UC Berkeley

The following dissertation discusses the development and application of novel synthetic methodologies for the rearrangement of benzene-fused saturated heterocycles through both thermal and photochemical strategies.Chapter 1 describes an exploration of the photochemical reactivity of diketones with regards to the ring contraction of piperidines and tetrahydropyrans. While the isomerization of the piperidine core to the 5,5-azabicyclooctane scaffold was unsuccessful, studies comparing diketone and aryl ketone photochemical reactivity on tetrahydropyran substrates where both ketones had productive reactivity. Chapter 2 describes the development of a method for the single-atom nitrogen-to-carbon replacement in isoindoline scaffolds. The described transformation is enabled by a two-step one pot protocol involving both a thermal Stevens rearrangement ring expansion and photochemical ring contraction. This work represents a novel exploration of the photochemical ring contraction on N-alkyl, and benzene-fused systems. In cases with electron-withdrawing alkyl groups, divergent reactivity can be observed where the nitrogen atom is not fully removed from the ring, and from these observations, new conclusions regarding the photochemical and thermal stability of the ring contraction products are described. Chapter 3 describes the development of a reductive amination reaction which reductively aminates the C–C bond attached to ketones and aldehydes. By extending this concept of traceless reactive handles, we showed that known C–H oxidation technologies could be leveraged to install ketones and aldehydes, which facilitate the C–C amination process, along with concomitant reduction of the carbonyl functionality. In this way, our developed method enables the formal insertion of a single nitrogen atom into C–C bonds of hydrocarbon feedstocks without a reliance on strain. Among a vast array of applications, this method was applied to the late-stage C–C amination of complex frameworks, enabling rapid access to otherwise-difficult-to-access scaffolds, including an aza-steroid and aza-cannabanoid. Chapter 4 describes the development of a traceless reactive handle strategy for the single atom skeletal editing of saturated cyclic amines through constitutional isomerization, thus avoiding vestigial functional groups in the desired product. Notably, by using known methods for amine N- oxidation to generate isolable hydroxylamine intermediates, these hydroxylamine functional groups serve to facilitate a reductive rearrangement reaction catalyzed bytris(pentafluorophenyl)borane using a silane terminal reductant, converting piperidines to pyrrolidines. The mechanism of the reaction was investigated with in-depth DFT calculations of the potential energy surface (PES), and the method was applied to the constitutional isomerization of FDA-approved drugs, such as dextromethorphan and PaxilTM. Chapter 5 describes the development a photochemical method for the formal 1,2-transposition of aryl ketone, ester, carboxylic acid, and amide functional groups. This methodology is enabled by a photochemical isomerization of dihydrobenzofurans to a de-aromatized and highly electrophilic spiro-cyclopropane species that can be intercepted by a halide nucleophile to drive the described isomerization. This method enables the facile diversification of drug-like molecules with dihydrobenzofuran cores. The mechanism of the photochemical process is examined by time-course study to determine that the photochemical process is likely radical-mediated.