Metal-Mediated Couplings of Primary Alcohols with Amines and Carbohydrates

The work presented in this thesis was performed at the Department of Chemistry of the Technical University of Denmark during a three year Ph.D. program. The thesis involves two distinct Projects related to organometallic and carbohydrate chemistry. Project 1: Dehydrogenative synthesis of imines from alcohols and amines catalyzed by a ruthenium N-heterocyclic carbene complex. The successful method development and application of a convenient and direct (one step) synthesis of imines from alcohols and amines is described. The developed method provides quick andextended access to structurally diverse and synthetically important imines. The reaction is catalyzed by the ruthenium N-heterocyclic carbene complex [RuCl₂(IiPr)(p-cymene)] (3) and proceeds in the
presence of the ligand DABCO and molecular sieves with concomitant extrusion of water and hydrogen. A range of different primary alcohols and amines have been coupled in the presence of the catalyst to afford the corresponding imines in moderate to good yields. Optically pure amines gave the corresponding imines without any sign of racemization. Moreover, the one-pot diastereoselective addition of different organometallic reagents to the imine, obtained from the coupling between benzyl alcohol and (R)-1-phenylethylamine, was performed. To address specifics of the reaction mechanism, different experiments with deuterium-labeled benzyl alcohol were carried out indicating that that the catalytically active species is a ruthenium dihydride. The reaction is proposed to proceed by initial dehydrogenation of the alcohol to the aldehyde, which stays coordinated to the ruthenium centre. Then, nucleophilic attack of the amine
affords the hemiaminal, which is released from ruthenium and converted into the imine. Project 2: Tin-mediated regioselective 6-O-glycosylations of unprotected phenyl 1-thioglycopyranosides Chemical glycosylation is of outstanding importance to access biologically relevant carbohydrate structures, but classical methods suffer from the disadvantage of extensive protecting group manipulations. Thus, approaches to reduce the number of steps connected to chemical synthesis are highly important. In this thesis approaches to the regioselective glycosylation of fully unprotected phenyl 1-thio-glycopyranoside acceptors via tin activation are described. Tin-mediated Koenigs-Knorr glycosylation of phenyl 1-thio-β-D-glucopyranoside (28), phenyl 1-thio-β-Dgalactopyranoside (32) and phenyl 1-thio-α-D-mannopyranoside (33) with different bromide donors afforded the corresponding (1→6) linked disaccharides in good to moderate yields. The disaccharides obtained from the first coupling can be activated as donors for subsequent tinmediated glycosylation reactions. The activation has been performed following two different strategies. The first involved one-step activation with a thiophilic reagent, while the second
employed a two-step activation which entailed first formation of a glycosyl halide, and then activation with a halophilic reagent. This last approach is of particular interest; in fact, thioglycosides can be used as acceptors enabling an iterative oligosaccharide synthesis. Following these strategies a number of different trisaccharides have been successfully synthesized.