Reactions of salicylaldehydes with alkyl cyanoacetates on the surface of solid catalysts: Syntheses of 4H-chromene derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01195-3

Substituted 4H-chromene derivatives are a new class of compounds that bind Bcl-2 protein and induce apoptosis in tumor cells. Here we report an efficient synthetic method for the preparation of these compounds from salicylaldehyde derivatives and alkyl cyanoacetates under solid-phase catalysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01195-3

Tetrahedron Letters 41 (2000) 6993±6996
Reactions of salicylaldehydes with alkyl cyanoacetates on the
surface of solid catalysts: syntheses of 4H-chromene
derivatives
Niefang Yu, James M. Aramini, Markus W. Germann and Ziwei Huang*
Kimmel Cancer Center, Je€erson Medical College, Thomas Je€erson University, Philadelphia, PA 19107, USA
Received 19 May 2000; revised 29 June 2000; accepted 30 June 2000
Abstract
Substituted 4H-chromene derivatives are a new class of compounds that bind Bcl-2 protein and induce
apoptosis in tumor cells. Here we report an ecient synthetic method for the preparation of these com-
pounds from salicylaldehyde derivatives and alkyl cyanoacetates under solid-phase catalysis. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: 4H-chromene; cyclization; Bcl-Z protein; apoptosis; anti-cancer agents.
Bcl-2 and a family of related proteins regulate apoptosis or programmed cell death, and are
implicated in a number of human diseases such as cancer.1 Speci®cally, Bcl-2 can contribute to
neoplastic cell expansion by preventing normal cell turnover caused by physiological cell death
mechanisms. High levels of the Bcl-2 gene expression are found in a wide variety of human can-
cers and can lead to tumor cell resistance to conventional chemotherapy and radiotherapy.2
Synthetic peptides that bind to a functional surface pocket of Bcl-2 have in vitro activity for
inducing apoptosis in cell-free systems3 and in HeLa cells.4 Furthermore, Bcl-2 binding peptides
containing a fatty acid as a cell permeable moiety can induce apoptosis in vitro and have in vivo
activity in slowing human myeloid leukemia growth in severe combined immunode®cient mice.5
These studies suggest that peptides or other small molecular ligands targeted at the Bcl-2 surface
pocket could have important clinical applications.
We have recently discovered an organic compound, 1 (HA14-1), that exhibits a binding activity
for the surface pocket of Bcl-2 protein (IC50=9 mM) and induces apoptosis of tumor cells.6 The
discovery of this Bcl-2 binding compound provides a promising lead for the development of
potential anti-cancer agents, and prompted us to undertake chemical synthesis of a series of
modi®ed analogs of 1 in order to study its structure±activity relationship and increase its potency.
* Corresponding author. Tel: 215 503-4564; fax: 215 923-2117; e-mail: zhuang@nana.jci.tju.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01195-3

6994
Surprisingly, a survey of the literature revealed that the synthesis of the derivatives of 1 has
received little attention in the past. To our knowledge, only two methods for the preparation of
analogs of 1 have been reported. The ®rst method developed by Fujimoto and Sakurai7 involved
the cyclization of salicylaldehyde derivatives with alkyl cyanoacetates in the presence of ammo-
nium acetate at 5±10ꢀC which gave derivatives of 1. The reaction temperature (5±10ꢀC) was cru-
cial for obtaining the desired products. If the temperature was just slightly raised to 15±25ꢀC, the
reaction failed to give the desired product. In another procedure developed by Roudier and
Foucaud,8 aluminium oxide (Al2O3) was used as the catalyst instead of ammonium acetate and
this approach has been applied in a limited number of examples.
Here we report an alternative procedure for the preparation of 4H-chromenes under mild
conditions using molecular sieve 3A as the catalyst (Scheme 1). A typical reaction is as follow: To
a suspension of the 5-bromosalicylaldehyde (0.010 mol) in dry ethyl alcohol (30 ml) was added
ethyl cyanoacetate (0.022 mol) and 3.0 grams of molecular sieve 3A powder (Aldrich Chemical
Company). The resulting mixture was stirred at room temperature overnight (14 h). Most of the
5-bromosalicylaldehyde disappeared within the ®rst 2 h as determined by TLC. The molecular
sieve was then ®ltered o€ and washed with tetrahydrofuran three times. The ®ltrate was com-
bined and solvent was removed under vacuum. The residue solidi®ed when cooled at ^24ꢀC for
2 h. The desired product was obtained by crystallization in 85% ethanol as a single diastereo-
isomeric pair. The yield was 86%.
Scheme 1.
Other types of molecular sieves, such as molecular sieves 4A and 5A, as well as Al2O3, were
also compared using this procedure. All solid catalysts tested catalyzed the reactions, with type-
3A giving the best yields (Table 1). Table 2 summarizes several examples of the application of this
new method using molecular sieve 3A. In most cases, good to excellent yields were obtained.9
In summary, we have developed an alternative procedure for the synthesis of 4H-chromene
derivatives. Our method features mild reaction conditions, generally high yields, and facile
manipulation. This new method has been used to synthesize a series of analogs for investigating

6995
Table 1
Comparison of various solid catalysts
Table 2
Preparation of 4H-chromene derivatives by using molecular sieve 3A
the structure±activity relationship of HA14-1 (manuscripts in preparation). The development of
such a synthetic strategy should facilitate e€orts in further lead optimization and drug development.
Acknowledgements
This work was supported by grants from the American Cancer Society and the Sidney Kimmel
Foundation for Cancer Research.
References
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6996
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7. Fujimoto, A.; Sakurai, A. Synthesis 1977, 871±872.
8. Roudier, J. F.; Foucaud, A. Synthesis 1984, 159±160.
1
9. Data for 3a: H NMR (600 MHz, DMSO-d6, ꢀ): 1.33 (3H, t, J=7.11 Hz, -CH3), 1.35 (3H, t, J=7.12 Hz, -CH3),
3.98 (1H, d, J=3.52 Hz, aliphatic-H), 4.28 (3H, q, J=7, 12 Hz, -OCH2Me and -OCH-Me), 4.33 (1H, m,
-OCHMe), 4.68 (1H, d, J=3.52 Hz, aliphatic-H), 6.10±6.90 (2H, b, -NH2), 6.98 (1H, d, J=8.70 Hz, aromatic-H),
7.26 (1H, d, J=2.30 Hz, aromatic-H), 7.41 (1H, dd, J=2.30, 8.70 Hz, aromatic-H). IR (cycles/cm^1): 1710, 1725,
1745. MS calculated for C17H17BrN2O5: 409.24; found: 410 (M+ +1).