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| Home > Publications database > Lipase-catalyzed kinetic resolution: Synthesis and application of axially chiral biphenols |
| Book/Dissertation / PhD Thesis | FZJ-2025-04404 |
2025
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
Jülich
ISBN: 978-3-95806-854-4
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Please use a persistent id in citations: doi:10.34734/FZJ-2025-04404
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.
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