Synthesis of an analogue of lavendamycin and of conformationally restricted derivatives by cyclization via a hemiaminal intermediate

Article abstract of DOI:10.1016/j.tetlet.2007.06.100

Quinoline 12 was obtained by a Friedl?nder reaction from 2-aminobenzaldehyde and methyl acetoacetate. Reduction, silylation then oxidation provided compound 8a. A Pictet-Spengler reaction between the latter and tryptophan methyl ester yielded compound 14,

Full text of DOI:10.1016/j.tetlet.2007.06.100

Tetrahedron Letters 48 (2007) 6014–6018
Synthesis of an analogue of lavendamycin and of conformationally
restricted derivatives by cyclization via a hemiaminal intermediate
*
*
´
Arnaud Nourry, Stephanie Legoupy and Franc¸ois Huet
`
´
Laboratoire de Synthese Organique, UCO2M, UMR CNRS 6011, Universite du Maine, Avenue Olivier Messiaen,
72085 Le Mans Cedex 9, France
Received 5 March 2007; revised 7 May 2007; accepted 19 June 2007
Available online 24 June 2007
Abstract—Quinoline 12 was obtained by a Friedla¨nder reaction from 2-aminobenzaldehyde and methyl acetoacetate. Reduction,
silylation then oxidation provided compound 8a. A Pictet–Spengler reaction between the latter and tryptophan methyl ester yielded
compound 14, then compound 7 by desilylation. Numerous attempts to prepare a cyclized derivative of this analogue of lavendam-
ycin 7 by conventional ways failed. Fortunately, a good result was obtained via a hemiaminal intermediate and compound 21 was
thus obtained in satisfactory yield. A conjugate addition occurred in the course of its reduction which led to compound 22. Biologi-
cal tests were carried out with compound 7 and the conformationally restricted analogues 21 and 22.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
syntheses of this interesting compound, or of ester deri-
vatives, were carried out4 as well as the ones of various
analogues.5 Structure–activity relationships have been
discussed.
Lavendamycin 1,1 (Fig. 1) a natural product from Strep-
tomyces lavendulae, showed antimicrobial and cytotoxic
properties2 and displayed a significant activity against
topoisomerases I (MIC = 0.1 lg/mL).3 However, its
biological interest is limited by its toxicity that may be
linked to the presence of the quinone moiety. Numerous
In a previous work of our group in this area5h we pre-
pared several esters I and acids II without the amino-
quinone moiety and the methyl group of C cycle, and
with various substituents R1–R7. These syntheses were
based on a Pictet–Spengler type reaction carried out in
the presence of a catalytic amount of pyridinium
p-toluenesulfonate, starting from III and IV. We thus
obtained the desired esters I, and then acids II by
saponification. The biological tests showed that these
compounds maintained a part of the biological proper-
ties of the parent molecule. We also observed that
unsubstituted product II with R1 to R7 = H, and the
derived compound bearing a C cycle substituted by a
methyl group, as in lavendamycin, had the same
activities.
O
A
R1
R2
R3
B
N
N
C
CO2H
Me
N
CO2R
H2N
N
O
R4
HN
HN
D
I, R = Me
II, R = H
1
E
R7
R5
R6
R1
CO2Me
NH2
R2
R3
R5
R6
N
CHO
N
H
R4
III
IV
When comparing structures of compounds I and II and
the ones of the most important known inhibitor of
topoisomerases I, camptothecin itself, 26 and analogues,
and also of some other inhibitors such as azaIQD 3,3
nitidine 4, and isofagaridine 5,7 it appears that all of
them have a rigid structure (Fig. 2). With the hope to
obtain products more interesting than I and II, we then
envisioned to synthesize the conformationally restricted
analogue 6, or related compounds. We thought that this
R7
Figure 1.
Keywords: Lavendamycin; Hemiaminal; Nitrogen heterocycles; Cycli-
zation; Topoisomerase.
