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 t o undergo spontaneous loss of chloride, and the resulting cationic rad ical loses a proton to give a 3'-keto intermediate. Successive beta-el iminations produce a Michael acceptor which causes inactivation. This hypothesis would predict rapid loss of mesylate or tosylate anions fro m 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 sh ould 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-(me syl and tosyl) and 2'-fluoro compounds underwent direct radical-mediat ed hydrogenolysis of the thionocarbonate group to give 3'-deoxy-2'-sub stituted products, whereas 2'-(azido, bromo, chloro, iodo, and methylt hio)-3'-thionocarbonates gave 2',3'-didehydro-2',3'-dideoxy derivative s via loss of 2'-substituents from an incipient C3' radical. These res ults are in harmony with loss of radicals, but not anions, from C2'. T he well-known radical-mediated hydrogenolytic cleavage of halogen and methylthio (slow) groups from C2' of the S'-hydroxy (unprotected) prec ursors and reduction of 2'-azides to amines occurred with tributylstan nane/AIBN. Triphenylsilane/dibenzoyl peroxide gave parallel (but slowe r) 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, chemoselectiv e differentiation of certain functional groups is possible with triphe nylsilane and tributylstannane. Reduction of azides to amines with tri butylstannane is known, but hydrogenolytic deazidation (slow) with tri phenylsilane in the absence of amine formation appears to be novel.