Experimental and Theoretical Studies on Stereo- and Regioselectivity in Intramolecular Nitrone−Alkene Cycloaddition of Hept-6-enoses Derived from Carbohydrates

The effect of blocking groups and stereochemistry of the substituents on the regio- and stereoselectivity
in intramolecular nitrone−alkene cycloaddition (INAC) of hept-6-enoses are reported. l-ribo-Hept-6-enose 12 and d-lyxo-hept-6-enose 15, both containing a 2,3-O-isopropylidene blocking group, and l-xylo-hept-6-enose 23 and d-arabino-hept-6-enose 30, both with a 2,3-O-trans-diacetal blocking group, were
prepared from d-ribose and d-arabinose, respectively. With N-alkyl hydroxylamine, lactols 12 and 15
underwent an INAC reaction to give cis-fused isoxazolidines exclusively whereas lactols 23 and 30 gave
a mixture of cis-, trans-fused isoxazolidines (cyclohexanols) and bridged isoxazolidines (cycloheptanols).
With the 2,3-O-trans-diacetal protecting group, the bridged bicyclo[4.2.1]isoxazolidines (cycloheptanols),
via the endo mode of INAC cyclization, were synthesized for the first time from unbranched sugar
derivatives 23 and 30. The stereochemical outcomes of these reactions were rationalized on the basis of
transition state energies obtained by computation. The present INAC showed trivial temperature, but
significant solvent dependence. For lactols 23 and 30, performing the INAC in 2-propanol gave the best
yields of fused isoxazolidines (cyclohexanols) whereas in dichloromethane afforded the best yields of
bridged isoxazolidines (cycloheptanols).