Abstract
An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).
Highlights
In the interdisciplinary research field of chemical biology and drug discovery, diversityoriented synthesis is an interesting model for the production of large chemical libraries of small molecules, bearing multiple functional groups, in order to explore their influence into the biological properties of those substrates [1,2,3]
The Ugi reaction consists on a nucleophilic attack of an isonitrile 6 to an iminium ion 5, a salt composed of a carboxylic acid 4 and an imine 3, which is often generated in situ from a carbonyl derivative 1 and an amine 2
Despite the difficulty often observed for the utilization of ketones or ketimines in Ugi reactions, α-phosphorated ketimines react under mild conditions to give the Ugi adducts after the spontaneous cleavage of the amide moiety
Summary
In the interdisciplinary research field of chemical biology and drug discovery, diversityoriented synthesis is an interesting model for the production of large chemical libraries of small molecules, bearing multiple functional groups, in order to explore their influence into the biological properties of those substrates [1,2,3]. The most characteristic chemical shift of α-aminophosphonate 13a in 13C NMR is certainly the doublet corresponding to the quaternary carbon directly bonded to the phosphonate that appears at δC = 68.5 ppm and presents a strong coupling with the phosphorus atom (1JPC = 157.2 Hz). The presence of the tosyl group is here deduced from the chemical shift corresponding to its para-methyl substituent at δC = 21.6 ppm and the aromatic carbons with two signals at δC = 126.5 and 129.1 ppm for each of the two couples of the equivalent CH carbons of the aromatic ring, as well as another two signals for the two quaternary carbons at δC = 142.4 and 139.2 ppm, the latter seen as a doublet due to the coupling with the phosphorus atom (4JPC = 1.6 Hz). Phosphonic acid derivative 23 did not provide any toxicity against A549 cell line (Table 1, Entry 10)
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