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Dienes. Control of 1.2and 1.4-Addition Pathways and the Synthesis of Aza-and Oxa-bicyclic Systems

Aziridinocyclobutenes react with electron-deficient or ringstrained alkenes to produce 7-azanorbornenes in a novel 1,3-dipolar cycloaddition reaction suitable for BLOCK assembly protocols. Benzo-7-azanorbornadiene and 7-heterobridged analogues react stereoselectively to produce compounds with syn-facial orientation of their bridges. 7-Azanorbornanes have received much interest following the discovery of the analgesic properties of epibatidine 1 (Scheme 1) and several specialist syntheses of this alkaloid have appeared in the recent literature. 4 Higher norbornalogues of 7-azanorbornanes, on the other hand, are uncommon and one of the rare examples is the doubly Nbridged adduct 2 reported by Sasaki et al. as the minor product (21%) in the cycloaddition of N-t Boc-isoindole with N-t Boc-7-azabenzonorbornadiene. 5 Scheme 1Following the success of our recently described ACE reaction (Scheme 2, equation 1) for the synthesis of 7-oxanorbornenes, 6 we reasoned that the development of an aziridine equivalent (aza-ACE reaction, Scheme 2, equation 2) held much potential for the synthesis of N-bridged alicyclics, especially 7-azanorbornanes. This is the subject of the present letter where we demonstrate the versatility of this new BLOCK reaction by the synthesis of the first examples of syn-facial polynorbornane systems containing multiple N-bridges. 7 Scheme 2The aziridinocyclobutane 8 required to test the potential of the aza-ACE coupling reaction was prepared as outlined in Scheme 3. Conversion of the benzonorbornadiene 3 8 to the cyclobutene-1,2-diester 4 followed the established method of Mitsudo and co-workers, which employs the ruthenium-catalysed addition of dimethyl acetylene dicarboxylate 4 (DMAD). 9 Conversion of cyclobutene 5 to the triazoline 7 10 was achieved by thermal addition of benzyl azide 6 and elimination of dinitrogen to produce aziridine 8 10 was conducted photochemically (Hanovia 450 watt Hg lamp, quartz, benzene, RT). The synthesis of aziridinocyclobutane 8 was achieved in 40% overall yield for the three step process from the readily available benzonorbornadiene 3.The reactivity of the N-benzyl aziridinocyclobutane 8 towards 1,3-dipolar cycloaddition was assessed initially by reaction with excess DMAD 4 (benzene at reflux) which produced the 1:1-adduct 10. 10 The structure of 10 was supported by NMR data and presumed to arise via attack of the DMAD onto the α-face of the 1,3-dipolar intermediate 9, formed by ring-opening of the aziridine (Scheme 3). Support for this proposal is provided by the formation of a yellow colour when aziridine 8 is heated alone in toluene. 11 Colour formation is lost on cooling and regenerated on heating, indicating the reversibility of the ring-opening process; further, the colour is discharged immediately on the addition of dipolarophiles like dimethyl fumarate. Scheme 3High stereoselectivity is observed in the reaction of the aziridine 7 with ethylenic dienophiles, eg maleic anhydride 11 forms a single product, shown to be the exo-fused adduct 12 10 by the existence of ...

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced epimerization alpha to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer and hence syn-isoepiboxidine.

Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-position via a methylene "spacer" (including the beta-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituents and also to further homologation at the 1-position. Displacements with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative) require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated; nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with concomitant decarboxylation).

Homoepibatidine 2 and dihomoepibatidine 3 have been synthesised from the 8-azabicyclo[3.2.1]oct-6-ene 8 and the 9-azabicyclo[4.2.1]oct-7-ene 9, respectively, the key precursors for reductive Heck coupling reactions. Alternative routes starting from cyclohepta-and cycloocta-1,3-diene are described; deoxygenation of tropane and homotropane epoxides provides a convenient route to 8 and 9. The enantiomers of 2 show similar potency at nicotinic receptors to the corresponding epibatidine enantiomers; the affinity of 3 is lower.

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