*
Corresponding authors. Tel.: +33 2 4383 3338; fax: +33 2 4383 3902
(F.H.); e-mail addresses: fhuet@univ-lemans.fr; slegoupy@univ-
lemans.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.100

A. Nourry et al. / Tetrahedron Letters 48 (2007) 6014–6018
6015
O
H
N
O
O
O
N
MeO
MeO
N
OMe
N
O
O
N
N
O
Me
Et
2
3
4
OH
O
O
N
N
N
N
HO
Me
6
OMe
CO2H
5
Figure 2.
aim could be attained by carrying out a cyclization reac-
tion between the pyrrole nitrogen and a suitable substi-
tuent on the B cycle.
of the hydroxyl group was necessary and then oxidation
to aldehydes 8a (P = TBDPS), 8b (P = Bn) and 8c
(P = Ac) gave good results. Numerous reactions
between 8a or 8b or 8c and tryptophan methyl ester 9
were then carried out with or without a catalyst.11 The
best result was obtained from 8a at high temperature
and without a catalyst. Compound 14 was thus obtained
in a reasonable yield (46%) and desilylation provided the
desired hydroxyester 7.
2. Results and discussion
Our strategy to prepare compound 6 or related products
was to carry out an intramolecular cyclization from
intermediate 7 or a derivative (Scheme 1). This com-
pound would be available by a Pictet–Spengler reac-
tion5h from a substituted quinoline 8 and tryptophan
methyl ester 9.
We then tried to find efficient conditions to prepare the
target molecule 6, or other cyclized products, from com-
pound 7 by an intramolecular reaction. One of the diffi-
culties was the poor solubility of this alcohol in most of
the organic solvents, even in dimethylsulfoxide. How-
ever, an acceptable solubility was observed in N-methyl-
pyrrolidinone (NMP). We then tried to carry out the
Mitsunobu reaction from compound 7, under different
conditions, and particularly in NMP. It failed to give
the desired product and led to recovering of the starting
material. This failure may be due to an inappropriate
pKa of the nucleophile.12
Friedla¨nder reaction between 2-aminobenzaldehyde 118
obtained by reduction of 2-nitrobenzaldehyde 10 with
iron powder in acidic medium9 and methyl acetoacetate
led to product 12.10 The best result (Scheme 2) for
reduction to alcohol 13 was obtained with DIBAL-H.
When this alcohol was oxidized by selenium dioxide,5h
the corresponding aldehyde was not obtained likely
due to reactions such as lactol formation. Protection
OH
CO2Me
N
CO2Me
OP
CHO
NH2
N
6
N
HN
N
H
7
9
8, P = protecting group
Scheme 1.
Me
OMe
CO2Me
Me
CHO
NO2
CHO
NH2
iron powder, 10 M HCl
68%
O
O
N
MeOH, piperidine
92%
10
12
11
CH2OH
Me
1) t-BuPh2SiCl
DIBAL-H, −78˚C
8a: P = TBDPS
12
2) SeO2
97%
95%
N
13
OTBDPS
CO2Me
n-Bu4NF
N
N
refl. p-xylene, 16 h
46%
8a
9
HN
7
75%
14
Scheme 2.

6016
A. Nourry et al. / Tetrahedron Letters 48 (2007) 6014–6018
Another possibility was to replace the hydroxyl group
by a leaving group to make possible the nucleophilic
attack of the pyrrole nitrogen. Numerous attempts to
obtain mesylate, tosylate, triflate or halides were unsuc-
cessful and led either to recovery of the starting material
or to degradation of products. In contrast, another
attempt with acetic anhydride gave the corresponding
acetate 15 (86%) (Scheme 3). We then tested the possibil-
ity of nucleophilic substitution in a more simple case,
from acetate 1613 derived from alcohol 13 and indole.
