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Open Access Publications from the University of California

Scholarly Works (141 results)

  • Article
  • Peer Reviewed
UC Berkeley Previously Published Works (2017)
One ultimate goal of synthetic chemistry is to install or manipulate any functional group at any position of a molecule. This Account discusses the potential and possible approaches to use catalysis to enable a reaction to occur at one of many C-H bonds or at one of several nearly identical functional groups.
    Cover page: Catalyst-Controlled Site-Selective Bond Activation
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2016)
    This Perspective presents the fundamental principles, the elementary reactions, the initial catalytic systems, and the contemporary catalysts that have converted C-H bond functionalization from a curiosity to a reality for synthetic chemists. Many classes of elementary reactions involving transition-metal complexes cleave C-H bonds at typically unreactive positions. These reactions, coupled with a separate or simultaneous functionalization process lead to products containing new C-C, C-N, and C-O bonds. Such reactions were initially studied for the conversion of light alkanes to liquid products, but they have been used (and commercialized in some cases) most often for the synthesis of the more complex structures of natural products, medicinally active compounds, and aromatic materials. Such a change in direction of research in C-H bond functionalization is remarkable because the reactions must occur at an unactivated C-H bond over functional groups that are more reactive than the C-H bond toward classical reagents. The scope of reactions that form C-C bonds or install functionality at an unactivated C-H bond will be presented, and the potential future utility of these reactions will be discussed.
      Cover page: Evolution of C–H Bond Functionalization from Methane to Methodology
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2014)
      We report Ir-catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β-unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62-94% yield with 90-98% ee and >20:1 branched-to-linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI-9826.
        Cover page: Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2014)
        Reported herein is the iridium-catalyzed regio- and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ-allylated products selectively in 60-84% yield and 90-98% ee.
          Cover page: Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2015)
          Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH2- group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time. For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom. Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation. Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen 'click' cycloadditions and the Staudinger ligation. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment--for example, to fluorescent tags or 'handles' for affinity chromatography--directly on complex molecular structures.
            Cover page: Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization
            • Thesis
            • Peer Reviewed
            UC Berkeley Electronic Theses and Dissertations (2018)

            The following dissertation discusses the development of catalytic enantioselective silylation of aryl, cyclopropyl and unactivated aliphatic C–H bonds. This work also includes in-depth studies that reveal the mechanism of the enantioselective silylation and the origin of enantioselectivity.

            Chapter 1 reviews transition metal-catalyzed reactions that functionalize C–H bonds with an emphasis on enantioselective transformations. This review describes the representative strategies of C–H bond functionalization to obtain site-selectivity. Discussions on the development of enantioselective functionalizations of C–H bonds with representative examples follow.

            Chapter 2 discusses the development of rhodium-catalyzed enantioselecitve silylation of aryl C–H bonds. Hydrosilyl ethers that are formed in situ by hydrosilylation of benzophenone or its derivatives undergo enantioselective C−H silylation in the presence of a rhodium catalyst. Enantioenriched benzoxasilole products from the silylation process undergo a range of transformations to form C−C, C−O, C−I, or C−Br bonds without erosion of enantiomeric excess.

            Chapter 3 discusses experimental and theoretical studies on the mechanism of
 rhodium-catalyzed enantioselective silylation of aryl C−H bonds. The identity of the resting states of the catalyst, the kinetic data, and the results of DFT calculations provide detailed insights into the mechanism of intramolecular enantioselective silylation of aryl C−H bonds and the origin of enantioselectivity.

            Chapter 4 discusses the development of rhodium-catalyzed enantioselecitve silylation of cyclopropyl C–H bonds. Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo enantioselective silylation of cyclopropyl C–H bonds in the presence of a rhodium catalyst. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao–Fleming oxidation to form cyclopropanols with conservation of the ee value from the C–H silylation.

