First Synthesis of All of the cis-Fused Stereoisomers of Phosphonic and Phosphinic Analogues of Octahydrocyclopenta[b]pyrrole-2-carboxylic Acid

 

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Abstract

We present the first stereoselective synthesis of phosphonic and phosphinic analogues not only of (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, the pivotal intermediate in ramipril synthesis, but also of all its cis-fused stereoisomers. Key to this accomplishment is the highly diastereoselective synthesis of cis-fused bicyclic (3aS,6aS)- and (3aR,6aR)-hexahydrocyclopenta[b]pyrrol-2-one using Meyers’ tricyclic lactam methodology. The nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to chiral N-acyliminium ions affords the diastereoisomers, which are easily separated by column chromatography. The diastereoselectivity in the nucleophilic addition of the phosphorus reagents is completely consistent with our previous reports and all synthesized compounds were fully characterized.

Publication History

Received: 18 March 2025

Accepted after revision: 23 April 2025

Article published online:
20 May 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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• Supplementary Material