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Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2022)

The following dissertation discusses the development and application of transition metal-catalyzed C–C bond functionalization in strained heterocycles. The first focus of this work will be directed toward the formation of unstrained, fused-ring saturated aza-cycles through C–H/C–C bond cleavage/functionalization. A further focus was directed toward the construction of medium-sized oxacycles through C–C bond formation/cleavage of cyclobutenol derivatives.

Chapter 1. A C–H/C–C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles

Our efforts toward the synthesis of fused aza-cycles from unfunctionalized cyclic amines by leveraging the release of ring strain is described. Specifically, the C−H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from α-ketoamide precursors under mild, visible light conditions. Regioselective cleavage of a C–C bond in the β-lactams using a Rh-complex followed by a cascade reaction of decarbonylation, 1,4-addition to an electrophile, and aldol cyclization reactions led to N-fused bicycles.

Chapter 2. Construction of Seven-Membered Oxacycles Using a Rh-catalyzed Cascade C–C formation/Cleavage of Cyclobutenol Derivatives

A method for synthesizing seven-membered oxacycles through the molecular remodeling of four-membered cyclobutenols derived from the commercially available squaric acid by leveraging their inherent strain and enone moiety is described. Notably, the use of Xantphos type ligands and rhodium complexes facilitated access to versatile oxepane derivatives through sequential intermolecular oxa-Michael addition and intramolecular migratory insertion followed by a C–C cleavage event.

    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2024)
    Herein, we describe the synthesis of substituted oxepane derivatives through the skeletal remodeling of 4-hydroxy-2-cyclobutenones, which are readily prepared from commercially available dialkyl squarates upon their reaction with acrylonitrile. Mechanistically, a Rh(I)-catalyzed C-C bond formation and cleavage cascade is proposed. Specifically, a fused [3.2.0] bicycle is proposed to form from dialkyl squarate-derived cyclobutenols via an unusual Rh(I)-catalyzed intermolecular oxa-Michael addition of a tertiary alcohol with acrylonitrile, followed by an intramolecular conjugate addition/migratory insertion. Subsequent C(sp3)-C(sp3) bond cleavage through a Rh-catalyzed β-carbon elimination is then theorized to furnish the oxepane scaffold. Computational studies support the formation of an intermediate [3.2.0] bicycle but also point to an alternative pathway for the formation of the oxepane products involving a Rh(III) intermediate. Additional studies have shown the overall process to be stereoretentive. The functional groups that are introduced in this process can be leveraged to form fused or bridged ring systems.
      Cover page: Construction of Seven-Membered Oxacycles Using a Rh(I)-Catalyzed Cascade C-C Formation/Cleavage of Cyclobutenol Derivatives.
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2020)
      Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-β-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2022)
        Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.
          Cover page: General Synthetic Approach to Diverse Taxane Cores
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2020)
          The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.
            • Article
            • Peer Reviewed
            UC Berkeley Previously Published Works (2020)
            Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-β-lactams under mild, visible light conditions using a Norrish-Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-β-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.
              Cover page: C–C Cleavage Approach to C–H Functionalization of Saturated Aza-Cycles
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