Stereoselective Synthesis of 2-Deoxyoligosaccharides.New Aprroaches to the Synthesis of Digitoxin and P-57

Resumo

In the present work, a complete study for the synthesis of 2-deoxy-glycosides is described, applyinga strategy previously developed in our group for the preparation of 2-deoxy-2-iodo-pyranoses. Thisstrategy, that involves Wittig¨CHorner olefination from fully protected furanoses to give alkenyl sulfides,electrophilic¨Cinduced cyclization to furnish 2-deoxy-2-iodo-pyranosyl thioglycosides, gives access to anew type of glycosyl donor that can be used in glycosylation reactions of the desired glycosyl acceptors togive 2-deoxy-2-iodo-glycosides.This method is based, on one hand, in the availability of sulfanylmethylphosphine oxides to performthe olefination reaction over the furanoses. The usual access to these reagents is the Arbuzov reaction,that requires chloro derivatives as starting materials that are not easy to prepare and in many cases areunstable. Furthermore, the efficiency of the cyclization is limited by the obtaintion of E/Z alkene mixturesin the olefination step, because Z alkenes were proved to be reluctant to cyclization.To increase the efficiency of the whole process, two implementations were studied in this work.First, a new approach for the preparation of sulfanylmethylphosphine oxides was investigated startingfrom (tosyloxymethyl)phosphine oxide. The method was also extended to heteroatomic substitutedmethylphosphine oxides (X, Se, Te, NR2, etc).Application of these novel sulfanylmethylphosphine oxides in the olefination of ribo- andarabinofuranoses resulted in the formation of the corresponding sulfanyl alkenes with increased E/Zstereoselectivity.The sulfanyl ribo and arabino alkenes were investigated in the iodonium¨Cinduced cyclizationreaction. The effect of the bulkiness of the substituent at sulfur was studied and the results of cyclizationcompared to that of phenyl at the phenylsulfanyl parent compound. Cyclization of the arabino derivativesled to 6-endo cyclization products in lower yields whereas the t-butylsulfanyl arabino-1-hex-enitolproceeded in higher yield. No cyclization took place from 2,6-dimethylphenyl arabino-1-hex-enitol. Theyields in al cases were higher from ribo-hex-enitols than from the corresponding arabino-hex-enitol.Glycosylation of some of the allopyranoside thioglycosides synthesized were explored andcompared with those obtained from phenylsulfanyl parent thioglycoside. t-Butyl thioglycoside wasreacted with cholesterol to render alloglycoside product as an anomeric mixture in higher yield withoutalmost affecting the stereoselectivity whereas with 2,6-dimethylphenyl thioglycoside the stereoselectivityincreased but the yield was lower.The synthesis of septanosides was studied starting from pyranosides with the strategy of Wittig¨CHorner olefination and subsequent electrophile¨Cinduced cyclization reaction, but the desired 7-endocyclization did no work with secondary alcohols. To overcome this problem, starting fromconformationally¨Crestricted 2,3-O-isopropylidenefuranosides, hex-1-enitols with a free primary hydroxylfunction were prepared, from which 7-endo cyclization reaction took place to furnish the desiredoxepanes with moderate yields.The total syntheses of 2,6-dideoxyoligosaccharides digitoxin and appetite suppressant P57, withcommon 2,6-dideoxypyranose units, were explored, applying the three-step (olefination¨Ccyclization¨Cglycosylation) methodology. For the synthesis of common intermediate C, two different permanentprotecting groups for free hydtoxyl group at C-3 were used: benzyl ethers for digitoxin and methyl ethersfor P57. Different silyl groups (TBS, TES and TBDPS) were used for hydroxyl at C-4 that requiredtemporary protection. Olefination of the different 6-deoxyribofuranoses rendered the corresponding 5-Osilylhex-1-enitols (167, 169, and 173) as a consequence of silyl migration from hydroxyl at C-4 to C-5,altogether with the expected 4-O-silyl hex-1-enitols (164, 168, and 172). These products were analyzedby 1D and 2D NMR techniques.5-O-TES, 5-O-TBS or 5-O-TBDPS protected hex-1-enitols were submitted to iodonium¨Cinducedcyclization reactions to afford exclusively 5-endo cyclization products. Furthermore, 5-endo cyclizationproduct 2-iodofuranose 189 was formed as a major product by cyclization from the C-4 unprotected enitol176.Digitoxin and P57 synthesis will be reconsidered in a near future using other protecting groups thatdo not migrate under the basic conditions of the olefination.