Stereocontrolled Addition of π-type Nucleophiles to a Bicyclic N-Acyliminium Ion. New Access to trans-2,6-Disubstituted Piperidine Substructures

Abstract

Bicyclic N-acyliminium ion I, generated in situ by treatment of aminoether 4 with Lewis acids, smoothly reacted with π-type nucleophiles, leading exclusively to the trans adducts.2,6-Disubstituted piperidine substructures are found in a large number of alkaloids and in many biologically active compounds . 1 Many studies have been devoted to the synthesis of the predominantly naturally occurring cis-2,6-disubstituted piperidines. On the other hand, preparations of the trans homologues have attracted much less attention. 2,3 The most stereoselective method reported for the synthesis of these latter compounds consists in the nucleophilic addition of alkylcopper reagents to the N-acyliminium ion obtained from the pipecolic acid derivative precursor 2. 3 However, when the latter is treated with synthetically more versatile π-type nucleophiles, the cis stereoisomers are selectively obtained (de >90%). 4 This result has been attributed to A (1,3) strain. 3 Similar facial selectivities have been observed with homologous N-acyliminium ion stemming from proline derivative 1. 5 In sharp contrast with these observations, we recently showed that nucleophilic additions of π-type nucleophiles to bicyclic aminoether 3 in the presence of a Lewis acid, afforded trans pyrrolidine derivatives generally with high selectivity. 6 We thus envisioned an extension of this methodology starting from the homologous bicyclic oxazolidinone 4 and wish to report herein the success of our endeavours towards the synthesis of trans-2,6-disubstituted piperidines via the stereoselective formation of C-C bonds. 7

Imines, enamines and oximes

“…107 Treatment of the aminoether 47 with Lewis acids leads to the generation of the bicyclic N-acyliminium ion 48 which reacts in turn with π-nucleophiles to give trans adducts 49 in 56-95% yields (Scheme 17). 108 An intramolecular cyclisation of a γ-alkyne onto an N-acyliminium ion is the key step in a projected synthesis of Roseophilin. 109 A novel allene-terminated N-acyliminium ion cyclisation is used to prepare a 7-azabicyclo[4.2.1]nonane-4,8dione skeleton, an intermediate used in studies towards the total synthesis of the oxindole alkaloid Gelsedine.…”

A Novel Route to Chiral trans‐6‐Alkyl‐2‐hydroxymethyl‐1,2,5,6‐tetrahydropyridines by Allylation of Chiral Imines and Ring‐Closing Metathesis − Total Synthesis of (−)‐3‐epi‐Deoxoprosopinine

“…Indeed, the C-2 chemical shift of the trans isomer was generally at 51 ppm whereas the cis isomer appeared 7 ppm downfield (δ ϭ 58 ppm). [16] This difference can be attributed to the gauche 1Ϫ4 interaction (also called the γ-effect) between R and C-2, which is only possible in the trans isomer (Figure 4). [17] In the case of our compounds, the 13 C NMR spectroscopic data of C-2, in the range 50.6 to 51.2 ppm, were in total accordance with the data expected for trans isomers.…”

Lewis Acid Mediated Diastereoselective Allylation of 3-Menthyloxycarbonyl-5,6-dihydropyridin-4-ones

“…Along with our efforts towards the synthesis of enantiopure α-substituted piperidine moieties from naturally occurring amino acid, 1 we are currently investigating a new access to these structures by means of diastereoselective reactions using commercially available substrates and chiral auxiliaries. To this end, we selected conjugate 1,4addition on 2,3-dihydro-4-pyridones A (Figure 1) bearing a menthyloxycarbonyl as the N-protecting group and the chiral auxiliary.…”