Design, Development, and Scale-Up of a Selective <i>meso</i>-Epoxide Desymmetrization Process

A pilot-plant scale desymmetrization of the cyclic <i>meso</i>-epoxide <b>4b</b>, using a chiral lithium amide prepared from symmetrical diamine <b>17</b>, was designed and implemented to provide allylic alcohol <b>3b</b> in high yield and greater than 99% ee. This chiral alcohol was converted to ketone <b>2b</b>, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine <b>17</b> was prepared from a readily available chiral precursor, (<i>R</i>)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide <b>4b</b> showed that diamine <b>17</b> provided an optimal combination of selectivity and scaleability for this process.