Application of nitrile oxide-isoxazoline chemistry for the synthesis of 2-ulosonic acid analogues

• Main Author: Todd, Christine Joy
• Published: University of Edinburgh 1995
• Subjects: 547.78
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.662975

Nitrile oxide-isoxazoline methodology has been employed in a novel convergent approach towards 2-ulosonic acid analogues, in particular those of 3-deoxy-D-<I>arabino</I>-2-heptulosonic acid (DAH) and 3-deoxy-D-<I>manno</I>-octulosonic acid (KDO). It involves regio- and diastereoselective [3+2] cycloaddition of a nitrile oxide to carbohydrate alk-1-enes containing four, five or six carbons, yielding 2-isoxazolines. Subsequent deprotection followed by reductive hydrolytic cleavage affords the 2-ulosonic acid analogues. The four carbon alkene 1,2-dideoxy-3,4-<I>0</I>-cyclohexylidene-D-<I>glycero</I>-1-enitol was chosen as a model alkene on which to establish the methodology which could then be applied directly to the two target classes of compounds. Cycloadditions were performed using four nitrile oxides: ethoxycarbonylformonitrile oxide, benzonitrile oxide, acetonitrile oxide and (diethoxyphosphoryl)acetonitrile oxide. These proceeded in 40-88% yield with moderate π-facial selectivity (54-65% dc) in favour of <I>Erythro</I> adducts, with the major product in each case possessing S-configuration at the new asymmetric centre, C-5. This selectivity can be rationalised in terms of the 'inside alkoxy effect' proposed by Houk <I>et al</I>, and the 'homoallylic' modification offered by De Micheli <I>et al.</I> In an attempt to control selectivity in the nitrile oxide cycloaddition reactions, a dispiroketal protecting group was utilised. However, the increase in steric bulk and presence of a six-membered ring as the protecting group incorporating the diol, rather than the five-membered ring, does not appear to influence π-facial selectivity. Cycloadditions were also performed using the five carbon alkenes 1,2-dideoxy-3,5-<I>0</I>-ethylidene-D-<I>erythro</I>-pent-1-enitol and 1,2-dideoxy-3,5-<I>0</I>-benzylidene-D-<I>threo</I>-pent-1-enitol. With the former alkene these proceeded in 40-80% yield but with minimal π-facial selectivity (4-6% DE). However, changing the homoallylic substituent from axial to equatorial in the later alkene significantly increased the selectivity (to 62-64% de). In both instances the major product was shown by X-ray crystallography to possess <I>S</I>-configuration at the new chiral centre (C-5) corresponding to a <I>threo</I> relationship about the C-5/C-6 bond. The corresponding acetate derivatives also yielded <I>threo</I> adducts preferentially.