            Chapter 5 discusses the development of iridium-catalyzed silylation of unactivated sp3 C–H bonds of amines. The introduction of silylmethyl group on a secondary amine allows a site-selective functionalization of β-C–H bonds of amines to form silapyrrolidines. Development of both non-enantioselective and enantioselective catalysts is described. The silapyrrolidne product serves as a precursor to 1,2-amino alcohols by the oxidation of the silapyrrolidines, leading to an overall site-selective, and even enantioselective, oxidation of amines at the β-C–H bonds.

              Cover page: Transition Metal-Catalyzed Enantioselective Silylation of C–H bonds: Reaction Development and Mechanistic Studies
              • Article
              • Peer Reviewed
              UC Berkeley Previously Published Works (2018)
              peri-Disubstituted naphthalenes exhibit interesting physical properties and unique chemical reactivity, due to the parallel arrangement of the bonds to the two peri-disposed substituents. Regioselective installation of a functional group at the position peri to 1-substituted naphthalenes is challenging due to the steric interaction between the existing substituent and the position at which the second one would be installed. We report an iridium-catalyzed borylation of the C-H bond peri to a silyl group in naphthalenes and analogous polyaromatic hydrocarbons. The reaction occurs under mild conditions with wide functional group tolerance. The silyl group and the boryl group in the resulting products are precursors to a range of functional groups bound to the naphthalene ring through C-C, C-O, C-N, C-Br and C-Cl bonds.
                Cover page: Iridium‐Catalyzed, Silyl‐Directed, peri‐Borylation of C−H Bonds in Fused Polycyclic Arenes and Heteroarenes
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2015)
                The enol silanes of vinylogous esters and amides are classic dienes for Diels-Alder reactions. Here, we report their reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti-muscarinic drug, fesoterodine.
                  Cover page: Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides
                  • Article
                  • Peer Reviewed
                  UC Berkeley Previously Published Works (2022)
                  Enantioselective reactions that install functional groups at the positions of unactivated C-H bonds can be envisioned to produce intermediates for the synthesis of the active ingredients in pharmaceuticals and agrochemicals directly from simple feedstocks. Among these C-H bond functionalization reactions, those that form carbon-silicon (C-Si) and carbon-boron (C-B) bonds have been pursued because the products of these reactions can be converted to those containing a wide range of functional groups and because compounds containing silicon and boron possess unique properties that can be valuable for medicinal and materials chemistry. Although the silylation and borylation of C-H bonds have undergone extensive development during the past two decades, enantioselective versions of these reactions were not known until a few years ago. In this Minireview, we present the rapid development of enantioselective silylation and borylation of C-H bonds, with an emphasis on the design and development of the types of chiral ligands needed to achieve these reactions and an intention to inspire an expansion of these types of transformations.
                    Cover page: Development of Chiral Ligands for the Transition‐Metal‐Catalyzed Enantioselective Silylation and Borylation of C−H Bonds
                    • Article
                    • Peer Reviewed
                    UC Berkeley Previously Published Works (2021)
                    Here, we report a class of ligands based on oxalohydrazide cores and N-amino pyrrole and N-amino indole units that generates long-lived copper catalysts for couplings that form the C-O bonds in biaryl ethers. These Cu-catalyzed coupling of phenols with aryl bromides occurred with turnovers up to 8000, a value which is nearly two orders of magnitude higher than those of prior couplings to form biaryl ethers and nearly an order of magnitude higher than those of any prior copper-catalyzed coupling of aryl bromides and chlorides. This ligand also led to copper systems that catalyze the coupling of aryl chlorides with phenols and the coupling of aryl bromides and iodides with primary benzylic and aliphatic alcohols. A wide variety of functional groups including nitriles, halides, ethers, ketones, amines, esters, amides, vinylarenes, alcohols and boronic acid esters were tolerated, and reactions occurred with aryl bromides in pharmaceutically related structures.
                      Cover page: Oxalohydrazide Ligands for Copper‐Catalyzed C−O Coupling Reactions with High Turnover Numbers
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