Access to Optically Active 3‐Substituted Piperidines by Ring Expansion of Prolinols and Derivatives

Abstract

The ring expansion of prolinols via an aziridinium intermediate gives C3-substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

“…A large number of nitrogencontaining saturated cyclic compounds are known as antibiotics, analgesics, antidepressants, anticancer, anti-HIV, and anti-HCV agents. [1][2][3] According to the medicinal chemistry literature, there are two main fields of interest with respect to the structures of the present drug candidates: the popularity of organofluorine scaffolds and of azaheterocycles. [4][5][6][7][8][9] Saturated N-heterocycles are building blocks in synthetic bioactive products and medicinal compounds.…”

“…In the development of new pharmaceuticals three-dimensional, functionalized scaffolds with saturated building blocks, especially saturated N-heterocycles, are used preferably. [1][2][3] Figure 1 shows some representative N-heterocyclic structures with biological relevance. [10][11][12][13][14] Fluorine-containing organic molecules (except only a few representatives) are practically absent in nature, but they have received significant interest in drug research.…”

Synthesis of Substituted α-Trifluoromethyl Piperidinic Derivatives

“…The ring expansion of pyrrolidines to piperidines via an aziridinium intermediate under kinetic and thermodynamic conditions is well-established [23,24,25,26,27,28]. This method was used to access piperidines 30 , 30′ from prolinols 29 , 29′ .…”

Synthesis of 3,3‐Dichloropiperidines and Further Functionalization via Pd‐Catalyzed Cross‐Coupling Reactions of the Dichloromethylene Moiety

“…Syntheses of C3‐substituted piperidines have therefore been studied extensively over the past decades . Syntheses can be divided in four major groups.…”

“…The second approach towards C3‐substituted piperidines is the ring expansion/rearrangement of pyrrolidines via an aziridinium intermediate (Schemeà – path b). [2a], This transformation can be achieved enantioselectively when enantiopure prolinols are used as starting materials. A third approach, more suitable for more substituted piperidines, builds up the piperidine ring starting from a tertiary amine containing one or two unsaturated groups via cycloaddition reactions, radical cyclizations or metathesis reactions (Schemeà – path c).…”