 30 and 31, or 40 and 41, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Lavendamycin; PicteteSpengler reaction; Cyclization; Topoisomerase
1. Introduction
conformationally restricted derivatives such as 3 and 4. As
numerous known inhibitors of topoisomerases I such as campto-
thecin itself 26 and analogues, and others,3,7 have a rigid struc-
ture, this cyclization might induce an increased activity. After
numerous difficulties we found a suitable way. Compound 5
was obtained via a PicteteSpengler reaction. Its oxidation
with DesseMartin periodinane (DMP) led to a hemiaminal in-
termediate and then to compound 4. The latter was reduced to
another cyclized product 3. The objective was thus achieved
but we encountered another difficulty. Compounds 3, 4, and 5
have a very low solubility. This made difficult, and probably
poorly significant, the biological evaluation. However, it
appeared that one of the cyclized products, 3, had a stronger
activity than compound 5.
Lavendamycin 1 (Scheme 1) a natural product from Strep-
tomyces lavendulae,1 showed cytotoxic properties2 and a sig-
nificant activity against topoisomerases I.3 These interesting
results gave rise to much work in this area. Several syntheses
of this compound and of ester derivatives were carried out.4
Various analogues were also synthesized.5 Structureeactivity
relationships have been discussed.
A limitation to the possibility of exploiting the biological
interest of lavendamycin is its toxicity that may be partly due
to the presence of the quinone moiety of cycle A. We showed,
several years ago,5h that compounds I with a modified cycle
A, without the methyl group on cycle C and with various substit-
uents R1eR7, maintained a part of the biological properties of
the parent molecule. In a more recent work,5o we obtained a sim-
plified analogue 5, substituted with a hydroxymethyl group on
cycle B. Our objective was to test the possibility of using this
substituent to carry out an intramolecular cyclization to obtain
Our hypothesis was then partly validated but it was indis-
pensable to check it with related compounds. We then planned
to use the same strategy to prepare substituted derivatives.
These substituents might increase the solubility and also the
biological activity.
Afterward we envisioned to synthesize compounds II, III, and
IV bearing one or several substituents, which are present in re-
lated compounds with interesting biological activities (Fig. 1).
As an amino group is present on cycle A of lavendamycin, and
alsoofstreptonigrin 8, aninhibitor oftopoisomerase II,8 wechose
* Corresponding authors. Tel.: þ33 2 43 83 33 38; fax: þ33 2 43 83 39 02.
E-mail addresses: slegoupy@univ-lemans.fr (S. Legoupy), fhuet@
univ-lemans.fr (F. Huet).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.016

2242
A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
R1
O
A
R2
R3
N
CO2R
B
N
N
N
C
CO2H
Me
H2N
R4
I, R = Me or H
R7
O
HN
HN
D
E
1
R5
R6
O
N
O
O
N
N
N
N
N
O
O
N
H
N
Et
3
4
2
OH
CO2Me
CO2Me
OH
N
CO2Me
NH2
OP
+
CO2Me
N
+
4
N
CHO
HN
N
H
5
6, P = protecting group
7
Scheme 1.
to prepare compounds with such a group, either free or protected,
at the same position. We also planned to prepare compounds with
another substituent, and especially a methoxy group, ortho to the
latter, as in streptonigrin. Another possibility was to add an ethyl
group on cycle B as in irinotecan (camptoÔ) 9, an inhibitor of
topoisomerase I especially used in treatment of colon cancer.9
used a similar way to the one used for preparation of com-
pound 4.5o Several attempts of Friedlander reaction between
¨
diaminoaldehyde 10 and methyl acetoacetate were carried
out with and without protection of one of both amino groups,
with various ratios of the reagents and different reaction times.
Using of an excess of methyl acetoacetate (3.1 equiv) and of
a long reaction time (5 days) led to a satisfying yield and to
a lowering of the amount of byproduct resulting from a revers-
ible attack of the 4-amino group of diaminoaldehyde 10 to
methyl acetoacetate. Subsequent tosylation provided quinoline
12 (Scheme 2). After several attempts to reduce compound 12,
and related products with various protecting groups or with
a free amino group, the best result was obtained using com-
pound 12 itself, and with diisobutylaluminium hydride as the
reducing agent. Silylation and then oxidation with selenium
dioxide provided compound 15. A PicteteSpengler reaction
with tryptophan methyl ester followed by desilylation yielded
one of the target molecules 17. The latter was subjected to
oxidation with DesseMartin periodinane (DMP) in N-methyl-
pyrrolidone (NMP). As in the case of synthesis of compound
4,5o oxidation of the CH2OH group into CHO, cyclization
into a hemiaminal and then oxidation of the latter into the de-
sired molecule 18 occurred in one pot. Attempt of detosylation
only led to an insoluble product. Therefore we decided to sub-
mit the protected products to the biological tests (see below).
As the previous way was successful, we envisioned to use
the same reaction sequence for obtaining compounds 30 and
31 (Scheme 3). Dinitration of 3-methoxybenzaldehyde10 pro-
vided a mixture of the three expected products (20e22). Sep-
aration of a 20þ21 mixture and then reduction11 yielded the
starting diaminoaldehyde 23, which was used to prepare these
both desired products 30 and 31.
2. Results and discussion
To attain one of our objectives, preparation of compounds
II and III with only a free or protected amino group, we
O
MeO
N
Et
N
CO2H
Me
H2N
N
N
O
O
O
N
H2N
HO
O
N
8
O
O
9
Et
MeO
R3
OH
OMe
R2
OH
N
R3
N
O
N
R2
CO2Me
N
R12N
N
R12N
HN
II
III
CO2Me
R3
O
N
R2
R1 = H or protecting group
R2 = H or OMe or other substituent
R3 = H or Et
R12N
N
H
N
IV
CO2Me
We then tested several possibilities to prepare the starting di-
amino compound 33 for the synthesis of analogue 40 and then of
Figure 1.

A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
c (13, 91%),
2243
a (11, 76%),
d (14, 96%),
CO2Me
OTBDPS
CHO
CHO
NH2
b (82%)
e (96%)
p-Ts2N
N
12
Me
p-Ts2N
N
N
H2N
10
15
O
OTBDPS
CO2Me
g (17, 84%),
h (34%)
N
p-Ts2N
N
f
p-Ts2N
N
46%
16
HN
N
18
CO2Me
Scheme 2. (a) MeeCOeCH2eCO2Me, MeOH, piperidine; (b) NaH, THF, p-Ts2O; (c) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (d) t-BuPh2SiCl, DMF, imidazole; (e) SeO2,
dioxane; (f) tryptophan methyl ester, p-xylene; (g) n-Bu4NF, THF; (h) DMP, NMP, pyridine.
the cyclized derivative 41 (Scheme 4). Two attempts involving
reaction of ethylmagnesium bromide with 2,5-dinitrobenzalde-
hyde or FriedeleCrafts reaction with N-(3-acetylaminophenyl)-
acetamide gave bad results. Fortunately Sugasawa reaction12
from diaminobenzene yielded the desired product in moderate
yield but in one step. The subsequent reactions gave the ex-
pected compounds 40 and then 41.
led to the conformationally restricted derivatives, more inter-
esting on the biological point of view.
4. Experimental
4.1. General
Biological tests in cell culture with 60 different tumor cells
were carried out by the National Cancer Institute for compounds
18, 30, 31, 40, and 41. The cyclized products 31 and 41 were
more active than the parent compounds 30 and 40. Therefore,
these results confirm the interest of preparing such cyclized de-
rivatives. The better GI50 were in the range of 10ꢀ6 M and most
of the LC50 were higher than 10ꢀ4 M.
