Organocatalyzed Conjugate Addition for the Total Synthesis of Natural Products and Development of Relay Catalytic Methodology



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This dissertation covers two projects utilizing organodiol catalyzed conjugate addition. The first project uses BINOL-derived organocatalysts to synthesize indolyl-propylene glycol natural products. The second project covers reactivity of organodiol catalyzed conjugate addition with vinylogous ester and amide electrophiles alongside the development of relay catalysis. Organocatalyzed conjugate addition has been used in the pursuit of the synthesis of natural products, primarily mucronatins A and B. These natural products are challenging to synthesize due to the need for stereoselective synthesis in the presence of sensitive diindole cores. Previously developed methods allow for the conjugate addition of heteroaryl trifluoroborate salt nucleophiles to electron-rich electrophiles containing indoles. Mucronatins A and B are only two examples of these types of structures, and similar structures have also been targeted. The reactivity of the diol catalysts previously utilized by our group and intriguing results from mechanistic studies led us to consider using very electron-rich electrophiles as conjugate addition partners. Vinylogous esters and amides were tested as electrophiles and were found to undergo conjugate addition, followed by elimination of the -leaving group. This reactivity was optimized for the synthesis of polyunsaturated ketones and ene/ynones with a simplified organodiol catalyst. This reactivity was further explored to synthesize the dienones from the alkyne precursors of vinylogous esters and amides directly. Using catalytic amounts of methyl aniline, the reaction could be performed in one step without the need to isolate vinylogous esters and amides. This relay catalytic process was optimized for a faster reaction rate and superior yields when compared to the sequence of two individual steps.



conjugate addition, natural products, total synthesis, methodology, organocatalysis, relay catalysis


Portions of this document appear in: Sundstrom, Sasha, Thien S. Nguyen, and Jeremy A. May. "Relay Catalysis To Synthesize β-Substituted Enones: Organocatalytic Substitution of Vinylogous Esters and Amides with Organoboronates." Organic Letters 22, no. 4 (2020): 1355-1359.