Stereoselective synthesis of 2-deoxoligosaccharides

Identificador:  TDX:795

Handle: https://hdl.handle.net/20.500.11797/TDX795

Autores:  Boutureira Martin, Omar

Resumen:
Stereoselective Synthesis of 2-Deoxyoliogosaccharides<br/>Autor: Omar Boutureira Martín<br/><br/> The research described in this thesis aims to investigate a new method for the stereoselective synthesis of 2-deoxyglycosides and oligosaccharides based on a new access to 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl glycosyl donors that would not be limited by the availability of pyranoid glycals and by the stereoselective addition of electrophiles.<br/> Chapter 3 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 iodo-hexopyranosyl glycosides from furanoses. The procedure involves three reactions: Wittig-Horner olefination to give alkenyl sulfanyl derivatives, electrophilic iodine-induced cyclization to give phenyl 2-deoxy-2-iodo-1-thiopyranosides, a new type of glycosyl donor, and glycosylation. The olefination reaction afforded alkenyl sulfanyl derivatives in good to excellent yields, except in cases where the conformational freedom is constrained by cyclic protecting groups such as 3,4-O-isopropylidene. The cyclization reaction proceeds with complete regio- and stereoselectivity. The reaction proceeds exclusively as 6-endo cyclization to give phenyl 1-thiopyranoside derivatives. The stereochemistry of the iodine at C-2 is always cis to the neighboring alkoxy group, except for lyxo derivatives which lack cyclic protecting groups. This is a key point in the overall process because the iodine controls the stereoselectivity of the glycosylation reaction. The yield of the cyclization depends on the configuration of the starting material; it is very good for substrates with a ribo or xylo configuration, but more modest for those with an arabino or lyxo configuration. The glycosylation reaction proceeded with good yields and good to excellent stereoselectivities. The glycosidic bond created in the major isomers was always trans to the iodine at C-2. Although phenyl 2-deoxy-2-iodo-1-thioglycosyl donors of all configurations can be accessed using the proposed procedure, it is particularly effective in providing 2-deoxy-2 iodo-&#946;-D-gulo- and -&#946;-D-allo-glycosides. These glycosides are precursors of 2-deoxyglycosides of ribo and xylo configuration, which are difficult to obtain by the classical methodology starting from glycals.<br/> Since 2-deoxy-2-iodo-1-thioglycosides are activated in conditions similar to those used to induce the cyclization, 2-deoxy-2-iodopyranosides were synthesized from sulfanyl alkenes using a 'one pot' consecutive cyclization and glycosylation process. The 'one pot' procedure has the advantage that it starts directly from the very stable acyclic alkenyl sulfide precursors and does not require isolation of the glycosyl donors. The overall strategy is fairly straightforward and operationally simple. Compared with the stepwise procedure, the 'one pot' process gave significantly improved yields with similar or slightly lower selectivities. Furthermore, the 'one pot' procedure was successfully applied to the synthesis of 2-deoxy- and 2,6-dideoxyglycosides.<br/> Chapter 4 describes our investigation into the application of the general procedure for the stereoselective synthesis of 2-deoxy-2 phenylselenenyl-hexopyranosyl glycosides from furanoses. We developed 2-deoxy-2-phenylselenenyl-1-thioglycosides as a new class of glycosyl donors that provide access to 2-deoxyglycosides. The cyclization reaction proceeds with complete regio- and stereoselectivity enhanced by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group. We have also demonstrated that the glycosylation of 2-deoxy-2-phenylselenenyl-1-thioglycosides is highly substrate dependent. Although glycosylation products of all configurations can be accessed by employing the present methodology, it is particularly effective in providing 2-deoxy-2-phenylselenenyl-&#61538;-D-gulo- and -&#61538;-D-allo-glycosides. In particular, regardless of the nature of the solvent employed, the high &#946;-selectivity observed in gulo (&#945;/&#946; ratio 1:14) and more modest in allo (&#945;/&#946; ratio 1:4) series is comparable to that previously observed for analogous glycosylation reactions of 2-deoxy-2-iodo-1-thio-D-gulo- (&#945;/&#946; ratio 1:16) and -D-allo-glycosyl donors (&#945;/&#946; ratio 1:6). Furthermore, the use of phenylselenenyl group at C-2 gave us some insight into the likely pathway of glycosylation reactions by using 2-deoxy-2-phenylselenenyl-1-thioglycosyl donors. Since the stereoselectivity observed is similar to that obtained using 2-deoxy-2-iodo-1-thioglycosides it can be concluded that this explanation is general for the different glycosylations assisted by chalcogens and halogens at C-2.<br/> Since 2-deoxy-2-iodo- and 2-deoxy-2-phenylselenenyl-1-thioglycosides have been evaluated as a new class of glycosyl donors, we became interested in the preparation of other useful glycosyl donors such as 2-deoxy-2-iodo-1-selenoglycosides, and exploit their higher reactivity in developing milder and orthogonal stereoselective glycosylation protocols by using this methodology. Thus, carbohydrate-based vinyl selenides of arabino, ribo, and 2-deoxy-ribo configurations were prepared by Wittig-type reactions of various protected furanoses. Moderate yields were always obtained due to nature and reactivity of both carbohydrate lactols and selenium-based olefinating reagents under the conditions tested. The reaction with electrophiles proved to be challenging and no cyclization products were obtained. The preparation of vinyl selenides proved to be much more difficult than the related vinyl sulfides, which can be prepared in good yields using Wittig-Horner reaction.<br/> Chapter 5 reports olefin cross metathesis reaction between carbohydrate-derived hydroxy alkenes and electron-rich olefinic partners with commercially available ruthenium-based catalysts. Microwave irradiation effectively accelerates the cross metathesis reaction of electron-rich olefins although some of the conversions remained low. Cross metathesis can only be achieved with hydroxy alkenes derived from 2-deoxysugars. In contrast, the hydroxy alkenes bearing an allylic alkoxy group neither isomerizes nor couples under similar conditions.<br/> Chapter 6 reports a new method for accessing pyranoid glycals of different configurations by a short route that uses readily available starting materials, and conventional transformations. Our method is particularly valuable for the synthesis of non-readily accessible glycals such as D-allal and D-gulal that are valuable products to prepare some oligosaccharide molecules with biologically interesting properties.<br/> A series of 2-deoxy-2-iodopyranoses were evaluated as precursors that provide access to pyranoid glycals and 2-iodoglycals from sulfanyl alkenes. This synthetic route involves consecutive cyclization and hydrolysis reactions followed by treatment of the resulting lactol under Gins' dehydrative glycosylation conditions. Despite the fact that this procedure has proved to be an efficient and general glycosylation method, its application to 2-deoxy-2-iodopyranoses did not afford the expected products. Although the observed product distribution (glycals, 2-iodoglycals, and 1,1'-disaccharides) revealed that this reaction is very sensitive to the configuration of the 2-deoxy-2-iodopyranose, 2-iodo pyranoid glycals can be almost exclusively obtained in good yields by employing 3,4-O-isopropylidene as a cyclic bifunctional protecting group.