NMR spectra were recorded on a Bruker Avance 400 spec-
trometer. All melting points are uncorrected. Elemental analyses
were performed by the service of microanalyses, CNRS, ICSN,
Gif sur Yvette. High resolution mass spectra were recorded on
Varian Matt 311 (CRMPO, Rennes), or on Waters-Micromass
GCT Premier spectrometers. Infrared spectra were measured
with a Nicolet AVATAR 370 DTGS spectrometer.
4.2. 7-Amino-2-methylquinoline-3-carboxylic acid methyl
ester 11
3. Conclusion
These results show that the synthetic way including a Fried-
landler reaction and a PicteteSpengler reaction as the two key
steps is efficient to prepare several lavendamycin analogues.
The subsequent cyclizations via hemiaminal intermediates
Methyl acetoacetate (4.64 g, 39.99 mmol) and then piperi-
dine (0.7 mL, 7.08 mmol) were added to a stirred solution of
2,4-diaminobenzaldehyde (1.755 g, 12.9 mmol) in anhydrous
methanol (60 mL). Heating at reflux for 120 h, cooling,
¨
NO2
NO2
MeO
CHO
MeO
O2N
CHO
NO2
MeO
CHO
NO2
MeO
O2N
CHO
a
19
20
22
21
20/21/22 = 27:3:70
Separation provides 20 + 21 83:17 (22 and 5%, respectively, from 19) and 22 (47% from 19)
c (24, quant.),
d (25, 86%)
MeO
OTBDPS
CHO
MeO
H2N
CHO
NH2
b
20 + 21
e (26, 83%)
f (27, 89%)
g (96%)
83:17
p-Ts2N
N
23
28
51% (with respect to
the amount of 20)
O
N
MeO
OTBDPS
CO2Me
MeO
p-Ts2N
i (30, 75%),
j (45%)
N
N
p-Ts2N
N
h
N
53%
29
HN
31
CO2Me
Scheme 3. (a) HNO3, H2SO4; (b) Fe, HCl, EtOH; (c) MeeCOeCH2eCO2Me, MeOH, piperidine; (d) NaH, THF, Ts2O; (e) DIBAL-H, CH2Cl2, ꢀ78 ꢁC;
(f) t-BuPh2SiCl, DMF, imidazole; (g) SeO2, dioxane; (h) tryptophan methyl ester, p-xylene; (i) n-Bu4NF, THF; (j) DMP, NMP, pyridine.

2244
A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
Et
N
O
b (34, 90%),
OTBDPS
CHO
a
c (35, 92%)
Et
47%
NH2
d (36, 89%)
e (37, 86%)
f (quant.)
H2N
p-Ts2N
H2N
Et
NH2
32
38
33
Et
O
OTBDPS
CO2Me
h (40, 71%),
i (17%)
N
N
p-Ts2N
N
g
p-Ts2N
N
34%
39
HN
N
41
CO2Me
Scheme 4. (a) EtCN, BCl3, AlCl3, C2H4Cl2; (b) MeeCOeCH2eCO2Me, MeOH, H2SO4; (c) NaH, THF, Ts2O; (d) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (e) t-BuPh2SiCl,
DMF, imidazole; (f) SeO2, dioxane; (g) tryptophan methyl ester, p-xylene; (h) n-Bu4NF, THF; (i) DMP, NMP, pyridine.
evaporation, and then column chromatography on silica gel
(cyclohexane/EtOAc 2:1) provided compound 11 (2.124 g,
76%) as a yellow solid. Rf¼0.22 (cyclohexane/EtOAc 1:3).
Mp 151.5e153.0 ꢁC. 1H NMR (400 MHz, CDCl3) d 8.58 (1H,
s), 7.62 (1H, d, J¼8.7 Hz), 7.10 (1H, d, J¼2.1 Hz), 6.93 (1H,
dd, J¼2.1, 8.7 Hz), 4.31 (2H, br s, NH2), 3.93 (3H, s), 2.93
(3H, s). 13C NMR (100 MHz, CDCl3) d 167.1, 159.3, 150.7,
150.0, 139.8, 130.0, 119.5, 119.4, 118.3, 108.0, 52.0, 25.8. IR
(ATR) (cmꢀ1): 3397, 3166, 1701, 1593, 1499, 1438, 1389,
1273, 1212, 1182, 1070. Anal. Calcd for C12H12N2O2: C,
66.65; H, 5.59; N, 12.96. Found: C, 66.39; H, 5.64; N, 12.94.
CH2Cl2 (66 mL). After 2.5 h of stirring at the same temperature,
methanol (30 mL) was added dropwise and the mixture was
allowed to warm up to room temperature. Addition of a 30%
solution of potassium and sodium tartrate (60 mL), stirring for
30 min, decantation, extraction of the aqueous phase with
CH2Cl2 (3ꢂ80 mL), washing of the combined organic phases
with a saturated solution of NaHCO3 (40 mL), and then with
brine (40 mL), drying (MgSO4), evaporation, and then column
chromatography on silica gel (CH2Cl2/MeOH 1:0/99:1) pro-
vided compound 13 (3.621, 91%) as a white solid. Rf¼0.41
1
(CH2Cl2/MeOH 9:1). Mp 207e208 ꢁC. H NMR (400 MHz,
DMSO-d6) d 8.29 (1H, s), 8.00 (1H, d, J¼8.7 Hz), 7.73 (4H,
d, J¼8.3 Hz), 7.51e7.49 (5H, m), 7.10 (1H, dd, J¼2.1,
8.7 Hz), 5.54 (1H, t, J¼5.3 Hz, OH), 4.71 (2H, d, J¼5.3 Hz),
2.60 (3H, s), 2.46 (6H, s). 13C NMR (100 MHz, DMSO-d6)
d 158.7, 145.5, 136.3 (2C), 135.6, 133.3, 131.7, 130.7, 130.0
(4C), 128.7, 128.0 (4C), 127.8, 127.4, 60.1, 22.1, 21.1 (2C).
IR (ATR) (cmꢀ1): 3153, 1597, 1496, 1370, 1344, 1167, 1086,
928, 811, 670, 658, 546. HRMS calcd for C18H17N2O3S
(MꢀTs)þ: 341.0960, found: 341.0930.
4.3. 7-Di-p-tosylamino-2-methylquinoline-3-carboxylic acid
methyl ester 12
Sodium hydride (1.96 g of a 60% suspension in oil,
48.85 mmol) was added under nitrogen and with stirring to
a cooled solution (0 ꢁC) of compound 11 (2.113 g, 9.77 mmol)
in anhydrous THF (95 mL). After 10 min, p-toluenesulfonic an-
hydride (15.9 g, 48.85 mmol) was added and then the reaction
mixture was stirred at room temperature for 2 days. Methanol
(30 mL) was added dropwise and the reaction mixture was evap-
orated. Addition of CH2Cl2 (20 mL) to the residue, washing of
the resulting solution with water (5 mL), drying (MgSO4), evap-
oration, and then column chromatography on silica gel (cyclo-
hexane/EtOAc 3:1/0:1) provided compound 12 (4.193, 82%)
as a white solid. Rf¼0.44 (cyclohexane/EtOAc 1:1). Mp
4.5. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-2-
methylquinoline 14
Imidazole (1.22 g, 18 mmol) and tert-butyldiphenylsilyl
chloride (2.8 mL, 10.8 mmol) were added to a solution of com-
pound 13 (3.574 g, 7.20 mmol) in anhydrous DMF (35 mL). The
reaction mixture was stirred for 15 h and then a saturated solu-
tion of NaHCO3 (30 mL) was added. Extraction with CH2Cl2
(3ꢂ10 mL), washingof the combined organicphases with brine,
drying (MgSO4), and then column chromatography on silica
gel (cyclohexane/EtOAc 9:1) provided compound 14 (5.097 g,
96%) as a white solid. Rf¼0.37 (cyclohexane/EtOAc 2:1). Mp
1
197.3e198.4 ꢁC. H NMR (400 MHz, CDCl3) d 8.74 (1H, s),
7.83e7.81 (6H, m), 7.34 (4H, d, J¼8.4 Hz), 7.19 (1H, dd,
J¼2.1, 8.6 Hz), 3.99 (3H, s), 2.98 (3H, s), 2.47 (6H, s). 13C
NMR (100 MHz, CDCl3) d 166.5, 159.5, 148.3, 145.2, 139.4,
137.0, 136.4, 132.0, 129.7 (4C), 129.3, 129.1, 128.6 (4C),
126.2, 124.8, 52.5, 25.6, 21.7 (2C). IR (ATR) (cmꢀ1): 1730,
1593, 1370, 1283, 1185, 1160, 1066, 929, 809, 666. HRMS
calcd for C19H17N2O4S (MꢀTs)þ: 369.0909, found: 369.0877.
