| This study focused on asymmetric synthesis of biologically important molecules beta- lactones or beta-lactams through a formal [2 + 2] cycloaddition of ketenes and aldehydes or imines, and hydrogenation reaction on ketene heterodimers leading to dipropionate and deoxypropionate derivatives. 31P NMR was utilized as a tool for mechanistic studies of the new phosphine catalyzed [2 + 2] reactions.;We firstly developed the method of a BINAPHANE-catalyzed formal [2 + 2]cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that provides access to a variety of highly substituted beta-lactams (16 examples). The BINAPHANE catalytic system displays moderate to excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples with dr ≥ 90:10).;We then extended the substrate scope for the methodology of chiral phosphine-catalyzed formal [2 + 2] cycloaddition of aldehydes and ketoketenes, to achiral aldehydes (both aromatic and aliphatic) and alkylarylketenes or dialkylketenes. A preference for formation of the trans diastereomer was observed in these reactions. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained by monitoring the 31P NMR spectrum and by comparison of these results with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction.;We then extended this methodology further to the diastereoselective synthesis of filactones bearing two or three stereogenic centers, from disubstituted ketenes and a- or beta-chiral aldehydes. Tri-n -butylphosphine was found to be the optimal nucleophilic catalyst in terms of effecting both good yield (up to 79%) and diastereoselectivy (dr ≥3:1 for 8 examples, up to 10:1) in beta-lactone formation.;We lastly developed a stereodivergent and diastereoselective procedure to access dipropionate and deoxypropionate derivatives through Pd/C-catalyzed hydrogenation or hydrogenolysis of enantioenriched ketene heterodimers. Catalytic hydrogenation of the E-isomer of ketene heterodimer beta-lactones provides access to syn, anti-beta-lactones (dipropionate derivatives) bearing three stereogenic centers (dr up to 19:1), while catalytic hydrogenolysis of the Z-isomer of ketene heterodimers facilitates access to anti-deoxypropionate derivatives (dr up to 13:1). Mechanistic analysis suggest that beta-syn-elimination from a hydropalladated intermediate is a key step in the formation of the deoxypropionate derivatives. |
