A short entry to enantiopure 2-substituted 1,4-benzodioxanes by efficient resolution methods

Abstract

( R)-1,4-Benzodioxane-2-carboxilic acid ( R)- 1 was obtained by resolution of the racemic acid 1 with stoichiometric or nonstoichiometric (+)-dehydroabietylamine (+)- 2 in high chemical yield and enantiomeric excess. ( S)- 1 was isolated from the mother liquors of the crystallisation of ( R)- 1·(+)- 2 and its enantiomeric excess maximised by recrystallisation procedures involving a precipitation under kinetic control or, alternatively, by conversion into the methyl ester followed by a single crystallisation. The different mechanisms of the two S enrichments is well explained by the binary phase diagrams of the acid and of the ester, which show that the former is a racemic compound, whereas the latter a conglomerate. The DSC analyses were extended to 2-hydroxymethyl- and 2-mesyloxymethyl-1,4-benzodioxane, establishing that the alcohol forms a racemic compound, while its mesyl ester a conglomerate. On the basis of these results, different resolution strategies can be designed to obtain useful homochiral 2-substituted 1,4-benzodioxanes coupling the resolution of 1 via diastereomeric salt formation with the enantiomeric enrichments by recrystallisations, preferably of its conglomerate forming derivatives.