Reductively triggered internal cyclisation reactions

Abstract

Reductively triggered internal cyclisation reactions have been investigated as a prodrug system for the hypoxia selective release of aromatic nitrogen mustards. The observed pseudo-first-order rate coefficients of cyclisation of several model 2-aminoaryl-acetamides and propanamides have been measured. Cyclisation was observed to be strongly influenced by stereochemistry, whereas electron withdrawal from the amine-bearing ring resulted in a comparatively modest slowing of the rate of cyclisation. Protonation of the leaving group appeared to increase the rate of cyclisation, while changes in 4-substitution on the leaving amine had little effect on this rate. The cyclisation of 2-(2-aminophenyl) alkanamides was found to be subject to general catalysis by acidic buffer components, and rate determining formation of the tetrahedral intermediate has been proposed. Ring closure reactions of several 2-hydroxylaminophenylalkanamides have been studied by γ-radiolysis. HPLC methods have been developed for the separation of reduction and cyclisation products. Reduction stoichiometry implicates the hydroxylamine as the predominant reduction product of radiolysis of the 2-nitrophenylalkanamide precursors, which varied in the nature of substitution of the nitrobenzyl ring, 4-substitution of the leaving aniline, and overall geometry. Cyclisation via the hydroxylamino was observed to be significantly faster than that of its amino counterparts, and was similarly influenced by changes in geometry. The hydroxylamine undergoes a base catalysed, oxygen dependent reaction under aerobic conditions. This reaction did not appear to be influenced by the geometry of the compound. Substitution of the hydroxylamine-bearing ring with a carboxamide group (CONHR σp = 0.36) lowered the pH at which hydroxylamino-amide cyclisation was slowest, compared with its unsubstituted counterpart. The reaction was found to be aided by electron-withdrawal from the leaving amine. Rate determining breakdown of the tetrahedral intermediate has been proposed. Preliminary investigations have been made on 2-nitrophenyl alkyl esters and a 2,6-dinitrophenylamide prodrug system. Rapid, reductively triggered release of coupled phenols and amines has been observed from the nitro-esters and -amides, respectively. In contrast to amino-amide and hydroxylamino-amide cyclisation, gem-dimethyl substitution did not facilitate reductive release from the nitro-ester. The inability to measure the rates of reductive release in radiolysis solutions suggests that these reactions occur significantly faster than hydroxylamino-amide ring closure. Molecular mechanics calculations have been undertaken to investigate relationships between the geometry of 2-aminoarylalkanamides, and rates of cyclisation. The distance between, and angle of approach of the nucleophilic and electrophilic centres in the calculated minimum-energy conformer did not display a correlation with cyclisation rates.