Preparation of Polysubstituted Pyrans Toward the Synthesis of Biologically Active Compounds

• Author / Creator

  Rybak, Taras I

• Polyfunctionalized pyrans are among the most common structures in bioactive molecules. Based on the ubiquity of the pyran framework in natural and synthetic molecules, there is a need to develop more efficient methods of synthesizing and functionalizing the pyran motif. Due to recent interest in increasing the three-dimensionality of potentially bioactive molecules, applying asymmetric reactions to access the pyran framework is highly desirable. This thesis describes new efforts to develop and utilize stereochemically enriched dihydropyrans for the synthesis of biologically-active molecules. Chapter 1 provides a summary of the most common methods to synthesize and functionalize pyran structures. These methods were effectively used towards the syntheses of diverse classes of biologically active molecules containing polyfunctionalized pyran cores. Chapter 2 describes efforts made toward the synthesis of small dihydropyran-containing molecules analogous to laulimalide, an antimitotic and potentially useful chemotherapeutic natural product. Previous work attempting to identify the key pharmacophores of laulimalide was used to propose structurally simpler analogues. These analogues were modeled for binding affinity using computational analysis to propose a synthetic target. Early attempts were made at developing a short synthetic route to this target compound. In Chapter 3, early efforts towards expanding the utility of the Suzuki-Miyaura reaction beyond the classical sp2–sp2 bond formation are summarized. The analysis of novel cross-coupling reactions led to the first stereospecific and regiodivergent allylic Suzuki-Miyaura crosscoupling reaction. This unique method, which forms carbon-carbon sp3–sp2 bonds on enantioenriched heterocyclic allylboronates, is discussed. The ligand-controlled cross-coupling reaction effectively produces a broad range of aryl- and alkenyl-coupled pyrans with high stereospecificity and regioselectivity. Enantioenriched 2-ethoxy dihydropyranyl boronate substrates, synthesized from an asymmetric inverse electron demand oxa-[4+2] cycloaddition, were used in the cross-coupling reaction. The allylic cross-coupling was applied to the synthesis of polyfuntionalized pyrans. Furthermore, based on the spectroscopic and X-ray crystallographic analysis of the derivatized products, the stereospecificity of these reactions was confirmed and a more generalized mechanism was proposed. Lastly, this method was utilized towards the synthesis of the natural product goniothalesdiol A, as well as the successful total synthesis of the antiosteoporotic natural product diospongin B.

• Subjects / Keywords

  • Cross-coupling
  • Diospongin B
  • Suzuki-Miyaura
  • Laulimalide

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3N58D16T

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.