Development of Jacobsen asymmetric epoxidation and sharpless asymmetric dihydroxylation methods for the large-scale preparation of a chiral dihydrobenzofuran epoxide

Two well-known methodologies, the Jacobsen asymmetric epoxidation (AE) and the Sharpless asymmetric dihydroxylation (AD) followed by epoxidation, were evaluated for the large-scale preparation of a chiral dihydrobenzofuran epoxide. The AE method was improved by substituting ethanol for dichloromethane for the dissolution of meta-chloroperbenzoic acid (m-CPBA). This change in solvent had a significant impact on scaleability of the AE procedure by preventing crystallization of the m-CPBA during addition to the cold reaction mixture. Factors affecting the enantiomeric excess and yield of the chiral epoxide resulting from AD followed by epoxidation were studied. The Sharpless AD reaction provided the intermediate chiral diol as a solid with high ee (>98.5%). The Sharpless-Kolb conversion of the chiral diol to a chiral epoxide was modified to potassium tert-butoxide/tetrahydrofuran to obtain the product in good yield (74-84%) and high ee (>98%). Both the AE and AD processes were scaled up to prepare large quantities of the chiral epoxide.