No abstract

An efficient synthetic approach for the construction of fluorine‐containing piperidine γ‐amino acid derivatives has been developed. The synthetic concept was based on oxidative ring opening of an unsaturated bicyclic γ‐lactam (Vince‐lactam) through its ring C=C bond, followed by double reductive amination of the diformyl intermediate performed with various fluoroalkylamines. The method has been extended towards the access of alkylated and perfluoroalkylated substances and for γ‐lactam derivatives. The transformations proceeded with stereocontrol: the configuration of the stereocenters in the products were predetermined by the configuration of the chiral centers of the starting γ‐lactam. The method could be extended for the access to enantiopure piperidine γ‐amino esters.

Fluorine‐containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N‐heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine‐containing saturated N‐heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine‐containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.

Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecy clopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams by transformation of the ring olefinic bond through three different regio-and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro-and levorotatory cyclohexane analogues of icofungipen.

Functionalized dialdehydes are considered important substrates that can be transformed into various substituted heterocyclic, alicyclic, and polysubstituted compounds. Here, we report a robust stereocontrolled procedure for the synthesis of novel functionalized trifluoromethyl-containing piperidine and azepane derivatives, based on oxidative ring cleavage of the C=C bond of diversely substituted cycloalkenes, followed by reductive ring closure of the diformyl intermediates in the presence of fluorine-containing amines.