De Novo Synthesis of Bicyclic Carbohydrates and Polyhydroxylated Lipids

Abstract

The de novo synthesis of carbohydrates is the preparation of sugars from achiral precursors using asymmetric catalysis. This approach can enable the synthesis of targets that are difficult to achieve using the chiral pool. Furan derivatives are widely used precursors in de novo strategies, via a combination of reactions such as the Noyori asymmetric transfer hydrogenation (ATH), Achmatowicz rearrangement, and palladium-catalyzed glycosylation. In this thesis, these reactions were explored in the preparation of bicyclic carbohydrates and polyhydroxylated lipids from achiral ketoenolester precursors. The first targets of this thesis were the bicyclic monosaccharide bradyrhizose and its oligosaccharides. This carbohydrate is a component of the lipopolysaccharide (LPS) of some strains of nitrogen-fixing bacteria. A novel de novo route was envisioned for the preparation of bradyrhizose and its α-(1→7)-disaccharide via a common cyclic dienone intermediate, which was obtained from 2-acetylfuran. Attempts at using this intermediate in a Pd-glycosylation strategy for the synthesis of the disaccharide were not successful. A route to the monosaccharide was extensively investigated but was not completed due to problems in establishing the correct configuration at one stereocentre of the molecule. Bradyrhizose diastereomers were prepared in these studies and were analyzed for their isomeric composition in D2O. The next targets of this work were the polyhydroxylated lipids avocadyne, avocadene and avocadane, as well as all their stereoisomers. These lipids are fatty alcohols found in avocados, and have diverse biological applications. A library of 12 compounds was prepared in three to five steps from a common achiral acylpyruvate precursor via a combination of Noyori ATH and diastereoselective reductions. The compounds were used in structure–activity relationships studies for their anti-leukemic activity. The final targets of this thesis were lactone and lactol analogues of the bicyclic octodiose from the aminoglycoside antibiotic apramycin. These analogues were successfully prepared from 2-acetylfuran via Noyori ATH, Achmatowicz rearrangement, and isocyanate annulation reactions. The use of both the lactone and the lactol in glycosylation reactions was investigated in preliminary studies, and the lactol will be further investigated for its potential use as an acceptor in dual B-/Pd-catalyzed glycosylations.