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

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.