Asymmetric Synthesis of Amines via Metal-Catalyzed Additions of Organometallic Reagents

With greater than 80% of all drugs and drug candidates containing the amine functionality,1 the amine is one of the most prevalent functional groups in medicinal chemistry. As a result, new methods to access amine products are critically important. Additions of nucleophiles to N tert-butanesulfinyl imines are one of the most prevalent approaches for the asymmetric synthesis of amines. Extensive reviews of N-tert -butanesulfinamide chemistry have been published recently, 2 and this thesis will not try to replicate those works. Instead, new methods to synthesize amines via sulfinamide chemistry and the literature relevant to these methods will be discussed.;Chapter 1 describes the first examples of Rh-catalyzed additions of aryl boron reagents to N-suflinyl ketimines, which access six important classes of tertiary carbinamine pharniacophores. Additions to highly activated N-tert-butanesulfinyl ketimines derived from 3-oxetanone, 3-azetidinone, and isatin proceed in excellent yields and in the case of isatin-derived ketimines with excellent diastereoselectivity. Additionally, less activated N-sulfinyl ketimines derived from cyclohexanone, piperidin-4-one, and tetrahydropyran-4-one react readily under similar conditions when employing the less hindered isopropanesulfinyl group. An improved synthesis of isopropanesulfinamide and recycling of the isopropylsulfinyl group are also reported.;Chapter 2 details the development of additions of Knochel-type benzyl zinc reagents to N-tert-butanesuflinyl aldimines. Notably, additions of these sp3-hybridized reagents demonstrate good functional-group compatibility, adding chemoselectively to imines in the presence of esters and nitriles. Moreover, addition to a glyceraldehyde-derived N-tert- butanesulfinyl imine proceeds in high yield and with exceptional selectivity to provide rapid entry to hydroxyethylamine-based aspartyl protease inhibitors.;Chapter 3 describes additions of alpha-amido trifluoroborates to carbonyl derivatives, which represent the first application of alpha-amino boronic acid derivatives in Rh-catalyzed couplings. Reactions of alpha-sulf namido trifluoroborates with trifluoromethyl ketones proceed in reasonable yields and with good diastereoselectivity. The potential of this method is further highlighted by the exploration of a variety of nitrogen substituents and addition to other electrophiles including benzaldehyde and trityl-protected isatin.;Chapter 4 details the development of an improved method to access synthetically useful and pharmaceutically relevant alpha-amino boronic acid derivatives. The asymmetric borylation of N-tert-butanesulfinyl imines with bis(pinacolato)diboron is achieved using a Cu(II) catalyst system. The Cu(II)-catalyzed reaction is performed on the benchtop in air at room temperature using commercially available and inexpensive reagents at low catalyst loadings. A variety of N-tert-butanesulfinyl imines, including ketimines, react readily to provide the corresponding a-sulfinamido boronate esters in good yields and with high stereoselectivity. This transformation is also applied to the telescoped synthesis of a-sulfinamido trifluoroborates.