Stereoselective synthesis of 3,4-disubstituted and 3,4,5-trisubstituted piperidines by Lewis acid-catalysed ene cyclisation of 4-aza-1,7-dienes.
The thermal or Lewis acid-catalysed ene cyclisation of a variety of 4-aza-1,7-dienes afforded 3,4-disubstituted or 3,4,5-trisubstituted piperidines. Activation of the enophile with a single ester facilitated a thermal ene cyclisation, although the reaction was not amenable to Lewis acid catalysis. With other activating groups on the enophile it was found that Lewis acid catalysis was facile, although there was a fine balance between the desired ene cyclisation and the competing hetero-Diels-Alder reaction, with the product distribution being influenced by the activating group on the enophile, the nature of the ene component, and the Lewis acid used. Activation of the enophile with an oxazolidinone function facilitated Lewis acid-catalysed cyclisation to afford mixtures of ene and hetero-Diels-Alder products. Activating the enophile with two ester groups gave a substrate that underwent a very facile ene cyclisation catalysed by MeAlCl(2) to give the corresponding trans 3,4-disubstituted piperidines with diastereomeric ratios of >200 : 1.
Walker
Stephen M
SM
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Williams
Jodi T
JT
Russell
Alexander G
AG
Kariuki
Benson M
BM
Snaith
John S
JS
D000143:Acids / Q000737:chemistry*; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D000143:Acids; D001372:Aza Compounds; D010880:Piperidines