1
169.5e170.8 ꢁC. H NMR (400 MHz, CDCl3) d 8.20 (1H, s),
7.84 (4H, d, J¼8.3 Hz), 7.80 (1H, s), 7.75 (1H, d, J¼8.6 Hz),
7.72e7.70 (4H, m), 7.47e7.38 (6H, m), 7.33 (4H, d,
J¼8.3 Hz), 7.13 (1H, d, J¼8.6 Hz), 4.87 (2H, s), 2.56 (3H, s),
2.47 (6H, s), 1.14 (9H, s). 13C NMR (100 MHz, CDCl3)
d 158.0, 146.5, 145.0, 136.6, 135.4 (4C), 134.5, 134.3, 132.9,
132.5, 131.8, 130.0, 129.6 (4C), 128.6 (4C), 128.5, 128.3,
127.9 (4C), 127.7, 63.1, 26.8 (3C), 22.5, 21.7 (2C), 19.3. IR
(ATR) (cmꢀ1): 2930, 2856, 1596, 1492, 1378, 1359, 1169,
4.4. 7-Di-p-tosylamino-3-hydroxymethyl-2-
methylquinoline 13
DIBAL-H (28.0 mL of a 1 M solution in toluene, 28.0 mmol)
was added under nitrogen and with stirring to a cooled solution
(ꢀ78 ꢁC) of compound 12 (4.193 g, 7.99 mmol) in anhydrous

A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
2245
1111, 1046, 934, 809, 703, 660, 544. Anal. Calcd for
C41H42N2O5S2Si: C, 67.00; H, 5.76; N, 3.81. Found: C, 66.89;
H, 5.68; N, 3.64.
with stirring to a solution of compound 16 (300 mg,
0.317 mmol) in anhydrous THF (2.5 mL). After 1 day of stir-
ring at room temperature and then evaporation, a mixture of
petroleum ether/EtOAc 1:4 (7 mL) was added. Stirring and
heating of the mixture, filtration with heating, and recupera-
tion of the solid provided compound 17 (188 mg, 84%) as
4.6. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-
quinoline-2-carbaldehyde 15
1
a pale yellow solid. Mp 231e232 ꢁC. H NMR (400 MHz,
Freshly sublimed SeO2 (966 mg, 8.71 mmol) was added
under nitrogen and with stirring to a solution of compound
14 (4.919 g, 6.70 mmol) in anhydrous dioxane (63 mL). The
reaction mixture was refluxed for 2.5 h. Cooling, filtration,
evaporation of the filtrate, and then column chromatography
on silica gel (cyclohexane/EtOAc 5:1) provided compound
15 (4.842 g, 96%) as a pale yellow solid. Rf¼0.33 (cyclohex-
ane/EtOAc 4:1). Mp 92.1e94.7 ꢁC. 1H NMR (400 MHz,
CDCl3) d 10.17 (1H, s), 8.80 (1H, s), 8.00 (1H, s), 7.92 (1H,
d, J¼8.7 Hz), 7.85 (4H, d, J¼8.7 Hz), 7.71e7.70 (4H, m),
7.46e7.31 (11H, m), 5.38 (2H, s), 2.49 (6H, s), 1.19 (9H, s).
13C NMR (100 MHz, CDCl3) d 195.0, 149.7, 146.2, 145.3,
136.7, 136.4, 135.5, 135.4 (4C), 133.9, 133.3, 133.0, 131.9,
129.9 (2C), 129.8 (4C), 128.6 (5C), 127.9 (4C), 62.3, 27.0
(3C), 21.8 (2C), 19.5. IR (ATR) (cmꢀ1): 2929, 2856, 1710,
1596, 1427, 1379, 1168, 1112, 1084, 930, 812, 660, 545.
Anal. Calcd for C41H40N2O6S2Si: C, 65.75; H, 5.38; N,
3.74. Found: C, 65.51; H, 5.18; N, 3.50.
CDCl3) d 11.37 (1H, br s, NH), 8.93 (1H, s), 8.34 (1H, s),
8.25 (1H, d, J¼8.0 Hz), 8.04 (1H, d, J¼2.0 Hz), 7.89 (4H, d,
J¼8.3 Hz), 7.85 (1H, d, J¼8.6 Hz), 7.75e7.68 (2H, m),
7.45e7.42 (1H, m), 7.38 (4H, d, J¼8.0 Hz), 7.23 (1H, dd,
J¼2.0, 8.6 Hz), 6.83 (1H, t, J¼8.1 Hz, OH), 4.98 (2H, d,
J¼8.1 Hz), 4.08 (3H, s), 2.48 (6H, s). 13C NMR (100 MHz,
CDCl3) d 165.9, 157.8, 145.9, 145.4, 140.8, 139.4, 138.2,
137.0, 136.4, 136.1, 135.7, 135.6, 132.0, 131.1, 130.0, 129.7
(4C), 129.4, 128.7 (4C), 128.5, 128.1, 121.9, 121.5, 121.3,
118.2, 112.5, 64.5, 52.7, 21.8 (2C). IR (ATR) (cmꢀ1): 3338,
1719, 1492, 1431, 1374, 1358, 1253, 1234, 1169, 1027, 927,
659, 545. HRMS calcd for C37H30N4O7NaS2 (MþNa)þ:
729.1454, found: 729.1453.
4.9. 13-Di-p-tosylamino-9-oxo-9H-indolo[3,2,1-ij]quino-
[3,2,c]-1,5-naphthyiridine-2-carboxylic acid methyl ester 18
Anhydrous pyridine (215 mL, 2.55 mmol) and DMP
(163 mg, 0.383 mmol) were added under nitrogen and with stir-
ring to a solution of compound 17 (180 mg, 0.255 mmol) in
anhydrous NMP (1.75 mL). After 2 days of stirring at room
temperature, CH2Cl2 (15 mL) was added and the suspension
was successively washed with a 1:1 mixture of a 5% solution
of Na2S2O3 and of a saturated solution of NaHCO3 (8 mL),
a saturated solution of NaHCO3 (5 mL), 1 M HCl (5 mL),
and then brine (5 mL). This suspension was evaporated without
drying and then column chromatography on silica gel (CH2Cl2/
EtOAc 99:1/9:1) provided compound 18 (61 mg, 34%) as
a pale yellow solid. Rf¼0.59 (CH2Cl2/EtOAc 9:1). Mp
286e287 ꢁC. 1H NMR (400 MHz, CDCl3) d 9.56 (1H, s),
9.03 (1H, s), 8.85 (1H, d, J¼8.3 Hz), 8.44 (1H, s), 8.28 (1H,
d, J¼7.6 Hz), 8.12 (1H, d, J¼8.7 Hz), 7.89e7.84 (5H, m),
7.68e7.65 (1H, m), 7.40e7.38 (5H, m), 4.17 (3H, s), 2.51
(6H, s). 13C NMR (100 MHz, C2D2Cl4, 340 K) d 165.9,
158.7, 150.2, 149.6, 145.6, 144.9, 140.0, 139.3, 138.7, 136.6,
135.7, 134.7, 133.7, 132.1, 131.6, 131.3, 129.9, 128.6, 127.7,
126.3, 124.7, 124.6, 122.8, 118.7, 117.6, 53.1, 21.7 (2C). IR
(ATR) (cmꢀ1): 2921, 1713, 1693, 1594, 1488, 1433, 1356,
1278, 1233, 1165, 940, 809, 739. HRMS calcd for C37H26N4O7-
NaS2 (MþNa)þ: 725.1141, found: 725.1156.
