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Stereocontrolled Formation of Carbon-Carbon Bonds and Applications in the Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids and Isotopically Labelled (+)-Anatoxin-a

  • Author(s): Lacharity, Jacob Joseph
  • Advisor(s): Zakarian, Armen
  • et al.

The asymmetric formation of carbon-carbon bonds is a fundamentally important transformation in modern organic chemistry. Such methods enable the rapid generation of molecular complexity from simple precursors and are essential to the synthesis of natural product scaffolds and pharmaceuticals. This dissertation focuses on the development of novel approaches to the stereoselective construction of carbon-carbon bonds and their application toward the synthesis of complex, bioactive alkaloids.

The first chapter of this dissertation focuses on a total synthesis of the Nuphar thioalkaloids, a series of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies. Two critical stereocenters in the natural products were established through asymmetric (hetero)arylacetic acid alkylation, following a protocol developed previously in our group. The unique 2,2,4,4-tetrasubstituted thiolane core was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ through the coupling of a spirocyclic thietane with a copper carbenoid. This biodivergent strategy was crucial to obtaining chemoselective access to two unsymmetrically oxidized congeners in this family, (+)-6-hydroxythiobinupharidine and (–)-6-hydroxythionuphlutine, with the latter being synthesized for the first time.

The second chapter focuses on a systematic investigation into the Ireland-Claisen rearrangement of α-alkoxy esters. Our studies have shown the selectivity of the rearrangement to be highly sensitive to both the nature of the metal cation and the corresponding amide of the base used for enolate formation. We have demonstrated that, in many cases, both diastereomeric Ireland-Claisen products could be accessed from the same starting material, expanding the scope of this already powerful transformation and streamlining its application in organic synthesis.

The third chapter outlines our asymmetric total synthesis of (+)-[13C4]-anatoxin-a. The unique requirements associated with isotope incorporation inspired a new, robust, and highly scalable route, providing access to substantial quantities of this valuable internal standard for use in the detection and precise quantification of anatoxin-a in freshwater. A highlight of the synthesis is a method that leverages a cyclic iminium ion rearrangement to achieve dynamic kinetic resolution in an enantioselective Morita-Baylis-Hillman (MBH) cyclization.

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