An efficient synthesis of (R)- and (S)-2-(aminomethyl)piperidine dihydrochloride Gildas Deniau, Thomas Moraux, David O’Hagan * , Alexandra M. Z. Slawin School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife KY16 9ST, UK article info Article history: Received 10 September 2008 Accepted 17 September 2008 Available online 22 October 2008 abstract The synthesis of the dihydrochloride salts of (R)-1 and (S)-1 2-(aminomethyl)piperidine is reported start- ing from either (S) or (R) lysine, respectively. A key step in the synthetic protocol involves the in situ for- mation of aziridinium 8, which then undergoes an intramolecular ring opening with concomitant piperidinium ring formation, in a stereoselective manner. The route offers a practical synthesis of (R)-1 and (S)-1, and it should make them more accessible for exploration in asymmetric catalysis or as building blocks in pharmaceutical research. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Chiral diamines form an important class of compounds that have found a wide range of applications in chemistry, particularly as bidentate ligands for the design of asymmetric catalysts. 1,2 The enantiomers of 2-(aminomethyl)piperidine (R)-1 and (S)-1 are attractive structural motifs; however, they have not been widely used in the design of chiral ligands, most probably, due to their limited availability. 3,4 Indeed, (R)-1 and (S)-1 are not commercially available, although these enantiomers have been prepared by the resolution of the racemate, 4 or from the enantiomers of pipecolic acid by a sequential amidation and reduction protocol. 5,6 These methods do not constitute a practical route to (R)-1 and (S)-1 in reasonable quantities, and consequently the exploration of these stereoisomers in bidentate ligand design has been limited. Beyond asymmetric catalysis, enantiopure amines continue to find an important role as building blocks in pharmaceutical development, and a ready source of (R)-1 and (S)-1 would also contribute to that activity (see Fig. 1). 7,8 2. Results and discussion Herein, we report an efficient synthesis of the enantiomers of 2- (aminomethyl)piperidine dihydrochloride (R)-1 and (S)-1 from the amino acids (S)-L- and (R)-D-lysine (see Scheme 1). (S)-L-Lysine monohydrochloride (S)-2 was perbenzylated by treatment with benzyl bromide in ethanol using K 2 CO 3 as a base, following the protocol of Beaulieu and Wernic. 9 This resulted in an efficient conversion to the pentabenzyl amino acid derivative (S)-3 in almost quantitative yield. Reduction of (S)-3 with LiAlH 4 gave the corresponding alcohol (S)-4 in 89% yield. With (S)-4 in hand, two routes to the 1,1-dibenzyl-2-((dibenzylamino)methyl)- piperidinium chloride 5 were explored. The first attempt involved the use of fluorinating reagent Et 2 NSF 3 (DAST). It is known that the treatment of N,N-dibenzyl-a-aminoalcohols with DAST produces an aziridinium intermediate in situ, which then undergoes ring opening by fluoride ion attack (paths b and c) to predominantly form the most substituted alkyl fluorine (path b). 10 In our case, (Scheme 2), it was anticipated that the peripheral dibenzylamine moiety of (S)-4 would compete with the fluoride ions to open the aziridinium intermediate (S)-8 by a 6-exo-tet ring closure process (path a) to produce piperidinium (R)-5. It was also expected that the stereochemical course of aziridinium ring opening (paths a and b) would occur with an inversion of configuration as illus- trated in Scheme 2. The DAST reaction at room temperature gave a mixture of com- pounds 5, 6 and 7 in a ratio of 83:15:2, but with a moderate overall conversion. When silica gel (SiO 2 ) was added as a suspension in DCM to the reaction mixture (SiO 2 –DAST, 6.0:1.5 equiv), the con- version to piperidinium 5 increased to 80% with only very minor traces of the fluorinated products 6 and 7. The silica is clearly sequestering fluoride ions from solution, and is rendering the reac- tion cleaner and more efficient overall. Other reagents were then 0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2008.09.015 * Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808. E-mail address: do1@st-and.ac.uk (D. O’Hagan). NH 2 + , Cl - NH 3 + , Cl - (S)-1 NH 2 + , Cl - NH 3 + , Cl - (R)-1 Figure 1. (R)- and (S)-2-(aminomethyl)piperidine dihydrochloride. Tetrahedron: Asymmetry 19 (2008) 2330–2333 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy