Abstract
The present paper reports the synthesis and spectroscopic characterization of few N-2′-hydroxyethyl-substituted azacholestanes using BF3-OEt2, TiCl4, SnCl4, and H2SO4as catalysts in moderate yields by a modified version of Schmidt reaction. A notable feature is the passivity of SnCl4in case of 3β-acetoxy-N-2′-hydroxyethyl-6-aza-B-homo-5α-cholestan-7-one and 3β-chloro-N-2′-hydroxyethyl-6-aza-B-homo-5α-cholestan-7-one. However, the reaction was unsuccessful in case of N-2′-Hydroxyethyl-6-aza-B-homo-5α-cholestan-7-one. Another striking aspect is the attainment of high yield in case of H2SO4as catalyst. The semisolid compounds are characterized using various spectroscopic techniques such as FT-IR,1H-NMR and mass spectra, and microanalytical data. A reaction mechanism has been proposed on the basis of previous studies. Moreover, the compounds have also been screened for theirin vitrocytotoxicity against human colon carcinoma cell line, HCT116, and human liver hepatocellular carcinoma cell line, HepG2, using doxorubicin as standard. On the basis of IC50values, 3β-chloro-N-2′-hydroxyethyl-6-aza-B-homo-5α-cholestan-7-one (5) was found to inhibit the cancer cells most effectively.
Highlights
Steroidal chemistry has been an area of intense research not from an organic chemist perspective and for an endocrinologist because of its fundamental importance in an array of biological functions [1]. e replacement of one or more carbon atoms of a steroidal moiety by a heteroatom alters its chemical properties which in certain cases lead to development of useful molecules or drugs [2]
Insertion of nitrogen into steroidal as well as nonsteroidal nucleus has been effected by the reaction of steroidal ketones as well as nonsteroidal ketones with hydrazoic acid in the presence of protonic or Lewis acids [3,4,5,6,7,8,9,10]. e Beckmann rearrangement of oximes and Schmidt reaction is one of the well-known protocols for the synthesis of lactams. e heterosteroids, azasteroids are obtained by this protocol [11,12,13,14]
BF3–OEt2 (% yield) reaction. e accessible steroidal ketones (1, 2 and 3) were synthesized by the literature method [43,44,45,46]. e experiments were carried out with above ketones (1, 2, and 3) and 2-azidoethanol in dichloromethane. us, when 2azidoethanol was added to a solution of steroidal ketone (1) in BF3–OEt2, TiCl4, SnCl4, or H2SO4, respectively, vigorous gas evolution was observed immediately. en a saturated aqueous NaHCO3 solution was added in the reaction mixture followed by standard workup resulted in the formation of desired N-substituted azasteroid (4) (Scheme 1)
Summary
Steroidal chemistry has been an area of intense research not from an organic chemist perspective and for an endocrinologist because of its fundamental importance in an array of biological functions [1]. e replacement of one or more carbon atoms of a steroidal moiety by a heteroatom alters its chemical properties which in certain cases lead to development of useful molecules or drugs [2]. Lactams are important molecules owing to their versatility as intermediate in the preparation of both synthetically and biologically active compounds [15, 16]. Guarna and coworkers have synthesized and explored the biological application of a novel class of potent azasteroidal inhibitors having nuclear nitrogen atom at position C-10 of the steroidal ketones [28]. Despite the development of a number of methods, the Schmidt and Beckmann reactions remain the most convenient and general protocol for insertion of nitrogen atom into the steroidal nucleus [33,34,35,36,37,38,39]. On reaction with hydroxyalkyl azide in the presence of different Lewis acids (BF3–OEt2, TiCl4, or SnCl4) and protonic acid (H2SO4), it gives 3ββ-acetoxy-N-2 -hydroxyalkyl6-aza-B-homo-5αα-cholestan-7-one (4) and its analogues 5 and 6, respectively
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