op060225f_si_001.pdf (95.08 kB)
Design, Development, and Scale-Up of a Selective meso-Epoxide Desymmetrization Process
journal contribution
posted on 2007-05-18, 00:00 authored by David L. Varie, Christopher Beck, Sandra K. Borders, Molly D. Brady, Jason S. Cronin, Tracy K. Ditsworth, David A. Hay, David W. Hoard, Richard C. Hoying, Ryan J. Linder, Richard D. Miller, Eric D. Moher, Jacob R. Remacle, John A. Rieck, David D. Anderson, Paul N. Dodson, Mindy B. Forst, Duane A. Pierson, Joseph A. TurpinA pilot-plant scale desymmetrization of the cyclic meso-epoxide
4b, using a chiral lithium amide prepared from symmetrical
diamine 17, was designed and implemented to provide allylic
alcohol 3b in high yield and greater than 99% ee. This chiral
alcohol was converted to ketone 2b, a key intermediate in a
new asymmetric synthesis of LY459477. Chiral diamine 17 was
prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction
mixture and reused. Studies performed to probe the mechanism
of the rearrangement reaction of epoxide 4b showed that
diamine 17 provided an optimal combination of selectivity and
scaleability for this process.