Nitrile oxide/isoxazoline approach to higher sugars

• Main Author: Young, Anne A.
• Published: University of Edinburgh 1990
• Subjects: 572.56
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664139

The application of nitrile oxide/isoxazoline chemistry towards the synthesis of higher sugars (monosaccharides containing seven or more contiguous carbon atoms) has been investigated. This convergent approach, involving the cycloaddition of sugar derived alkene and nitrile oxide fragments and subsequent manipulation of the resulting isoxazoline, has much of the product stereochemistry preselected. Three ω-unsaturated monosaccharides were chosen for study: the D-glucose-derived six carbon unit (<i>94</i>), its C-3 epimer (<i>102</i>) and a seven carbon alkene, (<i>97</i>), prepared from D-galactose. Benzonitrile oxide was employed in preliminary studies as a model 1,3-dipole to probe the π-facial selectivity of cycloaddition to these alkenes. Cycloadditions with the carbohydrate derived nitrile oxides (<i>117</i>), (<i>121</i>) and (<i>125</i>) were subsequently examined. For alkenes (<i>94</i>) and (<i>97</i>) a high degree of stereoselectivity (typically <i>ca</i> 85:15) favouring the formation of the <i>erythro</i> 2-isoxazoline was obtained. This observation can be rationalised in terms of the 'inside alkoxy effect' proposed by Houk in which the allylic oxygen occupies the <i>inside</i> position in the transition state. D-<i>Ribo</i>-alkene (<i>102</i>) proved to be an exception; cycloaddition with ethoxycarbonylformonitrile oxide (<i>117</i>) occurred with negligible stereoselectivity (51:49). This result demonstrates the role played by the homoallylic oxygen in determining the stereoselectivity. Pd/C mediated reductive hydrolytic cleavage of the 2-isoxazolines unmasked the β-hydroxy ketone functionality of the deoxy-ulose derivatives. Subsequent reduction furnished a pair of separable diastereomeric 1,3-diols, whose stereochemistry was determined by examination of the ^1H n.m.r. spectra of the corresponding isopropylidene ketals. A series of deoxy -octose, -nonose, -decose, -dodecose and -tridecose monosaccharides have been thus prepared. Finally, other aspects of isoxazoline chemistry have been investigated. The reduction of isoxazoline (<i>123</i>) by lithium aluminium hydride afforded the <i>syn</i>-γ-amino alcohol (<i>176</i>) as the only isolated product. <i>Trans</i> α-enones (<i>174</i>) and (<i>175</i>) were synthesised stereospecifically by dehydration of the corresponding β-hydroxy ketones.