| dc.description.abstract | Lipid secondary metabolites are increasingly receiving the attention of researchers for their nutritional and pharmaceutical properties. In a previous study on secondary metabolites of Sclerochloa dura, a plant used in folk medicine in the Balkan region, a novel sulfolipid containing a linolenoyl moiety was isolated and shown to have anti-inflammatory properties. Due to low natural abundance of this sulfolipid in the Sclerochloa dura plant matter, an effort to procure it, and its derivatives, by synthetic means was launched. This study provides the first contributions towards this objective.
Throughout the synthetic work presented in this thesis, the main emphasis has been put on the objective of developing a key intermediate suited for the insertion of functional groups in C-1, C-3 and C-6 of the sulfoquinovosyl backbone. To this end, two starting materials, D-glucose and 1,2;5,6-di-O-isopropylidene-α-D-glucofuranose, were evaluated in terms of suitability. The furanoid starting material eventually proved superior in terms of selective functionalization through a concomitant rearrangement-glycosylation reaction. This reaction allowed the insertion of an anomeric allyl ether, as a precursor to the glycerol moiety in the target molecule, as well as a benzyl-like ether, serving as atemporary protecting group, in C-3. The products obtained from this key reaction were employed in four protection schemes involving silyl ethers as permanent protecting groups. The exploration of these protecting group manipulations, combined with the insertion of a thioacetate moiety on C-6 via a Mitsunobu-type reaction, led to development of two potential key intermediates with benzyl or naphthyl ether in C-3.
These key intermediates were subsequently evaluated in terms of compatibility with two crucial synthetic transformations; the conversion of the allyl group to a glycerol moiety, and the deprotection and subsequent esterification in the 3-position. Dihydroxylation of the allyl group was carried with OsO4 and the asymmetric AD-mix reagents. An increase in selectivity towards the S-diastereomer in the diol products was observed when AD-mix were used, though this selectivity came at the cost of lower conversion. Interestingly, the AD-mix reagents also exhibited a kinetic preference for α-anomers. Protection of the diol products as acetonides allowed diastereomeric resolution by chromatographic means. In the deprotection of the hydroxyl on C-3, the benzyl intermediate failed when appropriate reaction conditions could not be established. The naphthyl intermediate was successfully cleaved under oxidative conditions. The resulting 3-OH product could not be esterified due to sterical hindrance from the neighboring silyl groups. Consequently, silyl groups proved unsuitable as permanent protecting groups.
Through a minor modification of the protection scheme developed for silyl protected intermediates, a new key intermediate based on acetyl protecting groups was procured. This intermediate exhibited similar, though less pronounced, selectivity for the S-diastereomer in the dihydroxylation of the allyl group. With lowered steric crowding in the acetyl protected intermediate, the esterification reaction proceeded smoothly. The esterified compounds were subsequently oxidated under three different sets of conditions in order to furnish the desired sulfonic acid moiety in C-6. Regrettably, none of the oxidative conditions explored were well tolerated by the linolenoyl moiety. Furthermore, conditions for global deprotection of the permanent acetyl protecting groups could not be established.
Although the target product was not obtained in the course of this work, a synthetic approach towards this sulfolipid class has largely been developed. The basic synthetic pathway towards esterified late-stage intermediates has been mapped out, leaving the identification of an appropriate permanent protecting group and the establishment of milder S-oxidation conditions as the only remaining obstacles for procuring the target product and its derivatives. | en_US |
