FULL PAPER Stereocontrolled Alkylation of Chiral Pyridinium Salt Toward a Short Enantioselective Access to 2-Alkyl- and 2,6-Dialkyl-1,2,5,6-Tetrahydropyridines Be ´range `re Guilloteau-Bertin, [a] Delphine Compe `re, [a] Laurent Gil, [b] Christian Marazano,* [a] and Bhupesh C. Das [a] Keywords: Alkaloids / Alkylations / Asymmetric synthesis / Grignard reactions / Nitrogen heterocycles 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 dihydropyrid- Introduction The enantioselective synthesis of six-membered nitrogen heterocycles has been the subject of a large number of stud- ies during the past few years due to the interest of these intermediates in natural alkaloid and medicinal chemistry. As a consequence, efficient methods are now available for preparing chiral 2- and 2,6-substituted piperidines. [1] How- ever, few methods are available concerning the correspond- ing enantiopure substituted tetrahydropyridines. [2] There- fore, we now present a strategy which is briefly summarized in Scheme 1. The main features of this approach are: (a) selective alkylation with Grignard reagents [3–5] of pyridin- ium salts 1 (Scheme 1), now readily available from chiral primary amines; [6] (b) protonation of the resulting dihy- dropyridines 2 to give dihydropyridinium salt equivalents 3; [7] (c) additional treatment with a Grignard reagent af- fording the 2,6-disubstituted tetrahydropyridines 4. Scheme 1. General strategy for the enantioselective construction of substituted tetrahydropyridines The interest of this approach is illustrated by the short synthesis from salt 1c (Scheme 2) of (-)-lupetidin, (+)- solenopsin A and indolizidines (-)-5 and (-)-6, this last synthesis being designed as an example of further ring elab- oration of the tetrahydropyridines 4. [a] Institut de Chimie des Substances Naturelles, C.N.R.S. Avenue de la Terrasse, 91198 Gif-Sur-Yvette CEDEX, France Fax: (internat.) + 33-1/69077247 E-mail: marazano@icsn.cnrs-gif.fr [b] Departamento de Quimica, ICEB, Universidad Federal de Ouro Preto, Campus Morro de Cruzeiro, 35400.00, Ouro Preto, MG, Brazil Eur. J. Org. Chem. 2000, 1391-1399  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1434-193X/00/0408-1391 $ 17.50+.50/0 1391 ine intermediates 11b cyclize to give the new oxazolidine de- rivatives 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. Scheme 2. Representative examples of the syntheses Results and Discussion We first investigated the reactions of Grignard reagents with salts 1a–b (Scheme 3 and Table 1). As reported earl- ier, [3,4] the use of a lipophilic counter anion (dodecylsulfate, see 1b) ensures a good solubility of pyridinium salts in or- ganic solvents but was not necessarily required in this par- ticular case. Since the resulting dihydropyridine interme- diates 7 were too unstable to be isolated, the crude reaction mixtures were reduced with NaBH 4 , affording the tetrahy- dropyridines 8a–c as major products. As expected, the re- gioselectivity of the attack at position 2 decreases with rela- tively hindered Grignard reagents to give predominantly at- tack at position 4 of the pyridinium ring, resulting, for ex- ample, in the formation of major piperidines 10d and 10e . In contrast to the 3-substituted series, [3] but in agreement with our recent results in the isoquinoline series, [4] the ste- reoselectivity of attack at position 2 does not exceed 50%. Despite this modest selectivity, the method constitutes a fairly convenient approach to tetrahydropyridines such as 8a considering its shortness and simplicity. The absolute configuration of derivative 8c was confirmed by a correla- tion with the known alkaloid (+)-coniine (vide infra) and by further elaboration of products from tetrahydropyridine 8a by epoxidation reactions. [8]