However the reaction did not work, but replacement
of this poor leaving group by iodide led to the expected
product 18. This good result led us to try to prepare the
iodide derivative of 7 from 15 under the same experi-
mental conditions. Unfortunately the reaction led either
to unidentified products or to degradation depending on
temperature, solvent or reaction time. Another attempt
to prepare a bromide derivative from the silylated com-
pound 14 under various conditions also failed. Finally
we tested another possibility involving the introduction
of the leaving group early in the synthesis and we carried
out a Pictet–Spengler reaction between 3-bromomethyl-
quinoline-2-carbaldehyde and tryptophan methyl ester.
Once more, only degradation occurred.
obtain compound 21 without detecting the intermediate
aldehyde (Scheme 4). However, this experiment needed
a large excess of oxidant and a long reaction time (12
days). Moreover the yield was low (19%). We then
examined other conditions, and the Dess-Martin period-
inane (DMP)14 (1.5 equiv) gave the best result. Com-
pound 21 was thus obtained in an acceptable yield of
50% for the three steps (oxidation, cyclization, new
oxidation). This formation of compound 21 likely
involves the intermediate formation of aldehyde 19 that
is sufficiently reactive to give hemiaminal 20. The latter
is not stable under these experimental conditions and is
oxidized to compound 21. Using an excess of reagent
(2.1 equiv) resulted in a slight lowering of the yield
(45%). Stability of hemiaminals is usually low, except
in particular cases such as when intramolecular hydro-
gen bonding interactions are involved15 or when the
compound is included in a metallocycle.16 In the case
of intermediate 20 an oxidation to compound 21 occurs.
In principle the amount of oxidant used (1.5 equiv) is
not sufficient for both oxidations, but the overall yield
is moderate. Therefore, the possibility of oxidation of
20 by DMP cannot be rejected. However, this oxidation
may also occur by air oxygen as it was observed in sim-
ilar cases.17
As the first two routes failed, we envisioned a less clas-
sical possibility. We planned to oxidize compound 7 to
replace the hydroxymethyl group by a formyl group,
with the hope that a subsequent nucleophilic attack of
the pyrrole moiety would work. In a first experiment
with manganese dioxide, we were pleased to directly
Our objective of preparing a conformationally restricted
analogue of lavendamycin was thus achieved but we also
examined if preparation of the reduced product 6 would
be possible from compound 21. We choose BH3ÆTHF in
view of reducing only the amide function.18 As a matter
OAc
N
CO2Me
OAc
Ac2O, NMP
N
7
indole,
no
NaH, DMF
Ac2O
97%
HN
13
N
Me
N
reaction
15
16
indole,
NaH, DMF
I
Me3SiCl, NaI
87%
16
15
N
Me
61%
N
Me
17
18
Me3SiCl, NaI
degradation or unidentified products
Scheme 3.
O
DMP (1.5 eq.)
Pyridine
N
7
50%
N
N
21
CO2Me
OH
CHO
N
N
CO2Me
N
7
21
N
HN
N
CO2Me
19
20
Scheme 4.

A. Nourry et al. / Tetrahedron Letters 48 (2007) 6014–6018
6017
OH
O
BH3.THF
51%
N
N
21
N
N
H
N
N
22
CO2Me
CO2Me
Scheme 5.
3. Riou, J.-F.; Helissey, P.; Grondard, L.; Giorgi-Renault, S.
Mol. Pharmacol. 1991, 40, 699–706.
of fact we were surprised to obtain a product 22, which
might exist in two tautomeric forms, and resulting from
a conjugate reduction (Scheme 5). Purification and iden-
tification of this compound 22, as the ones of compounds
7 and 21, were complicated by its low solubility. It was
identified thanks to NMR spectra that revealed, in par-
ticular, the presence of a 13C signal of a methylene group
in the 13C DEPT 135 experiment, at 26 ppm, and to
HRMS which confirmed the presence of an oxygen more
with respect to the structure of the expected product (6).
