Phosphodiester Alkylation with a Quinone Methide

Abstract

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.

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

“…Turnbull reported the investigation of the reactivity of a p-quinone methide with mildly nucleophilic phosphodiesters as models for nucleic acid polymers (Scheme 23) [59]. They studied the reaction of dialkyl phosphates with a p-quinone methide to determine the potential for alkylation to produce trialkyphosphates.…”

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

“…The investigation of such molecules and reactions could then be used as a methodt od evelop effective therapeuticsf or in vitro and in vivo re-alkylation of aged AChE. [154][155][156] The first report of alkylation of ap hosphodiester was published by Turnbull and co-worker in 1999. [154] This study made use of a p-quinonem ethide generated from mixing 2,4,6-trimethylphenol with silver oxide in organic solution (Figure 42).…”

“…[154][155][156] The first report of alkylation of ap hosphodiester was published by Turnbull and co-worker in 1999. [154] This study made use of a p-quinonem ethide generated from mixing 2,4,6-trimethylphenol with silver oxide in organic solution (Figure 42). Upon the generation of the QM, an organic solution of tetrabutylammonium dibenzyl phosphate was added,b ut no product was observed by 1 HNMR spectroscopy until the addition of MsOH.…”

“…Initialreaction showing the potential of QM alkylation of phosphodiesters. [154] Figure 43. Subsequent study showing the potentialofQ Ma lkylation of phosphodiesters.…”

Organocatalyzed Decarboxylation of Naturally Occurring Cinnamic Acids: Potential Role in Flavoring Chemicals Production

“…Quinone methides are common reactive intermediates extensively employed by nature, particularly in the mechanism of action displayed by a variety of bioactive compounds [25,26]. The stability of such intermediates is essential to evaluate the outcome of the reaction.…”