Exploration of Novel Silyl Derived d1 Synthon Equivalents

Northwestern University, Evanston IL

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Abstract

? DESCRIPTION (provided by applicant): Novel catalytic chemical methods are indispensable tools for the advancement of biology and medicine in the 21st century, as facile access to various privileged, bioactive molecules extends the reach of science in these areas. From a conceptual standpoint, the greatest challenge to further develop catalytic methods is cultivating new reactions that go beyond conventional bond polarity and access inverted states, known as umpolung. Umpolung represents a complementary approach to natural polarity strategies, the development of which is necessary since some molecules can be synthesized much more rapidly via these bond disconnections or are completely inaccessible through conventional bond disconnections. Changing the polarity of a carbon attached to heteroatoms (i.e. carbonyls and alcohols) from positive to negative is an example of creating a polarity-inverted operator, d1 in this case. Silylated alcohols have been previously shown to operate in such a manner, but exploration in this area has been sparse. Organosilanes are a versatile and prolific group of small molecules that possess diverse reactivity patterns easily modulated by exploiting the well-defined characteristics of silicon. Our laboratory has been exploring the utility of using 1,2-Broo rearrangements to derive d1 synthons from ?-silyl alcohols. The work thus far has inspired further avenues of exploration. We hypothesize that the fundamental development of these new d1 synthons coupled with their integration with robust transition metal catalyzed processes will facilitate significant innovationin the areas of chemical synthesis, bioorganic chemistry, and ultimately medicine. Specific Aim 1 will focus on further exploring the fundamental reactivity of that 1,2-Brook rearrangement derived carbon nucleophiles with epoxides and aziridines to potentially offer stereoselective routes to 1,3-diols and 1,3-aminoalcohols, which are privileged motifs biologically active molecules. Our lab has further developed ?-siloxytrifluoroborate salts from siloxy alcohols, which can be used as a d1 operator in transition metal catalyzed reactions. Specific Aim 2 will focus on the integration of these salts in state-of-the-art copper mediated reactions, specifically conjugate addition reactions and hypervalent iodide reactions. Development of these reactions will lead to the synthesis of biologically relevant, enantioenriched scaffolds and ultimately prove to the chemical community the utility of using d1 strategies.