4.7. 1-[(7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxy-
methyl)-quinolin-2-yl]-9H-b-carboline-3-carboxylic acid
methyl ester 16
Compound 15 (1.000 g, 1.34 mmol) was added under nitro-
gen and with stirring to a solution of tryptophan methyl ester
(439 mg, 2.01 mmol) in anhydrous p-xylene (22 mL). The
reaction mixture was refluxed for 17 h. Cooling, evaporation,
and then column chromatography on silica gel (cyclohexane/
EtOAc 6:1) provided compound 16 (577 mg, 46%) as a white
solid. Rf¼0.70 (cyclohexane/EtOAc 1:1). Mp 225e226 ꢁC. 1H
NMR (400 MHz, CDCl3) d 11.41 (1H, br s, NH), 9.07 (1H, s),
8.88 (1H, s), 8.22 (1H, d, J¼7.9 Hz), 8.04 (1H, s), 7.96 (1H, d,
J¼8.6 Hz), 7.92 (4H, d, J¼8.4 Hz), 7.79e7.77 (4H, m), 7.72
(1H, d, J¼8.2 Hz), 7.68e7.66 (1H, m), 7.42e7.34 (11H, m),
7.26e7.23 (1H, m), 5.95 (2H, s), 3.53 (3H, s), 2.49 (6H, s),
1.21 (9H, s). 13C NMR (100 MHz, CDCl3) d 166.8, 155.3,
145.3, 145.2, 140.5, 138.6, 138.0, 136.9, 136.5, 136.0, 135.4
(4C), 135.0, 134.4, 133.6, 131.8, 130.6, 129.7 (5C), 129.5,
129.0, 128.9, 128.8 (4C), 128.2, 127.8 (4C), 121.8, 121.7,
121.0, 118.0, 112.3, 64.6, 52.0, 27.0 (3C), 21.8 (2C), 19.5.
IR (ATR) (cmꢀ1): 3371, 2949, 2856, 1712, 1593, 1491,
1429, 1385, 1169, 1107, 1061, 923, 702, 656, 545. Anal. Calcd
for C54H50N4O8S2Si: C, 67.35; H, 5.12; N, 5.93. Found: C,
67.18; H, 5.01; N, 5.76.
4.10. 5-Methoxy-2,4-dinitrobenzaldehyde 20, 3-methoxy-2,4-
dinitrobenzaldehyde 21, and 3-methoxy-2,6-dinitro-
benzaldehyde 22
4.8. 1-[(7-Di-p-tosylamino-3-hydroxymethyl)-quinolin-2-yl]-
9H-b-carboline-3-carboxylic acid methyl ester 17
3-Methoxybenzaldehyde (500 mg, 3.67 mmol) was added
dropwise at ꢀ10 ꢁC to a stirred solution of a mixture of fum-
ing nitric acid (0.8 mL) and of concentrated H2SO4 (0.8 mL).
The stirring was then kept for 1 h at the same temperature and
then for 1 h at room temperature. The reaction mixture was
Glacial acetic acid (120 mL) and TBAF (0.95 mL of a 1 M
solution in THF, 0.951 mmol) were added under nitrogen and

2246
A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
poured into ice (3 g). The precipitate was filtered and rinsed
with a small amount of cooled water. Recuperation of the solid,
139.9, 120.9, 119.7, 105.9, 105.3, 56.4, 52.5, 24.7. IR (ATR)
(cmꢀ1): 2593, 2374, 1690, 1618, 1591, 1498, 1436, 1229,
1176, 1033, 1004. Anal. Calcd for C13H14N2O3$0.1H2O: C,
62.94; H, 5.77; N, 11.29. Found: C, 62.76; H, 5.78; N, 11.21.
1
evaporation, and then H NMR analysis showed the presence
of compounds 20, 21, and 22 in the 27:3:70 ratios, respec-
tively. Column chromatography on silica gel (cyclohexane/
EtOAc 4:1) provided compound 22 (394 mg, 47%) and
a non-separable mixture of compounds 20 and 21 (224 mg)
in an 83:17 ratio, respectively. Data for 20: yellow solid.
4.13. 7-Di-p-tosylamino-6-methoxy-2-methylquinoline
3-carboxylic acid methyl ester 25
1
Rf¼0.51 (cyclohexane/EtOAc 1:1). Mp 121.5e124.0 ꢁC. H
Reaction of compound 24 (221 mg, 0.897 mmol) with the
same experimental conditions as that for the preparation of
compound 12, but with cyclohexane/EtOAc 4:1 as the eluent
for the column chromatography provided compound 25
(429 mg, 86%) as a white solid. Rf¼0.66 (cyclohexane/EtOAc
NMR (400 MHz, CDCl3) d 10.55 (1H, s), 8.70 (1H, s), 7.56
(1H, s), 4.15 (3H, s). 13C NMR (100 MHz, CDCl3) d 186.7,
156.6, 140.7, 140.3, 136.1, 123.2, 114.0, 57.9. IR (ATR)
(cmꢀ1): 3113, 3067, 1698, 1589, 1518, 1489, 1384, 1333,
1281, 1251, 1159, 1046, 922, 872, 736. Anal. Calcd for
C8H6N2O6: C, 42.49; H, 2.67; N, 12.39. Found: C, 42.47; H,
2.72; N, 12.40. Data for 21: yellow solid. Rf¼0.51 (cyclohex-
1
1:3). Mp 207e208 ꢁC. H NMR (400 MHz, CDCl3) d 8.62
(1H, s), 7.89 (1H, s), 7.84 (4H, d, J¼8.3 Hz), 7.32 (4H, d,
J¼8.3 Hz), 7.05 (1H, s), 3.98 (3H, s), 3.53 (3H, s), 2.94
(3H, s), 2.48 (6H, s). 13C NMR (100 MHz, CDCl3) d 166.7,
156.8, 155.2, 144.9, 143.8, 138.2, 137.0, 133.6, 129.3 (5C),
128.8 (4C), 127.8, 124.9, 106.5, 55.5, 52.5, 25.3, 21.7 (2C).
IR (ATR) (cmꢀ1): 2923, 2852, 1724, 1597, 1488, 1372,
1165, 1084, 928, 812, 667. Anal. Calcd for C27H26N2O7S2:
C, 58.47; H, 4.72; N, 5.05. Found: C, 58.36; H, 4.86; N, 4.92.
