The Reactivity of Thymine and Thymidine 5,6-Epoxides with Organometallic Reagents – A Route to Thymidine (6-4) Photoproduct Analogues

This
report describes an efficient procedure for the generation
and isolation of various thymine and thymidine 5,6-epoxides from the
corresponding trans-5,6-bromohydrins by reaction
with triethylamine. The quantitative isolation of the epoxides, accomplished
by solvent precipitation of triethylamine hydrobromide, enabled their
regiospecific ring-opening at C6 position by organometallic nucleophiles.
The reaction was amenable to a broad range of alkyl, aryl, alkenyl,
and alkynyl organomagnesium, -zinc, -aluminum, or -boron reagents,
although the reactivity was strongly affected by the electronic effects
of N3 protecting group. Additionally, the reaction featured excellent cis-diastereoselectivity providing access to C6-carbon-functionalized
dihydrothymidine cis-alcohols, which are synthetic
derivatives of UV-induced DNA lesions, namely, thymidine (6-4) photoproducts.