UC Berkeley

The following dissertation discusses the development and application of new conceptual frameworks for the synthesis of complex organic molecules. The focus of this work is divided into three conceptually related, but synthetically distinct categories within the fields of synthetic methodological development and the total synthesis of natural products.Chapter 1 describes the development of a C–C cleavage/cross-coupling approach for the synthesis of macrocyclic compounds. Important physical-organic insights were gleaned through computational chemistry using Density Functional Theory (DFT), elucidating a clear trend between the ring size of the product and the efficiency of the reaction, and establishing that the kinetic and thermodynamic challenges associated with macrocyclization reactions can be addressed through strain-release and transition metal-mediated reaction templating. The method developed was applied to the synthesis of a number of Resorcylic Acid Lactone (RAL) natural products.Chapter 2 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 by tris(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 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 concise synthesis of the complex sesquiterpenoid alkaloid natural product, hispidospermidin, using an “Inside-Out” strategy. In contrast to the three previous landmark syntheses, all of which employ mid-to-late construction if the maximally bridged ring, our work constructs the bicyclo[3.1.1]nonane core in the very first step of the synthesis. Other key steps include the development of a Giese conjugate addition of a bridgehead radical to methylacrylate to forge the quaternary center of the natural product; a phosphine-mediated isomerization reaction was discovered which enabled the construction of the challenging trans-hydrindane moiety of the natural product; lastly, a desaturation was employed to enable the construction of the tetrahydrofuran at a late stage. Analysis of the complexity landscape of each of the four syntheses reveals a correlation between the step of the synthesis in which the primary complexity element is synthesized and the overall step count, i.e., an earlier bicycle construction is associated with a more efficient route.