Synthesis of Human Milk Oligosaccharides and Regioselective Ring Opening of Oxabicycles

Abstract

This thesis involves two distinct topics related to carbohydrate and organometallic chemistry. The first chapter includes chemical synthesis of oligosaccharides present in human milk. Human milk oligosaccharides are a family of structurally diverse glycans, which are highly unique for human milk. These oligosaccharides participate in multiple mechanisms by which breast-fed infants become protected against infections and they are believed to serve as nutrients for the early brain development. The synthesized oligosaccharides are based on the motif Gal1–3/4GlcNAc1– 3Gal1–4Glc, which is the core of many human milk oligosaccharides. Three distinct human milk oligosaccharides were synthezised; Lacto-N-tetraose, Lacto-N-fucopentaose I and Lacto-N-neofucopentaose I. A one-pot strategy was developed for the synthesis of the tetrasaccharide backbone core based on the different reactivity of thioglycoside donors and acceptors. The tetrasaccharides were formed both by sequential and the developed one-pot method. Deprotection of the protecting group at the C-2-position on the galactose moiety liberated an acceptor for the fucosylation eventually creating the two linear pentasaccharides Lacto-N-fucopentaose I and Lacto-N-neofucopentaose I. The scope of the developed one-pot method was further enhanced by performing selective 1-4 glucosylations utilizing a glucosamine building block containing two free hydroxy groups. Furthermore, this work was executed in the hope to synthesize the branched oligosaccharide Lacto-N-fucopentaose III where the fucose is also attached in the same pot. In addition, pNP-neuraminic acid was synthesized for the purpose to perform activity studies on enzymes. The enzymes were designed to perform sialyl transfer reactions in the synthesis human milk oligosaccharides containing neuraminic acid. OH O HO HO O OH O HO O HO OH HO O OH O NHAc OH O O HO HO O HOOH OH Lacto-N-fucopentaose OH O HO HO O OH O HO O HO OH O O OH HO NHAc Lacto-N-neofucopentaose OH O O HO HO O HOOH OH The second chapter describes the regioselective ring opening of enantiopure oxabicycles primarily by the use of rhodium catalysts and phosphine ligands. The ring opened iii products were similar to compounds, which had shown to be potential protein Bcl-XL antagonists, a target for future drugs in cancer treatment. The aim was to create a general asymmetric ring opening method of several enantiopure oxabicycles having different functional moieties attached to the ring. By employing a [Rh(COD)Cl]2 catalyst with a Josiphos ligand, it was possible to perform the ring opening of oxabicycles with ester moieties in good yield end excellent regioselectivity. Other functional groups showed to be more challenging, therefore several alterations of the functional groups were performed to form oxabicycles, which could be ring opened regioselectively by the [Rh(COD)Cl]2 catalyst and Josiphos ligand.