Stereoselective Rearrangement of (Trifluoromethyl)prolinols to Enantioenriched 3-Substituted 2-(Trifluoromethyl)piperidines

Abstract

3-Substituted 2-(trifluoromethyl)piperidines B were synthesized by ring expansion of (trifluoromethyl)prolinols A, which were obtained from L-proline via an aziridinium intermediate C. The ring opening of the (trifluoromethyl)aziridinium intermediate by different nucleophiles is regio- and diastereoselective.

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

“…[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. Five-, six-, and sevenmembered frameworks are the most common structural units.…”

“…β-Fluoroamine and trifluoroamine moieties are also present in various fluorinecontaining derivatives with biological relevance (Figure 3). [4][5][6][7] There has been a great interest in fluorine-containing pyrrolidines or piperidines in pharmaceutical chemistry, which are elements of various drugs. [26] Although fluorinated azepanes are much less studied, they may also have wide attention in pharmaceutical design in the future.…”

“…Taking into consideration of the high biorelevance of saturated N-heterocycles [1][2][3][4][5][6][7][8][9] and organofluorine molecules, [15][16][17] the combination of these molecular structures is a hot topic in synthetic and medicinal chemistry. The synthetic methods…”

Synthesis of Substituted α-Trifluoromethyl Piperidinic Derivatives

“…Prolinols 29 and 29′ were prepared from l -proline in a seven-step sequence [29]. When prolinols 29 and 29′ were treated with DAST, I 2 /PPh 3 or by Tf 2 O, followed by the addition of different nucleophiles (alcohols, amines, thiols, cuprates, cyanides), a diversity of 2-(trifluoromethyl)- 3-substituted piperidines 30 and 30′ were obtained with good diastereo- and enantioselectivities (de > 94% and ee > 99%).…”

“…When prolinols 29 and 29′ were treated with DAST, I 2 /PPh 3 or by Tf 2 O, followed by the addition of different nucleophiles (alcohols, amines, thiols, cuprates, cyanides), a diversity of 2-(trifluoromethyl)- 3-substituted piperidines 30 and 30′ were obtained with good diastereo- and enantioselectivities (de > 94% and ee > 99%). The regioselective attack of the nucleophiles on the aziridinium intermediates VII / VII′ is due to the presence of the CF 3 group (Scheme 14) [29,30]. …”