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Synfacts 2025; 21(03): 313
DOI: 10.1055/a-2518-3661
Innovative Drug Discovery and Development

Synthesis of Eglumegad

Rezensent(en):
Dirk Trauner
,
Robert Gaston
Monn JA *, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD. Eli Lilly and Company, Indianapolis, USA and Lilly Research Centre, Ltd., Windelsham, UK
Design, Synthesis, and Pharmacological Characterization of (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY354740): A Potent, Selective, and Orally Active Group 2 Metabotropic Glutamate Receptor Agonist Possessing Anticonvulsant and Anxiolytic Properties.

J. Med. Chem. 1997;
40: 528-537
DOI: 10.1021/jm9606756
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Keywords

Corey–Chaykovsky cyclopropanation - Bucherer–Bergs hydantoin - mGluR2/3 inhibitor - anticonvulsant - anxiolytic - eglumegad

Significance

In 1997, Eli Lilly & Company first reported the design and synthesis of eglumegad (also known as eglumetad), a group 2 metabotropic glutamate receptor (mGluR2/3) inhibitors. The mGluR2/3 receptors were popular targets for the treatment of anxiety and addiction-related disorders. Eglumegad was structurally designed with the intention of matching the confirmation of the natural substrate, L-glutamate. The authors established the pharmacology of eglumegad and provided an efficient asymmetric synthesis.


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Comment

Starting from 2-cyclopentenone, sulfur ylide 1 was employed under optimized conditions to deliver cyclopropyl intermediate 2 with high diastereoselectivity. Compound 2 was then subjected to Bucherer–Bergs conditions to provide a diastereomeric mixture of hydantoins 3a and 3b. After crystallization, rac-3a was partially saponified and purified using chiral resolution. The enantiopure hydantoin salt was then hydrolyzed and esterified for isolation. A final saponification of the diester and an ion-exchange column provided eglumegad.


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Publikationsverlauf

Artikel online veröffentlicht:
25. Februar 2025

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