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Title: Application of nitrile oxide-isoxazoline chemistry for the synthesis of 2-ulosonic acid analogues
Author: Todd, Christine Joy
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1995
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Nitrile oxide-isoxazoline methodology has been employed in a novel convergent approach towards 2-ulosonic acid analogues, in particular those of 3-deoxy-D-arabino-2-heptulosonic acid (DAH) and 3-deoxy-D-manno-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-3,4-0-cyclohexylidene-D-glycero-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 Erythro 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 et al, and the 'homoallylic' modification offered by De Micheli et al. 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-3,5-0-ethylidene-D-erythro-pent-1-enitol and 1,2-dideoxy-3,5-0-benzylidene-D-threo-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 S-configuration at the new chiral centre (C-5) corresponding to a threo relationship about the C-5/C-6 bond. The corresponding acetate derivatives also yielded threo adducts preferentially.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available