Rhodium- and Iridium-Catalyzed Allylic Substitution Reactions with Unstabilized Nucleophiles: Construction of Acyclic Ternary Carbon Stereogenic Centers

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Catalysis, Allylic Substitution, Unstabilized Nucleophiles
The transition metal-catalyzed allylic substitution is an important cross-coupling reaction for the construction of carbon-carbon bonds. Although the palladium-catalyzed reactions are more widely studied, other transition metals such as rhodium and iridium-catalyzed variants, have emerged as versatile tools for the construction of carbon-carbon bonds in a stereospecific and enantioselective manner, respectively. However the nucleophiles utilized in these processes are mainly stabilized nucleophiles rather than unstabilized nucleophiles. This thesis is focused on the development of transition metal-catalyzed allylic substitution reactions with unstabilized nucleophiles, which is divided into four chapters: a comprehensive review followed by two research chapters and a chapter with future directions. Chapter 1 commences with an introduction about the transition metal-catalyzed allylic substitution reactions that includes mechanistic aspects of the process and a comprehensive review on using unstabilized nucleophiles. The review is divided into subsections based on the type of allylic substrates (acyclic and cyclic) and organometallic reagents (e.g., aryl, alkyl, alkenyl etc.) utilized. Chapter 2 highlights the development of a regio- and diastereoselective rhodium-catalyzed allylic substitution with unstabilized benzyl nucleophiles. Following a brief introduction and mechanistic features of rhodium-catalyzed allylic substitution reactions, our work with unstabilized benzyl nucleophiles for the construction of ternary benzyl motifs will be discussed. The last part of this chapter outlines the development of diastereoselective variant for the construction of contiguous stereogenic centers, which represent the first example of this type of process. Chapter 3 illustrates the development of an enantioselective iridium-catalyzed allylic substitution with Reformatsky reagents. This chapter begins with a brief introduction and mechanistic details about the iridium-catalyzed allylic substitution reactions followed by our approach towards utilizing Reformatsky reagents for the construction of enantioenriched homoallylic ester motifs. Finally, in Chapter 4 our initial progress towards the enantioselective allylic benzylation protocol using unstabilized benzylzinc reagents is discussed along with future directions to improve the methodology. In summary, the thesis defines novel rhodium- and iridium-catalyzed protocols for the regioselective coupling of unstabilized nucleophiles with allylic alcohol derivatives in either a diastereo- or enantioselective manner. It is expected that these observations will inspire additional contributions particularly for the synthesis of important synthetic targets.
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