Acyl radicals: Their generation and use as nucleotide radical precursors, fluorous diselenide chemistry

This thesis describes efforts in the generation of acyl radicals and their use as nucleotide radical precursors. Fluorous diselenide chemistry is also described. In the introduction (chapter one), the fragmentation mechanism of C4'-nucleotide radicals is briefly reviewed. The effect of 2'-methoxy substitution group on fragmentation is also addressed. Special focus is placed on the effect of bases on the fragmentation and preparation of C4'alpha-deoxynucleotide radical precursors. Fluorous biphase systems and their application to radical chemistry are also introduced. In chapter two, a novel method of generating acyl radicals under tin free, non-reducing conditions is presented. Arene diazonium salts were used as precursors of aryl radicals in functionalized thiolesters. The acyl radical is generated by an intramolecular substitution of aryl radicals onto sulfur of the thiolester. The problem of purification and disposal as in the case of using tin is therefore avoided. Chapter three describes the preparation of fluorous diselenides, which were reduced in situ to inhibit tin-mediated radical rearrangement reactions. A highly concentrated solution of one of these selenols was used to significantly inhibit a cyclopropylcarbinyl ring opening. Combined with the use of a modified continuous extractor, this selenol was recovered and pure hydrocarbon products were isolated. In chapter four, an asymmetric synthesis of C4'alpha-substituted deoxynucleotides and a kinetic study of C4'alpha nucleotide radical reactions is presented. The important intermediate 4' alpha-substituted methyl deoxyribofuranoside was prepared from dimethyl L-tartrate. Coupling of this substance with standard purine and pyrimidine bases, promoted by tin tetrachloride, provided the corresponding 4 'alpha-substituted nucleotides with moderate yield and selectivity. A series of related bicyclic donors, derived by forming a beta-lactone between the 3-OH and the 4'alpha-carboxy group, were prepared and assayed in coupling reactions. In non-polar solvents good endo-selectivity was observed whereas in acetonitrile the exo-anomers were preferentially obtained. The precursors of C4'alpha-nucleotide radicals were prepared from these intermediates and used in the kinetic study. The competition kinetics were conducted under different concentrations of stannane and it was found that the fragmentation of guanosine was too fast to be measured accurately; however, the fragmentation rates of adenosine, cytidine and thymidine were obtained.