The development of palladium- and copper-catalyzed transformations for the asymmetric synthesis of biologically active small molecules [electronic resource]

The continued demand for efficient chemo-, regio-, and stereoselective organic transformations motivates the development of new chemical reactions. Transition metal catalysis represents a powerful method for the construction of carbon-carbon, carbon-hydrogen, and carbon-heteroatom bonds in a highly selective fashion. This dissertation describes the development of several new transition metal-catalyzed organic reactions useful in the preparation of various chiral small molecules, including both fundamental organic "building block" compounds and structurally complex natural products and pharmaceutical agents. We report a new strategy for the synthesis of chiral beta-alkynyl esters, ketones, and sulfones via sequential palladium-catalyzed carbon-carbon bond formation and copper-catalyzed carbon-hydrogen bond formation. The process is operationally straightforward, compatible with a broad range of substrates, and delivers the targets in high yields with excellent levels of enantioselectivity. It is compatible with both oxygen and nitrogen functionality, and this enabled the rapid elaboration of the products into a diverse set of chiral heterocycles. The sequential catalysis protocol was employed in a concise, enantioselective synthesis of AMG 837, a potent agonist of G-protein coupled receptor 40. Recognizing both the biological relevance of chiral alkaloids and the synthetic challenges associated with the construction of quaternary, all-carbon stereocenters, we pursued a palladium-catalyzed asymmetric allylic alkylation that effected carbon-carbon bond formation on prochiral oxindole nucleophiles. Although prior research has demonstrated that allylic alkylation reactions of geminal dicarboxylate electrophiles typically yield branched products as the result of ipso-addition, we identify conditions wherein oxindoles react with a dipivaloyl electrophile to afford linear enol pivalate compounds. A mild hydrolysis reaction converts these products into the aldehyde that formally results from asymmetric conjugate addition to acrolein, a challenging transformation with limited literature precedent. These adducts are established precursors to tricyclic alkaloid scaffolds of pharmaceutical interest. Chiral gamma-heteroatom-substituted cycloalkenones are well-established organic "building blocks" that are widely used in the synthesis of complex molecules. The exposure of meso-1,4-allylic dibenzoates to chiral phosphine-ligated palladium salts in the presence of a potassium nitronate nucleophile promotes a unique oxidative desymmetrization reaction. This process yields enantiopure gamma-benzoyloxy cyclopentenones, cyclohexenones, and cycloheptenones. We describe the elaboration of these products into diverse, enantioenriched oxygen- and nitrogen-substituted cycloalkenones via subsequent palladium-catalyzed allylic alkylation reactions involving heteroatom nucleophiles. Separately, we employ enantiopure gamma-benzoyloxy cyclohexenones in short, asymmetric syntheses of enantio- and diastereomerically diverse epoxyquinoid natural products. We further highlight the utility of palladium catalysis in complex molecule synthesis through the development of a unique, intramolecular carbon-carbon bond-forming reaction that generates a strained enyne and through an asymmetric formal synthesis of aliskiren, a renin inhibitor used in the treatment of hypertension.

Keywords: Chemistry.
Advisor: Trost Barry M. primary advisor. Thesis advisor
Burns Noah
Du Bois Justin advisor. Thesis advisor