NITRILE OXIDES IN MEDICINAL CHEMISTRY .2. SYNTHESIS OF THE 2 ENANTIOMERS OF DIHYDROMUSCIMOL

The cycloaddition of bromonitrile oxide to monosubstituted olefins has a high regioselectivity yielding 3-bromo-5-substituted isoxazolines contaminated by minor amounts (4-9%) of the 4-substituted isomer. The adducts of bromonitrile oxide to allyl a3lcohol and N-protected allylamine were employed as key intermediates in the preparation of racemic dihydromuscimol (DHM). The synthesis of (R)-(-)- and (S)-(+)-DHM was accomplished by using the two diastereomers obtained by the cycloaddition of bromonitrile oxide to (S)-(+)-isopropylidene-3-buten-1,2-diol. The enantiomeric excesses of (R)-(-)- and (S)-(+)-DHM, determined by capillary GLC on the appropriate precursors, were 98.8 and >99.0 %. A spectroscopic survey of the tautomerism of 3-hydroxyisoxazolines indicates the predominant or exclusive occurrence of the NH form.