Base-induced isomerisation of epoxide 13 gives an azanortricyclanol 17 which is a precursor for a novel free-radical induced rearrangement to 6-substituted 2-azabicyclo[2.2.1]hept-5-enes 28-31. Compound 31 undergoes selective exo-face hydrogenation to give the 6-substituted 2-azabicyclo[2.2.1]heptane 33 (structure confirmed by X-ray crystallographic analysis). Deprotection of 33 gives epibatidine analogue 2 which has been shown to bind with high affinity at rat brain nicotinic acetylcholine receptors.

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Base-induced isomerisation of epoxide 9 gives an azanortricyclanol 10 which is a precursor for a novel free-radical induced rearrangement to 6-substituted 2-azabicyclo[2.2.1]-5-heptenes 14a-c; 14c (R = 6-chloro-3-pyridinyl) is converted to the epibatidine analogue 2.In 1992 Daly and coworkers reported the isolation and structural elucidation of the alkaloid epibatidine 1. 1 Epibatidine has attracted considerable attention from the scientific community due to its novel structure combined with the fact that it is a highly potent non-opioid analgesic nicotinic acetylcholine receptor (nAChR) agonist. 2 Unfortunately, epibatidine 1 is toxic or even lethal at doses only slightly higher than its effective analgesic dose, however it is a significant therapeutic lead in the important search for nAChR modulators having a wider separation between antinociceptive and toxic effects. 3 In this context we considered a structurally interesting target would be endo-6-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]-heptane (2), since it represents an isomer of epibatidine in which the nitrogen in the rigid bicyclo[2.2.1]heptyl framework is translocated from the 7-to the 2-position but maintains the same connectivity and similar relative orientation to the chloropyridyl substituent. We envisaged the epibatidine analogue 2 being derived from exo-selective hydrogenation of a 6-substituted 2-azabicyclo[2.2.1]-5-heptene 3 and describe here our preliminary results on a method to prepare such systems and a synthesis of 2.The 2-azabicyclo[2.2.1]heptyl ring system can be most easily prepared by aza Diels-Alder reaction using cyclopentadiene. 4 Although exo-5-aryl substituted 2-azabicyclo[2.2.1]heptanes have recently been prepared by such a cycloaddition followed by a reductive Heck reaction, 5 6-substituted systems are not accessible by this pathway. 6 Our strategy (Scheme 1) employs a rearrangement via lithiation of an achiral epoxide (4 to 5) (making it potentially amenable to asymmetric synthesis by enantioselective deprotonation), 7 followed by a radical rearrangement (6 to 7). A related radical rearrangement (8-aza-to 6-azabicyclo[3.2.1]oct-2-en-7-yl radical) was reported by Rigby and Pigge in 1996. 8 In order to examine this chemistry, the achiral epoxide 9 was prepared by epoxidation 9 (76%) 10 of the known 11 alkene 8 (available in three steps from N-Boc pyrrole and tosyl ethyne) (Scheme 2). Base-induced rearrangement of the epoxide 9 using LDA gave azanortricyclanol 10 (52%). 12 Radical deoxygenation 13 of azanortricyclanol 10 gave the known 5 2-azabicyclo[2.2.1]heptene 11 (60%) as the only isolated product. The well-studied (all carbon) norbornenyl-nortricyclyl radical equilibrium is known to produce a mixture of norbornene and nortricyclene on reduction with Bu 3 SnH. 14 In the present case the radical 7 (R = H) which leads to the 2-aza alkene 11 may be strongly preferred due to a stabilising effect of the radical by the N-Boc group and/or a larger CH-N-CH angle in 7 (compared with 6) which promotes amide-type resonance. 15 Schem...

Enantioselektive Erzeugung und intermolekulares Abfangen eines Lithiumcarbenoids erfolgt bei der Reaktion von Epoxiden aus 2,5‐Dihydrofuran, 2,5‐Dihydropyrrol sowie Oxa‐ und Aza‐bicyclo[n.2.1]alkenen (n=2, 3) mit Organolithiumverbindungen in Gegenwart externer chiraler Liganden. Diese Methode kann zur Synthese wichtiger ungesättigter Diole und Aminoalkohole verwendet werden (siehe Schema; NBoc=N‐t‐Butoxycarbonyl).

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