Biomimetic Simulation of Free Radical-Initiated Cascade Reactions Postulated To Occur at the Active Site of Ribonucleotide Reductases¹

Treatment of 5‘- O- nitro esters of nucleosides with tributylstannane and AIBN at elevated temperatures caused β-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-β- d - ribo- hexofuranosyl)adenine or uracil nucleosides derived from d -glucose] resulted in generation of a 6‘-oxygen radical followed by abstraction of H3‘ by a [1,5]-hydrogen shift. Radical quenching with tributyltin deuteride gave 3‘-[ 2 H]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 of homonucleosides containing a 2‘-chloro ( 30 ) or 2‘- O- tosyl ( 40 ) substituent resulted in complete disappearance of starting material and generation of ( R )-2-(2-hydroxyethyl)-3(2 H )-furanone ( 33 ). Generation of a 6‘-oxygen radical, [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 heterocyclic base from C1‘ to give 33 . This radical-initiated cascade simulates reactions 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 undergo deuterium transfer followed by β-elimination of the base to give the deuterated furanone 33, as observed. This is in harmony with a new mechanism for substrate reduction of nucleotides to give 2‘-deoxy products. Generation of a C3‘ radical from 30 and loss of a chlorine atom by β-radical elimination would result in conjugate elimination of base and generation of 33 without incorporation of deuterium, as observed. Thus, one-electron elimination processes (as well as the previously postulated two-electron loss with groups from C2‘) must be considered with mechanism-based inactivators of ribonucleotide reductases. Biomimetic reactions and new mechanistic considerations are discussed.