Radical-mediated heterocycle functionalization: Methodology development and natural product synthesis.

摘要

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-CH 3OC6H4NPh, 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 Cl3 CBr 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.