2024-03-29T13:07:16Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/90242017-09-13T19:36:51Zcom_10803_311col_10803_335
nam a 5i 4500
electrophile-induced
cyclization
wittig-horner
stereoselective
oxepenes
p57
digitoxin
Stereoselective Synthesis of 2-Deoxyoligosaccharides.New Aprroaches to the Synthesis of Digitoxin and P-57
[Tarragona] :
Universitat Rovira i Virgili,
2011
Accés lliure
http://hdl.handle.net/10803/9024
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AAMMDDs2011 sp ||||fsm||||0|| 0 cat|c
9788469195239
Köver, Andrea,
autor
Tesi
Doctorat
Universitat Rovira i Virgili. Departament de Química Analítica i Química Orgànica
2008
Universitat Rovira i Virgili. Departament de Química Analítica i Química Orgànica
Tesis i dissertacions electròniques
Castillón Miranda, Sergio,
supervisor acadèmic
Díaz Giménez, Yolanda,
supervisor acadèmic
TDX
In the present work, a complete study for the synthesis of 2-deoxy-glycosides is described, applying<br/>a strategy previously developed in our group for the preparation of 2-deoxy-2-iodo-pyranoses. This<br/>strategy, that involves Wittig¨CHorner olefination from fully protected furanoses to give alkenyl sulfides,<br/>electrophilic¨Cinduced cyclization to furnish 2-deoxy-2-iodo-pyranosyl thioglycosides, gives access to a<br/>new type of glycosyl donor that can be used in glycosylation reactions of the desired glycosyl acceptors to<br/>give 2-deoxy-2-iodo-glycosides.<br/>This method is based, on one hand, in the availability of sulfanylmethylphosphine oxides to perform<br/>the olefination reaction over the furanoses. The usual access to these reagents is the Arbuzov reaction,<br/>that requires chloro derivatives as starting materials that are not easy to prepare and in many cases are<br/>unstable. Furthermore, the efficiency of the cyclization is limited by the obtaintion of E/Z alkene mixtures<br/>in the olefination step, because Z alkenes were proved to be reluctant to cyclization.<br/>To increase the efficiency of the whole process, two implementations were studied in this work.<br/>First, a new approach for the preparation of sulfanylmethylphosphine oxides was investigated starting<br/>from (tosyloxymethyl)phosphine oxide. The method was also extended to heteroatomic substituted<br/>methylphosphine oxides (X, Se, Te, NR2, etc).<br/>Application of these novel sulfanylmethylphosphine oxides in the olefination of ribo- and<br/>arabinofuranoses resulted in the formation of the corresponding sulfanyl alkenes with increased E/Z<br/>stereoselectivity.<br/>The sulfanyl ribo and arabino alkenes were investigated in the iodonium¨Cinduced cyclization<br/>reaction. The effect of the bulkiness of the substituent at sulfur was studied and the results of cyclization<br/>compared to that of phenyl at the phenylsulfanyl parent compound. Cyclization of the arabino derivatives<br/>led to 6-endo cyclization products in lower yields whereas the t-butylsulfanyl arabino-1-hex-enitol<br/>proceeded in higher yield. No cyclization took place from 2,6-dimethylphenyl arabino-1-hex-enitol. The<br/>yields in al cases were higher from ribo-hex-enitols than from the corresponding arabino-hex-enitol.<br/>Glycosylation of some of the allopyranoside thioglycosides synthesized were explored and<br/>compared with those obtained from phenylsulfanyl parent thioglycoside. t-Butyl thioglycoside was<br/>reacted with cholesterol to render alloglycoside product as an anomeric mixture in higher yield without<br/>almost affecting the stereoselectivity whereas with 2,6-dimethylphenyl thioglycoside the stereoselectivity<br/>increased but the yield was lower.<br/>The synthesis of septanosides was studied starting from pyranosides with the strategy of Wittig¨C<br/>Horner olefination and subsequent electrophile¨Cinduced cyclization reaction, but the desired 7-endo<br/>cyclization did no work with secondary alcohols. To overcome this problem, starting from<br/>conformationally¨Crestricted 2,3-O-isopropylidenefuranosides, hex-1-enitols with a free primary hydroxyl<br/>function were prepared, from which 7-endo cyclization reaction took place to furnish the desired<br/>oxepanes with moderate yields.<br/>The total syntheses of 2,6-dideoxyoligosaccharides digitoxin and appetite suppressant P57, with<br/>common 2,6-dideoxypyranose units, were explored, applying the three-step (olefination¨Ccyclization¨C<br/>glycosylation) methodology. For the synthesis of common intermediate C, two different permanent<br/>protecting groups for free hydtoxyl group at C-3 were used: benzyl ethers for digitoxin and methyl ethers<br/>for P57. Different silyl groups (TBS, TES and TBDPS) were used for hydroxyl at C-4 that required<br/>temporary protection. Olefination of the different 6-deoxyribofuranoses rendered the corresponding 5-Osilyl<br/>hex-1-enitols (167, 169, and 173) as a consequence of silyl migration from hydroxyl at C-4 to C-5,<br/>altogether with the expected 4-O-silyl hex-1-enitols (164, 168, and 172). These products were analyzed<br/>by 1D and 2D NMR techniques.<br/>5-O-TES, 5-O-TBS or 5-O-TBDPS protected hex-1-enitols were submitted to iodonium¨Cinduced<br/>cyclization reactions to afford exclusively 5-endo cyclization products. Furthermore, 5-endo cyclization<br/>product 2-iodofuranose 189 was formed as a major product by cyclization from the C-4 unprotected enitol<br/>176.<br/>Digitoxin and P57 synthesis will be reconsidered in a near future using other protecting groups that<br/>do not migrate under the basic conditions of the olefination.
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