Higher Sugar Analogs and Carbohydrate-Derived Molecular Diversity

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URI: http://hdl.handle.net/10900/94666
Dokumentart: PhDThesis
Date: 2019-11-13
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Chemie
Advisor: Ziegler, Thomas (Prof. Dr.)
Day of Oral Examination: 2019-11-08
DDC Classifikation: 500 - Natural sciences and mathematics
540 - Chemistry and allied sciences
Keywords: Kohlenhydrate , Organische Chemie , Oxidation , Zucker , Synthese , Chemische Synthese
Other Keywords:
organic chemistry
chemical synthesis
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Initial synthetic studies identified Dess-Martin oxidation to be the method of choice for the formation of the unknown, sensitive allyl 3,4,6-tri-O-benzyl-b-D-arabino-hexopyranoside-2-ulose. In a similar manner, the respective known 3,4,6-O-benzylated b-benzyl and b-methyl 2-keto-glycosides (2-ulosides) could be obtained from the corresponding 2-OH-unprotected glucosides. In a project directed towards the synthesis of 1,2-annulated carbohydrates with a trans-decalin structure (polyhydroxylated 2,10-dioxadecalins), the respective allyl 2-uloside underwent vinylation of the 2-ketone, followed by ring-closing metathesis. Stereoselective syn- or anti-dihydroxylation and debenzylation afforded the wanted 1,2-pyran-annulated target structures as a new class of bicyclic carbohydrate derivatives with the previously undescribed b-manno-configuration. Structural characterizations of the highly polar annulated sugars included NMR analysis in D2O. Furthermore, X-ray crystallography confirmed the structure of the respective syn-isomer, and provided insight into a dense network of hydrogen-bonding interactions. Structurally related published 1,2-annulated sugars have been reported to be carbohydrate mimetics acting as inhibitors for natural glycosidase enzymes. Following a related synthetic route, the corresponding benzyl 2-uloside was treated with alkynyllithium species, either derived from propiolaldehyde acetals or from propargyl alcohol derivatives, to afford the 2-C-alkynylated mannosides. A sequence comprising partial hydrogenation of the alkyne, followed by syn- or anti-dihydroxylation, afforded 1,2,3-trihydroxyprop-1-ylbranched mannosides with diverse stereochemical configurations of the hydroxylated side chain. These trihydroxypropyl-branched intermediates were converted into 2-spirofuranosepyranoses, reducing carbohydrate hybrid molecules with previously undescribed structure, via selective primary alcohol oxidation. For this transformation, a new oxidation protocol utilizing the known combination TEMPO/trichloroisocyanuric acid in combination with an optimized solvent/buffer system was developed. Global debenzylation of the spirofuranose intermediates yielded 4-C-formyl octoses with diverse configurations of the C-2/3 stereogenic centers as complex mixtures of cyclic hemiacetal isomers. Detailed structural NMR studies in D2O identified the major isomers to be the annulated 1,5-pyranose-9-7-pyranose forms, or the 1,4-furanose-9,7-pyranose spiro-forms, and thus, isomeric forms with two hemiacetal functionalities. The corresponding 9,7-pyranose-1,9-pyranose isomeric forms (acetal-hemiacetal forms), structurally related to the natural product bradyrhizose, were not identified to be major constituents of these complex higher sugars. In a concluding project, all three benzylated 2-keto-glucosides (b-allyl/benzyl/methyl 2-ulosides) were transformed into the corresponding 3,6- di-O-benzyl-4-deoxy-b-D-glycero-hex-3-enopyranoside-2-uloses (3,2-enolones) by base-induced elimination of benzyl alcohol. Reactivity studies revealed that these 3,4-unsaturated 2-ketoglucosides undergo a rearrangement into racemic 2-benzyloxy-4-benzyloxymethyl-4-hydroxy-5-alkoxycyclopent-2-enones in the presence of basic reagents (potassium tert-butoxide) in DMF. Mechanistic considerations for this previously undescribed rearrangement were established, and discussed in the context of related published transformations, which were reported to give the regioisomeric 5-hydroxy-substituted cyclopent-2-enones.

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