A divergent approach toward synthesis of myo-inositol phosphates: Acyl migrations and regioselectivity

Syntheses of all possible 9 and 12 regioisomers of myo-inositol tetrakis- and tris-phosphates(IP4 and IP3), respectively were accomplished from myo-inositol via its di- and tri-benzoate derivatives. The requisite sets of myo-inositol benzoate intermediates were most conveniently produced by base-catalyzed migration of the benzoate group followed by suitable separation methods. Kinetics of the acyl migration showed that generally cis migrations are faster than trans migrations but not to the extent to give a high selectivity. However, a reasonable degree of cis/trans selectivity could be observed in compounds with rigid conformations. The acyl migration rate increases with increasing solvent polarity indicating that the intermediate or transition state involved is more polar than the stating material. 1,2:4,5-Di-O-isopropylidene-myo-inositol shows a high degree of regioselectivity in reactions such as alkylation, acylation and silylation at 3-OH in preference to 6-OH. The origin of the regioselectivity was found to be the enhanced nucleophilicity of the 3-alkoxide due to its interaction with the cis-vicinal oxygen of the isopropylidene group possibly via ''through-space alpha effect''.