Trapping phosphodiester-quinone methide adducts through in situ lactonization

The goal of in situ modification of DNA via phosphodiester alkylation has l ed to our design of quinone methide derivatives capable of alkylating dialk yl phosphates. A series of catechol derivatives were investigated to trap t he phosphodiester-quinone methide alkylation adduct through in situ lactoni zation. The catechol derivatives were uniquely capable of characterizable p -quinone methide formation for mechanistic clarity. These investigations re vealed that with a highly reactive lactonization group (phenyl eater), lact onization competed with quinone methide formation. Lactone-forming groups o f lower reactivity (methyl ester, n-propyl ester, and dimethyl amide) allow ed quinone methide formation followed by phosphodiester alkylation; however , they were ineffective at in situ lactonization to drain the phosphodieste r alkylation equilibrium to the desired phosphotriester product. The deriva tives tethered with lactone-forming functionality of intermediate reactivit y (chloro-, trichloro-, and trifluoroethyl esters), allowed quinone methide formation, phosphodiester alkylation, and in situ lactonization to efficie ntly afford the trapped phosphotriester adduct.