Biomimetic simulation of free radical-initiated cascade reactions postulated to occur at the active site of ribonucleotide reductases

Treatment of 5'-O-nitro esters of nucleosides with tributylstannane and AIB N at elevated temperatures caused beta-scission of the resulting 5'-oxygen radical to give formaldehyde and dehomologated erythrofuranosyl nucleosides . Analogous treatment of 6'-O-nitro esters of homonucleosides [(5-deoxy-bet a-D-ribo-hexofuranosyl)-adenine or uracil nucleosides derived from D-glucos e] resulted in generation of a 6'-oxygen radical followed by abstraction of H3' by a [1,5]-hydrogen shift. Radical quenching with tributyltin deuterid e gave 3'-[H-2]-homonucleosides. This deuterium transfer, and inversion of configuration at C3' with unprotected homonucleosides, confirmed the relay- generation of C3' free radicals. Analogous treatment of 6'-O-nitro esters o f homonucleosides containing a 2'-chloro (30) or 2'-O-tosyl (40) substituen t resulted in complete disappearance of starting material and generation of (R)-2-(2-hydroxyethyl)-3(2H)-furanone (33). Generation of a 6'-oxygen radi cal, [1,5]-hydrogen shift of H3' to give a C3' radical, and loss of the 2'- substituent would give unstable intermediates that could lose the heterocyc lic base from C1' to give 33. This radical-initiated cascade simulates reac tions postulated to occur at the active site of ribonucleotide reductases. Generation of a C3' radical from 40 and loss of toluenesulfonic acid via a [1,2]-electron shift would generate a radical intermediate that could under go deuterium transfer followed by beta-elimination of the base to give the deuterated furanone 33, as observed. This is in harmony with a new mechanis m for substrate reduction of nucleotides to give 2'-deoxy products. Generat ion of a C3' radical from 30 and loss of a chlorine atom by beta-radical el imination would result in conjugate elimination of base and generation of 3 3 without incorporation of deuterium, as observed. Thus, one-electron elimi nation processes (as well as the previously postulated two-electron loss wi th groups from C2') must be considered with mechanism-based inactivators of ribonucleotide reductases. Biomimetic reactions and new mechanistic consid erations are discussed.