Secondary metabolites often demonstrate potent biological activity, but rarely exhibit the pharmacokinetic or pharmacodynamic properties that are required for safe medical use in humans. Typically, these properties can be imparted by synthetic modification of the molecule's structure. Recently, C-H functionalizaton chemistry has greatly impacted the strategies used to modify chemical structures. However, chemoselective C-H functionalization of complex natural products with transition metal catalysts can be challenging because there are many C-H bonds in each molecule that may react competitively with a given catalyst. A practical strategy for overcoming poor chemoselectivity is to employ a directing group to control the site of reaction at a particular C-H bond. These directed C-H functionalization reactions may then be employed as a tool in the development of new therapeutic agents through selective functionalization of complex natural products. The goal of this proposal is to develop novel disilane directing groups to create a method for the selective silylation and borylation of aliphatic C-H bonds. This objective is achieved by allowing a silicon-containing directing group to react with a transition metal catalyst, consequently tethering the active catalyst adjacent to the C-H bond targeted for functionalization. First, we will examine the effect of tether length on regioselectivity of the reaction. Preliminary calculations indicate that regioselective 1,2-, 1,4- and 1,-6-functionalizations are thermodynamically feasible with the new directing groups proposed herein. Second, to broaden the synthetic value of C-H functionalization products, we wlll expand directed C-H functionalization reactions by achieving borylation of aliphatic C-H bonds. In all cases, bioactive molecules are proposed as substrates to test chemoselectivity on complex structures relevant to the pharmaceutical industry. Next, we will study the electronic factors that govern silyl-directed C-H activation. We propose to use 15N-enriched ligands to study the composition of the catalyst during catalytic reactions by NMR spectroscopy. Lastly, we propose to synthesize and isolate the catalyst resting state and to determine whether there is a correlation between the s- donating ability of the silyl directing group and rate of C-H functionalization. The C-H functionalization platform described herein constitutes a promising strategy for the selective functionalization of C-H bonds in complex molecules. We envision this approach being applied not only to the synthesis and modificaiton of bioactive molecules, but also to the construction of diverse libraries for use in medicinal chemistry.

Public Health Relevance

The activation of carbon-hydrogen bonds constitutes an important strategy for the rapid construction of highly functionalized, pharmaceutically relevant molecules. A series of novel chemical handles are proposed for the transition metal-catalyzed functionalization of carbon-hydrogen bonds that are unreactive toward conventional synthetic methods. These reactions will be performed on intricate molecular frameworks, demonstrating their applicability toward the synthesis of complex molecules with medicinally significant bioactivity, as well as their potential role for diversification of chemical libraries in pharmaceuitcal screening collections.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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University of California Berkeley
Schools of Arts and Sciences
United States
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