1
ane/EtOAc 1:1). H NMR (400 MHz, CDCl3) d 9.98 (1H, s),
8.13 (1H, d, J¼8.5 Hz), 7.84 (1H, d, J¼8.5 Hz), 4.07 (3H,
s). 13C NMR (100 MHz, CDCl3) d 184.8, 146.5, 130.5,
127.3, 125.4, 65.3. Data for 22: yellow solid. Rf¼0.24 (cyclo-
hexane/EtOAc 1:1). 1H NMR (400 MHz, CDCl3) d 10.34
(1H, s), 8.40 (1H, d, J¼9.3 Hz), 7.31 (1H, d, J¼9.3 Hz),
4.08 (3H, s). 13C NMR (100 MHz, CDCl3) d 184.8, 155.9,
139.5 (2C), 129.7, 128.5, 114.7, 57.7.
4.14. 7-Di-p-tosylamino-3-hydroxymethyl-6-methoxy-2-
methylquinoline 26
4.11. 2,4-Diamino-5-methoxybenzaldehyde 23
Reaction of compound 25 (2.723 g, 4.91 mmol) with the
same experimental conditions as that for the preparation of
compound 13 provided compound 25 (2.142 g, 83%) as a white
solid. Rf¼0.34 (CH2Cl2/MeOH 9:1). Mp 228e229 ꢁC. 1H
NMR (400 MHz, DMSO-d6) d 8.16 (1H, s), 7.70 (4H, d,
J¼8.3 Hz), 7.56 (1H, s), 7.47 (4H, d, J¼8.3 Hz), 7.41 (1H,
s), 5.49 (1H, t, J¼5.2 Hz, OH), 4.68 (2H, d, J¼5.2 Hz), 3.47
(3H, s), 2.55 (3H, s), 2.45 (6H, s). 13C NMR (100 MHz,
DMSO-d6) d 155.7, 154.0, 145.1, 140.6, 136.3, 136.0, 132.2,
130.7, 129.5 (4C), 129.0, 128.2 (4C), 125.1, 106.7, 60.2,
55.4, 21.8, 21.1 (2C). IR (ATR) (cmꢀ1): 1597, 1493, 1373,
1348, 1166, 943, 670, 548. HRMS calcd for C19H19N2O4S
(MꢀTs)þ: 371.1066, found: 371.1083.
Iron powder (19.5 g, 348 mmol), water (32 mL), and 10 M
HCl (0.75 mL, 7.5 mmol) were added to a solution of a mixture
of compounds 20 and 21 (83:17, 3.673 g of 20, 16.2 mmol) in
EtOH (127 mL). The reaction mixture was mechanically
stirred at 95 ꢁC for 1.5 h. Cooling, filtration, washing of the
solid with EtOH (25 mL), evaporation, and then column chro-
matography on silica gel (cyclohexane/EtOAc/Et3N 40:55:5)
provided compound 23 (1.14 g, 51%) as an orange solid.
1
Rf¼0.33 (cyclohexane/EtOAc 1:3). Mp 174.9e176.0 ꢁC. H
NMR (400 MHz, acetone-d6) d 9.49 (1H, s), 6.83 (1H, s),
6.51 (2H, br s, NH2); 6.01 (1H, s), 5.32 (2H, br s, NH2),
3.78 (3H, s). 13C NMR (100 MHz, acetone-d6) d 191.0,
150.6, 147.9, 140.7, 116.5, 111.2, 99.5, 57.2. IR (ATR)
(cmꢀ1): 3453, 3330, 2837, 2760, 2522, 2493, 1601, 1583,
1515, 1410, 1314, 1157, 1022, 854, 743. Anal. Calcd for
C8H10N2O2$0.15H2O: C, 56.90; H, 6.15; N, 16.59. Found:
C, 56.91; H, 6.08; N, 16.34.
4.15. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-
6-methoxy-2-methylquinoline 27
Reaction of compound 26 (2.142 g, 4.07 mmol) with the
same experimental conditions as that for the preparation of
compound 14 provided compound 27 (2.768 g, 89%) as a white
solid. Rf¼0.43 (cyclohexane/EtOAc 2:1). Mp 191.7e192.5 ꢁC.
1H NMR (400 MHz, CDCl3) d 8.11 (1H, s), 7.89 (1H, s), 7.87
(4H, d, J¼8.2 Hz), 7.73e7.71 (4H, m), 7.49e7.39 (6H, m),
7.32 (4H, d, J¼8.2 Hz), 7.01 (1H, s), 4.86 (2H, s), 3.55 (3H,
s), 2.52 (3H, s), 2.47 (6H, s), 1.15 (9H, s). 13C NMR
(100 MHz, CDCl3) d 155.2, 154.8, 144.6, 141.7, 137.2,
135.4 (4C), 134.5, 133.4, 132.9, 131.3, 130.0 (2C), 129.2
(4C), 128.9 (4C), 127.9 (4C), 126.6, 106.1, 63.2, 55.4, 26.8
(3C), 22.2, 21.7 (2C), 19.4. IR (ATR) (cmꢀ1): 2929, 2856,
1596, 1490, 1375, 1354, 1166, 930, 702, 547. Anal. Calcd
4.12. 7-Amino-6-methoxy-2-methylquinoline 3-carboxylic
acid methyl ester 24
Reaction of compound 23 (1.14 g, 6.86 mmol) with the
same experimental conditions as that for the preparation of
compound 11, but with cyclohexane/EtOAc 1:1/1:3 as the
eluent for the column chromatography provided compound
24 (1.691 g, quant.) as a white solid. Rf¼0.26 (cyclohexane/
1
EtOAc 1:3). Mp 216e217 ꢁC. H NMR (400 MHz, CDCl3)
d 8.53 (1H, s), 7.12 (1H, s), 6.97 (1H, s), 4.51 (2H, br s,
NH2), 3.98 (3H, s), 3.93 (3H, s), 2.91 (3H, s). 13C NMR
(100 MHz, CD3OD) d 168.6, 157.3, 150.1, 147.9, 146.6,

A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
2247
for C42H44N2O6S2Si: C, 65.94; H, 5.80; N, 3.66. Found: C,
65.86; H, 5.60; N, 3.42.
137.1 (4C), 136.7, 136.1, 134.0, 131.1, 130.0, 129.4, 129.3,
129.1 (4C), 128.1, 121.9, 121.7, 121.4, 117.9, 112.6, 106.2,
64.5, 55.6, 52.6, 21.6 (2C). IR (ATR) (cmꢀ1): 3371, 1718,
1491, 1377, 1250, 1170, 1012, 926, 868, 660. Anal. Calcd for
C38H32N4O8S2$0.25H2O: C, 61.57; H, 4.42; N, 7.56. Found:
C, 61.33; H, 4.47; N, 7.53.
4.16. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-
6-methoxyquinoline-2-carbaldehyde 28
Reaction of compound 27 (163 mg, 0.213 mmol) with the
same experimental conditions as that for the preparation of
compound 15 provided compound 28 (160 mg, 96%) as a white
solid. Rf¼0.38 (cyclohexane/EtOAc 4:1). Mp 146.1e147.7 ꢁC.
1H NMR (400 MHz, CDCl3) d 10.13 (1H, s), 8.64 (1H, s), 8.06
(1H, s), 7.87 (4H, d, J¼8.3 Hz), 7.72e7.70 (4H, m), 7.46e7.34
(10H, m), 7.10 (1H, s), 5.38 (2H, s), 3.62 (3H, s), 2.48 (6H, s),
1.19 (9H, s). 13C NMR (100 MHz, CDCl3) d 194.9, 157.5,
147.7, 145.0, 141.7, 137.1, 137.0, 135.4 (4C), 135.1, 133.1,
132.0, 129.9 (2C), 129.4 (4C), 128.9 (4C), 128.3, 127.9 (4C),
105.8, 62.4, 55.7, 27.0 (3C), 21.7 (2C), 19.5. IR (ATR)
(cmꢀ1): 2926, 2853, 1705, 1619, 1596, 1489, 1380, 1221,
1169, 1083, 928, 659, 545. HRMS calcd for C42H42N2O7SiS2
(MþNa)þ: 801.2100, found: 801.2111.
