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.