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Design, Development, and Scale-Up of a Selective meso-Epoxide Desymmetrization Process

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journal contribution
posted on 18.05.2007, 00:00 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. Turpin
A 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.