A prophase Study on applying Conia-ene reation in constructing bicyclo[3,3,1]nonane ring

The bicyclo[3, 3, 1] nonane ring system is the main structural feature in the lycopodium alkaloids. There are many methods to build the [3, 3, 1] bridged ring system, Herein, we designed to use indium Lewis acid which can activate the triple bond to construct [3, 3, 1] bridged ring system via Conia-ene reaction, and described a prophase study of applying Conia-ene reaction to construct such bicycle[3, 3, 1] nonane ring. The bicyclo [3, 3, l]nonane ring system has been gaining keen interest not only from the chemistry itself, but also from the point that this system is of the main structural feature of the lycopodium alkaloids which are acetyl cholinesterase inhibitors. In view of the possibility of total syntheses of these alkaloids via the route first forming bicyclo[3, 3, 1] nonane ring system, traditional synthetic approach was investigated toward these alkaloids via the underlying route (Scheme 1), which was rationalized by Raphael and his coworkers([1]). The route deals with the preparation of the cyclization products first through Michael addition of bicyclo[3, 3, I] nonane with acrolein and other compounds. Intramolecular Aldol condensation of beta-(1-ethoxycarbonyl-2-oxo-5-methylcyclohexyl)-propionaldehyde(2), which was obtained. from the reaction of ethyl 2-oxo-5 -methylcyclo-hexanecarboxylate(1)with acrolein in the presence of catalytic amount of sodium ethoxide at -60 degrees C, then underwent smoothly with hydrochloric acid in acetone to afford the cyclized products(3) quantitatively. A series of subsequent reactions, particular functional groups in different position of the ring gave different target structures([2]). In our study, we try to build the bicycle[3, 3, l]nonane ring through Conia-ene reaction([3,4,5]), so we made a pre-designed simulation test to verify the feasibility. In Scheme 2, under the action of different base, dianion could be obtained from acetoacetic acid ester (1). Then selective alkylation product (6) was got from the reaction of dianion with electrophile (5). It is worth mentioning that we had originally planned to use 4-iodobutyne as the electrophile, but its boiling point is too low to operation, so TMS group was introduced to raise the boiling point[6]. With precursor (6) in hand, we studied to build the cyclic compound (7) through Conia-ene reaction with In(OTf)(3)([7]) and successfully obtained the desired product 7 in about 80% yield. If there is a ring substitution in the beta-keto ester, we could obtain a bridged system. So we conclude it is feasible to use Conia-ene reaction to construct the bicycle[3, 3, l]nonane ring system. [GRAPHICS] Scheme 2 (I)NaH, n-BuLi, THF, 60%; (II) In(OTf)(3), acetonitrile, 80%.