Preparation of Enantiopure 3-Aminopiperidine and 3-Aminoazepane Derivatives from Ornithine and Lysine. Consecutive Syntheses of Pharmacologically Active Analogs, Such as Besifloxacin

Abstract

In recent years, 3-aminopiperidine and 3-aminoazepane have been identified as important pharmacophores that led to the development of drugs having several billion dollar global revenues. Although the number of protocols for the resolution of suitable racemic derivatives is steadily increasing, there is an ongoing demand for new synthetic methods to prepare enantiomerically pure analogs from readily available starting materials. Herein, we report the cyclization of methyl esters derived from natural ornithine and lysine as well as their enantiomeric counterparts. Lactam synthesis was regularly performed on a lab scale of up to 150 mmol per batch. Protection and subsequent reduction to enantiopure 3-(tritylamino)piperidine and 3-(tritylamino)azepane allowed the selective derivatization of the heterocyclic nitrogen. Deprotection gave access to a set of building blocks that were applied to the synthesis of eight molecules reported to be pharmacologically active in drug research. For example, besifloxacin was prepared in only a few steps starting from D-lysine.

Palladium‐Catalyzed/Mn(OAc)3‐Mediated 1,2‐Diazidation and 1,2‐Acetoxy/Hydroxylation of N‐Allyl Sulfonamides

“…[9] 1,2-Diazide compounds are ideal precursors of vicinal primary diamines or bis-triazolyl derivatives, which have proven to be important motifs in biologically active compounds. [10] The literature reports different approaches to obtain 1,2-diazides from alkenes. As to the transition-metal catalyzed protocols, iron-and copper-based catalysts are the most used for the generation of an azido radical that in turn interacts with an appropriate alkene function enabling a cascade difunctionalization.…”