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. 2021 Mar 16;26(6):1654.
doi: 10.3390/molecules26061654.

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

Adrián López-Francés  1 , Xabier Del Corte  1 , Edorta Martínez de Marigorta  1 , Francisco Palacios  1 , Javier Vicario  1
Affiliations

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

Adrián López-Francés et al. Molecules. .

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).

Keywords: Ugi reaction; antiproliferative effect; multicomponent synthesis; tetrasubstituted carbons; α-aminophosphonates.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
The accepted mechanism for an Ugi reaction.
Figure 1
Figure 1
Phosphonopeptides mimic the transition state for peptide cleavage.
Scheme 2
Scheme 2
Scope for the Ugi reaction of α-ketiminophosphonates 10.
Scheme 3
Scheme 3
Ugi reaction of N-tosyl ketimines 10 and 14, phenyl acetic acid 11 and isocyanides 12.
Scheme 4
Scheme 4
Ugi reaction of ketimines 10l,m.
Scheme 5
Scheme 5
Ugi reaction of N-tosyl ketimine 10a, thioacetic acid 17 and methyl isocyanoacetate 12b.
Scheme 6
Scheme 6
Hydrolysis of phosphonate ester 13b.
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