Efficient Separation of Diastereomeric Mixtures of syn- and anti-2,4-Pentanediol

A simple and practical process was developed for the efficient separation of diastereomeric syn - and anti -2,4-pentanediol by selective acetalization of a diastereomeric mixture of the 2,4-pentanediols and selective hydrolysis of the corresponding acetals. The process relies upon the reaction rate differences of syn -2,4-pentanediol ( syn -diol) and anti 2,4-pentanediol ( anti -diol) in acetalization and of the corresponding acetals in hydrolysis: the syn -diol reacts faster to form a more stable acetal than the anti -diol, which in turn is more susceptible to hydrolysis by Brønsted acid. Acetalization of a 2,4-pentanediol diastereomeric mixture ( syn / anti = 45:55) with acetophenone (0.95 equiv relative to syn -diol) leads to the formation of a syn -enriched acetal mixture with a syn / anti diastereomeric ratio (dr s / a ) of 6:1, leaving an anti -enriched diol mixture (dr s / a = 1:7). Subsequent kinetic resolution via selective hydrolysis of the minor anti -acetal with a catalytic amount of 1.0 N HCl at ambient temperature affords the pure syn -acetal (dr s / a > 99:1) in the organic phase and the anti -enriched 2,4-pentanediols (dr s / a = 1:6) in the aqueous phase, which are conveniently separated by a phase cut. Hydrolysis of the syn -acetal is facile in alcohol solvents at elevated temperatures (60–80 °C), yielding the pure syn -diol. A second acetalization of the anti -enriched 2,4-pentanediols leads to the pure anti -2,4-pentanediol. This separation gives the syn -diol in 75–79% yield with dr s / a > 99:1 and the anti -diol in 79–85% yield with dr a / s > 98:2. Additionally, the acetophenone used for the acetalization can be recovered in 88–92% yield, and therefore, the overall process is high-yielding, atom-economical, and potentially recyclable.