Development and Application of a Regioselective Nickel-Catalyzed Macrocyclization Method; and Development of Bench Stable Sugar Silanes for Use in Copper-Catalyzed Dehydrogenative Silylations.

Investigating the biosynthesis of natural products and their bioactivity modes of action can lead to the proposal of new chemical structures that are more potent drugs than the natural products themselves. Synthesis of these compounds is accomplished through the use of chemical and/or biochemical methods. In this thesis, several different methodological advances have been made in synthetic and biosynthetic areas related to the synthesis of macrolide natural products. The P450 monooxygenase PikC is utilized in a chemoenzymatic fashion to hydroxylate unnatural substrates. This enzyme oxidizes two differently sized rings to macrolide natural products in nature. Exploiting this promiscuity, the sugar desosamine was appended to a number of simple aglycones for use as a remote directing group. Several of these unnatural substrates were oxidized to mono-hydroxylated products by PikC. Through LCMS comparison of the enzymatic products with authentic samples, it was determined that the C-H bonds furthest from the anchoring group were selectively oxidized. A synthetic macrocyclization technique that allows the synthesis of two differently sized rings from the same starting material was also explored. This methodology utilitizes nickel-catalyzed reductive couplings that have been shown to switch the regioselectivity of alkyne addition to aldehydes by switching the ligand on the metal. Here, the regioselectivities previously observed in intermolecular couplings or biased intramolecular systems were generalized in the nickel-catalyzed reductive macrocyclization of terminal alkynes and aldehydes to yield either the endo or exocyclic product from a single substrate. Finally, a simple procedure is introduced that uses bench stable starting materials for the synthesis of tethered carbohydrate-aglycone molecules for use in intramolecular glycosylation. The identity of a sugar moiety can play an important role in the biosynthesis and bioactivity of natural products; thus, methodologies to produce glycosides easily and stereospecifically are attractive. Diisopropyl sugar silanes have been shown to be competent substrates in the copper-catalyzed O-H insertion into a variety of alcohol substrates. These user friendly reagents are stable to chromatography and storage, representing an improvement over previously used dimethyl sugar silanes, which decompose readily under standard storage conditions. The products formed also participate in the desired intramolecular glycosylation reaction.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97868/1/arknauff_1.pd