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Design, Synthesis and Study of Potent Small Molecule Antifungal Synergizers and Palladium-Carbene Mediated C–C and C–N Bond Formations

  • Author(s): Ilandari Dewage, Udara Anulal Premachandra
  • Advisor(s): Van Vranken, David L
  • et al.
Abstract

ABSTRACT OF THE DISSERTATION

Design, Synthesis and Study of Potent Small Molecule Antifungal Synergizers

and

Palladium-Carbene Mediated C–C and C¬–N Bond Formations

By

Ilandari Dewage Udara Anulal Premachandra

Doctor of Philosophy in Chemistry

University of California, Irvine, 2016

Professor David L Van Vranken, Chair

The doctoral studies described herein include two distinct aspects. One involves the design, synthesis and study of small molecule antifungal synergizers and the other consists of novel palladium-catalyzed C–C and C¬–N bond formations.

Spiroindolinones and dihydroisoquinolines were previously reported to enhance the antifungal effect of Candida albicans. A different diastereomer of a lead spiroindolinone, CID 6584729 was synthesized and shown to have synergy with fluconazole against C. albicans. Various other analogues of spiroindolinones and dihydroisoquinolines were designed, synthesized and studied. Many of the compounds were shown to enhance the antifungal activity of fluconazole against C. albicans, some with exquisite potency. One spirocyclic compound, which we have named synazo-1 and one dihydroisoquinoline analogue, compound 3-19 were shown to enhance fluconazole activity against several resistant clinical isolates with low EC50 values. Both of these compounds exhibit true synergy with fluconazole, with FIC indices below 0.5 in both susceptible and resistant strains. Synazo-1 and compound 3-19 also exhibited low intrinsic cytotoxicity in mammalian cells.

In a separate project, vinyl iodide were shown to be useful precursors in palladium-catalyzed transformations to gain access to η3-allylpalladium intermediates that resist β-hydride elimination and to generate cyclodimerization and cyclopropanation adducts in synthetically useful yields.

Most palladium-catalyzed reactions involving insertion of alkylidenes with α-hydrogens undergo β-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were utilized to generate η3-allylpalladium intermediates and preserve the sp3 center adjacent to the carbene. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was found to be low, suggesting lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol.

Vinyl iodides were shown to undergo palladium-catalyzed dimerizations and cyclization to generate pyrrolidine and piperidine dimers connected by a trans-ethylene bridge. The dimerization generates the skeleton of the alkaloid, hyalbidone in a single step. A crossover experiment is consistent with a Michael-type addition to vinylpalladium cation to generate Pd(0) alkylidene intermediate. A palladium-catalyzed intramolecular aminocyclopropanation of norbornenes with vinyl halides was shown to generate cycolpropylcarbinyl adducts in good yields. Stabilized enolate nucleophiles were also employed in these transformations.

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