Enantioenriched Cyclic Boronates as Versatile Building Blocks: Synthesis, Mechanism and Applications

  • Author / Creator
    Clement, Helen
  • Since the discovery and development of the famed Suzuki-Miyaura cross-coupling reaction, organoboron compounds have gained increasing attention as small molecule building blocks in organic synthesis and drug discovery efforts. In this regard, enantioenriched alkyl boronic esters are ideal synthetic intermediates due to their low toxicity, configurational stability and versatile reactivity. As a result, catalytic enantioselective approaches to boronic esters have seen remarkable advancements within the past decade. Although a variety of enantioenriched boronic ester scaffolds continue to accumulate in the organoboron literature, the number of catalytic methodologies to afford linear, hydrocarbon-based scaffolds with limited functionality other than the boronate group has become pervasive. In this regard, this thesis focuses on the development of methodologies to access novel enantioenriched cyclic and heterocyclic chiral boronates with increased functionality. The products obtained have potential to be versatile building blocks in medicinal chemistry. Chapter 2 describes efforts to expand the substrate scope of a powerful methodology previously reported by the Hall Group, namely the borylative migration of enol sulfonates. To-date the borylative migration had only been applied to the synthesis of pyranyl and piperidinyl allylic boronates. The substrate scope expansion of the palladium-catalyzed enantioselective borylative migration reaction is explored for five different novel electrophiles. An optimization for the 7-membered nitrogen-containing azepane ring is achieved. The applicability of the allylic boronate product is displayed in the synthesis of a small set of novel α-hydroxyalkyl dehydroazepanes upon aldehyde allylboration. The utility of the developed approach is portrayed in the synthesis of the azepane derivative of the biologically active piperidine-based amino alcohol, β-conhydrine. Considering the difficulty in expanding the borylative migration to new electrophiles, a better mechanistic understanding of this reaction is desirable. In this regard, Chapter 3 describes efforts to decipher a reasonable catalytic pathway by which the unique borylative migration reaction of pyranyl and piperidinyl electrophiles may occur using a combined experimental and computational approach. In a collaborative effort with an expert of computational chemistry, a detailed discussion of the potential steps in the catalytic cycle is presented. Key insights throughout this study suggest a rate-limiting oxidative addition, a substrate-controlled palladium hydride alkene isomerization and that the amine base has multiple roles in the reaction. In the end, a new mechanistic perspective of the borylative migration reaction is provided. The focus of Chapter 4 moves to the synthesis of four membered rings, specifically the synthesis of novel cyclobutylboronates. An optimization of the first catalytic enantioselective approach to tertiary cyclobutylboronates is described, using copper-catalyzed borylation of α,β-disubstituted cyclobutenones. The project includes the development of a novel reliable synthetic approach to the cyclobutenone substrates. In a collaborative effort with chemists from Pfizer Inc., a high-throughput-ligand screening study reveals an appropriate starting point for the challenging borylation of interest. Optimization of the conjugate borylation allows a general approach to enantioenriched tertiary cyclobutylboronates. The utility of the products is displayed by chemoselective functional group manipulations of both the ketone and boronic ester moieties.

  • Subjects / Keywords
  • Graduation date
    Spring 2020
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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