Complexity-building Transformations Enabled by Brønsted Base Organocatalysis and Progress Toward the Total Synthesis of the Veratrum Alkaloids Jervine, Cyclopamine, and Veratramine Public Deposited

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  • March 20, 2019
  • Horwitz, Matthew
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • I. Asymmetric Organocatalytic Reductive Coupling Reactions between Isatins and Aldehydes A fully organic phosphite-mediated stereoselective reductive coupling reaction between isatins and aldehydes was developed. A Pudovik-phospha-Brook sequence was used to invert the polarity of the isatin, which allowed the formation of an enolate intermediate. Subsequent aldol-type addition into aldehydes provided a new carbon-carbon bond and two new stereocenters with high yields and stereoselectivities using a chiral triaminoiminophosphorane organocatalyst. Using this novel umpolung reaction, chemically differentiated diols were formed and a new two-electron pathway for reductive coupling of carbonyl reaction partners was demonstrated. II. Asymmetric Organocatalytic Reductive Coupling Reactions between Benzylidene Pyruvates and Aldehydes Utilizing the previously developed two-election reductive coupling mechanism, dimethyl phosphite was used as an organic reductant to reductively couple benzylidene pyruvates and aldehydes. Though a larger number of selectivity issues were present in this case, the desired mode of carbonyl coupling was enabled in a stereoselective fashion using a chiral triaryliminophosphorane catalyst. Using this reaction manifold, a range of highly functionalized stereodyads were generated in high diastereoselectivity, enantioselectivity, and yield. The reaction was demonstrated to work on gram scale. III. Phosphazene-catalyzed Desymmetrization of Cyclohexadienones by Intramolecular Dithiane Addition A phosphazene-catalyzed desymmetrization reaction of dithiane-tethered cyclohexadienones is established. Using the ester-bound dithiane nucleophile, a conjugate addition reaction was found to be possible using catalytic P2-tBu phosphazene base. A series of products containing two nascent stereocenters was synthesized in a racemic sense. Chiral iminophosphorane catalysts were studied but were found to not give enantioenrichment in the product. Deprotection of the dithiane and desulfurization were studied but proved unsuccessful. An independent synthesis of the alpha-ketolactone that would result from dithiane deprotection also failed using an oxidative deacylation strategy, suggesting an inherent product stability issue. IV. Diastereoselective Organocatalytic Addition of alpha-Angelica Lactone to beta-Halo-alpha-ketoesters A diastereoselective addition of alpha-angelica lactone to beta-halo-alpha-ketoesters is discussed. Using commercial quinidine as an organocatalyst, three contiguous stereocenters were set in a relative sense. The scope of the reaction demonstrated that high diastereoselectivity was possible in several cases with either a beta-bromo or beta-chloro substituent on the alpha-ketoester, though yields were moderate. A stereochemical model was developed to explain the observed outcome. Though alpha-angelica lactones are most commonly nucleophilic at the gamma-position, this reaction was found to proceed with an observed alpha-nucleophilicity of the alpha-angelica lactone. Hydrogenation of the product was found to result in a diastereoselective formation of a fourth stereocenter by delivery of hydrogen to the least hindered face of the alkene. V. Progress Toward the Total Synthesis of the Veratrum Alkaloids Jervine, Cyclopamine, and Veratramine Efforts toward a de novo total synthesis of the Veratrum alkaloids jervine, cyclopamine, and veratramine are presented. A novel synthetic approach relying on oxidative dearomatization of a tyrosine derivative and local desymmetrization of a cyclohexadienone was developed. Starting from a known racemic beta-methyltyrosine derivative with two stereocenters set in a relative sense, a third stereocenter in the E ring of jervine and cyclopamine was conveniently set with a borohydride reduction. The oxidative dearomatization sequence was found to lead to the desired 6-5 framework necessary for the DE ring system of jervine and cyclopamine, but a competitive cyclization process necessitated further revisions to the route. VI. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters A conjugate addition of nitroalkanes to enone diester electrophiles was used to provide two new stereocenters in polyfunctionalized products. A one-pot procedure for the synthesis of the starting materials from diazo compounds and Wittig reagents was developed and used to generate a wide range of substrates. A triaryliminophosphorane organocatalyst enabled high stereoselectivity in the conjugate addition reaction. Reduction of the nitro group and diastereoselective cyclization led to the formation of a third stereocenter in the lactam products.
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Rights statement
  • In Copyright
  • Nicewicz, David
  • Brustad, Eric
  • Meek, Simon
  • Miller, Alexander
  • Johnson, Jeffrey
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

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