Lewis Acid Mediated Approaches for the Generation of 4- and 5-Membered Ring Systems

• Author / Creator

  Gelozia, Shorena

• The presence of complex polycyclic skeletons is a commonly encountered phenomenon in natural products and biologically active compounds. Having diverse synthetic approaches for accessing them is vital for the effective development of the pharmaceutical industry. Among other strategies, pericyclic reactions, such as electrocyclizations and cycloadditions, are very powerful tools to generate cyclic templates. While Nazarov electrocyclization is a well-known method for synthesizing cyclopentanones, intercepting the reaction intermediates opens the door for their further functionalization. The [2+2] cycloaddition is a step-economical procedure to obtain strained cyclobutane structures. This thesis will discuss some recent advances in a relatively new concept of double interrupted Nazarov cyclization mediated by organoaluminum reagent, as well as a less commonly used thermal approach for the synthesis of cyclobutane derivatives.Chapter 1 describes fundamentals of 4 and 6electrocyclization reactions, along with some recent advances in this field. Conceptual differences in their photochemical and thermal variants will be showcased in a multitude of examples. Their practical usefulness will be demonstrated by their use in the total synthesis of natural products and bioactive substrates.Chapter 2 tells the detailed story about organoaluminum mediated double interrupted Nazarov cyclization, in which the sequence of electrocyclization is productively combined with the subsequent nucleophilic trapping via methyl migration, followed by electrophilic capture through Simmons-Smith cyclopropanation. This new approach allows the access to bicyclic alcohols, further derivatization of which could convert them into their 6-membered equivalents via various ring expansion strategies.Conversion of the Nazarov substrates into their 6 analogues by adding extra conjugation and their treatment with Lewis acids instead of 6 electrocyclization underwent some unexpected formal [2+2] cycloadditions, the details of which will be disclosed in Chapter 3. Use of structurally similar but qualitatively different haloboranes resulted in dissimilar results, which along with product diversification emphasizes the versatility of the method.To circumvent the problem of insufficient heart contraction, various calcium signaling pathways are attempted to be affected. Increasing myofilament sensitivity towards calcium without increasing intracellular ion concentration is one of the strategies which could be achieved via tight binding of small molecules to the target protein Troponin C. In Chapter 4, our attempts to synthesize a library of those small molecules with better calcium sensitizing effect will be described.

• Subjects / Keywords

  • Nazarov
  • electrocyclization
  • Simmons-Smith
  • cyclopropanation
  • organoaluminum
  • cycloaddition
  • Lewis acid

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-v77g-mn11

• License

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