Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells

Abstract

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N–C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2H-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O- or S-nucleophiles to the starting 2H-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested.

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

“…They presented an IC 50 Value of 16.14 ± 1.14 µM and 14.56 ± 2.53 µM, respectively ( López-Francés et al, 2021 ). The same group also reported antiproliferative effect on A549 cells of some novel a-aminophosphonic acid derivatives 9–11 synthesized through the addition of O- and S- nucleophiles to 2H-azirines ( Supplementary Scheme S8 ) ( Carrraminana et al, 2020 ). All the compounds 9–11 showed selectivity on cancer cells (A549) over non-malignant cells (MCR-5).…”

2H‐Azirines: Recent Progress in Synthesis and Applications

“…Interestingly, Palacios and co‐workers [148] described the addition of oxygen and sulfur nucleophiles to C=N bond of 2H ‐azirines to afford aminophosphine oxides and phosphonates, some of which exhibit very good activity against the human lung adenocarcinoma (A549) cell line in vitro (Scheme 95b). The choice of products relied on the nature of the nucleophile.…”

Diastereoselective ZnCl2-Mediated Joullié–Ugi Three-Component Reaction for the Preparation of Phosphorylated N-Acylaziridines from 2H-Azirines

“…We have been previously involved in the chemistry of phosphorus-substituted 2 H -azirines for the synthesis of phosphorylated cyanoaziridines [ 30 ] and their ring expansion [ 31 ], hybrid molecules such as azirino[2,1- b ]benzo[ e ][1,3]oxazines [ 45 ] or α-aminophosphonic acid derivatives [ 46 ]. In continuation of our previous research works, as depicted in ( Scheme 1 , Equation (5)), here, we describe a diastereoselective approach to phosphorylated N -acylaziridine 2-carboxamide derivatives through the JU-3CR using phosphorus-substituted 2 H -azirines such as 3-membered cyclic imines, carboxylic acids and isocyanides ( Figure 2 ).…”