4.19. 13-Di-p-tosylamino-12-methoxy-9-oxo-9H-
indolo[3,2,1-ij]quino[3,2,c]-1,5-naphthyiridine-2-carboxylic
acid methyl ester 31
Reaction of compound 30 (180 mg, 0.244 mmol) with the
same experimental conditions as that for the preparation of
compound 18, but with CH2Cl2/EtOAc 98:2/9:1 as the elu-
ent for the column chromatography provided compound 31
(80 mg, 45%) as a pale yellow solid. Rf¼0.66 (CH2Cl2/EtOAc
1
9:1). Mp 289e290 ꢁC. H NMR (400 MHz, CDCl3) d 9.32
(1H, s), 8.96 (1H, s), 8.79 (1H, d, J¼8.2 Hz), 8.52 (1H, s),
8.22 (1H, d, J¼8.0 Hz), 7.91 (4H, d, J¼8.3 Hz), 7.80 (1H,
dd, J¼1.1, 8.4 Hz), 7.61 (1H, dd, J¼0.8, 7.8 Hz), 7.39 (4H,
d, J¼8.3 Hz), 7.26 (1H, s), 4.16 (3H, s), 3.58 (3H, s), 2.51
(6H, s). 13C NMR (100 MHz, C2D2Cl4, 340 K) d 165.8,
158.8, 156.9, 147.4, 145.9, 145.1, 144.8, 139.3, 138.0, 137.2,
136.0, 135.5, 134.2, 132.0, 131.7, 131.4, 129.7, 129.5, 128.9,
126.2, 124.8, 122.8, 118.3, 117.6, 106.9, 55.8, 53.0, 21.7
(2C). IR (ATR) (cmꢀ1): 2953, 1716, 1687, 1590, 1482, 1379,
1346, 1249, 1166, 1084, 1017, 927, 660, 547. HRMS calcd
for C38H28N4O8NaS2 (MþNa)þ: 755.1246, found: 755.1223.
4.17. 1-[(7-Di-p-tosylamino-3-tert-butyldiphenylsilan-
oxymethyl-6-methoxy)-quinolin-2-yl]-9H-b-carboline-3-
carboxylic acid methyl ester 29
Reaction of compound 28 (159 mg, 0.204 mmol) with the
same experimental conditions as that for the preparation of com-
pound 16 provided compound 29 (106 mg, 53%) as a white
solid. Rf¼0.53 (cyclohexane/EtOAc 1:1). Mp 250e251 ꢁC. 1H
NMR (400 MHz, CDCl3) d 11.42 (1H, br s, NH), 8.91 (1H, s),
8.87 (1H, s), 8.23 (1H, d, J¼7.9 Hz), 8.09 (1H, s), 7.94 (4H, d,
J¼8.3 Hz), 7.79e7.73 (5H, m), 7.68e7.65 (1H, m),
7.43e7.35 (11H, m), 7.16 (1H, s), 5.94 (2H, s), 3.64 (3H, s),
3.53 (3H, s), 2.49 (6H, s), 1.21 (9H, s). 13C NMR (100 MHz,
CDCl3) d 166.9, 155.7, 152.9, 144.9, 140.5, 140.4, 139.0,
138.1, 137.0, 136.7, 135.8, 135.4 (4C), 133.7 (2C), 132.9,
130.4, 130.0, 129.7, 129.3 (4C), 129.1 (4C), 128.9, 127.8
(4C), 127.2, 121.8, 121.7, 120.9, 117.7, 112.4, 106.3, 64.7,
55.5, 51.9, 27.1 (3C), 21.7 (2C), 19.5. IR (ATR) (cmꢀ1): 3360,
2927, 2851, 1702, 1492, 1432, 1376, 1361, 1261, 1244, 1168,
1071, 659, 549. Anal. Calcd for C54H50N4O8S2Si: C, 66.51;
H, 5.17; N, 5.75. Found: C, 66.54; H, 5.21; N, 5.40.
4.20. (2,4-Diaminophenyl)propan-3-one 3313
Propionitrile (611 mg, 11.1 mmol) was added to a solution
of 1,3-diaminobenzene (1.00 g, 9.25 mmol) in C2H4Cl2
(19 mL). The mixture was cooled to 0 ꢁC and then BCl3
(10.2 mL of a 1 M solution in hexane, 10.2 mmol) and
AlCl3 (1.36 g, 10.18 mmol) were progressively added with
stirring at this temperature. The reaction mixture was allowed
to warm up to room temperature and then it was heated at re-
flux for 3 h. Cooling, adding of 2 M HCl (30 mL), heating at
reflux for 30 min, cooling, adding of a 10% solution of
NaOH until pH>10, extraction of the aqueous phase with
CH2Cl2 (4ꢂ80 mL), washing of the combined organic phases
with brine (30 mL), drying (MgSO4), and then column chro-
matography on silica gel (cyclohexane/EtOAc 4:1/3:1) pro-
vided compound 33 (709 mg, 47%) as a white solid. Rf¼0.49
(EtOAc). 1H NMR (400 MHz, DMSO-d6) d 7.43 (1H, d,
J¼8.8 Hz) 7.07 (2H, br s, NH2), 5.84 (1H, dd, J¼2.1,
8.8 Hz), 5.76 (1H, d, J¼2.1 Hz), 5.70 (2H, br s, NH2), 2.73
(2H, q, J¼7.4 Hz), 1.03 (3H, t, J¼7.4 Hz). 13C NMR
(100 MHz, DMSO-d6) d 198.8, 153.7, 153.4, 132.9, 108.0,
103.7, 97.0, 30.7, 9.4.
4.18. 1-[(7-Di-p-tosylamino-3-hydroxymethyl-6-methoxy)-
quinolin-2-yl]-9H-b-carboline-3-carboxylic acid methyl
ester 30
Reaction of compound 29 (620 mg, 0.636 mmol) with the
same experimental conditions as that for the preparation of com-
pound 17 provided compound 30 (351 mg, 75%) as a pale pink
solid. Mp 242e243 ꢁC. 1H NMR (400 MHz, C2D2Cl4, 340 K)
d 11.29 (1H, br s, NH), 8.84 (1H, s), 8.18 (1H, d, J¼7.8 Hz),
8.14 (1H, s), 8.01 (1H, s), 7.78 (4H, d, J¼8.0 Hz), 7.66e7.57
(2H, m), 7.36e7.31 (1H, m), 7.26 (4H, d, J¼8.0 Hz), 7.02
(1H, s), 6.37 (1H, br s, OH), 4.90 (2H, s), 3.99 (3H, s), 3.50
(3H, s), 2.38 (6H, s). 13C NMR (100 MHz, C2D2Cl3, 340 K)
d 166.0, 156.3, 155.3, 145.2 (2C), 141.3, 141.0, 138.8, 137.9,
4.21. 7-Amino-4-ethyl-2-methylquinoline-3-carboxylic acid
methyl ester 34
Methyl acetoacetate (1.41 g, 12.18 mmol) and then concen-
trated sulfuric acid (0.35 mL) were added to a solution of

2248
A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
compound 33 (1.00 g, 6.09 mmol) in anhydrous MeOH
(27 mL). Heating at reflux for 16 h, cooling, evaporation, add-
ing of CH2Cl2 (15 mL), washing of the solution with a satu-
rated solution of NaHCO3 (5 mL), and then with brine (5 mL),
drying (MgSO4), and then column chromatography on silica
gel (cyclohexane/EtOAc 1:1) provided compound 34 (1.338,
90%) as a pale yellow solid. Rf¼0.20 (cyclohexane/EtOAc
1:3). Mp 170.2e171.5 ꢁC. 1H NMR (400 MHz, CD3OD)
d 7.82 (1H, d, J¼9.0 Hz), 7.05 (1H, dd, J¼2.3, 9.0 Hz), 7.02
(1H, d, J¼2.3 Hz), 3.95 (3H, s), 2.93 (2H, q, J¼7.6 Hz),
2.53 (3H, s), 1.27 (3H, t, J¼7.6 Hz). 13C NMR (100 MHz,
CD3OD) d 171.3, 155.6, 152.4, 150.7, 149.8, 126.3, 124.4,
120.0, 118.6, 107.6, 52.9, 24.2, 23.1, 15.8. IR (ATR)
(cmꢀ1): 3127, 2322, 1716, 1617, 1579, 1506, 1430, 1283,
1219, 1176, 855, 822. Anal. Calcd for C14H16N2O2: C,
68.83; H, 6.60; N, 11.47. Found: C, 68.52; H, 6.46; N, 11.46.