Some dearomatizations of a pyridinic cycle in the case of
reduction of quinoline systems have already been ob-
served.19 Concerning the both possible tautomeric forms
of compound 22, it is not easy to determinate which one
is predominant, however IR data are more consistent
with a preference for the lactam form.20
4. (a) Hibino, S.; Okazaki, M.; Sato, K.; Morita, I.;
Ichikawa, M. Heterocycles 1983, 20, 1957–1958; (b)
Hibino, S.; Okazaki, M.; Ichikawa, M.; Sato, K.; Ishizu,
T. Heterocycles 1985, 23, 261–264; (c) Kende, A. S.;
Ebetino, F. H. Tetrahedron Lett. 1984, 25, 923–926; (d)
Kende, A. S.; Ebetino, F. H.; Battista, R.; Boatman, R. J.;
Lorah, D. P.; Lodge, E. Heterocycles 1984, 21, 91–106; (e)
Rao, A. V. R.; Chavan, S. P.; Sivadasan, L. Indian J.
Chem. B 1984, 23B, 496–497; (f) Rao, A. V. R.; Chavan, S.
P.; Sivadasan, L. Tetrahedron 1986, 42, 5065–5071; (g)
Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25,
3175–3178; (h) Boger, D. L.; Duff, S. R.; Panek, J. S.;
Yasuda, M. J. Org. Chem. 1985, 50, 5782–5789; (i) Boger,
D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem.
1985, 50, 5790–5795; (j) Molina, P.; Fresneda, P. M.;
´
Canovas, M. Tetrahedron Lett. 1992, 33, 2891–2894; (k)
Molina, P.; Murcia, F.; Fresneda, P. M. Tetrahedron Lett.
1994, 35, 1453–1456; (l) Behforouz, M.; Gu, Z.; Cai, W.;
Horn, M. A.; Ahmadian, M. J. Org. Chem. 1993, 58,
7089–7091; (m) Behforouz, M.; Haddad, J.; Cai, W.;
Arnold, M. B.; Mohammadi, F.; Sousa, A. G.; Horn, M.
A. J. Org. Chem. 1996, 61, 6552–6555; (n) Ciufolini, M.
A.; Bishop, M. J. J. Chem. Soc., Chem. Commun. 1993,
1463–1464; (o) Rocca, P.; Marsais, F.; Godard, A.;
3. Conclusions
Finally, we obtained the simplified analogue of lavenda-
mycin 7 by a short way. Thanks to the presence of the
hydroxymethyl group on the B cycle several possibilities
of cyclization were conceivable. The more classical ways
failed, but a good result was obtained for preparation of
compound 21 via a hemiaminal. Conjugate reduction
provided compound 22.
´
Quequiner, G. Tetrahedron Lett. 1993, 34, 2937–2940.
5. (a) Boger, D. L.; Yasuda, M. Heterocycles 1986, 24, 1067–
1073; (b) Boger, D. L.; Yasuda, M.; Mitscher, L. A.;
Drake, S. D.; Kitos, P. A.; Thompson, S. C. J. Med.
Chem. 1987, 30, 1918–1928; (c) Hibino, S.; Okazaki, M.;
Ichikawa, M.; Sato, K.; Motoshima, A.; Ueki, H. Chem.
Pharm. Bull. 1986, 34, 1376–1379; (d) Hafuri, Y.; Take-
mori, E.; Oogose, K.; Inouye, Y.; Nakamura, S.; Kita-
hara, Y.; Nakahara, S.; Kuno, A. J. Antibiot. 1988, 41,
1471–1478; (e) Godard, A.; Rocca, P.; Fourquez, J.-M.;
Biological tests in cell culture with 60 different tumour
cells were carried out for compounds 7, 21 and 22 by
the National Cancer Institute. Unfortunately, they only
showed a moderate activity.21 However their poor solu-
bility in all the solvents is not a favourable point. It
should be interesting to apply this strategy to synthesize
substituted related compounds which could be probably
more soluble.
