Radical mediated heterocycle functionalization: methodology development and natural product synthesis

Substituted heterocycles are common building-blocks for biologically relevant molecules and represent challenging synthetic targets. Due to limited methods available for their preparation and derivatization, direct C-H functionalization protocols offer considerable advantages. Radical chemistry has shown great potential in this regard; however traditional approaches are unattractive due to poor selectivity and harsh reaction conditions. Visible light photoredox catalysis, on the other hand, is a mild alternative for alkyl radical generation and has proven its utility in organic synthesis. The work encompassed in this thesis details the efforts towards the development of practical photoredox-based functionalizations of heterocycles. Specific focus is placed upon overcoming obstacles pertaining to H-atom abstraction, back electron transfer, and redox strength of photocatalysts to achieve efficient C-Br bond reductions, amine oxidations, and C-C bond formations. In pursuit of these objectives, a C2-selective malonation of indoles and other electron-rich heteroarenes was accomplished in high yields using photocatalyst Ru(bpy)3Cl2, p-CH3OC6H4NPh, and blue LEDs as the light source. Use of a triarylamine over a trialkylamine suppressed H-atom abstraction and promoted C-C bond formation. Subsequent exploitation of the reductive quenching cycle of Ru(bpy)3Cl2 and use of Cl3CBr as an alternative oxidant led to an oxidative nucleophilic trapping of tetrahydroisoquinolines to provide a diverse set of analogues. Finally, photoredox catalysis was utilized for the creation of C-C bonds in the context of complex molecule synthesis. A variety of bromopyrroloindolines and indoles were coupled to furnish C3-C3' and C3-C2' bisindole alkaloids, which was successfully applied to the total synthesis of gliocladin C and related analogues. Moreover, fine-tuning of the redox cycle with photocatalyst Ir(ppy)2(dtbbpy)PF6 and LiB(cat)2 as the reductive quencher enabled the coupling less-reactive substrates and suppression of back electron transfer