4.24. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-
4-ethyl-2-methylquinoline 37
Reaction of compound 36 (2.134 g, 4.07 mmol) with the
same experimental conditions as that for the preparation of
compound 14, but with cyclohexane/EtOAc 9:1 as the eluent
for the column chromatography provided compound 37
(2.656 g, 86%) as a white solid. Rf¼0.55 (cyclohexane/EtOAc
2:1). Mp 169.1e170.0 ꢁC. 1H NMR (400 MHz, CDCl3) d 7.91
(1H, d, J¼9.0 Hz), 7.84 (4H, d, J¼8.3 Hz), 7.76 (1H, d,
J¼2.2 Hz), 7.72e7.71 (4H, m), 7.49e7.39 (6H, m), 7.34
(4H, d, J¼8.3 Hz), 7.14 (1H, dd, J¼2.2, 9.0 Hz), 4.85 (2H,
s), 2.91 (2H, q, J¼7.6 Hz), 2.71 (3H, s), 2.48 (6H, s), 1.13
(3H, t, J¼7.6 Hz), 1.07 (9H, s). 13C NMR (100 MHz,
CDCl3) d 160.6, 148.3, 147.1, 145.0, 136.6, 135.7 (4C),
134.4, 133.0, 132.6, 130.3, 130.0, 129.7 (4C), 128.6 (4C),
128.1, 127.8 (4C), 126.7, 125.0, 59.8, 26.9 (3C), 23.9, 21.7
(2C), 21.2, 19.3, 15.5. IR (ATR) (cmꢀ1): 1589, 1492, 1379,
1358, 1171, 1086, 1021, 926, 812, 686, 600, 544. Anal. Calcd
for C43H46N2O5S2Si: C, 67.68; H, 6.08; N, 3.67. Found: C,
67.61; H, 6.08; N, 3.79.
4.22. 7-Di-p-tosylamino-4-ethyl-2-methylquinoline-3-
carboxylic acid methyl ester 35
Reaction of compound 34 (1.283 g, 5.25 mmol) with the
same experimental conditions as that for the preparation of
compound 12, but with cyclohexane/EtOAc 5:1 as the eluent
for the column chromatography provided compound 27
(2.656 g, 92%) as a white solid. Rf¼0.45 (cyclohexane/EtOAc
1:1). Mp 164.5e165.7 ꢁC. 1H NMR (400 MHz, CDCl3) d 7.99
(1H, d, J¼8.9 Hz), 7.82 (4H, d, J¼8.2 Hz), 7.77 (1H, d,
J¼2.2 Hz), 7.33 (4H, d, J¼8.2 Hz), 7.22 (1H, dd, J¼2.2,
8.9 Hz), 4.01 (3H, s), 3.01 (2H, q, J¼7.6 Hz), 2.67 (3H, s),
2.48 (6H, s), 1.35 (3H, t, J¼7.6 Hz). 13C NMR (100 MHz,
CDCl3) d 169.2, 155.8, 147.6, 147.1, 145.2, 136.4, 135.5,
132.8, 129.7 (4C), 129.0, 128.6 (4C), 128.3, 125.4, 124.9,
52.6, 23.8, 23.6, 21.8 (2C), 15.2. IR (ATR) (cmꢀ1): 2927,
1731, 1587, 1495, 1437, 1373, 1357, 1270, 1165, 1080, 923,
868, 814, 660, 549. Anal. Calcd for C28H28N2O6S2: C,
60.85; H, 5.11; N, 5.07. Found: C, 60.62; H, 5.22; N, 4.95.
4.25. 7-Di-p-tosylamino-3-tert-butyldiphenylsilanoxymethyl-
4-ethylquinoline-2-carbaldehyde 38
Reaction of compound 37 (2.620 g, 3.43 mmol) with the
same experimental conditions as that for the preparation of
compound 15, but with cyclohexane/EtOAc 6:1 as the eluent
for the column chromatography provided compound 38
(2.670 g, quant.) as a pale pink solid. Rf¼0.27 (cyclohexane/
1
EtOAc 4:1). Mp 202e203 ꢁC. H NMR (400 MHz, CDCl3)
d 10.16 (1H, s), 8.02 (4H, d, J¼9.1 Hz), 7.96 (1H, d,
J¼2.2 Hz), 7.85 (4H, d, J¼8.4 Hz), 7.70e7.67 (4H, m),
7.47e7.31 (11H, m), 5.30 (2H, s), 3.04 (2H, q, J¼7.6 Hz),
2.49 (6H, s), 1.15 (3H, t, J¼7.6 Hz), 1.04 (9H, s). 13C NMR
(100 MHz, CDCl3) d 193.5, 152.2, 151.3, 146.9, 145.3,
136.5, 135.8 (4C), 135.5, 134.2, 133.1, 131.2, 131.0, 129.9
(2C), 129.8 (4C), 128.6 (4C), 127.7 (4C), 125.1, 57.1, 26.8
(3C), 21.8 (2C), 21.1, 19.3, 15.3. IR (ATR) (cmꢀ1): 2958,
2858, 1704, 1594, 1443, 1365, 1349, 1174, 1083, 1045, 937,
811, 706, 545. Anal. Calcd for C43H44N2O6S2Si: C, 66.47;
H, 5.71; N, 3.61. Found: C, 66.31; H, 5.67; N, 3.54.
4.23. 7-Di-p-tosylamino-4-ethyl-3-hydroxymethyl-2-
methylquinoline 36
Reaction of compound 35 (2.602 g, 7.99 mmol) with the
same experimental conditions as that for the preparation of
compound 13, but with cyclohexane/EtOAc 1:0/98:2 as
the eluent for the column chromatography provided compound
36 (2.194 g, 89%) as a white solid. Rf¼0.42 (CH2Cl2/MeOH
4.26. 1-[(7-Di-p-tosylamino-3-tert-butyldiphenyl-
silanoxymethyl-6-methoxy)-4-ethylquinolin-2-yl]-
9H-b-carboline-3-carboxylic acid methyl ester 39
1
9:1). Mp 197.5e198.5 ꢁC. H NMR (400 MHz, DMSO-d6)
d 8.16 (1H, d, J¼9.0 Hz), 7.73 (4H, d, J¼8.4 Hz), 7.50 (4H,
d, J¼8.4 Hz), 7.45 (1H, d, J¼2.2 Hz), 7.16 (1H, dd, J¼2.2,
9.0 Hz), 5.18 (1H, t, J¼4.9 Hz, OH), 4.71 (2H, d,
J¼4.9 Hz), 3.17 (2H, q, J¼7.5 Hz), 2.74 (3H, s), 2.45 (6H,
s), 1.23 (3H, t, J¼7.5 Hz). 13C NMR (100 MHz, DMSO-d6)
d 160.6, 147.6, 146.1, 145.5, 135.6, 133.4, 131.9, 131.4,
130.0 (4C), 128.0 (4C), 127.7, 126.3, 125.6, 56.7, 23.5, 21.1
(2C), 20.6, 15.5. IR (ATR) (cmꢀ1): 1587, 1492, 1374, 1359,
1166, 927, 872, 811, 658, 607, 548. Anal. Calcd for
C27H28N2O5S2$0.2H2O: C, 61.39; H, 5.42; N, 5.30. Found:
C, 61.39; H, 5.35; N, 5.12.
