FULL PAPER DOI: 10.1002/ejoc.200601009 Synthesis of Enantioenriched 2- and 2,6-Substituted Piperidin-3-ols from α-Dibenzylamino Aldehydes José M. Andrés, [a] Rafael Pedrosa,* [a] and Alfonso Pérez-Encabo [a] Dedicated to Professor Joan Bosch on occasion of his 60th birthday Keywords: Asymmetric synthesis / Amino aldehydes / Deoxocassine / Deoxoprosophylline / 3-Piperidinols Homochiral α-dibenzylamino aldehydes react with 4-buten- ylmagnesium bromide in diethyl ether at 0 °C to yield anti- β-amino alcohols in excellent yield and dr . These anti dia- stereoisomers were transformed into enantioenriched 2- and 2,6-substituted 3-piperidinols in good yields. Introduction 3-Hydroxylated piperidines are abundant in nature and some of them display potent physiological effects. [1] In this context, several synthetic methods have been developed for the synthesis of polysubstituted piperidine alkaloids. [2] Dif- ferent methods that allow the formation of a piperidine ring [3] in racemic [4] or in enantioenriched forms have been described. Some of these strategies employed an asymmet- ric synthesis methodology, [5] but in most approaches an enantiopure substance was used as the starting material: amines, [6] amino acids, [7] and sugar derivatives [8] have been the most commonly used starting materials. As a part of our investigations [9] exploring the chemistry of chiral α-dibenzylamino aldehydes derived from natural α-amino acids, we herein wish to disclose an efficient syn- thesis of enantiopure 2- and 2,6-substituted 3-hydroxy- piperidines starting from this class of compound. As summarized in the retrosynthetic analysis shown in Scheme 1, the 2-mono- (R 2 = H) or 2,6-substituted (R 2 = alkyl) 3-piperidinols can be traced back to δ-amino-γ-hy- droxy carbonyl compound A through a stereoselective in- tramolecular reductive amination reaction. Compound A may be prepared by elaboration of olefin B, which in turn can be easily obtained by nucleophilic addition of 4-buten- ylmagnesium bromide to homochiral α-dibenzylamino al- dehyde C derived from natural α-amino acids. [a] Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Doctor Mergelina s/n, 47011 Valladolid, Spain Fax: +34-983-423013 E-mail: pedrosa@qo.uva.es Eur. J. Org. Chem. 2007, 1803–1810 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1803 (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) Scheme 1. Results and Discussion The 2- and 2,6-substituted 3-hydroxypiperidines were synthesized starting from α-dibenzylamino aldehydes 1a–c readily prepared [10] from commercially available α-amino acids. These aldehydes reacted with 4-butenylmagnesium bromide in diethyl ether at 0°C to afford the Felkin–Anh anti-2a–c amino alcohols in good yields and with excellent diastereoselectivities (Scheme 2 and Table 1). Diastereoisomeric amino alcohols anti- and syn-2a–c were separated by flash chromatography and their stereo- chemistry determined by conversion into the corresponding oxazolidinones, as described previously for related com- pounds. [9c] As summarized in Scheme 3, the synthesis of enantio- enriched 2-substituted 3-hydroxypiperidines 5a–c starts from amino alcohols anti-2a, [11] 2b, or anti-2c previously pro- tected as acetates anti-3a, b, and anti-3c, respectively. γ-Ace- toxy-δ-dibenzylamino aldehydes anti-4a, b, and anti-4c were obtained in 70–75% yields by oxidative cleavage of the double bond with N-methylmorpholine N-oxide (NMO)