Examination of Chemoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions and Efforts Towards a Concise Total Synthesis of Sparteine
Langdon, Steven 1988-
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This thesis is broadly subdivided into two topics: the development and exploration of a methodology for catalyst-controlled chemoselective cross-benzoin reactions using N-heterocyclic carbenes, and efforts towards a concise and scalable total synthesis of sparteine. The first chapter of this work begins with a brief overview of carbenes with an emphasis on N-heterocyclic carbenes (NHCs) and their applications in organocatalysis. Synthetic routes and considerations in the formation of NHCs for organocatalysis follow. A historical overview of the advances in first homo-benzoin and subsequently cross-benzoin reactions highlights current limitations with these systems, with an emphasis on the need for specific substrate functionalization to achieve high degrees of chemoselectivity. Finally, the chapter concludes with a discussion of experimental and computational studies on the mechanism of these reactions. Chapter two contains a historical overview of sparteine, its isomers, and the practical uses for this natural product. Isolation techniques and a proposed biosynthesis precede reported partial and complete syntheses of sparteine, a potential synthetic precursor (anaferine), and a surrogate compound developed to replace sparteine in synthetic applications. A brief overview of amine-catalyzed Mannich reactions rounds out the chapter and provides context for the proposed synthetic route to sparteine. A description of the development and exploration of chemoselective NHC-catalyzed cross-benzoin reactions is described in Chapter three. After illustrating that chemoselectivity is tied to ring size in the catalyst backbone, a broad range of substrates and reaction conditions are shown to be amenable to the new methodology. The method represents the first instance of chemoselectivity in cross-benzoin reactions between two aldehydes that does not rely on steric differences between the substrates for control. A detailed mechanistic study combining both computational and experimental results follows, highlighting those features of the catalyst leading to chemoselectivity. With ongoing efforts to add a high degree of enantioselectivity to the catalytic system, the chapter concludes with the development and application of a new approach for the synthesis of both achiral and chiral triazolium salts. Returning to the total synthesis of sparteine, the fourth chapter of this thesis first outlines several possible synthetic routes to access sparteine through Mannich reactions with a precursor, anaferine. A substantial body of work covers attempts to locate reproducible reaction conditions for a concise synthesis of this precursor. The chapter culminates in the completed four-step synthesis of anaferine and concludes with a discussion of how it could be used in the synthesis of sparteine and, eventually, its diastereomers genisteine and pusilline.
DegreeDoctor of Philosophy (Ph.D.)
CommitteeWard, Dale E; Abrams, Suzanne; Laprairie, Robert; Urquhart, Stephen
Copyright DateOctober 2018
density functional theory