´
Rovera, J.-C.; Marsais, F.; Quequiner, G. Tetrahedron
Lett. 1993, 34, 7919–7922; (f) Molina, P.; Fresneda, P. M.;
´
Garcıa-Zafra, S.; Almendros, P. Tetrahedron Lett. 1994,
35, 8851–8854; (g) Haffer, G.; Nickisch, K.; Tilstam, U.
Heterocycles 1998, 48, 993–998; (h) Barbier, C.; Joissains,
A.; Commerc¸on, A.; Riou, J.-F.; Huet, F. Heterocycles
2000, 53, 37–48; (i) Behforouz, M.; Merriman, R. L. U.S.
Patent. No 5,552,611 1996; (j) Behforouz, M.; Merriman,
R. L. U.S. Patent. No 5,646,150 1997; (k) Behforouz, M.;
Cai, W.; Stocksdale, M. G.; Lucas, J. S.; Jung, J. Y.;
Briere, D.; Wang, A.; Katen, K. S.; Behforouz, N. C. J.
Med. Chem. 2003, 46, 5773–5780; (l) Fang, Y.; Linardic,
C. M.; Richardson, D. A.; Cai, W.; Behforouz, M.;
Abraham, R. Mol. Cancer Ther. 2003, 2, 517–526; (m)
Seradj, H.; Cai, W.; Erasga, N. O.; Chenault, D. V.;
Knuckles, K. A.; Ragains, J. R.; Behforouz, M. Org. Lett.
2004, 6, 473–476; (n) Hassani, M.; Cai, W.; Holley, D. C.;
Lineswala, J. P.; Maharjan, B. R.; Ebrahimian, G. R.;
Seradj, H.; Stocksdale, M. G.; Mohammadi, F.; Marvin,
C. C.; Gerdes, J. M.; Beall, H. D.; Behforouz, M. J. Med.
Chem. 2005, 48, 7733–7749, See also several of the Ref.
4.
Acknowledgement
We thank the local section of Sarthe of the Ligue Natio-
nale contre le Cancer for a fellowship to A.N., National
Cancer Institute for the biological tests and Dr. Alain
Commerc¸on for interesting discussions.
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, 4595–4598.
2. Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.;
O’Herron, F. A.; Nettleton, D. E. J. Antibiot. 1982, 35,
259–265.
6. For a review see: Du, W. Tetrahedron 2003, 59, 8649–
8687.

6018
A. Nourry et al. / Tetrahedron Letters 48 (2007) 6014–6018
7. Fang, S.-D.; Wang, L.-K.; Hecht, S. M. J. Org. Chem.
1H, NH), 8,93 (s, 1H, arom H), 8.26–8.23 (m, 3H, arom
H), 7.88 (dd, J = 1.2, 8.1 Hz, 1H, arom H), 7.81 (ddd,
J = 1.5, 6.9, 8.4 Hz, 1H, arom H), 7.73–7.61 (m, 3H, arom
H), 7.42 (ddd, J = 1.0, 6.9, 7.9 Hz, 1H, arom H), 6.94
(t, J = 8.0 Hz, 1H, OH), 4.97 (d, J = 8.0 Hz, 2H, CH2),
4.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, C2D2Cl4,
60 ꢁC): d = 166.0 (C@O), 156.4, 146.2, 141.0, 139.4, 138.9,
137.2, 135.8, 134.7, 130.9, 130.1, 129.3, 128.6, 127.7, 127.6
(2C), 121.9, 121.6, 121.3, 117.8, 112.5, 64.5 (CH2), 52.5
(CH3) ppm. Anal. Calcd for C23H17N3O3, 0.3 H2O: C,
71.05; H, 4.56; N, 10.81. Found: C, 71.00; H, 4.48; N,
10.63. Compound 21: Anhydrous pyridine (0.5 mL) and
Dess-Martin periodinane (364 mg, 0.858 mmol) were
added under nitrogen to a stirred solution of compound
7 (219 mg, 0.572 mg) in anhydrous NMP (3.9 mL). The