Reaction of compound 38 (423 g, 1.94 mmol) with the
same experimental conditions as that for the preparation of
compound 15, except that reflux time was reduced to 5 h,
and CH2Cl2 was used as the eluent for the column chromatog-
raphy provided compound 39 (427 mg, 34%) as a pale yellow
1
solid. Rf¼0.71 (CH2Cl2/EtOAc 9:1). Mp 126.5e128 ꢁC. H
NMR (400 MHz, CDCl3) d 9.61 (1H, br s NH), 8.85 (1H, s),
8.24 (1H, d, J¼8.6 Hz), 8.13 (1H, d, J¼7.9 Hz), 7.88 (1H, d,
J¼2.2 Hz), 7.86 (4H, d, J¼8.3 Hz), 7.66e7.58 (2H, m),
7.40 (1H, ddd, J¼1.0, 6.9, 7.9 Hz), 7.36e7.33 (5H, m),

A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
2249
7.24e7.20 (6H, m), 7.08e7.05 (4H, m), 5.63 (2H, s), 3.95
(3H, s), 3.26 (2H, q, J¼7.6 Hz), 2.45 (6H, s), 1.33 (3H, t,
J¼7.6 Hz), 0.69 (9H, s). 13C NMR (100 MHz, CDCl3)
d 166.4, 157.0, 151.8, 146.4, 145.3, 140.9, 140.8, 136.5,
136.4, 136.3, 135.2 (4C), 135.0, 133.1, 133.0, 132.7, 130.4,
129.7 (4C), 129.4 (2C), 129.0, 128.6 (4C), 127.6, 127.3
(4C), 125.3, 121.9, 121.8, 120.9, 117.8, 112.2, 59.0, 52.4,
26.4 (3C), 21.8, 21.7 (2C), 18.8, 15.2. IR (ATR) (cmꢀ1):
2930, 2359, 1712, 1595, 1493, 1428, 1378, 1356, 1258,
1168, 925, 811, 701, 659, 546. HRMS calcd for
C55H52N4O7S2Si: 972.3047, found: 972.3033.
130.8, 130.1 (4C), 128.6 (4C), 128.1, 126.3, 126.2, 124.4,
123.0, 121.5, 118.9, 117.8, 53.4, 23.4, 22.0 (2C), 15.4. IR
(ATR) (cmꢀ1): 2923, 1719, 1682, 1553, 1376, 1355, 1293,
1277, 1260, 1231, 1167, 925, 798. HRMS calcd for
C39H31N4O7S2 (MþH)þ: 731.1634, found: 731.1645.
Acknowledgements
We thank the local section of Sarthe of the Ligue Nationale
contre le cancer for a fellowship to A.N., M. Sylvain Dalenc¸on
for his participation to this work during a stay in our labora-
tory, and National Cancer Institute for the biological tests.
4.27. 1-[(7-Di-p-tosylamino-3-hydroxymethyl-6-methoxy)-7-
ethylquinolin-2-yl]-9H-b-carboline-3-carboxylic acid methyl
ester 40
References and notes
1. Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.; Gould, S. J.;
Tann, C.-H.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595e4598.
2. Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.; O’Herron, F. A.;
Nettleton, D. E. J. Antibiot. 1982, 35, 259e265.
Reaction of compound 39 (345 mg, 0.354 mmol) was car-
ried out with the same experimental conditions as that for
the preparation of compound 17. After 15 h at room tempera-
ture, evaporation, addition of EtOAc to the residue (20 mL),
washing of the organic phase with water (5 mL), and then
with brine (5 mL), evaporation, and then column chromatogra-
phy on silica gel (cyclohexane/EtOAc 3:1/2:1) provided
compound 40 (185 mg, 71%) as a pale yellow solid.
Rf¼0.20 (cyclohexane/EtOAc 1:1). Mp 226e228 ꢁC. 1H
NMR (400 MHz, C2D2Cl4) d 10.83 (1H, br s, NH), 8.91
(1H, s), 8.22 (1H, d, J¼7.8 Hz), 8.10 (1H, d, J¼9.0 Hz),
7.95 (1H, s), 7.77 (4H, d, J¼8.3 Hz), 7.70e7.61 (2H, m),
7.40e7.36 (1H, m), 7.32 (4H, d, J¼8.3 Hz), 7.18 (1H, dd,
J¼2.1, 8.9 Hz), 6.45 (1H, t, J¼7.8 Hz, OH), 4.79 (2H, d,
J¼7.8 Hz), 4.01 (3H, s), 3.38 (2H, q, J¼7.4 Hz), 2.41 (6H,
s), 1.39 (3H, t, J¼7.4 Hz). 13C NMR (100 MHz, C2D2Cl4)
d 166.0, 158.1, 151.8, 146.1, 145.9, 140.9, 139.3, 137.0,
136.1, 135.7, 135.1, 133.0, 132.9, 131.1, 129.9 (4C), 129.6,
129.5, 128.7 (4C), 127.6, 125.6, 122.1, 121.5 (2C), 118.2,
112.6, 58.3, 53.9, 53.0, 21.8 (2C), 15.6. IR (ATR) (cmꢀ1):
3369, 1713, 1375, 1355, 1261, 1170, 927, 735, 659, 547.
HRMS calcd for C39H34N4O7S2: 734.1869, found: 734.1881.
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compound 18, but with cyclohexane/CH2Cl2 8:2/0:1 and
then CH2Cl2/EtOAc 98:2 as the eluents for the column
chromatography provided compound 41 (10 mg, 17%) as
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´
7919e7922; (f) Molina, P.; Fresneda, P. M.; Garcıa-Zafra, S.; Almendros,
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1
211 ꢁC. H NMR (400 MHz, C2D2Cl4) d 8.87 (1H, s), 8.80
(1H, d, J¼8.2 Hz), 8.37 (1H, d, J¼2.0 Hz), 8.34 (1H, d,
J¼9.2 Hz), 8.20 (1H, d, J¼7.8 Hz), 7.80e7.75 (5H, m),
7.60e7.56 (1H, m), 7.34 (4H, d, J¼8.1 Hz), 7.29 (1H, dd,
J¼2.0, 9.2 Hz), 4.10 (3H, s), 4.00 (2H, q, J¼7.1 Hz), 2.44
(6H, s), 1.55 (3H, t, J¼7.1 Hz). 13C NMR (100 MHz,
C2D2Cl4) d 165.9, 160.4, 159.4, 150.2, 149.1, 145.9, 144.2,
139.7, 137.7, 136.1, 135.4, 134.1, 134.0, 131.6, 131.5,

2250
A. Nourry et al. / Tetrahedron 64 (2008) 2241e2250
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