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

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.

Key words

stereoselective synthesis - α-aminophosphonic acids - α-aminophosphinic acids - nitrogen heterocycles - N-acyliminium ions - amino acids

Publikationsverlauf

Eingereicht: 18. März 2025

Angenommen nach Revision: 23. April 2025

Artikel online veröffentlicht:
20. Mai 2025

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