New Radical Approaches to C–C Bond Formation in Small Molecules
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Radical chemistry has emerged as a cornerstone in modern organic synthesis, providing chemists with numerous new tools to rapidly expand reactivity and chemical space in academic and industrial research. However, the high reactivity of organic radicals is a double-edged sword, as the selectivity of these fleeting intermediates can be difficult to control in the presence of multiple chemotypes. In addition, catalyst-controlled regio- and stereoselective reactions involving free radical intermediates remain limited, and the discovery of such processes is still highly desirable. From the perspective of creating new molecules, carbon-carbon bond forming reactions are among the most important transformations in organic chemistry. In this regard, the development of catalytic strategies that enable new C–C bond forming transformations with precise control over chemo-, regio-, and stereoselectivity could substantially impact organic synthesis.In this dissertation, we begin with an overview of historical development of radical organic chemistry (chapter 1). In the same chapter, we present a brief introduction to radical relay catalysis and showcase recent advance of this strategy in organic synthesis. More relevant to the major strategy used in this dissertation, historical achievements and recent innovation of TiIII/IV redox catalysis are discussed in detail in this chapter with an emphasis on the general mechanistic principle. In chapter 2, we present the development of a TiIII-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C–Cl bond featuring TiIII -mediated Cl atom abstraction. Evidence suggests that the active TiIII catalyst is generated from the TiIV precursor in a Lewis-acid-assisted electron transfer process. In chapter 3, we report a systematic mechanistic study on Ti-catalyzed enantioselective [3+2] cycloaddition of cyclopropyl ketone and alkenes in collaboration with Sigman group. In this reaction, through a suite of computational and experimental mechanistic studies, catalyst distortion was elucidated to dictate stereochemical outcomes. The mechanistic insights aided in our search for an improved catalyst, which substantially expanded the reaction scope and provided a collection of synthetically interesting products in high diastereo- and enantioselectivity. A catalyst–substrate matrix based on the new catalysts allowed for the development of an MLR statistical model that could predict the performance of each catalyst with a novel substrate. The predictive power of this model was demonstrated through accurate prediction of enantioselectivity outcomes for various substrates in reactions with the improved catalyst. Work presented in this chapter demonstrates the utility of mechanistic studies in guiding catalyst optimization toward a more broadly applicable transformation. In chapter 4, we show the development a reductive strategy for the generation of Co-H species from readily available acetic acid and demonstrate its application in the deuteration and hydroarylation of alkenes. The reaction development was guided by systematic spectroscopic and electroanalytical techniques, which provided both qualitative and quantitative information about the formation, identity, and reactivity of Co-H intermediates. At the end of each chapter, we summarize the development of these radical transformations and raise up questions. For each system, we try to not only point out the limitation of current reactions but also provide an outlook for the future direction.
Wolczanski, Peter Thomas; Lambert, Tristan H.
Chemistry and Chemical Biology
Ph. D., Chemistry and Chemical Biology
Doctor of Philosophy
dissertation or thesis