Diazirines, glycosidation

Vasella et al. introduced an approach to glycoside synthesis using the glycosylidene carbene generated from the diazirine sugar as a novel type of glycosyl donor. The... 

Two examples of the applicability of anomeric carbenes were reported by VaseUa et al. [167,168]. The first demonstrated the utility of olefinic substrates such as Al-phenylmaleimide, acrylonitrile and dimethylmaleate for the formation of glycosidic cyclopropanes. The carbene precursor in this example was the glucose-derived diazirine. As shown in Scheme 7.55, the use of dimethylmaleate produced a mixture of diastereomers with a combined yield of 72%. Although not presented as a schematic, the second and more dramatic example was used to functionalize fullerenes. 

Thermal or photolytic treatment of the diazirine illustrated here in the presence of a range of alcohols [MeOH, EtOH, Me2CHOH, Me3COH, F3CCH2OH, and (F3C)2C(Me)OH] produces the correponding glycosides. The diastereoselectivity varies with the acidity of the alcohol, the nature of the solvent, and the reaction temperature.231... 

An entirely novel approach to glycosylation uses glycosylideneaziridines which can be oxidised to the relatively unstable diazirines from which glycosylidene carbenes are produced on warming to room temperature. In the presence of alcohols these give glycosides by insertion reactions (Scheme 1) attempts to... 

The preparation of the a//o-configurated diazirine (84) derived from N-acetyl glucosamine has also been described. It reacts with acrylonitrile in a similar way to (83) to give all four isomeric cyclopropane derivatives. Attempts to convert (84) into an 0-glycoside using isopropanol failed with only the oxazolidine being isolated following NHAc participation. 

Synthesis of amino-sugar glycosides is covered in Chapter 3, the formation of 2-acetamido-2-deoxy-D-glucosides from diazirines via glycosyl carbenes in Chapter 10, and the conversion of a deoxynojirimycin derivative into 2,6-dideoxy-2,6-imino-L-gulonic acid in Chapter 18. 

Glycosidation by diazirines has been studied by using equivalent amoimts of glycosyl acceptor and donor. It is expected that yields of the products increase with excess diazirine occasionally this was shown to be so. Solvents have not systematically been optimized, but toluene, THF, and dioxane seem well suited early experiments were mostly performed in dichloromethane. 

The course of the glycosidation of hydroxy compounds by glycosylidene diazirines is mainly dictated by four factors ... 

Glycosidation by Glycosylidene Diazirines 159 Table 1. Kinetic parameters for the thermolysis of 1-aziglycoses in MeOH. 

Scheme 2. Glycosidation of alcohols by glycosylidene carbenes derived from diazirines.

The influence of pK and the insensitivity to steric hindrance is seen from the gly-cosylation of fluorinated alcohols (Figure Ic) [18]. Glycosidation of trifluoroetha-nol, hexafluoro-2-propanol, and hexafluoro-tert-butanol by one equivalent of the diazirine 7 in dioxane yielded the anomeric glycosides in yields of 70-74% and in P-d/u-d ratios ranging from 77 32 to 95 5. The solvent has an influence on the anomeric ratio, which changes for hexafluoro-tcrt-butanol from P-d/o-d = 84 16 (75%) in dichloromethane to 98 2 (80%) in DME. The formation, upon glycosidation in propionitrile at -60 °C, of the imino ether 31 (55%) besides the glycosides evidences the formation of an oxycarbenium cation, its solvation, and the preferred axial attack of the solvent. 

These results confirm the strong influence of hydrogen-bonds on the result of glycosidation and characterize these diazirines as subtle, reactivity-based tools for the investigation of intra- and intermolecular hydrogen-bonds and their influence on regio- and diastereoselective glycosidation. 

Exploratory experiments have shown that glycosylidene carbenes also insert into the N-H bond of sulfonamides, whereas carboxamides yield esters, as illustrated by the product obtained from an A-Boc-asparagine benzyl ester (Figure 7c) [32]. Presumably, such esters are formed by hydrolysis of the initially formed imino ether 0-glycosides, suggesting that glycosylidene diazirines may be used for (selective ) cleavage of peptidic bonds. 

Vasella s group has reported a series of new glycosylidene diazirines, for example 8, which undergo thermolysis in methanol to give methyl glycosides. Kinetic studies indicate the importance of... 

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