Improved alkylation and product stability in phosphotriester formation through quinone methide reactions with dialkyl phosphates.

Investigating reactions of functionalized p-quinone methides continues to advance our design of a reagent being developed for controlled, in situ modification of DNA via phosphodiester alkylation. Previously reported investigations of p-quinone methides derived from catechols allowed for trapping of isolable trialkyl phosphates for characterization and mechanistic information. However, lactone formation with these derivatives required long reaction times, resulting in an unfavorable mixture of trialkyl phosphate and hydrolysis products. To enhance the rate and efficacy of trialkyl phosphate formation and trapping, a phenol derived p-quinone methide has been designed to enforce a conformation favoring lactonization of the dialkyl phosphate alkylated intermediate. The relative rates of phosphodiester alkylation and subsequent trapping of the phosphotriester adduct have been examined by UV and (1)H NMR analysis for p-quinone methide precursor 1 and the corresponding control, 1'. The incorporation of a methyl group at the meta-position of 1 (relative to 1') significantly improves the rate of lactionization to provide a much higher yield of the desired product, lactonized phosphotriester 5. The control reaction with 1' afforded only a minor amount of the corresponding lactonized trialkyl phosphate 5'.

Phosphodiester Alkylation with a Quinone Methide.

Despite the wide array of studies involving DNA alkylation and cleavage with quinone methide generating compounds, there have been no reports on the alkylation of phosphodiesters with quinone methides. We have investigated the reaction of dialkyl phosphates with a p-quinone methide in order to determine the potential for alkylation to produce trialkyphosphates. These studies have revealed that a phosphodiester can be alkylated with a p-quinone methide when promoted by a Brønsted acid. The role of the Brønsted acid is to sufficiently activate the p-quinone methide to allow phosphodiester addition to occur. The alkyl substituents of the phosphodiester have been found to effect the reactivity of the dialkyl phosphate under the reaction conditions examined. Equilibrium conversions up to 83% trialkyl phosphate formation have been achieved.