Stereocontrolled Alkylation of Chiral Pyridinium Salt Toward a Short Enantioselective Access to 2-Alkyl- and 2,6-Dialkyl-1,2,5,6-Tetrahydropyridines

Abstract

Treatment of salts 1a‐b with Grignard reagents gives, after reduction of the resulting unstable dihydropyridines 7, the tetrahydropyridines 8a‐c, with modest selectivities but in very few steps and under practical conditions. Higher stereo‐ and regioselectivities are obtained with salt 1c which gives the tetrahydropyridines 15a‐e. In addition, the dihydropyridine intermediates 11b cyclize to give the new oxazolidine derivatives 12a‐e, which turn out to be good precursors of the 2,6‐trans‐disubstituted tetrahydropyridines 21a‐e. Selective syntheses of (−)‐lupetidin, (+)‐solenopsin, and indolizidines (−)‐5 and (−)‐6 are presented as representative examples of applications.

Recent developments in the chemistry of dihydropyridines

“…16 Regio-and diastereoselective additions of Grignard reagents have been performed upon homochiral N-alkylpyridinium 18 and isoquinolinium salts. 17 These compounds are conveniently prepared via the Zincke reaction, and when the chiral auxiliary bears a hydroxy group, the addition process may be repeated, and stereoselective double alkylations become feasible. Several piperidines, indolizidines and isoquinoline derivatives have been prepared in enantiopure form (Scheme 5).…”

Modified Fry Cyanation of a Chiral Pyridinium Salt: Asymmetric Syntheses of (–)‐Coniine and (–)‐Solenopsin A

“…As shown in Scheme , chiral N ‐alkylpyridinium salts 3 , which are derived from ( R )‐(+)‐1‐phenylethylamine through the Zincke reaction, have occupied an interesting but somewhat understated position 11. Marazano and Guilloteau‐Bertin reported that the addition of Grignard reagents to 3a (X – = dodecyl sulfate) yielded unstable 1,2‐dihydropyridine 4a , which was converted in a two‐step procedure into alkaloids 1 and 2 11a. However, the regioselectivity of the attack at C‐2 decreases with bulky Grignard reagents, and the stereoselectivities do not exceed 75:25 dr .…”

An Enantioselective Entry to Substituted 6-Membered Nitrogen Heterocycles from Chiral Pyridinium Salts via Selective Epoxidation of Tetrahydropyridine Intermediates

“…Reactions of salts 1 with Grignard reagents offer in particular a very short entry to 2-alkyl or 2,6-dialkyl substituted tetrahydropyridines 2. 3 The presence of a double bond in these heterocycles is of particular interest since it can be potentially used for introduction of further functionalities, thus allowing an enantioselective access to a number of highly substituted piperidines.…”