Identifier: TDX:789
Authors: Arnés Novau, Xavier
Abstract:
2-Deoxy and 2,6-dideoxy glycosides are frequently found as single structural elements or, more frequently, as components of oligosaccharides, in antibiotics and anticancer agents such as antracyclines (cyclamicine 0), active antibiotics (erytromicines, angucyclines) and pharmacological compounds used in cardiac insufficiency treatment (cardiac glycosides such as digitoxine), etc.<br/>Therefore, methods for the efficient and stereoselective construction of deoxyglycosidic linkages will have useful applications in medicinal and bioorganic chemistry by allowing to understand biological mechanisms and elaborate new and less toxic drugs.<br/>On the other hand, in the nucleoside field, some 2'-deoxy and 2',3'-dideoxy-nucleosides are inhibitors of inverse transcriptase of AIDS virus, and they are often used in its treatment.<br/>In two cases, the lack of a stereodirecting neighbouring group adjacent to the anomeric center makes 2-deoxyglycoside synthesis a particular challenge. Moreover, the absence of electron-withdrawing substituent at C-2 makes the glycosidic bond much more acid labile, giving rise to easy hydrolysis or anomerization.<br/>In this context, the goal of this work is develop new synthetic methods for the stereoselective synthesis of 2-deoxy-oligosaccharides and nucleosides starting from 2-deoxy-2-iodo-pyranosides and furanosides. These glycosil donors are trying to obtain by intramolecular and stereoselective cyclization induced by electrophilic iodine and starting from polihydroxi-pentenylsulfides and polihydroxi-hexenylsulfides as substrates. This method would allow to prepare glycosil donors with iodine at position 2 by means of a procedure that does not require the use of glycals.<br/>It has been prepared different polihydroxi-alkenylsulfides following two different synthetic strategies, starting from quiral products in all cases (2,3-diisopropiliden-D-glyceraldehide, (R)-glycidol, D-arabinose o D-ribose). These strategies are summarized:<br/>a) 2-Fenilsulfanil ethene unit incorporation. Using PhSCΞCH as sinthon, and after LiAIH4 alkyne reduction.<br/>b) Introduction of a monocarbonated unit together the fenilsulfanil group (SPh). Using carbanions in olefination reactions.<br/>In olefination reactions it has been observed a different behaviour depending on the reagents used and the reaction conditions, but without differences depending on the starting sugar. In Wittig-Horner reaction, it has been obtained the best results, yields over 70% for the majority E isomer.<br/>It has been studied cyclization reactions of phenyl dihidroxy-pentenylsulfydes, with different protecting groups, induced by iodine electrophiles, and the conclusions are:<br/>a) The reaction is completely regioselective giving endo cyclization products by closing the cycle over the carbon which is adjacent to sulphur atom.<br/>b) Cyclization reaction is quimioselective, and it's always obtained 1-hydroxi-2iodo-tetrahydrofuranes mixtures by means of 5-endo cyclizations and SPh group activation, and a tetrahydropyrane by mans of 6-endo cyclization.<br/>It has been studied cyclization reactions of phenyl tetra hydroxi-hexenylsuIfides induced by iodine electrophiles that have provided 2-iodo-1-thio-glycosides, and the conclusions are:<br/>a) The cyclization takes place exclusively trough 6-endo path.<br/>b) The cyclization is steroselective starting from one isomer E or Z.<br/>c) The stereoselectivity of the reaction is governed by a stereoelectronic effect<br/>called 'inside-alkoxy'.<br/>d) It's very difficult to avoid the SPh group activation on the obtained thioglicosydes.<br/>2-lodo-1-thioglicosides has been used as a glycosil donors in glycosidation reactions with different alcohols. That has allowed to obtain a-manno-2-iodo-glycosides and β-alo-2-iodo-glycosides with good yields and excellent stereoselectivities, specially on the manno derivatives.<br/>By the same way it has been prepared hydroxi-enolethers following the same synthetic strategies.<br/>The cyclization reactions of hydroxi-enolethers with fluorine electrophilic reagents has provided fluorinated compounds, such as a 2-ethoxy-3-fluoro-tetrahydrofurane, which could be assembled as a 2-fluoro-furanoside precursor of 2-fluoro-nucleosides.<br/>In the case of hydroxi-enolethers with alilic substitution, it's not obtained the cyclated product, but an α,β-insaturat product is obtained as a result of an OBn group elimination.
Repositori URV