Selective palladium-catalyzed oxidations of polyols and carbohydrates [electronic resource]

The selective oxidation of alcohols, polyols, and carbohydrates is a formidable challenge, but would constitute an enabling advance in synthetic methodology. The selective oxidation of vicinal diols provides a convenient strategy to α-hydroxyketones, common motifs in natural products and pharmaceuticals. Traditional stoichiometric oxidants suffer from competitive C-C cleavage and overoxidation. The chemoselectivity requirements for precise manipulation of sugar molecules are even more exacting, requiring not only discrimination between primary and secondary alcohols, but also between multiple secondary alcohols in similar chemical environments. We have demonstrated that the cationic palladium catalyst [(neocuproine)Pd(OAc)]2(OTf)2 (1) selectively transforms simple diols and complex polyols to their respective α-hydroxyketones. These diol oxidations proceeded in both organic and aqueous solvents. Benzoquinone, molecular oxygen, and air were all found to be competent terminal oxidants for diol oxidation, but aerobic oxidations using 1 required Pd loadings of around 10% due to oxidative degradation of the neocuproine ligand. Guided by the mechanistic hypothesis that competitive auto-oxidation by radical hydrogen atom abstraction reactions was responsible for the oxidative degradation of the neocuproine ligand, we implemented a number of strategies to arrest this degradation process. Ligand modification was performed to reduce the susceptibility of the ligand benzylic groups towards oxidation. Aromatic "sacrificial reductants" such as ethylbenzene as well as phenolic antioxidant additives were successfully introduced to increase catalyst lifespan. Carbohydrate oxidation catalyzed by 1 was investigated. An aerobic oxidation protocol using 1 for selectively converting alkyl and azide-functionalized glucosides to their 3-ketoglycoside counterparts was developed, integrating the previously described methods for increasing catalyst lifespan. Conformationally restricting axial hydroxyl-bearing sugars provided a way to selectively oxidize mannose and galactose derivatives (which are unselectively oxidized by previously described methods). Reaction outcomes for the oxidations of several glycosides were rigorously characterized, revealing the effects of hydroxyl orientation and other functionalities on oxidation regioselectivity. In the course of these studies, divergent solvent-dependent regioselectivity was observed for these glycoside oxidations, with oxidations performed in 2,2,2-trifluoroethanol enabling epimizeration of axial hydroxyl-bearing glycosides. Through these strategies, a variety of stereochemically and functionally diverse glycosides were selectively oxidized using 1. Finally, diol oxidations using electron-deficient ketones and aldehydes (such as 1,1,1-trifluoroacetone) as hydrogen acceptors are described. Competition experiments highlight the favorabilities of aldehydes as hydrogen acceptors compared to their ketone counterparts. Instances of intermolecular and intramolecular hydride transfer during 1,2-propanediol oxidation were observed. Findings from these transfer hydrogenation studies were used to rationalize the unusual regiochemical outcomes observed in glycoside oxidations carried out in 2,2,2-trifluoroethanol.

Keywords: Chemistry.
Advisor: Waymouth Robert M. primary advisor. Thesis advisor
Trost Barry M. advisor. Thesis advisor
Wender Paul A. advisor. Thesis advisor