Selective radical-chain epimerisation at electron-rich chiral tertiary C–H centres using thiols as protic polarity-reversal catalysts

Abstract

Radical-chain epimerisation at chiral tertiary CH centres adjacent to ethereal oxygen atoms can be brought about in the presence of thiols, the function of which is to act as protic polarity-reversal catalysts for hydrogen-atom transfer between pairs of nucleophilic α-alkoxyalkyl radicals. The viability of the method is demonstrated by epimerisation of a series of simple molecules that contain two chiral centres and then the procedure is applied to more complex carbohydrate-based systems, where it is possible to convert a readily available diastereoisomer into a rarer one in a straightforward manner. Of necessity, epimerisation always proceeds in the direction of thermodynamic equilibrium and, in general, the results obtained are in accord with the predictions of molecular mechanics calculations using the MMX force-field. When the required isomer is less stable than the starting diastereoisomer, thiol-catalysed epimerisation of a suitable derivative of the parent can provide a means to obtain the desired compound in satisfactory yield, after deprotection of the epimerised derivative. This strategy is demonstrated for the conversion of trans-cyclohexane-1,2-diol into the less stable cis-isomer and for related contra-thermodynamic isomerisation of some carbohydrates, as well as for the conversion of meso-1,2-diphenylethane-1,2-diol into the dl-form. Thiol-catalysed epimerisation at a CH centre adjacent to an ether-oxygen atom is much faster than at a similar centre adjacent to an amido-nitrogen atom, a result that can be understood in terms of the importance of polar effects on the rate of abstraction of hydrogen by electrophilic thiyl radicals.