Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums

Abstract

The origin of the variation in the regioselectivity of the nucleophilic ring-opening of a series of bicyclic aziridinium ions derived from N-alkylprolinols was investigated by quantum chemical computations (M06-2X/6-31+G(d,p)—SMD). These aziridiniums differ only in the degree and the stereochemistry of fluoro substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic gauche effect influences the conformation of the adjoining five-membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring-opening.

Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions

“…Primarily the obtained crystal structures confirm the bicyclic structure of the aziridinium ion proposed as the intermediate of the reaction of our 3‐chloropiperidines with nucleophiles, while the structure of 11 is congruent with an already described aziridinium ion obtained by a different method [14] . Furthermore, the boat‐like structures of these intermediates match the computational calculations for C4 fluorinated bicyclic aziridinium ions obtained from the corresponding prolinol derivatives [15] . Comparison of the two structures also allows assumptions about the reactivity of the benzyl substituted aziridinium ion 11 compared to the butyl analogue 10 a .…”

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

“…Quantum chemical computation studies will be necessary to fully understand the regioselectivity of the attack of nucleophiles on the aziridinium intermediates 49. 50…”

Synthetic Applications of Aziridinium Ions

“…Following pathway "a", nonpeptidic NK-1 receptor antagonist L-733060 ( 48) was realized starting from 3-hydroxy-2-phenyl piperidine (47) [56,70]. Most cases with diethylaminosulfur trifluoride (DAST) have yielded enlarged fluorinated piperidine ring compounds (50) from hydroxymethylpyrrolidine (49) via fluorine-driven ring opening in a stereoselective manner [71,72]. Application of various nucleophiles through pathway "a" or "b" gives an efficient synthetic strategy to prepare various aza-cyclic valuables (Figure 5).…”

“…Following pathway "a", nonpeptidic NK-1 receptor antagonist L-733060 ( 48) was realized starting from 3-hydroxy-2-phenyl piperidine (47) [56,70]. Most cases with diethylaminosulfur trifluoride (DAST) have yielded enlarged fluorinated piperidine ring compounds (50) from hydroxymethylpyrrolidine (49) via fluorine-driven ring opening in a stereoselective manner [71,72]. This reaction, generation, and ring opening of a bisaziridinium ion (52) from 3-hydroxy-3-trifluoromethyl piperidine (51) with removal of the hydroxy group could also be applicable for the synthesis of biologically important α-trifluoromethyl pyrrolidines (53) (Scheme 14) [73,74].…”