reaction mixture was stirred at room temp. for 2d, then
CH2Cl2 (15 mL) was added. The heterogeneous organic
phase was successively washed with a 1:1 mixture (12 mL)
of 5% Na2S2O3 solution and of a saturated solution of
NaHCO3, a saturated solution of NaHCO3 (6 mL), 1 M
HCl (6 mL) and then brine (6 mL). The resulting suspen-
sion was evaporated without drying. Adding of MeOH
(15 mL), heating (ꢀ55 ꢁC), filtration with heating and
recuperation of the solid provided 21 (108 mg, 50%) as a
yellow solid. Mp 304–306 ꢁC. 1H NMR (400 MHz,
C2D2Cl4, 60 ꢁC): d = 9.46 (s, 1H), 8.85 (s, 1H), 8.75 (d,
J = 8.1 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.17 (d,
J = 7.7 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.96 (ddd,
J = 1.3, 7.2, 8.3 Hz, 1H), 7.77–7.68 (m, 2H), 7.56 (ddd,
J = 0.6, 7.2, 7.8 Hz, 1H), 4.10 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, C2D2Cl4, 60 ꢁC): d = 165.8 (C@O,
ester), 159.1, 150.3 (C@O, amide), 148.8, 144.6, 140.2,
139.3, 136.1, 134.5, 133.3, 131.9, 131.4, 130.4, 129.4, 128.5,
127.5, 126.1, 124.7, 123.6, 122.7, 118.5, 117.5, 53.0 (CH3)
ppm. HRMS Calcd for C23H13N3O3: 379.0957. Found:
379.0957. Compound 22: A 1 M solution of BH3ÆTHF
(0.65 mL, 0.632 mmol) was added under nitrogen to a
stirred suspension of compound 21 (60 mg, 0.158 mmol) in
anhydrous THF (1.8 mL). The heterogeneous mixture was
heated at reflux for 5 h, then it was cooled, and a 6 M
solution of HCl was added (80 lL). The resulting suspen-
sion was evaporated and the crude product was heated
(ꢀ55 ꢁC) with MeOH (5 mL). A filtration with heating
and recuperation of the solid provided 22 (31 mg, 51%) as
a yellow solid. Mp 295–297 ꢁC. 1H NMR (400 MHz,
CDCl3): d = 8.80 (s, 1H, H-3), 8.65 (d, J = 8.2 Hz, 1H),
8.20 (br s, 1H, OH), 8.12 (d, J = 7.7 Hz, 1 H), 7.71 (ddd,
J = 1.0, 8.2, 8.3 Hz, 1H), 7.50 (ddd, J = 0.7, 7.8, 7.9 Hz,
1H), 7.20–7.15 (m, 2H), 7.01 (ddd, J = 0.9, 7.2, 7.5 Hz,
1H), 6.97 (d, J = 7.8 Hz, 1H), 4.17 (s, 2H, CH2), 4.11 (s,
3H, CH3) ppm. 13C NMR (100 MHz, C2D2Cl4, 67 ꢁC):
d = 165.4 (C@O), 159.4, 142.6, 142.4, 140.4, 135.9, 132.2,
131.2, 130.5, 129.7, 129.4, 127.6, 124.9, 123.9, 122.7, 120.3,
118.3, 118.2, 116.9, 115.6, 104.9, 52.8 (CH3), 26.0 (CH2)
ppm. HRMS Calcd for C23H15N3O3: 381.1113. Found:
381.1129.
1993, 58, 5025–5027.
8. Smith, L. I.; Opie, J. W. Org. Synth. 1955, Coll. Vol. 3, 56–
57.
9. Thummel, R. P.; Chirayil, S.; Hery, C.; Lim, J.-L.; Wang,
T.-L. J. Org. Chem. 1993, 58, 1666–1671.
10. (a) Ehrig, V.; Bien, H. S.; Klauke, E.; Schutze, D. I. West
German Pat. No. 2,730,061 1979; (b) Cheng, C.-C.; Yan,
S.-J. Org. React. 1982, 28, 37–201.
