Asymmetric Synthesis of Methylphenidate and Quinolizidinones by Addition of Aldehydes to Piperidine-Based Conjugated N-Acyl­iminium Ions

Abstract

Dedicated to Prof. Paolo Crotti on the occasion of his 70th birthday N R O 2 steps 3 steps N H Ph OMe O ·HCl d-threo methylphenidate (Ritalin) RCH 2 CHO synergistic catalysis N OH PG R = Me, Et PG = Cbz R = Ph PG = Boc R = Ph, e.r. 98:2, d.r. >15:1 R= alkyl, e.r. up to 90:10, d.r. ca 1:1 1 step quinolizidine alkaloids (-)-207I and (+)-epi-217I N R O PG H AbstractThe synergistic effect of Lewis acids and MacMillan organocatalyst allows the α-regioselective and enantioselective α-amidoalkylation of piperidine derivatives with enolizable aldehydes. The potentiality of the synthetic method is illustrated by a short asymmetric synthesis of the eutomer of the blockbuster drug Ritalin and by a concise formal synthesis of 1-alkyl-4-substituted quinolizidine alkaloids.The catalytic enantioselective installation of carbon nucleophiles into the piperidine scaffold continues to be an intense area of research as it constitutes a suitable platform to obtain naturally occurring alkaloids and substances of pharmaceutical interest. 1 N-Acyliminium ions are well recognized reactive intermediates, which have also been widely used for the asymmetric synthesis of piperidines using diastereoselective approaches, 2 or chiral metal catalysts. 3 On the other hand, the use of enantioselective asymmetric enamine organocatalysis in combination with N-acyliminium ions remains a challenging area. Solutions to this problem were recently reported for 'biased' aromatic N-acyliminium ions such as isoquinolinium ions, 4 and quinolinium ion, 5 while the direct asymmetric functionalization of more difficult to generate piperidine-based N-acyliminium ions with aldehydes has remained elusive until very recently. 5b,6 It should be noted that the use of α,β-unsaturated N-acyliminium ions such as 1 has been largely underdeveloped (Scheme 1). 7 Asymmetric addition to a conjugated N-acyliminium ion of this kind have only been reported by Matsumura and co-workers using enolates starting from electrochemically generated α-alkoxy derivative 2 (i.e., an N,O-acetal). 8 The vinylogouos γ-hydroxy(alkoxy)derivatives 3, easily obtained via Luche reduction of the corresponding 4-oxo-1,2,3,4-tetrahydropyridine, have been used as precursors of conjugated N-acyliminium ion 1 only in nonasymmetric Ferrier-type reactions. 9 In principle, a conjugated N-acylimium ion has two reaction sites (α-and γ-positions) and this fact poses regioselectivity issues. On the other hand, as herein reported, this structural feature is a necessary prerequisite to attain reactivity with aldehydes, paving the way for the introduction of chirality at the attacking carbon framework into a piperidine scaffold. Applications to a novel concise enantioselective approach to 1,4-disubstituted quinolizidine-based alkaloids and to a short asymmetric synthesis of d-threo-methylphenidate (Ritalin) are also reported. Scheme 1 Possible precursors of conjugated piperidine-based N-acyliminium ions and preliminary results 1) LA, L1 (20 mol%) PhCH 2 CHO, toluene, 0 °C N H N O Bn t-Bu