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Preparation of Optically Enriched Allylic Heterocyclic Organoboronates and Their Application in the Efficient Synthesis of Biologically Active Compounds

  • Author / Creator
    Jinyue, Ding
  • Organic chemistry is, has been, and will remain, a reliable tool for creating nearly any target molecule. Modern organic synthesis, however, is leaning towards the themes of efficiency, selectivity and strategy. In the midst of a potential energy crisis and global resource shortage, the primary goal of modern organic chemists is to access target molecules in an economically efficient and environmentally benign fashion. In this regard, organoboron reagents represent a promising solution to this challenge. These versatile compounds can be applied in a diverse range of chemical transformations to construct C−C or C−heteroatom bonds with efficacy. These reactions often exhibit high levels of chemo- and stereo-selectivity, allowing the desired products to be synthesized with little to no waste product. In addition to their attractive synthetic versatility, most organoboron derivatives present superior stability and environment-friendly features. In this thesis, efficient synthetic methods were developed to provide synthetically valuable chiral alkylboronates. These methods are based on an “early introduction” strategy, which applies established asymmetric synthetic protocols on substrates bearing a pre-installed boronyl unit. Subsequently, practical synthetic applications of novel chiral alkylboronates were also investigated, leading to a variety of biologically important natural products and pharmaceutical drugs. As a class of newly emerged synthetic intermediates, chiral β-boronyl carbonyl compounds exhibit attractive synthetic utility in stereoselective C−C bond formation reactions and carbonyl modifications. In Chapters 2 and 3, catalytic asymmetric conjugate reduction reactions of 3-boronyl-3-alkyl, aryl α,β-unsaturated esters with organosilane reagents were developed. As a novel approach to access this class of chiral alkylboronates, the methods also allowed the use of organosilanes as the nucleophilic hydride source, which has the advantage of being air-stable, inexpensive and environmentally friendly. Along with exploring more efficient preparative methods for chiral alkylboronates, my studies also involved expanding their synthetic applications, including new bond formation methods with controlled regio-, stereoselectivities as well as asymmetric total syntheses of biologically active target molecules. In Chapter 4, through careful optimization, chiral dehydropiperidinyl boronates were accessed in gram-scale and high optical purity. This scaffold was then employed as the key intermediate for a concise enantioselective total synthesis of the antimalarial drug mefloquine. The absolute configuration and antimalarial activity of all resulting mefloquine stereoisomers and their analogues were also investigated. Moreover, efforts toward an asymmetric total synthesis of the more challenging alkaloid quinine were also initiated. These syntheses and their optimization are detailed at Chapter 4. The ultimate challenge for the application of chiral allylic heterocyclic boronates would be their use in stereospecific Suzuki-Miyaura cross-coupling reactions, which has long been regarded as one of the last frontiers in cross-coupling chemistry. This challenge is not only due to the notorious restrictions imposed upon the Suzuki-Miyaura coupling of secondary alkylboronates, but also from the control of regio- and stereoselectivity. Upon careful examination of a chiral catalytic system and other reaction conditions, a ligand controlled regiodivergent and enantiospecific cross-coupling of these chiral allylic heterocyclic boronates was achieved with high efficiency. It also found useful applications in the formal syntheses of the alkaloid (+)-anabasine and the antidepressant drug (+)-paroxetine. Detailed optimization, substrate scope, and synthetic applications will be described in Chapter 5.

  • Subjects / Keywords
  • Graduation date
    2014-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3HD7NZ16
  • 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.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Hall, Dennis G.
  • Examining committee members and their departments
    • Blakemore, Paul R. (Department of Chemistry)
    • Clive, Derrick L. J. (Department of Chemistry)
    • Lucy, Charles A. (Department of Chemistry)
    • Stryker, Jeffrey M. (Department of Chemistry)