11. Effects of the following catalysts were examined: pyridi-
nium p-toluenesulfonate, Me3SiCl, AcOH, CF3CO2H,
BF3ÆEt2O.
12. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L.
Org. React. 1992, 42, 335–656.
13. Basavaiah, D.; Reddy, R. M.; Kumaragurubaran, N.;
Sharada, D. S. Tetrahedron 2002, 58, 3693–3697.
14. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7278; (b) Frigerio, M.; Santagostino, M.; Sputore, S.
J. Org. Chem. 1999, 64, 4537–4538.
15. Suni, V.; Kurup, M. R. P.; Nethaji, M. J. Mol. Struct.
2005, 749, 177–182, and references cited therein.
´
16. El Mail, R.; Garralda, M. A.; Hernandez, R.; Ibarlucea,
L.; Pinilla, E.; Torres, M. R. Organometallics 2000, 19,
5310–5317.
17. (a) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K.
Tetrahedron Lett. 1987, 28, 5895–5898; (b) Hiroya, K.;
Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136.
18. Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912–916.
19. (a) Kajino, M.; Meguro, K. Heterocycles 1990, 31, 2153–
2161; (b) Vasse, J.-L.; Levacher, V.; Bourguignon, J.
Dupas G. J. Chem. Soc., Chem. Commun. 2002, 2256–
2257.
20. Selected preparation procedures and data. Compound 14:
Compound 8a (65 mg, 0.153 mmol) was added under
nitrogen to a stirred solution of tryptophan methyl ester
(50 mg, 0.230 mmol) in anhydrous p-xylene (2.5 mL).
After 16 h of stirring at reflux, cooling, evaporation and
column chromatography on silica gel (cyclohexane/
AcOEt, 95:5) provided 14 (44 mg, 46%) as a yellow solid.
1
Mp 220–221 ꢁC. H NMR (400 MHz, CDCl3): d = 11.68
(br s, 1H, NH), 9.03 (s, 1H), 8.86 (s, 1H), 8.27 (d,
J = 8.1 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.99 (d,
J = 8.1 Hz, 1H), 7.83–7.77 (m, 5H), 7.69–7.60 (m, 3H),
7.42–7.33 (m, 7H), 5.93 (s, 2H, CH2), 3.53 (s, 3H, CH3),
1.21 (s, 9H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.0 (C@O), 154.2, 145.4, 140.5, 139.2, 136.9, 136.1,
135.8, 135.5, 134.6, 133.8, 130.3, 129.6, 129.3, 128.8, 128.4,
128,0, 127.7 (2C), 127.1, 121.8, 121.7, 120.8, 117.7, 112.2,
64.6 (CH2), 51.9 (CH3), 27.1 (C(CH3)3); 19.5 (C(CH3)3)
ppm. Anal. Calcd for C39H35N3O3Si: C, 75.33; H, 5.67; N,
6.76. Found: C, 75.31; H, 5.73; N, 6.74. Compound 7:
Glacial CH3CO2H (0.6 mL) and a 1 M solution of n-
Bu4NF in THF (4.8 mL, 4.8 mmol) were added under
nitrogen to a stirred solution of compound 14 (998 mg,
1.61 mmol) in THF (11 mL). After 12 h of stirring at room
temp. then evaporation, a mixture of petroleum ether/
AcOEt, 1:4 (20 mL) was added. Stirring and heating of the
mixture, filtration with heating and recuperation of the
solid provided pure 7 (460 mg, 75%) as a yellow solid. Mp
260–262 ꢁC. 1H NMR (400 MHz, CDCl3): d = 11.67 (br s,
21. For instance, for leukemia CCRF-CEM cells, the GI50
were 2.55 · 10À5, >1.00 · 10À4, 2.19 · 10À6 M, for com-
pounds 7, 21, 22, respectively, and the LC50 were >1.00 ·
10À4 M for the three compounds.