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@PHDTHESIS{Ganardi:1047601,
      author       = {Ganardi, Ruth Christine},
      title        = {{L}ipase-catalyzed kinetic resolution: {S}ynthesis and
                      application of axially chiral biphenols},
      volume       = {51},
      school       = {Düsseldorf},
      type         = {Dissertation},
      address      = {Jülich},
      publisher    = {Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag},
      reportid     = {FZJ-2025-04404},
      isbn         = {978-3-95806-854-4},
      series       = {Bioorganische Chemie an der Heinrich-Heine-Universität im
                      Forschungszentrum Jülich},
      pages        = {423},
      year         = {2025},
      note         = {Dissertation, Düsseldorf, 2025},
      abstract     = {In this work, the atroposelective synthesis of
                      tetra-ortho-substituted biphenols was studied. The focus was
                      on the construction and application of the important
                      2,2′-biphenol building block 1, which represents a common
                      motif of various aromatic polyketide dimers (Figure 1).
                      Central aspects of this study were the enzymatic kinetic
                      resolution for the isolation of enantiopure biphenol 1 and
                      the application of the biphenol building block 1 in the
                      total synthesis of dimeric polyketides. Figure 1 Structure
                      of 2,2′-biphenol building block rac-1 and target natural
                      products: γ-binaphthopyrones 2–3 and bicoumarins 4–5.
                      The challenging construction of the sterically hindered
                      2,2′-biphenol building block rac‑1 was performed and
                      discussed, based on the reaction procedures of Greb et
                      al.[1, 2] Therefore, racemic homocouplings via Lipshutz
                      coupling and Miyaura borylation Suzuki coupling (MBSC) were
                      compared, leading to the isolation of the axially chiral
                      biphenol rac‑1 in overall $50\%$ yield over eight steps
                      starting from commercially available starting material. The
                      atroposelective transformation of the racemic biphenol
                      substrate rac‑1 was investigated by an enzyme screening of
                      hydrolases. A scalable enzymatic kinetic resolution method
                      was established by applying commercially available Candida
                      rugosa lipase (CRL) for the atroposelective hydrolysis of
                      biphenyl dipropionate. Optimization of this reaction system
                      revealed the major influence of the diester’s fatty acid
                      chain length and the choice of the solvent system on the
                      enzyme’s selectivity and activity. In addition to the
                      established resolution method, investigations were carried
                      out to evaluate the applicability of the enzymatic kinetic
                      resolution on a biphenol substrate scope. The aim was to
                      study the influence of the substitution pattern on the
                      enzyme’s activity and selectivity. In order to address a
                      broader substrate scope, the homocoupling via directed
                      ortho-metalation was investigated. This eliminated the need
                      for regioselective bromination. A homocoupling via directed
                      ortho-cupration (DOC) using an organoamidocuprate was used
                      for the isolation of biphenyl products in yields up to
                      $64\%.$ Yet, this method proved to exhibit different
                      regioselectivities depending on the substitution pattern. In
                      summary, a dedicated library of eight axially chiral
                      biphenols were obtained, which were used in the
                      CRL-catalyzed resolution under the optimized conditions. The
                      results of the enzymatic kinetic resolution showed that the
                      choice of the para-substituents had a minor effect on the
                      enzyme’s activity $(47–58\%)$ and selectivity
                      $(79–>99\%$ ee). In contrast, the orthosubstituents had a
                      major effect on the enzyme’s activity and selectivity and
                      resulted in a drop of conversion and selectivity. Finally,
                      the isolated enantiopure biphenol 1 was applied in the total
                      synthesis of dimeric polyketides. Here, the total syntheses
                      towards γ-binaphthopyrones ustilaginoidin A (2) and F (3)
                      were investigated (Figure 1). The key step in this approach
                      is the annulation reaction with the electrophilic pyrone.
                      The first total synthesis of the γ-naphthopyrone monomer of
                      ustilaginoidin F (3) was achieved with a total yield of
                      $49\%$ in two steps. The optimized conditions for the
                      synthesis of the γ-naphthopyrone monomer were transferred
                      on the total synthesis of dimeric ustilaginoidin F (3).
                      However, bidirectional Myers’ annulation proved to be
                      rather challenging and led only to mono-annulation. At last,
                      the axially chiral bicoumarins (M)-isokotanin A (4) and
                      (P)-isokotanin C (5) were chosen as alternative targets
                      (Figure 1). Upon utilization of the enantiopure biphenol 1
                      in the developed synthesis route, enantiopure (M)-isokotanin
                      A (4) was successfully obtained in $11\%$ overall yield over
                      eight steps. Compared to known asymmetric routes, the
                      combination of the metal-catalyzed homocoupling and the
                      enzymatic resolution enables a scalable and more efficient
                      method towards a common intermediate in the synthetic
                      pathway with a reduction of hazardous chemicals.},
      cin          = {IBOC},
      cid          = {I:(DE-Juel1)IBOC-20090406},
      pnm          = {2172 - Utilization of renewable carbon and energy sources
                      and engineering of ecosystem functions (POF4-217)},
      pid          = {G:(DE-HGF)POF4-2172},
      typ          = {PUB:(DE-HGF)3 / PUB:(DE-HGF)11},
      doi          = {10.34734/FZJ-2025-04404},
      url          = {https://juser.fz-juelich.de/record/1047601},
}