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

被引：7

作者：

Zhang, Ji ^{[1
]}

Blazecka, Peter G. ^{[1
]}

Pflum, Derek A. ^{[1
]}

Bozelak, Joseph ^{[1
]}

Vrieze, Derek ^{[1
]}

Colbry, Norman L. ^{[1
]}

Hoge, Garrett ^{[1
]}

Boyles, David C. ^{[1
]}

Samas, Brian ^{[1
]}

Curran, Timothy T. ^{[1
]}

Osuma, Augustine T.

Johnson, Paul

Kesten, Suzanne

Schwarz, Jacob B.

Goodman, Annise

Plummer, Mark

Akin, Anne ^{[2
]}

Huang, Yun ^{[2
]}

Lovdahl, Michael ^{[2
]}

Thorpe, Andrew J.

机构：

[1] Pfizer Inc, Michigan Labs, Res API, Ann Arbor, MI 48105 USA

[2] Pfizer Inc, Michigan Labs, Pfizer Global Res & Dev, Analyt API, Ann Arbor, MI 48105 USA

来源：

TETRAHEDRON LETTERS | 2009年 / 50卷 / 11期

关键词：

Chiral beta-amino acid; beta-Ketoester; Oxazolidinone; Asymmetric conjugate addition; Organocuprate; Stereoselective catalytic hydrogenation; N-SULFINYL IMINES; ASYMMETRIC-SYNTHESIS; ALPHA-AMINO; ENANTIOSELECTIVE SYNTHESIS; ALPHA; BETA-DISUBSTITUTED; (E)-ENOYLSULTAMS; STEREOSELECTIVE-SYNTHESIS; CONJUGATE ADDITIONS; CARBOXYLIC-ACIDS; NEUROPATHIC PAIN; PREGABALIN;

D O I：

10.1016/j.tetlet.2008.12.111

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

A chiral beta-amino acid containing three contiguous chiral centers was synthesized efficiently in 11 steps, employing enantio-enriched beta-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 alpha(2)delta-protein that is a recognized drug target for the treatment of a variety of diseases. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1167 / 1170

页数：4

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