Synthesis and site-specific incorporation of a bay-region cis ring-opened tetrahydro epoxide-deoxyadenosine adduct into a DNA oligomer

Abstract

Chemical synthesis of the 1,2,3,4-tetrahydrophenanthrene 3,4-epoxide adducts resulting from benzylic, cis ring-opening of the epoxide by the exocyclic amino group of 2'-deoxyadenosine (dA) is described. The approach taken consists of coupling (±)-cis-3-hydroxy-4-amino-1,2,3,4-tetrahydrophenanthrene with a 6-fluoro analogue of dA in which the furanose hydroxyl groups are protected. The required amino alcohol was obtained by reaction of 1,2-dihydrophenanthrene with osmium tetraoxide to form the cis 3,4-diol conversion to the trans chlorohydrin benzoate via its orthobenzoate, displacement of the benzylic chloride by azide, hydrolysis to the cis azido alcohol. Coupling of the amino alcohol with the 3',5'-bis-O-(tert-butyldimethylsilyl) derivative of 6-fluoro-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine results in a pair of diastereomers that are readily separated by HPLC on silica gel