Nucleic acid related compounds .91. Biomimetic reactions are in harmony with loss of 2'-substituents as free radicals (not anions) during mechanism-based inactivation of ribonucleotide reductases. Differential interactions of azide, halogen, and alkylthio groups with tributylstannane and triphenylsilane

The initial step in the mechanism-based inactivation of ribonucleotide reductases by 2'-chloro-2'-deoxynucleotides is abstraction of H3' by a proximal free radical on the enzyme. The C3' radical is postulated to undergo spontaneous loss of chloride, and the resulting cationic radical loses a proton to give a 3'-keto intermediate. Successive beta-eliminations produce a Michael acceptor which causes inactivation. This hypothesis would predict rapid loss of mesylate or tosylate anions from C2', but sluggish loss of azide or thiomethoxide. in contrast, loss of azido and methylthio radicals from C2' should occur readily whereas homolysis to give (methyl or tolylsulfonyl)oxy and fluoro radicals should be energetically prohibitive. Protected 3'-O-(phenoxythiocarbonyl)-2'-substitute nucleosides were treated with tributylstannane/AIBN or triphenylsilane/dibenzoyl peroxide in refluxing toluene. The 2'-O-(mesyl and tosyl) and 2'-fluoro compounds underwent direct radical-mediated hydrogenolysis of the thionocarbonate group to give 3'-deoxy-2'-substituted products, whereas 2'-(azido, bromo, chloro, iodo, and methylthio)-3'-thionocarbonates gave 2',3'-didehydro-2',3'-dideoxy derivatives via loss of 2'-substituents from an incipient C3' radical. These results are in harmony with loss of radicals, but not anions, from C2'. The well-known radical-mediated hydrogenolytic cleavage of halogen and methylthio (slow) groups from C2' of the S'-hydroxy (unprotected) precursors and reduction of 2'-azides to amines occurred with tributylstannane/AIBN. Triphenylsilane/dibenzoyl peroxide gave parallel (but slower) hydrogenolysis with the 2'-(iodo, bromo, and methylthio) compounds, but cleavage of the 2'-chloro group was very slow and no reduction of 2'-azides to amines was detected. Rather, the latter system effected slow hydrogenolytic removal of the 2'-azido group. Thus, chemoselective differentiation of certain functional groups is possible with triphenylsilane and tributylstannane. Reduction of azides to amines with tributylstannane is known, but hydrogenolytic deazidation (slow) with triphenylsilane in the absence of amine formation appears to be novel.