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The efficient synthesis of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, a chiral β-amino acid with potent affinity for the α2δ protein

2009; Elsevier BV; Volume: 50; Issue: 11 Linguagem: Inglês

10.1016/j.tetlet.2008.12.111

1873-3581

Ji Zhang, Peter G. Blazecka, Derek A. Pflum, J. Bozelak, Derek Vrieze, Norman L. Colbry, Garrett Hoge, David C. Boyles, Brian Samas, Timothy T. Curran, Augustine T. Osuma, Paul D. Johnson, Suzanne R. Kesten, Jacob B. Schwarz, Annise Goodman, Mark S. Plummer, Anne Akin, Yun Huang, Michael Lovdahl, Andrew Thorpe,

Biochemical and Molecular Research

A chiral β-amino acid containing three contiguous chiral centers was synthesized efficiently in 11 steps, employing enantio-enriched β-ketoester as a key intermediate, via stereoselective catalytic hydrogenation of the corresponding enamide. Stereoselective 1,4-addition of a methyl group and protonation were key to the preparation of the desired acid 12. Mild and efficient reaction conditions were applied to the enamine formation and protection to avoid epimerization at C-4 of compounds 13 and 14. The final compound was found to display potent affinity for the α2δ-protein that is a recognized drug target for the treatment of a variety of diseases.